U.S. patent application number 12/018266 was filed with the patent office on 2008-05-15 for cyclic derivatives as modulators of chemokine receptor activity.
This patent application is currently assigned to Bristol-Myers Squibb Company. Invention is credited to Percy H. Carter, Robert J. Cherney, John V. Duncia, Daniel S. Gardner, Joseph B. Santella.
Application Number | 20080114052 12/018266 |
Document ID | / |
Family ID | 32869560 |
Filed Date | 2008-05-15 |
United States Patent
Application |
20080114052 |
Kind Code |
A1 |
Cherney; Robert J. ; et
al. |
May 15, 2008 |
CYCLIC DERIVATIVES AS MODULATORS OF CHEMOKINE RECEPTOR ACTIVITY
Abstract
The present application describes modulators of MCP-1 of formula
(I): ##STR1## or pharmaceutically acceptable salt forms thereof,
useful for the prevention of rheumatoid arthritis, multiple
sclerosis, atherosclerosis and asthma, processes for preparing and
intermediates thereof.
Inventors: |
Cherney; Robert J.;
(Newtown, PA) ; Carter; Percy H.; (Princeton,
NJ) ; Duncia; John V.; (Newtown, PA) ;
Gardner; Daniel S.; (Furlong, PA) ; Santella; Joseph
B.; (Springfield, PA) |
Correspondence
Address: |
LOUIS J. WILLE;BRISTOL-MYERS SQUIBB COMPANY
PATENT DEPARTMENT
P O BOX 4000
PRINCETON
NJ
08543-4000
US
|
Assignee: |
Bristol-Myers Squibb
Company
|
Family ID: |
32869560 |
Appl. No.: |
12/018266 |
Filed: |
January 23, 2008 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11545584 |
Oct 10, 2006 |
7338947 |
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12018266 |
Jan 23, 2008 |
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10776828 |
Feb 11, 2004 |
7183270 |
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11545584 |
Oct 10, 2006 |
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60446850 |
Feb 12, 2003 |
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Current U.S.
Class: |
514/422 ;
514/424; 514/518; 548/543 |
Current CPC
Class: |
C07D 211/88 20130101;
C07D 403/12 20130101; A61P 9/00 20180101; A61P 9/10 20180101; A61P
17/06 20180101; A61P 31/00 20180101; C07D 495/04 20130101; C07D
401/12 20130101; C07D 223/12 20130101; C07D 409/12 20130101; A61P
19/02 20180101; C07D 207/273 20130101; C07D 207/277 20130101; C07D
403/04 20130101; C07D 207/34 20130101; C07D 417/12 20130101; A61P
37/06 20180101; A61P 31/18 20180101; A61P 35/00 20180101; A61P
37/00 20180101; A61P 9/04 20180101; C07D 471/04 20130101; A61P
19/00 20180101; A61P 17/00 20180101; A61P 11/00 20180101; C07D
487/04 20130101; C07D 405/06 20130101; C07D 211/76 20130101; C07D
207/416 20130101; A61P 11/06 20180101; C07D 417/08 20130101; A61P
29/00 20180101 |
Class at
Publication: |
514/422 ;
514/424; 514/518; 548/543 |
International
Class: |
A61K 31/4025 20060101
A61K031/4025; A61K 31/4015 20060101 A61K031/4015; C07D 403/02
20060101 C07D403/02 |
Claims
1. A compound of formula (I): ##STR143## or a stereoisomer or a
pharmaceutically acceptable salt thereof, wherein: ring B is a
cycloalkyl group of 3 to 8 carbon atoms wherein the cycloalkyl
group is saturated or partially unsaturated; or a heterocycle of 3
to 7 atoms wherein the heterocycle is saturated or partially
unsaturated, the heterocycle containing a heteroatom selected from
--O--, --S--, --S(.dbd.O)--, --S(.dbd.O).sub.2--, and
--N(R.sup.4)--, the heterocycle optionally containing a --C(O)--;
ring B being substituted with 0-2 R.sup.5; X is selected from O or
S; Z is selected from a bond, --NR.sup.8C(O)--, --NR.sup.8C(S)--,
--NR.sup.8C(O)NH--, --NR.sup.8C(S)NH--, --NR.sup.8SO.sub.2--,
--NR.sup.8SO.sub.2NH--, --C(O)NR.sup.8--, --OC(O)NR.sup.8--,
--NR.sup.8C(O)O--, --(CR.sup.15R.sup.15).sub.l--,
--CR.sup.14.dbd.CR.sup.14--, --CR.sup.15R.sup.15C(O)--,
--C(O)CR.sup.15R.sup.15--, CR.sup.15R.sup.15C(.dbd.N--OR.sup.16)--,
--O--CR.sup.14R.sup.14--, --CR.sup.14R.sup.14--O--, --O--,
--NR.sup.9--, --NR.sup.9--CR.sup.14R.sup.14--,
--CR.sup.14R.sup.14--NR.sup.9--, --S(O).sub.p--,
--S(O).sub.p--CR.sup.14R.sup.14--,
--CR.sup.14R.sup.14--S(O).sub.p--, and --S(O).sub.p--NR.sup.9--;
wherein neither Z nor R.sup.13 are connected to a carbon atom
labeled (b); bond (a) is a single or double bond; alternatively,
when n is equal to 2, two atoms labeled (b) may join through a
double bond; E is selected from --S(O).sub.pCHR.sup.e--,
--CHR.sup.eNR.sup.e--, --C(O)--NR.sup.e--, --NR.sup.eC(O)NR.sup.e,
SO.sub.2--NR.sup.e--, and --NR.sup.eSO.sub.2NR.sup.e--; R.sup.e is
independently selected from H and C.sub.1-3 alkyl; R.sup.1 is
selected from a C.sub.6-10 aryl group substituted with 0-5 R.sup.6
and a 5-10 membered heteroaryl system containing 1-4 heteroatoms
selected from N, O, and S, substituted with 0-3 R.sup.6; R.sup.2 is
selected from a C.sub.6-10 aryl group substituted with 0-5 R.sup.7
and a 5-10 membered heteroaryl system containing 1-4 heteroatoms
selected from N, O, and S, substituted with 0-3 R.sup.7; R.sup.4 is
selected from H, C.sub.1-6 alkyl, C.sub.3-8 alkenyl, C.sub.3-8
alkynyl, (CRR).sub.tOH, (CRR).sub.tSH, (CRR).sub.tOR.sup.4d,
(CHR).sub.tSR.sup.4d, (CRR).sub.tNR.sup.4aR.sup.4a,
(CR'R').sub.qC(O)OH, (CRR).sub.rC(O)R.sup.4b,
(CRR).sub.rC(O)NR.sup.4aR.sup.4a,
(CRR).sub.tOC(O)NR.sup.4aR.sup.4a,
(CRR).sub.tNR.sup.4aC(O)OR.sup.4d,
(CRR).sub.tNR.sup.4aC(O)R.sup.4b, (CRR).sub.rC(O)OR.sup.4d,
(CRR).sub.tOC(O)R.sup.4b, (CRR).sub.rS(O).sub.pR.sup.4b,
(CRR).sub.rS(O).sub.2NR.sup.4aR.sup.4a,
(CRR).sub.tNR.sup.4aS(O).sub.2R.sup.4b, C.sub.1-6 haloalkyl, a
(CRR).sub.r--C.sub.3-10 carbocyclic residue substituted with 0-3
R.sup.4e, and a (CHR).sub.r-4-10 membered heterocyclic system
containing 1-4 heteroatoms selected from N, O, and S, substituted
with 0-2 R.sup.4e; R.sup.4a, at each occurrence, is independently
selected from H, methyl substituted with 0-1 R.sup.4c, C.sub.2-6
alkyl substituted with 0-3 R.sup.4e, C.sub.3-8 alkenyl substituted
with 0-3 R.sup.4e, C.sub.3-8 alkynyl substituted with 0-3 R.sup.4e,
a (CH.sub.2).sub.r--C.sub.3-10 carbocyclic residue substituted with
0-4 R.sup.4e, and a (CHR).sub.r-4-10 membered heterocyclic system
containing 1-4 heteroatoms selected from N, O, and S, substituted
with 0-2 R.sup.4e; R.sup.4b, at each occurrence, is selected from
H, C.sub.1-6 alkyl substituted with 0-3 R.sup.4e, C.sub.3-8 alkenyl
substituted with 0-3 R.sup.4e, C.sub.3-8 alkynyl substituted with
0-3 R.sup.4e, a (CH.sub.2).sub.r--C.sub.3-6 carbocyclic residue
substituted with 0-2 R.sup.4e, and a (CHR).sub.r-4-10 membered
heterocyclic system containing 1-4 heteroatoms selected from N, O,
and S, substituted with 0-2 R.sup.4e; R.sup.4c is independently
selected from --C(O)R.sup.4b, --C(O)OR.sup.4d,
--C(O)NR.sup.4fR.sup.4f, and (CH.sub.2).sub.rphenyl; R.sup.4d, at
each occurrence, is selected from methyl, CF.sub.3, C.sub.2-6 alkyl
substituted with 0-3 R.sup.4e, C.sub.3-8 alkenyl substituted with
0-3 R.sup.4e, C.sub.3-8 alkynyl substituted with 0-3 R.sup.4e, and
a C.sub.3-10 carbocyclic residue substituted with 0-3 R.sup.4e;
R.sup.4e, at each occurrence, is selected from C.sub.1-6 alkyl,
C.sub.2-8 alkenyl, C.sub.2-8 alkynyl, (CH.sub.2).sub.rC.sub.3-6
cycloalkyl, Cl, F, Br, I, CN, NO.sub.2, (CF.sub.2).sub.rCF.sub.3,
(CH.sub.2).sub.rOC.sub.1-5 alkyl, OH, SH,
(CH.sub.2).sub.rSC.sub.1-5 alkyl,
(CH.sub.2).sub.rNR.sup.4fR.sup.4f, --C(O)R.sup.4i, --C(O)OR.sup.4j,
--C(O)NR.sup.4hR.sup.4h, --OC(O)NR.sup.4hR.sup.4h,
--NR.sup.4hC(O)NR.sup.4hR.sup.4h, --NR.sup.4hC(O)OR.sup.4j, and
(CH.sub.2).sub.rphenyl; R.sup.4f, at each occurrence, is selected
from H, C.sub.1-6 alkyl, C.sub.3-6 cycloalkyl, and phenyl;
R.sup.4h, at each occurrence, is independently selected from H,
C.sub.1-6 alkyl, C.sub.3-8 alkenyl, C.sub.3-8 alkynyl, and a
(CH.sub.2).sub.r--C.sub.3-10 carbocyclic; R.sup.4i, at each
occurrence, is selected from H, C.sub.1-6 alkyl, C.sub.3-8 alkenyl,
C.sub.3-8 alkynyl, and a (CH.sub.2).sub.rOC.sub.3-6 carbocyclic
residue; R.sup.4j, at each occurrence, is selected from CF.sub.3,
C.sub.1-6 alkyl, C.sub.3-8 alkenyl, C.sub.3-8 alkynyl, and a
C.sub.3-10 carbocyclic residue; R.sup.5, at each occurrence, is
independently selected from H, .dbd.O, CO.sub.--6 alkyl, C.sub.2-8
alkenyl, C.sub.2-3 alkynyl, (CRR).sub.rOH, (CRR).sub.rSH,
(CRR).sub.rOR.sup.5d, (CRR).sub.rSR.sup.5d,
(CRR).sub.rNR.sup.5aR.sup.5a,
(CRR).sub.rN(.fwdarw.O)R.sup.5aR.sup.5a, N.sub.3,
(CRR).sub.rC(O)OH, (CRR).sub.rC(O)R.sup.5b,
(CRR).sub.rC(O)NR.sup.5aR.sup.5a, (CRR).sub.rNR.sup.5aC(O)R.sup.5b,
(CRR).sub.rOC(O)NR.sup.5aR.sup.5a,
(CRR).sub.rNR.sup.5aC(O)OR.sup.5d,
(CRR).sub.rNR.sup.5aC(O)NR.sup.5aR.sup.5a,
(CRR).sub.rNR.sup.5aC(O)H, (CRR).sub.rC(O)OR.sup.5d,
(CRR).sub.rOC(O)R.sup.5b, (CRR).sub.rS(O).sub.pR.sup.5b,
(CRR).sub.rS(O).sub.2N.sup.5aR.sup.5a,
(CRR).sub.rNR.sup.5aS(O).sub.2R.sup.5b,
(CRR).sub.rNR.sup.5aS(O).sub.2NR.sup.5aR.sup.5a, C.sub.1-6
haloalkyl, a (CRR).sub.r--C.sub.3-10 carbocyclic residue
substituted with 0-3 R.sup.5c, and a (CRR).sub.r-5-10 membered
heterocyclic system containing 1-4 heteroatoms selected from N, O,
and S, substituted with 0-2 R.sup.5c; R.sup.5a, at each occurrence,
is independently selected from H, methyl substituted with 0-1
R.sup.5g, C.sub.2-6 alkyl substituted with 0-2 R.sup.5e, C.sub.3-8
alkenyl substituted with 0-2 R.sup.5e, C.sub.3-8 alkynyl
substituted with 0-2 R.sup.5e, a (CH.sub.2).sub.r--C.sub.3-10
carbocyclic residue substituted with 0-5 R.sup.5e, and a
(CH.sub.2).sub.r-5-10 membered heterocyclic system containing 1-4
heteroatoms selected from N, O, and S, substituted with 0-3
R.sup.e; R.sup.5b, at each occurrence, is selected from C.sub.1-6
alkyl substituted with 0-3 R.sup.5e, C.sub.3-8 alkenyl substituted
with 0-2 R.sup.5e, C.sub.3-8 alkynyl substituted with 0-2 R.sup.e,
a (CH.sub.2).sub.r--C.sub.3-6 carbocyclic residue substituted with
0-2 R.sup.5e, and a (CH.sub.2).sub.r-5-6 membered heterocyclic
system containing 1-4 heteroatoms selected from N, O, and S,
substituted with 0-3 R.sup.5e; R.sup.5c, at each occurrence, is
selected from C.sub.1-6 alkyl, C.sub.2-8 alkenyl, C.sub.2-8
alkynyl, (CH.sub.2).sub.rC.sub.3-6 cycloalkyl, Cl, Br, I, F,
(CF.sub.2).sub.rCF.sub.3, NO.sub.2, CN,
(CH.sub.2).sub.rNR.sup.5fR.sup.5f, (CH.sub.2).sub.rOH,
(CH.sub.2).sub.rOC.sub.1-4 alkyl, (CH.sub.2).sub.rSC.sub.1-4 alkyl,
(CH.sub.2).sub.rC(O)OH, (CH.sub.2).sub.rC(O)R.sup.5b,
(CH.sub.2).sub.rC(O)NR.sup.5fR.sup.5f,
(CH.sub.2).sub.rOC(O)NR.sup.5fR.sup.5f,
(CH.sub.2).sub.rNR.sup.5fC(O)R.sup.5b,
(CH.sub.2).sub.rC(O)OC.sub.1-4 alkyl,
(CH.sub.2).sub.rNR.sup.5fC(O)OC.sub.1-4 alkyl,
(CH.sub.2).sub.rOC(O)R.sup.5b,
(CH.sub.2).sub.rC(.dbd.NR.sup.5f)NR.sup.5fR.sup.5f,
(CH.sub.2).sub.rS(O).sub.pR.sup.5b,
(CH.sub.2).sub.rNHC(.dbd.NR.sup.5f)NR.sup.5fR.sup.5f,
(CH.sub.2).sub.rS(O).sub.2NR.sup.5fR.sup.5f,
(CH.sub.2).sub.rNR.sup.5fS(O).sub.2R.sup.5b, and
(CH.sub.2).sub.rphenyl substituted with 0-3 R.sup.5e; R.sup.5d, at
each occurrence, is selected from methyl, CF.sub.3, C.sub.2-6 alkyl
substituted with 0-2 R.sup.5e, C.sub.3-8 alkenyl substituted with
0-2 R.sup.5e, C.sub.3-8 alkynyl substituted with 0-2 R.sup.5e, and
a C.sub.3-10 carbocyclic residue substituted with 0-3 R.sup.5e;
R.sup.5e, at each occurrence, is selected from C.sub.1-6 alkyl,
C.sub.2-8 alkenyl, C.sub.2-8 alkynyl, C.sub.3-6 cycloalkyl, Cl, F,
Br, I, CN, NO.sub.2, (CF.sub.2).sub.rCF.sub.3,
(CH.sub.2).sub.rOC.sub.1-5 alkyl, OH, SH,
(CH.sub.2).sub.rSC.sub.1-5 alkyl,
(CH.sub.2).sub.rNR.sup.5fR.sup.5f, and (CH.sub.2).sub.rphenyl;
R.sup.5f, at each occurrence, is selected from H, C.sub.1-5 alkyl,
and C.sub.3-6 cycloalkyl; R.sup.5g is independently selected from
--C(O)R.sup.5b, --C(O)OR.sup.5d, --C(O)NR.sup.5fR.sup.5f, --CN, and
(CH.sub.2).sub.rphenyl; R, at each occurrence, is selected from H,
C.sub.1-5 alkyl substituted with R.sup.5e, C.sub.2-8 alkenyl,
C.sub.2-8 alkynyl, (CH.sub.2).sub.rC.sub.3-6 cycloalkyl, and
(CH.sub.2).sub.rphenyl substituted with R.sup.5e; R.sup.6, at each
occurrence, is selected from C.sub.1-8 alkyl, C.sub.2-8 alkenyl,
C.sub.2-8 alkynyl, (CH.sub.2).sub.rC.sub.3-6 cycloalkyl, Cl, Br, I,
F, NO.sub.2, CN; (CR'R').sub.rNR.sup.6aR.sup.6a, (CR'R').sub.rOH,
(CR'R').sub.rO(CR'R').sub.rR.sup.6d, (CR'R').sub.rSH,
(CR'R').sub.rC(O)H, (CR'R').sub.rS(CR'R').sub.rR.sup.6d,
(CR'R').sub.rSC(O)(CR'R').sub.rR.sup.6b, (CR'R').sub.rC(O)OH,
(CR'R').sub.rC(O)(CR'R').sub.rR.sup.6b,
(CR'R').sub.rN.sup.6aR.sup.6a, (CR'R').sub.rC(O)NR.sup.6aR.sup.6a,
(CR'R').sub.rNR.sup.6fC(O)(CR'R').sub.rR.sup.6b,
(CR'R').sub.rC(O)O(CR'R').sub.rR.sup.6d,
(CR'R').sub.rOC(O)(CR'R').sub.rR.sup.6b,
(CR'R').sub.rOC(O)NR.sup.6a(CR'R').sub.rR.sup.6d,
(CR'R').sub.rNR.sup.6aC(O)NR.sup.6a(CR'R').sub.rR.sup.6d,
(CR'R').sub.rNR.sup.6aC(S)NR.sup.6a(CR'R').sub.rR.sup.6d,
(CR'R').sub.rNR.sup.6fC(O)O(CR'R').sub.rR.sup.6b,
(CR'R').sub.rC(.dbd.NR.sup.6f)NR.sup.6aR.sup.6a,
(CR'R').sub.rNHC(.dbd.NR.sup.6f)NR.sup.6fR.sup.6f,
(CR'R').sub.rS(O).sub.p(CR'R').sub.rR.sup.6b,
(CR'R').sub.rS(O).sub.2NR.sup.6aR.sup.6a,
(CR'R').sub.rNR.sup.6fS(O).sub.2NR.sup.6aR.sup.6a,
(CR'R').sub.rNR.sup.6fS(O).sub.2(CR'R').sub.rR.sup.6b, C.sub.1-6
haloalkyl, C.sub.2-8 alkenyl substituted with 0-3 R', C.sub.2-8
alkynyl substituted with 0-3 R', (CR'R').sub.rphenyl substituted
with 0-3 R.sup.6e, and a (CH.sub.2).sub.r-5-6 membered heterocyclic
system containing 1-2 heteroatoms selected from N, O, and S,
substituted with 0-2 R.sup.6e; alternatively, two R.sup.6 on
adjacent atoms on R.sup.1 may join to form a cyclic acetal;
R.sup.6a, at each occurrence, is selected from H, methyl
substituted with 0-1 R.sup.6g, C.sub.2-6 alkyl substituted with 0-2
R.sup.6e, C.sub.3-8 alkenyl substituted with 0-2 R.sup.6e,
C.sub.3-8 alkynyl substituted with 0-2 R.sup.6e, a
(CH.sub.2).sub.r--C.sub.3-10 carbocyclic residue substituted with
0-5 R.sup.6e, and a (CH.sub.2).sub.r-5-10 membered heterocyclic
system containing 1-4 heteroatoms selected from N, O, and S,
substituted with 0-2 R.sup.6e; R.sup.6b, at each occurrence, is
selected from H, C.sub.1-6 alkyl substituted with 0-2 R.sup.6e,
C.sub.3-8 alkenyl substituted with 0-2 R.sup.6e, C.sub.3-8 alkynyl
substituted with 0-2 R.sup.6e, a (CH.sub.2).sub.rC.sub.3-6
carbocyclic residue substituted with 0-3 R.sup.6e, and a
(CH.sub.2).sub.r-5-6 membered heterocyclic system containing 1-4
heteroatoms selected from N, O, and S, substituted with 0-2
R.sup.6e; R.sup.6d, at each occurrence, is selected from C.sub.3-8
alkenyl substituted with 0-2 R.sup.6e, C.sub.3-8 alkynyl
substituted with 0-2 R.sup.6e, methyl, CF.sub.3, C.sub.2-6 alkyl
substituted with 0-3 R.sup.6e, C.sub.2-4 haloalkyl, a
(CH.sub.2).sub.r--C.sub.3-10 carbocyclic residue substituted with
0-3 R.sup.6e, and a (CH.sub.2).sub.r-5-6 membered heterocyclic
system containing 1-4 heteroatoms selected from N, O, and S,
substituted with 0-3 R.sup.6e; R.sup.6e, at each occurrence, is
selected from C.sub.1-6 alkyl, C.sub.2-8 alkenyl, C.sub.2-8
alkynyl, (CH.sub.2).sub.rC.sub.3-6 cycloalkyl, Cl, F, Br, I, CN,
NO.sub.2, (CF.sub.2).sub.rCF.sub.3, (CH.sub.2).sub.rOC.sub.1-5
alkyl, OH, SH, (CH.sub.2).sub.rSC.sub.1-5 alkyl,
(CH.sub.2).sub.rNR.sup.6fR.sup.6f, and (CH.sub.2).sub.rphenyl;
R.sup.6f, at each occurrence, is selected from H, C.sub.1-5 alkyl,
and C.sub.3-6 cycloalkyl, and phenyl; R.sup.6g is independently
selected from --C(O)R.sup.6b, --C(O)OR.sup.6d,
--C(O)NR.sup.6fR.sup.6f, and (CH.sub.2).sub.rphenyl; R.sup.7, at
each occurrence, is selected from C.sub.1-8 alkyl, C.sub.2-8
alkenyl, C.sub.2-8 alkynyl, (CH.sub.2).sub.rC.sub.3-6 cycloalkyl,
Cl, Br, I, F, NO.sub.2, CN, (CR'R').sub.rNR.sup.7aR.sup.7a,
(CR'R').sub.rOH, (CR'R').sub.rO(CR'R').sub.rR.sup.7d,
(CR'R').sub.rSH, (CR'R').sub.rC(O)H,
(CR'R').sub.rS(CR'R').sub.rR.sup.7d, (CR'R').sub.rC(O)OH,
(CR'R').sub.rC(O)(CR'R').sub.rR.sup.7b,
(CR'R').sub.rC(O)NR.sup.7aR.sup.7a, (CR'R').sub.rNR.sup.7fC(O)
(CR'R').sub.rR.sup.7b, (CR'R').sub.rC(O)O(CR'R').sub.rR.sup.7d,
(CR'R').sub.rOC(O)(CR'R').sub.rR.sup.7b,
(CR'R').sub.rOC(O)NR.sup.7a(CR'R').sub.rR.sup.7a,
(CR'R').sub.rNR.sup.7aC(O)NR.sup.7a(CR'R').sub.rR.sup.7a,
(CR'R').sub.rNR.sup.7fC(O)O(CR'R').sub.rR.sup.7d,
(CR'R').sub.rC(.dbd.NR.sup.7f)NR.sup.7aR.sup.7a,
(CR'R').sub.rNHC(.dbd.NR.sup.7f)NR.sup.7fR.sup.7f,
(CR'R').sub.rS(O).sub.p(CR'R').sub.rR.sup.7b,
(CR'R').sub.rS(O).sub.2NR.sup.7aR.sup.7a,
(CR'R').sub.rNR.sup.7aS(O).sub.2NR.sup.7aR.sup.7a,
(CR'R').sub.rNR.sup.7fS(O).sub.2(CR'R').sub.rR.sup.7b, C.sub.1-6
haloalkyl, C.sub.2-8 alkenyl substituted with 0-3 R', C.sub.2-8
alkynyl substituted with 0-3 R', (CR'R').sub.rC.sub.3-10
carbocyclic residue and (CR'R').sub.rphenyl substituted with 0-3
R.sup.7e; alternatively, two R.sup.7 on adjacent atoms on R.sup.2
may join to form a cyclic acetal; R.sup.7a, at each occurrence, is
independently selected from H, methyl substituted with 0-1
R.sup.7g, C.sub.2-6 alkyl substituted with 0-2 R.sup.7e, C.sub.3-8
alkenyl substituted with 0-2 R.sup.7e, C.sub.3-8 alkynyl
substituted with 0-2 R.sup.7e, a (CH.sub.2).sub.r--C.sub.3-10
carbocyclic residue substituted with 0-5 R.sup.7e, and a
(CH.sub.2).sub.r-5-10 membered heterocyclic system containing 1-4
heteroatoms selected from N, O, and S, substituted with 0-2
R.sup.7e; R.sup.7b, at each occurrence, is selected from C.sub.1-6
alkyl substituted with 0-2 R.sup.7e, C.sub.3-8 alkenyl substituted
with 0-2 R.sup.7e, C.sub.3-8 alkynyl substituted with 0-2 R.sup.7e,
a (CH.sub.2).sub.rC.sub.3-6 carbocyclic residue substituted with
0-3 R.sup.7e, and a (CH.sub.2).sub.r-5-5 membered heterocyclic
system containing 1-4 heteroatoms selected from N, O, and S,
substituted with 0-2 R.sup.7e; R.sup.7d, at each occurrence, is
selected from C.sub.3-8 alkenyl substituted with 0-2 R.sup.7e,
C.sub.3-8 alkynyl substituted with 0-2 R.sup.7e, methyl, CF.sub.3,
C.sub.2-4 haloalkyl, C.sub.2-6 alkyl substituted with 0-3 R.sup.7e,
a (CH.sub.2).sub.r--C.sub.3-10 carbocyclic residue substituted with
0-3 R.sup.7e, and a (CH.sub.2).sub.r-5-6 membered heterocyclic
system containing 1-4 heteroatoms selected from N, O, and S,
substituted with 0-3 R
.sup.7e; R.sup.7e, at each occurrence, is selected from C.sub.1-6
alkyl, C.sub.2-8 alkenyl, C.sub.2-8 alkynyl,
(CH.sub.2).sub.rC.sub.3-6 cycloalkyl, Cl, F, Br, I, CN, NO.sub.2,
(CF.sub.2).sub.rCF.sub.3, (CH.sub.2).sub.rOC.sub.1-5 alkyl, OH, SH,
C(O)OC.sub.1-5 alkyl, (CH.sub.2).sub.rSC.sub.1-5 alkyl,
(CH.sub.2).sub.rNR.sup.7fR.sup.7f, and (CH.sub.2).sub.rphenyl;
R.sup.7f, at each occurrence, is selected from H, C.sub.1-5 alkyl,
and C.sub.3-6 cycloalkyl, and phenyl; R.sup.7g is independently
selected from --C(O)R.sup.7b, --C(O)OR.sup.7d,
--C(O)NR.sup.7fR.sup.7f, and (CH.sub.2).sub.rphenyl; R', at each
occurrence, is selected from H, C.sub.1-6 alkyl substituted with
R.sup.6e, C.sub.2-8 alkenyl, C.sub.2-8 alkynyl,
(CH.sub.2).sub.rC.sub.3-6 cycloalkyl, and (CH.sub.2).sub.rphenyl
substituted with R.sup.6e; R.sup.8 is selected from H, C.sub.1-4
alkyl, and C.sub.3-4 cycloalkyl; R.sup.9 is selected from H,
C.sub.1-4 alkyl, C.sub.3-4 cycloalkyl, --C(O)H, and
--C(O)--C.sub.1-4alkyl; R.sup.10 is independently selected from H,
and C.sub.1-4alkyl substituted with 0-1 R.sup.10b, alternatively,
two R.sup.10 form .dbd.O; R.sup.10b, at each occurrence, is
independently selected from --OH, --SH, NR.sup.10cR.sup.10c,
--C(O)NR.sup.10cR.sup.10c, and --NHC(O)R.sup.10c; R.sup.10c is
selected from H, C.sub.1-4 alkyl and C.sub.3-6 cycloalkyl; R.sup.11
is selected from H, C.sub.1-4 alkyl, (CHR).sub.qOH, (CHR).sub.qSH,
(CHR).sub.qOR.sup.11d, (CHR).sub.qS(O).sub.pR.sup.11d,
(CHR).sub.rC(O)R.sup.11b, (CHR).sub.rNR.sup.11aR.sup.11a,
(CHR).sub.rC(O)NR.sup.11aR.sup.11a,
(CHR).sub.rC(O)NR.sup.11aOR.sup.11d,
(CHR).sub.qNR.sup.11aC(O)R.sup.11b,
(CHR).sub.qNR.sup.11aC(O)OR.sup.11d,
(CHR).sub.qOC(O)NR.sup.11aR.sup.11a, (CHR).sub.rC(O)OR.sup.11d, a
(CHR).sub.r--C.sub.3-6 carbocyclic residue substituted with 0-5
R.sup.11e, and a (CHR).sub.r-5-10 membered heterocyclic system
containing 1-4 heteroatoms selected from N, O, and S, substituted
with 0-3 R.sup.11e; R.sup.11a, at each occurrence, is independently
selected from H, C.sub.1-4 alkyl, C.sub.3-4 alkenyl, C.sub.3-4
alkynyl, (CH.sub.2).sub.rC.sub.3-6 cycloalkyl, a
(CH.sub.2).sub.r--C.sub.3-6 carbocyclic residue substituted with
0-5 R.sup.11e, and a (CH.sub.2).sub.r-5-6 membered heterocyclic
system containing 1-4 heteroatoms selected from N, O, and S,
substituted with 0-3 R.sup.11e; R.sup.11b, at each occurrence, is
independently selected from C.sub.1-4 alkyl, C.sub.2-4 alkenyl,
C.sub.2-4 alkynyl, a (CH.sub.2).sub.r--C.sub.3-6 carbocyclic
residue substituted with 0-2 R.sup.11e, and a (CH.sub.2).sub.r-5-6
membered heterocyclic system containing 1-4 heteroatoms selected
from N, O, and S, substituted with 0-3 R.sup.11e; R.sup.11d, at
each occurrence, is independently selected from H, methyl,
--CF.sub.3, C.sub.2-4 alkyl, C.sub.3-6 alkenyl, C.sub.3-6 alkynyl,
a C.sub.3-6 carbocyclic residue substituted with 0-3 R.sup.11e, and
a (CH.sub.2).sub.r-5-6 membered heterocyclic system containing 1-4
heteroatoms selected from N, O, and S, substituted with 0-3
R.sup.11e; R.sup.11e, at each occurrence, is selected from
C.sub.1-6 alkyl, C.sub.2-8 alkenyl, C.sub.2-8 alkynyl, C.sub.3-6
cycloalkyl, Cl, F, Br, I, CN, NO.sub.2, (CF.sub.2).sub.rCF.sub.3,
(CH.sub.2).sub.rOC.sub.1-5 alkyl, OH, --O--C.sub.1-6 alkyl, SH,
(CH.sub.2).sub.rSC.sub.1-5 alkyl,
(CH.sub.2).sub.rNR.sup.11fR.sup.11f, and (CH.sub.2).sub.rphenyl;
R.sup.11f, at each occurrence, is selected from H, C.sub.1-6 alkyl,
and C.sub.3-6 cycloalkyl; R.sup.12 is selected from H, C.sub.1-4
alkyl, (CHR).sub.qOH, (CHR).sub.qSH, (CHR).sub.qOR.sup.12d,
(CHR).sub.qS(O).sub.pR.sup.12d, (CHR).sub.rC(O)R.sup.12b,
(CHR).sub.rNR.sup.12aR.sup.12a, (CHR).sub.rC(O)NR.sup.12aR.sup.12a,
(CHR).sub.rC(O)NR.sup.12aOR.sup.12d,
(CHR).sub.qR.sup.12aC(O)R.sup.12b,
(CHR).sub.qNR.sup.12aC(O)OR.sup.12d,
(CHR).sub.qCC(O)NR.sup.12aR.sup.12a, (CHR).sub.rC(O)OR.sup.12d, a
(CHR).sub.r--C.sub.3-6 carbocyclic residue substituted with 0-5
R.sup.12e, and a (CHR).sub.r-5-10 membered heterocyclic system
containing 1-4 heteroatoms selected from N, O, and S, substituted
with 0-3 R.sup.12e; R.sup.12a, at each occurrence, is independently
selected from H, C.sub.1-4 alkyl, C.sub.3-4 alkenyl, C.sub.3-4
alkynyl, (CH.sub.2).sub.rC.sub.3-6 cycloalkyl, a
(CH.sub.2).sub.r--C.sub.3-6 carbocyclic residue substituted with
0-5 R.sup.12e, and a (CH.sub.2).sub.r-5-6 membered heterocyclic
system containing 1-4 heteroatoms selected from N, O, and S,
substituted with 0-3 R.sup.12e; R.sup.12b, at each occurrence, is
independently selected from C.sub.1-4 alkyl, C.sub.2-4 alkenyl,
C.sub.2-4 alkynyl, a (CH.sub.2).sub.r--C.sub.3-6 carbocyclic
residue substituted with 0-2 R.sup.12e, and a (CH.sub.2).sub.r-5-6
membered heterocyclic system containing 1-4 heteroatoms selected
from N, O, and S, substituted with 0-3 R.sup.12e; R.sup.12d, at
each occurrence, is independently selected from H, methyl,
--CF.sub.3, C.sub.2-4 alkyl, C.sub.3-6 alkenyl, C.sub.3-6 alkynyl,
a C.sub.3-6 carbocyclic residue substituted with 0-3 R.sup.12e, and
a (CH.sub.2).sub.r-5-6 membered heterocyclic system containing 1-4
heteroatoms selected from N, O, and S, substituted with 0-3
R.sup.12e; R.sup.12e, at each occurrence, is selected from
C.sub.1-6 alkyl, C.sub.2-8 alkenyl, C.sub.2-8 alkynyl, C.sub.3-6
cycloalkyl, Cl, F, Br, I, CN, NO.sub.2, (CF.sub.2).sub.rCF.sub.3,
(CH.sub.2).sub.rOC.sub.1-5 alkyl, OH, O--C.sub.1-6 alkyl, SH,
(CH.sub.2).sub.rSC.sub.1-5 alkyl,
(CH.sub.2).sub.rNR.sup.12fR.sup.12f, and (CH.sub.2).sub.rphenyl;
R.sup.12f, at each occurrence, is selected from H, C.sub.1-6 alkyl,
and C.sub.3-6 cycloalkyl; R.sup.13, at each occurrence, is
independently selected from H, and C.sub.1-4alkyl substituted with
0-1 R.sup.13b, --OH, --NH.sub.2, F, Cl, Br, I, --OR.sup.13a,
--N(R.sup.13a).sub.2, and C.sub.1-4 alkyl substituted with 0-3
R.sup.13b; R.sup.13a is selected from H, C.sub.1-4 alkyl and
C.sub.3-6 cycloalkyl; R.sup.13b, at each occurrence, is
independently selected from --OH, --SH, --N.sup.13cR.sup.13c,
--C(O)NR.sup.13cR.sup.13c, and --NHC(O)R.sup.13c; R.sup.13c is
selected from H, C.sub.1-4 alkyl and C.sub.3-6 cycloalkyl;
R.sup.14, at each occurrence, is independently selected from H and
C.sub.1-4alkyl; alternatively, two R.sup.14s, along with the carbon
atom to which they are attached, join to form a C.sub.3-6
carbocyclic ring; R.sup.15, at each occurrence, is independently
selected from H, C.sub.1-4alkyl, OH, NH.sub.2, O--C.sub.1-4 alkyl,
NR.sup.15aR.sup.15a, C(O)NR.sup.15aR.sup.15a,
NR.sup.15aC(O)R.sup.1Sb, NR.sup.15aC(O)OR.sup.15d,
OC(O)NR.sup.15aR.sup.15a, and (CHR).sub.rC(O)OR.sup.15d;
alternatively, two R.sup.15s, along with the carbon atom or atoms
to which they are attached, join to form a C.sub.3-6 carbocyclic
ring; R.sup.15a, at each occurrence, is independently selected from
H, and C.sub.1-4 alkyl; R.sup.15b, at each occurrence, is
independently selected from C.sub.1-4 alkyl, C.sub.3-6 alkenyl, and
C.sub.3-6 alkynyl; R.sup.15d, at each occurrence, is independently
selected from C.sub.1-4 alkyl, C.sub.3-6 alkenyl, and C.sub.3-6
alkynyl; R.sup.16 is selected from C.sub.1-4 alkyl; l is selected
from 1, 2 and 3; n is selected from 0, 1, 2, and 3; m is selected
from 0 and 1; p, at each occurrence, is independently selected from
0, 1, and 2; q, at each occurrence, is independently selected from
1, 2, 3, and 4; r, at each occurrence, is independently selected
from 0, 1, 2, 3, and 4; t, at each occurrence, is independently
selected from 2, 3, and 4; s is selected from 0 and 1.
2. A compound of claim 1, wherein the compound is of formula (I):
##STR144## or a stereoisomer or a pharmaceutically acceptable salt
thereof, wherein: ring B is a cycloalkyl group of 3 to 8 carbon
atoms wherein the cycloalkyl group is saturated or partially
unsaturated; or a heterocycle of 3 to 7 atoms wherein the
heterocycle is saturated or partially unsaturated, the heterocycle
containing a heteroatom selected from --O--, --S--, --S(.dbd.O)--,
S(.dbd.O).sub.2--, and --N(R.sup.4)--, the heterocycle optionally
containing a --C(O)--; ring B being substituted with 0-2 R.sup.5; X
is selected from O or S; Z is selected from a bond,
--NR.sup.8C(O)--, --NR.sup.8C(S)--, --NR.sup.8C(O)NH--,
--NR.sup.8C(S)NH--, --NR.sup.8SO.sub.2, --N.sup.8SO.sub.2NH--,
--C(O)NR.sup.8--, --OC(O)NR.sup.8--, --NR.sup.8C(O)O,
--(CR.sup.15R.sup.15).sub.l--, --CR.sup.14.dbd.CR.sup.14--,
--CR.sup.15R.sup.15C(O)--, --C(O)CR.sup.15R.sup.15--,
CR.sup.15R.sup.15C(.dbd.N--OR.sup.16)--, --O--CR.sup.14R.sup.14--,
--CR.sup.14R.sup.14--O--, --O--, --NR.sup.9--,
--NR.sup.9--CR.sup.14R.sup.14--, --CR.sup.14R.sup.14--NR.sup.9--,
--S(O).sub.p--, --S(O).sub.p--CR.sup.14R.sup.14--,
--CR.sup.14R.sup.14--S(O).sub.p--, and --S(O).sub.p--NR.sup.9--;
wherein neither Z nor R.sup.13 are connected to a carbon atom
labeled (b); bond (a) is a single or double bond; alternatively,
when n is equal to 2, two atoms labeled (b) may join through a
double bond; E is selected from --S(O).sub.pCHR.sup.e--,
--CHR.sup.eNR.sup.e--, --C(O)--NR.sup.e--, NR.sup.eC(O)NR.sup.e--,
SO.sub.2--NR.sup.e--, and --NR.sup.eSO.sub.2NR.sup.e--; R.sup.e is
independently selected from H and C.sub.1-3 alkyl; R.sup.1 is
selected from a C.sub.6-10 aryl group substituted with 0-5 R.sup.6
and a 5-10 membered heteroaryl system containing 14 heteroatoms
selected from N, O, and S, substituted with 0-3 R.sup.6; R.sup.2 is
selected from a C.sub.6-10 aryl group substituted with 0-5 R.sup.7
and a 5-10 membered heteroaryl system containing 1-4 heteroatoms
selected from N, O, and S, substituted with 0-3 R.sup.7; R.sup.4 is
selected from H, C.sub.1-6 alkyl, C.sub.3-8 alkenyl, C.sub.3-8
alkynyl, (CRR).sub.tOH, (CRR).sub.tSH, (CRR).sub.tOR.sup.4d,
(CHR).sub.tSR.sup.4d, (CRR).sub.tNR.sup.4aR.sup.4a,
(CRR).sub.qC(O)OH, (CRR).sub.rC(O)R.sup.4b,
(CRR).sub.rC(O)NR.sup.4aR.sup.4a,
(CRR).sub.tOC(O)NR.sup.4aR.sup.4a,
(CRR).sub.tNR.sup.4aC(O)OR.sup.4d,
(CRR).sub.tNR.sup.4aC(O)R.sup.4b, (CRR).sub.rC(O)OR.sup.4d,
(CRR).sub.tOC(O)R.sup.4b, (CRR).sub.rS(O).sub.pR.sup.4b,
(CRR).sub.rS(O).sub.2NR.sup.4aR.sup.4a,
(CRR).sub.tNR.sup.4aS(O).sub.2R.sup.4b, C.sub.1-6 haloalkyl, a
(CRR).sub.r--C.sub.3-10 carbocyclic residue substituted with 0-3
R.sup.4e, and a (CHR).sub.r-4-10 membered heterocyclic system
containing 1-4 heteroatoms selected from N, O, and S, substituted
with 0-2 R.sup.4e; R.sup.4a, at each occurrence, is independently
selected from H, methyl substituted with 0-1 R.sup.4c, C.sub.2-6
alkyl substituted with 0-3 R.sup.4e, C.sub.3-8 alkenyl substituted
with 0-3 R.sup.4e, C.sub.3-8 alkynyl substituted with 0-3 R.sup.4e,
a (CH.sub.2).sub.r--C.sub.3-10 carbocyclic residue substituted with
0-4 R.sup.4e, and a (CHR).sub.r-4-10 membered heterocyclic system
containing 1-4 heteroatoms selected from N, O, and S, substituted
with 0-2 R.sup.4e; R.sup.4b, at each occurrence, is selected from
H, C.sub.1-6 alkyl substituted with 0-3 R.sup.4e, C.sub.3-8 alkenyl
substituted with 0-3 R.sup.4e, C.sub.3-8 alkynyl substituted with
0-3 R.sup.4e, a (CH.sub.2).sub.r--C.sub.3-6 carbocyclic residue
substituted with 0-2 R.sup.4e, and a (CHR).sub.r-4-10 membered
heterocyclic system containing 1-4 heteroatoms selected from N, O,
and S, substituted with 0-2 R.sup.4e; R.sup.4c is independently
selected from --C(O)R.sup.4b, --C(O)OR.sup.4d,
--C(O)NR.sup.4fR.sup.4f, and (CH.sub.2).sub.rphenyl; R.sup.4d, at
each occurrence, is selected from methyl, CF.sub.3, C.sub.2-6 alkyl
substituted with 0-3 R.sup.4e, C.sub.3-8 alkenyl substituted with
0-3 R.sup.4e, C.sub.3-8 alkynyl substituted with 0-3 R.sup.4e, and
a C.sub.3-10 carbocyclic residue substituted with 0-3 R.sup.4e;
R.sup.4e, at each occurrence, is selected from C.sub.1-5 alkyl,
C.sub.2-8 alkenyl, C.sub.2-8 alkynyl, (CH.sub.2).sub.rC.sub.3-6
cycloalkyl, Cl, F, Br, I, CN, NO.sub.2, (CF.sub.2).sub.rCF.sub.3,
(CH.sub.2).sub.rOC.sub.1-5 alkyl, OH, SH,
(CH.sub.2).sub.rSC.sub.1-5 alkyl,
(CH.sub.2).sub.rNR.sup.4fR.sup.4f, --C(O)R.sup.4i, --C(O)OR.sup.4j,
--C(O)NR.sup.4hR.sup.4h, --OC(O)NR.sup.4hR.sup.4h,
--NR.sup.4hC(O)NR.sup.4hR.sup.4h, --NR.sup.4hC(O)OR.sup.4j, and
(CH.sub.2).sub.rphenyl; R.sup.4f, at each occurrence, is selected
from H, C.sub.1-6 alkyl, C.sub.3-6 cycloalkyl, and phenyl;
R.sup.4h, at each occurrence, is independently selected from H,
C.sub.1-6 alkyl, C.sub.3-8 alkenyl, C.sub.3-8 alkynyl, and a
(CH.sub.2).sub.r--C.sub.3-10 carbocyclic; R.sup.4i, at each
occurrence, is selected from H, C.sub.1-6 alkyl, C.sub.3-8 alkenyl,
C.sub.3-8 alkynyl, and a (CH.sub.2).sub.r--C.sub.3-6 carbocyclic
residue; R.sup.4j, at each occurrence, is selected from CF.sub.3,
C.sub.1-6 alkyl, C.sub.3-8 alkenyl, C.sub.3-8 alkynyl, and a
C.sub.3-10 carbocyclic residue; R.sup.5, at each occurrence, is
independently selected from H, .dbd.O, C.sub.1-6 alkyl, C.sub.2-8
alkenyl, C.sub.2-8 alkynyl, (CRR).sub.rOH, (CRR).sub.rSH,
(CRR).sub.rOR.sup.5d, (CRR).sub.rSR.sup.5d,
(CRR).sub.rNR.sup.5aR.sup.5d, (CRR).sub.rC(O)OH,
(CRR).sub.rC(O)R.sup.5b, (CRR).sub.rC(O)NR.sup.5aR.sup.5a,
(CRR).sub.rNR.sup.5aC(O)R.sup.5b,
(CRR).sub.rOC(O)NR.sup.5aR.sup.5a,
(CRR).sub.rNR.sup.5aC(O)OR.sup.5d,
(CRR).sub.rNR.sup.5aC(O)NR.sup.5aR.sup.5a,
(CRR).sub.rNR.sup.5aC(O)H, (CRR).sub.rC(O)OR.sup.5d,
(CRR).sub.rOC(O)R.sup.5b, (CRR).sub.rS(O).sub.pR.sup.5b,
(CRR).sub.rS(O).sub.2NR.sup.5aR.sup.5a,
(CRR).sub.rNR.sup.5aS(O).sub.2R.sup.5b,
(CRR).sub.rNR.sup.5aS(O).sub.2NR.sup.5aR.sup.5a, C.sub.1-6
haloalkyl, a (CRR).sub.r--C.sub.3-10 carbocyclic residue
substituted with 0-3 R.sup.5c, and a (CRR).sub.r-5-10 membered
heterocyclic system containing 1-4 heteroatoms selected from N, O,
and S, substituted with 0-2 R.sup.5c; R.sup.5a, at each occurrence,
is independently selected from H, methyl substituted with 0-1
R.sup.5g, C.sub.2-6 alkyl substituted with 0-2 R.sup.5e, C.sub.3-8
alkenyl substituted with 0-2 R.sup.5a, C.sub.3-8 alkynyl
substituted with 0-2 R.sup.5e, a (CH.sub.2).sub.r--C.sub.3-10
carbocyclic residue substituted with 0-5 R.sup.5e, and a
(CH.sub.2).sub.r-5-10 membered heterocyclic system containing 1-4
heteroatoms selected from N, O, and S, substituted with 0-3
R.sup.5e; R.sup.5b, at each occurrence, is selected from C.sub.1-6
alkyl substituted with 0-3 R.sup.5e, C.sub.3-8 alkenyl substituted
with 0-2 R.sup.5e, C.sub.3-8 alkynyl substituted with 0-2 R.sup.5e,
a (CH.sub.2).sub.r--C.sub.3-6 carbocyclic residue substituted with
0-2 R.sup.5e, and a (CH.sub.2).sub.r-5-6 membered heterocyclic
system containing 1-4 heteroatoms selected from N, O, and S,
substituted with 0-3 R.sup.5e; R.sup.5c, at each occurrence, is
selected from C.sub.1-6 alkyl, C.sub.2-8 alkenyl, C.sub.2-8
alkynyl, (CH.sub.2).sub.rC.sub.3-6 cycloalkyl, Cl, Br, I, F,
(CF.sub.2).sub.rCF.sub.3, NO.sub.2, CN,
(CH.sub.2).sub.rNR.sup.5fR.sup.5f, (CH.sub.2).sub.rOH,
(CH.sub.2).sub.rOC.sub.1-4 alkyl, (CH.sub.2).sub.rSC.sub.1-4 alkyl,
(CH.sub.2).sub.rC(O)OH, (CH.sub.2).sub.rC(O)R.sup.5b,
(CH.sub.2).sub.rC(O)NR.sup.5fR.sup.5f,
(CH.sub.2)rOC(O)NR.sup.5fR.sup.5f,
(CH.sub.2).sub.rNR.sup.5fC(O)R.sup.5b,
(CH.sub.2).sub.rC(O)OC.sub.1-4 alkyl,
(CH.sub.2).sub.rNR.sup.5fC(O)OC.sub.1-4 alkyl,
(CH.sub.2).sub.rOC(O)R.sup.5b,
(CH.sub.2).sub.rC(.dbd.NR.sup.5f)NR.sup.5fR.sup.5f,
(CH.sub.2).sub.rS(O).sub.pR.sup.5b,
(CH.sub.2).sub.rNHC(NR.sup.5)NR.sup.5 f R.sup.5 f
(CH.sub.2).sub.rS(O).sub.2NR.sup.5fR.sup.5f,
(CH.sub.2).sub.rNR.sup.5fS(O).sub.2--R.sup.5b, and
(CH.sub.2).sub.rphenyl substituted with 0-3 R.sup.5e; R.sup.5d, at
each occurrence, is selected from methyl, CF.sub.3, C.sub.2-6 alkyl
substituted with 0-2 R.sup.5e, C.sub.3-8 alkenyl substituted with
0-2 R.sup.5e, C.sub.3-8 alkynyl substituted with 0-2 R.sup.5e, and
a C.sub.3-10 carbocyclic residue substituted with 0-3 R.sup.5e;
R.sup.5e, at each occurrence, is selected from C.sub.1-6 alkyl,
C.sub.2-8 alkenyl, C.sub.2-8 alkynyl, C.sub.3-6 cycloalkyl, Cl, F,
Br, I, CN, NO.sub.2, (CF.sub.2).sub.rCF.sub.3,
(CH.sub.2).sub.rOC.sub.1-5 alkyl, OH, SH,
(CH.sub.2).sub.rSC.sub.1-5 alkyl,
(CH.sub.2).sub.rNR.sup.5fR.sup.5f, and (CH.sub.2).sub.rphenyl;
R.sup.5f, at each occurrence, is selected from H, C.sub.1-6 alkyl,
and C.sub.3-6 cycloalkyl; R.sup.5g is independently selected from
C(O)R.sup.5b, --C(O)OR.sup.5d, --C(O)NR.sup.5fR.sup.5f, and
(CH.sub.2).sub.rphenyl; R, at each occurrence, is selected from H,
C.sub.1-6 alkyl substituted with R.sup.5e, C.sub.2-8 alkenyl,
C.sub.2-8 alkynyl, (CH.sub.2).sub.rC.sub.3-6 cycloalkyl, and
(CH.sub.2).sub.rphenyl substituted with R.sup.5e; R.sup.6, at each
occurrence, is selected from C.sub.1-8 alkyl, C.sub.2-8 alkenyl,
C.sub.2-8 alkynyl, (CH.sub.2).sub.rC.sub.3-6 cycloalkyl, Cl, Br, I,
F, NO.sub.2, CN, (CR'R').sub.rNR.sup.6aR.sup.6a, (CR'R').sub.rOH,
(CR'R').sub.rO(CR'R').sub.rR.sup.6d, (CR'R').sub.rSH,
(CR'R').sub.rC(O)H, (CR'R').sub.rS(CR'R').sub.rR.sup.6d,
(CR'R').sub.rSC(O) (CR'R').sub.rR.sup.6b, (CR'R').sub.rC(O)OH,
(CR'R').sub.rC(O)(CR'R').sub.rR.sup.6b,
(CR'R').sub.rNR.sup.6aR.sup.6a, (CR'R').sub.rC(O)NR.sup.6aR.sup.6a,
(CR'R').sub.rNR.sup.6fC(O)(CR'R').sub.rR.sup.6b,
(CR'R').sub.rC(O)O(CR'R').sub.rR.sup.6d,
(CR'R').sub.rOC(O)(CR'R').sub.rR.sup.6b,
(CR'R').sub.rOC(O)NR.sup.6a(CR'R').sub.rR.sup.6d,
(CR'R').sub.rNR.sup.6aC(O)NR.sup.6a(CR'R').sub.rR.sup.6d,
(CR'R').sub.rNR.sup.6aC(s)NR.sup.6a(CR'R').sub.rR.sup.6d,
(CR'R').sub.rNR.sup.6fC(O)O(CR'R').sub.rR.sup.6b,
(CR'R').sub.rC(.dbd.NR.sup.6f)NR.sup.6aR.sup.6a,
(CR'R').sub.rNHC(.dbd.NR.sup.6f)NR.sup.6fR.sup.6f,
(CR'R').sub.rS(O).sub.p(CR'R').sub.rR.sup.6b,
(CR'R').sub.rS(O).sub.2NR.sup.6aR.sup.6a,
(CR'R').sub.rNR.sup.6fS(O).sub.2NR.sup.6aR.sup.6a,
(CR'R').sub.rNR.sup.6fS(O).sub.2(CR'R').sub.rR.sup.6b, C.sub.1-6
haloalkyl, C.sub.2-8 alkenyl substituted with 0-3 R', C.sub.2-8
alkynyl substituted with 0-3 R', (CR'R').sub.rphenyl substituted
with 0-3 R.sup.6e, and a (CH.sub.2).sub.r-5-6 membered heterocyclic
system containing 1-2 heteroatoms selected from N, O, and S,
substituted with 0-2 R.sup.5e; alternatively, two R.sup.6 on
adjacent atoms on R.sup.1 may join to form a cyclic acetal;
R.sup.6a, at each occurrence, is selected from H, methyl
substituted with 0-1 R.sup.6g, C.sub.2-6 alkyl substituted with 0-2
R.sup.6e, C.sub.3-8 alkenyl substituted with 0-2 R.sup.6e,
C.sub.3-8 alkynyl substituted with 0-2 R.sup.6e, a
(CH.sub.2).sub.r--C.sub.3-10 carbocyclic residue substituted with
0-5 R.sup.6e, and a (CH.sub.2).sub.r-5-10 membered heterocyclic
system containing 1-4 heteroatoms selected from N, O, and S,
substituted with 0-2 R.sup.6e; R.sup.6b, at each occurrence, is
selected from H, C.sub.1-6 alkyl substituted with 0-2 R.sup.6e,
C.sub.3-8 alkenyl substituted with 0-2 R.sup.6e, C.sub.3-8 alkynyl
substituted with 0-2 R.sup.6e, a (CH.sub.2).sub.rC.sub.3-6
carbocyclic residue substituted with 0-3 R.sup.6e, and a
(CH.sub.2).sub.r-5-6 membered heterocyclic system containing 1-4
heteroatoms selected from N, O, and S, substituted with 0-2
R.sup.6e; R.sup.6d, at each occurrence, is selected from C.sub.3-8
alkenyl substituted with 0-2 R.sup.6e, C.sub.3-8 alkynyl
substituted with 0-2 R.sup.6e, methyl, CF.sub.3, C.sub.2-6 alkyl
substituted with 0-3 R.sup.6e, C.sub.2-4 haloalkyl, a
(CH.sub.2).sub.r--C.sub.3-10 carbocyclic residue substituted with
0-3 R.sup.6e, and a (CH.sub.2).sub.r-5-6 membered heterocyclic
system containing 1-4 heteroatoms selected from N, O, and S,
substituted with 0-3 R.sup.6e; R.sup.6e, at each occurrence, is
selected from C.sub.1-6 alkyl, C.sub.2-8 alkenyl, C.sub.2-8
alkynyl, (CH.sub.2).sub.rC.sub.3-6 cycloalkyl, Cl, F, Br, I, CN,
NO.sub.2, (CF.sub.2).sub.rCF.sub.3, (CH.sub.2).sub.rOC.sub.1-5
alkyl, OH, SH, (CH.sub.2).sub.rSC.sub.1-5 alkyl,
(CH.sub.2).sub.rNR.sup.6fR.sup.6f, and (CH.sub.2).sub.rphenyl;
R.sup.6f, at each occurrence, is selected from H, C.sub.1-5 alkyl,
and C.sub.3-6 cycloalkyl, and phenyl; R.sup.6g is independently
selected from --C(O)R.sup.6b, --C(O)OR.sup.6d,
--C(O)NR.sup.6fR.sup.6f, and (CH.sub.2).sub.rphenyl; R.sup.7, at
each occurrence, is selected from C.sub.1-8 alkyl, C.sub.2-8
alkenyl, C.sub.2-8 alkynyl, (CH.sub.2).sub.rC.sub.3-6 cycloalkyl,
Cl, Br, I, F, NO.sub.2, CN, (CR'R').sub.rNR.sup.7aR.sup.7a,
(CR'R').sub.rOH, (CR'R').sub.rO(CR'R').sub.rR.sup.7d,
(CR'R').sub.rSH, (CR'R').sub.rC(O)H,
(CR'R').sub.rS(CR'R').sub.rR.sup.7d, (CR'R').sub.rC(O)OH,
(CR'R').sub.rC(O)(CR'R').sub.rR.sup.7b,
(CR'R').sub.rC(O)NR.sup.7aR.sup.7a,
(CR'R').sub.rNR.sup.7fC(O)(CR'R').sub.rR.sup.7b,
(CR'R').sub.rC(O)O(CR'R').sub.rR.sup.7d,
(CR'R').sub.rOC(O)(CR'R').sub.rR.sup.7b,
(CR'R').sub.rOC(O)NR.sup.7a(CR'R').sub.rR.sup.7a,
(CR'R').sub.rNR.sup.7aC(O)NR.sup.7a(CR'R').sub.rR.sup.7a,
(CR'R').sub.rNR.sup.7fC(O)O(CR'R').sub.rR.sup.7d,
(CR'R').sub.rC(.dbd.NR.sup.7f)NR.sup.7aR.sup.7a,
(CR'R').sub.rNHC(.dbd.NR.sup.7f)NR.sup.7fR.sup.7f,
(CR'R').sub.rS(O).sub.p(CR'R').sub.rR.sup.7b,
(CR'R').sub.rS(O).sub.2NR.sup.7aR.sup.7a,
(CR'R').sub.rNR.sup.7aS(O).sub.2NR.sup.7aR.sup.7a,
(CR'R').sub.rNR.sup.7fS(O).sub.2(CR'R').sub.rR.sup.7b, C.sub.1-6
haloalkyl, C.sub.2-8 alkenyl substituted with 0-3 R', C.sub.2-8
alkynyl substituted with 0-3 R', and (CR'R').sub.rphenyl
substituted with 0-3 R.sup.7e; alternatively, two R.sup.7 on
adjacent atoms on R.sup.2 may join to form a cyclic acetal;
R.sup.7a, at each occurrence, is independently selected from H,
methyl substituted with 0-1 R.sup.7g, C.sub.2-6 alkyl substituted
with 0-2 R.sup.7e, C.sub.3-8 alkenyl substituted with 0-2 R.sup.7e,
C.sub.3-8 alkynyl substituted with 0-2 R.sup.7e, a
(CH.sub.2).sub.r--C.sub.3-10 carbocyclic residue substituted with
0-5 R.sup.7e, and a (CH.sub.2).sub.r-5-10 membered heterocyclic
system containing 1-4 heteroatoms selected from N, O, and S,
substituted with 0-2 R.sup.7e; R.sup.7b, at each occurrence, is
selected from C.sub.1-6 alkyl substituted with 0-2 R.sup.7e,
C.sub.3-8 alkenyl substituted with 0-2 R.sup.7e, C.sub.3-8 alkynyl
substituted with 0-2 R.sup.7e, a (CH.sub.2).sub.rC.sub.3-6
carbocyclic residue substituted with 0-3 R.sup.7e, and a
(CH.sub.2).sub.r-5-6 membered heterocyclic system containing 1-4
heteroatoms selected from N, O, and S, substituted with 0-2
R.sup.7e; R.sup.7d, at each occurrence, is selected from C.sub.3-8
alkenyl substituted with 0-2 R.sup.7e, C.sub.3-8 alkynyl
substituted with 0-2 R.sup.7e, methyl, CF.sub.3, C.sub.2-4
haloalkyl, C.sub.2-6 alkyl substituted with 0-3 R.sup.7e, a
(CH.sub.2).sub.r--C.sub.3-10 carbocyclic residue substituted with
0-3 R.sup.7e, and a (CH.sub.2).sub.r-5-6 membered heterocyclic
system containing 1-4 heteroatoms selected from N, O, and S,
substituted with 0-3 R.sup.7e; R.sup.7e, at each occurrence, is
selected from C.sub.1-6
alkyl, C.sub.2-8 alkenyl, C.sub.2-8 alkynyl,
(CH.sub.2).sub.rC.sub.3-6 cycloalkyl, Cl, F, Br, I, CN, NO.sub.2,
(CF.sub.2).sub.rCF.sub.3, (CH.sub.2).sub.rOC.sub.1-5 alkyl, OH, SN,
C(O)OC.sub.1-5 alkyl, (CH.sub.2).sub.rSC.sub.1-5 alkyl,
(CH.sub.2).sub.rNR.sup.7fR.sup.7f, and (CH.sub.2).sub.rphenyl;
R.sup.7f, at each occurrence, is selected from H, C.sub.1-5 alkyl,
and C.sub.3-6 cycloalkyl, and phenyl; R.sup.7g is independently
selected from --C(O)R.sup.7b, --C(O)OR.sup.7d,
--C(O)NR.sup.7fR.sup.7f, and (CH.sub.2).sub.rphenyl; R', at each
occurrence, is selected from H, C.sub.1-6 alkyl substituted with
R.sup.6e, C.sub.2-8 alkenyl, C.sub.2-8 alkynyl,
(CH.sub.2).sub.rC.sub.3-6 cycloalkyl, and (CH.sub.2).sub.rphenyl
substituted with R.sup.6e; R.sup.8 is selected from H, C.sub.1-4
alkyl, and C.sub.3-4 cycloalkyl; R.sup.9 is selected from H,
C.sub.1-4 alkyl, C.sub.3-4 cycloalkyl, --C(O)H, and
--C(O)--C.sub.1-4alkyl; R.sup.10 is independently selected from H,
and C.sub.1-4alkyl substituted with 0-1 R.sup.10b; R.sup.10b, at
each occurrence, is independently selected from --OH, --SH,
--NR.sup.10cR.sup.10c, --C(O)NR.sup.10cR.sup.10c, and
--NHC(O)R.sup.10c; R.sup.10c is selected from H, C.sub.1-4 alkyl
and C.sub.3-6 cycloalkyl; R.sup.11 is selected from H, C.sub.1-4
alkyl, (CHR).sub.qOH, (CHR).sub.qSH, (CHR).sub.qOR.sup.11d,
(CHR).sub.qS(O).sub.pR.sup.11d, (CHR).sub.rC(O)R.sup.11b,
(CHR).sub.rNR.sup.11aR.sup.11a, (CHR).sub.rC(O)NR.sup.11aR.sup.11a,
(CHR).sub.rC(O)NR.sup.11aOR.sup.11d,
(CHR).sub.qNR.sup.11aC(O)R.sup.11b,
(CHR).sub.qNR.sup.11aC(O)OR.sup.11d,
(CHR).sub.rOC(O)NR.sup.11aR.sup.11a, (CHR).sub.rC(O)OR.sup.11d, a
(CHR).sub.r--C.sub.3-6 carbocyclic residue substituted with 0-5
R.sup.11e, and a (CHR).sub.r-5-10 membered heterocyclic system
containing 1-4 heteroatoms selected from N, O, and S, substituted
with 0-3 R.sup.11e; R.sup.11a, at each occurrence, is independently
selected from H, C.sub.1-4 alkyl, C.sub.3-4 alkenyl, C.sub.3-4
alkynyl, (CH.sub.2).sub.rC.sub.3-6 cycloalkyl, a
(CH.sub.2).sub.r--C.sub.3-6 carbocyclic residue substituted with
0-5 R.sup.11e, and a (CH.sub.2).sub.r-5-6 membered heterocyclic
system containing 1-4 heteroatoms selected from N, O, and S,
substituted with 0-3 R.sup.11e; R.sup.11b, at each occurrence, is
independently selected from C.sub.1-4 alkyl, C.sub.2-4 alkenyl,
C.sub.2-4 alkynyl, a (CH.sub.2).sub.r--C.sub.3-6 carbocyclic
residue substituted with 0-2 R.sup.11e, and a (CH.sub.2).sub.r-5-6
membered heterocyclic system containing 1-4 heteroatoms selected
from N, O, and S, substituted with 0-3 R.sup.11e; R.sup.11d, at
each occurrence, is independently selected from H, methyl,
--CF.sub.3, C.sub.2-4 alkyl, C.sub.3-6 alkenyl, C.sub.3-6 alkynyl,
a C.sub.3-6 carbocyclic residue substituted with 0-3 R.sup.11e, and
a (CH.sub.2).sub.r-5-6 membered heterocyclic system containing 1-4
heteroatoms selected from N, O, and S, substituted with 0-3
R.sup.11e; R.sup.11e, at each occurrence, is selected from
C.sub.1-6 alkyl, C.sub.2-8 alkenyl, C.sub.2-8 alkynyl, C.sub.3-6
cycloalkyl, Cl, F, Br, I, CN, NO.sub.2, (CF.sub.2).sub.rCF.sub.3,
(CH.sub.2).sub.rOC.sub.1-5 alkyl, OH, --O--C.sub.1-6 alkyl, SH,
(CH.sub.2).sub.rSC.sub.1-5 alkyl,
(CH.sub.2).sub.rNR.sup.11fR.sup.11f, and (CH.sub.2).sub.rphenyl;
R.sup.11f, at each occurrence, is selected from H, C.sub.1-6 alkyl,
and C.sub.3-6 cycloalkyl; R.sup.12 is selected from H, C.sub.1-4
alkyl, (CHR).sub.qOH, (CHR).sub.qSH, (CHR).sub.qOR.sup.12d,
(CHR).sub.qS(O).sub.pR.sup.12d, (CHR).sub.rC(O)R.sup.12b,
(CHR).sub.rNR.sup.12aR.sup.12a, (CHR).sub.rC(O)NR.sup.12aR.sup.12a,
(CHR).sub.rC(O)NR.sup.12aOR.sup.12d,
(CHR).sub.qNR.sup.12aC(O)R.sup.12b,
(CHR).sub.qNR.sup.12aC(O)OR.sup.12d,
(CHR).sub.qOC(O)NR.sup.12aR.sup.12a, (CHR).sub.rC(O)OR.sup.12d, a
(CHR).sub.r--C.sub.3-6 carbocyclic residue substituted with 0-5
R.sup.12e, and a (CHR).sub.r-5-10 membered heterocyclic system
containing 1-4 heteroatoms selected from N, O, and S, substituted
with 0-3 R.sup.12e; R.sup.12a, at each occurrence, is independently
selected from H, C.sub.1-4 alkyl, C.sub.3-4 alkenyl, C.sub.3-4
alkynyl, (CH.sub.2).sub.rC.sub.3-6 cycloalkyl, a
(CH.sub.2).sub.r--C.sub.3-6 carbocyclic residue substituted with
0-5 R.sup.12e, and a (CH.sub.2).sub.r-5-6 membered heterocyclic
system containing 1-4 heteroatoms selected from N, O, and S,
substituted with 0-3 R.sup.12e; R.sup.12b, at each occurrence, is
independently selected from C.sub.1-4 alkyl, C.sub.2-4 alkenyl,
C.sub.2-4 alkynyl, a (CH.sub.2).sub.r--C.sub.3-6 carbocyclic
residue substituted with 0-2 R.sup.12e, and a (CH.sub.2).sub.r-5-6
membered heterocyclic system containing 1-4 heteroatoms selected
from N, O, and S, substituted with 0-3 R.sup.12e; R.sup.12d, at
each occurrence, is independently selected from H, methyl,
--CF.sub.3, C.sub.2-4 alkyl, C.sub.3-6 alkenyl, C.sub.3-6 alkynyl,
a C.sub.3-6 carbocyclic residue substituted with 0-3 R.sup.12e, and
a (CH.sub.2).sub.r-5-6 membered heterocyclic system containing 1-4
heteroatoms selected from N, O, and S, substituted with 0-3
R.sup.12e; R.sup.12e, at each occurrence, is selected from
C.sub.1-6 alkyl, C.sub.2-8 alkenyl, C.sub.2-8 alkynyl, C.sub.3-6
cycloalkyl, Cl, F, Br, I, CN, NO.sub.2, (CF.sub.2).sub.rCF.sub.3,
(CH.sub.2).sub.rOC.sub.1-5 alkyl, OH, --O--C.sub.1-6 alkyl, SH,
(CH.sub.2).sub.rSC.sub.1-5 alkyl,
(CH.sub.2).sub.rNR.sup.12fR.sup.12f, and (CH.sub.2).sub.rphenyl;
R.sup.12f, at each occurrence, is selected from H, C.sub.1-6 alkyl,
and C.sub.3-6 cycloalkyl; R.sup.13, at each occurrence, is
independently selected from H, and C.sub.1-4alkyl substituted with
0-1 R.sup.13b, --OH, --NH.sub.2, F, Cl, Br, I, --OR.sup.13a,
--N(R.sup.13a).sub.2, and C.sub.1-4 alkyl substituted with 0-3
R.sup.13b; R.sup.13a is selected from H, C.sub.1-4 alkyl and
C.sub.3-6 cycloalkyl; R.sup.13b, at each occurrence, is
independently selected from --OH, --SH, --NR.sup.13cR.sup.13c,
--C(O)NR.sup.13cR.sup.13c, and --NHC(O)R.sup.13c; R.sup.13c is
selected from H, C.sub.1-4 alkyl and C.sub.3-6 cycloalkyl;
R.sup.14, at each occurrence, is independently selected from H and
C.sub.1-4alkyl; alternatively, two R.sup.14s, along with the carbon
atom to which they are attached, join to form a C.sub.3-6
carbocyclic ring; R.sup.15, at each occurrence, is independently
selected from H, C.sub.1-4alkyl, OH, NH.sub.2, --O--C.sub.1-4
alkyl, NR.sup.15aR.sup.15a, C(O)NR.sup.15aR.sup.15a,
NR.sup.15aC(O)R.sup.15b, NR.sup.15aC(O)OR.sup.15d,
OC(O)NR.sup.15aR.sup.15a, and (CHR).sub.rC(O)OR.sup.15d;
alternatively, two R.sup.15s, along with the carbon atom or atoms
to which they are attached, join to form a C.sub.3-6 carbocyclic
ring; R.sup.15a, at each occurrence, is independently selected from
H, and C.sub.1-4 alkyl; R.sup.15b, at each occurrence, is
independently selected from C.sub.1-4 alkyl, C.sub.3-6 alkenyl, and
C.sub.3-6 alkynyl; R.sup.15d, at each occurrence, is independently
selected from C.sub.1-4 alkyl, C.sub.3-6 alkenyl, and C.sub.3-6
alkynyl; R.sup.16 is selected from C.sub.1-4 alkyl; l is selected
from 1, 2 and 3; n is selected from 0, 1, 2, and 3; m is selected
from 0 and 1; p, at each occurrence, is independently selected from
0, 1, and 2; q, at each occurrence, is independently selected from
1, 2, 3, and 4; r, at each occurrence, is independently selected
from 0, 1, 2, 3, and 4; t, at each occurrence, is independently
selected from 2, 3, and 4; s is selected from 0 and 1.
3. The compound of claim 2, wherein m is 0.
4. The compound of claim 3, wherein: ring B is selected from
##STR145## ring B being optionally substituted with 0-1 R.sup.5;
and R.sup.11 and R.sup.12 are H.
5. The compounds of claim 4, wherein: R.sup.5, at each occurrence,
is independently selected from H, C.sub.1-6 alkyl, C.sub.2-8
alkenyl, C.sub.2-8 alkynyl, (CRR).sub.rOH, (CRR).sub.rSH,
(CRR).sub.rOR.sup.5d, (CRR).sub.rSR.sup.5d,
(CRR).sub.rNR.sup.5aR.sup.5a, (CRR).sub.rC(O)OH,
(CRR).sub.rC(O)R.sup.5b, (CRR).sub.rC(O)NR.sup.5aR.sup.5a,
(CRR).sub.rNR.sup.5aC(O)R.sup.5b, (CRR).sub.rN.sup.5aC(O)OR.sup.5d,
(CRR).sub.rOC(O)NR.sup.5aR.sup.5a,
(CHR).sub.rNR.sup.5aC(O)NR.sup.5aR.sup.5a,
CRR(CRR).sub.rNR.sup.5aC(O)H, (CRR).sub.rC(O)OR.sup.5b,
(CRR).sub.rOC(O)R.sup.5b, (CRR).sub.rS(O).sub.pR.sup.5b,
(CRR).sub.rS(O).sub.2NR.sup.5aR.sup.5a,
(CRR).sub.rNR.sup.5aS(O).sub.2R.sup.5b, and C.sub.1-6 haloalkyl;
R.sup.5a, at each occurrence, is independently selected from H,
methyl, C.sub.1-6 alkyl substituted with 0-2 R.sup.56 wherein the
alkyl is selected from ethyl, propyl, i-propyl, butyl, i-butyl,
pentyl, hexyl, C.sub.3 alkenyl substituted with 0-1 R.sup.5e,
wherein the alkenyl is selected from allyl, C.sub.3 alkynyl
substituted with 0-1 R.sup.5e wherein the alkynyl is selected from
propynyl, and a (CH.sub.2).sub.r--C.sub.3-4 carbocyclic residue
substituted with 0-5 R.sup.5e, wherein the carbocyclic residue is
selected from cyclopropyl, and cyclobutyl; R.sup.5b, at each
occurrence, is selected from C.sub.1-6 alkyl substituted with 0-2
R.sup.5e, wherein the alkyl is selected from methyl, ethyl, propyl,
i-propyl, butyl, i-butyl, pentyl, and hexyl, a
(CH.sub.2).sub.r--C.sub.3-4 carbocyclic residue substituted with
0-2 R.sup.5e, wherein the carbocyclic residue is selected from
cyclopropyl, and cyclobutyl; and R.sup.5d, at each occurrence, is
selected from methyl, CF.sub.3, C.sub.2-6 alkyl substituted with
0-2 R.sup.5e, wherein the alkyl is selected from methyl, ethyl,
propyl, i-propyl, butyl, i-butyl, pentyl, and hexyl, C.sub.3-8
alkenyl, C.sub.3-8 alkynyl, and a C.sub.3-10 carbocyclic residue
substituted with 0-3 R.sup.5e.
6. The compound of claim 5, wherein: R.sup.4 is selected from H,
C.sub.1-6 alkyl, C.sub.3-8 alkenyl, C.sub.3-8 alkynyl,
(CRR).sub.tOH, (CRR).sub.tSH, (CRR).sub.tOR.sup.4d,
(CRR).sub.tSR.sup.4d, (CRR).sub.tNR.sup.4aR.sup.4a,
(CRR).sub.qC(O)OH, (CRR).sub.rC(O)R.sup.4b,
(CRR).sub.rC(O)NR.sup.4aR.sup.4a, (CRR).sub.tNR.sup.4aC(O)R.sup.4b,
(CRR).sub.tOC(O)NR.sup.4aR.sup.4a,
(CRR).sub.tNR.sup.4aC(O)OR.sup.4d,
(CRR).sub.tNR.sup.4aC(O)R.sup.4b, (CRR).sub.rC(O)OR.sup.4b,
(CRR).sub.tOC(O)R.sup.4b, (CRR).sub.rS(O).sub.pR.sup.4b,
(CRR).sub.rS(O).sub.2NR.sup.4aR.sup.4a,
(CRR).sub.rNR.sup.4aS(O).sub.2R.sup.4b; R, at each occurrence, is
independently selected from H, methyl, ethyl, propyl, allyl,
propynyl, (CH.sub.2).sub.rC.sub.3-6 cycloalkyl, and
(CH.sub.2).sub.rphenyl substituted with R.sup.6e, R.sup.5, at each
occurrence, is independently selected from H, methyl, ethyl,
propyl, i-propyl, butyl, i-butyl, allyl, propynyl,
(CH.sub.2).sub.rOH, (CH.sub.2).sub.rOR.sup.5d,
(CH.sub.2).sub.rNR.sup.5aR.sup.5a, (CH.sub.2).sub.rC(O)OH,
(CH.sub.2).sub.rC(O)R.sup.5b,
(CH.sub.2).sub.rC(O)NR.sup.5aR.sup.5a,
(CH.sub.2).sub.rNR.sup.5aC(O)R.sup.5b,
(CH.sub.2).sub.rOC(O)NR.sup.5aR.sup.5a,
(CH.sub.2).sub.rNR.sup.5aC(O)OR.sup.5d,
(CH.sub.2).sub.rNR.sup.5aC(O)R.sup.5b,
(CH.sub.2).sub.rC(O)OR.sup.5b, (CH.sub.2).sub.rOC(O)R.sup.5b,
(CH.sub.2).sub.rNR.sup.5aS(O).sub.2R.sup.5b, and C.sub.1-6
haloalkyl; R.sup.5a, at each occurrence, is independently selected
from H, methyl, ethyl, propyl, i-propyl, butyl, i-butyl, pentyl,
hexyl, cyclopropyl, and cyclobutyl; and r, at each occurrence, is
selected from 0, 1, and 2.
7. The compound of claim 6, wherein: R.sup.1 is selected from
phenyl substituted with 0-2 R.sup.6, naphthyl substituted with 0-2
R.sup.6, and a 5-10 membered heteroaryl system containing 1-4
heteroatoms selected from N, O, and S, substituted with 0-3 R.sup.6
wherein the heteroaryl is selected from indolyl, benzimidazolyl,
benzofuranyl, benzothiofuranyl, benzoxazolyl, benzthiazolyl,
benzo[b]thiophene, benztriazolyl, benztetrazolyl, benzisoxazolyl,
benzisothiazolyl, benzimidazalonyl, cinnolinyl, furanyl,
imidazolyl, indazolyl, indolyl, isoquinolinyl, isothiazolyl,
isoxazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl,
pyrido[2,3-d]pyrimidinyl, pyrimido[5,4-d]pyrimidinyl,
thieno[3,2-d]pyrimidinyl, pyridinyl, pyrimidinyl, pyrrolyl,
pyrrolo[2,1-f][1,2,4]triazine, quinazolinyl, quinolinyl, thiazolyl,
thienyl, and tetrazolyl; R.sup.2 is selected from phenyl
substituted with 0-2 R.sup.7, and a 5-10 membered heteroaryl system
containing 1-4 heteroatoms selected from N, O, and S, substituted
with 0-3 R.sup.7 wherein the heteroaryl is selected from indolyl,
benzimidazolyl, benzofuranyl, benzothiofuranyl, benzoxazolyl,
benzthiazolyl, benzo[b]thiophene, benztriazolyl, benztetrazolyl,
benzisoxazolyl, benzisothiazolyl, benzimidazalonyl, cinnolinyl,
furanyl, imidazolyl, indazolyl, indolyl, isoquinolinyl
isothiazolyl, isoxazolyl, oxazolyl, phthalazinyl, pyrazinyl,
pyrazolyl, pyridazinyl, pyridyl, pyrido[2,3-d]pyrimidinyl,
thieno[3,2-d]pyrimidinyl, pyridinyl, pyrimidinyl, pyrrolyl,
pyrrolo[2,1-f][1,2,4]triazine, quinazolinyl, quinolinyl, thiazolyl,
thienyl, and tetrazolyl; R.sup.4 is selected from H, methyl, ethyl,
propyl, i-propyl, butyl, i-butyl, allyl, propynyl, (CRR).sub.qOH,
(CRR).sub.tSH, (CRR).sub.tOR.sup.4d, (CRR).sub.tSR.sup.4d,
(CRR).sub.tNR.sup.4aR.sup.4a, (CRR).sub.qC(O)OH,
(CRR).sub.rC(O)R.sup.4b, (CRR).sub.rC(O)NR.sup.4aR.sup.4a,
(CRR).sub.tNR.sup.4aC(O)R.sup.4b,
(CRR).sub.tOC(O)NR.sup.4aR.sup.4a,
(CRR).sub.tNR.sup.4aC(O)OR.sup.4d,
(CRR).sub.tNR.sup.4aC(O)R.sup.4b, (CRR).sub.rC(O)OR.sup.4b,
(CRR).sub.tOC(O)R.sup.4b, (CRR).sub.rS(O).sub.pR.sup.4b,
(CRR).sub.rS(O).sub.2NR.sup.4aR.sup.4a,
(CRR).sub.rNR.sup.4aS(O).sub.2R.sup.4b; R.sup.4a, at each
occurrence, is independently selected from H, methyl substituted
with 0-1 R.sup.4c, C.sub.2-6 alkyl substituted with 0-3 R.sup.4e
wherein C.sub.2-6 is selected from ethyl, propyl, i-propyl, butyl,
i-butyl, t-butyl, pentyl and hexyl, and a
(CH.sub.2).sub.r--C.sub.3-6 carbocyclic residue substituted with
0-4 R.sup.4e wherein the carbocyclic residue is selected from
cyclopropyl, cyclohexyl, and phenyl; R.sup.4b is selected from H,
methyl, ethyl, propyl, i-propyl, butyl, i-butyl, t-butyl, pentyl,
and cyclopropyl; R.sup.4d is selected from methyl, ethyl, propyl,
i-propyl, butyl, i-butyl, t-butyl, pentyl, and cyclopropyl; and
R.sup.8 is selected from H, methyl, ethyl, propyl, i-propyl, and
cyclopropyl.
8. The compound of claim 7, wherein: R.sup.6, at each occurrence,
is selected from C.sub.1-8 alkyl, C.sub.2-8 alkenyl, C.sub.2-8
alkynyl, (CR'R').sub.rC.sub.3-6 cycloalkyl, Cl, Br, I, F, NO.sub.2,
CN, (CR'R').sub.rN.sup.6aR.sup.6a, (CR'R').sub.rOH,
(CR'R').sub.rO(CR'R').sub.rR.sup.6d, (CR'R').sub.rSH,
(CR'R').sub.rC(O)H, (CR'R').sub.rS(CR'R').sub.rR.sup.6d,
(CR'R').sub.rC(O)OH, (CR'R').sub.rC(O)(CR'R').sub.rR.sup.6b,
(CR'R').sub.rC(O)NR.sup.6aR.sup.6a, (CR'R').sub.rNR.sup.6fC(O)
(CR'R').sub.rR.sup.6b, (CR'R').sub.rC(O)O(CR'R').sub.rR.sup.6d,
(CR'R').sub.rNR.sup.6aC(O)NR.sup.6aR.sup.6a,
(CR'R').sub.rNR.sup.6aC(S)NR.sup.6aR.sup.6a, (CR'R').sub.rOC(O)
(CR'R').sub.rR.sup.6b,
(CR'R').sub.rS(O).sub.p(CR'R').sub.rR.sup.6b,
(CR'R').sub.rS(O).sub.2NR.sup.6aR.sup.6a,
(CR'R').sub.rNR.sup.6fS(O).sub.2(CR'R').sub.rR.sup.6b,
(CR'R').sub.rNR.sup.6fS(O).sub.2 NR.sup.6aR.sup.6a, C.sub.1-6
haloalkyl, and (CR'R').sub.rphenyl substituted with 0-3 R.sup.6e,
and a (CH.sub.2).sub.r-5-6 membered heterocyclic system containing
1-2 heteroatoms selected from N, O, and S, substituted with 0-2
R.sup.6e; R.sup.6a, at each occurrence, is independently selected
from H, methyl, ethyl, propyl, i-propyl, butyl, i-butyl, t-butyl,
pentyl, hexyl, cyclopropyl and phenyl; R.sup.6b, at each
occurrence, is selected from methyl, ethyl, propyl, i-propyl,
butyl, i-butyl, t-butyl, pentyl, hexyl, cyclopropyl, and phenyl;
R.sup.5d, at each occurrence, is selected from methyl, CF.sub.3,
ethyl, propyl, i-propyl, butyl, i-butyl, t-butyl, pentyl, hexyl,
cyclopropyl, and phenyl; R.sup.6e, at each occurrence, is selected
from C.sub.1-6 alkyl, C.sub.2-8 alkenyl, C.sub.2-8 alkynyl,
(CH.sub.2).sub.rC.sub.3-6 cycloalkyl, Cl, F, Br, I, CN, NO.sub.2,
(CF.sub.2).sub.rCF.sub.3, (CH.sub.2).sub.rOC.sub.1-5 alkyl, OH, SH,
(CH.sub.2).sub.rSC.sub.1-5 alkyl,
(CH.sub.2).sub.rNR.sup.6fR.sup.6f, and (CH.sub.2).sub.rphenyl;
R.sup.6f, at each occurrence, is selected from H, methyl, ethyl,
propyl, i-propyl, butyl, i-butyl, t-butyl, pentyl, hexyl,
cyclopropyl, and phenyl; R.sup.7 is selected from methyl, ethyl,
propyl, i-propyl, butyl, i-butyl, s-butyl, t-butyl, pentyl, hexyl,
(CR'R').sub.rC.sub.3-6 cycloalkyl, Cl, Br, I, F, NO.sub.2, CN,
(CR'R').sub.rNR.sup.7aR.sup.7a, (CR'R').sub.rOH,
(CR'R').sub.rO(CH).sub.rR.sup.7d, (CR'R').sub.rSH,
(CR'R').sub.rC(O)H, (CR'R').sub.rS(CR'R').sub.rR.sup.7d,
(CR'R').sub.rC(O)OH, (CR'R').sub.rC(O)(CR'R').sub.rR.sup.7b,
(CR'R').sub.rC(O)NR.sup.7aR.sup.7a,
(CR'R').sub.rNR.sup.7fC(O)(CR'R').sub.rR.sup.7b,
(CR'R').sub.rC(O)O(CR'R').sub.rR.sup.7d, (CR'R').sub.rOC(O)
(CR'R').sub.rR.sup.7b, (CR'R').sub.rNR.sup.7aC(O)NR.sup.7aR.sup.7a,
(CR'R').sub.rNR.sup.7aC(O)O(CR'R').sub.rR.sup.7d,
(CR'R').sub.rS(O).sub.p(CR'R').sub.rR.sup.7b,
(CR'R').sub.rS(O).sub.2NR.sup.7aR.sup.7a,
(CR'R').sub.rNR.sup.7fS(O).sub.2(CR'R').sub.rR.sup.7b, C.sub.1-6
haloalkyl, and (CR'R').sub.rphenyl substituted with 0-3 R.sup.7e;
R.sup.7a, at each occurrence, is selected from H, methyl, ethyl,
propyl, i-propyl, butyl, i-butyl, t-butyl, pentyl, hexyl,
prop-2-enyl, 2-methyl-2-propenyl, cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, CH.sub.2cyclopropyl, and benzyl; R.sup.7b,
at each occurrence, is selected from methyl, ethyl, propyl,
i-propyl, butyl, i-butyl, t-butyl, pentyl, hexyl, cyclopropyl,
cyclopentyl, CH.sub.2-cyclopentyl, cyclohexyl, CH.sub.2-cyclohexyl,
CF.sub.3, pyrrolidinyl, morpholinyl, piperizinyl substituted with
0-1 R.sup.7e, and azetidinyl; R.sup.7d, at each occurrence, is
selected from methyl, CF.sub.3, CF.sub.2CF.sub.3, CHF.sub.2,
CH.sub.2F, ethyl, propyl, i-propyl, butyl, i-butyl, t-butyl,
pentyl, hexyl, and cyclopropyl; R.sup.7e, at each occurrence, is
selected from C.sub.1-6 alkyl, C.sub.2-8 alkenyl, C.sub.2-8
alkynyl, (CH.sub.2).sub.rC.sub.3-6 cycloalkyl, Cl, F, Br, I, CN,
NO.sub.2, (CF.sub.2).sub.rCF.sub.3, (CH.sub.2).sub.rOC.sub.1-5
alkyl, OH, SH, C(O)OC.sub.1-5 alkyl, (CH.sub.2).sub.rSC.sub.1-5
alkyl, (CH.sub.2).sub.rNR.sup.7fR.sup.7f, and
(CH.sub.2).sub.rphenyl; R.sup.7f, at each occurrence, is selected
from H, methyl, ethyl, propyl, i-propyl, butyl, i-butyl, t-butyl,
pentyl, hexyl, cyclopropyl, and phenyl; and r is 0 or 1.
9. The compound of claim 8, wherein: R.sup.7 is selected from
methyl, ethyl, propyl, i-propyl, butyl, i-butyl, s-butyl, pentyl,
hexyl, Cl, Br, I, F, CN, NO.sub.2, NR.sup.7aR.sup.7a,
NHC(O)NHR.sup.7a, NR.sup.7aC(O)R.sup.7b, NR.sup.7aC(O)OR.sup.7d,
CF.sub.3, CF.sub.2CF.sub.3, CHF.sub.2, CH.sub.2F, OCF.sub.3,
C(O)R.sup.7b, C(O)OR.sup.7d, NR.sup.7fC(O)NR.sup.7aR.sup.7a,
NHS(O).sub.2R.sup.7b, ##STR146##
10. The compound of claim 9, wherein: ring B is selected from
##STR147## ring B being optionally substituted with 0-1 R.sup.5; Z
is selected from a bond, --NR.sup.8C(O)--, --C(O)NH--, and
--NC(O)NH--; R.sup.1 is selected from a C.sub.6-10 aryl group
substituted with 0-3 R.sup.6 wherein the aryl group is selected
from phenyl and naphthyl, and a 5-10 membered heteroaryl system
containing 1-4 heteroatoms selected from N and O, substituted with
0-3 R.sup.6 wherein the heteroaryl system is selected from indolyl,
pyridinyl, pyrimidinyl, pyrido[2,3-d]pyrimidinyl,
thieno[3,2-d]pyrimidinyl, imidazyolyl, and pyrrolyl R.sup.2 is
phenyl substituted with 0-2 R.sup.7; R.sup.4 is selected from H,
methyl, ethyl, propyl, i-propyl, butyl, i-butyl, t-butyl, pentyl,
hexyl, and (CH.sub.2).sub.rC(O)R.sup.4b; R.sup.6 is selected from
methyl, ethyl, propyl, i-propyl, butyl, F, Cl, Br, I, NO.sub.2, CN,
O(CH.sub.2).sub.rR.sup.6d, C(O)H, C(O)R.sup.6d, C(O)OH, SR.sup.6d,
NR.sup.6aR.sup.6a, NC(O)R.sup.6b, OC(O)R.sup.6b,
S(O).sub.pR.sup.6b, (CHR').sub.rS(O).sub.2NR.sup.6aR.sup.6a, and
CF.sub.3; R.sup.6a is H, methyl, or ethyl; R.sup.6b is H, methyl,
ethyl, propyl, i-propyl or butyl; R.sup.6d is methyl, phenyl,
CF.sub.3, and (CH.sub.2)-phenyl; and r is 0 or 1.
11. The compound of claim 10, wherein: ring B is selected from
##STR148## ring B being substituted with 0-1 R.sup.5; R.sup.1 is
selected from a C.sub.6-10 aryl group substituted with 0-3 R.sup.6
wherein the aryl group is selected from phenyl, and a S-10 membered
heteroaryl system containing 1-4 heteroatoms selected from N and O,
substituted with 0-3 R.sup.6 wherein the heteroaryl system is
selected from indolyl and pyridinyl; R.sup.4 is selected from H,
methyl, ethyl, propyl, i-propyl, butyl, i-butyl, t-butyl, pentyl,
hexyl, allyl and (CH.sub.2).sub.rC(O)R.sup.4b; R.sup.5 is selected
from H, OH, OCH.sub.3, and NR.sup.5aR.sup.5a; R.sup.5a is selected
from H, methyl, ethyl, propyl, i-propyl, butyl, s-butyl, i-butyl,
t-butyl, pentyl, hexyl, allyl, propargyl, cyclopropyl,
cyclopropylmethyl, acetyl, methylsulfonyl, --C(O)CF.sub.3,
C(.dbd.N)NH.sub.2, benzyl, and --C(O)O-t-butyl; R.sup.6 is selected
from methyl, ethyl, propyl, i-propyl, butyl, vinyl, F, Cl, Br, I,
CN, NR.sup.6aR.sup.6a, C(O)H, C(O)OH, C(O)R.sup.6b, SR.sup.6d,
S(O).sub.pR.sup.6d, S(O).sub.2NR.sup.6aR.sup.6a, CF.sub.3, and
CH.sub.2OH; R.sup.6b is H, methyl, ethyl, propyl, i-propyl or
butyl; R.sup.6d is methyl; R.sup.7 is selected from methyl, ethyl,
propyl, i-propyl, butyl, i-butyl, s-butyl, pentyl, hexyl, Cl, Br,
I, F, CN, NO.sub.2, NR.sup.7aR.sup.7a, NHC(O)NHR.sup.7a,
NR.sup.7aC(O)R.sup.7b, NR.sup.7aC(O)OR.sup.7d, CF.sub.3,
CF.sub.2CF.sub.3, CHF.sub.2, CH.sub.2F, OCF.sub.3,
OCF.sub.2CF.sub.3, OCHF.sub.2, and OCH.sub.2F, C(O)OR.sup.7d,
C(O)R.sup.7b, NR.sup.7fC(O)NR.sup.7aR.sup.7a, NHS(O).sub.2R.sup.7b,
##STR149## R.sup.7a is selected from H, methyl, ethyl, propyl,
i-propyl, butyl, i-butyl, t-butyl, pentyl, neo-pentyl, cyclopropyl,
cyclobutyl, cyclopentyl, and cyclohexyl; R.sup.7b is selected from
cyclohexyl and CF.sub.3; and R.sup.7d is selected from methyl,
ethyl, propyl, i-propyl, butyl, i-butyl, and t-butyl.
12. The compound of claim 11, wherein: ring B is selected from
##STR150## ring B being substituted with 0-1 R.sup.5; R.sup.1 is
selected from a C.sub.6-10 aryl group substituted with 0-3 R.sup.6
wherein the aryl group is phenyl; R.sup.6 is selected from methyl,
ethyl, propyl, i-propyl, F, Cl, Br, CN, SCH.sub.3, and CF.sub.3;
R.sup.7 is selected from methyl, ethyl, propyl, i-propyl, butyl,
i-butyl, s-butyl, t-butyl, pentyl, hexyl, phenyl, adamantyl,
benzyl, Cl, Br, I, F, CN, NO.sub.2, NR.sup.7aR.sup.7a, OR.sup.7d,
NHC(O)NHR.sup.7a, NR.sup.7aC(O)R.sup.7b, NR.sup.7aC(O)OR.sup.7d,
CF.sub.3, CF.sub.2CF.sub.3, CHF.sub.2, CH.sub.2F, OCF.sub.3,
OCF.sub.2CF.sub.3, OCHF.sub.2, and OCH.sub.2F, C(O)OR.sup.7d,
C(O)R.sup.7b, and NR.sup.7fC(O)NR.sup.7aR.sup.7a; R.sup.7a is
selected from H, methyl, ethyl, propyl, i-propyl, butyl, i-butyl,
t-butyl, pentyl, neo-pentyl, cyclopropyl, cyclobutyl, cyclopentyl,
and cyclohexyl.
13. The compound of claim 12, wherein E is selected from
--CH.sub.2--NH--, --C(O)--NH-- and --SO.sub.2--CH.sub.2--.
14. The compound of claim 1, wherein B is ##STR151## ring B being
substituted with 0-1 R.sup.5; and R.sup.5 is selected from H,
N(.fwdarw.O)R.sup.5aR.sup.5a, N.sub.3, NR.sup.5aC(O)R.sup.5b,
NR.sup.5aC(O)H, NR.sup.5aC(O)OR.sup.5d,
NR.sup.5aC(O)NR.sup.5aR.sup.5a, and NR.sup.5aR.sup.5a, and a
(CH.sub.2).sub.r-5-6 membered heterocyclic system containing 1-2
heteroatoms selected from N, O, and S, substituted with 0-2 Me,
wherein the heterocyclic system is selected from pyrrolidinyl,
piperidinyl, pyrrolidin-2-one, and isothiazolidine 1,1-dioxide.
15. The compound of claim 12, wherein Z is selected from a bond,
--NR.sup.8C(O)--, --CO)NH--, and --NHC(O)NH--.
16. The compound of claim 12, wherein R.sup.6 is selected from
methyl, ethyl, propyl, i-propyl, butyl, vinyl, F, Cl, Br, I, C(O)H,
C(O)R.sup.6b, SR.sup.6d, S(O).sub.pR.sup.6d, CF.sub.3, and
CH.sub.2OH; R.sup.6b is H, methyl, ethyl, propyl, i-propyl or
butyl; R.sup.6d is methyl; R.sup.7 is selected from Cl, Br,
NR.sup.7aR.sup.7a, NR.sup.7aC(O)OR.sup.7d, NHC(O)NHR.sup.7a,
OCF.sub.3, and CF.sub.3; R.sup.7a is selected from H, methyl,
ethyl, propyl, i-propyl, butyl, i-butyl, t-butyl, pentyl,
neo-pentyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl;
R.sup.7d is selected from methyl, ethyl, propyl, i-propyl, butyl,
i-butyl, and t-butyl.
17. The compound of claim 1, wherein the compound is of formula
(Ia) or (Ic) ##STR152##
18. The compound of claim 1, wherein the compound is of formula (I)
is selected:
2-{(3S)-1-[(1,2-cis)-2-(4-Methylsulfanyl-benzoylamino)-cyclohexyl]-2-oxo--
pyrrolidin-3-ylcarbamoyl}-4-trifluoromethyl-phenyl)-carbamic acid
tert-butyl ester;
2-{(3S)-1-[(1,2-cis)2-(4-Methylsulfanyl-benzoylamino)-cyclohexyl]-2-oxo-p-
yrrolidin-3-ylcarbamoyl}-4-trifluoromethyl-phenyl)-amino;
N-{(3S)-1-[(1S,2R,4R)-(Isopropyl-methyl-amino)-2-(toluene-4-sulfonylmethy-
l)-cyclohexyl]-2-oxo-pyrrolidin-3-yl}-3-trifluoromethyl-benzamide;
N-{(3S)-1-[(1S,2R,4S)-(Isopropyl-methyl-amino)-2-(toluene-4-sulfonylmethy-
l)-cyclohexyl]-2-oxo-pyrrolidin-3-yl}-3-trifluoromethyl-benzamide;
N-{(3S)-1-[(1S,2R,4R)-2-Benzenesulfonylmethyl-(isopropyl-methyl-amino)-cy-
clohexyl]-2-oxo-pyrrolidin-3-yl}-3-trifluoromethyl-benzamide;
N-{(3S)-1-[(1S,2R,4S)-2-Benzenesulfonylmethyl-4-(isopropyl-methyl-amino)--
cyclohexyl]-2-oxo-pyrrolidin-3-yl}-3-trifluoromethyl-benzamide;
N-{(3S)-1-[(1S,2R,4R)-2-Benzenesulfonylmethyl-4-(isopropyl-ethyl-amino)-c-
yclohexyl]-2-oxo-pyrrolidin-3-yl}-3-trifluoromethyl-benzamide;
N-{(3S)-1-[(1S,2R,4S)-2-Benzenesulfonylmethyl-4-(isopropyl-ethyl-amino)-c-
yclohexyl]-2-oxo-pyrrolidin-3-yl}-3-trifluoromethyl-benzamide;
N-{(3S)-1-[(1S,2R,4R)-2-Benzenesulfonylmethyl-4-(isopropyl-cyclopropylmet-
hyl-amino)-cyclohexyl]-2-oxo-pyrrolidin-3-yl}-3-trifluoromethyl-benzamide;
(.+-.)
N-{(3S*)-1-[(1S*,2R*,4R*)-4-Azido-2-(4-methylsulfanyl-benzenesulf-
onylmethyl)-cyclohexyl]-3-methyl-2-oxo-pyrrolidin-3-yl}-3-trifluoromethyl--
benzamide; (.+-.)
N-{(3S*)-1-[(1S*,2R*,4R*)-4-Amino-2-(4-methylsulfanyl-benzenesulfonylmeth-
yl)-cyclohexyl]-3-methyl-2-oxo-pyrrolidin-3-yl}-3-trifluoromethyl-benzamid-
e; (.+-.)
N-{(3S*)-1-[(1S*,2R*,4R*)-4-Isopropylamino-2-(4-methylsulfanyl--
benzenesulfonylmethyl)-cyclohexyl]-3-methyl-2-oxo-pyrrolidin-3-yl}-3-trifl-
uoromethyl-benzamide; (.+-.)
N-{(3S*)-1-[(1S*,2R*,4R*)-4-(Isopropyl-methyl-amino)-2-(4-methylsulfanyl--
benzenesulfonylmethyl)-cyclohexyl]-3-methyl-2-oxo-pyrrolidin-3-yl}-3-trifl-
uoromethyl-benzamide; (.+-.)
N-{(3S*)-1-[(1S*,2R*,4R*)-4-(Isopropyl-prop-2-ynyl-amino)-2-(4-methylsulf-
anyl-benzenesulfonylmethyl)-cyclohexyl]-3-methyl-2-oxo-pyrrolidin-3-yl}-3--
trifluoromethyl-benzamide; (.+-.)
N-{(3S*)-[(1S*,2R*,4R*)-4-(Cyclopropylmethyl-isopropyl-amino)-2-(4-methyl-
sulfanyl-benzenesulfonylmethyl)-cyclohexyl]-3-methyl-2-oxo-pyrrolidin-3-yl-
}-3-trifluoromethyl-benzamide;
N-{(3S)-1-[4-(Isopropyl-methyl-amino)-2-(4-methylsulfanyl-benzenesulfonyl-
methyl)-cyclohexyl]-2-oxo-pyrrolidin-3-yl}-N-methyl-3-trifluoromethyl-benz-
amide;
N-{(3S)-1-[(1S,2R,4R)-4-(Isopropyl-methyl-amino)-2-(4-methylsulfan-
yl-benzenesulfonylmethyl)-cyclohexyl]-2-oxo-pyrrolidin-3-yl}-3-trifluorome-
thyl-benzamide;
1-{(3S)-1-[(1S,2R,4R)-4-(Isopropyl-methyl-amino)-2-(4-methylsulfanyl-benz-
enesulfonylmethyl)-cyclohexyl]-2-oxo-pyrrolidin-3-yl}-3-(3-trifluoromethyl-
-phenyl)-urea;
N-{(3S)-1-[(1S,2R,4R)-4-(Isopropyl-methyl-amino)-2-(4-methylsulfanyl-benz-
enesulfonylmethyl)-cyclohexyl]-2-oxo-pyrrolidin-3-yl}-3-trifluoromethyl-be-
nzenesulfonamide;
N-{(3S)-1-[(1S,2R,4R)-4-(Isopropyl-methyl-amino)-2-(4-methylsulfanyl-benz-
enesulfonylmethyl)-cyclohexyl]-2-oxo-pyrrolidin-3-yl}-benzamide;
{(3S)-1-[(1S,2R,4R)-2-Benzenesulfonylmethyl-4-(isopropyl-methyl-amino)-cy-
clohexyl]-2-oxo-pyrrolidin-3-yl}-3-(3-trifluoromethyl-phenyl)-urea;
N-[(3S)-1-((1S,2R,4R)-2-Benzenesulfonylmethyl-4-isopropylamino-cyclohexyl-
)-2-oxo-pyrrolidin-3-yl]-3-trifluoromethyl-benzamide;
N-{(3S)-1-[(1S,2R,4R)-4-(Allyl-isopropyl-amino)-2-benzenesulfonylmethyl-c-
yclohexyl]-2-oxo-pyrrolidin-3-yl}-3-trifluoromethyl-benzamide;
1-((1S,2R)-2-Benzenesulfonylmethyl-4-isopropylamino-cyclohexyl)-2-oxo-pyr-
rolidine-3-carboxylic acid (3-trifluoromethyl-phenyl)-amide;
1-((1S,2R)-2-Benzenesulfonylmethyl-4-isopropylamino-cyclohexyl)-2-oxo-pyr-
rolidine-3-carboxylic acid (3-trifluoromethyl-phenyl)-amide;
(2-{(3S)-1-[(1S,2R)-2-(4-Methylsulfanyl-benzylamino)-cyclohexyl-2-oxo-pyr-
rolidin-3-ylcarbamoyl}-4-trifluoromethyl-phenyl)-carbamic acid
tert-butyl ester;
N-{(3S)-1-[(1S,2R,4R)-2-Benzenesulfonylmethyl-4(R)-(isopropyl-pro-
pyl-amino)-cyclohexyl]-2-oxo-pyrrolidin-3-yl}-3-trifluoromethyl-benzamide;
(.+-.)
1-[(1S*,2R*,4R*)-4-Isopropylamino-2-(4-methylsulfanyl-benzenesulf-
onylmethyl)-cyclohexyl]-4-(3-trifluoromethyl-phenyl)-5,6-dihydro-1H-pyridi-
n-2-one; (.+-.)
1-[(1S*,2R*,4R*)-4-Isopropylamino-2-(4-benzenesulfonylmethyl)-cyclohexyl]-
-4-(3-trifluoromethyl-phenyl)-5,6-dihydro-1H-pyridin-2-one; (.+-.)
1-[(1S*,2R*,4R*)-4-Isopropylmethylamino-2-(4-methylsulfanyl-benzenesulfon-
ylmethyl)-cyclohexyl]-4-(3-trifluoromethyl-phenyl)-5,6-dihydro-1H-pyridin--
2-one; (.+-.)
1-[(1S*,2R*,4R*)-4-Amino-2-(4-methylsulfanyl-benzenesulfonylmethyl)-cyclo-
hexyl]-4-(3-trifluoromethoxyphenyl)-5,6-dihydro-1H-pyridin-2-one;
(.+-.)
1-[(1S*,2R*,4R*)-4-Isopropylamino-2-(4-methylsulfanyl-benzenesulfonylmeth-
yl)-cyclohexyl]-4-(3-trifluoromethoxyphenyl)-5,6-dihydro-1H-pyridin-2-one;
(.+-.)
1-[(1S*,2R*,4R*)-4-Isopropylamino-2-(4-benzenesulfonylmethyl)-cyc-
lohexyl]-4-(3-trifluoromethyl-phenyl)-piperidin-2-one;
(S)-3-(3-(trifluoromethyl)benzylamino)-1-((1S,2R,4R)-4-(isopropyl(methyl)-
amino)-2-((4-(methylthio)phenylsulfonyl)methyl)cyclohexyl)pyrrolidin-2-one-
;
3(R)-(3-(trifluoromethyl)phenethyl)-1-((1S,2R,4R/S)-4-(isopropylamino)--
2-(phenylsulfonylmethyl)cyclohexyl)pyrrolidin-2-one
trifluoroacetate
3(S)-(3-(Trifluoromethyl)phenethyl)-1-((1S,2R,4R/S)-4-(isopropylamino)-2--
(phenylsulfonylmethyl)cyclohexyl)pyrrolidin-2-one trifluoroacetate
N--((S)-1-((1S,2R,4R)-4-(isopropyl(methyl)amino)-2-(phenylsulfonylmethyl)-
cyclohexyl)-2-oxoazepan-3-yl)-3-(trifluoromethyl)benzamide;
N--((S)-1-((1S,2R,4R)-4-(dimethylamino)-2-(phenylsulfonylmethyl)cyclohexy-
l)-2-oxopiperidin-3-yl)-3-(trifluoromethyl)benzamide;
(R*)-1-((1S*,2R*,4R*)-4-(isopropyl(methyl)amino)-2-(phenylsulfonylmethyl)-
cyclohexyl)-3-((2-(3-(trifluoromethyl)phenyl)-1,3-dioxolan-2-yl)methyl)pyr-
rolidin-2-one; (S*)-1-((1S*,2R*,4R*)-4-(isopropyl
methyl)amino-2-(phenylsulfonylmethyl)cyclohexyl)-3-((2-(3-(trifluoromethy-
l)phenyl)-1,3-dioxolan-2-yl)methyl)pyrrolidin-2-one;
(S*)-3-(2-oxo-2-(3-(trifluoromethylphenyl)ethyl)-1-((1S*,2R*,4R*)-4-(isop-
ropyl(methyl)amino)-2-(phenylsulfonylmethyl)cyclohexyl)pyrrolidin-2-one;
(R*)-3-(2-oxo-2-(3-(trifluoromethyl)phenyl)ethyl)-1-((1S*,2R*,4R*)-4-(iso-
propyl(methyl)amino)-2-(phenylsulfonylmethyl)cyclohexyl)pyrrolidin-2-one;
(R*)-3-(2-hydroxy-2-(3-(trifluoromethyl)phenyl)ethyl)-1-((1S*,2R*,4R*)-4--
(isopropyl(methyl)amino)-2-(phenylsulfonylmethyl)cyclohexyl)pyrrolidin-2-o-
ne;
(S*)-3-(2-hydroxy-2-(3-(trifluoromethyl)phenyl)ethyl)-1-((1S*,2R*,4R*-
)-4-(isopropyl(methyl)amino)-2-(phenylsulfonylmethyl)cyclohexyl)pyrrolidin-
-2-one;
((S*)-1-((1S*,2R*,4R*)-4-(isopropyl(methyl)amino)-2-(phenylsulfon-
ylmethyl)cyclohexyl)-3-(-2-(methoxyimino)-2-(3-(trifluoromethyl)phenyl)eth-
yl)pyrrolidin-2-one;
((R*)-1-((1S*,2R*,4R*)-4-(isopropyl(methyl)amino)-2-(phenylsulfonylmethyl-
)cyclohexyl)-3-(-2-(methoxyimino)-2-(3-(trifluoromethyl)phenyl)ethyl)pyrro-
lidin-2-one;
1-((1S*,2R*,4R*)-4-(amino)-2-(phenylsulfonylmethyl)cyclohexyl)-3-(7-(trif-
luoromethyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one;
1-((1S*,2R*,4R*)-4-(isopropylamino)-2-(phenylsulfonylmethyl)cyclohexyl)-3-
-(7-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one;
1-((1S*,2R*,4R*)-4-(isopropyl(methyl)amino)-2-(phenylsulfonylmethyl)cyclo-
hexyl)-3-(7-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one;
1-((1S*,2R*,4R*)-4-(isopropyl(ethyl)amino)-2-(phenylsulfonylmethyl)cycloh-
exyl)-3-(7-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one;
1-((1S*,2R*,4R*)-4-(Diethylamino)-2-(phenylsulfonylmethyl)cyclohexyl)-3-(-
7-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one;
1-((1S,2R,4R)-4-(Isopropyl(methyl)amino)-2-(phenylsulfonylmethyl)cyclohex-
yl)-3-(naphthalen-1-ylamino)pyrrolidin-2-one;
3-(Benzo[b]thiophen-3-ylamino)-1-((1S,2R,4R)-4-(isopropyl(methyl)amino)-2-
-(phenylsulfonylmethyl)cyclohexyl)pyrrolidin-2-one;
(S)-3-(6-chloroquinazolin-4-ylamino)-1-((1S,2R,4R)-4-(isopropyl(methyl)am-
ino)-2-(phenylsulfonylmethyl)cyclohexyl)pyrrolidin-2-one;
(S)-3-(6,8-dichloroquinazolin-4-ylamino)-1-((1S,2R,4R)-4-(isopropyl(methy-
l)amino)-2-(phenylsulfonylmethyl)cyclohexyl)pyrrolidin-2-one;
3,5-Dichloro-N--((S)-1-((1S,2R,4R)-4-(isopropyl(methyl)amino)-2-(phenylsu-
lfonylmethyl)cyclohexyl)-2-oxopyrrolidin-3-yl)benzamide;
N--((S)-1-((1S,2R,4R)-4-(isopropyl(methyl)amino)-2-(phenylsulfonylmethyl)-
cyclohexyl)-2-oxopyrrolidin-3-yl)-3-(trifluoromethoxy)benzamide;
3-((E)-3(R*)-(trifluoromethyl)styryl)-1-((1S*,2R*,4R*)-4-(isopropyl(methy-
l)amino)-2-(phenylsulfonylmethyl)cyclohexyl)pyrrolidin-2-one;
1-((1S*,2R*,4R*)-4-(isopropyl(methyl)amino)-2-(phenylsulfonylmethyl)cyclo-
hexyl)-3(R*)-((E/Z)-2-(3-(trifluoromethyl)phenyl)prop-1-enyl)pyrrolidin-2--
one;
N-(1-((1S,2R,4R)-4-(isopropyl(methyl)amino)-2-(phenylsulfonylmethyl)-
cyclohexyl)-2-oxopyrrolidin-3(R)-yl)benzamidede;
N--((S)-1-((1S,2R,4R)-4-(Isopropyl(methyl)amino)-2-(phenylsulfonylmethyl)-
cyclohexyl)-2-oxopyrrolidin-3-yl)-3,5-bis(trifluoromethyl)benzamide;
2-Amino-N-(1-((1S,2R,4R)-4-(isopropyl(methyl)amino)-2-(phenylsulfonylmeth-
yl)cyclohexyl)-2-oxopyrrolidin-3(R)-yl)-5-(trifluoromethoxy)benzamide;
(R)-1-((1S,2R,4R)-4-(isopropyl(methyl)amino)-2-(phenylsulfonylmethyl)cycl-
ohexyl)-3-(6-(trifluoromethyl)quinolin-4-ylamino)pyrrolidin-2-one;
(S)-1-((1S,2R,4R)-4-(isopropyl(methyl)amino)-2-(phenylsulfonylmethyl)cycl-
ohexyl)-3-(6-(trifluoromethyl)quinolin-4-ylamino)pyrrolidin-2-one;
(R)-1-((1S,2R,4R)-4-(isopropyl(methyl)amino)-2-(phenylsulfonylmethyl)cycl-
ohexyl)-3-(7-(trifluoromethyl)quinolin-4-ylamino)pyrrolidin-2-one;
(S)-1-((1S,2R,4R)-4-(isopropyl(methyl)amino)-2-(phenylsulfonylmethyl)cycl-
ohexyl)-3-(7-(trifluoromethyl)quinolin-4-ylamino)pyrrolidin-2-one;
3-(2-(Phenyl)phenylamino)-1-((1S,2R,4R)-4-(isopropyl(methyl)amino)-2-(phe-
nylsulfonylmethyl)cyclohexyl)pyrrolidin-2-one;
3-(3,5-Bis(trifluoromethyl)phenylamino)-1-((1S,2R,4R)-4-(isopropyl(methyl-
)amino)-2-(phenylsulfonylmethyl)cyclohexyl)pyrrolidin-2-one;
1-((1S,2R,4R)-4-(Isopropyl(methyl)amino)-2-(phenylsulfonylmethyl)cyclohex-
yl)-3-(2-(trifluoromethyl)phenylamino)pyrrolidin-2-one;
1-((1S,2R,4R)-4-(Isopropyl(methyl)amino)-2-(phenylsulfonylmethyl)cyclohex-
yl)-3-(2-methoxyphenylamino)pyrrolidin-2-one;
1-((1S,2R,4R)-4-(Isopropyl(methyl)amino)-2-(phenylsulfonylmethyl)cyclohex-
yl)-3-(3-(trifluoromethyl)phenylamino)pyrrolidin-2-one;
1-((1S,2R,4R)-4-(Isopropyl(methyl)amino)-2-(phenylsulfonylmethyl)cyclohex-
yl)-3-(4-(trifluoromethyl)phenylamino)pyrrolidin-2-one;
3-Chloro-N--((S)-1-((1S,2R,4R)-4-(isopropyl(methyl)amino)-2-(phenylsulfon-
ylmethyl)cyclohexyl)-2-oxopyrrolidin-3-yl)benzamide;
3-Fluoro-N--((S)-1-((1S,2R,4R)-4-(isopropyl(methyl)amino)-2-(phenylsulfon-
ylmethyl)cyclohexyl)-2-oxopyrrolidin-3-yl)-5-(trifluoromethyl)benzamide;
tert-Butyl
(1R,3R,4S)-4-((S)-2-oxo-3-(3-(trifluoromethyl)benzamido)pyrrolidin-1-yl)--
3-(phenylsulfonylmethyl)cyclohexylcarbamate;
N--((S)-2-Oxo-1-((1S,2R,4R)-4-(phenylamino)-2-(phenylsulfonylmethyl)cyclo-
hexyl)pyrrolidin-3-yl)-3-(trifluoromethyl)benzamide;
N-(2-Oxo-1-((1S,2R,4R)-2-(phenylsulfonylmethyl)-4-(pyridin-4-ylamino)cycl-
ohexyl)pyrrolidin-3-yl)-3-(trifluoromethyl)benzamide;
N-(2-Oxo-1-((1S,2R,4R)-2-(phenylsulfonylmethyl)-4-(thiazol-2-ylamino)cycl-
ohexyl)pyrrolidin-3-yl)-3-(trifluoromethyl)benzamide; Methyl
(1R,3R,4S)-4-((S)-2-oxo-3-(3-(trifluoromethyl)benzamido)pyrrolidin-1-yl)--
3-(phenylsulfonylmethyl)cyclohexylcarbamate;
N--((S)-1-((1S,2R,4R)-4-Formamido-2-(phenylsulfonylmethyl)cyclohexyl)-2-o-
xopyrrolidin-3-yl)-3-(trifluoromethyl)benzamide;
1-((1R,3R,4S)-4-((S)-2-Oxo-3-(3-(trifluoromethyl)benzamido)pyrrolidin-1-y-
l)-3-(phenylsulfonylmethyl)cyclohexyl)urea;
1-Methyl-3-((1R,3R,4S)-4-((S)-2-oxo-3-(3-(trifluoromethyl)benzamido)pyrro-
lidin-1-yl)-3-(phenylsulfonylmethyl)cyclohexyl)urea;
N--((S)-2-Oxo-1-((1S,2R,4R)-4-(2-oxopyrrolidin-1-yl)-2-(phenylsulfonylmet-
hyl)cyclohexyl)pyrrolidin-3-yl)-3-(trifluoromethyl)benzamide;
N--((S)-1-((1S,2R,4R)-4-(1,1-dioxido-isothiazolidin-2-yl)-2-(phenylsulfon-
ylmethyl)cyclohexyl)-2-oxopyrrolidin-3-yl)-3-(trifluoromethyl)benzamide;
N--((S)-1-((1S,2R,4R)-2-((4-Chlorophenylsulfonyl)methyl)-4-(isopropyl(met-
hyl)amino)cyclohexyl)-2-oxopyrrolidin-3-yl)-3-fluoro-5-(trifluoromethyl)be-
nzamide;
3-Chloro-N--((S)-1-((1S,2R,4R)-2-((4-chlorophenylsulfonyl)methyl-
)-4-(isopropyl(methyl)amino)cyclohexyl)-2-oxopyrrolidin-3-yl)benzamide;
N--((S)-1-((1S,2R,4R)-2-((4-chlorophenylsulfonyl)methyl)-4-(isopropyl(met-
hyl)amino)cyclohexyl)-2-oxopyrrolidin-3-yl)-3,5-bis(trifluoromethyl)benzam-
ide; tert-Butyl
2-(((S)-1-((1S,2R,4R)-2-((4-chlorophenylsulfonyl)methyl)-4-(isopropyl(met-
hyl)amino)cyclohexyl)-2-oxopyrrolidin-3-yl)carbamoyl)-4-(trifluoromethoxy)-
phenylcarbamate;
2-Amino-N--((S)-1-((1S,2R,4R)-2-((4-chlorophenylsulfonyl)methyl)-4-(isopr-
opyl(methyl)amino)cyclohexyl)-2-oxopyrrolidin-3-yl)-5-(trifluoromethoxy)be-
nzamide;
N--((S)-1-((1S,2R,4R)-2-((4-Chlorophenylsulfonyl)methyl)-4-(isop-
ropyl(methyl)amino)cyclohexyl)-2-oxopyrrolidin-3-yl)-3-(trifluoromethoxy)b-
enzamide;
N--((S)-1-((1S,2R,4R)-2-((4-Chlorophenylsulfonyl)methyl)-4-(iso-
propyl(methyl)amino)cyclohexyl)-2-oxopyrrolidin-3-yl)-3-(trifluoromethyl)b-
enzamide;
3,5-Dichloro-N--((S)-1-((1S,2R,4R)-2-((4-chlorophenylsulfonyl)m-
ethyl)-4-(isopropyl(methyl)amino)cyclohexyl)-2-oxopyrrolidin-3-yl)benzamid-
e;
3-Chloro-N--((S)-1-((1S,2R,4R)-2-((4-chlorophenylsulfonyl)methyl)-4-(i-
sopropyl(methyl)amino)cyclohexyl)-2-oxopyrrolidin-3-yl)benzamide
N-Oxide;
N--((S)-1-((1S,2R,4R)-2-((4-Chlorophenylsulfonyl)methyl)-4-(isopropyl(met-
hyl)amino)cyclohexyl)-2-oxopyrrolidin-3-yl)-3-(trifluoromethyl)benzamide
N-Oxide;
N--((S)-1-((1S,2R,4R)-2-((4-Chlorophenylsulfonyl)methyl)-4-(iso-
propyl(methyl)amino)cyclohexyl)-2-oxopyrrolidin-3-yl)-3-fluoro-5-(trifluor-
omethyl)benzamide N-Oxide;
N--((S)-1-((1S,2R,4R)-4-(Isopropyl(methyl)amino)-2-(phenylsulfonylmethyl)-
cyclohexyl)-2-oxopyrrolidin-3-yl)-3-(trifluoromethyl)benzamide
N-Oxide;
N--((S)-1-((1S,2R,4R)-4-(isopropyl(methyl)amino)-2-((4-isopropylphenylsul-
fonyl)methyl)cyclohexyl)-2-oxopyrrolidin-3-yl)-3-(trifluoromethyl)benzamid-
e;
N--((S)-1-((1S,2R,4R)-4-(isopropyl(methyl)amino)-2-(o-tolylsulfonylmet-
hyl)cyclohexyl)-2-oxopyrrolidin-3-yl)-3-(trifluoromethyl)benzamide;
N--((S)-1-((1S,2R,4R)-2-((4-Fluorophenylsulfonyl)methyl)-4-(isopropyl(met-
hyl)amino)cyclohexyl)-2-oxopyrrolidin-3-yl)-3-(trifluoromethyl)benzamide;
3-Chloro-N-((S)-1-((1S,2R,4R)-4-(isopropyl(methyl)amino)-2-(tosylmethyl)c-
yclohexyl)-2-oxopyrrolidin-3-yl)benzamide;
2-Amino-N--((S)-1-((1S,2R,4R)-4-(isopropyl(methyl)amino)-2-(tosylmethyl)c-
yclohexyl)-2-oxopyrrolidin-3-yl)-5-(trifluoromethoxy)benzamidemide;
1-[(1S,2R,4R)-(4-Amino-2-benzenesulfonyl-methylcyclohexyl)-4-(3-trifluoro-
methylphenyl)]-5,6-dihydro-1H-pyridin-2-one;
1-([(1S,2R,4R)-2-benzenesulfonylmethyl-4-isopropylamino-cyclohexyl)-4-(3--
trifluoromethylphenyl)]-5,6-dihydro-1H-pyridin-2-one;
1-[(1S,2R,4R)-2-benzenesulfonylmethyl-4-(isopropyl-methyl-amino)cyclohexy-
l]-4-(3-trifluoromethyl-phenyl)-5,6-dihydro-1H-pyridin-2-one;
1-[(1S,2R,4R)-2-benzenesulfonylmethyl-4-(isopropyl-ethyl-amino)cyclohexyl-
]-4-(3-trifluoromethyl-phenyl)-5,6-dihydro-1H-pyridin-2-one;
1-[1S,2R,4R)-2-Benzenesulfonylmethyl-4-(isopropyl-methyl-amino)-cyclohexy-
l]-(3S)-3-(6-chloro-2-trifluoromethyl-quinazolin-4-ylamino)-pyrrolidin-2-o-
ne;
1-[(1S,2R,4R)-2-benzenesulfonylmethyl-4-(isopropyl-methyl-amino)-cycl-
ohexyl]-(3S)-3-(7-chloro-quinazolin-4-ylamino)-pyrrolidin-2-one;
1-[(1S,2R,4R)-2-benzenesulfonylmethyl-4-(isopropyl-methyl-amino)-cyclohex-
yl]-(3S)-3-(2,6-dichloro-quinazolin-4-ylamino)-pyrrolidin-2-one;
1-[(1S,2R,4R)-2-benzenesulfonylmethyl-4-(isopropyl-methyl-amino)-cyclohex-
yl]-(3S)-3-(6-chloro-2-dimethylamino-quinazolin-4-ylamino)-pyrrolidin-2-on-
e;
1-[(1S,2R,4R)-2-benzenesulfonylmethyl-4-(isopropyl-methyl-amino)-cyclo-
hexyl]-(3S)-3-(6-chloro-2-hydroxy-quinazolin-4-ylamino)-pyrrolidin-2-one;
1-[(1S,2R,4R)-2-benzenesulfonylmethyl-4-(isopropyl-methyl-amino)-cyclohex-
yl]-(3S)-3-(6-trifluoromethyl-quinazolin-4-ylamino)-pyrrolidin-2-one;
1-[(1S,2R,4R)-2-benzenesulfonylmethyl-4-(isopropyl-methyl-amino)-cyclohex-
yl]-(3S)-3-(6-tert-butyl-thieno[3,2-d]pyrimidin-4-ylamino)-pyrrolidin-2-on-
e;
1-[(1S,2R,4R)-2-benzenesulfonylmethyl-4-(isopropyl-methyl-amino)-cyclo-
hexyl]-(3S)-3-(6-tert-butyl-2-trifluoromethyl-thieno[3,2-d]pyrimidin-4-yla-
mino)-pyrrolidin-2-one;
1-[(1S,2R,4R)-2-benzenesulfonylmethyl-4-(isopropyl-methyl-amino)-cyclohex-
yl]-(3S)-3-(6-tert-butyl-pyrrolo[2,1-f][1,2,4]triazin-4-ylamino)-pyrrolidi-
n-2-one;
(3S)-3-(6-Adamantan-1-yl-pyrrolo[2,1-f][1,2,4]triazin-4-ylamino)-
-1-[(1S,2R,4R)-2-benzenesulfonylmethyl-4-(isopropyl-methyl-amino)-cyclohex-
yl]-pyrrolidin-2-one; 3-Methyl-2-phenyl-3H-imidazole-4-carboxylic
acid
{(3S)-1-[(1S,2R,4R)-2-benzenesulfonylmethyl-4-(isopropyl-methyl-amino)-cy-
clohexyl]-2-oxo-pyrrolidin-3-yl}-amide;
1-Methyl-2-phenyl-1H-imidazole-4-carboxylic acid
{(3S)-1-[(1S,2R,4R)-2-benzenesulfonylmethyl-4-(isopropyl-methyl-amino)-cy-
clohexyl]-2-oxo-pyrrolidin-3-yl}-amide;
3-Benzyl-2-phenyl-3H-imidazole-4-carboxylic acid
{(3S)-1-[(1S,2R,4R)-2-benzenesulfonylmethyl-4-(isopropyl-methyl-amino)-cy-
clohexyl]-2-oxo-pyrrolidin-3-yl}-amide;
1-Benzyl-2-phenyl-1H-imidazole-4-carboxylic acid
{(3S)-1-[(1S,2R,4R)-2-benzenesulfonylmethyl-4-(isopropyl-methyl-amino)-cy-
clohexyl]-2-oxo-pyrrolidin-3-yl}-amide;
2-Phenyl-3H-imidazole-4-carboxylic acid
{(3S)-1-[(1S,2R,4R)-2-benzenesulfonylmethyl-4-(isopropyl-methyl-amino)-cy-
clohexyl]-2-oxo-pyrrolidin-3-yl}-amide; Preparation of
1-[(1S,2R,4R)-2-benzenesulfonylmethyl-4-(isopropyl-methyl-amino)-cyclohex-
yl]-(3S)-3-(6,7-dimethoxy-quinazolin-4-ylamino)-pyrrolidin-2-one;
1-[(1S,2R,4R)-2-benzenesulfonylmethyl-4-(isopropyl-methyl-amino)-cyclohex-
yl]-(3S)-3-(6-fluoro-quinazolin-4-ylamino)-pyrrolidin-2-one;
1-[(1S,2R,4R)-2-benzenesulfonylmethyl-4-(isopropyl-methyl-amino)-cyclohex-
yl]-(3S)-3-(6-methyl-quinazolin-4-ylamino)-pyrrolidin-2-one;
1-[(1S,2R,4R)-2-benzenesulfonylmethyl-4-(isopropyl-methyl-amino)-cyclohex-
yl]-(3S)-3-(6-phenyl-thieno[2,3-d]pyrimidin-4-ylamino)-pyrrolidin-2-one;
1-[(1S,2R,4R)-2-benzenesulfonylmethyl-4-(isopropyl-methyl-amino)-cyclohex-
yl]-(3S)-3-(6-chloro-2-propyl-pyrido[2,3-d]pyrimidin-4-ylamino)-pyrrolidin-
-2-one;
1-[(1S,2R,4R)-2-benzenesulfonylmethyl-4-(isopropyl-methyl-amino)--
cyclohexyl]-(3S)-3-(6-chloro-2-isopropyl-quinazolin-4-ylamino)-pyrrolidin--
2-one;
1-[(1S,2R,4R)-2-benzenesulfonylmethyl-4-(isopropyl-methyl-amino)-c-
yclohexyl]-(3S)-3-(2-tert-butyl-6-chloro-quinazolin-4-ylamino)-pyrrolidin--
2-one;
1-[(1S,2R,4R)-2-benzenesulfonylmethyl-4-(isopropyl-methyl-amino)-c-
yclohexyl]-(3S)-3-(6-chloro-2-methyl-quinazolin-4-ylamino)-pyrrolidin-2-on-
e; 1-[(1Sr
2R,4R)-2-benzenesulfonylmethyl-4-(isopropyl-methyl-amino)-cyclohexyl]-(3S-
)-3-(6-chloro-2-ethyl-quinazolin-4-ylamino)-pyrrolidin-2-one;
N-{(3S)-1-[(1S,2R,4R)-2-benzenesulfonylmethyl-4-(isopropyl-methyl-amino)--
cyclohexyl]-2,5-dioxo-pyrrolidin-3-yl}-3-trifluoromethyl-benzamide;
N-{(3S)-1-[-(1S,2R,4R)-2-Benzenesulfonylmethyl-4-(isopropyl-methyl-amino)-
-cyclohexyl]-2-oxo-pyrrolidin-3-yl}-4-adamantan-1-yl-1H-pyrrole-2-carboxam-
ide;
N-{(3S)-1-[-(1S,2R,4R)-2-Benzenesulfonylmethyl-4-(isopropyl-methyl-a-
mino)-cyclohexyl]-2-oxo-pyrrolidin-3-yl}-4-adamantan-1-yl-1-methyl-1H-pyrr-
ole-2-carboxamide;
1-[(1S,2R,4R)-2-Benzenesulfonylmethyl-4-(isopropyl-methyl-amino)-cyclohex-
yl]-(3S)-3-(6-tert-butyl-pyrimido[5,4-d]pyrimidin-4-ylamino)-pyrrolidin-2--
one; 5-Bromo-2-tert-butyl-pyrimidine-4-carboxylic acid
{(3S)-1-[(1S,2R,4R)-2-benzenesulfonylmethyl-4-(isopropyl-methyl-amino)-cy-
clohexyl]-2-oxo-pyrrolidin-3-yl}-amide;
2-tert-Butyl-pyrimidine-4-carboxylic acid
{(3S*)-1-[(1S*,2R*,4R*)-2-benzenesulfonylmethyl-4-(isopropyl-methyl-amino-
)-cyclohexyl]-2-oxo-pyrrolidin-3-yl}-amide;
2-tert-Butyl-5-phenyl-pyrimidine-4-carboxylic acid
{(3S)-1-[(1S,2R,4R)-2-benzenesulfonylmethyl-4-(isopropyl-methyl-amino)-cy-
clohexyl]-2-oxo-pyrrolidin-3-yl}-amide;
N-{(3S)-1-[1S,2R,4R)-2-benzenesulfonylmethyl-4-(isopropyl-methyl-amino)-c-
yclohexyl]-2-oxo-pyrrolidin-3-yl}-3-tert-butyl-benzamide;
N-{(3S)-1-[(1S,2R,4R)-2-benzenesulfonylmethyl-4-(isopropyl-methyl-amino)--
cyclohexyl]-2-oxo-pyrrolidin-3-yl}-3-bromo-5-tert-butyl-benzamide;
1-[(1S,2R,4R)-2-benzenesulfonylmethyl-4-(isopropyl-methyl-amino)-cyclohex-
yl]-(3S)-3-(pyrido[2,3-d]pyrimidin-4-ylamino)-pyrrolidin-2-one;
1-[(1S,2R,4R)-2-benzenesulfonylmethyl-4-(isopropyl-methyl-amino)-cyclohex-
yl]-(3S)-3-(6-chloro-pyrido[2,3-d]pyrimidin-4-ylamino)-pyrrolidin-2-one;
1-[(1S,2R,4R)-2-benzenesulfonylmethyl-4-(isopropyl-methyl-amino)-cyclohex-
yl]-(3S)-3-(6-chloro-2-trifluoromethyl-pyrido[2,3-d]pyrimidin-4-ylamino)-p-
yrrolidin-2-one;
1-[(1S,2R,4R)-2-benzenesulfonylmethyl-4-(isopropyl-methyl-amino)-cyclohex-
yl]-(3S)-3-(6-trifluoromethoxy-pyrido[2,3-d]pyrimidin-4-ylamino)-pyrrolidi-
n-2-one;
1-[(1S,2R,4R)-2-benzenesulfonylmethyl-4-(isopropyl-methyl-amino)-
-cyclohexyl]-(3S)-3-(6-chloro-2-methylamino-quinazolin-4-ylamino)-pyrrolid-
in-2-one; (3S)-3-(6-Fluoro-quinazolin-4-ylamino)-1-[(1S
2R,4R)-4-(isopropyl-methyl-amino)-2-(toluene-4-sulfonylmethyl)-cyclohexyl-
]-pyrrolidin-2-one;
N-{1-[(1S,2R,4R)-2-benzenesulfonylmethyl-4-(isopropyl-methyl-amino)-cyclo-
hexyl]-2-oxo-pyrrolidin-(3S)-3-yl}-2-chloro-5-trifluoromethyl-benzamide;
(S)-3-(6-Bromoquinazolin-4-ylamino)-1-((1S,2R,4R)-4-(isopropyl(methyl)ami-
no)-2-(phenylsulfonylmethyl)cyclohexyl)pyrrolidin-2-one;
(S)-3-(6,7-Difluoroquinazolin-4-ylamino)-1-((1S,2R,4R)-4-(isopropyl(methy-
l)amino)-2-(phenylsulfonylmethyl)cyclohexyl)pyrrolidin-2-one;
(S)-3-(6-Methoxyquinazolin-4-ylamino)-1-((1S,2R,4R)-4-(isopropyl(methyl)a-
mino)-2-(phenylsulfonylmethyl)cyclohexyl)pyrrolidin-2-one;
((S)-1-((1S,2R,4R)-4-(isopropyl(methyl)amino)-2-(phenylsulfonylmethyl)cyc-
lohexyl)-3-(quinazolin-4-ylamino)pyrrolidin-2-one;
3-Phenyl-N--((S)-1-((1S,2R,4R)-4-(isopropyl(methyl)amino)-2-(phenylsulfon-
ylmethyl)cyclohexyl)-2-oxopyrrolidin-3-yl)benzamide;
(S)-3-(6-Iodoquinazolin-4-ylamino)-1-((1S,2R,4R)-4-(isopropyl(methyl)amin-
o)-2-(phenylsulfonylmethyl)cyclohexyl)pyrrolidin-2-one;
3-Tert-butyl-4-hydroxy-N--((S)-1-((1S,2R,4R)-4-(isopropyl(methyl)amino)-2-
-(phenylsulfonylmethyl)cyclohexyl)-2-oxopyrrolidin-3-yl)benzamide;
3-Amino-5-tert-butyl-N--((S)-1-((1S,2R,4R)-4-(isopropyl(methyl)amino)-2-(-
phenylsulfonylmethyl)cyclohexyl)-2-oxopyrrolidin-3-yl)thiophene-2-carboxam-
ide;
N--((S)-1-((1S,2R,4R)-4-(Isopropyl(methyl)amino)-2-(phenylsulfonylme-
thyl)cyclohexyl)-2-oxopyrrolidin-3-yl)-2-methyl-5-phenylfuran-3-carboxamid-
e;
N--((S)-1-((1S,2R,4R)-4-(Isopropyl(methyl)amino)-2-(phenylsulfonylmeth-
yl)cyclohexyl)-2-oxopyrrolidin-3-yl)-5-nitrofuran-2-carboxamide;
and
N--((S)-1-((1S,2R,4R)-4-(Isopropyl(methyl)amino)-2-(phenylsulfonylmethyl)-
cyclohexyl)-2-oxopyrrolidin-3-yl)-4-phenylthiophene-2-carboxamide.
19. A pharmaceutical composition, comprising a pharmaceutically
acceptable carrier and a therapeutically effective amount of a
compound of claim 1.
20. A method for modulation of chemokine receptor activity
comprising administering to a patient in need thereof a
therapeutically effective amount of a compound of claim 1.
21. A method for modulation of MCP-1, MCP-2, MCP-3 and MCP-4, and
MCP-5 activity that is mediated by the CCR2 receptor comprising
administering to a patient in need thereof a therapeutically
effective amount of a compound of claim 1.
22. A method for modulation of MCP-1 activity comprising
administering to a patient in need thereof a therapeutically
effective amount of a compound of claim 1.
23. A method for treating disorders, comprising administering to a
patient in need thereof a therapeutically effective amount of a
compound of claim 1, said disorders being selected from
osteoarthritis, aneurism, fever, cardiovascular effects, Crohn's
disease, congestive heart failure, autoimmune diseases,
HIV-infection, HIV-associated dementia, psoriasis, idiopathic
pulmonary fibrosis, transplant arteriosclerosis, physically- or
chemically-induced brain trauma, inflammatory bowel disease,
alveolitis, colitis, systemic lupus erythematosus, nephrotoxic
serum nephritis, glomerularnephritis, asthma, multiple sclerosis,
artherosclerosis, rheumatoid arthritis, restinosis, organ
transplantation, and cancer.
24. The method for treating disorders, of claim 23, wherein said
disorders being selected from psoriasis, idiopathic pulmonary
fibrosis, transplant arteriosclerosis, physically- or
chemically-induced brain trauma, inflammatory bowel disease,
alveolitis, colitis, systemic lupus erythematosus, nephrotoxic
serum nephritis, glomerularnephritis, asthma, multiple sclerosis,
artherosclerosis, rheumatoid arthritis restinosis, organ
transplantation, and cancer.
25. The method for treating disorders, of claim 24, wherein said
disorders being selected from alveolitis, colitis, systemic lupus
erythematosus, nephrotoxic serum nephritis, glomerularnephritis,
asthma, multiple sclerosis, artherosclerosis, rheumatoid arthritis
restinosis, organ transplantation, and cancer.
26. The method for treating disorders, of claim 25, wherein said
disorders being selected from asthma, multiple sclerosis,
artherosclerosis, and rheumatoid arthritis.
27. A method for treating inflammatory diseases, comprising
administering to a patient in need thereof a therapeutically
effective amount of a compound of claim 1.
28. A method for modulation of CCR2 activity comprising
administering to a patient in need thereof a therapeutically
effective amount of a compound of claim 1.
29. The method for treating disorders, of claim 25, wherein said
disorders being selected from restinosis, organ transplantation,
and cancer.
30. A compound of Formula (II) ##STR153## wherein W is selected
from H, I, and Br; Pg, at each occurrence, is independently
selected from an amine protecting group.
31. The compound of claim 30, wherein W is selected from H, I, and
Br; and Pg, at each occurrence, is independently selected from
benzyloxycarbonyl (Cbz) and tert-butyloxycarbonyl (Boc).
32. A process for preparing a compound of Formula (Ia) ##STR154##
or salt or stereoisomer thereof: wherein E is selected from
--S(O).sub.pCHR.sup.e--, --CHR.sup.eNR.sup.e--, --C(O)--NR.sup.e--,
--NR.sup.eC(O)NR.sup.e--, --SO.sub.2--NR.sup.e--, and
NR.sup.eSO.sub.2NR.sup.e--; R.sup.e is independently selected from
H and C.sub.1-3 alkyl; X is selected from O or S; Z is selected
from a bond, --NR.sup.8C(O)--, --NR.sup.8C(S)--,
--NR.sup.8C(O)NH--, --NR.sup.8C(S)NH--, --NR.sup.8SO.sub.2--,
--NR.sup.8SO.sub.2NH--, --C(O)NR.sup.8--, --OC(O)NR.sup.8--,
--NR.sup.8C(O)O--, --(CR.sup.15R.sup.15).sub.l--,
--CR.sup.14.dbd.C--R.sup.4--, --CR.sup.15R.sup.15C(O)--,
--C(O)CR.sup.15R.sup.15--, CR.sup.15R.sup.15C(.dbd.N--OR.sup.16)--,
--O--CR.sup.14R.sup.14--, --CR.sup.14R.sup.14--O--, --O--,
--NR.sup.9--, --NR.sup.9--CR.sup.14R.sup.14--,
--CR.sup.14R.sup.14--NR.sup.9--, --S(O).sub.p--,
--S(O).sub.p--CR.sup.14R.sup.14--,
--CR.sup.14R.sup.14--S(O).sub.p--, and --S(O).sub.p--NR.sup.9--;
wherein neither Z nor R.sup.13 are connected to a carbon atom
labeled (b); bond (a) is a single or double bond; alternatively,
when n is equal to 2, two atoms labeled (b) may join through a
double bond; R.sup.1 is selected from a C.sub.6-10 aryl group
substituted with 0-5 R.sup.6 and a 5-10 membered heteroaryl system
containing 1-4 heteroatoms selected from N, O, and S, substituted
with 0-3 R.sup.6; R.sup.2 is selected from a C.sub.6-10 aryl group
substituted with 0-5 R.sup.7 and a 5-10 membered heteroaryl system
containing 1-4 heteroatoms selected from N, O, and S, substituted
with 0-3 R.sup.7; R.sup.5, at each occurrence, is independently
selected from H, (CRR).sub.rOH, (CRR).sub.rSH,
(CRR).sub.rOR.sup.5d, (CRR).sub.rSR.sup.5d,
(CRR).sub.rNR.sup.5aR.sup.5a,
(CRR).sub.rN(.fwdarw.O)R.sup.5aR.sup.5a,
(CRR).sub.rNR.sup.5aC(O)R.sup.5b,
(CRR).sub.rOC(O)NR.sup.5aR.sup.5a,
(CRR).sub.rNR.sup.5aC(O)OR.sup.5d,
(CRR).sub.rNR.sup.5aC(O)NR.sup.5aR.sup.5a,
(CRR).sub.rNR.sup.5aC(O)H, (CRR).sub.rOC(O)R.sup.5b,
(CRR).sub.rS(O).sub.pR.sup.5b,
(CRR).sub.rS(O).sub.2NR.sup.5aR.sup.5a,
(CRR).sub.rNR.sup.5aS(O).sub.2R.sup.5b,
(CRR).sub.rNR.sup.5aS(O).sub.2NR.sup.5aR.sup.5a, and a
(CRR).sub.r-5-10 membered heterocyclic system containing 1-4
heteroatoms selected from N, O, and S, substituted with 0-2
R.sup.5c; R.sup.5a, at each occurrence, is independently selected
from H, methyl substituted with 0-1 R.sup.5g, C.sub.2-6 alkyl
substituted with 0-2 R.sup.5e, C.sub.3-8 alkenyl substituted with
0-2 R.sup.5e, C.sub.3-8 alkynyl substituted with 0-2 R.sup.5e, a
(CH.sub.2).sub.r--C.sub.3-10 carbocyclic residue substituted with
0-5 R.sup.5e, and a (CH.sub.2).sub.r-5-10 membered heterocyclic
system containing 1-4 heteroatoms selected from N, O, and S,
substituted with 0-3 R.sup.5e, R.sup.5b, at each occurrence, is
selected from C.sub.1-6 alkyl substituted with 0-3 R.sup.5e,
C.sub.3-8 alkenyl substituted with 0-2 R.sup.5e, C.sub.3-8 alkynyl
substituted with 0-2 R.sup.5e, a (CH.sub.2).sub.r--C.sub.3-6
carbocyclic residue substituted with 0-2 R.sup.5e, and a
(CH.sub.2).sub.r-5-6 membered heterocyclic system containing 1-4
heteroatoms selected from N, O, and S, substituted with 0-3
R.sup.5e; R.sup.5c, at each occurrence, is selected from C.sub.1-6
alkyl, C.sub.2-8 alkenyl, C.sub.2-8 alkynyl,
(CH.sub.2).sub.rC.sub.3-6 cycloalkyl, Cl, Br, I, F,
(CF.sub.2).sub.rCF.sub.3, NO.sub.2, CN,
(CH.sub.2).sub.rNR.sup.5fR.sup.5f, (CH.sub.2).sub.rOH,
(CH.sub.2).sub.rOC.sub.1-4 alkyl, (CH.sub.2).sub.rSC.sub.1-4 alkyl,
(CH.sub.2).sub.rC(O)OH, (CH.sub.2).sub.rC(O)R.sup.5b,
(CH.sub.2).sub.rC(O)NR.sup.5fR.sup.5f,
(CH.sub.2).sub.rOC(O)NR.sup.5fR.sup.5f,
(CH.sub.2).sub.rNR.sup.5fC(O)R.sup.5b,
(CH.sub.2).sub.rC(O)OC.sub.1-4 alkyl,
(CH.sub.2).sub.rNR.sup.5fC(O)OC.sub.1-4 alkyl,
(CH.sub.2).sub.rOC(O)R.sup.5b,
(CH.sub.2).sub.rC(.dbd.NR.sup.5f)NR.sup.5fR.sup.5f,
(CH.sub.2).sub.rS(O).sub.pR.sup.5b,
(CH.sub.2).sub.rNHC(.dbd.NR.sup.5f)NR.sup.5fR.sup.5f,
(CH.sub.2).sub.rS(O).sub.2NR.sup.5fR.sup.5f,
(CH.sub.2).sub.rNR.sup.5fS(O).sub.2R.sup.5b, and
(CH.sub.2).sub.rphenyl substituted with 0-3 R.sup.5e; R.sup.5d, at
each occurrence, is selected from methyl, CF.sub.3, C.sub.2-6 alkyl
substituted with 0-2 R.sup.5e, C.sub.3-8 alkenyl substituted with
0-2 R.sup.5e, C.sub.3-8 alkynyl substituted with 0-2 R.sup.5e, and
a C.sub.3-10 carbocyclic residue substituted with 0-3 R.sup.5e;
R.sup.5e, at each occurrence, is selected from C.sub.1-6 alkyl,
C.sub.2-8 alkenyl, C.sub.2-8 alkynyl, C.sub.3-6 cycloalkyl, Cl, F,
Br, I, CN, NO.sub.2, (CF.sub.2).sub.rCF.sub.3,
(CH.sub.2).sub.rOC.sub.1-5 alkyl, OH, SH,
(CH.sub.2).sub.rSC.sub.1-5 alkyl,
(CH.sub.2).sub.rNR.sup.5fR.sup.5f, and (CH.sub.2).sub.rphenyl;
R.sup.5f, at each occurrence, is selected from H, C.sub.1-6 alkyl,
and C.sub.3-6 cycloalkyl; R.sup.5g is independently selected from
--C(O)R.sup.5b, --C(O)OR.sup.5d, --C(O)NR.sup.5fR.sup.5f, --CN, and
(CH.sub.2).sub.rphenyl; R, at each occurrence, is selected from H,
C.sub.1-6 alkyl substituted with R.sup.5e, C.sub.2-8 alkenyl,
C.sub.2-8 alkynyl, (CH.sub.2).sub.rC.sub.3-6 cycloalkyl, and
(CH.sub.2).sub.rphenyl substituted with R.sup.5e; R.sup.6, at each
occurrence, is selected from C.sub.1-8 alkyl, C.sub.2-8 alkenyl,
C.sub.2-8 alkynyl, (CH.sub.2).sub.rC.sub.3-6 cycloalkyl, Cl, Br, I,
F, NO.sub.2, CN, (CR'R').sub.rNR.sup.6aR.sup.6a, (CR'R').sub.rOH,
(CR'R').sub.rO(CR'R').sub.rR.sup.6d, (CR'R').sub.rSH,
(CR'R').sub.rC(O)H, (CR'R').sub.rS(CR'R').sub.rR.sup.6d,
(CR'R').sub.rSC(O)(CR'R').sub.rR.sup.6b, (CR'R').sub.rC(O)OH,
(CR'R').sub.rC(O) (CR'R').sub.rR.sup.6b,
(CR'R').sub.rNR.sup.6aR.sup.6a, (CR'R').sub.rC(O)NR.sup.6aR.sup.6a,
(CR'R').sub.rNR.sup.6fC(O) (CR'R').sub.rR.sup.6b,
(CR'R').sub.rC(O)O(CR'R').sub.rR.sup.6d, (CR'R').sub.rOC(O)
(CR'R').sub.rR.sup.6b,
(CR'R').sub.rOC(O)NR.sup.6a(CR'R').sub.rR.sup.6d,
(CR'R').sub.rNR.sup.6aC(O)NR.sup.6a(CR'R').sub.rR.sup.6d,
(CR'R').sub.rNR.sup.6aC(S)NR.sup.6a(CR'R').sub.rR.sup.6d,
(CR'R').sub.rNR.sup.6fC(O)O(CR'R').sub.rR.sup.6b,
(CR'R').sub.rC(.dbd.NR.sup.6f)NR.sup.6aR.sup.6a,
(CR'R').sub.rNHC(.dbd.NR.sup.6f)NR.sup.6fR.sup.6f,
(CR'R').sub.rS(O).sub.p(CR'R').sub.rR.sup.6b,
(CR'R').sub.rS(O).sub.2NR.sup.6aR.sup.6a,
(CR'R').sub.rNR.sup.6fS(O).sub.2NR.sup.6aR.sup.6a,
(CR'R').sub.rNR.sup.6fS(O).sub.2(CR'R').sub.rR.sup.6b, C.sub.1-6
haloalkyl, C.sub.2-8 alkenyl substituted with 0-3 R', C.sub.2-8
alkynyl substituted with 0-3 R', (CR'R').sub.rphenyl substituted
with 0-3 R.sup.6e, and a (CH.sub.2).sub.r-5-6 membered heterocyclic
system containing 1-2 heteroatoms selected from N, O, and S,
substituted with 0-2 R.sup.6e; alternatively, two R.sup.6 on
adjacent atoms on R.sup.1 may join to form a cyclic acetal;
R.sup.6a, at each occurrence, is selected from H, methyl
substituted with 0-1 R.sup.6g, C.sub.2-6 alkyl substituted with 0-2
R.sup.6e, C.sub.3-8 alkenyl substituted with 0-2 R.sup.6e,
C.sub.3-8 alkynyl substituted with 0-2 R.sup.6e, a
(CH.sub.2).sub.r--C.sub.3-10 carbocyclic residue substituted with
0-5 R.sup.6e, and a (CH.sub.2).sub.r-5-10 membered heterocyclic
system containing 1-4 heteroatoms selected from N, O, and S,
substituted with 0-2 R.sup.6e; R.sup.6b, at each occurrence, is
selected from H, C.sub.1-6 alkyl substituted with 0-2 R.sup.6e,
C.sub.3-8 alkenyl substituted with 0-2 R.sup.6e, C.sub.3-8 alkynyl
substituted with 0-2 R.sup.6e, a (CH.sub.2).sub.rC.sub.3-6
carbocyclic residue substituted with 0-3 R.sup.6e, and a
(CH.sub.2).sub.r-5-6 membered heterocyclic system containing 1-4
heteroatoms selected from N, O, and S, substituted with 0-2
R.sup.6e; R.sup.6d, at each occurrence, is selected from C.sub.3-8
alkenyl substituted with 0-2 R.sup.6e, C.sub.3-8 alkynyl
substituted with 0-2 R.sup.6e, methyl, CF.sub.3, C.sub.2-6 alkyl
substituted with 0-3 R.sup.6e, C.sub.2-4 haloalkyl, a
(CH.sub.2).sub.r--C.sub.3-10 carbocyclic residue substituted with
0-3 R.sup.6e, and a (CH.sub.2).sub.r-5-6 membered heterocyclic
system containing 1-4 heteroatoms selected from N, O, and S,
substituted with 0-3 R.sup.6e; R.sup.6e, at each occurrence, is
selected from C.sub.1-6 alkyl, C.sub.2-8 alkenyl, C.sub.2-8
alkynyl, (CH.sub.2).sub.rC.sub.3-6 cycloalkyl, Cl, F, Br, I, CN,
NO.sub.2, (CF.sub.2).sub.rCF.sub.3, (CH.sub.2).sub.rOC.sub.1-5
alkyl, OH, SH, (CH.sub.2).sub.rSC.sub.1-5 alkyl,
(CH.sub.2).sub.rNR.sup.6fR.sup.6f, and (CH.sub.2).sub.rphenyl;
R.sup.6f, at each occurrence, is selected from H, C.sub.1-5 alkyl,
and C.sub.3-6 cycloalkyl, and phenyl; R.sup.6g is independently
selected from --C(O)R.sup.6b, --C(O)OR.sup.6d,
--C(O)NR.sup.6fR.sup.6f, and (CH.sub.2).sub.rphenyl; R.sup.7, at
each occurrence, is selected from C.sub.1-8 alkyl, C.sub.2-8
alkenyl, C.sub.2-8 alkynyl, (CH.sub.2).sub.rC.sub.3-6 cycloalkyl,
Cl, Br, I, F, NO.sub.2, CN, (CR'R').sub.rNR.sup.7aR.sup.7a,
(CR'R').sub.rOH, (CR'R').sub.rO(CR'R').sub.rR.sup.7d,
(CR'R').sub.rSH, (CR'R').sub.rC(O)H,
(CR'R').sub.rS(CR'R').sub.rR.sup.7d, (CR'R').sub.rC(O)OH,
(CR'R').sub.rC(O)(CR'R').sub.rR.sup.7b,
(CR'R').sub.rC(O)NR.sup.7aR.sup.7a,
(CR'R').sub.rNR.sup.7fC(O)(CR'R').sub.rR.sup.7b,
(CR'R').sub.rC(O)O(CR'R').sub.rR.sup.7d,
(CR'R').sub.rOC(O)(CR'R').sub.rR.sup.7b,
(CR'R').sub.rOC(O)NR.sup.7a(CR'R').sub.rR.sup.7a,
(CR'R').sub.rNR.sup.7aC(O)NR.sup.7a(CR'R').sub.rR.sup.7a,
(CR'R').sub.rNR.sup.7fC(O)O(CR'R').sub.rR.sup.7d,
(CR'R').sub.rC(.dbd.NR.sup.7f)NR.sup.7aR.sup.7a,
(CR'R').sub.rNHC(.dbd.NR.sup.7f)NR.sup.7fR.sup.7f,
(CR'R').sub.rS(O).sub.p(CR'R').sub.rR.sup.7b,
(CR'R').sub.rS(O).sub.2NR.sup.7aR.sup.7a,
(CR'R').sub.rNR.sup.7aS(O).sub.2NR.sup.7aR.sup.7a,
(CR'R').sub.rNR.sup.7fS(O).sub.2(CR'R').sub.rR.sup.7b, C.sub.1-6
haloalkyl, C.sub.2-8 alkenyl substituted with 0-3 R', C.sub.2-8
alkynyl substituted with 0-3 R', (CR'R').sub.rC.sub.3-10
carbocyclic residue and (CR'R').sub.rphenyl substituted with 0-3
R.sup.7e; alternatively, two R.sup.7 on adjacent atoms on R.sup.2
may join to form a cyclic acetal; R.sup.7a, at each occurrence, is
independently selected from H, methyl substituted with 0-1
R.sup.7g, C.sub.2-6 alkyl substituted with 0-2 R.sup.7e, C.sub.3-8
alkenyl substituted with 0-2 R.sup.7e, C.sub.3-8 alkynyl
substituted with 0-2 R.sup.7e, a (CH.sub.2).sub.r--C.sub.3-10
carbocyclic residue substituted with 0-5 R.sup.7e, and a
(CH.sub.2).sub.r-5-10 membered heterocyclic system containing 1-4
heteroatoms selected from N, O, and S, substituted with 0-2
R.sup.7e; R.sup.7b, at each occurrence, is selected from C.sub.1-6
alkyl substituted with 0-2 R.sup.7e, C.sub.3-8 alkenyl substituted
with 0-2 R.sup.7e, C.sub.3-8 alkynyl substituted with 0-2 R.sup.7e,
a (CH.sub.2).sub.rC.sub.3-6 carbocyclic residue substituted with
0-3 R.sup.7e, and a (CH.sub.2).sub.r-5-6 membered heterocyclic
system containing 1-4 heteroatoms selected from N, O, and S,
substituted with 0-2 R.sup.7e; R.sup.7d, at each occurrence, is
selected from C.sub.3-8 alkenyl substituted with 0-2 R.sup.7e,
C.sub.3-8 alkynyl substituted with 0-2 R.sup.7e, methyl, CF.sub.3,
C.sub.2-4 haloalkyl, C.sub.2-6 alkyl substituted with 0-3 R.sup.7e,
a (CH.sub.2).sub.r--C.sub.3-10 carbocyclic residue substituted with
0-3 R.sup.7e, and a (CH.sub.2).sub.r-5-6 membered heterocyclic
system containing 1-4 heteroatoms selected from N, O, and S,
substituted with 0-3 R.sup.7e; R.sup.7e, at each occurrence, is
selected from C.sub.1-6 alkyl, C.sub.2-8 alkenyl, C.sub.2-8
alkynyl, (CH.sub.2).sub.rC.sub.3-6 cycloalkyl, Cl, F, Br, I, CN,
NO.sub.2, (CF.sub.2).sub.rCF.sub.3, (CH.sub.2).sub.rOC.sub.1-5
alkyl, OH, SH, C(O)OC.sub.1-5 alkyl, (CH.sub.2).sub.rSC.sub.1-5
alkyl, (CH.sub.2).sub.rNR.sup.7fR.sup.7f, and
(CH.sub.2).sub.rphenyl; R.sup.7f, at each occurrence, is selected
from H, C.sub.1-5 alkyl, and C.sub.3-6 cycloalkyl, and phenyl;
R.sup.7g is independently selected from --C(O)R.sup.7b,
--C(O)OR.sup.7d, --C(O)NR.sup.7fR.sup.7f, and
(CH.sub.2).sub.rphenyl; R', at each occurrence, is selected from H,
C.sub.1-6 alkyl substituted with R.sup.6e, C.sub.2-8 alkenyl,
C.sub.2-8 alkynyl, (CH.sub.2).sub.rC.sub.3-6 cycloalkyl, and
(CH.sub.2).sub.rphenyl substituted with R.sup.6e; R.sup.8 is
selected from H, C.sub.1-4 alkyl, and C.sub.3-4 cycloalkyl; R.sup.9
is selected from H, C.sub.1-4 alkyl, C.sub.3-4 cycloalkyl, --C(O)H,
and --C(O)--C.sub.1-4alkyl; R.sup.10 is independently selected from
H, and C.sub.1-4alkyl substituted with 0-1 R.sup.10b,
alternatively, two R.sup.10 form .dbd.O; R.sup.10b, at each
occurrence, is independently selected from --OH, --SH,
--NR.sup.10cR.sup.10c, --C(O)NR.sup.10cR.sup.10c, and
--NHC(O)R.sup.10c; R.sup.10c is selected from H, C.sub.1-4 alkyl
and C.sub.3-6 cycloalkyl; R.sup.14, at each occurrence, is
independently selected from H and C.sub.1-4alkyl; alternatively,
two R.sup.14s, along with the carbon atom to which they are
attached, join to form a C.sub.3-6 carbocyclic ring; R.sup.15, at
each occurrence, is independently selected from H, C.sub.1-4alkyl,
OH, NH.sub.2, --O--C.sub.1-4 alkyl, NR.sup.15aR.sup.15a,
C(O)NR.sup.15aR.sup.15a, NR.sup.15aC(O)R.sup.15b,
NR.sup.15aC(O)OR.sup.15d, OC(O)NR.sup.15aR.sup.15a, and
(CHR).sub.rC(O)OR.sup.15d; alternatively, two R.sup.15s, along with
the carbon atom or atoms to which they are attached, join to form a
C.sub.3-6 carbocyclic ring; R.sup.15a, at each occurrence, is
independently selected from H, and C.sub.1-4 alkyl; R.sup.15b, at
each occurrence, is independently selected from C.sub.1-4 alkyl,
C.sub.3-6 alkenyl, and C.sub.3-6 alkynyl; R.sup.15d, at each
occurrence, is independently selected from C.sub.1-4 alkyl,
C.sub.3-6 alkenyl, and C.sub.3-6 alkynyl; R.sup.16 is selected from
C.sub.1-4 alkyl; l is selected from 1, 2 and 3; n is selected from
0, 1, 2, and 3; p, at each occurrence, is independently selected
from 0, 1, and 2; q, at each occurrence, is independently selected
from 1, 2, 3, and 4; r, at each occurrence, is independently
selected from 0, 1, 2, 3, and 4; is selected from 0 and 1; and t,
at each occurrence, is independently selected from 2, 3, and 4; the
steps comprising reacting a compound of Formula IV, ##STR155## with
an electrophile and base to give a compound of Formula II;
##STR156## wherein W is selected from H, I, and Br; Pg, at each
occurrence, is independently selected from an amine protecting
group; reacting a compound of Formula II to give the compound of
Formula (Ia).
33. A process for preparing a compound of Formula (II) ##STR157##
or salt or stereoisomer thereof, comprising reacting a compound of
Formula (IV) ##STR158## with an electrophile and a baser wherein W
is selected from I and Br; Pg, at each occurrence, is independently
selected from an amine protecting group.
34. The process of claim 33 wherein the electrophile is selected
from iodine, bromine, N-bromo-succimide, and N-iodosuccinimide; and
the base is selected from n-butyl lithium, lithium diisopropylamide
(LDA), sodium hydride, lithium bis(trimethylsilyl)amide, potassium
bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)-amide, and
Li--Al(O-tButyl).sub.4.
35. A process for preparing a compound of Formula (IIa) ##STR159##
or salt or stereoisomer thereof, comprising reduction of a compound
of Formula (II) with a reducing agent; ##STR160## wherein W is
selected from I and Br, and Pg, at each occurrence, is
independently selected from an amine protecting group.
36. The process of claim 35, wherein the reducing agent is selected
from tris-(trimethylsilyl)silane, zinc metal, tributyltin hydride
and AIBN.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] The present application claims the priority benefits of U.S.
Provisional Application No. 60/446,850, filed Feb. 12, 2003, which
is expressly incorporated fully herein by reference.
FIELD OF THE INVENTION
[0002] This invention relates generally to modulators of chemokine
receptor activity, pharmaceutical compositions containing the same,
and methods of using the same as agents for treatment and
prevention of inflammatory diseases, allergic and autoimmune
diseases, and in particular, asthma, rheumatoid arthritis,
atherosclerosis, and multiple sclerosis, processes of forming and
intermediates thereof.
BACKGROUND OF THE INVENTION
[0003] Chemokines are chemotactic cytokines, of molecular weight
6-15 kDa, that are released by a wide variety of cells to attract
and activate, among other cell types, macrophages, T and B
lymphocytes, eosinophils, basophils and neutrophils (reviewed in:
Luster, New Eng. J. Bed. 1998, 338, 436-445 and Rollins, Blood
1997, 90, 909-928). There are two major classes of chemokines, CXC
and CC, depending on whether the first two cysteines in the amino
acid sequence are separated by a single amino acid (CXC) or are
adjacent (CC). The CXC chemokines, such as interleukin-8 (IL-8),
neutrophil-activating protein-2 (NAP-2) and melanoma growth
stimulatory activity protein (MGSA) are chemotactic primarily for
neutrophils and T lymphocytes, whereas the CC chemokines, such as
RANTES, MIP-1.alpha., MIP-1.beta., the monocyte chemotactic
proteins (MCP-1, MCP-2, MCP-3, MCP-4, and MCP-5) and the eotaxins
(-1 and -2) are chemotactic for, among other cell types,
macrophages, T lymphocytes, eosinophils, dendritic cells, and
basophils. There also exist the chemokines lymphotactin-1,
lymphotactin-2 (both C chemokines), and fractalkine (a CX.sub.3C
chemokine) that do not fall into either of the major chemokine
subfamilies.
[0004] The chemokines bind to specific cell-surface receptors
belonging to the family of G-protein-coupled
seven-transmembrane-domain proteins (reviewed in: Horuk, Trends
Pharm. Sci. 1994, 15, 159-165) which are termed "chemokine
receptors." On binding their cognate ligands, chemokine receptors
transduce an intracellular signal though the associated trimeric G
proteins, resulting in, among other responses, a rapid increase in
intracellular calcium concentration, changes in cell shape,
increased expression of cellular adhesion molecules, degranulation,
and promotion of cell migration. There are at least ten human
chemokine receptors that bind or respond to CC chemokines with the
following characteristic patterns (reviewed in Zlotnik and Oshie
Immunity 2000, 12, 121): CCR-1 (or "CKR-1" or "CC-CKR-1")
[MIP-1.alpha., MCP-3, MCP-4, RANTES] (Ben-Barruch, et al., Cell
1993, 72, 415-425, and Luster, New Eng. J. Med. 1998, 338,
436-445); CCR-2A and CCR-2B (or "CKR-2A"/"CKR-2B" or
"CC-CKR-2A"/"CC-CKR-2B") [MCP-1, MCP-2, MCP-3, MCP-4, MCP-5]
(Charo, et al., Proc. Natl. Acad. Sci. USA 1994, 91, 2752-2756, and
Luster, New Eng. J. Med. 1998, 338, 436-445); CCR-3 (or "CKR-3" or
"CC-CKR-3") [eotaxin-1, eotaxin-2, RANTES, MCP-3, MCP-4]
(Combadiere, et al., J. Biol. Chem. 1995, 270, 16491-16494, and
Luster, New Eng. J. Med. 1998, 338, 436-445); CCR-4 (or "CKR-4" or
"CC-CKR-41") [TARC, MDC] (Power, et al., J. Biol. Chem. 1995, 270,
19495-19500, and Luster, New Eng. J. Med. 1998, 338, 436-445);
CCR-5 (or "CKR-5" OR "CC-CKR-5") [MIP-1.alpha., RANTES,
MIP-1.beta.] (Sanson, et al., Biochemistry 1996, 35, 3362-3367);
CCR-6 (or "CKR-6" or "CC-CKR-6") [LARC] (Baba, et al., J. Biol.
Chem. 1997, 272, 14893-14898); CCR-7 (or "CKR-7" or "CC-CKR-7")
[ELC] (Yoshie et al., J. Leukoc. Biol. 1997, 62, 634-644); CCR-8
(or "CKR-8" or "CC-CKR-8") [I-309] (Napolitano et al., J. Immunol.,
1996, 157, 2759-2763); CCR-10 (or "CKR-10" or "CC-CKR-10") [MCP-1,
MCP-3] (Bonini, et al., DNA and Cell Biol. 1997, 16, 1249-1256);
and CCR-11 [MCP-1, MCP-2, and MCP-4] (Schweickert, et al., J. Biol.
Chem. 2000, 275, 90550).
[0005] In addition to the mammalian chemokine receptors, mammalian
cytomegaloviruses, herpesviruses and poxviruses have been shown to
express, in infected cells, proteins with the binding properties of
chemokine receptors (reviewed in: Wells and Schwartz, Curr. Opin.
Biotech. 1997, 8, 741-748). Human CC chemokines, such as RANTES and
MCP-3, can cause rapid mobilization of calcium via these virally
encoded receptors. Receptor expression may be permissive for
infection by allowing for the subversion of normal immune system
surveillance and response to infection. Additionally, human
chemokine receptors, such as CXCR4, CCR2, CCR3, CCR5 and CCR8, can
act as co-receptors for the infection of mammalian cells by
microbes as with, for example, the human immunodeficiency viruses
(HIV).
[0006] The chemokines and their cognate receptors have been
implicated as being important mediators of inflammatory,
infectious, and immunoregulatory disorders and diseases, including
asthma and allergic diseases, as well as autoimmune pathologies
such as rheumatoid arthritis and atherosclerosis (reviewed in: P.
H. Carter, Current Opinion in Chemical Biology 2002, 6, 510;
Trivedi, et al, Ann. Reports Med. Chem. 2000, 35, 191; Saunders and
Tarby, Drug Disc. Today 1999, 4, 80; Premack and Schall, Nature
Medicine 1996, 2, 1174). For example, the chemokine monocyte
chemoattractant-1 (MCP-1) and its receptor CC Chemokine Receptor 2
(CCR-2) play a pivotal role in attracting leukocytes to sites of
inflammation and in subsequently activating these cells. When the
chemokine MCP-1 binds to CCR-2, it induces a rapid increase in
intracellular calcium concentration, increased expression of
cellular adhesion molecules, cellular degranulation, and the
promotion of leukocyte migration. Demonstration of the importance
of the MCP-1/CCR-2 interaction has been provided by experiments
with genetically modified mice. MCP-1 -/- mice had normal numbers
of leukocytes and macrophages, but were unable to recruit monocytes
into sites of inflammation after several different types of immune
challenge (Bao Lu, et al., J. Exp. Med. 1998, 187, 601). Likewise,
CCR-2-/- mice were unable to recruit monocytes or produce
interferon-.gamma. when challenged with various exogenous agents;
moreover, the leukocytes of CCR-2 null mice did not migrate in
response to MCP-1 (Landin Boring, et al., J. Clin. Invest. 1997,
100, 2552), thereby demonstrating the specificity of the
MCP-1/CCR-2 interaction. Two other groups have independently
reported equivalent results with different strains of CCR-2-/- mice
(William A. Kuziel, et al., Proc. Natl. Acad. Sci. USA 1997, 94,
12053, and Takao Kurihara, et al., J. Exp. Med. 1997, 186, 1757).
The viability and generally normal health of the MCP-1 -/- and
CCR-2-/- animals is noteworthy, in that disruption of the
MCP-1/CCR-2 interaction does not induce physiological crisis. Taken
together, these data lead one to the conclusion that molecules that
block the actions of MCP-1 would be useful in treating a number of
inflammatory and autoimmune disorders. This hypothesis has now been
validated in a number of different animal disease models, as
described below.
[0007] It is known that MCP-1 is upregulated in patients with
rheumatoid arthritis (Alisa Koch, et al., J. Clin. Invest. 1992,
90, 772-779). Moreover, several studies have demonstrated the
potential therapeutic value of antagonism of the MCP-1/CCR2
interaction in treating rheumatoid arthritis. A DNA vaccine
encoding MCP-1 was shown recently to ameliorate chronic
polyadjuvant-induced arthritis in rats (Sawsan Youssef, et al., J.
Clin. Invest. 2000, 106, 361). Likewise, inflammatory disease
symptoms could be controlled via direct administration of
antibodies for MCP-1 to rats with collagen-induced arthritis
(Hiroomi Ogata, et al., J. Pathol. 1997, 182, 106), or
streptococcal cell wall-induced arthritis (Ralph C. Schimmer, et
al., J. Immunol. 1998, 160, 1466). Perhaps most significantly, a
peptide antagonist of MCP-1, MCP-1 (9-76), was shown both to
prevent disease onset and to reduce disease symptoms (depending on
the time of administration) in the MRL-lpr mouse model of arthritis
(Jiang-Hong Gong, et al., J. Exp. Med. 1997, 186, 131).
[0008] It is known that MCP-1 is upregulated in atherosclerotic
lesions, and it has been shown that circulating levels of MCP-1 are
reduced through treatment with therapeutic agents, plays a role in
disease progression (Abdolreza Rezaie-Majd, et al, Arterioscler.
Thromb. Vasc. Biol. 2002, 22, 1194-1199). Four key studies have
demonstrated the potential therapeutic value of antagonism of the
MCP-1/CCR2 interaction in treating atherosclerosis. For example,
when MCP-1 -/- mice are mated with LDL receptor-deficient mice, an
83% reduction in aortic lipid deposition was observed (Long Gu, et
al., Mol. Cell. 1998, 2, 275). Similarly, when MCP-1 was
genetically ablated from mice which already overexpressed human
apolipoprotein B, the resulting mice were protected from
atherosclerotic lesion formation relative to the MCP-1 +/+ apoB
control mice (Jennifa Gosling, et al., J. Clin. Invest. 1999, 103,
773). Likewise, when CCR-2 -/- mice are crossed with apolipoprotein
E -/- mice, a significant decrease in the incidence of
atherosclerotic lesions was observed (Landin Boring, et al, Nature
1998, 394, 894). Finally, when apolipoprotein E -/- mice are
administered a gene encoding a peptide antagonist of CCR2, then
lesion size is decreased and plaque stability is increased (W. Ni,
et al. Circulation 2001, 103, 2096-2101).
[0009] It is known that MCP-1 is upregulated in human multiple
sclerosis, and it has been shown that effective therapy with
interferon b-1b reduces MCP-1 expression in peripheral blood
mononuclear cells, suggesting that MCP-1 plays a role in disease
progression (Carla Iarlori, et al., J. Neuroimmunol. 2002, 123,
170-179). Other studies have demonstrated the potential therapeutic
value of antagonism of the MCP-1/CCR-2 interaction in treating
multiple sclerosis; all of these studies have been demonstrated in
experimental autoimmune encephalomyelitis (EAE), the conventional
animal model for multiple sclerosis. Administration of antibodies
for MCP-1 to animals with EAE significantly diminished disease
relapse (K. J. Kennedy, et al., J. Neuroimmunol. 1998, 92, 98).
Furthermore, two recent reports have now shown that CCR-2 -/- mice
are resistant to EAE (Brian T. Fife, et al., J. Exp. Med. 2000,
192, 899; Leonid Izikson, et al., J. Exp. Med. 2000, 192,
1075).
[0010] It is known that MCP-1 is upregulated in patients who
develop bronchiolitis obliterans syndrome after lung
transplantation (Martine Reynaud-Gaubert, et al., J. of Heart and
Lung Transplant., 2002, 21, 721-730; John Belperio, et al., J.
Clin. Invest. 2001, 108, 547-556). In a murine model of
bronchiolitis obliterans syndrome, administration of an antibody to
MCP-1 led to attenuation of airway obliteration; likewise, CCR2 -/-
mice were resistant to airway obliteration in this same model (John
Belperio, et al., J. Clin. Invest. 2001, 108, 547-556). These data
suggest that antagonism of MCP-1/CCR2 may be beneficial in treating
rejection of organs following transplantation.
[0011] Other studies have demonstrated the potential therapeutic
value of antagonism of the MCP-1/CCR2 interaction in treating
asthma. Sequestration of MCP-1 with a neutralizing antibody in
ovalbumin-challenged mice resulted in marked decrease in bronchial
hyperresponsiveness and inflammation (Jose-Angel Gonzalo, et al.,
J. Exp. Med. 1998, 188, 157). It proved possible to reduce allergic
airway inflammation in Schistosoma mansoni egg-challenged mice
through the administration of antibodies for MCP-1 (Nicholas W.
Lukacs, et al., J. Immunol. 1997, 158, 4398). Consistent with this,
MCP-1 -/- mice displayed a reduced response to challenge with
Schistosoma mansoni egg (Bao Lu, et al., J. Exp. Med. 1998, 187,
601).
[0012] Other studies have demonstrated the potential therapeutic
value of antagonism of the MCP-1/CCR2 interaction in treating
kidney disease. Administration of antibodies for MCP-1 in a murine
model of glomerularnephritis resulted in a marked decrease in
glomerular crescent formation and deposition of type I collagen
(Clare M. Lloyd, et al., J. Exp. Med. 1997, 185, 1371). In
addition, MCP-1 -/- mice with induced nephrotoxic serum nephritis
showed significantly less tubular damage than their MCP-1
+/+counterparts (Gregory H. Tesch, et al., J. Clin. Invest. 1999,
103, 73).
[0013] One study has demonstrated the potential therapeutic value
of antagonism of the MCP-1/CCR2 interaction in treating systemic
lupus erythematosus. Crossing of MCP-1-/- mice with MRL-FAS.sup.lPr
mice--the latter of which have a fatal autoimmune disease that is
analogous to human systemic lupus erythematosus--results mice that
have less disease and longer survival than the wildtype
MRL-FAS.sup.lPr mice (Gregory H. Tesch, et al., J. Exp. Med. 1999,
190, 1813).
[0014] One study has demonstrated the potential therapeutic value
of antagonism of the MCP-1/CCR2 interaction in treating colitis.
CCR-2 -/- mice were protected from the effects of dextran sodium
sulfate-induced colitis (Pietro G. Andres, et al., J. Immunol.
2000, 164, 6303).
[0015] One study has demonstrated the potential therapeutic value
of antagonism of the MCP-1/CCR2 interaction in treating alveolitis.
When rats with IgA immune complex lung injury were treated
intravenously with antibodies raised against rat MCP-1 (JE), the
symptoms of alveolitis were partially alleviated (Michael L. Jones,
et al., J. Immunol. 1992, 149, 2147).
[0016] One study has demonstrated the potential therapeutic value
of antagonism of the MCP-1/CCR2 interaction in treating cancer.
When immunodeficient mice bearing human breast carcinoma cells were
treated with an anti-MCP-1 antibody, inhibition of lung
micrometastases and increases in survival were observed (Rosalba
Salcedo, et al., Blood 2000, 96, 34-40).
[0017] One study has demonstrated the potential therapeutic value
of antagonism of the MCP-1/CCR2 interaction in treating restinosis.
Mice deficient in CCR2 showed reductions in the intimal area and in
the intima/media ratio (relative to wildtype littermates) after
injury of the femoral artery (Merce Roque, et al. Arterioscler.
Thromb. Vasc. Biol. 2002, 22, 554-559).
[0018] Other studies have provided evidence that MCP-1 is
overexpressed in various disease states not mentioned above. These
reports provide correlative evidence that MCP-1 antagonists could
be useful therapeutics for such diseases. Two reports described the
overexpression of MCP-1 in the intestinal epithelial cells and
bowel mucosa of patients with inflammatory bowel disease (H. C.
Reinecker, et al., Gastroenterology 1995, 108, 40, and Michael C.
Grimm, et al., J. Leukoc. Biol. 1996, 59, 804). Two reports
describe the overexpression of MCP-1 rats with induced brain trauma
(J. S. King, et al., J. Neuroimmunol. 1994, 56, 127, and Joan W.
Berman, et al., J. Immunol. 1996, 156, 3017). Another study has
demonstrated the overexpression of MCP-1 in rodent cardiac
allografts, suggesting a role for MCP-1 in the pathogenesis of
transplant arteriosclerosis (Mary E. Russell, et al. Proc. Natl.
Acad. Sci. USA 1993, 90, 6086). The overexpression of MCP-1 has
been noted in the lung endothelial cells of patients with
idiopathic pulmonary fibrosis (Harry N. Antoniades, et al., Proc.
Natl. Acad. Sci. USA 1992, 89, 5371). Similarly, the overexpression
of MCP-1 has been noted in the skin from patients with psoriasis
(M. Deleuran, et al., J. Dermatol. Sci. 1996, 13, 228, and R.
Gillitzer, et al., J. Invest. Dermatol. 1993, 101, 127). Finally, a
recent report has shown that MCP-1 is overexpressed in the brains
and cerebrospinal fluid of patients with HIV-1-associated dementia
(Alfredo Garzino-Demo, WO 99/46991).
[0019] It should also be noted that CCR-2 has been implicated as a
co-receptor for some strains of HIV (B. J. Doranz, et al., Cell
1996, 85, 1149). It has also been determined that the use of CCR-2
as an HIV co-receptor can be correlated with disease progression
(Ruth I. Connor, et al., J. Exp. Med. 1997, 185, 621). This finding
is consistent with the recent finding that the presence of a CCR-2
mutant, CCR2-64I, is positively correlated with delayed onset of
HIV in the human population (Michael W. Smith, et al., Science
1997, 277, 959). Although MCP-1 has not been implicated in these
processes, it may be that MCP-1 antagonists that act via binding to
CCR-2 may have beneficial therapeutic effects in delaying the
disease progression to AIDS in HIV-infected patients.
[0020] Recently, a number of groups have described the development
of small molecule antagonists of MCP-1 (reviewed in: Bharat K.
Trivedi, et al, Ann. Reports Med. Chem. 2000, 35, 191). Workers at
Teijen and Combichem reported the use of cyclic amines (A) as MCP-1
(Tatsuki Shiota, et al., WO 99/25686; Tatsuki Shiota, et al., WO
00/69815) and MIP-1.alpha. (Christine Tarby and Wilna Moree, WO
00/69820) antagonists. These compounds are distinguished from those
of the present invention (I) by the requirement for the central
cyclic amine grouping. ##STR2##
[0021] Workers at Bristol-Myers Squibb have reported the use of
acyclic diamines (B) as MCP-1 antagonists (Percy Carter and Robert
Cherney, WO-02/50019). ##STR3##
[0022] Workers at Bristol-Myers Squibb have reported the use of
cyclic diamines (C) as MCP-1 antagonists (Robert Cherney,
WO-02/060859). ##STR4##
[0023] Workers at Pfizer have reported the use of bicyclic diamines
(D) as MCP-1 antagonists (Roberto Colon-Cruz, et al.,
WO-02/070523). ##STR5##
[0024] A number of other groups have also described the development
of small molecule antagonists of the MCP-1/CCR-2 interaction. To
date, indolopiperidines (Ian T. Forbes, et al., Bioorg. Med. Chem.
Lett. 2000, 10, 1803), spiropiperidines (Tara Mirzadegan, et al.,
J. Biol. Chem. 2000, 275, 25562), quaternary amines (Masanori Baba,
et al., Proc. Natl. Acad. Sci. 1999, 96, 5698), 2-substituted
indoles (Alan Faull and Jason Kettle, WO 00/46196; Andrew John
Barker, et al., WO 99/07351; Andrew John Barker, et al., WO
99/07678), pyrazolone derivatives (Janak Khimchand Padia, et al.,
U.S. Pat. No. 6,011,052, 2000), 2-substituted benzimidazoles (David
Thomas Connor, et al., WO 98/06703), N,N-dialkylhomopiperazines (T.
Shiota, et al., WO 97/44329), bicyclic pyrroles (Andrew J. Barker,
et al., WO 99/40913 and Andrew J. Barker, et al., WO 99/40914), and
5-aryl pentadienamides (K. G. Carson, et al., Cambridge Health Tech
Institute Chemokine Symposium, McLean, Va., USA, 1999) have all
been reported as MCP-1 antagonists.
[0025] The foregoing reference compounds are readily distinguished
structurally from the present invention by virtue of substantial
differences in the terminal functionality, the attachment
functionality, or the core functionality. The prior art does not
disclose nor suggest the unique combination of structural fragments
that embody in the novel compounds described herein. Furthermore,
the prior art does not disclose or suggest that the compounds of
the present invention would be antagonists of MCP-1.
[0026] It should be noted that CCR-2 is also the receptor for the
chemokines MCP-2, MCP-3, MCP-4, and MCP-5 (Luster, New Eng. J. Med.
1998, 338, 436-445). Since the new compounds of formula (I)
described herein antagonize MCP-1 by binding to the CCR-2 receptor,
it may be that these compounds of formula (I) are also effective
antagonists of the actions of MCP-2, MCP-3, MCP-4, and MCP-5 that
are mediated by CCR-2. Accordingly, when reference is made herein
to "antagonism of MCP-1," it is to be assumed that this is
equivalent to "antagonism of chemokine stimulation of CCR-2."
SUMMARY OF THE INVENTION
[0027] Accordingly, the present invention provides novel
antagonists or partial agonists/antagonists of MCP-1 receptor
activity, or pharmaceutically acceptable salts or prodrugs
thereof.
[0028] The present invention provides pharmaceutical compositions
comprising a pharmaceutically acceptable carrier and a
therapeutically effective amount of at least one of the compounds
of the present invention or a pharmaceutically acceptable salt or
prodrug form thereof.
[0029] The present invention provides a method for treating
rheumatoid arthritis, multiple sclerosis, and atherosclerosis,
comprising administering to a host in need of such treatment a
therapeutically effective amount of at least one of the compounds
of the present invention or a pharmaceutically acceptable salt or
prodrug form thereof.
[0030] The present invention provides a method for treating
inflammatory diseases, comprising administering to a host in need
of such treatment a therapeutically effective amount of at least
one of the compounds of the present invention or a pharmaceutically
acceptable salt or prodrug form thereof.
[0031] The present invention provides novel cyclic derivatives for
use in therapy.
[0032] The present invention provides the use of novel cyclic
derivatives for the manufacture of a medicament for the treatment
of inflammatory diseases.
[0033] The present invention is directed to methods of preparing
the compounds of the present invention, and intermediates
thereof.
[0034] These and other features of the invention, which will become
apparent during the following detailed description, have been
achieved by the inventors' discovery that compounds of formula (I):
##STR6## or stereoisomers or pharmaceutically acceptable salts
thereof, wherein B, B, Z, m, n, s, carbon b, bond (a), R.sup.1,
R.sup.2, R.sup.10, R.sup.11, R.sup.12, and R.sup.13 are defined
below, are effective modulators of chemokine activity.
DETAILED DESCRIPTION OF EMBODIMENTS OF THE PRESENT INVENTION
[0035] [1] Thus, in another embodiment, the present invention
provides novel compounds of formula (I): ##STR7## or a stereoisomer
or a pharmaceutically acceptable salt thereof, wherein: [0036] ring
B is a cycloalkyl group of 3 to 8 carbon atoms wherein the
cycloalkyl group is saturated or partially unsaturated; or a
heterocycle of 3 to 7 atoms wherein the heterocycle is saturated or
partially unsaturated, the heterocycle containing a heteroatom
selected from --O--, --S--, --S(.dbd.O)--, --S(.dbd.O).sub.2--, and
--N(R.sup.4)--, the heterocycle optionally containing a --C(O)--;
ring B being substituted with 0-2 R.sup.5; [0037] X is selected
from O or S; [0038] Z is selected from a bond, --NR.sup.8C(O)--,
--NR.sup.8C(S)--, --NR.sup.8C(O)NH--, --NR.sup.8C(S)NH--,
--NR.sup.8SO.sub.2--, --NR.sup.8SO.sub.2NH--, --C(O)NR.sup.8--,
--OC(O)NR.sup.8--, --NR.sup.8C(O)O--,
--(CR.sup.15R.sup.15).sub.l--, --CR.sup.14.dbd.CR.sup.14--,
--CR.sup.15R.sup.15C(O)--, --C(O)CR.sup.15R.sup.15--,
CR.sup.15R.sup.15C(.dbd.N--OR.sup.16)--, --O--CR.sup.14R.sup.14--,
--CR.sup.14R.sup.14--O--, --O--, --NR.sup.9--,
--NR.sup.9--CR.sup.14R.sup.14--, --CR.sup.14R.sup.14--NR.sup.9--,
--S(O).sub.p--, --S(O).sub.p--CR.sup.14R.sup.14--,
--CR.sup.14R.sup.14--S(O).sub.p--, and --S(O).sub.p--NR.sup.9--;
[0039] wherein neither Z nor R.sup.13 are connected to a carbon
atom labeled (b); [0040] bond (a) is a single or double bond;
[0041] alternatively, when n is equal to 2, two atoms labeled (b)
may join through a double bond; [0042] E is selected from
--S(O).sub.pCHR.sup.e--, --CHR.sup.eNR.sup.e--, --C(O)--NR.sup.e--,
--NR.sup.eC(O)NR.sup.e--, --SO.sub.2--NR.sup.e--, and
NR.sup.eSO.sub.2NR.sup.e; [0043] R.sup.e is independently selected
from H and C.sub.1-3 alkyl; [0044] R.sup.1 is selected from a
C.sub.6-10 aryl group substituted with 0-5 R.sup.6 and a 5-10
membered heteroaryl system containing 1-4 heteroatoms selected from
N, O, and S, substituted with 0-3 R.sup.6; [0045] R.sup.2 is
selected from a C.sub.6-10 aryl group substituted with 0-5 R.sup.7
and a 5-10 membered heteroaryl system containing 1-4 heteroatoms
selected from N, O, and S, substituted with 0-3 R.sup.7; [0046]
R.sup.4 is selected from H, C.sub.1-6 alkyl, C.sub.3-8 alkenyl,
C.sub.3-8 alkynyl, (CRR).sub.tOH, (CRR).sub.tSH,
(CRR).sub.tOR.sup.4d, (CRR).sub.tSR.sup.4d,
(CRR).sub.tNR.sup.4aR.sup.4a, (CRR).sub.qC(O)OH,
(CRR).sub.rC(O)R.sup.4b, (CRR).sub.rC(O)NR.sup.4aR.sup.4a,
(CRR).sub.tOC(O)NR.sup.4aR.sup.4a,
(CRR).sub.tNR.sup.4aC(O)OR.sup.4d,
(CRR).sub.tNR.sup.4aC(O)R.sup.4b, (CRR).sub.rC(O)OR.sup.4d,
(CRR).sub.tOC(O)R.sup.4b, (CRR).sub.rS(O).sub.pR.sup.4b,
(CRR).sub.rS(O).sub.2NR.sup.4aR.sup.4a,
(CRR).sub.tNR.sup.4aS(O).sub.2R.sup.4b, C.sub.1-6 haloalkyl, a
(CRR).sub.r--C.sub.3-10 carbocyclic residue substituted with 0-3
R.sup.4e, and a (CHR).sub.r-4-10 membered heterocyclic system
containing 1-4 heteroatoms selected from N, O, and Si substituted
with 0-2 R.sup.4e; [0047] R.sup.4a, at each occurrence, is
independently selected from H, methyl substituted with 0-1
R.sup.4c, C.sub.2-6 alkyl substituted with 0-3 R.sup.4e, C.sub.3-8
alkenyl substituted with 0-3 R.sup.4e, C.sub.3-8 alkynyl
substituted with 0-3 R.sup.4e, a (CH.sub.2).sub.r--C.sub.3-10
carbocyclic residue substituted with 0-4 R.sup.4e, and a
(CHR).sub.r-4-10 membered heterocyclic system containing 1-4
heteroatoms selected from N, O, and S, substituted with 0-2
R.sup.4e; [0048] R.sup.4b, at each occurrence, is selected from H,
C.sub.1-6 alkyl substituted with 0-3 R.sup.4e, C.sub.3-8 alkenyl
substituted with 0-3 R.sup.4e, C.sub.3-8 alkynyl substituted with
0-3 R.sup.4e, a (CH.sub.2).sub.r--C.sub.3-6 carbocyclic residue
substituted with 0-2 R.sup.4e, and a (CHR).sub.r-4-10 membered
heterocyclic system containing 1-4 heteroatoms selected from N, O,
and S, substituted with 0-2 R.sup.4e; [0049] R.sup.4c is
independently selected from --C(O)R.sup.4b, --C(O)OR.sup.4d,
--C(O)NR.sup.4fR.sup.4f, and (CH.sub.2).sub.rphenyl; [0050]
R.sup.4d, at each occurrence, is selected from methyl, CF.sub.3,
C.sub.2-6 alkyl substituted with 0-3 R.sup.4e, C.sub.3-8 alkenyl
substituted with 0-3 R.sup.4e, C.sub.3-8 alkynyl substituted with
0-3 R.sup.4e, and a C.sub.3-10 carbocyclic residue substituted with
0-3 R.sup.4e; [0051] R.sup.4e, at each occurrence, is selected from
C.sub.1-6 alkyl, C.sub.2-8 alkenyl, C.sub.2-8 alkynyl,
(CH.sub.2).sub.rC.sub.3-6 cycloalkyl, Cl, F, Br, I, CN, NO.sub.2,
(CF.sub.2).sub.rCF.sub.3, (CH.sub.2).sub.rOC.sub.1-5 alkyl, OH, SH,
(CH.sub.2).sub.rSC.sub.1-5 alkyl,
(CH.sub.2).sub.rNR.sup.4fR.sup.4f, --C(O)R.sup.4i, --C(O)OR.sup.4j,
--C(O)NR.sup.4hR.sup.4h, --OC(O)NR.sup.4hR.sup.4h,
--NR.sup.4hC(O)NR.sup.4hR.sup.4h, --NR.sup.4hC(O)OR.sup.4j, and
(CH.sub.2).sub.rphenyl; [0052] R.sup.4f, at each occurrence, is
selected from H, C.sub.1-6 alkyl, C.sub.3-6 cycloalkyl, and phenyl;
[0053] R.sup.4h, at each occurrence, is independently selected from
H, C.sub.1-6 alkyl, C.sub.3-8 alkenyl, C.sub.3-8 alkynyl, and a
(CH.sub.2).sub.r--C.sub.3-10 carbocyclic; [0054] R.sup.4i, at each
occurrence, is selected from H, C.sub.1-6 alkyl, C.sub.3-8 alkenyl,
C.sub.3-8 alkynyl, and a (CH.sub.2).sub.r--C.sub.3-6 carbocyclic
residue; [0055] R.sup.4j, at each occurrence, is selected from
CF.sub.3, C.sub.1-6 alkyl, C.sub.3-8 alkenyl, C.sub.3-8 alkynyl,
and a C.sub.3-10 carbocyclic residue; [0056] R.sup.5, at each
occurrence, is independently selected from H, .dbd.O, C.sub.1-6
alkyl, C.sub.2-8 alkenyl, C.sub.2-8 alkynyl, (CRR).sub.rOH,
(CRR).sub.rSH, (CRR).sub.rOR.sup.5d, (CRR).sub.rSR.sup.5d,
(CRR).sub.rNR.sup.5aR.sup.5a,
(CRR).sub.rN(.fwdarw.O)R.sup.5aR.sup.5a, N.sub.3,
(CRR).sub.rC(O)OH, (CRR).sub.rC(O)R.sup.5b,
(CRR).sub.rC(O)NR.sup.5aR.sup.5a, (CRR).sub.rNR.sup.5aC(O)R.sup.5b,
(CRR).sub.rOC(O)NR.sup.5aR.sup.5a,
(CRR).sub.rNR.sup.5aC(O)OR.sup.5d,
(CRR).sub.rNR.sup.5aC(O)NR.sup.5aR.sup.5a,
(CRR).sub.rNR.sup.5aC(O)H, (CRR).sub.rC(O)OR.sup.5d,
(CRR).sub.rOC(O)R.sup.5b, (CRR).sub.rS(O).sub.pR.sup.5b,
(CRR).sub.rS(O).sub.2NR.sup.5aR.sup.5a,
(CRR).sub.rNR.sup.5aS(O).sub.2R.sup.5b,
(CRR).sub.rNR.sup.5aS(O).sub.2NR.sup.5aR.sup.5a, C.sub.1-6
haloalkyl, a (CRR).sub.r--C.sub.3-10 carbocyclic residue
substituted with 0-3 R.sup.5c, and a (CRR).sub.r-5-10 membered
heterocyclic system containing 1-4 heteroatoms selected from N, O,
and S, substituted with 0-2 R.sup.5c; [0057] R.sup.5a, at each
occurrence, is independently selected from H, methyl substituted
with 0-1 R.sup.5g, C.sub.2-6 alkyl substituted with 0-2 R.sup.5e,
C.sub.3-8 alkenyl substituted with 0-2 R.sup.5e, C.sub.3-8 alkynyl
substituted with 0-2 R.sup.5e, a (CH.sub.2).sub.r--C.sub.3-10
carbocyclic residue substituted with 0-5 R.sup.5e, and a
(CH.sub.2).sub.r-5-10 membered heterocyclic system containing 1-4
heteroatoms selected from N, O, and S, substituted with 0-3
R.sup.5e; [0058] R.sup.5b, at each occurrence, is selected from
C.sub.1-6 alkyl substituted with 0-3 R.sup.5e, C.sub.3-8 alkenyl
substituted with 0-2 R.sup.5e, C.sub.3-8 alkynyl substituted with
0-2 R.sup.5e, a (CH.sub.2).sub.r--C.sub.3-6 carbocyclic residue
substituted with 0-2 R.sup.5e, and a (CH.sub.2).sub.r-5-6 membered
heterocyclic system containing 1-4 heteroatoms selected from N, O,
and S, substituted with 0-3 R.sup.5e; [0059] R.sup.5c, at each
occurrence, is selected from C.sub.1-6 alkyl, C.sub.2-8 alkenyl,
C.sub.2-8 alkynyl, (CH.sub.2).sub.rC.sub.3-6-cycloalkyl, Cl, Br, I,
F, (CF.sub.2).sub.rCF.sub.3, NO.sub.2, CN,
(CH.sub.2).sub.rNR.sup.5fR.sup.5f, (CH.sub.2).sub.rOH,
(CH.sub.2).sub.rOC.sub.1-4 alkyl, (CH.sub.2).sub.rSC.sub.1-4 alkyl,
(CH.sub.2).sub.rC(O)OH, (CH.sub.2).sub.rC(O)R.sup.5b,
(CH.sub.2).sub.rC(O)NR.sup.5fR.sup.5f,
(CH.sub.2).sub.rOC(O)NR.sup.5fR.sup.5f,
(CH.sub.2).sub.rNR.sup.5fC(O)R.sup.5b,
(CH.sub.2).sub.rC(O)OC.sub.1-4 alkyl,
(CH.sub.2).sub.rNR.sup.5fC(O)OC.sub.1-4 alkyl,
(CH.sub.2).sub.rOC(O)R.sup.5b,
(CH.sub.2).sub.rC(.dbd.NR.sup.5R.sup.5f)NR.sup.5fR.sup.5f,
(CH.sub.2).sub.rS(O).sub.pR.sup.5b,
(CH.sub.2).sub.rNHC(.dbd.NR.sup.5f)NR.sup.5fR.sup.5f,
(CH.sub.2).sub.rS(O).sub.2NR.sup.5fR.sup.5f,
(CH.sub.2).sub.rNR.sup.5fS(O).sub.2R.sup.5b, and
(CH.sub.2).sub.rphenyl substituted with 0-3 R.sup.5e; [0060]
R.sup.5d, at each occurrence, is selected from methyl, CF.sub.3,
C.sub.2-6 alkyl substituted with 0-2 R.sup.5e, C.sub.3-8 alkenyl
substituted with 0-2 R.sup.5e, C.sub.3-8 alkynyl substituted with
0-2 R.sup.5e, and a C.sub.3-10 carbocyclic residue substituted with
0-3 R.sup.5e; [0061] R.sup.5e, at each occurrence, is selected from
C.sub.1-6 alkyl, C.sub.2-8 alkenyl, C.sub.2-8 alkynyl, C.sub.3-6
cycloalkyl, Cl, F, Br, I, CN, NO.sub.2, (CF.sub.2).sub.rCF.sub.3,
(CH.sub.2).sub.rOC.sub.1-5 alkyl, OH, SH,
(CH.sub.2).sub.rSC.sub.1-5 alkyl,
(CH.sub.2).sub.rNR.sup.5fR.sup.5f, and (CH.sub.2).sub.rphenyl;
[0062] R.sup.5f, at each occurrence, is selected from H, C.sub.1-6
alkyl, and C.sub.3-6 cycloalkyl; [0063] R.sup.5g is independently
selected from --C(O)R.sup.5b, --C(O)OR.sup.5d,
--C(O)NR.sup.5fR.sup.5f, --CN, and (CH.sub.2).sub.rphenyl; [0064]
R, at each occurrence, is selected from H, C.sub.1-6 alkyl
substituted with R.sup.5e, C.sub.2-8 alkenyl, C.sub.2-8 alkynyl,
(CH.sub.2).sub.rC.sub.3-6 cycloalkyl, and (CH.sub.2).sub.rphenyl
substituted with R.sup.5e; [0065] R.sup.6, at each occurrence, is
selected from C.sub.1-8 alkyl, C.sub.2-8 alkenyl, C.sub.2-8
alkynyl, (CH.sub.2).sub.rC.sub.3-6 cycloalkyl, Cl, Br, I, F,
NO.sub.2, CN, (CR'R').sub.rN.sup.6aR.sup.6a, (CR'R').sub.rOH,
(CR'R').sub.rO(CR'R').sub.rR.sup.6d, (CR'R').sub.rSH,
(CR'R').sub.rC(O)H, (CR'R').sub.rS(CR'R').sub.rR.sup.6d,
(CR'R').sub.rSC(O)(CR'R').sub.rR.sup.6b, (CR'R').sub.rC(O)OH,
(CR'R').sub.rC(O)(CR'R').sub.rR.sup.6b,
(CR'R').sub.rNR.sup.6aR.sup.6a, (CR'R').sub.rC(O)NR.sup.6aR.sup.6a,
(CR'R').sub.rNR.sup.6fC(O)(CR'R').sub.rR.sup.6b,
(CR'R').sub.rC(O)O(CR'R').sub.rR.sup.6d,
(CR'R').sub.rOC(O)(CR'R').sub.rR.sup.6b,
(CR'R').sub.rOC(O)NR.sup.6a(CR'R').sub.rR.sup.6d,
(CR'R').sub.rNR.sup.6aC(O)NR.sup.6a(CR'R').sub.rR.sup.6d,
(CR'R').sub.rNR.sup.6aC(S)NR.sup.6a(CR'R').sub.rR.sup.6d,
(CR'R').sub.rNR.sup.6fC(O)O(CR'R').sub.rR.sup.6b,
(CR'R').sub.rC(.dbd.NR.sup.6f)NR.sup.6aR.sup.6a,
(CR'R').sub.rNHC(.dbd.NR.sup.6f)NR.sup.6fR.sup.6f,
(CR'R').sub.rS(O).sub.p(CR'R').sub.rR.sup.6b,
(CR'R').sub.rS(O).sub.2NR.sup.6aR.sup.6a,
(CR'R').sub.rNR.sup.6fS(O).sub.2NR.sup.6aR.sup.6a,
(CR'R').sub.rNR.sup.6fS(O).sub.2(CR'R').sub.rR.sup.6b, C.sub.1-6
haloalkyl, C.sub.2-8 alkenyl substituted with 0-3 R', C.sub.2-8
alkynyl substituted with 0-3 R', (CR'R').sub.rphenyl substituted
with 0-3 R.sup.6e, and a (CH.sub.2).sub.r-5-6 membered heterocyclic
system containing 1-2 heteroatoms selected from N, O, and S,
substituted with 0-2 R.sup.6e; [0066] alternatively, two R.sup.6 on
adjacent atoms on R.sup.1 may join to form a cyclic acetal; [0067]
R.sup.6a, at each occurrence, is selected from H, methyl
substituted with 0-1 R.sup.6g, C.sub.2-6 alkyl substituted with 0-2
R.sup.6e, C.sub.3-8 alkenyl substituted with 0-2 R.sup.6e,
C.sub.3-8 alkynyl substituted with 0-2 R.sup.6e, a
(CH.sub.2).sub.r--C.sub.3-10 carbocyclic residue substituted with
0-5 R.sup.6e, and a (CH.sub.2).sub.r-5-10 membered heterocyclic
system containing 1-4 heteroatoms selected from N, O, and S,
substituted with 0-2 R.sup.6e; [0068] R.sup.6b, at each occurrence,
is selected from H, C.sub.1-6 alkyl substituted with 0-2 R.sup.6e,
C.sub.3-8 alkenyl substituted with 0-2 R.sup.6e, C.sub.3-8 alkynyl
substituted with 0-2 R.sup.6e, a (CH.sub.2).sub.rC.sub.3-6
carbocyclic residue substituted with 0-3 R.sup.6e, and a
(CH.sub.2).sub.r-5-6 membered heterocyclic system containing 1-4
heteroatoms selected from N, O, and S, substituted with 0-2
R.sup.6e; [0069] R.sup.6d, at each occurrence, is selected from
C.sub.3-8 alkenyl substituted with 0-2 R.sup.6e, C.sub.3-8 alkynyl
substituted with 0-2 R.sup.6e, methyl, CF.sub.3, C.sub.2-6 alkyl
substituted with 0-3 R.sup.6e, C.sub.2-4 haloalkyl, a
(CH.sub.2).sub.r--C.sub.3-10 carbocyclic residue substituted with
0-3 R.sup.6e, and a (CH.sub.2).sub.r-5-6 membered heterocyclic
system containing 1-4 heteroatoms selected from N, O, and S,
substituted with 0-3 R.sup.6e; [0070] R.sup.6e, at each occurrence,
is selected from C.sub.1-6 alkyl, C.sub.2-8 alkenyl, C.sub.2-8
alkynyl, (CH.sub.2).sub.rC.sub.3-6 cycloalkyl, Cl, F, Br, I, CN,
NO.sub.2, (CF.sub.2).sub.rCF.sub.3, (CH.sub.2).sub.rOC.sub.1-5
alkyl, OH, SH, (CH.sub.2).sub.rSC.sub.1-5 alkyl,
(CH.sub.2).sub.rNR.sup.6fR.sup.6f, and (CH.sub.2).sub.rphenyl;
[0071] R.sup.6f, at each occurrence, is selected from H, C.sub.1-5
alkyl, and C.sub.3-6 cycloalkyl, and phenyl; [0072] R.sup.6g is
independently selected from --C(O)R.sup.6b, --C(O)OR.sup.6d,
--C(O)NR.sup.6fR.sup.6f, and (CH.sub.2).sub.rphenyl; [0073]
R.sup.7, at each occurrence, is selected from C.sub.1-8 alkyl,
C.sub.2-8 alkenyl, C.sub.2-8 alkynyl, (CH.sub.2).sub.rC.sub.3-6
cycloalkyl, Cl, Br, I, F, NO.sub.2, CN,
(CR'R').sub.rNR.sup.7aR.sup.7a, (CR'R').sub.rOH,
(CR'R').sub.rO(CR'R').sub.rR.sup.7d, (CR'R').sub.rSH,
(CR'R').sub.rC(O)H, (CR'R').sub.rS(CR'R').sub.rR.sup.7d,
(CR'R').sub.rC(O)OH, (CR'R').sub.rC(O)(CR'R').sub.rR.sup.7b,
(CR'R').sub.rC(O)NR.sup.7aR.sup.7a,
(CR'R').sub.rNR.sup.7fC(O)(CR'R').sub.rR.sup.7b,
(CR'R').sub.rC(O)O(CR'R').sub.rR.sup.7d,
(CR'R').sub.rOC(O)(CR'R').sub.rR.sup.7b,
(CR'R').sub.rOC(O)NR.sup.7a(CR'R').sub.rR.sup.7a,
(CR'R').sub.rNR.sup.7aC(O)NR.sup.7a(CR'R').sub.rR.sup.7a,
(CR'R').sub.rNR.sup.7fC(O)O(CR'R').sub.rR.sup.7d,
(CR'R').sub.rC(.dbd.NR.sup.7f)NR.sup.7aR.sup.7a,
(CR'R').sub.rNHC(.dbd.NR.sup.7f)NR.sup.7fR.sup.7f,
(CR'R').sub.rS(O).sub.p(CR'R').sub.rR.sup.7b,
(CR'R').sub.rS(O).sub.2NR.sup.7aR.sup.7a,
(CR'R').sub.rNR.sup.7aS(O).sub.2NR.sup.7aR.sup.7a,
(CR'R').sub.rNR.sup.7fS(O).sub.2(CR'R').sub.rR.sup.7b, C.sub.1-6
haloalkyl, C.sub.2-8 alkenyl substituted with 0-3 R', C.sub.2-8
alkynyl substituted with 0-3 R', (CR'R').sub.rC.sub.3-10
carbocyclic residue and (CR'R').sub.rphenyl substituted with 0-3
R.sup.7e; [0074] alternatively, two R.sup.7 on adjacent atoms on
R.sup.2 may join to form a cyclic acetal; [0075] R.sup.7a, at each
occurrence, is independently selected from H, methyl substituted
with 0-1 R.sup.7g, C.sub.2-6 alkyl substituted with 0-2 R.sup.7e,
C.sub.3-8 alkenyl substituted with 0-2 R.sup.7e, C.sub.3-8 alkynyl
substituted with 0-2 R.sup.7e, a (CH.sub.2).sub.r--C.sub.3-10
carbocyclic residue substituted with 0-5 R.sup.7e, and a
(CH.sub.2).sub.r-5-10 membered heterocyclic system containing 1-4
heteroatoms selected from N, O, and S, substituted with 0-2
R.sup.7e; [0076] R.sup.7b, at each occurrence, is selected from
C.sub.1-6 alkyl substituted with 0-2 R.sup.7e, C.sub.3-8 alkenyl
substituted with 0-2 R.sup.7e, C.sub.3-8 alkynyl substituted with
0-2 R.sup.7e, a (CH.sub.2).sub.rC.sub.3-6 carbocyclic residue
substituted with 0-3 R.sup.7e, and a (CH.sub.2).sub.r-5-6 membered
heterocyclic system containing 1-4 heteroatoms selected from N, O,
and S, substituted with 0-2 R.sup.7e; [0077] R.sup.7d, at each
occurrence, is selected from C
.sub.3-8 alkenyl substituted with 0-2 R.sup.7e, C.sub.3-8 alkynyl
substituted with 0-2 R.sup.7e, methyl, CF.sub.3, C.sub.2-4
haloalkyl, C.sub.2-6 alkyl substituted with 0-3 R.sup.7e, a
(CH.sub.2).sub.r--C.sub.3-10 carbocyclic residue substituted with
0-3 R.sup.7e, and a (CH.sub.2).sub.r-5-6 membered heterocyclic
system containing 1-4 heteroatoms selected from N, O, and S,
substituted with 0-3 R.sup.7e; [0078] R.sup.7e, at each occurrence,
is selected from C.sub.1-6 alkyl, C.sub.2-8 alkenyl, C.sub.2-8
alkynyl, (CH.sub.2).sub.rC.sub.3-6 cycloalkyl, Cl, F, Br, I, CN,
NO.sub.2, (CF.sub.2).sub.rCF.sub.3, (CH.sub.2).sub.rOC.sub.1-5
alkyl, OH, SH, C(O)OC.sub.1-5 alkyl, (CH.sub.2).sub.rSC.sub.1-5
alkyl, (CH.sub.2).sub.rNR.sup.7fR.sup.7f, and
(CH.sub.2).sub.rphenyl; [0079] R.sup.7f, at each occurrence, is
selected from H, C.sub.1-5 alkyl, and C.sub.3-6 cycloalkyl, and
phenyl; [0080] R.sup.7g is independently selected from
--C(O)R.sup.7b, --C(O)OR.sup.7, --C(O)NR.sup.7fR.sup.7f, and
(CH.sub.2).sub.rphenyl; [0081] R', at each occurrence, is selected
from H, C.sub.1-6 alkyl substituted with R.sup.6e, C.sub.2-8
alkenyl, C.sub.2-8 alkynyl, (CH.sub.2).sub.rC.sub.3-6 cycloalkyl,
and (CH.sub.2).sub.rphenyl substituted with R.sup.6e; [0082]
R.sup.8 is selected from H, C.sub.1-4 alkyl, and C.sub.3-4
cycloalkyl; [0083] R.sup.9 is selected from H, C.sub.1-4 alkyl,
C.sub.3-4 cycloalkyl, --C(O)H, and --C(O)--C.sub.1-4alkyl; [0084]
R.sup.10 is independently selected from H, and C.sub.1-4alkyl
substituted with 0-1 R.sup.10b, alternatively, two R.sup.10 form
.dbd.O; [0085] R.sup.10b, at each occurrence, is independently
selected from --OH, --SH, --NR.sup.10cR.sup.10c,
--C(O)NR.sup.10cR.sup.10c, and --NHC(O)R.sup.10c; [0086] R.sup.10c
is selected from H, C.sub.1-4 alkyl and C.sub.3-6 cycloalkyl;
[0087] R.sup.11 is selected from H, C.sub.1-4 alkyl, (CHR).sub.qOH,
(CHR).sub.qSH, (CHR).sub.qOR.sup.11d,
(CHR).sub.qS(O).sub.pR.sup.11d, (CHR).sub.rC(O)R.sup.11b,
(CHR).sub.rNR.sup.11aR.sup.11a, (CHR).sub.rC(O)NR.sup.11aR.sup.11a,
(CHR).sub.rC(O)NR.sup.11aOR.sup.11d,
(CHR).sub.qNR.sup.11aC(O)R.sup.11b,
(CHR).sub.qNR.sup.11aC(O)OR.sup.11d,
(CHR).sub.qOC(O)NR.sup.11aR.sup.11a, (CHR).sub.rC(O)OR.sup.11d, a
(CHR).sub.r--C.sub.3-6 carbocyclic residue substituted with 0-5
R.sup.11e, and a (CHR).sub.r-5-10 membered heterocyclic system
containing 1-4 heteroatoms selected from N, O, and S, substituted
with 0-3 R.sup.11e; [0088] R.sup.11a, at each occurrence, is
independently selected from H, C.sub.1-4 alkyl, C.sub.3-4 alkenyl,
C.sub.3-4 alkynyl, (CH.sub.2).sub.rC.sub.3-6 cycloalkyl, a
(CH.sub.2).sub.r--C.sub.3-6 carbocyclic residue substituted with
0-5 R.sup.11e, and a (CH.sub.2).sub.r-5-6 membered heterocyclic
system containing 1-4 heteroatoms selected from N, O, and S,
substituted with 0-3 R.sup.11e; [0089] R.sup.11b, at each
occurrence, is independently selected from C.sub.1-4 alkyl,
C.sub.2-4 alkenyl, C.sub.2-4 alkynyl, a (CH.sub.2).sub.r--C.sub.3-6
carbocyclic residue substituted with 0-2 R.sup.11e, and a
(CH.sub.2).sub.r-5-6 membered heterocyclic system containing 1-4
heteroatoms selected from N, O, and S, substituted with 0-3
R.sup.11e; [0090] R.sup.11d, at each occurrence, is independently
selected from H, methyl, --CF.sub.3, C.sub.2-4 alkyl, C.sub.3-6
alkenyl, C.sub.3-6 alkynyl, a C.sub.3-6 carbocyclic residue
substituted with 0-3 R.sup.11e, and a (CH.sub.2).sub.r-5-6 membered
heterocyclic system containing 1-4 heteroatoms selected from N, O,
and S, substituted with 0-3 R.sup.11e; [0091] R.sup.11e, at each
occurrence, is selected from C.sub.1-6 alkyl, C.sub.2-8 alkenyl,
C.sub.2-8 alkynyl, C.sub.3-6 cycloalkyl, Cl, F, Br, I, CN,
NO.sub.2, (CF.sub.2).sub.rCF.sub.3, (CH.sub.2).sub.rOC.sub.1-5
alkyl, OH, --O--C.sub.1-6 alkyl, SH, (CH.sub.2).sub.rSC.sub.1-5
alkyl, (CH.sub.2).sub.rNR.sup.11fR.sup.11f, and
(CH.sub.2).sub.rphenyl; [0092] R.sup.11f, at each occurrence, is
selected from H, C.sub.1-6 alkyl, and C.sub.3-6 cycloalkyl; [0093]
R.sup.12 is selected from H, C.sub.1-4 alkyl, (CHR).sub.qOH,
(CHR).sub.qSH, (CHR).sub.qOR.sup.12d,
(CHR).sub.qS(O).sub.pR.sup.12d, (CHR).sub.rC(O)R.sup.12b,
(CHR).sub.rNR.sup.12aR.sup.12a, (CHR).sub.rC(O)NR.sup.12aR.sup.12a,
(CHR).sub.rC(O)NR.sup.12aOR.sup.12d,
(CHR).sub.qR.sup.12aC(O)R.sup.12b,
(CHR).sub.qNR.sup.12aC(O)OR.sup.12d,
(CHR).sub.qOC(O)NR.sup.12aR.sup.12a, (CHR).sub.rC(O)OR.sup.12d, a
(CHR).sub.r--C.sub.3-6 carbocyclic residue substituted with 0-5
R.sup.12e, and a (CHR).sub.r-5-10 membered heterocyclic system
containing 1-4 heteroatoms selected from N, O, and S, substituted
with 0-3 R.sup.12e; [0094] R.sup.12a, at each occurrence, is
independently selected from H, C.sub.1-4 alkyl, C.sub.3-4 alkenyl,
C.sub.3-4 alkynyl, (CH.sub.2).sub.rC.sub.3-6 cycloalkyl, a
(CH.sub.2).sub.r--C.sub.3-6 carbocyclic residue substituted with
0-5 R.sup.12e, and a (CH.sub.2).sub.r-5-6 membered heterocyclic
system containing 1-4 heteroatoms selected from N, O, and S,
substituted with 0-3 R.sup.12e; [0095] R.sup.12b, at each
occurrence, is independently selected from C.sub.1-4 alkyl,
C.sub.2-4 alkenyl, C.sub.2-4 alkynyl, a (CH.sub.2).sub.r--C.sub.3-6
carbocyclic residue substituted with 0-2 R.sup.12e, and a
(CH.sub.2).sub.r-5-6 membered heterocyclic system containing 1-4
heteroatoms selected from N, O, and S, substituted with 0-3
R.sup.12e; [0096] R.sup.12d, at each occurrence, is independently
selected from H, methyl, --CF.sub.3, C.sub.2-4 alkyl, C.sub.3-6
alkenyl, C.sub.3-6 alkynyl, a C.sub.3-6 carbocyclic residue
substituted with 0-3 R.sup.12e, and a (CH.sub.2).sub.r-5-6 membered
heterocyclic system containing 1-4 heteroatoms selected from N, O,
and S, substituted with 0-3 R.sup.12e; [0097] R.sup.12e, at each
occurrence, is selected from C.sub.1-6 alkyl, C.sub.2-8 alkenyl,
C.sub.2-8 alkynyl, C.sub.3-6 cycloalkyl, Cl, F, Br, I, CN,
NO.sub.2, (CF.sub.2).sub.rCF.sub.3, (CH.sub.2).sub.rOC.sub.1-5
alkyl, OH, --O--C.sub.1-6 alkyl, SH, (CH.sub.2).sub.rSC.sub.1-5
alkyl, (CH.sub.2).sub.rNR.sup.12fR.sup.12f, and
(CH.sub.2).sub.rphenyl; [0098] R.sup.12f, at each occurrence, is
selected from H, C.sub.1-6 alkyl, and C.sub.3-6 cycloalkyl; [0099]
R.sup.13, at each occurrence, is independently selected from H, and
C.sub.1-4alkyl substituted with 0-1 R.sup.13b, --OH, --NH.sub.2, F,
Cl, Br, I, --OR.sup.13a, --N(R.sup.13a).sub.2, and C.sub.1-4 alkyl
substituted with 0-3 R.sup.13b; [0100] R.sup.13a is selected from
H, C.sub.1-4 alkyl and C.sub.3-6 cycloalkyl; [0101] R.sup.13b, at
each occurrence, is independently selected from --OH, --SH,
NR.sup.13cR.sup.13c, --C(O)NR.sup.13cR.sup.13c, and
--NHC(O)R.sup.13c; [0102] R.sup.13c is selected from H, C.sub.1-4
alkyl and C.sub.3-6 cycloalkyl; [0103] R.sup.14, at each
occurrence, is independently selected from H and C.sub.1-4alkyl;
[0104] alternatively, two R.sup.14s, along with the carbon atom to
which they are attached, join to form a C.sub.3-6 carbocyclic ring;
[0105] R.sup.15, at each occurrence, is independently selected from
H, C.sub.1-4alkyl, OH, NH.sub.2, O--C.sub.1-4 alkyl,
NR.sup.15aR.sup.15a, C(O)NR.sup.15aR.sup.15a,
NR.sup.15aC(O)R.sup.15b, NR.sup.15aC(O)OR.sup.15d,
OC(O)NR.sup.15aR.sup.15a, and (CHR).sub.rC(O)OR.sup.15d; [0106]
alternatively, two R.sup.15s, along with the carbon atom or atoms
to which they are attached, join to form a C.sub.3-6 carbocyclic
ring; [0107] R.sup.15a, at each occurrence, is independently
selected from H, and C.sub.1-4 alkyl; [0108] R.sup.15b, at each
occurrence, is independently selected from C.sub.1-4 alkyl,
C.sub.3-6 alkenyl, and C.sub.3-6 alkynyl; [0109] R.sup.15d, at each
occurrence, is independently selected from C.sub.1-4 alkyl,
C.sub.3-6 alkenyl, and C.sub.3-6 alkynyl; [0110] R.sup.16 is
selected from C.sub.1-4 alkyl; [0111] l is selected from 1, 2 and
3; [0112] n is selected from 0, 1, 2, and 3; [0113] m is selected
from 0 and 1; [0114] p, at each occurrence, is independently
selected from 0, 1, and 2; [0115] q, at each occurrence, is
independently selected from 1, 2, 3, and 4; [0116] r, at each
occurrence, is independently selected from 0, 1, 2, 3, and 4;
[0117] t, at each occurrence, is independently selected from 2, 3,
and 4; [0118] s is selected from 0 and 1. [2] Thus, in another
embodiment, the present invention provides novel compounds of
formula (I): ##STR8## or a stereoisomer or a pharmaceutically
acceptable salt thereof, wherein: [0119] ring B is a cycloalkyl
group of 3 to 8 carbon atoms wherein the cycloalkyl group is
saturated or partially unsaturated; or a heterocycle of 3 to 7
atoms wherein the heterocycle is saturated or partially
unsaturated, the heterocycle containing a heteroatom selected from
--O--, --S--, --S(.dbd.O)--, --S(.dbd.O).sub.2--, and
--N(R.sup.4)--, the heterocycle optionally containing a --C(O)--;
ring B being substituted with 0-2 R.sup.5; [0120] X is selected
from O or S; [0121] Z is selected from a bond, --NR.sup.8C(O)--,
--NR.sup.8C(S)--, --NR.sup.8C(O)NH--, --NR.sup.8C(S)NH--,
--NR.sup.8SO.sub.2--, --NR.sup.8SO.sub.2NH--, --C(O)NR.sup.8--,
--OC(O)NR.sup.8--, --NR.sup.8C(O)O--,
--(CR.sup.15R.sup.15).sub.l--, --CR.sup.14.dbd.CR.sup.14--,
--CR.sup.15R.sup.15C(O)--, --C(O)CR.sup.15R.sup.15--,
CR.sup.15R.sup.15C(.dbd.N--OR.sup.16)--, --O--CR.sup.14R.sup.14--,
--CR.sup.14R.sup.14--O--, --O--, --NR.sup.9--,
--NR.sup.9--CR.sup.14R.sup.14--, --CR.sup.14R.sup.14--NR.sup.9--,
--S(O).sub.p--, --S(O).sub.p--CR.sup.14R.sup.14--,
--CR.sup.14R.sup.14--S(O).sub.p-- and --S(O).sub.p--NR.sup.9--;
[0122] wherein neither Z nor R.sup.13 are connected to a carbon
atom labeled (b); [0123] bond (a) is a single or double bond;
[0124] alternatively, when n is equal to 2, two atoms labeled (b)
may join through a double bond; [0125] E is selected from
--S(O).sub.pCHR.sup.e--, --CHR.sup.eNR.sup.e--, --C(O)--NR.sup.e--,
--NR.sup.eC(O)NR.sup.e--, --SO.sub.2--NR.sup.e--, and
--NR.sup.eSO.sub.2NR.sup.e--; [0126] R.sup.e is independently
selected from H and C.sub.1-3 alkyl; [0127] R.sup.1 is selected
from a C.sub.6-10 aryl group substituted with 0-5 R.sup.6 and a
5-10 membered heteroaryl system containing 1-4 heteroatoms selected
from N, O, and S, substituted with 0-3 R.sup.6; [0128] R.sup.2 is
selected from a C.sub.6-10 aryl group substituted with 0-5 R.sup.7
and a 5-10 membered heteroaryl system containing 1-4 heteroatoms
selected from N, O, and S, substituted with 0-3 R.sup.7; [0129]
R.sup.4 is selected from H, C.sub.1-6 alkyl, C.sub.3-8 alkenyl,
C.sub.3-8 alkynyl, (CRR).sub.tOH, (CRR).sub.tSH,
(CRR).sub.tOR.sup.4d, (CHR).sub.tSR.sup.4d,
(CRR).sub.tNR.sup.4aR.sup.4a, (CRR).sub.qC(O)OH,
(CRR).sub.rC(O)R.sup.4b, (CRR).sub.rC(O)NR.sup.4aR.sup.4a,
(CRR).sub.tOC(O)NR.sup.4aR.sup.4a,
(CRR).sub.tNR.sup.4aC(O)OR.sup.4d,
(CRR).sub.tNR.sup.4aC(O)R.sup.4b, (CRR).sub.rC(O)OR.sup.4d,
(CRR).sub.tOC(O)R.sup.4b, (CRR).sub.rS(O).sub.pR.sup.4b,
(CRR).sub.rS(O).sub.2NR.sup.4aR.sup.4a,
(CRR).sub.tNR.sup.4aS(O).sub.2R.sup.4b, C.sub.1-6 haloalkyl, a
(CRR).sub.rC.sub.3-10 carbocyclic residue substituted with 0-3
R.sup.4e, and a (CHR).sub.r-4-10 membered heterocyclic system
containing 1-4 heteroatoms selected from N, O, and S, substituted
with 0-2 R.sup.4e; [0130] R.sup.4a, at each occurrence, is
independently selected from H, methyl substituted with 0-1
R.sup.4c, C.sub.2-6 alkyl substituted with 0-3 R.sup.4e, C.sub.3-6
alkenyl substituted with 0-3 R.sup.4e, C.sub.3-8 alkynyl
substituted with 0-3 R.sup.4e, a (CH.sub.2).sub.r--C.sub.3-10
carbocyclic residue substituted with 0-4 R.sup.4e, and a
(CHR).sub.r-4-10 membered heterocyclic system containing 1-4
heteroatoms selected from N, O, and S, substituted with 0-2
R.sup.4e; [0131] R.sup.4b, at each occurrence, is selected from H,
C.sub.1-6 alkyl substituted with 0-3 R.sup.4e, C.sub.3-8 alkenyl
substituted with 0-3 R.sup.4e, C.sub.3-8 alkynyl substituted with
0-3 R.sup.4e, a (CH.sub.2).sub.r--C.sub.3-6 carbocyclic residue
substituted with 0-2 R.sup.4e, and a (CHR).sub.r-410 membered
heterocyclic system containing 1-4 heteroatoms selected from N, O,
and S, substituted with 0-2 R.sup.4e; [0132] R.sup.4c is
independently selected from --C(O)R.sup.4b, --C(O)OR.sup.4d,
--C(O)NR.sup.4fR.sup.4f, and (CH.sub.2).sub.rphenyl; [0133]
R.sup.4d, at each occurrence, is selected from methyl, CF.sub.3,
C.sub.2-6 alkyl substituted with 0-3 R.sup.4e, C.sub.3-8 alkenyl
substituted with 0-3 R.sup.4e, C.sub.3-8 alkynyl substituted with
0-3 R.sup.4e, and a C.sub.3-10 carbocyclic residue substituted with
0-3 R.sup.4e; [0134] R.sup.4e, at each occurrence, is selected from
C.sub.1-6 alkyl, C.sub.2-8 alkenyl, C.sub.2-8 alkynyl,
(CH.sub.2).sub.rC.sub.3-6 cycloalkyl, Cl, F, Br, I, CN, NO.sub.2,
(CF.sub.2).sub.rCF.sub.3, (CH.sub.2).sub.rOC.sub.1-5 alkyl, OH, SH,
(CH.sub.2).sub.rSC.sub.1-5 alkyl,
(CH.sub.2).sub.rNR.sup.4fR.sup.4f, --C(O)R.sup.4i, --C(O)OR.sup.4j,
--C(O)NR.sup.4hR.sup.4h, OC(O)NR.sup.4hR.sup.4h,
--NR.sup.4hC(O)NR.sup.4hR.sup.4h, NR.sup.4hC(O)OR.sup.4j, and
(CH.sub.2).sub.rphenyl; [0135] R.sup.4f, at each occurrence, is
selected from H, C.sub.1-6 alkyl, C.sub.3-6 cycloalkyl, and phenyl;
[0136] R.sup.4h, at each occurrence, is independently selected from
H, C.sub.1-6 alkyl, C.sub.3-8 alkenyl, C.sub.3-8 alkynyl, and a
(CH.sub.2).sub.r--C.sub.3-10 carbocyclic; [0137] R.sup.4i, at each
occurrence, is selected from H, C.sub.1-6 alkyl, C.sub.3-8 alkenyl,
C.sub.3-8 alkynyl, and a (CH.sub.2).sub.r--C.sub.3-6 carbocyclic
residue; [0138] R.sup.4j, at each occurrence, is selected from
CF.sub.3, C.sub.1-6 alkyl, C.sub.3-8 alkenyl, C.sub.3-8 alkynyl,
and a C.sub.3-10 carbocyclic residue; [0139] R.sup.5, at each
occurrence, is independently selected from H, .dbd.O, C.sub.1-6
alkyl, C.sub.2-8 alkenyl, C.sub.2-8 alkynyl, (CRR).sub.rOH,
(CRR).sub.rSH, (CRR).sub.rOR.sup.5d, (CRR).sub.rSR.sup.5d,
(CRR).sub.rNR.sup.5aR.sup.5a, (CRR).sub.rC(O)OH,
(CRR).sub.rC(O)R.sup.5b, (CRR).sub.rC(O)NR.sup.5aR.sup.5a,
(CRR).sub.rNR.sup.5aC(O)R.sup.5b,
(CRR).sub.rOC(O)NR.sup.5aR.sup.5a,
(CRR).sub.rNR.sup.5aC(O)OR.sup.5d,
(CRR).sub.rNR.sup.5aC(O)NR.sup.5aR.sup.5a,
(CRR).sub.rNR.sup.5aC(O)H, (CRR).sub.rC(O)OR.sup.5d,
(CRR).sub.rOC(O)R.sup.5b, (CRR).sub.rS(O).sub.pR.sup.5b,
(CRR).sub.rS(O).sub.2NR.sup.5aR.sup.5a,
(CRR).sub.rNR.sup.5aS(O).sub.2R.sup.5b,
(CRR).sub.rNR.sup.5aS(O).sub.2NR.sup.5aR.sup.5a, C.sub.1-6
haloalkyl, a (CRR).sub.r--C.sub.3-10 carbocyclic residue
substituted with 0-3 R.sup.5c, and a (CRR).sub.r-5-10 membered
heterocyclic system containing 1-4 heteroatoms selected from N, O,
and S, substituted with 0-2 R.sup.5c; [0140] R.sup.5a, at each
occurrence, is independently selected from H, methyl substituted
with 0-1 R.sup.5g, C.sub.2-6 alkyl substituted with 0-2 R.sup.5e,
C.sub.3-8 alkenyl substituted with 0-2 R.sup.5e, C.sub.3-8 alkynyl
substituted with 0-2 R.sup.5e, a (CH.sub.2).sub.r--C.sub.3-10
carbocyclic residue substituted with 0-5 R.sup.5e, and a
(CH.sub.2).sub.r-5-10 membered heterocyclic system containing 1-4
heteroatoms selected from N, O, and S, substituted with 0-3 R
.sup.5e; [0141] R.sup.5b, at each occurrence, is selected from
C.sub.1-6 alkyl substituted with 0-3 R.sup.5e, C.sub.3-8 alkenyl
substituted with 0-2 R.sup.5e, C.sub.3-8 alkynyl substituted with
0-2 R.sup.5e, a (CH.sub.2).sub.r--C.sub.3-6 carbocyclic residue
substituted with 0-2 R.sup.5e, and a (CH.sub.2).sub.r-5-6 membered
heterocyclic system containing 1-4 heteroatoms selected from N, O,
and S, substituted with 0-3 R.sup.5e; [0142] R.sup.5c, at each
occurrence, is selected from C.sub.1-6 alkyl, C.sub.2-8 alkenyl,
C.sub.2-8 alkynyl, (CH.sub.2).sub.rC.sub.3-6 cycloalkyl, Cl, Br, I,
F, (CF.sub.2).sub.rCF.sub.3, NO.sub.2, CN,
(CH.sub.2).sub.rNR.sup.5fR.sup.5f, (CH.sub.2).sub.rOH,
(CH.sub.2).sub.rOC.sub.1-4 alkyl, (CH.sub.2).sub.rSC.sub.1-4 alkyl,
(CH.sub.2).sub.rC(O)OH, (CH.sub.2).sub.rC(O)R.sup.5b,
(CH.sub.2).sub.rC(O)NR.sup.5fR.sup.5f,
(CH.sub.2).sub.rOC(O)NR.sup.5fR.sup.5,
(CH.sub.2).sub.rNR.sup.5fC(O)R.sup.5b,
(CH.sub.2).sub.rC(O)OC.sub.1-4 alkyl,
(CH.sub.2).sub.rNR.sup.5fC(O)OC.sub.1-4 alkyl,
(CH.sub.2).sub.rOC(O)R.sup.5b,
(CH.sub.2).sub.rC(.dbd.NR.sup.5f)NR.sup.5fR.sup.5f,
(CH.sub.2).sub.rS(O).sub.pR.sup.5b,
(CH.sub.2).sub.rNHC(.dbd.NR.sup.5f)NR.sup.5fR.sup.5f,
(CH.sub.2).sub.rS(O).sub.2NR.sup.5fR.sup.5f,
(CH.sub.2).sub.rR.sup.5fS(O).sub.2R.sup.5b, and
(CH.sub.2).sub.rphenyl substituted with 0-3 R.sup.5e; [0143]
R.sup.5d, at each occurrence, is selected from methyl, CF.sub.3,
C.sub.2-6 alkyl substituted with 0-2 R.sup.5e, C.sub.3-8 alkenyl
substituted with 0-2 R.sup.5e, C.sub.3-8 alkynyl substituted with
0-2 R.sup.5e, and a C.sub.3-10 carbocyclic residue substituted with
0-3 R.sup.5e; [0144] R.sup.5e, at each occurrence, is selected from
C.sub.1-6 alkyl, C.sub.2-8 alkenyl, C.sub.2-8 alkynyl, C.sub.3-6
cycloalkyl, Cl, F, Br, I, CN, NO.sub.2, (CF.sub.2).sub.rCF.sub.3,
(CH.sub.2).sub.rOC.sub.1-5 alkyl, OH, SH,
(CH.sub.2).sub.rSC.sub.1-5 alkyl,
(CH.sub.2).sub.rNR.sup.5fR.sup.5f, and (CH.sub.2).sub.rphenyl;
[0145] R.sup.5f, at each occurrence, is selected from H, C.sub.1-6
alkyl, and C.sub.3-6 cycloalkyl; [0146] R.sup.5g is independently
selected from --C(O)R.sup.5b, --C(O)OR.sup.5d,
--C(O)NR.sup.5fR.sup.5f, and (CH.sub.2).sub.rphenyl; [0147] R, at
each occurrence, is selected from H, C.sub.1-6 alkyl substituted
with R.sup.5e, C.sub.2-8 alkenyl, C.sub.2-8 alkynyl,
(CH.sub.2).sub.rC.sub.3-6 cycloalkyl, and (CH.sub.2).sub.rphenyl
substituted with R.sup.5e; [0148] R.sup.6, at each occurrence, is
selected from C.sub.1-8 alkyl, C.sub.2-8 alkenyl, C.sub.2-8
alkynyl, (CH.sub.2).sub.rC.sub.3-6 cycloalkyl, Cl, Br, I, F,
NO.sub.2, CN, (CR'R').sub.rNR.sup.6aR.sup.6a, (CR'R').sub.rOH,
(CR'R').sub.rO(CR'R').sub.rR.sup.6d, (CR'R').sub.rSH,
(CR'R').sub.rC(O)H, (CR'R').sub.rS(CR'R').sub.rR.sup.6d,
(CR'R').sub.rSC(O)(CR'R').sub.rR.sup.6b, (CR'R').sub.rC(O)OH,
(CR'R').sub.rC(O)(CR'R').sub.rR.sup.6b,
(CR'R').sub.rNR.sup.6aR.sup.6a, (CR'R').sub.rC(O)NR.sup.6aR.sup.6a,
(CR'R').sub.rNR.sup.6fC(O)(CR'R').sub.rR.sup.6b,
(CR'R').sub.rC(O)O(CR'R').sub.rR.sup.6d,
(CR'R').sub.rOC(O)(CR'R').sub.rR.sup.6b,
(CR'R').sub.rOC(O)NR.sup.6a(CR'R').sub.rR.sup.6d,
(CR'R').sub.rNR.sup.6aC(O)NR.sup.6a(CR'R').sub.rR.sup.6d,
(CR'R').sub.rNR.sup.6aC(S)NR.sup.6a(CR'R').sub.rR.sup.6d,
(CR'R').sub.rNR.sup.6fC(O)O(CR'R').sub.rR.sup.6b,
(CR'R').sub.rC(.dbd.NR.sup.6f)NR.sup.6aR.sup.6a,
(CR'R').sub.rNHC(.dbd.NR.sup.6f)NR.sup.6fR.sup.6f,
(CR'R').sub.rS(O).sub.p(CR'R').sub.rR.sup.6b,
(CR'R').sub.rS(O).sub.2NR.sup.6aR.sup.6a,
(CR'R').sub.rNR.sup.6fS(O).sub.2NR.sup.6aR.sup.6a,
(CR'R').sub.rNR.sup.6fS(O).sub.2(CR'R').sub.rR.sup.6b, C.sub.1-6
haloalkyl, C.sub.2-8 alkenyl substituted with 0-3 R', C.sub.2-8
alkynyl substituted with 0-3 R', (CR'R').sub.rphenyl substituted
with 0-3 R.sup.6e, and a (CH.sub.2).sub.r-5-6 membered heterocyclic
system containing 1-2 heteroatoms selected from N, O, and S,
substituted with 0-2 R.sup.6e; [0149] alternatively, two R.sup.6 on
adjacent atoms on R.sup.1 may join to form a cyclic acetal; [0150]
R.sup.6a, at each occurrence, is selected from H, methyl
substituted with 0-1 R.sup.6g, C.sub.2-6 alkyl substituted with 0-2
R.sup.6e, C.sub.3-8 alkenyl substituted with 0-2 R.sup.6e,
C.sub.3-8 alkynyl substituted with 0-2 R.sup.6e, a
(CH.sub.2).sub.r--C.sub.3-10 carbocyclic residue substituted with
0-5 R.sup.6e, and a (CH.sub.2).sub.r-5-10 membered heterocyclic
system containing 1-4 heteroatoms selected from N, O, and S,
substituted with 0-2 R.sup.6e; [0151] R.sup.6b, at each occurrence,
is selected from H, C.sub.1-6 alkyl substituted with 0-2 R.sup.6e,
C.sub.3-8 alkenyl substituted with 0-2 R.sup.6e, C.sub.3-8 alkynyl
substituted with 0-2 R.sup.6e, a (CH.sub.2).sub.rC.sub.3-6
carbocyclic residue substituted with 0-3 R.sup.6e, and a
(CH.sub.2).sub.r-5-6 membered heterocyclic system containing 1-4
heteroatoms selected from N, O, and S, substituted with 0-2
R.sup.6e; [0152] R.sup.6d, at each occurrence, is selected from
C.sub.3-8 alkenyl substituted with 0-2 R.sup.6e, C.sub.3-8 alkynyl
substituted with 0-2 R.sup.6e, methyl, CF.sub.3, C.sub.2-6 alkyl
substituted with 0-3 R.sup.6e, C.sub.2-4 haloalkyl, a
(CH.sub.2).sub.r--C.sub.3-10 carbocyclic residue substituted with
0-3 R.sup.6e, and a (CH.sub.2).sub.r-5-6 membered heterocyclic
system containing 1-4 heteroatoms selected from N, O, and S,
substituted with 0-3 R.sup.6e; [0153] R.sup.6e, at each occurrence,
is selected from C.sub.1-6 alkyl, C.sub.2-8 alkenyl, C.sub.2-8
alkynyl, (CH.sub.2).sub.rC.sub.3-6 cycloalkyl, Cl, F, Br, I, CN,
NO.sub.2, (CF.sub.2).sub.rCF.sub.3, (CH.sub.2).sub.rOC.sub.1-5
alkyl, OH, SH, (CH.sub.2).sub.rSC.sub.1-5 alkyl,
(CH.sub.2).sub.rNR.sup.6fR.sup.6f, and (CH.sub.2).sub.rphenyl;
[0154] R.sup.6f, at each occurrence, is selected from H, C.sub.1-5
alkyl, and C.sub.3-6 cycloalkyl, and phenyl; [0155] R.sup.6g is
independently selected from --C(O)R.sup.6b, --C(O)OR.sup.6d,
--C(O)NR.sup.6fR.sup.6f, and (CH.sub.2).sub.rphenyl; [0156]
R.sup.7, at each occurrence, is selected from C.sub.1-8 alkyl,
C.sub.2-8 alkenyl, C.sub.2-8 alkynyl, (CH.sub.2).sub.rC.sub.3-6
cycloalkyl, Cl, Br, I, F, NO.sub.2, ON,
(CR'R').sub.rNR.sup.7aR.sup.7a, (CR'R').sub.rOH,
(CR'R').sub.rO(CR'R').sub.rR.sup.7d, (CR'R').sub.rSH,
(CR'R').sub.rC(O)H, (CR'R').sub.rS(CR'R').sub.rR.sup.7d,
(CR'R').sub.rC(O)OH, (CR'R').sub.rC(O)(CR'R').sub.rR.sup.7b,
(CR'R').sub.rC(O)NR.sup.7aR.sup.7a,
(CR'R').sub.rNR.sup.7fC(O)(CR'R').sub.rR.sup.7b,
(CR'R').sub.rC(O)O(CR'R').sub.rR.sup.7d,
(CR'R').sub.rOC(O)(CR'R').sub.rR.sup.7b,
(CR'R').sub.rOC(O)NR.sup.7a(CR'R').sub.rR.sup.7a,
(CR'R').sub.rNR.sup.7aC(O)NR.sup.7a(CR'R').sub.rR.sup.7a,
(CR'R').sub.rNR.sup.7fC(O)O(CR'R').sub.rR.sup.7d,
(CR'R').sub.rC(.dbd.NR.sup.7f)NR.sup.7aR.sup.7a,
(CR'R').sub.rNHC(.dbd.NR.sup.7f)NR.sup.7fR.sup.7f,
(CR'R').sub.rS(O).sub.p(CR'R').sub.rR.sup.7b,
(CR'R').sub.rS(O).sub.2NR.sup.7aR.sup.7a,
(CR'R').sub.rNR.sup.7aS(O).sub.2NR.sup.7aR.sup.7a,
(CR'R').sub.rNR.sup.7fS(O).sub.2(CR'R').sub.rR.sup.7b, C.sub.1-6
haloalkyl, C.sub.2-8 alkenyl substituted with 0-3 R', C.sub.2-8
alkynyl substituted with 0-3 R', and (CR'R').sub.rphenyl
substituted with 0-3 R.sup.7e; [0157] alternatively, two R.sup.7 on
adjacent atoms on R.sup.2 may join to form a cyclic acetal; [0158]
R.sup.7a, at each occurrence, is independently selected from H,
methyl substituted with 0-1 R.sup.7g, C.sub.2-6 alkyl substituted
with 0-2 R.sup.7e, C.sub.3-8 alkenyl substituted with 0-2 R.sup.7e,
C.sub.3-8 alkynyl substituted with 0-2 R.sup.7e, a
(CH.sub.2).sub.r--C.sub.3-10 carbocyclic residue substituted with
0-5 R.sup.7e, and a (CH.sub.2).sub.r-5-10 membered heterocyclic
system containing 1-4 heteroatoms selected from N, O, and S,
substituted with 0-2 R.sup.7e; [0159] R.sup.7b, at each occurrence,
is selected from C.sub.1-6 alkyl substituted with 0-2 R.sup.7e,
C.sub.3-8 alkenyl substituted with 0-2 R.sup.7e, C.sub.3-8 alkynyl
substituted with 0-2 R.sup.7e, a (CH.sub.2).sub.rC.sub.3-6
carbocyclic residue substituted with 0-3 R.sup.7e, and a
(CH.sub.2).sub.r-5-G membered heterocyclic system containing 1-4
heteroatoms selected from N, O, and S, substituted with 0-2
R.sup.7e; [0160] R.sup.7d, at each occurrence, is selected from
C.sub.3-8 alkenyl substituted with 0-2 R.sup.7e, C.sub.3-8 alkynyl
substituted with 0-2 R.sup.7e, methyl, CF.sub.3, C.sub.2-4
haloalkyl, C.sub.2-6 alkyl substituted with 0-3 R.sup.7e, a
(CH.sub.2).sub.r--C.sub.3-10 carbocyclic residue substituted with
0-3 R.sup.7e, and a (CH.sub.2).sub.r-5-6 membered heterocyclic
system containing 1-4 heteroatoms selected from N, O, and S,
substituted with 0-3 R.sup.7e; [0161] R.sup.7e, at each occurrence,
is selected from C.sub.1-6 alkyl, C.sub.2-8 alkenyl, C.sub.2-8
alkynyl, (CH.sub.2).sub.rC.sub.3-6 cycloalkyl, Cl, F, Br, I, CN,
NO.sub.2, (CF.sub.2).sub.rCF.sub.3, (CH.sub.2).sub.rOC.sub.1-5
alkyl, OH, SH, C(O)OC.sub.1-5 alkyl, (CH.sub.2).sub.rSC.sub.1-15
alkyl, (CH.sub.2).sub.rNR.sup.7fR.sup.7f, and
(CH.sub.2).sub.rphenyl; [0162] R.sup.7f, at each occurrence, is
selected from H, C.sub.1-5 alkyl, and C.sub.3-6 cycloalkyl, and
phenyl; [0163] R.sup.7g is independently selected from
--C(O)R.sup.7b, --C(O)OR.sup.7d, --C(O)NR.sup.7fR.sup.7f, and
(CH.sub.2).sub.rphenyl; [0164] R', at each occurrence, is selected
from H, C.sub.1-6 alkyl substituted with R.sup.6e, C.sub.2-8
alkenyl, C.sub.2-8 alkynyl, (CH.sub.2).sub.rC.sub.3-6 cycloalkyl,
and (CH.sub.2).sub.rphenyl substituted with R.sup.6e; [0165]
R.sup.8 is selected from H, C.sub.1-4 alkyl, and C.sub.3-4
cycloalkyl; [0166] R.sup.9 is selected from H, C.sub.1-4 alkyl,
C.sub.3-4 cycloalkyl, --C(O)H, and --C(O)--C.sub.1-4alkyl; [0167]
R.sup.10 is independently selected from H, and C.sub.1-4alkyl
substituted with 0-1 R.sup.10b; [0168] R.sup.10b, at each
occurrence, is independently selected from --OH, --SH,
NR.sup.10cR.sup.10c, --C(O)NR.sup.10cR.sup.10c, and
--NHC(O)R.sup.10c; [0169] R.sup.10c is selected from H, C.sub.1-4
alkyl and C.sub.3-6 cycloalkyl; [0170] R.sup.11 is selected from H,
C.sub.1-4 alkyl, (CHR).sub.qOH, (CHR).sub.qSH,
(CHR).sub.qOR.sup.11d, (CHR).sub.qS(O).sub.pR.sup.11d,
(CHR).sub.rC(O)R.sup.11b, (CHR).sub.rNR.sup.11aR.sup.11a,
(CHR).sub.rC(O)NR.sup.11aR.sup.11a,
(CHR).sub.rC(O)NR.sup.11aOR.sup.11d,
(CHR).sub.qR.sup.11aC(O)R.sup.11b,
(CHR).sub.qNR.sup.11aC(O)OR.sup.11d, (CHR)OC(O)NR.sup.11aR.sup.11a,
(CHR).sub.rC(O)OR.sup.11d, a (CHR).sub.r--C.sub.3-6 carbocyclic
residue substituted with 0-5 R.sup.11e, and a (CHR).sub.r-5-10
membered heterocyclic system containing 1-4 heteroatoms selected
from N, O, and S, substituted with 0-3 R.sup.11e; [0171] R.sup.11a,
at each occurrence, is independently selected from H, C.sub.1-4
alkyl, C.sub.3-4 alkenyl, C.sub.3-4 alkynyl,
(CH.sub.2).sub.rC.sub.3-6 cycloalkyl, a (CH.sub.2).sub.r--C.sub.3-6
carbocyclic residue substituted with 0-5 R.sup.11e, and a
(CH.sub.2).sub.r-5-6 membered heterocyclic system containing 1-4
heteroatoms selected from N, O, and S, substituted with 0-3
R.sup.11e; [0172] R.sup.11b, at each occurrence, is independently
selected from C.sub.1-4 alkyl, C.sub.2-4 alkenyl, C.sub.2-4
alkynyl, a (CH.sub.2).sub.r--C.sub.3-6 carbocyclic residue
substituted with 0-2 R.sup.11e, and a (CH.sub.2).sub.r-5-6 membered
heterocyclic system containing 1-4 heteroatoms selected from N, O,
and S, substituted with 0-3 R.sup.11e; [0173] R.sup.11d, at each
occurrence, is independently selected from H, methyl, --CF.sub.3,
C.sub.2-4 alkyl, C.sub.3-6 alkenyl, C.sub.3-6 alkynyl, a C.sub.3-6
carbocyclic residue substituted with 0-3 R.sup.11e, and a
(CH.sub.2).sub.r-5-6 membered heterocyclic system containing 1-4
heteroatoms selected from N, O, and S, substituted with 0-3
R.sup.11e; [0174] R.sup.11e, at each occurrence, is selected from
C.sub.1-6 alkyl, C.sub.2-9 alkenyl, C.sub.2-8 alkynyl, C.sub.3-6
cycloalkyl, Cl, F, Br, I, CN, NO.sub.2, (CF.sub.2).sub.rCF.sub.3,
(CH.sub.2).sub.rOC.sub.1-5 alkyl, OH, --O--C.sub.1-6 alkyl, SH,
(CH.sub.2).sub.rSC.sub.1-5 alkyl,
(CH.sub.2).sub.rNR.sup.11fR.sup.11f, and (CH.sub.2).sub.rphenyl;
[0175] R.sup.11f, at each occurrence, is selected from H, C.sub.1-6
alkyl, and C.sub.3-6 cycloalkyl; [0176] R.sup.12 is selected from
H, C.sub.1-4 alkyl, (CHR).sub.qOH, (CHR).sub.qSH,
(CHR).sub.qOR.sup.12d, (CHR).sub.qS(O).sub.pR.sup.12d,
(CHR).sub.rC(O)R.sup.12b, (CHR).sub.rNR.sup.12aR.sup.12a,
(CHR).sub.rC(O)NR.sup.12aR.sup.12a,
(CHR).sub.rC(O)NR.sup.12aOR.sup.12d,
(CHR).sub.qNR.sup.12aC(O)R.sup.12b,
(CHR).sub.qNR.sup.12aC(O)OR.sup.12d,
(CHR).sub.qOC(O)NR.sup.12aR.sup.12a, (CHR).sub.rC(O)O.sup.12d, a
(CHR).sub.r--C.sub.3-6 carbocyclic residue substituted with 0-5
R.sup.12e, and a (CHR).sub.r-5-10 membered heterocyclic system
containing 1-4 heteroatoms selected from N, O, and S, substituted
with 0-3 R.sup.12e; [0177] R.sup.12a, at each occurrence, is
independently selected from H, C.sub.1-4 alkyl, C.sub.3-4 alkenyl,
C.sub.3-4 alkynyl, (CH.sub.2).sub.rC.sub.3-6 cycloalkyl, a
(CH.sub.2).sub.r--C.sub.3-6 carbocyclic residue substituted with
0-5 R.sup.12e, and a (CH.sub.2).sub.r-5-6 membered heterocyclic
system containing 1-4 heteroatoms selected from N, O, and S,
substituted with 0-3 R.sup.12e; [0178] R.sup.12b, at each
occurrence, is independently selected from C.sub.1-4 alkyl,
C.sub.2-4 alkenyl, C.sub.2-4 alkynyl, a (CH.sub.2).sub.r--C.sub.3-6
carbocyclic residue substituted with 0-2 R.sup.12e, and a
(CH.sub.2).sub.r-5-6 membered heterocyclic system containing 1-4
heteroatoms selected from N, O, and S, substituted with 0-3
R.sup.12e; [0179] R.sup.12d, at each occurrence, is independently
selected from H, methyl, --CF.sub.3, C.sub.2-4 alkyl, C.sub.3-6
alkenyl, C.sub.3-6 alkynyl, a C.sub.3-6 carbocyclic residue
substituted with 0-3 R.sup.12e, and a (CH.sub.2).sub.r-5-6 membered
heterocyclic system containing 1-4 heteroatoms selected from N, O,
and S, substituted with 0-3 R.sup.12e; [0180] R.sup.12e, at each
occurrence, is selected from C.sub.1-6 alkyl, C.sub.2-8 alkenyl,
C.sub.2-8 alkynyl, C.sub.3-6 cycloalkyl, Cl, F, Br, I, CN,
NO.sub.2, (CF.sub.2).sub.rCF.sub.3, (CH.sub.2).sub.rOC.sub.1-5
alkyl, OH, --O--C.sub.1-6 alkyl, SH, (CH.sub.2).sub.rSC.sub.1-5
alkyl, (CH.sub.2).sub.rNR.sup.12fR.sup.12f, and
(CH.sub.2).sub.rphenyl; [0181] R.sup.12f, at each occurrence, is
selected from H, C.sub.1-6 alkyl, and C.sub.3-6 cycloalkyl; [0182]
R.sup.13, at each occurrence, is independently selected from H, and
C.sub.1-4alkyl substituted with 0-1 R.sup.13b, --OH, --NH.sub.2, F,
Cl, Br, I, --OR.sup.13a, --N(R.sup.13a).sub.2, and C.sub.1-4 alkyl
substituted with 0-3 R.sup.13b; [0183] R.sup.13a is selected from
H, C.sub.1-4 alkyl and C.sub.3-6 cycloalkyl; [0184] R.sup.13b, at
each occurrence, is independently selected from --OH, --SH,
NR.sup.13cR.sup.13c, --C(O)NR.sup.13cR.sup.13c, and
--NHC(O)R.sup.13c; [0185] R.sup.13c is selected from H, C.sub.1-4
alkyl and C.sub.3-6 cycloalkyl; [0186] R.sup.14, at each
occurrence, is independently selected from H and C.sub.1-4alkyl;
[0187] alternatively, two R.sup.14s, along with the carbon atom to
which they are attached, join to form a C
.sub.3-6 carbocyclic ring; [0188] R.sup.15, at each occurrence, is
independently selected from H, C.sub.1-4alkyl, OH, NH.sub.2,
--O--C.sub.1-4 alkyl, NR.sup.15aR.sup.15a, C(O)NR.sup.15aR.sup.15a,
NR.sup.15aC(O)R.sup.15b, NR.sup.15aC(O)OR.sup.15d,
OC(O)NR.sup.15aR.sup.15a, and (CHR).sub.rC(O)OR.sup.15d; [0189]
alternatively, two R.sup.15s, along with the carbon atom or atoms
to which they are attached, join to form a C.sub.3-6 carbocyclic
ring; [0190] R.sup.15a, at each occurrence, is independently
selected from H, and C.sub.1-4 alkyl; [0191] R.sup.15b, at each
occurrence, is independently selected from C.sub.1-4 alkyl,
C.sub.3-6 alkenyl, and C.sub.3-6 alkynyl; [0192] R.sup.15d, at each
occurrence, is independently selected from C.sub.1-4 alkyl,
C.sub.3-6 alkenyl, and C.sub.3-6 alkynyl; [0193] R.sup.16 is
selected from C.sub.1-4 alkyl; [0194] l is selected from 1, 2 and
3; [0195] n is selected from 0, 1, 2, and 3; [0196] m is selected
from 0 and 1; [0197] p, at each occurrence, is independently
selected from 0, 1, and 2; [0198] q, at each occurrence, is
independently selected from 1, 2, 3, and 4; [0199] r, at each
occurrence, is independently selected from 0, 1, 2, 3, and 4;
[0200] t, at each occurrence, is independently selected from 2, 3,
and 4; [0201] s is selected from 0 and 1. [3] Thus, in a another
embodiment, the present invention provides novel compounds of
formula (I) m is 0.
[0202] In another embodiment, the present invention provides novel
compounds of formula (I), wherein: [0203] ring B is selected from
##STR9## [0204] ring B being optionally substituted with 0-1
R.sup.5; and R.sup.11 and R.sup.12 are H.
[0205] In another embodiment, the present invention provides novel
compounds of formula (I), wherein: [0206] R.sup.5, at each
occurrence, is independently selected from H, C.sub.1-6 alkyl,
C.sub.2-8 alkenyl, C.sub.2-8 alkynyl, (CRR).sub.rOH, (CRR).sub.rSH,
(CRR).sub.rOR.sup.5d, (CRR).sub.rSR.sup.5d,
(CRR).sub.rNR.sup.5aR.sup.5a, (CRR).sub.rC(O)OH,
(CRR).sub.rC(O)R.sup.5b, (CRR).sub.rC(O)NR.sup.5aR.sup.5a,
(CRR).sub.rNR.sup.5aC(O)R.sup.5b,
(CRR).sub.rNR.sup.5aC(O)OR.sup.5d,
(CRR).sub.rOC(O)NR.sup.5aR.sup.5a,
(CHR).sub.rNR.sup.5aC(O)NR.sup.5aR.sup.5a,
CRR(CRR).sub.rNR.sup.5aC(O)H, (CRR).sub.rC(O)OR.sup.5b,
(CRR).sub.rOC(O)R.sup.5b, (CRR).sub.rS(O).sub.pR.sup.5b,
(CRR).sub.rS(O).sub.2NR.sup.5aR.sup.5a,
(CRR).sub.rNR.sup.5aS(O).sub.2R.sup.5b, and C.sub.1-6 haloalkyl;
[0207] R.sup.5a, at each occurrence, is independently selected from
H, methyl, C.sub.1-6 alkyl substituted with 0-2 R.sup.5e wherein
the alkyl is selected from ethyl, propyl, i-propyl, butyl, i-butyl,
pentyl, hexyl, C.sub.3 alkenyl substituted with 0-1 R.sup.5e,
wherein the alkenyl is selected from allyl, C.sub.3 alkynyl
substituted with 0-1 R.sup.5e wherein the alkynyl is selected from
propynyl, and a (CH.sub.2).sub.r--C.sub.3-4 carbocyclic residue
substituted with 0-5 R.sup.5e, wherein the carbocyclic residue is
selected from cyclopropyl, and cyclobutyl; [0208] R.sup.5b, at each
occurrence, is selected from C.sub.1-6 alkyl substituted with 0-2
R.sup.5e, wherein the alkyl is selected from methyl, ethyl, propyl,
i-propyl, butyl, i-butyl, pentyl, and hexyl, a
(CH.sub.2).sub.r--C.sub.3-4 carbocyclic residue substituted with
0-2 R.sup.5e, wherein the carbocyclic residue is selected from
cyclopropyl, and cyclobutyl; and [0209] R.sup.5d, at each
occurrence, is selected from methyl, CF.sub.3, C.sub.2-6 alkyl
substituted with 0-2 R.sup.5e, wherein the alkyl is selected from
methyl, ethyl, propyl, i-propyl, butyl, i-butyl, pentyl, and hexyl,
C.sub.3-8 alkenyl, C.sub.3-8 alkynyl, and a C.sub.3-10 carbocyclic
residue substituted with 0-3 R.sup.5e.
[0210] In another embodiment, the present invention provides novel
compounds of formula (I), wherein: [0211] R.sup.5, at each
occurrence, is independently selected from H, C.sub.1-6 alkyl,
C.sub.2-8 alkenyl, C.sub.2-8 alkynyl, (CRR).sub.rOH, (CRR).sub.rSH,
(CRR).sub.rOR.sup.5d, (CRR).sub.rSR.sup.5d,
(CRR).sub.rNR.sup.5aR.sup.5a, (CRR).sub.rN(O)R.sup.5aR.sup.5a,
N.sub.3, (CRR).sub.rC(O)OH, (CRR).sub.rC(O)R.sup.5b,
(CRR).sub.rC(O)NR.sup.5aR.sup.5a, (CRR).sub.rNR.sup.5aC(O)R.sup.5b,
(CRR).sub.rNR.sup.5aC(O)OR.sup.5d,
(CRR).sub.rOC(O)NR.sup.5aR.sup.5a,
(CHR).sub.rNR.sup.5aC(O)NR.sup.5aR.sup.5a,
CRR(CRR).sub.rNR.sup.5aC(O)H, (CRR).sub.rC(O)OR.sup.5b,
(CRR).sub.rOC(O)R.sup.5b, (CRR).sub.rS(O).sub.pR.sup.5b,
(CRR).sub.rS(O).sub.2NR.sup.5aR.sup.5a,
(CRR).sub.rNR.sup.5aS(O).sub.2R.sup.5b, and C.sub.1-6 haloalkyl;
[0212] R.sup.5a, at each occurrence, is independently selected from
H, methyl, C.sub.1-6 alkyl substituted with 0-2 R.sup.5e wherein
the alkyl is selected from ethyl, propyl, i-propyl, butyl, i-butyl,
pentyl, hexyl, C.sub.3 alkenyl substituted with 0-1 R.sup.5e,
wherein the alkenyl is selected from allyl, C.sub.3 alkynyl
substituted with 0-1 R.sup.5e wherein the alkynyl is selected from
propynyl, and a (CH.sub.2).sub.r--C.sub.3-4 carbocyclic residue
substituted with 0-5 R.sup.5e, wherein the carbocyclic residue is
selected from cyclopropyl, and cyclobutyl; [0213] R.sup.5b, at each
occurrence, is selected from C.sub.1-6 alkyl substituted with 0-2
R.sup.5e, wherein the alkyl is selected from methyl, ethyl, propyl,
i-propyl, butyl, i-butyl, pentyl, and hexyl, a
(CH.sub.2).sub.r--C.sub.3-4 carbocyclic residue substituted with
0-2 R.sup.5e, wherein the carbocyclic residue is selected from
cyclopropyl, and cyclobutyl; and [0214] R.sup.5d, at each
occurrence, is selected from methyl, CF.sub.3, C.sub.2-6 alkyl
substituted with 0-2 R.sup.5e, wherein the alkyl is selected from
methyl, ethyl, propyl, i-propyl, butyl, i-butyl, pentyl, and hexyl,
C.sub.3-8 alkenyl, C.sub.3-8 alkynyl, and a C.sub.3-10 carbocyclic
residue substituted with 0-3 R.sup.5e.
[0215] In another embodiment, the present invention provides novel
compounds of formula (I), wherein: [0216] R.sup.4 is selected from
H, C.sub.1-6 alkyl, C.sub.3-8 alkenyl, C.sub.3-8 alkynyl,
(CRR).sub.qOH, (CRR).sub.tSH, (CRR).sub.tOR.sup.4d,
(CRR).sub.tSR.sup.4d, (CRR).sub.tNR.sup.4aR.sup.4a,
(CRR).sub.qC(O)OH, (CRR).sub.rC(O)R.sup.4b,
(CRR).sub.rC(O)NR.sup.4aR.sup.4a, (CRR).sub.tNR.sup.4aC(O)R.sup.4b,
(CRR).sub.tOC(O)NR.sup.4aR.sup.4a,
(CRR).sub.tNR.sup.4aC(O)OR.sup.4d,
(CRR).sub.tNR.sup.4aC(O)R.sup.4b, (CRR).sub.rC(O)OR.sup.4b,
(CRR).sub.tOC(O)R.sup.4b, (CRR).sub.rS(O).sub.pR.sup.4b,
(CRR).sub.rS(O).sub.2NR.sup.4aR.sup.4a,
(CRR).sub.rNR.sup.4aS(O).sub.2R.sup.4b; [0217] R, at each
occurrence, is independently selected from H, methyl, ethyl,
propyl, allyl, propynyl, (CH.sub.2).sub.rC.sub.3-6 cycloalkyl, and
(CH.sub.2).sub.rphenyl substituted with R.sup.6e; [0218] R.sup.5,
at each occurrence, is independently selected from H, methyl,
ethyl, propyl, i-propyl, butyl, i-butyl, allyl, propynyl,
(CH.sub.2).sub.rOH, (CH.sub.2).sub.rOR.sup.5d,
(CH.sub.2).sub.rNR.sup.5aR.sup.5a, (CH.sub.2).sub.rC(O)OH,
(CH.sub.2).sub.rC(O)R.sup.5b,
(CH.sub.2).sub.rC(O)NR.sup.5aR.sup.5a,
(CH.sub.2).sub.rNR.sup.5aC(O)R.sup.5b,
(CH.sub.2).sub.rOC(O)NR.sup.5aR.sup.5a,
(CH.sub.2).sub.rNR.sup.5aC(O)OR.sup.5d,
(CH.sub.2).sub.rNR.sup.5aC(O)R.sup.5b,
(CH.sub.2).sub.rC(O)OR.sup.5b, (CH.sub.2).sub.rOC(O)R.sup.5b,
(CH.sub.2).sub.rNR.sup.5aS(O).sub.2R.sup.5b, and C.sub.1-6
haloalkyl; [0219] R.sup.5a, at each occurrence, is independently
selected from H, methyl, ethyl, propyl, i-propyl, butyl, i-butyl,
pentyl, hexyl, cyclopropyl, and cyclobutyl; and [0220] r, at each
occurrence, is selected from 0, 1, and 2.
[0221] In another embodiment, the present invention provides novel
compounds of formula (I), wherein: [0222] R.sup.1 is selected from
phenyl substituted with 0-2 R.sup.6, naphthyl substituted with
0-2R.sup.6, and a 5-10 membered heteroaryl system containing 1-4
heteroatoms selected from N, O, and S, substituted with 0-3 R.sup.6
wherein the heteroaryl is selected from indolyl, benzimidazolyl,
benzofuranyl, benzothiofuranyl, benzoxazolyl, benzthiazolyl,
benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl,
benzimidazalonyl, cinnolinyl, furanyl, imidazolyl, indazolyl,
indolyl, isoquinolinyl, isothiazolyl, isoxazolyl, oxazolyl,
pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyridinyl, pyrimidinyl,
pyrrolyl, quinazolinyl, quinolinyl, thiazolyl, thienyl, and
tetrazolyl; [0223] R.sup.2 is selected from phenyl substituted with
0-2 R.sup.7, and a 5-10 membered heteroaryl system containing 1-4
heteroatoms selected from N, O, and S, substituted with 0-3 R.sup.7
wherein the heteroaryl is selected from indolyl, benzimidazolyl,
benzofuranyl, benzothiofuranyl, benzoxazolyl, benzthiazolyl,
benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl,
benzimidazalonyl, cinnolinyl, furanyl, imidazolyl, indazolyl,
indolyl, isoquinolinyl isothiazolyl, isoxazolyl, oxazolyl,
phthalazinyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl,
pyridinyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl,
thiazolyl, thienyl, and tetrazolyl; [0224] R.sup.4 is selected from
H, methyl, ethyl, propyl, i-propyl, butyl, i-butyl, allyl,
propynyl, (CRR).sub.qOH, (CRR).sub.tSH, (CRR).sub.tOR.sup.4d,
(CRR).sub.tSR.sup.4d, (CRR).sub.tNR.sup.4aR.sup.4a,
(CRR).sub.qC(O)OH, (CRR).sub.rC(O)R.sup.4b,
(CRR).sub.rC(O)NR.sup.4aR.sup.4a, (CRR).sub.tNR.sup.4aC(O)R.sup.4b,
(CRR).sub.tOC(O)NR.sup.4aR.sup.4a,
(CRR).sub.tNR.sup.4aC(O)OR.sup.4d,
(CRR).sub.tNR.sup.4aC(O)R.sup.4b, (CRR).sub.rC(O)OR.sup.4b,
(CRR).sub.tOC(O)R.sup.4b, (CRR).sub.rS(O).sub.pR.sup.4b,
(CRR).sub.rS(O).sub.2NR.sup.4aR.sup.4a,
(CRR).sub.rNR.sup.4aS(O).sub.2R.sup.4b; [0225] R.sup.4a, at each
occurrence, is independently selected from H, methyl substituted
with 0-1 R.sup.4c, C.sub.2-6 alkyl substituted with 0-3 R.sup.4e
wherein C.sub.2-6 is selected from ethyl, propyl, i-propyl, butyl,
i-butyl, t-butyl, pentyl and hexyl, and a
(CH.sub.2).sub.r--C.sub.3-6 carbocyclic residue substituted with
0-4 R.sup.4e wherein the carbocyclic residue is selected from
cyclopropyl, cyclohexyl, and phenyl; [0226] R.sup.4b is selected
from H, methyl, ethyl, propyl, i-propyl, butyl, i-butyl, t-butyl,
pentyl, and cyclopropyl; [0227] R.sup.4d is selected from methyl,
ethyl, propyl, i-propyl, butyl, i-butyl, t-butyl, pentyl, and
cyclopropyl; and [0228] R.sup.8 is selected from H, methyl, ethyl,
propyl, i-propyl, and cyclopropyl.
[0229] In another embodiment, the present invention provides novel
compounds of formula (I), wherein: [0230] R.sup.1 is selected from
phenyl substituted with 0-2 R.sup.6, naphthyl substituted with 0-2
R.sup.6, and a 5-10 membered heteroaryl system containing 1-4
heteroatoms selected from N, O, and S, substituted with 0-3 R.sup.6
wherein the heteroaryl is selected from indolyl, benzimidazolyl,
benzofuranyl, benzothiofuranyl, benzoxazolyl, benzthiazolyl,
benzo[b]thiophene, benztriazolyl, benztetrazolyl, benzisoxazolyl,
benzisothiazolyl, benzimidazalonyl, cinnolinyl, furanyl,
imidazolyl, indazolyl, indolyl, isoquinolinyl, isothiazolyl,
isoxazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl,
pyrido[2,3-d]pyrimidinyl, pyrimido[5,4-d]pyrimidinyl,
thieno[3,2-d]pyrimidinyl, pyridinyl, pyrimidinyl, pyrrolyl,
pyrrolo[2,1-f][1,2,4]triazine, quinazolinyl, quinolinyl, thiazolyl,
thienyl, and tetrazolyl; [0231] R.sup.2 is selected from phenyl
substituted with 0-2 R.sup.7, and a 5-10 membered heteroaryl system
containing 1-4 heteroatoms selected from N, O, and S, substituted
with 0-3 R.sup.7 wherein the heteroaryl is selected from indolyl,
benzimidazolyl, benzofuranyl, benzothiofuranyl, benzoxazolyl,
benzthiazolyl, benzo[b]thiophene, benztriazolyl, benztetrazolyl,
benzisoxazolyl, benzisothiazolyl, benzimidazalonyl, cinnolinyl,
furanyl, imidazolyl, indazolyl, indolyl, isoquinolinyl
isothiazolyl, isoxazolyl, oxazolyl, phthalazinyl, pyrazinyl,
pyrazolyl, pyridazinyl, pyridyl, pyrido[2,3-d]pyrimidinyl,
thieno[3,2-d]pyrimidinyl, pyridinyl, pyrimidinyl, pyrrolyl,
pyrrolo[2,1-f][1,2,4]triazine, quinazolinyl, quinolinyl, thiazolyl,
thienyl, and tetrazolyl; [0232] R.sup.4 is selected from H, methyl,
ethyl, propyl, i-propyl, butyl, i-butyl, allyl, propynyl,
(CRR).sub.qOH, (CRR).sub.tSH, (CRR).sub.tOR.sup.4d,
(CRR).sub.tSR.sup.4d, (CRR).sub.tNR.sup.4aR.sup.4a,
(CRR).sub.qC(O)OH, (CRR).sub.rC(O)R.sup.4b,
(CRR).sub.rC(O)NR.sup.4aR.sup.4a, (CRR).sub.tNR.sup.4aC(O)R.sup.4b,
(CRR).sub.tOC(O)NR.sup.4aR.sup.4a,
(CRR).sub.tNR.sup.4aC(O)OR.sup.4d,
(CRR).sub.tNR.sup.4aC(O)R.sup.4b, (CRR).sub.rC(O)OR.sup.4b,
(CRR).sub.tOC(O)R.sup.4b, (CRR).sub.rS(O).sub.pR.sup.4b,
(CRR).sub.rS(O).sub.2NR.sup.4aR.sup.4a,
(CRR).sub.rNR.sup.4aS(O).sub.2R.sup.4b; [0233] R.sup.4a, at each
occurrence, is independently selected from H, methyl substituted
with 0-1 R.sup.4c, C.sub.2-6 alkyl substituted with 0-3 R.sup.4e
wherein C.sub.2-6 is selected from ethyl, propyl, i-propyl, butyl,
i-butyl, t-butyl, pentyl and hexyl, and a
(CH.sub.2).sub.r--C.sub.3-6 carbocyclic residue substituted with
0-4 R.sup.4e wherein the carbocyclic residue is selected from
cyclopropyl, cyclohexyl, and phenyl; [0234] R.sup.4b is selected
from H, methyl, ethyl, propyl, i-propyl, butyl, i-butyl, t-butyl,
pentyl, and cyclopropyl; [0235] R.sup.4d is selected from methyl,
ethyl, propyl, i-propyl, butyl, i-butyl, t-butyl, pentyl, and
cyclopropyl; and [0236] R.sup.8 is selected from H, methyl, ethyl,
propyl, i-propyl, and cyclopropyl.
[0237] In another embodiment, the present invention provides novel
compounds of formula (I), wherein: [0238] R.sup.6, at each
occurrence, is selected from C.sub.1-8 alkyl, C.sub.2-8 alkenyl,
C.sub.2-8 alkynyl, (CRR).sub.rC.sub.3-6 cycloalkyl, Cl, Br, I, F,
NO.sub.2, CN, (CRR).sub.rNR.sup.6aR.sup.6a, (CRR).sub.rOH,
(CRR).sub.rO(CRR).sub.rR.sup.6d, (CRR).sub.rSH, (CRR).sub.rC(O)H,
(CRR).sub.rS(CRR).sub.rR.sup.6d, (CRR).sub.rC(O)OH,
(CRR).sub.rC(O)(CRR).sub.rR.sup.6b,
(CRR).sub.rC(O)NR.sup.6aR.sup.6a,
(CRR).sub.rNR.sup.6fC(O)(CRR).sub.rR.sup.6b,
(CRR).sub.rC(O)O(CRR).sub.rR.sup.6d,
(CRR).sub.rNR.sup.6aC(O)NR.sup.6aR.sup.6a,
(CRR).sub.rNR.sup.6aC(s)NR.sup.6aR.sup.6a,
(CRR).sub.rOC(O)(CRR).sub.rR.sup.6b,
(CRR).sub.rS(O).sub.p(CRR).sub.rR.sup.6b,
(CRR).sub.rS(O).sub.2NR.sup.6aR.sup.6a,
(CRR).sub.rNR.sup.6fS(O).sub.2(CRR).sub.rR.sup.6b,
(CRR).sub.rNR.sup.6fS(O).sub.2 NR.sup.6aR.sup.6a, C.sub.1-6
haloalkyl, and (CRR).sub.rphenyl substituted with 0-3 R.sup.6e, and
a (CH.sub.2).sub.r-5-6 membered heterocyclic system containing 1-2
heteroatoms selected from N, O, and S, substituted with 0-2
R.sup.6e; [0239] R.sup.6a, at each occurrence, is independently
selected from H, methyl, ethyl, propyl, i-propyl, butyl, i-butyl,
t-butyl, pentyl, hexyl, cyclopropyl and phenyl; [0240] R.sup.6b, at
each occurrence, is selected from methyl, ethyl, propyl, i-propyl,
butyl, i-butyl, t-butyl, pentyl, hexyl, cyclopropyl, and phenyl;
[0241] R.sup.6d, at each occurrence, is selected from methyl,
CF.sub.3, ethyl, propyl, i-propyl, butyl, i-butyl, t-butyl, pentyl,
hexyl, cyclopropyl, and phenyl; [0242] R.sup.6e, at each
occurrence, is selected from C.sub.1-6 alkyl, C.sub.2-8 alkenyl,
C.sub.2-8 alkynyl, (CH.sub.2).sub.rC.sub.3-6 cycloalkyl, Cl, F, Br,
I, CN, NO.sub.2, (CF.sub.2).sub.rCF.sub.3,
(CH.sub.2).sub.rOC.sub.1-5 alkyl, OH, SH,
(CH.sub.2).sub.rSC.sub.1-5 alkyl,
(CH.sub.2).sub.rNR.sup.6fR.sup.6f, and (CH.sub.2).sub.rphenyl;
[0243] R.sup.6f, at each occurrence, is selected from H, methyl,
ethyl, propyl, i-propyl, butyl, i-butyl, t-butyl, pentyl, hexyl,
cyclopropyl, and phenyl; [0244] R.sup.7 is selected from methyl,
ethyl, propyl, i-propyl, butyl, i-butyl, s-butyl, t-butyl, pentyl,
hexyl, (CRR).sub.rC.sub.3-6 cycloalkyl, Cl, Br, I, F, NO.sub.2, CN,
(CRR).sub.rNR.sup.7aR.sup.7a, (CRR).sub.rOH,
(CRR).sub.rO(CH).sub.rR.sup.7d, (CRR).sub.rSH, (CRR).sub.rC(O)H,
(CRR).sub.rS(CRR).sub.rR.sup.7d, (CRR).sub.rC(O)OCH,
(CRR).sub.rC(O)(CRR).sub.rR.sup.7b,
(CRR).sub.rC(O)NR.sup.7aR.sup.7a,
(CRR).sub.rNR.sup.7fC(O)(CRR).sub.rR.sup.7b,
(CRR).sub.rC(O)O(CRR).sub.rR.sup.7d,
(CRR).sub.rOC(O)(CRR).sub.rR.sup.7b,
(CRR).sub.rNR.sup.7aC(O)NR.sup.7aR.sup.7a,
(CRR).sub.rNR.sup.7aC(O)O(CRR).sub.rR.sup.7d,
(CRR).sub.rS(O).sub.p(CRR).sub.rR.sup.7b,
(CRR).sub.rS(O).sub.2NR.sup.7aR.sup.7a,
(CRR).sub.rNR.sup.7fS(O).sub.2(CRR).sub.rR.sup.7b, C.sub.1-6
haloalkyl, and (CRR).sub.rphenyl substituted with 0-3 R.sup.7e;
[0245] R.sup.7a, at each occurrence, is selected from H, methyl,
ethyl, propyl, i-propyl, butyl, i-butyl, t-butyl, pentyl, hexyl,
prop-2-enyl, 2-methyl-2-propenyl, cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, CH.sub.2cyclopropyl, and benzyl; [0246]
R.sup.7b, at each occurrence, is selected from methyl, ethyl,
propyl, i-propyl, butyl, i-butyl, t-butyl, pentyl, hexyl,
cyclopropyl, cyclopentyl, CH.sub.2-cyclopentyl, cyclohexyl,
CH.sub.2-cyclohexyl, CF.sub.3, pyrrolidinyl, morpholinyl,
piperizinyl substituted with 0-1 R.sup.7e, and azetidinyl; [0247]
R.sup.7d, at each occurrence, is selected from methyl, CF.sub.3,
CF.sub.2CF.sub.3, CH.sub.2F.sub.2, CH.sub.2F, ethyl, propyl,
i-propyl, butyl, i-butyl, t-butyl, pentyl, hexyl, and cyclopropyl;
[0248] R.sup.7e, at each occurrence, is selected from C.sub.1-6
alkyl, C.sub.2-8 alkenyl, C.sub.2-8 alkynyl,
(CH.sub.2).sub.rC.sub.3-6 cycloalkyl, Cl, F, Br, I, CN, NO.sub.2,
(CF.sub.2).sub.rCF.sub.3, (CH.sub.2).sub.rOC.sub.1-5 alkyl, OH, SH,
C(O)OC.sub.1-5 alkyl, (CH.sub.2).sub.rSC.sub.1-5 alkyl,
(CH.sub.2).sub.rNR.sup.7fR.sup.7f, and (CH.sub.2).sub.rphenyl;
[0249] R.sup.7f, at each occurrence, is selected from H, methyl,
ethyl, propyl, i-propyl, butyl, i-butyl, t-butyl, pentyl, hexyl,
cyclopropyl, and phenyl; and [0250] r is 0 or 1.
[0251] In another embodiment, the present invention provides novel
compounds of formula (I), wherein: [0252] R.sup.6, at each
occurrence, is selected from C.sub.1-8 alkyl, C.sub.2-8 alkenyl,
C.sub.2-8 alkynyl, (CR'R').sub.rC.sub.3-6 cycloalkyl, Cl, Br, I, F,
NO.sub.2, CN, (CR'R').sub.rNR.sup.6aR.sup.6a, (CR'R').sub.rOH,
(CR'R').sub.rO(CR'R').sub.rR.sup.6d, (CR'R').sub.rSH,
(CR'R').sub.rC(O)H, (CR'R').sub.rS(CR'R').sub.rR.sup.6d,
(CR'R').sub.rC(O)OH, (CR'R').sub.rC(O)(CR'R').sub.rR.sup.6b,
(CR'R').sub.rC(O)NR.sup.6aR.sup.6a,
(CR'R').sub.rNR.sup.6fC(O)(CR'R').sub.rR.sup.6b,
(CR'R').sub.rC(O)O(CR'R').sub.rR.sup.6d,
(CR'R').sub.rNR.sup.6aC(O)NR.sup.6aR.sup.6a,
(CR'R').sub.rNR.sup.6aC(S)NR.sup.6aR.sup.6a,
(CR'R').sub.rOC(O)(CR'R').sub.rR.sup.6b,
(CR'R').sub.rS(O).sub.p(CR'R').sub.rR.sup.6b,
(CR'R').sub.rS(O).sub.2NR.sup.6aR.sup.6a,
(CR'R').sub.rNR.sup.6fS(O).sub.2(CR'R').sub.rR.sup.6b,
(CR'R').sub.rNR.sup.6fS(O).sub.2 NR.sup.6aR.sup.6a, C.sub.1-6
haloalkyl, and (CR'R').sub.rphenyl substituted with 0-3 R.sup.6e,
and a (CH.sub.2).sub.r-5-6 membered heterocyclic system containing
1-2 heteroatoms selected from N, O, and S, substituted with 0-2
R.sup.6e; [0253] R.sup.6a, at each occurrence, is independently
selected from H, methyl, ethyl, propyl, i-propyl, butyl, i-butyl,
t-butyl, pentyl, hexyl, cyclopropyl and phenyl; [0254] R.sup.6b, at
each occurrence, is selected from methyl, ethyl, propyl, i-propyl,
butyl, i-butyl, t-butyl, pentyl, hexyl, cyclopropyl, and phenyl;
[0255] R.sup.6d, at each occurrence, is selected from methyl,
CF.sub.3, ethyl, propyl, i-propyl, butyl, i-butyl, t-butyl, pentyl,
hexyl, cyclopropyl, and phenyl; [0256] R.sup.6e, at each
occurrence, is selected from C.sub.1-6 alkyl, C.sub.2-8 alkenyl,
C.sub.2-8 alkynyl, (CH.sub.2).sub.rC.sub.3-6 cycloalkyl, Cl, F, Br,
I, CN, NO.sub.2, (CF.sub.2).sub.rCF.sub.3,
(CH.sub.2).sub.rOC.sub.1-5 alkyl, OH, SH,
(CH.sub.2).sub.rSC.sub.1-5 alkyl,
(CH.sub.2).sub.rNR.sup.6fR.sup.6f, and (CH.sub.2).sub.rphenyl;
[0257] R.sup.6f, at each occurrence, is selected from H, methyl,
ethyl, propyl, i-propyl, butyl, i-butyl, t-butyl, pentyl, hexyl,
cyclopropyl, and phenyl; [0258] R.sup.7 is selected from methyl,
ethyl, propyl, i-propyl, butyl, i-butyl, s-butyl, t-butyl, pentyl,
hexyl, (CR'R').sub.rC.sub.3-6 cycloalkyl, Cl, Br, I, F, NO.sub.2,
CN, (CR'R').sub.rNR.sup.7aR.sup.7a, (CR'R').sub.rOH,
(CR'R').sub.rO(CH).sub.rR.sup.7d, (CR'R').sub.rSH,
(CR'R').sub.rC(O)H, (CR'R').sub.rS(CR'R').sub.rR.sup.7d,
(CR'R').sub.rC(O)OH, (CR'R').sub.rC(O)(CR'R').sub.rR.sup.7b,
(CR'R').sub.rC(O)NR.sup.7aR.sup.7a,
(CR'R').sub.rNR.sup.7fC(O)(CR'R').sub.rR.sup.7b,
(CR'R').sub.rC(O)O(CR'R').sub.rR.sup.7d,
(CR'R').sub.rOC(O)(CR'R').sub.rR.sup.7b,
(CR'R').sub.rNR.sup.7aC(O)NR.sup.7aR.sup.7a,
(CR'R').sub.rNR.sup.7aC(O)O(CR'R').sub.rR.sup.7d,
(CR'R').sub.rS(O).sub.p(CR'R').sub.rR.sup.7b,
(CR'R').sub.rS(O).sub.2NR.sup.7aR.sup.7a,
(CR'R').sub.rNR.sup.7fS(O).sub.2(CR'R').sub.rR.sup.7b, C.sub.1-6
haloalkyl, adamantyl, and (CR'R').sub.rphenyl substituted with 0-3
R.sup.7e; [0259] R.sup.7a, at each occurrence, is selected from H,
methyl, ethyl, propyl, i-propyl, butyl, i-butyl, t-butyl, pentyl,
hexyl, prop-2-enyl, 2-methyl-2-propenyl, cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, CH.sub.2cyclopropyl, and benzyl; [0260]
R.sup.7b, at each occurrence, is selected from methyl, ethyl,
propyl, i-propyl, butyl, i-butyl, t-butyl, pentyl, hexyl,
cyclopropyl, cyclopentyl, CH.sub.2-cyclopentyl, cyclohexyl,
CH.sub.2-cyclohexyl, CF.sub.3, pyrrolidinyl, morpholinyl,
piperizinyl substituted with 0-1 R.sup.7e, and azetidinyl; [0261]
R.sup.7d, at each occurrence, is selected from methyl, CF.sub.3,
CF.sub.2CF.sub.3, CHF.sub.2, CH.sub.2F, ethyl, propyl, i-propyl,
butyl, i-butyl, t-butyl, pentyl, hexyl, and cyclopropyl; [0262]
R.sup.7e, at each occurrence, is selected from C.sub.1-6 alkyl,
C.sub.2-8 alkenyl, C.sub.2-8 alkynyl, (CH.sub.2).sub.rC.sub.3-6
cycloalkyl, Cl, F, Br, I, CN, NO.sub.2, (CF.sub.2).sub.rCF.sub.3,
(CH.sub.2).sub.rOC.sub.1-5 alkyl, OH, SH, C(O)OC.sub.1-5 alkyl,
(CH.sub.2).sub.rSC.sub.1-5 alkyl,
(CH.sub.2).sub.rNR.sup.7fR.sup.7f, and (CH.sub.2).sub.rphenyl;
[0263] R.sup.7f, at each occurrence, is selected from H, methyl,
ethyl, propyl, i-propyl, butyl, i-butyl, t-butyl, pentyl, hexyl,
cyclopropyl, and phenyl; and [0264] r is 0 or 1.
[0265] In another embodiment, the present invention provides novel
compounds of formula (I), wherein: [0266] R.sup.7 is selected from
methyl, ethyl, propyl, i-propyl, butyl, i-butyl, s-butyl, pentyl,
hexyl, Cl, Br, I, F, CN, NO.sub.2, NR.sup.7aR.sup.7a,
NHC(O)NHR.sup.7a, NR.sup.7aC(O)R.sup.7b, NR.sup.7aC(O)OR.sup.7d,
CF.sub.3, CF.sub.2CF.sub.3, CHF.sub.2, CH.sub.2F, OCF.sub.3,
C(O)R.sup.7b, C(O)OR.sup.7d, NR.sup.7fC(O)N.sup.7aR.sup.7a,
NHS(O).sub.2R.sup.7b, ##STR10##
[0267] In another embodiment, the present invention provides novel
compounds of formula (I), wherein: [0268] R.sup.7 is selected from
methyl, ethyl, propyl, i-propyl, butyl, i-butyl, s-butyl, pentyl,
hexyl, Cl, Br, I, F, CN, NO.sub.2, NR.sup.7aR.sup.7a,
NHC(O)NHR.sup.7a, NR.sup.7aC(O)R.sup.7b, NR.sup.7aC(O)OR.sup.7d,
CF.sub.3, CF.sub.2CF.sub.3, CHF.sub.2, CH.sub.2F, OCF.sub.3,
C(O)R.sup.7b, C(O)OR.sup.7d, NR.sup.7fC(O)NR.sup.7aR.sup.7a,
NHS(O).sub.2R.sup.7b, adamantyl, ##STR11##
[0269] In another embodiment, the present invention provides novel
compounds of formula (I), wherein: [0270] ring B is selected from
##STR12## [0271] ring B being optionally substituted with 0-1
R.sup.5; [0272] Z is selected from a bond, --NR.sup.8C(O)--,
--C(O)NH--, and --NHC(O)NH--; [0273] R.sup.1 is selected from a
C.sub.6-10 aryl group substituted with 0-3 R.sup.6 wherein the aryl
group is selected from phenyl and naphthyl, and a 5-10 membered
heteroaryl system containing 1-4 heteroatoms selected from N and O,
substituted with 0-3 R.sup.6 wherein the heteroaryl system is
selected from indolyl and pyridinyl; [0274] R.sup.2 is phenyl
substituted with 0-2 R.sup.7; [0275] R.sup.4 is selected from H,
methyl, ethyl, propyl, i-propyl, butyl, i-butyl, t-butyl, pentyl,
hexyl, and (CH.sub.2).sub.rC(O)R.sup.4b; [0276] R.sup.6 is selected
from methyl, ethyl, propyl, i-propyl, butyl, F, Cl, Br, I,
NO.sub.2, CN, O(CH.sub.2).sub.rR.sup.6d, C(O)H, C(O)R.sup.6d,
C(O)OH, SR.sup.6d, NR.sup.6aR.sup.6a, NC(O)R.sup.6b, OC(O)R.sup.6b,
S(O).sub.pR.sup.6b, (CHR').sub.rS(O).sub.2NR.sup.6aR.sup.6a, and
CF.sub.3; [0277] R.sup.6a is H, methyl, or ethyl; [0278] R.sup.6b
is H, methyl, ethyl, propyl, i-propyl or butyl; [0279] R.sup.6d is
methyl, phenyl, CF.sub.3, and (CH.sub.2)-phenyl; and [0280] r is 0
or 1.
[0281] In another embodiment, the present invention provides novel
compounds of formula (I), wherein: [0282] R.sup.1 is selected from
a C.sub.6-10 aryl group substituted with 0-3 R.sup.6 wherein the
aryl group is selected from phenyl and naphthyl, and a 5-10
membered heteroaryl system containing 1-4 heteroatoms selected from
N and O, substituted with 0-3 R.sup.6 wherein the heteroaryl system
is selected from indolyl, pyridinyl, pyrimidinyl,
pyrido[2,3-d]pyrimidinyl, thieno[3,2-d]pyrimidinyl, imidazolyl, and
pyrrolyl.
[0283] In another embodiment, the present invention provides novel
compounds of formula (I), wherein: [0284] ring B is selected from
##STR13## [0285] ring B being substituted with 0-1 R.sup.5; [0286]
R.sup.1 is selected from a C.sub.6-10 aryl group substituted with
0-3 R.sup.6 wherein the aryl group is selected from phenyl, and a
5-10 membered heteroaryl system containing 1-4 heteroatoms selected
from N and O, substituted with 0-3 R.sup.6 wherein the heteroaryl
system is selected from indolyl and pyridinyl; [0287] R.sup.4 is
selected from H, methyl, ethyl, propyl, i-propyl, butyl, i-butyl,
t-butyl, pentyl, hexyl, allyl and (CH.sub.2).sub.rC(O)R.sup.4b;
[0288] R.sup.5 is selected from H, OH, OCH.sub.3, and
NR.sup.5aR.sup.5a; [0289] R.sup.5a is selected from H, methyl,
ethyl, propyl, i-propyl, butyl, s-butyl, i-butyl, t-butyl, pentyl,
hexyl, allyl, propargyl, cyclopropyl, cyclopropylmethyl, acetyl,
methylsulfonyl, --C(O)CF.sub.3, C(.dbd.N)NH.sub.2, benzyl, and
--C(O)O-t-butyl; [0290] R.sup.6 is selected from methyl, ethyl,
propyl, i-propyl, butyl, vinyl, F, Cl, Br, I, CN,
NR.sup.6aR.sup.6a, C(O)H, C(O)OH, C(O)R.sup.6b, SR.sup.6d,
S(O).sub.pR.sup.6d, S(O).sub.2NR.sup.6aR.sup.6a, CF.sub.3, and
CH.sub.2OH; [0291] R.sup.6b is H, methyl, ethyl, propyl, i-propyl
or butyl; [0292] R.sup.6d is methyl; [0293] R.sup.7 is selected
from methyl, ethyl, propyl, i-propyl, butyl, i-butyl, s-butyl,
pentyl, hexyl, Cl, Br, I, F, CN, NO.sub.2, NR.sup.7aR.sup.7a,
NHC(O)NHR.sup.7a, NR.sup.7aC(O)R.sup.7b, NR.sup.7aC(O)OR.sup.7d,
CF.sub.3, CF.sub.2CF.sub.3, CHF.sub.2, CH.sub.2F, OCF.sub.3,
OCF.sub.2CF.sub.3, OCHF.sub.2 and OCH.sub.2F, C(O)OR.sup.7d,
C(O)R.sup.7b, NR.sup.7fC(O)NR.sup.7aR.sup.7a, NHS(O).sub.2R.sup.7b,
##STR14## [0294] R.sup.7a is selected from H, methyl, ethyl,
propyl, i-propyl, butyl, i-butyl, t-butyl, pentyl, neo-pentyl,
cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl; [0295]
R.sup.7b is selected from cyclohexyl and CF.sub.3; and [0296]
R.sup.7d is selected from methyl, ethyl, propyl, i-propyl, butyl,
i-butyl, and t-butyl.
[0297] In another embodiment, the present invention provides novel
compounds of formula (I), wherein: [0298] ring B is selected from
##STR15## [0299] ring B being substituted with 0-1 R.sup.5; [0300]
R.sup.1 is selected from a C.sub.6-10 aryl group substituted with
0-3 R.sup.6 wherein the aryl group is selected from phenyl, and a
5-10 membered heteroaryl system containing 1-4 heteroatoms selected
from N and O, substituted with 0-3 R.sup.6 wherein the heteroaryl
system is selected from indolyl and pyridinyl; [0301] R.sup.4 is
selected from H, methyl, ethyl, propyl, i-propyl, butyl, i-butyl,
t-butyl, pentyl, hexyl, allyl and (CH.sub.2).sub.rC(O)R.sup.4b;
[0302] R.sup.5 is selected from H, OH, OCH.sub.3,
N(.fwdarw.O)R.sup.5aR.sup.5a, N.sub.3, NR.sup.5aC(O)R.sup.5b,
NR.sup.5aC(O)H, NR.sup.5aC(O)OR.sup.5d,
NR.sup.5aC(O)NR.sup.5aR.sup.5a, and NR.sup.5aR.sup.5a, and a
(CH.sub.2).sub.r-5-6 membered heterocyclic system containing 1-2
heteroatoms selected from N, O, and S, substituted with 0-2
R.sup.5e, wherein the heterocyclic system is selected from
pyrrolidinyl, piperidinyl, pyrrolidin-2-one, and isothiazolidine
1,1-dioxide; [0303] R.sup.5a is selected from H, methyl substituted
with 0-1 R.sup.5g, ethyl substituted with 0-1 R.sup.5e, propyl,
i-propyl, butyl, s-butyl, i-butyl, t-butyl, pentyl, hexyl, allyl,
propargyl, cyclopropyl, cyclopropylmethyl, phenyl, benzyl,
pyridin-3-yl, thiazolyl; [0304] R.sup.6 is selected from methyl,
ethyl, propyl, i-propyl, butyl, vinyl, F, Cl, Br, I, CN,
NR.sup.6aR.sup.6a, C(O)H, C(O)OH, C(O)R.sup.6b, SR.sup.6d,
S(O).sub.pR.sup.6d, S(O).sub.2NR.sup.6aR.sup.6a, CF.sub.3, and
CH.sub.2OH; [0305] R.sup.6b is H, methyl, ethyl, propyl, i-propyl
or butyl; [0306] R.sup.6d is methyl; [0307] R.sup.7 is selected
from methyl, ethyl, propyl, i-propyl, butyl, i-butyl, s-butyl,
t-butyl, pentyl, hexyl, phenyl, adamantyl, benzyl, Cl, Br, I, F,
CN, NO.sub.2, NR.sup.7aR.sup.7a, OR.sup.7d, NHC(O)NHR.sup.7a,
NR.sup.7aC(O)R.sup.7b, NR.sup.7aC(O)OR.sup.7d, CF.sub.3,
CF.sub.2CF.sub.3, CHF.sub.2, CH.sub.2F, OCF.sub.3,
OCF.sub.2CF.sub.3, OCHF.sub.2, and OCH.sub.2F, C(O)OR.sup.7d,
C(O)R.sup.7b, NR.sup.7fC(O)NR.sup.7aR.sup.7a, NHS(O).sub.2R.sup.7b,
##STR16## [0308] R.sup.7a is selected from H, methyl, ethyl,
propyl, i-propyl, butyl, i-butyl, t-butyl, pentyl, neo-pentyl,
cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl; [0309]
R.sup.7b is selected from cyclohexyl and CF.sub.3; and [0310]
R.sup.7d is selected from methyl, ethyl, propyl, i-propyl, butyl,
i-butyl, and t-butyl.
[0311] In another embodiment, the present invention provides novel
compounds of formula (I), wherein: [0312] ring B is selected from
##STR17## [0313] ring B being substituted with 0-1 R.sup.5; [0314]
R.sup.1 is selected from a C.sub.6-10 aryl group substituted with
0-3 R.sup.6 wherein the aryl group is phenyl, and a 5-10 membered
heteroaryl system containing 1 heteroatoms selected from N and O,
substituted with 0-3 R.sup.6 wherein the heteroaryl system is
indolyl; [0315] R.sup.5 is selected from H, OH, OCH.sub.3, and
NR.sup.5aR.sup.5a; [0316] R.sup.5a is selected from H, methyl,
ethyl, propyl, i-propyl, butyl, s-butyl, i-butyl, t-butyl, pentyl,
hexyl, allyl, propargyl, cyclopropyl, cyclopropylmethyl, acetyl,
methylsulfonyl, --C(O)CF.sub.3, C(.dbd.N)NH.sub.2, benzyl, and
--C(O)O-t-butyl; [0317] R.sup.6 is selected from methyl, ethyl,
propyl, i-propyl, Cl, Br, CN, C(O)CH.sub.3, C(O)OH, OCH.sub.3,
NR.sup.6aR.sup.6a, SCH.sub.3, S(O).sub.2NR.sup.6aR.sup.6a, and
CF.sub.3; [0318] R.sup.6a is H, methyl, ethyl, propyl, i-propyl,
butyl, propargyl, cyclopropyl, allyl; [0319] R.sup.7 is selected
from Cl, Br, CN, NR.sup.7aR.sup.7a, CF.sub.3, CF.sub.2CF.sub.3,
CHF.sub.2, CH.sub.2F, OCF.sub.3, OCF.sub.2CF.sub.3, OCHF.sub.2, and
OCH.sub.2F; and [0320] R.sup.7a is selected from H, methyl, ethyl,
propyl, i-propyl, butyl, i-butyl, t-butyl, pentyl, neo-pentyl,
cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
[0321] In another embodiment, the present invention provides novel
compounds of formula (I), wherein: [0322] ring B is selected from
##STR18## [0323] ring B being substituted with 0-1 R.sup.5; [0324]
R.sup.1 is selected from a C.sub.6-10 aryl group substituted with
0-3 R.sup.6 wherein the aryl group is phenyl; [0325] R.sup.6 is
selected from methyl, ethyl, propyl, i-propyl, F, Cl, Br, CN,
SCH.sub.3, and CF.sub.3; [0326] R.sup.7 is selected from methyl,
ethyl, propyl, i-propyl, butyl, i-butyl, s-butyl, t-butyl, pentyl,
hexyl, phenyl, adamantyl, benzyl, Cl, Br, I, F, CN, NO.sub.2,
NR.sup.7aR.sup.7a, OR.sup.7d, NHC(O)NHR.sup.7a,
NR.sup.7aC(O)R.sup.7b, NR.sup.7aC(O)COR.sup.7d, CF.sub.3,
CF.sub.2CF.sub.3, CHF.sub.2, CH.sub.2F, OCF.sub.3,
OCF.sub.2CF.sub.3, OCHF.sub.2, and OCH.sub.2F, C(O)OR.sup.7d,
C(O)R.sup.7b, and NR.sup.7fC(O)NR.sup.7aR.sup.7a; [0327] R.sup.7a
is selected from H, methyl, ethyl, propyl, i-propyl, butyl,
i-butyl, t-butyl, pentyl, neo-pentyl, cyclopropyl, cyclobutyl,
cyclopentyl, and cyclohexyl.
[0328] In another embodiment, the present invention provides novel
compounds of formula (I), wherein:
E is selected from --CH.sub.2--NH--, --C(O)--NH-- and
--SO.sub.2--CH.sub.2--.
[0329] In another embodiment, the present invention provides novel
compounds of formula (I), wherein: B is ##STR19## ring B being
substituted with 0-1 R.sup.5; and [0330] R.sup.5 is selected from H
and NR.sup.5aR.sup.5a; [0331] R.sup.5a is selected from H, methyl,
ethyl, propyl, i-propyl, butyl, s-butyl, i-butyl, t-butyl, pentyl,
hexyl, propargyl, allyl, cyclopropylmethyl, cyclopropyl, and
phenyl.
[0332] In another embodiment, the present invention provides novel
compounds of formula (I), wherein: [0333] Z is selected from a
bond, NR.sup.8C(O)--, --C(O)NH--, and --NHC(O)--.
[0334] In another embodiment, the present invention provides novel
compounds of formula (I), wherein: [0335] R.sup.6 is selected from
methyl, ethyl, propyl, i-propyl, butyl, vinyl, F, Cl, Br, I, C(O)H,
C(O)R.sup.6b, SR.sup.6d, S(O).sub.pR.sup.6d, CF.sub.3, and
CH.sub.2OH; [0336] R.sup.6b is H, methyl, ethyl, propyl, i-propyl
or butyl; [0337] R.sup.6d is methyl; [0338] R.sup.7 is selected
from Cl, Br, NR.sup.7aR.sup.7a, NR.sup.7aC(O)OR.sup.7d,
NHC(O)NHR.sup.7a, OCF.sub.3, and CF.sub.3; [0339] R.sup.7a is
selected from H, methyl, ethyl, propyl, i-propyl, butyl, i-butyl,
t-butyl, pentyl, neo-pentyl, cyclopropyl, cyclobutyl, cyclopentyl,
and cyclohexyl; [0340] R.sup.7d is selected from methyl, ethyl,
propyl, i-propyl, butyl, i-butyl, and t-butyl.
[0341] In another embodiment, the present invention provides novel
compounds of formula (Ia) or (Ic), wherein: ##STR20##
[0342] In another embodiment, the present invention provides novel
compounds of formula (Ib), wherein: ##STR21##
[0343] In another embodiment, the present invention provides novel
compounds of formula (I), wherein the compound is selected from the
compounds of the examples.
[0344] In another embodiment, the present invention is directed to
a pharmaceutical composition, comprising a pharmaceutically
acceptable carrier and a therapeutically effective amount of a
compound of Formula (I).
[0345] In another embodiment, the present invention is directed to
a method for modulation of chemokine or chemokine receptor activity
comprising administering to a patient in need thereof a
therapeutically effective amount of a compound of Formula (I).
[0346] In another embodiment, the present invention is directed to
a method for modulation of CCR-2 receptor activity comprising
administering to a patient in need thereof a therapeutically
effective amount of a compound of Formula (I).
[0347] In another embodiment, the present invention is directed to
a method for modulation of MCP-1, MCP-2, MCP-3 and MCP-4, and MCP-5
activity that is mediated by the CCR2 receptor comprising
administering to a patient in need thereof a therapeutically
effective amount of a compound of Formula (I).
[0348] In another embodiment, the present invention is directed to
a method for modulation of MCP-1 activity comprising administering
to a patient in need thereof a therapeutically effective amount of
a compound of Formula (I).
[0349] In another embodiment, the present invention is directed to
a method for treating disorders, comprising administering to a
patient in need thereof a therapeutically effective amount of a
compound of Formula (I), said disorders being selected from
osteoarthritis, aneurism, fever, cardiovascular effects, Crohn's
disease, congestive heart failure, autoimmune diseases,
HIV-infection, HIV-associated dementia, psoriasis, idiopathic
pulmonary fibrosis, transplant arteriosclerosis, physically- or
chemically-induced brain trauma, inflammatory bowel disease,
alveolitis, colitis, systemic lupus erythematosus, nephrotoxic
serum nephritis, glomerularnephritis, asthma, multiple sclerosis,
artherosclerosis, rheumatoid arthritis, restinosis, organ
transplantation, and cancer.
[0350] In another embodiment, the present invention is directed to
a method for treating disorders, of Formula (I), wherein said
disorders being selected from psoriasis, idiopathic pulmonary
fibrosis, transplant arteriosclerosis, physically- or
chemically-induced brain trauma, inflammatory bowel disease,
alveolitis, colitis, systemic lupus erythematosus, nephrotoxic
serum nephritis, glomerularnephritis, asthma, multiple sclerosis,
artherosclerosis, and rheumatoid arthritis, restinosis, organ
transplantation, and cancer.
[0351] In another embodiment, the present invention is directed to
a method for treating disorders, of Formula (I), wherein said
disorders being selected from alveolitis, colitis, systemic lupus
erythematosus, nephrotoxic serum nephritis, glomerularnephritis,
asthma, multiple sclerosis, artherosclerosis, and rheumatoid
arthritis, restinosis, organ transplantation, and cancer.
[0352] In another embodiment, the present invention is directed to
a method for treating disorders, of Formula (I), wherein said
disorders being selected from asthma, multiple sclerosis,
artherosclerosis, and rheumatoid arthritis.
[0353] In another embodiment, the present invention is directed to
a method for treating disorders, of Formula (I), wherein said
disorders being selected from restinosis, organ transplantation,
and cancer.
[0354] In another embodiment, the present invention is directed to
a method for treating rheumatoid arthritis, comprising
administering to a patient in need thereof a therapeutically
effective amount of a compound of Formula (I).
[0355] In another embodiment, the present invention is directed to
a method for treating multiple sclerosis, comprising administering
to a patient in need thereof a therapeutically effective amount of
a compound of Formula (I).
[0356] In another embodiment, the present invention is directed to
a method for treating atherosclerosis, comprising administering to
a patient in need thereof a therapeutically effective amount of a
compound of Formula (I).
[0357] In another embodiment, the present invention is directed to
a method for treating asthma, comprising administering to a patient
in need thereof a therapeutically effective amount of a compound of
Formula (I).
[0358] In another embodiment, the present invention is directed to
a method for treating restinosis, comprising administering to a
patient in need thereof a therapeutically effective amount of a
compound of Formula (I).
[0359] In another embodiment, the present invention is directed to
a method for treating organ transplantation, comprising
administering to a patient in need thereof a therapeutically
effective amount of a compound of Formula (I).
[0360] In another embodiment, the present invention is directed to
a method for treating cancer, comprising administering to a patient
in need thereof a therapeutically effective amount of a compound of
Formula (I).
[0361] In another embodiment, the present invention is directed to
a method for treating inflammatory diseases, comprising
administering to a patient in need thereof a therapeutically
effective amount of a compound of Formula (I).
[0362] In another embodiment, the present invention is directed to
a method for treating inflammatory diseases which are at least
partially mediated by CCR-2, comprising administering to a patient
in need thereof a therapeutically effective amount of a compound of
Formula (I).
[0363] In another embodiment, the present invention is directed to
a method for modulation of CCR2 activity comprising administering
to a patient in need thereof a therapeutically effective amount of
a compound of Formula (I).
[0364] In another embodiment, the present invention is directed the
use of a compound of Formula (I) in the preparation of a medicament
for the treatment of osteoarthritis, aneurism, fever,
cardiovascular effects, Crohn's disease, congestive heart failure,
autoimmune diseases, HIV-infection, HIV-associated dementia,
psoriasis, idiopathic pulmonary fibrosis, transplant
arteriosclerosis, physically- or chemically-induced brain trauma,
inflammatory bowel disease, alveolitis, colitis, systemic lupus
erythematosus, nephrotoxic serum nephritis, glomerularnephritis,
asthma, multiple sclerosis, artherosclerosis, and rheumatoid
arthritis.
[0365] In another embodiment, the present invention is directed to
a compound of formula (I) for use in therapy.
[0366] In another embodiment, the present invention is directed to
a compound of formula (Ia) ##STR22##
[0367] In another embodiment, the present invention is directed to
a compound of formula (Ib) ##STR23##
[0368] In another embodiment, the present invention is directed to
a compound of formula (Ic) ##STR24##
[0369] In another embodiment, ring B is selected from ##STR25##
[0370] ring B being optionally substituted with 0-1 R.sup.5. In
another embodiment, ring B is selected from ##STR26## In another
embodiment, ring B is selected from ##STR27## ##STR28## [0371] ring
B being substituted with 0-1 R.sup.5; [0372] In another embodiment,
ring B is ##STR29## [0373] ring B being substituted with 0-1
R.sup.5; [0374] In another embodiment, E is --S(O).sub.pCH.sub.2--
[0375] In another embodiment, E is --C(O)NH--. [0376] In another
embodiment, E is --CH.sub.2NH--. [0377] In another embodiment, Z is
selected from a bond, --NR.sup.8C(O)--, --NR.sup.8C(O)NH--,
--NR.sup.8SO.sub.2--, --NR.sup.8SO.sub.2NH--, --C(O)NR.sup.8--,
--(CR.sup.15R.sup.15).sub.l--, --CR.sup.14.dbd.CR.sup.14--,
--CR.sup.15R.sup.15C(O)--, --C(O)CR.sup.15R.sup.15--,
--O--CR.sup.14R.sup.14--, --CR.sup.14R.sup.14--O--, --O--,
--NR.sup.9--, --NR.sup.9--CR.sup.14R.sup.14--,
--CR.sup.14R.sup.14--NR.sup.9--, --S(O).sub.p--,
--S(O).sub.p--CR.sup.14R.sup.14--,
--CR.sup.14R.sup.14--S(O).sub.p--, and --S(O).sub.p--NR.sup.9--.
[0378] In another embodiment, Z is selected from a bond,
--NR.sup.8C(O)--, --NR.sup.8C(O)NH--, --C(O)NR.sup.8--,
--(CR.sup.15R.sup.15).sub.l--, --CR.sup.15R.sup.15C(O)--,
--C(O)CR.sup.15R.sup.15--, O--CR.sup.14R.sup.14--,
--CR.sup.14R.sup.14--O--, --O--, --NR.sup.9--,
--NR.sup.9--CR.sup.14R.sup.14--, --CR.sup.14R.sup.14--NR.sup.9--,
--S(O).sub.p--, --S(O).sub.p--CR.sup.14R.sup.14--, and
--S(O)--NR.sup.9--. [0379] In another embodiment, Z is selected
from a bond, --NR.sup.8C(O)--, --NR.sup.8C(O)NH--, and
--C(O)NR.sup.8--. [0380] In another embodiment, Z is selected from
a bond, --NR.sup.8C(O)--, --C(O)NH--, and --NHC(O)NH--. [0381] In
another embodiment, Z is selected from --C(O)NH--. [0382] In
another embodiment, Z is selected from a bond, and --NHC(O)--;
[0383] In another embodiment, Z is a bond. [0384] In another
embodiment, R.sup.4 is selected from H, C.sub.1-6 alkyl, C.sub.3-8
alkenyl, C.sub.3-8 alkynyl, (CRR).sub.qOH, (CHR).sub.sSH,
(CRR).sub.tOR.sup.4d, (CHR).sub.tSR.sup.4d,
(CHR).sub.tNR.sup.4aR.sup.4a, (CHR).sub.qC(O)OH,
(CHR).sub.rC(O)R.sup.4b, (CHR).sub.rC(O)NR.sup.4aR.sup.4a,
(CRR).sub.tNR.sup.4aC(O)R.sup.4b,
(CRR).sub.tOC(O)NR.sup.4aR.sup.4a,
(CRR).sub.tNR.sup.4aC(O)OR.sup.4d,
(CRR).sub.tNR.sup.4aC(O)R.sup.4b, (CHR).sub.rC(O)OR.sup.4b,
(CRR).sub.tOC(O)R.sup.4b, (CHR).sub.rS(O).sub.pR.sup.4b,
(CHR).sub.rS(O).sub.2 NR.sup.4aR.sup.4a,
(CHR).sub.rNR.sup.4aS(O).sub.2R.sup.4b; and [0385] R, at each
occurrence, is independently selected from H, methyl, ethyl,
propyl, allyl, propynyl, (CH.sub.2).sub.rC.sub.3-6 cycloalkyl, and
(CH.sub.2).sub.rphenyl substituted with R.sup.6e. [0386] In another
embodiment, R.sup.4 is selected from H, methyl, ethyl, propyl,
i-propyl, butyl, i-butyl, allyl, propynyl, (CRR).sub.qOH,
(CRR).sub.tSH, (CRR).sub.tOR.sup.4d, (CRR).sub.tSR.sup.4d,
(CRR).sub.tNR.sup.4aR.sup.4a, (CRR).sub.qC(O)OH,
(CRR).sub.rC(O)R.sup.4b, (CRR).sub.rC(O)N.sup.4aR.sup.4a,
(CRR).sub.tNR.sup.4aC(O)R.sup.4b,
(CRR).sub.tOC(O)NR.sup.4aR.sup.4a,
(CRR).sub.tNR.sup.4aC(O)OR.sup.4d,
(CRR).sub.tNR.sup.4aC(O)R.sup.4b, (CRR).sub.rC(O)OR.sup.4b,
(CRR).sub.tOC(O)R.sup.4b, (CRR).sub.rS(O).sub.pR.sup.4b,
(CRR).sub.rS(O).sub.2NR.sup.4aR.sup.4a,
(CRR).sub.rNR.sup.4aS(O).sub.2R.sup.4b. [0387] R.sup.4b is selected
from H, methyl, ethyl, propyl, i-propyl, butyl, i-butyl, t-butyl,
pentyl, and cyclopropyl; and [0388] R.sup.4d is selected from
methyl, ethyl, propyl, i-propyl, butyl, i-butyl, t-butyl, pentyl,
and cyclopropyl. [0389] In another embodiment, R.sup.4 is selected
from H, methyl, ethyl, propyl, i-propyl, butyl, i-butyl, allyl,
propynyl, (CH.sub.2).sub.rC(O)R.sup.4b. [0390] In another
embodiment, R.sup.5, at each occurrence, is independently selected
from H, C.sub.1-6 alkyl, C.sub.2-8 alkenyl, C.sub.2-8 alkynyl,
(CRR).sub.rOH, (CRR).sub.rSH, (CRR).sub.rOR.sup.5d,
(CRR).sub.rSR.sup.5d, (CRR).sub.rNR.sup.5aR.sup.5a,
(CRR).sub.rN(O)R.sup.5aR.sup.5a, N.sub.3, (CRR).sub.rC(O)OH,
(CRR).sub.rC(O)R.sup.5b, (CRR).sub.rC(O)NR.sup.5aR.sup.5a,
(CRR).sub.rNR.sup.5aC(O)R.sup.5b,
(CRR).sub.rNR.sup.5aC(O)OR.sup.5d,
(CRR).sub.rOC(O)NR.sup.5aR.sup.5a,
(CHR).sub.rNR.sup.5aC(O)NR.sup.5aR.sup.5a,
(CRR).sub.rNR.sup.5aC(O)H, (CRR).sub.rC(O)OR.sup.5b,
(CRR).sub.rOC(O)R.sup.5b, (CRR).sub.rS(O).sub.pR.sup.5b,
(CRR).sub.rS(O).sub.2NR.sup.5aR.sup.5a,
(CRR).sub.rNR.sup.5aS(O).sub.2R.sup.5b, and C.sub.1-6 haloalkyl.
[0391] In another embodiment, R.sup.5 is selected from H, OH,
OCH.sub.3, N(.fwdarw.O)R.sup.5aR.sup.5a, N.sub.3,
NR.sup.5aC(O)R.sup.5b, NR.sup.5aC(O)H, NR.sup.5aC(O)OR.sup.5d,
NR.sup.5aC(O)NR.sup.5aR.sup.5a, and NR.sup.5aR.sup.5a, and a
(CH.sub.2).sub.r-5-6 membered heterocyclic system containing 1-2
heteroatoms selected from N, O, and S, substituted with 0-2
R.sup.5e, wherein the heterocyclic system is selected from
pyrrolidinyl, piperidinyl, pyrrolidin-2-one, and isothiazolidine
1,1-dioxide; [0392] R.sup.5a is selected from H, methyl substituted
with 0-1 R.sup.5g, ethyl substituted with 0-1 R.sup.5e, propyl,
i-propyl, butyl, s-butyl, i-butyl, t-butyl, pentyl, hexyl, allyl,
propargyl, cyclopropyl, cyclopropylmethyl, phenyl, benzyl,
pyridin-3-yl, thiazolyl. [0393] In another embodiment, R.sup.5 is
selected from H, N(.fwdarw.O)R.sup.5aR.sup.5a, N.sub.3,
NR.sup.5aC(O)R.sup.5b, NR.sup.5aC(O)H, NR.sup.5aC(O)OR.sup.5d,
NR.sup.5aC(O)NR.sup.5aR.sup.5a, and NR.sup.5aR.sup.5a, and a
(CH.sub.2).sub.r-5-6 membered heterocyclic system containing 1-2
heteroatoms selected from N, O, and S, substituted with 0-2
R.sup.5e, wherein the heterocyclic system is selected from
pyrrolidinyl, piperidinyl, pyrrolidin-2-one, and isothiazolidine
1,1-dioxide. [0394] In another embodiment, R.sup.5, at each
occurrence, is independently selected from H, C.sub.1-6 alkyl,
C.sub.2-8 alkenyl, C.sub.2-8 alkynyl, (CH.sub.2).sub.rOH,
(CH.sub.2).sub.rSH, (CH.sub.2).sub.rOR.sup.5d,
(CH.sub.2).sub.rSR.sup.5d, (CH.sub.2).sub.rNR.sup.5aR.sup.5a,
(CH.sub.2).sub.rN(O)R.sup.5aR.sup.5a, N.sub.3,
(CH.sub.2).sub.rC(O)OH, (CH.sub.2).sub.rC(O)R.sup.5b,
(CH.sub.2).sub.rC(O)NR.sup.5aR.sup.5a,
(CH.sub.2).sub.rNR.sup.5aC(O)R.sup.5b,
(CH.sub.2).sub.rNR.sup.5aC(O)OR.sup.5d,
(CH.sub.2).sub.rOC(O)NR.sup.5aR.sup.5a,
(CHR).sub.rNR.sup.5aC(O)NR.sup.5aR.sup.5a,
(CH.sub.2).sub.rNR.sup.5aC(O)H, (CH.sub.2).sub.rC(O)OR.sup.5b,
(CH.sub.2).sub.rOC(O)R.sup.5b, (CH.sub.2).sub.rS(O).sub.pR.sup.5b,
(CH.sub.2).sub.rS(O).sub.2NR.sup.5aR.sup.5a,
(CH.sub.2).sub.rNR.sup.5aS(O).sub.2R.sup.5b, and C.sub.1-6
haloalkyl. [0395] In another embodiment, R.sup.5, at each
occurrence, is independently selected from H, methyl, ethyl,
propyl, i-propyl, butyl, i-butyl, allyl, propynyl,
(CH.sub.2).sub.rOH, (CH.sub.2).sub.rOR.sup.5d,
(CH.sub.2).sub.rNR.sup.5aR.sup.5a, (CH.sub.2).sub.rC(O)OH,
(CH.sub.2).sub.rC(O)R.sup.5b,
(CH.sub.2).sub.rC(O)NR.sup.5aR.sup.5a,
(CH.sub.2).sub.rNR.sup.5aC(O)R.sup.5b,
(CH.sub.2).sub.rOC(O)NR.sup.5aR.sup.5a,
(CH.sub.2).sub.rNR.sup.5aC(O)OR.sup.5d,
(CH.sub.2).sub.rNR.sup.5aC(O)R.sup.5b,
(CH.sub.2).sub.rC(O)OR.sup.5b, (CH.sub.2).sub.rOC(O)R.sup.5b,
(CH.sub.2).sub.rNR.sup.5aS(O).sub.2R.sup.5b, and C.sub.1-6
haloalkyl; and [0396] R.sup.5a, at each occurrence, is
independently selected from H, methyl, ethyl, propyl, i-propyl,
butyl, i-butyl, pentyl, hexyl, cyclopropyl, and cyclobutyl. [0397]
In another embodiment, R.sup.5, at each occurrence, is
independently selected from H, OH, OR.sup.5d,
(CH.sub.2).sub.rNR.sup.5aR.sup.5a,
(CH.sub.2).sub.rNR.sup.5aC(O)R.sup.5b, and
(CH.sub.2).sub.rNR.sup.5aC(O)OR.sup.5d. [0398] In another
embodiment, R.sup.1 is selected from phenyl substituted with 0-2
R.sup.6, naphthyl substituted with 0-2 R.sup.6, and a 5-10 membered
heteroaryl system containing 1-4 heteroatoms selected from N, O,
and S, substituted with 0-3 R.sup.6 wherein the heteroaryl is
selected from indolyl, benzimidazolyl, benzofuranyl,
benzothiofuranyl, benzoxazolyl, benzthiazolyl, benztriazolyl,
benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazalonyl,
cinnolinyl, furanyl, imidazolyl, indazolyl, indolyl, isoquinolinyl
isothiazolyl, isoxazolyl, oxazolyl, pyrazinyl, pyrazolyl,
pyridazinyl, pyridyl, pyridinyl, pyrimidinyl, pyrrolyl,
quinazolinyl, quinolinyl, thiazolyl, thienyl, and tetrazolyl.
[0399] In another embodiment, R.sup.1 is selected from a C.sub.6-10
aryl group substituted with 0-3 R.sup.6 wherein the aryl group is
selected from phenyl and naphthyl, and a 5-10 membered heteroaryl
system containing 1-4 heteroatoms selected from N and O,
substituted with 0-3 R.sup.6 wherein the heteroaryl system is
selected from furanyl, indolyl, benzothiazolyl, and benzotriazolyl.
[0400] In another embodiment, R.sup.1 is selected from phenyl
substituted with 0-2 R.sup.6, naphthyl substituted with 0-2
R.sup.6, and a 5-10 membered heteroaryl system containing 1-4
heteroatoms selected from N, O, and S, substituted with 0-3 R.sup.6
wherein the heteroaryl is selected from indolyl, benzimidazolyl,
benzofuranyl, benzothiofuranyl, benzoxazolyl, benzthiazolyl,
benzo[b]thiophene, benztriazolyl, benztetrazolyl, benzisoxazolyl,
benzisothiazolyl, benzimidazalonyl, cinnolinyl, furanyl,
imidazolyl, indazolyl, indolyl, isoquinolinyl, isothiazolyl,
isoxazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl,
pyrido[2,3-d]pyrimidinyl, pyrimido[5,4-d]pyrimidinyl,
thieno[3,2-d]pyrimidinyl, pyridinyl, pyrimidinyl, pyrrolyl,
pyrrolo[2,1-f][1,2,4]triazine, quinazolinyl, quinolinyl, thiazolyl,
thienyl, and tetrazolyl. [0401] In another embodiment, R.sup.1 is
selected from a C.sub.6-10 aryl group substituted with 0-3 R.sup.6
wherein the aryl group is selected from phenyl and naphthyl, and a
5-10 membered heteroaryl system containing 1-4 heteroatoms selected
from N and O, substituted with 0-3 R.sup.6 wherein the heteroaryl
system is selected from indolyl, pyridinyl, pyrimidinyl,
pyrido[2,3-d]pyrimidinyl, thieno[3,2-d]pyrimidinyl, imidazolyl, and
pyrrolyl. [0402] In another embodiment, R.sup.1 is selected from a
C.sub.6-10 aryl group substituted with 0-3 R.sup.6 wherein the aryl
group is selected from phenyl, and a 5-10 membered heteroaryl
system containing 1-4 heteroatoms selected from N and O,
substituted with 0-3 R.sup.6 wherein the heteroaryl system is
selected from indolyl and pyridinyl. [0403] In another embodiment,
R.sup.1 is selected from a C.sub.6-10 aryl group substituted with
0-3 R.sup.6 wherein the aryl group is phenyl. [0404] In another
embodiment, R.sup.2 is selected from phenyl substituted with 0-2
R.sup.7, and a 5-10 membered heteroaryl system containing 1-4
heteroatoms selected from N, O, and S, substituted with 0-3 R.sup.7
wherein the heteroaryl is selected from benzimidazolyl,
benzofuranyl, benzothiofuranyl, benzoxazolyl, benzthiazolyl,
benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl,
benzimidazalonyl, cinnolinyl, furanyl, imidazolyl, indazolyl,
indolyl, isoquinolinyl isothiazolyl, isoxazolyl, oxazolyl,
pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyridinyl, pyrimidinyl,
pyrrolyl, quinazolinyl, quinolinyl, thiazolyl, thienyl, and
tetrazolyl. [0405] In another embodiment, R.sup.2 is selected from
phenyl substituted with 0-2 R.sup.7. [0406] In another embodiment,
R.sup.2 is selected from phenyl substituted with 0-2 R.sup.7, and a
5-10 membered heteroaryl system containing 1-4 heteroatoms selected
from N, O, and S, substituted with 0-3 R.sup.7 wherein the
heteroaryl is selected from indolyl, naphthalenyl, phthalazinyl,
cinnolinyl, quinolinyl, isoquinolinyl, indazolyl, and quinazolinyl,
benzimidazolyl, benzofuranyl, benzothiofuranyl, benzoxazolyl,
benzthiazolyl, benzisoxazolyl, and benzisothiazolyl. [0407] In
another embodiment, R.sup.2 is selected from phenyl substituted
with 0-2 R.sup.7, and a 5-10 membered heteroaryl system containing
1-4 heteroatoms selected from N, O, and S, substituted with 0-3
R.sup.7 wherein the heteroaryl is selected from indolyl,
benzimidazolyl, benzofuranyl, benzothiofuranyl, benzoxazolyl,
benzthiazolyl, benzo[b]thiophene, benztriazolyl, benztetrazolyl,
benzisoxazolyl, benzisothiazolyl, benzimidazalonyl, cinnolinyl,
furanyl, imidazolyl, indazolyl, indolyl, isoquinolinyl
isothiazolyl, isoxazolyl, oxazolyl, phthalazinyl, pyrazinyl,
pyrazolyl, pyridazinyl, pyridyl, pyrido[2,3-d]pyrimidinyl,
thieno[3,2-d]pyrimidinyl, pyridinyl, pyrimidinyl, pyrrolyl,
pyrrolo[2,1-f][1,2,4]triazine, quinazolinyl, quinolinyl, thiazolyl,
thienyl, and tetrazolyl. [0408] In another embodiment, Z is a bond
and R.sup.2 is selected from a 5-10 membered heteroaryl system
containing 1-4 heteroatoms selected from N, O, and S, substituted
with 0-3 R.sup.7 wherein the heteroaryl is selected from indolyl,
naphthalenyl, phthalazinyl, cinnolinyl, quinolinyl, isoquinolinyl,
indazolyl, and quinazolinyl, benzimidazolyl, benzofuranyl,
benzothiofuranyl, benzoxazolyl, benzthiazolyl, benzisoxazolyl, and
benzisothiazolyl. [0409] In another embodiment, R.sup.6, at each
occurrence, is selected from C.sub.1-8 alkyl, C.sub.2-8 alkenyl,
C.sub.2-8 alkynyl, (CH.sub.2).sub.rC.sub.3-6 cycloalkyl, Cl, Br, I,
F, NO.sub.2, CN, (CH.sub.2).sub.rNR.sup.6aR.sup.6a,
(CH.sub.2).sub.rOH, (CH.sub.2).sub.rO(CH.sub.2).sub.rR.sup.6d,
(CH.sub.2).sub.rSH, (CH.sub.2).sub.rC(O)H,
(CH.sub.2).sub.rS(CH.sub.2).sub.rR.sup.6d, (CH.sub.2).sub.rC(O)OH,
(CH.sub.2).sub.rC(O)(CH.sub.2).sub.rR.sup.6b,
(CH.sub.2).sub.rC(O)NR.sup.6aR.sup.6a,
(CH.sub.2).sub.rNR.sup.6fC(O)(CH.sub.2).sub.rR.sup.6b,
(CH.sub.2).sub.rC(O)O(CH.sub.2).sub.rR.sup.6d,
(CH.sub.2).sub.rOC(O)(CH.sub.2).sub.rR.sup.6b,
(CH.sub.2).sub.rS(O).sub.p(CH.sub.2).sub.rR.sup.6b,
(CH.sub.2).sub.rS(O).sub.2NR.sup.6aR.sup.6a,
(CH.sub.2).sub.rNR.sup.6fS(O).sub.2(CH.sub.2).sub.rR.sup.6b,
(CH.sub.2).sub.rNR.sup.6fS(O).sub.2 NR.sup.6aR.sup.6a, C.sub.1-6
haloalkyl, and (CH.sub.2).sub.rphenyl substituted with 0-3
R.sup.6e; [0410] R.sup.6a, at each occurrence, is independently
selected from H, methyl, ethyl, propyl, i-propyl, butyl, i-butyl,
t-butyl, pentyl, hexyl, cyclopropyl and phenyl; [0411] R.sup.6b, at
each occurrence, is selected from methyl, ethyl, propyl, i-propyl,
butyl, i-butyl, t-butyl, pentyl, hexyl, cyclopropyl, and phenyl;
[0412] R.sup.6d, at each occurrence, is selected from methyl,
CF.sub.3, ethyl, propyl, i-propyl, butyl, i-butyl, t-butyl, pentyl,
hexyl, cyclopropyl, and phenyl; [0413] R.sup.6e, at each
occurrence, is selected from C.sub.1-6 alkyl, C.sub.2-8 alkenyl,
C.sub.2-8 alkynyl, (CH.sub.2).sub.rC.sub.3-6 cycloalkyl, Cl, F, Br,
I, CN, NO.sub.2, (CF.sub.2).sub.rCF.sub.3,
(CH.sub.2).sub.rOC.sub.1-5 alkyl, OH, SH,
(CH.sub.2).sub.rSC.sub.1-5 alkyl,
(CH.sub.2).sub.rNR.sup.6fR.sup.6f, and (CH.sub.2).sub.rphenyl; and
[0414] R.sup.6f, at each occurrence, is selected from H, methyl,
ethyl, propyl, i-propyl, butyl, i-butyl, t-butyl, pentyl, hexyl,
cyclopropyl, and phenyl. [0415] In another embodiment, R.sup.6 is
selected from methyl, ethyl, propyl, i-propyl, butyl, F, Cl, Br, I,
NO.sub.2, CN, O(CH.sub.2).sub.rR.sup.6d, C(O)H, SR
.sup.6d, NR.sup.6aR.sup.6a, OC(O)R.sup.6b, S(O).sub.pR.sup.6b,
(CHR').sub.rS(O).sub.2NR.sup.6aR.sup.6a, CF.sub.3; [0416] R.sup.6a
is H, methyl, or ethyl; [0417] R.sup.6b is H or methyl; and [0418]
R.sup.6d is methyl, phenyl, CF.sub.3, and (CH.sub.2)-phenyl. [0419]
In another embodiment, R.sup.7 is selected from methyl, ethyl,
propyl, i-propyl, butyl, i-butyl, s-butyl, t-butyl, pentyl, hexyl,
(CH.sub.2).sub.rC.sub.3-6 cycloalkyl, Cl, Br, I, F, NO.sub.2, CN,
(CH.sub.2).sub.rNR.sup.7aR.sup.7a, (CH.sub.2).sub.rOH,
(CH.sub.2).sub.rO(CH).sub.rR.sup.7d, (CH.sub.2).sub.rSH,
(CH.sub.2).sub.rC(O)H, (CH.sub.2).sub.rS(CH.sub.2).sub.rR.sup.7d,
(CH.sub.2).sub.rC(O)OH,
(CH.sub.2).sub.rC(O)(CH.sub.2).sub.rR.sup.7b,
(CH.sub.2).sub.rC(O)NR.sup.7aR.sup.7a,
(CH.sub.2).sub.rNR.sup.7fC(O)(CH.sub.2).sub.rR.sup.7b,
(CH.sub.2).sub.rC(O)O(CH.sub.2).sub.rR.sup.7d,
(CH.sub.2).sub.rOC(O)(CH.sub.2).sub.rR.sup.7b,
(CH.sub.2).sub.rNR.sup.7aC(O)NR.sup.7aR.sup.7a,
(CH.sub.2).sub.rNR.sup.7aC(O)O(CH.sub.2).sub.rR.sup.7d,
(CH.sub.2).sub.rS(O).sub.p(CH.sub.2).sub.rR.sup.7b,
(CH.sub.2).sub.rS(O).sub.2NR.sup.7aR.sup.7a,
(CH.sub.2).sub.rNR.sup.7fS(O).sub.2(CH.sub.2).sub.rR.sup.7b,
C.sub.1-6 haloalkyl, and (CH.sub.2).sub.rphenyl substituted with
0-3 R.sup.7e; [0420] R.sup.7a, at each occurrence, is selected from
H, methyl, ethyl, propyl, i-propyl, butyl, i-butyl, t-butyl,
pentyl, hexyl, and cyclopropyl; [0421] R.sup.7b, at each
occurrence, is selected from methyl, ethyl, propyl, i-propyl,
butyl, i-butyl, t-butyl, pentyl, hexyl, and cyclopropyl; [0422]
R.sup.7d, at each occurrence, is selected from methyl, CF.sub.3,
ethyl, propyl, i-propyl, butyl, i-butyl, t-butyl, pentyl, hexyl,
and cyclopropyl; [0423] R.sup.7e, at each occurrence, is selected
from C.sub.1-6 alkyl, C.sub.2-8 alkenyl, C.sub.2-8 alkynyl,
(CH.sub.2).sub.rC.sub.3-6 cycloalkyl, Cl, F, Br, I, CN, NO.sub.2,
(CF.sub.2).sub.rCF.sub.3, (CH.sub.2).sub.rOC.sub.1-5 alkyl, OH, SH,
(CH.sub.2).sub.rSC.sub.1-5 alkyl,
(CH.sub.2).sub.rNR.sup.7fR.sup.7f, and (CH.sub.2).sub.rphenyl; and
[0424] R.sup.7f, at each occurrence, is selected from H, methyl,
ethyl, propyl, i-propyl, butyl, i-butyl, t-butyl, pentyl, hexyl,
cyclopropyl, and phenyl. [0425] In another embodiment, R.sup.7 is
selected from methyl, ethyl, propyl, i-propyl, butyl, i-butyl,
s-butyl, pentyl, hexyl, Cl, Br, I, F, NO.sub.2, NR.sup.7aR.sup.7a,
NHC(O)NHR.sup.7a, NR.sup.7aC(O)R.sup.7b, NR.sup.7aC(O)OR.sup.7d,
CF.sub.3, OCF.sub.3, C(O)R.sup.7b, NR.sup.7fC(O)NHR.sup.7a, and
NHS(O).sub.2R.sup.7b. [0426] In another embodiment, R.sup.7 is
selected from methyl, ethyl, propyl, i-propyl, butyl, i-butyl,
s-butyl, t-butyl, pentyl, hexyl, (CR'R').sub.rC.sub.3-6 cycloalkyl,
Cl, Br, I, F, NO.sub.2, CN, (CR'R').sub.rNR.sup.7aR.sup.7a,
(CR'R').sub.rOH, (CR'R').sub.rO(CH).sub.rR.sup.7d, (CR'R').sub.rSH,
(CR'R').sub.rC(O)H, (CR'R').sub.rS(CR'R').sub.rR.sup.7d,
(CR'R').sub.rC(O)OH, (CR'R').sub.rC(O)(CR'R').sub.rR.sup.7b,
(CR'R').sub.rC(O)NR.sup.7aR.sup.7a,
(CR'R').sub.rNR.sup.7fC(O)(CR'R').sub.rR.sup.7b,
(CR'R').sub.rC(O)O(CR'R').sub.rR.sup.7d,
(CR'R').sub.rOC(O)(CR'R').sub.rR.sup.7b,
(CR'R').sub.rNR.sup.7aC(O)NR.sup.7aR.sup.7a,
(CR'R').sub.rNR.sup.7aC(O)O(CR'R').sub.rR.sup.7d,
(CR'R').sub.rS(O).sub.p(CR'R').sub.rR.sup.7b,
(CR'R').sub.rS(O).sub.2NR.sup.7aR.sup.7a,
(CR'R').sub.rNR.sup.7fS(O).sub.2(CR'R').sub.rR.sup.7b, C.sub.1-6
haloalkyl, adamantyl, and (CR'R').sub.rphenyl substituted with 0-3
R.sup.7e. [0427] In another embodiment, R.sup.7 is selected from
methyl, ethyl, propyl, i-propyl, butyl, i-butyl, s-butyl, pentyl,
hexyl, Cl, Br, I, F, CN, NO.sub.2, NR.sup.7aR.sup.7a,
NHC(O)NHR.sup.7a, NR.sup.7aC(O)R.sup.7b, NR.sup.7aC(O)OR.sup.7d,
CF.sub.3, CF.sub.2CF.sub.3, CHF.sub.2, CH.sub.2F, OCF.sub.3,
C(O)R.sup.7b, C(O)OR.sup.7d, NR.sup.7fC(O)NR.sup.7aR.sup.7a,
NHS(O).sub.2R.sup.7b, adamantyl, ##STR30## [0428] In another
embodiment, R.sup.7 is selected from methyl, ethyl, propyl,
i-propyl, butyl, i-butyl, s-butyl, t-butyl, pentyl, hexyl, phenyl,
adamantyl, benzyl, Cl, Br, I, F, CN, NO.sub.2, NR.sup.7aR.sup.7a,
OR.sup.7d, NHC(O)NHR.sup.7a, NR.sup.7aC(O)R.sup.7b,
NR.sup.7aC(O)OR.sup.7d, CF.sub.3, CF.sub.2CF.sub.3, CHF.sub.2,
CH.sub.2F, OCF.sub.3, OCF.sub.2CF.sub.3, OCHF.sub.2, and
OCH.sub.2F, C(O)OR.sup.7d, C(O)R.sup.7b,
NR.sup.7fC(O)NR.sup.7aR.sup.7a, NHS(O).sub.2R.sup.7b, ##STR31##
[0429] R.sup.7a is selected from H, methyl, ethyl, propyl,
i-propyl, butyl, i-butyl, t-butyl, pentyl, neo-pentyl, cyclopropyl,
cyclobutyl, cyclopentyl, and cyclohexyl; [0430] R.sup.7b is
selected from cyclohexyl and CF.sub.3; and [0431] R.sup.7d is
selected from methyl, ethyl, propyl, i-propyl, butyl, i-butyl, and
t-butyl. [0432] In another embodiment, R.sup.7 is selected from
methyl, ethyl, propyl, i-propyl, butyl, i-butyl, s-butyl, t-butyl,
pentyl, hexyl, phenyl, adamantyl, benzyl, Cl, Br, I, F, CN,
NO.sub.2, NR.sup.7aR.sup.7a, OR.sup.7d, NHC(O)NHR.sup.7a,
NR.sup.7aC(O)R.sup.7b, NR.sup.7aC(O)OR.sup.7d, CF.sub.3,
CF.sub.2CF.sub.3, CHF.sub.2, CH.sub.2F, OCF.sub.3,
OCF.sub.2CF.sub.3, OCHF.sub.2, and OCH.sub.2F, C(O)OR.sup.7d,
C(O)R.sup.7b, and NR.sup.7fC(O)NR.sup.7aR.sup.7a; [0433] R.sup.7a
is selected from H, methyl, ethyl, propyl, i-propyl, butyl,
i-butyl, t-butyl, pentyl, neo-pentyl, cyclopropyl, cyclobutyl,
cyclopentyl, and cyclohexyl. [0434] In another embodiment, R.sup.7
is selected from methyl, ethyl, propyl, i-propyl, butyl, i-butyl,
s-butyl, pentyl, hexyl, Cl, Br, I, F, NO.sub.2, NR.sup.7aR.sup.7a,
NHC(O)NHR.sup.7a, NR.sup.7aC(O)R.sup.7b, NR.sup.7aC(O)OR.sup.7d,
CF.sub.3, OCF.sub.3, C(O)OR.sup.7d, C(O)R.sup.7b,
NR.sup.7fC(O)NR.sup.7aR.sup.7a, NHS(O).sub.2R.sup.7b, ##STR32##
[0435] In another embodiment, R.sup.7a is selected from H, methyl,
ethyl, propyl, i-propyl, butyl, i-butyl, t-butyl, pentyl,
neo-pentyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl;
[0436] R.sup.7b is selected from cyclohexyl and CF.sub.3; and
[0437] R.sup.7d is selected from methyl, ethyl, propyl, i-propyl,
butyl, i-butyl, and t-butyl, [0438] In another embodiment, R.sup.8
is H. [0439] In another embodiment, R.sup.11 and R.sup.12 are H.
[0440] In another embodiment, if ring B is not substituted with at
least one R.sup.5 which is to --NR.sup.5aR.sup.5a, than Z must be
--NR.sup.8C(O)-- or --NR.sup.8C(O)NH--. [0441] In another
embodiment, the present invention is directed to compounds of
formula (II) which are useful as intermediates is the preparation
of compounds of formula (I), wherein ##STR33## W is H or I. [0442]
In another embodiment, the present invention is directed to
compounds of formula (III) which are useful as intermediates in the
preparation of compounds of formula (I), wherein ##STR34## X, Z,
R.sup.2, R.sup.13, and n are as described above. [0443] In another
embodiment, the present invention is directed to process of
preparing compounds of formula (II), wherein ##STR35## W is H or I;
comprising converting a compound of formula (IV) ##STR36## [0444]
into a compound of formula (II) by use of an electrophile and base.
[0445] In another embodiment, the present invention is directed to
process of preparing a compound of formula (III), ##STR37## X, Z,
R.sup.2, R.sup.13, and n are as described above, comprising
converting a compound of formula (IV) ##STR38## [0446] into a
compound of formula (II) by use of an electrophile and base. [0447]
In another embodiment, the present invention is directed to process
of preparing compounds of formula (I), comprising converting a
compound of formula (IV) ##STR39## [0448] into a compound of
formula (II) by use of an electrophile and base ##STR40## [0449] In
another embodiment, the present invention is directed to process of
preparing compounds of formula (I), comprising converting a
compound of formula (IV) ##STR41## [0450] into a compound of
formula (II) by use of an electrophile and base, wherein the base
is Butyl lithium and the electrophile is iodine ##STR42##
[0451] In another embodiment, the present invention is directed
compound of Formula (II) ##STR43## or salt or stereoisomer thereof,
wherein W is selected from H, I, and Br; Pg, at each occurrence, is
independently selected from an amine protecting group.
[0452] In another embodiment, the present invention is directed to
a compound of formula (II), wherein
W is selected from H, I, and Br; and
[0453] Pg, at each occurrence, is independently selected from
benzyloxycarbonyl (Cbz) and tert-butyloxycarbonyl (Boc).
[0454] In another embodiment, the present invention is directed to
a process of preparing a compound of formula (Ia), ##STR44## or
salt or stereoisomer thereof: wherein [0455] E is selected from
--S(O).sub.pCHR.sup.e--, --CHR.sup.eNR.sup.e--, --C(O)--NR.sup.e--,
--NR.sup.eC(O)NR.sup.e, --SO.sub.2--NR.sup.e--, and
NR.sup.eSO.sub.2NR.sup.e--; [0456] R.sup.e is independently
selected from H and C.sub.1-3 alkyl; [0457] X is selected from O or
S; [0458] Z is selected from a bond, --NR.sup.8C(O)--,
--NR.sup.8C(S)--, --NR.sup.8C(O)NH--, --NR.sup.8C(S)NH--,
--NR.sup.8SO.sub.2--, --NR.sup.8SO.sub.2NH--, --C(O)NR.sup.8--,
--OC(O)NR.sup.8--, --NR.sup.8C(O)O--,
--(CR.sup.15R.sup.15).sub.l--, --CR.sup.14.dbd.CR.sup.14--,
--CR.sup.15R.sup.15C(O)--, --C(O)CR.sup.15R.sup.15--,
CR.sup.15R.sup.15C(.dbd.N--OR.sup.16)--, --O--CR.sup.14R.sup.14--,
--CR.sup.14R.sup.14--O--, --O--, --NR.sup.9--,
--NR.sup.9--CR.sup.14R.sup.14--, --CR.sup.14R.sup.14--NR.sup.9--,
--S(O).sub.p--, --S(O).sub.p--CR.sup.14R.sup.14--,
--CR.sup.14R.sup.14--S(O).sub.p--, and --S(O).sub.p--NR.sup.9--;
[0459] wherein neither Z nor R.sup.13 are connected to a carbon
atom labeled (b); [0460] bond (a) is a single or double bond;
[0461] alternatively, when n is equal to 2, two atoms labeled (b)
may join through a double bond; [0462] R.sup.1 is selected from a
C.sub.6-10 aryl group substituted with 0-5 R.sup.6 and a 5-10
membered heteroaryl system containing 1-4 heteroatoms selected from
N, O, and S, substituted with 0-3 R.sup.6; [0463] R.sup.2 is
selected from a C.sub.6-10 aryl group substituted with 0-5 R.sup.7
and a 5-10 membered heteroaryl system containing 1-4 heteroatoms
selected from N, O, and S, substituted with 0-3 R.sup.7; [0464]
R.sup.5, at each occurrence, is independently selected from H,
(CRR).sub.rOH, (CRR).sub.rSH, (CRR).sub.rOR.sup.5d,
(CRR).sub.rSR.sup.5d, (CRR).sub.rNR.sup.5aR.sup.5a,
(CRR).sub.rN(.fwdarw.O)R.sup.5aR.sup.5a,
(CRR).sub.rNR.sup.5aC(O)R.sup.5b,
(CRR).sub.rOC(O)NR.sup.5aR.sup.5a,
(CRR).sub.rNR.sup.5aC(O)OR.sup.5d,
(CRR).sub.rNR.sup.5aC(O)NR.sup.5aR.sup.5a,
(CRR).sub.rNR.sup.5aC(O)H, (CRR).sub.rOC(O)R.sup.5b,
(CRR).sub.rS(O).sub.pR.sup.5b,
(CRR).sub.rS(O).sub.2NR.sup.5aR.sup.5a,
(CRR).sub.rNR.sup.5aS(O).sub.2R.sup.5b,
(CRR).sub.rNR.sup.5aS(O).sub.2NR.sup.5aR.sup.5a, and a
(CRR).sub.r-5-10 membered heterocyclic system containing 1-4
heteroatoms selected from N, O, and S, substituted with 0-2
R.sup.5c; [0465] R.sup.5a, at each occurrence, is independently
selected from H, methyl substituted with 0-1 R.sup.5g, C.sub.2-6
alkyl substituted with 0-2 R.sup.5e, C.sub.3-8 alkenyl substituted
with 0-2 R.sup.5e, C.sub.3-8 alkynyl substituted with 0-2 R.sup.5e,
a (CH.sub.2).sub.r--C.sub.3-10 carbocyclic residue substituted with
0-5 R.sup.5e, and a (CH.sub.2).sub.r-5-10 membered heterocyclic
system containing 1-4 heteroatoms selected from N, O, and S,
substituted with 0-3 R.sup.5e; [0466] R.sup.5b, at each occurrence,
is selected from C.sub.1-6 alkyl substituted with 0-3 R.sup.5e,
C.sub.3-8 alkenyl substituted with 0-2 R.sup.5e, C.sub.3-8 alkynyl
substituted with 0-2 R.sup.5e, a (CH.sub.2).sub.r--C.sub.3-6
carbocyclic residue substituted with 0-2 R.sup.5e, and a
(CH.sub.2).sub.r-5-6 membered heterocyclic system containing 1-4
heteroatoms selected from N, O, and S, substituted with 0-3
R.sup.5e; [0467] R.sup.5c, at each occurrence, is selected from
C.sub.1-6 alkyl, C.sub.2-8 alkenyl, C.sub.2-8 alkynyl,
(CH.sub.2).sub.rC.sub.3-6 cycloalkyl, Cl, Br, I, F,
(CF.sub.2).sub.rCF.sub.3, NO.sub.2, CN,
(CH.sub.2).sub.rNR.sup.5fR.sup.5f, (CH.sub.2).sub.rOH,
(CH.sub.2).sub.rOC.sub.1-4 alkyl, (CH.sub.2).sub.rSC.sub.1-4 alkyl,
(CH.sub.2).sub.rC(O)OH, (CH.sub.2).sub.rC(O)R.sup.5b,
(CH.sub.2).sub.rC(O)NR.sup.5fR.sup.5f,
(CH.sub.2)rOC(O)NR.sup.5fR.sup.5f,
(CH.sub.2).sub.rNR.sup.5fC(O)R.sup.5b,
(CH.sub.2).sub.rC(O)OC.sub.1-4 alkyl,
(CH.sub.2).sub.rNR.sup.5fC(O)OC.sub.1-4 alkyl,
(CH.sub.2).sub.rOC(O)R.sup.5b,
(CH.sub.2).sub.rC(.dbd.NR.sup.5f)NR.sup.5fR.sup.5f,
(CH.sub.2).sub.rS(O).sub.pR.sup.5b,
(CH.sub.2).sub.rNHC(.dbd.NR.sup.5f)NR.sup.5fR.sup.5f,
(CH.sub.2).sub.rS(O).sub.2NR.sup.5fR.sup.5f,
(CH.sub.2).sub.rNR.sup.5fS(O).sub.2R.sup.5b, and
(CH.sub.2).sub.rphenyl substituted with 0-3 R.sup.5e; [0468]
R.sup.5d, at each occurrence, is selected from methyl, CF.sub.3,
C.sub.2-6 alkyl substituted with 0-2 R.sup.5e, C.sub.3-8 alkenyl
substituted with 0-2 R.sup.5e, C.sub.3-8 alkynyl substituted with
0-2 R.sup.5e, and a C.sub.3-10 carbocyclic residue substituted with
0-3 R.sup.5e; [0469] R.sup.e, at each occurrence, is selected from
C.sub.1-6 alkyl, C.sub.2-8 alkenyl, C.sub.2-8 alkynyl, C.sub.3-6
cycloalkyl, Cl, F, Br, I, CN, NO.sub.2, (CF.sub.2).sub.rCF.sub.3,
(CH.sub.2).sub.rOC.sub.1-5 alkyl, OH, SH,
(CH.sub.2).sub.rSC.sub.1-5 alkyl,
(CH.sub.2).sub.rNR.sup.5fR.sup.5f, and (CH.sub.2).sub.rphenyl;
[0470] R.sup.5f, at each occurrence, is selected from H, C.sub.1-6
alkyl, and C.sub.3-6 cycloalkyl; [0471] R.sup.5g is independently
selected from --C(O)R.sup.5b, --C(O)OR.sup.5d,
--C(O)NR.sup.5fR.sup.5f, --CN, and (CH.sub.2).sub.rphenyl; [0472]
R, at each occurrence, is selected from H, C.sub.1-6 alkyl
substituted with R.sup.5e, C.sub.2-8 alkenyl, C.sub.2-8 alkynyl,
(CH.sub.2).sub.rC.sub.3-6 cycloalkyl, and (CH.sub.2).sub.rphenyl
substituted with R.sup.5e; [0473] R.sup.6, at each occurrence, is
selected from C.sub.1-8 alkyl, C.sub.2-8 alkenyl, C.sub.2-8
alkynyl, (CH.sub.2).sub.rC.sub.3-6 cycloalkyl, Cl, Br, I, F,
NO.sub.2, CN, (CR'R').sub.rNR.sup.6aR.sup.6a, (CR'R').sub.rOH,
(CR'R').sub.rO(CR'R').sub.rR.sup.6d, (CR'R').sub.rSH,
(CR'R').sub.rC(O)H, (CR'R').sub.rS(CR'R').sub.rR.sup.6d,
(CR'R').sub.rSC(O)(CR'R').sub.rR.sup.6b, (CR'R').sub.rC(O)OH,
(CR'R').sub.rC(O)(CR'R').sub.rR.sup.6b,
(CR'R').sub.rNR.sup.6aR.sup.6a, (CR'R').sub.rC(O)NR.sup.6aR.sup.6a,
(CR'R').sub.rNR.sup.6fC(O)(CR'R').sub.rR.sup.6b,
(CR'R').sub.rC(O)O(CR'R').sub.rR.sup.6d,
(CR'R').sub.rOC(O)(CR'R').sub.rR.sup.6b,
(CR'R').sub.rOC(O)NR.sup.6a(CR'R').sub.rR.sup.6d,
(CR'R').sub.rNR.sup.6aC(O)NR.sup.6a(CR'R').sub.rR.sup.6d,
(CR'R').sub.rNR.sup.6aC(S)NR.sup.6a(CR'R').sub.rR.sup.6d,
(CR'R').sub.rNR.sup.6fC(O)O(CR'R').sub.rR.sup.6b,
(CR'R').sub.rC(.dbd.NR.sup.6f)NR.sup.6aR.sup.6a,
(CR'R').sub.rNHC(.dbd.NR.sup.6f)NR.sup.6fR.sup.6f,
(CR'R').sub.rS(O).sub.p(CR'R').sub.rR.sup.6b,
(CR'R').sub.rS(O).sub.2NR.sup.6aR.sup.6a,
(CR'R').sub.rNR.sup.6fS(O).sub.2NR.sup.6aR.sup.6a,
(CR'R').sub.rNR.sup.6fS(O).sub.2(CR'R').sub.rR.sup.6b, C.sub.1-6
haloalkyl, C.sub.2-8 alkenyl substituted with 0-3 R', C.sub.2-8
alkynyl substituted with 0-3 R', (CR'R').sub.rphenyl substituted
with 0-3 R.sup.6e, and a (CH.sub.2).sub.r-5-6 membered heterocyclic
system containing 1-2 heteroatoms selected from N, O, and S,
substituted with 0-2 R.sup.6e; [0474] alternatively, two R.sup.6 on
adjacent atoms on R.sup.1 may join to form a cyclic acetal; [0475]
R.sup.6a, at each occurrence, is selected from H, methyl
substituted with 0-1 R.sup.6g, C.sub.2-6 alkyl substituted with 0-2
R.sup.6e, C.sub.3-8 alkenyl substituted with 0-2 R.sup.6e,
C.sub.3-8 alkynyl substituted with 0-2 R.sup.6e, a
(CH.sub.2).sub.r--C.sub.3-10 carbocyclic residue substituted with
0-5 R.sup.6e, and a (CH.sub.2).sub.r-5-10 membered heterocyclic
system containing 1-4 heteroatoms selected from N, O, and S,
substituted with 0-2 R.sup.6e; [0476] R.sup.6b, at each occurrence,
is selected from H, C.sub.1-6 alkyl substituted with 0-2 R.sup.6e,
C.sub.3-8 alkenyl substituted with 0-2 R.sup.6e, C.sub.3-8 alkynyl
substituted with 0-2 R.sup.6e, a (CH.sub.2).sub.rC.sub.3-6
carbocyclic residue substituted with 0-3 R.sup.6e, and a
(CH.sub.2).sub.r-5-6 membered heterocyclic system containing 1-4
heteroatoms selected from N, O, and S, substituted with 0-2
R.sup.6e; [0477] R.sup.6d, at each occurrence, is selected from
C.sub.3-8 alkenyl substituted with 0-2 R.sup.6e, C.sub.3-8 alkynyl
substituted with 0-2 R.sup.6e, methyl, CF.sub.3, C.sub.2-6 alkyl
substituted with 0-3 R.sup.6e, C.sub.2-4 haloalkyl, a
(CH.sub.2).sub.r--C.sub.3-10 carbocyclic residue substituted with
0-3 R.sup.6e, and a (CH.sub.2).sub.r-5-6 membered heterocyclic
system containing 1-4 heteroatoms selected from N, O, and S,
substituted with 0-3 R.sup.6e; [0478] R.sup.6e, at each occurrence,
is selected from C.sub.1-6 alkyl, C.sub.2-8 alkenyl, C.sub.2-8
alkynyl, (CH.sub.2).sub.rC.sub.3-6 cycloalkyl, Cl, F, Br, I, CN,
NO.sub.2, (CF.sub.2).sub.rCF.sub.3, (CH.sub.2).sub.rOC.sub.1-5
alkyl, OH, SH, (CH.sub.2).sub.rSC.sub.1-5 alkyl,
(CH.sub.2).sub.rNR.sup.6fR.sup.6f, and (CH.sub.2).sub.rphenyl;
[0479] R.sup.6f, at each occurrence, is selected from H, C.sub.1-5
alkyl, and C.sub.3-6 cycloalkyl, and phenyl; [0480] R.sup.6g is
independently selected from --C(O)R.sup.6b, --C(O)OR.sup.6d,
--C(O)NR.sup.6fR.sup.6f, and (CH.sub.2).sub.rphenyl; [0481]
R.sup.7, at each occurrence, is selected from C.sub.1-18 alkyl,
C.sub.2-8 alkenyl, C.sub.2-8 alkynyl, (CH.sub.2).sub.rC.sub.3-6
cycloalkyl, Cl, Br, I, F, NO.sub.2, CN,
(CR'R').sub.rNR.sup.7aR.sup.7a, (CR'R').sub.rOH,
(CR'R').sub.rO(CR'R').sub.rR.sup.7d, (CR'R').sub.rSH,
(CR'R').sub.rC(O)H, (CR'R').sub.rS(CR'R').sub.rR.sup.7d,
(CR'R').sub.rC(O)OH, (CR'R').sub.rC(O)(CR'R').sub.rR.sup.7b,
(CR'R').sub.rC(O)NR.sup.7aR.sup.7a,
(CR'R').sub.rNR.sup.7fC(O)(CR'R').sub.rR.sup.7b,
(CR'R').sub.rC(O)O(CR'R').sub.rR.sup.7d,
(CR'R').sub.rOC(O)(CR'R').sub.rR.sup.7b,
(CR'R').sub.rOC(O)NR.sup.7a(CR'R').sub.rR.sup.7a,
(CR'R').sub.rNR.sup.7aC(O)NR.sup.7a(CR'R').sub.rR.sup.7a,
(CR'R').sub.rNR.sup.7fC(O)O(CR'R').sub.rR.sup.7d,
(CR'R').sub.rC(.dbd.NR.sup.7f)NR.sup.7aR.sup.7a,
(CR'R').sub.rNHC(.dbd.NR.sup.7f)NR.sup.7fR.sup.7f,
(CR'R').sub.rS(O).sub.p(CR'R').sub.rR.sup.7b,
(CR'R').sub.rS(O).sub.2NR.sup.7aR.sup.7a,
(CR'R').sub.rNR.sup.7aS(O).sub.2NR.sup.7aR.sup.7a,
(CR'R').sub.rNR.sup.7fS(O).sub.2(CR'R').sub.rR.sup.7b, C.sub.1-6
haloalkyl, C.sub.2-8 alkenyl substituted with 0-3 R', C.sub.2-8
alkynyl substituted with 0-3 R', (CR'R').sub.rC.sub.3-10
carbocyclic residue and (CR'R').sub.rphenyl substituted with 0-3
R.sup.7e; [0482] alternatively, two R.sup.7 on adjacent atoms on
R.sup.2 may join to form a cyclic acetal; [0483] R.sup.7a, at each
occurrence, is independently selected from H, methyl substituted
with 0-1 R.sup.7g, C.sub.2-6 alkyl substituted with 0-2 R.sup.7e,
C.sub.3-8 alkenyl substituted with 0-2 R.sup.7e, C.sub.3-8 alkynyl
substituted with 0-2 R.sup.7e, a (CH.sub.2).sub.r--C.sub.3-10
carbocyclic residue substituted with 0-5 R.sup.7e, and a
(CH.sub.2).sub.r-5-10 membered heterocyclic system containing 1-4
heteroatoms selected from N, O, and S, substituted with 0-2
R.sup.7e; [0484] R.sup.7b, at each occurrence, is selected from
C.sub.1-6 alkyl substituted with 0-2 R.sup.7e, C.sub.3-8 alkenyl
substituted with 0-2 R.sup.7e, C.sub.3-8 alkynyl substituted with
0-2 R.sup.7e, a (CH.sub.2).sub.rC.sub.3-6 carbocyclic residue
substituted with 0-3 R.sup.7e, and a (CH.sub.2).sub.r-5-6 membered
heterocyclic system containing 1-4 heteroatoms selected from N, O,
and S, substituted with 0-2 R.sup.7e; [0485] R.sup.7d, at each
occurrence, is selected from C.sub.3-8 alkenyl substituted with 0-2
R.sup.7e, C.sub.3-8 alkynyl substituted with 0-2 R.sup.7e, methyl,
CF.sub.3, C.sub.2-4 haloalkyl, C.sub.2-6 alkyl substituted with 0-3
R.sup.7e, a (CH.sub.2).sub.r--C.sub.3-10 carbocyclic residue
substituted with 0-3 R.sup.7e, and a (CH.sub.2).sub.r-5-6 membered
heterocyclic system containing 1-4 heteroatoms selected from N, O,
and S, substituted with 0-3 R.sup.7e; [0486] R.sup.7e, at each
occurrence, is selected from C.sub.1-6 alkyl, C.sub.2-8 alkenyl,
C.sub.2-8 alkynyl, (CH.sub.2).sub.rC.sub.3-6 cycloalkyl, Cl, F, Br,
I, CN, NO.sub.2, (CF.sub.2).sub.rCF.sub.3,
(CH.sub.2).sub.rOC.sub.1-5 alkyl, OH, SH, C(O)OC.sub.1-5 alkyl,
(CH.sub.2).sub.rSC.sub.1-5 alkyl,
(CH.sub.2).sub.rNR.sup.7fR.sup.7f, and (CH.sub.2).sub.rphenyl;
[0487] R.sup.7f, at each occurrence, is selected from H, C.sub.1-5
alkyl, and C.sub.3-6 cycloalkyl, and phenyl; [0488] R.sup.7g is
independently selected from --C(O)R.sup.7b, --C(O)OR.sup.7d,
--C(O)NR.sup.7fR.sup.7f, and (CH.sub.2).sub.rphenyl; [0489] R', at
each occurrence, is selected from H, C.sub.1-6 alkyl substituted
with R.sup.6e, C.sub.2-8 alkenyl, C.sub.2-8 alkynyl,
(CH.sub.2).sub.rC.sub.3-6 cycloalkyl, and (CH.sub.2).sub.rphenyl
substituted with R.sup.6e; [0490] R.sup.8 is selected from H,
C.sub.1-4 alkyl, and C.sub.3-4 cycloalkyl; [0491] R.sup.9 is
selected from H, C.sub.1-4 alkyl, C.sub.3-4 cycloalkyl, --C(O)H,
and --C(O)--C.sub.1-4alkyl; [0492] R.sup.10 is independently
selected from H, and C.sub.1-4alkyl substituted with 0-1 R.sup.10b,
alternatively, two R.sup.10 form .dbd.O; [0493] R.sup.10b, at each
occurrence, is independently selected from --OH, --SE,
--NR.sup.10cR.sup.10c, --C(O)N.sup.10cR.sup.10c, and
--NHC(O)R.sup.10c; [0494] R.sup.10c is selected from H, C.sub.1-4
alkyl and C.sub.3-6 cycloalkyl; [0495] R.sup.14, at each
occurrence, is independently selected from H and C.sub.1-4alkyl,
[0496] alternatively, two R.sup.14s, along with the carbon atom to
which they are attached, join to form a C.sub.3-6 carbocyclic ring;
[0497] R.sup.15, at each occurrence, is independently selected from
H, C.sub.1-4alkyl, OH, NH.sub.2, --O--C.sub.1-4 alkyl,
NR.sup.15aR.sup.15a, C(O)NR.sup.15aR.sup.15a,
NR.sup.15aC(O)R.sup.15b, NR.sup.15aC(O)OR.sup.15d,
OC(O)NR.sup.15aR.sup.15a, and (CHR).sub.rC(O)OR.sup.15d; [0498]
alternatively, two R.sup.15s, along with the carbon atom or atoms
to which they are attached, join to form a C.sub.3-6 carbocyclic
ring; [0499] R.sup.15a, at each occurrence, is independently
selected from H, and C.sub.1-4 alkyl; [0500] R.sup.15b, at each
occurrence, is independently selected from C.sub.1-4 alkyl,
C.sub.3-6 alkenyl, and C.sub.3-6 alkynyl; [0501] R.sup.15d, at each
occurrence, is independently selected from C.sub.1-4 alkyl,
C.sub.3-6 alkenyl, and C.sub.3-6 alkynyl; [0502] R.sup.16 is
selected from C.sub.1-4 alkyl; [0503] l is selected from 1, 2 and
3; [0504] n is selected from 0, 1, 2, and 3; [0505] p, at each
occurrence, is independently selected from 0, 1, and 2; [0506] q,
at each occurrence, is independently selected from 1, 2, 3, and 4;
[0507] r, at each occurrence, is independently selected from 0, 1,
2, 3, and 4; [0508] s is selected from 0 and 1; and [0509] t, at
each occurrence, is independently selected from 2, 3, and 4; the
steps comprising reacting a compound of Formula IV, ##STR45##
[0510] with an electrophile and base to give a compound of Formula
II; ##STR46## wherein W is selected from H, I, and Br; [0511] Pg,
at each occurrence, is independently selected from an amine
protecting group; [0512] reacting a compound of Formula II to give
the compound of Formula (Ia).
[0513] In another embodiment, the present invention is directed to
a process of preparing a compound of Formula (II), wherein
##STR47## or salt or stereoisomer thereof, comprising reacting a
compound of Formula (IV) ##STR48## with an electrophile and a base,
wherein W is selected from I and Br; Pg, at each occurrence, is
independently selected from an amine protecting group.
[0514] In another embodiment, the present invention is directed to
a process of preparing a compound of Formula (II), wherein [0515]
the electrophile is selected from iodine, bromine,
N-bromo-succimide, and N-iodosuccinimide; and [0516] the base is
selected from n-butyl lithium, lithium diisopropylamide (LDA),
sodium hydride, lithium bis(trimethylsilyl)amide, potassium
bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)-amide, and
Li--Al(O-tButyl).sub.4.
[0517] In another embodiment, the present invention is directed to
a process of preparing a compound of Formula (IIa), wherein
##STR49## comprising reduction of a compound of Formula (II) with a
reducing agent; ##STR50## wherein W is selected from I and Br, and
Pg, at each occurrence, is independently selected from an amine
protecting group.
[0518] In another embodiment, the present invention is directed to
a process of preparing a compound of Formula (IIa), wherein the
reducing agent is selected from tris-(trimethylsilyl)silane, zinc
metal, tributyltin hydride and AIBN.
[0519] The invention may be embodied in other specific forms
without departing from the spirit or essential attributes thereof.
This invention also encompasses all combinations of alternative
aspects of the invention noted herein. It is understood that any
and all embodiments of the present invention may be taken in
conjunction with any other embodiment to describe additional
embodiments of the present invention. Furthermore, any elements of
an embodiment are meant to be combined with any and all other
elements from any of the embodiments to describe additional
embodiments.
DEFINITIONS
[0520] The compounds herein described may have asymmetric centers.
Compounds of the present invention containing an asymmetrically
substituted atom may be isolated in optically active or racemic
forms. It is well known in the art how to prepare optically active
forms, such as by resolution of racemic forms or by synthesis from
optically active starting materials. 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. All chiral, diastereomeric, racemic forms and all geometric
isomeric forms of a structure are intended, unless the specific
stereochemistry or isomeric form is specifically indicated.
[0521] The processes of the present invention are contemplated to
be practiced on at least a multigram scale, kilogram scale,
multikilogram scale, or industrial scale. Multigram scale, as used
herein, is preferably the scale wherein at least one starting
material is present in 10 grams or more, more preferably at least
50 grams or more, even more preferably at least 100 grams or more.
Multikilogram scale, as used herein, is intended to mean the scale
wherein more than one kilogram of at least one starting material is
used. Industrial scale as used herein is intended to mean a scale
which is other than a laboratory scale and which is sufficient to
supply product sufficient for either clinical tests or distribution
to consumers.
[0522] Suitable ether solvents include, but are not intended to be
limited to, dimethoxymethane, tetrahydrofuran, 1,3-dioxane,
1,4-dioxane, furan, diethyl ether, ethylene glycol dimethyl ether,
ethylene glycol diethyl ether, diethylene glycol dimethyl ether,
diethylene glycol diethyl ether, triethylene glycol dimethyl ether,
or t-butyl methyl ether. Suitable hydrocarbon solvents include, but
are not intended to be limited to, benzene, cyclohexane, pentane,
hexane, toluene, cycloheptane, methylcyclohexane, heptane,
ethylbenzene, m-, o-, or p-xylene, octane, indane, nonane, or
naphthalene.
[0523] As used herein, the term "amine protecting group" (or
"N-protected") refers to any group known in the art of organic
synthesis for the protection of amine groups. As used herein, the
term "amine protecting group reagent" refers to any reagent known
in the art of organic synthesis for the protection of amine groups
which may be reacted with an amine to provide an amine protected
with an amine protecting group. The "amine protecting group" should
be compatible with other reaction conditions. Such amine protecting
groups include those listed in Greene and Wuts, "Protective Groups
in Organic Synthesis" John Wiley & Sons, New York (1991) and
"The Peptides: Analysis, Synthesis, Biology, Vol. 3, Academic
Press, New York (1981), the disclosure of which is hereby
incorporated by reference. Examples of amine protecting groups
include, but are not limited to, the following: 1) acyl types such
as formyl, trifluoroacetyl, and p-toluenesulfonyl; 2) aromatic
carbamate types such as benzyloxycarbonyl (Cbz) and substituted
benzyloxycarbonyls, 1-(p-biphenyl)-1-methylethoxycarbonyl, and
9-fluorenylmethyloxycarbonyl (Fmoc); 3) aliphatic carbamate types
such as tert-butyloxycarbonyl (Boc), ethoxycarbonyl,
diisopropylmethoxycarbonyl, and allyloxycarbonyl; and 4) cyclic
alkyl carbamate types such as cyclopentyloxycarbonyl and
adamantyloxycarbonyl.
[0524] Amine protecting groups may include, but are not limited to
the following:
2,7-di-t-butyl-[9-(10,10-dioxo-10,10,10,10-tetrahydrothio-xanthyl)]methyl-
oxycarbonyl; 2-trimethylsilylethyloxycarbonyl;
2-phenylethyloxycarbonyl; 1,1-dimethyl-2,2-dibromoethyloxycarbonyl;
1-methyl-1-(4-biphenylyl)ethyloxycarbonyl; benzyloxycarbonyl;
p-nitrobenzyloxycarbonyl; 2-(p-toluenesulfonyl)ethyloxycarbonyl;
m-chloro-p-acyloxybenzyloxycarbonyl;
5-benzyisoxazolylmethyloxycarbonyl; p-(dihydroxyboryl
benzyloxycarbonyl; m-nitrophenyloxycarbonyl;
o-nitrobenzyloxycarbonyl; 3,5-dimethoxybenzyloxycarbonyl;
3,4-dimethoxy-6-nitrobenzyloxycarbonyl;
N'-p-toluenesulfonylaminocarbonyl; t-amyloxycarbonyl;
p-decyloxybenzyloxycarbonyl; diisopropylmethyloxycarbonyl;
2,2-dimethoxycarbonylvinyloxycarbonyl;
di(2-pyridyl)methyloxycarbonyl; or 2-furanylmethyloxycarbonyl.
[0525] A suitable selective reducing agent is a reagent or
combination of reagents which will selectively reduce the W group
in the compound of Formula (II) to a hydrogen without altering the
character of the other substitutents. Suitable selective reducing
agents include, but are not limited to,
tris-(trimethylsilyl)silane, zinc metal, tributyltin hydride and
catalytic versions, see Gregory Fu, Org. Syn. (2002), 78, 239-248
which is hereby incorporated by reference, and AIBN
(2,2'-Azobisisobutyronitrile).
[0526] One enantiomer of a compound of Formula I may display
superior activity compared with the other. Thus, all of the
stereochemistries are considered to be a part of the present
invention. When required, separation of the racemic material can be
achieved by HPLC using a chiral column or by a resolution using a
resolving agent such as camphonic chloride as in Steven D. Young,
et al, Antimicrobial Agents and Chemotheraphy, 1995, 2602-2605.
[0527] The term "substituted," as used herein, means that any one
or more hydrogens on the designated atom or ring is replaced with a
selection from the indicated group, provided that the designated
atom's or ring atom's normal valency is not exceeded, and that the
substitution results in a stable compound. When a substituent is
keto (i.e., .dbd.O), then 2 hydrogens on the atom are replaced.
[0528] When any variable (e.g., R.sup.10) occurs more than one time
in any constituent or formula for a compound, its definition at
each occurrence is independent of its definition at every other
occurrence. Thus, for example, if a group is shown to be
substituted with 0-2 R.sup.10, then said group may optionally be
substituted with up to two R.sup.10 groups and R.sup.10 at each
occurrence is selected independently from the definition of
R.sup.10. Also, combinations of substituents and/or variables are
permissible only if such combinations result in stable
compounds.
[0529] When a bond to a substituent is shown to cross a bond
connecting two atoms in a ring, then such substituent may be bonded
to any atom on the ring. When a substituent is listed without
indicating the atom via which such substituent is bonded to the
rest of the compound of a given formula, then such substituent may
be bonded via any atom in such substituent. Combinations of
substituents and/or variables are permissible only if such
combinations result in stable compounds.
[0530] As used herein, "C.sub.1-8 alkyl" is intended to include
both branched and straight-chain saturated aliphatic hydrocarbon
groups having the specified number of carbon atoms, examples of
which include, but are not limited to, methyl, ethyl, n-propyl,
i-propyl, n-butyl, i-butyl, sec-butyl, t-butyl, pentyl, and hexyl.
C.sub.1-8 alkyl, is intended to include C.sub.1, C.sub.2, C.sub.3,
C.sub.4, CO, C.sub.6, C.sub.7, and C.sub.8 alkyl groups. "Alkenyl"
is intended to include hydrocarbon chains of either a straight or
branched configuration and one or more unsaturated carbon-carbon
bonds which may occur in any stable point along the chain, such as
ethenyl, propenyl, and the like. "Alkynyl" is intended to include
hydrocarbon chains of either a straight or branched configuration
and one or more unsaturated triple carbon-carbon bonds which may
occur in any stable point along the chain, such as ethynyl,
propynyl, and the like. "C.sub.3-6 cycloalkyl" is intended to
include saturated ring groups having the specified number of carbon
atoms in the ring, including mono-, bi-, or poly-cyclic ring
systems, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
and cycloheptyl in the case of C.sub.7 cycloalkyl. C.sub.3-6
cycloalkyl, is intended to include C.sub.3, C.sub.4, C.sub.5, and
C.sub.6 cycloalkyl groups
[0531] "Halo" or "halogen" as used herein refers to fluoro, chloro,
bromo, and iodo; and "haloalkyl" is intended to include both
branched and straight-chain saturated aliphatic hydrocarbon groups,
for example CF.sub.3, having the specified number of carbon atoms,
substituted with 1 or more halogen (for example --C.sub.vF.sub.w
where v=1 to 3 and w=1 to (2v+1)).
[0532] As used herein, the term "5-6-membered cyclic ketal", is
intended to mean 2,2-disubstituted 1,3-dioxolane or
2,2-disubstituted 1,3-dioxane and their derivatives.
[0533] As used herein, "carbocycle" or "carbocyclic residue" is
intended to mean any stable 3, 4, 5, 6, or 7-membered monocyclic or
bicyclic or 7, 8, 9, 10, 11, 12, or 13-membered bicyclic or
tricyclic, any of which may be saturated, partially unsaturated, or
aromatic. Examples of such carbocycles include, but are not limited
to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,
adamantyl, cyclooctyl; [3.3.0]bicyclooctane, [4.3.0]bicyclononane,
[4.4.0]bicyclodecane (decalin), [2.2.2]bicyclooctane, fluorenyl,
phenyl, naphthyl, indanyl, adamantyl, or tetrahydronaphthyl
(tetralin).
[0534] As used herein, the term "heterocycle" or "heterocyclic
system" is intended to mean a stable 5, 6, or 7-membered monocyclic
or bicyclic or 7, 8, 9, or 10-membered bicyclic heterocyclic ring
which is saturated, partially unsaturated or unsaturated
(aromatic), and which consists of carbon atoms and 1, 2, 3, or 4
heteroatoms independently selected from the group consisting of N,
NH, O and S and including any bicyclic group in which any of the
above-defined heterocyclic rings is fused to a benzene ring. The
nitrogen and sulfur heteroatoms may optionally be oxidized. The
heterocyclic ring may be attached to its pendant group at any
heteroatom or carbon atom which results in a stable structure. The
heterocyclic rings described herein may be substituted on carbon or
on a nitrogen atom if the resulting compound is stable. If
specifically noted, a nitrogen in the heterocycle may optionally be
quaternized. It is preferred that when the total number of S and O
atoms in the heterocycle exceeds 1, then these heteroatoms are not
adjacent to one another. As used herein, the term aromatic
heterocyclic system, or "heteroaryl" is intended to mean a stable
5- to 7-membered monocyclic or bicyclic or 7- to 10-membered
bicyclic heterocyclic aromatic ring which consists of carbon atoms
and from 1 to 4 heteroatoms independently selected from the group
consisting of N, O and S and is aromatic in nature.
[0535] Examples of heterocycles include, but are not limited to,
1H-indazole, 2-pyrrolidonyl, 2H,6H-1,5,2-dithiazinyl, 2H-pyrrolyl,
1H-indolyl, 4-piperidonyl, 4aH-carbazole, 4H-quinolizinyl,
6H-1,2,5-thiadiazinyl, acridinyl, azocinyl, benzimidazolyl,
benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl,
benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl,
benzisothiazolyl, benzimidazalonyl, carbazolyl, 4aH-carbazolyl,
.beta.-carbolinyl, chromanyl, chromenyl, cinnolinyl,
decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl,
dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl,
imidazolidinyl, imidazolinyl, imidazolyl, indazolyl, indolenyl,
indolinyl, indolizinyl, indolyl, isobenzofuranyl, isochromanyl,
isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl
(benzimidazolyl), isothiazolyl, isoxazolyl, morpholinyl,
naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl,
1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl,
1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinylperimidinyl,
phenanthridinyl, phenanthrolinyl, phenarsazinyl, phenazinyl,
phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl,
piperazinyl, piperidinyl, pteridinyl, piperidonyl, 4-piperidonyl,
pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl,
pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole,
pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl,
pyrrolidinyl, pyrrolinyl, pyrrolyl, quinazolinyl, quinolinyl,
4H-quinolizinyl, quinoxalinyl, quinuclidinyl, carbolinyl,
tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl,
6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl,
1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl,
thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl,
thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl,
1,2,5-triazolyl, 1,3,4-triazolyl, tetrazolyl, and xanthenyl. In
another aspect of the invention, the heterocycles include, but are
not limited to, pyridinyl, thiophenyl, furanyl, indazolyl,
benzothiazolyl, benzimidazolyl, benzothiaphenyl, benzofuranyl,
benzoxazolyl, benzisoxazolyl, quinolinyl, isoquinolinyl,
imidazolyl, indolyl, isoidolyl, piperidinyl, piperidonyl,
4-piperidonyl, piperonyl, pyrrazolyl, 1,2,4-triazolyl,
1,2,3-triazolyl, tetrazolyl, thiazolyl, oxazolyl, pyrazinyl, and
pyrimidinyl. Also included are fused ring and spiro compounds
containing, for example, the above heterocycles.
[0536] Examples of heteroaryls are 1H-indazole,
2H,6H-1,5,2-dithiazinyl, indolyl, 4aH-carbazole, 4H-quinolizinyl,
6H-1,2,5-thiadiazinyl, acridinyl, azocinyl, benzimidazolyl,
benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl,
benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl,
benzisothiazolyl, benzimidazalonyl, carbazolyl, 4aH-carbazolyl,
.beta.-carbolinyl, chromanyl, chromenyl, cinnolinyl,
decahydroquinolinyl, 2H, 6H-1,5,2-dithiazinyl,
dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl,
imidazolidinyl, imidazolinyl, imidazolyl, indazolyl, indolenyl,
indolinyl, indolizinyl, indolyl, isobenzofuranyl, isochromanyl,
isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl
(benzimidazolyl), isothiazolyl, isoxazolyl, morpholinyl,
naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl,
1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl,
1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinylperimidinyl,
phenanthridinyl, phenanthrolinyl, phenarsazinyl, phenazinyl,
phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl,
piperazinyl, piperidinyl, pteridinyl, piperidonyl, 4-piperidonyl,
pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl,
pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole,
pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl,
pyrrolidinyl, pyrrolinyl, pyrrolyl, quinazolinyl, quinolinyl,
4H-quinolizinyl, quinoxalinyl, quinuclidinyl, carbolinyl,
tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl,
6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl,
1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl,
thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl,
thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl,
1,2,5-triazolyl, 1,3,4-triazolyl, tetrazolyl, and xanthenyl. In
another aspect of the invention, examples of heteroaryls are
indolyl, benzimidazolyl, benzofuranyl, benzothiofuranyl,
benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl,
benzisoxazolyl, benzisothiazolyl, benzimidazalonyl, cinnolinyl,
furanyl, imidazolyl, indazolyl, indolyl, isoquinolinyl
isothiazolyl, isoxazolyl, oxazolyl, pyrazinyl, pyrazolyl,
pyridazinyl, pyridyl, pyridinyl, pyrimidinyl, pyrrolyl,
quinazolinyl, quinolinyl, thiazolyl, thienyl, and tetrazolyl.
[0537] As used herein, the term "cyclic acetal" or the phrase when
two variables "join to form a cyclic acetal" is intended to mean
the substituent --O--CH.sub.2--O--.
[0538] 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.
[0539] As used herein, "pharmaceutically acceptable salts" refer to
derivatives of the disclosed compounds wherein the parent compound
is modified by making acid or base salts thereof. 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 include
the conventional non-toxic salts or the quaternary ammonium salts
of the parent compound formed, for example, from non-toxic
inorganic or organic acids. For example, such conventional
non-toxic salts include those derived from inorganic acids such as
hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric
and the like; and the salts prepared from organic acids such as
acetic, propionic, succinic, glycolic, stearic, lactic, malic,
tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic,
phenylacetic, glutamic, benzoic, salicylic, sulfanilic,
2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane
disulfonic, oxalic, isethionic, and the like.
[0540] 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 are preferred. Lists
of suitable salts are found in Remington's Pharmaceutical Sciences,
17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418, the
disclosure of which is hereby incorporated by reference.
[0541] Since prodrugs are known to enhance numerous desirable
qualities of pharmaceuticals (e.g., solubility, bioavailability,
manufacturing, etc . . . ) the compounds of the present invention
may be delivered in prodrug form. Thus, the present invention is
intended to cover prodrugs of the presently claimed compounds,
methods of delivering the same and compositions containing the
same.
[0542] "Prodrugs" are intended to include any covalently bonded
carriers which release an active parent drug of the present
invention in vivo when such prodrug is administered to a mammalian
subject. Prodrugs the present invention are prepared by modifying
functional groups present in the compound in such a way that the
modifications are cleaved, either in routine manipulation or in
vivo, to the parent compound. Prodrugs include compounds of the
present invention wherein a hydroxy, amino, or sulfhydryl group is
bonded to any group that, when the prodrug of the present invention
is administered to a mammalian subject, it cleaves to form a free
hydroxyl, free amino, or free sulfhydryl group, respectively.
Examples of prodrugs include, but are not limited to, acetate,
formate and benzoate derivatives of alcohol and amine functional
groups in the compounds of the present invention.
[0543] "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. The present
invention is intended to embody stable compounds.
[0544] "Therapeutically effective amount" is intended to include an
amount of a compound of the present invention alone or an amount of
the combination of compounds claimed or an amount of a compound of
the present invention in combination with other active ingredients
effective to inhibit MCP-1 or effective to treat or prevent
inflammatory disorders.
[0545] As used herein, "treating" or "treatment" cover the
treatment of a disease-state in a mammal, particularly in a human,
and include: (a) preventing the disease-state from occurring in a
mammal, in particular, when such mammal is predisposed to the
disease-state but has not yet been diagnosed as having it; (b)
inhibiting the disease-state, i.e., arresting it development;
and/or (c) relieving the disease-state, i.e., causing regression of
the disease state.
Synthesis
[0546] The compounds of the present invention can be prepared in a
number of ways well known to one skilled in the art of organic
synthesis. The compounds of the present invention can be
synthesized using the methods described below, together with
synthetic methods known in the art of synthetic organic chemistry,
or variations thereon as appreciated by those skilled in the art.
Preferred methods include, but are not limited to, those described
below. All references cited herein are hereby incorporated in their
entirety herein by reference.
[0547] The novel compounds of this invention may be prepared using
the reactions and techniques described in this section. The
reactions are performed in solvents appropriate to the reagents and
materials employed and are suitable for the transformations being
effected. Also, in the description of the synthetic methods
described below, it is to be understood that all proposed reaction
conditions, including choice of solvent, reaction atmosphere,
reaction temperature, duration of the experiment and work up
procedures, are chosen to be the conditions standard for that
reaction, which should be readily recognized by one skilled in the
art. It is understood by one skilled in the art of organic
synthesis that the functionality present on various portions of the
molecule must be compatible with the reagents and reactions
proposed. Such restrictions to the substituents which are
compatible with the reaction conditions will be readily apparent to
one skilled in the art and alternate methods must then be used.
This will sometimes require a judgment to modify the order of the
synthetic steps or to select one particular process scheme over
another in order to obtain a desired compound of the invention. It
will also be recognized that another major consideration in the
planning of any synthetic route in this field is the judicious
choice of the protecting group used for protection of the reactive
functional groups present in the compounds described in this
invention. An authoritative account describing the many
alternatives to the trained practitioner is Greene and Wuts
(Protective Groups In Organic Synthesis, Wiley and Sons, 1999).
[0548] A series of compounds of formula 4 can be synthesized as
shown in Scheme 1. Many cyclic amines 1 are available (Cherney, R.
J. PCT 02/060859 and PCT 03/075853; and in U.S. Patent Application
No. 60/362,604, filed Mar. 8, 2002, both of which are hereby
incorporated by reference) and can be coupled to acid 2. The
resulting amide 3 can be cyclized (Freidinger et al., J. Org. Chem.
1982, 47, 104) via the activated thioether to the desired lactam 4.
##STR51##
[0549] A series of compounds of formula 7 can be synthesized as
shown in Scheme 2. The cyclic amine 1 can be coupled to an
appropriate carboxylate to afford amide 5. This material can be
cyclized under Mitsunobu conditions to afford .beta.-lactam 6
(Townsend et al., J. Amer. Chem. Soc. 1990, 112, 760). The
protecting group can be removed and an appropriate group can be
installed (through coupling or another methodology) to deliver the
desired target 7. ##STR52##
[0550] A series of compounds of formula 10 can be synthesized by
the methods shown in Scheme 3. Amine 1 can be coupled to an
appropriate carboxylate 8. The resulting amide 9 can be cyclized
via the aldehyde to afford the target 10. ##STR53##
[0551] A series of compounds of formula 4 can also be synthesized
as shown in Scheme 4. Amine 1 can be converted into 12 via a
reductive amination. The secondary amine 12 can be cyclized under a
variety of conditions to give the target 4. ##STR54##
[0552] A series of compounds of formula 16 can be synthesized as
shown in Scheme 5. Amine 1 can be converted into 14 via a Michael
reaction. Treatment of 14 with a phosphonate and base affords 15.
This material can be cyclized through the carboxylate to give 16.
##STR55##
[0553] A series of compounds of formula 21 can be synthesized as
shown in Scheme 6. The appropriate thioester 17 can be converted
into the aldehyde 18. Reductive amination of 1 with 18 gives the
secondary amine 19. This material can be cyclized through the
carboxylate to give 20. The protecting group can be removed and an
appropriate R.sup.2 group can be coupled to afford target 21.
##STR56##
[0554] The synthesis of R.sup.2=pyrimido[5,4-d]pyrimidin-4-01 is
shown in Scheme 7. ##STR57##
[0555] Intermediates such as 27 can be saponified and coupled to 20
where PG=H.sub.2. The bromine can also be removed via
hydrogenation, or used in Suzuki-type couplings for further
elaboration. The conversion of 27 to 28 is performed by the method
of Buchwald and Yin, J. Am. Chem. Soc., (124), 6043, 2002.
[0556] The synthesis of R.sup.2=quinazolines and their analogs
wherein the benzene moiety can also be replaced by a heterocycle
are made by the procedures illustrated in Schemes 8 and 8a. Note
that for clarity, benzoic acids and derivatives were drawn.
However, it is to be understood that the benzene ring can be
replaced with heterocycles. R.sup.1 in Schemes 8 and 8a represents
everything to the left of Z in formula (I) where Z=NH. R.sup.2 and
R.sup.3 are the usual substituents found on amines such as H,
alkyl, etc., familiar to one skilled in the art and within the
scope of R.sup.7a in this application.
[0557] Substituted anthranilic acids in Scheme 8 can be synthesized
from BOC-protected anilines via ortho-directed metallation followed
by quenching with CO.sub.2. Bromo or iodo substituted quinazolines
in Schemes 8 and 8a can undergo Suzuki-type couplings for further
elaboration. ##STR58## ##STR59##
[0558] Compounds containing a succinimide linker can be synthesized
by the methods shown in Scheme 9. Amine 1 is coupled to a protected
aspartic acid derivative to yield succinimide 47 which can be
deprotected and coupled to a carboxylic acid by the usual means
familiar to one skilled in the art to yield the compounds of this
invention, 48. ##STR60##
[0559] Many core rings 1 have been described (see Cherney PTC
WO/03075853 and others above). Others can be synthesized from
anhydride openings or the corresponding amino esters (52) or acid
esters (51) as shown in Scheme 10. As described (see Bolm et al. J.
Org. Chem. 2000, 65, 6984), anhydride 50 can be opened to the acid
ester 51. A Curtius reaction, or another rearrangement, on the
carboxylate of 51 can provide the carbamate 52. Hydrolysis of the
ester gives the acid 53 which can be converted to the primary amide
54. This primary amide 54 can be converted in one pot to the
bicyclic 57 (through the intermediate 55) or transformed in a
discrete step to acyl carbamate 55 and cyclized with the use of
many different electrophiles and bases (see Taguchi et al. J. Org.
Chem. 1997, 62, 7330) to give the bicyclic 57. The carboxylate 53
can also undergo cyclizations to the lactone 56. These compounds
(56, 57, 58) serve as versatile intermediates because they can be
opened in many ways to give substituted rings 59. These substituted
rings 59 can then be incorporated into Schemes 1, 2, 3, 4, 5, 6,
and 9 acting as compound 1. ##STR61##
[0560] More generally, compounds 55-58 may be prepared as described
in Scheme 10a. Compounds of Formula (IV), wherein an amine
protecting group is as described above, are converted into
compounds of Formula (II) by way of an electrophile and base in a
suitable solvent. ##STR62##
[0561] Suitable solvents for the reaction are generally the ether
solvents or non reactive hydrocarbon solvents as described above,
or mixtures thereof. In particular, the solvents are selected from
THF, toluene, and mixtures thereof. Additional non-reactive
solvents such as other aromatic solvents (e.g., benzene, anisole,
or quinoline) can also be used.
[0562] Suitable electrophiles for the reaction include, but are not
limited to, iodine, bromine, N-bromosuccinimide, N-iodosuccinimide,
N-(phenylseleno)phthalimide, and benzenesulfenyl chloride. Suitable
bases for the reaction include, but are not limited to, alkyl
lithium such as n-butyl lithium, lithium diisopropylamide (LDA),
sodium hydride, lithium bis(trimethylsilyl)amide, potassium
bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide,
Li--Al(O-tButyl).sub.4.
[0563] The reaction may be run at temperatures from about
-22.degree. C. to about room temperature and alternatively, from
about 0.degree. C. to about room temperature.
[0564] The amine protecting group includes all of those defined
above and each may be selected independently to allow for
differential removal of the protecting groups from the amine.
[0565] Scheme 11 shows how compounds like 59 can be converted into
the final compounds of interest. A compound like 58 can be
reductively opened to compound 59 (RX=BocHN, R'=HO, Z=H.sub.2,
R.sup.2=Cbz). Treatment of 59 with Mitsunobu-like conditions
(ArSSAr and nBu.sub.3P, wherein Ar may be any of the substituents
described by R.sup.1 in the claims) or substitution conditions
yields compound 60. This can be oxidized a number of ways to give
the sulfone 61. Removal of the benzyl carbamate gives the primary
amine 62. This can be incorporated into one of the Schemes 1-6 to
afford 63. The Boc carbamate can then be removed, and the primary
amine can be substituted in a variety of ways to the desired final
compound 64. ##STR63## ##STR64##
[0566] In a similar way, Scheme 12 shows how a compound like 58 can
be converted into a final compound of interest by changing the
order of Scheme 11. The benzyl carbamate of 58 can be removed to
give the primary amine 65. This can be incorporated into one of the
Schemes 1-6 to afford 66. The reductive opening of 66 gives 67.
Treatment of 67 with Mitsunobu-like conditions (ArSSAr and
nBu.sub.3P) or substitution conditions yields compound 68, which
can be oxidized to the same compound 63 as above, ##STR65##
[0567] The variables described in the schemes may be the same or
different than those described in the claims. They are not meant to
limit the claims.
[0568] When required, separation of the racemic material can be
achieved by HPLC using a chiral column or by a resolution using a
resolving agent such as camphonic chloride as in Steven D. Young,
et al, Antimicrobial Agents and Chemotheraphy, 1995, 2602-2605.
[0569] Other features of the invention will become apparent in the
course of the following descriptions of exemplary embodiments which
are given for illustration of the invention and are not intended to
be limiting thereof.
EXAMPLES
[0570] Abbreviations used in the Examples are defined as follows:
"1.times." for once, "2.times." for twice, "3.times." for thrice,
".degree. C." for degrees Celsius, "g" for gram or grams, "mg" for
milligram or milligrams, "mL" for milliliter or milliliters,
".sup.1H" for proton, "h" for hour or hours, "M" for molar, "min"
for minute or minutes, "MHz" for megahertz, "MS" for mass
spectroscopy, "NMR" for nuclear magnetic resonance spectroscopy,
"rt" for room temperature, "tlc" for thin layer chromatography,
"EtOAc" for ethyl acetate, "v/v" for volume to volume ratio, "aq"
for aqueous solutions. "R" and "S" are stereochemical designations
familiar to those skilled in the art. Compound names are provided
by the program ChemDraw Ultra (6.0).
Example 1
2-{(3S)-1-[(1,2-cis)-2-(4-Methylsulfanyl-benzoylamino)-cyclohexyl]-2-oxo-p-
yrrolidin-3-ylcarbamoyl}-4-trifluoromethyl-phenyl)-carbamic acid
tert-butyl ester
[0571] (1a) Cis (.+-.)-(2-amino-cyclohexyl)-carbamic acid benzyl
ester trifluoroacetic acid salt (620 mg) (Cherney, R. J. PCT Int
Appl. (2000), WO 0260859) was dissolved in DMF (6 mL) prior to the
addition of 4-methylmorpholine (0.56 mL) and N-Boc-L-Met-OH (512.0
mg). After cooling to 0.degree. C., BOP Reagent (907.1 mg) was
added. The resulting mixture was warmed to rt and was stirred
overnight. EtOAc was added along with 1 N HCl solution. The EtOAc
layer was washed with 1 N HCl (aq), NaHCO.sub.3 solution (aq), and
brine. The EtOAc was dried (MgSO.sub.4), filtered, and
concentrated. Flash chromatography of the resulting residue gave an
inseparable mixture of diastereomers
cis-[2-(2(S)-tert-butoxycarbonylamino-4-methylsulfanyl-butyrylamino)-cycl-
ohexyl]-carbamic acid benzyl ester (921 mg) which was taken
forward. MS found: (M+Na).sup.+=502.4.
[0572] (1b) A portion (910 mg) of the above derivative (1a) was
dissolved in MeI (12 mL). After stirring overnight at rt, the
solution was concentrated and dried. The resulting material was
dissolved in DMF (15 mL) and CH.sub.2Cl.sub.2 (15 mL) and cooled to
0.degree. C. prior to the addition of 60% NaH (258.4 mg). After
stirring 3 h at rt, EtOAc and brine were added. The EtOAc layer was
washed with brine, dried (MgSO.sub.4), filtered, and concentrated.
Flash chromatography of the resulting residue gave the mixture of
diastereomers
cis-[1-(2-benzyloxycarbonylamino-cyclohexyl)-2-oxo-pyrrolidin-3(S)-yl]-ca-
rbamic acid benzyl ester (358 mg). MS found:
(M+Na).sup.+=454.4.
[0573] (1c) A portion (340 mg) of the above derivative (1b) was
dissolved in CH.sub.2Cl.sub.2 (2 mL) and cooled to 0.degree. C.
prior to the addition of TFA. After 1 h at rt, the mixture was
concentrated. A portion (270 mg) of the resulting residue was
dissolved in DMF (5 mL) prior to the addition of 4-methylmorpholine
(0.24 mL) and 2-(tert-butoxycarbonyl)amino-5-trifluoromethylbenzoic
acid (220 mg) (Takagishi et al., Synlett 1992, 360). After cooling
to 0.degree. C., BOP Reagent (322 mg) was added. The resulting
mixture was warmed to rt and was stirred overnight. EtOAc was added
along with 1 N HCl solution. The EtOAc layer was washed with 1 N
HCl (aq), NaHCO.sub.3 solution (aq), and brine. The EtOAc was dried
(MgSO.sub.4), filtered, and concentrated. Flash chromatography of
the resulting residue gave the mixture of diastereomers
cis-{2-[1-(2-benzyloxycarbonylamino-cyclohexyl)-2-oxo-pyrrolidin-3(S)-ylc-
arbamoyl]-4-trifluoromethyl-phenyl}-carbamic acid tert-butyl ester
(196 mg). MS found: (M+Na).sup.+=641.4.
[0574] (1d) A portion (180 mg) of the above derivative (1c) was
dissolved in MeOH prior to the addition of 10% Pd/C (40 mg). A
hydrogen balloon was added and the mixture was stirred for 3 h. The
Pd/C was filtered off and the solvent was concentrated to a mixture
of diastereomers
cis-{2-[1-(2-amino-cyclohexyl)-2-oxo-pyrrolidin-3(S)-ylcarbamoyl]-4-trifl-
uoromethyl-phenyl}-carbamic acid tert-butyl ester (140 mg). MS
found: (M+H).sup.+=485.4.
[0575] (1e) A portion (70 mg) of the above derivative (1d) was
dissolved in DMF (5 mL) prior to the addition of 4-methylmorpholine
(0.05 mL) and 4-(methylthio)benzoic acid (52 mg). After cooling to
0.degree. C., BOP Reagent (77 mg) was added. The resulting mixture
was warmed to rt and was stirred overnight. EtOAc was added along
with 1 N HCl solution. The EtOAc layer was washed with 1 N HCl
(aq), NaHCO.sub.3 solution (aq), and brine. The EtOAc was dried
(MgSO.sub.4), filtered, and concentrated. Flash chromatography of
the resulting residue gave the title mixture of diastereomers (76
mg) MS found: (M+H).sup.+=635.4.
Example 2
2-{(3S)-1-[(1,2-cis)2-(4-Methylsulfanyl-benzoylamino)-cyclohexyl]-2-oxo-py-
rrolidin-3-ylcarbamoyl}-4-trifluoromethyl-phenyl)-amino
(2a) A portion (19 mg) of the above Example 1 was dissolved in
CH.sub.2Cl.sub.2 (2 mL) and cooled to 0.degree. C. prior to the
addition of TFA. After 1 h at rt, the mixture was concentrated and
dried. This gave the title compound (17 mg). MS found:
(M+H).sup.+=535.4.
Example 3
N-{(3S)-1-[(1S,2R,4R)-(Isopropyl-methyl-amino)-2-(toluene-4-sulfonylmethyl-
)-cyclohexyl]-2-oxo-pyrrolidin-3-yl}-3-trifluoromethyl-benzamide
[0576] (3a) 1,4-Cyclohexanedione mono-ethylene ketal (25 g) was
dissolved in THF and cooled to -78.degree. C. 1M Lithium
bis(trimethylsily)amide (160 mL) in THF was added dropwise. After
30 min, ethyl cyanoformate (15.9 mL) was added dropwise. After 60
min, the solution was poured into EtOAc and water containing ice.
The organic layer was washed with water and brine before it was
dried and concentrated. This crude was filtered through a plug of
silica to give the 8-oxo-1,4-dioxa-spiro[4.5]decane-7-carboxylic
acid ethyl ester (32.4 g). MS found: (M+H).sup.+=228.9
[0577] (3b) The above derivative (3a) (36.5 g) was dissolved in
toluene (500 mL) prior to the addition of (S)-methylbenzyl amine
(23 mL) and ytterbium (III) triflate (0.37 g). This mixture was
stirred at reflux for 3 h. After cooling to rt overnight, the
solvent was removed to a golden oil. This oil was dissolved in
acetonitrile (420 ml) prior to the addition of acetic acid (100 mL)
and NaBH(OAc).sub.3 (67.8 g). The mixture was stirred for 5 days at
rt. The solvent was removed before being redissolved in
CH.sub.2Cl.sub.2. After cooling in an ice bath, 1N NaOH was added
(pH=8). The organic layer was washed with brine, dried, filtered,
and concentrated. Flash chromatography of the resulting residue
gave
8(S)-(1(S)-phenyl-ethylamino)-1,4-dioxa-spiro[4.5]decane-7(R)-carbox-
ylic acid ethyl ester (26.2 g): .sup.1H NMR (CDCl.sub.3, .delta.
ppm, 300 MHz) 1.31 (m, 6H), 1.46 (m, 1H), 1.6-1.84 (m, 4H), 2.1 (t,
1H), 2.85 (m, 1H), 3.16 (m, 1H), 3.76 (m, 1H), 3.93 (m, 4H), 4.19
(q, 2H), 7.2-7.4 (m, 5H).
[0578] (3c) The above derivative (3b) (16.3 g) was dissolved in
Et.sub.2O (160 mL) and cooled to 0.degree. C. 1M Lithium aluminum
hydride in THF (117.3 mL) was added dropwise. After the addition,
the solution was stirred for 2 hr at 0.degree. C. The reaction was
quenched with water (4.4 mL) and then 1N NaOH (17.6 mL). The solids
were filtered off through a pad of celite. The filtrate was
concentrated to an oil. This material was dissolved in MeOH (20 mL)
prior to the addition of 20% Pd(OH).sub.2 (3 g). This solution was
placed on a Parr apparatus at 50 psi. The solution was mixed
overnight. The palladium was filtered off and the solution was
concentrated. The resulting oil was dissolved in THF (160 mL) and
water (20 mL) prior to the addition of triethylamine (8.8 mL).
After cooling to 0.degree. C., dibenzyl dicarbonate (18.2 g) was
added. The solution was warmed to rt and was stirred overnight.
Ethyl acetate was added along with brine. The organic layer was
washed with brine, dried, filtered, and concentrated. Flash
chromatography of the resulting residue gave
(7R,8S)-(7-hydroxymethyl-1,4-dioxa-spiro[4.5]dec-8-yl)-carbamic
acid benzyl ester (9.8 g). MS found: (M+H).sup.+=322.2.
[0579] (3d) A portion (100 mg) of the above derivative (3c) was
dissolved in THF (10 mL) prior to the addition of
tri-n-butylphosphine (0.86 mL). 4-Bromophenyl disulfide (233 mg)
was added and the solution was stirred in a 75.degree. C. oil bath.
After 5 h, the reaction was cooled to rt and flash chromatography
gave
(7R,8S)-[7-(4-bromo-phenylsulfanylmethyl)-1,4-dioxa-spiro[4.5]dec-8-yl]-c-
arbamic acid benzyl ester (137 mg). .sup.1H NMR (CDCl.sub.3,
.delta. ppm, 300 MHz) 1.39 (t, 1H), 1.5-1.9 (m, 9H), 2.05 (m,
1H)/2.73 (m, 1H), 3.0 (dd, 1H), 3.93 (m, 4H), 4.08 (m, 1H), 4.9 (br
d, 1H), 5.1 (s, 2H), 7.17 (d, 2H), 7.36 (m, 7H).
[0580] (3e) A portion (2.5 g) of the above derivative (3d) was
dissolved in CH.sub.2Cl.sub.2 (100 mL) and cooled to 0.degree. C.
prior to the addition 65% m-CPBA (3.1 g). After 2 h, the solution
was washed with saturated NaHCO.sub.3 solution, brine solution,
dried, filtered, and concentrated. Flash chromatography of the
resulting residue gave
(7R,8S)-[7-(4-bromo-benzenesulfonylmethyl)-1,4-dioxa-spiro[4.5]dec-8-yl]--
carbamic acid benzyl ester (2.59 g). MS found:
(M+H).sup.+=525.9.
[0581] (3f) A portion (2.1 g) of the above derivative (3e) was
dissolved in DMF (10 mL) prior to the addition of
PdCl.sub.2(PPh.sub.3).sub.2 (56 mg) and Sn(Me).sub.4 (0.8 mL). The
resulting solution was heated in an oil bath at 80.degree. C. Four
addition portions of Sn(Me).sub.4 (0.8 mL each) were added over 3
days. After cooling, EtOAc and brine were added. The organic layer
was washed with brine, dried, filtered, and concentrated. Flash
chromatography of the resulting residue gave
(7R,8S)-([7-(toluene-4-sulfonylmethyl)-1,4-dioxa-spiro[4.5]dec-8-yl]-carb-
amic acid benzyl ester (1.0 g). MS found: (M+H).sup.+=460.3.
[0582] (3g) A portion (1.0 g) of the above derivative (3f) was
dissolved in MeOH prior to the addition of 10% Pd/C (120 mg). A
hydrogen balloon was added and the mixture was stirred for 1.5 h.
The Pd/C was filtered off and the solvent was concentrated to
(7R,8S)-7-(toluene-4-sulfonylmethyl)-1,4-dioxa-spiro[4.5]dec-8-ylamine
(740 mg). MS found: (M+H).sup.+=326.3.
[0583] (3h) A portion (730 mg) of the above derivative (3g) was
dissolved in DMF prior to the addition of 4-methylmorpholine (0.74
mL) and N-Cbz-L-Met-OH (889.8 mg). After cooling to 0.degree. C.,
BOP Reagent (1.4 g) was added. The resulting mixture was warmed to
rt and was stirred overnight. EtOAc was added along with 1 N HCl
solution. The EtOAc layer was washed with 1 N HCl (aq), NaHCO.sub.3
solution (aq), and brine. The EtOAc was dried (MgSO.sub.4),
filtered, and concentrated. Flash chromatography of the resulting
residue gave
{(1S)-3-methylsulfanyl-1-[(7R,8S)-7-(toluene-4-sulfonylmethyl)-1,4-dioxa--
spiro[4.5]dec-8-ylcarbamoyl]-propyl}-carbamic acid benzyl ester
(1.1 g). MS found: (M+Na).sup.+=613.4.
[0584] (3i) A portion (330 mg) of the above derivative (3h) was
dissolved in MeI (6 mL). After stirring overnight at rt, the
solution was concentrated and dried. A portion (50 mg) of the
resulting material was dissolved in DMF (1.5 mL) prior to the
addition of Cs.sub.2CO.sub.3 (133 mg). After stirring overnight at
rt, EtOAc and brine were added. The EtOAc layer was washed with
brine, dried (MgSO.sub.4), filtered, and concentrated. Flash
chromatography of the resulting residue gave
{(3S)-2-oxo-1-[(7R,8S)-7-(toluene-4-sulfonylmethyl)-1,4-dioxa-spiro[4.5]d-
ec-8-yl]-pyrrolidin-3-yl}-carbamic acid benzyl ester (19 mg), MS
found: (M+Na).sup.+=565.3.
[0585] (3j) A portion (580 mg) of the above derivative (3i) was
dissolved in CH.sub.3CN (10 mL) prior to the addition of 1N HCl (10
mL). The mixture was stirred in a 60.degree. C. oil bath for 4 h.
After cooling the solution was concentrated. Flash chromatography
of the resulting residue gave
{(3S)-2-oxo-1-[(1S,2R)-4-oxo-2-(toluene-4-sulfonylmethyl)-cyclohexyl]-pyr-
rolidin-3-yl}-carbamic acid benzyl ester (270 mg). MS found:
(M+Na).sup.+=521.2.
[0586] (3k) The above derivative (3j) (270 mg) was dissolved in
Ti(OiPr).sub.4 (4 mL) prior to the addition of isopropylamine (0.4
mL). After 1.5 h, MeOH (7 mL) was added followed by NaBH.sub.4 (57
mg). After 1 h, the reaction was quenched by the addition of 0.1N
NaOH and filtered through celite. The filtrate was concentrated to
a mixture of diastereomers. Flash chromatography of the resulting
mixture gave two diastereomers:
({(3S)-1-[(1S,2R,4R)-isopropylamino-2-(toluene-4-sulfonylmethyl)-cyclohex-
yl]-2-oxo-pyrrolidin-3-yl}-carbamic acid benzyl ester (3ka) (59
mg), MS found: (M+H).sup.+=542.3; and
({(3S)-1-[(1S,2R,45)-isopropylamino-2-(toluene-4-sulfonylmethyl)-cyclohex-
yl]-2-oxo-pyrrolidin-3-yl}-carbamic acid benzyl ester (3kb) (28
mg), MS found: (M+H).sup.+=542.4.
[0587] (3l) The above derivative (3ka) (57 mg) was dissolved in
MeOH (1.3 mL) prior to the addition of 37% formaldehyde in water
(53 mg). After 1.5 h, NaBH.sub.3CN (10.4 mg) was added. After 1 h,
saturated NaHCO.sub.3 was added and some of the MeOH was removed.
EtOAc was added and the organic layer was washed with brine, dried,
filtered, and concentrated. The resulting residue was dissolved in
MeOH prior to the addition of 5% Pd/BaSO.sub.4 (100 mg). A hydrogen
balloon was added and the mixture was stirred. Two more portions
(50 mg each) of 5% Pd/BaSO.sub.4 were added. The reaction was
stirred for a total of 3 h. The Pd/BaSO.sub.4 was filtered off and
the solvent was concentrated. The resulting residue was dissolved
in DMF prior to the addition of 4-methylmorpholine (34 mg) and
3-trifluoromethyl-benzoic acid (32 mg). After cooling to 0.degree.
C., HATU (64 mg) was added. The resulting mixture was warmed to rt
and was stirred overnight. EtOAc was added along with saturated
NaHCO.sub.3 solution. The EtOAc layer was washed with NaHCO.sub.3
solution (aq), dried (MgSO.sub.4), filtered, and concentrated.
Reverse phase HPLC purification (gradient elution,
water/acetonitrile/TFA) of the resulting residue provided the title
compound (36 mg). MS found: (M+H).sup.+=594.3.
Example 4
N-{(3S)-1-[(1S,2R,4S)-(Isopropyl-methyl-amino)-2-(toluene-4-sulfonylmethyl-
)-cyclohexyl]-2-oxo-pyrrolidin-3-yl}-3-trifluoromethyl-benzamide
(4a) Derivative (3kb) (28 mg) was incorporated into Example (3l) to
give the title compound (8.1 mg). MS found: (M+H).sup.+=594.3.
Example 5
N-{(3S)-1-[(1S,2R,4R)-2-Benzenesulfonylmethyl-(isopropyl-methyl-amino)-cyc-
lohexyl]-2-oxo-pyrrolidin-3-yl}-3-trifluoromethyl-benzamide
(5a) Phenyl disulfide was incorporated into Example 3-step (3d) and
step (3f) was skipped to give two diastereomers. The first
diastereomer was the title compound (12.3 mg). MS found:
(M+H).sup.+=580.3.
Example 6
N-{(3S)-1-[(1S,2R,4S)-2-Benzenesulfonylmethyl-4-(isopropyl-methyl-amino)-c-
yclohexyl]-2-oxo-pyrrolidin-3-yl}-3-trifluoromethyl-benzamide
(6a) The second diastereomer from above (5a) was isolated as the
title compound. MS found: (M+H).sup.+=580.3.
Example 7
N-{(3S)-1-[(1S,2R,4R)-2-Benzenesulfonylmethyl-4-(isopropyl-ethyl-amino)-cy-
clohexyl]-2-oxo-pyrrolidin-3-yl}-3-trifluoromethyl-benzamide
(7a) Acetaldehyde was incorporated into Example 5 (in the analogous
step to 3l) to give two diastereomers. The first diastereomer was
the title compound (30 mg). MS found: (M+H).sup.+=594.3.
Example 8
N-{(3S)-1-[(1S,2R,4S)-2-Benzenesulfonylmethyl-4-(isopropyl-ethyl-amino)-cy-
clohexyl]-2-oxo-pyrrolidin-3-yl}3-trifluoromethyl-benzamide
(8a) The second diastereomer from above (7a) was the title compound
(7 mg) MS found: (M+H).sup.+=594.3.
Example 9
N-{(3S)-1-[(1S,2R,4R)-2-Benzenesulfonylmethyl-4-(isopropyl-cyclopropylmeth-
yl-amino)-cyclohexyl]-2-oxo-pyrrolidin-3-yl}-3-trifluoromethyl-benzamide
(9a) Cyclopropanecarboxaldehyde was incorporated into Example 5 (in
the analogous step to 3l) to give the title compound (25 mg). MS
found: (M+H).sup.+=620.3.
Example 10
(.+-.)
N-{(3S*)-1-[(1S*,2R*,4R*)-4-Azido-2-(4-methylsulfanyl-benzenesulfon-
ylmethyl)-cyclohexyl]-3-methyl-2-oxo-pyrrolidin-3-yl}-3-trifluoromethyl-be-
nzamide
[0588] (10a) 1-Methanesulfonyl-4-methylsulfanyl-benzene (3.4 g) was
dissolved in THF (40 mL) and cooled to -78.degree. C. prior to the
addition of 1.6 M nBuLi (10.4 mL). After 0.5 h, BF.sub.3. Et.sub.2O
(2.1 mL) was added followed by cis
(.+-.)-4-(benzyloxy)-1,2-epoxycyclohexane (2.3 g) (Chini et al. J.
Org. Chem. 1990, 55, 4265) in THF (20 mL). After an addition 1 h at
-78.degree. C., the solution was warmed to 0.degree. C. After 2 h,
the solution was cooled to -78.degree. C. and 1N HCl solution (aq)
was added. The solution was warmed to rt and EtOAc was added. The
organic layer was washed with brine, dried, filtered, and
concentrated. Flash chromatography of the resulting residue gave
(.+-.)(1R*,2R*,4S*)-4-benzyloxy-2-(4-methylsulfanyl-benzenesulfonylmethyl-
)-cyclohexanol (2.9 g) as the major product. MS found:
(M+H).sup.+=407.1.
[0589] (10b) A portion of the above material (1.9 g) was dissolved
in CH.sub.2Cl.sub.2 (15 mL) and cooled to 0.degree. C. prior to the
addition of Et.sub.3N (2 mL) and methanesulfonyl chloride (0.55
mL). After 1 h, the CH.sub.2Cl.sub.2 was removed and EtOAc was
added. This was washed with 1N HCl, saturated NaHCO.sub.3, and
brine. The organic layer was dried, filtered, and concentrated.
This solid was dissolved in DMSO (20 mL) prior to the addition of
NaN.sub.3 (2.35 g). This was heated at 80.degree. C. for 18 h.
After cooling to 0.degree. C., water was added and it was extracted
with EtOAc. The organic layer was washed with brine, dried,
filtered, and concentrated. Flash chromatography of the resulting
residue gave
(.+-.)(1S*,2R*,4S*)-4-benzyloxy-2-(4-methylsulfanyl-benzenesulfonylmethyl-
)-azidocyclohexane (1.4 g). MS found: (M-N.sub.3).sup.+=388.5.
[0590] (10c) A portion of the above material (1.3 g) was dissolved
in CH.sub.2Cl.sub.2 (15 mL) and cooled to -78.degree. C. prior to
the addition of 1.0M BCl.sub.3 (3.9 mL) in CH.sub.2Cl.sub.2. The
reaction was stirred at 0.degree. C. for 2 h. After cooling to
-78.degree. C., MeOH (8 mL) was added. The reaction was warmed to
0.degree. C. and then rt. The resulting solution was extracted with
CH.sub.2Cl.sub.2. The organic layer was washed with saturated
NaHCO.sub.3 solution (aq), brine, dried, filtered, and
concentrated. Flash chromatography of the resulting residue gave
(.+-.)(1S*,2R*,4S*)-4-hydroxy-2-(4-methylsulfanyl-benzenesulfonylmet-
hyl)-azidocyclohexane (1.1 g) MS found:
(M-HN.sub.3).sup.+=298.1.
[0591] (10d) The above material (1.1 g) was dissolved in MeOH (10
mL) prior to the addition of 5% Pd/BaSO.sub.4 (800 mg). A hydrogen
balloon was added and the solution was stirred for 4.0 h. The
palladium was filtered off and the solution was concentrated to
(.+-.)(1S*,2R*,4S*)-4-hydroxy-2-(4-methylsulfanyl-benzenesulfonylmethyl)--
cyclohexylamine: MS found: (M+H).sup.+=316.2. The resulting residue
was dissolved in THF (10 mL) and water (2 mL) prior to the addition
of Et.sub.3N (0.88 mL). This was cooled to 0.degree. C. and
Boc.sub.2O (761 mg) was added. The reaction was warmed to rt and
was stirred overnight. The reaction was quenched with water and
EtOAc. The EtOAc layer was washed with 1 N HCl solution,
NaHCO.sub.3 solution, and brine. The organic layer was dried,
filtered, and concentrated (1.44 g). This material (1.44 g) was
dissolved in CH.sub.2Cl.sub.2 (15 mL) and cooled to 0.degree. C.
prior to the addition of Et.sub.3N (1.3 mL) and methanesulfonyl
chloride (0.37 mL). After 1 h, the CH.sub.2Cl.sub.2 was removed and
EtOAc was added. This was washed with 1N HCl, saturated
NaHCO.sub.3, and brine. The organic layer was dried, filtered, and
concentrated. This solid was dissolved in DMSO (10 mL) prior to the
addition of NaN.sub.3 (1.03 g). This was heated at 80.degree. C.
for 18 h. After cooling to 0.degree. C., water was added and it was
extracted with EtOAc. The organic layer was washed with brine,
dried, filtered, and concentrated. Flash chromatography of the
resulting residue gave (.+-.)(1S*,2R*,4R*)-[4-azido-2-(4
methylsulfanyl-benzenesulfonylmethyl)-cyclohexyl]-carbamic acid
tert-butyl ester (1.2 g). MS found:
(M+Na+CH.sub.3CN).sup.+=504.3.
[0592] (10e) A portion of the above material (114 mg) was dissolved
in CH.sub.2Cl.sub.2 (2 mL) and cooled to 0.degree. C. prior to the
addition of TFA (2 mL). After the reaction was warmed to rt over 45
min, it was concentrated and dried. The resulting residue was
dissolved in DMF (4 mL) prior to the addition of HATU (166.7 mg)
and N-Boc-.alpha.-methyl-dl-Met-OH (101.7 mg). After cooling to
0.degree. C., diisopropylethylamine (0.74 mL) was added. The
resulting mixture was warmed to rt and was stirred overnight before
being concentrated. Flash chromatography of the resulting residue
gave
{1-[4-azido-2-(4-methylsulfanyl-benzenesulfonylmethyl)-cyclohexylcarbamoy-
l]-1-methyl-3-methylsulfanyl-propyl}-carbamic acid tert-butyl ester
(113 mg) as a mixture of diastereomers. MS found:
(M+H).sup.+=586.5.
[0593] (10f) The above derivative was dissolved in MeI (5 mL).
After stirring overnight at rt, the solution was concentrated and
dried. The resulting material was dissolved in DMF (4 mL) prior to
the addition of Cs.sub.2CO.sub.3 (380 mg). After stirring overnight
the solution was filtered and concentrated. Flash chromatography of
the resulting residue provided the bottom diastereomer (TLC 80%
EtOAc/Hex)
(.+-.){(3S*)-1-[(1S*,2R*,4R*)-4-azido-2(4-methylsulfanyl-benzenesulfonylm-
ethyl)-cyclohexyl]-3-methyl-2-oxo-pyrrolidin-3-yl}-carbamic acid
tert-butyl ester (36 mg). MS found: (M+Na).sup.+=538.5.
[0594] (10g) The above material was dissolved in CH.sub.2Cl.sub.2
(1 mm) and cooled to 0.degree. C. prior to the addition of TFA (1
mL). After the reaction was warmed to rt over 30 min, it was
concentrated and dried. The resulting residue was dissolved in
CH.sub.2Cl.sub.2 prior to the addition of diisopropylethylamine
(0.05 mL) and 3-(trifluoromethyl)benzoyl chloride (28 mg). After
stirring for 1.5 h, the reaction was diluted with CH.sub.2Cl.sub.2
and washed with water, 10% citric acid solution, NaHCO.sub.3
solution, and brine. The CH.sub.2Cl.sub.2 layer was dried
(MgSO.sub.4), filtered, and concentrated. Flash chromatography of
the resulting residue provided the title compound (24 mg). MS
found: (M+H).sup.+=610.5.
Example 11
(.+-.)
N-{(3S*)-1-[(1S*,2R*,4R*)-4-Amino-2-(4-methylsulfanyl-benzenesulfon-
ylmethyl)-cyclohexyl]-3-methyl-2-oxo-pyrrolidin-3-yl}-3-trifluoromethyl-be-
nzamide
[0595] (11a) Example 10 (20 mg) was dissolved in MeOH (2 mL) prior
to the addition of 5% Pd/BaSO.sub.4 (10 mg). A hydrogen balloon was
added and the mixture was stirred. After stirring 45 min, the
Pd/BaSO.sub.4 was filtered off and the solvent was concentrated to
give the title compound. MS found: (M+H).sup.+=584.5.
Example 12
(.+-.)
N-{(3S*)-1-[(1S*,2R*,4R*)-4-Isopropylamino-2(4-methylsulfanyl-benze-
nesulfonylmethyl)-cyclohexyl]-3-methyl-2-oxo-pyrrolidin-3-yl}-3-trifluorom-
ethyl-benzamide
[0596] (12a) Example 11 (16 mg) was dissolved in dichloroethane (1
mL) prior to the addition of glacial acetic acid (8 mg), acetone (8
mg), and NaBH(OAc).sub.3 (30 mg). After 20 h, the solution was
concentrated. The resulting residue was dissolved in EtOAc and
washed with saturated NaHCO.sub.3, water, and brine. The organic
layer was dried, filtered, and concentrated. Reverse phase HPLC
purification (gradient elution, water/acetonitrile/TFA) of the
resulting residue provided the title compound (13 mg). MS found:
(M+H).sup.+=626.6.
Example 13
(.+-.)
N-{(3S*)-1-[(1S*,2R*,4R*)-4-(Isopropyl-methyl-amino)-2-(4-methylsul-
fanyl-benzenesulfonylmethyl)-cyclohexyl]-3-methyl-2-oxo-pyrrolidin-3-yl}-3-
-trifluoromethyl-benzamide
[0597] (13a) Example 12 (22 mg) was dissolved in MeOH (1 mL) prior
to the addition of 37% formaldehyde in water (4 mg). After 15 min,
NaBH.sub.3CN (4 mg) was added. After 1 h, saturated NaHCO.sub.3 was
added and some of the MeOH was removed. EtOAc was added and the
organic layer was dried, filtered, and concentrated. Reverse phase
HPLC purification (gradient elution, water/acetonitrile/TFA) of the
resulting residue provided the title compound (13 mg). MS found:
(M+H).sup.+=640.6.
Example 14
(.+-.)
N-{(3S*)-1-[(1S*,2R*,4R*)-4-(Isopropyl-prop-2-ynyl-amino)-2-(4-meth-
ylsulfanyl-benzenesulfonylmethyl)-cyclohexyl]-3-methyl-2-oxo-pyrrolidin-3--
yl}-3-trifluoromethyl-benzamide
[0598] (14a) Example 12 (20 mg) was dissolved in acetonitrile (1
mL) prior to the addition of K.sub.2CO.sub.3 (22 mg) and propargyl
bromide (8 mg). After 4.75 h at 45.degree. C., the reaction was
cooled to rt. Saturated NaHCO.sub.3 was added and the reaction was
extracted with EtOAc. The organic layer was dried, filtered, and
concentrated. Reverse phase HPLC purification (gradient elution,
water/acetonitrile/TFA) of the resulting residue provided the title
compound (7 mg). MS found: (M+H).sup.+=664.6.
Example 15
(.+-.)
N-{(3S*)-1-[(1S*,2R*,4R*)-4-(Cyclopropylmethyl-isopropyl-amino)-2-(-
4-methylsulfanyl-benzenesulfonylmethyl)-cyclohexyl]-3-methyl-2-oxo-pyrroli-
din-3-yl}-3-trifluoromethyl-benzamide
(15a) Cyclopropanecarboxaldehyde was incorporated into Example 13
to give the title compound (11 mg). MS found (M+H).sup.+=680.6.
Example 16
N-{(3S)-1-[4-(Isopropyl-methyl-amino)-2-(4-methylsulfanyl-benzenesulfonylm-
ethyl)-cyclohexyl]-2-oxo-pyrrolidin-3-yl}-N-methyl-3-trifluoromethyl-benza-
mide
(16a) N(Me)Boc-L-Met-OH was incorporated into Example 10, step
(10e), and advanced in an analogous way to Example 12. This
procedure gave the title compound (31 mg) as a mixture of
diastereomers. MS found: (M+H).sup.+=640.3.
Example 17
N-{(3S)-1-[(1S,2R,4R)-4-(Isopropyl-methyl-amino)-2-(4-methylsulfanyl-benze-
nesulfonylmethyl)-cyclohexyl]-2-oxo-pyrrolidin-3-yl}-3-trifluoromethyl-ben-
zamide
(17a) N-Boc-L-Met-OH was incorporated into Example 16 to give the
title compound. MS found: (M+H).sup.+=626.3.
Example 18
1-{(3S)-1-[(1S,2R,4R)-4-(Isopropyl-methyl-amino)-2-(4-methylsulfanyl-benze-
nesulfonylmethyl)-cyclohexyl]-2-oxo-pyrrolidin-3-yl}-3-(3-trifluoromethyl--
phenyl)-urea
[0599] (18a)
{(3S)-1-[(1S,2R,4R)-4-Azido-2-(4-methylsulfanyl-benzenesulfonylmethyl)-cy-
clohexyl]-2-oxo-pyrrolidin-3-yl}-carbamic acid tert-butyl ester
(350 mg), from the synthesis of Example 17 (analogous to 10f), was
dissolved in MeOH (5 mL) prior to the addition of 5% Pd/BaSO.sub.4
(300 mg). A hydrogen balloon was added and the mixture was stirred.
After stirring 1 h, the Pd/BaSO.sub.4 was filtered off and the
solvent was concentrated to give
{(3S)-1-[(1S,2R,4R)-4-amino-2-(4-methylsulfanyl-benzenesulfonylmethy-
l)-cyclohexyl]-2-oxo-pyrrolidin-3-yl}-carbamic acid tert-butyl
ester (497 mg). MS found: (M-H).sup.-=496.5.
[0600] (18b) A portion of the above material (341 mg) was dissolved
in dichloroethane (5 mL) prior to the addition of acetone (0.25 mL)
and NaBH(OAc).sub.3 (436 mg). After 2 h, the solution was
concentrated. The resulting residue was dissolved in EtOAc and
washed with saturated NaHCO.sub.3. The organic layer was dried,
filtered, and concentrated. The resulting residue was dissolved in
MeOH (2 mL) prior to the addition of 37% formaldehyde in water (0.1
mL). After 15 min, NaBH.sub.3CN (111 mg) was added. After 2 h,
saturated NaHCO.sub.3 was added and some of the MeOH was removed.
EtOAc was added and the organic layer was dried, filtered, and
concentrated. This material was passed through a plug of silica and
concentrated. This material (300 mg) was dissolved in
CH.sub.2Cl.sub.2 (5 mL) prior to the addition of TFA (2.5 mL).
After 30 min, it was concentrated and dried. A portion of the
resulting residue (35 mg) was dissolved in DMF (1 mL) prior to the
addition of 4-methylmorpholine (0.02 mL) and
3-trifluoromethylphenyl isocyanate (0.013 mL). After 2 h, the
solution was concentrated. Reverse phase HPLC purification
(gradient elution, water/acetonitrile/TFA) of the resulting residue
provided the title compound (7 mg). MS found:
(M+H).sup.+=641.3.
Example 19
N-{(3S)-1-[(1S,2R,4R)-4-(Isopropyl-methyl-amino)-2-(4-methylsulfanyl-benze-
nesulfonylmethyl)-cyclohexyl]-2-oxo-pyrrolidin-3-yl}-3-trifluoromethyl-ben-
zenesulfonamide
(19a) 3-(Trifluoromethyl)phenylsulfonyl chloride (instead of
3-trifluoromethylphenyl isocyanate) and pyridine (instead of
4-methylmorpholine) were incorporated into Example 18 to give the
title compound. MS found: (M+H).sup.+=662.3.
Example 20
N-{(3S)-1-[(1S,2R,4R)-4-(Isopropyl-methyl-amino)-2-(4-methylsulfanyl-benze-
nesulfonylmethyl)-cyclohexyl]-2-oxo-pyrrolidin-3-yl}-benzamide
(20a) Benzoic acid was incorporated into Example 17 to give the
title compound. MS found: (M+H).sup.+=558.3.
Example 21
{(3S)-1-[(1S,2R,4R)-2-Benzenesulfonylmethyl-4-(isopropyl-methyl-amino)-cyc-
lohexyl]-2-oxo-pyrrolidin-3-yl}-3-(3-trifluoromethyl-phenyl)-urea
[0601] (21a) Example 18 (15 mg) was dissolved in MeOH (1 mL) prior
to the addition of 20% Pd(OH).sub.2 (20 mg). A hydrogen balloon was
added and the mixture was stirred. After stirring overnight, the
palladium was filtered off and the solvent was concentrated.
Reverse phase HPLC purification (gradient elution,
water/acetonitrile/TFA) of the resulting residue provided the title
compound. MS found: (M+H).sup.+=595.3.
Example 22
N-[(3S)-1-((1S,2R,4R)-2-Benzenesulfonylmethyl-4-isopropylamino-cyclohexyl)-
-2-oxo-pyrrolidin-3-yl]-3-trifluoromethyl-benzamide
[0602] (22a)
{(3S)-1-[(1S,2R,4R)-4-Azido-2-(4-methylsulfanyl-benzenesulfonylmethyl)-cy-
clohexyl]-2-oxo-pyrrolidin-3-yl}-carbamic acid tert-butyl ester
(240 mg), see example 18, was dissolved in CH.sub.2Cl.sub.2 (5 mL)
prior to the addition of TFA (2.5 mL). After 30 min, it was
concentrated and dried. The resulting residue was dissolved in DMF
prior to the addition of 4-methylmorpholine (0.25 mL) and
3-trifluoromethyl-benzoic acid (104.5 mg). BOP Reagent (64 mg) was
added and the mixture was stirred for 40 min. After concentration,
EtOAc was added along with 1N HCl solution. The EtOAc layer was
washed with NaHCO.sub.3 solution (aq) and brine, dried
(MgSO.sub.4), filtered, and concentrated. This material was passed
through a plug of silica and concentrated. The resulting material
(178 mg) was dissolved in MeOH (5 mL) prior to the addition of 20%
Pd(OH).sub.2 (100 mg). A hydrogen balloon was added and the mixture
was stirred. After stirring overnight, the palladium was filtered
off and the solvent was concentrated. A portion of this material
(68 mg) was dissolved in dichloroethane (2.5 mL) prior to the
addition of acetone (0.04 mL) and NaBH(OAc).sub.3 (64 mg). After 40
min, the solution was concentrated. The resulting residue was
dissolved in EtOAc and washed with saturated NaHCO.sub.3. The
organic layer was dried, filtered, and concentrated. Reverse phase
HPLC purification (gradient elution, water/acetonitrile/TFA) of the
resulting residue provided the title compound (66 mg). MS found:
(M+H).sup.+=566.4.
Example 23
N-{(3S)-1-[(1S,2R,4R)-4-(Allyl-isopropyl-amino)-2-benzenesulfonylmethyl-cy-
clohexyl]-2-oxo-pyrrolidin-3-yl}-3-trifluoromethyl-benzamide
[0603] (23a) Example 22 (17 mg) was dissolved in DMF (1 mL) prior
to the addition of K.sub.2CO.sub.3 (11 mg) and allyl bromide (0.003
mL). After stirring overnight, the reaction was filtered and
concentrated. Reverse phase HPLC purification (gradient elution,
water/acetonitrile/TFA) of the resulting residue provided the title
compound (5 mg). MS found: (M+H).sup.+=606.3.
Example 24
1-((1S,2R)-2-Benzenesulfonylmethyl-4-isopropylamino-cyclohexyl)-2-oxo-pyrr-
olidine-3-carboxylic acid (3-trifluoromethyl-phenyl)-amide
[0604] (24a) Phenyl disulfide was incorporated into Example 3, step
3d (in place of 4-bromophenyl disulfide), and advanced to step 3e
to give
(7R,8S)-(7-benzenesulfonylmethyl-1,4-dioxa-spiro[4.5]dec-8-yl)-carbamic
acid benzyl ester. This material (1.2 g) was dissolved in MeOH
prior to the addition of 10% Pd/C (250 mg). A hydrogen balloon was
added and the mixture was stirred for 5 h. The Pd/C was filtered
off and the solvent was concentrated to give
(7R,8S)-7-benzenesulfonylmethyl-1,4-dioxa-spiro[4.5]dec-8-ylamine
(826 mg). MS found: (M+H).sup.+=312.3.
[0605] (24b) A portion of this material (239 mg) was dissolved in
dichloroethane (4 mL) prior to the addition of
3,3-bis(methoxycarbonyl)propanal (160 mg) (Bunce et al. Org. Prep.
Proc. Int. 1987, 19, 67-71). The mixture was stirred for 1.5 h
before NaBH(OAc).sub.3 (195 mg) was added. After 2 h, EtOAc and
saturated NaHCO.sub.3 was added. The organic layer was washed with
additional saturated NaHCO.sub.3 solution. The organic layer was
dried, filtered, and concentrated to give
(7R,8S)-2-[2-(7-benzenesulfonylmethyl-1,4-dioxa-spiro[4.5]dec-8-ylamino)--
ethyl]-malonic acid dimethyl ester (203 mg). MS found:
(M+H).sup.+=470.4.
[0606] (24c) A portion of this material (52 mg) was dissolved in
MeOH prior to the addition of 0.5M NaOMe (0.05 mL) in MeOH. The
mixture was stirred overnight before being concentrated. EtOAc and
1N HCl was added. The organic layer was washed with additional 1N
HCl solution. The organic layer was dried, filtered, and
concentrated to give
(1-(7-benzenesulfonylmethyl-1,4-dioxa-spiro[4.5]dec-8-yl)-2-oxo-pyrrolidi-
ne-3-carboxylic acid methyl ester (42 mg) as a mixture of
diastereomers. MS found: (M+H).sup.+=460.3.
[0607] (24d) A portion of this material (110 mg) was dissolved in
THF (1 mL), MeOH (0.5 mL), and water (0.5 mL) at 0.degree. C. prior
to the addition of 1M LiOH (0.25 mL) in water. The reaction was
stirred for 2 h. EtOAc and 1N HCl was added. The organic layer was
washed with additional 1N HCl solution. The organic layer was
dried, filtered, and concentrated to give
1-(7-benzenesulfonylmethyl-1,4-dioxa-spiro[4.5]dec-8-yl)-2-oxo-py-
rrolidine-3-carboxylic acid (105 mg). MS found:
(M+H).sup.+=424.3.
[0608] (24e) This material was dissolved in DMF prior to the
addition of 4-methylmorpholine (0.08 mL) and
3-(trifluoromethyl)phenyl aniline (0.05 mL). HATU (114 mg) was
added and the mixture was stirred overnight. EtOAc was added along
with 1N HCl solution. The EtOAc layer was washed with NaHCO.sub.3
solution and brine, dried (MgSO.sub.4), filtered, and concentrated.
Flash chromatography of the resulting residue gave
1-(7-benzenesulfonylmethyl-1,4-dioxa-spiro[4.5]dec-8-yl)-2-oxo-pyrrolidin-
e-3-carboxylic acid (3-trifluoromethyl-phenyl)-amide. MS found:
(M+H).sup.+=567.3.
[0609] (24f) A portion of this material (118 mg) was dissolved in
acetone (1 mL) prior to the addition of 1N HCl (4 mL). The mixture
was heated at reflux for 3 h. After cooling, the solution was
concentrated. Flash chromatography of the resulting residue gave
two diastereomers of
1-(2-benzenesulfonylmethyl-4-oxo-cyclohexyl)-2-oxo-pyrrolidine-3-carboxyl-
ic acid (3-trifluoromethyl-phenyl)-amide as top (MS found:
(M-H).sup.-=521.3) and bottom (MS found: (M+Na).sup.+=545.2).
[0610] (24g) The above top diastereomer (53 mg) was dissolved in
Ti(OiPr).sub.4 (0.74 mL) prior to the addition of isopropylamine
(0.08 mL). After 1.5 h, MeOH (1.5 mL) was added followed by
NaBH.sub.4 (11 mg). After 1 h, the reaction was quenched by the
addition of 0.1N NaOH and filtered through celite. The filtrate was
concentrated to a mixture of diastereomers. Reverse phase HPLC
purification (gradient elution, water/acetonitrile/TFA) of the
resulting residue provided the title compound (15 mg) as a mixture
of diastereomers. MS found: (M+H).sup.+=566.3.
Example 25
1-((1S,2R)-2-Benzenesulfonylmethyl-4-isopropylamino-cyclohexyl)-2-oxo-pyrr-
olidine-3-carboxylic acid (3-trifluoromethyl-phenyl)-amide
[0611] (25a) The above bottom diastereomer from 24f (71 mg) was
dissolved in Ti(OiPr).sub.4 (0.7 mL) prior to the addition of
isopropylamine (0.08 mL). After 1.5 h, MeOH (1.5 mL) was added
followed by NaBH.sub.4 (11 mg). After 1 h, the reaction was
quenched by the addition of 0.1N NaOH and filtered through celite.
The filtrate was concentrated to a mixture of diastereomers.
Reverse phase HPLC purification (gradient elution,
water/acetonitrile/TFA) of the resulting residue provided the title
compound (22 mg) as a mixture of diastereomers. MS found:
(M+H).sup.+=566.5.
Example 26
(2-{(3S)-1-[(1S,2R)-2-(4-Methylsulfanyl-benzylamino)-cyclohexyl]-2-oxo-pyr-
rolidin-3-ylcarbamoyl}-4-trifluoromethyl-phenyl)-carbamic acid
tert-butyl ester
[0612] (26a) Flash chromatography of the mixture of diastereomers
in step (ic) gave the clean bottom isomer as
{2-[(3S)-1-((1S,2R)-2-benzyloxycarbonylamino-cyclohexyl)-2-oxo-pyrrolidin-
-3-ylcarbamoyl]-4-trifluoromethyl-phenyl}-carbamic acid tert-butyl
ester (MS found: (M-H).sup.-=617.2).
[0613] (26b) A portion of this material (50 mg) was dissolved in
MeOH (5 mL) prior to the addition of 10% Pd/C (10 mg). A hydrogen
balloon was added and the mixture was stirred for 3 h. The Pd/C was
filtered off and the solvent was concentrated. The resulting
residue was dissolved in dichloroethane (1.4 mL) prior to the
addition of glacial acetic acid (0.009 mL),
4-(methylthio)benzaldehyde (0.02 mL), and NaBH(OAc).sub.3 (31 mg).
After 20 h, the solution was concentrated. The resulting residue
was dissolved in EtOAc and washed with saturated NaHCO.sub.3
solution. The organic layer was dried, filtered, and concentrated.
Reverse phase HPLC purification (gradient elution,
water/acetonitrile/TFA) of the resulting residue provided the title
compound (15 mg). MS found: (M+H).sup.+=621.4.
Example 27
N-{(3S)-1-[(1S,2R,4R)-2-Benzenesulfonylmethyl-4(R)-(isopropyl-propyl-amino-
)-cyclohexyl]-2-oxo-pyrrolidin-3-yl}-3-trifluoromethyl-benzamide
(27a) Propionaldehyde was incorporated into Example 5 (in the
analogous step to 3l) to give two diastereomers. The first
diastereomer was the title compound (10 mg). MS found:
(M+H).sup.+=608.3.
Example 28
(.+-.)
1-[(1S*,2R*,4R*)-4-Isopropylamino-2-(4-methylsulfanyl-benzenesulfon-
ylmethyl)-cyclohexyl]-4-(3-trifluoromethyl-phenyl)-5,6-dihydro-1H-pyridin--
2-one
[0614] (28a) Vinylmagnesium bromide (40 mL of a 1.0 M THF solution,
40 mmol) was added to a dry round bottom flask under nitrogen. The
solution was cooled to -10.degree. C. and charged with
meta-trifluoromethylbenzaldehyde (5.0 g, 29 mmol). The reaction was
stirred for 1 h, warmed to RT and quenched with sat. NH.sub.4Cl.
The mixture was extracted with EtOAC three times, and the organic
extracts were dried (MgSO.sub.4) and concentrated in vacuo. The
crude material was purified via flash chromatography to give
1-(3-trifluoromethylphenyl)propen-1-ol as an oil (5.0 g, 87%
yield). A portion of 1-(3-trifluoromethylphenyl)-propen-1-ol (0.5
g, 2.5 mmol) was dissolved in acetone (20 mL). The resultant
solution was cooled to 0.degree. C., treated with Jones reagent
(1.14 mL of a 2.6 M solution, 2.96 mmol), and stirred for 10
minutes before being quenched with the addition of isopropyl
alcohol (1.5 mL). The mixture was stirred for 5 min at rt, diluted
with Et.sub.2O, filtered through Celite, washed with 10%
Na.sub.2SO.sub.3. The material was purified via filtration through
a plug of silica gel (1:1 Et.sub.2O:hexanes as eluant) to provide
the 1-(3-trifluoromethylphenyl)propenone as an oil (320 mg, 65%
yield), which solidified upon standing in the freezer. .sup.1H-NMR
(300 MHz, CDCl.sub.3): .delta. 8.20 (s, 1H), 8.13 (d, 1H, J=7.7
Hz), 7.64 (d, 1H, J=9.0 Hz), 7.64 (t, 1H, J=7.7 Hz), 7.16 (dd, 1H,
J=17.2, 10.6 Hz), 6.49 (dd, 1H, J=17.2, 1.5 Hz), 6.03 (dd, 1H,
J=10.6, 1.5 Hz).
[0615] (28b) The compound (.+-.)
[(1S*,2R*,4R*)-4-azido-2(4-methylsulfanyl-benzenesulfonylmethyl)-cyclohex-
yl]-carbamic acid tert-butyl ester (2.36 g, 5.36 mmol, see
procedure 10d above) was dissolved in 2:1 CH.sub.2Cl.sub.2/TFA and
stirred at rt for 1 h before being concentrated in vacuo. The
resulting residue was redissolved in 1N NaOH and this solution was
extracted twice with Et.sub.2O. The extracts were combined, washed
with brine, dried (MgSO.sub.4), filtered, and concentrated in
vacuo. The product amine was dissolved in MeOH (40 mL), cooled to
-10.degree. C., and treated with a solution of the
1-(3-trifluoromethylphenyl)propenone (1.09 g, 5.23 mmol) in MeOH
(10 mL). The reaction was stirred for 30 min at rt, diluted with
EtOAc, and washed successively with sat. NaHCO.sub.3 and brine. The
organic phase was dried (MgSO.sub.4), filtered, and concentrated in
vacuo. The resultant residue was purified by flash chromatography
to give the desired (.+-.)
3-[(1S*,2R*,4R*)-4-azido-2-(4-methylsulfanyl-benzenesulfonylmethyl)-cyclo-
hexylamino]-1-(3-trifluoromethyl-phenyl)-propan-1-one (2.0 g, 69%
yield). MS found: (M+H).sup.+=541.3.
[0616] (28c) To a cooled (0.degree. C.) solution of
dimethylphosphonoacetic acid tert-butyl ester (0.44 mL, 2.22 mmol)
in THF (20 mL) was added sodium hydride (94 mg, 60 wt % dispersion
in oil, 2.35 mmol) in one portion. The mixture was stirred for 30
minutes at O--C and then charged with a solution of (.+-.)
3-[(1S*,2R*,4R*)-4-azido-2-(4-methylsulfanyl-benzenesulfonylmethyl)-cyclo-
hexylamino]-1-(3-trifluoromethyl-phenyl)-propan-1-one (0.75 g, 1.38
mmol) in THF. The reaction was stirred for 64 h at rt, quenched
with sat. NH.sub.4Cl, and extracted twice with EtOAc. The organic
extracts were combined, washed with brine, dried
(Na.sub.2SO.sub.4), filtered, and concentrated in vacuo. The crude
residue was purified by flash chromatography to afford
diastereomerically-pure (.+-.)
E-[5-[(1S*,2R*,4R*)-4-azido-2-(4-methylsulfanyl-benzenesulfonylmethyl)-cy-
clohexylamino]-3-(3-trifluoromethyl-phenyl)-pent-2-enoic acid
tert-butyl ester] (0.26 g, 29% yield) and a number of impure
fractions of the same compound contaminated with its
Z-diastereomer. MS found: (M+H).sup.+=639.3.
[0617] (28d) The compound (.+-.)
E-[5-[(1S*,2R*,4R*)-4-azido-2-(4-methylsulfanyl-benzenesulfonylmethyl)-cy-
clohexylamino]-3-(3-trifluoromethyl-phenyl)-pent-2-enoic acid
tert-butyl ester] (0.26 g, 0.4 mmol) was dissolved in 2:1
CH.sub.2Cl.sub.2/TFA and stirred at rt for 1 h before being
concentrated in vacuo. The residue was redissolved in
CH.sub.2Cl.sub.2 and concentrated in vacuo; this procedure was
repeated once. The unpurified amino acid was dissolved in
CH.sub.2Cl.sub.2, and the resulting solution was sequentially
charged with N,N-diisopropylethylamine (0.3 mL, 1.6 mmol),
4-dimethylaminopyridine (54 mg, 0.44 mmol), and HATU (170 mg, 0.44
mmol). The mixture was stirred for 14 h at rt, quenched with sat.
NH.sub.4Cl, and extracted twice with EtOAc. The organic extracts
were combined, washed with brine, dried (Na.sub.2SO.sub.4),
filtered, and concentrated in vacuo. The crude residue was purified
by flash chromatography to afford (.+-.)
1-[(1S*,2R*,4R*)-4-azido-2-(4-methylsulfanyl-benzenesulfonylmethyl)-cyclo-
hexyl]-4-(3-trifluoromethyl-phenyl)-5,6-dihydro-1H-pyridin-2-one
(0.2 g, 89% yield). The entirety of this material was dissolved in
MeOH. The resultant solution was charged with 0.1 g of 10%
Pd/BaSO.sub.4, and the flask was evacuated and then back-filled
with hydrogen (1 atm). This procedure was repeated several times.
The reaction was stirred for 12 h and then filtered. The resultant
solution was concentrated in vacuo to provide (.+-.)
1-[(1S*,2R*,4R*)-4-amino-2-(4-methylsulfanyl-benzenesulfonylmethyl)-cyclo-
hexyl]-4-(3-trifluoromethyl-phenyl)-5,6-dihydro-1H-pyridin-2-one
(quantitative; .about.90% purity). MS found: (M+H).sup.+=538.
[0618] (28e) To a solution of (.+-.) 1-[(1S*,2R*,4R*)-4-amino-2-(4
methylsulfanyl-benzenesulfonylmethyl)-cyclohexyl]-4-(3-trifluoromethyl-ph-
enyl)-5,6-dihydro-1H-pyridin-2-one (0.36 mmol) in dichloroethane (6
mL) was added acetic acid (0.1 mL, 1.8 mmol), acetone (0.08 mL, 1.1
mmol), and sodium triacetoxyborohydride (0.23 g, 1.1 mmol). The
mixture was heated at 80.degree. C. for 1 h, cooled to rt, and
quenched with sat. NaHCO.sub.3, and extracted twice with EtOAc. The
organic extracts were combined, washed with brine, dried
(Na.sub.2SO.sub.4), filtered, and concentrated in vacuo. A portion
of the crude residue was purified by reverse-phase HPLC to provide
two fractions, one of which contained the title. MS found:
(M+H).sup.+=581.
Example 29
(.+-.)
1-[(1S*,2R*,4R*)-4-Isopropylamino-2-(4-benzenesulfonylmethyl)-cyclo-
hexyl]-4-(3-trifluoromethyl-phenyl)-5,6-dihydro-1H-pyridin-2-one
(29a) The title compound was isolated from a separate fraction of
the reverse-phase HPLC purification described in procedure 28e
above. MS found: (M+H).sup.+=535.
Example 30
(.+-.)
1-[(1S*,2R*,4R*)-4-Isopropylmethylamino-2-(4-methylsulfanyl-benzene-
sulfonylmethyl)-cyclohexyl]-4-(3-trifluoromethyl-phenyl)-5,6-dihydro-1H-py-
ridin-2-one
[0619] (30a) To a solution of (.+-.)
1-[(1S*,2R*,4R*)-4-isopropylamino-2-(4-methylsulfanyl-benzenesulfonyl-met-
hyl)-cyclohexyl]-4-(3-trifluoromethyl-phenyl)-5,6-dihydro-1H-pyridin-2-one
(0.18 mmol) in MeOH (4 mL) was added formaldehyde (0.09 mL of a 37
wt % solution in water, 1.08 mmol) and sodium cyanoborohydride
(0.023 g, 0.36 mmol). The reaction was stirred for 3 h, quenched
with sat. NaHCO.sub.3, and extracted twice with EtOAc. The organic
extracts were combined, washed with brine, dried
(Na.sub.2SO.sub.4), filtered, and concentrated in vacuo. The crude
residue was purified by reverse-phase HPLC to provide the title
compound. MS found: (M+H).sup.+=595.4.
Example 31
(.+-.)
1-[(1S*,2R*,4R*)-4-Amino-2-(4-methylsulfanyl-benzenesulfonylmethyl)-
-cyclohexyl]-4-(3-trifluoromethoxyphenyl)-5,6-dihydro-1H-pyridin-2-one
[0620] (31a) meta-Trifluoromethoxybenzaldehyde (4.63 g) was
incorporated into procedure (28a) above to provide
1-(3-trifluoromethoxyphenyl)propenone (2.57 g, 50% yield). A
portion of this material (0.35 g, 1.75 mmol) was carried through
procedures (28b)-(28d) to give a residue, which was purified by
reverse-phase HPLC to provide the title compound (0.043 g). MS
found: (M+H).sup.+=555.2.
Example 32
(.+-.)
1-[(1S*,2R*,4R*)-4-Isopropylamino-2-(4-methylsulfanyl-benzenesulfon-
ylmethyl)-cyclohexyl]-4-(3-trifluoromethoxyphenyl)-5,6-dihydro-1H-pyridin--
2-one
[0621] (32a) The product of procedure (31a), (.+-.)
1-[(1S*,2R*,4R*)-4-amino-2-(4-methylsulfanyl-benzene-sulfonylmethyl)-cycl-
ohexyl]-4-(3-trifluoromethoxyphenyl)-5,6-dihydro-1H-pyridin-2-one
(0.026 g, 0.046 mmol), was carried through procedure (28e) above to
afford the title compound (0.013 g, 47% yield) after purification
by reverse-phase HPLC. MS found: (M+H).sup.+=597.2.
Example 33
(.+-.)
1-[(1S*,2R*,4R*)-4-Isopropylamino-2-(4-benzenesulfonylmethyl)-cyclo-
hexyl]-4-(3-trifluoromethyl-phenyl)-piperidin-2-one
[0622] (33a) The product of procedure (28e), (.+-.)
1-[(1S*,2R*,4R*)-4-isopropylamino-2-(4-methylsulfanyl-benzenesulfonylmeth-
yl)-cyclohexyl]-4-(3-trifluoromethyl-phenyl)-5,6-dihydro-1H-pyridin-2-one
(.about.10 mg), was dissolved in MeOH. The resulting solution was
charged with .about.20 mg 10% Pd/C, stirred under 1 atm of H.sub.2
for 12 h, filtered, and concentrated in vacuo. The residue was
redissolved in MeOH. The resulting solution was charged with
.about.40 mg 10% Pd/C, stirred under 55 atm of H.sub.2 for 12 h,
filtered, and concentrated in vacuo. The residue was redissolved in
MeOH. The resulting solution was charged with .about.50 mg 10%
Pd/C, stirred under 55 atm of H.sub.2 for 36 h, filtered, and
concentrated in vacuo. The residue was dissolved in 0.5% TFA/MeCN
and concentrated in vacuo to afford a mixture of diastereomers as
the title compound as its TFA salt (10 mg). MS found:
(M+H).sup.+=537.
Example 34
(S)-3-(3-(trifluoromethyl)benzylamino)-1-((1S,2R,4R)-4-(isopropyl(methyl)a-
mino)-2-((4-(methylthio)phenylsulfonyl)methyl)cyclohexyl)pyrrolidin-2-one
(34a) 3-(Trifluoromethyl)benzaldehyde and sodium cyanoborohydride
(instead of 3-trifluoromethylphenyl isocyanate) in MeOH (instead of
DMF) were incorporated into Example 18 to give the title compound.
MS found: (M+H).sup.+=612.3.
Example 35
3(R')-(3-(trifluoromethyl)phenethyl)-1-((1S,2R,4R'/S)-4-(isopropylamino)-2-
-(phenylsulfonylmethyl)cyclohexyl)pyrrolidin-2-one
trifluoroacetate
[0623] (35a) 3-(Trifluoromethyl)phenethyl alcohol (10.0 g, 52.6
mmol), triphenylphosphine (17.9 g, 68.4 mmol), and imidazole (5.00
g, 73.6 mmol) were dissolved in acetonitrile (42 mL) and ether (70
mm), then the mixture was cooled to 0.degree. C. Iodine (18.7 g,
73.6 mmol) was added in portions, then the mixture was stirred for
4 h. The reaction mixture was diluted with ether (1 L), washed with
saturated Na.sub.2S.sub.2O.sub.3 (3.times.300 mm), aqueous
CuSO.sub.4 (2.times.300 mL), and brine (2.times.300 mL), dried over
Na.sub.2SO.sub.4, filtered, and concentrated to a volume of 200 mL.
The precipitate of triphenylphosphineoxide was removed by
filtration and the filtrate was triturated with ether/hexanes (2:1,
300 mL). Additional triphenylphosphine-oxide was removed by
filtration, and the filtrate was concentrated to dryness to provide
1-(2-iodoethyl)-3-trifluoromethylbenzene as a yellow oil (16.5 g,
quantitative): .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.54-7.35
(m, 4H), 3.37 (t, J=8.3 Hz, 2H), 3.24 (t, J=8.3 Hz, 2H); .sup.19F
NMR (282 MHz, CDCl.sub.3) .delta. -63.1.
[0624] (35b) To a 100-mL three-neck round-bottomed flask equipped
with a thermometer, addition funnel, and nitrogen inlet was added
diisopropylamine (2.4 mm, 17.2 mmol) in THF (4 mL). The solution
was cooled to -78.degree. C., then a solution of n-BuLi (2.5 M in
hexanes, 6.9 mL) was added slowly, followed by HMPA (3.1 mL, 18.0
mmol) and the reaction was stirred at this temperature for 30 min.
A solution of ethylpent-4-enoate (2.0 g, 15.6 mmol) in THF (15.6
mm) was added dropwise, then the mixture was stirred for 45 min. To
this mixture was added a solution of
1-(2-iodoethyl)-3-trifluoromethylbenzene (35a) (1.37 g, 4.58 mmol)
in THF (2 mL) and the resulting mixture was allowed to warm to room
temperature overnight. The mixture was diluted with ether (500 mL),
washed with water (2.times.250 mL), and brine (2.times.250 ml),
dried over Na.sub.2SO.sub.4, filtered, and evaporated. The residue
was purified by flash chromatography to provide
2-[2-(3-trifluoromethylphenyl)ethyl]pent-4-enoic acid ethyl ester
(529 mg, 39%) as a colorless oil: ESI MS m/z 301
[C.sub.16H.sub.19F.sub.3O.sub.2+H].sup.+.
[0625] (35c) 2-[2-(3-Trifluoromethylphenyl)ethyl]pent-4-enoic acid
ethyl ester (529 mg, 1.76 mmol) was dissolved in CH.sub.2Cl.sub.2
and cooled to -78.degree. C. The resulting solution was treated
with ozone until a light blue color was observed. The solution was
degassed with N.sub.2, then polymer-supported Ph.sub.3P (3 mmol/g,
882 mg, 2.64 mmol) was added and the mixture was stirred for 3 h at
room temperature. The solid was removed by filtration and rinsed
with CH.sub.2Cl.sub.2. Evaporation of the filtrate provided an oil,
which was purified by flash column chromatography (hexanes/ether)
to give ethyl
2-((1,2,3-trioxolan-4-yl)methyl)-4-(3-(trifluoromethyl)phenyl)butanoate
as a colorless oil (151 mg, 25%) and the desired ethyl
2-(2-oxoethyl)-4-(3-(trifluoromethyl)phenyl)butanoate as a
colorless oil (83 mg, 16%). A solution of ethyl
2-((1,2,3-trioxolan-4-yl)methyl)-4-(3-(trifluoromethyl)phenyl)butanoate
(150 mg, 431 .mu.mol) in CH.sub.2Cl.sub.2 (20 mL) was cooled to
-78.degree. C., then Me.sub.2S (0.3 mL, 4.1 mmol) was added and the
mixture was stirred for 2 d. The reaction mixture was diluted with
CH.sub.2Cl.sub.2 (300 mL), washed with water (2.times.100 mL), and
brine (100 mm), dried over Na.sub.2SO.sub.4, filtered, and
evaporated to provide additional ethyl
2-(2-oxoethyl)-4-(3-(trifluoromethyl)phenyl)butanoate (123 mg):
.sup.1H NMR (300 MHz CDCl.sub.3) .delta. 7.50-7.30 (m, 4H),
5.26-5.20 (m, 1H), 5.14 (d, J=1.6 Hz, 1H), 5.04 (d, J=6.3 Hz, 1H),
4.37 (q, J=7.0 Hz, 2H), 2.73-2.57 (m, 3H), 2.35-1.77 (m, 4H), 1.29
(t, J=7.1 Hz, 3H); .sup.19F NMR (282 MHz, CDCl.sub.3) .delta.
-63.0.
[0626] (35d) Ethyl
2-(2-oxoethyl)-4-(3-(trifluoromethyl)phenyl)butanoate (83 mg, 275
.mu.mol) and
(7R,8S)-7-(benzene-4-sulfonylmethyl)-1,4-dioxa-spiro[4.5]dec-8-ylamine
[3g by substitution of phenyl disulfide into step (3d) and skipping
step (3f)] (68 mg, 218 .mu.mol) were dissolved in
1,2-dichloroethane (2.3 mL). The resulting solution was stirred at
room temperature for 10 min, then sodium triacetoxyborohydride (58
mg, 275 .mu.mol) was added and the mixture was stirred overnight.
The reaction mixture was diluted with CH.sub.2Cl.sub.2 (400 mL),
washed with saturated NH.sub.4Cl (3.times.150 mL), and brine (200
mm), dried over Na.sub.2SO.sub.4, filtered and evaporated. The
residue was purified by flash column chromatography to give an
inseparable mixture of diastereomers
4-(7-benzenesulfonylmethyl-1,4-dioxaspiro[4.5]dec-8-ylamino)-2-[2-(3-trif-
luoromethylphenyl)ethyl]butyric acid ethyl ester (64 mg, 49%): ESI
MS m/z 598 [C.sub.30H.sub.38F.sub.3NO.sub.6S+H].sup.+.
[0627] (35e) The mixture of diastereomers from above (35d) (92 mg,
154 mmol) was dissolved in MeOH (10 mL) and NaOMe (85 mg) was
added. The mixture was heated at 50.degree. C. for 16 h, then
diluted with EtOAc (300 mL). The mixture was washed with water
(3.times.150 mL) and brine (200 mL), dried over Na.sub.2SO.sub.4,
and evaporated in vacuo to dryness. The residue was purified by
flash column chromatography to provide
(1S,2R)-1-(7-benzenesulfonylmethyl-1,4-dioxaspiro[4.5]dec-8-yl)-3-
(R)-[2-(3-trifluoromethylphenyl)ethyl]pyrrolidin-2-one (upper TLC
spot; 30 mg, 35%): .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.
7.88-7.80 (m, 2H), 7.62-7.35 (m, 7H), 4.03-3.70 (m, 6H), 3.52-3.39
(m, 1H), 3.37-3.25 (m, 1H), 3.06 (dd, J=14.6, 2.1 Hz, 1H),
2.88-2.67 (m, 3H), 2.33-1.55 (m, 11H); .sup.19F NMR (282 MHz,
CDCl.sub.3) .delta. -63.0; ESI MS m/z 552
[C.sub.28H.sub.32F.sub.3NO.sub.5S+H].sup.+; and (1S,
2R)-1-(7-benzenesulfonylmethyl-1,4-dioxaspiro[4.5]dec-8-yl)-3(S)-[2-(3-tr-
ifluoromethylphenyl)ethyl]pyrrolidin-2-one (lower TLC spot; 34 mg,
41%) .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.88-7.80 (m, 2H),
7.60-7.35 (m, 7H), 4.03-3.73 (m, 6H), 3.40-3.25 (m, 2H), 2.97 (dd,
J=14.3, 1.9 Hz, 1H), 2.80-2.62 (m, 3H), 2.40-1.40 (m, 11H);
.sup.19F NMR (282 MHz, CDCl.sub.3) .delta. -63.0; ESI MS m/z 552
[C.sub.28H.sub.32F.sub.3NO.sub.5S+H].sup.+.
[0628] (35f)
(1S,2R)-1-(7-benzenesulfonylmethyl-1,4-dioxaspiro[4.5]dec-8-yl)-3(R)-[2-(-
3-trifluoromethylphenyl)ethyl]pyrrolidin-2-one (29 mg, 53 mmol) and
p-TsOH (4 mg) in acetone (5 mL) was stirred overnight at room
temperature. A second portion of p-TsOH (4 mg) was added and the
reaction mixture was stirred for an additional 24 h. The solvent
was evaporated in vacuo and the residue was purified by flash
column chromatography to afford
(R)-3-(3-(trifluoromethyl)phenethyl)-1-((1S,2R)-4-oxo-2-(phenylsulfonylme-
thyl)cyclohexyl)pyrrolidin-2-one (17 mg, 64%) as a white solid: ESI
MS m/z 508 [C.sub.26H.sub.28F.sub.3NO.sub.4S+H].sup.+.
[0629] (35g) To a stirred mixture of the above compound (35f) (17
mg, 34 mmol) and titanium(IV) isopropoxide (0.5 mL, 1.67 mmol) was
added 2-propylamine (36 mg, 600 mmol). The mixture was stirred at
room temperature for 3 h, then MeOH (5 mL) was added, followed by
NaBH.sub.4 (3.5 mg, 94 mmol). After 2 h, the reaction mixture was
quenched with 0.5 M NaOH (30 mL) and the resulting mixture was
stirred for 2 h. The mixture was diluted with EtoAc (400 mL),
washed with 0.5 M NaOH (3.times.150 mL) and brine (200 mL), dried
over Na.sub.2SO.sub.4, filtered, and evaporated. Purification of
the residue by semi-preparative HPLC gave the title compound (10
mg) as a mixture of diastereomers: .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 8.00-7.75 (m, 2H), 7.73-7.30 (m, 7H), 4.60-1.50
(m, 20H), 1.49-1.20 (m, 6H).
Example 36
3(S)-(3-(Trifluoromethyl)phenethyl)-1-((1S,2R,4R/S)-4-(isopropylamino)-2-(-
phenylsulfonylmethyl)cyclohexyl)pyrrolidin-2-one
trifluoroacetate
[0630] (36a)
(1S,2R)-1-(7-Benzenesulfonylmethyl-1,4-dioxaspiro[4.5]dec-8-yl)-3(S)-[2-(-
3-trifluoromethylphenyl)ethyl]pyrrolidin-2-one (see, 35e) was
incorporated into Example 35, step (35f) to give the title compound
as a mixture of diastereomers. MS found: (M+H).sup.+=551.4.
Example 37
N--((S)-1-((1S,2R,4R)-4-(isopropyl(methyl)amino)-2-(phenylsulfonylmethyl)c-
yclohexyl)-2-oxoazepan-3-yl)-3-(trifluoromethyl)benzamide
trifluoroacetate
[0631] (37a) To a solution of
(S)-2-tert-butoxycarbonylamino-6-hydroxy-hexanoic acid (1 g, 6
mmol) in 30 mL of CH.sub.2Cl.sub.2 and 5 mL of MeOH at rt was
slowly added TMSCHN.sub.2 (10 mL), and the reaction mixture was
left with stirring for 1 h. The solvent was remove under reduced
pressure, and the resulting residue was diluted with water and
EtOAc. The organic layer was separated, dried over
Na.sub.2SO.sub.41 and concentrated to afford an oil
(S)-2-tert-butoxycarbonylamino-6-hydroxy-hexanoic acid methyl
ester. MS [M+H].sup.+ 262.
[0632] (37b) To a solution of oxalyl chloride (0.33 mL, 0.36 mmol)
in CH.sub.2Cl.sub.2 (10 mL) at -78 C was added DMSO (0.1 mL, 1.32
mmol). Ten minutes later, a solution of alcohol
(S)-2-tert-butoxycarbonylamino-6-hydroxy-hexanoic acid methyl ester
(144 mg, 0.55 mmol) in CH.sub.2Cl.sub.2 (10 mL) was added and
stirred for 15 min before iPr.sub.2NEt (0.5 mL, 2.7 mmol) was
added. The reaction mixture was allowed to warm up to 0 C and left
with stirring for 2 h before water and EtOAc were added. The
organic layer was separated, dried over Na.sub.2SO.sub.4, and
concentrated to afford to a crude oil
(S)-2-tert-butoxycarbonylamino-6-oxo-hexanoic acid methyl
ester.
[0633] (37c) To a solution of
(1S*,2R*,4R*)-4-azido-2-benzenesulfonylmethyl-cyclohexylamine (see
example 10, steps 10a-10d with the substitution of methyl phenyl
sulfone in step 10a and then treated with TFA) (135 mg, 0.45 mmol)
and (S)-2-tert-butoxycarbonylamino-6-oxo-hexanoic acid methyl ester
(140 mg, 0.55 mmol) in CH.sub.2Cl.sub.2 (15 mL) at rt was added
NaBH(OAc).sub.3 (194 mg, 0.9 mmol). After 16 h, the solution was
concentrated. The resulting residue was re-dissolved in EtOAc and
washed with saturated NaHCO.sub.3, water, and brine. The organic
layer was dried, filtered, and concentrated to afford to a crude
oil
(1S,2R,3S,4R)-6-(4-azido-2-benzenesulfonylmethyl-cyclohexylamino)-2-tert--
butoxycarbonylamino-hexanoic acid methyl ester. MS
[M+H].sup.+=538.
[0634] (37d) To a solution of
(1S,2R,3S,4R)-6-(4-azido-2-benzenesulfonylmethyl-cyclohexylamino)-2-tert--
butoxycarbonylamino-hexanoic acid methyl ester (270 mg) in THF (15
mL) and H.sub.2O (3 mL) at rt was added LiOH (24 mg). After 1 h,
the reaction was diluted with water and EtOAc. Upon adjusting the
pH value to 7, the organic layer was collected, dried, and
concentrated to afford to a crude oil (140 mg) which was
re-dissolved in DMF (15 mL), followed by the addition of HATU (132
mg, 0.34 mmol) and Hunig's base (0.06 mL, 0.34 mmol). The resulting
mixture was stirred for 16 before EtOAc was added. The EtOAc layer
was washed with 1 N HCl, NaHCO.sub.3 solution (aq), and brine. The
EtOAc was dried (MgSO.sub.4), filtered, and concentrated. Flash
chromatography of the resulting residue gave
[(3S)-1-(1S,2R,4R)-(4-azido-2-benzenesulfonylmethyl-cyclohexyl)-2-oxo-aze-
pan-3-yl]-carbamic acid tert-butyl ester (120 mg). MS found;
(M+H).sup.+=506.
[0635] (37e) To a solution of
[(3S)-1-(1S,2R,4R)-(4-azido-2-benzenesulfonylmethyl-cyclohexyl)-2-oxo-aze-
pan-3-yl]-carbamic acid tert-butyl ester (120 mg) in
CH.sub.2Cl.sub.2 (10 mL) was added TFA (3.3 mL). After 45 min, the
solution was diluted with NaHCO.sub.3 solution (aq) and EtOAc. The
organic layer was collected, dried, and concentrated to afford to a
crude oil
3-amino-(3S)-1-(1S,2R,4R)-(4-azido-2-benzenesulfonylmethyl-cyclohexyl)-az-
epan-2-one. MS [M+H].sup.+=406.
[0636] (37f) To a solution of
3-amino-(3S)-1-(1S,2R,4R)-(4-azido-2-benzenesulfonylmethyl-cyclohexyl)-az-
epan-2-one (50 mg, 0.12 mmol) in DMF (15 mL) was added
3-trifluoromethyl benzoic acid (28 mg, 0.15 mmol), HATU (57 mg,
0.15 mmol) and Hunig's base (0.03 ml, 0.15 mmol). The resulting
mixture was stirred for 16 h before EtoAc was added. The EtOAc
layer was washed with 1 N HCl, NaHCO.sub.3 solution (aq), and
brine. The EtOAc was dried (MgSO.sub.4), filtered, and
concentrated. Flash chromatography of the resulting residue gave
N-[(3S)-1-(1S,2R,4R)-(4-azido-2-benzenesulfonylmethyl-cyclohexyl)-2-oxo-a-
zepan-3-yl]-3-trifluoromethyl-benzamide (70 mg). MS found:
(M+H).sup.+=578.
[0637] (37g)
N-[(3S)-1-(1S,2R,4R)-(4-Azido-2-benzenesulfonylmethyl-cyclohexyl)-2-oxo-a-
zepan-3-yl]-3-trifluoromethyl-benzamide (70 mg) was dissolved in
MeOH (10 mL) prior to the addition of 10% Pd/C (20 mg). A hydrogen
balloon was added and the solution was stirred at rt for 16 h. The
palladium was filtered and the solvent was concentrated to
N-[(3S)-1-(1S,2R,4R)-(4-amino-2-benzenesulfonylmethyl-cyclohexyl)-2-oxo-a-
zepan-3-yl]-3-trifluoromethyl-benzamide. MS found:
(M+H).sup.+=552.
[0638] (37h) To a solution of
N-[(3S)-1-(1S,2R,4R)-(4-amino-2-benzenesulfonylmethyl-cyclohexyl)-2-oxo-a-
zepan-3-yl]-3-trifluoromethyl-benzamide (30 mg) in CH.sub.2Cl.sub.2
(15 mL) at rt was added NaBH(OAc).sub.3 (50 mg), acetone (2 mL),
and three drops of AcOH. After 2 h, formaldehyde (2 mL) was added
and the solution was stirred for another 2 h. The reaction mixture
was diluted with EtOAc and washed with saturated NaHCO.sub.3,
water, and brine. The organic layer was dried, filtered, and
concentrated to afford to a crude oil which was purified by
semi-preparative HPLC to give the title compound. MS
[M+H].sup.+=608.
Example 38
N--((S)-1-((1S,2R,4R)-4-(dimethylamino)-2-(phenylsulfonylmethyl)cyclohexyl-
)-2-oxopiperidin-3-yl)-3-(trifluoromethyl)benzamide
trifluoroacetate
(38a) (S)-2-tert-Butoxycarbonylamino-5-hydroxy-pentanoic acid
benzyl ester was incorporated into Example 37 (without acetone in
step 37h) to give the title compound. MS found:
(M+H).sup.+=566.
Example 39
(R*)-1-((1S*,2R*,4R*)-4-(isopropyl(methyl)amino-2-(phenylsulfonylmethyl)cy-
clohexyl)-3-((2-(3-(trifluoromethyl)phenyl)-1,3-dioxolan-2-yl)methyl)pyrro-
lidin-2-one
[0639] (39a) A mixture of methyl 3-bromopropionate (6a, 10.0 g,
60.0 mmol) and sodium iodide (11.2 g, 74.9 mmol) in acetone (60 mL)
was stirred for 30 min at room temperature, then heated at reflux
for 40 min. The mixture was cooled in an ice/water bath and the
white solid was filtered off, rinsing with acetone. The filtrate
was evaporated to dryness to provide methyl 3-iodopropionate (12.3
g, 96%) as a yellow oil: .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.
3.73 (s, 3H), 3.33 (t, J=7.2 Hz, 2H), 2.99 (t, J=7.2 Hz, 2H).
[0640] (39b) To a 250-mL three-neck round-bottomed flask equipped
with a thermometer, condenser, and nitrogen inlet was added Zn--Cu
couple (3.41 g, 52.1 mmol). A solution of methyl 3-iodopropionate
(7.27 g, 34.0 mmol) in benzene (67.7 mL) and DMA (4.5 mL) was added
over 5 min and the mixture was stirred at room temperature for 1 h,
then heated at 60.degree. C. for 5 h. A mixture of
Pd(PPh.sub.3).sub.4 (1.05 g, 0.906 mmol) in benzene (22.7 mL) was
added to the reaction and stirred at 60.degree. C. for 5 min. The
mixture was then removed from heat and 3-(trifluoromethyl)benzoyl
chloride (3.4 mm, 23 mmol) in benzene (11.3 mL) was added
immediately. After stirring for 2 h, the mixture was diluted with
EtOAc, washed with 1 M HCl (3.times.200 mL), NaHCO.sub.3
(2.times.200 mL) and brine (1.times.200 mm), dried over
Na.sub.2SO.sub.4, filtered, and evaporated. The crude material was
purified by CombiFlash chromatography (silica, 0-70% ether/hexanes)
to give 4-oxo-4-(3-trifluoromethylphenyl)butyric acid methyl ester
(5.35 g, 91%) as an orange oil: .sup.1H NMR (300 MHz CDCl.sub.3)
.delta. 8.24 (s, 1H), 8.17 (d, J=7.8 Hz, 1H), 7.84 (d, J=7.8 Hz,
1H), 7.63 (t, J=7.8 Hz, 1H), 3.72 (s, 3H), 3.35 (t, J=6.5 Hz, 2H),
2.81 (t, J=6.5 Hz, 2H); .sup.19F NMR (282 MHz, CDCl.sub.3) .delta.
-63.3; ESI MS m/z 261 [C.sub.12H.sub.11F.sub.3O.sub.3+H].sup.+.
[0641] (39c) A solution of 4-oxo-4-(3-trifluoromethylphenyl)butyric
acid methyl ester (2.47 g, 9.50 mmol), trimethylorthoformate (4.8
mL), p-TsOH (181 mg, 0.95 mmol) and ethylene glycol (7.3 mL) was
heated at 50.degree. C. for 3 h. The mixture was diluted with EtOAc
(500 mL), washed with saturated NaHCO.sub.3 (3.times.200 mL), water
(2.times.200 mL), and brine (150 mL), dried over Na.sub.2SO.sub.4,
filtered and evaporated to give a mixture of esters. The mixture
was stirred in MeOH (25 mL) with NaOMe (400 mg) at room temperature
for 6 h. The reaction was quenched with saturated NH.sub.4Cl and
the methanol was removed by evaporation. The residue was dissolved
in EtOAc, washed with saturated NH.sub.4Cl (2.times.200 mL), water
(2.times.200 mL) and brine (200 mL), dried over Na.sub.2SO.sub.4,
and evaporated to give
3-[2-(3-trifluoromethylphenyl)-[1,3]dioxolan-2-yl]propionic acid
methyl ester (2.71 g, 94%) as a light yellow oil: .sup.1H NMR (300
MHz, CDCl.sub.3) .delta. 7.73 (s, 1H), 7.65 (d, J=7.7 Hz, 1H), 7.56
(d, J=7.7 Hz, 1H), 7.47 (t, J=7.7 Hz, 1H), 4.10-3.99 (m, 2H),
3.80-3.70 (m, 2H), 3.65 (s, 3H), 2.44 (t, J=7.8 Hz, 2H), 2.24 (t,
J=7.8 Hz, 2H); .sup.19F NMR (282 MHz, CDCl.sub.3) .delta. -62.9;
ESI MS m/z 305 [C.sub.14H.sub.15F.sub.3O.sub.4+H].sup.+.
[0642] (39d) Diisopropylamine (1.74 mL, 12.5 mmol) was dissolved in
THF (6.2 mL) under a nitrogen atmosphere and cooled to -78.degree.
C. A solution of n-BuLi (2.5 M in hexanes, 5.3 mL) was added
dropwise, keeping the temperature below -67.degree. C. The reaction
was warmed to -15.degree. C. for 15 min, then cooled back down to
-78.degree. C. A solution of
3-[2-(3-trifluoromethylphenyl)-[1,3]dioxolan-2-yl]propionic acid
methyl ester (2.71 g, 8.90 mmol) in THF (1.5 ml) was added and the
mixture was stirred for 40 min. Allyl bromide (0.92 mL, 11 mmol)
and HMPA (0.46 mL, 2.7 mmol) were added simultaneously and the
reaction was stirred at room temperature overnight. The mixture was
diluted with EtOAc (400 mL), washed with saturated NH.sub.4Cl
(3.times.150 mL), water (2.times.150 mL), and brine (200 mL), dried
over Na.sub.2SO.sub.4, filtered, and evaporated. The residue was
purified by CombiFlash chromatography (silica, 0-40% ether/heptane)
to give
2-[2-(3-trifluoromethylphenyl)-[1,3]dioxolan-2-ylmethyl]pent-4-enoic
acid methyl ester (1.82 g, 59%) as a light yellow oil: .sup.1H NMR
(300 MHz, CDCl.sub.3) .delta. 7.73 (s, 1H), 7.64 (d, J=7.7 Hz, 1H),
7.56 (d, J=7.7 Hz, 1H), 7.46 (t, J=7.7 Hz, 1H), 5.80-5.61 (m, 1H),
5.10-4.97 (m, 2H), 4.10-3.90 (m, 2H), 3.80-3.60 (m, 5H), 2.83-2.68
(m, 1H), 2.50-2.13 (m, 3H), 1.97 (dd, J=14.7, 2.7 Hz, 1H); .sup.19F
NMR (282 MHz, CDCl.sub.3) .delta. -62.9; ESI MS m/z 345
[C.sub.17H.sub.19F.sub.3O.sub.4+H].sup.+.
[0643] (39e) A solution of
2-[2-(3-trifluoromethylphenyl)-[1,3]dioxolan-2-ylmethyl]pent-4-enoic
acid methyl ester (1.82 g, 5.29 mmol) in CH.sub.2Cl.sub.2 (250 mL)
was cooled to -78.degree. C. and ozone was bubbled into the
solution until a light blue solution was obtained. The solution was
degassed with nitrogen, then dimethylsulfide (4 mL) was added
dropwise. The mixture was stirred overnight at room temperature,
then heated at reflux for 24 h. The reaction was diluted with
CH.sub.2Cl.sub.2 (500 mL), washed with 1 M HCl (3.times.150 mL) and
brine (200 mL), dried over Na.sub.2SO.sub.4, filtered, and
evaporated. The residue was purified by CombiFlash chromatography
(silica, 0-50% ether/hexanes) to give aldehyde
4-oxo-2-[2-(3-trifluoromethylphenyl)-[1,3]dioxolan-2-ylmethyl]butyric
acid methyl ester (1.41 g, 77%) as a yellow oil: .sup.1H NMR (300
MHz, CDCl.sub.3) .delta. 9.74 (s, 1H), 7.72 (s, 1H), 7.63 (d, J=7.7
Hz, 1H), 7.57 (d, J=7.7 Hz, 1H), 7.47 (t, J=7.7 Hz, 1H), 4.12-3.95
(m, 2H), 3.83-3.64 (m, 5H), 3.27-3.13 (m, 1H), 2.98-2.70 (m, 2H),
2.40 (dd, J=14.8, 7.2 Hz, 1H), 2.04 (dd, J=14.8, 5.5 Hz, 1H);
.sup.19F NMR (282 MHz, CDCl.sub.3) .delta. -62.9.
[0644] (39f) A mixture of
(1S*,2R*,4R*)-4-azido-2-benzenesulfonylmethyl-cyclohexylamine (see
37c) (676 mg, 2.30 mmol) and
4-oxo-2-[2-(3-trifluoromethylphenyl)-[1,3]dioxolan-2-ylmethyl]butyric
acid methyl ester (794 mg, 2.30 mmol) in 1,2-dichloroethane (46 mL)
was stirred at room temperature overnight. The solvent was removed
under vacuum, then the residue was dissolved in MeOH (35 mL) and
cooled to 0.degree. C. Sodium borohydride (872 mg, 23.0 mmol) was
added in one portion and the mixture was stirred for 4 h. The
reaction was diluted with EtOAc (500 mL), washed with saturated
NaHCO.sub.3 (3.times.150 mL) and brine (200 mL), dried over
Na.sub.2SO.sub.4, filtered, and evaporated. The residue was
purified by CombiFlash chromatography (silica, 0-100%
ether/hexanes) to give a mixture of diastereomers methyl
4-((1S*,2R*,4R*)-4-azido-2-(phenylsulfonylmethyl)cyclohexylamino)-2-((2-(-
3-(trifluoromethyl)phenyl), 3-dioxolan-2-yl)methyl)butanoate (1.04
g, 70%) as a colorless oil: .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta. 8.00-7.88 (m, 2H), 7.75-7.52 (m, 6H), 7.51-7.41 (m, 1H),
4.17-3.88 (m, 2H), 3.80-3.60 (m, 5H), 3.59-3.48 (m, 1H), 3.45-3.30
(m, 1H), 3.10-2.98 (m, 1H), 2.85-2.55 (m, 3H), 2.50-2.20 (m, 3H),
2.00-1.30 (m, 9H); .sup.19F NMR (282 MHz, CDCl.sub.3) .delta.
-62.9, -62.8; ESI MS m/z 625
[C.sub.29H.sub.35F.sub.3N.sub.4O.sub.6S+H].sup.+.
[0645] (39g) A stirred mixture of diastereomers 39f (1.04 g, 1.66
mmol) and NaOMe (90 mg, 1.66 mg) in MeOH (20 mL) was heated at
reflux for 4 d. The solvent was removed under vacuum and the
residue was dissolved in EtOAc (350 mL). The organic mixture was
washed with saturated NH.sub.4Cl (3.times.100 mm), water (200 mL),
and brine (200 mL), dried over Na.sub.2SO.sub.4, filtered, and
evaporated. The crude material was purified by CombiFlash
chromatography followed by preparative TLC to give
(S*)-1-((1S*,2R*,4R*).sub.4-azido-2-(phenylsulfonylmethyl)cyclohexyl)-3-(-
(2-(3-(trifluoromethyl)phenyl)-1,3-dioxolan-2-yl)methyl)pyrrolidin-2-one
(39g-a, 359 mg, 36%) and
(R*)-1-((1S*,2R*,4R*)-4-azido-2-(phenylsulfonylmethyl)cyclohexyl)-3-((2-(-
3-(trifluoromethyl)phenyl)-1,3-dioxolan-2-yl)methyl)pyrrolidin-2-one
(39g-b, 322 mg, 33%) as white solids.
[0646] For 39g-a: .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.
7.90-7.82 (m, 2H), 7.73 (s, 1H), 7.70-7.43 (m, 6H), 4.10-3.90 (m,
3H), 3.81-3.57 (m, 3H), 3.55-3.42 (m, 1H), 3.40-3.20 (m, 3H),
2.61-2.47 (m, 3H), 2.27-2.10 (m, 2H), 2.00-1.63 (m, 7H); .sup.19F
NMR (282 MHz, CDCl.sub.3) .delta. -62.9; ESI MS m/z 593
[C.sub.28H.sub.31F.sub.3N.sub.4O.sub.5+H].sup.+.
[0647] For 39g-b: .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.
7.90-7.82 (m, 2H), 7.73 (s, 1H), 7.69-7.43 (m, 6H), 4.10-3.90 (m,
3H), 3.85-3.57 (m, 3H), 3.44-3.23 (m, 3H), 3.22-3.10 (m, 1H),
2.62-1.60 (m, 12H); .sup.19F NMR (282 MHz, CDCl.sub.3) .delta.
-62.9; ESI MS m/z 593
[C.sub.28H.sub.31F.sub.3N.sub.4O.sub.5S+H].sup.+.
[0648] (39h) A mixture of 39g-b (222 mg, 375 .mu.mol) and 10% Pd/C
(239 mg, 112 .mu.mol) in MeOH (150 mL) was hydrogenated (50 psi)
for 2 h. The mixture was filtered through diatomaceous earth
(infusorial earth) and the filtrate was evaporated under vacuum to
give
(R*)-1-((1S*,2R*,4R*)-4-amino-2-(phenylsulfonylmethyl)cyclohexyl)-3-((2-(-
3-(trifluoromethyl)phenyl)-1,3-dioxolan-2-yl)methyl)pyrrolidin-2-one
(39h-b, 169 mg, 80%) as a white solid: .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 7.87 (d, J=7.3 Hz, 2H), 7.68-7.35 (m, 7H), 4.22
(s, 1H), 4.02-3.60 (m, 5H), 3.50-3.14 (m, 4H), 2.80-2.63 (m, 1H),
2.60-1.60 (m, 12H); .sup.19F NMR (282 MHz, CDCl.sub.3) .delta.
-62.8; ESI MS m/z 567
[C.sub.28H.sub.33F.sub.3N.sub.2O.sub.5S+H].sup.+.
[0649] (39i) A mixture of 39h-b (170 mg, 300 .mu.mol), acetone (871
.mu.L, 11.9 .mu.mol), acetic acid (69.1 .mu.L, 1.20 mmol), and
sodium triacetoxyborohydride (255 mg, 1.20 mmol) in dichloroethane
(17 mL) was stirred at room temperature for 2 h. The reaction was
diluted with EtOAc (500 mL), washed with saturated NaHCO.sub.3
(3.times.150 mL), water (2.times.100 mL), and brine (150 mL), dried
over Na.sub.2SO.sub.4, filtered, and evaporated. The residue was
purified by CombiFlash chromatography (silica, 0-10%
MeOH/CH.sub.2Cl.sub.2) to provide
(R*)-1-((1S*,2R*,4R*)-4-(isopropylamino)-2-(phenylsulfonylmethyl)cyclohex-
yl)-3-((2-(3-(trifluoromethyl)phenyl)-1,3-dioxolan-2-yl)methyl)pyrrolidin--
2-one (39i-b, 106 mg, 58%) as a white solid: .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 7.89 (d, J=7.2 Hz, 2H), 7.68 (s, 1H), 7.64-7.39
(m, 6H), 4.20 (s, 1H), 4.05-3.90 (m, 2H), 3.81-3.60 (m, 3H),
3.48-3.11 (m, 4H), 3.10-2.88 (m, 1H), 2.60-2.10 (m, 5H), 2.09-1.60
(m, 8H), 1.43-1.00 (m, 6H); .sup.19F NMR (282 MHz, CDCl.sub.3)
.delta. -62.9; ESI MS m/z 609
[C.sub.31H.sub.39F.sub.3N.sub.2O.sub.5S+H].sup.+.
[0650] (39j) Compound 39i-b (103 mg, 168 .mu.mol) and 37%
formaldehyde (50 .mu.L, 1.8 mmol) were dissolved in MeOH (2 mL) and
stirred for 3 h at room temperature. Sodium cyanoborohydride (16
mg, 252 .mu.mol) was added and the mixture was stirred for 2 h. The
reaction was diluted with EtOAc (400 mL), washed with saturated
NaHCO.sub.3 (3.times.150 mL) and brine (100 mL), dried over
Na.sub.2SO.sub.4, filtered, and evaporated. The residue was
purified by CombiFlash chromatography (silica, 0-10%
CH.sub.2Cl.sub.2/MeOH) and then lyophilized from
CH.sub.3CN/H.sub.2O to give title compound (77 mg, 74%) as a white
solid: .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.90-7.82 (m, 2H),
7.71 (s, 1H), 7.68-7.42 (m, 6H), 4.15-3.92 (m, 3H), 3.80-3.00 (m,
7H), 2.71-2.10 (m, 9H), 1.93-1.40 (m, 9H), 1.17-0.95 (m, 6H);
.sup.19F NMR (282 MHz, CDCl.sub.3) .delta. -62.9; ESI MS m/z 623
[C.sub.32H.sub.41F.sub.3N.sub.2O.sub.5S+H].sup.+.
Example 40
(S*)-1-((1S*,2R*,4R*)-4-(isopropyl(methyl)amino)-2-(phenylsulfonylmethyl)c-
yclohexyl)-3-((2-(3-(trifluoromethyl)phenyl)-1,3-dioxolan-2-yl)methyl)pyrr-
olidin-2-one
(40a) Diastereomer 39g-a was incorporated into Example 39 (steps
39h-39j) to give the title compound. MS found: (M+H).sup.+=623.
Example 41
(S*)-3-(2-oxo-2-(3-(trifluoromethyl)phenyl)ethyl-1-((1S*,2R*,4R*)-4-(isopr-
opyl(methyl)amino)-2-(phenylsulfonylmethyl)cyclohexyl)pyrrolidin-2-one
[0651] (41a) A solution of Example 40 (74.4 mg, 0.120 mmol) in
CH.sub.3CN (0.9 mL) and 1 M HCl (0.9 mL) was heated at 60.degree.
C. for 5 h. The mixture was diluted with ethyl acetate (500 mL),
washed with satd NaHCO.sub.3 (3.times.150 mL) and brine
(2.times.100 mL), dried over Na.sub.2SO.sub.4, filtered, and
evaporated to dryness. The residue was lyophilized from
CH.sub.3CN/H.sub.2O to the title compound as a white solid (70.2
mg, >99): ESI MS m/z 579
[C.sub.30H.sub.37F.sub.3N.sub.2O.sub.4S+H].sup.+.
Example 42
(R*)-3-(2-oxo-2-(3-trifluoromethyl)phenylethyl)-1-((1S*,2R*,4R*)-4-(isopro-
pyl(methyl)amino)-2-(phenylsulfonylmethyl)cyclohexyl)pyrrolidin-2-one
(42a) Example 39 was incorporated into Example 41 to give the title
compound. MS found: (M+H).sup.+=579.
Example 43
(R*)-3-(2-hydroxy-2-(3-(trifluoromethyl)phenyl)ethyl)-1-((1S*,2R*,4R*)-4-(-
isopropyl(methyl)amino)-2-(phenylsulfonylmethyl)cyclohexyl)pyrrolidin-2-on-
e trifluoroacetate
[0652] (43a) To a solution of Example 42 (19.3 mg, 33.4 .mu.mol) in
MeOH (2 mL) was added sodium borohydride (6 mg, 167 .mu.mol). After
stirring for 1 h, the solvent was removed under vacuum. The residue
was dissolved in EtOAc (500 mL), washed with satd NaHCO.sub.3
(3.times.150 mL) and brine (2.times.100 mL), dried over
Na.sub.2SO.sub.4, filtered, and evaporated to dryness. The residue
was purified by preparative TLC (80:12:6:2
EtOAc/CHCl.sub.3/MeOH/NH.sub.4OH). The middle band was lyophilized
from CH.sub.3CN/H.sub.2O/TFA to give one diastereomer of the title
compound 43a-a (7.9 mg, 34%) as a colorless oil. The bottom band
was lyophilized from CH.sub.3CN/H.sub.2O/TFA to give the second
diastereomer of the title compound 43a-b (12.1 mg, 66%) as a
colorless oil.
[0653] For 43a-a: .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 11.13
(br, s, 1H), 8.00-7.89 (m, 2H), 7.75-7.40 (m, 7H), 5.06-4.93 (m,
1H), 4.40-4.29 (m, 1H), 4.10-3.03 (m, 12H), 3.02-2.90 (m, 1H),
2.89-2.50 (m, 5H), 2.41-2.25 (m, 1H), 2.21-1.60 (m, 10H), 1.48-1.40
(m, 3H), 1.38-1.20 (m, 4H); .sup.19F NMR (282 MHz, CDCl.sub.3)
.delta. -62.9, -76.3; ESI MS m/z 581
[C.sub.30H.sub.39F.sub.3N.sub.2O.sub.4S+H].sup.+.
[0654] For 43a-b: .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 10.95
(br, s, 1H), 7.98-7.89 (m, 2H), 7.76-7.40 (m, 7H), 4.90-4.80 (m,
1H), 4.40-4.30 (m, 1H), 4.10-3.90 (m, 1H), 3.89-3.70 (m, 1H),
3.60-3.48 (m, 1H), 3.42-3.02 (m, 2H), 3.01-2.90 (m, 1H), 2.89-2.55
(m, 6H), 2.40-2.00 (m, 8H), 1.99-1.55 (m, 4H), 1.50-1.40 (m, 3H),
1.37-1.20 (m, 5H); .sup.19F NMR (282 MHz, CDCl.sub.3) .delta.
-63.0, -76.4; EST MS m/z 581
[C.sub.30H.sub.39F.sub.3N.sub.2O.sub.4S+H].sup.+.
Example 44
(S*)-3-(2-hydroxy-2-(3-(trifluoromethyl)phenyl)ethyl)-1-((1S*,2R*,4R*)-4-(-
isopropyl(methyl)amino)-2-(phenylsulfonylmethyl)cyclohexyl)pyrrolidin-2-on-
e trifluoroacetate
(44a) Example 41 was incorporated into Example 43 to give the title
compound as a mixture of diastereomers. MS found:
(M+H).sup.+=581.
Example 45
((S*)-1-((1S*,2R*,4R*)-4-(isopropyl(methyl)amino)-2-(phenylsulfonylmethyl)-
cyclohexyl)-3-(-2-(methoxyimino)-2-(3-(trifluoromethyl)phenyl)ethyl)pyrrol-
idin-2-one trifluoroacetate
[0655] (45a) A stirred mixture of Example 41 (19.7 mg, 34 .mu.mol),
methoxylamine.HCl (17 mg, 204 .mu.mol), NaOAc (17 mg, 204 .mu.mol),
and MeOH (2 ml) was heated at 50.degree. C. for 24 h. The solvent
was removed under vacuum and the residue was dissolved in EtOAc
(500 mL). The organic mixture was washed with satd NaHCO.sub.3
(3.times.100 mL), water (200 mL), and brine (200 mL), dried over
Na.sub.2SO.sub.4, filtered, and evaporated. The residue was
lyophilized from CH.sub.3CN/H.sub.2O/TFA give the title compound as
a mixture of (E) and (Z) isomers (26.9 mg, 95%): .sup.1H NMR (500
MHz, CDCl.sub.3) .delta. 11.03 (s, 1H), 7.97-7.86 (m, 3H),
7.83-7.76 (m, 1H), 7.70-7.63 (m, 1H), 7.62-7.53 (m, 3H), 7.50-7.41
(m, 1H), 4.32-4.20 (m, 1H), 3.99 (s, 3H), 3.95-3.85 (m, 1H),
3.60-3.43 (m, 2H), 3.32-3.20 (m, 1H), 3.15-2.94 (m, 2H), 2.91-2.77
(m, 2H), 2.75-2.65 (m, 3H), 2.63-2.50 (m, 2H), 2.20-1.68 (m, 7H),
1.50-1.40 (m, 3H), 1.35-1.24 (m, 5H); .sup.19F NMR (282 MHz,
CDCl.sub.3) .delta. -63.1, -76.3; ESI MS m/z 608
[C.sub.31H.sub.40F.sub.3N.sub.3O.sub.4S+H].sup.+ 0.1.
Example 46
((R*)--(1S*,2R*,4R*)-4-(isopropyl(methyl)amino)-2-(phenylsulfonylmethyl)cy-
clohexyl)-3-(-2-(methoxyimino)-2-(3-(trifluoromethyl)-phenyl)ethyl)pyrroli-
din-2-one trifluoroacetate
[0656] (46a) Example 42 was incorporated into Example 45 to give
the title compound as a mixture of (E)/(Z). .sup.1H NMR (500 MHz,
CDCl.sub.3) .delta. 10.80 (Sr 1H), 7.98-7.85 (m, 3H), 7.81-7.40 (m,
6H), 4.40-4.21 (m, 1H), 4.10-3.84 (m, 3H), 3.83-3.77 (m, 1H),
3.74-3.58 (m, 1H), 3.50-3.15 (m, 3H), 3.14-2.89 (m, 3H), 2.85-2.68
(m, 4H), 2.65-2.49 (m, 2H), 2.20-1.98 (m, 5H), 1.93-1.62 (m, 2H),
1.50-1.38 (m, 3H), 1.35-1.20 (m, 5H); .sup.19F NMR (282 MHz,
CDCl.sub.3) .delta. -63.1, -76.3; ESIMS m/z 608
[C.sub.31H.sub.40F.sub.3N.sub.3O.sub.4S+H].sup.+.
Example 47
1-((1S*,2R*,4R*)-4-(amino)-2-(phenylsulfonylmethyl)cyclohexyl)-3-(7-(trifl-
uoromethyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one
trifluoroacetate
[0657] (47a) 3-(Trifluoromethyl)benzene-1,2-diamine (257 mg,
1.times.46 mmol) was dissolved in anhydrous DMF (7.5 mL). The
mixture was stirred at 0.degree. C. under N.sub.2 as
N-methylmorpholine (0.34 mL, 3.09 mmol), compound from Example 24d
(456 mg, 1.12 mmol), and
benzotriazol-1-yloxy-tris(dimethylamino)phosphonium
hexafluorophosphate (BOP reagent, 644 mg, 1.45 mmol) were added
sequentially. The mixture was allowed to warm to room temperature
and stirred for 14 h, then diluted with EtOAc, washed with 10%
aqueous HCl (3.times.), saturated NaHCO.sub.3 (1.times.), and brine
(1.times.), dried over Na.sub.2SO.sub.4, filtered and evaporated.
The residue was purified by flash column chromatography (silica,
50-100%, EtOAc/hexanes) to provide the two diastereomers of
N-(2-amino-3-(trifluoromethyl)phenyl)-1-((1S*,2R*,4R*)-4-(azido)-2-(pheny-
lsulfonylmethyl)cyclohexyl)-2-oxopyrrolidine-3-carboxamide as white
crushable foams: ESI MS m/z 565
[C.sub.25H.sub.27F.sub.3N.sub.6O.sub.4S+H].sup.+.
[0658] (47b) The diastereomers from above (47a) (136 mg, 0.241
mmol) and p-toluenesulfonic acid monohydrate (35 mg, 0.18 mmol)
were stirred in anhydrous toluene (35 mL). The reaction vessel was
fitted with a Dean-Stark trap and the mixture was heated to reflux,
at which point 10 mL of toluene was removed. The mixture was
further heated at reflux for 2 h, then allowed to cool to room
temperature, and the solvent was removed in vacuo. The residue was
purified by flash column chromatography (silica, 2-10%
MeOH/CH.sub.2Cl.sub.2) to provide
1-((1S*,2R*,4R*)-4-azido-2-(phenylsulfonylmethyl)cyclohexyl)-3-(7-(triflu-
oromethyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one as a mixture
of diastereomers (101 mg, 77%); .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta. 10.88-10.77 (m, 1H), 7.94-7.76 (m, 3H), 7.65-7.43 (m, 3H),
7.35-7.23 (m, 2H); ESI MS m/z 547
[C.sub.25H.sub.25F.sub.3N.sub.6O.sub.3S+H].sup.+.
[0659] (47c) To a solution of the above compound (47b) (154 mg,
0.282 mmol) in methanol (7 mL) was added 10% Pd/C (wet, 60 mg). The
mixture was hydrogenated (1 atm) for 14 h, then filtered through a
pad of diatomaceous earth and concentrated. The residue was
purified by preparative TLC (80:18:2 CHCl.sub.3/MeOH/NH.sub.4OH).
After concentrating the material in vacuo, the resulting oil was
dissolved in CH.sub.3CN/H.sub.2O/TFA and lyophilized to give the
title compound (29 mg, 16%) as a white solid and mixture of
diastereomers: ESI MS m/z 521
[C.sub.25H.sub.27F.sub.3N.sub.4O.sub.3S+H].sup.+.
Example 48
1-((1S*,2R*,4R*)-4-(isopropylamino)-2-(phenylsulfonylmethyl)cyclohexyl)-3--
(7-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one
trifluoroacetate
[0660] (48a) To a solution of Example 47 (67 mg, 0.13 mmol) in
1,2-dichloroethane (7.3 mL) was added acetone (0.38 mL, 5.2 mmol)
and acetic acid (30 .mu.L, 0.51 mmol). The resulting mixture was
stirred for 20 min, then sodium triacetoxyborohydride (110 mg, 0.52
mmol) was added. After stirring for 2 h, the mixture was diluted
with EtOAc and washed sequentially with saturated aqueous
NaHCO.sub.3, water, and brine. The organic phase was dried over
Na.sub.2SO.sub.4, filtered, and the solvent was removed in vacuo.
The resulting clear, glassy solid was dissolved in
CH.sub.3CN/H.sub.2O/TFA and lyophilized to provide the title
compound (5.1 mg, 6%) as a white solid and mixture of
diastereomers: ESI MS m/z 563
[C.sub.28H.sub.33F.sub.3N.sub.4O.sub.3S+H].sup.+.
Example 49
1-((1S*,2R*,4R*)-4-(isopropyl)methyl)amino)-2-(phenylsulfonylmethyl)cycloh-
exyl)-3-(7-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one
trifluoroacetate
[0661] (49a) To a solution of Example 48 (25 mg, 44 .mu.mol) in
methanol (1.5 mL) was added a solution of 37% aqueous formaldehyde
(14 mL, 178 .mu.mol). The resulting mixture was stirred for 2 h,
then sodium cyanoborohydride (5 mg, 67 .mu.mol) was added. After
stirring for 3 h, the mixture was treated with saturated aqueous
NaHCO.sub.3 and extracted with EtOAc. The organic layer was washed
with brine, dried over Na.sub.2SO.sub.4, filtered, and the solvent
removed in vacuo. The residue was purified by preparative TLC
(90:10:1 CHCl.sub.3/MeOH/NH.sub.4OH). After concentrating the
material in vacuo, the resulting oil was dissolved in
CH.sub.3CN/H.sub.2O/TFA and lyophilized to give the title compound
(10 mg, 33%) as a white solid and mixture of diastereomers: ESI MS
m/z 577 [C.sub.29H.sub.35F.sub.3N.sub.4O.sub.3S+H].sup.+.
Example 50
1-((1S*,2R*,4R*)-4-(isopropyl(ethyl)amino)-2-(phenylsulfonylmethyl)cyclohe-
xyl)-3-(7-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one
trifluoroacetate
[0662] (50a) To a solution of Example 48 (25 mg, 44 .mu.mol) in
1,2-dichloroethane (3.0 mL) was added acetaldehyde (13 .mu.L, 222
.mu.mol) and acetic acid (30 .mu.L, 0.14 mmol). The resulting
mixture was stirred for 20 min, then sodium triacetoxyborohydride
(38 mg, 0.18 mmol) was added. After stirring for 2 h, the mixture
was diluted with EtOAc and washed sequentially with saturated
aqueous NaHCO.sub.3, water, and brine. The organic phase was dried
over Na.sub.2SO.sub.4, filtered, and the solvent was removed in
vacuo. The residue was purified by preparative TLC (70:30
CH2Cl2/MeOH). After concentrating the material in vacuo, the
resulting oil was dissolved in CH.sub.3CN/H.sub.2O/TFA and
lyophilized to provide the title compound (10 mg, 34%) as a white
solid and mixture of diastereomers: ESI MS m/z 591
[C.sub.30H.sub.37F.sub.3N.sub.4O.sub.3S+H].sup.+.
Example 51
1-((1S*,2R*,4R*)-4-(Diethylamino)-2-(phenylsulfonylmethyl)cyclohexyl)-3-(7-
-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one
trifluoroacetate
[0663] (51a) To a solution of Example 47 (25 mg, 44 .mu.mol) in
1,2-dichloroethane (2.7 mL) was added acetaldehyde (28 .mu.L, 492
.mu.mol) and acetic acid (8 .mu.L, 96 .mu.mol). The resulting
mixture was stirred for 20 main, then sodium triacetoxyborohydride
(31 mg, 144 .mu.mol) was added. After stirring for 2 h, the mixture
was diluted with EtOAc and washed sequentially with saturated
aqueous NaHCO.sub.3, water, and brine. The organic phase was dried
over Na.sub.2SO.sub.4, filtered, and the solvent was removed in
vacuo. The residue was purified by preparative TLC (90:10:1
CHCl.sub.3/MeOH/NH.sub.4OH). After concentrating the material in
vacuo, the resulting oil was dissolved in CH.sub.3CN/H.sub.2O/TFA
and lyophilized to provide the title compound (8.5 mg, 26%) as a
white solid and mixture of diastereomers: ESI MS m/z 577
[C.sub.29H.sub.35F.sub.3N.sub.4O.sub.3S+H].sup.+.
Example 52
1-((1S,2R,4R)-4-(Isopropyl(methyl)amino)-2-(phenylsulfonylmethyl)cyclohexy-
l)-3-(naphthalen-1-ylamino)pyrrolidin-2-one trifluoroacetate
[0664] (52a)
(1S*,2R*,4R*)-4-azido-2-benzenesulfonylmethyl-cyclohexylamine
trifluoroacetate (see 37c) (2.5 g, 6.3 mmol) was dissolved in DMF
(15 mL) prior to the addition of BOP reagent (3.4 g) and
N-Boc-L-Met-OH (1.9 g). After cooling to 0.degree. C., NMM (2.6 mL)
was added. The resulting mixture was warmed to rt and was stirred
overnight. The solution was diluted with EtOAc, and was washed
successively with brine and sat. NaHCO.sub.3. The organic phase was
dried (MgSO.sub.4), filtered, and concentrated. Flash
chromatography of the resulting residue gave tert-butyl
(S)-1-((1S*,2R*,4R*)-4-azido-2-(phenylsulfonylmethyl)cyclohexylamino)-4-(-
methylthio)-1-oxobutan-2-ylcarbamate (2.8 g) as a mixture of
diastereomers. MS found: (M+H).sup.+=526.2.
[0665] (52b) The above derivative (52a) was dissolved in MeI (30
mL). After stirring overnight at rt, the solution was concentrated
and dried. The resulting material was dissolved in DMF (30 mL)
prior to the addition of Cs.sub.2CO.sub.3 (3.5 g). After stirring 3
h, the solution was diluted with EtOAc and was washed with brine.
The organic phase was dried (MgSO.sub.4), filtered, and
concentrated. Flash chromatography (1:2 up to 2:1 EtOAc/hexane) of
the resulting residue provided the bottom diastereomer tert-butyl
(S)-1-((1S,2R,4R)-4-azido-2-(phenylsulfonylmethyl)cyclohexyl)-2-oxopyrrol-
idin-3-ylcarbamate (600 mg). MS found: (M+H).sup.+=478.3.
[0666] (52c) A portion of the above material (52b) (30 mg) was
dissolved in MeOH (4 mL) prior to the addition of 10% Pd/C (20 mg).
A hydrogen balloon was added and the mixture was stirred. After
stirring 2 h, the Pd/C was filtered off and the solvent was
concentrated to give tert-butyl
(S)-1-((1S,2R,4R)-4-amino-2-(phenylsulfonylmethyl)cyclohexyl)-2-oxopyrrol-
idin-3-ylcarbamate (29 mg). MS found: (M+H).sup.+=452.2.
[0667] (52d) The above material (52c) was dissolved in
dichloroethane (5 mL) prior to the addition of glacial acetic acid
(0.2 mm), acetone (1.0 mL), and NaBH(OAc).sub.3 (20 mg). After 20
h, MeOH (4 mL) was added prior to the addition of 37% formaldehyde
in water (1 mL). After 15 min, NaBH.sub.3CN (20 mg) was added.
After 1 h, saturated NaHCO.sub.3 was added and some of the MeOH was
removed. EtOAc was added and the organic layer was dried, filtered,
and concentrated to give tert-butyl
(S)-1-((1S,2R,4R)-4-(isopropyl(methyl)amino)-2-(phenylsulfonylmethyl)cycl-
ohexyl)-2-oxopyrrolidin-3-ylcarbamate (15 mg). MS found:
(M+H).sup.+=508.3.
[0668] (52e) A portion of above material (52b) (160 mg) was
dissolved in CH.sub.2Cl.sub.2 (3 mL) and cooled to 0.degree. C.
prior to the addition of TFA (4 mL). After the reaction was warmed
to rt over 1 h, it was concentrated. This material was dissolved in
EtOAc (8 mL) prior to the addition of saturated Na.sub.2CO.sub.3
solution (3 mL). The organic phase was dried (Na.sub.2CO.sub.3),
filtered, and concentrated to afford free base
(S)-3-amino-1-((1S,2R,4R)-4(isopropyl(methyl)amino)-2-(phenylsulfony-
lmethyl)cyclohexyl)pyrrolidin-2-one (130 mg). MS found:
(M+H).sup.+=408.2.
[0669] (52f) A portion of the above material (52e) (30 mg, 74
.mu.mol), sodium tert-butoxide (14 mg, 140 .mu.mol), and toluene
(0.7 mL) were placed in a reaction tube equipped with a stir bar
and screw cap. After passing argon through the reaction mixture for
2 min, BINAP (8 mg, 13 .mu.mol), Pd.sub.2(dba).sub.3 (4 mg, 4
.mu.mol) and 1-bromonaphthalene (9 .mu.L, 61 .mu.mol) were added
sequentially. The mixture was evacuated again with argon, then
sealed and heated to 85.degree. C. overnight. After cooling to room
temperature, the mixture was diluted with ether, filtered through a
pad of diatomaceous earth, and concentrated. The residue was
purified by semi-preparative HPLC, then lyophilized to provide the
title compound (9.5 mg) as a gray solid and mixture of
diastereomers. ESI MS m/z 534
[C.sub.31H.sub.39N.sub.3O.sub.3S+H].sup.+.
Example 53
3-(Benzo[b]thiophen-3-ylamino)-1-((1S,2R,4R)-4-(isopropyl(methyl)amino)-2--
(phenylsulfonylmethyl)cyclohexyl)pyrrolidin-2-one
trifluoroacetate
[0670] (53a) A portion of the above amine (52e) (27 mg, 66
.mu.mol), sodium tert-butoxide (13 mg, 130 .mu.mol), and toluene
(0.7 mL) were placed in a reaction tube equipped with a stir bar
and screw cap. After passing argon through the reaction mixture for
2 min, 2-(di-t-butylphosphino)biphenyl (12 mg, 40 .mu.mol),
Pd.sub.2(dba).sub.3 (6 mg, 7 .mu.mol) and 3-bromothianaphthene (18
.mu.L, 130 .mu.mol) were added sequentially. The mixture was
evacuated again with argon, then sealed and stirred overnight. The
mixture was diluted with ether, filtered through a pad of
diatomaceous earth, and concentrated. The residue was purified by
preparative TLC (9:1 CH.sub.2Cl.sub.2/MeOH), then lyophilized to
provide the title compound (4.4 mg) as a light yellow solid and
mixture of diastereomers. ESI MS m/z 540
[C.sub.29H.sub.37N.sub.3O.sub.3S.sub.2+H].sup.+.
Example 54
(S)-3-(6-chloroquinazolin-4-ylamino)-1-((1S,2R,4R)-4-(isopropyl(methyl)ami-
no)-2-(phenylsulfonylmethyl)cyclohexyl pyrrolidin-2-one
trifluoroacetate
[0671] (54a) The above amine (52e) (20 mg), triethylamine (0.03
mL), and 4,6-dichloroquinazoline (15 mg) were dissolved in EtOH (2
mL) and placed in a microwave. The reaction was heated at
100.degree. C. for 22 min. The solution was filtered and the
filtrate was subjected to reverse phase HPLC purification (gradient
elution, water/acetonitrile/TFA) to provide the title compound
(11.3 mg). MS found: (M+H).sup.+=570.2.
Example 55
(S)-3-(6,8-dichloroquinazolin-4-ylamino)-1-((1S,2R,4R)-4-(isopropyl(methyl-
)amino)-2-(phenylsulfonylmethyl)cyclohexyl)pyrrolidin-2-one
trifluoroacetate
(55a) 4,6,8-Trichloroquinazoline was incorporated into Example 54
to give the title compound. MS found: (M+H).sup.+=604.2.
Example 56
3,5-Dichloro-N--((S)-1-((1S,2R,4R)-4-(isopropyl(methyl)amino)-2-(phenylsul-
fonylmethyl)cyclohexyl)-2-oxopyrrolidin-3-yl)benzamide
trifluoroacetate
[0672] (56a) Amine 52e (15 mg) was dissolved in DMF (2 mL) prior to
the addition of diisopropylethylamine (0.02 mL) and
3,5-dichlorobenzoic acid (10 mg). After cooling to 0.degree. C.,
BOP reagent (19 mg) was added. The resulting mixture was warmed to
rt and was stirred overnight. The solution was diluted with EtOAc
and was washed with sat. NaHCO.sub.3. The organic phase was dried
(MgSO.sub.4), filtered, and concentrated. Reverse phase HPLC
purification (gradient elution, water/acetonitrile/TFA) of the
resulting residue provided the title compound (1.0 mg). MS found:
(M+H).sup.+=580.
Example 57
N--((S)-1-((1S,2R,4R)-4-(isopropyl(methyl)amino)-2-(phenylsulfonylmethyl)c-
yclohexyl)-2-oxopyrrolidin-3-yl)-3-(trifluoromethoxy)benzamide
trifluoroacetate
(57a) 3-Trifluoromethoxybenzoic acid was incorporated into Example
56 to give the title compound. MS found: (M+H).sup.+=596.2.
Example 58
3-((E)-3(R*)-(trifluoromethyl
styryl)-1-((1S*,2R*,4R*)-4-(isopropyl(methyl)amino)-2-(phenylsulfonylmeth-
yl)cyclohexyl)pyrrolidin-2-one trifluoroacetate
[0673] (58a) Compound 39g-b (2.0 g) was dissolved in CH.sub.3CN (25
mL) and 1 M HCl (25 mL) was stirred at 60.degree. C. for 6 h. The
mixture was diluted with ethyl acetate (500 mL), washed with satd
NaHCO.sub.3 (3.times.150 mL) and brine (2.times.100 mL), dried over
Na.sub.2SO.sub.4, filtered, and evaporated to dryness to give
1-((1S*,2R*,4R*)-4-azido-2-(phenylsulfonylmethyl)cyclohexyl)-3(R*)-(3-(tr-
ifluoromethyl)benzoyl)pyrrolidin-2-one as a white solid (1.85 g).
ESI MS m/z 549
[C.sub.26H.sub.27F.sub.3N.sub.4O.sub.4S+H].sup.+.
[0674] (58b) A solution of LiHMDS (5.06 mL, 1 M in hexanes) in THF
(50.6 mL) was cooled to -78.degree. C. A precooled solution of
compound (58a) (2.80 g, 5.06 mmol) in THF (25 mL) was added
dropwise. The mixture was stirred for 1 h at -78.degree. C. then a
precooled solution of
2-[(N,N-bistrifluoromethylsulfonyl)amino]-5-chloropyridine (2.90 g,
7.38 mmol) in THF (30 mL) was added. After 90 min, the reaction was
warmed to -5.degree. C. and stirred for 2 h. The mixture was
diluted with EtOAc (800 mL), washed with satd NH.sub.4Cl
(3.times.150 mL) and brine (100 mL), dried over Na.sub.2SO.sub.4,
filtered, and concentrated, filtering off the
2-amino-5-chloropyridine byproduct. The filtrate was evaporated to
dryness, and purified by flash chromatography (silica-gel, 0-100%
EtOAc/hexanes) to give
2-(1-((1S*,2R*,4R*)-4-azido-2-(phenylsulfonylmethyl)cyclohexyl)-2-oxopyrr-
olidin-3-yl)-1-(3(R*)-(trifluoromethyl)phenyl)vinyl
trifluoromethanesulfonate (2.30 g, 67%) as a white solid: .sup.1H
NMR (300 MHz, CDCl.sub.3) .delta. 7.92-7.83 (m, 2H), 7.78-7.50 (m,
7H), 6.07 (d, J=9.0 Hz, 1H), 4.00-3.89 (m, 5H), 3.22 (dd, J=14.7,
3.4 Hz, 1H), 2.80-2.45 (m, 2H), 2.18-1.60 (m, 9H); .sup.19F NMR
(282 MHz, CDCl.sub.3) .delta. -63.4 (3F), -74.1 (3F).
[0675] (58c) A mixture of Pd(PPh.sub.3).sub.4 (25.5 mg, 22 .mu.mol)
and LiCl (140 mg, 3.29 mmol) in THF (3.28 mL) was stirred under
argon atmosphere. A solution of compound 58b (750 mg, 1.03 mmol) in
THF (3.68 mL) was added, followed by slow addition of tributyltin
hydride (.mu.L, 1.32 mmol). The mixture was stirred 4 h at room
temperature, diluted with EtOAc (500 mL), washed with satd
NaHCO.sub.3 (3.times.100 mL), brine (200 mL), dried over
Na.sub.2SO.sub.4, filtered, and evaporated. The residue was
purified by flash chromatography (silica gel with a plug of RF,
0-80% EtOAc/hexanes) to give the
3(R*)-((E)-3-(trifluoromethyl)styryl)-1-((1S*,2R*,4R*)-4-azido-2-(phenyls-
ulfonylmethyl)cyclohexyl)pyrrolidin-2-one (347 mg, 59%) as white
solids. ESI MS m/z 533
[C.sub.26H.sub.27F.sub.3N.sub.4O.sub.3S+H].sup.+.
[0676] (58d) A mixture of 58c (117 mg, 220 .mu.mol) and
triphenylphosphine (115 mg, 440 .mu.mol) in THF (10 mL) was stirred
at room temperature for 23 h. Water (2 mL) was added and the
mixture was stirred for 2 d. The volume was reduced under vacuum
and the residue was dissolved in EtOAc (500 nm). The mixture was
extracted with 1 M HCl (3.times.150 mL), and the aqueous layer was
made basic with 6 N NaOH, then extracted with EtOAc (3.times.150
mL). The organic layer was dried over Na.sub.2SO.sub.4, filtered,
and evaporated to give crude free amine. This material (24 mg, 47
.mu.mol), acetone (200 .mu.L, 2.73 mmol), and acetic acid (20
.mu.L, 348 .mu.mol) in 1,2-dichloroethane (4 mL) was stirred for 3
min, then treated with sodium triacetoxyborohydride (20 mg, 95
.mu.mol). After stirring the mixture for 1 h, the solvent was
removed under vacuum. The residue was dissolved in MeOH (4 mL),
then 37% aqueous formaldehyde (400 .mu.L) and sodium
cyanoborohydride (4.5 mg, 71 .mu.mol) were added. The mixture was
stirred 18 h, and the solvent was removed under vacuum. The residue
was purified by semi-preparative HPLC, and the product lyophilized
from CH.sub.3CN/H.sub.2O/TFA to give the title compound (23.8 mg).
ESI MS m/z 563
[C.sub.30H.sub.37F.sub.3N.sub.2O.sub.3S+H].sup.+.
Example 59
1-((1S*,2R*,4R*)-4-(isopropyl(methyl)amino)-2-(phenylsulfonylmethyl)cycloh-
exyl)-3(R*)-((E/Z)-2-(3-(trifluoromethyl)phenyl)prop-1-enyl)pyrrolidin-2-o-
ne trifluoroacetate
[0677] (59a) A suspension of copper bromide-dimethylsulfide (1.03
g, 5.01 mmol) in THF (10 mL) was cooled to -78.degree. C.
Methylmagnesium bromide (3 M in ether, 3.34 mL, 10 mmol) was added
dropwise, then the mixture was removed from the dry ice bath and
THF (3 mL) was added. After stirring for 7 min, the mixture was
cooled to -78.degree. C. A solution of compound 58b (569 mg) in THF
(11 mL) was added dropwise and the reaction mixture was stirred for
2 h. The mixture was diluted with EtOAc (500 mL), washed with satd
NH.sub.4Cl (3.times.100 mL) and brine (200 mL), dried over
Na.sub.2SO.sub.4, filtered, and evaporated. The residue was
purified by flash column chromatography (silica-gel, 0-70%,
THF/hexanes) to provide
1-((1S*,2R*,4R*)-4-azido-2-(phenylsulfonylmethyl)cyclohexyl)-3(R*-
)-((E/Z)-2-(3-(trifluoromethyl)phenyl)prop-1-enyl)pyrrolidin-2-one
(436 mg). ESI MS m/z 547
[C.sub.27H.sub.29F.sub.3N.sub.4O.sub.3S+H].sup.+.
(59b) The above material 59a was incorporated into Example 58 (step
58d) to give the title compound. MS found: (M+H).sup.+=577.
Example 60
N-(1-((1S,2R,4R)-4-(isopropyl(methyl)amino)-2-(phenylsulfonylmethyl)cycloh-
exyl)-2-oxopyrrolidin-3(R)-yl)benzamidede trifluoroacetate
(60a) Benzoic acid was incorporated into Example 56 to give the
title compound. MS found: (M+H).sup.+=512.
Example 61
N--((S)-1-((1S,2R,4R)-4-(Isopropyl(methyl)amino)-2-(phenylsulfonylmethyl)c-
yclohexyl)-2-oxopyrrolidin-3-yl)-3,5-bis(trifluoromethyl)benzamide
trifluoroacetate
[0678] (61a)
(1S,2R)-cis-2-Methoxycarbonyl-cyclohex-4-ene-1-carboxylic acid
(66.0 g, see Bolm et al. J. Org. Chem. 2000, 65, 6984-6991) was
dissolved in dry acetone (815 mL) prior to the addition of
triethylamine (43.4 g). This solution was cooled to 0.degree. C.
and ethyl chloroformate (46.7 g) was added. The resulting solution
was stirred 1 h before NaN.sub.3 (35.0 g) was added. The cooling
bath was removed, and the reaction was warmed to rt overnight. All
solid material was removed by filtration, and the solution was
partially concentrated. Water was slowly added and the organic
layer was separated. The aqueous layer was extracted with ether.
The combined organic layers were washed with water and brine before
they were dried, filtered, and concentrated. The resulting oil
(66.1 g) was dissolved in benzene (800 mL) and was warmed to a
gentle reflux. After 4 h, the solution was cooled back to rt.
Benzyl alcohol (37.5 g) and p-TsOH (1.5 g) were added, and the
solution was warmed back to a gentle reflux overnight. After
cooling to rt, the reaction was washed with NaHCO.sub.3 and brine,
dried, filtered, and concentrated to give
(1R,8S)-6-benzyloxycarbonylamino-cyclohex-3-enecarboxylic acid
methyl ester (97.7 g). MS found: (M+H).sup.+=290.2.
[0679] (61b) A sample of
(1R,6S)-6-benzyloxycarbonylamino-cyclohex-3-enecarboxylic acid
methyl ester (91.4 g) was dissolved in MeOH (500 mL) prior to the
dropwise addition of NaOH (25.3 g) in water (95 mL). After 3 h, the
solution was partially concentrated and an Et.sub.2O/water mixture
was added. The aqueous layer was separated and was acidified (pH
.about.2) with concentrated HCl. The resulting mixture was
extracted with EtOAc. The combined organic layers were washed with
water and brine before they were dried, filtered, and concentrated
to give (1R,6S)-6-benzyloxycarbonylamino-cyclohex-3-enecarboxylic
acid (72.7 g). MS found: (M+H).sup.+=276.2.
[0680] (61c) A sample of
(1R,6S)-6-benzyloxycarbonylamino-cyclohex-3-enecarboxylic acid (72
g) was dissolved in CH.sub.2Cl.sub.2 (750 mL) prior to the addition
of CDI (50.9 g). After 2.5 h water was added, and the solution was
extracted with CH.sub.2Cl.sub.2. The combined organic layers were
dried, filtered, and concentrated. The resulting material was
dissolved in CH.sub.2Cl.sub.2 and ammonia gas was bubbled through
the solution for 1.5 h. After stirring overnight, the majority of
the solvent was removed and Et.sub.2O was added. The product
precipitated as a white solid and was collected to give
(1R,6S)-6-carbamoylcyclohex-3-enyl)carbamic acid benzyl ester (61.5
g). MS found: (M+H).sup.+=275.3.
[0681] (61d) A sample of
(1R,6S)-6-carbamoylcyclohex-3-enyl)-carbamic acid benzyl ester
(30.7 g) was dissolved in THF (1100 mL) and NMP (220 mL). At
-78.degree. C., 2.3M n-BuLi (96.3 mL) was added dropwise. After 2
h, a solution of Boc.sub.2O (24.4 g) in THF (40 mL) was added
dropwise. This solution was stirred 1.2 h before it was quenched
with a saturated NH.sub.4CL solution. Water and Et.sub.2O were
added. The organic layer was filtered then washed with water,
brine, dried, filtered, and concentrated. Flash chromatography of
the resulting residue gave
(1R,6S)-(6-tert-butoxycarbonylaminocarbonyl-cyclohex-3-enyl)-carbamic
acid benzyl ester (29.2 g). MS found: (M+Na).sup.+=397.4.
[0682] (61e) A sample of
(1R,6S)-(6-tert-butoxycarbonyl-aminocarbonylcyclohex-3-enyl)carbamic
acid benzyl ester (29.0 g) was dissolved in THF (1290 mL). This was
cooled in an ice/brine bath prior to the addition of n-BuLi (1.5
mL, 2.4M). After 30 min, iodine (59.0 g) was added in a single
portion. The bath was removed, and the reaction was warmed to rt
overnight. The resulting solution was quenched with saturated
thiosulfate solution. Water and EtOAc were added. The organic layer
was washed with water, brine, dried, filtered, and concentrated.
The resulting slurry was diluted with Et.sub.2O and
(1R,2S,4S,5R)-2-benzyloxycarbonyl-amino-4-iodo-7-oxo-6-aza-bicyclo[3.2.1]-
octane-6-carboxylic acid tert-butyl ester (22.8 g) was collected by
vacuum filtration. MS found:
(M-C.sub.5H.sub.8O.sub.2+H).sup.+=401.1.
[0683] (61f) A sample of
(1R,2S,4S,5R)-2-benzyloxycarbonylamino-4-iodo-7-oxo-6-aza-bicyclo[3.2.1]o-
ctane-6-carboxylic acid tert-butyl ester (43.3 g) was dissolved in
benzene (580 mL) prior to the addition of Bu.sub.3SnH (27.8 g) and
AIBN (0.7 g). The resulting mixture was warmed to a gentle reflux
for 3 h. After cooling, the solvent was removed and hexane was
added. The resulting white solid was collected by vacuum filtration
to give (1R,2S,
SR)-2-benzyloxycarbonylamino-7-oxo-6-aza-bicyclo[3.2.1]octane-6-carboxyli-
c acid tert-butyl ester (29.5 g). MS found: (M+Na).sup.+=397.4.
[0684] (61g) A solution of
(1R,2S,5R)-2-benzyloxycarbonylamino-7-oxo-6-aza-bicyclo[3.2.1]octane-6-ca-
rboxylic acid tert-butyl ester (10.21 g, 27.3 mmol) in
tetrahydrofuran (200 mL) was treated with water (40 mL) and then
with sodium borohydride (5.16 g, 136 mmol). The mixture was stirred
at room temperature for 2 h, then was treated with saturated
aqueous sodium bicarbonate and stirred until the bubbling subsided.
The mixture was extracted three times with ethyl acetate. The
combined extracts were washed with saturated aqueous sodium
chloride, dried over sodium sulfate, and concentrated under vacuum.
The residue was recrystallized from ethyl acetate-hexane to provide
(1R,3R,4S)-(4-benzyloxy
carbonylamino-3-hydroxymethylcyclohexyl)carbamic acid tert-butyl
ester as a white solid (6.8 g); additional product (2.1 g) was
obtained by flash column chromatography of the residue from
concentration of the mother liquors, eluting with 40%, then 50%
ethyl acetate-hexane. MS found: (M+H).sup.+=379.28.
[0685] (61h) A solution of
(1R,3R,4S)-(4-benzyloxycarbonylamino-3-hydroxymethylcyclohexyl)carbamic
acid tert-butyl ester (3.49 g, 9.22 mmol) in tetrahydrofuran (40
mL) was treated with diphenyl disulfide (4.03 g, 18.4 mmol) and
tri-n-butylphosphine (4.6 mL, 18.4 mmol) and the solution was
heated at reflux for 17 h. The mixture was cooled and concentrated
under vacuum, and the residue was purified by flash column
chromatography, eluting with 10%, then 20% ethyl acetate-hexane, to
provide
(1S,2R,4R)-(4-tert-butoxycarbonylamino-2-phenyl-sulfanylmethylcyclohexyl)-
-carbamic acid benzyl ester (4.37 g) as a white glassy solid. MS
found: (M+H).sup.+=471.65.
[0686] (61i) A solution of
(1S,2R,4R)-(4-tert-butoxycarbonyl-amino-2-phenylsulfanylmethylcyclohexyl)-
carbamic acid benzyl ester (4.37 g, 9.22 mmol) in 2-propanol (100
mL) was treated with a solution of Oxone (11.34 g, 18.44 mmol) in
water (60 mL). The mixture was stirred at room temperature for 18
h, then was diluted with water and extracted with ethyl acetate.
The organic phases were washed with water, then with brine, then
were dried over sodium sulfate and concentrated under vacuum to
provide
(1S,2R,4R)-(2-benzene-sulfonylmethyl-4-tert-butoxycarbonylaminocyclohexyl-
)-carbamic acid benzyl ester (4.77 g) as a white glassy solid, used
without further purification. MS found: (M+H).sup.+=503.6.
[0687] (61j) A mixture of
(1S,2R,4R)-(2-benzene-sulfonylmethyl-4-tert-butoxycarbonylaminocyclohexyl-
)carbamic acid benzyl ester (2.96 g, 5.9 mmol) and 20% palladium
hydroxide on charcoal (Pearlman's catalyst, 2.0 g) in methanol (100
mL) was stirred under one atmosphere of hydrogen at room
temperature for 16.5 h. The mixture was filtered through Celite,
and the solids were washed with methanol. The filtrate was
concentrated under vacuum and the residue was dissolved in
dichloromethane. The solution was dried over sodium sulfate and
concentrated under vacuum to provide
(1R,3R,4S)-(4-amino-3-benzenesulfonylmethylcyclohexyl)-carbamic
acid tert-butyl ester (2.02 g) as a white glassy solid, used
without further purification. MS found: (M+H).sup.+=369.62.
[0688] (61k) This material (61j) was incorporated into Steps 52a to
52b (substituting N-Cbz-L-Met-OH for N-Boc-L-Met-OH) to give
tert-butyl
(1R,3R,4S)-4-((S)-2-oxo-3-(2-phenylacetamido)pyrrolidin-1-yl)-3-(phenylsu-
lfonylmethyl)cyclohexylcarbamate. MS found: (M+H).sup.+=586.6.
[0689] (61l) A portion of above material (61k) (2.0 g) was
dissolved in CH.sub.2Cl.sub.2 (5 mL) and cooled to 0.degree. C.
prior to the addition of TFA (7 mL). After the reaction was warmed
to rt over 1 h, it was concentrated and dried. This material,
acetone (993 mg), and acetic acid (1 mL) in 1,2-dichloroethane (15
mL) was stirred for 3 min, then treated with sodium
triacetoxyborohydride (1.4 g). After stirring for 20 h, MeOH (10
mL) was added followed by 37% aqueous formaldehyde (2 mL) and
sodium cyanoborohydride (427 mg) were added. The mixture was
stirred 3 h, and the solvent was removed under vacuum. The residue
was dissolved in EtOAc (200 min), washed with saturated
NaHCO.sub.3, dried over Mg.sub.2SO.sub.4, filtered, and evaporated
to provide
N--((S)-1-((1S,2R,4R)-4-(isopropyl(methyl)amino)-2-(phenylsulfonylmethyl)-
cyclohexyl)-2-oxopyrrolidin-3-yl)-2-phenylacetamide (2.7 g). MS
found: (M+H).sup.+=542.2.
[0690] (61m) A portion of above material (61l) (300 mg) was
dissolved in 33% (wt) HBr/AcOH (3 mL). After 30 min, Et.sub.2O (20
mL) was added and a white solid precipitated from solution. This
solid was collected to give
(S)-3-amino-1-((1S,2R,4R)-4-(isopropyl(methyl)amino)-2-(phenylsulfonylmet-
hyl)cyclohexyl)pyrrolidin-2-one dihydrogen bromide (300 mg). MS
found. (M+H).sup.+=408.2.
[0691] (61n) The above material (61m) was dissolved in EtOAc (8 mL)
prior to the addition of saturated Na.sub.2CO.sub.3 solution (3
mL). The organic phase was dried (Na.sub.2CO.sub.3), filtered, and
concentrated to afford free base
(S)-3-amino-1-((1S,2R,4R)-4-(isopropyl(methyl)amino)-2-(phenylsulfonylmet-
hyl)cyclohexyl)pyrrolidin-2-one (210 mg). MS found:
(M+H).sup.+=408.2.
[0692] (61o) A portion of the above material (61n) (30 mg) was
dissolved in DMF (1 mL) prior to the addition of NMM (29.3 mg) and
3,5-ditrifluoromethylbenzoic acid (16.2 mg). After cooling to
0.degree. C., BOP reagent (38 mg) was added. The resulting mixture
was warmed to rt and was stirred overnight. The solution was
diluted with EtOAc and was washed with sat. NaHCO.sub.3. The
organic phase was dried (MgSO.sub.4), filtered, and concentrated.
Reverse phase HPLC purification (gradient elution,
water/acetonitrile/TFA) of the resulting residue provided the title
compound (X.0 mg). MS found: (M+H).sup.+=648.
Example 62
2-Amino-N-(1-((1S,2R,4R)-4-(isopropyl(methyl)amino)-2-(phenylsulfonylmethy-
l)cyclohexyl)-2-oxopyrrolidin-3(R)-yl)-5-(trifluoromethoxy)benzamide
trifluoroacetate
[0693] (62a)
2-(tert-Butoxycarbonylamino)-5-(trifluoromethoxy)benzoic acid was
incorporated into Step (61o) to give the tert-butyl
2-((1-((1S,2R,4R)-4-(isopropyl(methyl)amino)-2-(phenylsulfonylmethyl)cycl-
ohexyl)-2-oxopyrrolidin-3(R)-yl)carbamoyl)-4-(trifluoromethoxy)phenylcarba-
mate. MS found: (M+H).sup.+=711.
[0694] (62b) The above material (62a) (20 mg) was dissolved in
CH.sub.2Cl.sub.2 (2 mL) and cooled to 0.degree. C. prior to the
addition of TFA (4 mL). After the reaction was warmed to rt over 30
min, it was concentrated and dried to provide the title compound.
MS found: (M+H).sup.+=611.
Example 63
(R)-1-((1S,2R,4R)-4-(isopropyl(methyl)amino)-2-(phenylsulfonylmethyl)cyclo-
hexyl)-3-(6-(trifluoromethyl)quinolin-4-ylamino)pyrrolidin-2-one
trifluoroacetate
[0695] (63a) Compound (61n) (30 mg), sodium tert-butoxide (10.1
mg), 4-chloro-6-trifluoromethylquinoline (25 mg), and toluene (1.3
mL) were placed in a reaction vial equipped with a stir bar and
screw cap. After passing argon through the reaction mixture for 2
min, acetato
(2'-di-t-butylphosphino-1,1'-biphenyl-2-yl)palladium(II) (1 mg) was
added and the solution was heated to 80.degree. C. overnight. After
cooling to room temperature, the mixture was concentrated and then
dissolved in MeOH before it was filtered. The filtrate was purified
by reverse phase HPLC purification (gradient elution,
water/acetonitrile/TFA) to provide two diastereomers. The first
diastereomer off the HPLC being the title compound (10.0 mg). MS
found: (M+H).sup.+=603.2.
Example 64
(S)-1-((1S,2R,4R)-4-(isopropyl(methyl)amino)-2-(phenylsulfonylmethyl)cyclo-
hexyl)-3-(6-(trifluoromethyl)quinolin-4-ylamino)pyrrolidin-2-one
trifluoroacetate
(64a) The second diastereomer off the HPLC from Example 63 is the
title compound. MS found: (M+H).sup.+=603.2.
Example 65
(R)-1-((1S,2R,4R)-4-(isopropyl(methyl)amino)-2-(phenylsulfonylmethyl)cyclo-
hexyl)-3-(7-(trifluoromethyl)quinolin-4-ylamino)pyrrolidin-2-one
trifluoroacetate
(65a) 4-Chloro-7-trifluoromethylquinoline was incorporated into
Example 63 to give the title compound as the first diastereomer. MS
found: (M+H).sup.+=603.2.
Example 66
(S)-1-((1S,2R,4R)-4-(isopropyl(methyl)amino)-2-(phenylsulfonylmethyl)cyclo-
hexyl)-3-(7-(trifluoromethyl)quinolin-4-ylamino)pyrrolidin-2-one
trifluoroacetate
(66a) The second diastereomer off the HPLC from Example 65 is the
title compound. MS found: (M+H).sup.+=603.2.
Example 67
3-(2-(Phenyl)phenylamino)-1-((1S,2R,4R)-4-(isopropyl(methyl)amino)-2-(phen-
ylsulfonylmethyl)cyclohexyl)pyrrolidin-2-one trifluoroacetate
(67a) 2-Bromo-biphenyl was incorporated into Example 63 to give the
title compound as a mixture of diastereomers. MS found:
(M+H).sup.+=560.3.
Example 68
3-(3,5-Bis(trifluoromethyl)phenylamino)-1-((1S,2R,4R)-4-(isopropyl(methyl)-
amino)-2-(phenylsulfonylmethyl)cyclohexyl)pyrrolidin-2-one
trifluoroacetate
(68a) 3,5-Ditrifluoromethyl-1-bromobenzene was incorporated into
Example 63 to give the title compound as a mixture of
diastereomers. MS found: (M+H).sup.+=620.2.
Example 69
1-((1S,2R,4R)-4-(Isopropyl(methyl)amino)-2-(phenylsulfonylmethyl)cyclohexy-
l)-3-(2-(trifluoromethyl)phenylamino)pyrrolidin-2-one
trifluoroacetate
(69a) 2-Trifluoromethyl-1-bromobenzene was incorporated into
Example 63 to give the title compound as a mixture of
diastereomers. MS found: (M+H).sup.+=552.3.
Example 70
1-((1S,2R,4R)-4-(Isopropyl(methyl)amino)-2-(phenylsulfonylmethyl)cyclohexy-
l)-3-(2-methoxyphenylamino)pyrrolidin-2-one trifluoroacetate
(70a) 2-Methoxy-1-bromobenzene was incorporated into Example 63 to
give the title compound as a mixture of diastereomers. MS found:
(M+H).sup.+=568.3.
Example 71
1-((1S,2R,4R)-4-(Isopropyl(methyl)amino)-2-(phenylsulfonylmethyl)cyclohexy-
l)-3-(3-(trifluoromethyl)phenylamino)pyrrolidin-2-one
trifluoroacetate
(71a) 3-Trifluoromethyl-1-bromobenzene was incorporated into
Example 63 to give the title compound as a mixture of
diastereomers. MS found: (M+H).sup.+=552.3.
Example 72
1-((1S,2R,4R)-4-(Isopropyl(methyl)amino)-2-(phenylsulfonylmethyl)cyclohexy-
l)-3-(4-(trifluoromethyl)phenylamino)pyrrolidin-2-one
trifluoroacetate
(72a) 4-Trifluoromethyl-1-bromobenzene was incorporated into
Example 63 to give the title compound as a mixture of
diastereomers. MS found: (M+H).sup.+=552.3.
Example 73
3-Chloro-N--((S)-1-((1S,2R,4R)-4-(isopropyl(methyl)amino)-2-(phenylsulfony-
lmethyl)cyclohexyl)-2-oxopyrrolidin-3-yl)benzamide
trifluoroacetate
(73a) 3-Chlorobenzoic acid was incorporated into Step (61o) to give
the title compound. MS found: (M+H).sup.+=546.
Example 74
3-Fluoro-N--((S)-1-((1S,2R,4R)-4-(isopropyl(methyl)amino)-2-(phenylsulfony-
lmethyl)cyclohexyl)-2-oxopyrrolidin-3-yl)-5-(trifluoromethyl)benzamide
trifluoroacetate
(74a) 3-Fluoro-5-trifluoromethylbenzoic acid was incorporated into
Step (61o) to give the title compound. MS found:
(M+H).sup.+=598.
Example 75
tert-Butyl
(1R,3R,4S)-4-((S)-2-oxo-3-(3-(trifluoromethyl)benzamido)pyrroli-
din-1-yl)-3-(phenylsulfonylmethyl)cyclohexylcarbamate
[0696] (75a) Compound (61k) (1.0 g) was dissolved in MeOH (15 mL)
prior to the addition 10% Pd/C (200 mg). A hydrogen balloon was
attached and the solution was stirred 18 h. The mixture was
filtered through Celite, and the solids were washed with methanol.
The filtrate was concentrated to provide tert-butyl
(1R,3R,4S)-4-((S)-3-amino-2-oxopyrrolidin-1-yl)-3-(phenylsulfonylmethyl)c-
yclohexylcarbamate (980 mg) as a white glassy solid, used without
further purification. MS found: (M+H).sup.+=452.2.
[0697] (75b) The above material (75a, 980 mg) was dissolved in DMF
prior to the addition of 4-methylmorpholine (NMM) (481.5 mg) and
3-trifluoromethyl-benzoic acid (581.7 mg). After cooling to
0.degree. C., BOP reagent (1.4 g) was added. The resulting mixture
was warmed to rt and was stirred overnight. EtOAc was added along
with saturated NaHCO.sub.3 solution. The EtOAc layer was washed
with NaHCO.sub.3 solution (aq), dried (MgSO.sub.4), filtered, and
concentrated. Flash chromatography of the resulting residue
provided the title compound (978 mg). MS found:
(M+H).sup.+=624.7.
Example 76
N--((S)-2-Oxo-1-((1S,2R,4R)-4-(phenylamino)-2-(phenylsulfonylmethyl)cycloh-
exyl)pyrrolidin-3-yl)-3-(trifluoromethyl)benzamide
trifluoroacetate
[0698] (76a) Example 75 (970 mg) was dissolved in CH.sub.2Cl.sub.2
(2 mL) and cooled to 0.degree. C. prior to the addition of TFA (7
mL). After the reaction was warmed to rt over 1 h, it was
concentrated and dried to provide
N--((S)-1-((1S,2R,4R)-4-amino-2-(phenylsulfonylmethyl)cyclohexyl)-
-2-oxopyrrolidin-3-yl)-3-(trifluoromethyl)benzamide
trifluoroacetate (1.01 g). MS found: (M+H).sup.+=524.1.
[0699] (76b) The above material (76b) was dissolved in EtOAc (10
mL) prior to the addition of saturated Na.sub.2CO.sub.3 solution (4
mL). The organic phase was dried (Na.sub.2CO.sub.3), filtered, and
concentrated to afford free base
N--((S)-1-((1S,2R,4R)-4-amino-2-(phenylsulfonylmethyl)cyclohexyl)-2-oxopy-
rrolidin-3-yl)-3-(trifluoromethyl)benzamide (850 mg). MS found:
(M+H).sup.+=524.1.
[0700] (76c) A portion of compound (76b) (10 mg), sodium
tert-butoxide (3.5 mg), bromobenzene (0.1 mL), and toluene (1.0 mL)
were placed in a reaction vial equipped with a stir bar and screw
cap. After passing argon through the reaction mixture for 2 min,
[Pd(.mu.-Br) (t-Bu.sub.3P)].sub.2 (1 mg) was added and the solution
was heated to 80.degree. C. overnight. After cooling to room
temperature, the mixture was concentrated and then dissolved in
MeOH before it was filtered. The filtrate was purified by reverse
phase HPLC purification (gradient elution, water/acetonitrile/TFA)
to provide the title compound (4.5 mg). MS found:
(M+H).sup.+=600.1.
Example 77
N-(2-Oxo-1-((1S,2R,4R)-2-(phenylsulfonylmethyl)-4-(pyridin-4-ylamino)cyclo-
hexyl)pyrrolidin-3-yl)-3-(trifluoromethyl)benzamide
trifluoroacetate
[0701] (77a) Sodium-tert-butoxide (11 mg, 0.114 mmol),
3-bromopyridine (14 mg, 0.086 mmol), and precatalyst acetato
(2-di-t-butylphosphino-1,1-biphenyl-2-yl)palladium(II) (2 mg, 0.004
mmol) were added to compound (76b) (30 mg) in toluene (2 mL),
degassed by bubbling argon for 30 min. The vial was sealed under
argon and the reaction heated overnight at 90.degree. C. Brine (1
mL) was added to quench the reaction and the mixture was evaporated
to dryness in vacuo. The crude residue was taken up in
acetonitrile/water (1:1, 2.5 mL) and purified by C18 HPLC
(acetonitrile/water 0.05% TFA) to give the title compound (6.7 mg)
as a mixture of diastereomers. ESI MS m/z 601
[C.sub.30H.sub.31F.sub.3N.sub.4O.sub.4S+H].sup.+.
Example 78
N-(2-Oxo-1-((1S,2R,4R)-2-(phenylsulfonylmethyl)-4-(thiazol-2-ylamino)cyclo-
hexylpyrrolidin-3-yl)-3-(trifluoromethyl)benzamide
trifluoroacetate
(78a) 2-Bromothiazole was incorporated into Example 77 to give the
title compound as a mixture of diastereomers. MS found:
(M+H).sup.+=607.
Example 79
Methyl
(1R,3R,4S)-4-((S)-2-oxo-3-(3-(trifluoromethyl)benzamido)pyrrolidin--
1-yl)-3-(phenylsulfonylmethyl)cyclohexylcarbamate
[0702] (79a) Compound 76a (20 mg) was dissolved in THF (4 mL) prior
to the addition of saturated NaHCO.sub.3 solution (0.5 mL) and
methyl chloroformate (0.5 mL). After 3 h, EtOAc was added along
with saturated NaHCO.sub.3 solution. The EtoAc layer was washed
with NaHCO.sub.3 solution (aq), dried (MgSO.sub.4), filtered, and
concentrated. Reverse phase HPLC purification (gradient elution,
water/acetonitrile/TFA) of the resulting residue provided the title
compound (9.3 mg). MS found: (M+H).sup.+=582.2.
Example 80
N--((S)-1-((1S,2R,4R)-4-Formamido-2-(phenylsulfonylmethyl)cyclohexyl)-2-ox-
opyrrolidin-3-yl)-3-(trifluoromethyl)benzamide
[0703] (80a) Compound 76a (30 mg) was dissolved in DMF prior to the
addition of 4-methylmorpholine (NMM) (481.5 mg) and concentrated
formic acid (0.1 mL). After cooling to 0.degree. C., EDC (20 mg)
was added. The resulting mixture was warmed to rt and was stirred
overnight. EtOAc was added along with saturated NaHCO.sub.3
solution. The EtOAc layer was washed with NaHCO.sub.3 solution
(aq), dried (MgSO.sub.4), filtered, and concentrated. Reverse phase
HPLC purification (gradient elution, water/acetonitrile/TFA) of the
resulting residue provided the title compound (9.1 mg). MS found:
(M+H).sup.+=552.3.
Example 81
1-((1R,3R,4S)-4-((S)-2-Oxo-3-(3-(trifluoromethyl)benzamido)pyrrolidin-1-yl-
)-3-(phenylsulfonylmethyl)cyclohexyl)urea
[0704] (81a) Compound 76a (77 mg) was dissolved in CH.sub.2Cl.sub.2
(2 mL) at 0.degree. C. prior to the addition of 2,6-lutidine (51
mg) and phenyl chloroformate (38 mg). After 1 h at rt,
CH.sub.2Cl.sub.2 was added along with saturated NaHCO.sub.3
solution. The organic layer was washed with NaHCO.sub.3 solution
(aq), dried (MgSO.sub.4), filtered, and concentrated. Flash
chromatography of the resulting residue provided phenyl
(1R,3R,4S)-4-((S)-2-oxo-3-(3-(trifluoromethyl)benzamido)pyrrolidin-
-1-yl)-3-(phenylsulfonylmethyl)cyclohexylcarbamate (43.7 mg). MS
found: (M+H).sup.+=644.3.
[0705] (81b) A portion of the above compound (81a) (20 mg) was
dissolved in DMSO (1 mL) prior to the addition of concentrated
ammonium hydroxide solution (0.5 mL). After 1 h, the mixture was
filtered. The filtrate was purified by reverse phase HPLC
purification (gradient elution, water/acetonitrile/TFA) to provide
the title compound (4.9 mg). MS found: (M+H).sup.+=567.3.
Example 82
1-Methyl-3-((1R,3R,4S)-4-((S)-2-oxo-3-(3-(trifluoromethyl)benzamido)pyrrol-
idin-1-yl)-3-(phenylsulfonylmethyl)cyclohexyl)urea
(82a) 2.0 M Methylamine in THF was incorporated into Example 81 to
give the title compound. MS found: (M+H).sup.+=581.3.
Example 83
N--((S)-2-oxo-1-((1S,2R,4R)-4-(2-oxopyrrolidin-1-yl)-2-(phenylsulfonylmeth-
yl)cyclohexyl)pyrrolidin-3-yl)-3-(trifluoromethyl)benzamide
[0706] (83a) 4-Chlorobutyrylchloride (27 mg, 0.191 mmol) was added
dropwise to compound 76b (50 mg) and triethylamine (97 mg, 0.722
mmol) in CH.sub.2Cl.sub.2 (2 mL) at room temperature under
nitrogen. After 1 h the reaction was diluted with ethyl acetate (12
mL) then washed with water (1.times.5 mL), 10% citric acid
(1.times.5 mL), sat'd NaHCO.sub.3 (1.times.5 mL), and brine
(1.times.5 mL), dried over MgSO.sub.4, and evaporated to dryness.
The residue was purified by flash chromatography (silica gel, 80%
ethyl acetate/hexanes to 10% methanol/ethyl acetate) to provide
N--((S)-1-((1S,2R,4R)-4-(4-chlorobutanamido)-2-(phenylsulfonylmet-
hyl)cyclohexyl)-2-oxopyrrolidin-3-yl)-3-(trifluoromethyl)benzamide
as a clear film (40 mg). ESI MS m/z 628
[C.sub.29H.sub.33ClF.sub.3N.sub.3O.sub.5S+H].sup.+.
[0707] (83b) The above compound (83a) (40 mg) in THF (1 mL) was
added to sodium hydride (60% in mineral oil, 5 mg, 0.128 mmol) in
THF (2 mL) at room temperature under nitrogen. After 3 h the
reaction was quenched with sat'd NH.sub.4Cl (5 mL) and extracted
with ethyl acetate (3.times.5 mL). The combined organic extracts
were washed with brine (1.times.5 mL), dried over MgSO.sub.4, then
evaporated to dryness. The residue was purified using C18 HPLC
(acetonitrile/water 0.05% TFA) to give the title compound (21.7 mg)
as a white powder after lyophilization. ESI MS m/z 592
[C.sub.29H.sub.32F.sub.3N.sub.3O.sub.5S+H].sup.+.
Example 84
N--((S)-1-((1S,2R,4R)-4-(1,1-dioxido-isothiazolidin-2-yl)-2-(phenylsulfony-
lmethyl)cyclohexyl)-2-oxopyrrolidin-3-yl)-3-(trifluoromethyl)benzamide
(84a) 3-Chloropropanesulfonylchloride was incorporated into Example
83 (in place of 4-chlorobutyrylchloride) to give the title
compound. MS found: (M+H).sup.+=628.
Example 85
N--((S)-1-((1S,2R,4R)-2-((4-Chlorophenylsulfonyl)methyl)-4-(isopropyl(meth-
yl)amino)cyclohexyl)-2-oxopyrrolidin-3-yl)-3-fluoro-5-(trifluoromethyl)ben-
zamide trifluoroacetate
[0708] (85a) A portion of compound (61g) (500 mg) and 10% Pd/C (112
mg) in MeOH (150 mL) was hydrogenated at 40 psi on a Paar shaker
for 4 h. The mixture was filtered through diatomaceous earth,
rinsed with MeOH, then evaporated to dryness to give tert-butyl
(1R,3R,4S)-4-amino-3-(hydroxymethyl)cyclohexylcarbamate as a
colorless oil (348 mg). ESI MS m/z 245
[C.sub.12H.sub.24N.sub.2O.sub.3+H].sup.+.
[0709] (85b) To a portion of the above (85a) (4.14 g) in
CH.sub.2Cl.sub.2 (169 mL) was added sodium bicarbonate (1.53 g),
followed by dropwise addition of TrocCl (2.48 mL). The mixture was
stirred at room temperature overnight, then diluted with
CH.sub.2Cl.sub.2 (800 mL), washed with satd NaHCO.sub.3
(3.times.150 mL) and brine (100 mL), dried over Na.sub.2SO.sub.4,
filtered, and concentrated to
(1S,2R,4R)-(4-tert-butoxycarbonylamino-2-hydroxymethylcyclohexyl)carbamic
acid 2,2,2-trichloroethyl ester (7.14 g) as a white solid. ESI MS
m/z 319 [C.sub.15H.sub.25Cl.sub.3N.sub.2O.sub.5-Boc+H].sup.+.
[0710] (85c) A mixture of 85b (7.14 g),
bis(p-chlorophenyl)disulfide (9.76 g, 34 mmol), and
tri-n-butylphosphine (26 mL, 187 mmol) in THF (426 mL) was stirred
under a nitrogen atmosphere at 75.degree. C. for 16 h. The solvent
was removed under vacuum, the residue was diluted with MeCN (800
mL), washed with hexanes (4.times.200 mL), concentrated, and flash
chromatography (silica-gel, 0-50% ether/hexanes) afforded
(1R,3R,4S)-[3-(4-chlorophenylsulfanylmethyl)-4-(2,2,2-trichloroethoxycarb-
onylamino)-cyclohexyl]carbamic acid tert-butyl ester (6.73 g) as a
white solid: .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.30-7.18
(m, 4H), 5.06 (d, J=99.2 Hz, 1H), 4.78 (d, J=12.1 Hz, 1H), 4.69 (d,
J=12.1 Hz, 1H), 4.46 (d, J=7.5 Hz, 1H), 4.20-4.09 (m, 1H), 3.42 (br
s, 1H), 2.94 (dd, J=13.4, 7.2 Hz, 1H), 2.69 (dd, J=13.4, 7.2 Hz,
1H), 2.22-2.08 (m, 1H), 2.05-1.78 (m, 3H), 1.68-1.38 (m, 10H),
1.34-0.82 (m, 2H).
[0711] (85d) A solution of 85c (6.73 g) in CH.sub.2Cl.sub.2 (41 mL)
was cooled to 0.degree. C.; 3-chloroperoxy-benzoic acid (70%, 6.38
g, 25.8 mmol) was added portion-wise. The mixture was stirred for 4
h, then diluted with CH.sub.2Cl.sub.2 (800 mL), washed with satd
NaHCO.sub.3 (3.times.150 mL) and brine (100 mL), dried over
Na.sub.2SO.sub.4, filtered, and concentrated to give
(1R,3R,4S)-[3-(4-chlorobenzenesulfonylmethyl)-4-(2,2,2-trichloroethoxycar-
bonylamino) cyclohexyl]carbamic acid tert-butyl ester (7.13 g) as
an off-white solid. ESI MS m/z 478
[C.sub.21H.sub.28Cl.sub.4N.sub.2O.sub.6S-Boc+H].sup.+.
[0712] (85e) To a solution of 85d (1.00 g) in THF (16 mL) was added
glacial acetic acid (33 mL), followed by activated zinc dust (3.00
g). The mixture was stirred for 8 h, then diluted with EtOAc (500
mL), washed with satd Na.sub.2CO.sub.3 (3.times.150 mL) and brine
(100 mL), dried over Na.sub.2SO.sub.4, filtered, and concentrated.
The residue was purified by CombiFlash chromatography (silica-gel,
MeOH/CH.sub.2Cl.sub.2) to give tert-butyl
(1R,3R,4S)-4-amino-3-((4-chlorophenylsulfonyl)methyl)cyclohexylcarbamate
(561 mg) as yellow solid. ESI MS m/z 403
[C.sub.18H.sub.27ClN.sub.2O.sub.4S+H].sup.+.
[0713] (85f) To a solution of 85e (561 mg) and N-Cbz-L-methionine
(591 mg) in DMF (9.3 mL), cooled to 0.degree. C., was added
N-methylmorpholine (458 .mu.L) and BOP reagent (925 mg). The
mixture was stirred overnight at room temperature, then diluted
with EtOAc (500 mL), washed with satd NaHCO.sub.3 (3.times.150 mL),
NH.sub.4Cl (3.times.150 mL), 5% aqueous LiCl (3.times.150 mL), and
brine (100 mL), dried over Na.sub.2SO.sub.4, filtered, and
concentrated to give crude
(1R,3R,4S)-[4-(2-benzyloxycarbonylamino-4-methylsulfanylbutyrylamino)-3-(-
4-chlorobenzenesulfonylmethyl)cyclohexyl]carbamic acid tert-butyl
ester (953 mg) as a yellow solid. ESI MS m/z 668
[C.sub.31H.sub.42ClN.sub.3O.sub.7S.sub.2+H].sup.+.
[0714] (85g) A mixture of 85f (6.42 g, 9.60 mmol) and iodomethane
(70 mL) was stirred overnight at room temperature. Methylene
chloride (200 mL) was added and the iodomethane was azeotroped off
under vacuum, repeating 6-8 times. The residue was dissolved in
CH.sub.2Cl.sub.2 (200 mL), concentrated to 1/4 volume under vacuum,
and the resultant white solid was filtered (2.47 g, sulfonium salt
by-product). The filtrate was concentrated to provide a yellow
solid (6.80 g), which was used without further purification. This
yellow solid (6.80 g), cesium carbonate (5.47 g, 16.8 mmol), and
DMF (129 mL) was stirred 6 h at room temperature. More cesium
carbonate (5.47 g, 16.8 mmol) was added and the reaction was
stirred overnight. The mixture was diluted with EtOAc (1 L), washed
with water (3.times.600 mL), 5% aqueous LiCl (3.times.600 mL), and
brine (450 mL), dried over Na.sub.2SO.sub.4, filtered, and
concentrated. The residue was purified by flash chromatography
(silica-gel, 50-100% EtOAc/hexanes) to give
(1S,2R,4R)-{1-[4-tert-butoxycarbonylamino-2-(4-chlorobenzenesulfo-
nylmethyl)cyclohexyl]-2-oxo-pyrrolidin-3-yl}carbamic acid benzyl
ester (3.21 g) as white solid. ESI MS m/z 620
[C.sub.30H.sub.38Cl.sub.1N.sub.3O.sub.7S+H].sup.+.
[0715] (85h) Compound 85g was incorporated into step 62b to give
benzyl
(S)-1-((1S,2R,4R)-4-amino-2-((4-chlorophenylsulfonyl)methyl)cyclohexyl)-2-
-oxopyrrolidin-3-ylcarbamate: .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta. 10.46 (br, s, 3H), 7.90-7.60 (m, 4H), 7.55-7.42 (m, 2H),
7.40-7.29 (m, 3H), 5.65 (d, J=7.3 Hz, 1H), 4.88 (s, 2H), 4.34-4.09
(m, 2H), 3.86-3.64 (m, 1H), 3.60-3.20 (m, 4H), 2.77-2.30 (m, 3H),
2.20-1.70 (m, 6H).
[0716] (85i) A mixture of 85h (875 mg, 1.38 mmol), acetone (3.03
mL, 41.4 mmol), and acetic acid (159 .mu.L, 2.76 mmol) in
1,2-dichloroethane (30 mL) was stirred for 3 min, then treated with
sodium triacetoxyborohydride (585 mg, 2.76 mmol). After stirring
the mixture for 3 h, more acetone (4 mL), acetic acid (0.4 mL), and
sodium triacetoxyborohydride (300 mg, 1.42 mmol) were added. After
stirring the reaction mixture overnight, the solvent was removed
under vacuum. The residue was dissolved in MeOH (30 mL); 37%
aqueous formaldehyde (6 mL) and sodium cyanoborohydride (130 mg,
2.07 mmol) were added. The mixture was stirred 8 h. The solvent was
removed under vacuum; the residue was taken up in CH.sub.2Cl.sub.2
(300 mL), washed with satd NaHCO.sub.3 (3.times.100 mL) and brine
(100 mL), dried over Na.sub.2SO.sub.4, filtered, and concentrated
under vacuum to afford benzyl
(S)-1-((1S,2R,4R)-2-((4-chlorophenylsulfonyl)methyl)-4-(isopropyl(methyl)-
amino)cyclohexyl)-2-oxopyrrolidin-3-ylcarbamate (707 mg) as a
yellow solid. ESI MS m/z 576
[C.sub.29H.sub.38ClN.sub.3O.sub.5S+H].sup.+.
[0717] (85j) A mixture of 85i (536 mg) and 33% HBr in HOAc (15 mL)
was stirred 30 minutes at room temperature. The mixture was
triturated with ether (3.times.50 mL) and the residue was dissolved
in MeOH (50 mL). The solvent was evaporated under vacuum to provide
(S)-3-amino-1-((1S,2R,4R)-2-((4-chlorophenylsulfonyl)methyl)-4-(isopropyl-
(methyl)amino)cyclohexyl)pyrrolidin-2-one dihydrogen bromide (436
mg) as a tan solid, which was used without further purification in
the next step. ESI MS m/z 442
[C.sub.21H.sub.32ClN.sub.3O.sub.3S+H].sup.+.
[0718] (85k) To a solution of crude 85j (92 mg) and
3-fluoro-5-(trifluoromethyl)benzoic acid (48 mg) in DMF (1.01 mL),
cooled to 0.degree. C., was added N-methylmorpholine (50 .mu.L) and
BOP reagent (101 mg). The mixture was stirred overnight at room
temperature, diluted with EtOAc (500 mL), washed with satd
NaHCO.sub.3 (3.times.150 mL), NH.sub.4Cl (3.times.150 mL), 5%
aqueous LiCl (3.times.150 mL), and brine (100 mL), dried over
Na.sub.2SO.sub.4, filtered, and concentrated. The residue was
purified by semi-preparative HPLC to give the title compound (71.2
mg) as a .TFA salt after lyophilization from MeCN/H.sub.2O. ESI MS
m/z 632 [C.sub.29H.sub.34ClF.sub.4N.sub.3O.sub.4S+H].sup.+.
Example 86
3-Chloro-N--((S)-1-((1S,2R,4R)-2-((4-chlorophenylsulfonyl)methyl)-4-(isopr-
opyl(methyl)amino)cyclohexyl)-2-oxopyrrolidin-3-yl)benzamide
trifluoroacetate
(86a) 3-Chlorobenzoic acid was incorporated into Example 85 (step
85k) to give the title compound. MS found; (M+H).sup.+=580.
Example 87
N--((S)-1-((1S,2R,4R)-2-((4-chlorophenylsulfonyl)methyl)-4-(isopropyl(meth-
yl)amino)cyclohexyl)-2-oxopyrrolidin-3-yl)-3,5-bis(trifluoromethyl)benzami-
de trifluoroacetate
(87a) 3,5-Bis(trifluoromethyl)benzoic acid was incorporated into
Example 85 (step 85k) to give the title compound. MS found:
(M+H).sup.+=683.
Example 88
tert-Butyl
2-(((S)-1-((1S,2R,4R)-2-((4-chlorophenylsulfonyl)methyl)-4-(iso-
propyl(methyl)amino)cyclohexyl)-2-oxopyrrolidin-3-yl)carbamoyl)-4-(trifluo-
romethoxy)phenylcarbamate
(88a) 2-tert-Butoxycarbonylamino-5-trifluoromethoxybenzoic acid was
incorporated into Example 85 (step 85k) to give the title compound.
MS found: (M+H).sup.+=746.
Example 89
2-Amino-N--((S)-1-((1S,2R,4R)-2-((4-chlorophenylsulfonyl)methyl)-4-(isopro-
pyl(methyl)amino)cyclohexyl)-2-oxopyrrolidin-3-yl)-5-(trifluoromethoxy)ben-
zamide trifluoroacetate
(89a) Example 88 was incorporated into Example 62 (step 62b) to
give the title compound. MS found: (M+H).sup.+=645.
Example 90
N--((S)-1-((1S,2R,4R)-2-((4-Chlorophenylsulfonyl)methyl)-4-(isopropyl(meth-
yl)amino)cyclohexyl)-2-oxopyrrolidin-3-yl)-3-(trifluoromethoxy)benzamide
trifluoroacetate
(90a) 3-Trifluoromethoxybenzoic acid was incorporated into Example
85 (step 85k) to give the title compound. MS found:
(M+H).sup.+=630.2.
Example 91
N--((S)-1-((1S,2R,4R)-2-((4-Chlorophenylsulfonyl)methyl)-4-(isopropyl(meth-
yl)amino)cyclohexyl)-2-oxopyrrolidin-3-yl)-3-(trifluoromethyl)benzamide
trifluoroacetate
(91a) 3-Trifluoromethylbenzoic acid was incorporated into Example
85 (step 85k) to give the title compound. MS found:
(M+H).sup.+=614.0.
Example 92
3,5-Dichloro-N--((S)-1-((1S,2R,4R)-2-((4-chlorophenylsulfonyl)methyl)-4-(i-
sopropyl(methyl)amino)cyclohexyl)-2-oxopyrrolidin-3-yl)benzamide
trifluoroacetate
(92a) 3,5-Dichlorobenzoic acid was incorporated into Example 85
(step 85k) to give the title compound. MS found:
(M+H).sup.+=614.2.
Example 93
3-Chloro-N--((S)-1-((1S,2R,4R)-2-((4-chlorophenylsulfonyl)methyl)-4-(isopr-
opyl(methyl)amino)cyclohexyl)-2-oxopyrrolidin-3-yl)benzamide
N-Oxide
[0719] (93a) A solution of Example 86 (13.6 mg) in CH.sub.2Cl.sub.2
(1.5 mL) was cooled to 0.degree. C., then 3-chloroperoxybenzoic
acid (77%, 10 mg) was added portion-wise. The mixture was stirred
for 1.25 h, then diluted with CH.sub.2Cl.sub.2 (400 mL), washed
with sand NaHCO.sub.3 (3.times.100 mL) and brine (100 mL), dried
over Na.sub.2SO.sub.4, filtered, and concentrated. The residue was
purified by semi-preparative HPLC to give the title compound (6.8
mg, 57%) as a white solid after lyophilization from MeCN/aqueous
TEA. ESI MS m/z 596
[C.sub.28H.sub.35Cl.sub.2N.sub.3O.sub.5S+H].sup.+.
Example 94
N--((S)-1-((1S,2R,4R)-2-((4-Chlorophenylsulfonyl)methyl)-4-(isopropyl(meth-
yl)amino)cyclohexyl)-2-oxopyrrolidin-3-yl)-3-(trifluoromethyl)benzamide
N-Oxide
(94a) Example 91 was incorporated into Example 93 to give the title
compound. MS found: (M+H).sup.+=630.3.
Example 95
N--((S)-1-((1S,2R,4R)-2-((4-Chlorophenylsulfonyl)methyl)-4-(isopropyl(meth-
yl)amino)cyclohexyl)-2-oxopyrrolidin-3-yl)-3-fluoro-5-(trifluoromethyl)ben-
zamide N-Oxide
(95a) Example 85 was incorporated into Example 93 to give the title
compound. MS found. (M+H).sup.+=649.1.
Example 96
N--((S)-1-((1S,2R,4R)-4-(Isopropyl(methyl)amino)-2-(phenylsulfonylmethyl)c-
yclohexyl)-2-oxopyrrolidin-3-yl)-3-(trifluoromethyl)benzamide
N-Oxide
(96a) Example 5 was incorporated into Example 93 to give the title
compound. MS found: (M+H).sup.+=596.3.
Example 97
N--((S)-1-((1S,2R,4R)-4-(isopropyl(methyl)amino)-2-((4-isopropylphenylsulf-
onyl)methyl)cyclohexyl)-2-oxopyrrolidin-3-yl)-3-(trifluoromethyl)benzamide
Trifluoroacetate
[0720] (97a) The compound from step 61f (4.0 g) was dissolved in
MeOH (30 mL) prior to the addition of 10% Pd/C (600 mg). A hydrogen
balloon was added and the mixture was stirred for 3 h. The Pd/C was
filtered off and the solvent was concentrated to give
(1R,2S,5R)-tert-butyl
2-amino-7-oxo-6-aza-bicyclo[3.2.1]octane-6-carboxylate (2.5 g). MS
found: (M+H).sup.+=241.1
[0721] (97b) This material (97a) was incorporated into Steps 52a to
52b (substituting N-Cbz-L-Met-OH for N-Boc-L-Met-OH) to give
(1R,2S,5R)-tert-butyl
2-((S)-3-(benzyloxycarbonyl)-2-oxopyrrolidin-1-yl)-7-oxo-6-aza-bicyclo[3.-
2.1]octane-6-carboxylate. MS found: (M+H).sup.+=458.3.
[0722] (97c) A mixture of 97b (1.20 g) and 10% Pd/C (558 mg) in
MeOH (200 mL) was hydrogenated at 1 atm for 4 h. The mixture was
filtered through diatomaceous earth with MeOH wash and evaporated
to dryness to give (1R,2S,5R)-tert-butyl
2-((S)-3-amino-2-oxopyrrolidin-1-yl)-7-oxo-6-aza-bicyclo[3.2.1]octane-6-c-
arboxylate (779 mg) as a yellow solid that was used without further
purification in the next step: .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta. 4.40-4.15 (m, 2H), 3.68 (t, J=99.0 Hz, 1H), 3.53-3.40 (m,
2H), 3.28-3.12 (m, 1H), 2.70-2.60 (m, 1H), 2.46-2.10 (m, 6H),
1.96-1.60 (m, 5H), 1.54 (s, 9H).
[0723] (97d) To a mixture of 97c (779 mg),
3-(trifluoromethyl)benzoic acid (687 mg), and DMF (12 mL), cooled
to 0.degree. C., was added N-methylmorpholine (793 .mu.L, 7.23
mmol) and BOP reagent (1.60 g, 3.61 mmol). The mixture was stirred
overnight at room temperature, diluted with EtOAc (800 mL), washed
with satd NaHCO.sub.3 (3.times.150 mL), NH.sub.4Cl (3.times.150
mL), 5% aqueous LiCl (3.times.150 mL), and brine (100 mL), dried
over Na.sub.2SO.sub.4, filtered, and concentrated. The residue was
purified by flash chromatography (silica gel, 0-15%
MeOH/CH.sub.2Cl.sub.2) to give (1R,2S,5R)-tert-butyl
7-oxo-2-((S)-2-oxo-3-(3-(trifluoromethyl)benzamido)pyrrolidin-1-yl)-6-aza-
-bicyclo[3.2.1]octane-6-carboxylate (1.20 g) as white solid. ESI MS
m/z 496 [C.sub.24H.sub.28F.sub.3N.sub.3O.sub.5S+H].sup.+.
[0724] (97e) To a solution of 97d (1.20 g, 2.42 mmol) in THF (18.6
mL) and water (3.6 mL) was added sodium borohydride (460 mg, 12.1
mmol) portion wise. After stirring the mixture for three hours,
satd NaHCO.sub.3 (50 mL) was added and the mixture was stirred for
an additional 15 min. The mixture was diluted with ethyl acetate
(500 mL), washed with satd NaHCO.sub.3 (3.times.150 mL) and brine
(100 mL), dried over Na.sub.2SO.sub.4, filtered, and concentrated
to give tert-butyl
(1R,3R,4S)-3-(hydroxymethyl)-4-((S)-2-oxo-3-(3-(trifluoromethyl)benzamido-
)pyrrolidin-1-yl)cyclohexylcarbamate (1.12 g) as a white solid. ESI
MS m/z 500 [C.sub.24H.sub.32F.sub.3N.sub.3O.sub.5+H].sup.+.
[0725] (97f) A mixture of 97e (100 mg),
bis(p-1,2-bis(4-isopropylphenyl)disulfane (121 mg), and
tri-n-butylphosphine (0.3 mL) in THF (5 mL) was stirred under a
nitrogen atmosphere at 75.degree. C. for 16 h. The solvent was
removed under vacuum, the residue was diluted with MeCN (500 mL),
washed with hexanes (4.times.200 mL), concentrated, and preparative
TLC afforded tert-butyl
(1R,3R,4S)-3-((4-isopropylphenylthio)methyl)-4-((S)-2-oxo-3-(3-(trifluoro-
methyl)benzamido)pyrrolidin-1-yl)cyclohexylcarbamate (79.7 mg) as a
mixture of isomers. ESI MS m/z 634
[C.sub.24H.sub.32F.sub.3N.sub.3O.sub.5+H].sup.+.
[0726] (97g) The compound from above (97f) was incorporated into
Step 3e to give tert-butyl
(1R,3R,4S)-3-((4-isopropylphenylsulfonyl)methyl)-4-((S)-2-oxo-3-(3-(trifl-
uoromethyl)benzamido)pyrrolidin-1-yl)cyclohexylcarbamate: .sup.1H
NMR (300 MHz, CDCl.sub.3) .delta. 8.10-7.76 (m, 4H), 7.75-7.62 (m,
1H), 7.61-7.30 (m, 3H), 4.90-4.04 (m, 2H), 3.87-3.20 (m, 4H),
3.13-2.86 (m, 1H), 2.80-2.42 (m, 1H), 2.36-1.50 (m, 25H), 0.99-0.75
(m, 4H); .sup.19F NMR (282 MHz, CDCl.sub.3) .delta. -63.1,
-63.2.
(97h) The compound from above (97g) was incorporated into Step 611
to give the title compound after HPLC. MS found:
(M+H).sup.+=622.3.
Example 98
N--((S)-1-((1S,2R,4R)-4-(isopropyl(methyl)amino)-2-(o-tolylsulfonylmethyl)-
cyclohexyl)-2-oxopyrrolidin-3-yl)-3-(trifluoromethyl)benzamide
trifluoroacetate
(98a) 1,2-diortho-tolyldisulfane was incorporated into Example 97
from Step 97f to 97h to give the title compound. MS found:
(M+H).sup.+=594.6.
Example 99
N--((S)-1-((1S,2R,4R)-2-((4-Fluorophenylsulfonyl)methyl)-4-(isopropyl(meth-
yl)amino)cyclohexyl)-2-oxopyrrolidin-3-yl)-3-(trifluoromethyl)benzamide
trifluoroacetate
(99a) 1,2-bis(4-Fluorophenyl)disulfane was incorporated into
Example 97 from Step 97f to 97h to give the title compound. MS
found: (M+H).sup.+=598.5.
Example 100
3-Chloro-N--((S)-1-((1S,2R,4R)-4-(isopropyl(methyl)amino)-2-(tosylmethyl)c-
yclohexyl)-2-oxopyrrolidin-3-yl)benzamide trifluoroacetate
(100a) Compound 97b was incorporated into Step 97e to give
(1S,2R,4R)-(1-[4-tert-butoxycarbonylamino-2-(hydroxymethyl)cyclohexyl]-2--
oxo-pyrrolidin-3-yl)carbamic acid benzyl ester. MS found:
(M+H).sup.+=462.
[0727] (100b) Compound 100a was incorporated into Step 97f (with
1,2-dipara-tolyldisulfane instead of
bis(p-1,2-bis(4-isopropylphenyl)disulfane) and then Step 97g to
give
(1S,2R,4R)-{1-[4-tert-butoxycarbonylamino-2-(4-methylbenzenesulfonylmethy-
l)cyclohexyl]-2-oxo-pyrrolidin-3-yl}carbamic acid benzyl ester. MS
found: (M+H).sup.+=600.
(100c) Compound 100b was taken into Steps 85h-85j to give
(S)-3-amino-1-((1S,2R,4R)-2-((4-methylphenylsulfonyl)methyl)-4-(isopropyl-
(methyl)amino)cyclohexyl)pyrrolidin-2-one dihydrogen bromide. MS
found: (M+H).sup.+=584.
(100d) Compound 100c was taken into Step 85k (with 3-chlorobenzoic
acid instead 3-fluoro-5-trifluoromethyl-benzoic acid) to give the
title compound. MS found: (M+H).sup.+=560.2.
Example 101
2-Amino-N--((S)-1-((1S,2R,4R)-4-(isopropyl(methyl)amino)-2-(tosylmethyl)cy-
clohexyl)-2-oxopyrrolidin-3-yl)-5-(trifluoromethoxy)benzamidemide
trifluoroacetate
[0728] (101a) 2-(tert-Butoxycarbonyl)-5-(trifluoromethyl)benzoic
acid was incorporated into Step (100d) to give tert-butyl
2-(((S)-1-((1S,2R,4R)-4-(isopropyl(methyl)amino)-2-(tosylmethyl)cyclohexy-
l)-2-oxopyrrolidin-3-yl)carbamoyl)-4-(trifluoromethoxy)phenylcarbamate.
MS found: (M+H).sup.+=725.
[0729] (101b) The above material (101a) (20 mg) was dissolved in
CH.sub.2Cl.sub.2 (2 mL) and cooled to 0.degree. C. prior to the
addition of TFA (4 mL). After the reaction was warmed to rt over 30
min, it was concentrated and dried to provide the title compound.
MS found: (M+H).sup.+=625.2.
Example 102
1-[(1S,2R,4R)-(4-Amino-2-benzenesulfonyl-methylcyclohexyl)-4-(3-trifluorom-
ethylphenyl]-5,6-dihydro-1H-pyridin-2-one
[0730] (102a) A solution of compound 61j (1.45 g, 3.9 mmol) in
methanol (10 mL) was stirred on an ice bath and treated dropwise
over 40 min with a solution of 1-(3-trifluoromethylphenyl)propenone
(see procedure 28a, 786 mg, 3.9 mmol). The mixture was stirred at
room temperature for 2 h, then was concentrated under vacuum. The
residue was purified by flash column chromatography, eluting with
55% ethyl acetate-hexane, to provide
(1R,3R,4S)-{3-benzene-sulfonylmethyl-4-[3-oxo-3-(3-trifluoromethylphenyl)-
-propylamino]cyclohexyl}carbamic acid tert-butyl ester (1.16 g) as
a white glassy solid. MS found: (M+H).sup.+=569.35.
[0731] (102b) A suspension of sodium hydride (60%, 176 mg, 4.4
mmol) in tetrahydrofuran (5 mL) was stirred on an ice bath and
treated dropwise over 5 min with dimethylphosphonoacetic acid
tert-butyl ester (0.79 mL, 4.0 mmol). The mixture was stirred at
room temperature for 25 min, then was cooled on an ice bath and
treated with a solution of
(1R,3R,4S)-{3-benzenesulfonylmethyl-4-[3-oxo-3-(3-trifluoromethylphenyl)--
propylamino]cyclohexyl}carbamic acid tert-butyl ester (1.138 g, 2.0
mmol) in tetrahydrofuran (5 mL). The mixture was stirred at room
temperature for 2.5 h, then was treated with saturated aqueous
ammonium chloride. The mixture was extracted with ethyl acetate,
and the organic extracts were dried over sodium sulfate and
concentrated under vacuum. The residue was purified by flash column
chromatography, eluting with 25% ethyl acetate-hexane, to provide
the E isomer of
5-([1S,2R,4R]-2-benzenesulfonylmethyl-4-tert-butoxycarbonyl-aminocyclohex-
ylamino)-3-(3-trifluoromethylphenyl)pent-2-enoic acid tert-butyl
ester (511 mg) as a white solid. MS found: (M+H).sup.+=667.41.
Further elution with 40% ethyl acetate-hexane provided the
corresponding Z isomer (567 mg) as a white glassy solid. MS found:
(M+H).sup.+=667.41.
[0732] (102c) A solution of the E isomer of
5-([1S,2R,4R]-2-benzenesulfonylmethyl-4-tert-butoxycarbonylaminocyclohexy-
l-amino)-3-(3-trifluoromethylphenyl)pent-2-enoic acid tert-butyl
ester (495 mg) in dichloromethane (10 mL) was treated with
trifluoroacetic acid (5 mL). After standing at room temperature for
4 h, the mixture was concentrated under vacuum to provide the E
isomer of
5-([1S,2R,4R]-4-amino-2-benzenesulfonylmethylcyclohexylamino)-3-(3-triflu-
oromethyl-phenyl)pent-2-enoic acid, bis-trifluoroacetic acid salt,
as a white glassy solid (736 mg) containing excess trifluoro-acetic
acid. MS found: (M+H).sup.+=511.20. Without further purification,
this material was dissolved in dichloromethane (5 mL) and 20,
treated sequentially with diisopropylethylamine (0.78 mL, 4.45
mmol), 4-(N,N-dimethylamino)pyridine (91 mg, 0.74 mmol) and TBTU
(262 mg, 0.82 mmol). The solution was stirred at room temperature
for 17.5 h, then was diluted with dichloromethane, washed with
saturated aqueous sodium bicarbonate, dried over sodium sulfate and
concentrated under vacuum. The residue was purified by flash column
chromatography, eluting with 4% methanol-dichloromethane containing
0.4% aqueous ammonia, and then by reverse phase HPLC. The resulting
product was converted to the free base by partitioning between 1N
sodium hydroxide and ethyl acetate to provide the title product
(130 mg) as a white glassy foam. MS found: (M+H).sup.+=493.37.
Example 103
1-([(1S,2R,4R)-2-benzenesulfonylmethyl-4-isopropylamino-cyclohexyl)-4-(3-t-
rifluoromethylphenyl)-5,6-dihydro-1H-pyridin-2-one
[0733] (103a) A solution of
1-[(1S,2R,4R)-(4-amino-2-benzenesulfonyl-methylcyclohexyl)-4-(3-trifluoro-
methylphenyl)]-5,6-dihydro-1H-pyridin-2-one (120 mg, 0.243 mmol) in
1,2-dichloroethane (2.5 mL) was treated sequentially with acetone
(0.054 mL, 0.071 mmol), acetic acid (0.07 mL, 1.22 mmol) and sodium
triacetoxyborohydride (155 mg, 0.731 mmol). The mixture was stirred
at room temperature for 3 h, then was concentrated under vacuum.
The residue was partitioned between saturated aqueous sodium
bicarbonate and ethyl acetate, and the organic extracts were dried
over sodium sulfate and concentrated under vacuum to provide the
title product (110 mg) as a white glassy solid. MS found:
(M+H).sup.+=535.21.
Example 104
1-[(1S,2R,4R)-2-benzenesulfonylmethyl-4-(isopropyl-methyl-amino)cyclohexyl-
]-4-(3-trifluoromethyl-phenyl)-5,6-dihydro-1H-pyridin-2-one
[0734] (104a) A solution of
1-([(1S,2R,4R)-2-benzenesulfonylmethyl-4-isopropylamino-cyclohexyl)-4-(3--
trifluoromethylphenyl)-5,6-dihydro-1H-pyridin-2-one (41 mg, 0.077
mmol) in methanol (1 mL) was treated with aqueous formaldehyde
(37%, 0.029 mL, 0.383 mmol) and the mixture was stirred for 45 min.
Sodium cyanoborohydride (7 mg, 0.115 mmol) was added, and the
mixture stirred at room temperature for 2 h. Water was added and
the mixture was extracted with ethyl acetate. The extracts were
washed with brine, dried over sodium sulfate and concentrated under
vacuum to provide the title product (42 mg) as a white glassy
solid. MS found: (M+H).sup.+=548.67.
Example 105
1-[(1S,2R,4R)-2-benzenesulfonylmethyl-4-(isopropyl-ethyl-amino)cyclohexyl]-
-4-(3-trifluoromethyl-phenyl)-5,6-dihydro-1H-pyridin-2-one
[0735] (105a) Following the procedure of Example 104 but
substituting acetaldehyde for aqueous formaldehyde,
1-([(1S,2R,4R)-2-benzenesulfonylmethyl-4-isopropylamino-cyclohexyl)-4-(3--
trifluoromethylphenyl)-5,6-dihydro-1H-pyridin-2-one (43 mg, 0.08
mmol) was converted to the title product (45 mg) as a white glassy
solid. MS found: (M+H).sup.+=563.29.
Example 106
1-[1S,2R,4R)-2-Benzenesulfonylmethyl-4-(isopropyl-methyl-amino)-cyclohexyl-
]-(3S)-3-(6-chloro-2-trifluoromethyl-quinazolin-4-ylamino)-pyrrolidin-2-on-
e, TFA salt
Part A. Preparation of
6-Chloro-2-trifluoromethyl-quinazolin-4-ol
[0736] 2-Amino-5-chlorobenzamide (Avocado) (1.00 g, 5.86 mmol, 1.0
eq.) and ethyl trifluoroacetate (4.19 mL, 35.2 mmol, 6.0 eq.) were
dissolved in 50 mL of ethanol at rt under nitrogen and followed by
the addition of 3.09 M sodium ethoxide in ethanol (11.38 mL, 35.2
mmol, 6.0 eq.) The mixture was refluxed 20 hours. Cooled to rt.
Added 10 mL of 10% HOAc/H2O, Solids formed which were filtered,
rinsed with 5 mL H2O, then dissolved in 20 mL of EtOAc/THF. Dried
and stripped in vacuo to give 1.35 g of amber solids. LCMS detects
(M+H)+=249.
Part B. Preparation of 4,6-Dichloro-2-trifluoromethyl
quinazoline
[0737] 6-Chloro-2-trifluoromethyl-quinazolin-4-ol (1.35 g, 5.43
mmol, 1 eq.), phosphorous oxychloride (4.88 mL, 52.4 mmol, 9.64
eq.) and triethylamine (2.43 mL, 17.4 mmol, 3.21 eq.) were refluxed
for 2 hours. Stripped 3.times. from methylene chloride then
dissolved in methylene chloride and rinsed 3.times. with saturated
sodium bicarbonate, 1.times. with brine. Dried and stripped in
vacuo to give an amber oil. Purified over silica gel in 9:1
Hexanes/EtOAc. Obtained 800 mg of off-white solids as product. The
product was used immediately in Example 1 Part C.
Part C
[0738]
(3S)-3-Amino-1-[(1S,2R,4R)-2-benzenesulfonylmethyl-4-(isopropyl-me-
thyl-amino)-cyclohexyl]-pyrrolidin-2-one (40 mg, 0.0982 mmol, 1
eq., see compound 52e), 4,6-dichloro-2-trifluoromethyl-quinazoline
(239 mg, 0.105 mmol, 1 eq.) and triethylamine (55 ul, 0.419, 4 eq.)
were dissolved in 3 mL of ethanol then microwaved at 100.degree. C.
until reaction was complete by LCMS. Purified by LCMS. Obtained 17
mg of product. LCMS detects (M+H)+=638.
Example 107
1-[(1S,2R,4R)-2-benzenesulfonylmethyl-4-(isopropyl-methyl-amino)-cyclohexy-
l]-(3S)-3-(7-chloro-quinazolin-4-ylamino)-pyrrolidin-2-one, TFA
salt
Part A. Preparation of 7-Chloro-quinazolin-4-ol
[0739] 2-Amino-4-chloro-benzoic acid (1.00 g, 11.7 mmol, 1.0 eq.),
formamidine acetate (3.64 mL, 35.0 mmol, 3 eq.), and ethoxyethanol
(20 mL) were refluxed under nitrogen overnight. Cooled to rt. Added
25 mL of diethyl ether. Solids precipitated. Filtered off solids.
Pumped under high vacuum to give 2.75 g of white solids as product.
LCMS detects (M+H)+=181.
Part B. Preparation of 4,7-Dichloro-quinazoline
[0740] 7-Chloro-quinazolin-4-ol (1.1 g, 6.09 mmol, 1 eq.),
phosphorous oxychloride (5.47 mL, 58.7 mmol, 9.00 eq.) and
triethylamine (2.73 mL, 19.6 mmol, 3.21 eq.) were refluxed for 2
hours. Stripped then restripped 3.times. from methylene chloride,
then dissolved in methylene chloride and rinsed 3.times. with
saturated sodium bicarbonate, 1.times. with brine. Dried and
stripped in vacuo to give an amber oil, Purified over silica gel in
9:1 to 3:1 Hexanes/EtOAc. Obtained 1.00 g of tan solids as product.
LCMS detects (M+H)+=199.
107. Part C. Preparation of
1-[(1S,2R,4R)-2-benzenesulfonylmethyl-4-(isopropyl-methyl-amino)-cyclohex-
yl]-(3S)-3-(7-chloro-quinazolin-4-ylamino)-pyrrolidin-2-one, TFA
salt
Followed the procedure of Example 106c starting from
(3S*)-3-amino-1-[(1S*,2R*,4R*)-2-benzenesulfonylmethyl-4-(isopropyl-methy-
l-amino)-cyclohexyl]-pyrrolidin-2-one and 4,7-dichloro-quinazoline.
LCMS detects (M+H)+=570.
Example 108
Part A Preparation of 6-Chloro-quinazoline-2,4-diol
[0741] 2-Amino-5-chlorobenzamide (Avocado) (3.00 g, 17.5 mmol, 1.0
eq.) was suspended in 105 mL of H.sub.2O and 1.75 mL of HOAc at rt.
A 12 mL solution of H.sub.2O and sodium cyanate (2.80 g, 43.0 mmol,
2.46 eq.) was then added slowly. Stirred at 35.degree. C. for 1
hour. Added 31.26 mL of 1.0 N NaOH slowly. Solids precipitated.
Cooled to 0.degree. C. Carefully added conc. HCl to pH=3. Filtered
solids. Solids were then stirred in diethyl ether then refiltered
and pumped under high vacuum to give 3.36 grams of tan solids as
product. LCMS detects (M+H)+=197.
Part B. Preparation of 2,4,6-Trichloro-quinazoline
[0742] 6-Chloro-quinazoline-2,4-diol (0.50 g, 2.54 mmol, 1 eq.),
phosphorous oxychloride (2.14 mL, 22.9 mmol, 9 eq.) and
2,6-lutidine (0.44 mL, 3.82 mmol, 1.5 eq.) were refluxed under
nitrogen for 2 hours. The reaction was stripped then restripped
3.times. from methylene chloride, then dissolved in methylene
chloride and rinsed 3.times. with saturated sodium bicarbonate,
1.times. with brine. Dried and stripped in vacuo to give an amber
oil. Purified over silica gel in 9:1 to 3:1 Hexanes/EtOAc. Obtained
0.22 g of light colored solids as product. .sup.1H NMR (400 MHz)
(CD.sub.3OD) .delta. 8.36 (s, 1H), 8.09 (d, 1H, J=7 Hz), 7.97 (d,
1H, J=7 Hz).
Example 108
Part C. Preparation of
1-[(1S,2R,4R)-2-benzenesulfonylmethyl-4-(isopropyl-methyl-amino)-cyclohex-
yl]-(3S)-3-(2,6-dichloro-quinazolin-4-ylamino)-pyrrolidin-2-one,
TFA salt
[0743]
(3S)-3-Amino-1-[(1S,2R,4R)-2-benzenesulfonylmethyl-4-(isopropyl-me-
thyl-amino)-cyclohexyl]-pyrrolidin-2-one (75 mg, 0.184 mmol, 1
eq.), 2,4,6-trichloro-quinazoline (43 mg, 0.184 mmol, 1 eq.)
N,N-diisopropylethylamine (64 mL, 0.368 mmol, 2 eq.) in THF (3 mL)
were refluxed overnight. Purified by HPLC. Obtained 62 mg of white
solids. LCMS detects (M+H)+=604.
Example 109
Preparation of
1-[(1S,2R,4R)-2-benzenesulfonylmethyl-4-(isopropyl-methyl-amino)-cyclohex-
yl]-(3S)-3-(6-chloro-2-dimethylamino-quinazolin-4-ylamino)-pyrrolidin-2-on-
e, TFA salt
[0744]
1-[(1S*,2R*,4R*)-2-benzenesulfonylmethyl-4-(isopropyl-methyl-amino-
)-cyclohexyl]-(3S*)-3-(2,6-dichloro-quinazolin-4-ylamino)-pyrrolidin-2-one
(27 mg, 0.0375 mmol, 1 eq.), 2.0 M dimethylamine in THF (0.94 ml,
1.88 mmol, 50 eq.), and THF (1 mL) were refluxed until reaction was
complete by LCMS. Purified by HPLC. Obtained 22 mg of white solids
as product. LCMS detects (M+H)+=613.
Example 110
Preparation of
1-[(1S,2R,4R)-2-benzenesulfonylmethyl-4-(isopropyl-methyl-amino)-cyclohex-
yl]-(3S)-3-(6-chloro-2-hydroxy-quinazolin-4-ylamino)-pyrrolidin-2-one,
TFA salt
[0745]
1-[(1S,2R,4R)-2-benzenesulfonylmethyl-4-(isopropyl-methyl-amino)-c-
yclohexyl]-(3S)-3-(2,6-dichloro-quinazolin-4-ylamino)-pyrrolidin-2-one
(20 mg) and dimethyl sulfoxide (2 mL) were heated at 60.degree. C.
under nitrogen until reaction was complete by LCMS. Purified by
HPLC to give 6.0 mg of white solids as product. LCMS detects
(M+H)+=586.
Example 111
Part A. Preparation of 6-Trifluoromethyl-quinazolin-4-ol
[0746] 2-Amino-5-trifluoromethyl-benzamide (ButtPark) (1.00 g, 4.90
mmol, 1 eq.) and formic acid (3.30 mL, 87.2 mmol, 17.8 eq.) were
refluxed for 2.5 hours. Cooled to rt then added water (10 mL).
Stirred 15 minutes then filtered off solids which were present. The
solids were dried at 110.degree. C. for 3 hours to give 520 mg of
white solids as product. LCMS detects (M+H)+=215.
Part B. Preparation of 4-Chloro-6-trifluoromethyl-quinazoline
[0747] 6-Trifluoromethyl-quinazolin-4-ol (0.95 g, 4.44 mol, 1 eq.),
phosphorous oxychloride (2.48 mL, 26.6 mmol, 6 eq.) and
triethylamine (3.71 mL, 26.6 mmol, 6 eq.) were refluxed for 2.5
hours. Stripped 3.times. from methylene chloride then dissolved in
methylene chloride and rinsed 3.times. with saturated NaHCO3,
1.times. with brine. Dried and stripped in vacuo to give and amber
oil. Purified over silica gel in 9:1 Hexanes/EtOAc. Obtained 560 mg
of off-white solids as product. The product was used immediately in
Ex 111 part C.
Example 111
Part C. Preparation of
1-[(1S,2R,4R)-2-benzenesulfonylmethyl-4-(isopropyl-methyl-amino)-cyclohex-
yl]-(3S)-3-(6-trifluoromethyl-quinazolin-4-ylamino)-pyrrolidin-2-one,
TFA salt
[0748] Followed the procedure of Example 106 Part C starting from
(3S)-3-amino-1-[(1S,2R,4R)-2-benzenesulfonylmethyl-4-(isopropyl-methyl-am-
ino)-cyclohexyl]-pyrrolidin-2-one and
4-Chloro-6-trifluoromethyl-quinazoline. Purified by HPLC. Obtained
57 mg of white solids as title product. LCMS detects
(M+H)+=604.
Example 112
Part A. Preparation of 6-tert-Butyl-thieno[3,2-d]pyrimidin-4-ol
[0749] 3-Amino-5-tert-butyl-thiophene-2-carboxylic acid methyl
ester (1.00 g, 4.69 mmol, 1 eq.), formamidine acetate (1.46 g, 4.69
mmol, 3 eq.) and 2-ethoxyethanol (10 mL) were refluxed under
nitrogen for 4 hours. Purified over silica gel in 3:1 to 1:1
Hexanes/ethyl acetate to 100% ethyl acetate to obtain 970 mg of
yellow solids as product. LCMS detects (M+H)+=209.
Part B. Preparation of
6-tert-Butyl-4-chloro-thieno[3,2-d]pyrimidine
[0750] 6-tert-Butyl-thieno[3,2-d]pyrimidin-4-ol (500 mg, 2.40 mmol,
1 eq.) and phosphorous oxychloride (4.48 mL, 48.0 mmol, 20 eq.)
were refluxed under nitrogen for 1.5 hours. Stripped 3.times. from
methylene chloride then dissolved in methylene chloride and rinsed
3.times. with saturated NaHCO3, 1.times. with brine. Dried and
stripped in vacuo to give 250 mg of amber solids as product. LCMS
detects (M+H)+=227.
Example 112
Part C. Preparation of
1-[(1S,2R,4R)-2-benzenesulfonylmethyl-4-(isopropyl-methyl-amino)-cyclohex-
yl]-(3S)-3-(6-tert-butyl-thieno[3,2-d]pyrimidin-4-ylamino)-pyrrolidin-2-on-
e, TFA salt
[0751] Followed the procedure of Example 106 Part C starting from
(3S)-3-amino-1-[(1S,2R,4R)-2-benzenesulfonylmethyl-4-(isopropyl-methyl-am-
ino)-cyclohexyl]-pyrrolidin-2-one and
6-tert-butyl-4-chloro-thieno[3,2-d]pyrimidine. Purified by HPLC to
give 6.0 mg of white solids as title product. LCMS detects
(M+H)+=598.
Example 113
Part A. Preparation of
6-tert-Butyl-2-trifluoromethyl-thieno[3,2-d]pyrimidin-4-ol
[0752] 3-Amino-5-tert-butyl-thiophene-2-carboxylic acid methyl
ester (0.50 g, 2.34 mmol, 1 eq.) and trifluoroacetamidine (263 mg,
2.34 mmol, 1 eq.) were heated neat at 150.degree. C. until reaction
was complete by TLC. Cooled to rt then dissolved resultant solids
in chloroform. Dried and stripped in vacuo to give 540 mg of white
solids as product. LCMS detects (M+H)+=277.
Part B. Preparation of
6-tert-Butyl-4-chloro-2-trifluoromethyl-thieno[3,2-d]pyrimidine
Followed the procedure of Example 112 Part B starting from
6-tert-Butyl-2-trifluoromethyl-thieno[3,2-d]pyrimidin-4-ol. LCMS
detects (M+H)+=295.
Example 113
Part C Preparation of
1-[(1S,2R,4R)-2-benzenesulfonylmethyl-4-(isopropyl-methyl-amino)-cyclohex-
yl]-(3S)-3-(6-tert-butyl-2-trifluoromethyl-thieno[3,2-d]pyrimidin-4-ylamin-
o)-pyrrolidin-2-one, TFA salt
Followed the procedure of Example 106 Part C starting from
6-tert-butyl-4-chloro-2-trifluoromethyl-thieno[3,2-d]pyrimidine.
Purified by HPLC. LCMS detects (M+H)+=666.
Example 114
Part A. Preparation of Ethyl
3-(tert-Butyl)-pyrrole-5-carboxylate
[0753] The above compound was synthesized by the methods disclosed
in Example 129 employing tert-butylchloride in place of
1-chloroadamantane and foregoing the initial 30 minute heating
period. MS found: (M+H)+=196.28.
Part B. Preparation of Ethyl
3-tert-Butyl-1-aminopyrrole-5-carboxylate
[0754] Preparation of monochloramine by the Method of John Hynes,
Jr., et al., J. Org. Chem., 2004, in press: NH.sub.4Cl (3 g, 56
mmol, was mixed in ether (110 mL) and cooled to -5.degree. C.
Concentrated NH.sub.4OH (4.7 mL) was then added followed by
dropwise addition of bleach (Chlorox, 72 mL) over 15 minutes. The
mixture was stirred for 15 minutes, the layers separated and the
organic layer washed with brine. The organic layer was dried over
powdered CaCl.sub.2 in the freezer for 1 h and used for the
subsequent step immediately.
[0755] Ethyl 3-(tert-butyl)pyrrole-5-carboxylate (obtained from
Part A) (1.67 g, 8.6 mmol, 1 eq) was dissolved in DMF. Sodium
hydride (60% suspension in oil) (0.41 g, 10 mmol, 1.2 eq) was then
added thereto cautiously and stirred for 45 minutes at RT under
nitrogen. Monochloramine was then added (0.15M in ether, 68.4 mL,
10 mmol, 1.2 eq). The next morning, the reaction is quenched with
saturated aqueous Na.sub.2S.sub.2O.sub.3, diluted with water and
extracted into ether. The ether layer is dried, filtered and
stripped to yield 3.19 g of product as a yellow oil which
eventually crystallized as long needles. MS found:
(M+H)+=211.34.
Part C. Preparation of
6-tert-Butyl-pyrrolo[2,1-f][1,2,4]triazin-4-ol
[0756] Ethyl 3-tert-Butyl-1-aminopyrrole-5-carboxylate (1.00 g,
4.76 mmol, 1 eq), formamidine acetate (1.46 g, 14.3 mmol, 3 eq.)
and ethoxyethanol (10 mL) were mixed and refluxed for 3 hours. The
solvent was stripped and then restripped from chloroform (3.times.)
to yield a solid. This solid was stirred in 5 mL MeOH, filtered,
and the collected solids rinsed with Et.sub.2O and dried to yield
233 mg of a white solid as product. LCMS found:
(M+H)+.sup.+=191.
Part D. Preparation of
6-tert-Butyl-4-chloro-pyrrolo[2,1-f][1,2,4]triazine
[0757] The compound from Part C immediately above (0.43 mg, 2.26
mmol, 1 eq.) and POCl3 (4.21 mL, 45.2 mmol, 20 eq.) were mixed and
refluxed for 4 hours. The mixture was stripped then restripped
3.times. from methylene chloride and then dissolved in methylene
chloride and rinsed 3.times. with sat'd NaHCO.sub.3, 1.times. with
brine. Dried and stripped in vacuo to give 490 mg of an amber oil.
LCMS detects (M+H)+=210.
Example 114
Part E. Preparation of
1-[(1S,2R,4R)-2-benzenesulfonylmethyl-4-(isopropyl-methyl-amino)-cyclohex-
yl]-(3S)-3-(6-tert-butyl-pyrrolo[2,1-f][1,2,4]triazin-4-ylamino)-pyrrolidi-
n-2-one
The above compound was synthesized using the procedure of Example
106 Part C starting from of
6-tert-Butyl-4-chloro-pyrrolo[2,1-f][1,2,4]triazine. LCMS detects
(M+H)+581.
Example 115
Part A. Preparation of
6-Adamant-1-yl-4-chloro-pyrrolo[2,1-f][1,2,4]triazine
The above compound was prepared from ethyl
3-(adamanty-1-yl)-pyrrole-5-carboxylate by the procedures in
Example 114, parts A, B, and C beginning with ethyl
3-(Adamanty-1-yl)-pyrrole-5-carboxylate (Example 129). Mass found:
(M+H)+.sup.+=288.22.
Example 115
Part B. Preparation of
(3S)-3-(6-Adamantan-1-yl-pyrrolo[2,1-f][1,2,4]triazin-4-ylamino)-1-[(1S,2-
R,4R)-2-benzenesulfonylmethyl-4-(isopropyl-methyl-amino)-cyclohexyl]-pyrro-
lidin-2-one
[0758]
3S-3-Amino-1-[(1S,2R,4R)-2-benzenesulfonylmethyl-4-(isopropyl-meth-
yl-amino)-cyclohexyl]-pyrrolidin-2-one (49 mg, 0.12 mmol, 1 eq),
6-adamant-1-yl-4-chloro-pyrrolo[2,1-f][1,2,4]triazine (46 mg, 0.18
mmol, 1.5 eq), triethylamine (0.066 mL, 0.48 mmol, 4 eq) and
ethanol (1.7 mL) were microwaved at 100.degree. C. for 1 hour. The
contents were stripped and flash chromatographed in 100% EtOAc to
4:1 chloroform/methanol to yield 49 mg of a white powder. This
powder was taken up in methylene chloride and washed with water
(3.times.). The organic layer was dried and stripped to yield 30 mg
of a white powder. Mass found: (M+H)+.sup.+=659.49.
Example 116
Part A. Preparation of 2-Phenyl-3H-imidazole-4-carboxylic acid
methyl ester
[0759] Phenylamidoxime (5.00 g, 36.7 mmol, 1 eq.), methyl
propriolate (3.27 mL, 36.7 mmol, 1 eq.), and methanol (25 mL) were
refluxed overnight under nitrogen. The reaction was stripped
2.times. from toluene. Added diphenyl ether (20 mL then heated at
200.degree. C. overnight. Cooled to rt. Added ethyl acetate (50
mL). Rinsed 2.times. with brine. The organic layer was dried and
stripped in vacuo to give an amber oil. Triturated solids with
diethyl ether. Obtained 2.84 g of tan solids as product. LCMS
detects (M+H)+=203.
Part B. Preparation of 3-Methyl-2-phenyl-3H-imidazole-4-carboxylic
acid methyl ester and 1-Methyl-2-phenyl-1H-imidazole-4-carboxylic
acid methyl ester
[0760] 2-Phenyl-3H-imidazole-4-carboxylic acid methyl ester (250
mg, 1.24 mmol, 1 eq.) was dissolved in THF (10 mL) at rt under
nitrogen then cooled to 0.degree. C. Potassium hexamethyldisilazane
(0.5 M in toluene) (2.72 mL, 1.36 mmol, 1.1 eq.) was added dropwise
via an addition funnel. Stirred 10 minutes. Added iodomethane (85
mL, 1.36 mmol, 1.1 eq.). Stirred overnight at rt. Added saturated
NH.sub.4Cl (20 mL), and extracted 2.times. with methylene chloride.
The organic layers were combined, dried and stripped in vacuo to
give 225 mg of an amber oil as product. LCMS detects
(M+H)+=217.
Part C. Preparation of 3-Methyl-2-phenyl-3H-imidazole-4-carboxylic
acid and 1-Methyl-2-phenyl-1H-imidazole-4-carboxylic acid
[0761] 3-Methyl-2-phenyl-3H-imidazole-4-carboxylic acid methyl
ester and its isomer (225 mg, 1.04 mmol, 1 eq.), 4 N NaOH (1.30 mL,
5.20 mmol, 5 eq.) and THF (5 mL) were mixed at rt then refluxed for
2 hours then stirred overnight at rt. Stripped off the THF, added
water then rinsed 1.times. with diethyl ether. The basic aqueous pH
was adjusted to 3 with conc. HCl. The aqueous was then extracted
3.times. with chloroform (10 mL). The chloroform layers were
combined, dried and stripped in vacuo to give 30 mg of a film as
product. LCMS detects (M+H)+=203.
Example 116
Part D. Preparation of 3-Methyl-2-phenyl-3H-imidazole-4-carboxylic
acid
{(3S)-1-[(1S,2R,4R)-2-benzenesulfonylmethyl-4-(isopropyl-methyl-amino)-cy-
clohexyl]-2-oxo-pyrrolidin-3-yl}-amide, TFA salt and
1-Methyl-2-phenyl-1H-imidazole-4-carboxylic acid
{(3S)-1-[(1S,2R,4R)-2-benzenesulfonylmethyl-4-(isopropyl-methyl-amino)-cy-
clohexyl]-2-oxo-pyrrolidin-3-yl}-amide
[0762]
(3S)-3-Amino-1-[(1S,2R,4R)-2-benzenesulfonylmethyl-4-(isopropyl-me-
thyl-amino)-cyclohexyl]-pyrrolidin-2-one (and other isomer) (50 mg,
0.124 mmol, 1 eq.), 3-methyl-2-phenyl-3H-imidazole-4-carboxylic
acid (30 mg, 0.148 mmol, 1.2 eq.), 1-hydroxybenzotriazole hydrate
(HOBT) (20 mg, 0.148 mmol, 1.2 eq.),
1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide HCl (EDCI) (28 mg,
0.148 mmol, 1.2 eq.), triethylamine (35 .mu.L, 0.247 mmol, 2 eq.)
and THF (5 mL were stirred at rt under nitrogen overnight. Purified
by LCMS. Obtained 50 mg of white solids as product. LCMS detects
(M+H)+=592.
Example 117
Part A. Preparation of 3-Benzyl-2-phenyl-3H-imidazole-4-carboxylic
acid methyl ester and 1-Benzyl-2-phenyl-1H-imidazole-4-carboxylic
acid methyl ester
[0763] 2-Phenyl-3H-imidazole-4-carboxylic acid methyl ester (250
mg, 1.24 mmol, 1 eq.) was dissolved in THF (10 mL) at rt under
nitrogen then cooled to 0.degree. C. Potassium hexamethyldisilazane
(0.5 M in toluene) (2.72 mL, 1.36 mmol, 1.1 eq.) was added dropwise
via an addition funnel. Stirred 10 minutes. Added benzylbromide
(0.16 mL, 1.36 mmol, 1.1 eq.). Stirred overnight at rt. Added
saturated NH.sub.4Cl (20 mL), and extracted 2.times. with methylene
chloride. The organic layers were combined, dried and stripped in
vacuo to give 200 mg of an amber oil as product. LCMS detects
(M+H)+=293.
Part B. Preparation of 3-Benzyl-2-phenyl-3H-imidazole-4-carboxylic
acid and 1-Benzyl-2-phenyl-1H-imidazole-4-carboxylic acid
[0764] 3-Benzyl-2-phenyl-3H-imidazole-4-carboxylic acid methyl
ester (200 mg, 0.684 mmol, 1 eq.) and other isomer, 4 N NaOH (0.86
mL, 3.42 mmol, 5 eq.) and THF (5 mL) were mixed at rt then refluxed
for 2 hours then stirred overnight at rt. Stripped off the THF,
added water then rinsed 1.times. with diethyl ether. The basic
aqueous pH was adjusted to 3 with conc. HCl. The aqueous was then
extracted 3.times. with chloroform (10 mL). The chloroform layers
were combined, dried and stripped in vacuo to give 390 mg of an
amorphous solid as product. LCMS detects (M+H)+=279.
Example 117
Part C. Preparation of 3-Benzyl-2-phenyl-3H-imidazole-4-carboxylic
acid
{(3S)-1-[(1S,2R,4R)-2-benzenesulfonylmethyl-4-(isopropyl-methyl-amino)-cy-
clohexyl]-2-oxo-pyrrolidin-3-yl}-amide, TFA salt and
1-Benzyl-2-phenyl-1H-imidazole-4-carboxylic acid
{(3S)-1-[(1S,2R,4R)-2-benzenesulfonylmethyl-4-(isopropyl-methyl-amino)-cy-
clohexyl]-2-oxo-pyrrolidin-3-yl}-amide, TFA salt
[0765] Followed the procedure of Example 116, Part D starting from
(3S)-3-amino-1-[(1S,2R,4R)-2-benzenesulfonylmethyl-4-(isopropyl-methyl-am-
ino)-cyclohexyl]-pyrrolidin-2-one and
3-benzyl-2-phenyl-3H-imidazole-4-carboxylic acid and its other
isomer. Obtained 21 mg of off-white solids as product. LCMS detects
(M+H)+=668.
Example 118
Preparation of 2-Phenyl-3H-imidazole-4-carboxylic acid
{(3S)-1-[(1S,2R,4R)-2-benzenesulfonylmethyl-4-(isopropyl-methyl-amino)-cy-
clohexyl]-2-oxo-pyrrolidin-3-yl}-amide, TFA salt
[0766] 3-Benzyl-2-phenyl-3H-imidazole-4-carboxylic acid
{(3S*)-1-[(1S,2R,4R)-2-benzenesulfonylmethyl-4-(isopropyl-methyl-amino)-c-
yclohexyl]-2-oxo-pyrrolidin-3-yl}-amide and its other isomer (15
mg) 5 mL methanol, and 20% Pd(OH).sub.2 (10 mg) were hydrogenated
until completion by TLC on a Parr shaker at 50 psi. Filtration
through fiberglass filter paper under nitrogen and removal of
solvent in vacuo yielded 6 mg of product. LCMS detects
(M+H)+=578.
Example 119
Part A. Preparation of 6,7-Dimethoxy-quinazolin-4-ol
Followed the procedure of Example 107 Part A starting from
2-amino-4,5-dimethoxy-benzoic acid. LCMS detects (M+H)+=207.
Part B. Preparation of 4-Chloro-6,7-dimethoxy-quinazoline
[0767] 6,7-Dimethoxy-quinazolin-4-ol (1.00 g, 4.85 mmol, 1 eq.),
phosphorous oxychloride (4.07 mL, 43.6 mmol, 9.00 eq.) and
triethylamine (6.08 mL, 43.6 mmol, 9 eq.) were refluxed for 2
hours. Stripped then restripped 3.times. from methylene chloride
then dissolved in methylene chloride and rinsed 3.times. with
saturated sodium bicarbonate, 1.times. with brine. Dried and
stripped in vacuo to give an amber oil. Purified over silica gel in
9:1 to 3:1 Hexanes/EtOAc. Obtained 0.84 g of off-white solids as
product. LCMS detects (M+H)+=225.
Example 119
Part C. Preparation of
1-[(1S,2R,4R)-2-benzenesulfonylmethyl-4-(isopropyl-methyl-amino)-cyclohex-
yl]-(3S)-3-(6,7-dimethoxy-quinazolin-4-ylamino)-pyrrolidin-2-one,
TFA salt
Followed the procedure of Example 106 Part C starting from
(3S)-3-Amino-1-[(1S,2R,4R)-2-benzenesulfonylmethyl-4-(isopropyl-methyl-am-
ino)-cyclohexyl]-pyrrolidin-2-one and
4-chloro-6,7-dimethoxy-quinazoline. LCMS detects (M+H)+=596.
Example 120
Part A. Preparation of 6-Fluoro-quinazolin-4-ol
Followed the procedure of Example 107 Part A starting with
2-amino-5-fluorobenzoic acid. .sup.1H NMR (400 MHz) (CD.sub.3OD) ?
8.06 (s, 1H), 7.87 (m, 1H), 7.75 (m, 1H), 7.62 (m, 1H).
Part B. Preparation of 4-Chloro-6-fluoro-quinazoline
Followed the procedure of Example 112 Part B starting with
6-fluoroquinazolin-4-ol. LCMS detects (M+H)+=183.
Example 120
Part C. Preparation of
1-[(1S,2R,4R)-2-benzenesulfonylmethyl-4-(isopropyl-methyl-amino)-cyclohex-
yl]-(3S)-3-(6-fluoro-quinazolin-4-ylamino)-pyrrolidin-2-one, TFA
salt
Followed the procedure of Example 106 Part C starting from
(3S)-3-Amino-1-[(1S,2R,4R)-2-benzenesulfonylmethyl-4-(isopropyl-methyl-am-
ino)-cyclohexyl]-pyrrolidin-2-one and
4-chloro-6-fluoro-quinazoline. Purified by HPLC. LCMS detects
(M+H)+=554.
Example 121
Part A. Preparation of 6-Methyl-quinazolin-4-ol
Followed the procedure of Example 107 Part A starting from
2-Amino-5-methyl-benzoic acid. .sup.1H NMR (400 MHz) (CD.sub.3OD)
.delta. 8.00 (m, 2H), 7.68 (d, 1H, J=7 Hz), 7.59 (d, 1H, J=7 Hz),
2.47 (s, 3H).
Part B. Preparation of 4-Chloro-6-methyl-quinazoline
Followed the procedure of Example 111 Part B starting with
6-methylquinazolin-4-ol. LCMS detects (M+H)+=179.
Example 121
Part B. Preparation of
1-[(1S,2R,4R)-2-benzenesulfonylmethyl-4-(isopropyl-methyl-amino)-cyclohex-
yl]-(3S)-3-(6-methyl-quinazolin-4-ylamino)-pyrrolidin-2-one, TFA
salt
Followed the procedure of Example 106 Part C starting from
(3S)-3-amino-1-[(1S,2R,4R)-2-benzenesulfonylmethyl-4-(isopropyl-methyl-am-
ino)-cyclohexyl]-pyrrolidin-2-one and
4-chloro-6-methyl-quinazoline. Purified by HPLC. LCMS detects
(M+H)+=550.
Example 122
Part A. Preparation of 6-Phenyl-thieno[2,3-d]pyrimidin-4-ol
Followed the procedure of Example 112 Part A starting from
2-Amino-5-phenyl-thiophene-3-carboxylic acid methyl ester. LCMS
detects (M+H)+=229.
Part B. Preparation of
4-Chloro-6-phenyl-thieno[2,3-d]pyrimidine
Followed the procedure of Example 112 Part B starting with
6-Phenyl-thieno[2,3-d]pyrimidin-4-ol. LCMS detects (M+H)+=247.
Example 122
Part C. Preparation of
1-[(1S,2R,4R)-2-benzenesulfonylmethyl-4-(isopropyl-methyl-amino)-cyclohex-
yl]-(3S)-3-(6-phenyl-thieno[2,3-d]pyrimidin-4-ylamino)-pyrrolidin-2-one,
TFA salt
[0768] Followed the procedure of Example 106 Part C starting from
(3S)-3-Amino-1-[(1S,2R,4R)-2-benzenesulfonylmethyl-4-(isopropyl-methyl-am-
ino)-cyclohexyl]-pyrrolidin-2-one and of
4-chloro-6-phenyl-thieno[2,3-d]pyrimidine. Purified by HPLC. LCMS
detects (M+H)+=618.
Example 123
Part A. Preparation of 2-Butyrylamino-5-chloro-benzamide
[0769] 2-Amino-5-chlorobenzamide (1.10 g, 6.5 mmol, 1 eq.), 1.000 N
NaOH (6.50 mL, 6.5 mmol, 1 eq.) and THF (20 mL) were mixed and
stirred at 0.degree. C. To this mixture was added butyryl chloride
dropwise (0.68 mL, 6.50 mmol, 1 eq.). More acid chloride and base
were added to drive reaction to completion. The reaction was
allowed to warm to rt. After 4 days the reaction was worked up by
adding ethyl acetate, washing with 1 N HCl (3.times.), saturated
sodium bicarbonate (1.times.), and brine (1.times.). The organic
layer was dried and stripped to yield 1.44 g of a white powder as
product. LCMS detects (M+H)+=241.0.
Part B. Preparation of 6-Chloro-2-propyl-quinazolin-4-ol
[0770] 2-Butyrylamino-5-chloro-benzamide (1.08 g, 4.49 mmol, 1
eq.), 1.000 N NaOH (13.46 mL, 13.5 mmol, 3 eq.) and ethanol (10 mL)
were mixed and stirred at rt for 15 minutes. The mixture was
acidified to pH=2 with 1.000 N HCl. The mixture was extracted with
ethyl acetate. Solids that did not dissolve were filtered and
rinsed with diethyl ether to dry. Obtained 810 mg of a white solid
product. LCMS detects (M+H)+=223.
Part C Preparation of 4,6-Dichloro-2-propyl-quinazoline
[0771] 6-Chloro-2-propyl-quinazolin-4-ol (810 mg, 3.64 mmol, 1
eq.), phosphorous oxychloride (3.30 mL, 35.1 mmol, 9.64 eq.) and
triethylamine (1.63 mL, 11.7 mmol, 3.21 eq.) were refluxed for 2
hours. Stripped 3.times. from methylene chloride then dissolved in
methylene chloride and rinsed 3.times. with saturated sodium
bicarbonate, 1.times. with brine. Dried and stripped in vacuo to
give an amber oil. Purified over silica gel in 9:1 Hexanes/EtOAc.
Obtained 510 mg of off-white solids as product. The product was
used immediately in Example 121 Part D.
Example 123
Part D. Preparation of
1-[(1S,2R,4R)-2-benzenesulfonylmethyl-4-(isopropyl-methyl-amino)-cyclohex-
yl]-(3S)-3-(6-chloro-2-propyl-pyrido[2,3-d]pyrimidin-4-ylamino)-pyrrolidin-
-2-one, TFA salt
[0772]
1-[(1S,2R,4R)-2-benzenesulfonylmethyl-4-(isopropyl-methyl-amino)-c-
yclohexyl]-(3S)-3-(6-chloro-2-propyl-pyrido[2,3-d]pyrimidin-4-ylamino)-pyr-
rolidin-2-one, TFA salt was prepared from
(3S)-3-amino-1-[(1S,2R,4R)-2-benzenesulfonylmethyl-4-(isopropyl-methyl-am-
ino)-cyclohexyl]-pyrrolidin-2-one and
4,6-dichloro-2-propyl-quinazoline using the conditions described in
Example 106 Part C. MS (ES+)=613 (M+H).sup.+.
Example 124
Part A. Preparation of
1-[(1S,2R,4R)-2-benzenesulfonylmethyl-4-(isopropyl-methyl-amino)-cyclohex-
yl]-(3S)-3-(6-chloro-2-isopropyl-quinazolin-4-ylamino)-pyrrolidin-2-one,
TFA salt
The above compound was synthesized from isobutyryl chloride using
the procedures found in Example 123, Parts A-D. MS (ES+)=612
(M+H).sup.+.
Example 125
Preparation of
1-[(1S,2R,4R)-2-benzenesulfonylmethyl-4-(isopropyl-methyl-amino)-cyclohex-
yl]-(3S)-3-(2-tert-butyl-6-chloro-quinazolin-4-ylamino)-pyrrolidin-2-one,
TFA salt
The above compound was synthesized from 2,2-Dimethyl-propionyl
chloride using the procedures found in Example 123, Parts A-D. LCMS
detects (M+H)+=626.
Example 126
Part A. Preparation of 6-Chloro-2-methyl-quinazolin-4-ol
[0773] 2-Amino-5-chlorobenzoic acid (3.58 g, 20.9 mmol, 1 eq.),
acetamidine hydrochloride (2.36 g, 25.1 mmol, 1.2 eq.) and
2-ethoxyethanol (70 mL) were mixed and refluxed for 48 h. The
resultant solids were filtered and dried to yield 1.57 g of yellow
solid product. MS (ES+)=195/197 (M+H)+.sup.+.
Part B. Preparation of 4,6-Dichloro-2-methyl-quinazoline
[0774] 6-Chloro-2-methyl-quinazolin-4-ol (0.75 g, 3.90 mmol, 1
eq.), phosphorous oxychloride (3.47 mL, 37.4 mmol, 9.64 eq.) and
triethylamine (1.62 mL, 12.5 mmol, 3.21 eq.) were refluxed for 4
hours. The mixture was stripped twice from toluene and the residue
dissolved in ethyl acetate. The organic layer was washed with
saturated NH.sub.4Cl (2.times.), dried and stripped. The residue
was flash chromatographed in 3:2 ethyl acetate/hexanes to yield 400
mg of a light yellow solid product. MS (ES+)=213/215/217
(M+H)+.sup.+.
Example 126
Part C. Preparation of
1-[(1S,2R,4R)-2-benzenesulfonylmethyl-4-(isopropyl-methyl-amino)-cyclohex-
yl]-(3S)-3-(6-chloro-2-methyl-quinazolin-4-ylamino)-pyrrolidin-2-one
The above compound was synthesized following the procedure of
Example 106 Part C using the product from Part B immediately above.
MS (ES+)=585 (M+H)+.sup.+.
Example 127
Preparation of
1-[(1S,2R,4R)-2-benzenesulfonylmethyl-4-(isopropyl-methyl-amino)-cyclohex-
yl]-(3S)-3-(6-chloro-2-ethyl-quinazolin-4-ylamino)-pyrrolidin-2-one
The above compound was synthesized by the procedures in Example 126
beginning with propionamidine hydrochloride. MS (ES+)=599
(M+H)+.sup.+.
Example 128
Part A. Preparation of
{(3S)-1-[(1S,2R,4R)-2-benzenesulfonylmethyl-4
(isopropyl-methyl-amino)-cyclohexyl]-2,5-dioxo-pyrrolidin-3-yl}-carbamic
acid tert-butyl ester
[0775]
(1S,2R,4R)-2-Benzenesulfonylmethyl-N4-isopropyl-N4-methyl-cyclohex-
ane-1,4-diamine (300 mg, 0.93 mmol, 1 eq.), L-N--BOC-Aspartic acid
(216 mg, 0.93 mmol, 1.0 eq.), 1-hydroxybenzotriazole hydrate (HOBT)
(275 mg, 2.03 mmol, 2.2 eq.),
1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide HCl (EDCI) (390 mg,
2.03 mmol, 2.2 eq.), triethylamine (0.39 mL, 2.77 mmol, 3 eq.) and
methylene chloride (15 mL) were stirred at 0.degree. C. and allowed
to warm to rt under nitrogen overnight. The mixture was washed with
2 N sodium carbonate, water (1.times.) and the organic layer dried
and stripped. The residue was purified over silica gel in 100%
ethyl acetate to 4:1 methylene chloride/methanol to 4:1 methylene
chloride/2N NH3 in methanol. Obtained 60 mg of product. LCMS
detects (M+H)+=522.
Part B. Preparation of
(3S)-3-Amino-1-[(1S,2R,4R)-2-benzenesulfonylmethyl-4-(isopropyl-methyl-am-
ino)-cyclohexyl]-pyrrolidine-2,5-dione
[0776]
{(3S)-1-[(1S,2R,4R)-2-benzenesulfonylmethyl-4-(isopropyl-methyl-am-
ino)-cyclohexyl]-2,5-dioxo-pyrrolidin-3-yl}-carbamic acid
tert-butyl ester (60 mg), TFA (1 mL), and methylene chloride (3 mL)
were mixed and stirred overnight at rt. The mixture was stripped
and restripped from methylene chloride (3.times.) to yield 60 mg of
an oil. LCMS detects (M+H)+=374.
Example 128
Part C. Preparation of
N-{(3S)-1-[(1S,2R,4R)-2-benzenesulfonylmethyl-4-(isopropyl-methyl-amino)--
cyclohexyl]-2,5-dioxo-pyrrolidin-3-yl}-3-trifluoromethyl-benzamide,
TFA salt
[0777]
(3S)-3-Amino-1-[((1S,2R,4R)-2-benzenesulfonylmethyl-4-(isopropyl-m-
ethyl-amino)-cyclohexyl]-pyrrolidine-2,5-dione (60 mg, 0.092 mmol,
1 eq), 3-trifluoromethylbenzoyl chloride (0.014 mL, 0.092 mmol, 1
eq.), triethylamine (0.039 mL, 0.28 mmol, 3 eq.) and THF (3 mL)
were mixed and stirred at rt with the acid chloride being added
last. The reaction mixture was stripped and purified by LCMS to
yield 5.5 mg of product. LCMS detects (M+H)+=594.
Example 129
Part A. Preparation of Ethyl
3-(Adamanty-1-yl)-pyrrole-5-carboxylate
[0778] Ethyl pyrrole-2-carboxylate (2.09 g, 15 mmol, 1 eq), was
added to a mixture of gallium(III) chloride (2.90 g, 16.5 mmol, 1.1
eq) in carbon disulfide (40 mL) and the contents heated at
40.degree. C. for 30 min. Afterwards, 1-chloroadamantane (2.82 g,
16.5 mmol, 1.1 eq), was added thereto and the contents heated for
another 40 minutes. The reaction was poured onto a mixture of ice
and 1N HCl, and extracted with chloroform. The extracts were washed
with saturated sodium bicarbonate, dried (MgSO4) and the solvent
stripped to yield a crude solid.
Recrystallization from EtOAc yielded 2 crops. 1.sup.st crop
wt.=0.67 grams. 2.sup.nd crop wt.=1.10 grams. MS found:
(M+H)+=274.44 and 274.45, respectively.
Part B. Preparation of 3-(Adamanty-1-yl)-pyrrole-5-carboxylic
Acid
[0779] The compound obtained from Part A immediately above (0.29 g,
1.1 mmol, 1 eq), 1.000 N NaOH (2.20 mL, 2.2 mmol, 2 eq) and MeOH
(15 mL) were mixed and stirred overnight. After only partial
reaction, more 1.000 N NaOH (21 mL) together with more MeOH to
dissolve were added and the contents refluxed for 4 hours. The
contents were acidified to pH=1 with 1H HCl. The MeOH was stripped
off to yield solids and aqueous. The mixture was extracted with
EtOAc, the EtOAc layers were combined, washed with brine, dried
(MgSO.sub.4) and stripped to yield 250 mg of a white powder. MS
found: (M+H)+=246.44.
Example 129
Part C. Preparation of
N-{(3S)-1-[-(1S,2R,4R)-2-Benzenesulfonylmethyl-4-(isopropyl-methyl-amino)-
-cyclohexyl]-2-oxo-pyrrolidin-3-yl}-4-adamantan-1-yl-1H-pyrrole-2-carboxam-
ide, TFA salt
[0780]
(3S)-1-[1S,2R,4R-2-benzenesulfonylmethyl-4-(isopropyl-methyl-amino-
)-cyclohexyl]-pyrrolidin-2-one (45 mg, 0.11 mmol, 1 eq),
3-(adamanty-1-yl)-pyrrole-5-carboxylic acid (27 mg, 0.11 mmol, 1
eq), HOBT (15 mg, 0.11 mmol, 1 eq),
1-[3-(dimethylaminopropyl)]-3-ethylcarbodiimide hydrochloride
(EDCI) (21 mg, 0.11 mmol, 1 eq), and methylene chloride (5 mL) were
mixed and stirred overnight. The contents were stripped and
purified by LCMS. Lyophillization yielded 45 mg of a white solid.
MS found: (M+H)+=635.58.s
Example 130
Part A. Preparation of Ethyl
3-(Adamanty-1-yl)-1-methylpyrrole-5-carboxylate
[0781] Ethyl 3-(adamanty-1-yl)-pyrrole-5-carboxylate (obtained from
Example 129) (0.20 g, 0.7 mmol, 1 eq) was dissolved in THF (20 mL).
Potassium bis(trimethylsilyl)amide (0.5 M in Tol, 1.62 mL, 0.81
mmol, 1.1 eq) was added thereto followed by iodomethane (0.102 mL,
1.6 mmol, 2.2 eq). The next day, the same amounts of potassium
bis(trimethylsilyl)amide and iodomethane were again added to drive
the reaction to completion. In 4 h, the reaction was finished.
Ethyl acetate was added (100 mL) and the organic layer was washed
with water (2.times.), brine, dried (MgSO4) and stripped to yield
600 mg of product which was used as is in the next step. MS found:
(M+H).sup.+=288.16.
Part B. Preparation of
3-(Adamanty-1-yl)-1-methylpyrrole-5-carboxylate
[0782] Saponification of ethyl
3-(Adamanty-1-yl)-1-methylpyrrole-5-carboxylate (entire contents
from Part A) by the procedure in Example 129 Part B yielded 160 mg
of product. MS found: (M-H)+=258.10.
Example 130
Part C. Preparation of
N-{(3S)-1-[-(1S,2R,4R)-2-Benzenesulfonylmethyl-4-(isopropyl-methyl-amino)-
-cyclohexyl]-2-oxo-pyrrolidin-3-yl}-4-adamantan-1-yl-1-methyl-1H-pyrrole-2-
-carboxamide, TFA salt
[0783]
(3S)-3-Amino-1-[(1S,2R,4R)-2-benzenesulfonylmethyl-4-(isopropyl-me-
thyl-amino)-cyclohexyl]-pyrrolidin-2-one (49 mg, 0.12 mmol, 1 eq),
3-(adamanty-1-yl)-pyrrole-5-carboxylic acid (31 mg, 0.12 mmol, 1
eq), HOBT (16 mg, 0.12 mmol, 1 eq),
1-[3-(dimethylaminopropyl)]-3-ethylcarbodiimide hydrochloride
(EDCI) (23 mg, 0.11 mmol, 1 eq), and methylene chloride (5 mL) were
mixed and stirred overnight. The contents were stripped and
dissolved in EtOAc, washed with 1N HCl (1.times.), 1N NaOH
(2.times.), brine (1.times.), dried and stripped. The residue was
flash chromatographed in 1:1 hexane/EtOAc to 100% EtOAc to 4:1
chloroform/methanol to yield 31 mg of a yellow glass. MS found:
(M+H)+=649.32.
Example 131
Part A. Preparation of 5-Bromo-2-tert-butyl-pyrimidine-4-carboxylic
acid
[0784] A 22% solution of sodium ethoxide in ethanol (53 mL, 165
mmol) was added dropwise to a magnetically stirred suspension of
tert-butylcarbamadine hydrochloride (20.0 g, 146 mMol) in ethanol
(100 mL). When the addition was complete, the yellow suspension was
warmed to 50.degree. C., the heating mantle was removed, and a
solution of mucobromic acid (15.7 g, 61 mMol) in ethanol (50 mL)
was added dropwise at a rate which did not allow the temperature to
exceed 55.degree. C. When this addition was complete, a 22%
solution of sodium ethoxide in ethanol (32 mL, 98 mMol) was added
dropwise, then the mixture was allowed to cool to room temperature.
The suspension was filtered, the solids were rinsed with ethanol
(2.times.20 mL), and the combined filtrates were concentrated
in-vacuo. The residue thus obtained was stirred in 2 N aqueous HCl
(30 mL). The resulting solids were collected by filtration, rinsed
with ice-cold water (2.times.20 mL), and air dried to yield 12.1 g
of a beige powder as product. MS (ES+)=259, 261 (M+H).sup.+.
Yield=76%.
Part B. Preparation of 5-Bromo-2-tert-butyl-pyrimidine-4-carboxylic
acid methyl ester
[0785] A 2.0 M hexanes solution of trimethylsilyldiazomethane (11.8
mL, 23.62 mMol) was added dropwise to a stirring solution of
5-bromo-2-tert-butyl-pyrimidine-4-carboxylic acid (6.12 g, 23.62
mmol) in 9:1 benzene/methanol (100 mL), and the reaction was
stirred for 2 days. TLC analysis showed that the reaction was
complete, so the mixture was concentrated in-vacuo. The residue was
dissolved in ethyl acetate (100 mL), washed with water (3.times.20
mL), dried over sodium sulfate, then concentrated in-vacuo.
Purified over silica gel, eluting with 10% ethyl acetate/hexanes,
to yield 5.2 g of a colorless oil as product. MS (ES+)=273, 275
(M+H).sup.+. Yield=81%.
Part C. Preparation of
5-tert-Butoxycarbonylamino-2-tert-butyl-pyrimidine-4-carboxylic
acid methyl ester
[0786] A flame dried reaction tube charged with tert-butylcarbamate
(140 mg, 1.2 mmol), cesium carbonate (456 mg, 1.4 mmol),
4,5-bis(diphenylphosphino)-9,9-dimethylxanthane (18 mg, 0.03 mMol),
and tris(dibenzylidineacetone)dipalladium(0) (19 mg, 0.02 mMol) was
evacuated under vacuum, then backfilled with argon. Dioxane (2 mL)
and 5-bromo-2-tert-butyl-pyrimidine-4-carboxylic acid methyl ester
(273 mg, 1.0 mMol) were added, and the mixture was degassed under
vacuum. The tube was then backfilled with argon, sealed, and heated
at 100.degree. C. for 2 hours. Analysis by LC/MS showed complete
consumption of starting bromide. The mixture was diluted with
methylene chloride (20 mL), filtered to remove solids, and
concentrated in-vacuo. The residue was purified over silica gel,
eluting with 10% ethyl acetate/heptane, to yield 152 mg of white
solids as product. MS (ES+)=310 (M+H).sup.+. Yield 50%.
Part D. Preparation of 5-Amino-2-tert-butyl-pyrimidine-4-carboxylic
acid methyl ester, HCl salt
[0787]
5-tert-Butoxycarbonylamino-2-tert-butyl-pyrimidine-4-carboxylic
acid methyl ester (2.4 g, 7.75 mMol) was dissolved in a 4 M
solution of HCl in dioxane (30 mL). After 10 minutes of stirring, a
thick white solid precipitated. The reaction was allowed to stir
overnight, during which time the mixture became a homogenous, amber
solution. Concentrated in-vacuo, and the residue was stripped from
toluene (2.times.50 mL) followed by methylene chloride (3.times.50
mL) to remove excess HCl. The resulting 1.85 g of yellow solids was
used without further purification in the next step. MS (ES+)=210
(M+H).sup.+.
Part E. Preparation of
6-tert-Butyl-pyrimido[5,4-d]pyrimidin-4-ol
[0788] A mixture of 5-amino-2-tert-butyl-pyrimidine-4-carboxylic
acid methyl ester, HCl salt (1.1 g, 4.48 mMol) and formamidine
acetate (1.86 g, 17.90 mMol) in 2-ethoxyethanol (20 mL) was heated
at reflux for 5 hours. LC/MS analysis showed the reaction to be
essentially complete, so the mixture was cooled to room
temperature, then concentrated in-vacuo. The residue was purified
over silica gel, eluting with ethyl acetate, 1% methanol/ethyl
acetate, then 2% methanol/ethyl acetate to yield 1.06 g of a beige
solid as product. MS (ES+)=205 (M+H).sup.+. Yield=94%.
Part F. Preparation of
2-tert-Butyl-8-chloro-pyrimido[5,4-d]pyrimidine
[0789] 6-tert-Butyl-pyrimido[5,4-d]pyrimidin-4-ol (210 mg, 1.03
mMol) was dissolved in phosphorous oxychloride (10 mL), and the
mixture was heated at reflux for 4 hours. The solution was
concentrated in-vacuo, then stripped from methylene chloride
(3.times.50 mL) to remove excess phosphorous oxychloride. The
residue was stirred for 10 minutes in saturated sodium bicarbonate
(50 mL), then extracted with ethyl acetate (3.times.30 mm). The
combined organic phases were washed with water (30 mL), followed by
brine (30 mL), dried over sodium sulfate, then concentrated
in-vacuo. The residue was purified over silica gel, eluting with
50% ethyl acetate/heptane, to yield 150 mg of a white solid as
product. NMR (500 MHz, CDCl3) .delta. 9.61 (s, 1H), 9.15 (s, 1H),
1.52 (s, 9H).
Example 131
Part G. Preparation of
1-[(1S,2R,4R)-2-Benzenesulfonylmethyl-4-(isopropyl-methyl-amino)-cyclohex-
yl]-(3S)-3-(6-tert-butyl-pyrimido[5,4-d]pyrimidin-4-ylamino)-pyrrolidin-2--
one, TFA salt
[0790] The titled compound was prepared from
(3S)-3-amino-1-[(1S,2R,4R)-2-benzenesulfonylmethyl-4-(isopropyl-methyl-am-
ino)-cyclohexyl]-pyrrolidin-2-one and
2-tert-butyl-8-chloro-pyrimido[5,4-d]pyrimidine using the
conditions described in JBS Example 106, Part C. MS (ES+)=594
(M+H).sup.+.
Example 132
Example 132
Preparation of 5-Bromo-2-tert-butyl-pyrimidine-4-carboxylic acid
{(3S)-1-[(1S,2R,4R)-2-benzenesulfonylmethyl-4-(isopropyl-methyl-amino)-cy-
clohexyl]-2-oxo-pyrrolidin-3-yl}-amide, TFA salt
[0791]
(3S)-3-Amino-1-[(1S,2R,4R)-2-benzenesulfonylmethyl-4-(isopropyl-me-
thyl-amino)-cyclohexyl]-pyrrolidin-2-one (93 mg, 0.23 mmol),
5-bromo-2-tert-butyl-pyrimidine-4-carboxylic acid, (60 mg, 0.23
mMol), HOBT (68 mg, 0.50 mmol), triethylamine (96 .mu.L, 0.69
mMol), and EDCI (96 mg, 0.50 mMol) were combined in
CH.sub.2Cl.sub.2 (2 mL), and the mixture was stirred overnight at
room temperature. The mixture was diluted with ethyl acetate (15
mL), and washed with saturated NaHCO.sub.3 (3.times.5 mL), water (5
mL), and brine (5 mL). The organic phase was dried over sodium
sulfate, and concentrated in-vacuo. The residue was purified by
reverse phase HPLC, using a Phenomenex Luna 10.mu., C18 (2),
250.times.50 mm column, under the following conditions: 10% to 70%
acetonitrile in water (0.05% TFA in each solvent) over 30 minutes.
The reaction yielded 13 mg of white powder as product. MS (ES+)=570
(M+H).
Example 133
Preparation of 2-tert-Butyl-pyrimidine-4-carboxylic acid
{(3S*)-1-[(1S*,2R*,4R*)-2-benzenesulfonylmethyl-4-(isopropyl-methyl-amino-
)-cyclohexyl]-2-oxo-pyrrolidin-3-yl}-amide, TFA salt
[0792] A solution of 5-bromo-2-tert-butyl-pyrimidine-4-carboxylic
acid
{(3S)-1-[(1S,2R,4R)-2-benzenesulfonylmethyl-4-(isopropyl-methyl-amino)-cy-
clohexyl]-2-oxo-pyrrolidin-3-yl}-amide, TFA salt (30 mg, 0.04 mMol)
in methanol (10 mL) was hydrogenated at 50 psi in the presence of 1
N aqueous sodium hydroxide (80 .mu.L, 0.08 mMol) and 10% palladium
on activated carbon (20 mg) for 2 hours. The catalyst was removed
by filtration, and the filtrate was concentrated in-vacuo. The
residue was purified by reverse phase HPLC, using a Phenomenex Luna
10.mu., C18 (2), 250.times.50 mm column, under the following
conditions: 10% to 70% acetonitrile in water (0.05% TFA in each
solvent) over 30 minutes. The reaction yielded 25 mg of white
powder as product. MS (ES+)=648 (M+H).
Example 134
Preparation of 2-tert-Butyl-5-phenyl-pyrimidine-4-carboxylic acid
{(3S)-1-[(1S,2R,4R)-2-benzenesulfonylmethyl-4-(isopropyl-methyl-amino)-cy-
clohexyl]-2-oxo-pyrrolidin-3-yl}-amide, TFA salt
[0793] 5-Bromo-2-tert-butyl-pyrimidine-4-carboxylic acid
{(3S)-1-[(1S,2R,4R)-2-benzenesulfonylmethyl-4-(isopropyl-methyl-amino)-cy-
clohexyl]-2-oxo-pyrrolidin-3-yl}-amide, TFA salt (80 mg, 0.10
mMol), phenyl boronic acid (26 mg, 0.21 in mMol), and 2.0 M aqueous
K.sub.3PO.sub.4 solution (210 .mu.L, 0.42 mMol) were combined in 2
mL of DMF in a microwave reaction tube, and the solution was
degassed under vacuum, then backfilled with argon.
[0794] Tetrakis(triphenylphosphine)palladium(0) (20 mg, 0.01 mMol)
was added, and the mixture was again degassed as described above.
The tube was sealed, and the reaction mixture was heated via
microwave at 150.degree. C. for 30 minutes. The reaction was
cooled, some solids were removed by filtration and rinsed with
ethyl acetate, and the combined filtrates were concentrated
in-vacuo. The residue was purified by reverse phase HPLC, using a
Phenomenex Luna 10.mu., C18 (2), 250.times.50 mm column, under the
following conditions: 10% to 70% acetonitrile in water (0.05% TFA
in each solvent) over 30 minutes. The reaction yielded 27 mg of
white powder as product. MS (ES+)=646 (M+H).
Example 135
Part A. Preparation of 3-tert-Butyl-benzoic acid
[0795] A mixture of the commercially available methyl
3-bromo-5-tert-butylbenzoate (700 mg, 2.58 mMol), aqueous NaOH (1
N, 7.75 mL, 7.75 mMol), and Pearlman's catalyst (100 mg) in
methanol (20 mL) was hydrogenated at 50 psi for 22 hours. The
catalyst was removed by filtration and rinsed with a small amount
of methanol. The filtrate was concentrated in-vacuo to remove
methanol, and the aqueous mixture was acidified with 1 N HCl (10
mL), then extracted with ethyl acetate (3.times.20 mL). The
combined organic phases were dried over sodium sulfate, then
concentrated in-vacuo. Analysis of the resulting material by LC/MS
showed that the ester had hydrolyzed to the carboxylic acid, but
that the bromide was still present. The material was dissolved in
methanol (20 mL), and hydrogenated overnight at 50 psi in the
presence of 1 N aqueous NaOH (5.2 mL, 5.2 mMol) and 10% palladium
on activated carbon (50 mg). Analysis of the crude reaction mixture
by LC/MS showed that the bromine was still present, so Pearlman's
catalyst (200 mg) was added, and hydrogenation at 50 psi was
continued for 23 hours. MS showed that the reaction was now
complete, so the reaction was worked up as described previously in
this example to yield 376 mg of white powder as product. MS
(AP-)=177 (M-H)+.sup.+. Yield=81%.
Example 135
Part B. Preparation of N-{(3S)-1-[(1S,2R,
4R)-2-benzenesulfonylmethyl-4-(isopropyl-methyl-amino)-cyclohexyl]-2-oxo--
pyrrolidin-3-yl}-3-tert-butyl-benzamide, TFA salt
The titled compound was prepared from
(3S)-3-amino-1-[(1S,2R,4R)-2-benzenesulfonylmethyl-4-(isopropyl-methyl-am-
ino)-cyclohexyl]-pyrrolidin-2-one and 3-tert-Butyl-benzoic acid
using the conditions described in Example 132. MS (ES+)=568
(M+H).
Example 136
Part A. Preparation of Lithium 3-bromo-5-tert-butylbenzoate
[0796] A solution of the commercially available
methyl-3-bromo-5-tert-butylbenzoate (87 mg, 0.32 mMol) in THF (2
mL) was treated with 0.5 N aqueous lithium hydroxide (0.71 mL, 0.35
mMol), and the mixture was stirred at room temperature for six
hours. The THF was stripped in-vacuo, and the aqueous solution was
freeze dried to yield 112 mg of light brown solids. This material
was used as-is in the next step.
Example 136
Part B. Preparation of N-{(3S)-1-[(1S,2R,
4R)-2-benzenesulfonylmethyl-4-(isopropyl-methyl-amino)-cyclohexyl]-2-oxo--
pyrrolidin-3-yl}-3-bromo-5-tert-butyl-benzamide, TFA salt
[0797]
(3S)-3-Amino-1-[(1S,2R,4R)-2-benzenesulfonylmethyl-4-(isopropyl-me-
thyl-amino)-cyclohexyl]-pyrrolidin-2-one (39 mg, 0.10 mmol),
lithium-3-bromo-5-tert-butylbenzoate (25 mg, 0.10 mMol),
diisoproplyethylamine (84 .mu.L, 0.48 mMol), and HATU (37 mg, 0.10
mMol) were combined in CH.sub.2Cl.sub.2 (2 mL), and the mixture was
stirred overnight at room temperature. The mixture was diluted with
ethyl acetate (15 mL) and washed with saturated NaHCO.sub.3
(3.times.5 mL), water (5 mL), and brine (5 mm). The organic phase
was dried over sodium sulfate, and concentrated in-vacuo. The
residue was purified by reverse phase HPLC, using a Phenomenex Luna
10.mu., C18 (2), 250.times.50 mm column, under the following
conditions: 10% to 70% acetonitrile in water (0.05% TFA in each
solvent) over 30 minutes. The reaction yielded 17 mg of white
powder as product. MS (ES+)=647 (M+H).sup.+.
Example 137
Part A. Preparation of Pyrido[2,3-d]pyrimidin-4-ol
[0798] A mixture of 2-aminonicotinic acid (880 mg, 6.4 mMol) and
formamidine acetate (2.0 g, 19.1 mMol) in 2-ethoxyethanol (25 mm)
was heated at reflux overnight. The solution was allowed to come to
room temperature and stand for 2 hours, then the resulting
precipitate was collected by filtration, rinsed with 2-ethoxy
ethanol (2.times.5 mL), diethyl ether (20 mL), and air dried to
yield 525 mg of a gray powder as product. MS (ES+)=148 (M+H).sup.+.
Yield=56%.
Part B. Preparation of 4-Chloro-pyrido[2,3-d]pyrimidine
[0799] A solution of pyrido[2,3-d]pyrimidin-4-ol (490 mg, 3.33
mmol), triethylamine (4.4 mL, 31.6 mMol), and phosphorous
oxychloride (2.8 mL, 30 mMol) was heated at reflux for 2 hours. The
mixture was concentrated in-vacuo, and the residue was stripped
from methylene chloride (3.times.50 mL) to remove excess
phosphorous oxychloride. The residue was dissolved in ethyl acetate
(100 mm), saturated sodium bicarbonate (100 mL) was added
carefully, causing vigorous gas evolution, and the mixture was
stirred for ten minutes. The layers were separated, the organic
phase was washed with saturated sodium bicarbonate (30 mL), water
(30 mL), brine (30 mL), dried over sodium sulfate, then
concentrated in-vacuo. The residue was purified over silica gel,
eluting with 40% ethyl acetate/heptane, to yield 92 mg of a tan
solid as product. MS (ES+)=166 (M+H).sup.+. Yield=17%.
Example 137
Part C. Preparation of
1-[(1S,2R,4R)-2-benzenesulfonylmethyl-4-(isopropyl-methyl-amino)-cyclohex-
yl]-(3S)-3-(pyrido[2,3-d]pyrimidin-4-ylamino)-pyrrolidin-2-one, TFA
salt
[0800] The titled compound was prepared from
(3S)-3-amino-1-[(1S,2R,4R)-2-benzenesulfonylmethyl-4-(isopropyl-methyl-am-
ino)-cyclohexyl]-pyrrolidin-2-one and
4-Chloro-pyrido[2,3-d]pyrimidine using the conditions described in
Example 106, Part C. MS (ES+)=537 (M+H).sup.+.
Example 138
Part A. Preparation of 2-Amino-nicotinic acid ethyl ester
[0801] A 60% sodium hydride suspension in mineral oil (1.28 g, 32
mMol) was added to a stirring suspension of 2-aminonicotinic acid
(4.21 g, 30 mMol) in DMF (50 mL), and the mixture was gently heated
until gas evolution was observed. The suspension was stirred at
room temperature for 4 hours, after which a homogeneous amber
solution was observed. Iodoethane (4.75 g, 30 mmol) was added, and
the mixture was allowed to stir overnight at room temperature. The
solution was concentrated in-vacuo, the residue was taken up in 9:1
ethyl acetate/hexane (200 mL), washed with water (5.times.50 mL),
and brine (50 mL), dried over sodium sulfate, then concentrated
in-vacuo. The residue was purified over silica gel, eluting with
25%-50% ethyl acetate/hexane, to yield 3.6 g of colorless solids as
product. NMR (500 MHz, DMSO) .delta. 8.20 (dd, 1H, J=5 Hz, 2 Hz),
8.06 (dd, 1H, J=8 Hz, 2 Hz), 7.16 (s, 2H), 6.63 (dd, 1H, J=8 Hz, 5
Hz), 4.28 (q, 2H, J=7 Hz), 1.30 (t, 3H, J=7 Hz). Yield=72%.
Part B. Preparation of 2-Amino-5-chloro-nicotinic acid ethyl
ester
[0802] A solution of 2-amino-nicotinic acid ethyl ester (3.60 g,
21.7 mMol) in methanol (100 mL) was treated with HCl gas via sparge
tube for 5 minutes, causing the colorless solution to turn yellow.
The solution was concentrated in-vacuo, then stripped from methanol
(2.times.50 mL) to remove excess HCl. The residue was dissolved in
methanol (100 mL), treated with tert-butyl hypochlorite (2.6 g,
23.8 mMol), and the mixture was allowed to stir overnight at room
temperature. Analysis by TLC showed that some starting material
remained, so additional tert-butyl hypochlorite (0.47 g, 4.3 mMol)
was added, and stirring was continued overnight. Analysis by TLC
showed that all starting material had been consumed. The solution
was concentrated in-vacuo, the residue was taken up in methylene
chloride (150 mL), washed with saturated sodium bicarbonate
(3.times.50 mL), 5% aqueous sodium thiosulfate (3.times.50 mL),
water (50 mL), brine (50 mL), dried over sodium sulfate, and
concentrated in-vacuo. The residue was purified over silica gel,
eluting with 20%-30% ethyl acetate/heptane, to yield 1.50 g of
colorless solids as product. MS (AP+)=201 (M+H).sup.+.
Yield=35%.
Part C. Preparation of 6-Chloro-pyrido[2,3-d]pyrimidin-4-ol
[0803] A mixture of 2-amino-5-chloro-nicotinic acid ethyl ester
(1.5 g, 7.38 mMol) and formamidine acetate (3.1 g, 29.51 mMol) in
2-ethoxyethanol (50 mL) was heated at reflux overnight. The
solution was cooled to room temperature, and allowed to stand for 2
hours. The resulting precipitate was collected by filtration,
rinsed with a small amount of 2-ethoxyethanol followed by diethyl
ether (10 mL), and allowed to air dry. The filtrate was
concentrated in-vacuo, and the residue was triturated with
methylene chloride. The resulting solids were combined with the
solids from the earlier filtration, and this material was
crystallized from methanol to yield 475 mg of tan needles as
product, in three crops. MS (ES+)=182 (M+H).sup.+. Yield=37%.
Part D. Preparation of 4,6-Dichloro-pyrido[2,3-d]pyrimidine
[0804] The titled compound was prepared from
6-Chloro-pyrido[2,3-d]pyrimidin-4-ol using the conditions described
in Example 131, Part F. MS (ES+)=201 (M+H).sup.+. Yield=85%.
Example 138
Part E. Preparation of
1-[(1S,2R,4R)-2-benzenesulfonylmethyl-4-(isopropyl-methyl-amino)-cyclohex-
yl]-(3S)-3-(6-chloro-pyrido[2,3-d]pyrimidin-4-ylamino)-pyrrolidin-2-one,
TFA salt
[0805] The titled compound was prepared from
(3S)-3-amino-1-[(1S,2R,4R)-2-benzenesulfonylmethyl-4-(isopropyl-methyl-am-
ino)-cyclohexyl]-pyrrolidin-2-one and
4,6-Dichloro-pyrido[2,3-d]pyrimidine using the conditions described
in Example 106, part C. MS (ES+)=572 (M+H).sup.+.
Example 139
Part A. Preparation of
6-Chloro-2-trifluoromethyl-pyrido[2,3-d]pyrimidin-4-ol
[0806] The titled compound was prepared from
2-Amino-5-chloro-nicotinic acid ethyl ester and
trifluoromethylacetamidine using the conditions described in
Example 113, part A. MS (ES+)=250 (M+H).sup.+.
Part B. Preparation of
4,6-Dichloro-2-trifluoromethyl-pyrido[2,3-d]pyrimidine
[0807] The titled compound was prepared from
6-Chloro-2-trifluoromethyl-pyrido[2,3-d]pyrimidin-4-ol using the
conditions described in Example 131, part F. MS (ES+)=268
(M+H).sup.+.
Example 139
Part C. Preparation of
1-[(1S,2R,4R)-2-benzenesulfonylmethyl-4-(isopropyl-methyl-amino)-cyclohex-
yl]-(3S)-3-(6-chloro-2-trifluoromethyl-pyrido[2,3-d]pyrimidin-4-ylamino)-p-
yrrolidin-2-one.
[0808] The titled compound was prepared from
(3S)-3-amino-1-[(1S,2R,4R)-2-benzenesulfonylmethyl-4-(isopropyl-methyl-am-
ino)-cyclohexyl]-pyrrolidin-2-one and
4,6-dichloro-2-trifluoromethyl-pyrido[2,3-d]pyrimidine using the
conditions described in Example 106, part C. MS (ES+)=639
(M+H).sup.+.
Example 140
Part A. Preparation of (4-Trifluoromethoxy-phenyl)-carbamic acid
tert-butyl ester
[0809] A solution of 4-(trifluoromethyl)phenyl isocyanate (9.75 g,
48.0 mMol) in THF (100 mL) was cooled to 0.degree. C., and a 1.0 M
THF solution of potassium tert-butoxide (53 mL, 53 mMol) was added
dropwise. The mixture was allowed to warm to room temperature, and
stirred for 7 hours. The solution was poured into a mixture of
saturated ammonium chloride solution (200 mL), and diethyl ether
(200 mL). Enough water was added to redissolve the ammonium
chloride that had crashed out, the mixture was shaken in a
separatory funnel, and the layers were separated. The organic phase
was washed with saturated ammonium chloride (100 mL), water (100
mL), brine (100 mL), dried over sodium sulfate, and concentrated
in-vacuo. The residue was purified over silica gel, eluting with
10%-20% ethyl acetate/heptane to yield 11.7 g of white solids as
product. NMR (500 MHz, DMSO) .delta. 9.54 (s, 1H), 7.54 (d, 2H, J=7
Hz), 7.23 (d, 21, J=8 Hz), 1.45 (s, 9H). Yield=88%.
Part B. Preparation of
2-tert-Butoxycarbonylamino-5-trifluoromethoxy-benzoic acid
[0810] A solution of (4-trifluoromethoxy-phenyl)-carbamic acid
tert-butyl ester (2.31 g, 8.33 mMol) in anhydrous THF (50 mL) at
-78.degree. C. was treated with a 1.4 M solution of
sec-butyllithium in cyclohexane (13 mL, 18.33 mMol), at a rate
which did not allow the internal temperature to exceed -60.degree.
C. The solution was stirred at -78.degree. C. for 15 minutes, then
allowed to warm to -40.degree. C. and stirred for 2.5 hours. The
reaction was treated with gaseous CO.sub.2, stirred 30 minutes
while warming to -20.degree. C., then quenched with saturated
ammonium chloride. The mixture was warmed to room temperature, and
extracted with ethyl acetate (3.times.50 mL). The combined organic
phases were washed with water (50 mL), brine (50 ml), dried over
sodium sulfate, and concentrated in-vacuo. The residue was
triturated with hot heptane to yield 1.9 g of white powder as
product. NMR (500 MHz, DMSO) .delta. 12.89 (s, 1H), 8.24 (d, 1H,
J=9 Hz), 7.84 (s, 1H), 7.21 (d, 1H, J=7 Hz), 1.51 (s, 9 Hz).
Yield=72%.
Part C. Preparation of 2-Amino-5-trifluoromethoxy-benzoic acid, HCl
salt
[0811] 2-tert-Butoxycarbonylamino-5-trifluoromethoxy-benzoic acid
(1.9 g, 5.91 mMol) was dissolved in a 4 N HCl solution in dioxane
(15 mL), and the resulting suspension was stirred at room
temperature for 6 hours. Analysis by LC/MS showed that the reaction
was incomplete, so concentrated HCl (1 ml) was added, followed by
methylene chloride (20 mL) to dissolve the solids, and the reaction
was stirred overnight at room temperature. The mixture was
concentrated in-vacuo, then stripped from methanol (3.times.50 mL)
to remove any excess HCl. The resulting solids were used as-is in
the next step. MS (ES+)=222 (M+H).sup.+.
Part D. Preparation of 6-Trifluoromethoxy-quinazolin-4-ol
[0812] A mixture of 2-amino-5-trifluoromethoxy-benzoic acid, HCl
salt (1.52 g, 5.91 mmol), and formamidine acetate (1.84 g, 17.73
mMol) in 2-ethoxyethanol (20 mL) was heated at reflux for 2 hours.
Analysis by LC/MS showed that the reaction was complete, so the
mixture was concentrated in-vacuo, and the residue was purified
over silica gel, eluting with 50% ethyl acetate/heptane-100% ethyl
acetate, to yield 1.1 g of white solids as product. MS (ES+)=231
(M+H).sup.+. Yield=82%.
Part E. Preparation of 4-Chloro-6-trifluoromethoxy-quinazoline
[0813] The titled compound was prepared from
6-trifluoromethoxy-quinazolin-4-ol using the conditions described
in example 137, part B. MS (ES+)=249 (M+H).sup.+.
Example 140
Part F. Preparation of
1-[(1S,2R,4R)-2-benzenesulfonylmethyl-4-(isopropyl-methyl-amino)-cyclohex-
yl]-(3S)-3-(6-trifluoromethoxy-pyrido[2,3-d]pyrimidin-4-ylamino)-pyrrolidi-
n-2-one, TFA salt
[0814] The titled compound was prepared from
(3S)-3-amino-1-[(1S,2R,4R)-2-benzenesulfonylmethyl-4-(isopropyl-methyl-am-
ino)-cyclohexyl]-pyrrolidin-2-one and of
4-chloro-6-trifluoromethoxy-quinazoline using the conditions
described in example 106, part C. MS (ES+)=620 (M+H).sup.+.
Example 141
Preparation of
1-[(1S,2R,4R)-2-benzenesulfonylmethyl-4-(isopropyl-methyl-amino)-cyclohex-
yl]-(3S)-3-(6-chloro-2-methylamino-quinazolin-4-ylamino)-pyrrolidin-2-one,
TFA salt
[0815]
1-[(1S,2R,4R)-2-benzenesulfonylmethyl-4-(isopropyl-methyl-amino)-c-
yclohexyl]-(3S)-3-(2,6-dichloro-quinazolin-4-ylamino)-pyrrolidin-2-one
(35 mg, 0.0487 mmol, 1 eq.), 2.0 M mono-methylamine in THF (1.22
mL, 2.44 mmol, 50 eq.), and THF (1 mL) were microwaved at
100.degree. C. until reaction was complete by LCMS. Purified by
HPLC. Obtained 60 mg of white solids as product. LCMS detects
(M+H)+=599.
Example 142
Preparation of
(3S)-3-(6-Fluoro-quinazolin-4-ylamino)-1-[(1S,2R,4R)-4-(isopropyl-methyl--
amino)-2-(toluene-4-sulfonylmethyl)-cyclohexyl]-pyrrolidin-2-one,
TFA salt
[0816] Followed the procedure of Example 106 Part C starting from
(3S)-3-amino-1-[(1S,2R,4R)-4-(isopropyl-methyl-amino)-2-(toluene-4-sulfon-
ylmethyl)-cyclohexyl]-pyrrolidin-2-one (10c) and
4-chloro-6-fluoro-quinazoline. Purified by HPLC. LCMS detects
(M+H)+=568.
Example 143
Preparation of
N-{1-[(1S,2R,4R)-2-benzenesulfonylmethyl-4-(isopropyl-methyl-amino)-cyclo-
hexyl]-2-oxo-pyrrolidin-(3S)-3-yl}-2-chloro-5-trifluoromethyl-benzamide,
TFA salt
Followed the procedure of Example 116 Part D starting from
2-chloro-5-trifluoromethyl-benzoic acid. Purified by HPLC. LCMS
detects (M+H)+=614.
The next step: ESI MS m/z 507
[C.sub.26H.sub.29F.sub.3N.sub.2O.sub.3S+H].sup.+.
Example 144
(S)-3-(6-Bromoquinazolin-4-ylamino)-1-((1S,2R,4R)-4-(isopropyl(methyl)amin-
o)-2-(phenylsulfonylmethyl)cyclohexyl)pyrrolidin-2-one, TFA
salt
(144a) 6-Bromo-4-chloroquinazoline was incorporated into Example
106, Part C give the title compound. MS found (M+H).sup.+=615.
Example 145
(S)-3-(6,7-Difluoroquinazolin-4-ylamino)-1-((1S,2R,4R)-4-(isopropyl(methyl-
)amino)-2-(phenylsulfonylmethyl)cyclohexyl)pyrrolidin-2-one, TFA
salt
(145a) 4-Chloro-6,7-difluoroquinazoline was incorporated into
Example 106, Part C give the title compound. MS found:
(M+H).sup.+=572.
Example 146
(S)-3-(6-Methoxyquinazolin-4-ylamino)-1-((1S,2R,4R)-4-(isopropyl(methyl)am-
ino)-2-(phenylsulfonylmethyl)cyclohexyl)pyrrolidin-2-one, TFA
salt
(146a) 4-Chloro-6-methoxyquinazoline was incorporated into Example
106, Part C give the title compound. MS found: (M+H).sup.+=566.
Example 147
((S)-1-((1S,2R,4R)-4-(isopropyl(methyl)amino)-2-(phenylsulfonylmethyl)cycl-
ohexyl)-3-(quinazolin-4-ylamino)pyrrolidin-2-one, TFA salt
(147a) 4-Chloroquinazoline was incorporated into Example 106, Part
C give the title compound. MS found: (M+H).sup.+=536.
Example 148
3-Phenyl-N--((S)-1-((1S,2R,4R)-4-(isopropyl(methyl)amino)-2-(phenylsulfony-
lmethyl)cyclohexyl)-2-oxopyrrolidin-3-yl)benzamide, TFA salt
(148a) 3-Phenyl-benzoic acid was incorporated into Example 132 give
the title compound. MS found: (M+H).sup.+=588.
Example 149
(S)-3-(6-Iodoquinazolin-4-ylamino)-1-((1S,2R,4R)-4-(isopropyl(methyl)amino-
)-2-(phenylsulfonylmethyl)cyclohexyl)pyrrolidin-2-one, TEA salt
(149a) 4-Chloro-6-iodoquinazoline was incorporated into Example
106, Part C give the title compound. MS found (M+H).sup.+=662.
Example 150
3-Tert-butyl-4-hydroxy-N--((S)-1-((1S,2R,4R)-4-(isopropyl(methyl)amino)-2--
(phenylsulfonylmethyl)cyclohexyl)-2-oxopyrrolidin-3-yl)benzamide,
TFA salt
(150a) 3-Tert-butyl-4-hydroxybenzoic acid was incorporated into
Example 132 give the title compound. MS found: (M+H).sup.+=584.
Example 151
3-Amino-5-tert-butyl-N--((S)-1-((1S,2R,4R)-4-(isopropyl(methyl)amino)-2-(p-
henylsulfonylmethyl)cyclohexyl)-2-oxopyrrolidin-3-yl)thiophene-2-carboxami-
de, TFA salt
(151a) 3-Amino-5-tert-butylthiophene-2-carboxylic acid was
incorporated into Example 132 give the title compound. MS found:
(M+H).sup.+=589.
Example 152
N--((S)-1-((1S,2R,4R)-4-(Isopropyl(methyl)amino)-2-(phenylsulfonylmethyl)c-
yclohexyl)-2-oxopyrrolidin-3-yl)-2-methyl-5-phenylfuran-3-carboxamide,
TFA salt
(152a) 2-Methyl-5-phenylfuran-3-carboxylic acid was incorporated
into Example 132 give the title compound. MS found:
(M+H).sup.+=592.
Example 153
N--((S)-1-((1S,2R,4R)-4-(Isopropyl(methyl)amino)-2-(phenylsulfonylmethyl)c-
yclohexyl)-2-oxopyrrolidin-3-yl)-5-nitrofuran-2-carboxamide, TFA
salt
(153a) 5-Nitrofuran-2-carboxylic acid was incorporated into Example
132 give the title compound. MS found: (M+H).sup.+=547.
Example 154
N--((S)-1-((1S,2R,4R)-4-(Isopropyl(methyl)amino)-2-(phenylsulfonylmethyl)c-
yclohexyl)-2-oxopyrrolidin-3-yl)-4-phenylthiophene-2-carboxamide,
TFA salt
(154a) 4-Phenylthiophene-2-carboxylic acid was incorporated into
Example 132 give the title compound. MS found: (M+H).sup.+=594.
Example 155
N--((S)-2-Oxo-1-((1S,2R,4R)-2-(phenylsulfonylmethyl)-4-(pyrrolidin-1-yl)cy-
clohexyl)pyrrolidin-3-yl)-3-(trifluoromethyl)benzamide, TFA
salt
[0817] (155a) Tert-butyl
(S)-1-((1S,2R,4R)-4-amino-2-(phenylsulfonylmethyl)cyclohexyl)-2-oxopyrrol-
idin-3-ylcarbamate (52c) (80 mg) was dissolved in DMF prior to the
addition 1,4-dibromobutane and K.sub.2CO.sub.3 (75 mg). After 16 h,
water and EtOAc were added. The organic layer was dried, filtered,
and concentrated. The resulting residue was dissolved in
CH.sub.2Cl.sub.2 (2 mL) and cooled to 0.degree. C. prior to the
addition of TEA (2 mL). After the reaction was warmed to rt over 1
h, it was concentrated and dried. This material was dissolved in
DMF prior to the addition of (iPr).sub.2NEt (0.03 mL) and
3-trifluoromethylbenzoic acid (33 mg). After cooling to 0.degree.
C., HATU (78 mg) was added. The resulting mixture was warmed to rt
and was stirred overnight. The solution was diluted with EtOAc and
was washed with sat. NaHCO.sub.3. The organic phase was dried
(MgSO.sub.4), filtered, and concentrated. Reverse phase HPLC
purification (gradient elution, water/acetonitrile/TFA) of the
resulting residue provided the title compound (5 mg). MS found:
(M+H).sup.+=578.3.
[0818] Table 1 contains representative examples of the present
invention. Each of the following structural formulas are to be used
in the indicated example (Ex) range paired with the given R.sup.1
and R.sup.2 substituent. The R.sup.1 and R.sup.2 described in the
tables may be the same or different than those described in the
claims TABLE-US-00001 TABLE 1 ##STR66## EX. 1-2 ##STR67## EX.
3,17,18,20,21 ##STR68## EX. 4,6 ##STR69## EX.
5,7,9,22,23,27,56,57,60 ##STR70## EX. 8 ##STR71## EX. 10-15
##STR72## EX. 16 ##STR73## EX. 19,34 ##STR74## EX. 24,25 ##STR75##
EX. 26 ##STR76## EX. 28,29,32 ##STR77## EX. 30,31 ##STR78## EX. 33
##STR79## EX. 35,36 ##STR80## EX. 37 ##STR81## Ex. 38 ##STR82## Ex.
39,40 ##STR83## Ex. 41,42,45,46 ##STR84## Ex. 47-51 ##STR85## Ex.
52,53,63-72 ##STR86## Ex. 58,59 ##STR87## Ex. 61,62,73-84,155
##STR88## Ex. 85-92,97-101 ##STR89## Ex. 93-96 ##STR90## Ex.
102-105 MS Ex R.sup.1 R.sup.2 [M + H] 1 4-(methylthio)phenyl
2-(t-butoxycarbonyl)amino- 635.4 5-trifluoromethylphenyl M + H 2
4-(methylthio)phenyl 2-amino-5- 535.4 trifluoromethylphenyl M + H 3
4-methylphenyl 3-trifluoromethylphenyl 594.3 4 4-methylphenyl
3-trifluoromethylphenyl 594.3 5 methyl 3-trifluoromethylphenyl
580.3 6 phenyl 3-trifluoromethylphenyl 580.3 7 ethyl
3-trifluoromethylphenyl 594.3 8 phenyl 3-trifluoromethylphenyl
594.3 9 cyclopropylmethyl 3-trifluoromethylphenyl 620.3 10 azido
3-trifluoromethylphenyl 610.5 11 amino 3-trifluoromethylphenyl
584.5 12 isopropylamino 3-trifluoromethylphenyl 626.6 13
isopropyl(methyl)amino 3-trifluoromethylphenyl 640.6 14
isopropyl(propargyl) 3-trifluoromethylphenyl 664.6 amino 15
isopropyl(cyclopropyl 3-trifluoromethylphenyl 680.6 methyl)amino 16
4-(methylthio)phenyl 3-trifluoromethylphenyl 640.3 17
4-(methylthio)phenyl 3-trifluoromethylphenyl 626.3 18
4-(methylthio)phenyl 3-(trifluoromethyl)phenyl 641.3 amino 19
4-(methylthio)phenyl 3-(trifluoromethyl)phenyl 662.3 sulfonyl 20
4-(methylthio)phenyl phenyl 558.3 21 phenyl
3-(trifluoromethyl)phenyl 595.3 amino 22 H 3-trifluoromethylphenyl
566.4 23 allyl 3-trifluoromethylphenyl 606.3 24 H
3-trifluoromethylphenyl 566.3 25 H 3-trifluoromethylphenyl 566.5 26
4-(methylthio)phenyl 2-(t-butoxycarbonyl)amino- 621.4
5-trifluoromethylphenyl 27 propyl 3-trifluoromethylphenyl 608.3 28
4-(methylthio)phenyl 3-trifluoromethylphenyl 581 29 phenyl
3-trifluoromethylphenyl 535 30 isopropyl(methyl)amino
3-trifluoromethylphenyl 595.4 31 amino 3-trifluoromethoxyphenyl
555.2 32 4-(methylthio)phenyl 3-trifluoromethoxyphenyl 597.2 33
4-(methylthio)phenyl 3-trifluoromethylphenyl 537 34
4-(methylthio)phenyl 3-(trifluoromethyl)phenyl 612.3 methylene 35 H
3-(trifluoromethyl)phenyl NMR ethylene 36 H
3-(trifluoromethyl)phenyl 551.4 ethylene 37 methyl
3-trifluoromethylphenyl 608 38 methyl 3-trifluoromethylphenyl 566
39 methyl 3-trifluoromethylphenyl 623 40 methyl
3-trifluoromethylphenyl 623 41 methyl O 579 42 methyl O 579 43
methyl OH 581 44 methyl OH 581 45 methyl methoxyamino 608 46 methyl
methoxyamino 608 47 amino trifluoromethyl 521 48 isopropylamino
trifluoromethyl 563 49 isopropyl(methyl)amino trifluoromethyl 577
50 isopropyl(ethyl)amino trifluoromethyl 591 51 diethylamino
trifluoromethyl 577 52 isopropyl(methyl)amino 1-naphthalenyl 534 53
isopropyl(methyl)amino 3-benzo[b]thiophenyl 540 54
isopropyl(methyl)amino 6-chloroquinazolin-4-yl 570.2 55
isopropyl(methyl)amino 6,8-dichloroquinazolin-4-yl 604.2 56 methyl
3,5-dichlorophenyl 580 57 methyl 3-trifluoromethoxylphenyl 596.2 58
methyl H 563 59 methyl methyl 577 60 methyl phenyl 512 61
isopropyl(methyl)amino 3,5-bis-trifluoromethyl- 648 phenyl 62
isopropyl(methyl)amino 2-amino-5-trifluoro- 611 methoxyphenyl 63
isopropyl(methyl)amino 6-trifluoromethylquinolin- 603.2 4-yl 64
isopropyl(methyl)amino 6-trifluoromethylquinolin- 603.2 4-yl 65
isopropyl(methyl)amino 7-trifluoromethylquinolin- 603.2 4-yl 66
isopropyl(methyl)amino 7-trifluoromethylquinolin- 603.2 4-yl 67
isopropyl(methyl)amino 2-phenyl-phenyl 560.3 68
isopropyl(methyl)amino 3,5-bis-trifluoromethyl- 620.2 phenyl 69
isopropyl(methyl)amino 2-trifluoromethylphenyl 552.3 70
isopropyl(methyl)amino 2-trifluoromethoxyphenyl 568.3 71
isopropyl(methyl)amino 3-trifluoromethylphenyl 552.3 72
isopropyl(methyl)amino 4-trifluoromethylphenyl 552.3 73
isopropyl(methyl)amino 3-chlorophenyl 546 74 isopropyl(methyl)amino
3-fluoro-5- 648 trifluoromethylphenyl 75 t-butoxycarbonylamino
3-trifluoromethylphenyl 624.7 76 phenyl 3-trifluoromethylphenyl
600.1 77 pyridin-3-yl 3-trifluoromethylphenyl 601 78 thiazolin-2-yl
3-trifluoromethylphenyl 607 79 methoxycarbonylamino
3-trifluoromethylphenyl 582.2 80 formamidyl 3-trifluoromethylphenyl
552.3 81 aminocarbonylamino 3-trifluoromethylphenyl 567.3 82
(methylamino)carbonyl 3-trifluoromethylphenyl 581.3 amino 83
2-oxo-pyrrolidin-1-yl 3-trifluoromethylphenyl 592 84 1,1-dioxido-
3-trifluoromethylphenyl 628 isothiazolidin-2-yl 85 4-chlorophenyl
3-fluoro-5- 632 trifluoromethylphenyl 86 4-chlorophenyl
3-chlorophenyl 580 87 4-chlorophenyl 3,5-bis- 683
trifluoromethylphenyl 88 4-chlorophenyl 2-tert- 746
butoxycarbonylamino-5- trifluoromethoxyphenyl 89 4-chlorophenyl
2-amino-5- 645 trifluoromethoxyphenyl 90 4-chlorophenyl
3-trifluoromethoxyphenyl 630.2 91 4-chlorophenyl
3-trifluoromethylphenyl 614.0 92 4-chlorophenyl
3,5-bis-chloro-phenyl 614.2 93 4-chlorophenyl 3-chlorophenyl 596 94
4-chlorophenyl 3-trifluoromethylphenyl 630.3 95 4-chlorophenyl
3-fluoro-5- 649.1 trifluoromethylphenyl 96 phenyl
3-trifluoromethylphenyl 596.3 97 4-isopropyl-phenyl
3-trifluoromethylphenyl 622.3 98 2-methyl-phenyl
3-trifluoromethylphenyl 594.6 99 4-fluoro-phenyl
3-trifluoromethylphenyl 598.5 100 4-methyl-phenyl 3-chloro-phenyl
560.2 101 4-methyl-phenyl 2-amino-5- 625.2 trifluoromethoxyphenyl
102 amino 3-trifluoromethylphenyl 493.4 103 isopropylamino
3-trifluoromethylphenyl 535.2 104 isopropyl(methyl)amino
3-trifluoromethylphenyl 548.7 105 isopropyl(ethyl)amino
3-trifluoromethylphenyl 563.3 155 pyrrolidin-1-yl
3-trifluoromethylphenyl 578.3
[0819] TABLE-US-00002 TABLE A ##STR91## No. R MS 144 ##STR92## 615
145 ##STR93## 572 146 ##STR94## 566 137 ##STR95## 537 147 ##STR96##
536 140 ##STR97## 620 120 ##STR98## 554 138 ##STR99## 572 139
##STR100## 639 131 ##STR101## 594 135 ##STR102## 568 132 ##STR103##
648 136 ##STR104## 647 150 ##STR105## 584 133 ##STR106## 570 148
##STR107## 588 134 ##STR108## 646 121 ##STR109## 550 109 ##STR110##
613 110 ##STR111## 586 111 ##STR112## 604 112 ##STR113## 598 113
##STR114## 666 122 ##STR115## 618 124 ##STR116## 612 115 ##STR117##
659 151 ##STR118## 539 152 ##STR119## 592 153 ##STR120## 547 154
##STR121## 594 116 ##STR122## 592 117 ##STR123## 668 118 ##STR124##
577 143 ##STR125## 614 129 ##STR126## 636 130 ##STR127## 649 119
##STR128## 596 125 ##STR129## 626 126 ##STR130## 585 127 ##STR131##
599 106 ##STR132## 638 123 ##STR133## 613 141 ##STR134## 599 107
##STR135## 570 108 ##STR136## 604 114 ##STR137## 581 149 ##STR138##
662
[0820] TABLE-US-00003 TABLE B ##STR139## 142 ##STR140## 568
[0821] TABLE-US-00004 TABLE C ##STR141## 128 ##STR142## 594
UTILITY
[0822] Compounds of formula I are shown to be modulators of
chemokine receptor activity using assays know by those skilled in
the art. In this section, we describe these assays and give their
literature reference. By displaying activity in these assays of
MCP-1 antagonism, compounds of formula I are expected to be useful
in the treatment of human diseases associated with chemokines and
their cognate receptors. The definition of activity in these assays
is a compound demonstrating an IC.sub.50 of 20 .mu.M or lower in
concentration when measured in a particular assay.
Antagonism of MCP-1 Binding to Human PBMC
(Yoshimura et al., J. Immunol. 1990, 145, 292)
[0823] Compounds of the present invention have activity in the
antagonism of MCP-1 binding to human PBMC (human peripheral blood
mononuclear cells) described here.
[0824] Millipore filter plates (#MABVN1250) are treated with 100
.mu.l of binding buffer (0.5% bovine serum albumin, 20 mM HEPES
buffer and 5 mM magnesium chloride in RPMI 1640 media) for thirty
minutes at room temperature. To measure binding, 50 .mu.l of
binding buffer, with or without a known concentration compound, is
combined with 50 .mu.l of .sup.125-I labeled human MCP-1 (to give a
final concentration of 150 pM radioligand) and 50 .mu.l of binding
buffer containing 5.times.10.sup.5 cells. Cells used for such
binding assays can include human peripheral blood mononuclear cells
isolated by Ficoll-Hypague gradient centrifugation, human monocytes
(Weiner et al., J. Immunol. Methods. 1980, 36, 89), or the THP-1
cell line which expresses the endogenous receptor. The mixture of
compound, cells and radioligand are incubated at room temperature
for thirty minutes. Plates are placed onto a vacuum manifold,
vacuum applied, and the plates washed three times with binding
buffer containing 0.5M NaCl. The plastic skirt is removed from the
plate, the plate allowed to air dry, the wells punched out and
counted. The percent inhibition of binding is calculated using the
total counts obtained in the absence of any competing compound and
the background binding determined by addition of 100 nM MCP-1 in
place of the test compound.
Antagonism of MCP-1-Induced Calcium Influx
(Sullivan, et al. Methods Mol. Biol., 114, 125-133 (1999)
[0825] Compounds of the present invention have activity in the
antagonism of MCP-1-induced calcium influx assay described
here.
[0826] Calcium mobilization is measured using the fluorescent
Ca.sup.2+ indicator dye, Fluo-3. Cells are incubated at
8.times.10.sup.5 cells/ml in phosphate-buffered saline containing
0.1% bovine serum albumin, 20 mM HEPES buffer, 5 mM glucose, 1%
fetal bovine serum, 4 .mu.M Fluo-3 AM and 2.5 mM probenecid for 60
minutes at 37.degree. C. Cells used for such calcium assays can
include human monocytes isolated as described by Weiner et al., J.
Immunol. Methods, 36, 89-97 (1980) or cell lines which expresses
the endogenous CCR2 receptor such as THP-1 and MonoMac-6. The cells
are then washed three times in phosphate-buffered saline containing
0.1% bovine serum albumin, 20 mM HEPES, 5 mM glucose and 2.5 mM
probenecid. The cells are resuspended in phosphate-buffered saline
containing 0.5% bovine serum albumin, 20 mM HEPES and 2.5 mM
probenecid at a final concentration of 2-4.times.10.sup.6 cells/ml.
Cells are plated into 96-well, black-wall microplates (100
.mu.l/well) and the plates centrifuged at 200.times.g for 5
minutes. Various concentrations of compound are added to the wells
(50 .mu.l/well) and after 5 minutes, 50 .mu.l/well of MCP-1 is
added to give a final concentration of 10 nM. Calcium mobilization
is detected by using a fluorescent-imaging plate reader. The cell
monolayer is excited with an argon laser (488 nM) and
cell-associated fluorescence measured for 3 minutes, (every second
for the first 90 seconds and every 10 seconds for the next 90
seconds). Data are generated as arbitrary fluorescence units and
the change in fluorescence for each well determined as the maximum
minimum differential. Compound-dependent inhibition is calculated
relative to the response of MCP-1 alone.
Antagonism of MCP-1-Induced Human PBMC Chemotaxis
(Bacon et al., Brit. J. Pharmacol. 1988, 95, 966)
[0827] Compounds of the present invention have activity in the
antagonism of MCP-1-induced human PBMC chemotaxis assay described
here.
[0828] Neuroprobe MBA96-96-well chemotaxis chamber, Polyfiltronics
MPC 96 well plate, and Neuroprobe polyvinylpyrrolidone-free
polycarbonate PFDS 8-micron filters are warmed in a 37.degree. C.
incubator. Human Peripheral Blood Mononuclear Cells (PBMCs) (Boyum
et al., Scand. J. Clin. Lab Invest. Suppl. 1968, 97, 31), freshly
isolated via the standard ficoll density separation method, are
suspended in DMEM at 1.times.10.sup.7 c/ml and warmed at 37.degree.
C. A 60 nM solution of human MCP-1 is also warmed at 37.degree. C.
Dilutions of test compounds are made up at 2.times. the
concentration needed in DMEM. The PBMC suspension and the 60 nm
MCP-1 solution are mixed 1:1 in polypropylene tubes with prewarmed
DMEM with or without a dilution of the test compounds. These
mixtures are warmed in a 37.degree. C. tube warmer. To start the
assay, add the MCP-1/compound mixture into the wells of the
Polyfiltronics MPC 96 well plate that has been placed into the
bottom part of the Neuroprobe chemotaxis chamber. The approximate
volume is 400 .mu.l to each well and there should be a positive
meniscus after dispensing. The 8 micron filter is placed gently on
top of the 96 well plate, a rubber gasket is attached to the bottom
of the upper chamber, and the chamber is assembled, A 200 .mu.l
volume of the cell suspension/compound mixture is added to the
appropriate wells of the upper chamber. The upper chamber is
covered with a plate sealer, and the assembled unit is placed in a
37.degree. C. incubator for 45 minutes. After incubation, the plate
sealer is removed and all the remaining cell suspension is
aspirated off. The chamber is disassembled and the filter gently
removed. While holding the filter at a 90 degree angle, unmigrated
cells are washed away using a gentle stream of phosphate buffered
saline and the top of the filter wiped with the tip of a rubber
squeegee. Repeat this wash twice more. The filter is air dried and
then immersed completely in Wright Geimsa stain for 45 seconds. The
filter is then washed by soaking in distilled water for 7 minutes,
and then a 15 second additional wash in fresh distilled water. The
filter is again air dried. Migrated cells on the filter are
quantified by visual microscopy.
[0829] Mammalian chemokine receptors provide a target for
interfering with or promoting immune cell function in a mammal,
such as a human. Compounds that inhibit or promote chemokine
receptor function are particularly useful for modulating immune
cell function for therapeutic purposes. Accordingly, the present
invention is directed to compounds which are useful in the
prevention and/or treatment of a wide variety of inflammatory,
infectious, and immunoregulatory disorders and diseases, including
asthma and allergic diseases, infection by pathogenic microbes
(which, by definition, includes viruses), as well as autoimmune
pathologies such as the rheumatoid arthritis and
atherosclerosis.
[0830] For example, an instant compound which inhibits one or more
functions of a mammalian chemokine receptor (e.g., a human
chemokine receptor) may be administered to inhibit (i.e., reduce or
prevent) inflammation or infectious disease. As a result, one or
more inflammatory process, such as leukocyte emigration, adhesion,
chemotaxis, exocytosis (e.g., of enzymes, histamine) or
inflammatory mediator release, is inhibited.
[0831] Similarly, an instant compound which promotes one or more
functions of the mammalian chemokine receptor (e.g., a human
chemokine) as administered to stimulate (induce or enhance) an
immune or inflammatory response, such as leukocyte emigration,
adhesion, chemotaxis, exocytosis (e.g., of enzymes, histamine) or
inflammatory mediator release, resulting in the beneficial
stimulation of inflammatory processes. For example, eosinophils can
be recruited to combat parasitic infections. In addition, treatment
of the aforementioned inflammatory, allergic and autoimmune
diseases can also be contemplated for an instant compound which
promotes one or more functions of the mammalian chemokine receptor
if one contemplates the delivery of sufficient compound to cause
the loss of receptor expression on cells through the induction of
chemokine receptor internalization or the delivery of compound in a
manner that results in the misdirection of the migration of
cells.
[0832] In addition to primates, such as humans, a variety of other
mammals can be treated according to the method of the present
invention. For instance, mammals, including but not limited to,
cows, sheep, goats, horses, dogs, cats, guinea pigs, rats or other
bovine, ovine, equine, canine, feline, rodent or murine species can
be treated. However, the method can also be practiced in other
species, such as avian species. The subject treated in the methods
above is a mammal, male or female, in whom modulation of chemokine
receptor activity is desired. "Modulation" as used herein is
intended to encompass antagonism, agonism, partial antagonism
and/or partial agonism.
[0833] Diseases or conditions of human or other species which can
be treated with inhibitors of chemokine receptor function, include,
but are not limited to: inflammatory or allergic diseases and
conditions, including respiratory allergic diseases such as asthma,
allergic rhinitis, hypersensitivity lung diseases, hypersensitivity
pneumonitis, eosinophilic cellulitis (e.g., Well's syndrome),
eosinophilic pneumonias (e.g., Loeffler's syndrome, chronic
eosinophilic pneumonia), eosinophilic fasciitis (e.g., Shulman's
syndrome), delayed-type hypersensitivity, interstitial lung
diseases (ILD) (e.g., idiopathic pulmonary fibrosis, or ILD
associated with rheumatoid arthritis, systemic lupus erythematosus,
ankylosing spondylitis, systemic sclerosis, Sjogren's syndrome,
polymyositis or dermatomyositis); systemic anaphylaxis or
hypersensitivity responses, drug allergies (e.g., to penicillin,
cephalosporins), eosinophilia-myalgia syndrome due to the ingestion
of contaminated tryptophan, insect sting allergies; autoimmune
diseases, such as rheumatoid arthritis, psoriatic arthritis,
multiple sclerosis, systemic lupus erythematosus, myasthenia
gravis, juvenile onset diabetes; glomerulonephritis, autoimmune
thyroiditis, Behcet's disease; graft rejection (e.g., in
transplantation), including allograft rejection or
graft-versus-host disease; inflammatory bowel diseases, such as
Crohn's disease and ulcerative colitis; spondyloarthropathies;
scleroderma; psoriasis (including T-cell mediated psoriasis) and
inflammatory dermatoses such as an dermatitis, eczema, atopic
dermatitis, allergic contact dermatitis, urticaria; vasculitis
(e.g., necrotizing, cutaneous, and hypersensitivity vasculitis);
eosinophilic myositis, eosinophilic fasciitis; cancers with
leukocyte infiltration of the skin or organs. Other diseases or
conditions in which undesirable inflammatory responses are to be
inhibited can be treated, including, but not limited to,
reperfusion injury, atherosclerosis, certain hematologic
malignancies, cytokine-induced toxicity (e.g., septic shock,
endotoxic shock), polymyositis, dermatomyositis. Infectious
diseases or conditions of human or other species which can be
treated with inhibitors of chemokine receptor function, include,
but are not limited to, HIV.
[0834] Diseases or conditions of humans or other species which can
be treated with promoters of chemokine receptor function, include,
but are not limited to: immunosuppression, such as that in
individuals with immunodeficiency syndromes such as AIDS or other
viral infections, individuals undergoing radiation therapy,
chemotherapy, therapy for autoimmune disease or drug therapy (e.g.,
corticosteroid therapy), which causes immunosuppression;
immunosuppression due to congenital deficiency in receptor function
or other causes; and infections diseases, such as parasitic
diseases, including, but not limited to helminth infections, such
as nematodes (round worms); (Trichuriasis, Enterobiasis,
Ascariasis, Hookworm, Strongyloidiasis, Trichinosis, filariasis);
trematodes (flukes) (Schistosomiasis, Clonorchiasis), cestodes
(tape worms) (Echinococcosis, Taeniasis saginata, Cysticercosis);
visceral worms, visceral larva migraines (e.g., Toxocara),
eosinophilic gastroenteritis (e.g., Anisaki sp., Phocanema sp.),
cutaneous larva migraines (Ancylostoma braziliense, Ancylostoma
caninum). The compounds of the present invention are accordingly
useful in the prevention and treatment of a wide variety of
inflammatory, infectious and immunoregulatory disorders and
diseases.
[0835] In addition, treatment of the aforementioned inflammatory,
allergic and autoimmune diseases can also be contemplated for
promoters of chemokine receptor function if one contemplates the
delivery of sufficient compound to cause the loss of receptor
expression on cells through the induction of chemokine receptor
internalization or delivery of compound in a manner that results in
the misdirection of the migration of cells.
[0836] In another aspect, the instant invention may be used to
evaluate the putative specific agonists or antagonists of a G
protein coupled receptor. The present invention is directed to the
use of these compounds in the preparation and execution of
screening assays for compounds that modulate the activity of
chemokine receptors. Furthermore, the compounds of this invention
are useful in establishing or determining the binding site of other
compounds to chemokine receptors, e.g., by competitive inhibition
or as a reference in an assay to compare its known activity to a
compound with an unknown activity. When developing new assays or
protocols, compounds according to the present invention could be
used to test their effectiveness. Specifically, such compounds may
be provided in a commercial kit, for example, for use in
pharmaceutical research involving the aforementioned diseases. The
compounds of the instant invention are also useful for the
evaluation of putative specific modulators of the chemokine
receptors. In addition, one could utilize compounds of this
invention to examine the specificity of G protein coupled receptors
that are not thought to be chemokine receptors, either by serving
as examples of compounds which do not bind or as structural
variants of compounds active on these receptors which may help
define specific sites of interaction.
[0837] The compounds of the present invention are used to treat or
prevent disorders selected from rheumatoid arthritis,
osteoarthritis, septic shock, atherosclerosis, aneurism, fever,
cardiovascular effects, haemodynamic shock, sepsis syndrome post
ischemic reperfusion injury, malaria, Crohn's disease, inflammatory
bowel diseases, mycobacterial infection, meningitis, psoriasis,
congestive heart failure, fibrotic diseases, cachexia, graft
rejection, autoimmune diseases, skin inflammatory diseases,
multiple sclerosis, radiation damage, hyperoxic alveolar injury,
HIV, HIV dementia, non-insulin dependent diabetes mellitus, asthma,
allergic rhinitis, atopic dermatitis, idiopathic pulmonary
fibrosis, bullous pemphigoid, helminthic parasitic infections,
allergic colitis, eczema, conjunctivitis, transplantation, familial
eosinophilia, eosinophilic cellulitis, eosinophilic pneumonias,
eosinophilic fasciitis, eosinophilic gastroenteritis, drug induced
eosinophilia, cystic fibrosis, Churg-Strauss syndrome, lymphoma,
Hodgkin's disease, colonic carcinoma, Felty's syndrome,
sarcoidosis, uveitis, Alzheimer, Glomerulonephritis, and systemic
lupus erythematosus.
[0838] In another aspect, the compounds are used to treat or
prevent inflammatory disorders selected from rheumatoid arthritis,
osteoarthritis, atherosclerosis, aneurism, fever, cardiovascular
effects, Crohn's disease, inflammatory bowel diseases, psoriasis,
congestive heart failure, multiple sclerosis, autoimmune diseases,
skin inflammatory diseases.
[0839] In another aspect, the compounds are used to treat or
prevent inflammatory disorders selected from rheumatoid arthritis,
osteoarthritis, atherosclerosis, Crohn's disease, inflammatory
bowel diseases, and multiple sclerosis.
[0840] Combined therapy to prevent and treat inflammatory,
infectious and immunoregulatory disorders and diseases, including
asthma and allergic diseases, as well as autoimmune pathologies
such as rheumatoid arthritis and atherosclerosis, and those
pathologies noted above is illustrated by the combination of the
compounds of this invention and other compounds which are known for
such utilities. For example, in the treatment or prevention of
inflammation, the present compounds may be used in conjunction with
an anti-inflammatory or analgesic agent such as an opiate agonist,
a lipoxygenase inhibitor, a cyclooxygenase-2 inhibitor, an
interleukin inhibitor, such as an interleukin-1 inhibitor, a tumor
necrosis factor inhibitor, an NMDA antagonist, an inhibitor or
nitric oxide or an inhibitor of the synthesis of nitric oxide, a
non-steroidal anti-inflammatory agent, a phosphodiesterase
inhibitor, or a cytokine-suppressing anti-inflammatory agent, for
example with a compound such as acetaminophen, aspirin, codeine,
fentaynl, ibuprofen, indomethacin, ketorolac, morphine, naproxen,
phenacetin, piroxicam, a steroidal analgesic, sufentanyl,
sunlindac, interferon alpha and the like. Similarly, the instant
compounds may be administered with a pain reliever; a potentiator
such as caffeine, an H2-antagonist, simethicone, aluminum or
magnesium hydroxide; a decongestant such as phenylephrine,
phenylpropanolamine, pseudophedrine, oxymetazoline, ephinephrine,
naphazoline, xylometazoline, propylhexedrine, or
levodesoxy-ephedrine; and antitussive such as codeine, hydrocodone,
caramiphen, carbetapentane, or dextramethorphan; a diuretic; and a
sedating or non-sedating antihistamine. Likewise, compounds of the
present invention may be used in combination with other drugs that
are used in the treatment/prevention/suppression or amelioration of
the diseases or conditions for which compound of the present
invention are useful. Such other drugs may be administered, by a
route and in an amount commonly used therefore, contemporaneously
or sequentially with a compound of the present invention. When a
compound of the present invention is used contemporaneously with
one or more other drugs, a pharmaceutical composition containing
such other drugs in addition to the compound of the present
invention may be used. Accordingly, the pharmaceutical compositions
of the present invention include those that also contain one or
more other active ingredients, in addition to a compound of the
present invention.
[0841] Examples of other active ingredients that may be combined
with a compound of the present invention, either administered
separately or in the same pharmaceutical compositions, include, but
are not limited to: (a) integrin antagonists such as those for
selectins, ICAMs and VLA-4; (b) steroids such as beclomethasone,
methylprednisolone, betamethasone, prednisone, dexamethasone, and
hydrocortisone; (c) immunosuppressants such as cyclosporin,
tacrolimus, rapamycin and other FK-506 type immunosuppressants; (d)
antihistamines (H1-histamine antagonists) such as bromopheniramine,
chlorpheniramine, dexchlorpheniramine, triprolidine, clemastine,
diphenhydramine, diphenylpyraline, tripelennamine, hydroxyzine,
methdilazine, promethazine, trimeprazine, azatadine,
cyproheptadine, antazoline, pheniramine pyrilamine, astemizole,
terfenadine, loratadine, cetirizine, fexofenadine,
descarboethoxyloratadine, and the like; (e) non-steroidal
anti-asthmatics such as b2-agonists (terbutaline, metaproterenol,
fenoterol, isoetharine, albuterol, bitolterol, and pirbuterol),
theophylline, cromolyn sodium, atropine, ipratropium bromide,
leukotriene antagonists (zafirlukast, montelukast, pranlukast,
iralukast, pobilukast, SKB-102,203), leukotriene biosynthesis
inhibitors (zileuton, BAY-1005); (f) non-steroidal antiinflammatory
agents (NSAIDs) such as propionic acid derivatives (alminoprofen,
benxaprofen, bucloxic acid, carprofen, fenbufen, fenoprofen,
fluprofen, flurbiprofen, ibuprofen, indoprofen, ketoprofen,
miroprofen, naproxen, oxaprozin, pirprofen, pranoprofen, suprofen,
tiaprofenic acid, and tioxaprofen), acetic acid derivatives
(indomethacin, acemetacin, alclofenac, clidanac, diclofenac,
fenclofenac, fenclozic acid, fentiazac, furofenac, ibufenac,
isoxepac, oxpinac, sulindac, tiopinac, tolmetin, zidometacin, and
zomepirac), fenamic acid derivatives (flufenamic acid, meclofenamic
acid, mefenamic acid, niflumic acid and tolfenamic acid),
biphenylcarboxylic acid derivatives (diflunisal and flufenisal),
oxicams (isoxicam, piroxicam, sudoxicam and tenoxican), salicylates
(acetyl salicylic acid, sulfasalazine) and the pyrazolones
(apazone, bezpiperylon, feprazone, mofebutazone, oxyphenbutazone,
phenylbutazone); (g) cyclooxygenase-2 (COX-2) inhibitors; (h)
inhibitors of phosphodiesterase type IV (PDE-IV); (I) other
antagonists of the chemokine receptors; (j) cholesterol lowering
agents such as HMG-COA reductase inhibitors (lovastatin,
simvastatin and pravastatin, fluvastatin, atorvsatatin, and other
statins), sequestrants (cholestyramine and colestipol), nicotonic
acid, fenofibric acid derivatives (gemfibrozil, clofibrat,
fenofibrate and benzafibrate), and probucol; (k) anti-diabetic
agents such as insulin, sulfonylureas, biguanides (metformin),
a-glucosidase inhibitors (acarbose) and glitazones (troglitazone ad
pioglitazone); (l) preparations of interferons (interferon
alpha-2a, interferon-2B, interferon alpha-N3, interferon beta-1a,
interferon beta-1b, interferon gamma-1b); (m) antiviral compounds
such as efavirenz, nevirapine, indinavir, ganciclovir, lamivudine,
famciclovir, and zalcitabine; (o) other compound such as
5-aminosalicylic acid an prodrugs thereof, antimetabolites such as
azathioprine and 6-mercaptopurine, and cytotoxic cancer
chemotherapeutic agents. The weight ratio of the compound of the
present invention to the second active ingredient may be varied and
will depend upon the effective doses of each ingredient.
[0842] Generally, an effective dose of each will be used. Thus, for
example, when a compound of the present invention is combined with
an NSAID the weight ratio of the compound of the present invention
to the NSAID will generally range from about 1000:1 to about
1:1000, or alternatively from about 200:1 to about 1:200.
Combinations of a compound of the present invention and other
active ingredients will generally also be within the aforementioned
range, but in each case, an effective dose of each active
ingredient should be used.
[0843] The compounds are administered to a mammal in a
therapeutically effective amount. By "therapeutically effective
amount" it is meant an amount of a compound of Formula I that, when
administered alone or in combination with an additional therapeutic
agent to a mammal, is effective to prevent or ameliorate the
thromboembolic disease condition or the progression of the
disease.
Dosage and Formulation
[0844] The compounds of this invention can be administered in such
oral dosage forms as tablets, capsules (each of which includes
sustained release or timed release formulations), pills, powders,
granules, elixirs, tinctures, suspensions, syrups, and emulsions.
They may also be administered in intravenous (bolus or infusion),
intraperitoneal, subcutaneous, or intramuscular form, all using
dosage forms well known to those of ordinary skill in the
pharmaceutical arts. They can be administered alone, but generally
will be administered with a pharmaceutical carrier selected on the
basis of the chosen route of administration and standard
pharmaceutical practice.
[0845] The dosage regimen for the compounds of the present
invention will, of course, vary depending upon known factors, such
as the pharmacodynamic characteristics of the particular agent and
its mode and route of administration; the species, age, sex,
health, medical condition, and weight of the recipient; the nature
and extent of the symptoms; the kind of concurrent treatment; the
frequency of treatment; the route of administration, the renal and
hepatic function of the patient, and the effect desired. A
physician or veterinarian can determine and prescribe the effective
amount of the drug required to prevent, counter, or arrest the
progress of the thromboembolic disorder.
[0846] By way of general guidance, the daily oral dosage of each
active ingredient, when used for the indicated effects, will range
between about 0.001 to 1000 mg/kg of body weight, or between about
0.01 to 100 mg/kg of body weight per day, or alternatively, between
about 1.0 to 20 mg/kg/day. Intravenously, the doses will range from
about 1 to about 10 mg/kg/minute during a constant rate infusion.
Compounds of this invention may be administered in a single daily
dose, or the total daily dosage may be administered in divided
doses of two, three, or four times daily.
[0847] Compounds of this invention can be administered in
intranasal form via topical use of suitable intranasal vehicles, or
via transdermal routes, using transdermal skin patches. When
administered in the form of a transdermal delivery system, the
dosage administration will, of course, be continuous rather than
intermittent throughout the dosage regimen.
[0848] The compounds are typically administered in admixture with
suitable pharmaceutical diluents, excipients, or carriers
(collectively referred to herein as pharmaceutical carriers)
suitably selected with respect to the intended form of
administration, that is, oral tablets, capsules, elixirs, syrups
and the like, and consistent with conventional pharmaceutical
practices.
[0849] For instance, for oral administration in the form of a
tablet or capsule, the active drug component can be combined with
an oral, non-toxic, pharmaceutically acceptable, inert carrier such
as lactose, starch, sucrose, glucose, methyl cellulose, magnesium
stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol
and the like; for oral administration in liquid form, the oral drug
components can be combined with any oral, non-toxic,
pharmaceutically acceptable inert carrier such as ethanol,
glycerol, water, and the like. Moreover, when desired or necessary,
suitable binders, lubricants, disintegrating agents, and coloring
agents can also be incorporated into the mixture. Suitable binders
include starch, gelatin, natural sugars such as glucose or
beta-lactose, corn sweeteners, natural and synthetic gums such as
acacia, tragacanth, or sodium alginate, carboxymethylcellulose,
polyethylene glycol, waxes, and the like. Lubricants used in these
dosage forms include sodium oleate, sodium stearate, magnesium
stearate, sodium benzoate, sodium acetate, sodium chloride, and the
like. Disintegrators include, without limitation, starch, methyl
cellulose, agar, bentonite, xanthan gum, and the like.
[0850] The compounds of the present invention can also be
administered in the form of liposome delivery systems, such as
small unilamellar vesicles, large unilamellar vesicles, and
multilamellar vesicles. Liposomes can be formed from a variety of
phospholipids, such as cholesterol, stearylamine, or
phosphatidylcholines.
[0851] Compounds of the present invention may also be coupled with
soluble polymers as targetable drug carriers. Such polymers can
include polyvinylpyrrolidone, pyran copolymer,
polyhydroxypropylmethacrylamide-phenol,
polyhydroxyethylaspartamidephenol, or polyethyleneoxide-polylysine
substituted with palmitoyl residues. Furthermore, the compounds of
the present invention may be coupled to a class of biodegradable
polymers useful in achieving controlled release of a drug, for
example, polylactic acid, polyglycolic acid, copolymers of
polylactic and polyglycolic acid, polyepsilon caprolactone,
polyhydroxy butyric acid, polyorthoesters, polyacetals,
polydihydropyrans, polycyanoacylates, and crosslinked or
amphipathic block copolymers of hydrogels. Dosage forms
(pharmaceutical compositions) suitable for administration may
contain from about 1 milligram to about 100 milligrams of active
ingredient per dosage unit. In these pharmaceutical compositions
the active ingredient will ordinarily be present in an amount of
about 0.5-95% by weight based on the total weight of the
composition.
[0852] Gelatin capsules may contain the active ingredient and
powdered carriers, such as lactose, starch, cellulose derivatives,
magnesium stearate, stearic acid, and the like. Similar diluents
can be used to make compressed tablets. Both tablets and capsules
can be manufactured as sustained release products to provide for
continuous release of medication over a period of hours. Compressed
tablets can be sugar coated or film coated to mask any unpleasant
taste and protect the tablet from the atmosphere, or enteric coated
for selective disintegration in the gastrointestinal tract. Liquid
dosage forms for oral administration can contain coloring and
flavoring to increase patient acceptance. In general, water, a
suitable oil, saline, aqueous dextrose (glucose), and related sugar
solutions and glycols such as propylene glycol or polyethylene
glycols are suitable carriers for parenteral solutions. Solutions
for parenteral administration may contain a water soluble salt of
the active ingredient, suitable stabilizing agents, and if
necessary, buffer substances. Antioxidizing agents such as sodium
bisulfite, sodium sulfite, or ascorbic acid, either alone or
combined, are suitable stabilizing agents. Also used are citric
acid and its salts and sodium EDTA. In addition, parenteral
solutions can contain preservatives, such as benzalkonium chloride,
methyl or propyl-paraben, and chlorobutanol.
[0853] Suitable pharmaceutical carriers are described in
Remington's Pharmaceutical Sciences, Mack Publishing Company, a
standard reference text in this field. Representative useful
pharmaceutical dosage-forms for administration of the compounds of
this invention can be illustrated as follows:
[0854] Capsules
[0855] A large number of unit capsules can be prepared by filling
standard two-piece hard gelatin capsules each with 100 milligrams
of powdered active ingredient, 150 milligrams of lactose, 50
milligrams of cellulose, and 6 milligrams magnesium stearate.
Soft Gelatin Capsules
[0856] A mixture of active ingredient in a digestible oil such as
soybean oil, cottonseed oil or olive oil may be prepared and
injected by means of a positive displacement pump into gelatin to
form soft gelatin capsules containing 100 milligrams of the active
ingredient. The capsules should be washed and dried.
Tablets
[0857] Tablets may be prepared by conventional procedures so that
the dosage unit is 100 milligrams of active ingredient, 0.2
milligrams of colloidal silicon dioxide, 5 milligrams of magnesium
stearate, 275 milligrams of microcrystalline cellulose, 11
milligrams of starch and 98.8 milligrams of lactose. Appropriate
coatings may be applied to increase palatability or delay
absorption.
Injectable
[0858] A parenteral composition suitable for administration by
injection may be prepared by stirring 1.5% by weight of active
ingredient in 10% by volume propylene glycol and water. The
solution should be made isotonic with sodium chloride and
sterilized.
Suspension
[0859] An aqueous suspension can be prepared for oral
administration so that each 5 mL contain 100 mg of finely divided
active ingredient, 200 mg of sodium carboxymethyl cellulose, 5 mg
of sodium benzoate, 1.0 g of sorbitol solution, U.S.P., and 0.025
mL of vanillin. Where the compounds of this invention are combined
with other anticoagulant agents, for example, a daily dosage may be
about 0.1 to 100 milligrams of the compound of Formula I and about
1 to 7.5 milligrams of the second anticoagulant, per kilogram of
patient body weight. For a tablet dosage form, the compounds of
this invention generally may be present in an amount of about 5 to
10 milligrams per dosage unit, and the second anti-coagulant in an
amount of about 1 to 5 milligrams per dosage unit. Where two or
more of the foregoing second therapeutic agents are administered
with the compound of Formula I, generally the amount of each
component in a typical daily dosage and typical dosage form may be
reduced relative to the usual dosage of the agent when administered
alone, in view of the additive or synergistic effect of the
therapeutic agents when administered in combination. Particularly
when provided as a single dosage unit, the potential exists for a
chemical interaction between the combined active ingredients. For
this reason, when the compound of Formula I and a second
therapeutic agent are combined in a single dosage unit they are
formulated such that although the active ingredients are combined
in a single dosage unit, the physical contact between the active
ingredients is minimized (that is, reduced). For example, one
active ingredient may be enteric coated. By enteric coating one of
the active ingredients, it is possible not only to minimize the
contact between the combined active ingredients, but also, it is
possible to control the release of one of these components in the
gastrointestinal tract such that one of these components is not
released in the stomach but rather is released in the intestines.
One of the active ingredients may also be coated with a material
which effects a sustained-release throughout the gastrointestinal
tract and also serves to minimize physical contact between the
combined active ingredients. Furthermore, the sustained-released
component can be additionally enteric coated such that the release
of this component occurs only in the intestine. Still another
approach would involve the formulation of a combination product in
which the one component is coated with a sustained and/or enteric
release polymer, and the other component is also coated with a
polymer such as a low viscosity grade of hydroxypropyl
methylcellulose (HPMC) or other appropriate materials as known in
the art, in order to further separate the active components. The
polymer coating serves to form an additional barrier to interaction
with the other component.
[0860] These as well as other ways of minimizing contact between
the components of combination products of the present invention,
whether administered in a single dosage form or administered in
separate forms but at the same time by the same manner, will be
readily apparent to those skilled in the art, once armed with the
present disclosure.
[0861] Obviously, numerous modifications and variations of the
present invention are possible in light of the above teachings. It
is therefore to be understood that within the scope of the appended
claims, the invention may be practiced otherwise that as
specifically described herein.
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