U.S. patent application number 14/994346 was filed with the patent office on 2016-05-05 for novel substituted pyrazolo-piperazines as casein kinase 1 d/e inhibitors.
The applicant listed for this patent is BRISTOL-MYERS SQUIBB COMPANY. Invention is credited to Erika M. V. Araujo, Subba Reddy Bandreddy, Rajesh Onkardas Bora, Chetan Padmakar Darne, Bireshwar Dasgupta, Shilpa Maheshwarappa Holehatti, Sakthi Kumaran Janakiraman, Selvakumar Kumaravel, Peiying Liu, Mallikarjuna Rao Mettu, Dibakar Mullick, Jalathi Surendran Nair, Bradley C. Pearce, Nagalakshmi Pulicharla, Chandrasekhar Reddy Rachamreddy, Ramesh Kumar Sistla, Arul Mozhi Subbiah Karuppiah, Upender Velaparthi, Mark D. Wittman.
Application Number | 20160122358 14/994346 |
Document ID | / |
Family ID | 51952052 |
Filed Date | 2016-05-05 |
United States Patent
Application |
20160122358 |
Kind Code |
A1 |
Velaparthi; Upender ; et
al. |
May 5, 2016 |
NOVEL SUBSTITUTED PYRAZOLO-PIPERAZINES AS CASEIN KINASE 1 D/E
INHIBITORS
Abstract
The invention provides compounds of Formula (I): ##STR00001##
and pharmaceutically acceptable salts thereof. The compounds of
Formula (I) inhibit protein kinase activity thereby making them
useful as anticancer agents.
Inventors: |
Velaparthi; Upender;
(Cheshire, CT) ; Darne; Chetan Padmakar; (Orange,
CT) ; Liu; Peiying; (Madison, CT) ; Wittman;
Mark D.; (Wallingford, CT) ; Pearce; Bradley C.;
(East Hampton, CT) ; Araujo; Erika M. V.;
(Woodbridge, CT) ; Dasgupta; Bireshwar; (East
Hampton, CT) ; Nair; Jalathi Surendran; (Bangalore,
IN) ; Janakiraman; Sakthi Kumaran; (Bangalore,
IN) ; Rachamreddy; Chandrasekhar Reddy; (Bangalore,
IN) ; Mettu; Mallikarjuna Rao; (Bangalore, IN)
; Subbiah Karuppiah; Arul Mozhi; (Bangalore, IN) ;
Bandreddy; Subba Reddy; (Bangalore, IN) ; Pulicharla;
Nagalakshmi; (Bangalore, IN) ; Bora; Rajesh
Onkardas; (Bangalore, IN) ; Holehatti; Shilpa
Maheshwarappa; (Davanagere District, IN) ; Kumaravel;
Selvakumar; (Bangalore, IN) ; Mullick; Dibakar;
(Howrah District, IN) ; Sistla; Ramesh Kumar;
(Bangalore, IN) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
BRISTOL-MYERS SQUIBB COMPANY |
Princeton |
NJ |
US |
|
|
Family ID: |
51952052 |
Appl. No.: |
14/994346 |
Filed: |
January 13, 2016 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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14541343 |
Nov 14, 2014 |
9273058 |
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14994346 |
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61904116 |
Nov 14, 2013 |
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Current U.S.
Class: |
514/210.18 ;
514/210.21; 514/233.2; 514/249; 514/250; 544/117; 544/230; 544/231;
544/238; 544/295; 544/346; 544/350 |
Current CPC
Class: |
C07D 519/00 20130101;
C07D 487/10 20130101; A61P 19/02 20180101; A61P 35/02 20180101;
C07D 491/147 20130101; A61P 35/00 20180101; C07D 487/04 20130101;
C07D 491/20 20130101; A61P 43/00 20180101; C07D 487/20 20130101;
A61P 25/00 20180101 |
International
Class: |
C07D 487/04 20060101
C07D487/04; C07D 487/20 20060101 C07D487/20; C07D 491/20 20060101
C07D491/20; C07D 487/10 20060101 C07D487/10; C07D 491/147 20060101
C07D491/147 |
Claims
1. A compound according to Formula (I): ##STR01013## or a
pharmaceutically acceptable salt thereof, wherein: X is
independently selected from 0 and NH; R.sub.1 is independently
selected from carbocyclyl substituted with 1-5 R.sub.5, and
heterocyclyl comprising carbon atoms and 1 to 3 heteroatoms
selected from N, NR.sub.4, O, S, and substituted with 1-5 R.sub.5;
R.sub.2 is independently selected from (i) alkyl optionally
substituted with F, Cl, Br, OR.sub.b, CN, NR.sub.aR.sub.a,
--C(.dbd.O)NR.sub.aR.sub.a, C.sub.2-6 alkenyl substituted with 0-5
R.sub.e, C.sub.2-6 alkynyl substituted with 0-5 R.sub.e,
carbocyclyl substituted with 1-8 R.sub.7, and heterocyclyl
comprising carbon atoms and 1 to 4 heteroatoms selected from N,
NR.sub.6, O, S, and substituted with 1-8 R.sub.7, (ii) cycloalkyl
substituted with 1-8 R.sub.7, and (iii) cycloheteroalkyl
substituted with 1-8 R.sub.7; R.sub.3a, R.sub.3b, R.sub.3c,
R.sub.3d, R.sub.3e and R.sub.3f are independently selected from H,
CN, C.sub.1-4alkyl substituted with 1-3 R.sub.8,
--C(.dbd.O)OR.sub.b, --C(.dbd.O)NR.sub.aR.sub.a,
--C(.dbd.O)R.sub.b, --NR.sub.aC(.dbd.O)R.sub.b,
--NR.sub.aC(.dbd.O)OR.sub.b, --(CH.sub.2).sub.r-carbocyclyl
substituted with 1-3 R.sub.8, and --(CH.sub.2).sub.r-heterocyclyl
substituted with 1-3 R.sub.8; alternatively, R.sub.3a and R.sub.3b,
or R.sub.3c and R.sub.3d, or R.sub.3e and R.sub.3f, together with
the carbon atom to which they are both attached form a spiral
carbocyclic or heterocyclic ring comprising carbon atoms and 1 to 4
heteroatoms selected from N, O, S, each substituted with 1-5
R.sub.8; alternatively, R.sub.3a and R.sub.3c or R.sub.3b and
R.sub.3d together form a heterocyclic ring comprising carbon atoms
and 1 to 4 heteroatoms selected from N, O, S, and substituted with
1-5 R.sub.8; R.sub.4 is independently selected from H, C.sub.1-4
alkyl substituted with 0-3 R.sub.e, --(CH.sub.2).sub.rCN,
--(CH.sub.2).sub.rOR.sub.b, (CH.sub.2).sub.rS(O).sub.pR.sub.c,
--(CH.sub.2).sub.rC(.dbd.O)R.sub.b,
--(CH.sub.2).sub.rNR.sub.aR.sub.a,
--(CH.sub.2).sub.rC(.dbd.O)NR.sub.aR.sub.a,
--(CH.sub.2).sub.rNR.sub.aC(.dbd.O)R.sub.b,
--(CH.sub.2).sub.rNR.sub.aC(.dbd.O)OR.sub.b,
--(CH.sub.2).sub.rOC(.dbd.O)NR.sub.aR.sub.a,
--(CH.sub.2).sub.rNR.sub.aC(.dbd.O)NR.sub.aR.sub.a,
--(CH.sub.2).sub.rC(.dbd.O)OR.sub.b,
--(CH.sub.2).sub.rS(O).sub.2NR.sub.aR.sub.a,
--(CH.sub.2).sub.rNR.sub.aS(O).sub.2NR.sub.aR.sub.a,
--(CH.sub.2).sub.rNR.sub.aS(O).sub.2R.sub.c,
(CH.sub.2).sub.r-carbocyclyl substituted with 0-3 R.sub.e, and
--(CH.sub.2).sub.r-heterocyclyl substituted with 0-3 R.sub.e;
R.sub.5, at each occurrence, is independently selected from H,
C.sub.1-4 alkyl substituted with 0-3 R.sub.e, F, Cl, Br, .dbd.O,
CN, NO.sub.2, --OR.sub.b, --(CH.sub.2).sub.rCN,
--(CH.sub.2).sub.rOR.sub.b, (CH.sub.2).sub.rS(O).sub.pR.sub.c,
--(CH.sub.2).sub.rC(.dbd.O)R.sub.b,
--(CH.sub.2).sub.rNR.sub.aR.sub.a,
--(CH.sub.2).sub.rC(.dbd.O)NR.sub.aR.sub.a,
--(CH.sub.2).sub.rNR.sub.aC(.dbd.O)R.sub.b,
--(CH.sub.2).sub.rNR.sub.aC(.dbd.O)OR.sub.b,
--(CH.sub.2).sub.rOC(.dbd.O)NR.sub.aR.sub.a,
--(CH.sub.2).sub.rNR.sub.aC(.dbd.O)NR.sub.aR.sub.a,
--(CH.sub.2).sub.rC(.dbd.O)OR.sub.b,
--(CH.sub.2).sub.rS(O).sub.2NR.sub.aR.sub.a,
--(CH.sub.2).sub.rNR.sub.aS(O).sub.2NR.sub.aR.sub.a,
--(CH.sub.2).sub.rNR.sub.aS(O).sub.2R.sub.c,
(CH.sub.2).sub.r-carbocyclyl substituted with 0-3 R.sub.e, and
--(CH.sub.2).sub.r-heterocyclyl substituted with 0-3 R.sub.e;
R.sub.6 is independently selected from H, --C(.dbd.O)R.sub.b,
--CO(.dbd.O)R.sub.b, --S(O).sub.pR.sub.c, C.sub.1-6 alkyl
substituted with 0-5 R.sub.e,
--(CH.sub.2).sub.r--C.sub.3-6carbocyclyl substituted with 0-5
R.sub.e, and --(CH.sub.2).sub.r-heterocyclyl substituted with 0-5
R.sub.e; R.sub.7, at each occurrence, is independently selected
from H, F, Cl, Br, .dbd.O, --(CR.sub.dR.sub.d).sub.rCN, NO.sub.2,
--(CR.sub.dR.sub.d).sub.rOR.sub.b, --S(O).sub.pR.sub.c,
--C(.dbd.O)R.sub.b, --(CR.sub.dR.sub.d).sub.rNR.sub.aR.sub.a,
--(CR.sub.dR.sub.d).sub.rC(.dbd.O)NR.sub.aR.sub.a,
--NR.sub.aC(.dbd.O)R.sub.b, --NR.sub.aC(.dbd.O)OR.sub.b,
--OC(.dbd.O)NR.sub.aR.sub.a, --NR.sub.aC(.dbd.O)NR.sub.aR.sub.a,
--(CR.sub.dR.sub.d).sub.rC(.dbd.O)OR.sub.b,
--S(O).sub.2NR.sub.aR.sub.a, --NR.sub.aS(O).sub.2NR.sub.aR.sub.a,
--NR.sub.aS(O).sub.2R.sub.c, C.sub.1-6 alkyl substituted with 0-5
R.sub.e, --(CR.sub.dR.sub.d).sub.r--C.sub.3-6carbocyclyl
substituted with 0-5 R.sub.e, and
--(CR.sub.dR.sub.d).sub.r-heterocyclyl substituted with 0-5
R.sub.e; R.sub.8, at each occurrence, is independently selected
from H, F, Cl, Br, CN, C.sub.1-6 alkyl substituted with 0-5
R.sub.e, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
--(CH.sub.2).sub.r--C.sub.3-6 cycloalkyl substituted with 0-5
R.sub.e, --(CH.sub.2).sub.r-aryl substituted with 0-5 R.sub.e,
--(CH.sub.2).sub.r-heterocyclyl substituted with 0-5 R.sub.e,
CO.sub.2H, --(CH.sub.2).sub.rOR.sub.b, and
--(CH.sub.2).sub.rNR.sub.aR.sub.a; R.sub.a, at each occurrence, is
independently selected from H, CN, C.sub.1-6 alkyl substituted with
0-5 R.sub.e, C.sub.2-6 alkenyl substituted with 0-5 R.sub.e,
C.sub.2-6 alkynyl substituted with 0-5 R.sub.e,
--(CH.sub.2).sub.r--C.sub.3-10carbocyclyl substituted with 0-5
R.sub.e, and --(CH.sub.2).sub.r-heterocyclyl substituted with 0-5
R.sub.e; or R.sub.a and R.sub.a together with the nitrogen atom to
which they are both attached form a heterocyclic ring substituted
with 0-5 R.sub.e; R.sub.b, at each occurrence, is independently
selected from H, C.sub.1-6 alkyl substituted with 0-5 R.sub.e,
C.sub.2-6 alkenyl substituted with 0-5 R.sub.e, C.sub.2-6 alkynyl
substituted with 0-5 R.sub.e,
--(CH.sub.2).sub.r--C.sub.3-10carbocyclyl substituted with 0-5
R.sub.e, and --(CH.sub.2).sub.r-heterocyclyl substituted with 0-5
R.sub.e; R.sub.c, at each occurrence, is independently selected
from C.sub.1-6 alkyl substituted with 0-5 R.sub.e, C.sub.2-6alkenyl
substituted with 0-5 R.sub.e, C.sub.2-6alkynyl substituted with 0-5
R.sub.e, C.sub.3-6carbocyclyl, and heterocyclyl; R.sub.d, at each
occurrence, is independently selected from H and C.sub.1-4alkyl
substituted with 0-5 R.sub.e; R.sub.e, at each occurrence, is
independently selected from F, Cl, Br, CN, NO.sub.2, .dbd.O,
C.sub.1-6 alkyl substituted with 0-5 R.sub.f, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, --(CH.sub.2).sub.r--C.sub.3-6 cycloalkyl,
--(CH.sub.2).sub.r-aryl, --(CH.sub.2).sub.r-heterocyclyl,
CO.sub.2H, --(CH.sub.2).sub.rOR.sub.f, SR.sub.f, and
--(CH.sub.2).sub.rNR.sub.fR.sub.f; R.sub.f, at each occurrence, is
independently selected from H, C.sub.1-5 alkyl optionally
substituted with F, Cl, Br, C.sub.3-6 cycloalkyl, and phenyl, or
R.sub.f and R.sub.f together with the nitrogen atom to which they
are both attached form a heterocyclic ring optionally substituted
with C.sub.1-4alkyl; p, at each occurrence, is independently
selected from zero, 1, and 2; and r, at each occurrence, is
independently selected from zero, 1, 2, 3, and 4.
2. The compound according to claim 1, having Formula (II):
##STR01014## or a pharmaceutically acceptable salt thereof,
wherein: R.sub.1 is independently selected from aryl substituted
with 1-4 R.sub.5, and 5- to 12-membered heteroaryl comprising
carbon atoms and 1 to 3 heteroatoms selected from N, NR.sub.4, O,
S, and substituted with 1-4 R.sub.5; R.sub.2 is independently
selected from (i) alkyl optionally substituted with F, Cl, Br,
OR.sub.b, CN, NR.sub.aR.sub.a, --C(.dbd.O)NR.sub.aR.sub.a,
C.sub.2-6 alkenyl substituted with 0-5 R.sub.e, C.sub.2-6 alkynyl
substituted with 0-5 R.sub.e, carbocyclyl substituted with 1-8
R.sub.7, and heterocyclyl comprising carbon atoms and 1 to 4
heteroatoms selected from N, NR.sub.6, O, S, and substituted with
1-8 R.sub.7, (ii) cycloalkyl substituted with 1-8 R.sub.7, and
(iii) cycloheteroalkyl substituted with 1-8 R.sub.7; R.sub.3a,
R.sub.3b, R.sub.3c, and R.sub.3d are independently selected from H,
CN, C.sub.1-4alkyl substituted with 1-3 R.sub.8,
--C(.dbd.O)OR.sub.b, --C(.dbd.O)NR.sub.aR.sub.a,
--C(.dbd.O)R.sub.b, --NR.sub.aC(.dbd.O)R.sub.b,
--NR.sub.aC(.dbd.O)OR.sub.b, --(CH.sub.2).sub.r-carbocyclyl
substituted with 1-3 R.sub.8, and --(CH.sub.2).sub.r-heterocyclyl
substituted with 1-3 R.sub.8; alternatively, R.sub.3a and R.sub.3b,
or R.sub.3c and R.sub.3d, or R.sub.3e and R.sub.3f, together with
the carbon atom to which they are both attached form a spiral
carbocyclic or heterocyclic ring comprising carbon atoms and 1 to 4
heteroatoms selected from N, O, S, each substituted with 0-5
R.sub.e; alternatively, R.sub.3a and R.sub.3c or R.sub.3b and
R.sub.3d together form a heterocyclic ring comprising carbon atoms
and 1 to 4 heteroatoms selected from N, O, S, and substituted with
0-5 R.sub.e; R.sub.4 is independently selected from H and C.sub.1-4
alkyl substituted with 0-3 R.sub.e; R.sub.5, at each occurrence, is
independently selected from H, C.sub.1-4 alkyl substituted with 0-3
R.sub.e, F, Cl, Br, .dbd.O, CN, NO.sub.2, --OR.sub.b,
--(CH.sub.2).sub.rCN, --(CH.sub.2).sub.rOR.sub.b,
(CH.sub.2).sub.rS(O).sub.pR.sub.c,
--(CH.sub.2).sub.rC(.dbd.O)R.sub.b,
--(CH.sub.2).sub.rNR.sub.aR.sub.a,
--(CH.sub.2).sub.rC(.dbd.O)NR.sub.aR.sub.a,
--(CH.sub.2).sub.rNR.sub.aC(.dbd.O)R.sub.b,
--(CH.sub.2).sub.rNR.sub.aC(.dbd.O)OR.sub.b,
--(CH.sub.2).sub.rOC(.dbd.O)NR.sub.aR.sub.a,
--(CH.sub.2).sub.rNR.sub.aC(.dbd.O)NR.sub.aR.sub.a,
--(CH.sub.2).sub.rC(.dbd.O)OR.sub.b,
--(CH.sub.2).sub.rS(O).sub.2NR.sub.aR.sub.a,
--(CH.sub.2).sub.rNR.sub.aS(O).sub.2NR.sub.aR.sub.a,
--(CH.sub.2).sub.rNR.sub.aS(O).sub.2R.sub.c,
(CH.sub.2).sub.r-carbocyclyl substituted with 0-3 R.sub.e, and
--(CH.sub.2).sub.r-heterocyclyl substituted with 0-3 R.sub.e;
R.sub.6 is independently selected from H, --C(.dbd.O)R.sub.b,
--CO(.dbd.O)R.sub.b, --S(O).sub.pR.sub.c, C.sub.1-6 alkyl
substituted with 0-5 R.sub.e,
--(CH.sub.2).sub.r--C.sub.3-6carbocyclyl substituted with 0-5
R.sub.e, and --(CH.sub.2).sub.r-heterocyclyl substituted with 0-5
R.sub.e; R.sub.7, at each occurrence, is independently selected
from H, F, Cl, Br, .dbd.O, --(CR.sub.dR.sub.d).sub.rCN, NO.sub.2,
--(CR.sub.dR.sub.d).sub.rOR.sub.b, --S(O).sub.pR.sub.c,
--C(.dbd.O)R.sub.b, --(CR.sub.dR.sub.d).sub.rNR.sub.aR.sub.a,
--(CR.sub.dR.sub.d).sub.rC(.dbd.O)NR.sub.aR.sub.a,
--NR.sub.aC(.dbd.O)R.sub.b, --NR.sub.aC(.dbd.O)OR.sub.b,
--OC(.dbd.O)NR.sub.aR.sub.a, --NR.sub.aC(.dbd.O)NR.sub.aR.sub.a,
--(CR.sub.dR.sub.d).sub.rC(.dbd.O)OR.sub.b,
--S(O).sub.2NR.sub.aR.sub.a, --NR.sub.aS(O).sub.2NR.sub.aR.sub.a,
--NR.sub.aS(O).sub.2R.sub.c, C.sub.1-6 alkyl substituted with 0-5
R.sub.e, --(CR.sub.dR.sub.d).sub.r--C.sub.3-6carbocyclyl
substituted with 0-5 R.sub.e, and
--(CR.sub.dR.sub.d).sub.r-heterocyclyl substituted with 0-5
R.sub.e; R.sub.8, at each occurrence, is independently selected
from H, F, Cl, Br, CN, C.sub.1-6 alkyl substituted with 0-5
R.sub.e, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
--(CH.sub.2).sub.r--C.sub.3-6 cycloalkyl substituted with 0-5
R.sub.e, --(CH.sub.2).sub.r-aryl substituted with 0-5 R.sub.e,
--(CH.sub.2).sub.r-heterocyclyl substituted with 0-5 R.sub.e,
CO.sub.2H, --(CH.sub.2).sub.rOR.sub.b, and
--(CH.sub.2).sub.rNR.sub.aR.sub.a; R.sub.a, at each occurrence, is
independently selected from H, CN, C.sub.1-6 alkyl substituted with
0-5 R.sub.e, C.sub.2-6 alkenyl substituted with 0-5 R.sub.e,
C.sub.2-6 alkynyl substituted with 0-5 R.sub.e,
--(CH.sub.2).sub.r--C.sub.3-10carbocyclyl substituted with 0-5
R.sub.e, and --(CH.sub.2).sub.r-heterocyclyl substituted with 0-5
R.sub.e; or R.sub.a and R.sub.a together with the nitrogen atom to
which they are both attached form a heterocyclic ring substituted
with 0-5 R.sub.e; R.sub.b, at each occurrence, is independently
selected from H, C.sub.1-6 alkyl substituted with 0-5 R.sub.e,
C.sub.2-6 alkenyl substituted with 0-5 R.sub.e, C.sub.2-6 alkynyl
substituted with 0-5 R.sub.e,
--(CH.sub.2).sub.r--C.sub.3-10carbocyclyl substituted with 0-5
R.sub.e, and --(CH.sub.2).sub.r-heterocyclyl substituted with 0-5
R.sub.e; R.sub.c, at each occurrence, is independently selected
from C.sub.1-6 alkyl substituted with 0-5 R.sub.e, C.sub.2-6alkenyl
substituted with 0-5 R.sub.e, C.sub.2-6alkynyl substituted with 0-5
R.sub.e, C.sub.3-6carbocyclyl, and heterocyclyl; R.sub.d, at each
occurrence, is independently selected from H and C.sub.1-4alkyl
substituted with 0-5 R.sub.e; R.sub.e, at each occurrence, is
independently selected from F, Cl, Br, CN, NO.sub.2, .dbd.O,
C.sub.1-6 alkyl substituted with 0-5 R.sub.f, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, --(CH.sub.2).sub.r--C.sub.3-6 cycloalkyl,
CO.sub.2H, --(CH.sub.2).sub.rOR.sub.f, SR.sub.f, and
--(CH.sub.2).sub.rNR.sub.fR.sub.f; R.sub.f, at each occurrence, is
independently selected from H, C.sub.1-5 alkyl, C.sub.3-6
cycloalkyl, and phenyl, or R.sub.f and R.sub.f together with the
nitrogen atom to which they are both attached form a heterocyclic
ring optionally substituted with C.sub.1-4alkyl; p, at each
occurrence, is independently selected from zero, 1, and 2; and r,
at each occurrence, is independently selected from zero, 1, 2, 3,
and 4.
3. The compound according to claim 2, wherein: R.sub.1 is
independently selected from aryl, pyridyl, pyrimidinyl, pyrazinyl,
pyridazinyl, triazinyl, furyl, thienyl, imidazolyl, thiazolyl,
indolyl, oxazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl,
indazolyl, 1,2,4-thiadiazolyl, isothiazolyl, quinolinyl,
isoquinolinyl, each substituted with 1-4 R.sub.4 and R.sub.5;
R.sub.4, at each occurrence, is independently selected from H and
C.sub.1-4 alkyl substituted with 0-3 R.sub.e; R.sub.5, at each
occurrence, is independently selected from H, C.sub.1-4 alkyl
substituted with 0-3 R.sub.e, F, Cl, Br, .dbd.O, CN, NO.sub.2,
--OR.sub.b, --S(O).sub.pR.sub.c, --CN, --OR.sub.b,
--(CH.sub.2).sub.rC(.dbd.O)R.sub.b,
--(CH.sub.2).sub.rNR.sub.aR.sub.a,
--(CH.sub.2).sub.rC(.dbd.O)NR.sub.aR.sub.a,
--(CH.sub.2).sub.rNHC(.dbd.O)R.sub.b,
--(CH.sub.2).sub.rNHC(.dbd.O)OR.sub.b,
--(CH.sub.2).sub.rOC(.dbd.O)NR.sub.aR.sub.a,
--(CH.sub.2).sub.rNHC(.dbd.O)NR.sub.aR.sub.a,
--(CH.sub.2).sub.rC(.dbd.O)OR.sub.b,
--(CH.sub.2).sub.rS(O).sub.2NR.sub.aR.sub.a,
--(CH.sub.2).sub.rNHS(O).sub.2NR.sub.aR.sub.a,
--(CH.sub.2).sub.rNHS(O).sub.2R.sub.c, (CH.sub.2).sub.r-carbocyclyl
substituted with 0-3 R.sub.e, and --(CH.sub.2).sub.r-heterocyclyl
substituted with 0-3 R.sub.e; R.sub.a, at each occurrence, is
independently selected from H, CN, C.sub.1-6 alkyl substituted with
0-5 R.sub.e, C.sub.2-6 alkenyl substituted with 0-5 R.sub.e,
C.sub.2-6 alkynyl substituted with 0-5 R.sub.e,
--(CH.sub.2).sub.r--C.sub.3-10carbocyclyl substituted with 0-5
R.sub.e, and --(CH.sub.2).sub.r-heterocyclyl substituted with 0-5
R.sub.e; or R.sub.a and R.sub.a together with the nitrogen atom to
which they are both attached form a heterocyclic ring substituted
with 0-5 R.sub.e; R.sub.b, at each occurrence, is independently
selected from H, C.sub.1-6 alkyl substituted with 0-5 R.sub.e,
C.sub.2-6 alkenyl substituted with 0-5 R.sub.e, C.sub.2-6 alkynyl
substituted with 0-5 R.sub.e,
--(CH.sub.2).sub.r--C.sub.3-10carbocyclyl substituted with 0-5
R.sub.e, and --(CH.sub.2).sub.r-heterocyclyl substituted with 0-5
R.sub.e; R.sub.c, at each occurrence, is independently selected
from C.sub.1-6 alkyl substituted with 0-5 R.sub.e, C.sub.2-6alkenyl
substituted with 0-5 R.sub.e, C.sub.2-6alkynyl substituted with 0-5
R.sub.e, C.sub.3-6carbocyclyl, and heterocyclyl; R.sub.e, at each
occurrence, is independently selected from F, Cl, Br, CN, NO.sub.2,
.dbd.O, C.sub.1-6 alkyl substituted with 0-5 R.sub.f, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, --(CH.sub.2).sub.r--C.sub.3-6
cycloalkyl, CO.sub.2H, --(CH.sub.2).sub.rOR.sub.f, SR.sub.f, and
--(CH.sub.2).sub.rNR.sub.fR.sub.f; R.sub.f, at each occurrence, is
independently selected from H, C.sub.1-5 alkyl, C.sub.3-6
cycloalkyl, and phenyl, or R.sub.f and R.sub.f together with the
nitrogen atom to which they are both attached form a heterocyclic
ring optionally substituted with C.sub.1-4alkyl; p, at each
occurrence, is independently selected from zero, 1, and 2; and r,
at each occurrence, is independently selected from zero, 1, 2, 3,
and 4.
4. The compound according to claim 3, wherein: R.sub.1 is
independently selected from ##STR01015## ##STR01016## R.sub.4, at
each occurrence, is independently selected from H, C.sub.1-4 alkyl
substituted with 0-3 R.sub.e; R.sub.5, at each occurrence, is
independently selected from H, C.sub.1-4 alkyl substituted with 0-3
R.sub.e, F, Cl, Br, .dbd.O, CN, NO.sub.2, --OR.sub.b,
--S(O).sub.pR.sub.c, --CN, --OR.sub.b,
--(CH.sub.2).sub.rC(.dbd.O)R.sub.b,
--(CH.sub.2).sub.rNR.sub.aR.sub.a,
--(CH.sub.2).sub.rC(.dbd.O)NR.sub.aR.sub.a,
--(CH.sub.2).sub.rNHC(.dbd.O)R.sub.b,
--(CH.sub.2).sub.rNHC(.dbd.O)OR.sub.b,
--(CH.sub.2).sub.rOC(.dbd.O)NR.sub.aR.sub.a,
--(CH.sub.2).sub.rNHC(.dbd.O)NR.sub.aR.sub.a,
--(CH.sub.2).sub.rC(.dbd.O)OR.sub.b,
--(CH.sub.2).sub.rS(O).sub.2NR.sub.aR.sub.a,
--(CH.sub.2).sub.rNHS(O).sub.2NR.sub.aR.sub.a,
--(CH.sub.2).sub.rNHS(O).sub.2R.sub.c,
(CH.sub.2).sub.r--C.sub.3-6cycloalkyl, --(CH.sub.2).sub.r-aryl
substituted with 0-3 R.sub.e, and --(CH.sub.2).sub.r-heterocyclyl
substituted with 0-3 R.sub.e; R.sub.a, at each occurrence, is
independently selected from H, CN, C.sub.1-6 alkyl substituted with
0-5 R.sub.e, C.sub.2-6 alkenyl substituted with 0-5 R.sub.e,
C.sub.2-6 alkynyl substituted with 0-5 R.sub.e,
--(CH.sub.2).sub.r--C.sub.3-10carbocyclyl substituted with 0-5
R.sub.e, and --(CH.sub.2).sub.r-heterocyclyl substituted with 0-5
R.sub.e; or R.sub.a and R.sub.a together with the nitrogen atom to
which they are both attached form a heterocyclic ring substituted
with 0-5 R.sub.e; R.sub.b, at each occurrence, is independently
selected from H, C.sub.1-6 alkyl substituted with 0-5 R.sub.e,
C.sub.2-6 alkenyl substituted with 0-5 R.sub.e, C.sub.2-6 alkynyl
substituted with 0-5 R.sub.e,
--(CH.sub.2).sub.r--C.sub.3-10carbocyclyl substituted with 0-5
R.sub.e, and --(CH.sub.2).sub.r-heterocyclyl substituted with 0-5
R.sub.e; R.sub.c, at each occurrence, is independently selected
from C.sub.1-6 alkyl substituted with 0-5 R.sub.e, C.sub.2-6alkenyl
substituted with 0-5 R.sub.e, C.sub.2-6alkynyl substituted with 0-5
R.sub.e, C.sub.3-6carbocyclyl, and heterocyclyl; R.sub.e, at each
occurrence, is independently selected from F, Cl, Br, CN, NO.sub.2,
.dbd.O, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
--(CH.sub.2).sub.r--C.sub.3-6 cycloalkyl, and CO.sub.2H; p, at each
occurrence, is independently selected from zero, 1, and 2; and r,
at each occurrence, is independently selected from zero, 1, 2, 3,
and 4.
5. The compound according to claim 4, having Formula (III),
##STR01017## or a pharmaceutically acceptable salt thereof,
wherein: R.sub.2 is independently selected from (i) alkyl
optionally substituted with F, Cl, Br, OR.sub.b, CN,
NR.sub.aR.sub.a, --C(.dbd.O)NR.sub.aR.sub.a, C.sub.2-6 alkenyl
substituted with 0-5 R.sub.e, C.sub.2-6 alkynyl substituted with
0-5 R.sub.e, carbocyclyl substituted with 1-8 R.sub.7, and
heterocyclyl comprising carbon atoms and 1 to 4 heteroatoms
selected from N, NR.sub.6, O, S, and substituted with 1-8 R.sub.7,
(ii) cycloalkyl substituted with 1-8 R.sub.7, and (iii)
cycloheteroalkyl substituted with 1-8 R.sub.7; R.sub.3a, R.sub.3b,
R.sub.3c, and R.sub.3d are independently selected from H, CN,
C.sub.1-4alkyl substituted with 1-3 R.sub.8, --C(.dbd.O)OR.sub.b,
--C(.dbd.O)NR.sub.aR.sub.a, --C(.dbd.O)R.sub.b,
--NR.sub.aC(.dbd.O)R.sub.b, --NR.sub.aC(.dbd.O)OR.sub.b,
--(CH.sub.2).sub.r-carbocyclyl substituted with 1-3 R.sub.8, and
--(CH.sub.2).sub.r-heterocyclyl substituted with 1-3 R.sub.8;
alternatively, R.sub.3a and R.sub.3b, or R.sub.3c and R.sub.3d,
together with the carbon atom to which they are both attached form
a spiral carbocyclic or heterocyclic ring comprising carbon atoms
and 1 to 4 heteroatoms selected from N, O, S, each substituted with
1-5 R.sub.8; alternatively, R.sub.3a and R.sub.3c or R.sub.3b and
R.sub.3d together form a heterocyclic ring comprising carbon atoms
and 1 to 4 heteroatoms selected from N, O, S, and substituted with
1-5 R.sub.8; R.sub.5, at each occurrence, is independently selected
from H, C.sub.1-4 alkyl substituted with 0-3 R.sub.e, F, Cl, Br,
--S(O).sub.pR.sub.c, --CN, --OR.sub.b, NR.sub.aR.sub.a,
C.sub.3-6cycloalkyl, aryl substituted with 0-3 R.sub.e, and
heterocyclyl substituted with 0-3 R.sub.e; R.sub.6 is independently
selected from H, --C(.dbd.O)R.sub.b, --CO(.dbd.O)R.sub.b,
--S(O).sub.pR.sub.c, C.sub.1-6 alkyl substituted with 0-5 R.sub.e,
--(CH.sub.2).sub.r--C.sub.3-6carbocyclyl substituted with 0-5
R.sub.e, and --(CH.sub.2).sub.r-heterocyclyl substituted with 0-5
R.sub.e; R.sub.7, at each occurrence, is independently selected
from H, F, Cl, Br, .dbd.O, --(CR.sub.dR.sub.d).sub.rCN, NO.sub.2,
--(CR.sub.dR.sub.d).sub.rOR.sub.b, --S(O).sub.pR.sub.c,
--C(.dbd.O)R.sub.b, --(CR.sub.dR.sub.d).sub.rNR.sub.aR.sub.a,
--(CR.sub.dR.sub.d).sub.rC(.dbd.O)NR.sub.aR.sub.a,
--NR.sub.aC(.dbd.O)R.sub.b, --NR.sub.aC(.dbd.O)OR.sub.b,
--OC(.dbd.O)NR.sub.aR.sub.a, --NR.sub.aC(.dbd.O)NR.sub.aR.sub.a,
--(CR.sub.dR.sub.d).sub.rC(.dbd.O)OR.sub.b,
--S(O).sub.2NR.sub.aR.sub.a, --NR.sub.aS(O).sub.2NR.sub.aR.sub.a,
--NR.sub.aS(O).sub.2R.sub.c, C.sub.1-6 alkyl substituted with 0-5
R.sub.e, --(CR.sub.dR.sub.d).sub.r--C.sub.3-6carbocyclyl
substituted with 0-5 R.sub.e, and
--(CR.sub.dR.sub.d).sub.r-heterocyclyl substituted with 0-5
R.sub.e; R.sub.8, at each occurrence, is independently selected
from H, F, Cl, Br, CN, C.sub.1-6 alkyl substituted with 0-5
R.sub.e, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
--(CH.sub.2).sub.r--C.sub.3-6 cycloalkyl substituted with 0-5
R.sub.e, --(CH.sub.2).sub.r-aryl substituted with 0-5 R.sub.e,
--(CH.sub.2).sub.r-heterocyclyl substituted with 0-5 R.sub.e,
CO.sub.2H, --(CH.sub.2).sub.rOR.sub.b, and
--(CH.sub.2).sub.rNR.sub.aR.sub.a; R.sub.a, at each occurrence, is
independently selected from H, CN, C.sub.1-6 alkyl substituted with
0-5 R.sub.e, C.sub.2-6 alkenyl substituted with 0-5 R.sub.e,
C.sub.2-6 alkynyl substituted with 0-5 R.sub.e,
--(CH.sub.2).sub.r--C.sub.3-10carbocyclyl substituted with 0-5
R.sub.e, and --(CH.sub.2).sub.r-heterocyclyl substituted with 0-5
R.sub.e; or R.sub.a and R.sub.a together with the nitrogen atom to
which they are both attached form a heterocyclic ring substituted
with 0-5 R.sub.e; R.sub.b, at each occurrence, is independently
selected from H, C.sub.1-6 alkyl substituted with 0-5 R.sub.e,
C.sub.2-6 alkenyl substituted with 0-5 R.sub.e, C.sub.2-6 alkynyl
substituted with 0-5 R.sub.e,
--(CH.sub.2).sub.r--C.sub.3-10carbocyclyl substituted with 0-5
R.sub.e, and --(CH.sub.2).sub.r-heterocyclyl substituted with 0-5
R.sub.e; R.sub.c, at each occurrence, is independently selected
from C.sub.1-6 alkyl substituted with 0-5 R.sub.e, C.sub.2-6alkenyl
substituted with 0-5 R.sub.e, C.sub.2-6alkynyl substituted with 0-5
R.sub.e, C.sub.3-6carbocyclyl, and heterocyclyl; R.sub.d, at each
occurrence, is independently selected from H and C.sub.1-4alkyl
substituted with 0-5 R.sub.e; R.sub.e, at each occurrence, is
independently selected from F, Cl, Br, CN, NO.sub.2, .dbd.O,
CO.sub.2H, C.sub.1-6 alkyl substituted with 0-5 R.sub.f, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, --(CH.sub.2).sub.r--C.sub.3-6
cycloalkyl, --(CH.sub.2).sub.rOR.sub.f, SR.sub.f, and
--(CH.sub.2).sub.rNR.sub.fR.sub.f; R.sub.f, at each occurrence, is
independently selected from H, C.sub.1-5 alkyl, C.sub.3-6
cycloalkyl, and phenyl, or R.sub.f and R.sub.f together with the
nitrogen atom to which they are both attached form a heterocyclic
ring optionally substituted with C.sub.1-4alkyl; p, at each
occurrence, is independently selected from zero, 1, and 2; and r,
at each occurrence, is independently selected from zero, 1, 2, 3,
and 4.
6. The compound according to claim 5, wherein: R.sub.2 is
independently selected from ##STR01018## ##STR01019## R.sub.3a and
R.sub.3b are independently selected from H, CH.sub.2CH.sub.3,
CH.sub.3, CH.sub.2OH, CH.sub.2CH.sub.2OH,
CH.sub.2CH.sub.2OC.sub.1-4alkyl, CH.sub.2F, CHF.sub.2,
CH.sub.2CH.sub.2F, CF.sub.3, CH.sub.2OCHF.sub.2, CH.sub.2CN,
CH.sub.2CH.sub.2CN, CH.sub.2OC.sub.1-4alkyl, C(CH.sub.3).sub.3,
CH(CH.sub.3).sub.2, C(CH.sub.3).sub.20H, C(CH.sub.3).sub.2F,
C(.dbd.O)NH--C.sub.3-6cycloalkyl, C(.dbd.O)NH-heterocyclyl, and
--CH.sub.2-heterocyclyl, wherein the heterocyclyl is independently
selected from ##STR01020## R.sub.3c and R.sub.3d are independently
selected from H, CH.sub.3, CH(CH.sub.3).sub.2, CF.sub.3, and
C.sub.3-6 cycloalkyl; R.sub.5, at each occurrence, is independently
selected from H, C.sub.1-4 alkyl substituted with 0-3 R.sub.e, F,
Cl, Br, --S(O).sub.pR.sub.c, --CN, --OR.sub.b, NR.sub.aR.sub.a,
C.sub.3-6cycloalkyl, and aryl substituted with 0-3 R.sub.e;
R.sub.7, at each occurrence, is independently selected from H, F,
Cl, Br, .dbd.O, --(CH.sub.2).sub.rCN, NO.sub.2,
--(CH.sub.2).sub.rOR.sub.b, --S(O).sub.pR.sub.c,
--C(.dbd.O)R.sub.b, --NR.sub.aR.sub.a, --C(.dbd.O)NR.sub.aR.sub.a,
--NHC(.dbd.O)R.sub.b, --NHC(.dbd.O)OR.sub.b,
--OC(.dbd.O)NR.sub.aR.sub.a, --NHC(.dbd.O)NR.sub.aR.sub.a,
--C(.dbd.O)OR.sub.b, --S(O).sub.2NR.sub.aR.sub.a,
--NHS(O).sub.2NR.sub.aR.sub.a, --NHS(O).sub.2R.sub.c, C.sub.1-6
alkyl substituted with 0-5 R.sub.e, aryl substituted with 0-5
R.sub.e, and heterocyclyl substituted with 0-5 R.sub.e; R.sub.8, at
each occurrence, is independently selected from H, F, Cl, Br, CN,
C.sub.1-6 alkyl substituted with 0-5 R.sub.e,
--(CH.sub.2).sub.r--C.sub.3-6 cycloalkyl substituted with 0-5
R.sub.e, --(CH.sub.2).sub.r-aryl substituted with 0-5 R.sub.e,
--(CH.sub.2).sub.r-heterocyclyl substituted with 0-5 R.sub.e,
CO.sub.2H, --(CH.sub.2).sub.rOR.sub.b, and
--(CH.sub.2).sub.rNR.sub.aR.sub.a; R.sub.a, at each occurrence, is
independently selected from H, CN, C.sub.1-6 alkyl substituted with
0-5 R.sub.e, C.sub.2-6 alkenyl substituted with 0-5 R.sub.e,
C.sub.2-6 alkynyl substituted with 0-5 R.sub.e,
--(CH.sub.2).sub.r--C.sub.3-10carbocyclyl substituted with 0-5
R.sub.e, and --(CH.sub.2).sub.r-heterocyclyl substituted with 0-5
R.sub.e; or R.sub.a and R.sub.a together with the nitrogen atom to
which they are both attached form a heterocyclic ring substituted
with 0-5 R.sub.e; R.sub.b, at each occurrence, is independently
selected from H, C.sub.1-6 alkyl substituted with 0-5 R.sub.e,
C.sub.2-6 alkenyl substituted with 0-5 R.sub.e, C.sub.2-6 alkynyl
substituted with 0-5 R.sub.e, aryl substituted with 0-5 R.sub.e,
and heterocyclyl substituted with 0-5 R.sub.e; R.sub.c, at each
occurrence, is independently selected from C.sub.1-6 alkyl
substituted with 0-5 R.sub.e, C.sub.3-6carbocyclyl, and
heterocyclyl; R.sub.e, at each occurrence, is independently
selected from F, Cl, Br, CN, NO.sub.2, .dbd.O, CO.sub.2H, C.sub.1-6
alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, and
--(CH.sub.2).sub.r--C.sub.3-6 cycloalkyl; p, at each occurrence, is
independently selected from zero, 1, and 2; and r, at each
occurrence, is independently selected from zero, 1, 2, 3, and
4.
7. The compound according to claim 6, wherein: R.sub.2 is
independently selected from ##STR01021## R.sub.3a and R.sub.3b are
independently H; R.sub.3c and R.sub.3d are independently H;
R.sub.5, at each occurrence, is independently selected from H, F,
Cl, and Br.
8. The compound according to claim 5, wherein: R.sub.2 is
independently selected from ##STR01022## R.sub.3a and R.sub.3b are
independently selected from H, CH.sub.2CH.sub.3, CH.sub.3,
CH.sub.2OH, CH.sub.2CH.sub.2OH, CH.sub.2CH.sub.2OC.sub.1-4alkyl,
CH.sub.2F, CHF.sub.2, CH.sub.2CH.sub.2F, CF.sub.3,
CH.sub.2OCHF.sub.2, CH.sub.2CN, CH.sub.2CH.sub.2CN,
CH.sub.2OC.sub.1-4alkyl, C(CH.sub.3).sub.3, CH(CH.sub.3).sub.2,
C(CH.sub.3).sub.2OH, C(CH.sub.3).sub.2F,
C(.dbd.O)NH--C.sub.3-6cycloalkyl, C(.dbd.O)NH-heterocyclyl, and
--CH.sub.2-heterocyclyl, wherein the heterocyclyl is independently
selected from ##STR01023## R.sub.3c and R.sub.3d are independently
selected from H, CH.sub.3, CH(CH.sub.3).sub.2, CF.sub.3, and
C.sub.3-6 cycloalkyl; R.sub.5, at each occurrence, is independently
selected from H, C.sub.1-4 alkyl substituted with 0-3 R.sub.e, F,
Cl, Br, --S(O).sub.pR.sub.c, --CN, --OR.sub.b, NR.sub.aR.sub.a,
C.sub.3-6cycloalkyl, and aryl substituted with 0-3 R.sub.e;
R.sub.7, at each occurrence, is independently selected from H, F,
Cl, Br, .dbd.O, --(CH.sub.2).sub.rCN, NO.sub.2,
--(CH.sub.2).sub.rOR.sub.b, --S(O).sub.pR.sub.c,
--C(.dbd.O)R.sub.b, --NR.sub.aR.sub.a, --C(.dbd.O)NR.sub.aR.sub.a,
--NHC(.dbd.O)R.sub.b, --NHC(.dbd.O)OR.sub.b,
--OC(.dbd.O)NR.sub.aR.sub.a, --NHC(.dbd.O)NR.sub.aR.sub.a,
--C(.dbd.O)OR.sub.b, --S(O).sub.2NR.sub.aR.sub.a,
--NHS(O).sub.2NR.sub.aR.sub.a, --NHS(O).sub.2R.sub.c, C.sub.1-6
alkyl substituted with 0-5 R.sub.e, aryl substituted with 0-5
R.sub.e, and heterocyclyl substituted with 0-5 R.sub.e; R.sub.8, at
each occurrence, is independently selected from H, F, Cl, Br, CN,
C.sub.1-6 alkyl substituted with 0-5 R.sub.e,
--(CH.sub.2).sub.r--C.sub.3-6 cycloalkyl substituted with 0-5
R.sub.e, --(CH.sub.2).sub.r-aryl substituted with 0-5 R.sub.e,
--(CH.sub.2).sub.r-heterocyclyl substituted with 0-5 R.sub.e,
CO.sub.2H, --(CH.sub.2).sub.rOR.sub.b, and
--(CH.sub.2).sub.rNR.sub.aR.sub.a; R.sub.a, at each occurrence, is
independently selected from H, CN, C.sub.1-6 alkyl substituted with
0-5 R.sub.e, C.sub.2-6 alkenyl substituted with 0-5 R.sub.e,
C.sub.2-6 alkynyl substituted with 0-5 R.sub.e,
--(CH.sub.2).sub.r--C.sub.3-10carbocyclyl substituted with 0-5
R.sub.e, and --(CH.sub.2).sub.r-heterocyclyl substituted with 0-5
R.sub.e; or R.sub.a and R.sub.a together with the nitrogen atom to
which they are both attached form a heterocyclic ring substituted
with 0-5 R.sub.e; R.sub.b, at each occurrence, is independently
selected from H, C.sub.1-6 alkyl substituted with 0-5 R.sub.e,
C.sub.2-6 alkenyl substituted with 0-5 R.sub.e, C.sub.2-6 alkynyl
substituted with 0-5 R.sub.e, aryl substituted with 0-5 R.sub.e,
and heterocyclyl substituted with 0-5 R.sub.e; R.sub.c, at each
occurrence, is independently selected from C.sub.1-6 alkyl
substituted with 0-5 R.sub.e, C.sub.3-6carbocyclyl, and
heterocyclyl; R.sub.e, at each occurrence, is independently
selected from F, Cl, Br, CN, NO.sub.2, .dbd.O, CO.sub.2H C.sub.1-6
alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, and
--(CH.sub.2).sub.r--C.sub.3-6 cycloalkyl; p, at each occurrence, is
independently selected from zero, 1, and 2; and r, at each
occurrence, is independently selected from zero, 1, 2, 3, and
4.
9. The compound according to claim 5, or a pharmaceutically
acceptable salt thereof, wherein R.sub.3a and R.sub.3b, or R.sub.3c
and R.sub.3d, together with the carbon atom to which they are both
attached form a spiral carbocyclic or heterocyclic ring comprising
carbon atoms and 1 to 4 heteroatoms selected from N, O, S, each
substituted with 1-5 R.sub.8.
10. The compound according to claim 9, having Formula (IV):
##STR01024## or a pharmaceutically acceptable salt thereof,
wherein: Ring A is C.sub.3-6cycloalkyl or heterocyclyl; R.sub.2 is
independently selected from ##STR01025## ##STR01026## ##STR01027##
R.sub.5, at each occurrence, is independently selected from H,
C.sub.1-4 alkyl substituted with 0-3 R.sub.e, F, Cl, Br,
--S(O).sub.pR.sub.c, --CN, --OR.sub.b, NR.sub.aR.sub.a,
C.sub.3-6cycloalkyl, aryl substituted with 0-3 R.sub.e, and
heterocyclyl substituted with 0-3 R.sub.e; R.sub.7, at each
occurrence, is independently selected from H, F, Cl, Br, CN,
NO.sub.2, --OR.sub.b, --S(O).sub.pR.sub.c, --C(.dbd.O)R.sub.b,
--NR.sub.aR.sub.a, --C(.dbd.O)NR.sub.aR.sub.a,
--NHC(.dbd.O)R.sub.b, --NHC(.dbd.O)OR.sub.b,
--OC(.dbd.O)NR.sub.aR.sub.a, --NHC(.dbd.O)NR.sub.aR.sub.a,
--C(.dbd.O)OR.sub.b, --S(O).sub.2NR.sub.aR.sub.a, C.sub.1-6 alkyl
substituted with 0-5 R.sub.e, aryl substituted with 0-5 R.sub.e,
and heterocyclyl substituted with 0-5 R.sub.e; R.sub.8, at each
occurrence, is independently selected from H, F, Cl, Br, CN,
C.sub.1-6 alkyl substituted with 0-5 R.sub.e, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, --(CH.sub.2).sub.r--C.sub.3-6 cycloalkyl
substituted with 0-5 R.sub.e, --(CH.sub.2).sub.r-aryl substituted
with 0-5 R.sub.e, --(CH.sub.2).sub.r-heterocyclyl substituted with
0-5 R.sub.e, CO.sub.2H, --(CH.sub.2).sub.rOR.sub.b, and
--(CH.sub.2).sub.rNR.sub.aR.sub.a; R.sub.a, at each occurrence, is
independently selected from H, CN, C.sub.1-6 alkyl substituted with
0-5 R.sub.e, C.sub.2-6 alkenyl substituted with 0-5 R.sub.e,
C.sub.2-6 alkynyl substituted with 0-5 R.sub.e,
--(CH.sub.2).sub.r--C.sub.3-10carbocyclyl substituted with 0-5
R.sub.e, and --(CH.sub.2).sub.r-heterocyclyl substituted with 0-5
R.sub.e; or R.sub.a and R.sub.a together with the nitrogen atom to
which they are both attached form a heterocyclic ring substituted
with 0-5 R.sub.e; R.sub.b, at each occurrence, is independently
selected from H, C.sub.1-6 alkyl substituted with 0-5 R.sub.e,
C.sub.2-6 alkenyl substituted with 0-5 R.sub.e, C.sub.2-6 alkynyl
substituted with 0-5 R.sub.e, aryl substituted with 0-5 R.sub.e,
and heterocyclyl substituted with 0-5 R.sub.e; R.sub.c, at each
occurrence, is independently selected from C.sub.1-6 alkyl
substituted with 0-5 R.sub.e, C.sub.3-6carbocyclyl, and
heterocyclyl; R.sub.e, at each occurrence, is independently
selected from F, Cl, Br, CN, NO.sub.2, .dbd.O, CO.sub.2H, C.sub.1-6
alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, and
--(CH.sub.2).sub.r--C.sub.3-6 cycloalkyl; p, at each occurrence, is
independently selected from zero, 1, and 2; and r, at each
occurrence, is independently selected from zero, 1, 2, 3, and
4.
11. The compound according to claim 5, or a pharmaceutically
acceptable salt thereof, wherein: R.sub.3a and R.sub.3c together
form a carbocyclic or heterocyclic ring comprising carbon atoms and
1 to 4 heteroatoms selected from N, O, S, wherein the carbocyclic
or heterocyclic ring is substituted with 1-5 R.sub.8; and R.sub.3b
and R.sub.3d are independently selected from H and
C.sub.1-4alkyl.
12. The compound according to claim 11, having Formula (V):
##STR01028## or a pharmaceutically acceptable salt thereof,
wherein: R.sub.2 is independently selected from ##STR01029##
##STR01030## ##STR01031## R.sub.5, at each occurrence, is
independently selected from H, C.sub.1-4 alkyl substituted with 0-3
R.sub.e, F, Cl, Br, --S(O).sub.pR.sub.c, --CN, --OR.sub.b,
NR.sub.aR.sub.a, C.sub.3-6cycloalkyl, aryl substituted with 0-3
R.sub.e, and heterocyclyl substituted with 0-3 R.sub.e; R.sub.7, at
each occurrence, is independently selected from H, F, Cl, Br, CN,
NO.sub.2, --OR.sub.b, --S(O).sub.pR.sub.c, --C(.dbd.O)R.sub.b,
--NR.sub.aR.sub.a, --C(.dbd.O)NR.sub.aR.sub.a,
--NHC(.dbd.O)R.sub.b, --NHC(.dbd.O)OR.sub.b,
--OC(.dbd.O)NR.sub.aR.sub.a, --NHC(.dbd.O)NR.sub.aR.sub.a,
--C(.dbd.O)OR.sub.b, --S(O).sub.2NR.sub.aR.sub.a, C.sub.1-6 alkyl
substituted with 0-5 R.sub.e, aryl substituted with 0-5 R.sub.e,
and heterocyclyl substituted with 0-5 R.sub.e; R.sub.a, at each
occurrence, is independently selected from H, CN, C.sub.1-6 alkyl
substituted with 0-5 R.sub.e, C.sub.2-6 alkenyl substituted with
0-5 R.sub.e, C.sub.2-6 alkynyl substituted with 0-5 R.sub.e,
--(CH.sub.2).sub.r--C.sub.3-10carbocyclyl substituted with 0-5
R.sub.e, and --(CH.sub.2).sub.r-heterocyclyl substituted with 0-5
R.sub.e; or R.sub.a and R.sub.a together with the nitrogen atom to
which they are both attached form a heterocyclic ring substituted
with 0-5 R.sub.e; R.sub.b, at each occurrence, is independently
selected from H, C.sub.1-6 alkyl substituted with 0-5 R.sub.e,
C.sub.2-6 alkenyl substituted with 0-5 R.sub.e, C.sub.2-6 alkynyl
substituted with 0-5 R.sub.e, aryl substituted with 0-5 R.sub.e,
and heterocyclyl substituted with 0-5 R.sub.e; R.sub.c, at each
occurrence, is independently selected from C.sub.1-6 alkyl
substituted with 0-5 R.sub.e, C.sub.3-6carbocyclyl, and
heterocyclyl; R.sub.e, at each occurrence, is independently
selected from F, Cl, Br, CN, NO.sub.2, .dbd.O, CO.sub.2H, C.sub.1-6
alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, and
--(CH.sub.2).sub.r--C.sub.3-6 cycloalkyl; p, at each occurrence, is
independently selected from zero, 1, and 2; and r, at each
occurrence, is independently selected from zero, 1, 2, 3, and
4.
13. A pharmaceutical composition comprising one or more compounds
of any one of claims 1-12 and a pharmaceutically acceptable
carrier.
14. A method of inhibiting casein kinase I.delta./.epsilon.
activity in a patient, comprising administering to the patient in
need thereof, a therapeutically effective amount of one or more
compounds according to any one of claims 1-12.
15. A method for treating a disease, with the pathological
conditions of which the activation of casein kinase
I.delta./.epsilon. is associated, wherein the method comprises
administering to a patient, a pharmaceutical composition
comprising, as an active ingredient of one or more compounds
according to any one of claims 1-12, or the salt thereof, wherein
the disease is selected from a circadian rhythm disorder, a
neurodegenerative disease, and cancer.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. Ser. No.
14/541,343, filed Nov. 14, 2014 (now allowed), which claims the
priority benefit of U.S. provisional patent application No.
61/904,116, filed on Nov. 14, 2013, which is incorporated herein in
their entirety.
FIELD OF THE INVENTION
[0002] The invention relates to novel substituted pyrazoles useful
as protein kinase inhibitors. This invention also relates to
methods of using the compounds in the treatment of proliferative
and other types of diseases and to pharmaceutical compositions
containing the compounds.
BACKGROUND OF THE INVENTION
[0003] The invention relates to substituted pyrazole compounds
which inhibit protein kinase enzymes, compositions which contain
protein kinase inhibiting compounds and methods of using inhibitors
of protein kinase enzymes to treat diseases which are characterized
by an overexpression or upregulation of protein kinases. Protein
kinases mediate intracellular signal transduction by affecting a
phosphoryl transfer from a nucleoside triphosphate to a protein
acceptor that is involved in a signaling pathway. There are a
number of kinases and pathways through which extracellular and
other stimuli cause a variety of cellular responses to occur inside
the cell. An extracellular stimulus may affect one or more cellular
responses related to cell growth, migration, differentiation,
secretion of hormones, activation of transcription factors, muscle
contraction, glucose metabolism, control of protein synthesis and
regulation of cell cycle.
[0004] Many diseases are associated with abnormal cellular
responses triggered by protein kinase-mediated events. These
diseases include autoimmune diseases, inflammatory diseases,
neurological and neurodegenerative diseases, cancer, cardiovascular
diseases, allergies and asthma, Alzheimer's disease or
hormone-related diseases. Accordingly, there has been a substantial
effort in medicinal chemistry to find protein kinase inhibitors
that are effective as therapeutic agents.
[0005] Serine/threonine kinases are a class of protein kinases that
are among the most promising drug targets for future small molecule
inhibitors. Inhibition of serine/threonine kinases is likely to
have relevance to the treatment of cancer, diabetes and a variety
of inflammatory disorders. The successful development of
GLEEVEC.RTM. as a Bcr/Abl protein kinase inhibitor has provided
further evidence that protein kinases are valid drug targets for
potential cancer therapies.
[0006] Casein kinase 1 (CK1) belongs to the serine/threonine kinase
family. In mammals, the enzyme exists in seven isozymic forms:
.alpha., .beta., .gamma.1, .gamma.2, .gamma.3, .delta., and
.epsilon.. By phosphorylating different substrate proteins, these
isoforms are able to activate, inactivate, stabilize, or
destabilize the functions of the proteins, regulating the functions
of various types of different organisms. For example, a tumor
suppressor factor p53 and an oncogene mdm2, which are both
important proteins for controlling abnormal cell growth, are
substrates of casein kinase 1.
[0007] Mammalian casein kinase 1.delta. and casein kinase
1.epsilon. are key regulators of diverse cellular growth and
survival processes including Wnt signaling, DNA repair and
circadian rhythms. They have a kinase domain that is similar to
those of other isoforms. However, the N-terminal and C-terminal
domains thereof are different from those of other isoforms. The
C-terminal domain has a plurality of autophosphorylation sites, and
it is considered to be involved in regulation of autoenzyme
activity. Phosphorylation of p53 by casein kinase 1.delta. or
casein kinase 1.epsilon. leads to a consequent change in the
interaction between p53 and mdm2. It has also been known that
casein kinase 1.epsilon. or casein kinase 1.delta. is involved in a
regulatory protein associated with the formation of a spindle as a
central body during cell division, and that the casein kinase
1.delta. or casein kinase 1.epsilon. is involved in apoptosis
mediated by TRAIL (tumor necrosis factor-related apoptosis inducing
factor) and Fas. It has been further reported that inhibition of
casein kinase 1.epsilon. or casein kinase 1.delta. by a
nonselective casein kinase 1 inhibitory compound IC261 reduces
pancreatic tumor cell growth in vitro and in vivo (Brockschmidt et
al., Gut, 57(6):799-806 (2008)). Hence, a medicament inhibiting the
function of casein kinase 1.delta. or casein kinase 1.epsilon.
would be expected to exert important phenotypic and therapeutic
effects broadly in development and disease, especially cancer.
[0008] The present invention relates to a new class substituted
pyrazoles found to be effective in inhibiting casein kinase
1.delta. or casein kinase 1.epsilon.. These novel compounds are
provided to be useful as pharmaceuticals with desirable stability,
bioavailability, therapeutic index and toxicity values that are
important to their drugability.
SUMMARY OF THE INVENTION
[0009] The invention is directed to substituted pyrazole compounds
of Formulae (I)-(VI) or stereoisomers, tautomers, pharmaceutically
acceptable salts, solvates or prodrugs thereof, which inhibit
protein kinase enzymes, especially protein kinase CK1 for the
treatment of cancer.
[0010] The present invention also provides processes and
intermediates for making the compounds of the present invention or
stereoisomers, tautomers, pharmaceutically acceptable salts,
solvates, or prodrugs thereof.
[0011] The present invention also provides pharmaceutical
compositions comprising a pharmaceutically acceptable carrier and
at least one of the compounds of the present invention or
stereoisomers, tautomers, pharmaceutically acceptable salts,
solvates, or prodrugs thereof.
[0012] The present invention also provides methods for inhibiting
the activity of protein kinase CK1 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
stereoisomers, tautomers, pharmaceutically acceptable salts,
solvates, or prodrugs thereof.
[0013] The present invention also provides methods for treating
cancers 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 stereoisomers, tautomers,
pharmaceutically acceptable salts, solvates, or prodrugs
thereof.
[0014] The present invention also provides the compounds of the
present invention or stereoisomers, tautomers, pharmaceutically
acceptable salts, solvates, or prodrugs thereof, for use in
therapy.
[0015] The present invention also provides the use of the compounds
of the present invention or stereoisomers, tautomers,
pharmaceutically acceptable salts, solvates, or prodrugs thereof,
in preparing a medicament for the treatment of cancer in a human
patient, particularly a cancer receptive to treatment via
inhibition of the CK1 enzyme.
[0016] These and other features of the invention will be set forth
in the expanded form as the disclosure continues.
DETAILED DESCRIPTION OF THE INVENTION
[0017] The invention provides for novel substituted pyrazole
compounds useful as therapeutic agents, pharmaceutical compositions
employing such novel compounds and for methods of using such
compounds.
[0018] In accordance with the invention, there are disclosed
compounds of Formula (I) including enantiomers, diastereomers,
tautomers, pharmaceutically-acceptable salts, prodrugs, hydrates,
or solvates thereof,
##STR00002##
wherein: [0019] X is independently selected from O and NH; [0020]
R.sub.1 is independently selected from carbocyclyl substituted with
1-5 R.sub.5, and heterocyclyl comprising carbon atoms and 1 to 3
heteroatoms selected from N, NR.sub.4, O, S, and substituted with
1-5 R.sub.5; [0021] R.sub.2 is independently selected from (i)
alkyl optionally substituted with F, Cl, Br, OR.sub.b, CN,
NR.sub.aR.sub.a, --C(.dbd.O)NR.sub.aR.sub.a, C.sub.2-6 alkenyl
substituted with 0-5 R.sub.e, C.sub.2-6 alkynyl substituted with
0-5 R.sub.e, carbocyclyl substituted with 1-8 R.sub.7, and
heterocyclyl comprising carbon atoms and 1 to 4 heteroatoms
selected from N, NR.sub.6, O, S, and substituted with 1-8 R.sub.7,
(ii) cycloalkyl substituted with 1-8 R.sub.7, and (iii)
cycloheteroalkyl substituted with 1-8 R.sub.7; [0022] R.sub.3a,
R.sub.3b, R.sub.3e, R.sub.3d, R.sub.3e and R.sub.3f are
independently selected from H, CN, C.sub.1-4alkyl substituted with
1-3 [0023] R.sub.8, --C(.dbd.O)OR.sub.b,
--C(.dbd.O)NR.sub.aR.sub.a, --C(.dbd.O)R.sub.b,
--NR.sub.aC(.dbd.O)R.sub.b, --NR.sub.aC(.dbd.O)OR.sub.b,
--(CH.sub.2).sub.r-carbocyclyl substituted with 1-3 R.sub.8, and
--(CH.sub.2).sub.r-heterocyclyl substituted with 1-3 R.sub.8;
[0024] alternatively, R.sub.3a and R.sub.3b, or R.sub.3c and
R.sub.3d, or R.sub.3e and R.sub.3f, together with the carbon atom
to which they are both attached form a spiral carbocyclic or
heterocyclic ring comprising carbon atoms and 1 to 4 heteroatoms
selected from N, O, S, each substituted with 1-5 R.sub.8; [0025]
alternatively, R.sub.3a and R.sub.3c or R.sub.3b and R.sub.3d
together form a heterocyclic ring comprising carbon atoms and 1 to
4 heteroatoms selected from N, O, S, and substituted with 1-5
R.sub.8; [0026] R.sub.4 is independently selected from H, C.sub.1-4
alkyl substituted with 0-3 R.sub.e, --(CH.sub.2).sub.rCN,
--(CH.sub.2).sub.rOR.sub.b, [0027]
(CH.sub.2).sub.rS(O).sub.pR.sub.c,
--(CH.sub.2).sub.rC(.dbd.O)R.sub.b,
--(CH.sub.2).sub.rNR.sub.aR.sub.a,
--(CH.sub.2).sub.rC(.dbd.O)NR.sub.aR.sub.a,
--(CH.sub.2).sub.rNR.sub.aC(.dbd.O)R.sub.b,
--(CH.sub.2).sub.rNR.sub.aC(.dbd.O)OR.sub.b,
--(CH.sub.2).sub.rOC(.dbd.O)NR.sub.aR.sub.a,
--(CH.sub.2).sub.rNR.sub.aC(.dbd.O)NR.sub.aR.sub.a,
--(CH.sub.2).sub.rC(.dbd.O)OR.sub.b,
--(CH.sub.2).sub.rS(O).sub.2NR.sub.aR.sub.a,
--(CH.sub.2).sub.rNR.sub.aS(O).sub.2NR.sub.aR.sub.a,
--(CH.sub.2).sub.rNR.sub.aS(O).sub.2R.sub.c,
(CH.sub.2).sub.r-carbocyclyl substituted with 0-3 R.sub.e, and
--(CH.sub.2).sub.r-heterocyclyl substituted with 0-3 R.sub.e;
[0028] R.sub.5, at each occurrence, is independently selected from
H, C.sub.1-4 alkyl substituted with 0-3 R.sub.e, F, Cl, Br, .dbd.O,
CN, NO.sub.2, --OR.sub.b, --(CH.sub.2).sub.rCN,
--(CH.sub.2).sub.rOR.sub.b, [0029]
(CH.sub.2).sub.rS(O).sub.pR.sub.c,
--(CH.sub.2).sub.rC(.dbd.O)R.sub.b,
--(CH.sub.2).sub.rNR.sub.aR.sub.a,
--(CH.sub.2).sub.rC(.dbd.O)NR.sub.aR.sub.a,
--(CH.sub.2).sub.rNR.sub.aC(.dbd.O)R.sub.b,
--(CH.sub.2).sub.rNR.sub.aC(.dbd.O)OR.sub.b,
--(CH.sub.2).sub.rOC(.dbd.O)NR.sub.aR.sub.a,
--(CH.sub.2).sub.rNR.sub.aC(.dbd.O)NR.sub.aR.sub.a,
--(CH.sub.2).sub.rC(.dbd.O)OR.sub.b,
--(CH.sub.2).sub.rS(O).sub.2NR.sub.aR.sub.a,
--(CH.sub.2).sub.rNR.sub.aS(O).sub.2NR.sub.aR.sub.a,
--(CH.sub.2).sub.rNR.sub.aS(O).sub.2R.sub.c,
(CH.sub.2).sub.r-carbocyclyl substituted with 0-3 R.sub.e, and
--(CH.sub.2).sub.r-heterocyclyl substituted with 0-3 R.sub.e;
[0030] R.sub.6 is independently selected from H,
--C(.dbd.O)R.sub.b, --CO(.dbd.O)R.sub.b, --S(O).sub.pR.sub.c,
C.sub.1-6 alkyl substituted with 0-5 R.sub.e,
--(CH.sub.2).sub.r--C.sub.3-6carbocyclyl substituted with 0-5
R.sub.e, and --(CH.sub.2).sub.r-heterocyclyl substituted with 0-5
R.sub.e; [0031] R.sub.7, at each occurrence, is independently
selected from H, F, Cl, Br, .dbd.O, --(CR.sub.dR.sub.d).sub.rCN,
NO.sub.2, --(CR.sub.dR.sub.d).sub.rOR.sub.b, --S(O).sub.pR.sub.c,
--C(.dbd.O)R.sub.b, --(CR.sub.dR.sub.d).sub.rNR.sub.aR.sub.a,
--(CR.sub.dR.sub.d).sub.rC(.dbd.O)NR.sub.aR.sub.a,
--NR.sub.aC(.dbd.O)R.sub.b, --NR.sub.aC(.dbd.O)OR.sub.b,
--OC(.dbd.O)NR.sub.aR.sub.a, --NR.sub.aC(.dbd.O)NR.sub.aR.sub.a,
--(CR.sub.dR.sub.d).sub.rC(.dbd.O)OR.sub.b,
--S(O).sub.2NR.sub.aR.sub.a, --NR.sub.aS(O).sub.2NR.sub.aR.sub.a,
--NR.sub.aS(O).sub.2R.sub.c, C.sub.1-6 alkyl substituted with 0-5
R.sub.e, --(CR.sub.dR.sub.d).sub.r--C.sub.3-6carbocyclyl
substituted with 0-5 R.sub.e, [0032] and
--(CR.sub.dR.sub.d).sub.r-heterocyclyl substituted with 0-5
R.sub.e; [0033] R.sub.8, at each occurrence, is independently
selected from H, F, Cl, Br, CN, C.sub.1-6 alkyl substituted with
0-5 R.sub.e, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
--(CH.sub.2).sub.r--C.sub.3-6 cycloalkyl substituted with 0-5
R.sub.e, --(CH.sub.2).sub.r-aryl substituted with 0-5 R.sub.e,
--(CH.sub.2).sub.r-heterocyclyl substituted with 0-5 R.sub.e,
CO.sub.2H, --(CH.sub.2).sub.rOR.sub.b, and
--(CH.sub.2).sub.rNR.sub.aR.sub.a; [0034] R.sub.a, at each
occurrence, is independently selected from H, CN, C.sub.1-6 alkyl
substituted with 0-5 R.sub.e, C.sub.2-6 alkenyl substituted with
0-5 R.sub.e, C.sub.2-6 alkynyl substituted with 0-5 R.sub.e,
--(CH.sub.2).sub.r--C.sub.3-10carbocyclyl substituted with 0-5
R.sub.e, and --(CH.sub.2).sub.r-heterocyclyl substituted with 0-5
R.sub.e; or R.sub.a and R.sub.a together with the nitrogen atom to
which they are both attached form a heterocyclic ring substituted
with 0-5 R.sub.e; [0035] R.sub.b, at each occurrence, is
independently selected from H, C.sub.1-6 alkyl substituted with 0-5
R.sub.e, C.sub.2-6 alkenyl substituted with 0-5 R.sub.e, C.sub.2-6
alkynyl substituted with 0-5 R.sub.e,
--(CH.sub.2).sub.r--C.sub.3-10carbocyclyl substituted with 0-5
R.sub.e, and --(CH.sub.2).sub.r-heterocyclyl substituted with 0-5
R.sub.e; [0036] R.sub.c, at each occurrence, is independently
selected from C.sub.1-6 alkyl substituted with 0-5 R.sub.e,
C.sub.2-6alkenyl substituted with 0-5 R.sub.e, C.sub.2-6alkynyl
substituted with 0-5 R.sub.e, C.sub.3-6carbocyclyl, and
heterocyclyl; [0037] R.sub.d, at each occurrence, is independently
selected from H and C.sub.1-4alkyl substituted with 0-5 R.sub.e;
[0038] R.sub.e, at each occurrence, is independently selected from
F, Cl, Br, CN, NO.sub.2, .dbd.O, C.sub.1-6 alkyl substituted with
0-5 R.sub.f, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
--(CH.sub.2).sub.r--C.sub.3-6 cycloalkyl, --(CH.sub.2).sub.r-aryl,
--(CH.sub.2).sub.r-heterocyclyl, CO.sub.2H,
--(CH.sub.2).sub.rOR.sub.f, SR.sub.f, and
--(CH.sub.2).sub.rNR.sub.fR.sub.f; [0039] R.sub.f, at each
occurrence, is independently selected from H, C.sub.1-5 alkyl
optionally substituted with F, Cl, Br, C.sub.3-6 cycloalkyl, and
phenyl, or R.sub.f and R.sub.f together with the nitrogen atom to
which they are both attached form a heterocyclic ring optionally
substituted with C.sub.1-4alkyl; [0040] p, at each occurrence, is
independently selected from zero, 1, and 2; and [0041] r, at each
occurrence, is independently selected from zero, 1, 2, 3, and
4.
[0042] In another aspect, there are disclosed compounds of Formula
(II) including enantiomers, diastereomers, tautomers,
pharmaceutically acceptable salts, prodrugs, hydrates, or solvates
thereof,
##STR00003##
wherein: [0043] R.sub.1 is independently selected from aryl
substituted with 1-4 R.sub.5, and 5- to 12-membered heteroaryl
comprising carbon atoms and 1 to 3 heteroatoms selected from N,
NR.sub.4, O, S, and substituted with 1-4 R.sub.5; [0044] R.sub.2 is
independently selected from (i) alkyl optionally substituted with
F, Cl, Br, OR.sub.b, CN, NR.sub.aR.sub.a,
--C(.dbd.O)NR.sub.aR.sub.a, C.sub.2-6 alkenyl substituted with 0-5
R.sub.e, C.sub.2-6 alkynyl substituted with 0-5 R.sub.e,
carbocyclyl substituted with 1-8 R.sub.7, and heterocyclyl
comprising carbon atoms and 1 to 4 heteroatoms selected from N,
NR.sub.6, O, S, and substituted with 1-8 R.sub.7, (ii) cycloalkyl
substituted with 1-8 R.sub.7, and (iii) cycloheteroalkyl
substituted with 1-8 R.sub.7; [0045] R.sub.3a, R.sub.3b, R.sub.3c,
and R.sub.3d are independently selected from H, CN, C.sub.1-4alkyl
substituted with 1-3 [0046] R.sub.8, --C(.dbd.O)OR.sub.b,
--C(.dbd.O)NR.sub.aR.sub.a, --C(.dbd.O)R.sub.b,
--NR.sub.aC(.dbd.O)R.sub.b, --NR.sub.aC(.dbd.O)OR.sub.b,
--(CH.sub.2).sub.r-carbocyclyl substituted with 1-3 R.sub.8, and
--(CH.sub.2).sub.r-heterocyclyl substituted with 1-3 R.sub.8;
[0047] alternatively, R.sub.3a and R.sub.3b, or R.sub.3c and
R.sub.3d, or R.sub.3e and R.sub.3f, together with the carbon atom
to which they are both attached form a spiral carbocyclic or
heterocyclic ring comprising carbon atoms and 1 to 4 heteroatoms
selected from N, O, S, each substituted with 0-5 R.sub.e; [0048]
alternatively, R.sub.3a and R.sub.3c or R.sub.3b and R.sub.3d
together form a heterocyclic ring comprising carbon atoms and 1 to
4 heteroatoms selected from N, O, S, and substituted with 0-5
R.sub.e; [0049] R.sub.4 is independently selected from H and
C.sub.1-4 alkyl substituted with 0-3 R.sub.e; [0050] R.sub.5, at
each occurrence, is independently selected from H, C.sub.1-4 alkyl
substituted with 0-3 R.sub.e, F, Cl, Br, .dbd.O, CN, NO.sub.2,
--OR.sub.b, --(CH.sub.2).sub.rCN, --(CH.sub.2).sub.rOR.sub.b,
(CH.sub.2).sub.rS(O).sub.pR.sub.c,
--(CH.sub.2).sub.rC(.dbd.O)R.sub.b,
--(CH.sub.2).sub.rNR.sub.aR.sub.a,
--(CH.sub.2).sub.rC(.dbd.O)NR.sub.aR.sub.a,
--(CH.sub.2).sub.rNR.sub.aC(.dbd.O)R.sub.b,
--(CH.sub.2).sub.rNR.sub.aC(.dbd.O)OR.sub.b,
--(CH.sub.2).sub.rOC(.dbd.O)NR.sub.aR.sub.a,
--(CH.sub.2).sub.rNR.sub.aC(.dbd.O)NR.sub.aR.sub.a,
--(CH.sub.2).sub.rC(.dbd.O)OR.sub.b,
--(CH.sub.2).sub.rS(O).sub.2NR.sub.aR.sub.a,
--(CH.sub.2).sub.rNR.sub.aS(O).sub.2NR.sub.aR.sub.a,
--(CH.sub.2).sub.rNR.sub.aS(O).sub.2R.sub.c,
(CH.sub.2).sub.r-carbocyclyl substituted with 0-3 R.sub.e, and
--(CH.sub.2).sub.r-heterocyclyl substituted with 0-3 R.sub.e;
[0051] R.sub.6 is independently selected from H,
--C(.dbd.O)R.sub.b, --CO(.dbd.O)R.sub.b, --S(O).sub.pR.sub.c,
C.sub.1-6 alkyl substituted with 0-5 R.sub.e,
--(CH.sub.2).sub.r--C.sub.3-6carbocyclyl substituted with 0-5
R.sub.e, and --(CH.sub.2).sub.r-heterocyclyl substituted with 0-5
R.sub.e; [0052] R.sub.7, at each occurrence, is independently
selected from H, F, Cl, Br, .dbd.O, --(CR.sub.dR.sub.d).sub.rCN,
NO.sub.2, --(CR.sub.dR.sub.d).sub.rOR.sub.b, --S(O).sub.pR.sub.c,
--C(.dbd.O)R.sub.b, --(CR.sub.dR.sub.d).sub.rNR.sub.aR.sub.a,
--(CR.sub.dR.sub.d).sub.rC(.dbd.O)NR.sub.aR.sub.a,
--NR.sub.aC(.dbd.O)R.sub.b, --NR.sub.aC(.dbd.O)OR.sub.b,
--OC(.dbd.O)NR.sub.aR.sub.a, --NR.sub.aC(.dbd.O)NR.sub.aR.sub.a,
--(CR.sub.dR.sub.d).sub.rC(.dbd.O)OR.sub.b,
--S(O).sub.2NR.sub.aR.sub.a, --NR.sub.aS(O).sub.2NR.sub.aR.sub.a,
--NR.sub.aS(O).sub.2R.sub.c, C.sub.1-6 alkyl substituted with 0-5
R.sub.e, --(CR.sub.dR.sub.d).sub.r--C.sub.3-6carbocyclyl
substituted with 0-5 R.sub.e, and
--(CR.sub.dR.sub.d).sub.r-heterocyclyl substituted with 0-5
R.sub.e; [0053] R.sub.8, at each occurrence, is independently
selected from H, F, Cl, Br, CN, C.sub.1-6 alkyl substituted with
0-5 R.sub.e, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
--(CH.sub.2).sub.r--C.sub.3-6 cycloalkyl substituted with 0-5
R.sub.e, --(CH.sub.2).sub.r-aryl substituted with 0-5 R.sub.e,
--(CH.sub.2).sub.r-heterocyclyl substituted with 0-5 R.sub.e,
CO.sub.2H, --(CH.sub.2).sub.rOR.sub.b, and
--(CH.sub.2).sub.rNR.sub.aR.sub.a; [0054] R.sub.a, at each
occurrence, is independently selected from H, CN, C.sub.1-6 alkyl
substituted with 0-5 R.sub.e, C.sub.2-6 alkenyl substituted with
0-5 R.sub.e, C.sub.2-6 alkynyl substituted with 0-5 R.sub.e,
--(CH.sub.2).sub.r--C.sub.3-10carbocyclyl substituted with 0-5
R.sub.e, and --(CH.sub.2).sub.r-heterocyclyl substituted with 0-5
R.sub.e; or R.sub.a and R.sub.a together with the nitrogen atom to
which they are both attached form a heterocyclic ring substituted
with 0-5 R.sub.e; [0055] R.sub.b, at each occurrence, is
independently selected from H, C.sub.1-6 alkyl substituted with 0-5
R.sub.e, C.sub.2-6 alkenyl substituted with 0-5 R.sub.e, C.sub.2-6
alkynyl substituted with 0-5 R.sub.e,
--(CH.sub.2).sub.r--C.sub.3-10carbocyclyl substituted with 0-5
R.sub.e, and --(CH.sub.2).sub.r-heterocyclyl substituted with 0-5
R.sub.e; [0056] R.sub.c, at each occurrence, is independently
selected from C.sub.1-6 alkyl substituted with 0-5 R.sub.e,
C.sub.2-6alkenyl substituted with 0-5 R.sub.e, C.sub.2-6alkynyl
substituted with 0-5 R.sub.e, C.sub.3-6carbocyclyl, and
heterocyclyl; [0057] R.sub.d, at each occurrence, is independently
selected from H and C.sub.1-4alkyl substituted with 0-5 R.sub.e;
[0058] R.sub.e, at each occurrence, is independently selected from
F, Cl, Br, CN, NO.sub.2, .dbd.O, C.sub.1-6 alkyl substituted with
0-5 R.sub.f, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
--(CH.sub.2).sub.r--C.sub.3-6 cycloalkyl, CO.sub.2H,
--(CH.sub.2).sub.rOR.sub.f, SR.sub.f, and
--(CH.sub.2).sub.rNR.sub.fR.sub.f; [0059] R.sub.f, at each
occurrence, is independently selected from H, C.sub.1-5 alkyl,
C.sub.3-6 cycloalkyl, and phenyl, or R.sub.f and R.sub.f together
with the nitrogen atom to which they are both attached form a
heterocyclic ring optionally substituted with C.sub.1-4alkyl;
[0060] p, at each occurrence, is independently selected from zero,
1, and 2; and [0061] r, at each occurrence, is independently
selected from zero, 1, 2, 3, and 4.
[0062] In another embodiment, there are disclosed compounds of
Formula (II) including enantiomers, diastereomers, tautomers,
pharmaceutically-acceptable salts, prodrugs, hydrates, or solvates
thereof, wherein: [0063] R.sub.1 is independently selected from
aryl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl,
furyl, thienyl, imidazolyl, thiazolyl, indolyl, oxazolyl,
isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, indazolyl,
1,2,4-thiadiazolyl, isothiazolyl, quinolinyl, isoquinolinyl, each
substituted with 1-4 R.sub.4 and R.sub.5; [0064] R.sub.4, at each
occurrence, is independently selected from H and C.sub.1-4 alkyl
substituted with 0-3 R.sub.e; [0065] R.sub.5, at each occurrence,
is independently selected from H, C.sub.1-4 alkyl substituted with
0-3 R.sub.e, F, Cl, Br, .dbd.O, CN, [0066] NO.sub.2, --OR.sub.b,
--S(O).sub.pR.sub.c, --CN, --OR.sub.b,
--(CH.sub.2).sub.rC(.dbd.O)R.sub.b,
--(CH.sub.2).sub.rNR.sub.aR.sub.a,
--(CH.sub.2).sub.rC(.dbd.O)NR.sub.aR.sub.a,
--(CH.sub.2).sub.rNHC(.dbd.O)R.sub.b,
--(CH.sub.2).sub.rNHC(.dbd.O)OR.sub.b,
--(CH.sub.2).sub.rOC(.dbd.O)NR.sub.aR.sub.a,
--(CH.sub.2).sub.rNHC(.dbd.O)NR.sub.aR.sub.a,
--(CH.sub.2).sub.rC(.dbd.O)OR.sub.b,
--(CH.sub.2).sub.rS(O).sub.2NR.sub.aR.sub.a,
--(CH.sub.2).sub.rNHS(O).sub.2NR.sub.aR.sub.a,
--(CH.sub.2).sub.rNHS(O).sub.2R.sub.c, (CH.sub.2).sub.r-carbocyclyl
substituted with 0-3 R.sub.e, and --(CH.sub.2).sub.r-heterocyclyl
substituted with 0-3 R.sub.e; [0067] R.sub.a, at each occurrence,
is independently selected from H, CN, C.sub.1-6 alkyl substituted
with 0-5 R.sub.e, C.sub.2-6 alkenyl substituted with 0-5 R.sub.e,
C.sub.2-6 alkynyl substituted with 0-5 R.sub.e,
--(CH.sub.2).sub.r--C.sub.3-10carbocyclyl substituted with 0-5
R.sub.e, and --(CH.sub.2).sub.r-heterocyclyl substituted with 0-5
R.sub.e; or R.sub.a and R.sub.a together with the nitrogen atom to
which they are both attached form a heterocyclic ring substituted
with 0-5 R.sub.e; [0068] R.sub.b, at each occurrence, is
independently selected from H, C.sub.1-6 alkyl substituted with 0-5
R.sub.e, C.sub.2-6 alkenyl substituted with 0-5 R.sub.e, C.sub.2-6
alkynyl substituted with 0-5 R.sub.e,
--(CH.sub.2).sub.r--C.sub.3-10carbocyclyl substituted with 0-5
R.sub.e, and --(CH.sub.2).sub.r-heterocyclyl substituted with 0-5
R.sub.e; [0069] R.sub.c, at each occurrence, is independently
selected from C.sub.1-6 alkyl substituted with 0-5 R.sub.e,
C.sub.2-6alkenyl substituted with 0-5 R.sub.e, C.sub.2-6alkynyl
substituted with 0-5 R.sub.e, C.sub.3-6carbocyclyl, and
heterocyclyl; [0070] R.sub.e, at each occurrence, is independently
selected from F, Cl, Br, CN, NO.sub.2, .dbd.O, C.sub.1-6 alkyl
substituted with 0-5 R.sub.f, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
--(CH.sub.2).sub.r--C.sub.3-6 cycloalkyl, CO.sub.2H,
--(CH.sub.2).sub.rOR.sub.f, SR.sub.f, and
--(CH.sub.2).sub.rNR.sub.fR.sub.f; [0071] R.sub.f, at each
occurrence, is independently selected from H, C.sub.1-5 alkyl,
C.sub.3-6 cycloalkyl, and phenyl, or R.sub.f and R.sub.f together
with the nitrogen atom to which they are both attached form a
heterocyclic ring optionally substituted with C.sub.1-4alkyl;
[0072] p, at each occurrence, is independently selected from zero,
1, and 2; [0073] r, at each occurrence, is independently selected
from zero, 1, 2, 3, and 4; and other variables are as defined in
Formula (II) above.
[0074] In another embodiment, there are disclosed compounds of
Formula (II) including enantiomers, diastereomers, tautomers,
pharmaceutically-acceptable salts, prodrugs, hydrates, or solvates
thereof, wherein: [0075] R.sub.1 is independently selected from
[0075] ##STR00004## ##STR00005## [0076] R.sub.4, at each
occurrence, is independently selected from H, C.sub.1-4 alkyl
substituted with 0-3 R.sub.e; [0077] R.sub.5, at each occurrence,
is independently selected from H, C.sub.1-4 alkyl substituted with
0-3 R.sub.e, F, Cl, Br, .dbd.O, CN, [0078] NO.sub.2, --OR.sub.b,
--S(O).sub.pR.sub.c, --CN, --OR.sub.b,
--(CH.sub.2).sub.rC(.dbd.O)R.sub.b,
--(CH.sub.2).sub.rNR.sub.aR.sub.a,
--(CH.sub.2).sub.rC(.dbd.O)NR.sub.aR.sub.a,
--(CH.sub.2).sub.rNHC(.dbd.O)R.sub.b,
--(CH.sub.2).sub.rNHC(.dbd.O)OR.sub.b,
--(CH.sub.2).sub.rOC(.dbd.O)NR.sub.aR.sub.a,
--(CH.sub.2).sub.rNHC(.dbd.O)NR.sub.aR.sub.a,
--(CH.sub.2).sub.rC(.dbd.O)OR.sub.b,
--(CH.sub.2).sub.rS(O).sub.2NR.sub.aR.sub.a,
--(CH.sub.2).sub.rNHS(O).sub.2NR.sub.aR.sub.a,
--(CH.sub.2).sub.rNHS(O).sub.2R.sub.c,
(CH.sub.2).sub.r--C.sub.3-6cycloalkyl, --(CH.sub.2).sub.r-aryl
substituted with 0-3 R.sub.e, and --(CH.sub.2).sub.r-heterocyclyl
substituted with 0-3 R.sub.e; [0079] R.sub.a, at each occurrence,
is independently selected from H, CN, C.sub.1-6 alkyl substituted
with 0-5 R.sub.e, C.sub.2-6 alkenyl substituted with 0-5 R.sub.e,
C.sub.2-6 alkynyl substituted with 0-5 R.sub.e,
--(CH.sub.2).sub.r--C.sub.3-10carbocyclyl substituted with 0-5
R.sub.e, and --(CH.sub.2).sub.r-heterocyclyl substituted with 0-5
R.sub.e; or R.sub.a and R.sub.a together with the nitrogen atom to
which they are both attached form a heterocyclic ring substituted
with 0-5 R.sub.e; [0080] R.sub.b, at each occurrence, is
independently selected from H, C.sub.1-6 alkyl substituted with 0-5
R.sub.e, C.sub.2-6 alkenyl substituted with 0-5 R.sub.e, C.sub.2-6
alkynyl substituted with 0-5 R.sub.e,
--(CH.sub.2).sub.r--C.sub.3-10carbocyclyl substituted with 0-5
R.sub.e, and --(CH.sub.2).sub.r-heterocyclyl substituted with 0-5
R.sub.e; [0081] R.sub.c, at each occurrence, is independently
selected from C.sub.1-6 alkyl substituted with 0-5 R.sub.e,
C.sub.2-6alkenyl substituted with 0-5 R.sub.e, C.sub.2-6alkynyl
substituted with 0-5 R.sub.e, C.sub.3-6carbocyclyl, and
heterocyclyl; [0082] R.sub.e, at each occurrence, is independently
selected from F, Cl, Br, CN, NO.sub.2, .dbd.O, C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, --(CH.sub.2).sub.r--C.sub.3-6
cycloalkyl, and CO.sub.2H; [0083] p, at each occurrence, is
independently selected from zero, 1, and 2; [0084] r, at each
occurrence, is independently selected from zero, 1, 2, 3, and 4;
[0085] and other variables are as defined in Formula (II)
above.
[0086] In another aspect, there are disclosed compounds of Formula
(III) including enantiomers, diastereomers, tautomers,
pharmaceutically-acceptable salts, prodrugs, hydrates, or solvates
thereof,
##STR00006##
wherein: [0087] R.sub.2 is independently selected from (i) alkyl
optionally substituted with F, Cl, Br, OR.sub.b, CN,
NR.sub.aR.sub.a, --C(.dbd.O)NR.sub.aR.sub.a, C.sub.2-6 alkenyl
substituted with 0-5 R.sub.e, C.sub.2-6 alkynyl substituted with
0-5 R.sub.e, carbocyclyl substituted with 1-8 R.sub.7, and
heterocyclyl comprising carbon atoms and 1 to 4 heteroatoms
selected from N, NR.sub.6, O, S, and substituted with 1-8 R.sub.7,
(ii) cycloalkyl substituted with 1-8 R.sub.7, and (iii)
cycloheteroalkyl substituted with 1-8 R.sub.7; [0088] R.sub.3a,
R.sub.3b, R.sub.3c, and R.sub.3d are independently selected from H,
CN, C.sub.1-4alkyl substituted with 1-3 [0089] R.sub.8,
--C(.dbd.O)OR.sub.b, --C(.dbd.O)NR.sub.aR.sub.a,
--C(.dbd.O)R.sub.b, --NR.sub.aC(.dbd.O)R.sub.b,
--NR.sub.aC(.dbd.O)OR.sub.b, --(CH.sub.2).sub.r-carbocyclyl
substituted with 1-3 R.sub.8, and --(CH.sub.2).sub.r-heterocyclyl
substituted with 1-3 R.sub.8; [0090] alternatively, R.sub.3a and
R.sub.3b, or R.sub.3c and R.sub.3d, together with the carbon atom
to which they are both attached form a spiral carbocyclic or
heterocyclic ring comprising carbon atoms and 1 to 4 heteroatoms
selected from N, O, S, each substituted with 1-5 R.sub.8; [0091]
alternatively, R.sub.3a and R.sub.3c or R.sub.3b and R.sub.3d
together form a heterocyclic ring comprising carbon atoms and 1 to
4 heteroatoms selected from N, O, S, and substituted with 1-5
R.sub.8; [0092] R.sub.5, at each occurrence, is independently
selected from H, C.sub.1-4 alkyl substituted with 0-3 R.sub.e, F,
Cl, Br, --S(O).sub.pR.sub.c, --CN, --OR.sub.b, NR.sub.aR.sub.a,
C.sub.3-6cycloalkyl, aryl substituted with 0-3 R.sub.e, and
heterocyclyl substituted with 0-3 R.sub.e; [0093] R.sub.6 is
independently selected from H, --C(.dbd.O)R.sub.b,
--CO(.dbd.O)R.sub.b, --S(O).sub.pR.sub.c, C.sub.1-6 alkyl
substituted with 0-5 R.sub.e,
--(CH.sub.2).sub.r--C.sub.3-6carbocyclyl substituted with 0-5
R.sub.e, and --(CH.sub.2).sub.r-heterocyclyl substituted with 0-5
R.sub.e; [0094] R.sub.7, at each occurrence, is independently
selected from H, F, Cl, Br, .dbd.O, --(CR.sub.dR.sub.d).sub.rCN,
NO.sub.2, --(CR.sub.dR.sub.d).sub.rOR.sub.b, --S(O).sub.pR.sub.c,
--C(.dbd.O)R.sub.b, --(CR.sub.dR.sub.d).sub.rNR.sub.aR.sub.a,
--(CR.sub.dR.sub.d).sub.rC(.dbd.O)NR.sub.aR.sub.a,
--NR.sub.aC(.dbd.O)R.sub.b, --NR.sub.aC(.dbd.O)OR.sub.b,
--OC(.dbd.O)NR.sub.aR.sub.a, --NR.sub.aC(.dbd.O)NR.sub.aR.sub.a,
--(CR.sub.dR.sub.d).sub.rC(.dbd.O)OR.sub.b,
--S(O).sub.2NR.sub.aR.sub.a, --NR.sub.aS(O).sub.2NR.sub.aR.sub.a,
--NR.sub.aS(O).sub.2R.sub.c, C.sub.1-6 alkyl substituted with 0-5
R.sub.e, --(CR.sub.dR.sub.d).sub.r--C.sub.3-6carbocyclyl
substituted with 0-5 R.sub.e, and
--(CR.sub.dR.sub.d).sub.r-heterocyclyl substituted with 0-5
R.sub.e; [0095] R.sub.8, at each occurrence, is independently
selected from H, F, Cl, Br, CN, C.sub.1-6 alkyl substituted with
0-5 R.sub.e, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
--(CH.sub.2).sub.r--C.sub.3-6 cycloalkyl substituted with 0-5
R.sub.e, --(CH.sub.2).sub.r-aryl substituted with 0-5 R.sub.e,
--(CH.sub.2).sub.r-heterocyclyl substituted with 0-5 R.sub.e,
CO.sub.2H, --(CH.sub.2).sub.rOR.sub.b, and
--(CH.sub.2).sub.rNR.sub.aR.sub.a; [0096] R.sub.a, at each
occurrence, is independently selected from H, CN, C.sub.1-6 alkyl
substituted with 0-5 R.sub.e, C.sub.2-6 alkenyl substituted with
0-5 R.sub.e, C.sub.2-6 alkynyl substituted with 0-5 R.sub.e,
--(CH.sub.2).sub.r--C.sub.3-10carbocyclyl substituted with 0-5
R.sub.e, and --(CH.sub.2).sub.r-heterocyclyl substituted with 0-5
R.sub.e; or R.sub.a and R.sub.a together with the nitrogen atom to
which they are both attached form a heterocyclic ring substituted
with 0-5 R.sub.e; [0097] R.sub.b, at each occurrence, is
independently selected from H, C.sub.1-6 alkyl substituted with 0-5
R.sub.e, C.sub.2-6 alkenyl substituted with 0-5 R.sub.e, C.sub.2-6
alkynyl substituted with 0-5 R.sub.e,
--(CH.sub.2).sub.r--C.sub.3-10carbocyclyl substituted with 0-5
R.sub.e, and --(CH.sub.2).sub.r-heterocyclyl substituted with 0-5
R.sub.e; [0098] R.sub.c, at each occurrence, is independently
selected from C.sub.1-6 alkyl substituted with 0-5 R.sub.e,
C.sub.2-6alkenyl substituted with 0-5 R.sub.e, C.sub.2-6alkynyl
substituted with 0-5 R.sub.e, C.sub.3-6carbocyclyl, and
heterocyclyl; [0099] R.sub.d, at each occurrence, is independently
selected from H and C.sub.1-4alkyl substituted with 0-5 R.sub.e;
[0100] R.sub.e, at each occurrence, is independently selected from
F, Cl, Br, CN, NO.sub.2, .dbd.O, CO.sub.2H, C.sub.1-6 alkyl
substituted with 0-5 R.sub.f, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
--(CH.sub.2).sub.r--C.sub.3-6 cycloalkyl,
--(CH.sub.2).sub.rOR.sub.f, SR.sub.f, and
--(CH.sub.2).sub.rNR.sub.fR.sub.f; [0101] R.sub.f, at each
occurrence, is independently selected from H, C.sub.1-5 alkyl,
C.sub.3-6 cycloalkyl, and phenyl, or R.sub.f and R.sub.f together
with the nitrogen atom to which they are both attached form a
heterocyclic ring optionally substituted with C.sub.1-4alkyl;
[0102] p, at each occurrence, is independently selected from zero,
1, and 2; and [0103] r, at each occurrence, is independently
selected from zero, 1, 2, 3, and 4.
[0104] In another embodiment, there are disclosed compounds of
formula (III) including enantiomers, diastereomers, tautomers,
pharmaceutically-acceptable salts, prodrugs, hydrates, or solvates
thereof, wherein: [0105] R.sub.2 is independently selected from
[0105] ##STR00007## ##STR00008## [0106] R.sub.3a and R.sub.3b are
independently selected from H, CH.sub.2CH.sub.3, CH.sub.3,
CH.sub.2OH, CH.sub.2CH.sub.2OH, CH.sub.2CH.sub.2OC.sub.1-4alkyl,
CH.sub.2F, CHF.sub.2, CH.sub.2CH.sub.2F, CF.sub.3,
CH.sub.2OCHF.sub.2, CH.sub.2CN, CH.sub.2CH.sub.2CN,
CH.sub.2OC.sub.1-4alkyl, C(CH.sub.3).sub.3, CH(CH.sub.3).sub.2,
C(CH.sub.3).sub.2OH, C(CH.sub.3).sub.2F,
C(.dbd.O)NH--C.sub.3-6cycloalkyl, C(.dbd.O)NH-heterocyclyl, and
--CH.sub.2-heterocyclyl, wherein the heterocyclyl is independently
selected from
[0106] ##STR00009## [0107] R.sub.3c and R.sub.3d are independently
selected from H, CH.sub.3, CH(CH.sub.3).sub.2, CF.sub.3, and
C.sub.3-6 cycloalkyl; [0108] R.sub.5, at each occurrence, is
independently selected from H, C.sub.1-4 alkyl substituted with 0-3
R.sub.e, F, Cl, Br, --S(O).sub.pR.sub.c, --CN, --OR.sub.b,
NR.sub.aR.sub.a, C.sub.3-6cycloalkyl, and aryl substituted with 0-3
R.sub.e; [0109] R.sub.7, at each occurrence, is independently
selected from H, F, Cl, Br, .dbd.O, --(CH.sub.2).sub.rCN, NO.sub.2,
--(CH.sub.2).sub.rOR.sub.b, --S(O).sub.pR.sub.c,
--C(.dbd.O)R.sub.b, --NR.sub.aR.sub.a, --C(.dbd.O)NR.sub.aR.sub.a,
--NHC(.dbd.O)R.sub.b, --NHC(.dbd.O)OR.sub.b,
--OC(.dbd.O)NR.sub.aR.sub.a, --NHC(.dbd.O)NR.sub.aR.sub.a,
--C(.dbd.O)OR.sub.b, --S(O).sub.2NR.sub.aR.sub.a,
--NHS(O).sub.2NR.sub.aR.sub.a, --NHS(O).sub.2R.sub.c, C.sub.1-6
alkyl substituted with 0-5 R.sub.e, aryl substituted with 0-5
R.sub.e, and heterocyclyl substituted with 0-5 R.sub.e; [0110]
R.sub.8, at each occurrence, is independently selected from H, F,
Cl, Br, CN, C.sub.1-6 alkyl substituted with 0-5 R.sub.e,
--(CH.sub.2).sub.r--C.sub.3-6 cycloalkyl substituted with 0-5
R.sub.e, --(CH.sub.2).sub.r-aryl substituted with 0-5 R.sub.e,
--(CH.sub.2).sub.r-heterocyclyl substituted with 0-5 R.sub.e,
CO.sub.2H, --(CH.sub.2).sub.rOR.sub.b, and
--(CH.sub.2).sub.rNR.sub.aR.sub.a; [0111] R.sub.a, at each
occurrence, is independently selected from H, CN, C.sub.1-6 alkyl
substituted with 0-5 R.sub.e, C.sub.2-6 alkenyl substituted with
0-5 R.sub.e, C.sub.2-6 alkynyl substituted with 0-5 R.sub.e,
--(CH.sub.2).sub.r--C.sub.3-10carbocyclyl substituted with 0-5
R.sub.e, and --(CH.sub.2).sub.r-heterocyclyl substituted with 0-5
R.sub.e; or R.sub.a and R.sub.a together with the nitrogen atom to
which they are both attached form a heterocyclic ring substituted
with 0-5 R.sub.e; [0112] R.sub.b, at each occurrence, is
independently selected from H, C.sub.1-6 alkyl substituted with 0-5
R.sub.e, C.sub.2-6 alkenyl substituted with 0-5 R.sub.e, C.sub.2-6
alkynyl substituted with 0-5 R.sub.e, aryl substituted with 0-5
R.sub.e, and heterocyclyl substituted with 0-5 R.sub.e; [0113]
R.sub.c, at each occurrence, is independently selected from
C.sub.1-6 alkyl substituted with 0-5 R.sub.e, C.sub.3-6carbocyclyl,
and heterocyclyl; [0114] R.sub.e, at each occurrence, is
independently selected from F, Cl, Br, CN, NO.sub.2, .dbd.O,
CO.sub.2H, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
and --(CH.sub.2).sub.r--C.sub.3-6 cycloalkyl; [0115] p, at each
occurrence, is independently selected from zero, 1, and 2; [0116]
r, at each occurrence, is independently selected from zero, 1, 2,
3, and 4; [0117] and other variables are as defined in Formula
(III) above.
[0118] In another embodiment, there are disclosed compounds of
formula (III) including enantiomers, diastereomers, tautomers,
pharmaceutically-acceptable salts, prodrugs, hydrates, or solvates
thereof, wherein: [0119] R.sub.2 is independently selected from
[0119] ##STR00010## [0120] R.sub.3a and R.sub.3b are independently
H; [0121] R.sub.3c and R.sub.3d are independently H; and [0122]
R.sub.5, at each occurrence, is independently selected from H, F,
Cl, and Br; [0123] and other variables are as defined in Formula
(III) above.
[0124] In another embodiment, there are disclosed compounds of
Formula (III) including enantiomers, diastereomers, tautomers,
pharmaceutically-acceptable salts, prodrugs, hydrates, or solvates
thereof, wherein: [0125] R.sub.2 is independently selected from
[0125] ##STR00011## [0126] R.sub.3a and R.sub.3b are independently
selected from H, CH.sub.2CH.sub.3, CH.sub.3, CH.sub.2OH,
CH.sub.2CH.sub.2OH, CH.sub.2CH.sub.2OC.sub.1-4alkyl, CH.sub.2F,
CHF.sub.2, CH.sub.2CH.sub.2F, CF.sub.3, CH.sub.2OCHF.sub.2,
CH.sub.2CN, CH.sub.2CH.sub.2CN, CH.sub.2OC.sub.1-4alkyl,
C(CH.sub.3).sub.3, CH(CH.sub.3).sub.2, C(CH.sub.3).sub.2OH,
C(CH.sub.3).sub.2F, C(.dbd.O)NH--C.sub.3-6cycloalkyl,
C(.dbd.O)NH-heterocyclyl, and --CH.sub.2-heterocyclyl, wherein the
heterocyclyl is independently selected from
[0126] ##STR00012## [0127] R.sub.3c and R.sub.3d are independently
selected from H, CH.sub.3, CH(CH.sub.3).sub.2, CF.sub.3, and
C.sub.3-6 cycloalkyl; [0128] R.sub.5, at each occurrence, is
independently selected from H, C.sub.1-4 alkyl substituted with 0-3
R.sub.e, F, Cl, Br, --S(O).sub.pR.sub.c, --CN, --OR.sub.b,
NR.sub.aR.sub.a, C.sub.3-6cycloalkyl, and aryl substituted with 0-3
R.sub.e; [0129] R.sub.7, at each occurrence, is independently
selected from H, F, Cl, Br, .dbd.O, --(CH.sub.2).sub.rCN, NO.sub.2,
--(CH.sub.2).sub.rOR.sub.b, --S(O).sub.pR.sub.c,
--C(.dbd.O)R.sub.b, --NR.sub.aR.sub.a, --C(.dbd.O)NR.sub.aR.sub.a,
--NHC(.dbd.O)R.sub.b, --NHC(.dbd.O)OR.sub.b,
--OC(.dbd.O)NR.sub.aR.sub.a, --NHC(.dbd.O)NR.sub.aR.sub.a,
--C(.dbd.O)OR.sub.b, --S(O).sub.2NR.sub.aR.sub.a,
--NHS(O).sub.2NR.sub.aR.sub.a, --NHS(O).sub.2R.sub.c, C.sub.1-6
alkyl substituted with 0-5 R.sub.e, aryl substituted with 0-5
R.sub.e, and heterocyclyl substituted with 0-5 R.sub.e; [0130]
R.sub.8, at each occurrence, is independently selected from H, F,
Cl, Br, CN, C.sub.1-6 alkyl substituted with 0-5 R.sub.e,
--(CH.sub.2).sub.r--C.sub.3-6 cycloalkyl substituted with 0-5
R.sub.e, --(CH.sub.2).sub.r-aryl substituted with 0-5 R.sub.e,
--(CH.sub.2).sub.r-heterocyclyl substituted with 0-5 R.sub.e,
CO.sub.2H, --(CH.sub.2).sub.rOR.sub.b, and
--(CH.sub.2).sub.rNR.sub.aR.sub.a; [0131] R.sub.a, at each
occurrence, is independently selected from H, CN, C.sub.1-6 alkyl
substituted with 0-5 R.sub.e, C.sub.2-6 alkenyl substituted with
0-5 R.sub.e, C.sub.2-6 alkynyl substituted with 0-5 R.sub.e,
--(CH.sub.2).sub.r--C.sub.3-10carbocyclyl substituted with 0-5
R.sub.e, and --(CH.sub.2).sub.r-heterocyclyl substituted with 0-5
R.sub.e; or R.sub.a and R.sub.a together with the nitrogen atom to
which they are both attached form a heterocyclic ring substituted
with 0-5 R.sub.e; [0132] R.sub.b, at each occurrence, is
independently selected from H, C.sub.1-6 alkyl substituted with 0-5
R.sub.e, C.sub.2-6 alkenyl substituted with 0-5 R.sub.e, C.sub.2-6
alkynyl substituted with 0-5 R.sub.e, aryl substituted with 0-5
R.sub.e, and heterocyclyl substituted with 0-5 R.sub.e; [0133]
R.sub.c, at each occurrence, is independently selected from
C.sub.1-6 alkyl substituted with 0-5 R.sub.e, C.sub.3-6carbocyclyl,
and heterocyclyl; [0134] R.sub.e, at each occurrence, is
independently selected from F, Cl, Br, CN, NO.sub.2, .dbd.O,
CO.sub.2H, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
and --(CH.sub.2).sub.r--C.sub.3-6 cycloalkyl; [0135] p, at each
occurrence, is independently selected from zero, 1, and 2; [0136]
r, at each occurrence, is independently selected from zero, 1, 2,
3, and 4; [0137] and other variables are as defined in Formula
(III) above.
[0138] In another embodiment, there are disclosed compounds of
Formula (III) including enantiomers, diastereomers, tautomers,
pharmaceutically-acceptable salts, prodrugs, hydrates, or solvates
thereof, wherein R.sub.3a and R.sub.3b, or R.sub.3c and R.sub.3d,
together with the carbon atom to which they are both attached form
a spiral carbocyclic or heterocyclic ring comprising carbon atoms
and 1 to 4 heteroatoms selected from N, O, S, each substituted with
1-5 R.sub.8; and other variables are as defined in Formula (III)
above.
[0139] In another aspect, there are disclosed compounds of Formula
(IV) including enantiomers, diastereomers, tautomers,
pharmaceutically-acceptable salts, prodrugs, hydrates, or solvates
thereof,
##STR00013##
wherein: [0140] Ring A is C.sub.3-6cycloalkyl or heterocyclyl;
[0141] R.sub.2 is independently selected from
[0141] ##STR00014## ##STR00015## ##STR00016## [0142] R.sub.5, at
each occurrence, is independently selected from H, C.sub.1-4 alkyl
substituted with 0-3 R.sub.e, F, Cl, Br, --S(O).sub.pR.sub.c, --CN,
--OR.sub.b, NR.sub.aR.sub.a, C.sub.3-6cycloalkyl, aryl substituted
with 0-3 R.sub.e, and heterocyclyl substituted with 0-3 R.sub.e;
[0143] R.sub.6 is independently selected from H,
--C(.dbd.O)R.sub.b, --CO(.dbd.O)R.sub.b, --S(O).sub.pR.sub.c,
C.sub.1-6 alkyl substituted with 0-5 R.sub.e,
--(CH.sub.2).sub.r--C.sub.3-6carbocyclyl substituted with 0-5
R.sub.e, and --(CH.sub.2).sub.r-heterocyclyl substituted with 0-5
R.sub.e; [0144] R.sub.7, at each occurrence, is independently
selected from H, F, Cl, Br, CN, [0145] NO.sub.2, --OR.sub.b,
--S(O).sub.pR.sub.c, --C(.dbd.O)R.sub.b, --NR.sub.aR.sub.a,
--C(.dbd.O)NR.sub.aR.sub.a, --NHC(.dbd.O)R.sub.b,
--NHC(.dbd.O)OR.sub.b, --OC(.dbd.O)NR.sub.aR.sub.a,
--NHC(.dbd.O)NR.sub.aR.sub.a, --C(.dbd.O)OR.sub.b,
--S(O).sub.2NR.sub.aR.sub.a, C.sub.1-6 alkyl substituted with 0-5
R.sub.e, aryl substituted with 0-5 R.sub.e, and heterocyclyl
substituted with 0-5 R.sub.e; [0146] R.sub.8, at each occurrence,
is independently selected from H, F, Cl, Br, CN, C.sub.1-6 alkyl
substituted with 0-5 R.sub.e, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
--(CH.sub.2).sub.r--C.sub.3-6 cycloalkyl substituted with 0-5
R.sub.e, --(CH.sub.2).sub.r-aryl substituted with 0-5 R.sub.e,
--(CH.sub.2).sub.r-heterocyclyl substituted with 0-5 R.sub.e,
CO.sub.2H, --(CH.sub.2).sub.rOR.sub.b, and
--(CH.sub.2).sub.rNR.sub.aR.sub.a; [0147] R.sub.a, at each
occurrence, is independently selected from H, CN, C.sub.1-6 alkyl
substituted with 0-5 R.sub.e, C.sub.2-6 alkenyl substituted with
0-5 R.sub.e, C.sub.2-6 alkynyl substituted with 0-5 R.sub.e,
--(CH.sub.2).sub.r--C.sub.3-10carbocyclyl substituted with 0-5
R.sub.e, and --(CH.sub.2).sub.r-heterocyclyl substituted with 0-5
R.sub.e; or R.sub.a and R.sub.a together with the nitrogen atom to
which they are both attached form a heterocyclic ring substituted
with 0-5 R.sub.e; [0148] R.sub.b, at each occurrence, is
independently selected from H, C.sub.1-6 alkyl substituted with 0-5
R.sub.e, C.sub.2-6 alkenyl substituted with 0-5 R.sub.e, C.sub.2-6
alkynyl substituted with 0-5 R.sub.e, aryl substituted with 0-5
R.sub.e, and heterocyclyl substituted with 0-5 R.sub.e; [0149]
R.sub.c, at each occurrence, is independently selected from
C.sub.1-6 alkyl substituted with 0-5 R.sub.e, C.sub.3-6carbocyclyl,
and heterocyclyl; [0150] R.sub.e, at each occurrence, is
independently selected from F, Cl, Br, CN, NO.sub.2, .dbd.O, and
CO.sub.2H, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
and --(CH.sub.2).sub.r--C.sub.3-6 cycloalkyl; [0151] p, at each
occurrence, is independently selected from zero, 1, and 2; and
[0152] r, at each occurrence, is independently selected from zero,
1, 2, 3, and 4.
[0153] In another embodiment, there are disclosed compounds of
Formula (III) including enantiomers, diastereomers, tautomers,
pharmaceutically-acceptable salts, prodrugs, hydrates, or solvates
thereof, wherein: [0154] R.sub.3a and R.sub.3c together form a
carbocyclic or heterocyclic ring comprising carbon atoms and 1 to 4
heteroatoms selected from N, O, S, wherein the carbocyclic or
heterocyclic ring is substituted with 1-5 R.sub.8; and [0155]
R.sub.3b and R.sub.3d are independently selected from H and
C.sub.1-4alkyl; [0156] and other variables are as defined in
Formula (III) above.
[0157] In another aspect, there are disclosed compounds of Formula
(V) including enantiomers, diastereomers, tautomers,
pharmaceutically-acceptable salts, prodrugs, hydrates, or solvates
thereof
##STR00017##
wherein: [0158] R.sub.2 is independently selected from
[0158] ##STR00018## ##STR00019## ##STR00020## [0159] R.sub.5, at
each occurrence, is independently selected from H, C.sub.1-4 alkyl
substituted with 0-3 R.sub.e, F, Cl, Br, --S(O).sub.pR.sub.c, --CN,
--OR.sub.b, NR.sub.aR.sub.a, C.sub.3-6cycloalkyl, aryl substituted
with 0-3 R.sub.e, and heterocyclyl substituted with 0-3 R.sub.e;
[0160] R.sub.6 is independently selected from H,
--C(.dbd.O)R.sub.b, --CO(.dbd.O)R.sub.b, --S(O).sub.pR.sub.c,
C.sub.1-6 alkyl substituted with 0-5 R.sub.e,
--(CH.sub.2).sub.r--C.sub.3-6carbocyclyl substituted with 0-5
R.sub.e, and --(CH.sub.2).sub.r-heterocyclyl substituted with 0-5
R.sub.e; [0161] R.sub.7, at each occurrence, is independently
selected from H, F, Cl, Br, CN, [0162] NO.sub.2, --OR.sub.b,
--S(O).sub.pR.sub.c, --C(.dbd.O)R.sub.b, --NR.sub.aR.sub.a,
--C(.dbd.O)NR.sub.aR.sub.a, --NHC(.dbd.O)R.sub.b,
--NHC(.dbd.O)OR.sub.b, --OC(.dbd.O)NR.sub.aR.sub.a,
--NHC(.dbd.O)NR.sub.aR.sub.a, --C(.dbd.O)OR.sub.b,
--S(O).sub.2NR.sub.aR.sub.a, C.sub.1-6 alkyl substituted with 0-5
R.sub.e, aryl substituted with 0-5 R.sub.e, and heterocyclyl
substituted with 0-5 R.sub.e; [0163] R.sub.a, at each occurrence,
is independently selected from H, CN, C.sub.1-6 alkyl substituted
with 0-5 R.sub.e, C.sub.2-6 alkenyl substituted with 0-5 R.sub.e,
C.sub.2-6 alkynyl substituted with 0-5 R.sub.e,
--(CH.sub.2).sub.r--C.sub.3-10carbocyclyl substituted with 0-5
R.sub.e, and --(CH.sub.2).sub.r-heterocyclyl substituted with 0-5
R.sub.e; or R.sub.a and R.sub.a together with the nitrogen atom to
which they are both attached form a heterocyclic ring substituted
with 0-5 R.sub.e; [0164] R.sub.b, at each occurrence, is
independently selected from H, C.sub.1-6 alkyl substituted with 0-5
R.sub.e, C.sub.2-6 alkenyl substituted with 0-5 R.sub.e, C.sub.2-6
alkynyl substituted with 0-5 R.sub.e, aryl substituted with 0-5
R.sub.e, and heterocyclyl substituted with 0-5 R.sub.e; [0165]
R.sub.c, at each occurrence, is independently selected from
C.sub.1-6 alkyl substituted with 0-5 R.sub.e, C.sub.3-6carbocyclyl,
and heterocyclyl; [0166] R.sub.e, at each occurrence, is
independently selected from F, Cl, Br, CN, NO.sub.2, .dbd.O,
CO.sub.2H, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
and --(CH.sub.2).sub.r--C.sub.3-6 cycloalkyl; [0167] p, at each
occurrence, is independently selected from zero, 1, and 2; and
[0168] r, at each occurrence, is independently selected from zero,
1, 2, 3, and 4.
[0169] All aspects of the compounds, including individual variable
definitions, may be combined with other aspects to form additional
compounds. For example, in one embodiment of Formula (I), R.sub.1
is phenyl and R.sub.2 is substituted alkyl. In another embodiment,
R.sub.1 is heteroaryl and R.sub.2 is C.sub.3-12cycloalkyl. In still
another embodiment, R.sub.1 is phenyl and R.sub.2 is
C.sub.3-12cycloalkyl.
[0170] In certain embodiments, the present invention includes
compounds of Formula (II), or stereoisomers, tautomers,
pharmaceutically acceptable salts, solvates, or prodrugs thereof,
wherein: [0171] R.sub.1 is phenyl substituted with 1-4 R.sub.5;
[0172] R.sub.2 is C.sub.1-6alkyl optionally substituted with F, Cl,
Br, OH, CN, and NR.sub.aR.sub.a; [0173] R.sub.3a and R.sub.3b are
independently selected from H, CH.sub.2CH.sub.3, CH.sub.3,
CH.sub.2OH, CH.sub.2CH.sub.2OH, CH.sub.2CH.sub.2OC.sub.1-4alkyl,
CH.sub.2F, CHF.sub.2, CH.sub.2CH.sub.2F, CF.sub.3,
CH.sub.2OCHF.sub.2, CH.sub.2CN, CH.sub.2CH.sub.2CN,
CH.sub.2OC.sub.1-4alkyl, C(CH.sub.3).sub.3, CH(CH.sub.3).sub.2,
C(CH.sub.3).sub.2OH, and C(CH.sub.3).sub.2F; [0174] R.sub.3c and
R.sub.3d are independently selected from H, CH.sub.3,
CH(CH.sub.3).sub.2, CF.sub.3, and C.sub.3-6 cycloalkyl; [0175]
R.sub.5, at each occurrence, is independently selected from H,
C.sub.1-4 alkyl substituted with 0-3 R.sub.e, F, Cl, Br, .dbd.O,
CN, NO.sub.2, --OR.sub.b, --(CH.sub.2).sub.rCN,
--(CH.sub.2).sub.rOR.sub.b, [0176]
(CH.sub.2).sub.rS(O).sub.pR.sub.c,
--(CH.sub.2).sub.rC(.dbd.O)R.sub.b,
--(CH.sub.2).sub.rNR.sub.aR.sub.a,
--(CH.sub.2).sub.rC(.dbd.O)NR.sub.aR.sub.a,
--(CH.sub.2).sub.rNR.sub.aC(.dbd.O)R.sub.b,
--(CH.sub.2).sub.rNR.sub.aC(.dbd.O)OR.sub.b,
--(CH.sub.2).sub.rOC(.dbd.O)NR.sub.aR.sub.a,
--(CH.sub.2).sub.rNR.sub.aC(.dbd.O)NR.sub.aR.sub.a,
--(CH.sub.2).sub.rC(.dbd.O)OR.sub.b,
--(CH.sub.2).sub.rS(O).sub.2NR.sub.aR.sub.a,
--(CH.sub.2).sub.rNR.sub.aS(O).sub.2NR.sub.aR.sub.a,
--(CH.sub.2).sub.rNR.sub.aS(O).sub.2R.sub.c,
(CH.sub.2).sub.r-carbocyclyl substituted with 0-3 R.sub.e, and
--(CH.sub.2).sub.r-heterocyclyl substituted with 0-3 R.sub.e;
[0177] R.sub.7, at each occurrence, is independently selected from
H, F, Cl, Br, .dbd.O, CN, [0178] NO.sub.2, --OR.sub.b,
--S(O).sub.pR.sub.c, --C(.dbd.O)R.sub.b,
--(CR.sub.dR.sub.d).sub.rNR.sub.aR.sub.a,
--(CR.sub.dR.sub.d).sub.rC(.dbd.O)NR.sub.aR.sub.a,
--NR.sub.aC(.dbd.O)R.sub.b, --NR.sub.aC(.dbd.O)OR.sub.b,
--OC(.dbd.O)NR.sub.aR.sub.a, --NR.sub.aC(.dbd.O)NR.sub.aR.sub.a,
--(CR.sub.dR.sub.d).sub.rC(.dbd.O)OR.sub.b,
--S(O).sub.2NR.sub.aR.sub.a, --NR.sub.aS(O).sub.2NR.sub.aR.sub.a,
--NR.sub.aS(O).sub.2R.sub.c, C.sub.1-6 alkyl substituted with 0-5
R.sub.e, --(CR.sub.dR.sub.d).sub.r--C.sub.3-6carbocyclyl
substituted with 0-5 R.sub.e, and
--(CR.sub.dR.sub.d).sub.r-heterocyclyl substituted with 0-5
R.sub.e; [0179] R.sub.a, at each occurrence, is independently
selected from H, CN, C.sub.1-6 alkyl substituted with 0-5 R.sub.e,
C.sub.2-6 alkenyl substituted with 0-5 R.sub.e, C.sub.2-6 alkynyl
substituted with 0-5 R.sub.e,
--(CH.sub.2).sub.r--C.sub.3-10carbocyclyl substituted with 0-5
R.sub.e, and --(CH.sub.2).sub.r-heterocyclyl substituted with 0-5
R.sub.e; or R.sub.a and R.sub.a together with the nitrogen atom to
which they are both attached form a heterocyclic ring substituted
with 0-5 R.sub.e; [0180] R.sub.b, at each occurrence, is
independently selected from H, C.sub.1-6 alkyl substituted with 0-5
R.sub.e, C.sub.2-6 alkenyl substituted with 0-5 R.sub.e, C.sub.2-6
alkynyl substituted with 0-5 R.sub.e,
--(CH.sub.2).sub.r--C.sub.3-10carbocyclyl substituted with 0-5
R.sub.e, and --(CH.sub.2).sub.r-heterocyclyl substituted with 0-5
R.sub.e; [0181] R.sub.c, at each occurrence, is independently
selected from C.sub.1-6 alkyl substituted with 0-5 R.sub.e,
C.sub.2-6alkenyl substituted with 0-5 R.sub.e, C.sub.2-6alkynyl
substituted with 0-5 R.sub.e, C.sub.3-6carbocyclyl, and
heterocyclyl; [0182] R.sub.e, at each occurrence, is independently
selected from F, Cl, Br, CN, NO.sub.2, .dbd.O, CO.sub.2H, C.sub.1-6
alkyl substituted with 0-5 R.sub.f, C.sub.2-6 alkenyl, C.sub.2-6
alkynyl, --(CH.sub.2).sub.r--C.sub.3-6 cycloalkyl,
--(CH.sub.2).sub.rOR.sub.f, SR.sub.f, and
--(CH.sub.2).sub.rNR.sub.fR.sub.f; [0183] R.sub.f, at each
occurrence, is independently selected from H, C.sub.1-5 alkyl,
C.sub.3-6 cycloalkyl, and phenyl, or R.sub.f and R.sub.f together
with the nitrogen atom to which they are both attached form a
heterocyclic ring optionally substituted with C.sub.1-4alkyl;
[0184] p, at each occurrence, is independently selected from zero,
1, and 2; and [0185] r, at each occurrence, is independently
selected from zero, 1, 2, 3, and 4.
[0186] In certain embodiments, the present invention includes
compounds of Formula (II), or stereoisomers, tautomers,
pharmaceutically acceptable salts, solvates, or prodrugs thereof,
wherein: [0187] R.sub.1 is phenyl substituted with 1-4 R.sub.5;
[0188] R.sub.2 is independently selected from
[0188] ##STR00021## ##STR00022## [0189] R.sub.3a and R.sub.3b are
independently selected from H, CH.sub.2CH.sub.3, CH.sub.3,
CH.sub.2OH, CH.sub.2CH.sub.2OH, CH.sub.2CH.sub.2OC.sub.1-4alkyl,
CH.sub.2F, CHF.sub.2, CH.sub.2CH.sub.2F, CF.sub.3,
CH.sub.2OCHF.sub.2, CH.sub.2CN, CH.sub.2CH.sub.2CN,
CH.sub.2OC.sub.1-4alkyl, C(CH.sub.3).sub.3, CH(CH.sub.3).sub.2,
C(CH.sub.3).sub.2OH, and C(CH.sub.3).sub.2F; [0190] R.sub.3c and
R.sub.3d are independently selected from H, CH.sub.3,
CH(CH.sub.3).sub.2, CF.sub.3, and C.sub.3-6 cycloalkyl; [0191]
R.sub.5, at each occurrence, is independently selected from H,
C.sub.1-4 alkyl substituted with 0-3 R.sub.e, F, Cl, Br, .dbd.O,
CN, NO.sub.2, --OR.sub.b, --(CH.sub.2).sub.rCN,
--(CH.sub.2).sub.rOR.sub.b, [0192]
(CH.sub.2).sub.rS(O).sub.pR.sub.c,
--(CH.sub.2).sub.rC(.dbd.O)R.sub.b,
--(CH.sub.2).sub.rNR.sub.aR.sub.a,
--(CH.sub.2).sub.rC(.dbd.O)NR.sub.aR.sub.a,
--(CH.sub.2).sub.rNR.sub.aC(.dbd.O)R.sub.b,
(CH.sub.2).sub.r-carbocyclyl substituted with 0-3 R.sub.e, and
--(CH.sub.2).sub.r-heterocyclyl substituted with 0-3 R.sub.e;
[0193] R.sub.7, at each occurrence, is independently selected from
H, F, Cl, Br, .dbd.O, CN, NO.sub.2, --OR.sub.b,
--S(O).sub.pR.sub.c, --C(.dbd.O)R.sub.b,
--(CR.sub.dR.sub.d).sub.rNR.sub.aR.sub.a,
--(CR.sub.dR.sub.d).sub.rC(.dbd.O)NR.sub.aR.sub.a,
--NR.sub.aC(.dbd.O)R.sub.b, --NR.sub.aC(.dbd.O)OR.sub.b,
--OC(.dbd.O)NR.sub.aR.sub.a, --NR.sub.aC(.dbd.O)NR.sub.aR.sub.a,
--(CR.sub.dR.sub.d).sub.rC(.dbd.O)OR.sub.b, C.sub.1-6 alkyl
substituted with 0-5 R.sub.e,
--(CR.sub.dR.sub.d).sub.r--C.sub.3-6carbocyclyl substituted with
0-5 R.sub.e, and --(CR.sub.dR.sub.d).sub.r-heterocyclyl substituted
with 0-5 R.sub.e; [0194] R.sub.a, at each occurrence, is
independently selected from H, CN, C.sub.1-6 alkyl substituted with
0-5 R.sub.e, C.sub.2-6 alkenyl substituted with 0-5 R.sub.e,
C.sub.2-6 alkynyl substituted with 0-5 R.sub.e,
--(CH.sub.2).sub.r--C.sub.3-10carbocyclyl substituted with 0-5
R.sub.e, and --(CH.sub.2).sub.r-heterocyclyl substituted with 0-5
R.sub.e; or R.sub.a and R.sub.a together with the nitrogen atom to
which they are both attached form a heterocyclic ring substituted
with 0-5 R.sub.e; [0195] R.sub.b, at each occurrence, is
independently selected from H, C.sub.1-6 alkyl substituted with 0-5
R.sub.e, C.sub.2-6 alkenyl substituted with 0-5 R.sub.e, C.sub.2-6
alkynyl substituted with 0-5 R.sub.e,
--(CH.sub.2).sub.r--C.sub.3-10carbocyclyl substituted with 0-5
R.sub.e, and --(CH.sub.2).sub.r-heterocyclyl substituted with 0-5
R.sub.e; [0196] R.sub.c, at each occurrence, is independently
selected from C.sub.1-6 alkyl substituted with 0-5 R.sub.e,
C.sub.2-6alkenyl substituted with 0-5 R.sub.e, C.sub.2-6alkynyl
substituted with 0-5 R.sub.e, C.sub.3-6carbocyclyl, and
heterocyclyl; [0197] R.sub.e, at each occurrence, is independently
selected from F, Cl, Br, CN, NO.sub.2, .dbd.O, CO.sub.2H, C.sub.1-6
alkyl substituted with 0-5 R.sub.f, C.sub.2-6 alkenyl, C.sub.2-6
alkynyl, --(CH.sub.2).sub.r--C.sub.3-6 cycloalkyl,
--(CH.sub.2).sub.rOR.sub.f, SR.sub.f, and
--(CH.sub.2).sub.rNR.sub.fR.sub.f; [0198] R.sub.f, at each
occurrence, is independently selected from H, C.sub.1-5 alkyl,
C.sub.3-6 cycloalkyl, and phenyl, or R.sub.f and R.sub.f together
with the nitrogen atom to which they are both attached form a
heterocyclic ring optionally substituted with C.sub.1-4alkyl;
[0199] p, at each occurrence, is independently selected from zero,
1, and 2; and [0200] r, at each occurrence, is independently
selected from zero, 1, 2, 3, and 4.
[0201] In certain embodiments, the present invention includes
compounds of Formula (II), or stereoisomers, tautomers,
pharmaceutically acceptable salts, solvates, or prodrugs thereof,
wherein: [0202] R.sub.1 is phenyl substituted with 1-4 R.sub.5;
[0203] R.sub.2 is cycloalkyl substituted with 1-5 R.sub.7; [0204]
R.sub.3a and R.sub.3b are independently selected from H,
CH.sub.2CH.sub.3, CH.sub.3, CH.sub.2OH, CH.sub.2CH.sub.2OH,
CH.sub.2CH.sub.2OC.sub.1-4alkyl, CH.sub.2F, CHF.sub.2,
CH.sub.2CH.sub.2F, CF.sub.3, CH.sub.2OCHF.sub.2, CH.sub.2CN,
CH.sub.2CH.sub.2CN, CH.sub.2OC.sub.1-4alkyl, C(CH.sub.3).sub.3,
CH(CH.sub.3).sub.2, C(CH.sub.3).sub.2OH, and C(CH.sub.3).sub.2F;
[0205] R.sub.3c and R.sub.3d are independently selected from H,
CH.sub.3, CH(CH.sub.3).sub.2, CF.sub.3, and C.sub.3-6 cycloalkyl;
[0206] R.sub.5, at each occurrence, is independently selected from
H, C.sub.1-4 alkyl substituted with 0-3 R.sub.e, F, Cl, Br, .dbd.O,
CN, NO.sub.2, --OR.sub.b, --(CH.sub.2).sub.rCN,
--(CH.sub.2).sub.rOR.sub.b, (CH.sub.2).sub.rS(O).sub.pR.sub.c,
--(CH.sub.2).sub.rC(.dbd.O)R.sub.b,
--(CH.sub.2).sub.rNR.sub.aR.sub.a,
--(CH.sub.2).sub.rC(.dbd.O)NR.sub.aR.sub.a,
--(CH.sub.2).sub.rNR.sub.aC(.dbd.O)R.sub.b,
--(CH.sub.2).sub.rNR.sub.aC(.dbd.O)OR.sub.b,
--(CH.sub.2).sub.rOC(.dbd.O)NR.sub.aR.sub.a,
--(CH.sub.2).sub.rNR.sub.aC(.dbd.O)NR.sub.aR.sub.a,
--(CH.sub.2).sub.rC(.dbd.O)OR.sub.b,
--(CH.sub.2).sub.rS(O).sub.2NR.sub.aR.sub.a,
--(CH.sub.2).sub.rNR.sub.aS(O).sub.2NR.sub.aR.sub.a,
--(CH.sub.2).sub.rNR.sub.aS(O).sub.2R.sub.c,
(CH.sub.2).sub.r-carbocyclyl substituted with 0-3 R.sub.e, and
--(CH.sub.2).sub.r-heterocyclyl substituted with 0-3 R.sub.e;
[0207] R.sub.7, at each occurrence, is independently selected from
H, F, Cl, Br, .dbd.O, CN, NO.sub.2, --OR.sub.b,
--S(O).sub.pR.sub.c, --C(.dbd.O)R.sub.b,
--(CR.sub.dR.sub.d).sub.rNR.sub.aR.sub.a,
--(CR.sub.dR.sub.d).sub.rC(.dbd.O)NR.sub.aR.sub.a,
--NR.sub.aC(.dbd.O)R.sub.b, --NR.sub.aC(.dbd.O)OR.sub.b,
--OC(.dbd.O)NR.sub.aR.sub.a, --NR.sub.aC(.dbd.O)NR.sub.aR.sub.a,
--(CR.sub.dR.sub.d).sub.rC(.dbd.O)OR.sub.b,
--S(O).sub.2NR.sub.aR.sub.a, --NR.sub.aS(O).sub.2NR.sub.aR.sub.a,
--NR.sub.aS(O).sub.2R.sub.c, C.sub.1-6 alkyl substituted with 0-5
R.sub.e, --(CR.sub.dR.sub.d).sub.r--C.sub.3-6carbocyclyl
substituted with 0-5 R.sub.e, and
--(CR.sub.dR.sub.d).sub.r-heterocyclyl substituted with 0-5
R.sub.e; [0208] R.sub.a, at each occurrence, is independently
selected from H, CN, C.sub.1-6 alkyl substituted with 0-5 R.sub.e,
C.sub.2-6 alkenyl substituted with 0-5 R.sub.e, C.sub.2-6 alkynyl
substituted with 0-5 R.sub.e,
--(CH.sub.2).sub.r--C.sub.3-10carbocyclyl substituted with 0-5
R.sub.e, and --(CH.sub.2).sub.r-heterocyclyl substituted with 0-5
R.sub.e; or R.sub.a and R.sub.a together with the nitrogen atom to
which they are both attached form a heterocyclic ring substituted
with 0-5 R.sub.e; [0209] R.sub.b, at each occurrence, is
independently selected from H, C.sub.1-6 alkyl substituted with 0-5
R.sub.e, C.sub.2-6 alkenyl substituted with 0-5 R.sub.e, C.sub.2-6
alkynyl substituted with 0-5 R.sub.e,
--(CH.sub.2).sub.r--C.sub.3-10carbocyclyl substituted with 0-5
R.sub.e, and --(CH.sub.2).sub.r-heterocyclyl substituted with 0-5
R.sub.e; [0210] R.sub.c, at each occurrence, is independently
selected from C.sub.1-6 alkyl substituted with 0-5 R.sub.e,
C.sub.2-6alkenyl substituted with 0-5 R.sub.e, C.sub.2-6alkynyl
substituted with 0-5 R.sub.e, C.sub.3-6carbocyclyl, and
heterocyclyl; [0211] R.sub.d, at each occurrence, is independently
selected from H and C.sub.1-4alkyl substituted with 0-5 R.sub.e;
[0212] R.sub.e, at each occurrence, is independently selected from
F, Cl, Br, CN, NO.sub.2, .dbd.O, CO.sub.2H, C.sub.1-6 alkyl
substituted with 0-5 R.sub.f, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
--(CH.sub.2).sub.r--C.sub.3-6 cycloalkyl,
--(CH.sub.2).sub.rOR.sub.f, SR.sub.f, and
--(CH.sub.2).sub.rNR.sub.fR.sub.f; [0213] R.sub.f, at each
occurrence, is independently selected from H, C.sub.1-5 alkyl,
C.sub.3-6 cycloalkyl, and phenyl, or R.sub.f and R.sub.f together
with the nitrogen atom to which they are both attached form a
heterocyclic ring optionally substituted with C.sub.1-4alkyl;
[0214] p, at each occurrence, is independently selected from zero,
1, and 2; and [0215] r, at each occurrence, is independently
selected from zero, 1, 2, 3, and 4.
[0216] In certain embodiments, the present invention includes
compounds of Formula (II), or stereoisomers, tautomers,
pharmaceutically acceptable salts, solvates, or prodrugs thereof,
wherein: [0217] R.sub.1 is phenyl substituted with 1-4 R.sub.5;
[0218] R.sub.2 is independently selected from
[0218] ##STR00023## [0219] R.sub.3a and R.sub.3b are independently
selected from H, CH.sub.2CH.sub.3, CH.sub.3, CH.sub.2OH,
CH.sub.2CH.sub.2OH, CH.sub.2CH.sub.2OC.sub.1-4alkyl, CH.sub.2F,
CHF.sub.2, CH.sub.2CH.sub.2F, CF.sub.3, CH.sub.2OCHF.sub.2,
CH.sub.2CN, CH.sub.2CH.sub.2CN, CH.sub.2OC.sub.1-4alkyl,
C(CH.sub.3).sub.3, CH(CH.sub.3).sub.2, C(CH.sub.3).sub.2OH, and
C(CH.sub.3).sub.2F; [0220] R.sub.3c and R.sub.3d are independently
selected from H, CH.sub.3, CH(CH.sub.3).sub.2, CF.sub.3, and
C.sub.3-6 cycloalkyl; [0221] R.sub.5, at each occurrence, is
independently selected from H, C.sub.1-4 alkyl substituted with 0-3
R.sub.e, F, Cl, Br, .dbd.O, CN, NO.sub.2, --OR.sub.b,
--(CH.sub.2).sub.rCN, --(CH.sub.2).sub.rOR.sub.b, [0222]
(CH.sub.2).sub.rS(O).sub.pR.sub.c,
--(CH.sub.2).sub.rC(.dbd.O)R.sub.b,
--(CH.sub.2).sub.rNR.sub.aR.sub.a,
--(CH.sub.2).sub.rC(.dbd.O)NR.sub.aR.sub.a,
--(CH.sub.2).sub.rNR.sub.aC(.dbd.O)R.sub.b,
--(CH.sub.2).sub.rNR.sub.aC(.dbd.O)OR.sub.b,
--(CH.sub.2).sub.rOC(.dbd.O)NR.sub.aR.sub.a,
--(CH.sub.2).sub.rNR.sub.aC(.dbd.O)NR.sub.aR.sub.a,
--(CH.sub.2).sub.rC(.dbd.O)OR.sub.b,
--(CH.sub.2).sub.rS(O).sub.2NR.sub.aR.sub.a,
--(CH.sub.2).sub.rNR.sub.aS(O).sub.2NR.sub.aR.sub.a,
--(CH.sub.2).sub.rNR.sub.aS(O).sub.2R.sub.c,
(CH.sub.2).sub.r-carbocyclyl substituted with 0-3 R.sub.e, and
--(CH.sub.2).sub.r-heterocyclyl substituted with 0-3 R.sub.e;
[0223] R.sub.7, at each occurrence, is independently selected from
H, F, Cl, Br, .dbd.O, CN, NO.sub.2, --OR.sub.b,
--S(O).sub.pR.sub.c, --C(.dbd.O)R.sub.b,
--(CR.sub.dR.sub.d).sub.rNR.sub.aR.sub.a,
--(CR.sub.dR.sub.d).sub.rC(.dbd.O)NR.sub.aR.sub.a,
--NR.sub.aC(.dbd.O)R.sub.b, --NR.sub.aC(.dbd.O)OR.sub.b,
--OC(.dbd.O)NR.sub.aR.sub.a, --NR.sub.aC(.dbd.O)NR.sub.aR.sub.a,
--(CR.sub.dR.sub.d).sub.rC(.dbd.O)OR.sub.b,
--S(O).sub.2NR.sub.aR.sub.a, --NR.sub.aS(O).sub.2NR.sub.aR.sub.a,
--NR.sub.aS(O).sub.2R.sub.c, C.sub.1-6 alkyl substituted with 0-5
R.sub.e, --(CR.sub.dR.sub.d).sub.r--C.sub.3-6carbocyclyl
substituted with 0-5 R.sub.e, and
--(CR.sub.dR.sub.d).sub.r-heterocyclyl substituted with 0-5
R.sub.e; [0224] R.sub.a, at each occurrence, is independently
selected from H, CN, C.sub.1-6 alkyl substituted with 0-5 R.sub.e,
C.sub.2-6 alkenyl substituted with 0-5 R.sub.e, C.sub.2-6 alkynyl
substituted with 0-5 R.sub.e,
--(CH.sub.2).sub.r--C.sub.3-10carbocyclyl substituted with 0-5
R.sub.e, and --(CH.sub.2).sub.r-heterocyclyl substituted with 0-5
R.sub.e; or R.sub.a and R.sub.a together with the nitrogen atom to
which they are both attached form a heterocyclic ring substituted
with 0-5 R.sub.e; [0225] R.sub.b, at each occurrence, is
independently selected from H, C.sub.1-6 alkyl substituted with 0-5
R.sub.e, C.sub.2-6 alkenyl substituted with 0-5 R.sub.e, C.sub.2-6
alkynyl substituted with 0-5 R.sub.e,
--(CH.sub.2).sub.r--C.sub.3-10carbocyclyl substituted with 0-5
R.sub.e, and --(CH.sub.2).sub.r-heterocyclyl substituted with 0-5
R.sub.e; [0226] R.sub.c, at each occurrence, is independently
selected from C.sub.1-6 alkyl substituted with 0-5 R.sub.e,
C.sub.2-6alkenyl substituted with 0-5 R.sub.e, C.sub.2-6alkynyl
substituted with 0-5 R.sub.e, C.sub.3-6carbocyclyl, and
heterocyclyl; [0227] R.sub.d, at each occurrence, is independently
selected from H and C.sub.1-4alkyl substituted with 0-5 R.sub.e;
[0228] R.sub.e, at each occurrence, is independently selected from
F, Cl, Br, CN, NO.sub.2, .dbd.O, CO.sub.2H, C.sub.1-6 alkyl
substituted with 0-5 R.sub.f, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
--(CH.sub.2).sub.r--C.sub.3-6 cycloalkyl,
--(CH.sub.2).sub.rOR.sub.f, SR.sub.f, and
--(CH.sub.2).sub.rNR.sub.fR.sub.f; [0229] R.sub.f, at each
occurrence, is independently selected from H, C.sub.1-5 alkyl,
C.sub.3-6 cycloalkyl, and phenyl, or R.sub.f and R.sub.f together
with the nitrogen atom to which they are both attached form a
heterocyclic ring optionally substituted with C.sub.1-4alkyl;
[0230] p, at each occurrence, is independently selected from zero,
1, and 2; and [0231] r, at each occurrence, is independently
selected from zero, 1, 2, 3, and 4.
[0232] In certain embodiments, the present invention includes
compounds of Formula (II), or stereoisomers, tautomers,
pharmaceutically acceptable salts, solvates, or prodrugs thereof,
wherein: [0233] R.sub.1 is phenyl substituted with 1-4 R.sub.5;
[0234] R.sub.2 is cycloheteroalkyl comprising carbon atoms and 1 to
4 heteroatoms selected from N, O, S, and substituted with 1-8
R.sub.7; [0235] R.sub.3a and R.sub.3b are independently selected
from H, CH.sub.2CH.sub.3, CH.sub.3, CH.sub.2OH, CH.sub.2CH.sub.2OH,
CH.sub.2CH.sub.2OC.sub.1-4alkyl, CH.sub.2F, CHF.sub.2,
CH.sub.2CH.sub.2F, CF.sub.3, CH.sub.2OCHF.sub.2, CH.sub.2CN,
CH.sub.2CH.sub.2CN, CH.sub.2OC.sub.1-4alkyl, C(CH.sub.3).sub.3,
CH(CH.sub.3).sub.2, C(CH.sub.3).sub.2OH, and C(CH.sub.3).sub.2F;
[0236] R.sub.3c and R.sub.3d are independently selected from H,
CH.sub.3, CH(CH.sub.3).sub.2, CF.sub.3, and C.sub.3-6 cycloalkyl;
[0237] R.sub.5, at each occurrence, is independently selected from
H, C.sub.1-4 alkyl substituted with 0-3 R.sub.e, F, Cl, Br, .dbd.O,
CN, NO.sub.2, --OR.sub.b, --(CH.sub.2).sub.rCN,
--(CH.sub.2).sub.rOR.sub.b, [0238]
(CH.sub.2).sub.rS(O).sub.pR.sub.c,
--(CH.sub.2).sub.rC(.dbd.O)R.sub.b,
--(CH.sub.2).sub.rNR.sub.aR.sub.a,
--(CH.sub.2).sub.rC(.dbd.O)NR.sub.aR.sub.a,
--(CH.sub.2).sub.rNR.sub.aC(.dbd.O)R.sub.b,
--(CH.sub.2).sub.rNR.sub.aC(.dbd.O)OR.sub.b,
--(CH.sub.2).sub.rOC(.dbd.O)NR.sub.aR.sub.a,
--(CH.sub.2).sub.rNR.sub.aC(.dbd.O)NR.sub.aR.sub.a,
--(CH.sub.2).sub.rC(.dbd.O)OR.sub.b,
--(CH.sub.2).sub.rS(O).sub.2NR.sub.aR.sub.a,
--(CH.sub.2).sub.rNR.sub.aS(O).sub.2NR.sub.aR.sub.a,
--(CH.sub.2).sub.rNR.sub.aS(O).sub.2R.sub.c,
(CH.sub.2).sub.r-carbocyclyl substituted with 0-3 R.sub.e, and
--(CH.sub.2).sub.r-heterocyclyl substituted with 0-3 R.sub.e;
[0239] R.sub.6 is independently selected from H,
--C(.dbd.O)R.sub.b, --CO(.dbd.O)R.sub.b, --S(O).sub.pR.sub.c,
C.sub.1-6 alkyl substituted with 0-5 R.sub.e,
--(CH.sub.2).sub.r--C.sub.3-6carbocyclyl substituted with 0-5
R.sub.e, and --(CH.sub.2).sub.r-heterocyclyl substituted with 0-5
R.sub.e; [0240] R.sub.7, at each occurrence, is independently
selected from H, F, Cl, Br, .dbd.O, CN, [0241] NO.sub.2,
--OR.sub.b, --S(O).sub.pR.sub.c, --C(.dbd.O)R.sub.b,
--(CR.sub.dR.sub.d).sub.rNR.sub.aR.sub.a,
--(CR.sub.dR.sub.d).sub.rC(.dbd.O)NR.sub.aR.sub.a,
--NR.sub.aC(.dbd.O)R.sub.b, --NR.sub.aC(.dbd.O)OR.sub.b,
--OC(.dbd.O)NR.sub.aR.sub.a, --NR.sub.aC(.dbd.O)NR.sub.aR.sub.a,
--(CR.sub.dR.sub.d).sub.rC(.dbd.O)OR.sub.b,
--S(O).sub.2NR.sub.aR.sub.a, --NR.sub.aS(O).sub.2NR.sub.aR.sub.a,
--NR.sub.aS(O).sub.2R.sub.c, C.sub.1-6 alkyl substituted with 0-5
R.sub.e, --(CR.sub.dR.sub.d).sub.r--C.sub.3-6carbocyclyl
substituted with 0-5 R.sub.e, and
--(CR.sub.dR.sub.d).sub.r-heterocyclyl substituted with 0-5
R.sub.e; [0242] R.sub.a, at each occurrence, is independently
selected from H, CN, C.sub.1-6 alkyl substituted with 0-5 R.sub.e,
C.sub.2-6 alkenyl substituted with 0-5 R.sub.e, C.sub.2-6 alkynyl
substituted with 0-5 R.sub.e,
--(CH.sub.2).sub.r--C.sub.3-10carbocyclyl substituted with 0-5
R.sub.e, and --(CH.sub.2).sub.r-heterocyclyl substituted with 0-5
R.sub.e; or R.sub.a and R.sub.a together with the nitrogen atom to
which they are both attached form a heterocyclic ring substituted
with 0-5 R.sub.e; [0243] R.sub.b, at each occurrence, is
independently selected from H, C.sub.1-6 alkyl substituted with 0-5
R.sub.e, C.sub.2-6 alkenyl substituted with 0-5 R.sub.e, C.sub.2-6
alkynyl substituted with 0-5 R.sub.e,
--(CH.sub.2).sub.r--C.sub.3-10carbocyclyl substituted with 0-5
R.sub.e, and --(CH.sub.2).sub.r-heterocyclyl substituted with 0-5
R.sub.e; [0244] R.sub.c, at each occurrence, is independently
selected from C.sub.1-6 alkyl substituted with 0-5 R.sub.e,
C.sub.2-6alkenyl substituted with 0-5 R.sub.e, C.sub.2-6alkynyl
substituted with 0-5 R.sub.e, C.sub.3-6carbocyclyl, and
heterocyclyl; [0245] R.sub.d, at each occurrence, is independently
selected from H and C.sub.1-4alkyl substituted with 0-5 R.sub.e;
[0246] R.sub.e, at each occurrence, is independently selected from
F, Cl, Br, CN, NO.sub.2, .dbd.O, CO.sub.2H, C.sub.1-6 alkyl
substituted with 0-5 R.sub.f, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
--(CH.sub.2).sub.r--C.sub.3-6 cycloalkyl,
--(CH.sub.2).sub.rOR.sub.f, SR.sub.f, and
--(CH.sub.2).sub.rNR.sub.fR.sub.f; [0247] R.sub.f, at each
occurrence, is independently selected from H, C.sub.1-5 alkyl,
C.sub.3-6 cycloalkyl, and phenyl, or R.sub.f and R.sub.f together
with the nitrogen atom to which they are both attached form a
heterocyclic ring optionally substituted with C.sub.1-4alkyl;
[0248] p, at each occurrence, is independently selected from zero,
1, and 2; and [0249] r, at each occurrence, is independently
selected from zero, 1, 2, 3, and 4.
[0250] In certain embodiments, the present invention includes
compounds of Formula (II), or stereoisomers, tautomers,
pharmaceutically acceptable salts, solvates, or prodrugs thereof,
wherein: [0251] R.sub.1 is phenyl substituted with 1-4 R.sub.5;
[0252] R.sub.2 is independently selected from
[0252] ##STR00024## [0253] R.sub.3a and R.sub.3b are independently
selected from H, CH.sub.2CH.sub.3, CH.sub.3, CH.sub.2OH,
CH.sub.2CH.sub.2OH, CH.sub.2CH.sub.2OC.sub.1-4alkyl, CH.sub.2F,
CHF.sub.2, CH.sub.2CH.sub.2F, CF.sub.3, CH.sub.2OCHF.sub.2,
CH.sub.2CN, CH.sub.2CH.sub.2CN, CH.sub.2OC.sub.1-4alkyl,
C(CH.sub.3).sub.3, CH(CH.sub.3).sub.2, C(CH.sub.3).sub.2OH, and
C(CH.sub.3).sub.2F; [0254] R.sub.3c and R.sub.3d are independently
selected from H, CH.sub.3, CH(CH.sub.3).sub.2, CF.sub.3, and
C.sub.3-6 cycloalkyl; [0255] R.sub.5, at each occurrence, is
independently selected from H, C.sub.1-4 alkyl substituted with 0-3
R.sub.e, F, Cl, Br, .dbd.O, CN, NO.sub.2, --OR.sub.b,
--(CH.sub.2).sub.rCN, --(CH.sub.2).sub.rOR.sub.b, [0256]
(CH.sub.2).sub.rS(O).sub.pR.sub.c,
--(CH.sub.2).sub.rC(.dbd.O)R.sub.b,
--(CH.sub.2).sub.rNR.sub.aR.sub.a,
--(CH.sub.2).sub.rC(.dbd.O)NR.sub.aR.sub.a,
--(CH.sub.2).sub.rNR.sub.aC(.dbd.O)R.sub.b,
--(CH.sub.2).sub.rNR.sub.aC(.dbd.O)OR.sub.b,
--(CH.sub.2).sub.rOC(.dbd.O)NR.sub.aR.sub.a,
--(CH.sub.2).sub.rNR.sub.aC(.dbd.O)NR.sub.aR.sub.a,
--(CH.sub.2).sub.rC(.dbd.O)OR.sub.b,
--(CH.sub.2).sub.rS(O).sub.2NR.sub.aR.sub.a,
--(CH.sub.2).sub.rNR.sub.aS(O).sub.2NR.sub.aR.sub.a,
--(CH.sub.2).sub.rNR.sub.aS(O).sub.2R.sub.c,
(CH.sub.2).sub.r-carbocyclyl substituted with 0-3 R.sub.e, and
--(CH.sub.2).sub.r-heterocyclyl substituted with 0-3 R.sub.e;
[0257] R.sub.6 is independently selected from H,
--C(.dbd.O)R.sub.b, --CO(.dbd.O)R.sub.b, --S(O).sub.pR.sub.c,
C.sub.1-6 alkyl substituted with 0-5 R.sub.e,
--(CH.sub.2).sub.r--C.sub.3-6carbocyclyl substituted with 0-5
R.sub.e, and --(CH.sub.2).sub.r-heterocyclyl substituted with 0-5
R.sub.e; [0258] R.sub.7, at each occurrence, is independently
selected from H, F, Cl, Br, .dbd.O, CN, [0259] NO.sub.2,
--OR.sub.b, --S(O).sub.pR.sub.c, --C(.dbd.O)R.sub.b,
--(CR.sub.dR.sub.d).sub.rNR.sub.aR.sub.a,
--(CR.sub.dR.sub.d).sub.rC(.dbd.O)NR.sub.aR.sub.a,
--NR.sub.aC(.dbd.O)R.sub.b, --NR.sub.aC(.dbd.O)OR.sub.b,
--OC(.dbd.O)NR.sub.aR.sub.a, --NR.sub.aC(.dbd.O)NR.sub.aR.sub.a,
--(CR.sub.dR.sub.d).sub.rC(.dbd.O)OR.sub.b, C.sub.1-6 alkyl
substituted with 0-5 R.sub.e,
--(CR.sub.dR.sub.d).sub.r--C.sub.3-6carbocyclyl substituted with
0-5 R.sub.e, and --(CR.sub.dR.sub.d).sub.r-heterocyclyl substituted
with 0-5 R.sub.e; [0260] R.sub.a, at each occurrence, is
independently selected from H, CN, C.sub.1-6 alkyl substituted with
0-5 R.sub.e, C.sub.2-6 alkenyl substituted with 0-5 R.sub.e,
C.sub.2-6 alkynyl substituted with 0-5 R.sub.e,
--(CH.sub.2).sub.r--C.sub.3-10carbocyclyl substituted with 0-5
R.sub.e, and --(CH.sub.2).sub.r-heterocyclyl substituted with 0-5
R.sub.e; or R.sub.a and R.sub.a together with the nitrogen atom to
which they are both attached form a heterocyclic ring substituted
with 0-5 R.sub.e; [0261] R.sub.b, at each occurrence, is
independently selected from H, C.sub.1-6 alkyl substituted with 0-5
R.sub.e, C.sub.2-6 alkenyl substituted with 0-5 R.sub.e, C.sub.2-6
alkynyl substituted with 0-5 R.sub.e,
--(CH.sub.2).sub.r--C.sub.3-10carbocyclyl substituted with 0-5
R.sub.e, and --(CH.sub.2).sub.r-heterocyclyl substituted with 0-5
R.sub.e; [0262] R.sub.c, at each occurrence, is independently
selected from C.sub.1-6 alkyl substituted with 0-5 R.sub.e,
C.sub.2-6alkenyl substituted with 0-5 R.sub.e, C.sub.2-6alkynyl
substituted with 0-5 R.sub.e, C.sub.3-6carbocyclyl, and
heterocyclyl; [0263] R.sub.d, at each occurrence, is independently
selected from H and C.sub.1-4alkyl substituted with 0-5 R.sub.e;
[0264] R.sub.e, at each occurrence, is independently selected from
F, Cl, Br, CN, NO.sub.2, .dbd.O, CO.sub.2H, C.sub.1-6 alkyl
substituted with 0-5 R.sub.f, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
--(CH.sub.2).sub.r--C.sub.3-6 cycloalkyl,
--(CH.sub.2).sub.rOR.sub.f, SR.sub.f, and
--(CH.sub.2).sub.rNR.sub.fR.sub.f; [0265] R.sub.f, at each
occurrence, is independently selected from H, C.sub.1-5 alkyl,
C.sub.3-6 cycloalkyl, and phenyl, or R.sub.f and R.sub.f together
with the nitrogen atom to which they are both attached form a
heterocyclic ring optionally substituted with C.sub.1-4alkyl;
[0266] p, at each occurrence, is independently selected from zero,
1, and 2; and [0267] r, at each occurrence, is independently
selected from zero, 1, 2, 3, and 4.
[0268] In certain embodiments, the present invention includes
compounds of Formula (II), or stereoisomers, tautomers,
pharmaceutically acceptable salts, solvates, or prodrugs thereof,
wherein: [0269] R.sub.1 is phenyl substituted with 1-4 R.sub.5;
[0270] R.sub.2 is independently selected from (i) C.sub.1-8alkyl,
optionally substituted with F, Cl, Br, OH, CN, NR.sub.aR.sub.a,
C(.dbd.O)NR.sub.aR.sub.a, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
carbocyclyl substituted with 1-8 R.sub.7, and heterocyclyl
comprising carbon atoms and 1 to 4 heteroatoms selected from N,
NR.sub.6, O, S, and substituted with 1-8 R.sub.7, (ii)
C.sub.3-20cycloalkyl substituted with 1-8 R.sub.7, and (iii)
cycloheteroalkyl substituted with 1-8 R.sub.7; [0271] R.sub.3a and
R.sub.3b together with the carbon atom to which they are both
attached form a spiral carbocyclic or heterocyclic ring comprising
carbon atoms and 1 to 4 heteroatoms selected from N, O, S, each
substituted with 0-5 R.sub.e; [0272] R.sub.4 is independently
selected from H and C.sub.1-4 alkyl substituted with 0-3 R.sub.e;
[0273] R.sub.5, at each occurrence, is independently selected from
H, C.sub.1-4 alkyl substituted with 0-3 R.sub.e, F, Cl, Br, .dbd.O,
CN, NO.sub.2, --OR.sub.b, --(CH.sub.2).sub.rCN,
--(CH.sub.2).sub.rOR.sub.b, [0274]
(CH.sub.2).sub.rS(O).sub.pR.sub.c,
--(CH.sub.2).sub.rC(.dbd.O)R.sub.b,
--(CH.sub.2).sub.rNR.sub.aR.sub.a,
--(CH.sub.2).sub.rC(.dbd.O)NR.sub.aR.sub.a,
--(CH.sub.2).sub.rNR.sub.aC(.dbd.O)R.sub.b,
--(CH.sub.2).sub.rNR.sub.aC(.dbd.O)OR.sub.b,
--(CH.sub.2).sub.rOC(.dbd.O)NR.sub.aR.sub.a,
--(CH.sub.2).sub.rNR.sub.aC(.dbd.O)NR.sub.aR.sub.a,
--(CH.sub.2).sub.rC(.dbd.O)OR.sub.b,
--(CH.sub.2).sub.rS(O).sub.2NR.sub.aR.sub.a,
--(CH.sub.2).sub.rNR.sub.aS(O).sub.2NR.sub.aR.sub.a,
--(CH.sub.2).sub.rNR.sub.aS(O).sub.2R.sub.c,
(CH.sub.2).sub.r-carbocyclyl substituted with 0-3 R.sub.e, and
--(CH.sub.2).sub.r-heterocyclyl substituted with 0-3 R.sub.e;
[0275] R.sub.6 is independently selected from H,
--C(.dbd.O)R.sub.b, --CO(.dbd.O)R.sub.b, --S(O).sub.pR.sub.c,
C.sub.1-6 alkyl substituted with 0-5 R.sub.e,
--(CH.sub.2).sub.r--C.sub.3-6carbocyclyl substituted with 0-5
R.sub.e, and --(CH.sub.2).sub.r-heterocyclyl substituted with 0-5
R.sub.e; [0276] R.sub.7, at each occurrence, is independently
selected from H, F, Cl, Br, .dbd.O, --(CR.sub.dR.sub.d).sub.rCN,
NO.sub.2, --(CR.sub.dR.sub.d).sub.rOR.sub.b, --S(O).sub.pR.sub.c,
--C(.dbd.O)R.sub.b, --(CR.sub.dR.sub.d).sub.rNR.sub.aR.sub.a,
--(CR.sub.dR.sub.d).sub.rC(.dbd.O)NR.sub.aR.sub.a,
--NR.sub.aC(.dbd.O)R.sub.b, --NR.sub.aC(.dbd.O)OR.sub.b,
--OC(.dbd.O)NR.sub.aR.sub.a, --NR.sub.aC(.dbd.O)NR.sub.aR.sub.a,
--(CR.sub.dR.sub.d).sub.rC(.dbd.O)OR.sub.b,
--S(O).sub.2NR.sub.aR.sub.a, --NR.sub.aS(O).sub.2NR.sub.aR.sub.a,
--NR.sub.aS(O).sub.2R.sub.c, C.sub.1-6 alkyl substituted with 0-5
R.sub.e, --(CR.sub.dR.sub.d).sub.r--C.sub.3-6carbocyclyl
substituted with 0-5 R.sub.e, and
--(CR.sub.dR.sub.d).sub.r-heterocyclyl substituted with 0-5
R.sub.e; [0277] R.sub.8, at each occurrence, is independently
selected from H, F, Cl, Br, CN, C.sub.1-6 alkyl substituted with
0-5 R.sub.e, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
--(CH.sub.2).sub.r--C.sub.3-6 cycloalkyl substituted with 0-5
R.sub.e, --(CH.sub.2).sub.r-aryl substituted with 0-5 R.sub.e,
--(CH.sub.2).sub.r-heterocyclyl substituted with 0-5 R.sub.e,
CO.sub.2H, --(CH.sub.2).sub.rOR.sub.b, and
--(CH.sub.2).sub.rNR.sub.aR.sub.a; [0278] R.sub.a, at each
occurrence, is independently selected from H, CN, C.sub.1-6 alkyl
substituted with 0-5 R.sub.e, C.sub.2-6 alkenyl substituted with
0-5 R.sub.e, C.sub.2-6 alkynyl substituted with 0-5 R.sub.e,
--(CH.sub.2).sub.r--C.sub.3-10carbocyclyl substituted with 0-5
R.sub.e, and --(CH.sub.2).sub.r-heterocyclyl substituted with 0-5
R.sub.e; or R.sub.a and R.sub.a together with the nitrogen atom to
which they are both attached form a heterocyclic ring substituted
with 0-5 R.sub.e; [0279] R.sub.b, at each occurrence, is
independently selected from H, C.sub.1-6 alkyl substituted with 0-5
R.sub.e, C.sub.2-6 alkenyl substituted with 0-5 R.sub.e, C.sub.2-6
alkynyl substituted with 0-5 R.sub.e,
--(CH.sub.2).sub.r--C.sub.3-10carbocyclyl substituted with 0-5
R.sub.e, and --(CH.sub.2).sub.r-heterocyclyl substituted with 0-5
R.sub.e; [0280] R.sub.c, at each occurrence, is independently
selected from C.sub.1-6 alkyl substituted with 0-5 R.sub.e,
C.sub.2-6alkenyl substituted with 0-5 R.sub.e, C.sub.2-6alkynyl
substituted with 0-5 R.sub.e, C.sub.3-6carbocyclyl, and
heterocyclyl; [0281] R.sub.d, at each occurrence, is independently
selected from H and C.sub.1-4alkyl substituted with 0-5 R.sub.e;
[0282] R.sub.e, at each occurrence, is independently selected from
F, Cl, Br, CN, NO.sub.2, .dbd.O, C.sub.1-6 alkyl substituted with
0-5 R.sub.f, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
--(CH.sub.2).sub.r--C.sub.3-6 cycloalkyl, CO.sub.2H,
--(CH.sub.2).sub.rOR.sub.f, SR.sub.f, and
--(CH.sub.2).sub.rNR.sub.fR.sub.f; [0283] R.sub.f, at each
occurrence, is independently selected from H, C.sub.1-5 alkyl,
C.sub.3-6 cycloalkyl, and phenyl, or R.sub.f and R.sub.f together
with the nitrogen atom to which they are both attached form a
heterocyclic ring optionally substituted with C.sub.1-4alkyl;
[0284] p, at each occurrence, is independently selected from zero,
1, and 2; and [0285] r, at each occurrence, is independently
selected from zero, 1, 2, 3, and 4.
[0286] In certain embodiments, the present invention includes
compounds of Formula (II), or stereoisomers, tautomers,
pharmaceutically acceptable salts, solvates, or prodrugs thereof,
wherein: [0287] R.sub.1 is phenyl substituted with 1-4 R.sub.5;
[0288] R.sub.2 is independently selected from (i) C.sub.1-8alkyl,
optionally substituted with F, Cl, Br, OH, CN, NR.sub.aR.sub.a,
C(.dbd.O)NR.sub.aR.sub.a, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
carbocyclyl substituted with 1-8 R.sub.7, and heterocyclyl
comprising carbon atoms and 1 to 4 heteroatoms selected from N,
NR.sub.6, O, S, and substituted with 1-8 R.sub.7, (ii)
C.sub.3-20cycloalkyl substituted with 1-8 R.sub.7, and (iii)
cycloheteroalkyl substituted with 1-8 R.sub.7; [0289] R.sub.3a and
R.sub.3c or R.sub.3b and R.sub.3d together form a heterocyclic ring
comprising carbon atoms and 1 to 4 heteroatoms selected from N, O,
S, and substituted with 0-5 R.sub.e; [0290] R.sub.4 is
independently selected from H and C.sub.1-4 alkyl substituted with
0-3 R.sub.e; [0291] R.sub.5, at each occurrence, is independently
selected from H, C.sub.1-4 alkyl substituted with 0-3 R.sub.e, F,
Cl, Br, .dbd.O, CN, NO.sub.2, --OR.sub.b, --(CH.sub.2).sub.rCN,
--(CH.sub.2).sub.rOR.sub.b, [0292]
(CH.sub.2).sub.rS(O).sub.pR.sub.c,
--(CH.sub.2).sub.rC(.dbd.O)R.sub.b,
--(CH.sub.2).sub.rNR.sub.aR.sub.a,
--(CH.sub.2).sub.rC(.dbd.O)NR.sub.aR.sub.a,
--(CH.sub.2).sub.rNR.sub.aC(.dbd.O)R.sub.b,
--(CH.sub.2).sub.rNR.sub.aC(.dbd.O)OR.sub.b,
--(CH.sub.2).sub.rOC(.dbd.O)NR.sub.aR.sub.a,
--(CH.sub.2).sub.rNR.sub.aC(.dbd.O)NR.sub.aR.sub.a,
--(CH.sub.2).sub.rC(.dbd.O)OR.sub.b,
--(CH.sub.2).sub.rS(O).sub.2NR.sub.aR.sub.a,
--(CH.sub.2).sub.rNR.sub.aS(O).sub.2NR.sub.aR.sub.a,
--(CH.sub.2).sub.rNR.sub.aS(O).sub.2R.sub.c,
(CH.sub.2).sub.r-carbocyclyl substituted with 0-3 R.sub.e, and
--(CH.sub.2).sub.r-heterocyclyl substituted with 0-3 R.sub.e;
[0293] R.sub.6 is independently selected from H,
--C(.dbd.O)R.sub.b, --CO(.dbd.O)R.sub.b, --S(O).sub.pR.sub.c,
C.sub.1-6 alkyl substituted with 0-5 R.sub.e,
--(CH.sub.2).sub.r--C.sub.3-6carbocyclyl substituted with 0-5
R.sub.e, and --(CH.sub.2).sub.r-heterocyclyl substituted with 0-5
R.sub.e; [0294] R.sub.7, at each occurrence, is independently
selected from H, F, Cl, Br, .dbd.O, --(CR.sub.dR.sub.d).sub.rCN,
NO.sub.2, --(CR.sub.dR.sub.d).sub.rOR.sub.b, --S(O).sub.pR.sub.c,
--C(.dbd.O)R.sub.b, --(CR.sub.dR.sub.d).sub.rNR.sub.aR.sub.a,
--(CR.sub.dR.sub.d).sub.rC(.dbd.O)NR.sub.aR.sub.a,
--NR.sub.aC(.dbd.O)R.sub.b, --NR.sub.aC(.dbd.O)OR.sub.b,
--OC(.dbd.O)NR.sub.aR.sub.a, --NR.sub.aC(.dbd.O)NR.sub.aR.sub.a,
--(CR.sub.dR.sub.d).sub.rC(.dbd.O)OR.sub.b,
--S(O).sub.2NR.sub.aR.sub.a, --NR.sub.aS(O).sub.2NR.sub.aR.sub.a,
--NR.sub.aS(O).sub.2R.sub.c, C.sub.1-6 alkyl substituted with 0-5
R.sub.e, --(CR.sub.dR.sub.d).sub.r--C.sub.3-6carbocyclyl
substituted with 0-5 R.sub.e, and
--(CR.sub.dR.sub.d).sub.r-heterocyclyl substituted with 0-5
R.sub.e; [0295] R.sub.8, at each occurrence, is independently
selected from H, F, Cl, Br, CN, C.sub.1-6 alkyl substituted with
0-5 R.sub.e, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
--(CH.sub.2).sub.r--C.sub.3-6 cycloalkyl substituted with 0-5
R.sub.e, --(CH.sub.2).sub.r-aryl substituted with 0-5 R.sub.e,
--(CH.sub.2).sub.r-heterocyclyl substituted with 0-5 R.sub.e,
CO.sub.2H, --(CH.sub.2).sub.rOR.sub.b, and
--(CH.sub.2).sub.rNR.sub.aR.sub.a; [0296] R.sub.a, at each
occurrence, is independently selected from H, CN, C.sub.1-6 alkyl
substituted with 0-5 R.sub.e, C.sub.2-6 alkenyl substituted with
0-5 R.sub.e, C.sub.2-6 alkynyl substituted with 0-5 R.sub.e,
--(CH.sub.2).sub.r--C.sub.3-10carbocyclyl substituted with 0-5
R.sub.e, and --(CH.sub.2).sub.r-heterocyclyl substituted with 0-5
R.sub.e; or R.sub.a and R.sub.a together with the nitrogen atom to
which they are both attached form a heterocyclic ring substituted
with 0-5 R.sub.e; [0297] R.sub.b, at each occurrence, is
independently selected from H, C.sub.1-6 alkyl substituted with 0-5
R.sub.e, C.sub.2-6 alkenyl substituted with 0-5 R.sub.e, C.sub.2-6
alkynyl substituted with 0-5 R.sub.e,
--(CH.sub.2).sub.r--C.sub.3-10carbocyclyl substituted with 0-5
R.sub.e, and --(CH.sub.2).sub.r-heterocyclyl substituted with 0-5
R.sub.e; [0298] R.sub.c, at each occurrence, is independently
selected from C.sub.1-6 alkyl substituted with 0-5 R.sub.e,
C.sub.2-6alkenyl substituted with 0-5 R.sub.e, C.sub.2-6alkynyl
substituted with 0-5 R.sub.e, C.sub.3-6carbocyclyl, and
heterocyclyl; [0299] R.sub.d, at each occurrence, is independently
selected from H and C.sub.1-4alkyl substituted with 0-5 R.sub.e;
[0300] R.sub.e, at each occurrence, is independently selected from
F, Cl, Br, CN, NO.sub.2, .dbd.O, C.sub.1-6 alkyl substituted with
0-5 R.sub.f, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
--(CH.sub.2).sub.r--C.sub.3-6 cycloalkyl, CO.sub.2H,
--(CH.sub.2).sub.rOR.sub.f, SR.sub.f, and
--(CH.sub.2).sub.rNR.sub.fR.sub.f; [0301] R.sub.f, at each
occurrence, is independently selected from H, C.sub.1-5 alkyl,
C.sub.3-6 cycloalkyl, and phenyl, or R.sub.f and R.sub.f together
with the nitrogen atom to which they are both attached form a
heterocyclic ring optionally substituted with C.sub.1-4alkyl;
[0302] p, at each occurrence, is independently selected from zero,
1, and 2; and [0303] r, at each occurrence, is independently
selected from zero, 1, 2, 3, and 4.
[0304] In another embodiment, there are disclosed compounds of
formula (VI):
##STR00025##
including enantiomers, diastereomers, tautomers,
pharmaceutically-acceptable salts, prodrugs, hydrates, or solvates
thereof, wherein: [0305] R.sub.2 is independently selected from
[0305] ##STR00026## [0306] R.sub.3a and R.sub.3b are independently
H; [0307] R.sub.3c and R.sub.3d are independently H; [0308]
R.sub.5, at each occurrence, is independently selected from H, F,
Cl, and Br.
[0309] In certain embodiments, the present invention includes
compounds of Formula (II), or stereoisomers, tautomers,
pharmaceutically acceptable salts, solvates, or prodrugs thereof,
wherein: [0310] R.sub.1 is heteroaryl comprising carbon atoms and 1
to 3 heteroatoms selected from N, NR.sub.4, O, S, wherein the
heteroaryl is substituted with 1-5 R.sub.5 and selected from
thiazolyl, oxazolyl, pyrazolyl, triazolyl, tetrazolyl,
thiadiazolyl, isoxazolyl, imidazolyl, pyridyl, pyrimidinyl,
pyrazinyl, pyridazinyl, indolyl, indazolyl, isoindolyl, indolinyl,
isoindolinyl, benzimidazolyl, benzothiazolyl, benzotriazolyl,
quinolinyl, and isoquinolinyl; [0311] R.sub.2 is C.sub.1-4alkyl
optionally substituted with F, Cl, Br, OH, CN, and NR.sub.aR.sub.a;
[0312] R.sub.3a, R.sub.3b, R.sub.3e, R.sub.3d, R.sub.3e and
R.sub.3f are independently selected from H, CN, C.sub.1-4alkyl
substituted with 1-3 [0313] R.sub.8, --C(.dbd.O)OR.sub.b,
--C(.dbd.O)NR.sub.aR.sub.a, --C(.dbd.O)R.sub.b,
--NR.sub.aC(.dbd.O)R.sub.b, --NR.sub.aC(.dbd.O)OR.sub.b,
--(CH.sub.2).sub.r-carbocyclyl substituted with 1-3 R.sub.8, and
--(CH.sub.2).sub.r-heterocyclyl substituted with 1-3 R.sub.8;
[0314] alternatively, R.sub.3a and R.sub.3b, or Rae and R.sub.3d,
or R.sub.3e and R.sub.3f, together with the carbon atom to which
they are both attached form a spiral carbocyclic or heterocyclic
ring comprising carbon atoms and 1 to 4 heteroatoms selected from
N, O, S, each substituted with 1-5 R.sub.8; [0315] alternatively,
R.sub.3a and Rae or R.sub.3b and R.sub.3d together form a
heterocyclic ring comprising carbon atoms and 1 to 4 heteroatoms
selected from N, O, S, and substituted with 1-5 R.sub.8; [0316]
R.sub.4 is independently selected from H and C.sub.1-4 alkyl
substituted with 0-3 R.sub.e; [0317] R.sub.5, at each occurrence,
is independently selected from H, C.sub.1-4 alkyl substituted with
0-3 R.sub.e, F, Cl, Br, .dbd.O, CN, NO.sub.2, --OR.sub.b,
--(CH.sub.2).sub.rCN, --(CH.sub.2).sub.rOR.sub.b, [0318]
(CH.sub.2).sub.rS(O).sub.pR.sub.c,
--(CH.sub.2).sub.rC(.dbd.O)R.sub.b,
--(CH.sub.2).sub.rNR.sub.aR.sub.a,
--(CH.sub.2).sub.rC(.dbd.O)NR.sub.aR.sub.a,
--(CH.sub.2).sub.rNR.sub.aC(.dbd.O)R.sub.b,
--(CH.sub.2).sub.rNR.sub.aC(.dbd.O)OR.sub.b,
--(CH.sub.2).sub.rOC(.dbd.O)NR.sub.aR.sub.a,
--(CH.sub.2).sub.rNR.sub.aC(.dbd.O)NR.sub.aR.sub.a,
--(CH.sub.2).sub.rC(.dbd.O)OR.sub.b,
--(CH.sub.2).sub.rS(O).sub.2NR.sub.aR.sub.a,
--(CH.sub.2).sub.rNR.sub.aS(O).sub.2NR.sub.aR.sub.a,
--(CH.sub.2).sub.rNR.sub.aS(O).sub.2R.sub.c,
(CH.sub.2).sub.r-carbocyclyl substituted with 0-3 R.sub.e, and
--(CH.sub.2).sub.r-heterocyclyl substituted with 0-3 R.sub.e;
[0319] R.sub.7, at each occurrence, is independently selected from
H, F, Cl, Br, .dbd.O, CN, [0320] NO.sub.2, --OR.sub.b,
--S(O).sub.pR.sub.c, --C(.dbd.O)R.sub.b,
--(CR.sub.dR.sub.d).sub.rNR.sub.aR.sub.a,
--(CR.sub.dR.sub.d).sub.rC(.dbd.O)NR.sub.aR.sub.a,
--NR.sub.aC(.dbd.O)R.sub.b, --NR.sub.aC(.dbd.O)OR.sub.b,
--OC(.dbd.O)NR.sub.aR.sub.a, --NR.sub.aC(.dbd.O)NR.sub.aR.sub.a,
--(CR.sub.dR.sub.d).sub.rC(.dbd.O)OR.sub.b,
--S(O).sub.2NR.sub.aR.sub.a, --NR.sub.aS(O).sub.2NR.sub.aR.sub.a,
--NR.sub.aS(O).sub.2R.sub.c, C.sub.1-6 alkyl substituted with 0-5
R.sub.e, --(CR.sub.dR.sub.d).sub.r--C.sub.3-6carbocyclyl
substituted with 0-5 R.sub.e, and
--(CR.sub.dR.sub.d).sub.r-heterocyclyl substituted with 0-5
R.sub.e; [0321] R.sub.a, at each occurrence, is independently
selected from H, CN, C.sub.1-6 alkyl substituted with 0-5 R.sub.e,
C.sub.2-6 alkenyl substituted with 0-5 R.sub.e, C.sub.2-6 alkynyl
substituted with 0-5 R.sub.e,
--(CH.sub.2).sub.r--C.sub.3-10carbocyclyl substituted with 0-5
R.sub.e, and --(CH.sub.2).sub.r-heterocyclyl substituted with 0-5
R.sub.e; or R.sub.a and R.sub.a together with the nitrogen atom to
which they are both attached form a heterocyclic ring substituted
with 0-5 R.sub.e; [0322] R.sub.b, at each occurrence, is
independently selected from H, C.sub.1-6 alkyl substituted with 0-5
R.sub.e, C.sub.2-6 alkenyl substituted with 0-5 R.sub.e, C.sub.2-6
alkynyl substituted with 0-5 R.sub.e,
--(CH.sub.2).sub.r--C.sub.3-10carbocyclyl substituted with 0-5
R.sub.e, and --(CH.sub.2).sub.r-heterocyclyl substituted with 0-5
R.sub.e; [0323] R.sub.c, at each occurrence, is independently
selected from C.sub.1-6 alkyl substituted with 0-5 R.sub.e,
C.sub.2-6alkenyl substituted with 0-5 R.sub.e, C.sub.2-6alkynyl
substituted with 0-5 R.sub.e, C.sub.3-6carbocyclyl, and
heterocyclyl; [0324] R.sub.e, at each occurrence, is independently
selected from F, Cl, Br, CN, NO.sub.2, .dbd.O, CO.sub.2H, C.sub.1-6
alkyl substituted with 0-5 R.sub.f, C.sub.2-6 alkenyl, C.sub.2-6
alkynyl, --(CH.sub.2).sub.r--C.sub.3-6 cycloalkyl,
--(CH.sub.2).sub.rOR.sub.f, SR.sub.f, and
--(CH.sub.2).sub.rNR.sub.fR.sub.f; [0325] R.sub.f, at each
occurrence, is independently selected from H, C.sub.1-5 alkyl,
C.sub.3-6 cycloalkyl, and phenyl, or R.sub.f and R.sub.f together
with the nitrogen atom to which they are both attached form a
heterocyclic ring optionally substituted with C.sub.1-4alkyl;
[0326] p, at each occurrence, is independently selected from zero,
1, and 2; and [0327] r, at each occurrence, is independently
selected from zero, 1, 2, 3, and 4.
[0328] In certain embodiments, the present invention includes
compounds of Formula (II), or stereoisomers, tautomers,
pharmaceutically acceptable salts, solvates, or prodrugs thereof,
wherein: [0329] R.sub.1 is heteroaryl comprising carbon atoms and 1
to 3 heteroatoms selected from N, NR.sub.4, O, S, wherein the
heteroaryl is substituted with 1-5 R.sub.5 and selected from
thiazolyl, oxazolyl, pyrazolyl, triazolyl, tetrazolyl,
thiadiazolyl, isoxazolyl, imidazolyl, pyridyl, pyrimidinyl,
pyrazinyl, pyridazinyl, indolyl, indazolyl, isoindolyl, indolinyl,
isoindolinyl, benzimidazolyl, benzothiazolyl, benzotriazolyl,
quinolinyl, and isoquinolinyl; [0330] R.sub.2 is cycloalkyl
substituted with 1-5 R.sub.7; [0331] R.sub.3a, R.sub.3b, R.sub.3c,
R.sub.3d, R.sub.3e and R.sub.3f are independently selected from H,
CN, C.sub.1-4alkyl substituted with 1-3 [0332] R.sub.8,
--C(.dbd.O)OR.sub.b, --C(.dbd.O)NR.sub.aR.sub.a,
--C(.dbd.O)R.sub.b, --NR.sub.aC(.dbd.O)R.sub.b,
--NR.sub.aC(.dbd.O)OR.sub.b, --(CH.sub.2).sub.r-carbocyclyl
substituted with 1-3 R.sub.8, and --(CH.sub.2).sub.r-heterocyclyl
substituted with 1-3 R.sub.8; [0333] alternatively, R.sub.3a and
R.sub.3b, or R.sub.3c and R.sub.3d, or R.sub.3e and R.sub.3f,
together with the carbon atom to which they are both attached form
a spiral carbocyclic or heterocyclic ring comprising carbon atoms
and 1 to 4 heteroatoms selected from N, O, S, each substituted with
1-5 R.sub.8; [0334] alternatively, R.sub.3a and R.sub.3c or
R.sub.3b and R.sub.3d together form a heterocyclic ring comprising
carbon atoms and 1 to 4 heteroatoms selected from N, O, S, and
substituted with 1-5 R.sub.8; [0335] R.sub.4 is independently
selected from H and C.sub.1-4 alkyl substituted with 0-3 R.sub.e;
[0336] R.sub.5, at each occurrence, is independently selected from
H, C.sub.1-4 alkyl substituted with 0-3 R.sub.e, F, Cl, Br, .dbd.O,
CN, NO.sub.2, --OR.sub.b, --(CH.sub.2).sub.rCN,
--(CH.sub.2).sub.rOR.sub.b, [0337]
(CH.sub.2).sub.rS(O).sub.pR.sub.c,
--(CH.sub.2).sub.rC(.dbd.O)R.sub.b,
--(CH.sub.2).sub.rNR.sub.aR.sub.a,
--(CH.sub.2).sub.rC(.dbd.O)NR.sub.aR.sub.a,
--(CH.sub.2).sub.rNR.sub.aC(.dbd.O)R.sub.b,
--(CH.sub.2).sub.rNR.sub.aC(.dbd.O)OR.sub.b,
--(CH.sub.2).sub.rOC(.dbd.O)NR.sub.aR.sub.a,
--(CH.sub.2).sub.rNR.sub.aC(.dbd.O)NR.sub.aR.sub.a,
--(CH.sub.2).sub.rC(.dbd.O)OR.sub.b,
--(CH.sub.2).sub.rS(O).sub.2NR.sub.aR.sub.a,
--(CH.sub.2).sub.rNR.sub.aS(O).sub.2NR.sub.aR.sub.a,
--(CH.sub.2).sub.rNR.sub.aS(O).sub.2R.sub.c,
(CH.sub.2).sub.r-carbocyclyl substituted with 0-3 R.sub.e, and
--(CH.sub.2).sub.r-heterocyclyl substituted with 0-3 R.sub.e;
[0338] R.sub.7, at each occurrence, is independently selected from
H, F, Cl, Br, .dbd.O, CN, [0339] NO.sub.2, --OR.sub.b,
--S(O).sub.pR.sub.c, --C(.dbd.O)R.sub.b,
--(CR.sub.dR.sub.d).sub.rNR.sub.aR.sub.a,
--(CR.sub.dR.sub.d).sub.rC(.dbd.O)NR.sub.aR.sub.a,
--NR.sub.aC(.dbd.O)R.sub.b, --NR.sub.aC(.dbd.O)OR.sub.b,
--OC(.dbd.O)NR.sub.aR.sub.a, --NR.sub.aC(.dbd.O)NR.sub.aR.sub.a,
--(CR.sub.dR.sub.d).sub.rC(.dbd.O)OR.sub.b,
--S(O).sub.2NR.sub.aR.sub.a, --NR.sub.aS(O).sub.2NR.sub.aR.sub.a,
--NR.sub.aS(O).sub.2R.sub.c, C.sub.1-6 alkyl substituted with 0-5
R.sub.e, --(CR.sub.dR.sub.d).sub.r--C.sub.3-6carbocyclyl
substituted with 0-5 R.sub.e, and
--(CR.sub.dR.sub.d).sub.r-heterocyclyl substituted with 0-5
R.sub.e; [0340] R.sub.a, at each occurrence, is independently
selected from H, CN, C.sub.1-6 alkyl substituted with 0-5 R.sub.e,
C.sub.2-6 alkenyl substituted with 0-5 R.sub.e, C.sub.2-6 alkynyl
substituted with 0-5 R.sub.e,
--(CH.sub.2).sub.r--C.sub.3-10carbocyclyl substituted with 0-5
R.sub.e, and --(CH.sub.2).sub.r-heterocyclyl substituted with 0-5
R.sub.e; or R.sub.a and R.sub.a together with the nitrogen atom to
which they are both attached form a heterocyclic ring substituted
with 0-5 R.sub.e; [0341] R.sub.b, at each occurrence, is
independently selected from H, C.sub.1-6 alkyl substituted with 0-5
R.sub.e, C.sub.2-6 alkenyl substituted with 0-5 R.sub.e, C.sub.2-6
alkynyl substituted with 0-5 R.sub.e,
--(CH.sub.2).sub.r--C.sub.3-10carbocyclyl substituted with 0-5
R.sub.e, and --(CH.sub.2).sub.r-heterocyclyl substituted with 0-5
R.sub.e; [0342] R.sub.c, at each occurrence, is independently
selected from C.sub.1-6 alkyl substituted with 0-5 R.sub.e,
C.sub.2-6alkenyl substituted with 0-5 R.sub.e, C.sub.2-6alkynyl
substituted with 0-5 R.sub.e, C.sub.3-6carbocyclyl, and
heterocyclyl; [0343] R.sub.d, at each occurrence, is independently
selected from H and C.sub.1-4alkyl substituted with 0-5 R.sub.e;
[0344] R.sub.e, at each occurrence, is independently selected from
F, Cl, Br, CN, NO.sub.2, .dbd.O, CO.sub.2H, C.sub.1-6 alkyl
substituted with 0-5 R.sub.f, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
--(CH.sub.2).sub.r--C.sub.3-6 cycloalkyl,
--(CH.sub.2).sub.rOR.sub.f, SR.sub.f, and
--(CH.sub.2).sub.rNR.sub.fR.sub.f; [0345] R.sub.f, at each
occurrence, is independently selected from H, C.sub.1-5 alkyl,
C.sub.3-6 cycloalkyl, and phenyl, or R.sub.f and R.sub.f together
with the nitrogen atom to which they are both attached form a
heterocyclic ring optionally substituted with C.sub.1-4alkyl;
[0346] p, at each occurrence, is independently selected from zero,
1, and 2; and [0347] r, at each occurrence, is independently
selected from zero, 1, 2, 3, and 4.
[0348] In certain embodiments, the present invention includes
compounds of Formula (II), or stereoisomers, tautomers,
pharmaceutically acceptable salts, solvates, or prodrugs thereof,
wherein: [0349] R.sub.1 is heteroaryl comprising carbon atoms and 1
to 3 heteroatoms selected from N, NR.sub.4, O, S, wherein the
heteroaryl is substituted with 1-5 R.sub.5 and selected from
thiazolyl, oxazolyl, pyrazolyl, triazolyl, tetrazolyl,
thiadiazolyl, isoxazolyl, imidazolyl, pyridyl, pyrimidinyl,
pyrazinyl, pyridazinyl, indolyl, indazolyl, isoindolyl, indolinyl,
isoindolinyl, benzimidazolyl, benzothiazolyl, benzotriazolyl,
quinolinyl, and isoquinolinyl; [0350] R.sub.2 is cycloheteroalkyl
comprising carbon atoms and 1 to 4 heteroatoms selected from N, O,
S, and substituted with 1-8 R.sub.7; [0351] R.sub.3a, R.sub.3b,
R.sub.3c, R.sub.3d, R.sub.3e and R.sub.3f are independently
selected from H, CN, C.sub.1-4alkyl substituted with 1-3 [0352]
R.sub.8, --C(.dbd.O)OR.sub.b, --C(.dbd.O)NR.sub.aR.sub.a,
--C(.dbd.O)R.sub.b, --NR.sub.aC(.dbd.O)R.sub.b,
--NR.sub.aC(.dbd.O)OR.sub.b, --(CH.sub.2).sub.r-carbocyclyl
substituted with 1-3 R.sub.8, and --(CH.sub.2).sub.r-heterocyclyl
substituted with 1-3 R.sub.8; [0353] alternatively, R.sub.3a and
R.sub.3b, or R.sub.3c and R.sub.3d, or R.sub.3e and R.sub.3f,
together with the carbon atom to which they are both attached form
a spiral carbocyclic or heterocyclic ring comprising carbon atoms
and 1 to 4 heteroatoms selected from N, O, S, each substituted with
1-5 R.sub.8; [0354] alternatively, R.sub.3a and R.sub.3c or
R.sub.3b and R.sub.3d together form a heterocyclic ring comprising
carbon atoms and 1 to 4 heteroatoms selected from N, O, S, and
substituted with 1-5 R.sub.8; [0355] R.sub.4 is independently
selected from H and C.sub.1-4 alkyl substituted with 0-3 R.sub.e;
[0356] R.sub.5, at each occurrence, is independently selected from
H, C.sub.1-4 alkyl substituted with 0-3 R.sub.e, F, Cl, Br, .dbd.O,
CN, NO.sub.2, --OR.sub.b, --(CH.sub.2).sub.rCN,
--(CH.sub.2).sub.rOR.sub.b, [0357]
(CH.sub.2).sub.rS(O).sub.pR.sub.c,
--(CH.sub.2).sub.rC(.dbd.O)R.sub.b,
--(CH.sub.2).sub.rNR.sub.aR.sub.a,
--(CH.sub.2).sub.rC(.dbd.O)NR.sub.aR.sub.a,
--(CH.sub.2).sub.rNR.sub.aC(.dbd.O)R.sub.b,
--(CH.sub.2).sub.rNR.sub.aC(.dbd.O)OR.sub.b,
--(CH.sub.2).sub.rOC(.dbd.O)NR.sub.aR.sub.a,
--(CH.sub.2).sub.rNR.sub.aC(.dbd.O)NR.sub.aR.sub.a,
--(CH.sub.2).sub.rC(.dbd.O)OR.sub.b,
--(CH.sub.2).sub.rS(O).sub.2NR.sub.aR.sub.a,
--(CH.sub.2).sub.rNR.sub.aS(O).sub.2NR.sub.aR.sub.a,
--(CH.sub.2).sub.rNR.sub.aS(O).sub.2R.sub.c,
(CH.sub.2).sub.r-carbocyclyl substituted with 0-3 R.sub.e, and
--(CH.sub.2).sub.r-heterocyclyl substituted with 0-3 R.sub.e;
[0358] R.sub.6 is independently selected from H,
--C(.dbd.O)R.sub.b, --CO(.dbd.O)R.sub.b, --S(O).sub.pR.sub.c,
C.sub.1-6 alkyl substituted with 0-5 R.sub.e,
--(CH.sub.2).sub.r--C.sub.3-6carbocyclyl substituted with 0-5
R.sub.e, and --(CH.sub.2).sub.r-heterocyclyl substituted with 0-5
R.sub.e; [0359] R.sub.7, at each occurrence, is independently
selected from H, F, Cl, Br, .dbd.O, CN, [0360] NO.sub.2,
--OR.sub.b, --S(O).sub.pR.sub.c, --C(.dbd.O)R.sub.b,
--(CR.sub.dR.sub.d).sub.rNR.sub.aR.sub.a,
--(CR.sub.dR.sub.d).sub.rC(.dbd.O)NR.sub.aR.sub.a,
--NR.sub.aC(.dbd.O)R.sub.b, --NR.sub.aC(.dbd.O)OR.sub.b,
--OC(.dbd.O)NR.sub.aR.sub.a, --NR.sub.aC(.dbd.O)NR.sub.aR.sub.a,
--(CR.sub.dR.sub.d).sub.rC(.dbd.O)OR.sub.b,
--S(O).sub.2NR.sub.aR.sub.a, --NR.sub.aS(O).sub.2NR.sub.aR.sub.a,
--NR.sub.aS(O).sub.2R.sub.c, C.sub.1-6 alkyl substituted with 0-5
R.sub.e, --(CR.sub.dR.sub.d).sub.r--C.sub.3-6carbocyclyl
substituted with 0-5 R.sub.e, and
--(CR.sub.dR.sub.d).sub.r-heterocyclyl substituted with 0-5
R.sub.e; [0361] R.sub.a, at each occurrence, is independently
selected from H, CN, C.sub.1-6 alkyl substituted with 0-5 R.sub.e,
C.sub.2-6 alkenyl substituted with 0-5 R.sub.e, C.sub.2-6 alkynyl
substituted with 0-5 R.sub.e,
--(CH.sub.2).sub.r--C.sub.3-10carbocyclyl substituted with 0-5
R.sub.e, and --(CH.sub.2).sub.r-heterocyclyl substituted with 0-5
R.sub.e; or R.sub.a and R.sub.a together with the nitrogen atom to
which they are both attached form a heterocyclic ring substituted
with 0-5 R.sub.e; [0362] R.sub.b, at each occurrence, is
independently selected from H, C.sub.1-6 alkyl substituted with 0-5
R.sub.e, C.sub.2-6 alkenyl substituted with 0-5 R.sub.e, C.sub.2-6
alkynyl substituted with 0-5 R.sub.e,
--(CH.sub.2).sub.r--C.sub.3-10carbocyclyl substituted with 0-5
R.sub.e, and --(CH.sub.2).sub.r-heterocyclyl substituted with 0-5
R.sub.e; [0363] R.sub.c, at each occurrence, is independently
selected from C.sub.1-6 alkyl substituted with 0-5 R.sub.e,
C.sub.2-6alkenyl substituted with 0-5 R.sub.e, C.sub.2-6alkynyl
substituted with 0-5 R.sub.e, C.sub.3-6carbocyclyl, and
heterocyclyl; [0364] R.sub.d, at each occurrence, is independently
selected from H and C.sub.1-4alkyl substituted with 0-5 R.sub.e;
[0365] R.sub.e, at each occurrence, is independently selected from
F, Cl, Br, CN, NO.sub.2, .dbd.O, CO.sub.2H, C.sub.1-6 alkyl
substituted with 0-5 R.sub.f, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
--(CH.sub.2).sub.r--C.sub.3-6 cycloalkyl,
--(CH.sub.2).sub.rOR.sub.f, SR.sub.f, and
--(CH.sub.2).sub.rNR.sub.fR.sub.f; [0366] R.sub.f, at each
occurrence, is independently selected from H, C.sub.1-5 alkyl,
C.sub.3-6 cycloalkyl, and phenyl, or R.sub.f and R.sub.f together
with the nitrogen atom to which they are both attached form a
heterocyclic ring optionally substituted with C.sub.1-4alkyl;
[0367] p, at each occurrence, is independently selected from zero,
1, and 2; and [0368] r, at each occurrence, is independently
selected from zero, 1, 2, 3, and 4.
[0369] In another embodiment, the present invention provides a
compound selected from any compounds or any subset list of
compounds exemplified in the present application.
[0370] The compounds of Formulae (I)-(VI) may form salts with
alkali metals such as sodium, potassium and lithium, with alkaline
earth metals such as calcium and magnesium, with organic bases such
as dicyclohexylamine, tributylamine, pyridine and amino acids such
as arginine, lysine and the like. Such salts can be formed as known
to those skilled in the art.
[0371] The compounds for Formulae (I)-(VI) may form salts with a
variety of organic and inorganic acids. Such salts include those
formed with hydrogen chloride, hydrogen bromide, methanesulfonic
acid, sulfuric acid, acetic acid, trifluoroacetic acid, oxalic
acid, maleic acid, benzenesulfonic acid, toluenesulfonic acid and
various others (e.g., nitrates, phosphates, borates, tartrates,
citrates, succinates, benzoates, ascorbates, salicylates and the
like). Such salts can be formed as known to those skilled in the
art.
[0372] In addition, zwitterions ("inner salts") may be formed.
[0373] The present invention is also intended to include all
isotopes of atoms occurring in the present compounds. Isotopes
include those atoms having the same atomic number but different
mass numbers. By way of general example and without limitation,
isotopes of hydrogen include deuterium and tritium. Isotopes of
carbon include .sup.13C and .sup.14C. Isotopically-labeled
compounds of the invention can generally be prepared by
conventional techniques known to those skilled in the art or by
processes analogous to those described herein, using an appropriate
isotopically-labeled reagent in place of the non-labeled reagent
otherwise employed.
[0374] Compounds of the Formulae (I)-(VI) may also have prodrug
forms. 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.
"Prodrugs" are intended to include any covalently bonded carriers
that release an active parent drug of the present invention in vivo
when such prodrug is administered to a mammalian subject. Prodrugs
of 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.
[0375] Various forms of prodrugs are well known in the art. For
examples of such prodrug derivatives, see: [0376] a) Bundgaard, H.,
ed., Design of Prodrugs, Elsevier (1985), and Widder, K. et al.,
eds., Methods in Enzymology, 112:309-396, Academic Press (1985);
[0377] b) Bundgaard, H., Chapter 5, "Design and Application of
Prodrugs", A Textbook of Drug Design and Development, pp. 113-191,
Krogsgaard-Larsen, P. et al., eds., Harwood Academic Publishers
(1991); and [0378] c) Bundgaard, H., Adv. Drug Deliv. Rev., 8:1-38
(1992);
[0379] It should further be understood that solvates (e.g.,
hydrates) of the compounds of Formulae (I)-(VI) are also within the
scope of the invention. Methods of solvation are generally known in
the art. The inventive compounds may either be in the free or
hydrate form.
[0380] Compounds of this invention may have one or more asymmetric
centers. Unless otherwise indicated, all chiral (enantiomeric and
diastereomeric) and racemic forms of compounds of the present
invention are included in the present invention. Many geometric
isomers of olefins, C.dbd.N double bonds, and the like can also be
present in the compounds, 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. The present compounds can 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. All chiral,
(enantiomeric and diastereomeric) and racemic forms and all
geometric isomeric forms of a structure are intended, unless the
specific stereochemistry or isomer form is specifically indicated.
When no specific mention is made of the configuration (cis, trans
or R or S) of a compound (or of an asymmetric carbon), then any one
of the isomers or a mixture of more than one isomer is intended.
The processes for preparation can use racemates, enantiomers, or
diastereomers as starting materials. All processes used to prepare
compounds of the present invention and intermediates made therein
are considered to be part of the present invention. When
enantiomeric or diastereomeric products are prepared, they can be
separated by conventional methods, for example, by chromatography
or fractional crystallization. Compounds of the present invention,
and salts thereof, may exist in multiple tautomeric forms, in which
hydrogen atoms are transposed to other parts of the molecules and
the chemical bonds between the atoms of the molecules are
consequently rearranged. It should be understood that all
tautomeric forms, insofar as they may exist, are included within
the invention.
DEFINITIONS
[0381] The following are definitions of terms used in this
specification and appended claims. The initial definition provided
for a group or term herein applies to that group or term throughout
the specification and claims, individually or as part of another
group, unless otherwise indicated.
[0382] In accordance with a convention used in the art, is used in
structural formulas herein to depict the bond that is the point of
attachment of the moiety or substituent to the core or backbone
structure.
[0383] A dash "-" that is not between two letters or symbols is
used to indicate a point of attachment for a substituent. For
example, --CONH.sub.2 is attached through the carbon atom.
[0384] As used herein, the term "alkyl" or "alkylene" is intended
to include both branched and straight-chain saturated aliphatic
hydrocarbon groups having the specified number of carbon atoms. For
example, "C.sub.1-10 alkyl" (or alkylene), is intended to include
C.sub.1, C.sub.2, C.sub.3, C.sub.4, C.sub.5, C.sub.6, C.sub.7,
C.sub.8, C.sub.9, and C.sub.10 alkyl groups. Additionally, for
example, "C.sub.1-C.sub.6 alkyl" denotes alkyl having 1 to 6 carbon
atoms. Alkyl groups can be unsubstituted or substituted so that one
or more of its hydrogens are replaced by another chemical group.
Example alkyl groups include, but are not limited to, methyl (Me),
ethyl (Et), propyl (e.g., n-propyl and isopropyl), butyl (e.g.,
n-butyl, isobutyl, t-butyl), pentyl (e.g., n-pentyl, isopentyl,
neopentyl), and the like.
[0385] "Haloalkyl" is intended to include both branched and
straight-chain saturated aliphatic hydrocarbon groups having the
specified number of carbon atoms, substituted with 1 or more
halogen. Examples of haloalkyl include, but are not limited to,
fluoromethyl, difluoromethyl, trifluoromethyl, trichloromethyl,
pentafluoroethyl, pentachloroethyl, 2,2,2-trifluoroethyl,
heptafluoropropyl, and heptachloropropyl. Examples of haloalkyl
also include "fluoroalkyl" which is intended to include both
branched and straight-chain saturated aliphatic hydrocarbon groups
having the specified number of carbon atoms, substituted with 1 or
more fluorine atoms.
[0386] The term "halogen" or "halo" refers to fluorine (F),
chlorine (CO, bromine (Br) and iodine.
[0387] "Haloalkoxy" or "haloalkyloxy" represents a haloalkyl group
as defined above with the indicated number of carbon atoms attached
through an oxygen bridge. For example, "C.sub.1-6 haloalkoxy", is
intended to include C.sub.1, C.sub.2, C.sub.3, C.sub.4, C.sub.5,
and C.sub.6 haloalkoxy groups. Examples of haloalkoxy include, but
are not limited to, trifluoromethoxy, 2,2,2-trifluoroethoxy,
pentafluorothoxy, and the like. Similarly, "haloalkylthio" or
"thiohaloalkoxy" represents a haloalkyl group as defined above with
the indicated number of carbon atoms attached through a sulphur
bridge; for example trifluoromethyl-S--, pentafluoroethyl-S--, and
the like.
[0388] As used herein, "carbocycle", "carbocyclic residue", or
"carbocyclyl" 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 hydrocarbon ring, any of which
may be saturated, partially unsaturated, unsaturated or aromatic.
Examples of such carbocycles include, but are not limited to,
cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl,
cyclohexyl, cycloheptenyl, cycloheptyl, cycloheptenyl, adamantyl,
cyclooctyl, cyclooctenyl, cyclooctadienyl, [3.3.0]bicyclooctane,
[4.3.0]bicyclononane, [4.4.0]bicyclodecane, [2.2.2]bicyclooctane,
fluorenyl, phenyl, naphthyl, indanyl, adamantyl, anthracenyl, and
tetrahydronaphthyl (tetralin). As shown above, bridged rings are
also included in the definition of carbocycle (e.g.,
[2.2.2]bicyclooctane). Preferred carbocycles, unless otherwise
specified, are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
phenyl, and indanyl. When the term "carbocycle", "carbocyclic
residue", or "carbocyclyl" is used, it is intended to include
"aryl". A bridged ring occurs when one or more carbon atoms link
two non-adjacent carbon atoms. Preferred bridges are one or two
carbon atoms. It is noted that a bridge always converts a
monocyclic ring into a tricyclic ring. When a ring is bridged, the
substituents recited for the ring may also be present on the
bridge.
[0389] The term "aryl" refers to monocyclic, bicyclic, tricyclic
aromatic hydrocarbon groups having 6 to 15 carbon atoms in the ring
portion, such as phenyl, naphthyl, biphenyl and diphenyl groups,
each of which may be substituted. Aryl groups which are bicyclic or
tricyclic must include at least one fully aromatic ring but the
other fused ring or rings may be aromatic or non-aromatic. When an
aryl is substituted with a further heterocyclic ring, said ring may
be attached to the aryl through a carbon atom or a heteroatom and
said ring in turn is optionally substituted with one to two
substituents as valence allows.
[0390] The terms "aryloxy", "arylamino", "arylalkylamino",
"arylthio", "arylalkanoylamino", "arylsulfonyl", "arylalkoxy",
"arylsulfinyl", "arylheteroaryl", "arylalkylthio", "arylcarbonyl",
"arylalkenyl", or "arylalkylsulfonyl" refer to an aryl or
substituted aryl bonded to an oxygen; an amino; an alkylamino; a
thio; an alkanoylamino; a sulfonyl; an alkoxy; a sulfinyl; a
heteroaryl or substituted heteroaryl; an alkylthio; a carbonyl; an
alkenyl; or an alkylsulfonyl, respectively.
[0391] The term "alkenyl" refers to straight or branched chain
hydrocarbon groups of 2 to 20 carbon atoms, preferably 2 to 15
carbon atoms, and most preferably 2 to 8 carbon atoms, having one
to four double bonds.
[0392] The term "alkynyl" refers to straight or branched chain
hydrocarbon groups of 2 to 20 carbon atoms, preferably 2 to 15
carbon atoms, and most preferably 2 to 8 carbon atoms, having one
to four triple bonds.
[0393] The term "cycloalkyl" refers to an optionally substituted,
saturated cyclic hydrocarbon ring systems, preferably containing 1
to 3 rings and 3 to 7 carbons per ring. Exemplary groups include
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,
cyclooctyl, cyclodecyl, cyclododecyl, and adamantyl. Exemplary
substituents include one or more alkyl groups as described above,
or one or more groups described above as alkyl substituents.
Accordingly, in compounds of Formula (I), the term "cycloalkyl"
includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
cycloheptyl, bicyclooctyl, etc., as well as the following ring
systems,
##STR00027##
and the like, which optionally may be substituted at any available
atoms of the ring(s). Preferred cycloalkyl groups include
cyclopropyl, cyclopentyl, cyclohexyl,
##STR00028##
[0394] The term "cycloheteroalkyl" or "heterocycloalkyl" means a
saturated or partially saturated 4-12 membered ring radical having
specified number of ring carbon atoms. The cycloheteroalkyl or
heterocycloalkyl contains 1 to 4 ring heteroatoms, which may be the
same or different, selected from N, O or S. The cycloheteroalkyl or
heterocycloalkyl ring optionally contains one or more double bonds.
It can be monocyclic, bicyclic, tricyclic, fused, bridged, or
spiro. For example, (C.sub.3-9)heterocycloalkyl means a ring
radical containing 3-9 ring carbon atoms. The term
"cycloheteroalkyl" or "heterocycloalkyl" is intended to include all
the possible isomeric forms. When the heteroatom is a ring nitrogen
atom connected to other ring atoms only by single bonds, it can be
substituted. Exemplary substituents, unless otherwise indicated,
include H, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl,
heteroaryl, heteroarylalkyl (preferably, H, C.sub.1-6 alkyl,
haloC.sub.1-6alkyl or C.sub.1-3alkylcarbonyl), each of which can be
optionally substituted with halogen, hydroxy, alkoxy, haloalkyl,
alkyl, etc. When the heteroatom is S, it can be optionally mono- or
di-oxygenated (i.e., --S(O)-- or --S(O).sub.2--).
[0395] As used herein, the term "heterocycle", "heterocyclyl",
"heterocyclic ring" or "heterocyclic group" is intended to mean a
stable 4-, 5-, 6-, or 7-membered monocyclic or bicyclic or 7-, 8-,
9-, 10-, 11-, 12-, 13-, or 14-membered bicyclic heterocyclic ring
which is saturated, partially unsaturated or fully unsaturated or
aromatic, and which consists of carbon atoms and 1, 2, 3 or 4
heteroatoms independently selected from N, 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 (i.e., N.fwdarw.O and
S(O).sub.p). The nitrogen atom may be substituted or unsubstituted
(i.e., N or NR wherein R is H or another substituent, if defined).
The heterocyclic ring may be attached to its pendant group at any
heteroatom or carbon atom that results in a stable structure. The
heterocyclic rings described herein may be substituted on a carbon
atom or on a nitrogen atom if the resulting compound is stable. A
nitrogen atom 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. It is preferred that the total number of S and O atoms
in the heterocycle is not more than 1. When the term "heterocycle",
"heterocyclyl", "heterocyclic ring" or "heterocyclic group" is
used, it is intended to include heteroaryl.
[0396] Examples of heterocycles include, but are not limited to,
acridinyl, azocinyl, benzimidazolyl, benzofuranyl,
benzothiofuranyl, benzoxazolyl, benzoxazolinyl, benzthiazolyl,
benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl,
benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl,
chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl,
2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran,
furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl,
1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl,
3H-indolyl, isatinoyl, isobenzofuranyl, isochromanyl, isoindazolyl,
isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl,
isothiazolopyridinyl, isoxazolyl, isoxazolopyridinyl,
methylenedioxyphenyl, morpholinyl, naphthyridinyl,
octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl,
1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl,
oxazolidinyl, oxazolyl, oxindolyl, pyrimidinyl, phenanthridinyl,
phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathinyl,
phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, piperidonyl,
4-piperidonyl, piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl,
pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole,
pyridoimidazole, pyridothiazole, pyridinyl, pyrimidinyl,
pyrrolidinyl, pyrrolinyl, 2-pyrrolidonyl, 2H-pyrrolyl, pyrrolyl,
quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl,
quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl,
tetrahydroquinolinyl, tetrazolyl, 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, and xanthenyl. Also included are fused ring and
spiro compounds containing, for example, the above
heterocycles.
[0397] Preferred 5- to 10-membered heterocycles include, but are
not limited to, pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl,
pyrazinyl, piperazinyl, piperidinyl, imidazolyl, imidazolidinyl,
indolyl, tetrazolyl, isoxazolyl, morpholinyl, oxazolyl,
oxadiazolyl, oxazolidinyl, tetrahydrofuranyl, thiadiazinyl,
thiadiazolyl, thiazolyl, triazinyl, triazolyl, benzimidazolyl,
1H-indazolyl, benzofuranyl, benzothiofuranyl, benztetrazolyl,
benzotriazolyl, benzisoxazolyl, benzoxazolyl, oxindolyl,
benzoxazolinyl, benzthiazolyl, benzisothiazolyl, isatinoyl,
isoquinolinyl, octahydroisoquinolinyl, tetrahydroisoquinolinyl,
tetrahydroquinolinyl, isoxazolopyridinyl, quinazolinyl, quinolinyl,
isothiazolopyridinyl, thiazolopyridinyl, oxazolopyridinyl,
imidazolopyridinyl, and pyrazolopyridinyl.
[0398] Preferred 5- to 6-membered heterocycles include, but are not
limited to, pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl,
pyrazinyl, piperazinyl, piperidinyl, imidazolyl, imidazolidinyl,
indolyl, tetrazolyl, isoxazolyl, morpholinyl, oxazolyl,
oxadiazolyl, oxazolidinyl, tetrahydrofuranyl, thiadiazinyl,
thiadiazolyl, thiazolyl, triazinyl, and triazolyl. Also included
are fused ring and spiro compounds containing, for example, the
above heterocycles.
[0399] Bridged rings are also included in the definition of
heterocycle. A bridged ring occurs when one or more atoms (i.e., C,
O, N, or S) link two non-adjacent carbon or nitrogen atoms.
Preferred bridges include, but are not limited to, one carbon atom,
two carbon atoms, one nitrogen atom, two nitrogen atoms, and a
carbon-nitrogen group. It is noted that a bridge always converts a
monocyclic ring into a tricyclic ring. When a ring is bridged, the
substituents recited for the ring may also be present on the
bridge.
[0400] The term "heteroaryl" refers to substituted and
unsubstituted aromatic 5- or 6-membered monocyclic groups, 9- or
10-membered bicyclic groups, and 11- to 14-membered tricyclic
groups which have at least one heteroatom (0, S or N) in at least
one of the rings, said heteroatom-containing ring preferably having
1, 2, or 3 heteroatoms selected from O, S, and N. Each ring of the
heteroaryl group containing a heteroatom can contain one or two
oxygen or sulfur atoms and/or from one to four nitrogen atoms
provided that the total number of heteroatoms in each ring is four
or less and each ring has at least one carbon atom. Heteroaryl
groups can be substituted or unsubstituted. The nitrogen atom may
be substituted or unsubstituted (i.e., N or NR wherein R is H or
another substituent, if defined). The nitrogen and sulfur
heteroatoms may optionally be oxidized (i.e., N.fwdarw.O and
S(O).sub.p) and the nitrogen atoms may optionally be
quaternized.
[0401] Heteroaryl groups which are bicyclic or tricyclic must
include at least one fully aromatic ring but the other fused ring
or rings may be aromatic or non-aromatic. The heteroaryl group may
be attached at any available nitrogen or carbon atom of any ring.
The heteroaryl ring system may contain zero, one, two or three
substituents.
[0402] Exemplary monocyclic heteroaryl groups include pyrrolyl,
pyrazolyl, pyrazolinyl, imidazolyl, oxazolyl, isoxazolyl,
thiazolyl, thiadiazolyl, isothiazolyl, furanyl, thienyl,
oxadiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl,
triazinyl and the like.
[0403] Exemplary bicyclic heteroaryl groups include indolyl,
benzothiazolyl, benzodioxolyl, benzoxazolyl, benzothienyl,
quinolinyl, dihydroisoquinolinyl, tetrahydroquinolinyl,
isoquinolinyl, benzimidazolyl, benzopyranyl, benzoxazinyl,
indolizinyl, benzofuranyl, chromonyl, coumarinyl, benzopyranyl,
cinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridyl, furopyridyl,
dihydroisoindolyl, and the like.
[0404] Exemplary tricyclic heteroaryl groups include carbazolyl,
benzidolyl, phenanthrollinyl, acridinyl, phenanthridinyl, xanthenyl
and the like.
[0405] The term "heteroatoms" shall include oxygen, sulfur and
nitrogen.
[0406] As referred to herein, the term "substituted" means that one
or more hydrogen atoms is replaced with a non-hydrogen group,
provided that normal valencies are maintained 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.
Keto substituents are not present on aromatic moieties. When a ring
system (e.g., carbocyclic or heterocyclic) is said to be
substituted with a carbonyl group or a double bond, it is intended
that the carbonyl group or double bond be part (i.e., within) of
the ring. Ring double bonds, as used herein, are double bonds that
are formed between two adjacent ring atoms (e.g., C.dbd.C, C.dbd.N,
or N.dbd.N).
[0407] When any variable 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 0-3 R.sub.e, then said group may optionally be
substituted with up to three R.sub.e groups and R.sub.e at each
occurrence is selected independently from the definition of
R.sub.e. Also, combinations of substituents and/or variables are
permissible only if such combinations result in stable
compounds.
Utility
[0408] The compounds of the invention may be used to modulate
kinase activities.
[0409] Applicants have discovered that compounds of Formulae
(I)-(VI) have particular utility in treating proliferative
conditions associated with the modulation of kinase activity, and
particularly the inhibition of serine/threonine kinase activities.
The compounds of the present invention can be used to treat
proliferative disorders associated with abnormal kinase activity.
As used herein, the terms "treating" and "treatment" encompass
either or both responsive and prophylaxis measures, e.g., measures
designed to inhibit or delay the onset of the disease or disorder,
achieve a full or partial reduction of the symptoms or disease
state, and/or to alleviate, ameliorate, lessen, or cure the disease
or disorder and/or its symptoms.
[0410] Accordingly, one aspect of the invention is the use of a
compound of the Formulae (I)-(VI), or a pharmaceutically acceptable
salt thereof in the manufacture of a medicament for use in the
production of an antiproliferative effect in a warm-blooded animal
such as a human being.
[0411] According to a further feature of the invention there is
provided a method for producing an antiproliferative effect in a
warm-blooded animal, such as a human being, in need of such
treatment which comprises administering to said animal an effective
amount of a compound of Formulae (I)-(VI) or a pharmaceutically
acceptable salt thereof as defined herein before.
[0412] The anti-proliferative treatment defined herein before may
be applied as a sole therapy or may involve, in addition to a
compound of the invention, one or more other substances and/or
treatments. Such treatment may be achieved by way of the
simultaneous, sequential or separate administration of the
individual components of the treatment. The compounds of this
invention may also be useful in combination with known anti-cancer
and cytotoxic agents and treatments, including radiation. Compounds
of Formulae (I)-(VI) may be used sequentially with known anticancer
or cytotoxic agents and treatment, including radiation when a
combination formulation is inappropriate.
[0413] The term "anti-cancer" agent includes any known agent that
is useful for the treatment of cancer including the following:
17.alpha.-ethinylestradiol, diethylstilbestrol, testosterone,
prednisone, fluoxymesterone, dromostanolone propionate,
testolactone, megestrolacetate, methylprednisolone,
methyl-testosterone, prednisolone, triamcinolone, chlorotrianisene,
hydroxyprogesterone, aminoglutethimide, estramustine,
medroxyprogesteroneacetate, leuprolide, flutamide, toremifene,
ZOLADEX.RTM.; matrix metalloproteinase inhibitors; VEGF inhibitors,
such as anti-VEGF antibodies (AVASTIN.RTM.) and small molecules
such as ZD6474 and SU6668; Vatalanib, BAY-43-9006, SU11248,
CP-547632, and CEP-7055; HER 1 and HER 2 inhibitors including
anti-HER2 antibodies (HERCEPTIN.RTM.); EGFR inhibitors including
gefitinib, erlotinib, ABX-EGF, EMD72000, 11F8, and cetuximab; Eg5
inhibitors, such as SB-715992, SB-743921, and MKI-833; pan Her
inhibitors, such as canertinib, EKB-569, CI-1033, AEE-788, XL-647,
mAb 2C4, and GW-572016; Src inhibitors, e.g., GLEEVEC.RTM. and
dasatinib; CASODEX.RTM. (bicalutamide, Astra Zeneca), Tamoxifen;
MEK-1 kinase inhibitors, MAPK kinase inhibitors, PI3 kinase
inhibitors; PDGF inhibitors, such as imatinib; antiangiogenic and
antivascular agents which, by interrupting blood flow to solid
tumors, render cancer cells quiescent by depriving them of
nutrition; castration, which renders androgen dependent carcinomas
non-proliferative; inhibitors of non-receptor and receptor tyrosine
kinases; inhibitors of integrin signaling; tubulin acting agents
such as vinblastine, vincristine, vinorelbine, vinflunine,
paclitaxel, docetaxel, 7-O-methylthiomethylpaclitaxel,
4-desacetyl-4-methylcarbonatepaclitaxel,
3'-tert-butyl-3'-N-tert-butyloxycarbonyl-4-deacetyl-3'-dephenyl-3'-N-debe-
nzoyl-4-O-methoxycarbonyl-paclitaxel, C-4 methyl carbonate
paclitaxel, epothilone A, epothilone B, epothilone C, epothilone D,
[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7-11-dihydroxy-8,8,10,12,16-pen-
tamethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-4-aza-17
oxabicyclo[14.1.0]heptadecane-5,9-dione (ixabepilone),
[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-3-[2-[2-(aminomethyl)-4-thiazol-
yl]-1-methylethenyl]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-4-17-dioxabic-
yclo[14.1.0]-heptadecane-5,9-dione, and derivatives thereof; other
CDK inhibitors, antiproliferative cell cycle inhibitors,
epidophyllotoxin, etoposide, VM-26; antineoplastic enzymes, e.g.,
topoisomerase I inhibitors, camptothecin, topotecan, SN-38;
procarbazine; mitoxantrone; platinum coordination complexes such as
cisplatin, carboplatin and oxaliplatin; biological response
modifiers; growth inhibitors; antihormonal therapeutic agents;
leucovorin; tegafur; antimetabolites such as purine antagonists
(e.g., 6-thioguanine and 6-mercaptopurine; glutamine antagonists,
e.g., DON (AT-125; d-oxo-norleucine); ribonucleotide reductase
inhibitors; mTOR inhibitors; and haematopoietic growth factors.
[0414] Additional cytotoxic agents include, cyclophosphamide,
doxorubicin, daunorubicin, mitoxanthrone, melphalan, hexamethyl
melamine, thiotepa, cytarabin, idatrexate, trimetrexate,
dacarbazine, L-asparaginase, bicalutamide, leuprolide,
pyridobenzoindole derivatives, interferons, and interleukins.
[0415] In the field of medical oncology it is normal practice to
use a combination of different forms of treatment to treat each
patient with cancer. In medical oncology the other component(s) of
such treatment in addition to the antiproliferative treatment
defined herein may be surgery, radiotherapy or chemotherapy. Such
chemotherapy may cover three main categories of therapeutic
agent:
[0416] (i) antiangiogenic agents that work by different mechanisms
from those defined herein before (for example, linomide, inhibitors
of integrin .alpha.v.beta.3 function, angiostatin, razoxane);
[0417] (ii) cytostatic agents such as antiestrogens (for example,
tamoxifen, toremifene, raloxifene, droloxifene, iodoxifene),
progestogens (for example, megestrol acetate), aromatase inhibitors
(for example, anastrozole, letrozole, borazole, exemestane),
antihormones, antiprogestogens, antiandrogens (for example,
flutamide, nilutamide, bicalutamide, cyproterone acetate), LHRH
agonists and antagonists (for example, gosereline acetate,
leuprolide), inhibitors of testosterone 5.alpha.-dihydroreductase
(for example, finasteride), farnesyltransferase inhibitors,
anti-invasion agents (for example, metalloproteinase inhibitors
such as marimastat and inhibitors of urokinase plasminogen
activator receptor function) and inhibitors of growth factor
function, (such growth factors include for example, EGF, FGF,
platelet derived growth factor and hepatocyte growth factor, such
inhibitors include growth factor antibodies, growth factor receptor
antibodies such as AVASTIN.RTM. (bevacizumab) and ERBITUX.RTM.
(cetuximab); tyrosine kinase inhibitors and serine/threonine kinase
inhibitors); and
[0418] (iii) antiproliferative/antineoplastic drugs and
combinations thereof, as used in medical oncology, such as
antimetabolites (for example, antifolates such as methotrexate,
fluoropyrimidines such as 5-fluorouracil, purine and adenosine
analogues, cytosine arabinoside); intercalating antitumor
antibiotics (for example, anthracyclines such as doxorubicin,
daunomycin, epirubicin and idarubicin, mitomycin-C, dactinomycin,
mithramycin); platinum derivatives (for example, cisplatin,
carboplatin); alkylating agents (for example, nitrogen mustard,
melphalan, chlorambucil, busulphan, cyclophosphamide, ifosfamide,
nitrosoureas, thiotepa; antimitotic agents (for example, vinca
alkaloids like vincristine, vinorelbine, vinblastine and
vinflunine) and taxoids such as TAXOL.RTM. (paclitaxel), Taxotere
(docetaxel) and newer microbtubule agents such as epothilone
analogs (ixabepilone), discodermolide analogs, and eleutherobin
analogs; topoisomerase inhibitors (for example, epipodophyllotoxins
such as etoposide and teniposide, amsacrine, topotecan,
irinotecan); cell cycle inhibitors (for example, flavopyridols);
biological response modifiers and proteasome inhibitors such as
VELCADE.RTM. (bortezomib).
[0419] As stated above, the Formulae (I)-(VI) compounds of the
invention are of interest for their antiproliferative effects. Such
compounds of the invention are expected to be useful in a wide
range of disease states including cancer, psoriasis, and rheumatoid
arthritis.
[0420] More specifically, the compounds of Formulae (I)-(VI) are
useful in the treatment of a variety of cancers, including (but not
limited to) the following: [0421] carcinoma, including that of the
prostate, pancreatic ductal adenocarcinoma, breast, colon, lung,
ovary, pancreas, and thyroid; [0422] tumors of the central and
peripheral nervous system, including neuroblastoma, glioblastoma,
and medulloblastoma; and [0423] other tumors, including melanoma
and multiple myeloma.
[0424] Due to the key role of kinases in the regulation of cellular
proliferation in general, inhibitors could act as reversible
cytostatic agents which may be useful in the treatment of any
disease process which features abnormal cellular proliferation,
e.g., benign prostate hyperplasia, familial adenomatosis polyposis,
neurofibromatosis, pulmonary fibrosis, arthritis, psoriasis,
glomerulonephritis, restenosis following angioplasty or vascular
surgery, hypertrophic scar formation and inflammatory bowel
disease.
[0425] The compounds of Formulae (I)-(VI) are especially useful in
treatment of tumors having a high incidence of serine/threonine
kinase activity, such as prostate, colon, lung, brain, thyroid and
pancreatic tumors. Additionally, the compounds of the invention may
be useful in treatment of sarcomas and pediatric sarcomas. By the
administration of a composition (or a combination) of the compounds
of this invention, development of tumors in a mammalian host is
reduced.
[0426] Compounds of Formulae (I)-(VI) may also be useful in the
treatment of other cancerous diseases (such as acute myelogenous
leukemia) that may be associated with signal transduction pathways
operating through kinases such as DYRK1a, CDK, and GSK3.beta.. The
inventive compositions may contain other therapeutic agents as
described above and may be formulated, for example, by employing
conventional solid or liquid vehicles or diluents, as well as
pharmaceutical additives of a type appropriate to the mode of
desired administration (e.g., excipients, binders, preservatives,
stabilizers, flavors, etc.) according to techniques such as those
well known in the art of pharmaceutical formulation.
[0427] Accordingly, the present invention further includes
compositions comprising one or more compounds of Formulae (I)-(VI)
and a pharmaceutically acceptable carrier.
[0428] A "pharmaceutically acceptable carrier" refers to media
generally accepted in the art for the delivery of biologically
active agents to animals, in particular, mammals. Pharmaceutically
acceptable carriers are formulated according to a number of factors
well within the purview of those of ordinary skill in the art.
These include, without limitation: the type and nature of the
active agent being formulated; the subject to which the
agent-containing composition is to be administered; the intended
route of administration of the composition; and, the therapeutic
indication being targeted. Pharmaceutically acceptable carriers
include both aqueous and non-aqueous liquid media, as well as a
variety of solid and semi-solid dosage forms. Such carriers can
include a number of different ingredients and additives in addition
to the active agent, such additional ingredients being included in
the formulation for a variety of reasons, e.g., stabilization of
the active agent, binders, etc., well known to those of ordinary
skill in the art. Descriptions of suitable pharmaceutically
acceptable carriers, and factors involved in their selection, are
found in a variety of readily available sources such as, for
example, Remington's Pharmaceutical Sciences, 17th Edition (1985),
which is incorporated herein by reference in its entirety.
[0429] The pharmaceutical compositions of the invention containing
the active ingredient may be in a form suitable for oral use, for
example, as tablets, troches, lozenges, aqueous or oily
suspensions, dispersible powders or granules, emulsions, hard or
soft capsules, or syrups or elixirs. Compositions intended for oral
use may be prepared according to any method known to the art for
the manufacture of pharmaceutical compositions and such
compositions may contain one or more agents selected from the group
consisting of sweetening agents, flavoring agents, coloring agents
and preserving agents in order to provide pharmaceutically elegant
and palatable preparations.
[0430] Formulations for oral use may also be presented as hard
gelatin capsules wherein the active ingredient is mixed with an
inert solid diluent, for example, calcium carbonate, calcium
phosphate or kaolin, or as soft gelatin capsules wherein the active
ingredient is mixed with water soluble carrier such as
polyethyleneglycol or an oil medium, for example peanut oil, liquid
paraffin, or olive oil.
[0431] The pharmaceutical compositions may be in the form of
sterile injectable aqueous solutions. Among the acceptable vehicles
and solvents that may be employed are water, Ringer's solution and
isotonic sodium chloride solution. The sterile injectable
preparation may also be a sterile injectable oil-in-water
microemulsion where the active ingredient is dissolved in the oily
phase. For example, the active ingredient may be first dissolved in
a mixture of soybean oil and lecithin. The oil solution then
introduced into a water and glycerol mixture and processed to form
a microemulation.
[0432] The injectable solutions or microemulsions may be introduced
into a patient's blood-stream by local bolus injection.
Alternatively, it may be advantageous to administer the solution or
microemulsion in such a way as to maintain a constant circulating
concentration of the instant compound. In order to maintain such a
constant concentration, a continuous intravenous delivery device
may be utilized. An example of such a device is the Deltec
CADD-PLUS.RTM. Model 5400 intravenous pump.
[0433] The pharmaceutical compositions may be in the form of a
sterile injectable aqueous or oleagenous suspension for
intramuscular and subcutaneous administration. This suspension may
be formulated according to the known art using those suitable
dispersing or wetting agents and suspending agents which have been
mentioned above.
[0434] The compounds of Formulae (I)-(VI) may be administered by
any means suitable for the condition to be treated, which may
depend on the need for site-specific treatment or quantity of drug
to be delivered. Topical administration is generally preferred for
skin-related diseases, and systematic treatment preferred for
cancerous or pre-cancerous conditions, although other modes of
delivery are contemplated. For example, the compounds may be
delivered orally, such as in the form of tablets, capsules,
granules, powders, or liquid formulations including syrups;
topically, such as in the form of solutions, suspensions, gels or
ointments; sublingually; buccally; parenterally, such as by
subcutaneous, intravenous, intramuscular or intrasternal injection
or infusion techniques (e.g., as sterile injectable aq. or non-aq.
solutions or suspensions); nasally such as by inhalation spray;
topically, such as in the form of a cream or ointment; rectally
such as in the form of suppositories; or liposomally. Dosage unit
formulations containing non-toxic, pharmaceutically acceptable
vehicles or diluents may be administered. The compounds may be
administered in a form suitable for immediate release or extended
release. Immediate release or extended release may be achieved with
suitable pharmaceutical compositions or, particularly in the case
of extended release, with devices such as subcutaneous implants or
osmotic pumps.
[0435] Exemplary compositions for topical administration include a
topical carrier such as Plastibase (mineral oil gelled with
polyethylene).
[0436] Exemplary compositions for oral administration include
suspensions which may contain, for example, microcrystalline
cellulose for imparting bulk, alginic acid or sodium alginate as a
suspending agent, methylcellulose as a viscosity enhancer, and
sweeteners or flavoring agents such as those known in the art; and
immediate release tablets which may contain, for example,
microcrystalline cellulose, dicalcium phosphate, starch, magnesium
stearate and/or lactose and/or other excipients, binders,
extenders, disintegrants, diluents and lubricants such as those
known in the art. The inventive compounds may also be orally
delivered by sublingual and/or buccal administration, e.g., with
molded, compressed, or freeze-dried tablets. Exemplary compositions
may include fast-dissolving diluents such as mannitol, lactose,
sucrose, and/or cyclodextrins. Also included in such formulations
may be high molecular weight excipients such as celluloses
(AVICEL.RTM.) or polyethylene glycols (PEG); an excipient to aid
mucosal adhesion such as hydroxypropyl cellulose (HPC),
hydroxypropyl methyl cellulose (HPMC), sodium carboxymethyl
cellulose (SCMC), and/or maleic anhydride copolymer (e.g.,
Gantrez); and agents to control release such as polyacrylic
copolymer (e.g., Carbopol 934). Lubricants, glidants, flavors,
coloring agents and stabilizers may also be added for ease of
fabrication and use.
[0437] Exemplary compositions for nasal aerosol or inhalation
administration include solutions which may contain, for example,
benzyl alcohol or other suitable preservatives, absorption
promoters to enhance absorption and/or bioavailability, and/or
other solubilizing or dispersing agents such as those known in the
art.
[0438] Exemplary compositions for parenteral administration include
injectable solutions or suspensions which may contain, for example,
suitable non-toxic, parenterally acceptable diluents or solvents,
such as mannitol, 1,3-butanediol, water, Ringer's solution, an
isotonic sodium chloride solution, or other suitable dispersing or
wetting and suspending agents, including synthetic mono- or
diglycerides, and fatty acids, including oleic acid.
[0439] Exemplary compositions for rectal administration include
suppositories which may contain, for example, suitable
non-irritating excipients, such as cocoa butter, synthetic
glyceride esters or polyethylene glycols, which are solid at
ordinary temperatures but liquefy and/or dissolve in the rectal
cavity to release the drug.
[0440] When a compound according to this invention is administered
into a human subject, the daily dosage will normally be determined
by the prescribing physician with the dosage generally varying
according to the age, weight, sex and response of the individual
patient, as well as the severity of the patient's symptoms.
Exemplary dosage amounts for a mammal may include from about 0.05
to 1000 mg/kg; 1-1000 mg/kg; 1-50 mg/kg; 5-250 mg/kg; 250-1000
mg/kg of body weight of active compound per day, which may be
administered in a single dose or in the form of individual divided
doses, such as from 1 to 4 times per day. It will be understood
that the specific dose level and frequency of dosage for any
particular subject may be varied and will depend upon a variety of
factors, including the activity of the specific compound employed,
the metabolic stability and length of action of that compound, the
species, age, body weight, general health, sex and diet of the
subject, the mode and time of administration, rate of excretion,
drug combination, and severity of the particular condition.
Preferred subjects for treatment include animals, most preferably
mammalian species such as humans, and domestic animals such as
dogs, cats, horses, and the like. Thus, when the term "patient" is
used herein, this term is intended to include all subjects, most
preferably mammalian species, that are affected by mediation of
protein kinase enzyme levels.
[0441] If formulated as a fixed dose, a combination product can,
for example, utilize a dosage of the compound of Formulae (I)-(VI)
within the dosage range described above and the dosage of another
anti-cancer agent/treatment within the approved dosage range for
such known anti-cancer agent/treatment. If a combination product is
inappropriate, the compounds of Formulae (I)-(VI) and the other
anti-cancer agent/treatment can, for example, be administered
simultaneously or sequentially. If administered sequentially, the
present invention is not limited to any particular sequence of
administration. For example, compounds of Formulae (I)-(VI) can be
administered either prior to, or after, administration of the known
anti-cancer agent or treatment.
Biological Assays
CK1.epsilon. and CK1.delta. Kinase Assays
[0442] The kinase assay was performed in V-bottom 384-well plates.
The final assay volume was 30 .mu.l prepared from 15 .mu.l
additions of enzyme, substrates (fluoresceinated peptide
FL-AHA-KRRRAL-PSER-VASLPGL-OH and ATP) and test compounds in assay
buffer (20 mM HEPES pH 7.4, 30 mM MgCl.sub.2, 0.015% Brij35 and 4
mM DTT). The reaction was incubated at room temperature for 22
hours and terminated by adding 45 .mu.l of 35 mM EDTA to each
sample. The reaction mixture was analyzed on the Caliper
LABCHIP.RTM.3000 (Caliper, Hopkinton, Mass.) by electrophoretic
separation of the unphosphorylated substrate and phosphorylated
product. Inhibition data were calculated by comparison of the no
enzyme control reactions for 100% inhibition and vehicle-only
reactions for 0% inhibition. The final concentration of reagents in
the assay were 200 pM CK1.epsilon. or CK1.delta., 50 .mu.M ATP, 1.5
.mu.M FL-AHA-KRRRAL-PSER-VASLPGL-OH, and 1.6% DMSO. Dose response
curves were generated to determine the concentration required to
inhibit 50% of the kinase activity (IC.sub.50). Compounds were
dissolved at 10 mM in dimethylsulfoxide (DMSO) and evaluated at
eleven concentrations. IC.sub.50 values were derived by non-linear
regression analysis.
[0443] The IC.sub.50 values of some representative compounds
obtained from the assays described above are shown in Table A.
TABLE-US-00001 TABLE A Example No. CK1.epsilon. (.mu.M) CK1.delta.
(.mu.M) 1 0.0903 0.0278 4 0.0381 0.0109 61 0.0072 0.0024 61 0.0050
0.0026 92 2.0000 0.4455 103 0.5406 0.0706 104 0.0013 0.0007 106
0.0293 0.0087 107 0.4001 0.1049 108 0.0024 0.0009 110 0.1556 0.0839
114 0.0430 0.0125 116 0.0798 0.0182 124 0.1177 0.1719 126 0.8441
0.4421 127 0.4439 0.3568 130 0.0895 0.0964 142 2.0000 0.8938 143
0.0333 0.0042 145 1.8160 1.0530 151 0.1791 0.1220 154 0.0277 0.0243
166 0.0003 0.0003 248 0.0004 0.0015 258 0.0007 0.0005 291 0.0014
0.0009 297 0.0003 0.0005 349 0.0201 0.0342 352 0.0198 0.0181 A30
0.0001 0.0003
[0444] The biological activity of the exemplified compounds of this
invention determined by the assays described above is shown in
Table B. IC.sub.50 ranges against CK1.epsilon. and CK1.delta. are
as follows: A=0.01-10 nM; B=10.01-100 nM; C=100.01-2000 nM.
TABLE-US-00002 TABLE B Example No. CK1.epsilon. CK1.delta. 1 B B 2
B B 3 B A 4 B B 5 B B 6 A A 7 B B 8 B B 9 A A 10 A A 11 B B 12 C B
13 B A 14 B B 15 C B 16 A A 17 B A 18 C B 19 A A 20 B B 21 A A 22 A
A 23 A -- 24 B B 25 B A 26 B B 27 B B 28 B B 29 B A 30 B B 31 A A
32 B B 33 B A 34 B A 35 A A 36 B A 37 A A 38 A A 39 B A 40 C B 41 A
A 42 C B 43 B B 44 B A 45 A A 46 B A 47 C B 48 C B 49 A A 50 A A 51
A A 52 B B 53 A A 54 A A 55 A A 56 A A 57 C B 58 A A 59 A A 60 A A
61 A A 62 A A 63 A A 64 B B 65 C C 66 B A 67 A A 68 B A 69 A A 70 A
A 71 A A 72 A A 73 A A 74 A A 75 B B 76 A A 77 A A 78 A A 79 A A 80
A A 81 A A 82 A A 83 B C 84 B A 85 A A 86 B A 87 B A 88 B B 89 B A
90 B A 91 C B 92 C C 93 A A 94 A A 95 A A 96 B B 97 B A 98 A A 99 A
A 100 A A 101 A A 102 B A 103 C B 104 A A 105 B A 106 B A 107 C B
108 A A 109 A A 110 C B 111 C C 112 C B 113 C B 114 B B 115 C B 116
B B 117 A A 118 C C 119 A A 120 C B 121 C B 122 C C 123 C B 124 C C
125 C C 126 C C 127 C C 128 A B 129 A A 130 B B 131 C C 132 C C 133
C C 134 C C 135 C C 136 C C 137 B A 138 C C 139 C B 140 C C 141 C C
142 C C 143 B A 144 C C 145 C C 146 C C 147 C C 148 A A 149 C B 150
B A 151 C C 152 A A 153 C C 154 B B 155 C C 156 A A 157 A A 158 A A
159 A A 160 A A 161 A A 162 A A 163 A A 164 A A 165 A A 166 A A 167
A A 168 A A 169 A A 170 A A 171 A A 172 A A 173 A A 174 A A 175 A A
176 A A 177 A A 178 A A 179 A A 180 A A 181 A A 182 A A 183 A A 184
A A 185 A A 186 A A 187 A A 188 A A 189 A A 190 A A 191 A A 192 A A
193 A A 194 A A 195 A A 196 A A 197 A A 198 A A 199 A A 200 A A 201
A A 202 A A 203 A A 204 A A 205 A A 206 A A 207 A A 208 A A 209 A A
210 A A 211 A A 212 A A 213 B B 214 B B 215 B A 216 C B 217 C B 218
B A 219 B B 220 A A 221 A A 222 A A 223 A A 224 A A 225 A A 226 A A
227 A A 228 A A 229 A A 230 A A 231 A A 232 A A 233 A A 234 A A 235
A A 236 A A 237 A A 238 A A 239 A A 240 A A 241 A A 242 A A 243 A A
244 A A 245 A A 246 A A
247 A A 248 A A 249 A A 250 A A 251 A A 252 A A 253 A A 254 A A 255
A A 256 A A 257 A A 258 A A 259 A A 260 A A 261 A A 262 A A 263 A A
264 A A 265 A A 266 A A 267 A A 268 -- A 269 A A 270 A A 271 A A
272 A A 273 A A 274 A A 275 A A 276 A A 277 A A 278 A A 279 A A 280
A A 281 A A 282 -- A 283 A A 284 A A 285 A A 286 A A 287 A A 288 A
A 289 -- -- 290 -- -- 291 A A 292 B B 293 A A 294 A A 295 A A 296 A
A 297 A A 298 A A 299 A A 300 A A 301 A A 302 -- -- 303 A A 304 A A
305 A A 306 A A 307 A A 308 A A 309 A A 310 A A 311 A A 312 A A 313
A A 314 A A 315 A A 316 A A 317 A A 318 A A 319 A A 320 A A 321 A A
322 A A 323 A A 324 A A 325 A A 326 A A 327 A A 328 A A 329 A A 330
A A 331 A A 332 A A 333 A A 334 A A 335 A A 336 -- -- 337 -- A 338
A A 339 A A 340 B A 341 A B 342 B B 343 A A 344 A A 345 A A 346 C C
347 A B 348 B C 349 B B 350 C -- 351 A A 352 B B 353 A A 354 A A A1
A A A2 A A A3 A A A4 A A A5 A A A6 A A A7 A A A8 A A A9 A A A10 A A
A11 A A A12 A B A13 A A A14 A A A15 A A A16 A B A17 B B A18 A A A19
B B A20 A A A21 A B A22 A A A23 B C A24 B C A25 A A A26 A A A27 A A
A28 A A A29 A A A30 A A A31 B B A32 A A A33 A A A34 A A A35 A A A36
A A A37 A B A38 A A A39 A A A40 A A A41 A A A42 A A A43 A A A44 A A
A45 A A A46 A A A47 A A A48 A A A49 A A A50 A A A51 A A A52 A A A53
A A A54 A A A55 A A A56 A A A57 A A A58 A A A59 A A A60 A A A61 A A
A62 A A A63 A A A64 A A A65 A A A66 A A A67 A A A68 A A A69 A A A70
A A A71 A A A72 A A A73 A A A74 A A A75 A A A76 A A A77 A A A78 A A
A79 A A A80 A A A81 A A A82 A A A83 A A A84 A A A85 A A A86 A A A87
A A A88 A A A89 A A A90 A A A91 A A A92 A A A93 A A A94 A A A95 B A
A96 A A A97 -- A A98 A A A99 -- A A100 A B A101 A A A102 A A A103 A
A A104 A A A105 -- A A106 C C A107 A A A108 B B A109 A A A110 A A
A111 A A A112 A A A113 A A A114 A A A115 A A A116 A A A117 B C A118
A A A119 B B A120 A A A121 B C A122 A A A123 -- B A124 -- A A125 B
B A126 A A A127 B C A128 -- A A129 A A A130 A A A131 B B A132 A A
A133 A A A134 A A A135 A A A136 A A A137 A A A138 A A A139 A A A140
A A
Methods of Preparation
[0445] The compounds of the present invention may be prepared by
methods such as those illustrated in the following schemes.
Solvents, temperatures, pressures, and other reaction conditions
may readily be selected by one of ordinary skill in the art.
Starting materials are commercially available or readily prepared
by one of ordinary skill in the art. These schemes are illustrative
and are not meant to limit the possible techniques one skilled in
the art may use to manufacture compounds disclosed herein.
Different methods may be evident to those skilled in the art.
Additionally, the various steps in the synthesis may be performed
in an alternate sequence or order to give the desired compound(s).
All documents cited herein are incorporated herein by reference in
their entirety.
[0446] In general, the time taken to complete a reaction procedure
will be judged by the person performing the procedure, preferably
with the aid of information obtained by monitoring the reaction by
methods such as HPLC or TLC. A reaction does not have to go to
completion to be useful to this invention. The methods for the
preparation of various heterocycles used to this invention can be
found in standard organic reference books, for example, Katritzky,
A. R. et al., eds., Comprehensive Heterocyclic Chemistry, The
Structure, Reactions, Synthesis and Uses, of Heterocyclic
Compounds, First Edition, Pergamon Press, New York (1984), and
Katritzky, A. R. et al., eds., Comprehensive Heterocyclic Chemistry
II, A Review of the Literature 1982-1995: The Structure, Reactions,
Synthesis and Uses, of Heterocyclic Compounds, Pergamon Press, New
York (1996).
[0447] Unless otherwise specified, the various substituents of the
compounds are defined in the same manner as the Formula (I)
compound of the invention.
[0448] HPLC Methods: Analytical HPLC/LC-MS retention time reported
for each Example and Intermediate uses one of the following general
analytical HPLC/LC-MS methods:
[0449] Method A: SunFire C18 (4.6.times.150) mm, 3.5.mu. column;
flow rate 1 mL/min; gradient time 15 min; 10% Solvent B to 100%
Solvent B; monitoring at 254 nm and 220 nm (Solvent A: 5%
Acetonitrile, 95% water, 0.05% TFA; Solvent B: 95% Acetonitrile, 5%
water, 0.05% TFA).
[0450] Method B: XBridge Phenyl (4.6.times.150) mm, 3.5.mu. column;
flow rate 1 mL/min; gradient time 15 min; 10% Solvent B to 100%
Solvent B; monitoring at 254 nm and 220 nm (Solvent A: 5%
Acetonitrile, 95% water, 0.05% TFA; Solvent B: 95% Acetonitrile, 5%
water, 0.05% TFA).
[0451] Method C: SunFire C18 (4.6.times.150) mm, 3.5.mu. column;
flow rate 1 mL/min; gradient time 23 min; 100% Solvent A to 100%
Solvent B and holding 100% Solvent B for 5 min. Monitoring at 254
nm and 220 nm (Solvent A: 5% Acetonitrile, 95% water, 0.05% TFA;
Solvent B: 95% Acetonitrile, 5% water, 0.05% TFA).
[0452] Method D: XBridge Phenyl (4.6.times.150) mm, 3.5.mu. column;
flow rate 1mL/min; gradient time 23 min; 100% Mobile Phase A to
100% Mobile Phase B and holding 100% Solvent B for 5 min.
Monitoring at 254 nm and 220 nm (Solvent A: 5% Acetonitrile, 95%
water, 0.05% TFA; Solvent B: 95% Acetonitrile, 5% water, 0.05%
TFA).
[0453] Method E: Column: Ascentis Express C18 (50.times.2.1) mm,
2.7 .mu.m; flow rate 1.1 mL/min; gradient time 3 min; Temperature:
50.degree. C., 0% Solvent B to 100% Solvent B; monitoring at 220 nm
(Solvent A: 95% water: 5% Acetonitrile; 10 mM NH.sub.4OAc; Solvent
B: 5% water: 95% Acetonitrile; 10 mM NH.sub.4OAc).
[0454] Method F: SunFire C 18 (4.6.times.150) mm, 3.5.mu. column,
flow rate 1 mL/min; gradient time 23 min; 10% Solvent B to 100%
Solvent B; monitoring at 254 nm to 220 nm (Solvent A: 5%
Acetonitrile, 95% water, 0.05% TFA; Solvent B: 95% Acetonitrile, 5%
water, 0.05% TFA).
[0455] Method G: XBridge Phenyl (4.6.times.150) mm, 3.5.mu. column,
flow rate 1 mL/min; gradient time 23 min; 10% Solvent B to 100%
Solvent B; monitoring at 254 nm to 220 nm (Solvent A: 5%
Acetonitrile, 95% water, 0.05% TFA; Solvent B: 95% Acetonitrile, 5%
water, 0.05% TFA).
[0456] Method H: Column: Waters BEH C18, 2.0.times.50 mm, 1.7-nm
particles; Mobile Phase A: 5:95 acetonitrile:water with 10 mM
ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with 10
mM ammonium acetate; Temperature: 40.degree. C.; Gradient: 0.5 min
hold at 0% B, 0-100% B over 4 minutes, then a 0.5-minute hold at
100% B; Flow: 1 mL/min.
[0457] Method I: Column: Waters BEH C18, 2.0.times.50 mm, 1.7-nm
particles; Mobile Phase A: 5:95 methanol:water with 10 mM ammonium
acetate; Mobile Phase B: 95:5 methanol:water with 10 mM ammonium
acetate; Temperature: 40.degree. C.; Gradient: 0.5 min hold at 0%
B, 0-100% B over 4 minutes, then a 0.5-minute hold at 100% B; Flow
rate: 0.5 mL/min.
[0458] Method J: Column: Ascentis Express C18 (50.times.4.6) mm,
2.7 nm, flow rate 4 mL/min; gradient: 0 to 100% Solvent B over 4
min; Temperature: 50.degree. C. Monitoring at 220 nm (Solvent A:
95:05 water: CH.sub.3CN with 10 mM NH.sub.4OAc and Solvent B: 05:95
water: CH.sub.3CN with 10 mM NH.sub.4OAc).
[0459] Method K: Column: Ascentis Express C18 (50.times.4.6) mm,
2.7 .mu.m, flow rate 4 mL/min; gradient: 0 to 100% Solvent B over 4
min; Temperature: 50.degree. C.; monitoring at 220 nm (Solvent A:
95:05 water: CH.sub.3CN with 0.1% TFA and Solvent B: 05:95 water:
CH.sub.3CN with 0.1% TFA).
[0460] Method L: Column: Ascentis Express C18 (50.times.2.1) mm,
2.7 .mu.m, flow rate 1.1 mL/min; gradient: 0 to 100% Solvent B over
3 min; Temperature: 50.degree. C.; monitoring at 220 nm (Solvent A:
95:05 water: CH.sub.3CN with 0.1% TFA and Solvent B: 05:95 water:
CH.sub.3CN with 0.1% TFA).
[0461] Method M: SunFire C18 (4.6.times.150) mm, 5.mu. column; flow
rate 1 mL/min; gradient time 15 min; 10% Solvent B to 100% Solvent
B; monitoring at 254 nm and 220 nm (Solvent A: 5% Acetonitrile, 95%
water, 0.05% TFA; Solvent B: 95% Acetonitrile, 5% water, 0.05%
TFA).
[0462] Method N: Column: Lux Cellulose-4 (250.times.4.6) mm, 5.mu.
column; flow rate 4 mL/min; Isocratic: 40% Mobile Phase B.
Temperature: Ambient at 287 nm (Mobile Phase A: CO.sub.2, Mobile
Phase B: 0.2% diethylamine in Methanol), Back pressure: 107 bar,
Diluents: Methanol.
[0463] Method O: Column: WHELK-O.RTM. 1 (R,R) (250.times.4.6) mm,
5.mu. column; Flow rate 3 mL/min; Isocratic: 25% Mobile Phase B.
Temperature: Ambient at 267 nm (Mobile Phase A: CO.sub.2, Mobile
Phase B: 0.2% diethylamine in Methanol), Back pressure: 100 bar,
Diluents: Methanol.
[0464] Method P: Column: CHIRALCEL.RTM.-OJH (250.times.4.6) mm,
5.mu. column; Mobile Phase B:Mobile Phase A (9:1); Mobile Phase B:
0.2% diethylamine in n-Hexane; Mobile Phase A:isopropanol:methanol
(1:1); flow rate: 1.0 mL/min
[0465] Method Q: Column: CHIRALPAK.RTM. AD-H (4.6.times.250) mm,
5.mu. column, Flow rate: 3 mL/min Isocratic: 30%; Temperature:
Ambient at 267 nm (Mobile Phase A: CO.sub.2, Mobile Phase B: 0.3%
diethylamine in Methanol), Back pressure: 100 bar, Diluents:
Methanol.
Abbreviations
[0466] The following abbreviations are used in the example section
below and elsewhere herein: [0467] Ac Acetyl [0468] Aq. Aqueous
[0469] BAIB bis(acetoxy)iodobenzene [0470] BMS Borane
dimethylsulfide [0471] BH.sub.3.THF Borane in tetrahydrofuran
[0472] Bn Benzyl [0473] Boc.sub.2O Di-tert-butyl dicarbonate [0474]
n-BuLi n-Butyllithium [0475] t-BuNCO 2-Isocyanato-2-methylpropane
[0476] CAN Ceric ammonium nitrate [0477] CDI
1,1'-Carbonyldiimidazole [0478] DAST Diethylaminosulfur trifluoride
[0479] dba Dibenzylideneacetone [0480] DBU
1,8-Diazabicyclo[5.4.0]undec-7-ene [0481] DCM Dichloromethane
[0482] DCE 1,2-Dichloroethene [0483] DEAD Diethyl azodicarboxylate
[0484] DEOXO-FLUOR.RTM. bis(2-methoxyethyl)aminosulfur trifluoride
[0485] DIAD Diisopropyl azodicarboxylate [0486] DTBAD
Di-tert-butylazodicarboxylate [0487] diglyme
1-Methoxy-2-(2-methoxyethoxy)ethane [0488] DIPEA or Hunig's base
Diisopropylethylamine [0489] DMAP 4-Dimethylaminopyridine [0490]
DMF Dimethyl formamide [0491] DMSO Dimethylsulfoxide [0492] DPPA
Diphenylphosphoryl azide [0493] dppf
1,1'-Bis(diphenylphosphino)ferrocene [0494] EtOAc Ethyl acetate
[0495] EtOH Ethanol [0496] EtI Iodoethane [0497] HATU
(O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluorophosphate) [0498] HPLC High-performance liquid
chromatography [0499] KHDMS Potassium bis(trimethylsilyl)amide
[0500] LAH lithium diisopropylamide [0501] LDA Lithium
aluminiumhydride [0502] LHMDS Lithium bis(trimethylsilyl)amide
[0503] MeOH Methanol [0504] MeI Iodomethane [0505] Ms
Methanesulfonyl [0506] NBS N-Bromosuccinimide [0507] NHDMS Sodium
hexamethyldisilizide [0508] NIS N-Iodosuccinimide [0509] NMP
N-Methyl-2-pyrrolidone [0510] PPh.sub.3 or TPP Triphenylphosphine
[0511] Pd(PPh.sub.3).sub.4 Tetrakis(triphenylphosphine)palladium(o)
[0512] Pd.sub.2(dba).sub.3 Tris(dibenzylideneacetone)dipalladium(0)
[0513] PdCl.sub.2(dppf)
[1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) [0514]
PTSA p-Toluenesulfonic acid [0515] Py Pyridine [0516] Ret. Time or
rt Retention Time [0517] RT Room Temperature [0518] SFC
Supercritical fluid chromatography [0519] SUPER-HYDRIDE.RTM.
Lithium triethylborohydride [0520] TBAF Tetrabutylammonium fluoride
[0521] TLC Thin layer chromatography [0522] TEMPO
2,2,6,6-Tetramethylpiperidinyloxy [0523] TEA or Et.sub.3N
Triethylamine [0524] TFA Trifluoroacetic acid [0525] Tf.sub.2O
Trifluoromethanesulfonic anhydride [0526] THF Tetrahydrofuran
[0527] TBSCl or TBDMS-Cl tert-Butyldimethylsilyl chloride [0528]
TMSCF.sub.3 Trifluoromethyltrimethylsilane [0529] TMSCN
Trimethylsilyl cyanide [0530] TBAI Tetrabutylammonium iodide [0531]
Ts-Cl p-Toluenesulfonyl chloride
##STR00029## ##STR00030## ##STR00031##
[0531] Intermediate 1A: Ethyl
4-(4-fluorophenyl)-2,4-dioxobutanoate
##STR00032##
[0533] To a solution of sodium ethoxide (351 mL, 21% in ethanol,
1629 mmol) was added 1-(4-fluorophenyl)ethanone (150 g, 1086 mmol)
in ethanol (100 mL) at 0.degree. C. under a nitrogen atmosphere and
the resulting reaction mixture was stirred at RT for 10 min.
Diethyl oxalate (156 mL, 1140 mmol) in ethanol (100 mL) was added
and reaction was allowed to stir at RT for 12 h. Reaction mixture
was cooled to 0.degree. C. and acidified with 1.5 N HCl and the
solid was filtered and the filtrate was diluted with water and
extracted with DCM (3.times.750 mL). The combined organic layer was
washed with brine, dried over Na.sub.2SO.sub.4, filtered and
concentrated to afford Intermediate 1A (180 g, 70%) which was taken
to next step without further purification. MS(ES): m/z=237
[M-H].sup.+; .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. ppm 15.2
(bs, 1H), 8.00-8.09 (m, 2H), 7.15-7.25 (m, 2H), 7.05 (s, 1H), 4.42
(q, J=7.15 Hz, 2H), 1.43 (t, J=7.15 Hz, 3H).
Intermediate 1B: Ethyl
3-(4-fluorophenyl)-1H-pyrazole-5-carboxylate
##STR00033##
[0535] To a solution of Intermediate 1A (120 g, 504 mmol) in
ethanol (1200 mL) was added hydrazine monohydrate (25.7 mL, 529
mmol) slowly and the resulting reaction mixture was refluxed for 1
h. Reaction mixture was cooled to RT, poured into ice cold water,
and the resultant solid dried under vacuum to afford Intermediate
1B (80 g, 67%). MS(ES): m/z=235 [M+H].sup.+; .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. ppm 7.75 (m, 2H), 7.12 (m, 2H), 7.07 (s, 1H),
4.42 (q, J=7.2 Hz, 2H), 1.42 (t, J=7.2 Hz, 3H).
Intermediate 1C: Ethyl
1-(2-bromoethyl)-3-(4-fluorophenyl)-1H-pyrazole-5-carboxylate
##STR00034##
[0537] To a solution of Intermediate 1B (135 g, 576 mmol) and
potassium carbonate (159 g, 1153 mmol) in acetonitrile (1400 mL)
was added 1,2-dibromoethane (59.6 mL, 692 mmol) and the resulting
reaction mixture was refluxed for 4 h. Acetonitrile was removed
under reduced pressure and the residue was diluted with water. The
aqueous layer was extracted with DCM (2.times.500 mL). The combined
organic layer was washed with brine, dried over Na.sub.2SO.sub.4,
filtered and concentrated. The residue was purified by ISCO using
880 g REDISEP.RTM. column and 1% methanol in chloroform as eluent.
Combined fractions were concentrated to afford Intermediate 1C (90
g, 45%). MS(ES): m/z=343 [M+H].sup.+; .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 7.91-7.97 (m, 2H), 7.41 (s, 1H),
7.24-7.30 (m, 2H), 4.96 (t, J=6.34 Hz, 2H), 4.36 (q, J=7.11 Hz,
2H), 3.90 (t, J=6.34 Hz, 2H), 1.35 (t, J=7.12 Hz, 3H).
Intermediate 1D:
5-Benzyl-2-(4-fluorophenyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one
##STR00035##
[0539] To a solution of Intermediate 1C (80 g, 234 mmol) and
potassium iodide (78 g, 469 mmol) in acetonitrile (800 mL) was
added benzyl amine (28.2 mL, 258 mmol) and the reaction mixture was
stirred at 90.degree. C. for 12 h. Acetonitrile was removed under
reduced pressure, crude was diluted with water and the aqueous
layer was extracted with DCM (3.times.500 mL). The combined organic
layer washed with brine, dried over Na.sub.2SO.sub.4, filtered and
concentrated. The residue was purified by silica gel chromatography
(120 g REDISEP.RTM. column, eluting with 1-2% methanol in
chloroform). Collected fractions were concentrated together to
afford Intermediate 1D (35 g, 46%). MS(ES): m/z=322 [M+H].sup.+;
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 7.71-7.83 (m, 2H),
7.29-7.42 (m, 5H), 7.14 (s, 1H), 7.06-7.12 (m, 2H), 4.78 (s, 2H),
4.32-4.40 (m, 2H), 3.63-3.75 (m, 2H).
Intermediate 1E:
5-Benzyl-2-(4-fluorophenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine
##STR00036##
[0541] To a solution of Intermediate 1D (23.00 g, 71.6 mmol) in THF
(230 mL) under N.sub.2 at -10.degree. C. was added LAH (59.6 mL,
2.4 M solution in THF, 143 mmol). Reaction mixture was allowed to
stir at room temperature for 12 h. Reaction mixture was quenched
with ice-cold water and filtered through CELITE.RTM. pad and the
filtrate was extracted with chloroform (3.times.150 mL). The
combined organic layer was washed with brine, dried over
Na.sub.2SO.sub.4, filtered and concentrated. The residue was
triturated with diethyl ether (2.times.150 mL) and the resulting
solid was filtered, rinsed with diethyl ether and dried to afford
Intermediate 1E (17 g, 77%). MS(ES): m/z=308 [M+H].sup.+; .sup.1H
NMR (300 MHz, CDCl.sub.3) .delta. ppm 7.67-7.82 (m, 2H), 7.31-7.47
(m, 5H), 7.01-7.14 (m, 2H), 6.19 (s, 1H), 4.22 (t, J=4.2 Hz, 2H),
3.73 (s, 2H), 3.70 (s, 2H), 2.97 (t, J=5.6 Hz, 2H).
Intermediate 1F:
2-(4-Fluorophenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine
##STR00037##
[0543] To a degassed solution of Intermediate 1E (17 g, 55.3 mmol)
in methanol (170 mL) was added 10% palladium on carbon (2.94 g,
2.77 mmol) and stirred under H.sub.2 atmospheric pressure for 3 h.
The reaction mixture was filtered through CELITE.RTM. pad, washed
with methanol (500 mL) and concentrated. The residue was triturated
with diethyl ether (2.times.100 mL) and the resulting solid was
filtered, rinsed with diethyl ether (200 mL) and dried under vacuum
to afford Intermediate 1F (9 g, 75%). MS(ES): m/z=218 [M+H].sup.+;
.sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. ppm 7.73-7.87 (m, 2H),
7.13-7.28 (m, 2H), 6.43 (s, 1H), 4.02 (t, J=5.57 Hz, 2H), 3.94 (s,
2H), 3.16 (t, J=5.57 Hz, 2H).
Intermediate 1G: tert-Butyl
2-(4-fluorophenyl)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate
##STR00038##
[0545] To a stirred solution of Intermediate 1F (9.50 g, 43.7 mmol)
and triethylamine (18.29 mL, 131 mmol) in DCM (80 mL) was added
Boc.sub.2O (19.09 g, 87 mmol) and DMAP (0.534 g, 4.37 mmol) and the
reaction mixture was stirred at RT for 12 h. DCM was removed under
reduced pressure and the residue was purified by ISCO using 120 g
REDISEP.RTM. column and 1-2% methanol in chloroform as eluent.
Collected fractions were concentrated together to afford
Intermediate 1G (11 g, 79%). MS(ES): m/z=318 [M+H].sup.+; .sup.1H
NMR (400 MHz, CDCl.sub.3) .delta. ppm 7.70-7.75 (m, 2H), 7.02-7.12
(m, 2H), 6.31 (s, 1H), 4.68 (s, 2H), 4.21 (t, J=5.4 Hz, 2H), 3.92
(t, J=5.7 Hz, 2H), 1.50 (s, 9H).
Intermediate 1H: tert-Butyl
2-(3-fluorophenyl)-3-iodo-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carbox-
ylate
##STR00039##
[0547] To a solution of Intermediate 1G (5.0 g, 15.76 mmol) in
dichloromethane (25 mL) was added NIS (5.32 g, 23.63 mmol) and
stirred at room temperature for 1 h. The reaction mixture was
diluted with DCM and washed with water. The organic layer was dried
over Na.sub.2SO.sub.4 and concentrated. The crude product was
purified by ISCO using 40 g silica column using 1-2% methanol in
chloroform as solvent. Collected fractions were concentrated
together to afford Intermediate 1H (6 g, 86%) as white solid.
MS(ES): m/z=444 [M+H].sup.+; .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. ppm 7.79 (m, 2H), 7.11 (m, 2H), 4.55 (s, 2H), 4.20 (t,
J=5.36 Hz, 2H), 3.92 (t, J=5.30 Hz, 2H), 1.52 (s, 9H).
Intermediate 1I: tert-Butyl
3-cyano-2-(3-fluorophenyl)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carbo-
xylate
##STR00040##
[0549] To a solution of Intermediate 1H (6.0 g, 13.54 mmol) in DMF
(10 mL) was added zinc cyanide (2.066 g, 17.60 mmol) and zinc
(0.265 g, 4.06 mmol) to give a brown suspension. The reaction
mixture was degassed under nitrogen for 15 min, added
Pd.sub.2(dba).sub.3 (0.620 g, 0.677 mmol), dppf (0.750 g, 1.354
mmol), and stirred at 90.degree. C. for 18 h. The reaction mixture
was quenched with water and the aqueous layer was extracted with
ethyl acetate (3.times.50 mL). Combined organic layer was washed
with aqueous ammonia (2.times.50 mL), water, dried over
Na.sub.2SO.sub.4, filtered and concentrated to afford crude
Intermediate 1I as a brown gummy solid. The residue was purified by
ISCO using 40 g REDISEP.RTM. silica gel column eluting with 3% MeOH
in chloroform. The collected fractions were concentrated together
to afford Intermediate 1I (3 g, 64%) as white solid. MS(ES):
m/z=343 [M+H].sup.+; .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta.
ppm 7.84-7.94 (m, 2H), 7.34-7.44 (m, 2H), 4.78 (s, 2H), 4.23 (t,
J=5.36 Hz, 2H), 3.87 (t, J=5.45 Hz, 2H), 1.46 (s, 9H).
Intermediate 1J: tert-Butyl
3-carbamoyl-2-(3-fluorophenyl)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4R)-c-
arboxylate
##STR00041##
[0551] To a solution of Intermediate 1I (3.0 g, 8.76 mmol) in MeOH
(10 mL) was added NaOH (10 mL, 10% NaOH solution, 25 mmol) and
H.sub.2O.sub.2 (2.5 mL, 30% w/v in H.sub.2O, 22 mmol). The reaction
mixture was stirred at room temperature for 3 h. Methanol was
removed from the reaction mixture and the residue was diluted with
10 mL of water and extracted with ethyl acetate (3.times.15 mL).
The combined organic layer was washed with water (15 mL), brine,
dried over Na.sub.2SO.sub.4, filtered and concentrated to afford
crude Intermediate 1J (3 g, 95%) as off-white solid, which was
taken to the next step without further purification. MS(ES):
m/z=361 [M+H].sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
ppm 7.66-7.71 (m, 2H), 7.22-7.30 (m, 2H), 6.94 (bs, 1H), 4.75 (s,
2H), 4.16 (t, J=5.40 Hz, 2H), 3.85 (t, J=5.36 Hz, 2H), 1.46 (s,
9H).
Intermediate 1K:
2-(3-Fluorophenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamid-
e
##STR00042##
[0553] To a solution of Intermediate 1J (3.0 g, 8.32 mmol) in
dichloromethane (20 mL) was added TFA (10.26 mL, 133 mmol) dropwise
at 0.degree. C. and stirred at room temperature for 3 h. Volatiles
were removed, and the residue was quenched with 10% NaHCO.sub.3
solution. The off-white solid product 1K (2 g, 92%) was filtered
and dried under vacuum and was used in the next step without
further purification. MS(ES): m/z=261 [M+H].sup.+; .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. ppm 7.66-7.73 (m, 2H), 7.22-7.25 (m,
2H), 7.21 (bs, 1H), 7.20 (bs, 1H), 3.98-4.05 (m, 4H), 3.13 (bs,
2H), 2.63 (s, 1H).
Compound 1:
N.sup.5-(tert-Butyl)-2-(3-fluorophenyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-
e-3,5(4H)-dicarboxamide
##STR00043##
[0555] To a solution of Intermediate 1K (30 mg, 0.115 mmol) in DMF
(1 mL) was added tert-butylisocyanate (28.6 mg, 0.288 mmol) at
0.degree. C. The reaction mixture was stirred at room temperature
for 3 h. The reaction mixture was quenched with water and extracted
with ethyl acetate (3.times.5 mL). The combined organic layer was
washed with water (2.times.5 mL), brine, dried over
Na.sub.2SO.sub.4 and concentrated to afford the crude product as
brown semi-solid. The residue was dissolved in a mixture of
acetonitrile and methanol and was purified via preparative HPLC.
Fractions containing the desired product (0.01 g, 24%) were
combined and dried under vacuum. MS(ES): m/z=360 [M+H].sup.+; HPLC
Ret. Time 6.66 min. and 6.14 min. (HPLC Methods A and B); .sup.1H
NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 7.69 (m, 2H), 7.25 (m, 2H),
7.25 (bs, 1H), 6.98 (bs, 1H), 6.26 (s, 1H), 4.69 (s, 2H), 4.11 (t,
J=5.7 Hz, 2H), 3.80 (t, J=5.7 Hz, 2H), 1.29 (s, 9H).
[0556] The Compounds shown in Table 1 have been prepared similar to
Compound 1 using Intermediate 1K and various isocyanate.
TABLE-US-00003 TABLE 1 Ret Ex. Time HPLC No. Structure Name [M +
H].sup.+ (min.) Method 2 ##STR00044##
2-(4-Fluorophenyl)-N.sup.5-isopropyl-6,7-
dihydropyrazolo[1,5-a]pyrazine-3,5(4H)- dicarboxamide 345 6.606
6.184 A B 3 ##STR00045## N.sup.5-Cyclohexyl-2-(4-fluorophenyl)-6,7-
dihydropyrazolo[1,5-a]pyrazine-3,5(4H)- dicarboxamide 386 7.948
7.838 A B
##STR00046## ##STR00047## ##STR00048##
Intermediate 4A: Ethyl 4-(3-fluorophenyl)-2,4-dioxobutanoate
##STR00049##
[0558] To a solution of sodium ethoxide (123 g, 362 mmol) in
ethanol (300 mL) at 0.degree. C. was added a solution of diethyl
oxalate (49.4 mL, 362 mmol) in ethanol (25 mL) and the resulting
solution was stirred for 10 min. 1-(3-Fluorophenyl)ethanone (50 g,
362 mmol) in ethanol (25 mL) was added and the reaction mixture was
stirred at room temperature for 16 h. Ethanol was distilled off
under reduced pressure and the residue obtained was quenched with
ice cold water and the brown product was filtered. This crude
product was purified by ISCO using 220 g silica gel column and 20%
ethyl acetate in hexane as eluent. The combined fractions were
concentrated to afford Intermediate 4A (62.5 g, 73%). MS(ES):
m/z=239 [M+H].sup.+; .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm
15.13 (bs, 1H), 7.77-7.83 (m, 1H), 7.67-7.73 (m, 1H), 7.51 (td,
J=8.03, 5.48 Hz, 1H), 7.29-7.37 (m, 1H), 7.28 (s, 1H), 4.43 (q,
J=7.18 Hz, 2H), 1.40-1.47 (m, 3H).
Intermediate 4B: Ethyl
3-(3-fluorophenyl)-1H-pyrazole-5-carboxylate
##STR00050##
[0560] To a solution of Intermediate 4A (100 g, 420 mmol) in
ethanol (250 mL) was added hydrazine (13.83 mL, 441 mmol) in
ethanol (250 mL) to give a brown solution. The reaction mixture was
stirred at 80.degree. C. for 2 h. Ethanol was removed under reduced
pressure and the residue was diluted with water and extracted with
ethyl acetate (3.times.100 mL). The combined organic layer was
washed with water (2.times.100 mL), brine, dried over
Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure.
The brown solid thus obtained was purified by ISCO using 20% ethyl
acetate in hexane as eluent. The combined fractions were
concentrated to afford Intermediate 4B (85 g, 86%) MS(ES): m/z=233
[M+H].sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 14.06
(bs, 1H), 7.68-7.75 (m, 2H), 7.45-7.55 (m, 1H), 7.36 (s, 1H), 7.20
(t, J=7.53 Hz, 1H), 4.34 (q, J=7.03 Hz, 2H), 1.34 (t, J=7.03 Hz,
3H).
Intermediate 4C: Ethyl
1-(2-((tert-butoxycarbonyl)amino)ethyl)-3-(3-fluorophenyl)-1H-pyrazole-5--
carboxylate
##STR00051##
[0562] A solution of 4B (12 g, 51.2 mmol) and PPh.sub.3 (20.16 g,
77 mmol) in THF (10 mL) at 0.degree. C. was added DIAD (14.94 mL,
77 mmol) in THF (10 mL) and the resulting reaction mixture was
stirred at the same temperature for 30 min.
tert-Butyl(2-hydroxyethyl)carbamate (9.91 g, 61.5 mmol) was then
added and the reaction mixture was stirred at room temperature for
2 h. The volatiles were evaporated from the reaction mixture under
reduced pressure and the resultant residue was quenched with ice.
The aqueous layer was extracted with ethyl acetate (3.times.1000
mL). The combined organic layer was washed with 1.5 N HCl
(2.times.100 mL), brine, dried over Na.sub.2SO.sub.4, filtered and
concentrated to afford crude product, which was purified by ISCO
(5:1 Hex/EtOAc; 120 g column). Collected fractions were
concentrated together to afford pale yellow solid 4C (16 g, 83%).
MS(ES): m/z=378 [M+H].sup.+; .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. ppm 7.54-7.59 (m, 1H), 7.48-7.54 (m, 1H), 7.36 (td, J=8.03,
6.02 Hz, 1H), 7.13 (s, 1H), 6.98-7.05 (m, 1H), 6.32 (bs, 1H), 4.98
(quin, J=6.27 Hz, 2H), 4.37 (q, J=7.19 Hz, 2H), 3.64 (d, J=5.02 Hz,
2H), 1.39-1.41 (m, 3H), 1.27 (s, 9H).
Intermediate 4D:
2-(3-Fluorophenyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one
##STR00052##
[0564] A 250 mL round-bottomed flask was charged with 4C (14 g,
37.1 mmol) and HCl in 1,4-dioxane (185 mL, 185 mmol) to give a
yellow solution. The reaction mixture was stirred at room
temperature for 2 h. The reaction mixture was concentrated under
reduced pressure and to this residue was added 10% NaHCO.sub.3
slowly until pH became 8.0. The aqueous layer was extracted with
ethyl acetate (3.times.100 mL) and the combined the organic layer
was washed with water (2.times.100 mL), brine, dried over
Na.sub.2SO.sub.4, filtered and concentrated to give the desired
product 4D as off-white solid, which was used in the next step
without purification. MS(ES): m/z=231 [M+H].sup.+; .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. ppm 8.26 (bs, 1H), 7.70-7.75 (m, 1H),
7.63-7.69 (m, 1H), 7.47 (td, J=8.03, 6.53 Hz, 1H), 7.11-7.20 (m,
1H), 4.32-4.40 (m, 2H), 3.65 (tt, J=4.64, 3.14 Hz, 2H).
Intermediate 4E:
2-(3-Fluorophenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine
##STR00053##
[0566] To a solution of Intermediate 4D (4.5 g, 19.46 mmol) in THF
(100 mL) at -10.degree. C. was added LAH (16.22 mL, 2.4 M in THF,
38.9 mmol) dropwise. The reaction mixture was stirred at room
temperature for 16 h, was quenched with saturated NH.sub.4Cl at
0.degree. C. and the aqueous layer was extracted with ethyl acetate
(3.times.50 mL). Combined organic layer was washed with water
(2.times.50 mL), brine, filtered through CELITE.RTM., dried over
Na.sub.2SO.sub.4 and concentrated to afford crude Compound 4E as
off-white solid (4 g, 90%), which was used in the next step without
purification. MS(ES): m/z=218 [M+H].sup.+; .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. ppm 7.53-7.59 (m, 1H), 7.50 (ddd, J=10.29,
2.55, 1.51 Hz, 1H), 7.35 (td, J=7.93, 6.04 Hz, 1H), 6.99 (tdd,
J=8.40, 8.40, 2.64, 0.94 Hz, 1H), 6.29 (s, 1H), 4.19 (t, J=5.67 Hz,
2H), 4.12 (s, 2H), 3.33-3.40 (m, 2H).
Intermediate 4F: tert-Butyl
2-(3-fluorophenyl)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate
##STR00054##
[0568] To a solution of Intermediate 4E (4.0 g, 20.71 mmol) in
dichloromethane (150 mL) was added triethylamine (7.70 mL, 55.2
mmol), and DMAP (0.225 g, 1.841 mmol) to give a colorless solution.
The reaction was cooled to 0.degree. C. and Boc.sub.2O (4.82 g,
22.10 mmol) was then added and the reaction mixture was stirred at
room temperature for 2 h. The reaction mixture was diluted with
dichloromethane (100 mL), washed with water (2.times.100 mL), dried
over Na.sub.2SO.sub.4, filtered and concentrated to afford crude
compound as off-white solid. The crude product was purified by
silica gel chromatography (24 g REDISEP.RTM. column, eluting with
30% ethyl acetate in hexane). Collected fractions were concentrated
together to afford Intermediate 4F (5 g, 86%) as white solid.
MS(ES): m/z=318 [M+H].sup.+; .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. ppm 7.53 (dt, J=7.53, 1.25 Hz, 1H), 7.47 (ddd, J=10.54,
2.51, 1.51 Hz, 1H), 7.31-7.38 (m, 1H), 6.95-7.03 (m, 1H), 6.35 (s,
1H), 4.69 (s, 2H), 4.22 (t, J=5.27 Hz, 2H), 3.92 (t, J=5.52 Hz,
2H), 1.51 (s, 9H).
Intermediate 4G: tert-Butyl
2-(3-fluorophenyl)-3-iodo-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carbox-
ylate
##STR00055##
[0570] To a solution of Intermediate 4F (5.0 g, 15.76 mmol) in
dichloromethane (25 mL) was added NIS (5.32 g, 23.63 mmol) and
stirred at room temperature for 2 h. The reaction mixture was
diluted with DCM and washed with water. The organic layer was dried
over Na.sub.2SO.sub.4 and concentrated to afford Intermediate 4G (6
g, 86%) as colorless semi-solid which was used in the next step
without any purification. MS(ES): m/z=444 [M+H].sup.+; .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. ppm 7.61-7.66 (m, 1H), 7.56 (ddd,
J=10.04, 2.51, 1.51 Hz, 1H), 7.39 (td, J=8.03, 6.02 Hz, 1H),
7.04-7.10 (m, 1H), 4.56 (bs, 2H), 4.22 (t, J=5.52 Hz, 2H), 3.92 (t,
J=5.52 Hz, 2H), 1.52 (s, 9H).
Intermediate 4H: tert-Butyl
3-cyano-2-(3-fluorophenyl)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carbo-
xylate
##STR00056##
[0572] To a solution of Intermediate 4G (5.0 g, 11.28 mmol) in DMF
(50 mL) was added zinc cyanide (1.722 g, 14.66 mmol) and zinc
(0.221 g, 3.38 mmol) to give a brown suspension. The reaction
mixture was degassed under nitrogen for 15 min and added
Pd.sub.2(dba).sub.3 (0.516 g, 0.564 mmol) and dppf (0.625 g, 1.128
mmol). The reaction mixture was stirred at 90.degree. C. for 18 h.
The reaction mixture was quenched with water and the aqueous layer
was extracted with ethyl acetate (3.times.50 mL). The combined
organic layer was and washed with aqueous ammonia (2.times.50 mL),
water, dried over Na.sub.2SO.sub.4, filtered and concentrated to
afford crude product as brown semi-solid. The crude was purified by
silica gel chromatography (40 g REDISEP.RTM. column, eluting with
50% EtOAc in hexane). Collected fractions concentrated together to
afford Intermediate 4H (3 g, 78%) as white solid. MS(ES): m/z=343
[M+H].sup.+; .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm
7.73-7.78 (m, 1H), 7.62-7.68 (m, 1H), 7.43 (td, J=8.03, 5.52 Hz,
1H), 7.08-7.15 (m, 1H), 4.82 (s, 2H), 4.24 (t, J=5.52 Hz, 2H), 3.96
(t, J=5.27 Hz, 2H), 1.52 (s, 9H).
Intermediate 4I: tert-Butyl
3-carbamoyl-2-(3-fluorophenyl)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-c-
arboxylate
##STR00057##
[0574] To a solution of Intermediate 4H (3.0 g, 8.76 mmol) in MeOH
(10 mL) was added NaOH (10 ml, 10% NaOH solution, 25 mmol) and
H.sub.2O.sub.2 (2.5 mL, 30% w/v in H.sub.2O, 22 mmol). The reaction
mixture was stirred at room temperature for 3 h. Methanol was
removed from the reaction mixture and the residue was diluted with
10 mL of water and extracted with ethyl acetate (3.times.15 mL).
Combined organic layer was washed with water (15 mL), brine, dried
over Na.sub.2SO.sub.4, filtered and concentrated to afford crude
Intermediate 4I (3 g, 95%) as off-white solid, which was used in
the next step without further purification. MS(ES): m/z=361
[M+H].sup.+; .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. ppm 7.53
(d, J=1.51 Hz, 1H), 7.43-7.50 (m, 2H), 7.32 (bs, 1H), 7.18-7.24 (m,
1H), 7.14 (bs, 1H), 4.75 (s, 2H), 4.17 (t, J=5.27 Hz, 2H), 3.85 (t,
J=5.52 Hz, 2H), 1.41-1.49 (m, 8H).
Intermediate 4J:
2-(3-Fluorophenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamid-
e
##STR00058##
[0576] To a solution of Intermediate 41 (3.0 g, 8.32 mmol) in
dichloromethane (20 mL) at 0.degree. C. was added TFA (10.26 mL,
133 mmol) dropwise and stirred at room temperature for 1 h. TFA was
removed from the reaction mixture and the residue was quenched with
10% NaHCO.sub.3 solution. The solid was filtered to obtain
Intermediate 4J (2 g, 92%) as off-white solid, which was used in
the next step without purification. MS(ES): m/z=261 [M+H].sup.+;
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 7.52-7.57 (m, 1H),
7.46-7.52 (m, 1H), 7.40-7.46 (m, 1H), 7.14-7.27 (m, 2H), 7.08 (bs,
1H), 4.03 (d, J=5.02 Hz, 4H), 3.13 (d, J=5.02 Hz, 2H), 2.64 (d,
J=6.02 Hz, 1H).
Compound 4:
N.sup.5-(tert-Butyl)-2-(3-fluorophenyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-
e-3,5(4H)-dicarboxamide
##STR00059##
[0578] To a solution of Intermediate 4J (50 mg, 0.192 mmol) in DMF
(2 mL) at 0.degree. C. was added tert-butylisocyanate (38 mg, 0.384
mmol). The reaction mixture was stirred at room temperature for 12
h, quenched with water and extracted with ethyl acetate (3.times.5
mL). The combined organic layer was washed with water (2.times.5
mL), brine, dried over Na.sub.2SO.sub.4, filtered and concentrated
to afford crude product as brown semi-solid. The residue was
further purified by preparative HPLC to afford pure product 4 as
white powder (40 mg, 57%). MS(ES): m/z=360 [M+H].sup.+; HPLC Ret.
Time 7.35 min. and 7.33 min. (HPLC Methods A and B); .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. ppm 7.51-7.54 (m, 1H), 7.47-7.50
(m, 1H), 7.44-7.46 (m, 1H), 7.18-7.24 (m, 1H), 4.74 (s, 2H), 4.17
(t, J=5.52 Hz, 2H), 3.85 (t, J=5.52 Hz, 2H), 1.45-1.48 (s, 9H).
General Methods to Synthesize Ureas:
Method A:
[0579] To a solution of Intermediate 4J (30 mg, 0.115 mmol) in DMF
(1 mL) was added the corresponding isocyanate (0.288 mmol) at
0.degree. C. and the reaction mixture was stirred at room
temperature for 3 h. The reaction mixture was quenched with water
and extracted with ethyl acetate (3.times.5 mL). The combined
organic layer was washed with water (2.times.5 mL), brine, dried
over Na.sub.2SO.sub.4, filtered and concentrated to afford crude
product. The crude product was further purified by preparative
HPLC.
Method B:
[0580] To a solution of primary amine (0.192 mmol) and
triethylamine (0.480 mmol) in tetrahydrofuran (3 mL) at 0.degree.
C. was added triphosgene (0.096 mmol) and the reaction mixture
stirred for 30 min. at the same temperature. Intermediate 4J (25
mg, 0.096 mmol) in THF was added and the solution was stirred at
room temperature for 2 h. Reaction progress was monitored by TLC.
The reaction mixture was quenched with water and extracted with
ethyl acetate (3.times.5 mL). The combined organic layer was washed
with 10% NaHCO.sub.3 (2.times.5 mL), water, dried over
Na.sub.2SO.sub.4 and concentrated to afford crude product as
off-white solid. The crude product was further purified by
preparative HPLC.
Method C:
[0581] To a solution of acid (0.192 mmol) and TEA (0.288 mmol) in
toluene (3 mL) was added diphenylphosphoryl azide (0.192 mmol) to
give a colorless solution. The reaction mixture was stirred at
90.degree. C. for 1.5 h and cooled to RT. Intermediate 4J (25 mg,
0.096 mmol) in THF was added and the reaction mixture was stirred
at 60.degree. C. for 4 h. Reaction progress was monitored by TLC.
The reaction mixture was quenched with water and extracted with
ethyl acetate (3.times.5 mL). The combined organic layer was washed
with 10% NaHCO.sub.3 (2.times.5 mL), water, dried over
Na.sub.2SO.sub.4 and concentrated to afford crude product as
off-white solid. The crude product was further purified by
preparative HPLC.
Method D:
[0582] To a solution of primary amine (0.192 mmol) and
triethylamine (0.480 mmol) in tetrahydrofuran (3 mL) at 0.degree.
C. were added phenyl chloroformate (0.096 mmol) and the reaction
mixture stirred for 60 min. at RT. The reaction mixture was
quenched with water and the phenyl carbamate formed was extracted
and the Intermediate 4J (25 mg, 0.096 mmol) in THF was added to the
extract and the resulting solution was stirred at room temperature
for 2 h. Reaction progress was monitored by TLC. The reaction
mixture was quenched with water and extracted with ethyl acetate
(3.times.5 mL). The combined organic layer was washed with 10%
NaHCO.sub.3 (2.times.5 mL), water, dried over Na.sub.2SO.sub.4 and
concentrated to afford crude product as off-white solid. The crude
product was further purified by preparative HPLC.
[0583] The Compounds described in Table 2 were synthesized
analogous to Compound 4 by reacting Intermediate 4J with
corresponding reagents.
TABLE-US-00004 TABLE 2 Ret Ex. Synthetic Time HPLC No. Structure
Name Method [M + H].sup.+ (min.) Method 5 ##STR00060##
2-(3-Fluorophenyl)-N.sup.5- isopropyl-6,7- dihydropyrazolo[1,5-a]
pyrazine-3,5(4H)- dicarboxamide A 346 6.41 5.79 A B 6 ##STR00061##
N.sup.5-Cyclohexyl-2-(3- fluorophenyl)-6,7- dihydropyrazolo[1,5-a]
pyrazine-3,5(4H)- dicarboxamide A 386 14.34 13.57 C D 7
##STR00062## N.sup.5-Cyclopropyl-2-(3- fluorophenyl)-6,7-
dihydropyrazolo[1,5-a] pyrazine-3,5(4H)- dicarboxamide B 344 6.06
5.39 A B 8 ##STR00063## N.sup.5-Cyclobutyl-2-(3- fluorophenyl)-6,7-
dihydropyrazolo[1,5-a] pyrazine-3,5(4H)- dicarboxamide B 358 6.89
6.48 A B 9 ##STR00064## N.sup.5-Cyclopentyl-2-(3-
fluorophenyl)-6,7- dihydropyrazolo[1,5-a] pyrazine-3,5(4H)-
dicarboxamide B 372 7.43 6.95 A B 10 ##STR00065##
N.sup.5-(4-Chlorophenyl)- 2-(3-fluorophenyl)-6,7-
dihydropyrazolo[1,5-a] pyrazine-3,5(4H)- dicarboxamide A 414 8.87
8.36 A B 11 ##STR00066## 2-(3-Fluorophenyl)-N.sup.5-
(1-methylcyclopropyl)- 6,7-dihydropyrazolo [1,5-a]pyrazine-
3,5(4H)-dicarboxamide C 358 6.46 6.06 A B 12 ##STR00067##
N.sup.5-(4,4- Difluorocyclohexyl)-2- (3-fluorophenyl)-6,7-
dihydropyrazolo[1,5-a] pyrazine-3,5(4H)- dicarboxamide B 422 7.42
6.63 A B 13 ##STR00068## 2-(3-Fluorophenyl)-N.sup.5-
(1,1,1-trifluoro-2- methylpropan-2-yl)- 6,7-dihydropyrazolo
[1,5-a]pyrazine- 3,5(4H)-dicarboxamide B 414 7.96 7.52 A B 14
##STR00069## 2-(3-Fluorophenyl)-N.sup.5- (3,3,3-trifluoropropyl)-
6,7-dihydropyrazolo [1,5-a]pyrazine- 3,5(4H)-dicarboxamide C 400
7.19 6.79 A B 15 ##STR00070## 2-(3-Fluorophenyl)-N.sup.5-
(2,2,2-trifluoroethyl)- 6,7-dihydropyrazolo [1,5-a]pyrazine-
3,5(4H)-dicarboxamide C 386 7.00 6.58 A B 16 ##STR00071##
2-(3-Fluorophenyl)-N.sup.5- (4-fluorophenyl)-6,7-
dihydropyrazolo[1,5-a] pyrazine-3,5(4H)- dicarboxamide B 398 7.99
7.62 A B 17 ##STR00072## 2-(3-Fluorophenyl)-N.sup.5-
(2-(4-fluorophenyl) propan-2-yl)-6,7- dihydropyrazolo[1,5-a]
pyrazine-3,5(4H)- dicarboxamide B 440 8.82 8.34 A B 18 ##STR00073##
2-(3-Fluorophenyl)-N.sup.5- (2,2,6,6- tetramethylpiperidin-4-
yl)-6,7- dihydropyrazolo[1,5-a] pyrazine-3,5(4H)- dicarboxamide B
443 9.09 10.11 C D 19 ##STR00074## N.sup.5-(Adamantan-2-yl)-
2-(3-fluorophenyl)-6,7- dihydropyrazolo[1,5-a] pyrazine-3,5(4H)-
dicarboxamide B 348 9.70 8.89 A B 20 ##STR00075##
2-(3-Fluorophenyl)-N.sup.5- (1-(trifluoromethyl) cyclopropyl)-6,7-
dihydropyrazolo[1,5-a] pyrazine-3,5(4H)- dicarboxamide B 412 7.25
6.77 A B 21 ##STR00076## 2-(3-Fluorophenyl)-N.sup.5-
(4-(trifluoromethyl) phenyl)-6,7- dihydropyrazolo[1,5-a]
pyrazine-3,5(4H)- dicarboxamide B 448 9.55 8.88 A B 22 ##STR00077##
N.sup.5-(Adamantan-1-yl)- 2-(3-fluorophenyl)-6,7-
dihydropyrazolo[1,5-a] pyrazine-3,5(4H)- dicarboxamide A 438 9.93
9.17 A B 23 ##STR00078## 2-(3-Fluorophenyl)-N.sup.5-
((2R,5S)-octahydro- 2,5-methanopentalen- 6a-yl)-6,7-
dihydropyrazolo[1,5-a] pyrazine-3,5(4H)- dicarboxamide C 424 9.30
8.62 A B 24 ##STR00079## N.sup.5-(Bicyclo[1.1.1] pentan-1-yl)-2-(3-
fluorophenyl)-6 7- dihydropyrazolo[1,5-a] pyrazine-3,5(4H)-
dicarboxamide B 370 7.16 6.91 A B 25 ##STR00080##
2-(3-Fluorophenyl)-N.sup.5- (2-phenylpropan-2-yl)-
6,7-dihydropyrazolo [1,5-a]pyrazine- 3,5(4H)-dicarboxamide B 422
8.53 8.10 A B 26 ##STR00081## N.sup.5-(2,5- Difluorophenyl)-2-(3-
fluorophenyl)-6,7- dihydropyrazolo[1,5-a] pyrazine-3,5(4H)-
dicarboxamide B 416 8.21 7.87 A B 27 ##STR00082##
2-(3-Fluorophenyl)-N.sup.5- (2,3,5-trifluorophenyl)-
6,7-dihydropyrazolo [1,5-a]pyrazine- 3,5(4H)-dicarboxamide B 434
9.69 9.03 A B 28 ##STR00083## N.sup.5-(2,3- Difluorophenyl)-2-(3-
fluorophenyl)-6,7- dihydropyrazolo[1,5-a] pyrazine-3,5(4H)-
dicarboxamide B 416 8.05 7.76 A B 29 ##STR00084## N.sup.5-(3,4-
Difluorophenyl)-2-(3- fluorophenyl)-6,7- dihydropyrazolo[1,5-a]
pyrazine-3,5(4H)- dicarboxamide B 416 8.72 8.25 A B 30 ##STR00085##
N.sup.5-(2,4- Difluorophenyl)-2-(3- fluorophenyl)-6,7-
dihydropyrazolo[1,5-a] pyrazine-3,5(4H)- dicarboxamide B 416 7.88
7.55 A B 31 ##STR00086## N.sup.5-(3,5- Difluorophenyl)-2-(3-
fluorophenyl)-6,7- dihydropyrazolo[1,5-a] pyrazine-3,5(4H)-
dicarboxamide B 416 9.04 8.54 A B 32 ##STR00087##
N.sup.5-(2-Chloro-4- fluorophenyl)-2-(3- fluorophenyl)-6,7-
dihydropyrazolo[1,5-a] pyrazine-3,5(4H)- dicarboxamide B 432 8.29
7.96 A B 33 ##STR00088## N.sup.5-(5-Chloro-2- fluorophenyl)-2-(3-
fluorophenyl)-6,7- dihydropyrazolo[1,5-a] pyrazine-3,5(4H)-
dicarboxamide B 432 8.79 8.41 A B 34 ##STR00089##
N.sup.5-(2-Chloro-5- (trifluoromethyl) phenyl)-2-(3-
fluorophenyl)-6,7- dihydropyrazolo[1,5-a] pyrazine-3,5(4H)-
dicarboxamide B 482 9.25 9.83 B A 35 ##STR00090##
N.sup.5-(4-Chloro-3- (trifluoromethyl) phenyl)-2-(3-
fluorophenyl)-6,7- dihydropyrazolo[1,5-a] pyrazine-3,5(4H)-
dicarboxamide B 482 9.64 10.37 B A 36 ##STR00091##
N.sup.5-(2-Fluoro-3- (trifluoromethyl) phenyl)-2-(3-
fluorophenyl)-6,7- dihydropyrazolo[1,5-a] pyrazine-3,5(4H)-
dicarboxamide B 466 8.79 9.26 B A 37 ##STR00092##
2-(3-Fluorophenyl)-N.sup.5- (4-(trifluoromethoxy) phenyl)-6,7-
dihydropyrazolo[1,5-a] pyrazine-3,5(4H)- dicarboxamide B 464 9.93
9.67 B A 38 ##STR00093## N.sup.5-(4-Cyano-3- (trifluoromethyl)
phenyl)-2-(3- fluorophenyl)-6,7- dihydropyrazolo[1,5-a]
pyrazine-3,5(4H)- dicarboxamide B 473 9.03 9.49 B A 39 ##STR00094##
N.sup.5-(2-Fluoro-5- (trifluoromethyl) phenyl)-2-(3-
fluorophenyl)-6,7- dihydropyrazolo[1,5-a] pyrazine-3,5(4H)-
dicarboxamide B 466 9.71 9.32 B A 40 ##STR00095##
2-(3-Fluorophenyl)-N.sup.5- (2,4,6-trifluorophenyl)-
6,7-dihydropyrazolo [1,5-a]pyrazine- 3,5(4H)-dicarboxamide B 434
8.39 7.76 B A 41 ##STR00096## 2-(3-Fluorophenyl)-N.sup.5-
(3-hydroxyadamantan- 1-yl)-6,7- dihydropyrazolo[1,5-a]
pyrazine-3,5(4H)- dicarboxamide B 454 7.22 6.70 B A 42 ##STR00097##
N.sup.5-(4- Fluorophenethyl)-2-(3- fluorophenyl)-6,7-
dihydropyrazolo[1,5-a] pyrazine-3,5(4H)- dicarboxamide A 426 1.276
E 43 ##STR00098## N.sup.5-(2,4- Dichlorophenyl)-2-(3-
fluorophenyl)-6,7- dihydropyrazolo[1,5-a] pyrazine-3,5(4H)-
dicarboxamide A 449 1.441 E 44 ##STR00099##
2-(3-Fluorophenyl)-N.sup.5- ((1R,2S)-2- phenylcyclopropyl)-
6,7-dihydropyrazolo [1,5-a]pyrazine- 3,5(4H)-dicarboxamide A 420
1.325 E 45 ##STR00100## N.sup.5-(2,4- Dichlorobenzyl)-2-(3-
fluorophenyl)-6,7- dihydropyrazolo[1,5-a] pyrazine-3,5(4H)-
dicarboxamide A 464 1.483 E 46 ##STR00101## N.sup.5-(3,4-
Dichlorobenzyl)-2-(3- fluorophenyl)-6,7- dihydropyrazolo[1,5-a]
pyrazine-3,5(4H)- dicarboxamide A 463 1.484 E 47 ##STR00102##
2-(3-Fluorophenyl)-N.sup.5- (4-methoxyphenethyl)-
6,7-dihydropyrazolo [1,5-a]pyrazine- 3,5(4H)-dicarboxamide A 438
1.230 E 48 ##STR00103## 2-(3-Fluorophenyl)-N.sup.5-
(2-(trifluoromethyl) phenyl)-6,7- dihydropyrazolo[1,5-a]
pyrazine-3,5(4H)- dicarboxamide A 448 1.269 E 49 ##STR00104##
N.sup.5-(3,4- Dichlorophenyl)-2-(3- fluorophenyl)-6,7-
dihydropyrazolo[1,5-a] pyrazine-3,5(4H)- dicarboxamide A 448 1.572
E 50 ##STR00105## 2-(3-Fluorophenyl)-N.sup.5- (3-(trifluoromethyl)
phenyl)-6,7- dihydropyrazolo[1,5-a] pyrazine-3,5(4H)- dicarboxamide
A 448 1.516 E 51 ##STR00106## 2-(3-Fluorophenyl)-N.sup.5-
(4-methoxyphenyl)- 6,7-dihydropyrazolo [1,5-a]pyrazine-
3,5(4H)-dicarboxamide A 410 1.134 E 52 ##STR00107##
2-(3-Fluorophenyl)-N.sup.5- (naphthalen-1-yl)-6,7-
dihydropyrazolo[1,5-a] pyrazine-3,5(4H)- dicarboxamide A 430 1.303
E 53 ##STR00108## N.sup.5-(3,5- Bis(trifluoromethyl) phenyl)-2-(3-
fluorophenyl)-6,7- dihydropyrazolo[1,5-a] pyrazine-3,5(4H)-
dicarboxamide A 516 1.837 E 54 ##STR00109##
N.sup.5-(3-Cyanophenyl)-2- (3-fluorophenyl)-6,7-
dihydropyrazolo[1,5-a] pyrazine-3,5(4H)- dicarboxamide A 405 1.190
E 55 ##STR00110## N.sup.5-(3,5- Dichlorophenyl)-2-(3-
fluorophenyl)-6,7- dihydropyrazolo[1,5-a] pyrazine-3,5(4H)-
dicarboxamide A 449 1.64 E 56 ##STR00111## N.sup.5-(3,5-
Dimethoxyphenyl)-2- (3-fluorophenyl)-6,7- dihydropyrazolo[1,5-a]
pyrazine-3,5(4H)- dicarboxamide A 440 1.248 E 57 ##STR00112##
N.sup.5-(4-Chloro-2- (trifluoromethyl) phenyl)-2-(3-
fluorophenyl)-6,7- dihydropyrazolo[1,5-a] pyrazine-3,5(4H)-
dicarboxamide A 482 1.466 E 58 ##STR00113##
2-(3-Fluorophenyl)-N.sup.5- (4-phenoxyphenyl)- 6,7-dihydropyrazolo
[1,5-a]pyrazine- 3,5(4H)-dicarboxamide A 472 1.613 E 59
##STR00114## 2-(3-Fluorophenyl)-N.sup.5- (naphthalen-2-yl)-6,7-
dihydropyrazolo[1,5-a] pyrazine-3,5(4H)- dicarboxamide A 430 1.459
E 60 ##STR00115## N.sup.5-(3-Chloro-4- fluorophenyl)-2-(3-
fluorophenyl)-6,7- dihydropyrazolo[1,5-a] pyrazine-3,5(4H)-
dicarboxamide A 432 1.424 E 61 ##STR00116##
N.sup.5-(4-Cyanophenyl)-2- (3-fluorophenyl)-6,7-
dihydropyrazolo[1,5-a] pyrazine-3,5(4H)- dicarboxamide A 405 1.186
E 62 ##STR00117## N.sup.5-([1,1'-Biphenyl]-4-
yl)-2-(3-fluorophenyl)- 6,7-dihydropyrazolo [1,5-a]pyrazine-
3,5(4H)-dicarboxamide A 456 1.621 E 63 ##STR00118##
N.sup.5-(4-(tert-Butyl) phenyl)-2-(3- fluorophenyl)-6,7-
dihydropyrazolo[1,5-a] pyrazine-3,5(4H)- dicarboxamide A 436 1.657
E 64 ##STR00119## N.sup.5-(2-Chloro-4- (trifluoromethyl)
phenyl)-2-(3- fluorophenyl)-6,7- dihydropyrazolo[1,5-a]
pyrazine-3,5(4H)- dicarboxamide A 482 1.610 E 65 ##STR00120##
N.sup.5-(2-Chloro-6- (trifluoromethyl) phenyl)-2-(3-
fluorophenyl)-6,7- dihydropyrazolo[1,5-a] pyrazine-3,5(4H)-
dicarboxamide A 482 1.259 E 66 ##STR00121## N.sup.5-(3,4-
Dimethoxyphenyl)-2- (3-fluorophenyl)-6,7- dihydropyrazolo[1,5-a]
pyrazine-3,5(4H)- dicarboxamide A 440 1.066 E 67 ##STR00122##
N.sup.5-(3-Chloro-4- methoxyphenyl)-2-(3- fluorophenyl)-6,7-
dihydropyrazolo[1,5-a] pyrazine-3,5(4H)- dicarboxamide A 444 1.310
E 68 ##STR00123## 2-(3-Fluorophenyl)-N.sup.5- (pyridin-3-yl)-6,7-
dihydropyrazolo[1,5-a] pyrazine-3,5(4H)- dicarboxamide A 381 0.886
E 69 ##STR00124## N.sup.5-(3-Fluoro-5- (trifluoromethyl)
phenyl)-2-(3-
fluorophenyl)-6,7- dihydropyrazolo[1,5-a] pyrazine-3,5(4H)-
dicarboxamide A 466 1.631 E 70 ##STR00125##
2-(3-Fluorophenyl)-N.sup.5- (3,4,5-trifluorophenyl)-
6,7-dihydropyrazolo [1,5-a]pyrazine- 3,5(4H)-dicarboxamide B 434
14.7 13.49 F G 71 ##STR00126## N.sup.5-(3-Fluoro-4-
(trifluoromethyl) phenyl)-2-(3- fluorophenyl)-6,7-
dihydropyrazolo[1,5-a] pyrazine-3,5(4H)- dicarboxamide B 466 16.11
14.73 F G 72 ##STR00127## 2-(3-Fluorophenyl)-N.sup.5-
(3-(trifluoromethoxy) phenyl)-6,7- dihydropyrazolo[1,5-a]
pyrazine-3,5(4H)- dicarboxamide B 464 15.59 14.07 F G 73
##STR00128## 2-(3-Fluorophenyl)-N.sup.5- (3-methoxyphenyl)-
6,7-dihydropyrazolo [1,5-a]pyrazine- 3,5(4H)-dicarboxamide B 410
11.76 11.05 F G 74 ##STR00129## N.sup.5-(2,2-Difluorobenzo
[d][1,3]dioxol-5-yl)-2- (3-fluorophenyl)-6,7-
dihydropyrazolo[1,5-a] pyrazine-3,5(4H)- dicarboxamide B 460 14.82
13.56 F G 75 ##STR00130## 2-(3-Fluorophenyl)-N.sup.5-
(6-methoxypyrimidin- 4-yl)-6,7- dihydropyrazolo[1,5-a]
pyrazine-3,5(4H)- dicarboxamide B 412 12.78 12.18 C D 76
##STR00131## N.sup.5-(3-Chloro-4- (difluoromethoxy) phenyl)-2-(3-
fluorophenyl)-6,7- dihydropyrazolo[1,5-a] pyrazine-3,5(4H)-
dicarboxamide B 480 9.16 9.59 B A 77 ##STR00132## N.sup.5,2-Bis(3-
fluorophenyl)-6,7- dihydropyrazolo[1,5-a] pyrazine-3,5(4H)-
dicarboxamide B 398 16.34 15.21 C D 78 ##STR00133##
2-(3-Fluorophenyl)-N.sup.5- (3-methoxy-4- (trifluoromethyl)
phenyl)-6,7- dihydropyrazolo[1,5-a] pyrazine-3,5(4H)- dicarboxamide
B 478 14.53 13.53 F G 79 ##STR00134## N.sup.5-(3-Chloro-4-
(trifluoromethyl) phenyl)-2-(3- fluorophenyl)-6,7-
dihydropyrazolo[1,5-a] pyrazine-3,5(4H)- dicarboxamide B 482 15.22
16.90 G F 80 ##STR00135## N.sup.5-(4-Fluoro-3- (trifluoromethyl)
phenyl)-2-(3- fluorophenyl)-6,7- dihydropyrazolo[1,5-a]
pyrazine-3,5(4H)- dicarboxamide B 466 15.43 13.97 F G 81
##STR00136## N.sup.5-(3,5- Dimethyladamantan-1-
yl)-2-(3-fluorophenyl)- 6,7-dihydropyrazolo [1,5-a]pyrazine-
3,5(4H)-dicarboxamide C 466 18.48 16.03 C D 82 ##STR00137##
2-(3-Fluorophenyl)-N.sup.5- (pyridazin-4-yl)-6,7-
dihydropyrazolo[1,5-a] pyrazine-3,5(4H)- dicarboxamide D 382 9.58
8.68 D C 83 ##STR00138## 2-(3-Fluorophenyl)-N.sup.5-
(6-methylpyridazin-3- yl)-6,7- dihydropyrazolo[1,5-a]
pyrazine-3,5(4H)- dicarboxamide D 396 9.79 9.27 D C 84 ##STR00139##
2-(3-Fluorophenyl)-N.sup.5- (pyrimidin-5-yl)-6,7-
dihydropyrazolo[1,5-a] pyrazine-3,5(4H)- dicarboxamide B 382 10.43
10.80 D C 85 ##STR00140## N.sup.5-(6-Chloropyridin-3-
yl)-2-(3-fluorophenyl)- 6,7-dihydropyrazolo [1,5-a]pyrazine-
3,5(4H)-dicarboxamide D 415 7.21 7.31 B A 86 ##STR00141##
2-(3-Fluorophenyl)-N.sup.5- (6-methylpyridin-3-yl)-
6,7-dihydropyrazolo [1,5-a]pyrazine- 3,5(4H)-dicarboxamide D 395
8.46 9.74 C D 87 ##STR00142## 2-(3-Fluorophenyl)-N.sup.5-
(6-fluoropyridin-3-yl)- 6,7-dihydropyrazolo [1,5-a]pyrazine-
3,5(4H)-dicarboxamide D 399 6.79 6.71 A B 88 ##STR00143##
2-(3-Fluorophenyl)-N.sup.5- (6-hydroxypyridin-3- yl)-6,7-
dihydropyrazolo[1,5-a] pyrazine-3,5(4H)- dicarboxamide D 397 9.57
9.86 D C 89 ##STR00144## N.sup.5-(4- (Difluoromethoxy)
phenyl)-2-(3- fluorophenyl)-6,7- dihydropyrazolo[1,5-a]
pyrazine-3,5(4H)- dicarboxamide B 446 8.53 8.82 B A 90 ##STR00145##
N.sup.5-(2-Chloropyridin-4- yl)-2-(3-fluorophenyl)-
6,7-dihydropyrazolo [1,5-a]pyrazine- 3,5(4H)-dicarboxamide D 415
7.22 7.10 A B 91 ##STR00146## 2-(3-Fluorophenyl)-N.sup.5-
(pyridazin-3-yl)-6,7- dihydropyrazolo[1,5-a] pyrazine-3,5(4H)-
dicarboxamide B 382 10.07 9.86 D C 92 ##STR00147##
2-(3-Fluorophenyl)-N.sup.5- (pyridin-4-yl)-6,7-
dihydropyrazolo[1,5-a] pyrazine-3,5(4H)- dicarboxamide D 381 8.81
8.49 A B 93 ##STR00148## 2-(3-Fluorophenyl)-N.sup.5-
(3-(methylsulfonyl) phenyl)-6,7- dihydropyrazolo[1,5-a]
pyrazine-3,5(4H)- dicarboxamide A 458 13.71 13.43 C D 94
##STR00149## N.sup.5-(3-Fluoro-5- hydroxyadamantan-1-
yl)-2-(3-fluorophenyl)- 6,7-dihydropyrazolo [1,5-a]pyrazine-
3,5(4H)-dicarboxamide C 472 13.06 12.08 C D 95 ##STR00150##
N.sup.5-(3- Fluoroadamantan-1- yl)-2-(3-fluorophenyl)-
6,7-dihydropyrazolo [1,5-a]pyrazine- 3,5(4H)-dicarboxamide C 456
8.32 9.03 B A 96 ##STR00151## 2-(3-Fluorophenyl)-N.sup.5-
(1-methyl-1H-pyrazol- 5-yl)-6,7- dihydropyrazolo[1,5-a]
pyrazine-3,5(4H)- dicarboxamide B 384 10.41 10.56 D C
##STR00152##
Intermediate 97A: tert-Butyl
4-(3-carbamoyl-2-(3-fluorophenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazi-
ne-5-carboxamido)piperidine-1-carboxylate
##STR00153##
[0585] To a solution of tert-butyl 4-aminopiperidine-1-carboxylate
(308 mg, 1.537 mmol) and TEA (0.536 mL, 3.84 mmol) in THF (3 mL)
was added triphosgene (228 mg, 0.768 mmol) at 0.degree. C. and
stirred for 30 min. at the same temperature. A solution of
Intermediate 4J (200 mg, 0.768 mmol) in THF was added and the
reaction mixture was stirred at room temperature for 2 h. The
reaction mixture was quenched with water and the aqueous layer was
extracted with ethyl acetate (3.times.5 mL). The combined organic
layer was washed with 10% NaHCO.sub.3 (2.times.5 mL), water, dried
over Na.sub.2SO.sub.4, filtered and concentrated. The crude product
was purified using reverse phase HPLC method to afford Intermediate
97A (300 mg, 80%) as a white solid. MS(ES): m/z=487 [M+H].sup.+;
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 7.51-7.55 (m, 1H),
7.42-7.51 (m, 2H), 7.35 (bs, 1H), 7.22 (m, 1H), 7.15 (bs, 1H), 6.70
(d, J=7.53 Hz, 1H), 4.72 (s, 2H), 4.14 (t, J=4.8 Hz, 2H), 3.89 (m,
2H), 3.84 (t, J=4.4 Hz, 2H), 3.65 (m, 1H), 2.85-2.78 (m, 2H), 1.75
(m, 2H), 1.41 (s, 9H), 1.32 (m, 2H).
Intermediate 97B:
2-(3-Fluorophenyl)-N.sup.5-(piperidin-4-yl)-6,7-dihydropyrazolo[1,5-a]pyr-
azine-3,5(4H)-dicarboxamide
##STR00154##
[0587] To a solution of Intermediate 97A (300 mg, 0.617 mmol) in
DCM (3 mL) was added TFA (0.238 mL, 3.08 mmol) at 0.degree. C. and
the reaction mixture was stirred at room temperature for 4 h. The
reaction mixture was concentrated and the resultant residue was
basified to pH.about.8.0 with 10% NaHCO.sub.3 solution. The aqueous
layer was extracted with DCM (3.times.5 mL) and the combined
organic layer was washed with water (2.times.5 mL), brine, dried
over Na.sub.2SO.sub.4, filtered and concentrated to afford
Intermediate 97B (200 mg, 80%) as white solid. MS(ES): m/z=387
[M+H].sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 8.50
(bs, 1H), 7.46 (m, 3H), 7.32 (bs, 1H), 7.21 (m, 1H), 7.11 (bs, 1H),
6.86 (d, J=7.03 Hz, 1H), 4.74 (s, 2H), 4.15 (t, J=5.27 Hz, 2H),
3.86 (t, J=5.27 Hz, 2H), 3.72 (m, 1H), 3.27 (s, 2H), 2.96 (m, 2H),
1.93 (m, 2H), 1.54 (m, 2H).
Compound 97
Method AA (Amides):
##STR00155##
[0589] To a solution of Intermediate 97B (0.025 g, 0.065 mmol) in
dry DMF (0.8 mL) was added HATU (0.049 g, 0.129 mmol) and DIPEA
(0.034 mL, 0.194 mmol). To this was added acetic acid (7 .mu.L,
0.129 mmol) and the reaction was stirred at RT for 16 h. The
reaction was monitored by TLC, which showed the completion of the
reaction. The DMF was removed under high vacuum. The reaction
mixture was quenched with 10% sodium bicarbonate solution and
extracted with DCM (3.times.30 mL). The combined organic layer was
washed with sodium bicarbonate solution, water, and brine, dried
over Na.sub.2SO.sub.4, filtered and concentrated to give the crude
product. The crude product was further purified by preparative HPLC
purification to afford the pure product 97 as a white solid (9 mg,
32%). MS(ES): m/z=429 [M+H].sup.+; HPLC Ret. Time 10.76 min. and
10.46 min. (HPLC Methods C and D); .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 7.51-7.56 (m, 1H), 7.42-7.51 (m, 2H),
7.34 (br. s., 1H), 7.17-7.23 (m, 1H), 7.14 (br. s., 1H), 6.67-6.75
(m, 1H), 4.73 (s, 2H), 4.30 (d, J=13.05 Hz, 1H), 4.14 (t, J=5.27
Hz, 2H), 3.84 (t, J=5.27 Hz, 2H), 3.79 (d, J=14.56 Hz, 1H),
3.66-3.75 (m, 1H), 3.08 (t, J=11.29 Hz, 1H), 2.57-2.67 (m, 1H),
2.00 (s, 3H), 1.72-1.86 (m, 2H), 1.35-1.44 (m, 1H), 1.27-1.34 (m,
1H).
Method AB (Sulfonamides):
[0590] To a solution of Intermediate 97B (0.025 g, 0.065 mmol) and
DIPEA (0.034 mL, 0.194 mmol) in dry DCM (0.8 mL) was added
cyclopropanesulfonyl chloride (0.018 g, 0.129 mmol) and the
reaction was stirred at RT for 16 hours. The reaction mixture was
quenched with 10% sodium bicarbonate solution and extracted with
DCM (3.times.30 ml). The combined organic layer was washed with
sodium bicarbonate solution, water, and brine, dried over
Na.sub.2SO.sub.4, filtered and concentrated to furnish the crude
product. The crude product was further purified by preparative HPLC
purification.
Method AC (Reductive Amination):
[0591] To a solution of Intermediate 97B (0.025 g, 0.065 mmol) in
dry DCM (0.5 mL) and methanol (0.5 mL) was added
3,3,3-trifluoropropanal (0.014 g, 0.129 mmol) and stirred at RT for
30 minutes. To this mixture, sodium cyanoborohydride (8.13 mg,
0.129 mmol) was added, the reaction mixture was stirred at RT for 3
h and the solvent was removed under reduced pressure. The residue
was partitioned between ethyl acetate and water, layers separated,
and the aqueous layer was extracted with EtOAc (3.times.10 mL). The
combined organic layer was washed with water, brine, dried over
Na.sub.2SO.sub.4 and concentrated under reduced pressure to afford
crude product, which was further purified by preparative HPLC
purification.
Method AD (Carbamates):
[0592] Step 1:
Pyridin-2-yl(1,1,1-trifluoro-2-methylpropan-2-yl)carbonate: To a
solution of di(pyridin-2-yl)carbonate (250 mg, 1.156 mmol) in DCM
(5 mL) was added DMAP (706 mg, 5.78 mmol) followed by DIPEA (0.202
mL, 1.156 mmol) and 1,1,1-trifluoro-2-methylpropan-2-ol (148 mg,
1.156 mmol). The reaction mixture was stirred at RT overnight,
concentrated and the crude was taken to the next step without
further purification.
[0593] Step 2: To a stirred solution of 97B (0.015 g, 0.039 mmol)
in DCM (1.500 mL) was added DIPEA (0.020 mL, 0.116 mmol) and
pyridin-2-yl (1,1,1-trifluoro-2-methylpropan-2-yl)carbonate (9.67
mg, 0.039 mmol) and resulting mixture was stirred at 25.degree. C.
overnight. The reaction mixture was concentrated and the crude
obtained was purified by preparative HPLC purification.
[0594] The Compounds described in Table 3 were synthesized
analogous to Compound 97 by reacting Intermediate 97B with
corresponding acids, sulfonyl chlorides and aldehydes.
TABLE-US-00005 TABLE 3 Ret. Ex. Synthetic Time HPLC No. Structure
Name method [M + H].sup.+ (min.) Method 98 ##STR00156## 2-(3-
Fluorophenyl)- N.sup.5-(1- pivaloylpiperidin- 4-yl)-6,7-
dihydropyrazolo [1,5-a] pyrazine-3,5(4H)- dicarboxamide AA 471
13.96 13.29 A B 99 ##STR00157## Methyl 4-(3- carbamoyl-2-(3-
fluorophenyl)- 4,5,6,7-tetra- hydropyrazolo [1,5-a]pyrazine-5-
carboxamido) piperidine-1- carboxylate AB 445 6.88 6.39 A B 100
##STR00158## Isopropyl 4-(3- carbamoyl-2-(3- fluorophenyl)-
4,5,6,7-tetra- hydropyrazolo [1,5-a]pyrazine- 5-carboxamido)
piperidine-1- carboxylate AB 473 8.01 7.40 A B 101 ##STR00159##
1,1,1-Trifluoro-2- methylpropan-2- yl 4-(3- carbamoyl-2-(3-
fluorophenyl)- 4,5,6,7-tetra- hydropyrazolo [1,5-a]pyrazine-5-
carboxamido) piperidine-1- carboxylate AD 541 9.026 8.726 A B 102
##STR00160## N.sup.5-(1-(Cyclo- propylsulfonyl) piperidin-4-
yl)-2-(3- fluorophenyl)-6,7- dihydropyrazolo [1,5-a]
pyrazine-3,5(4H)- dicarboxamide AB 491 7.38 6.96 A B 103
##STR00161## 2-(3- Fluorophenyl)- N.sup.5-(1-(3,3,3-
trifluoropropyl) piperidin-4-yl)-6,7- dihydropyrazolo [1,5-a]
pyrazine-3,5(4H)- dicarboxamide AC 483 9.28 10.56 C D
##STR00162## ##STR00163## ##STR00164##
Intermediate 104A: Diethyl
2-((dimethylamino)methylene)-3-oxosuccinate
##STR00165##
[0596] To a solution of diethyl oxalacetate sodium salt (100 g, 476
mmol) in ethanol (250.00 mL) was added
1,1-dimethoxy-N,N-dimethylmethanamine (113 g, 952 mmol) and the
reaction was stirred at room temperature for 30 min. Acetic acid
(54.5 mL, 952 mmol) was added slowly over a period of 3 h and
stirred at room temperature for 24 h. The volatile components were
evaporated under reduced pressure and the oily residue was purified
by silica gel chromatography (750 g REDISEP.RTM. column, eluting
with 30% EtOAc in hexane). Fractions containing the product were
combined and evaporated to afford Intermediate 104A (43 g, 30.8%).
MS(ES): m/z=244 [M+H].sup.+; .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. ppm 7.84 (s, 1H), 4.31 (q, J=7.2 Hz, 2H), 4.18 (q, J=5.4
Hz, 2H), 3.35 (s, 3H), 3.04 (s, 3H), 1.36 (t, J=7.2 Hz, 3H), 1.26
(t, J=7.2 Hz, 3H).
Intermediate 104B: Diethyl 1H-pyrazole-4,5-dicarboxylate
##STR00166##
[0598] To a stirred solution of 104A (45 g, 185 mmol) in ethanol
(150 mL) was added N.sub.2H.sub.4.HCl (12.67 g, 185 mmol) and the
reaction mixture was stirred at RT overnight. The volatiles were
evaporated under vacuum and the crude residue was dissolved in
water and was extracted with EtOAc (3.times.50 mL). The combined
organic layer was dried over Na.sub.2SO.sub.4, filtered and
evaporated under vacuum. The resulting crude product obtained was
purified by ISCO using EtOAc and hexane to afford 104B (21.00 g, 97
mmol, 52.4%). MS(ES): m/z=211 [M-H].sup.+; .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. ppm 8.22 (s, 1H) 4.48 (q, J=7.11 Hz, 2H) 4.36
(q, J=7.18 Hz, 2H) 1.33-1.49 (m, 6H).
Intermediate 104C: Diethyl 3-iodo-1H-pyrazole-4,5-dicarboxylate
##STR00167##
[0600] To a stirred solution of 104B (19 g, 90 mmol) in DMF (50 mL)
was added NIS (30.2 g, 134 mmol) and the reaction mixture was
stirred for 16 h at 115.degree. C. LCMS indicated the completion of
the reaction. DMF was evaporated, the crude was dissolved in EtOAc,
washed with water, sodium thiosulfate solution, dried, filtered and
evaporated under vacuum to furnish crude product, which was
purified by ISCO using EtOAc and hexane system. Fractions collected
at 18-20% EtOAc in hexane were evaporated to get 104C (12.5 g, 37.0
mmol, 41.3% yield). MS(ES): m/z=338 [M+H].sup.+; .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. ppm 14.25 (bs, 1H), 4.27 (m, 4H), 1.26
(m, 6H).
Intermediate 104D: Diethyl
1-(2-((tert-butoxycarbonyl)amino)ethyl)-3-iodo-1H-pyrazole-4,5-dicarboxyl-
ate
##STR00168##
[0602] To a stirred solution of Intermediate 104C (10.000 g, 29.6
mmol) in THF (100 mL) cooled at -5.degree. C. was added
triphenylphosphine (11.64 g, 44.4 mmol) and DIAD (8.63 mL, 44.4
mmol) dropwise and stirred for 30 min. at the same temperature.
Solution of tert-butyl(2-hydroxyethyl)carbamate (7.15 g, 44.4 mmol)
in THF (10 mL) was added at -5.degree. C. and the stirring was
continued for additional 1.5 h. The volatiles were evaporated under
vacuum and crude was purified by silica gel chromatography (120 g
REDISEP.RTM. column, eluting with 18% EtOAc in hexane). Fractions
containing the product were combined and evaporated to afford the
Intermediate 104D (8.2 g, 57%). MS(ES): m/z=482 [M+H].sup.+;
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 4.79 (bs, 1H),
4.28-4.48 (m, 6H), 3.58 (d, J=5.02 Hz, 2H), 1.43 (s, 9H), 1.33-1.40
(m, 6H).
Intermediate 104E: Ethyl
2-iodo-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxylate
##STR00169##
[0604] The Intermediate 104D (7 g, 14.54 mmol) was dissolved in HCl
in dioxane (2.210 mL, 4M solution, 72.7 mmol) and the reaction
mixture was stirred at RT for 3 h. Volatiles were evaporated from
the reaction mixture and the residue was dissolved in cold water
and basified by adding solid NaHCO.sub.3 (pH=8-9). The aqueous
layer was extracted with DCM (4.times.25 mL) and the combined
organic layer was dried, filtered and evaporated under vacuum at
60.degree. C. for 2 h to give 104E (4.750 g, 14.17 mmol, 97%).
MS(ES): m/z=336 [M+H].sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. ppm 8.43 (bs, 1H), 4.31-4.37 (m, 2H), 4.24 (q, J=7.11 Hz,
2H), 3.56-3.62 (m, 2H), 1.27 (t, J=7.09 Hz, 3H).
Intermediate 104F: Ethyl
2-iodo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxylate
##STR00170##
[0606] To a stirred solution of Intermediate 104E (5 g, 14.92 mmol)
in THF (200 mL) was added dropwise borane dimethyl sulfide complex
(15 mL, 158 mmol) at RT. The resulting mixture was stirred at RT
for 18 h. The reaction mixture was quenched with ethanol (100 mL)
slowly and stirred at 70.degree. C. for 4 h. Volatiles were
evaporated under vacuum and the crude was purified by ISCO using
methanol (2%) in chloroform as eluent to furnish 104F (2.9 g, 60%).
MS(ES): m/z=321 [M+H].sup.+; .sup.1H NMR (400 MHz, CD.sub.3OD)
.delta. ppm 4.25-4.34 (m, 2H), 4.22 (s, 2H), 4.12 (t, J=5.46 Hz,
2H), 3.20-3.28 (m, 2H), 1.38 (td, J=7.12, 1.69 Hz, 3H).
Intermediate 104G: Ethyl
5-(tert-butylcarbamoyl)-2-iodo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine--
3-carboxylate
##STR00171##
[0608] To a stirred solution of Intermediate 104F (2.4 g, 7.47
mmol) in THF (20 mL) was added 2-isocyanato-2-methylpropane (0.741
g, 7.47 mmol) and the reaction mixture was stirred for 1.5 h. The
volatiles were evaporated under reduced pressure. The crude was
purified by silica gel chromatography (120 g REDISEP.RTM. column,
eluting with 28% EtOAc in hexane). Fractions containing the product
were combined and evaporated to afford Intermediate 104G (2.2 g,
70%). MS(ES): m/z=421 [M+H].sup.+; .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 6.25 (s, 1H), 4.72 (s, 2H), 4.25 (q,
J=6.8 Hz, 2H), 4.10 (t, J=5.24 Hz, 2H), 3.75 (m, 2H), 1.30 (t,
J=7.2 Hz, 3H) 1.28 (s, 9H).
Intermediate 104H:
5-(tert-Butylcarbamoyl)-2-iodo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine--
3-carboxylic acid
##STR00172##
[0610] To a stirred solution of Intermediate 104G (2.1 g, 5.00
mmol) in EtOH (10 mL) and THF (5 mL) was added a solution of
lithium hydroxide (0.718 g, 30.0 mmol) in water (1 mL) and stirred
at RT for 5 h. Solvent was evaporated under reduced pressure and
the crude was dissolved in water and acidified with 1.5 N HCl at
0.degree. C. The resultant precipitate was filtered and dried under
vacuum to afford Intermediate 104H (1.8 g, 81%). MS(ES): m/z=393
[M+H].sup.+; .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. ppm 12.61
(s, 1H), 6.27 (s, 1H), 4.69 (s, 2H), 4.09 (t, J=5.26 Hz, 2H), 3.74
(t, J=5.26, 2H), 1.28 (s, 9H).
Intermediate 104I:
N.sup.5-(tert-Butyl)-2-iodo-6,7-dihydropyrazolo[1,5-a]pyrazine-3,5(4H)-di-
carboxamide
##STR00173##
[0612] To a stirred solution of Intermediate 104H (1.800 g, 4.59
mmol) in DMF (20 mL) was added ammonium chloride (1.473 g, 27.5
mmol), HATU (3.49 g, 9.18 mmol) and DIPEA (3.21 mL, 18.36 mmol) and
the resulting reaction mixture was stirred for 3 h at RT. DMF was
evaporated from the reaction mixture, water was added and extracted
with EtOAc. The combined organic layer was washed with cold water,
dried over Na.sub.2SO.sub.4 and concentrated under vacuum to give
the crude product, which was purified by ISCO using 70% ethyl
acetate in hexane as eluent. The fractions containing the desired
product were combined and evaporated to afford Intermediate 104I
(1.5 g, 85%). MS(ES): m/z=392 [M+H].sup.+; .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta. ppm 7.37 (bs, 1H), 6.86 (bs, 1H), 6.24 (s,
1H), 4.67 (s, 2H), 4.07 (t, J=5.31 Hz, 2H), 3.73 (t, J=5.31 Hz,
2H), 1.20 (s, 9H).
Compound 104:
N.sup.5-(tert-Butyl)-2-(3-chlorophenyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-
e-3,5(4H)-dicarboxamide
##STR00174##
[0614] To a stirred solution of 104I (120 mg, 0.307 mmol) and
(3-chloro-4-fluorophenyl)boronic acid (107 mg, 0.613 mmol) in
1,4-dioxane (2 mL) and water (0.20 mL) was added potassium
phosphate dibasic (160 mg, 0.920 mmol). The reaction mixture was
degassed for 5 min. with nitrogen,
PdCl.sub.2(dppf)-CH.sub.2Cl.sub.2 (12.52 mg, 0.015 mmol) was added
and stirred at 80.degree. C. for 5 h. Reaction progress was
monitored by LCMS. The reaction mixture was diluted with water (15
mL) and the aqueous layer was back extracted with ethyl acetate
(3.times.15 mL). The combined organic layer washed with brine
(2.times.25 mL), dried over Na.sub.2SO.sub.4, filtered and
concentrated. The crude product was purified by silica gel
chromatography (12 g REDISEP.RTM. column, eluting with 2% MeOH in
CHCl.sub.3). Fractions containing the product were combined and
evaporated to afford Compound 104 (35 mg, 29%) as an off-white
solid. HPLC retention time 8.42 min and 7.94 min (Methods A and B
respectively). MS(ES): m/z=394.2 [M+H].sup.+; .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 7.87 (dd, J=7.31, 2.16 Hz, 1H), 7.70
(ddd, J=8.64, 4.78, 2.20 Hz, 1H), 7.45 (t, J=9 Hz, 1H), 7.32 (br.s,
1H), 7.18 (br.s, 1H), 6.25 (s, 1H), 4.69 (s, 2H), 4.11 (t, J=5.40
Hz, 2H), 3.79 (t, J=5.40 Hz, 2H), 1.29 (s, 9H).
[0615] The Compounds described in Table 4 were synthesized
analogous to Compound 104 by reacting Intermediate 104I with
corresponding boronic acids.
TABLE-US-00006 TABLE 4 Ret. Ex. Time HPLC No. Structure Name [M +
H].sup.+ (min.) Method 105 ##STR00175##
N.sup.5-(tert-Butyl)-2-(3,5- difluorophenyl)-6,7-
dihydropyrazolo[1,5-a] pyrazine-3,5(4H)- dicarboxamide 378 7.929
8.332 A B 106 ##STR00176## N.sup.5-(tert-Butyl)-2-(3,4-
difluorophenyl)-6,7- dihydropyrazolo[1,5-a] pyrazine-3,5(4H)-
dicarboxamide 378 7.811 8.249 A B 107 ##STR00177##
N.sup.5-(tert-Butyl)-2-(2- fluorophenyl)-6,7-
dihydropyrazolo[1,5-a] pyrazine-3,5(4H)- dicarboxamide 360 7.23
7.50 A B 108 ##STR00178## N.sup.5-(tert-Butyl)-2-(3-
chlorophenyl)-6,7- dihydropyrazolo[1,5-a] pyrazine-3,5(4H)-
dicarboxamide 375 8.11 8.47 A B 109 ##STR00179##
N.sup.5-(tert-Butyl)-2-(3- methoxyphenyl)-6,7-
dihydropyrazolo[1,5-a] pyrazine-3,5(4H)- dicarboxamide 372 13.92
13.02 C D 110 ##STR00180## N.sup.5-(tert-Butyl)-2-(3-
(trifluoromethyl)phenyl)-6,7- dihydropyrazolo[1,5-a]
pyrazine-3,5(4H)- dicarboxamide 410 8.778 8.210 A B 111
##STR00181## N.sup.5-(tert-Butyl)-2-(pyridin-3-
yl)-6,7-dihydropyrazolo[1,5- a]pyrazine-3,5(4H)- dicarboxamide 343
7.373 7.996 C D 112 ##STR00182## N.sup.5-(tert-Butyl)-2-(2-
fluoropyridin-4-yl)-6,7- dihydropyrazolo[1,5-a] pyrazine-3,5(4H)-
dicarboxamide 361 10.988 D 113 ##STR00183##
N.sup.5-(tert-Butyl)-2-(5- fluoropyridin-3-yl)-6,7-
dihydropyrazolo[1,5-a] pyrazine-3,5(4H)- dicarboxamide 361 10.918
10.306 C D 114 ##STR00184## N.sup.5-(tert-Butyl)-2-(3-
cyanophenyl)-6,7- dihydropyrazolo[1,5-a] pyrazine-3,5(4H)-
dicarboxamide 367 13.465 12.598 C D 115 ##STR00185##
N.sup.5-(tert-Butyl)-2-(3-cyano-5- fluorophenyl)-6,7-
dihydropyrazolo[1,5-a] pyrazine-3,5(4H)- dicarboxamide 7.747 7.337
A B 116 ##STR00186## N.sup.5-(tert-Butyl)-2-phenyl-6,7-
dihydropyrazolo[1,5-a] pyrazine-3,5(4H)- dicarboxamide 342 1.027 E
117 ##STR00187## N.sup.5-(tert-Butyl)-2-(3,5- dichlorophenyl)-6,7-
dihydropyrazolo[1,5-a] pyrazine-3,5(4H)- dicarboxamide 410 1.47 E
118 ##STR00188## N.sup.5-(tert-Butyl)-2-(3-
(methylsulfonamido)phenyl)- 6,7-dihydropyrazolo[1,5-a]
pyrazine-3,5(4H)- dicarboxamide 435 0.929 E 119 ##STR00189##
N.sup.5-(tert-Butyl)-2-(quinolin-3- yl)-6,7-dihydropyrazolo[1,5-
a]pyrazine-3,5(4H)- dicarboxamide 393 1.051 E 120 ##STR00190##
2-(3-Aminophenyl)-N.sup.5-(tert- butyl)-6,7-dihydropyrazolo
[1,5-a]pyrazine-3,5(4H)- dicarboxamide 357 0.856 E 121 ##STR00191##
N.sup.5-(tert-Butyl)-2-(thiophen-3- yl)-6,7-dihydropyrazolo[1,5-
a]pyrazine-3,5(4H)- dicarboxamide 348 0.972 E 122 ##STR00192##
3-(5-(tert-Butylcarbamoyl)-3- carbamoyl-4,5,6,7-
tetrahydropyrazolo[1,5-a] pyrazin-2-yl)benzoic acid 386 0.614 E 123
##STR00193## N.sup.5-(tert-Butyl)-2-(3- carbamoylphenyl)-6,7-
dihydropyrazolo[1,5-a] pyrazine-3,5(4H)- dicarboxamide 385 0.776 E
124 ##STR00194## N.sup.5-(tert-Butyl)-2-(2,4- difluorophenyl)-6,7-
dihydropyrazolo[1,5-a] pyrazine-3,5(4H)- dicarboxamide 378 1.091 E
125 ##STR00195## N.sup.5-(tert-Butyl)-2-(2,6-
difluoropyridin-3-yl)-6,7- dihydropyrazolo[1,5-a] pyrazine-3,5(4H)-
dicarboxamide 379 0.986 E 126 ##STR00196##
N.sup.5-(tert-Butyl)-2-(pyridin-4- yl)-6,7-dihydropyrazolo[1,5-
a]pyrazine-3,5(4H)- dicarboxamide 343 7.548 7.983 C D 127
##STR00197## N.sup.5-(tert-Butyl)-2-(4- cyanophenyl)-6,7-
ddihydropyrazolo[1,5-a] pyrazine-3,5(4H)- dicarboxamide 376 13.058
12.571 C D 128 ##STR00198## N.sup.5-(tert-Butyl)-2-(3,5-
dimethylphenyl)-6,7- dihydropyrazolo[1,5-a] pyrazine-3,5(4H)-
dicarboxamide 370 1.307 E 129 ##STR00199##
N.sup.5-(tert-Butyl)-2-(3,4- dichlorophenyl)-6,7-
dihydropyrazolo[1,5-a] pyrazine-3,5(4H)- dicarboxamide 410 1.423 E
130 ##STR00200## N.sup.5-(tert-Butyl)-2-(2,3- dichlorophenyl)-6,7-
dihydropyrazolo[1,5-a] pyrazine-3,5(4H)- dicarboxamide 410 1.266 E
131 ##STR00201## N.sup.5-(tert-Butyl)-2-(2- carbamoylphenyl)-6,7-
dihydropyrazolo[1,5-a] pyrazine-3,5(4H)- dicarboxamide 385 0.733 E
132 ##STR00202## N.sup.5-(tert-Butyl)-2-(quinolin-5-
yl)-6,7-dihydropyrazolo[1,5- a]pyrazine-3,5(4H)- dicarboxamide 393
0.918 E 133 ##STR00203## N.sup.5-(tert-Butyl)-2-
(isoquinolin-4-yl)-6,7- dihydropyrazolo[1,5-a] pyrazine-3,5(4H)-
dicarboxamide 393 0.979 E 134 ##STR00204## N.sup.5-(tert-Butyl)-2-
(isoquinolin-5-yl)-6,7- dihydropyrazolo[1,5-a] pyrazine-3,5(4H)-
dicarboxamide 393 0.916 E 135 ##STR00205##
N.sup.5-(tert-Butyl)-2-(3- (methylsulfonamidomethyl)
phenyl)-6,7-dihydropyrazolo [1,5-a]pyrazine-3,5(4H)- dicarboxamide
449 0.922 E 136 ##STR00206## N.sup.5-(tert-Butyl)-2-(3-
sulfamoylphenyl)-6,7- dihydropyrazolo[1,5-a] pyrazine-3,5(4H)-
dicarboxamide 421 0.822 E 137 ##STR00207##
N.sup.5-(tert-Butyl)-2-(3-fluoro-5- methoxyphenyl)-6,7-
dihydropyrazolo[1,5-a] pyrazine-3,5(4H)- dicarboxamide 390 1.18 E
138 ##STR00208## N.sup.5-(tert-Butyl)-2-(3-
(trifluoromethoxy)phenyl)- 6,7-dihydropyrazolo[1,5-a]
pyrazine-3,5(4H)- dicarboxamide 426 1.416 E 139 ##STR00209##
N.sup.5-(tert-Butyl)-2-(4-fluoro-3- (trifluoromethyl)phenyl)-6,7-
dihydropyrazolo[1,5-a] pyrazine-3,5(4H)- dicarboxamide 428 1.424 E
140 ##STR00210## N.sup.5-(tert-Butyl)-2-(2-
chloroquinolin-3-yl)-6,7- dihydropyrazolo[1,5-a] pyrazine-3,5(4H)-
dicarboxamide 427 1.150 E 141 ##STR00211##
2-([1,1'-Biphenyl]-3-yl)-N.sup.5- (tert-butyl)-6,7-
dihydropyrazolo[1,5-a] pyrazine-3,5(4H)- dicarboxamide 418 9.383
8.932 A B 142 ##STR00212## N.sup.5-(tert-Butyl)-2-(pyrimidin-
5-yl)-6,7-dihydropyrazolo [1,5-a]pyrazine-3,5(4H)- dicarboxamide
344 9.416 8.804 C D 143 ##STR00213##
N.sup.5-(tert-Butyl)-2-(1H-indol- 6-yl)-6,7-dihydropyrazolo
[1,5-a]pyrazine-3,5(4H)- dicarboxamide 381 7.368 7.150 A B 144
##STR00214## N.sup.5-(tert-Butyl)-2-(4-
(methylsulfamoyl)phenyl)-6,7- dihydropyrazolo[1,5-a]
pyrazine-3,5(4H)- dicarboxamide 420 6.356 6.183 A B 145
##STR00215## N.sup.5-(tert-Butyl)-2-(1H- pyrazol-4-yl)-6,7-
dihydropyrazolo[1,5-a] pyrazine-3,5(4H)- dicarboxamide 332 9.380
8.760 C D 146 ##STR00216## N.sup.5-(tert-Butyl)-2-(2-
(pyrrolidin-1-yl)pyrimidin-5- yl)-6,7-dihydropyrazolo[1,5-a]
pyrazine-3,5(4H)- dicarboxamide 413 10.486 10.870 C D 147
##STR00217## N.sup.5-(tert-Butyl)-2-(2- morpholinopyrimidin-5-yl)-
6,7-dihydropyrazolo[1,5-a] pyrazine-3,5(4H)- dicarboxamide 429
11.715 11.137 C D 148 ##STR00218## N.sup.5-(tert-Butyl)-2-(5-
chloropyridin-3-yl)-6,7- dihydropyrazolo[1,5-a] pyrazine-3,5(4H)-
dicarboxamide 377 11.980 11.969 C D 149 ##STR00219##
2-(Benzo[d]thiazol-5-yl)-N.sup.5- (tert-butyl)-6,7-
dihydropyrazolo[1,5-a] pyrazine-3,5(4H)- dicarboxamide 399 6.621
6.505 A B 150 ##STR00220## N.sup.5-(tert-Butyl)-2-(3-
(methylthio)phenyl)-6,7- dihydropyrazolo[1,5-a] pyrazine-3,5(4H)-
dicarboxamide 388 8.062 7.836 A B 151 ##STR00221##
N.sup.5-(tert-Butyl)-2-(2,5- difluorophenyl)-6,7-
dihydropyrazolo[1,5-a] pyrazine-3,5(4H)- dicarboxamide 376 7.431
7.184 A B 152 ##STR00222## N.sup.5-(tert-Butyl)-2-(3-chloro-5-
methoxyphenyl)-6,7- dihydropyrazolo[1,5-a] pyrazine-3,5(4H)-
dicarboxamide 406 8.476 8.041 A B 153 ##STR00223##
N.sup.5-(tert-Butyl)-2-(1-methyl- 1H-pyrazol-4-yl)-6,7-
dihydropyrazolo[1,5-a] pyrazine-3,5(4H)- dicarboxamide 346 9.716
9.562 C D 154 ##STR00224## N.sup.5-(tert-Butyl)-2-(3-chloro-5-
cyanophenyl)-6,7- dihydropyrazolo[1,5-a] pyrazine-3,5(4H)-
dicarboxamide 401 8.297 7.933 A B 155 ##STR00225##
N.sup.5-(tert-Butyl)-2-(3-fluoro-5- (trifluoromethyl)phenyl)-6,7-
dihydropyrazolo[1,5-a] pyrazine-3,5(4H)- dicarboxamide 428 9.239
8.535 A B
##STR00226## ##STR00227##
Intermediate 156A: 5-tert-Butyl 3-ethyl
2-iodo-6,7-dihydropyrazolo[1,5-a]pyrazine-3,5(4H)-dicarboxylate
##STR00228##
[0617] To a stirred solution of 104F (0.7 g, 2.180 mmol) in
dichloromethane (10 mL) was added triethylamine (0.912 mL, 6.54
mmol) and Boc.sub.2O (0.952 g, 4.36 mmol). The resulting reaction
mixture was stirred at RT overnight and the reaction progress was
monitored by LCMS. Reaction mixture was diluted with
dichloromethane (20 mL), washed with water, brine, dried over
Na.sub.2SO.sub.4, filtered and concentrated. The crude product
obtained was purified by ISCO (24 g silica gel column) using
petroleum ether and ethyl acetate (9:1) mixture as eluent.
Fractions were collected and concentrated to afford Intermediate
156A (800 mg, 87%). MS(ES): m/z=422 [M+H].sup.+; .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. ppm 4.86 (s, 2H), 4.32 (q, J=6.8 Hz, 2H),
4.20 (m, 2H), 3.87 (t, J=5.6 Hz, 2H), 1.50 (s, 9H), 1.38 (t, J=7.2
Hz, 3H).
Intermediate 156B:
5-(tert-Butoxycarbonyl)-2-iodo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine--
3-carboxylic acid
##STR00229##
[0619] To a stirred solution of 156A (0.80 g, 1.899 mmol) in
methanol (7 mL) was added sodium hydroxide (0.760 g, 1.899 mmol) in
water (3 mL). The resulting reaction mixture was stirred at RT for
6 h. Methanol was removed under reduced pressure and the aqueous
layer was acidified with 1.5 N HCl solution. The aqueous layer was
back extracted with dichloromethane (3.times.25 mL). The combined
organic layer was dried over Na.sub.2SO.sub.4, filtered and
concentrated to give the desired Intermediate 156B (700 mg, 94%).
MS(ES): m/z=394 [M+H].sup.+; .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. ppm 4.89 (s, 2H), 4.22 (t, J=5.2 Hz, 2H), 3.88 (t, J=5.6
Hz, 2H), 1.51 (s, 9H).
Intermediate 156C: tert-Butyl
3-carbamoyl-2-iodo-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate
##STR00230##
[0621] To a stirred solution of 156B (0.700 g, 1.780 mmol) and
ammonium chloride (0.190 g, 3.56 mmol) in DMF (7 mL) were added
HATU (1.354 g, 3.56 mmol) and DIPEA (0.933 mL, 5.34 mmol).
Resulting reaction mixture was stirred at RT overnight. The
reaction mixture was diluted with water (20 mL) and the aqueous
layer was back extracted with ethyl acetate (2.times.30 mL). The
combined organic layer was washed with brine, dried over
Na.sub.2SO.sub.4, filtered and concentrated. The crude product was
purified by ISCO (24 g silica gel column) using 2% methanol in
chloroform as eluent to afford pure Intermediate 156C (670 mg,
96%). MS(ES): m/z=[M+H].sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. ppm 7.38 (bs, 1H), 6.86 (bs, 1H), 4.72 (s, 2H), 4.12 (t,
J=5.2 Hz, 2H), 3.77 (t, J=5.7 Hz, 2H), 1.43 (s, 9H).
Intermediate 156D: tert-Butyl
3-carbamoyl-2-(3-chlorophenyl)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-c-
arboxylate
##STR00231##
[0623] To a stirred solution of Intermediate 156C (500 mg, 1.275
mmol) and (3-chlorophenyl)boronic acid (399 mg, 2.55 mmol) in
1,4-dioxane (5 mL) and water (1 mL) was added and potassium
phosphate tribasic (666 mg, 3.82 mmol). The reaction mixture was
purged with nitrogen for 5 min. PdCl.sub.2(dppf)-CH.sub.2Cl.sub.2
(52.1 mg, 0.064 mmol) was added and the reaction mixture was
stirred at 80.degree. C. for 12 h. The reaction mixture was diluted
with water (20 mL) and extracted with ethyl acetate (3.times.25
mL). The combined organic layer was washed with brine, dried over
Na.sub.2SO.sub.4 and concentrated. The crude was purified by ISCO
(24 g silica column) using 2% methanol in chloroform. Fractions
were collected and concentrated to afford Intermediate 156D (380
mg, 79%). MS(ES): m/z=377 [M+H].sup.+; .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. ppm 7.60 (s, 1H), 7.46 (m, 3H), 5.32 (bs, 2H),
4.97 (s, 2H), 4.21 (t, J=5.1 Hz, 2H), 3.94 (t, J=5.7 Hz, 2H), 1.29
(s, 9H).
Intermediate 156E:
2-(3-Chlorophenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamid-
e
##STR00232##
[0625] To a stirred solution of 156D (350 mg, 0.929 mmol) in DCM
(10 mL) was added dropwise TFA (2 mL) at 0.degree. C. and the
reaction mixture was stirred at RT overnight. TFA and DCM were
removed under reduced pressure, crude was basified with saturated
sodium hydroxide solution, the resultant solid was filtered, washed
with water, dried under vacuum to afford 156E (250 mg, 97%).
MS(ES): m/z=277 [M+H].sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. ppm 7.71-7.73 (m, 1H), 7.65 (dt, J=7.04, 1.72 Hz, 1H),
7.37-7.45 (m, 2H), 7.20 (bs, 1H), 7.10 (bs, 1H), 4.00-4.05 (m, 4H),
3.12 (d, J=4.83 Hz, 2H), 2.63 (s, 1H).
Compound 156:
2-(3-Chlorophenyl)-N5-(3,4-difluorophenyl)-6,7-dihydropyrazolo[1,5-a]pyra-
zine-3,5(4H)-dicarboxamide
##STR00233##
[0627] To a stirred solution of 3,4-difluoroaniline (23.33 mg,
0.181 mmol) in DCM (2 mL) under nitrogen was added triethylamine
(0.025 mL, 0.181 mmol) and the reaction mixture was cooled to
0.degree. C. and triphosgene (26.8 mg, 0.090 mmol) in DCM (1 mL)
was added and stirred at the same temperature for 10 min. A
solution of 156E (25 mg, 0.090 mmol) in DMF (1 mL) was added
dropwise and the resulting reaction mixture was stirred at RT
overnight. It was diluted with water and the aqueous layer was back
extracted with ethyl acetate (3.times.10 mL). The combined organic
layer was washed with brine, dried over Na.sub.2SO.sub.4 and
concentrated. The crude product obtained was purified by reverse
phase preparative HPLC to afford pure product 156 as off-white
solid (10 mg, 25%). MS(ES): m/z=432 [M+H].sup.+; HPLC Ret. Time
9.92 min. and 8.82 min. (HPLC Methods A and B); .sup.1H NMR (400
MHz, CD.sub.3OD) .delta. ppm 7.68-7.71 (m, 1H), 7.60 (ddd, J=5.32,
3.47, 1.63 Hz, 1H), 7.48-7.53 (m, 1H), 7.44-7.48 (m, 2H), 7.16-7.20
(m, 2H), 5.01 (s, 2H), 4.31 (t, J=5.40 Hz, 2H), 4.08 (t, J=5.40 Hz,
2H).
General Methods for the Syntheses of Ureas:
Method A:
[0628] To a solution of Intermediate 156E (30 mg, 0.115 mmol) in
DMF (1 mL) was added the corresponding isocyanate (0.288 mmol) at
0.degree. C. The reaction mixture was stirred at room temperature
for 3 h. The reaction mixture was quenched with water and extracted
with ethyl acetate (3.times.5 mL). The combined organic layer was
washed with water (2.times.5 mL), brine solution, dried over
Na.sub.2SO.sub.4, filtered and concentrated to afford crude product
which was purified by preparative HPLC.
Method B:
[0629] To a solution of primary amine (0.192 mmol) and
triethylamine (0.480 mmol) in tetrahydrofuran (3 mL) at 0.degree.
C. was added triphosgene (0.096 mmol) and the reaction mixture
stirred for 30 min at the same temperature. Intermediate 156E (25
mg, 0.096 mmol) in DMF was added and the solution was stirred at RT
for 2 h. The reaction mixture was quenched with water and extracted
with ethyl acetate (3.times.5 mL). The combined organic layer was
washed with 10% NaHCO.sub.3 (2.times.5 mL), water, dried over
Na.sub.2SO.sub.4 and concentrated to afford crude product, which
was further purified by preparative HPLC.
Method C:
[0630] To a solution of carboxylic acid (0.153 mmol) in toluene (1
mL) was added TEA (0.071 mL, 0.509 mmol), followed by DPPA (0.044
mL, 0.204 mmol) to give a clear solution and the reaction mixture
was heated to 85.degree. C. and stirred for 1 h. The reaction
mixture was cooled to RT and to it was added a solution of
Intermediate 156E (27 mg, 0.102 mmol) in THF (0.5 mL) and stirred
at RT for 12 h. The reaction mixture was diluted with EtOAc (10
mL), washed with water, solution of 10% aq. NaHCO.sub.3, brine,
dried over Na.sub.2SO.sub.4, filtered and the filtrate concentrated
and concentrated to afford crude product which was further purified
by preparative HPLC.
Method D:
[0631] To a solution of primary amine (0.192 mmol) and
triethylamine (0.480 mmol) in tetrahydrofuran (3 mL) at 0.degree.
C. were added phenyl chloroformate (0.096 mmol) and the reaction
mixture stirred for 60 min at RT. The reaction mixture was quenched
with water and the phenyl carbamate formed was extracted and the
Intermediate 156E (25 mg, 0.096 mmol) in THF was added to the
extract and the resulting solution was stirred at room temperature
for 2 h. The reaction mixture was quenched with water and extracted
with ethyl acetate (3.times.5 mL). The combined organic layer was
washed with 10% NaHCO.sub.3 (2.times.5 mL), water, dried over
Na.sub.2SO.sub.4 and concentrated to afford crude product which was
further purified by preparative HPLC.
[0632] The Compounds described in Table 5 were synthesized
analogous to Compound 156 by reacting Intermediate 156E with
corresponding reagents.
TABLE-US-00007 TABLE 5 Ret Ex. Time HPLC No. Structure Name Method
[M + H].sup.+ (min.) Method 157 ##STR00234##
2-(3-Chlorophenyl)-N.sup.5-(4- fluorophenyl)-6,7-dihydropyrazolo
[1,5-a]pyrazine-3,5(4H)- dicarboxamide B 414 8.789 8.522 A B 158
##STR00235## N.sup.5-(4-Chloro-3-trifluoromethyl)
phenyl)-2-(3-chlorophenyl)-6,7- dihydropyrazolo[1,5-a]pyrazine-
3,5(4H)-dicarboxamide B 498 10.821 10.044 A B 159 ##STR00236##
2-(3-Chlorophenyl)-N.sup.5-(4-cyano-
3-(trifluoromethyl)phenyl)-6,7- dihydropyrazolo[1,5-a]pyrazine-
3,5(4H)-dicarboxamide B 487 10.126 9.668 A B 160 ##STR00237##
2-(3-Chlorophenyl)-N.sup.5-(3- (trifluoromethoxy)phenyl)-
6,7-dihydropyrazolo[1,5-a] pyrazine-3,5(4H)- dicarboxamide B 480
10.292 9.665 A B 161 ##STR00238## 2-(3-Chlorophenyl)-N.sup.5-(3-
cyanophenyl)-6,7- dihydropyrazolo[1,5-a] pyrazine-3,5(4H)-
dicarboxamide B 421 8.541 8.323 A B 162 ##STR00239##
2-(3-Chlorophenyl)-N.sup.5-(4- (trifluoromethoxy)phenyl)-
6,7-dihydropyrazolo[1,5-a] pyrazine-3,5(4H)- dicarboxamide B 480
10.148 9.559 A B 163 ##STR00240## 2-(3-Chlorophenyl)-N.sup.5-(3-
fluoro-4-(trifluoromethyl) phenyl)-6,7-dihydropyrazolo
[1,5-a]pyrazine-3,5(4H)- dicarboxamide B 482 10.510 9.833 A B 164
##STR00241## 2-(3-Chlorophenyl)-N.sup.5-(3,4- dichlorophenyl)-6,7-
dihydropyrazolo[1,5-a] pyrazine-3,5(4H)- dicarboxamide A 464 10.453
9.768 A B 165 ##STR00242## 2-(3-Chlorophenyl)-N.sup.5-(3-
fluoro-5-(trifluoromethyl) phenyl)-6,7-dihydropyrazolo
[1,5-a]pyrazine-3,5(4H)- dicarboxamide A 482 10.696 9.888 A B 166
##STR00243## 2-(3-Chlorophenyl)-N.sup.5-(4- cyanophenyl)-6,7-
dihydropyrazolo[1,5-a] pyrazine-3,5(4H)- dicarboxamide A 421 8.576
8.300 A B 167 ##STR00244## 2-(3-Chlorophenyl)-N.sup.5-(3-
fluorophenyl)-6,7- dihydropyrazolo[1,5-a]pyrazine-
3,5(4H)-dicarboxamide B 414 8.971 8.618 A B 168 ##STR00245##
2-(3-Chlorophenyl)-N.sup.5-(4- (trifluoromethyl)phenyl)-
6,7-dihydropyrazolo[1,5-a] pyrazine-3,5(4H)-dicarboxamide B 464
10.253 9.605 A B 169 ##STR00246## 2-(3-Chlorophenyl)-N.sup.5-(3,5-
difluorophenyl)-6,7- dihydropyrazolo[1,5-a]pyrazine-
3,5(4H)-dicarboxamide B 432 9.478 9.190 A B 170 ##STR00247##
2-(3-Chlorophenyl)-N.sup.5-(3- methoxyphenyl)-6,7-
dihydropyrazolo[1,5-a] pyrazine-3,5(4H)- dicarboxamide B 426 8.657
8.368 A B 171 ##STR00248## 2-(3-Chlorophenyl)-N.sup.5-(6-
chloropyridin-3-yl)- 6,7-dihydropyrazolo[1,5-a] pyrazine-3,5(4H)-
dicarboxamide D 431 8.037 7.886 A B 172 ##STR00249##
2-(3-Chlorophenyl)-N.sup.5-(1,1- difluoro-2-methylpropan-2-
yl)-6,7-dihydropyrazolo[1,5-a] pyrazine-3,5(4H)-dicarboxamide C
412.0 1.952 K 173 ##STR00250## 2-(3-Chlorophenyl)-N.sup.5-(2-(4-
cyanophenyl)propan-2-yl)-6,7- dihydropyrazolo[1,5-a]
pyrazine-3,5(4H)-dicarboxamide C 463 1.37 1.34 E L 174 ##STR00251##
2-(3-Chlorophenyl)-N.sup.5-(3,3- difluoro-2-methylbutan-2-yl)-
6,7-dihydropyrazolo[1,5-a] pyrazine-3,5(4H)-dicarboxamide C 426
1.289 1.314 L E 175 ##STR00252##
2-(3-Chlorophenyl)-N.sup.5-((1r,3r)- 3-fluorocyclobutyl)-6,7-
dihydropyrazolo[1,5-a] pyrazine-3,5(4H)- dicarboxamide C 392 1.06
1.07 L E 176 ##STR00253## 2-(3-Chlorophenyl)-N.sup.5-((1s,3s)-
3-fluorocyclobutyl)-6,7- dihydropyrazolo[1,5-a]
pyrazine-3,5(4H)-dicarboxamide C 392 7.484 7.133 A B 177
##STR00254## 2-(3-Chlorophenyl)-N.sup.5-((1s,3s)-
3-methoxycyclobutyl)-6,7- dihydropyrazolo[1,5-a]
pyrazine-3,5(4H)-dicarboxamide C 404 1.590 1.585 K J 178
##STR00255## 2-(3-Chlorophenyl)-N.sup.5-((1r,3r)-
3-methoxycyclobutyl)-6,7- dihydropyrazolo[1,5-a]
pyrazine-3,5(4H)-dicarboxamide C 404 1.009 E 179 ##STR00256##
2-(3-Chlorophenyl)-N.sup.5-((3,3- difluorocyclobutyl)
methyl)-6,7-dihydropyrazolo [1,5-a]pyrazine- 3,5(4H)-dicarboxamide
C 424.2 1.261 1.278 E L 180 ##STR00257##
2-(3-Chlorophenyl)-N.sup.5-((4,4- difluorocyclohexyl)
methyl)-6,7-dihydropyrazolo [1,5-a]pyrazine- 3,5(4H)-dicarboxamide
C 452 9.479 9.176 M B 181 ##STR00258## 2-(3-Chlorophenyl)-N.sup.5-
(spiro[2.3]hexan-5-yl)- 6,7-dihydropyrazolo[1,5-a]
pyrazine-3,5(4H)- dicarboxamide C 400.0 1.300 1.306 E L 182
##STR00259## 2-(3-Chlorophenyl)-N.sup.5-(6,6-
difluorospiro[3,3]heptan- 2-yl)-6,7-dihydropyrazolo
[1,5-a]pyrazine-3,5(4H)- dicarboxamide C 450.2 8.357 8.916 B A 183
##STR00260## 2-(3-Chlorophenyl)-N.sup.5-
((1R,3s,5S)-6,6-difluorobicyclo [3.1.0]hexan-3-yl)-6,7-
dihydropyrazolo[1,5-a] pyrazine-3,5(4H)- dicarboxamide C 436.0
1.961 1.967 E L 184 ##STR00261## 2-(3-Chlorophenyl)-N.sup.5-
((1R,3r,5S)-6,6- difluorobicyclo[3.1.0] hexan-3-yl)-6,7-
dihydropyrazolo[1,5-a] pyrazine-3,5(4H)- dicarboxamide C 436.0
2.048 2.030 E L
##STR00262##
Intermediate 185A: tert-Butyl
3-carbamoyl-2-(3-chloro-4-fluorophenyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-
e-5(4H)-carboxylate
##STR00263##
[0634] To a stirred solution of Intermediate 156C (5 g, 12.7 mmol),
(3-chloro-4-fluorophenyl)boronic acid (3.33 g, 19.12 mmol) in
1,4-dioxane (75 mL) and water (7.5 mL) was added and
K.sub.3PO.sub.4 (8.12 g, 38.2 mmol) and the reaction mixture was
purged with nitrogen for 5 min. PdCl.sub.2(dppf)-CH.sub.2Cl.sub.2
(0.521 g, 0.637 mmol) was added and the reaction mixture was
stirred at 80.degree. C. for 12 h. The reaction mixture was diluted
with water (75 mL) and extracted with EtOAc (3.times.75 mL). The
combined organic layer was washed with brine, dried over
Na.sub.2SO.sub.4, filtered and the filtrate concentrated. The crude
reaction mixture was purified by silica gel chromatography (24 g
REDISEP.RTM. column, eluting with 2% MeOH in CHCl.sub.3). Fractions
were collected and concentrated to afford Intermediate 185A (4.2 g,
78%) as white solid. MS(ES): m/z=395 [M+H].sup.+; .sup.1H NMR
.sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. ppm 7.81-7.87 (m, 1H),
7.63-7.72 (m, 1H), 7.47 (s, 1H), 7.15-7.37 (m, 2H), 4.74 (s, 2H),
4.16 (s, 2H), 3.80-3.88 (m, 2H), 1.45 (s, 9H).
Intermediate 185B:
2-(3-Chloro-4-fluorophenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-c-
arboxamide
##STR00264##
[0636] To a stirred solution of Intermediate 185A (4.2 g, 10.64
mmol) in DCM (15 mL) was added TFA (12.29 mL, 160 mmol) dropwise at
0.degree. C. and the reaction mixture was stirred at RT for 12 h.
The reaction mixture was concentrated under reduced pressure and
the crude was basified with saturated aq. NaOH solution and stirred
for 10 min. The solid product separated was filtered, washed with
water, and dried under vacuum to afford 185B as a white solid (2.8
g, 87%). MS(ES): m/z=295 [M+H].sup.+; .sup.1H NMR .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. ppm 7.86 (dd, J=7.53, 2.01 Hz, 1H), 7.69
(ddd, J=8.66, 4.89, 2.01 Hz, 1H), 7.44 (t, J=8.78 Hz, 1H),
7.11-7.20 (m, 2H), 3.99-4.04 (m, 4H), 3.12 (d, J=6.02 Hz, 2H), 2.62
(s, 1H).
[0637] Compound 185:
2-(3-Chloro-4-fluorophenyl)-N.sup.5-(1,1-difluoro-2-methylpropan-2-yl)-6,-
7-dihydropyrazolo[1,5-a]pyrazine-3,5(4H)-dicarboxamide
##STR00265##
[0638] A stirred solution of 3,3-difluoro-2,2-dimethylpropanoic
acid (28.1 mg, 0.204 mmol) in toluene (2 mL) at RT was added TEA
(0.043 mL, 0.305 mmol) and DPPA (0.047 mL, 0.204 mmol) and the
solution was stirred at 70.degree. C. for 2 h. The reaction mixture
was cooled to RT, to which was added Intermediate 185B (30 mg,
0.102 mmol) in THF (1 mL) and stirred for 12 h. The reaction mass
was diluted with ethyl acetate (5 mL), the organic layer was
separated, washed with 10% aqueous NaHCO.sub.3, water, brine, dried
over Na.sub.2SO.sub.4, filtered and the filtrate concentrated. The
crude compound was purified by preparative HPLC to afford Compound
185 as pale yellow solid (37 mg, 84% yield). The HPLC retention
times are 2.020 min and 2.030 min (Methods J and K respectively);
MS(ES):m/z=430.2[M+H].sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. ppm 7.79-7.90 (m, 1H), 7.63-7.76 (m, 1H), 7.41-7.52 (m,
1H), 7.2-7.4 (m, 2H) 6.66-6.74 (m, 1H), 6.24-6.62 (m, 1H),
4.64-4.79 (m, 2H), 4.06-4.17 (m, 2H), 3.78-3.91 (m, 2H), 1.25 (s,
6H).
[0639] The Compounds shown in Table 6 have been prepared similar to
Compound 185 by coupling of Intermediate 185B with various in-situ
generated isocyanates from different carboxylic acids.
TABLE-US-00008 TABLE 6 Ret Ex. Time HPLC No. Structure Name [M +
H].sup.+ (min.) Methods 186 ##STR00266## 2-(3-Chloro-4-
fluorophenyl)-N.sup.5-(1- cyano-2-methylpropan-2-
yl)-6,7-dihydropyrazolo [1,5-a]pyrazine-3,5(4H)- dicarboxamide 419
1.133 1.139 E L 187 ##STR00267## 2-(3-Chloro-4-
fluorophenyl)-N.sup.5-(2-(4- cyanophenyl)propan-2-
yl)-6,7-dihydropyrazolo [1,5-a]pyrazine-3,5(4H)- dicarboxamide 481
1.419 1.391 E L 188 ##STR00268## 2-(3-Chloro-4-
fluorophenyl)-N.sup.5-(3,3- difluoro-2-methylbutan- 2-yl)-6,7-
dihydropyrazolo[1,5-a] pyrazine-3,5(4H)- dicarboxamide 444 9.037
8.358 A B 189 ##STR00269## 2-(3-Chloro-4- fluorophenyl)-N.sup.5-
((1r,3r)-3- fluorocyclobutyl)-6,7- dihydropyrazolo[1,5-a]
pyrazine-3,5(4H)- dicarboxamide 410 1.22 1.23 L E 190 ##STR00270##
2-(3-Chloro-4- fluorophenyl)-N.sup.5- ((1s,3s)-3-
fluorocyclobutyl)-6,7- dihydropyrazolo[1,5-a] pyrazine-3,5(4H)-
dicarboxamide 410 7.795 7.504 A B 191 ##STR00271## 2-(3-Chloro-4-
fluorophenyl)-N.sup.5- ((1s,3s)-3- methoxycyclobutyl)-6,7-
dihydropyrazolo[1,5-a] pyrazine-3,5(4H)- dicarboxamide 422 1.651
1.655 J K 192 ##STR00272## 2-(3-Chloro-4- fluorophenyl)-N.sup.5-
((1r,3r)-3- methoxycyclobutyl)-6,7- dihydropyrazolo[1,5-a]
pyrazine-3,5(4H)- dicarboxamide 422 1.065 E 193 ##STR00273##
2-(3-Chloro-4- fluorophenyl)-N.sup.5-((3,3- difluorocyclobutyl)
methyl)-6,7- dihydropyrazolo[1,5-a] pyrazine-3,5(4H)- dicarboxamide
442.2 1.317 1.334 E L 194 ##STR00274## 2-(3-Chloro-4-
fluorophenyl)-N.sup.5-((4,4- difluorocyclohexyl) methyl)-6,7-
dihydropyrazolo[1,5-a] pyrazine-3,5(4H)- dicarboxamide 470 8.87
8.68 M B 195 ##STR00275## 2-(3-Chloro-4-
fluorophenyl)-N.sup.5-(spiro [2.3]hexan-5-yl)-6,7-
dihydropyrazolo[1,5-a] pyrazine-3,5(4H)- dicarboxamide 418.0 1.362
1.374 E L 196 ##STR00276## 2-(3-Chloro-4-
fluorophenyl)-N.sup.5-(6,6- difluorospiro[3.3]heptan- 2-yl)-6,7-
dihydropyrazolo[1,5-a] pyrazine-3,5(4H)- dicarboxamide 468.2 8.629
9.143 B A 197 ##STR00277## 2-(3-Chloro-4- fluorophenyl)-N.sup.5-
((1R,3s,5S)-6,6- difluorobicyclo[3.1.0] hexan-3-yl)-6,7-
dihydropyrazolo[1,5-a] pyrazine-3,5(4H)- dicarboxamide 454 2.025
2.026 E L 198 ##STR00278## 2-(3-Chloro-4- fluorophenyl)-N.sup.5-
((1R,3r,5S)-6,6- difluorobicyclo[3.1.0] hexan-3-yl)-6,7-
dihydropyrazolo[1,5-a] pyrazine-3,5(4H)- dicarboxamide 454 2.110
2.091 J K
##STR00279##
Intermediate 199A: tert-Butyl
3-carbamoyl-2-(3,4-dichlorophenyl)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4-
H)-carboxylate
##STR00280##
[0641] To a stirred solution of Intermediate 156C (9 g, 23 mmol),
(3,4-dichlorophenyl)boronic acid (6.57 g, 34.4 mmol) in 1,4-dioxane
(150 mL) and water (10 mL) was added K.sub.3PO.sub.4 (14.61 g, 68.8
mmol) and the reaction mixture was purged with nitrogen for 15 min.
PdCl.sub.2(dppf)-CH.sub.2Cl.sub.2 (1.124 g, 1.377 mmol) was added
and the reaction mixture was stirred at 80.degree. C. for 12 h. The
reaction mixture was diluted with water (300 mL) and extracted with
EtOAc (3.times.80 mL). The combined organic layer was washed with
brine, dried over Na.sub.2SO.sub.4, filtered and the filtrate
concentrated. The crude reaction mixture was purified by silica gel
chromatography (40 g REDISEP.RTM. column, eluting with 65% EtOAc in
hexanes). Fractions were collected and concentrated to afford
Intermediate 199A as pale yellow solid (8 g, 85%). MS(ES):
m/z=411.0 [M+1]+; .sup.1H NMR: (400 MHz, DMSO-d.sub.6) .delta. ppm
7.92-7.87 (m, 1H), 7.69-7.64 (m, 2H), 7.44-7.18 (m, 2H), 4.74 (s,
2H), 4.17 (t, 2H), 3.84 (t, 2H), 1.45 (s, 9H).
Intermediate 199B:
2-(3,4-Dichlorophenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carbox-
amide
##STR00281##
[0643] To a stirred solution of 199A (9 g, 21.88 mmol) in DCM (20
mL) was added dropwise TFA (15 mL, 21.88 mmol) at 0.degree. C. and
the reaction mixture was stirred at RT for 12 h. The volatiles were
removed under reduced pressure and crude product was basified with
a 10% aq. NaOH solution and stirred for 10 min. The solid product
separated was filtered, washed with water, and dried under vacuum
to afford 199B as an off-white solid (5.2 g, 76%). MS(ES):
m/z=311.0 [M+1].sup.+; .sup.1H NMR: (400 MHz, DMSO-d.sub.6) .delta.
ppm 7.92 (s, 1H), 7.67 (m, 2H), 7.32-7.09 (m, 2H), 4.02 (s, 4H),
3.12 (br. s., 2H), 2.70-2.58 (m, 1H).
Compound 199:
2-(3,4-Dichlorophenyl)-N.sup.5-(1,1-difluoro-2-methylpropan-2-yl)-6,7-dih-
ydropyrazolo[1,5-a]pyrazine-3,5(4H)-dicarboxamide
##STR00282##
[0645] A stirred solution of 3,3-difluoro-2,2-dimethylpropanoic
acid (26.6 mg, 0.193 mmol) in toluene (2 mL) at RT was added TEA
(0.040 mL, 0.289 mmol) and DPPA (0.044 mL, 0.193 mmol) and the
solution was stirred at 70.degree. C. for 2 h. The reaction mass
was cooled to RT and to it was added Intermediate 199B (30 mg,
0.096 mmol) dissolved in THF (1 mL) and the reaction mixture was
stirred at RT for 12 h. The reaction mass was diluted with ethyl
acetate (5 mL), the organic layer was separated, washed with 10%
aqueous solution of NaHCO.sub.3, water, brine, dried over
Na.sub.2SO.sub.4, filtered and the filtrate concentrated. The crude
compound was purified by preparative HPLC to afford Compound 199 as
pale yellow solid (33 mg, 76% yield). The HPLC retention times are
2.173 min and 2.179 min (Methods J and K respectively); MS(ES):
m/z=446.0 [M+H].sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
ppm 7.92 (s, 1H), 7.68 (s, 2H), 7.2-7.4 (m, 2H), 6.70 (s, 1H)
6.24-6.61 (m, 1H) 4.74 (s, 2H) 4.08-4.20 (m, 2H) 3.81-3.89 (m, 2H)
1.31 (s, 6H).
[0646] The Compounds shown in Table 7 have been prepared similar to
Compound 199 by coupling of Intermediate 199B with various in-situ
generated isocyanates from different carboxylic acids.
TABLE-US-00009 TABLE 7 Ret Ex. Time HPLC No. Structure Name [M +
H].sup.+ (min.) Methods 200 ##STR00283## N.sup.5-(2-(4-Cyanophenyl)
propan-2-yl)-2-(3,4- dichlorophenyl)-6,7- dihydropyrazolo[1,5-a]
pyrazine-3,5(4H)- dicarboxamide 497 1.54 1.53 E L 201 ##STR00284##
2-(3,4-Dichlorophenyl)- N.sup.5-(3,3-difluoro-2-
methylbutan-2-yl)-6,7- dihydropyrazolo[1,5-a] pyrazine-3,5(4H)-
dicarboxamide 460 1.536 1.528 L E 202 ##STR00285##
2-(3,4-Dichlorophenyl)- N.sup.5-((1r,3r)-3- fluorocyclobutyl)-6,7-
dihydropyrazolo[1,5-a] pyrazine-3,5(4H)- dicarboxamide 426 2.14
2.24 L E 203 ##STR00286## 2-(3,4-Dichlorophenyl)-
N.sup.5-((1s,3s)-3- fluorocyclobutyl)-6,7- dihydropyrazolo[1,5-a]
pyrazine-3,5(4H)- dicarboxamide 426 8.470 8.080 A B 204
##STR00287## 2-(3,4-Dichlorophenyl)- N.sup.5-((1r,3r)-3-
methoxycyclobutyl)-6,7- dihydropyrazolo[1,5-a] pyrazine-3,5(4H)-
dicarboxamide 438 1.200 E 205 ##STR00288## 2-(3,4-Dichlorophenyl)-
N.sup.5-((3,3- difluorocyclobutyl) methyl)-6,7-
dihydropyrazolo[1,5-a] pyrazine-3,5(4H)- dicarboxamide 458.2 1.446
1.462 E L 206 ##STR00289## 2-(3,4-Dichlorophenyl)- N.sup.5-((4,4-
difluorocyclohexyl) methyl)-6,7- dihydropyrazolo[1,5-a]
pyrazine-3,5(4H)- dicarboxamide 486 8.628 8.480 M B 207
##STR00290## 2-(3,4-Dichlorophenyl)- N.sup.5-(spiro[2.3]hexan-5-
yl)-6,7-dihydropyrazolo [1,5-a]pyrazine-3,5(4H)- dicarboxamide
434.0 1.487 1.484 E L 208 ##STR00291## 2-(3,4-Dichlorophenyl)-
N.sup.5-(6,6-difluorospiro [3.3]heptan-2-yl)-6,7-
dihydropyrazolo[1,5-a] pyrazine-3,5(4H)- dicarboxamide 484.0 9.095
9.676 B A
##STR00292##
Intermediate 209A: Benzyl
3-fluoro-2-(fluoromethyl)-2-methylpropanoate
##STR00293##
[0648] To a -20.degree. C. solution of benzyl
3-hydroxy-2-(hydroxymethyl)-2-methylpropanoate (1.0 g, 4.5 mmol) in
DCM (15 mL) was added DAST (1.767 mL, 13.38 mmol). The reaction
mixture was then allowed to warm to RT and stir for 12 h. The
reaction was quenched by the addition of a 10% aqueous solution of
NaHCO.sub.3 and the organic layer was separated. The aqueous layer
was extracted with DCM (2.times.25 mL). The combined organic layer
was dried over Na.sub.2SO.sub.4 and evaporated under reduced
pressure. The crude compound obtained was purified by silica gel
chromatography (12 g REDISEP.RTM. column, eluting with 10% EtOAc in
hexanes). Fractions containing the product were combined and
evaporated to afford the Intermediate 209A as a yellow oil (300 mg,
30% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm
7.30-7.43 (m, 5H), 5.04-5.22 (m, 2H), 4.45-4.71 (m, 4H), 1.19 (t,
J=1.76 Hz, 3H).
Intermediate 209B: 3-Fluoro-2-(fluoromethyl)-2-methylpropanoic
acid
##STR00294##
[0650] To a stirred solution of Intermediate 209A (0.300 g, 1.314
mmol) in EtOAc (5 mL) was added 10% Pd/C (0.140 g, 0.131 mmol). The
reaction mixture was stirred for 12 h under an atmosphere of
hydrogen (15 psi). The reaction mixture was then filtered through a
pad of CELITE.RTM. and the cake was washed with EtOAc. The filtrate
was concentrated under reduced pressure to afford Intermediate 209B
as a yellow liquid (160 mg, 88%). The crude product was used
without further purification. .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. ppm 13.02 (bs, 1H), 4.40-4.66 (m, 4H), 1.06-1.20 (m,
3H).
Compound 209:
2-(3-Chloro-4-fluorophenyl)-N.sup.5-(1,3-difluoro-2-methylpropan-2-yl)-6,-
7-dihydropyrazolo[1,5-a]pyrazine-3,5(4H)-dicarboxamide
##STR00295##
[0652] A stirred solution of Intermediate 209B (28.1 mg, 0.204
mmol) in toluene (2 mL) at RT under nitrogen was added TEA (0.043
mL, 0.305 mmol), DPPA (0.047 mL, 0.204 mmol) and the solution was
heated at 70.degree. C. and stirred for 2 h. The reaction mass was
cooled to RT and to it was added Intermediate 185B (30 mg, 0.102
mmol) in THF (1 mL) was added and the reaction mixture was stirred
at RT for 12 h. The reaction mass was diluted with ethyl acetate
(25 mL), the organic layer was separated, washed with a 10% aqueous
solution of NaHCO.sub.3, water, brine dried over Na.sub.2SO.sub.4,
filtered, and the filtrate evaporated. The crude compound was
purified by preparative HPLC to afford Compound 209 as pale yellow
solid (11 mg, 24% yield). The HPLC Retention times 1.963 min. and
1.968 min. (Methods J and K respectively); MS(ES): m/z=430.2
[M+H].sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 7.85
(dd, J=7.31, 2.16 Hz, 1H), 7.64-7.73 (m, 1H), 7.42-7.52 (m, 1H),
7.15-7.30 (m, 2H), 6.62 (s, 1H), 4.73 (s, 2H), 4.64 (s, 2H), 4.52
(s, 2H), 4.14 (s, 2H), 3.84 (s, 2H), 1.31 (t, J=2.07 Hz, 3H).
[0653] The Compounds shown in Table 8 have been prepared similar to
Compound 209 by coupling of in-situ generated isocyanate of 209B
with 185B analogs.
TABLE-US-00010 TABLE 8 Ret Ex. Time HPLC No. Structure Name [M +
H].sup.+ (min.) Methods 210 ##STR00296##
2-(3,4-Dichlorophenyl)-N.sup.5- (1,3-difluoro-2-methylpropan-
2-yl)-6,7-dihydropyrazolo [1,5-a]pyrazine-3,5(4H)- dicarboxamide
446.0 2.132 E 211 ##STR00297## 2-(3-Chlorophenyl)-N.sup.5-(1,3-
difluoro-2-methylpropan-2- yl)-6,7-dihydropyrazolo
[1,5-a]pyrazine-3,5(4H)- dicarboxamide 412.0 1.171 1.294 E L
##STR00298##
Intermediate 212A: Ethyl
2,2-dimethyl-3-(((methylthio)carbonothioyl)oxy)propanoate
##STR00299##
[0655] To a stirred solution of ethyl
3-hydroxy-2,2-dimethylpropanoate (3.0 g, 20.52 mmol) in DMF (15 mL)
was added DBU (3.10 g, 20.52 mmol) at RT followed by slow addition
of CS.sub.2 (3.12 g, 41.0 mmol) over a period of 10 minutes. The
reaction mixture was stirred at RT for 30 min, and then cooled to
10.degree. C. prior to addition of MeI (6.58 mL, 103 mmol). The
reaction mixture was stirred for 2 h at RT after which it was
quenched with ice water and extracted with diethyl ether
(2.times.25 mL). The combined organic layer was dried over
Na.sub.2SO.sub.4, filtered and the filtrate evaporated to afford
Intermediate 212A as a pale yellow liquid (3.0 g, 62%). .sup.1H NMR
(300 MHz, chloroform-d) .delta. ppm 4.59 (s, 2H), 4.19 (q, J=7.05
Hz, 2H), 2.55 (s, 3H), 1.23-1.29 (m, 9H).
Intermediate 212B: Ethyl
3-(trifluoromethoxy)cyclobutanecarboxylate
##STR00300##
[0657] To a stirred solution of NBS (1.899 g, 10.67 mmol) in DCM
(20 mL) at -40.degree. C. was added pyridine (1.0 mL, 12.8 mmol)
followed by a 70% solution of HF in pyridine (2.44 g, 85 mmol)
which was then stirred for 10 min at -40.degree. C. followed by 5
min at RT. The reaction mixture was cooled to 0.degree. C. prior to
the addition of a solution of Intermediate 212A (0.5 g, 2.13 mmol)
in DCM (10 mL) which then stirred for 1 h at the same temperature.
The reaction mixture became reddish brown and was then quenched
with a 10% aqueous solution of NaHSO.sub.3. A 10% aqueous solution
of NaOH was added to adjust the pH to 10 and the aqueous phase was
then extracted with diethyl ether (2.times.25 mL). The combined
organic layers were washed with a 1.5 N aqueous solution of HCl,
dried over Na.sub.2SO.sub.4, and evaporated to afford Intermediate
212B as a light brown liquid. It was reacted in the saponification
without further purification (100 mg, 22% yield).
Intermediate 212C: 3-(Trifluoromethoxy)cyclobutanecarboxylic
acid
##STR00301##
[0659] To a stirred solution of Intermediate 212B (0.10 g, 0.47
mmol) in THF (5 mL) was added NaOH (0.038 g, 0.943 mmol) in water
(1 mL) and the mixture was allowed to stir at 60.degree. C. for 4
h. The reaction mixture was quenched with a 1.5 N aqueous solution
of HCl and extracted with EtOAc (2.times.20 mL). The combined
organic layers were dried over Na.sub.2SO.sub.4, filtered and the
filtrate evaporated to afford Intermediate 212C as a light brown
liquid (30 mg, 35% yield). .sup.1H NMR (300 MHz, DMSO-d.sub.6)
.delta. ppm 12.01-12.03 (b s, 1H), 3.34 (m, 2H), 1.04 (s, 6H).
Compound 212:
2-(3-Chloro-4-fluorophenyl)-N.sup.5-(2-methyl-1-(trifluoromethoxy)propan--
2-yl)-6,7-dihydropyrazolo[1,5-a]pyrazine-3,5(4H)-dicarboxamide
##STR00302##
[0661] To a stirred solution of Intermediate 212C (95 mg, 0.509
mmol) in toluene (5 ml) was added TEA (0.118 mL, 0.848 mmol), DPPA
(0.047 mL, 0.204 mmol) and the reaction mixture was stirred at
90.degree. C. for 1 h. The reaction mixture was cooled RT and to it
was added a solution of Intermediate 185B (50 mg, 0.170 mmol) in
DMF (2 ml) and stirred at RT for 16 h. The reaction was quenched
with a 10% aqueous solution of NaHCO.sub.3 and extracted with EtOAc
(2.times.20 mL). The combined organic layer dried over
Na.sub.2SO.sub.4, filtered and the filtrate evaporated. The crude
compound was purified by preparative HPLC to afford Compound 212 as
an off-white solid (6 mg, 7% yield). HPLC retention times 9.95 min.
and 9.08 min. (Methods A and B respectively). MS(ES): m/z=478
[M+H].sup.+; .sup.1H NMR (400 MHz, MeOH-d.sub.1) .delta. ppm
7.75-7.77 (m, 1H), 7.58-7.62 (m, 1H), 7.29-7.33 (t, J=8.84 Hz, 1H),
4.85 (s, 2H), 4.23 (s, 2H), 4.18-4.21 (t, J=5.24 Hz, 2H), 3.90-3.92
(t, J=5.24 Hz, 2H), 1.37 (s, 6H).
##STR00303##
Intermediate 213A: Ethyl
2-(3-carbamoyl-2-(3-chloro-4-fluorophenyl)-4,5,6,7-tetrahydropyrazolo[1,5-
-a]pyrazine-5-carboxamido)-2-methylpropanoate
##STR00304##
[0663] To a stirred solution of
3-ethoxy-2,2-dimethyl-3-oxopropanoic acid (543 mg, 3.39 mmol) in
toluene (25 mL) at RT under nitrogen was added TEA (1.182 mL, 8.48
mmol), DPPA (0.731 mL, 3.39 mmol) and the reaction mixture was
heated to 85.degree. C. and stirred for 1 h. The reaction mass was
cooled to RT and in to it was added a solution of Intermediate 185B
(500 mg, 1.697 mmol) in THF (4 mL) and stirred at RT for 12 h. The
reaction mass was concentrated and the residue was extracted with
ethyl acetate (3.times.10 mL). The combined organic layer was
washed with water, brine, dried over Na.sub.2SO.sub.4, filtered and
the filtrate concentrated. The crude product was triturated with
diethyl ether to afford Intermediate 213A as an off-white solid
(550 mg, 70% yield). MS(ES): m/z=452 [M+1].sup.+; .sup.1H NMR (300
MHz, DMSO-d.sub.6) .delta. ppm 7.85 (dd, J=7.2, 2.3 Hz, 1H), 7.68
(s, 1H), 7.51-7.42 (m, 1H), 7.40-7.32 (m, 1H), 7.25-7.14 (m, 1H),
7.06 (s, 1H), 4.73 (s, 2H), 4.17-4.09 (m, 2H), 4.01 (q, J=7.2 Hz,
2H), 3.89-3.79 (m, 2H), 1.37 (s, 6H), 1.09 (t, J=7.0 Hz, 3H).
Intermediate 213B:
2-(3-Carbamoyl-2-(3-chloro-4-fluorophenyl)-4,5,6,7-tetrahydropyrazolo[1,5-
-a]pyrazine-5-carboxamido)-2-methylpropanoic acid
##STR00305##
[0665] To a solution of Intermediate 213A (500 mg, 1.106 mmol) in
ethanol (20 mL) and THF (20 mL) was added a solution of NaOH (89
mg, 2.213 mmol) in water (10 mL) and the reaction mixture was
stirred at RT for 8 h. The reaction mixture was concentrated to
dryness under reduced pressure. The crude product was dissolved in
water and the pH of solution was adjusted to 4 using a 1.5N aqueous
solution of HCl which was then stirred for 10 min. The precipitate
was filtered, dried and triturated with diethyl ether to afford
Intermediate 213B as pale brown solid (400 mg, 85%). MS(ES):
m/z=424 [M+H].sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
ppm 11.99 (s, 1H), 7.89-7.84 (m, 1H), 7.73-7.67 (m, 1H), 7.50-7.44
(m, 1H), 7.35 (s, 1H), 7.20 (br. s., 1H), 6.93 (s, 1H), 4.74 (s,
2H), 4.16-4.10 (m, 2H), 3.85 (d, J=5.5 Hz, 2H), 1.38 (s, 6H).
Intermediate 213:
2-(3-Chloro-4-fluorophenyl)-N.sup.5-(1-(cyclopropylamino)-2-methyl-1-oxop-
ropan-2-yl)-6,7-dihydropyrazolo[1,5-a]pyrazine-3,5(4H)-dicarboxamide
##STR00306##
[0667] To a suspension of Intermediate 213B (40 mg, 0.094 mmol),
HATU (71.8 mg, 0.189 mmol) and DIPEA (0.082 ml, 0.472 mmol) in DMF
(6 mL) was added cyclopropylamine (6.65 .mu.L, 0.094 mmol) and the
mixture was stirred at RT for 18 h. The reaction mixture was
quenched with ice cold water and extracted with EtOAc (3.times.25
mL). The organic layer was washed with brine, dried over
Na.sub.2SO.sub.4, filtered and the filtrate concentrated. The crude
product was purified by preparative HPLC to afford Compound 213 as
an off-white solid (13.5 mg, 30%). HPLC retention time 6.9 and 6.75
min (Methods B and C respectively). MS(ES): m/z=463 [M+H].sup.+;
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 7.86 (dd, J=7.28,
2.26 Hz, 1H), 7.64-7.74 (m, 1H), 7.38-7.50 (m, 2H), 7.14-7.37 (m,
2H), 6.65 (s, 1H), 4.74 (s, 2H), 4.14 (t, J=5.27 Hz, 2H), 3.83 (t,
J=5.27 Hz, 2H), 2.53-2.58 (m, 1H), 1.33 (s, 6H), 0.52-0.60 (m, 2H),
0.31-0.40 (m, 2H).
[0668] The Compounds shown in Table 9 have been prepared similar to
Compound 213 by coupling of Intermediate 213B with various
amines.
TABLE-US-00011 TABLE 9 Ret Ex. Time HPLC No. Structure Name [M +
H].sup.+ (min.) Methods 214 ##STR00307## 2-(3-Chloro-4-
fluorophenyl)-N.sup.5-(2- methyl-1-(methylamino)-1-
oxopropan-2-yl)-6,7- dihydropyrazolo[1,5-a] pyrazine-3,5(4H)-
dicarboxamide 437 6.25 6.38 B C 215 ##STR00308## 2-(3-Chloro-4-
fluorophenyl)-N.sup.5-(2- methyl-1-oxo-1-
(pyrrolidin-1-yl)propan-2- yl)-6,7-dihydropyrazolo
[1,5-a]pyrazine-3,5(4H)- dicarboxamide 477 6.92 6.80 C B 216
##STR00309## 2-(3-Chloro-4- fluorophenyl)-N.sup.5-(1-
(isopropylamino)-2- methyl-1-oxopropan-2-yl)-
6,7-dihydropyrazolo[1,5-a] pyrazine-3,5(4H)- dicarboxamide 465 7.22
6.89 B C 217 ##STR00310## 2-(3-Chloro-4-
fluorophenyl)-N.sup.5-(1-((2- methoxyethyl)amino)-2-
methyl-1-oxopropan-2-yl)- 6,7-dihydropyrazolo[1,5-a]
pyrazine-3,5(4H)- dicarboxamide 481 6.65 6.51 C B 218 ##STR00311##
2-(3-Chloro-4- fluorophenyl)-N.sup.5-(1- (dimethylamino)-2-methyl-
1-oxopropan-2-yl)-6,7- dihydropyrazolo[1,5-a] pyrazine-3,5(4H)-
dicarboxamide 451 6.62 6.50 C B 219 ##STR00312##
N.sup.5-(1-Amino-2-methyl-1- oxopropan-2-yl)-2-(3-
chloro-4-fluorophenyl)- 6,7-dihydropyrazolo[1,5-a]
pyrazine-3,5(4H)- dicarboxamide 423 6.12 6.27 B C
##STR00313##
Intermediate 220A: Ethyl
1-((tosyloxy)methyl)cyclobutanecarboxylate
##STR00314##
[0670] To a stirred ice-cooled solution of ethyl
1-(hydroxymethyl)cyclobutanecarboxylate (0.5 g, 3.16 mmol) in DCM
(5 mL) was added DMAP (0.386 g, 3.16 mmol) and p-TSCl (0.603 g,
3.16 mmol) and the reaction mixture was allowed to warm to RT and
stir for 16 h. The reaction mixture was diluted with water and
extracted with DCM (2.times.30 mL). The combined organic layer was
washed with a 1 N aqueous solution of HCl, brine, and then dried
over Na.sub.2SO.sub.4, filtered and the filtrate concentrated to
afford Intermediate 220A as a pale yellow oil (0.7 g, 71% yield).
.sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. ppm 7.81-7.76 (m, 2H),
7.54-7.45 (m, 2H), 4.25 (s, 2H), 4.12-3.95 (m, 5H), 2.31-2.17 (m,
2H), 2.00-1.73 (m, 4H), 1.08 (d, J=14.4 Hz, 3H).
Intermediate 220B: Ethyl 1-(cyanomethyl)cyclobutanecarboxylate
##STR00315##
[0672] To a stirred solution of Intermediate 220A (0.5 g, 1.601
mmol) in DMSO (2.5 mL) was added NaCN (0.196 g, 4.00 mmol) and the
reaction mixture was stirred at 80.degree. C. for 16 h. The
reaction mixture was diluted with water and extracted with diethyl
ether (3.times.30 mL). The combined organic layer was washed with
water, dried over Na.sub.2SO.sub.4, filtered and the filtrate
concentrated to afford Intermediate 220B as a brown oil (0.110 g,
41% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm
4.19-4.01 (m, 2H), 3.01-2.97 (m, 2H), 2.45-2.32 (m, 2H), 2.08-1.83
(m, 4H), 1.25-1.18 (m, 3H).
Intermediate 220C: 1-(Cyanomethyl)cyclobutanecarboxylic acid
##STR00316##
[0674] To a stirred solution of Intermediate 220B (0.110 g, 0.658
mmol) in ethanol (3.5 mL), THF (3.5 mL) and water (3 mL) was added
NaOH (0.079 g, 1.974 mmol) and the reaction mixture was stirred at
RT for 16 h. The reaction mixture was concentrated and the residue
was diluted with water (3 mL) and extracted with EtOAc (3.times.20
mL). The pH of the aqueous layer was adjusted to 3 using a 1.5N
aqueous solution of HCl and extracted with EtOAc (3.times.10 mL).
The combined organic layer was washed with water, dried over
Na.sub.2SO.sub.4, filtered and the filtrate concentrated. The
residual mass was then azeotroped with toluene to obtain the
Intermediate 220C as a brown oil (0.06 g, 66% yield). .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. ppm 12.65 (br. s., 1H), 3.04-2.79
(m, 2H), 2.42-2.17 (m, 2H), 2.09-1.67 (m, 4H).
Compound 220:
2-(3-Chloro-4-fluorophenyl)-N.sup.5-(1-(cyanomethyl)cyclobutyl)-6,7-dihyd-
ro pyrazolo[1,5-a]pyrazine-3,5(4H)-dicarboxamide
##STR00317##
[0676] To a stirred solution of Intermediate 220C (0.020 g, 0.145
mmol) in toluene (0.5 mL) was added TEA (0.081 mL, 0.578 mmol),
DPPA (0.078 mL, 0.361 mmol) and the reaction mixture was warmed to
90.degree. C. and stirred for 2 h. The reaction mixture was cooled
to RT and to it was added a solution of Intermediate 185B (0.040 g,
0.145 mmol) in THF (0.5 mL) and stirred at RT for 16 h. The
reaction mixture was quenched with a 10% aqueous solution of
NaHCO.sub.3 and extracted with EtOAc (3.times.10 mL). The combined
organic layer was washed with water, dried over Na.sub.2SO.sub.4,
filtered and the filtrate concentrated. The crude product was
purified by preparative HPLC to afford Compound 220 as a pale
yellow solid (20 mg, 32%). HPLC retention times 1.21 min. and 1.21
min. (Method E and L respectively). MS(ES): m/z=431 [M+H].sup.+;
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 7.85 (dd, J=7.28,
2.26 Hz, 1H), 7.66-7.71 (m, 1H), 7.46 (t, J=9.04 Hz, 1H), 7.34 (br.
s., 1H), 7.29 (s, 1H), 7.18 (br. s., 1H), 4.74 (s, 2H), 4.14 (t,
J=5.27 Hz, 2H), 3.86 (t, J=5.27 Hz, 2H), 3.11 (s, 2H), 2.17-2.27
(m, 2H), 2.02-2.11 (m, 2H), 1.78-1.91 (m, 2H).
[0677] The Compounds shown in Table 10 have been prepared similar
to Compound 220 by coupling of coupling of in-situ generated
isocyanate of 220C with 185B analogs.
TABLE-US-00012 TABLE 10 Ret Ex. Time HPLC No. Structure Name [M +
H].sup.+ (min.) Methods 221 ##STR00318##
2-(3-Chlorophenyl)-N.sup.5-(1- (cyanomethyl)cyclobutyl)-
6,7-dihydropyrazolo[1,5-a] pyrazine-3,5(4H)- dicarboxamide 413 1.15
1.15 E L 222 ##STR00319## N.sup.5-(1-(Cyanomethyl)
cyclobutyl)-2-(3,4- dichlorophenyl)-6,7- dihydropyrazolo[1,5-a]
pyrazine-3,5(4H)- dicarboxamide 447 1.34 1.34 E L
##STR00320##
Intermediate 223A: Ethyl
1-((difluoromethoxy)methyl)cyclobutanecarboxylate
##STR00321##
[0679] To a stirred solution of ethyl
1-(hydroxymethyl)cyclobutanecarboxylate (0.2 g, 1.264 mmol) in
acetonitrile (2 mL) was added Cut (0.120 g, 0.632 mmol) and the
reaction mass was heated to 50.degree. C.
2,2-Difluoro-2-(fluorosulfonyl)acetic acid (0.196 mL, 1.896 mmol)
added dropwise to the solution and the reaction mixture was stirred
at 50.degree. C. for 4 h. The reaction mixture was cooled to RT and
extracted with EtOAc (3.times.15 mL). The combined organic layer
was washed with a 10% aqueous solution of NaHCO.sub.3, dried over
Na.sub.2SO.sub.4, filtered and the filtrate concentrated to afford
Intermediate 223A as a brown oil (0.2 g, 76%). .sup.1H NMR (300
MHz, DMSO-d.sub.6) .delta. ppm 6.94-6.39 (m, 1H), 4.16-3.99 (m,
4H), 2.41-2.17 (m, 2H), 2.08-1.73 (m, 4H), 1.26-1.09 (m, 3H).
Intermediate 223B: 1-((Difluoromethoxy)methyl)cyclobutanecarboxylic
acid
##STR00322##
[0681] To a stirred solution of Intermediate 223A (0.263 g, 1.263
mmol) in ethanol (3.5 mL), THF (3.5 mL), and water (3 mL) was added
NaOH (0.152 g, 3.79 mmol) and the reaction mixture was stirred at
RT for 16 h. The reaction mixture was concentrated and the residue
dissolved in water and extracted with ethyl acetate (3.times.15
mL). The aqueous layer was then acidified to pH 2-3 using a 1.5 N
aqueous solution of HCl and extracted with EtOAc (3.times.15 mL).
The combined organic layer was washed with water, dried over
Na.sub.2SO.sub.4 and concentrated to afford Intermediate 223B as a
brown oil (0.08 g, 35% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. ppm 12.41 (s, 1H), 6.97-6.40 (m, 1H), 4.15-3.90 (m, 2H),
2.38-2.09 (m, 2H), 2.01-1.51 (m, 4H).
Compound 223:
2-(3-Chloro-4-fluorophenyl)-N.sup.5-(1-((difluoromethoxy)methyl)cyclobuty-
l)-6,7-dihydropyrazolo[1,5-a]pyrazine-3,5(4H)-dicarboxamide
##STR00323##
[0683] To a stirred solution of Intermediate 223B (0.024 g, 0.136
mmol) in toluene (1 mL) was added TEA (0.076 mL, 0.543 mmol), DPPA
(0.074 mL, 0.339 mmol) and the reaction mixture was heated to
90.degree. C. for 2 h. The reaction mixture was cooled to RT and to
it was added a solution of Intermediate 185B (0.040 g, 0.136 mmol)
in THF (0.5 mL) and stirred for 12 h. The reaction mixture was
quenched with a 10% aqueous solution of NaHCO.sub.3 and extracted
with EtOAc (3.times.10 mL). The combined organic layer was washed
with water, dried over Na.sub.2SO.sub.4, filtered and the filtrate
concentrated. The crude product was purified by preparative HPLC to
afford Compound 223 as an off-white solid (10 mg, 15%). HPLC
retention times 2.35 min. and 2.35 min. (Method E and L
respectively). MS(ES): m/z=472 [M+1].sup.+; .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 7.85 (dd, J=7.28, 2.26 Hz, 1H), 7.66-7.71
(m, 1H), 7.42-7.48 (m, 1H), 7.30-7.37 (m, 1H), 7.11-7.22 (m, 1H),
6.99 (s, 1H), 6.47-6.87 (m, 1H), 4.72 (s, 2H), 4.09-4.14 (t, J=5.52
Hz, 2H), 4.04 (s, 2H), 3.84 (t, J=5.52 Hz, 2H), 2.04-2.15 (m, 4H),
1.80 (d, J=9.04 Hz, 2H).
[0684] The Compounds shown in Table 11 have been prepared similar
to Compound 223 by coupling of in-situ generated isocyanate of 223B
with 185B analogs.
TABLE-US-00013 TABLE 11 Ret Ex. Time HPLC No. Structure Name [M +
H].sup.+ (min.) Methods 224 ##STR00324##
2-(3,4-Dichlorophenyl)-N.sup.5- (1-((difluoromethoxy)
methyl)cyclobulyl)-6,7- dihydropyrazolo[1,5-a] pyrazine-3,5(4H)-
dicarboxamide 488 2.48 2.50 L E 225 ##STR00325##
2-(3-Chlorophenyl)-N.sup.5-(1- ((difluoromethoxy)methyl)
cyclobutyl)-6,7- dihydropyrazolo[1,5-a] pyrazine-3,5(4H)-
dicarboxamide 454 2.30 2.30 L E
##STR00326##
Intermediate 226A:
2-(3,3-Difluorocyclobutyl)-2-methylpropanenitrile
##STR00327##
[0686] To a solution of 2-(3,3-difluorocyclobutyl)acetonitrile (300
mg, 2.288 mmol) in anhydrous THF (5 mL) was added a solution of LDA
(6.86 mL, 6.86 mmol, 1 M in THF) dropwise at 0.degree. C. and
stirred at the same temperature for 1 h. MeI (0.715 mL, 11.44 mmol)
was added dropwise at 0.degree. C. and the reaction mixture was
allowed to warm to RT and stir for 3 h. An aqueous saturated
solution of NH.sub.4Cl was added and the compound was extracted
with EtOAc (3.times.10 mL). The organic layer was washed with
brine, dried over Na.sub.2SO.sub.4, filtered and the filtrate
evaporated in vacuo. The residue was purified by silica gel
chromatography (12 g REDISEP.RTM. column, eluting with 30% EtOAc in
petroleum ether). Fractions containing the product were combined
and evaporated to afford the Intermediate 226A as a yellow oil (150
mg, 41%). .sup.1H NMR (400 MHz, chloroform-d) .delta. ppm 2.42-2.76
(m, 4H), 2.14 (td, J=8.66, 3.26 Hz, 1H), 1.317 (s, 6H).
Intermediate 226B: 2-(3,3-Difluorocyclobutyl)-2-methylpropanoic
acid
##STR00328##
[0688] To a solution of Intermediate 226A (150 mg, 0.942 mmol) in
ethanol (10 mL) and H.sub.2O (10 mL) was added a 10% aqueous
solution of NaOH (10 mL, 0.942 mmol) and the reaction mixture was
stirred at 90.degree. C. for 12 h. The reaction was then
concentrated and the pH of the resultant residue was adjusted to 4
with a 1.5 N aq. solution of HCl and then extracted with EtOAc
(3.times.10 mL). The combined organic layer was dried over
Na.sub.2SO.sub.4, filtered and the filtrate evaporated under
reduced pressure to afford Intermediate 226B as a yellow sticky
liquid (100 mg, 60%). .sup.1H NMR (400 MHz, chloroform-d) .delta.
ppm 12.30 (bs, 1H), 2.40-2.57 (m, 5H), 1.23 (s, 6H).
Compound 226:
2-(3-Chloro-4-fluorophenyl)-N.sup.5-(2-(3,3-difluorocyclobutyl)propan-2-y-
l)-6,7-dihydropyrazolo[1,5-a]pyrazine-3,5(4H)-dicarboxamide
##STR00329##
[0690] To a stirred solution of Intermediate 226B (18.14 mg, 0.102
mmol) in toluene (1 mL) at RT under nitrogen was added TEA (0.043
mL, 0.305 mmol), DPPA (0.047 mL, 0.204 mmol) and the mixture was
heated at 70.degree. C. for 2 h. The reaction mass was cooled to RT
and to it was added a solution of Intermediate 185B (30 mg, 0.102
mmol) in THF (1 mL) and stirred for 16 h. The reaction mass was
diluted with EtOAc (5 mL), the organic layer was separated, washed
successively with a 10% aqueous solution of NaHCO.sub.3, water and
brine, then dried over Na.sub.2SO.sub.4, filtered and the filtrate
concentrated under reduced pressure. The crude product was purified
by preparative HPLC to afford Compound 226 as a pale yellow solid
(20 mg, 41% yield). HPLC retention times are 1.528 min. and 1.525
min. (Methods E and L respectively). MS(ES): m/z=470.2 [M+H].sup.+;
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 7.85 (d, J=7.28 Hz,
1H), 7.63-7.71 (m, 1H), 7.47 (d, J=9.29 Hz, 1H), 7.12-7.4 (bs, 2H),
6.21 (s, 1H), 4.68 (s, 2H), 4.12 (s, 2H), 3.79 (s, 2H) 2.65-2.83
(m, 1H), 2.27-2.47 (m, 4H), 1.23 (s, 6H).
[0691] The Compounds shown in Table 12 have been prepared similar
to Compound 226 by coupling of in-situ generated isocyanate of 226B
with 185B analogs.
TABLE-US-00014 TABLE 12 Ret Ex. Time HPLC No. Structure Name [M +
H].sup.+ (min.) Methods 227 ##STR00330##
2-(3-Chlorophenyl)-N.sup.5-(2- (3,3-difluorocyclobutyl)
propan-2-yl)-6,7- dihydropyrazolo[1,5-a] pyrazine-3,5(4H)-
dicarboxamide 452.2 1.477 L 228 ##STR00331##
2-(3,4-Dichlorophenyl)-N.sup.5- (2-(3,3-difluorocyclobutyl)
propan-2-yl)-6,7- dihydropyrazolo[1,5-a] pyrazine-3,5(4H)-
dicarboxamide 486.2 1.652 1.597 E L
##STR00332##
Intermediate 229A: (3,3-Difluoro-1-methylcyclobutyl)methanol
##STR00333##
[0693] To a solution of the
3,3-difluoro-1-methylcyclobutanecarboxylic acid (150 mg, 0.999
mmol) in diethyl ether (5 mL) was added to a suspension of LAH
(2.198 mL, 2.198 mmol, 1M in THF) in diethyl ether (2 mL) at
-40.degree. C. The reaction mixture was stirred at -40.degree. C.
for 1 h and allowed to warm to RT and stirred for 15 h. The
reaction mass cooled to -40.degree. C. and quenched with sequential
addition of water (10 mL), 10% aqueous solution of NaOH (10 mL) and
water (10 mL). Diethyl ether (15 mL) was then added and the
solution was stirred for 2 h. The organic layer was separated and
the aqueous phase was extracted with diethyl ether (3.times.15 mL).
The combined organic layer was dried over Na.sub.2SO.sub.4,
filtered, and the filtrate concentrated under reduced pressure. The
crude sample was purified by silica gel chromatography (12 g
REDISEP.RTM. column, eluting with 30% EtOAc in petroleum ether).
Fractions containing the product were combined and evaporated to
afford the Intermediate 229A as a pale yellow oil (100 mg, 74%).
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 4.92 (t, J=5.52 Hz,
1H) 3.27 (d, J=4.02 Hz, 2H), 2.55-2.45 (m, 2H), 2.07-2.21 (m, 2H),
1.07-1.17 (m, 3H).
Intermediate 229B: (3,3-Difluoro-1-methylcyclobutyl)methyl
methanesulfonate
##STR00334##
[0695] To a solution of Intermediate 229A (100 mg, 0.735 mmol) and
TEA (0.102 mL, 0.735 mmol) in DCM was added methanesulfonyl
chloride (0.059 mL, 0.735 mmol) dropwise at 5.degree. C. and the
reaction mixture was stirred for 3 h. The reaction mass was diluted
with DCM, washed with water and brine, dried over Na.sub.2SO.sub.4,
filtered and the filtrate evaporated under reduced pressure. The
crude product was purified by silica gel chromatography (12 g
REDISEP.RTM. column, eluting with 30% EtOAc in petroleum ether).
Fractions containing the product were combined and evaporated to
afford the Intermediate 229B as a yellow oil (100 mg, 63.5%).
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 4.27 (s, 2H), 3.01
(s, 3H), 2.55-2.69 (m, 2H), 2.06-2.37 (m, 2H), 1.15 (s, 3H).
Intermediate 229C:
2-(3,3-Difluoro-1-methylcyclobutyl)acetonitrile
##STR00335##
[0697] To a solution of Intermediate 229B (200 mg, 0.934 mmol) in
DMSO (3 mL) was added NaCN (114 mg, 2.334 mmol) at RT and the
reaction mixture was heated to 80.degree. C. and stirred for 12 h.
The reaction mixture was cooled to RT, was diluted with water and
was extracted with EtOAc (3.times.10 mL). To the combined organic
layer was washed with water and brine, dried over Na.sub.2SO.sub.4,
filtered and the filtrate concentrated under reduced pressure. The
residue was purified by silica gel chromatography (12 g
REDISEP.RTM. column, eluting with 30% EtOAc in petroleum ether).
Fractions containing the product were combined and evaporated to
afford Intermediate 229C as a brown oil (100 mg, 74%). .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. ppm 2.56-2.42 (m, 6H), 1.17 (s,
3H).
Intermediate 229D: 2-(3,3-Difluoro-1-methylcyclobutyl)acetic
acid
##STR00336##
[0699] To a solution of Intermediate 229C (100 mg, 0.689 mmol) in
ethanol (1 mL) and H.sub.2O (1 mL) was added a 10% aq. solution of
NaOH (2 mL, 0.689 mmol) and the reaction mixture was stirred at
90.degree. C. for 12 h. The reaction mixture was concentrated and
the pH of the residue was adjusted to 4 with an aqueous solution of
1.5 N HCl, and the compound was extracted with EtOAc (3.times.10
mL). The combined organic layer was dried on Na.sub.2SO.sub.4,
filtered and the filtrate evaporated under reduced pressure to
afford Intermediate 229D as a yellow sticky liquid (80 mg, 71%).
The crude intermediate was taken as such for further reaction
without purification. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
ppm 12.14 (brs, 1H), 2.11-2.39 (m, 6H), 1.15 (s, 3H).
Compound 229:
2-(3-Chloro-4-fluorophenyl)-N.sup.5-((3,3-difluoro-1-methylcyclobutyl)met-
hyl)-6,7-dihydropyrazolo[1,5-a]pyrazine-3,5(4H)-dicarboxamide
##STR00337##
[0701] To a stirred solution of Intermediate 229D (16.71 mg, 0.102
mmol) in toluene (1 mL) at RT under nitrogen was added TEA (0.043
mL, 0.305 mmol), DPPA (0.047 mL, 0.204 mmol) and the reaction
mixture was heated at 70.degree. C. for 2 h. The reaction mass was
cooled to RT and to it was added a solution of Intermediate 185B
(30 mg, 0.102 mmol) in THF (1 mL) and stirred at RT for 16 h. The
reaction mass was diluted with ethyl acetate (5 mL), the organic
layer was separated, washed successively with an aqueous solution
of NaHCO.sub.3, water, brine, then dried over Na.sub.2SO.sub.4,
filtered and the filtrate concentrated under reduced pressure. The
crude product was purified by preparative HPLC to afford Compound
229 as a pale yellow solid (2 mg, 4%). The HPLC retention times are
1.484 min. and 1.500 min. (Methods E and L respectively); MS(ES):
m/z=456.2 [M+H].sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
ppm 7.85 (dd, J=7.31, 2.16 Hz, 1H), 7.68 (ddd, J=8.67, 4.78, 2.16
Hz, 1H), 7.42 (m, 1H), 7.36 (bs, 1H), 7.18 (bs, 1H), 7.11 (s, 1H),
4.76 (s, 2H), 4.14 (t, J=5.30 Hz, 2H), 3.86 (t, J=5.33 Hz, 2H),
3.17 (d, J=5.90 Hz, 2H), 2.55-2.70 (m, 2H), 2.17 (d, J=9.79 Hz,
2H), 1.15 (s, 3H).
[0702] The Compounds shown in Table 13 have been prepared similar
to Compound 229 coupling of in-situ generated isocyanate of 229D
with 185B analogs.
TABLE-US-00015 TABLE 13 Ret Ex. Time HPLC No. Structure Name [M +
H].sup.+ (min.) Methods 230 ##STR00338##
2-(3-Chlorophenyl)-N.sup.5- ((3,3-difluoro-1- methylcyclobulyl)
methyl)-6,7- dihydropyrazolo[1,5-a] pyrazine-3,5(4H)- dicarboxamide
438.2 1.432 1.458 E L 231 ##STR00339## 2-(3,4-Dichlorophenyl)-
N.sup.5-((3,3-difluoro-1- methylcyclobutyl) methyl)-6,7-
dihydropyrazolo[1,5-a] pyrazine-3,5(4H)- dicarboxamide 472.2 1.600
1.621 E L
##STR00340##
Intermediate 232A: Ethyl 2-(4,4-difluorocyclohexyl)propanoate
##STR00341##
[0704] To a solution of ethyl 2-(4,4-difluorocyclohexyl)acetate
(0.500 g, 2.424 mmol) in THF (10 mL) was added LDA (2.424 mL, 4.85
mmol, 2M in THF) dropwise at -78.degree. C. and the reaction
mixture was stirred at the same temperature for 45 min. MeI (0.606
mL, 9.70 mmol) was then added at -78.degree. C. and the reaction
mixture was slowly warmed to RT and stirred for 12 h. The reaction
mixture was quenched with a saturated aqueous solution of
NH.sub.4Cl and extracted with EtOAc (2.times.25 mL). The combined
organic layer was dried over Na.sub.2SO.sub.4, filtered and the
filtrate concentrated. The crude product was purified by silica gel
chromatography (12 g REDISEP.RTM. column, eluting with 5% EtOAc in
hexane). Fractions containing the product were combined and
evaporated to afford Intermediate 232A as a pale yellow liquid
(0.27 g, 50%). .sup.1H NMR (300 MHz, chloroform-d) .delta. ppm
4.22-4.08 (m, 1H), 2.32 (quin, J=7.1 Hz, 1H), 2.20-2.02 (m, 2H),
1.88-1.76 (m, 2H), 1.75-1.62 (m, 3H), 1.51-1.35 (m, 2H), 1.33-1.23
(m, 4H), 1.20-1.11 (m, 3H).
Intermediate 232B: Ethyl
2-(4,4-difluorocyclohexyl)-2-methylpropanoate
##STR00342##
[0706] To a solution of Intermediate 232A (0.27 g, 1.226 mmol) in
THF (5 mL) was added LDA (1.226 mL, 2.452 mmol, 2M in THF) dropwise
at -78.degree. C. and the resulting solution was stirred at the
same temperature for 45 min. MeI (0.307 mL, 4.90 mmol) was then
added at -78.degree. C. and the reaction mixture was allowed to
warmed to RT and stir for 12 h. The reaction mixture was quenched
with a saturated aqueous solution of NH.sub.4Cl and extracted with
EtOAc (2.times.25 mL). The combined organic layer was dried over
Na.sub.2SO.sub.4, filtered and the filtrate concentrated. The crude
product was purified by silica gel chromatography (12 g
REDISEP.RTM. column, eluting with 2% EtOAc in hexane.) Fractions
containing the product were combined and evaporated to afford
Intermediate 232B as a pale yellow liquid. (0.15 g, 55%). .sup.1H
NMR (300 MHz, DMSO-d.sub.6) .delta. ppm 4.07 (q, J=7.2 Hz, 2H),
2.01 (d, J=12.1 Hz, 2H), 1.92-1.74 (m, 2H), 1.73-1.53 (m, 4H),
1.31-1.20 (m, 2H), 1.11 (br. s., 4H), 1.03 (d, J=2.6 Hz, 6H).
Intermediate 232C: 2-(4,4-Difluorocyclohexyl)-2-methylpropanoic
acid
##STR00343##
[0708] To a solution of Intermediate 232B (0.15 g, 0.640 mmol) in
ethanol (2 mL) and water (1 mL) was added NaOH (0.256 g, 6.40 mmol)
and the reaction mixture was stirred at 80.degree. C. for 12 h. The
reaction mixture was concentrated under reduced pressure and the
residue was acidified with an aqueous solution of 1.5N HCl and
extracted with EtOAc (2.times.20 mL). The combined organic layer
was dried over Na.sub.2SO.sub.4, filtered and the filtrate
concentrated to afford Intermediate 232C as a yellow solid (90 mg,
68%). .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. ppm 12.20 (br.
s., 1H), 2.11-1.94 (m, 2H), 1.91-1.55 (m, 5H), 1.34-1.14 (m, 2H),
1.09-0.96 (m, 6H).
Compound 232:
2-(3-Chloro-4-fluorophenyl)-N.sup.5-(2-(4,4-difluorocyclohexyl)propan-2-y-
l)-6,7-dihydropyrazolo[1,5-a]pyrazine-3,5(4H)-dicarboxamide
##STR00344##
[0710] To a solution of Intermediate 232C (56.0 mg, 0.271 mmol) in
toluene (2 mL) was added TEA (0.057 mL, 0.407 mmol), DPPA (0.078
mL, 0.339 mmol) and the reaction mixture heated to 80.degree. C.
and stirred for 2 h. The reaction mixture was cooled to RT and to
it was added a solution of Intermediate 185B (40 mg, 0.136 mmol) in
THF (1 mL) and stirred for 12 h. The reaction mixture was diluted
with water (15 mL) and extracted with ethyl acetate (2.times.20
mL). The combined organic layer was washed with brine, dried over
Na.sub.2SO.sub.4, filtered and the filtrate concentrated. The crude
compound was purified by reverse phase preparative HPLC to afford
Compound 232 (37 mg, 52%). HPLC retention time 1.70 min. and 1.70
min. (Methods J and K respectively). MS(ES): m/z=498 [M+H].sup.+;
.sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 7.85 (dd, J=7.3, 2.3 Hz,
1H), 7.73-7.65 (m, 1H), 7.50-7.43 (m, 1H), 7.35 (br. s., 1H), 7.20
(br. s., 1H), 6.21 (s, 1H), 4.69 (s, 2H), 4.12 (t, J=5.0 Hz, 2H),
3.80 (t, J=5.3 Hz, 2H), 2.20 (t, J=12.0 Hz, 1H), 2.08-1.95 (m, 2H),
1.81-1.58 (m, 4H), 1.30-1.13 (m, 8H).
[0711] The Compounds shown in Table 14 have been prepared similar
to Compound 232 coupling of in-situ generated isocyanate of 232C
with 185B analogs.
TABLE-US-00016 TABLE 14 Ret Ex. Time HPLC No. Structure Name [M +
H].sup.+ (min.) Methods 233 ##STR00345##
2-(3-Chlorophenyl)-N.sup.5-(2- (4,4-difluorocyclohexyl)
propan-2-yl)-6,7- dihydropyrazolo[1,5-a] pyrazine-3,5(4H)-
dicarboxamide 480.2 9.125 10.088 B M 234 ##STR00346##
2-(3,4-Dichlorophenyl)-N.sup.5- (2-(4,4-difluorocyclohexyl)
propan-2-yl)-6,7- dihydropyrazolo[1,5-a] pyrazine-3,5(4H)-
dicarboxamide 514.3 1.817 1.817 E L
##STR00347##
Intermediate 235A: Ethyl
1-(difluoromethyl)cyclobutanecarboxylate
##STR00348##
[0713] To a solution of ethyl 1-formylcyclobutanecarboxylate (0.5
g, 3.20 mmol) was added DEOXO-FLUOR.RTM. (50% in THF) (2.36 mL,
6.40 mmol) and the solution was allowed to stir at RT for 16 h. The
reaction mixture was cooled to 0.degree. C. and quenched with a 10%
aqueous solution of NaHCO.sub.3 and extracted with ethyl acetate
(3.times.25 mL). The combined organic layer was washed with water,
dried over Na.sub.2SO.sub.4, filtered and the filtrate concentrated
to afford crude Intermediate 235A as brown oil (0.24 g, 42% yield).
The crude product was subjected to saponification conditions
without further purification.
Intermediate 235B: 1-(Difluoromethyl)cyclobutanecarboxylic acid
##STR00349##
[0715] To a stirred solution of Intermediate 235A (0.24 g, 1.347
mmol) in ethanol (3.5 mL), THF (3.5 mL) was added NaOH (0.162 g,
4.04 mmol) in water (3 mL) and the reaction mixture was stirred at
RT for 16 h. The reaction mixture was concentrated and the residue
was diluted with water (3 mL) and extracted with ethyl acetate. The
aqueous layer was then acidified to pH 3-4 using an aqueous
solution of 1.5 N HCl and extracted with ethyl acetate (3.times.25
mL). The combined organic layer was washed with water, dried over
Na.sub.2SO.sub.4, filtered and the filtrate concentrated. The
residual mass was then azeotroped with toluene to afford
Intermediate 235B as a brown solid (0.12 g, 59% yield). .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. ppm 13.33 (s, 1H), 6.55-5.94 (m,
1H), 3.28-3.03 (m, 2H), 2.41-2.10 (m, 2H), 2.00-1.68 (m, 2H).
Compound 235:
2-(3-Chloro-4-fluorophenyl)-N.sup.5-(1-(difluoromethyl)cyclobutyl)-6,7-di-
hydro pyrazolo[1,5-a]pyrazine-3,5(4H)-dicarboxamide
##STR00350##
[0717] To a stirred solution of Intermediate 235B (0.082 g, 0.543
mmol) in toluene (0.5 mL) was added TEA (0.076 mL, 0.543 mmol) and
DPPA (0.074 mL, 0.339 mmol) and the reaction mass was warmed to
90.degree. C. for 2 h. The reaction mixture was cooled to RT and to
it was added a solution of Intermediate 185B (0.04 g, 0.136 mmol)
in THF (0.5 mL) and stirred for 12 h. The reaction mixture was
quenched with an aqueous solution of 10% NaHCO.sub.3 and extracted
with ethyl acetate (3.times.10 mL). The combined organic layer was
washed with water, dried over Na.sub.2SO.sub.4, filtered and the
filtrate concentrated. The crude product was purified by
preparative HPLC to afford Compound 235 as pale yellow solid (10
mg, 17% yield). HPLC retention times 1.40 and 1.41 min (Method E
and L respectively). MS(ES): m/z=442 [M+1].sup.+; .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. ppm 7.85 (dd, J=7.28, 2.26 Hz, 1H), 7.68
(ddd, J=8.53, 4.77, 2.26 Hz, 1H), 7.43-7.49 (m, 1H), 7.35 (br. s.,
1H), 7.30 (s, 1H), 7.20 (br. s., 1H), 6.04-6.34 (m, 1H), 4.75 (s,
2H), 4.14 (t, J=5.27 Hz, 2H), 3.86 (t, J=5.52 Hz, 2H), 2.28-2.35
(m, 3H), 2.09-2.19 (m, 2H), 1.71-1.97 (m, 2H).
[0718] The Compounds shown in Table 15 have been prepared similar
to Compound 235 coupling of in-situ generated isocyanate of 235B
with 185B analogs.
TABLE-US-00017 TABLE 15 Ret Ex. Time HPLC No. Structure Name [M +
H].sup.+ (min.) Methods 236 ##STR00351##
2-(3-Chlorophenyl)-N.sup.5-(1- (difluoromethyl)cyclobutyl)-
6,7-dihydropyrazolo[1,5-a] pyrazine-3,5(4H)- dicarboxamide 424 1.43
1.41 E L 237 ##STR00352## 2-(3,4-Dichlorophenyl)-N.sup.5-(1-
(difluoromethyl)cyclobutyl)- 6,7-dihydropyrazolo[1,5-a]
pyrazine-3,5(4H)- dicarboxamide 458 1.54 1.54 E L
##STR00353##
Intermediate 238A: (1R,2R)-Methyl
2-formylcyclobutanecarboxylate
##STR00354##
[0720] To a stirred solution of (1S,2R)-methyl
2-(hydroxymethyl)cyclobutanecarboxylate (100 mg, 0.694 mmol) in DCM
(5 mL) was added bis(acetoxy)iodobenzene (335 mg, 1.040 mmol) and
TEMPO (10.84 mg, 0.069 mmol) at 0.degree. C. The temperature of the
reaction was allowed to slowly warm to RT and stirred for 6 h.
Water was added to reaction mass and the compound was extracted
with DCM (3.times.10 mL). The combined organic layer was dried over
Na.sub.2SO.sub.4, filtered and the filtrate evaporated. The crude
product was purified by silica gel chromatography (12 g
REDISEP.RTM. column, eluting with 40% EtOAc in petroleum ether).
Fractions containing the product were combined and evaporated to
afford Intermediate 238A as yellow oil (50 mg, 51% yield). .sup.1H
NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 9.62 (s, 1H) 3.71 (s, 3H),
3.69-3.36 (m, 2H), 2.31-2.16 (m, 4H).
Intermediate 238B: (1R,2R)-Methyl
2-(difluoromethyl)cyclobutanecarboxylate
##STR00355##
[0722] To a solution of Intermediate 238A (300 mg, 2.110 mmol) in
DCM (3 mL) was added DAST (0.697 mL, 5.28 mmol) at -20.degree. C.
The reaction mixture was slowly warmed to RT and stirred for 12 h.
The reaction mixture was quenched with a 10% aqueous solution of
NaHCO.sub.3 and extracted with DCM (3.times.10 mL). The combined
organic layer was dried over Na.sub.2SO.sub.4, filtered and the
filtrate evaporated under reduced pressure. The crude product was
purified by silica gel chromatography (12 g REDISEP.RTM. column,
eluting with 10% EtOAc in petroleum ether). Fractions containing
the product were combined and evaporated to afford Intermediate
238B as a yellow oil (200 mg, 58% yield). .sup.1H NMR (400 MHz,
chloroform-d) .delta. ppm 5.87-6.21 (m, 1H), 3.70 (s, 3H),
2.86-3.27 (m, 2H), 1.82-2.32 (m, 4H).
Intermediate 238C: (1R,2R)-2-(Difluoromethyl)cyclobutanecarboxylic
acid
##STR00356##
[0724] To a solution of Intermediate 238B (200 mg, 1.218 mmol) in
THF (1 mL), MeOH (0.3 mL) and water (1 mL) was added NaOH (97 mg,
2.437 mmol) and the resulting solution was stirred at RT for 12 h.
The volatiles were removed under reduced pressure and the residue
was added water and extracted with ethyl acetate. The pH of the
aqueous layer was adjusted to 4 using an aqueous solution of 1.5 N
HCl and the compounds were extracted with EtOAc (3.times.10 mL).
The combined organic layer was dried on Na.sub.2SO.sub.4, filtered
and filtrate evaporated under reduced pressure to afford
Intermediate 238C as a viscous liquid (120 mg, 65.6% yield). The
crude product was taken further without any purification. .sup.1H
NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 12.24 (bs, 1H), 5.87-6.21
(m, 1H), 3.03 (q, J=8.85 Hz, 1H), 2.89 (dd, J=8.82, 4.05 Hz, 1H)
1.94-2.14 (m, 2H) 1.79-1.94 (m, 2H).
Compound 238:
2-(3-Chloro-4-fluorophenyl)-N.sup.5-((1R,2S)-2-(difluoromethyl)cyclobutyl-
)-6,7-dihydropyrazolo[1,5-a]pyrazine-3,5(4H)-dicarboxamide
##STR00357##
[0726] A stirred solution of Intermediate 238C (15.28 mg, 0.102
mmol) in toluene (1 mL) was added TEA (0.043 mL, 0.305 mmol), DPPA
(0.047 mL, 0.204 mmol) and the reaction mixture was heated to
70.degree. C. for 2 h. The reaction mixture was cooled to RT and to
it was added a solution of Intermediate 185B (30 mg, 0.102 mmol) in
THF (1 mL) and stirred at RT for 16 h. The reaction mixture was
diluted with EtOAc (5 mL), the organic layer was separated, washed
with a 10% aqueous solution of NaHCO.sub.3, water, dried over
Na.sub.2SO.sub.4, filtered and the filtrate concentrated under
reduced pressure. The crude sample was purified by preparative HPLC
to afford Intermediate 238 as a pale yellow solid (14 mg, 31%
yield). The HPLC retention times are 1.314 min. and 1.302 min.
(Methods E and L respectively); MS(ES): m/z=442.2 [M+H].sup.+;
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 7.85 (dd, J=2.2, 7.3
Hz, 1H), 7.69 (ddd, J=2.2, 4.8, 8.7 Hz, 1H), 7.47 (dd, J=8.8, 9.3
Hz, 1H), 7.40-7.32 (m, 1H), 7.22 (d, J=7.4 Hz, 2H), 6.29-5.89 (m,
1H), 4.73 (s, 2H), 4.19-4.05 (m, 3H), 3.89-3.69 (m, 2H), 2.75 (dd,
J=8.7, 12.1 Hz, 1H), 2.15-2.01 (m, 1H), 1.94 (t, J=9.9 Hz, 1H),
1.80-1.55 (m, 2H).
[0727] The Compounds shown in Table 16 have been prepared similar
to Compound 238 coupling of in-situ generated isocyanate of 238C
with 185B analogs.
TABLE-US-00018 TABLE 16 Ret Ex. Time HPLC No. Structure Name [M +
H].sup.+ (min.) Methods 239 ##STR00358##
2-(3-Chlorophenyl)-N.sup.5- ((1R,2R)-2-(difluoromethyl)
cyclobutyl)-6,7- dihydropyrazolo[1,5-a] pyrazine-3,5(4H)-
dicarboxamide 424.2 1.257 1.245 E L 240 ##STR00359##
2-(3,4-Dichlorophenyl)-N.sup.5- ((1R,2R)-2-(dinuoromethyl)
cyclobutyl)-6,7- dihydropyrazolo[1,5-a] pyrazine-3,5(4H)-
dicarboxamide 458.2 1.442 1.433 E L
##STR00360##
Intermediate 241A: (1R,2R)-Methyl
2-((difluoromethoxy)methyl)cyclobutanecarboxylate
##STR00361##
[0729] To a solution of (1R,2R)-methyl
2-(hydroxymethyl)cyclobutanecarboxylate (100 mg, 0.694 mmol) in
acetonitrile (5 mL) was added CuI(I) (66.1 mg, 0.347 mmol) and the
reaction mixture was heated to 60.degree. C. To the stirred
solution was added 2,2-difluoro-2-(fluorosulphonyl)acetic acid (124
mg, 0.694 mmol) and the reaction mixture was stirred for an
additional 12 h at 60.degree. C. The reaction mixture was cooled to
0.degree. C., a saturated aqueous solution of NaHCO.sub.3 was added
and extracted with ethyl acetate (3.times.10 mL). The combined
organic layer was dried over Na.sub.2SO.sub.4, filtered and the
filtrate evaporated under reduced pressure to afford Intermediate
241A as a yellow oil (100 mg, 80%). The crude product was used in
the next step without further purification. .sup.1H NMR (300 MHz,
chloroform-d) .delta. ppm 5.92-6.56 (m, 1H), 3.86 (d, J=5.29 Hz,
2H), 3.70 (s, 3H), 3.01 (d, J=8.88 Hz, 2H), 2.18 (d, J=10.15 Hz,
2H), 1.68-2.02 (m, 2H).
Intermediate 241B:
(1R,2R)-2-((Difluoromethoxy)methyl)cyclobutanecarboxylic acid
##STR00362##
[0731] To a solution of Intermediate 241A (100 mg, 0.515 mmol) in a
1:0.3:1THF:MeOH:water was added NaOH (41.2 mg, 1.030 mmol) and the
resulting solution was stirred at RT for 12 h. The volatiles were
removed under reduced pressure and the aqueous layer was washed
with ethyl acetate. The pH of the aqueous layer was adjusted to 4
by adding an aqueous solution of 1.5 N HCl and extracted with ethyl
acetate (3.times.10 mL). The combined organic layer was dried over
Na.sub.2SO.sub.4 and evaporated under vacuum to afford Intermediate
241B as yellow sticky liquid (80 mg, 86%). .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta. ppm 12.10 (s, 1H), 6.35-6.95 (m, 1H),
3.74-3.89 (m, 2H), 2.85 (q, J=8.70 Hz, 1H) 2.63-2.77 (m, 1H)
1.95-2.10 (m, 4H).
Compound 241:
2-(3-Chloro-4-fluorophenyl)-N.sup.5-((1R,2R)-2-((difluoromethoxy)methyl)c-
yclobutyl)-6,7-dihydropyrazolo[1,5-a]pyrazine-3,5(4H)-dicarboxamide
##STR00363##
[0733] A stirred solution of Intermediate 241B (18.34 mg, 0.102
mmol) in toluene (1 mL) at RT under nitrogen was added TEA (0.043
mL, 0.305 mmol), DPPA (0.047 mL, 0.204 mmol) and the reaction
mixture was heated at 70.degree. C. for 2 h. The reaction mass was
cooled to RT and to it was added a solution of Intermediate 185B
(30 mg, 0.102 mmol) in THF (1 mL) and stirred for 16 h. The
reaction mass was diluted with ethyl acetate (5 mL) and the organic
layer was separated. The organic layer was washed sequentially with
an aqueous solution of 10% NaHCO.sub.3, water, and brine, then
dried over Na.sub.2SO.sub.4, filtered and the filtrate concentrated
under reduced pressure. The crude product was purified by
preparative HPLC to afford Compound 241 as pale yellow solid (10
mg, 20% yield). The HPLC Retention times are 1.453 min. and 1.467
min. (Methods J and K respectively); MS(ES): m/z=472.2[M+H].sup.+;
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 7.85 (dd, J=7.28,
2.13 Hz, 1H), 7.69 (ddd, J=8.63, 4.80, 2.13 Hz, 1H), 7.39-7.52 (m,
1H), 7.11-7.33 (2bs, 2H), 7.10 (d, J=7.34 Hz, 1H), 6.36-6.88 (m,
1H), 4.73 (s, 2H), 4.13 (t, J=5.27 Hz, 2H), 3.72-3.99 (m, 5H),
2.00-2.16 (m, 1H), 1.68-1.94 (m, 2H), 1.33-1.53 (m, 1H).
[0734] The Compounds shown in Table 17 have been prepared similar
to Compound 241 coupling of in-situ generated isocyanate of 241B
with 185B analogs.
TABLE-US-00019 TABLE 17 Ret Ex. Time HPLC No. Structure Name [M +
H].sup.+ (min.) Methods 242 ##STR00364##
2-(3-Chlorophenyl)-N.sup.5- ((1R,2R)-2- ((difluoromethoxy)
methyl)cyclobutyl)-6,7- dihydropyrazolo[1,5-a] pyrazine-3,5(4H)-
dicarboxamide 454.2 1.405 1.420 E L 243 ##STR00365##
2-(3,4-Dichlorophenyl)-N.sup.5- ((1R,2R)-2- ((difluoromethoxy)
methyl)cyclobutyl)-6,7- dihydropyrazolo[1,5-a] pyrazine-3,5(4H)-
dicarboxamide 488.2 1.565 1.576 E L
##STR00366##
Intermediate 244A: Ethyl
3-((difluoromethoxy)methyl)cyclobutanecarboxylate
##STR00367##
[0736] To a solution of CuI (0.120 g, 0.632 mmol) and ethyl
3-(hydroxymethyl)cyclobutanecarboxylate (0.2 g, 1.264 mmol) in MeCN
(5 mL) was added 2,2-difluoro-2-(fluorosulfonyl)acetic acid (0.195
mL, 1.896 mmol) dropwise warmed at 50.degree. C. and the reaction
mixture was stirred for 3 h. The reaction mixture was filtered
through a Buchner funnel and the filtrate was concentrated. The
crude product was purified by silica gel chromatography (40 g
REDISEP.RTM. column, eluting with 2% EtOAc in hexane). Fractions
containing the product were combined and evaporated to afford cis
and trans mixture of Intermediate 244A as a colorless oil (0.3 g,
55%). .sup.1H NMR (300 MHz, chloroform-d) .delta. ppm 5.93-6.50 (m,
1H), 4.07-4.24 (m, 2H), 3.59-3.76 (m, 2H), 2.95-3.19 (m, 1H),
2.47-2.58 (m, 1H), 2.21-2.43 (m, 2H), 1.98-2.16 (m, 2H), 1.19-1.35
(m, 3H).
Intermediate 244B: 3-((Difluoromethoxy)methyl)cyclobutanecarboxylic
acid
##STR00368##
[0738] The a solution of Intermediate 244A (0.3 g, 1.441 mmol) in
THF (5 mL) was added NaOH (0.144 g, 3.60 mmol) in water (2 mL) and
the resulting solution was stirred at RT for 16 h. The volatiles
were removed under a reduced pressure and pH was adjusted to 3 with
an aqueous solution of 1.0 N HCl and extracted with ethyl acetate
(3.times.10 mL). The combined organic layer was washed with water,
brine, dried over Na.sub.2SO.sub.4, filtered and the filtrate
concentrated to afford Intermediate 244B as a yellow liquid (0.15
g, 57%, cis and trans mixture). The crude product was reacted to
the next step without further purification. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 12.01 (br. s., 1H), 6.41-6.90 (m, 1H),
3.35-3.46 (m, 2H), 2.88-3.11 (m, 1H), 2.06-2.34 (m, 3H), 1.83-2.04
(m, 2H).
Compounds 244 and 245:
2-(3-Chlorophenyl)-N.sup.5-(3-((difluoromethoxy)methyl)cyclobutyl)-6,7-di-
hydropyrazolo[1,5-a]pyrazine-3,5(4H)-dicarboxamide
##STR00369##
[0740] A solution of Intermediate 244B (52.1 mg, 0.289 mmol), TEA
(0.081 mL, 0.578 mmol), DPPA (0.062 mL, 0.289 mmol) in toluene (5
mL) was heated to 90.degree. C. and stirred for 2 h. The reaction
mixture was cooled to RT and in to it was added a solution of
Intermediate 156E (60 mg, 0.193 mmol) in THF (1 mL) and stirred at
RT for 4 h. The reaction mixture was quenched with water and the
aq. layer was extracted with EtOAc (3.times.5 mL). The combined
organic layer was washed with an aqueous solution of 10%
NaHCO.sub.3, water, then dried over Na.sub.2SO.sub.4, filtered and
the filtrate concentrated to afford crude product. The crude
reaction mixture was purified by preparative TLC. The crude
material was loaded on a 0.5 mm silica gel plate which was
developed using 6% MeOH in CHCl.sub.3. Band containing the desired
product was separated and extracted into 10% MeOH in DCM, and was
then filtered and concentrated to afford mixture of Compounds 244
and 245 as an off-white solid. Individual isomers were separated
using preparative SFC.
[0741] Compound 244: Retention time 4.22 min (HPLC Method Q);
MS(ES): m/z=454 [M+H].sup.+; Yield=8 mg, 25%; .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 7.69-7.71 (m, 1H), 7.63 (dt, J=6.65, 1.95
Hz, 1H), 7.39-7.46 (m, 2H), 7.34 (br. s., 1H), 7.16 (br. s., 1H),
7.02 (d, J=7.53 Hz, 1H), 6.44-6.85 (m, 1H), 4.71 (s, 2H), 4.13 (s,
2H), 4.05 (d, J=7.53 Hz, 1H), 3.82 (s, 2H), 3.78 (d, J=6.02 Hz,
2H), 2.13-2.31 (m, 3H), 1.68-1.78 (m, 2H).
[0742] Compound 245: Retention time 4.88 min (HPLC Method Q);
MS(ES): m/z=454 [M+H].sup.+; Yield=8 mg, 25%; .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 7.70 (t, J=1.51 Hz, 1H), 7.61-7.66 (m,
1H), 7.39-7.47 (m, 2H), 7.34 (br. s., 1H), 7.17 (br. s., 1H), 7.11
(s, 1H), 6.48-6.88 (m, 1H), 4.72 (s, 2H), 4.18-4.27 (m, 1H), 4.13
(t, J=5.27 Hz, 2H), 3.88 (d, J=7.53 Hz, 2H), 3.83 (t, J=5.27 Hz,
2H), 2.36-2.46 (m, 1H), 1.99-2.17 (m, 4H).
##STR00370##
Intermediate 246A: 3-Methylcyclobutanecarboxylic acid
##STR00371##
[0744] A solution of benzyl 3-methylenecyclobutanecarboxylate (1.0
g, 4.94 mmol) and 10% Pd/C (0.526 g, 0.494 mmol) in ethanol (5 mL)
was stirred under a atmosphere of hydrogen (1 bar) for 3 h. The
reaction mixture was filtered through a Buchner funnel and the
filtrate was evaporated under reduced pressure to afford
Intermediate 246A as a mixture of cis and trans isomers (0.4 g,
70%, colorless liquid). This was used to the next step without
further purification. .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta.
ppm 2.70-3.05 (m, 1H), 2.13-2.45 (m, 3H), 1.61-1.84 (m, 2H), 1.08
(dd, J=6.99, 3.59 Hz, 1.6H) 0.93-1.02 (m, 1.4 H).
Compounds 246 and 247:
2-(3-Chloro-4-fluorophenyl)-N.sup.5-(3-methylcyclobutyl)-6,7-dihydropyraz-
olo[1,5-c]pyrazine-3,5(4H)-dicarboxamide
##STR00372##
[0746] A solution of Intermediate 246A (77 mg, 0.679 mmol), TEA
(0.142 mL, 1.018 mmol) and DPPA (0.146 mL, 0.679 mmol) in toluene
(5 mL) was stirred at 90.degree. C. for 2 h. The reaction mixture
was cooled to RT and to it was added a solution of Intermediate
185B (100 mg, 0.339 mmol) in THF (1 mL) and stirred at RT for 4 h.
The reaction mixture was quenched with water and the aqueous layer
was extracted with ethyl acetate (3.times.5 mL). The combined
organic layer was washed with an aqueous solution of 10% aq.
NaHCO.sub.3, water, dried over Na.sub.2SO.sub.4, filtered and the
filtrate concentrated to afford the crude product as an off-white
solid. The crude material was purified by preparative TLC. The
crude material was loaded on a 0.5 mm silica gel plate and
developed using 6% MeOH in CHCl.sub.3. The band containing the
desired product was separated and extracted into 10% MeOH in DCM,
filtered and the filtrate concentrated to afford a mixture cis and
trans isomers as an off-white solid. The individual isomers were
separated using preparative chiral SFC purification.
[0747] Compound 246: Retention time=21.82 min. (HPLC Method P);
MS(ES): m/z=406 [M+H].sup.+; Yield=13 mg, 9%; .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 7.85 (dd, J=7.28, 2.26 Hz, 1H), 7.64-7.71
(m, 1H), 7.47 (d, J=9.54 Hz, 1H), 7.34 (br. s., 1H), 7.17 (br. s.,
1H), 6.96 (d, J=7.53 Hz, 1H), 4.70 (s, 2H), 4.11 (t, J=5.27 Hz,
2H), 3.87-4.00 (m, 1H), 3.81 (t, J=5.52 Hz, 2H), 2.25-2.36 (m, 2H),
1.84-2.00 (m, 1H), 1.47-1.59 (m, 2H), 1.03 (d, J=6.53 Hz, 3H).
[0748] Compound 247: Retention time=26.26 min. (HPLC Method P);
MS(ES): m/z=406 [M+H].sup.+; Yield=13 mg, 9%; .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 7.85 (dd, J=7.28, 2.26 Hz, 1H), 7.64-7.71
(m, 1H), 7.47 (d, J=9.54 Hz, 1H), 7.34 (br. s., 1H), 7.17 (br. s.,
1H), 6.96 (d, J=7.53 Hz, 1H), 4.70 (s, 2H), 4.20-4.30 (m, 1H), 4.11
(t, J=5.27 Hz, 2H), 3.81 (t, J=5.52 Hz, 2H), 2.18-2.23 (m, 1H),
2.068-2.14 (m, 2H), 1.80-1.85 (m, 2H), 1.09-1.12 (d, J=6.53 Hz,
3H).
[0749] The Compounds shown in Table 18 have been prepared similar
to Compounds 246 and 247 by coupling of in-situ generated
isocyanate of 246A with 185B analogs.
TABLE-US-00020 TABLE 18 Ret Ex. Time HPLC No. Structure Name [M +
H].sup.+ (min.) Methods 248 ##STR00373##
2-(3,4-Dichlorophenyl)-N.sup.5-(3- methylcyclobutyl)-6,7-
dihydropyrazolo[1,5-a]pyrazine- 3,5(4H)-dicarboxamide 422 14.52 P
249 ##STR00374## 2-(3,4-Dichlorophenyl)-N.sup.5-(3-
methylcyclobutyl)-6,7- dihydropyrazolo[1,5-a]pyrazine-
3,5(4H)-dicarboxamide 422 17.37 P 250 ##STR00375##
2-(3-Chlorophenyl)-N.sup.5-(3- methylcyclobutyl)-6,7-
dihydropyrazolo[1,5-a]pyrazine- 3,5(4H)-dicarboxamide 388 4.54 P
251 ##STR00376## 2-(3-Chlorophenyl)-N.sup.5-(3-
methylcyclobutyl)-6,7- dihydropyrazolo[1,5-a]pyrazine-
3,5(4H)-dicarboxamide 388 5.34 P
##STR00377##
Intermediate 252A: Ethyl
3-(difluoromethyl)cyclobutanecarboxylate
##STR00378##
[0751] To a solution of ethyl 3-formylcyclobutanecarboxylate (0.6
g, 3.84 mmol) in DCM (5 mL) at -78.degree. C. was added DAST (1.015
mL, 7.68 mmol) and the reaction mixture was stirred at RT for 16 h.
The reaction mixture was quenched with a 10% aqueous solution of
NaHCO.sub.3 and the aqueous layer was extracted with DCM
(3.times.10 mL). The combined organic layer was washed with an
aqueous solution of 1.5 N HCl, brine, dried over Na.sub.2SO.sub.4,
filtered and concentrated to afford Intermediate 252A as yellow
liquid (0.5 g, 73%, mixture of cis and trans isomers). The crude
product was reacted to the next step without further purification.
.sup.1H NMR (400 MHz, chloroform-d) .delta. ppm 5.58-6.01 (m, 1H),
4.07-4.22 (m, 2H), 2.98-3.20 (m, 1H), 2.57-2.85 (m, 1H), 2.20-2.48
(m, 4H), 1.21-1.33 (m, 3H).
Intermediate 252B: 3-(Difluoromethyl)cyclobutanecarboxylic acid
##STR00379##
[0753] To a stirred solution of Intermediate 252A (0.2 g, 1.122
mmol) in THF (5 mL) was added NaOH (0.112 g, 2.81 mmol) in water (2
mL) at RT. After 16 h, THF was removed under a reduced pressure and
the pH of aqueous solution was adjusted to 3 using a 1.0 N aq.
solution of HCl and extracted with ethyl acetate (3.times.10 mL).
The combined organic layer was washed with water, brine, dried over
Na.sub.2SO.sub.4, filtered and the filtrate concentrated to afford
Intermediate 252B as yellow liquid (0.12 g, 71%, mixture of cis and
trans isomers). The crude product was used in a subsequent reaction
without further purification. .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. ppm 12.01-12.22 (m, 1H), 5.84-6.32 (m, 1H), 2.97-3.13 (m,
1H), 2.59-2.77 (m, 1H), 2.06-2.32 (m, 4H).
Compounds 252 and 253:
2-(3-Chloro-4-fluorophenyl)-N.sup.5-(3-(difluoromethyl)cyclobutyl)-6,7-di-
hydropyrazolo[1,5-a]pyrazine-3,5(4H)-dicarboxamide
##STR00380##
[0755] A solution of Intermediate 252B (54.3 mg, 0.361 mmol), TEA
(0.076 mL, 0.542 mmol) and DPPA (0.078 mL, 0.361 mmol) in toluene
(5 mL) was stirred at 90.degree. C. for 1.5 h. The reaction mixture
was cooled to RT and in to it was added a solution of Intermediate
185B (50 mg, 0.181 mmol) in THF and stirred at RT for 4 h. The
reaction mixture was quenched with water and extracted with ethyl
acetate (3.times.5 mL). The combined organic layer was washed with
a 10% aqueous solution of NaHCO.sub.3, water, and then dried over
Na.sub.2SO.sub.4, filtered and the filtrate concentrated. The crude
product was purified by preparative TLC. The crude material was
loaded on a 0.5 mm silica gel plate and developed using 6% MeOH in
CHCl.sub.3. Band containing desired product was removed and
extracted into 10% MeOH in DCM, filtered and concentrated to
offered Compounds 252 and 253 as off-white solid (mixture of cis
and trans isomers). Both isomers were separated by chiral SFC.
[0756] Compound 252: (13 mg, 21%); Retention time: 5.48 min (HPLC
Method N); MS(ES): m/z=442 [M+H].sup.+; .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 7.71 (t, J=1.51 Hz, 1H), 7.62-7.67 (m,
1H), 7.40-7.49 (m, 2H), 7.35 (br. s., 1H), 7.17 (br. s., 1H), 7.11
(d, J=7.53 Hz, 1H), 5.82-6.17 (m, 1H), 4.72 (s, 2H), 4.06-4.20 (m,
3H), 3.84 (t, J=5.52 Hz, 2H), 2.43 (d, J=18.07 Hz, 1H), 2.17-2.30
(m, 2H), 1.88-1.99 (m, 2H).
[0757] Compound 253: (10 mg, 16%); Retention time: 6.40 min (HPLC
Method N); MS(ES): m/z=442 [M+H]; .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 7.71 (s, 1H), 7.65 (s, 1H), 7.41-7.48 (m,
2H), 7.36 (br. s., 1H), 7.16-7.17 (m, J=7.03 Hz, 2H), 5.82-6.37 (m,
1H), 4.73 (s, 2H), 4.20-4.30 (m, 1H), 4.14 (br. s., 2H), 3.80-3.88
(m, 2H), 2.55-2.65 (m, 1H), 2.15-2.25 (m, 4H).
[0758] The Compounds shown in Table 19 have been prepared similar
to Compounds 252 and 253 by coupling of in-situ generated
isocyanate of 252B with 185B analogs.
TABLE-US-00021 TABLE 19 Ret Ex. Time HPLC No. Structure Name [M +
H].sup.+ (min.) Methods 254 ##STR00381##
2-(3,4-Dichlorophenyl)-N.sup.5-(3- (difluoromethyl)cyclobutyl)-6,7-
dihydropyrazolo[1,5-a]pyrazine- 3,5(4H)-dicarboxamide 459 4.1 Q 255
##STR00382## 2-(3,4-Dichlorophenyl)-N.sup.5-(3-
(difluoromethyl)cyclobutyl)-6,7- dihydropyrazolo[1,5-a]pyrazine-
3,5(4H)-dicarboxamide 459 5.79 Q 256 ##STR00383##
2-(3-Chlorophenyl)-N.sup.5-(3- (difluoromethyl)cyclobutyl)-6,7-
dihydropyrazolo[1,5-a]pyrazine- 3,5(4H)-dicarboxamide 424 6.44 N
257 ##STR00384## 2-(3-Chlorophenyl)-N.sup.5-(3-
(difluoromethyl)cyclobutyl)-6,7- dihydropyrazolo[1,5-a]pyrazine-
3,5(4H)-dicarboxamide 424 7.18 N
##STR00385##
Intermediate 258A: Ethyl
1-methyl-3-methylenecyclobutanecarboxylate
##STR00386##
[0760] To a stirred solution of LDA (60 mL, 54 mmol, 1.0 M in THF
(150 mL) at -78.degree. C., was added ethyl
3-methylenecyclobutanecarboxylate (5.0 g, 35.7 mmol) and the
reaction mixture was slowly allowed to warm to 0.degree. C. and
stir for 20 min. The reaction mixture was again cooled to
-78.degree. C. and MeI (8.92 mL, 143 mmol) was added and the
reaction mixture was warmed to RT and stirred for 16 h. The
reaction mixture was quenched with a saturated aq. solution of
NH.sub.4Cl and the aqueous layer was extracted with diethyl ether
(3.times.5 mL). The combined organic layer was washed with an
aqueous solution of 1.5N HCl, brine, then dried over
Na.sub.2SO.sub.4, filtered and the filtrate concentrated. The crude
product was purified by silica gel chromatography (24 g
REDISEP.RTM. column, eluting with 1% EtOAc in hexanes). Fractions
containing the product were combined and evaporated to afford
Intermediate 258A as a pale yellow liquid (3.5 g, 63%). .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. ppm 4.83-4.93 (m, 2H), 4.18 (q,
J=7.18 Hz, 3.12-3.24 (m, 2H), 2.41-2.55 (m, 2H), 1.45 (s, 3H),
1.23-1.36 (m, 3H).
Intermediate 258B: Ethyl
3-(hydroxymethyl)-1-methylcyclobutanecarboxylate
##STR00387##
[0762] To a solution of Intermediate 258A (1.0 g, 6.48 mmol) in
anhydrous THF (50 mL) at -10.degree. C. was added BH.sub.3.THF
(3.24 mL, 6.48 mmol, 2 M in THF) dropwise. The resulting reaction
mixture was allowed to warm to RT and stir for 4 h. The reaction
mixture was cooled to -20.degree. C., methanol (5 mL) was added and
stirred for 15 min. followed by the addition of a 10% aq. NaOH
solution (1 mL, 3.24 mmol) and H.sub.2O.sub.2 (0.596 mL, 9.73 mmol,
30% v/v) sequentially and the resultant reaction mixture was
stirred at RT for 2 h. It was then neutralized with an aqueous 1.5N
HCl and the aqueous layer was extracted with ethyl acetate
(3.times.15 mL). The combined organic layer was washed with water,
brine, and then dried over Na.sub.2SO.sub.4, filtered and the
filtrate concentrated to afford the crude product. The crude was
purified by silica gel chromatography (24 g REDISEP.RTM. column,
eluting with 30% EtOAc in hexanes). Fractions containing the
product were combined and evaporated to afford Intermediate 258B
pale yellow liquid (0.5 g, 45%, mixture of cis and trans isomers).
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 4.43-4.52 (m, 1H),
3.99-4.13 (m, 2H), 3.27-3.28 (m, 2H), 2.26-2.40 (m, 3H), 1.61-1.82
(m, 2H), 1.34 (s, 1H), 1.26 (s, 2H), 1.13-1.22 (m, 3H).
Intermediate 258C: Ethyl
3-formyl-1-methylcyclobutanecarboxylate
##STR00388##
[0764] To a solution of oxalyl chloride (0.549 mL, 6.27 mmol) in
DCM (15 mL) was added DMSO (0.890 mL, 12.54 mmol) as a solution in
DCM (5 mL) slowly at -78.degree. C. The resultant solution was
stirred for 30 min. prior to dropwise addition of Intermediate 258B
(0.5 g, 3.14 mmol) as solution in DCM (5 mL). The resultant mixture
was stirred for an additional 2 h at -78.degree. C. TEA (4.37 mL,
31.4 mmol) was added to the reaction and the reaction mixture was
allowed to stir at -78.degree. C. for 30 min. The mixture was then
warmed to RT and a saturated aqueous NH.sub.4Cl solution was added
and extracted with dichloromethane (3.times.10 mL). The combined
organic layer was washed with brine, dried over Na.sub.2SO.sub.4,
filtered and the filtrate concentrated under reduced pressure. The
crude product was purified by silica gel chromatography (12 g
REDISEP.RTM. column, eluting with 30% EtOAc in hexane). Fractions
containing the product were combined and evaporated to afford
Intermediate 258C as a pale yellow liquid (0.12 g, 22%, mixture of
cis and trans isomers). .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
ppm 9.63 (d, J=1.51 Hz, 1H), 3.95-4.15 (m, 2H), 3.08-3.28 (m, 1H),
2.53-2.61 (m, 2H), 2.16-2.28 (m, 1H), 1.93-2.14 (m, 2H), 1.37-1.43
(s, 1H), 1.21-1.30 (s, 2H), 1.13-1.21 (m, 3H).
Intermediate 258D: Ethyl
3-(difluoromethyl)-1-methylcyclobutanecarboxylate
##STR00389##
[0766] To a solution of Intermediate 258C (0.1 g, 0.588 mmol) in
DCM (5 mL) at -78.degree. C. was added DAST (0.155 mL, 1.175 mmol)
and the reaction mixture was stirred at RT for 16 h. The reaction
mixture was quenched with a 10% aq. solution of NaHCO.sub.3 and the
aqueous layer was extracted with DCM (3.times.10 mL). The combined
organic layers were washed with a 1.5N aq. solution of HCl,
followed by brine, and was then dried over Na.sub.2SO.sub.4,
filtered and concentrated to afford Intermediate 258D (0.08 g, 70%,
as a mixture of cis and trans isomers) as a yellow liquid. The
crude product was used in the next step without purification.
.sup.1H NMR (400 MHz, chloroform-d) .delta. ppm 5.58-6.01 (m, 1H),
4.07-4.22 (m, 2H), 2.61-2.85 (m, 1H), 2.47-2.56 (m, 2H), 1.85-2.05
(m, 2H), 1.36 (s, 1H), 1.28 (s, 2H), 1.21-1.26 (m, 3H).
Intermediate 258E: 3-(Difluoromethyl)-1-methylcyclobutanecarboxylic
acid
##STR00390##
[0768] A solution of Intermediate 258D (0.07 g, 0.364 mmol) and
NaOH (0.036 g, 0.910 mmol) in THF (2 mL) and water (1 mL) was
stirred at RT for 16 h. The volatiles were evaporated under reduced
pressure, the pH was adjusted to .about.3 with a 1.0N aq. solution
of HCl, and the aqueous layer was extracted with EtOAc (3.times.10
mL). The combined organic layers were washed with water, brine,
dried over Na.sub.2SO.sub.4, filtered and concentrated to afford
Intermediate 258E (0.05 g, 84%, a mixture of cis and trans isomers)
as a yellow liquid. The crude product was used in the next step
without purification. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
ppm 12.20-12.36 (m, 1H), 5.86-6.24 (m, 1H), 2.57-2.86 (m, 1H),
2.27-2.46 (m, 2H), 1.77-1.93 (m, 2H), 1.36 (s, 1H), 1.27 (s,
2H).
Compounds 258 and 259:
2-(3-Chloro-4-fluorophenyl)-N.sup.5-(3-(difluoromethyl)-1-methylcyclobuty-
l)-6,7-dihydropyrazolo[1,5-a]pyrazine-3,5(4H)-dicarboxamide
##STR00391##
[0770] A solution of Intermediate 258E (84 mg, 0.509 mmol), TEA
(0.142 mL, 1.018 mmol), DPPA (0.146 mL, 0.679 mmol) in toluene (5
mL) was stirred at 90.degree. C. for 2 h. The reaction mixture was
cooled to RT and to it was added a solution of Intermediate 185B
(100 mg, 0.339 mmol) in THF (3 mL) and stirred at RT for 4 h. The
reaction mixture was quenched with water and the aqueous layer was
extracted with ethyl acetate (3.times.5 mL). The combined organic
layer was washed with an aqueous solution of 10% NaHCO.sub.3,
water, dried over Na.sub.2SO.sub.4, filtered and the filtrate
concentrated. The crude product was purified by preparative TLC.
The crude product was loaded on a 0.5 mm silica gel plate and was
developed using 6% MeOH in CHCl.sub.3. The band containing the
desired product was removed and extracted with 10% MeOH in DCM,
filtered and concentrated to afford Compounds 258 and 259, a
mixture of cis and trans isomers, as an off-white solid. The
compound was subjected to chiral separation using preparative SFC
to afford the cis and trans isomers.
[0771] Compound 258: Retention times 8.64 min. (Method 0); Yield=10
mg, 6%; MS(ES): m/z=456 [M+H].sup.+; .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta. ppm 7.86 (dd, J=7.37, 2.08 Hz, 1H), 7.69
(ddd, J=8.69, 4.91, 2.27 Hz, 1H), 7.48 (d, J=9.44 Hz, 1H), 7.36
(br. s., 1H), 7.21 (br. s., 1H), 6.85 (s, 1H), 5.87-6.29 (m, 1H),
4.73 (s, 2H), 4.14 (t, J=5.29 Hz, 2H), 3.84 (t, J=5.10 Hz, 2H),
2.66-2.80 (m, 1H), 2.31-2.42 (m, 1H), 1.92 (dd, J=13.22, 7.93 Hz,
2H), 1.34 (s, 3H).
[0772] Compound 259: Retention time 11.9 min. (Method 0); Yield=21
mg, 13%; MS(ES): m/z=456 [M+H].sup.+; .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 7.86 (dd, J=7.28, 2.26 Hz, 1H), 7.69
(ddd, J=8.66, 4.64, 2.26 Hz, 1H) 7.44-7.53 (m, 1H), 7.36 (br. s.,
1H), 7.19 (br. s., 1H), 6.85 (s, 1H), 5.90-6.22 (m, 1H), 4.71 (s,
2H), 4.13 (t, J=5.27 Hz, 2H), 3.81 (t, J=5.27 Hz, 2H), 2.60 (d,
J=9.04 Hz, 1H), 2.16-2.26 (m, 2H), 1.96-2.06 (m, 2H), 1.24 (s,
3H).
##STR00392##
Intermediate 260A:
N.sup.5-(3-(Benzyloxy)-1-methylcyclobutyl)-2-(3-chloro-4-fluorophenyl)-6,-
7-dihydropyrazolo[1,5-a]pyrazine-3,5(4H)-dicarboxamide
##STR00393##
[0774] To a stirred solution of
3-(benzyloxy)-1-methylcyclobutanamine (64.9 mg, 0.339 mmol) in THF
(10 mL) was added TEA (0.14 mL, 1.357 mmol) followed by triphosgene
(100 mg, 0.339 mmol) at 0.degree. C. After stirring for 10 min, a
solution of Intermediate 185B (100 mg, 0.34 mmol) in THF (2 mL) was
added at 0.degree. C. and the resulting solution was allowed to
warm to RT and stir for 16 h. The reaction mixture was quenched
with a saturated aqueous solution of NH.sub.4Cl and extracted with
DCM (3.times.20 mL). The combined organic layers were dried over
Na.sub.2SO.sub.4 and evaporated to afford the crude reaction
mixture which was purified by silica gel chromatography (12 g
REDISEP.RTM. column, eluting with 2% MeOH in CHCl.sub.3). Fractions
containing the product were combined and evaporated to afford
Intermediate 260A (70 mg, 40% yield) as a pale yellow solid.
MS(ES): m/z=512 [M+H].sup.+.
Compound 260:
2-(3-Chloro-4-fluorophenyl)-N.sup.5-(3-hydroxy-1-methylcyclobutyl)-6,7-di-
hydropyrazolo[1,5-a]pyrazine-3,5(4H)-dicarboxamide
##STR00394##
[0776] To a stirred solution of Intermediate 260A (70 mg, 0.137
mmol) in DCM (10 mL), cooled to -78.degree. C., was added BCl.sub.3
(0.547 ml, 0.547 mmol, 1.0 M in DCM) and the resulting mixture was
allowed to warm to RT and stir for 16 h. The reaction mixture was
quenched with a saturated aqueous solution of NH.sub.4Cl and
extracted with DCM (3.times.25 mL). The combined organic layers
were dried over Na.sub.2SO.sub.4 and evaporated. The crude compound
was purified by preparative HPLC to afford Compound 260 as an
off-white solid (9.0 mg, 16% yield). HPLC Ret. Times 6.51 min. and
6.54 min. (HPLC Methods A and B). MS(ES): m/z=422 [M+H].sup.+;
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 7.86 (dd, J=7.31,
2.16 Hz, 1H), 7.69 (dt, J=6.24, 2.49 Hz, 1H), 7.43-7.48 (t, 1H),
7.11-7.41 (m, 2H), 6.96 (s, 1H), 6.68 (s, 1H), 4.90 (dd, J=10.42,
6.15 Hz, 1H), 4.70 (s, 2H), 4.08-4.18 (m, 2H), 3.97 (m, 1H), 3.82
(s, 2H), 2.45-2.56 (m, 1H), 2.26-2.38 (m, 1H), 1.95-1.98 (m, 1H),
1.70-1.75 (m, 1H), 1.74 (s, 1.5H), 1.24-1.40 (s, 1.5H).
##STR00395##
Intermediate 261A: (1s,3s)-Ethyl
3-(((methylthio)carbonothioyl)oxy)cyclobutanecarboxylate
##STR00396##
[0778] To a stirred solution of (1s,3s)-ethyl
3-hydroxycyclobutanecarboxylate (1.6 g, 11.10 mmol) in DMF (20 mL)
at 0.degree. C. was added DBU (3.34 g, 13.32 mmol). The resulting
mixture stirred for 10 min. prior to the addition of carbon
disulfide (2.68 mL, 44.4 mmol), followed by MeI (3.47 ml, 55.5
mmol), at 0.degree. C. The reaction mixture stirred at RT for 2 h.
The reaction was quenched with ice cold water and extracted with
diethyl ether (2.times.25 mL). The combined organic layers were
dried over Na.sub.2SO.sub.4 and concentrated under reduced
pressure. The crude product was purified by silica gel
chromatography (24 g REDISEP.RTM. column, eluting with 10% EtOAc in
hexanes). Fractions containing the product were combined and
evaporated to afford the Intermediate 261A as colorless liquid (2.2
g, 85%). .sup.1H NMR (300 MHz, chloroform-d) .delta. ppm; 5.43-5.54
(m, 1H), 4.13-4.24 (m, 2H), 2.73-2.86 (m, 3H), 2.45-2.56 (m, 5H),
1.24-1.33 (m, 3H).
Intermediate 261B: (1s,3s)-Ethyl
3-(trifluoromethoxy)cyclobutanecarboxylate
##STR00397##
[0780] To a stirred solution of NBS (8.35 g, 46.9 mmol) in DCM (20
ml) at -40.degree. C. was added pyridine (3.00 mL, 37.6 mmol)
followed by 70% HF in pyridine (10.73 g, 376 mmol) and stirred at
the same temperature for 10 min and warmed 0.degree. C. Thereafter
a solution of Intermediate 261A (2.2 g, 9.39 mmol) in DCM (10 mL)
was added at 0.degree. C. to the above stirred solution and stirred
for 1 h at the same temperature. Reaction mixture turned reddish
brown. It was quenched with 10% NaHSO.sub.3 followed by 10% NaOH
solution and the pH was made alkaline up to 10 and extracted with
DCM (2.times.50 ml). The combined organic layer was dried over
Na.sub.2SO.sub.4 and evaporated. The crude product was purified by
silica gel chromatography (24 g REDISEP.RTM. column, eluting with
10% EtOAc in hexane). Fractions containing the product were
combined and evaporated to afford the Intermediate 261B as
colorless liquid (0.5 g 25% yield), .sup.1H NMR (400 MHz,
chloroform-d) .delta. ppm; 4.52-4.62 (m, 1H), 4.11-4.19 (m, 2H),
2.56-2.79 (m, 5H), 1.24-1.30 (m, 3H).
Intermediate 261C:
(1s,3s)-3-(Trifluoromethoxy)cyclobutanecarboxylic acid
##STR00398##
[0782] To a stirred solution of Intermediate 261B (0.5 g, 2.357
mmol) in THF (10 mL) and ethanol (10 mL) was added a solution of
NaOH (0.189 g, 4.71 mmol) in water (5 mL) and the resulting
reaction mixture was stirred at RT for 16 h. After completion of
the reaction, the volatiles were evaporated and the crude reaction
mixture was quenched with a 1.5 N aqueous solution of HCl which was
then extracted with EtOAc (2.times.25 mL). The combined organic
layers were dried over Na.sub.2SO.sub.4 and evaporated to afford
Intermediate 261C as a light brown liquid which was reacted in the
Curtius rearrangement without any purification (0.3 g, 70%).
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 12.34 (br. s., 1H),
4.75 (quin, J=7.53 Hz, 1H), 2.53-2.75 (m, 3H), 2.24-2.32 (m,
2H).
Compound 261:
2-(3-Chloro-4-fluorophenyl)-N.sup.5-((1r,3r)-3-(trifluoromethoxy)cyclobut-
yl)-6,7-dihydropyrazolo[1,5-a]pyrazine-3,5(4H)-dicarboxamide
##STR00399##
[0784] To a stirred solution of Intermediate 261C (50 mg, 0.272
mmol) in toluene (3 mL) was added TEA (0.118 mL, 0.848 mmol) and
DPPA (0.047 mL, 0.204 mmol) and stirred at 90.degree. C. for 1 h.
The reaction mixture was cooled RT and to it was added a solution
of Intermediate 185B (50 mg, 0.170 mmol) in DMF (2 ml) and stirred
at RT for 15 h. The reaction was quenched with a 10% aqueous
solution of NaHCO.sub.3 and extracted with ethyl acetate
(2.times.20 mL). The combined organic layer was dried over
Na.sub.2SO.sub.4 and concentrated under a reduced pressure. The
crude product was purified by preparative HPLC to afford Compound
261 as an off-white solid (17 mg, 25% yield). HPLC Method A and B:
9.40 and 8.70 min respectively. MS(ES): m/z=476 [M+H].sup.+;
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm: 7.85 (dd, J=7.28,
2.20 Hz, 1H), 7.65-7.71 (m, 1H), 7.47 (t, J=9.04 Hz, 1H), 7.17 (d,
J=7.78 Hz, 2H), 4.73 (s, 2H), 4.52-4.61 (m, 1H), 4.14 (t, J=5.24
Hz, 2H), 3.80-3.91 (m, 3H), 2.63-2.71 (m, 2H), 2.18-2.27 (m,
2H).
[0785] The Compounds shown in Table 20 have been prepared similar
to Compound 261 by coupling of in-situ generated isocyanate of 261C
with 185B analogs.
TABLE-US-00022 TABLE 20 Ret Ex. Time HPLC No. Structure Name [M +
H].sup.+ (min.) Methods 262 ##STR00400##
2-(3-Chlorophenyl)-N.sup.5- ((1r,3r)-3- (trifluoromethoxy)
cyclobutyl)-6,7- dihydropyrazolo[1,5-a] pyrazine-3,5(4H)-
dicarboxamide 458 9.20 8.50 A B 263 ##STR00401##
2-(3,4-Dichlorophenyl)-N.sup.5- ((1r,3r)-3- (trifluoromethoxy)
cyclobutyl)-6,7- dihydropyrazolo[1,5-a] pyrazine-3,5(4H)-
dicarboxamide 492 10.00 9.30 A B
##STR00402##
Intermediate 264A: (1r,3r)-Ethyl
3-(((methylthio)carbonothioyl)oxy)cyclobutanecarboxylate
##STR00403##
[0787] To a stirred solution of (1r,3r)-ethyl
3-hydroxycyclobutanecarboxylate (2.8 g, 19.42 mmol) in DMF (20 mL)
at 0.degree. C. was added DBU (5.85 g, 23.31 mmol) and the solution
was stirred for 10 min. prior to the addition of carbon disulfide
(4.68 mL, 78 mmol), followed by MeI (6.07 mL, 97 mmol) at 0.degree.
C. The resulting red solution was stirred at RT for 15 h. The
reaction mixture was quenched with water and extracted with diethyl
ether (2.times.100 mL). The combined organic layers were dried over
Na.sub.2SO.sub.4 and evaporated to afford Intermediate 264A as a
light brown liquid (4.0 g, 88%). .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta. ppm 5.43-5.68 (m, 1H), 4.00-4.16 (t, 2H),
3.05-3.17 (m, 1H), 2.55-2.78 (m, 3H), 1.93-2.43 (m, 2H), 0.98-1.38
(m, 3H).
Intermediate 264B: (1r,3r)-Ethyl
3-(trifluoromethoxy)cyclobutanecarboxylate
##STR00404##
[0789] To a stirred solution of 1,3-dibromo-5,5-dimethylhydantoin
(5.49 g, 19.20 mmol) in DCM (30 ml) at -78.degree. C. was added 70%
HF in pyridine (6.65 ml, 26 mmol) and stirred at the same
temperature for 10 and then added Intermediate 264A (1.5 g, 6.4
mmol) in DCM (15 mL) and stirred at 0.degree. C. for 2 h. Reaction
mixture turned reddish brown. Reaction mixture was diluted with
diethyl ether, quenched with aqueous 10% NaOH to adjust the pH 10
and extracted with diethyl ether (2.times.100 mL). The combined
organic layer was dried over Na.sub.2SO.sub.4 and evaporated to
afford Intermediate 264B as a light brown colored liquid was taken
for the next step without any purification. (0.5 g, 37% yield).
Intermediate 264C:
(1r,3r)-3-(Trifluoromethoxy)cyclobutanecarboxylic acid
##STR00405##
[0791] To a stirred solution of Intermediate 264B (0.5 g, 2.36
mmol) in THF (10 mL) was added a solution of NaOH (0.189 g, 4.71
mmol) in water (2 mL) which was stirred at RT for 16 h. The
reaction mixture was concentrated and the residue was dissolved in
water and extracted with EtOAc. The pH of the aqueous layer was
adjusted to 3 with an aqueous solution of HCl and then extracted
with EtOAc (2.times.25 mL). The combined organic layers were dried
over Na.sub.2SO.sub.4 and evaporated to afford Intermediate 264C
(0.25 g, 58% yield) as a pale yellow liquid. The crude compound was
used directly in the Curtius rearrangement without purification.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 12.42 (br. s., 1H),
4.91 (quin, J=7.53 Hz, 1H), 3.05 (m, 1H), 2.47-2.56 (m, 4H).
Compound 264:
2-(3-Chloro-4-fluorophenyl)-N.sup.5-((1r,3r)-3-(trifluoromethoxy)cyclobut-
yl)-6,7-dihydropyrazolo[1,5-a]pyrazine-3,5(4H)-dicarboxamide
##STR00406##
[0793] To a stirred solution of Intermediate 264C (30 mg, 0.1 mmol)
in toluene (2 ml) was added TEA (0.071 ml, 0.51 mmol), DPPA (0.028
ml, 0.12 mmol) and heated at 90.degree. C. for 1 h. The reaction
mixture was cooled RT and to it was added a solution of
Intermediate 185B (30 mg, 0.1 mmol) in DMF (1 ml) and stirred at RT
for 15 h. The reaction mixture was quenched with 10% aqueous
solution of NaHCO.sub.3 and extracted with ethyl acetate
(2.times.20 mL). The combined organic layer was dried over
Na.sub.2SO.sub.4 and evaporated under reduced pressure. The crude
product was purified by preparative HPLC to afford Compound 264 as
an off-white solid (17 mg, 33% yield). HPLC retention times 9.4
min. and 8.8 min. (Methods A and B respectively). MS(ES): m/z=476
[M+H].sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm
7.87-7.81 (m, 1H), 7.71-7.64 (m, 1H), 7.48 (d, J=9.5 Hz, 1H), 7.36
(br. s., 1H), 7.22-7.08 (m, 2H), 5.03-4.94 (m, 1H), 4.73 (s, 2H),
4.28-4.17 (m, 1H), 4.13 (d, J=5.5 Hz, 2H), 3.83 (t, J=5.5 Hz, 2H),
2.48-2.35 (m, 4H).
[0794] The Compounds shown in Table 21 have been prepared similar
to Compound 264 by coupling of in-situ generated isocyanate of 264C
with 199B.
TABLE-US-00023 TABLE 21 Ret Ex. Time HPLC No. Structure Name [M +
H].sup.+ (min.) Methods 265 ##STR00407##
2-(3,4-Dichlorophenyl)-N.sup.5- ((1r,3r)-3- (trifluoromethoxy)
cyclobutyl)-6,7- dihydropyrazolo[1,5-a] pyrazine-3,5(4H)-
dicarboxamide 492 9.82 9.25 A B
##STR00408##
Intermediate 266A: (1r,3s)-Ethyl
3-(4-cyanophenoxy)cyclobutanecarboxylate
##STR00409##
[0796] To a solution of (1s,3s)-ethyl
3-hydroxycyclobutanecarboxylate (0.9 g, 6.24 mmol),
4-hydroxybenzonitrile (1.487 g, 12.49 mmol) and triphenylphosphine
(3.27 g, 12.49 mmol) in anhydrous THF (10 mL) was added a solution
of DEAD (2.451 mL, 12.49 mmol) in THF at RT. The reaction mixture
was then allowed to stir at 70.degree. C. for 3 h after which time
the volatiles were removed. The crude product was purified by
silica gel chromatography (12 g REDISEP.RTM. column, eluting with
10% EtOAc in hexanes). Fractions containing the product were
combined and evaporated to afford Intermediate 266A as a colorless
gummy solid (0.1 g, 14%). .sup.1H NMR (300 MHz, DMSO-d.sub.6)
.delta. ppm 7.87-7.59 (d, 2H), 7.14-6.84 (d, 2H), 5.04-4.78 (m,
1H), 4.12 (q, J=7.1 Hz, 2H), 3.27-3.05 (m, 1H), 2.69 (m, 2H),
2.45-2.25 (m, 2H), 1.21 (t, J=7.0 Hz, 3H).
Intermediate 266B: (1r,3r)-3-(4-Cyanophenoxy)cyclobutanecarboxylic
acid
##STR00410##
[0798] To a solution of Intermediate 266A (300 mg, 1.223 mmol) in
THF (2 mL) and water (1 mL) was added NaOH (147 mg, 3.67 mmol) at
RT. The reaction mixture was allowed to stir at RT for 12 h. The
reaction mixture was concentrated and the residue was acidified to
pH=2 with a 1.5N aqueous solution of HCl and extracted with EtOAc
(3.times.15 mL). The combined organic layers were dried over
Na.sub.2SO.sub.4, filtered and concentrated. The resulting solid
was triturated with Et.sub.2O (2.times.10 mL) to afford
Intermediate 266B as an off-white solid (0.15 g, 57%). .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. ppm 12.50-11.92 (br. s., 1H),
7.86-7.59 (d, 2H), 7.12-6.84 (d, 2H), 5.01-4.74 (m, 1H), 3.17-2.97
(m, 1H), 2.78-2.58 (m, 2H), 2.42-2.22 (m, 2H).
Compound 266:
2-(3-Chloro-4-fluorophenyl)-N.sup.5-((1r,3r)-3-(4-cyanophenoxy)cyclobutyl-
)-6,7-dihydropyrazolo[1,5-a]pyrazine-3,5(4H)-dicarboxamide
##STR00411##
[0800] To a stirred solution of Intermediate 266B (44.2 mg, 0.204
mmol) in toluene (1 mL) was added TEA (0.095 mL, 0.679 mmol), DPPA
(0.058 mL, 0.271 mmol) and the reaction mixture was heated to
90.degree. C. for 1 h. The reaction mixture was cooled to RT and to
it was added a solution of Intermediate 185B (40 mg, 0.136 mmol) in
THF (1 mL) and stirred for 12 h. The reaction mixture was diluted
with EtOAc (10 mL), washed with water and 10% aqueous solution of
NaHCO.sub.3, brine, dried over Na.sub.2SO.sub.4, filtered and the
filtrate concentrated. The crude product was further purified by
preparative HPLC to afford Compound 266 as an off-white solid (9
mg, 13%). HPLC retention times 1.555 and 1.547 min (Methods E and L
respectively). MS(ES): m/z=472 [M+1].sup.+; .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 7.85 (dd, J=2.0, 7.5 Hz, 1H), 7.78 (s,
2H), 7.71-7.64 (m, 1H), 7.47 (t, J=9.0 Hz, 1H), 7.36 (br. s., 1H),
7.19 (d, J=6.5 Hz, 2H), 7.00 (d, J=8.5 Hz, 2H), 4.93 (br. s., 1H),
4.74 (s, 2H), 4.29 (d, J=6.5 Hz, 1H), 4.19-4.11 (m, 2H), 3.85 (br.
s., 2H), 2.48-2.44 (m, 2H), 2.42-2.29 (m, 2H).
[0801] The Compounds shown in Table 22 have been prepared similar
to Compound 266 by coupling of in-situ generated isocyanate of 266B
with 185B analogs.
TABLE-US-00024 TABLE 22 Ret Ex. Time HPLC No. Structure Name [M +
H].sup.+ (min.) Methods 267 ##STR00412## 2-(3-Chlorophenyl)-
N.sup.5-((1r,3r)-3-(4- cyanophenoxy) cyclobutyl)-6,7-
dihydropyrazolo[1,5-a] pyrazine-3,5(4H)- dicarboxamide 491.2 1.511
1.504 E L 268 ##STR00413## N.sup.5-((1r,3r)-3-(4- Cyanophenoxy)
cyclobutyl)-2-(3,4- dichlorophenyl)-6,7- dihydropyrazolo[1,5-a]
pyrazine-3,5(4H)- dicarboxamide 525.2 1.660 1.654 E L
##STR00414##
Intermediate 269A: (1r,3r)-Benzyl 3-bromocyclobutanecarboxylate
##STR00415##
[0803] To a stirred solution of (1s,3s)-benzyl
3-hydroxycyclobutanecarboxylate (2.0 g, 9.7 mmol) in DCM (80 mL)
was added PPh.sub.3 (11.45 g, 43.6 mmol) followed by the addition
of CBr.sub.4 (12.86 g, 38.8 mmol) portionwise at 0.degree. C. The
reaction mixture was allowed to warm to RT and stir for 12 h. The
reaction mixture was quenched with water (10 mL) and extracted with
DCM (3.times.10 mL). The combined organic layers were dried over
Na.sub.2SO.sub.4, filtered and the filtrate concentrated. The crude
product was purified by silica gel chromatography (40 g
REDISEP.RTM. column, eluting with 5% EtOAc in hexanes). Fractions
containing the product were combined and evaporated to afford
Intermediate 269A as a colorless liquid (1.9 g, 73% yield). .sup.1H
NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 7.36 (s, 5H), 5.11 (s, 2H),
4.78-4.65 (m, 1H), 3.55-3.42 (m, 1H), 2.94-2.80 (m, 2H), 2.73-2.59
(m, 2H).
Intermediate 269B: (1s,3s)-Benzyl
3-(methylthio)cyclobutanecarboxylate
##STR00416##
[0805] To a solution of Intermediate 269A (400 mg, 1.486 mmol) in
DMF (4 mL) was added NaSMe (208 mg, 2.97 mmol) and the reaction
mixture was stirred at RT for 12 h. The reaction mixture was poured
into water (50 mL) and extracted with Et.sub.2O (3.times.30 mL).
The combined organic layer was washed with water, brine, dried over
Na.sub.2SO.sub.4, filtered and concentrated to afford Intermediate
269B as a colorless liquid (0.35 g, 100%). .sup.1H NMR (300 MHz,
chloroform-d) .delta. ppm 7.43-7.30 (m, 5H), 5.14 (s, 2H),
3.43-3.27 (m, 1H), 3.15-2.97 (m, 1H), 2.66-2.49 (m, 2H), 2.46-2.29
(m, 2H), 2.09 (s, 3H).
Intermediate 269C: (1s,3s)-3-(Methylthio)cyclobutanecarboxylic
acid
##STR00417##
[0807] To a solution of Intermediate 269B (200 mg, 0.846 mmol) in
THF (2 mL) and water (1 mL) was added NaOH (102 mg, 2.538 mmol) and
the reaction mixture was stirred at RT for 12 h. The reaction
mixture was concentrated, acidified to pH 2 with an aqueous
solution of 1.5 N HCl and extracted with EtOAc (3.times.15 mL). The
combined organic layer was dried over Na.sub.2SO.sub.4, filtered
and concentrated to afford Intermediate 269C as a colorless gum
(0.12 g, 97%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm
12.10 (br. s., 1H), 3.06-2.77 (m, 1H), 2.46-2.36 (m, 3H), 2.19-2.09
(m, 2H), 2.06-1.94 (s, 3H).
Compound 269:
2-(3-Chloro-4-fluorophenyl)-N.sup.5-((1s,3s)-3-(methylthio)cyclobutyl)-6,-
7-dihydropyrazolo[1,5-a]pyrazine-3,5(4H)-dicarboxamide
##STR00418##
[0809] To a solution of Intermediate 269C (74.4 mg, 0.509 mmol) in
toluene (2 mL) was added TEA (0.236 mL, 1.697 mmol), DPPA (0.146
mL, 0.679 mmol) and the clear solution was heated at 85.degree. C.
and stirred for 1 h. The reaction mixture was cooled to RT and to
it was added a solution of Intermediate 185B (100 mg, 0.339 mmol)
in THF (1 mL) and stirred at RT for 12 h. The reaction mixture was
diluted with EtOAc (10 mL) and washed successively with water, 10%
aqueous solution of NaHCO.sub.3, brine, then dried over
Na.sub.2SO.sub.4, filtered and concentrated. The crude product was
purified by preparative HPLC to afford Compound 269 as an off-white
solid (0.015 g, 10%). HPLC retention times 1.303 min. and 1.307
min. (Methods E and L respectively). MS(ES): m/z=438.2 [M+H].sup.+;
.sup.1H NMR: (400 MHz, DMSO-d.sub.6) .delta. ppm 7.85 (dd, J=7.53,
2.01 Hz, 1H), 7.63-7.73 (m, 1H), 7.47 (t, J=9.04 Hz, 1H), 7.35 (br.
s., 1H), 7.17 (d, J=10.04 Hz, 1H), 7.12 (d, J=8.03 Hz, 1H), 4.72
(s, 2H), 4.09-4.16 (m, 2H), 3.96-4.07 (m, 1H), 3.79-3.88 (m, 2H),
3.03 (tt, J=9.66, 7.40 Hz, 1H), 2.53-2.62 (m, 2H), 2.01-2.05 (s,
3H), 1.89-2.00 (m, 2H).
[0810] The Compounds shown in Table 23 have been prepared similar
to Compound 269 by coupling of in-situ generated isocyanate of 269C
with 185B analogs.
TABLE-US-00025 TABLE 23 Ret Ex. Time HPLC No. Structure Name [M +
H].sup.+ (min.) Methods 270 ##STR00419##
2-(3-Chlorophenyl)-N.sup.5- ((1s,3s)-3-(methylthio)
cyclobutyl)-6,7- dihydropyrazolo[1,5-a] pyrazine-3,5(4H)-
dicarboxamide 420.2 1.246 1.252 E L 271 ##STR00420##
2-(3,4-Dichlorophenyl)- N.sup.5-((1s,3s)-3-(methylthio)
cyclobutyl)-6,7- dihydropyrazolo[1,5-a] pyrazine-3,5(4H)-
dicarboxamide 454.2 1.425 1.432 E L
##STR00421##
Intermediate 272A: (1s,3s)-Benzyl
3-(methylsulfonyl)cyclobutanecarboxylate
##STR00422##
[0812] To a stirred solution of (1s,3s)-benzyl
3-(methylthio)cyclobutanecarboxylate (0.4 g, 1.693 mmol) in DCM (10
mL) was added mCPBA (2.337 g, 6.77 mmol) and the reaction mixture
was stirred at RT for 12 h. The reaction mixture was diluted with
DCM (40 mL) and washed successively with a saturated aqueous
solution of NaHSO.sub.3, 10% aq. solution of NaHCO.sub.3, and
brine, then dried over Na.sub.2SO.sub.4, filtered and concentrated
to afford Intermediate 272A as colorless semi-solid (0.35 g, 77).
.sup.1H NMR (400 MHz, chloroform-d) .delta. ppm 7.41-7.30 (m, 5H),
5.15 (s, 2H), 3.70 (m, 1H), 3.18 (m, 1H), 2.83 (m, 2H), 2.80 (s,
3H), 2.65-2.51 (m, 2H).
Intermediate 272B: (1s,3s)-3-(Methylsulfonyl)cyclobutanecarboxylic
acid
##STR00423##
[0814] To a stirred solution of Intermediate 272A (400 mg, 1.491
mmol) in THF (4 mL) and water (2 mL) was added NaOH (179 mg, 4.47
mmol) and the reaction mixture was stirred at RT for 12 h. The
reaction mixture was concentrated under reduced pressure and the pH
of the aqueous solution was adjusted to 2 with a 1.5N aq. solution
of HCl which was extracted with EtOAc (3.times.15 mL). The combined
organic layers were dried over Na.sub.2SO.sub.4, filtered and
concentrated. The crude product was purified by silica gel
chromatography (12 g REDISEP.RTM. column, eluting with 10% EtOAc in
hexanes). Fractions containing the product were combined and
evaporated to afford Intermediate 272B as an off-white solid (150
mg, 57%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm
12.60-12.22 (br. s., 1H), 3.90 (m, 1H), 3.09 (m, 1H), 2.85 (s, 3H),
2.46-2.33 (m, 4H).
Compound 272:
2-(3-Chloro-4-fluorophenyl)-N.sup.5-((1s,3s)-3-(methylsulfonyl)cyclobutyl-
)-6,7-dihydropyrazolo[1,5-a]pyrazine-3,5(4H)-dicarboxamide
##STR00424##
[0816] To a solution of Intermediate 272B (24.19 mg, 0.136 mmol) in
toluene (1 mL) was added TEA (0.095 mL, 0.679 mmol), DPPA (0.058
mL, 0.271 mmol) and the solution and stirred at 85.degree. C. for 1
h. The reaction mixture was cooled to RT and to it was added a
solution of Intermediate 185B (40 mg, 0.136 mmol) in THF (0.5 mL)
and stirred at RT for 12 h. The reaction mixture was diluted with
EtOAc (10 mL), washed with water, brine, dried over
Na.sub.2SO.sub.4, filtered and concentrated. The crude product
obtained was purified by preparative HPLC to afford Compound 272 as
an off-white solid (0.015 g, 23% yield). HPLC retention time 0.999
min. and 0.999 min. (Methods E and L respectively). MS(ES):
m/z=470.2 [M+H].sup.+; .sup.1H NMR: (400 MHz, DMSO-d.sub.6) .delta.
ppm 7.84 (dd, J=7.0, 2.0 Hz, 1H), 7.68 (ddd, J=8.5, 4.8, 2.3 Hz,
1H), 7.47 (d, J=9.5 Hz, 1H), 7.36 (br. s., 1H), 7.29 (d, J=7.5 Hz,
1H), 7.24-7.13 (m, 1H), 4.73 (s, 2H), 4.22-4.08 (m, 3H), 3.83 (t,
J=5.3 Hz, 2H), 3.72-3.60 (m, 1H), 2.86 (s, 3H), 2.48-2.40 (m, 2H),
2.32-2.20 (m, 2H).
[0817] The Compounds shown in Table 24 have been prepared similar
to Compound 272 by coupling of in-situ generated isocyanate of 272B
with 185B analogs.
TABLE-US-00026 TABLE 24 Ret Ex. Time HPLC No. Structure Name [M +
H].sup.+ (min.) Methods 273 ##STR00425##
2-(3-Chlorophenyl)-N.sup.5- ((1s,3s)-3- (methylsulfonyl)
cyclobutyl)-6,7- dihydropyrazolo[1,5-a] pyrazine-3,5(4H)-
dicarboxamide 452.2 0.941 0.938 E L 274 ##STR00426##
2-(3,4-Dichlorophenyl)- N.sup.5-((1s,3s)-3- (methylsulfonyl)
cyclobutyl)-6,7- dihydropyrazolo[1,5-a] pyrazine-3,5(4H)-
dicarboxamide 486.2 1.128 1.129 E L
##STR00427##
Intermediate 275A: (1r,3r)-Benzyl
3-fluoro-1-methylcyclobutanecarboxylate
##STR00428##
[0819] To a solution of benzyl 3-fluorocyclobutanecarboxylate (0.5
g, 2.4 mmol) and MeI (0.6 mL, 9.60 mmol) in THF (12 mL) at
-78.degree. C. under nitrogen was added a solution of KHMDS (19.21
mL, 0.5 M in toluene, 9.6 mmol) and allowed to stir at -78.degree.
C. for 6 h. The reaction was then warmed to RT and stirred further
for 16 h. The reaction mass was quenched with a saturated aq.
NH.sub.4Cl solution and extracted with diethyl ether (2.times.25
mL). The organic layer was washed with water, dried over
Na.sub.2SO.sub.4, filtered and the filtrate concentrated under
vacuum. The crude product was purified by silica gel chromatography
(4 g REDISEP.RTM. column, eluting with 25% EtOAc in hexane).
Fractions containing the product were combined and evaporated to
afford Intermediate 275A as colorless liquid (0.1 g, 19% yield).
.sup.1H NMR (400 MHz, chloroform-d) .delta. ppm 7.42-7.30 (m, 5H),
5.14 (s, 3H), 2.93-2.75 (m, 2H), 2.24-2.08 (m, 2H), 1.48 (s,
3H).
Intermediate 275B: (1r,3r)-3-Fluoro-1-methylcyclobutanecarboxylic
acid
##STR00429##
[0821] To a solution of Intermediate 275A (0.100 g, 0.450 mmol) in
ethanol (5 mL) and water (1 mL) was added a 5N aq. solution of NaOH
(0.45 mL, 2.250 mmol) and the reaction mixture was stirred at RT
for 4 h. The reaction mixture was concentrated under vacuum; the
residue was dissolved in water and extracted with diethyl ether
(2.times.10 mL). The organic layer was discarded; the pH of the aq.
layer was adjusted to 5 using a 2N aq. solution of HCl and was
extracted with DCM (2.times.10 mL). The combined organic layer was
dried over Na.sub.2SO.sub.4, filtered and the filtrate concentrated
to afford Intermediate 275B as pale yellow liquid (40 mg, 67%
yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 12.52 (br.
s., 1H), 5.17-4.94 (m, 1H), 2.73 (dt, J=10.3, 3.4 Hz, 2H), 2.06 (d,
J=6.0 Hz, 2H), 1.35 (s, 3H).
Compound 275:
2-(3-Chloro-4-fluorophenyl)-N.sup.5-((1r,3r)-3-fluoro-1-methylcyclobutyl)-
-6,7-dihydropyrazolo[1,5-a]pyrazine-3,5(4H)-dicarboxamide
##STR00430##
[0823] A stirred solution of Intermediate 275B (39.5 mg, 0.299
mmol) in toluene (5 mL) at RT under nitrogen was added TEA (0.189
mL, 1.357 mmol), DPPA (0.125 mL, 0.543 mmol) and heated at
85.degree. C. for 1 h. The reaction mass was cooled to RT and to it
was added a solution of Intermediate 185B (80 mg, 0.271 mmol) in
DMF and stirred at RT for 8 h. The reaction mass was concentrated
and the residue was partitioned between EtOAc and water. The
organic layer was separated, dried over sodium sulfate, filtered
and concentrated. The crude product was purified by silica gel
chromatography (4 g REDISEP.RTM. column, eluting with 10% MeOH in
CHCl.sub.3). Fractions containing the product were combined and
evaporated to afford Compound 275 as off-white solid (29.66 mg, 25%
yield). HPLC retention time 7.96 and 8.35 min (Methods B and C
respectively). MS(ES): m/z=425 [M+H].sup.+; .sup.1H NMR: (300 MHz,
DMSO-d.sub.6) .delta. ppm 7.84 (dd, J=7.37, 2.08 Hz, 1H), 7.63-7.73
(m, 1H), 7.46 (t, J=9.07 Hz, 1H), 7.16-7.39 (m, 2H), 6.83 (s, 1H),
4.94-5.26 (m, 1H).
##STR00431##
Intermediate 276A: Ethyl
3-(4-fluorophenyl)-3-hydroxycyclobutanecarboxylate
##STR00432##
[0825] To a stirred solution of ethyl 3-oxocyclobutanecarboxylate
(2 g, 14.07 mmol) in dry Et.sub.2O (30 mL), cooled to -80.degree.
C., was added 4-fluorophenyl magnesium bromide (16.88 mL, 16.88
mmol, 1 M in THF) dropwise. The reaction mixture was then allowed
to warm to RT and stir for an additional 2 h. The reaction mixture
was quenched with a saturated aq. solution of NH.sub.4Cl (50 mL)
and extracted with EtOAc (3.times.30 mL). The combined organic
layer was washed with brine, dried over Na.sub.2SO.sub.4, filtered
and concentrated. The crude reaction mixture was purified by silica
gel chromatography (24 g REDISEP.RTM. column, eluting with 15%
EtOAc in hexanes). Fractions containing the product were combined
and evaporated to afford Intermediate 276A as a colorless liquid
(1.7 g, 51%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 7.54
(dd, J=5.5, 9.0 Hz, 2H), 7.15 (t, J=8.8 Hz, 2H), 4.09 (q, J=7.4 Hz,
2H), 2.83-2.71 (m, 1H), 2.61 (s, 2H), 2.55-2.51 (m, 2H), 1.24-1.12
(t, 3H).
Intermediate 276B: ((1s,3s)-Ethyl
3-(4-fluorophenyl)cyclobutanecarboxylate
##STR00433##
[0827] To a solution of Intermediate 276A (1.7 g, 7.14 mmol) in
ethanol (50 mL) was added perchloric acid (0.429 mL, 7.14 mmol).
The reaction mixture was purged with an atmosphere of N.sub.2 prior
to the addition of Pd/C (600 mg). The reaction vessel is placed
under an atmosphere of H.sub.2 (balloon pressure) and the reaction
mixture is allowed to stir at RT for 12 h. The reaction mixture was
filtered and the filtrate was concentrated under reduced pressure.
The residue was partitioned between water and Et.sub.2O. The
organic layer was separated and the aqueous phase was extracted
with Et.sub.2O (3.times.30 mL). The combined organic layers were
washed with brine, dried over Na.sub.2SO.sub.4, filtered and
concentrated to afford Intermediate 276B as a colorless liquid (1.4
g, 88% yield). .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. ppm 7.24
(d, J=5.7 Hz, 2H), 7.19-7.05 (m, 2H), 4.07 (d, J=7.2 Hz, 2H),
3.51-3.36 (m, 1H), 3.20-3.03 (m, 1H), 2.53 (s, 2H), 2.27-2.08 (m,
2H), 1.19 (t, J=7.2 Hz, 3H).
Intermediate 276C: (1s,3s)-3-(4-Fluorophenyl)cyclobutanecarboxylic
acid
##STR00434##
[0829] To a solution of Intermediate 276B (100 mg, 0.450 mmol) in
THF (2 mL) and water (1 mL) was added NaOH (54.0 mg, 1.350 mmol)
and the reaction mixture was stirred at RT for 12 h. The reaction
mixture was concentrated and the residue was acidified to pH=2 with
a 1.5N aq. solution of HCl and the aq. solution was extracted with
EtOAc (3.times.15 mL). The combined organic layers were dried over
Na.sub.2SO.sub.4, filtered and concentrated to afford Intermediate
276C as a colorless gummy solid (70 mg, 80%). .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta. ppm 12.99 (br. s., 1H), 7.26 (dd, J=5.5, 8.5
Hz, 2H), 7.17-7.03 (m, 2H), 3.50-3.30 (m, 1H), 3.01 (s, 1H),
2.50-2.43 (m, 2H), 2.24-2.09 (m, 2H).
Compound 276:
2-(3-Chloro-4-fluorophenyl)-N.sup.5-((1s,3s)-3-(4-fluorophenyl)cyclobutyl-
)-6,7-dihydropyrazolo[1,5-a]pyrazine-3,5(4H)-dicarboxamide
##STR00435##
[0831] To a solution of Intermediate 276C (26.4 mg, 0.136 mmol) in
toluene (1 mL) was added TEA (0.095 mL, 0.679 mmol), DPPA (0.058
mL, 0.271 mmol) and the reaction mixture was stirred at 85.degree.
C. for 1 h. The reaction mixture was cooled to RT and to it was
added a solution of Intermediate 185B (40 mg, 0.136 mmol) in THF
(0.500 mL) and stirred at RT for 12 h. The reaction mixture was
diluted with EtOAc (10 mL) and washed with water, 10% NaHCO.sub.3,
brine, dried over Na.sub.2SO.sub.4, filtered and the filtrate
concentrated. The crude product was purified by preparative HPLC to
afford Compound 276 as an off-white solid (0.018 g, 27%). HPLC
retention times 1.649 min. and 1.651 min. (Methods E and L
respectively). MS(ES): m/z=486.2 [M+H].sup.+; .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 7.89-7.81 (m, 1H), 7.72-7.62 (m, 1H),
7.51-7.43 (m, 1H), 7.42-7.23 (m, 3H), 7.19 (br. s., 1H), 7.16-7.05
(m, 3H), 4.73 (s, 2H), 4.19-4.09 (m, 3H), 3.84 (t, J=5.3 Hz, 2H),
3.19-3.01 (m, 1H), 2.63-2.54 (m, 2H), 2.11-1.99 (m, 2H).
[0832] The Compounds shown in Table 25 have been prepared similar
to Compound 276 by coupling of in-situ generated isocyanate of 276C
with 185B analogs.
TABLE-US-00027 TABLE 25 Ret Ex. Time HPLC No. Structure Name [M +
H].sup.+ (min.) Methods 277 ##STR00436##
2-(3-Chlorophenyl)-N.sup.5- ((1s,3s)-3-(4- fluorophenyl)
cyclobutyl)-6,7- dihydropyrazolo[1,5-a] pyrazine-3,5(4H)-
dicarboxamide 468.3 1.606 1.608 E L 278 ##STR00437##
2-(3,4-Dichlorophenyl)- N.sup.5-((1s,3s)-3-(4- fluorophenyl)
cyclobutyl)-6,7- dihydropyrazolo[1,5-a] pyrazine-3,5(4H)-
dicarboxamide 502.2 1.758 1.761 E L
##STR00438## ##STR00439##
Intermediate 279A: Ethyl
3-hydroxy-3-(4-methoxyphenyl)cyclobutanecarboxylate
##STR00440##
[0834] To a solution of ethyl 3-oxocyclobutanecarboxylate (3.0 g,
21.1 mmol) in anhydrous Et.sub.2O (60 mL), cooled to -80.degree.
C., was added dropwise a solution of (4-methoxyphenyl)magnesium
bromide (50.6 mL, 25.3 mmol, 2M in THF). The reaction mixture was
allowed to warm to RT and stir for 2 h. The reaction mixture was
quenched with a saturated aq. solution of NH.sub.4Cl (20 mL) and
then extracted with EtOAc (3.times.30 mL). The combined organic
layers were washed with brine, dried over Na.sub.2SO.sub.4,
filtered and concentrated. The crude product was purified by silica
gel chromatography (40 g REDISEP.RTM. column, eluting with 15%
EtOAc in hexanes). Fractions containing the product were combined
and evaporated to afford Intermediate 279A as a colorless liquid (3
g, 57%). .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. ppm 7.42 (d,
J=8.7 Hz, 2H), 6.89 (d, J=8.7 Hz, 2H), 5.58 (s, 1H), 4.08 (d, J=7.2
Hz, 2H), 3.75 (s, 3H), 2.76-2.67 (m, 1H), 2.60 (s, 2H), 2.47 (s,
2H), 1.22-1.16 (m, 3H).
Intermediate 279B: (1s,3s)-Ethyl
3-(4-methoxyphenyl)cyclobutanecarboxylate
##STR00441##
[0836] To a solution of Intermediate 279A (3.0 g, 12 mmol) in
ethanol (100 mL) was added perchloric acid (0.721 mL, 11.99 mmol).
The reaction mixture was purged with an atmosphere of N.sub.2 prior
to the addition of palladium on carbon (1.020 g, 0.959 mmol). The
reaction vessels is placed under an atmosphere of H.sub.2 (balloon
pressure) and the reaction mixture is allowed to stir at RT for 12
h. The reaction mixture was filtered through a bed of CELITE.RTM.
and the filtrate was concentrated under reduced pressure. The crude
reaction mixture was purified by silica gel chromatography (24 g
REDISEP.RTM. column, eluting with 5% EtOAc in hexanes). Fractions
containing the product were combined and evaporated to afford
Intermediate 279B as a colorless gum (1.6 g, 57%). .sup.1H NMR (300
MHz, DMSO-d.sub.6) .delta. ppm 7.14 (d, J=8.3 Hz, 2H), 6.92-6.81
(d, 2H), 4.14-4.01 (m, 2H), 3.72 (s, 3H), 3.45-3.34 (m, 1H), 3.09
(s, 1H), 2.48-2.39 (m, 2H), 2.24-2.05 (m, 2H), 1.23-1.14 (t,
3H).
Intermediate 279C: (1s,3s)-3-(4-Methoxyphenyl)cyclobutanecarboxylic
acid
##STR00442##
[0838] To a solution of Intermediate 279B (200 mg, 0.854 mmol) in
THF (2 mL) and water (1 mL) was added NaOH (102 mg, 2.56 mmol) at
RT and the reaction mixture was stirred at RT for 12 h. The
reaction mixture was concentrated and the residue was acidified to
a pH of 2 with a 1.5N aq. solution of HC and extracted with EtOAc
(3.times.15 mL). The combined organic layer was dried over
Na.sub.2SO.sub.4, filtered and the filtrate concentrated to afford
Intermediate 279C as a colorless gum (0.15 g, 85%). .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. ppm 12.39-11.78 (br. s., 1H),
7.27-7.05 (d, 2H), 6.95-6.70 (d, 2H), 3.72 (s, 3H), 3.31-3.22 (m,
1H), 3.15-2.98 (m, 1H), 2.47 (m, 2H), 2.27-2.01 (m, 2H).
Compound 279:
2-(3-Chloro-4-fluorophenyl)-N.sup.5-((1s,3s)-3-(4-methoxyphenyl)cyclobuty-
l)-6,7-dihydropyrazolo[1,5-a]pyrazine-3,5(4H)-dicarboxamide
##STR00443##
[0840] To a solution of Intermediate 279C (52.5 mg, 0.254 mmol) in
toluene (1 mL) was added TEA (0.118 mL, 0.848 mmol), DPPA (0.073
mL, 0.339 mmol) and the reaction mixture was heated to 90.degree.
C. for 1 h. The reaction mixture was cooled to RT and to it was
added a solution of Intermediate 185B (40 mg, 0.136 mmol) in THF (1
mL) and stirred for 12 h. The reaction mixture was diluted with
EtOAc (10 mL), washed with a 10% aqueous solution of NaHCO.sub.3,
brine, dried over Na.sub.2SO.sub.4, filtered and the filtrate
concentrated. The crude product was purified by preparative HPLC to
afford Compound 279 as an off-white solid (15 mg, 17%). HPLC
retention times 1.655 min. and 1.663 min. (Methods E and L
respectively). MS(ES): m/z=498.3 [M+1].sup.+; .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 7.85 (dd, J=2.3, 7.3 Hz, 1H), 7.68 (ddd,
J=2.3, 4.8, 8.5 Hz, 1H), 7.51-7.41 (m, 1H), 7.36 (br. s., 1H),
7.30-7.14 (m, 3H), 7.09 (d, J=7.5 Hz, 1H), 6.91-6.83 (m, 2H), 4.74
(s, 2H), 4.19-4.06 (m, 3H), 3.84 (t, J=5.3 Hz, 2H), 3.75-3.67 (m,
3H), 3.07-2.95 (m, 1H), 2.61-2.53 (m, 2H), 2.08-1.95 (m, 2H).
[0841] The Compounds shown in Table 26 have been prepared similar
to Compound 279 by coupling of in-situ generated isocyanate of 279C
with 185B analogs.
TABLE-US-00028 TABLE 26 Ret Ex. Time HPLC No. Structure Name [M +
H].sup.+ (min.) Methods 280 ##STR00444## 2-(3,4-dichlorophenyl)-
N.sup.5-((1s,3s)-3-(4- methoxyphenyl) cyclobutyl)-6,7-
dihydropyrazolo[1,5-a] pyrazine-3,5(4H)- dicarboxamide 514.2 1.751
L 281 ##STR00445## 2-(3-Chlorophenyl)-N.sup.5- ((1s,3s)-3-(4-
methoxyphenyl) cyclobutyl)-6,7- dihydropyrazolo[1,5-a]
pyrazine-3,5(4H)- dicarboxamide 480.3 1.611 1.620 E L
##STR00446## ##STR00447##
Intermediate 282A: (1s,3s)-Ethyl
3-(4-hydroxyphenyl)cyclobutanecarboxylate
##STR00448##
[0843] To a solution of (1s,3s)-ethyl
3-(4-methoxyphenyl)cyclobutanecarboxylate (1.6 g, 6.83 mmol) in DCM
(40 mL) was added BBr3 (20.49 mL, 20.49 mmol) dropwise at 0.degree.
C. and the reaction mass was allowed to warm to RT and stir for 1
h. The reaction mixture was then diluted with DCM (30 mL), washed
with water (20 mL) and a 10% aqueous solution of NaHCO.sub.3 (20
mL), dried over Na.sub.2SO.sub.4, filtered and concentrated to
afford Intermediate 282A as colorless gum (0.9 g, 60%). .sup.1H NMR
(300 MHz, DMSO-d.sub.6) .delta. ppm 9.20 (s, 1H), 7.02 (d, J=8.3
Hz, 2H), 6.69 (d, J=8.3 Hz, 2H), 4.07 (d, J=7.2 Hz, 2H), 3.31-3.22
(m, 1H), 3.15-2.98 (m, 1H), 2.48-2.39 (m, 2H), 2.21-2.03 (m, 2H),
1.19 (t, J=7.0 Hz, 3H).
Intermediate 282B: (1s,3s)-Ethyl
3-(4-(((trifluoromethyl)sulfonyl)oxy)phenyl)cyclobutanecarboxylate
##STR00449##
[0845] To a solution of Intermediate 282A (0.2 g, 0.908 mmol) in
DCM (5 mL) was added pyridine (0.147 mL, 1.816 mmol) and followed
by dropwise introduction of trifluoromethanesulfonic anhydride
(0.229 mL, 1.362 mmol) at 0.degree. C. The reaction mixture was
allowed to warm to RT and stir for 1 h, after which it was diluted
with DCM (30 mL) and washed sequentially with a 10% aqueous
solution of NaHCO.sub.3 (15 mL), a 1.5N aq. solution of HCl (10
mL), and brine, then was dried over Na.sub.2SO.sub.4, filtered and
concentrated to afford Intermediate 282B as a brown liquid (0.3 g,
94%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 7.43 (d,
J=2.0 Hz, 4H), 4.08 (d, J=7.0 Hz, 2H), 3.59-3.46 (m, 1H), 3.22-3.10
(m, 1H), 2.63-2.54 (m, 2H), 2.30-2.16 (m, 2H), 1.20 (t, J=7.3 Hz,
3H).
Intermediate 282C: (1s,3s)-Ethyl
3-(4-cyanophenyl)cyclobutanecarboxylate
##STR00450##
[0847] To a solution of Intermediate 282B (0.3 g, 0.851 mmol) in
DMF (3 mL) was added zinc (0.017 g, 0.255 mmol) and zinc cyanide
(0.250 g, 2.129 mmol) at RT. The reaction mixture was degassed with
N.sub.2 for 15 min. prior to the addition of DPPF (0.047 g, 0.085
mmol) and Pd.sub.2(dba).sub.3 (0.039 g, 0.043 mmol). The resulting
solution was again degassed with N.sub.2 for 15 min. The reaction
mixture was heated to 90.degree. C. and stirred for 12 h. The
reaction mixture was quenched with water (40 mL) and extracted with
EtOAc (3.times.20 mL). The combined organic layer was dried over
Na.sub.2SO.sub.4, filtered and the filtrate concentrated. The crude
product was purified by silica gel chromatography (24 g
REDISEP.RTM. column, eluting with 10% EtOAc in hexane). Fractions
containing the product were combined and evaporated to afford
Intermediate 282C as a colorless liquid (0.15 g, 77%). .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. ppm 7.85-7.68 (d, 2H), 7.44 (d,
J=8.0 Hz, 2H), 4.08 (q, J=7.0 Hz, 2H), 3.70-3.46 (m, 1H), 3.18 (s,
1H), 2.65-2.54 (m, 2H), 2.24 (m, J=12.0 Hz, 2H), 1.23-1.16 (m,
3H).
Intermediate 282D: (1s,3s)-3-(4-Cyanophenyl)cyclobutanecarboxylic
acid
##STR00451##
[0849] To a solution of Intermediate 282C (0.17 g, 0.741 mmol) in
THF (2 mL) and water (2 mL) was added LiOH (0.036 g, 1.483 mmol) at
RT and the reaction mixture was stirred for 12 h. The reaction
mixture was concentrated and the residue was acidified to a pH of 2
with an aqueous solution of 1.5N HCl and extracted with EtOAc
(3.times.15 mL). The combined organic layer was dried over
Na.sub.2SO.sub.4, filtered and concentrated to afford Intermediate
282D as a colorless liquid (0.13 g, 87%). .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 12.34-12.02 (s, 1H), 7.79 (d, J=8.5 Hz,
2H), 7.44 (d, J=8.0 Hz, 2H), 3.66-3.41 (m, 1H), 3.18-2.98 (m, 1H),
2.66-2.53 (m, 2H), 2.31-2.10 (m, 2H).
Compound 282:
2-(3-Chloro-4-fluorophenyl)-N.sup.5-((1s,3s)-3-(4-cyanophenyl)cyclobutyl)-
-6,7-dihydropyrazolo[1,5-a]pyrazine-3,5(4H)-dicarboxamide
##STR00452##
[0851] To a solution of Intermediate 282D (41.0 mg, 0.204 mmol) in
toluene (1 mL) was added TEA (0.095 mL, 0.679 mmol), DPPA (0.058
mL, 0.271 mmol) and the reaction mixture was heated to 90.degree.
C. and stirred for 1 h. The reaction mixture was cooled to RT and
to it was added a solution of Intermediate 185B (40 mg, 0.136 mmol)
in THF (1 mL) and stirred for 12 h. The reaction mixture was
diluted with EtOAc (10 mL), washed successively with 10% aqueous
solution of NaHCO.sub.3, brine, dried over Na.sub.2SO.sub.4,
filtered and the filtrate concentrated. The crude product was
purified by preparative HPLC to afford Compound 282 as an off-white
solid (28 mg, 40%). HPLC retention times 1.569 and 1.603 min
(Methods E and L respectively). MS(ES): m/z=493.2 [M+1].sup.+;
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 7.86-7.83 (m, 1H),
7.81-7.78 (m, 2H), 7.68 (ddd, J=2.3, 4.8, 8.5 Hz, 1H), 7.51-7.44
(m, 3H), 7.36 (br. s., 1H), 7.19 (br. s., 1H), 7.11 (d, J=7.5 Hz,
1H), 4.73 (s, 2H), 4.22-4.08 (m, 3H), 3.84 (t, J=5.3 Hz, 2H),
3.24-3.16 (m, 1H), 2.69-2.58 (m, 2H), 2.15-2.06 (m, 2H).
[0852] The Compounds shown in Table 27 have been prepared similar
to Compound 282 by coupling of in-situ generated isocyanate of 282D
with 185B analogs.
TABLE-US-00029 TABLE 27 Ret Ex. Time HPLC No. Structure Name [M +
H].sup.+ (min.) Methods 283 ##STR00453## N.sup.5-((1s,3s)-3-(4-
Cyanophenyl)cyclobutyl)- 2-(3,4-dichlorophenyl)-
6,7-dihydropyrazolo[1,5- a]pyrazine-3,5(4H)- dicarboxamide 509.2
1.671 1.704 E L 284 ##STR00454## 2-(3-Chlorophenyl)-N.sup.5-
((1s,3s)-3-(4-cyanophenyl) cyclobutyl)-6,7- dihydropyrazolo[1,5-a]
pyrazine-3,5(4H)- dicarboxamide 475.3 1.546 1.553 E L
##STR00455##
Intermediate 285A: 2,2-Dimethylpropane-1,3-diyl
bis(4-methylbenzenesulfonate)
##STR00456##
[0854] To a stirred solution of p-toluenesulfonyl chloride (16.47
g, 86 mmol) in pyridine (20 mL) was added a solution of
2,2-dimethylpropane-1,3-diol (3.0 g, 28.8 mmol) in pyridine (20 mL)
at 0.degree. C. and the reaction mixture was allowed to stir at RT
for 16 h. After the completion of the reaction, the reaction
mixture was quenched with crushed ice and extracted with EtOAc
(2.times.100 mL). The combined organic layer was washed with a 1.5
N aq. solution of HCl, followed by water, then dried over
Na.sub.2SO.sub.4 and concentrated to afford Intermediate 285A as a
pale yellow solid (11 g, 93% yield). .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 7.70-7.77 (m, 4H), 7.47 (d, J=8.03 Hz,
4H), 3.72 (s, 4H), 2.42 (s, 6H), 0.77 (s, 6H).
Intermediate 285B: Diisopropyl
3,3-dimethylcyclobutane-1,1-dicarboxylate
##STR00457##
[0856] To a stirred suspension of NaH (2.036 g, 50.9 mmol, 60 wt %
oil suspension) in DMF (50 mL) was added diisopropyl malonate (3.19
g, 16.97 mmol) dropwise at RT and the reaction mixture was stirred
for 30 min. A solution of Intermediate 285A (7.0 g, 16.97 mmol) in
DMF (20 mL) was added and the resulting reaction mixture was
stirred at 140.degree. C. for 16 h. The reaction mixture was cooled
to RT, quenched with crushed ice and extracted with diethyl ether
(2.times.250 mL). The combined organic layers were washed with
water, dried over Na.sub.2SO.sub.4 and concentrated. The crude
product was purified by silica gel chromatography (40 g
REDISEP.RTM. column, eluting with 10% EtOAc in hexanes). Fractions
containing the product were combined and evaporated to afford
Intermediate 285B (1.5 g, 35%). .sup.1H NMR (300 MHz, chloroform-d)
.delta. ppm 5.00-5.14 (m, 2H), 2.34-2.38 (m, 4H), 1.21-1.34 (m,
12H), 1.11-1.15 (m, 6H).
Intermediate 285C: 3,3-Dimethylcyclobutane-1,1-dicarboxylic
acid
##STR00458##
[0858] To a stirred solution of Intermediate 285B (1.5 g, 5.85
mmol) in ethanol (20 ml) was added a solution of KOH (1.313 g,
23.41 mmol) in water (10 mL). The resulting solution was stirred at
80.degree. C. for 16 h. The reaction mixture was cooled to RT,
quenched with crushed ice and extracted with diethyl ether
(2.times.50 mL). The combined organic layers were dried over
Na.sub.2SO.sub.4 and evaporated to afford Intermediate 285C as a
viscous liquid (0.9 g, 89% yield). .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 12.64 (br. s., 2H), 2.17-2.29 (m, 4H),
1.01-1.12 (m, 6H).
Intermediate 285D: 3,3-Dimethylcyclobutanecarboxylic acid
##STR00459##
[0860] A solution of Intermediate 285C (250 mg, 1.452 mmol) in
pyridine (5 mL) was stirred at 120.degree. C. for 16 h. The
reaction mixture was then cooled to RT, quenched with a 1.5 N aq.
solution of HCl at 0.degree. C., and extracted with diethyl ether
(2.times.50 mL). The combined organic layers were washed with
brine, dried over Na.sub.2SO.sub.4 and evaporated to afford
Intermediate 285D as a viscous liquid (170 mg, 91% yield). .sup.1H
NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 2.90-3.02 (m, 1H),
1.84-1.95 (m, 4H), 1.07-1.14 (m, 3H), 0.99-1.07 (m, 3H).
Compound 285:
2-(3-Chloro-4-fluorophenyl)-N.sup.5-(3,3-dimethylcyclobutyl)-6,7-dihydrop-
yrazolo[1,5-a]pyrazine-3,5(4H)-dicarboxamide
##STR00460##
[0862] To a stirred solution of Intermediate 285D (13 mg, 0.1 mmol)
in toluene (2 ml) was added TEA (0.071 ml, 0.509 mmol), DPPA (0.028
ml, 0.122 mmol) and the reaction mixture was heated to 90.degree.
C. for 1 h. The reaction mixture was cooled to RT and to it was
added a solution of Intermediate 185B (30 mg, 0.102 mmol) in DMF (1
mL) and stirred at RT for 16 h. The reaction mixture was quenched
with 10% NaHCO.sub.3 and extracted with ethyl acetate (2.times.20
mL). The combined organic layer was dried over Na.sub.2SO.sub.4,
filtered and the filtrate evaporated under reduced pressure. The
crude product was purified by preparative HPLC to afford Compound
285 (20 mg, 46%). HPLC retention times 9.40 min. and 8.50 min.
(Methods A and B respectively). MS(ES): m/z=420 [M+H].sup.+;
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 7.81-7.90 (m, 1H),
7.64-7.74 (m, 1H), 7.42-7.46 (m, 1H), 7.14-7.40 (d, 2H), 6.98 (s,
1H), 4.72 (s, 2H), 4.06-4.20 (m, 3H), 3.82 (t, J=5.27 Hz, 2H),
1.95-2.05 (m, 2H), 1.72-1.83 (m, 2H), 1.11 (d, J=7.53 Hz, 6H).
[0863] The Compounds shown in Table 28 have been prepared similar
to Compound 285 by coupling of in-situ generated isocyanate of 285D
with 185B analogs.
TABLE-US-00030 TABLE 28 Ret Ex. Time HPLC No. Structure Name [M +
H].sup.+ (min.) Methods 286 ##STR00461##
2-(3-Chloro-4-fluorophenyl)- N.sup.5-(3,3-dimethylcyclobutyl)-
6,7-dihydropyrazolo[1,5-a] pyrazine-3,5(4H)- dicarboxamide 402 9.14
8.24 A B 287 ##STR00462## 2-(3,4-Dichlorophenyl)-N.sup.5-(3,3-
dimethylcyclobutyl)-6,7- dihydropyrazolo[1,5-a] pyrazine-3,5(4H)-
dicarboxamide 436 9.8 8.8 A B
##STR00463##
Intermediate 288A: Ethyl
3-fluoro-3-methylcyclobutanecarboxylate
##STR00464##
[0865] To a solution of ethyl
3-hydroxy-3-methylcyclobutanecarboxylate (500 mg, 3.16 mmol) in DCM
(5 mL) was added DAST (0.626 mL, 4.74 mmol) at -78.degree. C. and
the reaction mixture was slowly allowed to warm to RT and stir for
3 h. The reaction mixture was diluted with DCM (25 mL), washed with
H.sub.2O and a saturated aq. solution of NaHCO.sub.3, then dried
over Na.sub.2SO.sub.4, filtered and concentrated. The crude product
was purified by silica gel chromatography (12 g REDISEP.RTM.
column, eluting with 25% EtOAc in hexanes). Fractions containing
the product were combined and evaporated to afford Intermediate
288A as a pale yellow liquid (0.2 g, 40% yield). .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. ppm 4.08 (q, J=7.0 Hz, 2H), 3.22-3.09
(m, 1H), 2.60-2.53 (m, 1H), 2.37-2.22 (m, 3H), 1.44 (d, J=18 Hz,
3H), 1.22-1.11 (m, 3H).
Intermediate 288B: 3-Fluoro-3-methylcyclobutanecarboxylic acid
##STR00465##
[0867] To a solution of Intermediate 288A (0.2 g, 1.249 mmol) in
ethanol (2 mL) and H.sub.2O (1 mL) was added LiOH (0.060 g, 2.497
mmol) and the reaction mixture was stirred at RT for 12 h. Ethanol
was concentrated under reduced pressure and the residue was
acidified with a 1.5N aq. solution of HCl and extracted with DCM
(3.times.20 mL). The combined organic layers were dried over
Na.sub.2SO.sub.4, filtered and the filtrate concentrated to afford
288B as a yellow liquid (80 mg, 50% yield). .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 12.29 (br. s., 1H), 3.13-2.99 (m, 1H),
2.56-2.52 (m, 1H), 2.48-2.42 (m, 1H), 2.35-2.22 (m, 2H), 1.44 (d,
J=18 Hz, 3H).
Compound 288:
2-(3,4-Dichlorophenyl)-N.sup.5-(3-fluoro-3-methylcyclobutyl)-6,7-dihydrop-
yrazolo[1,5-a]pyrazine-3,5(4H)-dicarboxamide
##STR00466##
[0869] To a solution of Intermediate 288B (76 mg, 0.578 mmol) in
toluene (2 mL) was added TEA (0.121 mL, 0.868 mmol), DPPA (0.166
mL, 0.723 mmol) and the reaction mixture was stirred at 60.degree.
C. for 2 h. The reaction mixture was cooled to RT and to it was
added a solution of Intermediate 185B (90 mg, 0.289 mmol) in THF (1
mL) and stirred for 12 h. The reaction mixture was diluted with
water (25 mL) and extracted with ethyl acetate (3.times.20 mL). The
combined organic layer was washed with brine, dried over
Na.sub.2SO.sub.4, filtered and the filtrate concentrated. The crude
product was purified by preparative HPLC to afford Compound 288 as
an off-white solid (15 mg, 25% yield). MS(ES): m/z=423 [M+H].sup.+;
HPLC retention time 1.25 min and 1.29 min (Methods E and L
respectively). .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 7.84
(dd, J=7.28, 2.13 Hz, 1H), 7.67 (ddd, J=8.64, 4.82, 2.16 Hz, 1H),
7.46 (t, J=9.04 Hz, 1H), 7.34 (br. s., 1H), 7.17 (br. s., 1H), 7.07
(d, J=6.53 Hz, 1H), 4.72 (s, 2H), 4.18-4.28 (m, 1H), 4.13 (t,
J=5.27 Hz, 2H), 3.82 (t, J=5.33 Hz, 2H), 2.43-2.48 (m, 1H),
2.07-2.22 (m, 2H), 1.37-1.48 (m, 3H).
[0870] The Compounds shown in Table 29 have been prepared similar
to Compound 288 by coupling of in-situ generated isocyanate of 288B
with 185B analogs
TABLE-US-00031 TABLE 29 Ret Ex. Time HPLC No. Structure Name [M +
H].sup.+ (min.) Methods 289 ##STR00467##
2-(3-Chlorophenyl)-N.sup.5-(3- fluoro-3-methylcyclobutyl)-
6,7-dihydropyrazolo[1,5-a] pyrazine-3,5(4H)- dicarboxamide 406.2
7.609 7.955 B M 290 ##STR00468## 2-(3,4-Dichlorophenyl)-N.sup.5-(3-
fluoro-3-methylcyclobutyl)- 6,7-dihydropyrazolo[1,5-a]
pyrazine-3,5(4H)- dicarboxamide 440.2 8.447 8.893 B M
##STR00469##
Intermediate 291A: 3,3-Difluorocyclobutanecarboxylic acid
##STR00470##
[0872] To a solution of benzyl 3,3-difluorocyclobutanecarboxylate
(1.4 g, 6.2 mmol) in ethanol (50 mL) was added palladium on
activated carbon (500 mg) and the reaction mixture was stirred at
RT under an atmosphere of hydrogen (1 atm) for 12 h. The reaction
mixture was filtered through a pad of CELITE.RTM. and the filtrate
was concentrated to afford Intermediate 291A as pale yellow liquid
(550 mg, 65% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
ppm 12.97-12.76 (m, 1H), 3.04-2.91 (m, 1H), 2.89-2.64 (m, 4H).
Compound 291:
2-(3-Chloro-4-fluorophenyl)-N.sup.5-(3,3-difluorocyclobutyl)-6,7-dihydrop-
yrazolo[1,5-a]pyrazine-3,5(4H)-dicarboxamide
##STR00471##
[0874] A stirred solution of Intermediate 291A (236 mg, 1.731 mmol)
in toluene (12 mL) was added TEA (0.709 mL, 5.09 mmol), DPPA (0.467
mL, 2.036 mmol) and the reaction mixture was heated at 85.degree.
C. for 1 h. The reaction mass was cooled to RT and to it was added
a solution of Intermediate 185B (300 mg, 1.018 mmol) in THF (1 mL)
and stirred at RT for 8 h. The reaction mixture was diluted with
water and the aqueous layer was extracted with ethyl acetate
(2.times.15 mL). The combined organic layer was washed with brine,
dried over Na.sub.2SO.sub.4, filtered and the filtrate
concentrated. The crude product was purified by preparative HPLC to
afford Compound 291 as an off-white solid (121 mg, 27.5%). HPLC
retention times 7.98 min. and 5.58 min. (Methods B and A
respectively). MS(ES): m/z=428 [M+1].sup.+; .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 7.81-7.86 (m, 1H), 7.63-7.71 (m, 1H),
7.42-7.50 (m, 1H), 7.30-7.38 (m, 1H), 7.23-7.27 (m, 1H), 7.12-7.20
(m, 1H), 4.71-4.76 (m, 2H), 4.11-4.17 (m, 2H), 3.95-4.07 (m, 1H),
3.80-3.86 (m, 2H), 2.78-2.90 (m, 2H), 2.54-2.70 (m, 2H).
[0875] The Compounds shown in Table 30 have been prepared similar
to Compound 291 by coupling of in-situ generated isocyanate of 291A
with 185B analogs.
TABLE-US-00032 TABLE 30 Ret Ex. Time HPLC No. Structure Name [M +
H].sup.+ (min.) Methods 292 ##STR00472##
2-(3-Chlorophenyl)-N.sup.5- (3,3-difluorocyclobutyl)-
6,7-dihydropyrazolo[1,5- a]pyrazine-3,5(4H)- dicarboxamide 410 1.18
1.16 L E 293 ##STR00473## 2-(3,5-Dichlorophenyl)- N.sup.5-(3,3-
difluorocyclobutyl)-6,7- dihydropyrazolo[1,5-a] pyrazine-3,5(4H)-
dicarboxamide 444 1.39 1.39 L E 294 ##STR00474##
2-(3,4-Dichlorophenyl)- N.sup.5-(3,3- difluorocyclobutyl)-6,7-
dihydropyrazolo[1,5-a] pyrazine-3,5(4H)- dicarboxamide 444 1.35
1.35 L E 295 ##STR00475## 2-(3-Chloro-5-
fluorophenyl)-N.sup.5-(3,3- difluorocyclobutyl)-6,7-
dihydropyrazolo[1,5-a] pyrazine-3,5(4H)- dicarboxamide 428 1.26
1.27 L E
##STR00476##
Intermediate 296A: Benzyl
3,3-difluoro-1-methylcyclobutanecarboxylate
##STR00477##
[0877] To a solution of benzyl 3,3-difluorocyclobutanecarboxylate
(2 g, 8.84 mmol) and MeI (2.202 mL, 35.4 mmol), in THF (15 mL) at
-78.degree. C. under a N.sub.2 atmosphere was added a solution of
KHMDS (35.4 mL, 17.68 mmol, 0.5 M in toluene). The reaction mixture
was then stirred at -78.degree. C. for 6 h after which it was
allowed to warm to RT and stir overnight. The reaction mass was
then quenched with a saturated aq. solution of NH.sub.4Cl and
extracted with diethyl ether (3.times.25 mL). The combined organic
fractions were washed with water, dried over Na.sub.2SO.sub.4,
filtered and concentrated under vacuum. The crude product was
purified by silica gel chromatography (40 g REDISEP.RTM. column,
eluting with 20% EtOAc in hexanes). Fractions containing the
product were combined and evaporated to afford the Intermediate
296A as a pale yellow liquid (1.2 g, 56.5%). .sup.1H NMR (400 MHz,
chloroform-d) .delta. ppm 7.50-7.23 (m, 5H), 5.17 (s, 2H),
3.22-2.97 (m, 2H), 2.60-2.28 (m, 2H), 1.51 (s, 3H).
Intermediate 296B: 3,3-Difluoro-1-methylcyclobutanecarboxylic
acid
##STR00478##
[0879] To a solution of Intermediate 296A (1.2 g, 4.99 mmol) in
ethanol (5 mL) was added a 5N aq. solution of NaOH (4.99 mL, 24.97
mmol) and the reaction mixture was stirred at RT for 4 h. The
reaction mixture was concentrated under reduced pressure; the
residue was dissolved in water and extracted with diethyl ether
(3.times.5 mL). The pH of the aqueous solution was adjusted to 7.0
using a 2N aq. solution of HCl and extracted with DCM (3.times.10
mL). The combined organic layers were dried over Na.sub.2SO.sub.4,
filtered and concentrated to afford Intermediate 296B as a pale
yellow liquid (500 mg, 67%). .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. ppm 12.73-12.70 (m, 1H), 3.03-2.89 (m, 2H), 2.49-2.41 (m,
2H), 1.40 (s, 3H).
Compound 296:
2-(3-Chloro-4-fluorophenyl)-N.sup.5-(3,3-difluoro-1-methylcyclobutyl)-6,7-
-dihydropyrazolo[1,5-a]pyrazine-3,5(4H)-dicarboxamide
##STR00479##
[0881] To a solution of Intermediate 296B (30.6 mg, 0.204 mmol) in
toluene (6 mL) was added TEA (0.071 mL, 0.509 mmol), DPPA (0.047
mL, 0.204 mmol) and the reaction mixture was heated to 85.degree.
C. and stirred for 1 h. The reaction mass was cooled to RT and to
it was added a solution of Intermediate 185B (30 mg, 0.102 mmol) in
THF (1 mL) and stirred for 12 h. The reaction mixture was
concentrated and the residue was extracted with ethyl acetate
(3.times.10 mL). The combined organic layer was washed with water,
dried over sodium sulfate, filtered and the filtrate concentrated.
The crude product was purified by preparative HPLC to afford
Compound 296 as an off-white solid (16 mg, 34.8%). HPLC retention
time 1.33 min. and 1.35 min. (Methods J and K respectively).
MS(ES): m/z=442 [M+1].sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. ppm 7.82-7.89 (m, 1H), 7.66-7.73 (m, 1H), 7.43-7.51 (m,
1H), 7.09-7.33 (m, 3H), 4.73 (s, 2H), 4.12-4.18 (m, 2H), 3.78-3.88
(m, 2H), 2.80-2.94 (m, 2H), 2.55-2.65 (m, 2H), 1.45 (s, 3H).
[0882] The Compounds shown in Table 31 have been prepared similar
to Compound 296 by coupling of in-situ generated isocyanate of 296B
with 185B analogs.
TABLE-US-00033 TABLE 31 Ret Ex. Time HPLC No. Structure Name [M +
H].sup.+ (min.) Methods 297 ##STR00480##
2-(3,4-Dichlorophenyl)-N.sup.5- (3,3-difluoro-1-
methylcyclobutyl)-6,7- dihydropyrazolo[1,5-a] pyrazine-3,5(4H)-
dicarboxamide 458 1.48 1.47 L E 298 ##STR00481##
2-(3,5-Dichlorophenyl)-N.sup.5- (3,3-difluoro-1-
methylcyclobutyl)-6,7- dihydropyrazolo[1,5-a] pyrazine-3,5(4H)-
dicarboxamide 458 1.52 1.50 L E 299 ##STR00482##
2-(3-Chlorophenyl)-N.sup.5-(3,3- difluoro-1-methylcyclobutyl)-
6,7-dihydropyrazolo[1,5-a] pyrazine-3,5(4H)- dicarboxamide 424 7.95
8.51 B C 300 ##STR00483## 2-(3-Chloro-5-fluorophenyl)-
N.sup.5-(3,3-difluoro-1- methylcyclobutyl)-6,7-
dihydropyrazolo[1,5- a]pyrazine-3,5(4H)- dicarboxamide 442 1.35
1.44 E L
##STR00484##
Intermediate 301A: Benzyl
1-ethyl-3,3-difluorocyclobutanecarboxylate
##STR00485##
[0884] To a solution of benzyl 3,3-difluorocyclobutanecarboxylate
(500 mg, 2.210 mmol) and EtI (0.714 mL, 8.84 mmol) in THF (15 mL)
at -78.degree. C. under a N.sub.2 atmosphere was added a solution
of KHMDS (8.84 mL, 4.42 mmol, 0.5 M in toluene). The resulting
solution was stirred at -78.degree. C. for 6 h. The reaction was
then allowed to warm to RT and stirred overnight. The reaction mass
was then quenched with a saturated aq. solution of NH.sub.4Cl and
the aqueous layer was extracted with diethyl ether (3.times.25 mL).
The combined organic fractions were washed with water, dried over
Na.sub.2SO.sub.4, filtered and concentrated under vacuum. The crude
product was purified by silica gel chromatography (4 g REDISEP.RTM.
column, eluting with 15% EtOAc in hexanes). Fractions containing
the product were combined and evaporated to afford Intermediate
301A as a pale yellow liquid (200 mg, 35.6%). .sup.1H NMR (300 MHz,
chloroform-d) .delta. ppm 7.32-7.44 (m, 5H), 5.19 (s, 2H),
2.90-3.11 (m, 2H), 2.38-2.57 (m, 2H), 1.28 (dt, J=8.97, 7.03 Hz,
2H), 0.79-0.93 (m, 3H).
Intermediate 301B: 1-Ethyl-3,3-difluorocyclobutanecarboxylic
acid
##STR00486##
[0886] To a solution of Intermediate 301A (0.2 g, 0.787 mmol) in
ethanol (5 mL) and water (1 mL) was added a 5N aq. solution of NaOH
(0.787 mL, 3.93 mmol) and the reaction mixture was stirred at RT
for 4 h. The reaction mixture was concentrated under reduced
pressure and the residue was diluted with water and extracted with
diethyl ether (3.times.5 mL). The pH of the aqueous solution was
adjusted to 7.0 using a 2N aq. solution of HCl and the aqueous
phase was extracted with DCM (3.times.10 mL). The combined organic
layers were dried over Na.sub.2SO.sub.4, filtered and concentrated
to afford Intermediate 301B as a pale yellow liquid (50 mg, 38.7%).
.sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. ppm 12.63-12.75 (m,
1H), 2.80-2.97 (m, 2H), 2.57-245 (m, 2H), 1.77 (q, J=7.55 Hz, 2H),
0.81 (t, J=7.37 Hz, 3H).
Compound 301:
2-(3,4-Dichlorophenyl)-N.sup.5-(1-ethyl-3,3-difluorocyclobutyl)-6,7-dihyd-
ropyrazolo[1,5-a]pyrazine-3,5(4H)-dicarboxamide
##STR00487##
[0888] A stirred solution of Intermediate 301B (26.9 mg, 0.164
mmol) in toluene (4 mL) at RT under nitrogen was added TEA (0.067
mL, 0.482 mmol), DPPA (0.044 mL, 0.193 mmol) and heated at
85.degree. C. for 1 h. The reaction mass was cooled to RT and to it
was added a solution of Intermediate 185B (30 mg, 0.096 mmol) in
THF and stirred for 8 h. The reaction mixture was diluted with
water and the aqueous layer was extracted with ethyl acetate
(2.times.15 mL). The combined organic layer was washed with brine,
dried over Na.sub.2SO.sub.4, filtered and the filtrate
concentrated. The crude product obtained was purified by
preparative HPLC to afford Compound 301 as an off-white solid (18.1
mg, 40%). HPLC retention times 1.60 min. and 1.59 min. (Methods L
and E respectively). MS(ES): m/z=472 [M+1].sup.+; .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. ppm 7.89-7.92 (m, 1H), 7.65-7.70 (m,
2H), 7.22-7.43 (m, 2H), 7.09 (s, 1H), 4.72 (s, 2H), 4.14 (t, J=5.27
Hz, 2H), 3.84 (t, J=5.52 Hz, 2H), 2.70-2.83 (m, 2H), 2.53-2.65 (m,
2H), 1.79 (q, J=7.36 Hz, 2H), 0.77 (t, J=7.28 Hz, 3H).
##STR00488## ##STR00489##
Intermediate 302A: Isopropyl
3,3-dimethoxy-1-((((trifluoromethyl)sulfonyl)oxy)methyl)cyclobutanecarbox-
ylate
##STR00490##
[0890] To a solution of isopropyl
1-(hydroxymethyl)-3,3-dimethoxycyclobutanecarboxylate (1.5 g, 6.46
mmol) and 2,6-lutidine (1.122 mL, 9.69 mmol) in DCM (30 mL) cooled
to -78.degree. C., was added trifluoromethanesulfonic anhydride
(1.309 mL, 7.75 mmol) dropwise and the resulting solution was
stirred for 1 h. The reaction mixture was quenched with water and
extracted with DCM (3.times.25 mL). The combined organic layers
were washed sequentially with a saturated aq. solution of
NaHCO.sub.3, a 1N aq. solution of HCl and brine, then dried over
Na.sub.2SO.sub.4, filtered and concentrated to afford Intermediate
302A as a pale brown liquid (1.8 g, 77%). The crude product was
taken to the next step without further purification. .sup.1H NMR
(400 MHz, chloroform-d) .delta. ppm 4.99-5.13 (m, 1H), 4.79 (s,
2H), 3.16 (d, J=1.51 Hz, 6H), 2.62 (d, J=13.55 Hz, 2H), 2.22 (d,
J=14.05 Hz, 2H), 1.27 (d, J=6.53 Hz, 6H).
Intermediate 302B: Isopropyl
1-(fluoromethyl)-3,3-dimethoxycyclobutanecarboxylate
##STR00491##
[0892] To a solution of Intermediate 302A (1.8 g, 4.94 mmol) in THF
(30 mL) was added TBAF (5.93 mL, 5.93 mmol, 1M in THF) at
-78.degree. C. and the reaction mixture was stirred at RT for 1 h.
It was then quenched with ice-cold water and extracted with ethyl
acetate (3.times.25 mL). The combined organic layer was dried over
sodium sulfate, filtered and the filtrate concentrated. The crude
product was purified by silica gel chromatography (4 g REDISEP.RTM.
column, eluting with 25% ethyl acetate in hexanes). Fractions
containing the product were combined and evaporated to afford the
Intermediate 302B as a pale yellow liquid (0.8 g, 69%). .sup.1H NMR
(400 MHz, chloroform-d) .delta. ppm 5.06 (s, 1H), 4.51-4.72 (m,
2H), 3.15 (s, 6H), 2.56 (dd, J=13.55, 2.01 Hz, 2H), 2.21 (d,
J=14.06 Hz, 2H), 1.26 (d, J=6.02 Hz, 6H).
Intermediate 302C: Isopropyl
1-(fluoromethyl)-3-oxocyclobutanecarboxylate
##STR00492##
[0894] To a stirred solution of Intermediate 302B (0.6 g, 2.56
mmol) was added a conc. aq. solution of HCl (1.576 mL, 20.49 mmol)
and the reaction mass was stirred at RT for 16 h. The reaction was
extracted with DCM (3.times.10 mL) and the organic layer was washed
with water and a 10% aq. solution of NaHCO.sub.3, and then dried
over Na.sub.2SO.sub.4, filtered and concentrated to afford
Intermediate 302C as a pale yellow liquid (0.3 g, 62%). .sup.1H NMR
(400 MHz, chloroform-d) .delta. ppm 5.12 (s, 1H), 4.67-4.87 (m,
2H), 3.44-3.64 (m, 2H), 3.12-3.31 (m, 2H), 1.29 (d, J=6.53 Hz,
6H).
Intermediate 302D: Isopropyl
3,3-difluoro-1-(fluoromethyl)cyclobutanecarboxylate
##STR00493##
[0896] To a solution of Intermediate 302C (0.3 g, 1.594 mmol) in
DCM (6 mL) was added DAST (0.211 mL, 1.594 mmol) dropwise under
nitrogen and the reaction mixture was stirred at RT for 8 h. The
reaction mass was diluted with DCM (25 mL), washed sequentially
with a 10% aq. solution of NaHCO.sub.3, water and brine, then dried
over Na.sub.2SO.sub.4, filtered and the filtrate concentrated to
afford Intermediate 302D as a pale yellow liquid (0.25 g, 75%). The
crude compound was taken to the next step without further
purification. .sup.1H NMR (400 MHz, chloroform-d) .delta. ppm 5.08
(s, 1H), 4.46-4.84 (m, 2H), 3.03 (t, J=13.55 Hz, 2H), 2.58-2.79 (m,
2H), 1.15-1.32 (m, 6H).
Intermediate 302E:
3,3-Difluoro-1-(fluoromethyl)cyclobutanecarboxylic acid
##STR00494##
[0898] To a solution of Intermediate 302D (0.25 g, 1.189 mmol) in
ethanol (5 mL) was added NaOH (1.189 mL, 5.95 mmol, 5 M in water)
and the reaction mixture was stirred at RT for 8 h. The reaction
mixture was concentrated in vacuo, dissolved in water and extracted
with diethyl ether. The pH of the aq. solution was adjusted to 7
using a 2N aq. solution of HCl and extracted with DCM (3.times.10
mL). The combined organic layer was dried over Na.sub.2SO.sub.4,
filtered, and the filtrate concentrated to afford Intermediate 302E
as a pale yellow liquid (0.12 g, 60%). .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 13.02-13.40 (br. s., 1H), 4.53-4.76 (m,
2H), 2.95 (q, J=13.22 Hz, 2H), 2.59-2.78 (m, 2H).
Compound 302:
2-(3-Chlorophenyl)-N.sup.5-(3,3-difluoro-1-(fluoromethyl)cyclobutyl)-6,7--
dihydropyrazolo[1,5-a]pyrazine-3,5(4H)-dicarboxamide
##STR00495##
[0900] To a stirred solution of Intermediate 302E (26.7 mg, 0.159
mmol) in toluene (3 mL) was added TEA (0.101 mL, 0.723 mmol), DPPA
(0.066 mL, 0.289 mmol) and the solution was heated to 85.degree. C.
for 1 hr. The reaction mass was cooled to RT and to it was added a
solution of Intermediate 156E (40 mg, 0.145 mmol) in DMF (1 mL) and
the reaction mixture was stirred at RT for 8 h. It was then
concentrated and extracted with ethyl acetate (3.times.10 mL). The
combined organic layer was dried over Na.sub.2SO.sub.4, filtered
and the filtrate concentrated. The crude product was further
purified by preparative HPLC to afford Compound 302 as an off-white
solid (32 mg, 50%). HPLC retention times 1.41 min. and 1.41 min.
(Methods E and L respectively). MS(ES): m/z=441 [M+1].sup.+;
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 7.71 (t, J=1.76 Hz,
1H), 7.64 (dt, J=6.65, 1.95 Hz, 1H), 7.41-7.47 (m, 2H), 7.37 (s,
2H), 7.19 (br. s., 1H), 4.75 (s, 2H), 4.44-4.61 (m, 2H), 4.15 (t,
J=5.52 Hz, 2H), 3.86 (t, J=5.52 Hz, 2H), 2.81 (t, J=12.30 Hz,
4H).
[0901] The Compounds shown in Table 32 have been prepared similar
to Compound 302 by coupling of in-situ generated isocyanate of 302E
with 199B.
TABLE-US-00034 TABLE 32 Ret Ex. Time HPLC No. Structure Name [M +
H].sup.+ (min.) Methods 303 ##STR00496##
2-(3,4-Dichlorophenyl)-N.sup.5- (3,3-difluoro-1-
(fluoromethyl)cyclobutyl)- 6,7-dihydropyrazolo[1,5-a]
pyrazine-3,5(4H)- dicarboxamide 476 1.58 1.59 E L
##STR00497## ##STR00498##
Intermediate 304A: Isopropyl
1-formyl-3,3-dimethoxycyclobutanecarboxylate
##STR00499##
[0903] To a solution of isopropyl
1-(hydroxymethyl)-3,3-dimethoxycyclobutanecarboxylate (2.3 g, 9.90
mmol) in DCM (45 mL) was added iodosobenzene diacetate (4.78 g,
14.85 mmol) and TEMPO (0.155 g, 0.990 mmol) and the mixture was
stirred at RT for 8 h. The reaction mass was diluted with DCM (25
mL), washed with and a 10% aq. solution of NaHCO.sub.3, dried over
Na.sub.2SO.sub.4, filtered and the filtrate concentrated. The crude
product was purified by silica gel chromatography (40 g
REDISEP.RTM. column, eluting with 5% MeOH in CHCl.sub.3). Fractions
containing the product were combined and evaporated to afford
Intermediate 304A as a pale yellow liquid (1.3 g, 57%). .sup.1H NMR
(300 MHz, DMSO-d.sub.6) .delta. ppm 9.62 (s, 1H), 4.96 (s, 1H),
3.04 (d, J=7.18 Hz, 6H), 2.59-2.66 (m, 2H), 2.47 (m, 2H), 1.20 (d,
J=6.42 Hz, 6H).
Intermediate 304B: Isopropyl
1-(difluoromethyl)-3,3-dimethoxycyclobutanecarboxylate
##STR00500##
[0905] To a solution of Intermediate 304A (1.3 g, 5.65 mmol) in DCM
(20 mL) was added DAST (1.492 mL, 11.29 mmol) dropwise under
nitrogen and the resulting solution was stirred at RT for 16 h. The
reaction mass was diluted with DCM (25 mL), quenched with a 10% aq.
solution of NaHCO.sub.3, washed with water, brine,
Na.sub.2SO.sub.4, filtered and the filtrate concentrated to afford
Intermediate 304B (0.8 g, 56%). .sup.1H NMR (400 MHz, chloroform-d)
.delta. ppm 5.86-6.19 (m, 1H), 5.05-5.15 (m, 1H), 3.15 (d, J=3.51
Hz, 6H), 2.55-2.64 (m, 2H), 2.45 (d, J=13.55 Hz, 2H), 1.22-1.29 (m,
6H).
Intermediate 304C: Isopropyl
1-(difluoromethyl)-3-oxocyclobutanecarboxylate
##STR00501##
[0907] To a stirred solution of Intermediate 304B (300 mg, 1.189
mmol) was added a conc. aq. solution of HCl (0.457 mL, 5.94 mmol)
and the reaction mass was stirred at RT for 48 h. The reaction was
quenched with water and extracted with DCM (2.times.25 mL). The
organic layer was washed with water, a 10% aq. solution of
NaHCO.sub.3, dried over Na.sub.2SO.sub.4, filtered and the filtrate
concentrated. The crude product was purified by silica gel
chromatography (4 g REDISEP.RTM. column, eluting with 25% ethyl
acetate in hexanes). Fractions containing the product were combined
and evaporated to afford Intermediate 304C as a pale yellow liquid
(150 mg, 61%). .sup.1H NMR (400 MHz, chloroform-d) .delta. ppm 6.40
(s, 1H), 5.15 (s, 1H), 3.33-3.51 (m, 4H), 1.23-1.33 (m, 6H).
Intermediate 304D: Isopropyl
1-(difluoromethyl)-3,3-difluorocyclobutanecarboxylate
##STR00502##
[0909] To a solution of Intermediate 304C (150 mg, 0.727 mmol) in
DCM (10 mL) was added DAST (0.192 mL, 1.455 mmol) dropwise under
nitrogen. The reaction mixture was stirred at RT for 16 h, then
diluted with DCM (15 mL) and quenched with a 10% aq. solution of
NaHCO.sub.3. The organic layer was separated, washed with water,
brine, dried over Na.sub.2SO.sub.4, filtered and the filtrate
concentrated. The crude product was purified by silica gel
chromatography (4 g REDISEP.RTM. column, eluting with 10% ethyl
acetate in hexanes). Fractions containing the product were combined
and evaporated to afford Intermediate 304D as a pale yellow liquid
(90 mg, 54%). .sup.1H NMR (400 MHz, chloroform-d) .delta. ppm 6.16
(s, 1H), 5.03-5.18 (m, 1H), 2.89-3.06 (m, 4H), 1.22-1.35 (m,
6H).
Intermediate 304E:
1-(Difluoromethyl)-3,3-difluorocyclobutanecarboxylic acid
##STR00503##
[0911] To a solution of Intermediate 304D (500 mg, 2.191 mmol) in
ethanol (10 mL) and water (2 mL) was added NaOH (2.191 mL, 10.96
mmol, 5 M in water) and the resulting solution was stirred at RT
for 4 h. EtOH was removed under reduced pressure, and the aqueous
solution was acidified with a 1.5 N aq. solution of HCl which was
then extracted with DCM (3.times.30 mL). The combined organic layer
was washed with brine, dried over Na.sub.2SO.sub.4, filtered and
the filtrate was concentrated to afford Intermediate 304E as a pale
yellow liquid (300 mg, 74% yield). .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 13.87 (br. s., 1H), 6.21-6.63 (m, 1H),
2.77-3.11 (m, 4H).
Compound 304:
2-(3-Chloro-4-fluorophenyl)-N.sup.5-(1-(difluoromethyl)-3,3-difluorocyclo-
butyl)-6,7-dihydropyrazolo[1,5-a]pyrazine-3,5(4H)-dicarboxamide
##STR00504##
[0913] To a solution of Intermediate 304E (26.3 mg, 0.141 mmol) in
toluene (3 mL) was added TEA (0.090 mL, 0.643 mmol) and DPPA (0.059
mL, 0.257 mmol) and the resulting solution was heated at 85.degree.
C. for 1 h. The reaction mixture was cooled to RT and to it was
added a solution of Intermediate 185B (40 mg, 0.129 mmol) in DMF (1
mL) and stirred at RT for 8 h. It was concentrated and the residue
was extracted with ethyl acetate (3.times.10 mL). The combined
organic layer was dried over sodium sulfate, filtered and the
filtrate concentrated. The crude product was further purified by
preparative HPLC to afford Compound 304 as an off-white solid (18
mg, 28%). HPLC retention times 1.57 min. and 1.59 min. (Methods E
and L respectively). ES(MS): m/z=478 [M+1].sup.+; .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. ppm 7.90 (d, J=1.5 Hz, 1H), 7.72-7.63
(m, 3H), 7.45-7.21 (m, 2H), 6.47-6.11 (m, 1H), 4.77 (s, 2H), 4.17
(t, J=5.3 Hz, 2H), 3.88 (t, J=5.3 Hz, 2H), 3.06-2.91 (m, 2H),
2.90-2.76 (m, 2H).
[0914] The Compounds shown in Table 33 have been prepared similar
to Compound 304 by coupling of in-situ generated isocyanate of 282E
with 185B analogs.
TABLE-US-00035 TABLE 33 Ret Ex. Time HPLC No. Structure Name [M +
H].sup.+ (min.) Methods 305 ##STR00505##
2-(3,4-Dichlorophenyl)-N.sup.5- (1-(difluoromethyl)-3,3-
difluorocyclobutyl)-6,7- dihydropyrazolo[1,5-a] pyrazine-3,5(4H)-
dicarboxamide 494 1.66 1.71 E L 306 ##STR00506##
2-(3-Chlorophenyl)-N.sup.5-(1- (difluoromethyl)-3,3-
difluorocyclobutyl)-6,7- dihydropyrazolo[1,5-a] pyrazine-3,5(4H)-
dicarboxamide 460 1.52 1.55 E L
##STR00507##
Intermediate 307A: Ethyl
3-fluoro-1,3-dimethylcyclobutanecarboxylate
##STR00508##
[0916] To a solution of Intermediate 288A (0.13 g, 0.812 mmol) in
THF (2 mL) was added LDA (1.623 mL, 1.623 mmol, 1 M in THF)
dropwise at -78.degree. C. and the reaction mixture was stirred at
the same temperature for 45 min. MeI (0.203 mL, 3.25 mmol) was then
added at -78.degree. C. and the mixture was allowed to slowly warm
to RT and stir for 12 h. The reaction mixture was quenched with a
saturated aq. solution of NH.sub.4Cl and extracted with EtOAc
(2.times.25 mL). The combined organic layers were washed with
brine, dried over Na.sub.2SO.sub.4, filtered and concentrated to
afford Intermediate 307A as a yellow liquid (85 mg, 60%). The crude
product was reacted under saponification conditions without further
purification .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 4.08
(q, J=7.0 Hz, 2H), 2.60-2.53 (m, 1H), 2.37-2.22 (m, 3H), 1.44 (d,
J=18 Hz, 3H), 1.36 (s, 3H) 1.22-1.11 (m, 3H).
Intermediate 307B: 3-Fluoro-1,3-dimethylcyclobutanecarboxylic
acid
##STR00509##
[0918] To a solution of Intermediate 307A (85 mg, 0.360 mmol) in
ethanol (2 mL) was added NaOH (0.144 mL, 0.719 mmol, 5M aq.
solution) and the reaction mixture was stirred at RT for 12 h. The
volatiles were removed under reduced pressure, and the residue was
diluted with water (15 mL) and extracted with diethyl ether
(1.times.25 mL). The aqueous layer was then acidified with a 1.5N
aq. solution of HCl and extracted with EtOAc (2.times.25 mL). The
combined organic layer was dried over Na.sub.2SO.sub.4, filtered
and the filtrate concentrated to afford Intermediate 307B as a pale
yellow liquid (30 mg, 43%). .sup.1H NMR (300 MHz, DMSO-d.sub.6)
.delta. ppm 12.29 (br. s., 1H), 2.60-2.53 (m, 1H), 2.37-2.22 (m,
3H), 1.44 (d, J=18 Hz, 3H), 1.36 (s, 3H).
Compound 307:
2-(3-Chloro-4-fluorophenyl)-N.sup.5-(3-fluoro-1,3-dimethylcyclobutyl)-6,7-
-dihydropyrazolo[1,5-a]pyrazine-3,5(4H)-dicarboxamide
##STR00510##
[0920] To a solution of Intermediate 307B (29.8 mg, 0.204 mmol) in
toluene (2 mL) were added TEA (0.043 mL, 0.305 mmol), DPPA (0.058
mL, 0.254 mmol) and the reaction mixture was heated at 60.degree.
C. and stirred for 2 h. The reaction mixture was cooled to RT and
to it was added a solution of Intermediate 185B (30 mg, 0.102 mmol)
in THF (1 mL) and stirred for 12 h. The reaction mixture was
diluted with water (20 mL) and extracted with ethyl acetate
(2.times.25 mL). The combined organic layer was washed with brine,
dried over Na.sub.2SO.sub.4, filtered and the filtrate
concentrated. The crude product was purified by preparative HPLC to
afford Compound 307 as an off-white solid (7.55 mg, 17%). HPLC
retention time 5.901 min. and 8.366 min. (Methods A and B
respectively). MS(ES): m/z=438 [M+H].sup.+; .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 7.85 (dd, J=7.0, 2.0 Hz, 1H), 7.68 (ddd,
J=8.5, 4.8, 2.3 Hz, 1H), 7.46 (t, J=9.0 Hz, 1H), 7.36 (br. s., 1H),
7.20 (br. s., 1H), 6.88 (s, 1H), 4.71 (s, 2H), 4.12 (t, J=5.3 Hz,
2H), 3.82 (t, J=5.3 Hz, 2H), 2.44 (m, 2H), 2.29-2.17 (m, 2H), 1.46
(d, J=10.8 Hz, 3H), 1.43 (s, 3H).
##STR00511## ##STR00512##
Intermediate 308A:
1-(4-Fluorophenyl)-3,3-dimethoxycyclobutanecarbonitrile
##STR00513##
[0922] To a solution of NaH (1.302 g, 32.6 mmol, 60 wt % in mineral
oil) in dry DMF (10 mL) cooled to 0.degree. C., was added dropwise
a solution 2-(4-fluorophenyl)acetonitrile (2.0 g, 14.8 mmol) in DMF
(10 mL). To the stirred suspension at 0.degree. C. was then added
1,3-dibromo-2,2-dimethoxypropane (3.88 g, 14.80 mmol). The reaction
mixture was then heated to 60.degree. C. and stirred for 12 h. The
reaction mixture was cooled to RT, quenched with water and
extracted with EtOAc (3.times.20 mL). The combined organic layers
were washed with water and brine, dried over Na.sub.2SO.sub.4 and
evaporated. The crude compound was purified by silica gel
chromatography (24 g REDISEP.RTM. column, eluting with 20% EtOAc in
hexanes). Fractions containing the product were combined and
evaporated to afford Intermediate 308A as a yellow liquid (1.4 g,
40%). .sup.1H NMR (400 MHz, chloroform-d) .delta. ppm 7.45 (dd,
J=8.94, 5.05 Hz, 2H), 7.09 (t, J=8.66 Hz, 2H), 3.28 (s, 3H),
3.05-3.19 (m, 5H), 2.64-2.72 (m, 2H).
Intermediate 308B:
1-(4-Fluorophenyl)-3,3-dimethoxycyclobutanecarboxylic acid
##STR00514##
[0924] A solution of Intermediate 308A (1.4 g, 5.95 mmol) in
ethanol (20 mL) and H.sub.2O (20 mL) was added a 10% aq. solution
of NaOH (10 mL, 5.95 mmol) and the reaction mixture was heated at
reflux for 12 h. The reaction mixture was concentrated under
reduced pressure to afford Intermediate 308B (1.0 g, 66% yield) as
a gummy solid. The crude product was used in the subsequent
reaction without purification. .sup.1H NMR (400 MHz, chloroform-d)
.delta. ppm 7.45 (dd, J=8.94, 5.05 Hz, 2H), 7.09 (t, J=8.66 Hz,
2H), 2.82-3.0 (m, 8H), 2.64-2.72 (m, 2H).
Intermediate 308C: Methyl
1-(4-fluorophenyl)-3-oxocyclobutanecarboxylate
##STR00515##
[0926] To a stirred solution of Intermediate 308B (1.0 g, 3.93
mmol) in MeOH (15 mL) was added a concentrated aq. solution of HCl
(5 mL) and the solution was stirred at RT for 12 h. The volatiles
were removed under reduced pressure and the resulting residue was
purified by silica gel chromatography (24 g REDISEP.RTM. column,
eluting with 20% EtOAc in hexanes). Fractions containing the
product were combined and evaporated to afford Intermediate 308C as
a colorless oil (700 mg, 80%). .sup.1H NMR (400 MHz, chloroform-d)
.delta. ppm 7.45 (dd, J=8.94, 5.05 Hz, 2H), 7.09 (t, J=8.66 Hz,
2H), 3.89 (m, 2H), 3.71 (s, 3H), 3.57-3.72 (m, 2H).
Intermediate 308D: Methyl
3,3-difluoro-1-(4-fluorophenyl)cyclobutanecarboxylate
##STR00516##
[0928] To a solution of Intermediate 308C (600 mg, 2.70 mmol) in
DCM (15 mL) at -20.degree. C. was added DAST (0.535 mL, 4.05 mmol)
and the reaction mixture was stirred at RT for 12 h. The reaction
mixture was quenched by the addition of a 10% aq. solution of
NaHCO.sub.3 and extracted with DCM (3.times.15 mL). The combined
organic layer was dried over Na.sub.2SO.sub.4 and evaporated under
vacuum. The crude sample was purified by silica gel chromatography
(24 g REDISEP.RTM. column, eluting with 10% EtOAc in hexanes).
Fractions containing the product were combined and evaporated to
afford Intermediate 308D as a yellow oil (400 mg, 61%). .sup.1H NMR
(400 MHz, chloroform-d) .delta. ppm 7.20-7.32 (m, 2H), 7.05 (t,
J=8.69 Hz, 2H), 3.69 (s, 3H), 3.40-3.53 (m, 2H), 2.96-3.09 (m,
2H).
Intermediate 308E: 3,
3-Difluoro-1-(4-fluorophenyl)cyclobutanecarboxylic acid
##STR00517##
[0930] To a stirred solution of Intermediate 308D (400 mg, 1.638
mmol) in MeOH (5 mL), water (2 mL) and THF (2 mL) was added NaOH
(197 mg, 4.91 mmol) and stirred for 12 h at RT. The reaction
mixture was concentrated under vacuo and the pH of the residue was
adjusted to 2.0 using 1.5 N HCl and the compound was extracted with
ethyl acetate (3.times.10 mL). The combined organic layer was dried
over Na.sub.2SO.sub.4, filtered and the filtrate concentrated under
reduced pressure to afford Intermediate 308E as a pale yellow solid
(250 mg, 66%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm
13.03 (bs, 1H), 7.33-7.43 (m, 2H), 7.21 (m, 2H), 3.32-3.37 (m, 2H),
2.99-3.15 (m, 2H).
Compound 308:
2-(3-Chloro-4-fluorophenyl)-N.sup.5-(3,3-difluoro-1-(4-fluorophenyl)cyclo-
butyl)-6,7-dihydropyrazolo[1,5-a]pyrazine-3,5(4H)-dicarboxamide
##STR00518##
[0932] A stirred solution of Intermediate 308E (62.5 mg, 0.271
mmol) in toluene (2 mL) was added TEA (0.057 mL, 0.407 mmol), DPPA
(0.062 mL, 0.271 mmol) and the reaction mixture was heated to
70.degree. C. for 2 h. The reaction mass was cooled to RT and to it
was added a solution of Intermediate 185B (40 mg, 0.136 mmol) in
THF (1 mL) and the reaction mixture was stirred at RT for 12 h. The
reaction mass was diluted with ethyl acetate (5 mL), the organic
layer was separated, washed with a 10% aq. NaHCO.sub.3 solution,
water, brine, dried over Na.sub.2SO.sub.4, filtered and the
filtrate concentrated under vacuum. The crude compound was purified
by preparative HPLC to afford Compound 308 as a pale yellow solid
(54 mg, 75%). The HPLC Retention times are 2.339 min. and 2.344
min. (Methods J and K respectively); MS(ES): -m/z=522 [M+H].sup.+;
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 7.82-7.88 (m, 1H),
7.77-7.82 (m, 1H), 7.61-7.72 (m, 1H), 7.47 (s, 3H), 7.30-7.41 (m,
1H), 7.14 (s, 3H), 4.72 (s, 2H), 4.08-4.18 (m, 2H), 3.78-3.88 (m,
2H), 3.10-3.22 (m, 4H).
[0933] The Compounds shown in Table 34 have been prepared similar
to Compound 308 by coupling of in-situ generated isocyanate of 308E
with 185B analogs.
TABLE-US-00036 TABLE 34 Ret Ex. Time HPLC No. Structure Name [M +
H].sup.+ (min.) Methods 309 ##STR00519##
2-(3-Chlorophenyl)-N.sup.5-(3,3- difluoro-1-(4-fluorophenyl)
cyclobutyl)-6,7- dihydropyrazolo[1,5-a] pyrazine-3,5(4H)-
dicarboxamide 504.0 2.511 2.444 E L 310 ##STR00520##
2-(3,4-Dichlorophenyl)-N.sup.5- (3,3-difluoro-1-(4-
fluorophenyl)cyclobutyl)-6,7- dihydropyrazolo[1,5-a]
pyrazine-3,5(4H)- dicarboxamide 538.0 2.664 2.572 E L
##STR00521## ##STR00522##
Intermediate 311A:
3,3-Dimethoxy-1-(pyridin-3-yl)cyclobutanecarbonitrile
##STR00523##
[0935] To a stirred suspension of NaH (1.466 g, 36.6 mmol, 60% in
mineral oil) in DMF (25 mL) was added 2-(pyridin-3-yl)acetonitrile
(1.954 mL, 18.32 mmol) followed by 1,3-dibromo-2,2-dimethoxypropane
(4 g, 15.27 mmol) and the reaction mixture was warmed to 60.degree.
C. and stirred for 12 h. The reaction mixture was cooled to RT,
poured into water (250 mL) and extracted with EtOAc (3.times.50
mL). The organic layer was separated, washed with water, brine,
dried over Na.sub.2SO.sub.4, filtered and the filtrate
concentrated. The crude product was purified by silica gel
chromatography (40 g REDISEP.RTM. column, eluting with 50% EtOAc in
hexanes). Fractions containing the product were combined and
evaporated to afford Intermediate 311A as a white solid (2 g, 60%).
MS(ES): m/z=219.2 [M+F1]+; .sup.1H NMR (300 MHz, DMSO-d.sub.6)
.delta. ppm 8.71 (dd, J=0.8, 2.6 Hz, 1H), 8.58 (dd, J=1.7, 4.7 Hz,
1H), 7.89 (s, 1H), 7.51-7.45 (m, 1H), 3.19 (s, 3H), 3.08 (s, 3H),
2.89 (s, 1H), 2.83 (s, 1H), 2.78 (s, 1H), 2.73 (d, J=0.8 Hz,
1H).
Intermediate 311B:
3,3-Dimethoxy-1-(pyridin-3-yl)cyclobutanecarboxylic acid
##STR00524##
[0937] To a stirred solution of Intermediate 311A (2.2 g, 10.08
mmol) in EtOH (10 mL) was added a 10% aq. solution of NaOH (10 mL,
10 mmol) and the reaction mixture was stirred at 100.degree. C. for
12 h. EtOH was removed under reduced pressure and the pH of the aq.
solution was adjusted to 4 with a 1.5N aq. solution of HCl and
extracted with EtOAc (5.times.20 mL). The combined organic layer
was dried over Na.sub.2SO.sub.4, filtered and the filtrate
concentrated to afford Intermediate 311B as a pale yellow
semi-solid (1.4 g, 59%). MS(ES): m/z=238.0 [M+H].sup.+; .sup.1H NMR
(300 MHz, DMSO-d.sub.6) .delta. ppm 12.35 (br. s., 1H), 8.56-8.42
(m, 2H), 7.75-7.64 (m, 1H), 7.44-7.30 (m, 1H), 3.08 (s, 3H),
3.03-2.90 (m, 4H), 2.56 (d, J=13.2 Hz, 1H), 1.91 (s, 2H).
Intermediate 311C: Methyl
3-oxo-1-(pyridin-3-yl)cyclobutanecarboxylate
##STR00525##
[0939] To a solution of Intermediate 311B (1.4 g, 5.9 mmol) was
added methanolic HCl (10 mL, 5.90 mmol, 4M) and stirred at RT for
12 h. The volatiles were removed under reduced pressure, the
reaction mixture was then partitioned between a 10% aq. solution of
NaHCO.sub.3 and EtOAc. The organic layer was separated and the
aqueous phase was extracted with EtOAc (5.times.20 mL). The
combined organic layer was dried over Na.sub.2SO.sub.4, filtered
and the filtrate concentrated. The crude product was purified by
silica gel chromatography (24 g REDISEP.RTM. column, eluting with
50% EtOAc in hexanes). Fractions containing the product were
combined and evaporated to afford Intermediate 311C as a colorless
semi-solid (0.7 g, 58%). MS(ES): m/z=206.2 [M+H].sup.+; .sup.1H NMR
(300 MHz, DMSO-d.sub.6) .delta. ppm 8.62 (d, J=1.8 Hz, 1H), 8.53
(dd, J=1.6, 4.8 Hz, 1H), 7.89-7.70 (m, 1H), 7.51-7.19 (m, 1H),
3.92-3.72 (m, 4H), 3.64 (s, 3H).
Intermediate 311D: Methyl
3,3-difluoro-1-(pyridin-3-yl)cyclobutanecarboxylate
##STR00526##
[0941] To a stirred solution of Intermediate 311C (300 mg, 1.462
mmol) in DCM (10 mL) was added DAST (0.483 mL, 3.65 mmol) dropwise
at 0.degree. C. The resulting solution was then allowed to warm to
RT and stir for 12 h. The reaction mixture was quenched with a
saturated aq. solution of NaHCO.sub.3 at 0.degree. C. and the
organic layer was separated and the aq. layer was extracted with
DCM (2.times.10 mL). The combined organic layer was dried over
Na.sub.2SO.sub.4, filtered and the filtrate concentrated. The crude
product was purified by silica gel chromatography (24 g
REDISEP.RTM. column, eluting with 50% EtOAc in hexanes). Fractions
containing the product were combined and evaporated to afford
Intermediate 311D as a colorless liquid (250 mg, 75%). MS(ES):
m/z=228.2 [M+H].sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
ppm 8.62 (dd, J=1.0, 2.5 Hz, 1H), 8.54 (dd, J=1.5, 4.5 Hz, 1H),
7.87-7.77 (m, 1H), 7.45 (s, 1H), 3.64 (s, 3H), 3.44 (s, 2H), 3.28
(s, 2H).
Intermediate 311E: 2
3,3-Difluoro-1-(pyridin-3-yl)cyclobutanecarboxylic acid
##STR00527##
[0943] To a solution of Intermediate 311D (250 mg, 1.100 mmol) in
THF (2 mL) and water (1 mL) was added NaOH (132 mg, 3.30 mmol) and
the reaction mixture was stirred at RT for 12 h. The reaction
mixture was concentrated; the pH of the residue was adjusted to 2
with a 1.5N aq. solution of HCl and extracted with EtOAc
(3.times.15 mL). The combined organic layer was dried over
Na.sub.2SO.sub.4, filtered and concentrated to afford Intermediate
311E as a colorless semi-solid (160 mg, 68% yield). .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. ppm 12.35 (br. s., 1H), 8.65-8.54
(m, 1H), 8.53-8.46 (m, 1H), 7.83-7.74 (m, 1H), 7.46-7.35 (m, 1H),
3.47-3.35 (m, 2H), 3.23-3.08 (m, 2H).
Intermediate 311:
2-(3-Chloro-4-fluorophenyl)-N.sup.5-(3,3-difluoro-1-(pyridin-3-yl)cyclobu-
tyl)-6,7-dihydropyrazolo[1,5-a]pyrazine-3,5(4H)-dicarboxamide
##STR00528##
[0945] To a solution of Intermediate 311E (43.4 mg, 0.204 mmol) in
toluene (2 mL) was added TEA (0.095 mL, 0.679 mmol), DPPA (75 mg,
271 mmol) and the solution was heated to 85.degree. C. and stirred
for 1 h. The reaction mixture was cooled to RT and to it was added
a solution of Intermediate 185B (40 mg, 0.136 mmol) in THF (1 mL)
and stirred for 12 h. The reaction mixture was diluted with EtOAc
(10 mL), washed with water, solution of 10% aq. NaHCO.sub.3, brine,
dried over Na.sub.2SO.sub.4, filtered and the filtrate
concentrated. The crude product obtained was purified by
preparative HPLC to afford Compound 311 as an off-white solid
(0.005 g, 7%). HPLC retention time 1.242 min. and 1.014 min.
(Methods E and L respectively). MS(ES): m/z=505.2 [M+F1]+; .sup.1H
NMR: (400 MHz, DMSO-d.sub.6) .delta. ppm 8.67 (dd, J=2.51, 1.00 Hz,
1H), 8.38-8.50 (m, 1H), 7.89 (s, 1H), 7.80-7.86 (m, 2H), 7.68 (ddd,
J=8.66, 4.89, 2.01 Hz, 1H), 7.44-7.52 (m, 1H), 7.31-7.40 (m, 2H),
7.21 (br. s., 1H), 4.74 (s, 2H), 4.15 (t, J=5.27 Hz, 2H), 3.84 (t,
J=5.27 Hz, 2H), 3.09-3.29 (m, 4H).
[0946] The Compounds shown in Table 35 have been prepared similar
to Compound 311 by coupling of in-situ generated isocyanate of 311E
with 185B analogs.
TABLE-US-00037 TABLE 35 Ret Ex. Time HPLC No. Structure Name [M +
H].sup.+ (min.) Methods 312 ##STR00529##
2-(3-Chlorophenyl)-N.sup.5- (3,3-difluoro-1-(pyridin-3-
yl)cyclobutyl)-6,7- dihydropyrazolo[1,5-a] pyrazine-3,5(4H)-
dicarboxamide 487.2 1.188 0.963 E L 313 ##STR00530##
2-(3,4-Dichlorophenyl)- N.sup.5-(3,3-difluoro-1-
(pyridin-3-yl)cydobutyl)- 6,7-dihydropyrazolo[1,5-
a]pyrazine-3,5(4H)- dicarboxamide 521.2 1.365 1.118 E L
##STR00531## ##STR00532##
Intermediate 314A:
1-(4-Bromophenyl)-3,3-dimethoxycyclobutanecarbonitrile
##STR00533##
[0948] To a suspension of NaH (0.733 g, 18.32 mmol, 60% in mineral
oil) in DMF (14 mL) was added 2-(4-bromophenyl)acetonitrile (1.796
g, 9.16 mmol) followed by 1,3-dibromo-2,2-dimethoxypropane (2.0 g,
7.64 mmol) and the reaction mixture was heated to 60.degree. C. and
stirred for 12 h. The reaction mixture was cooled to RT, poured
into water (150 mL) and extracted with EtOAc (3.times.40 mL). The
combined organic layer was washed with brine, dried over
Na.sub.2SO.sub.4, filtered and the filtrate concentrated. The crude
product was purified by silica gel chromatography (24 g
REDISEP.RTM. column, eluting with 5% EtOAc in hexane). Fractions
containing the product were combined and evaporated to afford
Intermediate 314A as a white solid (2 g, 88%). .sup.1H NMR (300
MHz, DMSO-d.sub.6) .delta. ppm 7.68-7.57 (m, 2H), 7.46-7.40 (m,
2H), 3.18 (s, 3H), 3.08 (s, 1H), 3.07 (s, 3H), 3.05-3.02 (m, 1H),
2.74-2.71 (m, 1H), 2.70-2.67 (m, 1H).
Intermediate 314B:
1-(4-Bromophenyl)-3,3-dimethoxycyclobutanecarboxylic acid
##STR00534##
[0950] To a stirred solution of Intermediate 314A (2 g, 6.75 mmol)
in EtOH (10 mL) was added 10% aq. solution of NaOH (10 mL, 6.75
mmol) at RT and the reaction mixture was heated to 85.degree. C.
for 12 h. EtOH was removed under reduced pressure and the pH of the
resulting aq. solution was adjusted to 2 with a 1.5 N aq. solution
of HCl and extracted with EtOAc (5.times.20 mL). The combined
organic layer was washed with brine, dried over Na.sub.2SO.sub.4,
filtered and the filtrate concentrated to afford Intermediate 314B
as a pale yellow semi-solid (2 g, 94%). MS(ES): m/z=313.0
[M-1].sup.+; .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. ppm 12.39
(br. s., 1H), 7.66-7.39 (m, 2H), 7.34-7.11 (m, 2H), 3.07 (s, 3H),
3.00 (s, 3H), 2.95 (d, J=13.6 Hz, 1H), 2.43 (s, 1H), 1.91 (s,
2H).
Intermediate 314C: Methyl
1-(4-bromophenyl)-3-oxocyclobutanecarboxylate
##STR00535##
[0952] To a flask charged with Intermediate 314B (2.0 g, 6.35 mmol)
was added methanolic HCl (10 mL, 6.35 mmol, 4 M) and the reaction
mixture was stirred at RT for 12 h. The reaction mixture was
concentrated and the crude product was purified by silica gel
chromatography (24 g REDISEP.RTM. column, eluting with 7% EtOAc in
hexanes). Fractions containing the product were combined and
evaporated to afford Intermediate 314C as a colorless liquid (1.3
g, 72%). MS(ES): .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm
7.65-7.51 (m, 2H), 7.39-7.23 (m, 2H), 3.85-3.74 (m, 2H), 3.68-3.52
(m, 5H).
Intermediate 314D: Methyl
1-(4-bromophenyl)-3,3-difluorocyclobutanecarboxylate
##STR00536##
[0954] To a stirred solution of Intermediate 314C (1.2 g, 4.24
mmol) in DCM (50 mL) was added DAST (1.232 mL, 9.32 mmol) dropwise
at 0.degree. C. The reaction mixture was allowed to warm to RT and
stir for 12 h. The reaction mixture was quenched with an aq.
solution of NaHCO.sub.3 (20 mL) at 0.degree. C. and extracted with
DCM (3.times.10 mL). The combined organic layer was washed with
brine, dried over Na.sub.2SO.sub.4, and the filtrate concentrated.
The crude product was purified by silica gel chromatography (24 g
REDISEP.RTM. column, eluting with 8% EtOAc in hexanes). Fractions
containing the product were combined and evaporated to afford
Intermediate 314D as a colorless liquid (1 g, 77%). .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. ppm 7.68-7.51 (m, 2H), 7.41-7.26
(m, 2H), 3.62 (s, 3H), 3.49-3.34 (m, 2H), 3.17 (s, 2H).
Intermediate 314E: Methyl
1-(4-cyanophenyl)-3,3-difluorocyclobutanecarboxylate
##STR00537##
[0956] To a solution of Intermediate 314D (500 mg, 1.639 mmol) in
DMF (10 mL) was added Zn(CN).sub.2 (289 mg, 2.458 mmol) and the
reaction mixture was degassed with N.sub.2 gas for 15 min.
Pd.sub.2(dba).sub.3 (75 mg, 0.082 mmol) and
dicyclohexyl(2',6'-dimethoxy-[1,1'-biphenyl]-2-yl)phosphine (67.3
mg, 0.164 mmol) were then added and the reaction mixture was heated
at 120.degree. C. for 1 h. The reaction mixture was cooled to RT,
diluted with water (50 mL) and extracted with EtOAc (3.times.40
mL). The combined organic layer was washed with water, brine, dried
over Na.sub.2SO.sub.4, filtered and the filtrate concentrated. The
crude product was purified by silica gel chromatography (24 g
REDISEP.RTM. column, eluting with 10% EtOAc in hexane). Fractions
containing the product were combined and evaporated to afford
Intermediate 314E as a colorless liquid (350 mg, 85%). .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. ppm 7.87 (d, J=8.5 Hz, 2H), 7.58
(d, J=8.5 Hz, 2H), 3.62 (s, 3H), 3.51-3.37 (m, 2H), 3.28-3.13 (m,
2H).
Intermediate 314F:
1-(4-Cyanophenyl)-3,3-difluorocyclobutanecarboxylic acid
##STR00538##
[0958] To a stirred solution of Intermediate 314E (300 mg, 1.194
mmol) in THF (2 mL) and water (2 mL) was added LiOH (57.2 mg, 2.388
mmol) and the reaction mixture was stirred at RT for 12 h. The
reaction mixture was concentrated to remove THF and the aq. layer
was acidified to a pH of 2 with a 1.5N aq. solution of HCl and
extracted with EtOAc (3.times.15 mL). The combined organic layer
was washed with brine, dried over Na.sub.2SO.sub.4, filtered and
the filtrate concentrated to afford Intermediate 314F (230 mg, 81%)
as a colorless semi-solid. .sup.1H NMR (300 MHz, DMSO-d.sub.6)
.delta. ppm 12.39 (br. s., 1H), 7.91-7.79 (m, 2H), 7.62-7.49 (m,
2H), 3.50-3.25 (m, 2H), 3.11 (d, J=14.0 Hz, 2H).
Compound 314:
2-(3-Chloro-4-fluorophenyl)-N.sup.5-(1-(4-cyanophenyl)-3,3-difluorocyclob-
utyl)-6,7-dihydropyrazolo[1,5-a]pyrazine-3,5(4H)-dicarboxamide
##STR00539##
[0960] To a solution of Intermediate 314F (36.2 mg, 0.153 mmol) in
toluene (1 mL) was added TEA (0.071 mL, 0.509 mmol), DPPA (0.044
mL, 0.204 mmol) and the reaction mixture was heated to 85.degree.
C. and stirred for 1 h. The reaction mixture was cooled to RT and
to it was added a solution of Intermediate 185B (30 mg, 0.102 mmol)
in THF (0.5 mL) and stirred at RT for 12 h. The reaction mixture
was diluted with EtOAc (10 mL), washed successively with water, a
10% aq. solution of NaHCO.sub.3 and brine, then dried over
Na.sub.2SO.sub.4, filtered and concentrated. The crude product was
purified by preparative HPLC to afford Compound 314 as an off-white
solid (0.017 g, 32%). HPLC retention times 1.604 min. and 1.605
min. (Methods E and L respectively). MS(ES): m/z=529.2 [M+H].sup.+;
.sup.1H NMR: (400 MHz, DMSO-d.sub.6) .delta. ppm 7.92 (s, 1H),
7.86-7.77 (m, 3H), 7.67 (ddd, J=8.7, 4.9, 2.0 Hz, 1H), 7.64-7.58
(m, 2H), 7.50-7.41 (m, 1H), 7.36 (br. s., 1H), 7.18 (br. s., 1H),
4.73 (s, 2H), 4.14 (t, J=5.3 Hz, 2H), 3.84 (t, J=5.3 Hz, 2H), 3.17
(t, J=12.3 Hz, 4H).
[0961] The Compounds shown in Table 36 have been prepared similar
to Compound 314 by coupling of in-situ generated isocyanate of 314F
with 185B analogs.
TABLE-US-00038 TABLE 36 Ret Ex. Time HPLC No. Structure Name [M +
H].sup.+ (min.) Methods 315 ##STR00540##
2-(3-Chlorophenyl)-N.sup.5- (1-(4-cyanophenyl)-3,3-
difluorocyclobutyl)-6,7- dihydropyrazolo[1,5-a] pyrazine-3,5(4H)-
dicarboxamide 511.3 1.570 1.567 E L 316 ##STR00541##
N.sup.5-(1-(4-Cyanophenyl)- 3,3-difluorocyclobutyl)-
2-(3,4-dichlorophenyl)- 6,7-dihydropyrazolo[1,5-
a]pyrazine-3,5(4H)- dicarboxamide 545.2 1.644 1.648 E L
##STR00542##
Intermediate 317A: Benzyl
5-methylspiro[2.3]hexane-5-carboxylate
##STR00543##
[0963] To a solution of LDA (3.47 mL, 6.94 mmol. 2M in THF) in THF
(5 mL) cooled to -78.degree. C., was added dropwise a solution of
benzyl spiro[2.3]hexane-5-carboxylate (0.5 g, 2.312 mmol) in THF (2
mL). The resulting solution was stirred for 30 min. prior to the
dropwise addition of MeI (0.723 mL, 11.56 mmol) at -78.degree. C.
The resulting reaction mixture was allowed to warm to RT and stir
for 12 h. The reaction mixture was quenched with a saturated aq.
solution of NH.sub.4Cl (20 mL) and extracted with EtOAc (3.times.10
mL). The combined organic layer was washed with brine, dried over
Na.sub.2SO.sub.4, filtered and concentrated. The crude product was
purified by silica gel chromatography (24 g REDISEP.RTM. column,
eluting with 5% EtOAc in hexanes). Fractions containing the product
were combined and evaporated to afford the Intermediate 317A as a
colorless liquid (200 mg, 38% yield). MS(ES): m/z=231.2
[M+H].sup.+; .sup.1H NMR (400 MHz, chloroform-d) .delta. ppm
7.50-7.28 (m, 5H), 5.36-4.94 (s, 2H), 2.87-2.47 (m, 2H), 2.01-1.77
(m, 2H), 1.62-1.39 (s, 3H), 0.60-0.22 (m, 4H).
Intermediate 317B: 5-Methylspiro[2.3]hexane-5-carboxylic acid
##STR00544##
[0965] To a stirred solution of Intermediate 317A (200 mg, 0.868
mmol) in THF (2 mL) and water (1 mL) was added NaOH (104 mg, 2.61
mmol) at RT and the reaction mixture was warmed to 50.degree. C.
and stirred for 12 h. The reaction mixture was concentrated under a
reduced pressure, the residue was to pH 2 with a 1.5 N aq. solution
of HCl and extracted with Et.sub.2O (3.times.15 mL). The combined
organic layer was dried over Na.sub.2SO.sub.4, filtered and the
filtrate concentrated to afford Intermediate 317B as a colorless
liquid (0.12 g, 99%). .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta.
ppm 12.38-11.71 (m, 1H), 2.68-2.50 (m, 2H), 1.86-1.66 (m, 2H), 1.43
(s, 3H), 0.62-0.19 (m, 4H).
Compound 317:
2-(3-Chloro-4-fluorophenyl)-N.sup.5-(5-methylspiro[2.3]hexan-5-yl)-6,7-di-
hydropyrazolo[1,5-a]pyrazine-3,5(4H)-dicarboxamide
##STR00545##
[0967] To a solution of Intermediate 317B (28.5 mg, 0.204 mmol) in
toluene (3 mL) was added TEA (0.071 mL, 0.509 mmol), DPPA (0.044
mL, 0.204 mmol) and the solution was warmed to 85.degree. C. and
stirred for 1 h. The reaction mixture was cooled to RT and to it
was added a solution of Intermediate 185B (30 mg, 0.102 mmol) in
THF (1 mL) and stirred at RT for 12 h. The reaction mixture was
diluted with EtOAc (10 mL), washed with water, brine, dried over
Na.sub.2SO.sub.4, filtered and the filtrate concentrated. The crude
product obtained was purified by preparative HPLC to afford the
title Compound 317 as an off-white solid (0.009 g, 20% yield). HPLC
retention times 1.448 min. and 1.553 min. (Methods E and L
respectively). MS(ES): m/z=432.0 [M+H].sup.+; .sup.1H NMR: (400
MHz, DMSO-d.sub.6) .delta. ppm 7.86 (dd, J=7.28, 2.26 Hz, 1H), 7.69
(ddd, J=8.66, 4.64, 2.26 Hz, 1H), 7.42-7.52 (m, 1H), 7.07-7.39 (m,
2H), 6.94 (s, 1H), 4.71 (s, 2H), 4.13 (t, J=5.52 Hz, 2H), 3.82 (t,
J=5.27 Hz, 2H), 2.44 (d, J=12.55 Hz, 2H), 1.85-1.93 (m, 2H), 1.51
(s, 3H), 0.32-0.49 (m, 4H).
[0968] The Compounds shown in Table 37 have been prepared similar
to Compound 317 by coupling of in-situ generated isocyanate of 317B
with 185B analogs.
TABLE-US-00039 TABLE 37 Ret Ex. Time HPLC No. Structure Name [M +
H].sup.+ (min.) Methods 318 ##STR00546##
2-(3-Chlorophenyl)-N.sup.5-(5- methylspiro[2.3]hexan-5-yl)-6,7-
dihydropyrazolo[1,5-a]pyrazine- 3,5(4H)-dicarboxamide 414.0 1.459
1.449 E L 319 ##STR00547## 2-(3,4-Dichlorophenyl)-N.sup.5-(5-
methylspiro[2.3]hexan-5-yl)-6,7- dihydropyrazolo[1,5-a]pyrazine-
3,5(4H)-dicarboxamide 448.0 1.615 1.617 E L
##STR00548##
Intermediate 320A: Ethyl
1,1-difluorospiro[2.3]hexane-5-carboxylate
##STR00549##
[0970] The solution of ethyl 3-methylenecyclobutanecarboxylate (1
g, 7.13 mmol), Nat (0.214 g, 1.427 mmol) and TMSCF.sub.3 (2.54 g,
17.83 mmol) in THF (10 mL) was stirred at 65.degree. C. for 2 h.
The reaction mixture was quenched with a 10% aq. solution of
NaHCO.sub.3 and the aqueous layer was extracted with diethyl ether
(3.times.10 mL). The combined organic layer was washed with a 10%
aq. solution of NaHCO.sub.3, followed by brine, then dried over
Na.sub.2SO.sub.4, filtered and the filtrate concentrated. The crude
was purified by silica gel chromatography (12 g REDISEP.RTM.
column, eluting with 20% EtOAc in hexane). Fractions containing the
product were combined and evaporated to afford Intermediate 320A as
a pale yellow liquid (1 g, 73%, mixture of cis and trans isomers).
.sup.1H NMR (400 MHz, chloroform-d) .delta. ppm 4.13-4.24 (m, 2H)
2.56-2.65 (m, 1H), 2.01-2.06 (m, 2H), 1.91-1.98 (m, 2H) 1.16-1.45
(m, 5H).
Intermediate 320B: 1,1-Difluorospiro[2.3]hexane-5-carboxylic
acid
##STR00550##
[0972] To a solution of Intermediate 320A (1.0 g, 5.26 mmol) in THF
(2 mL) was added a solution of NaOH (0.526 g, 13.14 mmol) in water
(1 mL) and the reaction mixture was stirred at RT for 15 h. The
volatiles were removed under reduced pressure, the pH of the aq.
solution was adjusted to -3 using a 1 N aq. solution of HCl and the
aqueous layer was extracted with EtOAc (3.times.10 mL). The
combined organic layer was washed with water, brine, dried over
Na.sub.2SO.sub.4, filtered and concentrated to afford Intermediate
323 (0.8 g, 94%, cis and trans mixture) as a yellow liquid. The
crude product was used in the next step without further
purification. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 12.39
(br. s., 1H), 3.01-3.22 (m, 1H) 2.55-2.63 (m, 2H), 1.89-2.02 (m,
2H) 1.14-1.23 (m, 2H).
Compounds 320 and 321:
2-(3-Chloro-4-fluorophenyl)-N.sup.5-(1,1-difluorospiro[2.3]hexan-5-yl)-6,-
7-dihydropyrazolo[1,5-a]pyrazine-3,5(4H)-dicarboxamide
##STR00551##
[0974] A solution of Intermediate 320B (83 mg, 0.509 mmol), TEA
(0.142 mL, 1.018 mmol) and DPPA (0.11 mL, 0.509 mmol) in toluene
(10 mL) was heated to 90.degree. C. and stirred for 2 h. The
reaction mixture was cooled to RT and to it was added a solution of
Intermediate 185B (100 mg, 0.339 mmol) in THF (3 mL) and stirred
for 4 h. The reaction mixture was quenched with water and the aq
layer was extracted with ethyl acetate (3.times.5 mL). The combined
organic layer was washed with a 10% aq. solution of NaHCO.sub.3 and
then water, dried over Na.sub.2SO.sub.4, filtered and concentrated.
The crude material was purified by preparative TLC and was loaded
on a 0.5 mm silica gel plate and developed using 6% MeOH in
CHCl.sub.3. The band containing the desired product was separated
and extracted into 10% MeOH in DCM, then was filtered and
concentrated to afford mixture of 320 and 321 as an off-white
solid. The individual isomers were separated by preparative chiral
SFC.
[0975] Compound 320: Retention time 3.22 min (HPLC Method 0);
MS(ES): m/z=454 [M+H].sup.+; Yield=25 mg, 16%; .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. ppm 7.86 (dd, J=7.28, 2.26 Hz, 1H),
7.66-7.73 (m, 1H), 7.44-7.51 (m, 1H), 7.35 (br. s., 1H), 7.29 (d,
J=7.03 Hz, 1H), 7.19 (br. s., 1H), 4.75 (s, 2H), 4.12-4.25 (m, 3H),
3.85 (t, J=5.27 Hz, 2H), 2.37-2.44 (m, 2H), 2.24-2.32 (m, 2H), 1.38
(t, J=8.53 Hz, 2H).
[0976] Compound 321: Retention time 3.79 min (HPLC Method 0);
MS(ES): m/z=454 [M+H].sup.+; Yield=25 mg, 16%; .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. ppm 7.80-7.93 (m, 1H), 7.63-7.74 (m,
1H), 7.48 (d, J=9.54 Hz, 1H), 7.35 (br s, 1H), 7.17 (m, 2H), 4.74
(s, 2H), 4.20-4.31 (m, 1H), 4.14 (d, J=10.54 Hz, 2H), 3.77-3.93 (m,
2H), 2.39-2.49 (m, 1H), 2.22 (t, J=8.53 Hz, 4H), 1.42-1.46 (t,
J=8.53 Hz, 2H).
[0977] The Compounds shown in Table 38 have been prepared similar
to Compounds 320 and 321 by coupling of in-situ generated
isocyanate of 320B with 185B analogs.
TABLE-US-00040 TABLE 38 Ret Ex. Time HPLC No. Structure Name [M +
H].sup.+ (min.) Methods 322 ##STR00552##
2-(3-Chlorophenyl)-N.sup.5-(1,1- difluorospiro[2.3]hexan-5-yl)-6,7-
dihydropyrazolo[1,5-a]pyrazine- 3,5(4H)-dicarboxamide 436 4.92 N
323 ##STR00553## 2-(3-Chlorophenyl)-N.sup.5-(1,1-
difluorospiro[2.3]hexan-5-yl)-6,7- dihydropyrazolo[1,5-a]pyrazine-
3,5(4H)-dicarboxamide 436 6.83 N 324 ##STR00554##
2-(3,4-Dichlorophenyl)-N.sup.5-(1,1-
difluorospiro[2.3]hexan-5-yl)-6,7- dihydropyrazolo[1,5-a]pyrazine-
3,5(4H)-dicarboxamide 471 8.54 N 325 ##STR00555##
2-(3,4-Dichlorophenyl)-N.sup.5-(1,1-
difluorospiro[2.3]hexan-5-yl)-6,7- dihydropyrazolo[1,5-a]pyrazine-
3,5(4H)-dicarboxamide 471 9.88 N
##STR00556##
Intermediate 326A: Ethyl
1,1-difluoro-5-methylspiro[2.3]hexane-5-carboxylate
##STR00557##
[0979] A solution of KI (1.211 g, 7.30 mmol), Intermediate 258A
(0.5 g, 3.24 mmol), and diglyme (0.046 mL, 0.324 mmol) in
1,4-dioxane (1 mL) was heated to 115.degree. C. and stirred for 2
h. TMS-Cl (0.829 mL, 6.48 mmol) and methyl
2,2-difluoro-2-(fluorosulfonyl)acetate (1.246 g, 6.48 mmol) were
added and the resulting mixture was stirred for 2 h at 115.degree.
C. The reaction mixture was quenched with a 10% aq. solution of
NaHCO.sub.3 and the aqueous layer was extracted with diethyl ether
(3.times.10 mL). The combined organic layer was washed with a 10%
aq. solution of NaHCO.sub.3, followed by brine, then dried over
Na.sub.2SO.sub.4, filtered and concentrated. The crude reaction
material was purified by silica gel chromatography (12 g
REDISEP.RTM. column, eluting with 20% EtOAc in hexane). Fractions
containing the product were combined and evaporated to afford
Intermediate 326 (0.35 g, 53%, a mixture of cis and trans isomers)
as a pale yellow liquid. .sup.1H NMR (400 MHz, chloroform-d)
.delta. ppm 4.13-4.24 (m, 2H), 2.75 (d, J=13.55 Hz, 1H), 2.56-2.65
(m, 1H), 2.01-2.06 (m, 1H), 1.91-1.98 (m, 1H), 1.42-1.51 (m, 3H),
1.25-1.32 (m, 3H), 1.16-1.24 (m, 2H).
Intermediate 326B:
1,1-Difluoro-5-methylspiro[2.3]hexane-5-carboxylic acid
##STR00558##
[0981] To a solution of Intermediate 326A (0.5 g, 2.448 mmol) in
THF (10 mL) and water (5 mL) was added NaOH (0.245 g, 6.12 mmol)
and the reaction mixture was stirred at RT for 16 h. The volatiles
were removed from the reaction mixture and the pH of the resulting
residue was adjusted to .about.3 using a 1.0 N aq. solution of HCl.
The aqueous layer was extracted with EtOAc (3.times.10 mL). The
combined organic layer was washed with water, brine, dried over
Na.sub.2SO.sub.4, filtered and concentrated to afford Intermediate
326B (0.35 g, 81%, a mixture of cis and trans isomers) as a yellow
liquid used directly in the next step without purification. .sup.1H
NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 12.39 (br. s., 1H),
2.55-2.63 (m, 2H), 1.89-2.02 (m, 2H), 1.34-1.45 (m, 3H), 1.14-1.23
(m, 2H).
Compounds 326 and 327:
2-(3-Chloro-4-fluorophenyl)-N5-(1,1-difluoro-5-methylspiro[2.3]hexan-5-yl-
)-6,7-dihydropyrazolo[1,5-a]pyrazine-3,5(4H)-dicarboxamide
##STR00559##
[0983] To a solution of Intermediate 326B (90 mg, 0.509 mmol), TEA
(0.142 mL, 1.018 mmol) in toluene (10 mL) was added DPPA (0.110 mL,
0.509 mmol) and the reaction mixture was stirred at 90.degree. C.
for 2 h. The reaction mixture was cooled to RT and to it was added
a solution of Intermediate 185B (100 mg, 0.339 mmol) in THF (3 mL)
and stirred at RT for 4 h. The reaction mixture was quenched with
water and the aq. layer was extracted with ethyl acetate (3.times.5
mL). The combined organic layers were washed with a 10% aq.
solution of NaHCO.sub.3 and water, then dried over
Na.sub.2SO.sub.4, filtered and concentrated. The crude reaction
material was purified by preparative TLC and was loaded on a 0.5 mm
silica gel plate. The plate was developed using 6% MeOH in
CHCl.sub.3. The band containing the desired product was separated
and extracted into 10% MeOH in DCM, and was then filtered and
concentrated to afford cis and trans mixture of Compounds 326 and
327 as an off-white solid. The individual isomers were separated by
preparative chiral SFC.
[0984] Compound 326: Retention time=6.52 min (Method Q); MS(ES):
m/z=468 [M+H].sup.+; Yield=0.03 g, 18%; .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta. ppm 7.85 (dd, J=7.18, 2.27 Hz, 1H), 7.64-7.73
(m, 1H), 7.48 (d, J=9.07 Hz, 1H), 7.36 (br. s., 1H), 7.20 (br. s.,
1H), 7.08 (s, 1H), 4.72 (s, 2H), 4.09-4.17 (m, 2H), 3.82 (t, J=4.91
Hz, 2H), 2.53-2.61 (m, 2H), 2.04 (d, J=13.22 Hz, 2H), 1.32-1.44 (m,
5H).
[0985] Compound 327: Retention time=7.49 min (Method Q); MS(ES):
m/z=468 [M+H].sup.+; Yield=0.03 g, 18%; .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 7.85-7.89 (m, 1H), 7.66-7.73 (m, 1H),
7.48 (d, J=9.54 Hz, 1H), 7.35 (br. s., 1H), 7.20 (br. s., 1H), 6.97
(s, 1H), 4.73 (s, 2H), 4.15 (t, J=5.27 Hz, 2H), 3.84 (t, J=5.27 Hz,
2H), 2.57 (d, J=12.55 Hz, 2H), 2.00 (d, J=13.05 Hz, 2H), 1.51 (s,
3H), 1.42 (t, J=8.53 Hz, 2H).
[0986] The Compounds shown in Table 39 have been prepared similar
to Compounds 326 and 327 by coupling of in-situ generated
isocyanate of 326B with 185B analogs.
TABLE-US-00041 TABLE 39 Ret Ex. Time HPLC No. Structure Name [M +
H].sup.+ (min.) Methods 328 ##STR00560##
2-(3,4-Dichlorophenyl)-N.sup.5-(1,1-
difluoro-5-methylspiro[2.3]hexan- 5-yl)-6,7-dihydropyrazolo[1,5-a]
pyrazine-3,5(4H)-dicarboxamide 484 9.08 N 329 ##STR00561##
2-(3,4-Dichlorophenyl)-N.sup.5-(1,1-
difluoro-5-methylspiro[2.3]hexan- 5-yl)-6,7-dihydropyrazolo[1,5-a]
pyrazine-3,5(4H)-dicarboxamide 484 10.33 N 330 ##STR00562##
2-(3-Chlorophenyl)-N.sup.5-(1,1- difluoro-5-methylspiro[2.3]hexan-
5-yl)-6,7-dihydropyrazolo[1,5-a] pyrazine-3,5(4H)-dicarboxamide 450
6.59 N 331 ##STR00563## 2-(3-Chlorophenyl)-N.sup.5-(1,1-
difluoro-5-methylspiro[2.3]hexan- 5-yl)-6,7-dihydropyrazolo[1,5-a]
pyrazine-3,5(4H)-dicarboxamide 450 7.62 N
##STR00564##
Intermediate 332A: Benzyl 3-oxocyclopentanecarboxylate
##STR00565##
[0988] To a stirred solution of 3-oxocyclopentanecarboxylic acid
(1.5 g, 11.71 mmol) in DMF (20 mL) was added K.sub.2CO.sub.3 (1.780
g, 12.88 mmol) followed by benzyl bromide (1.360 mL, 11.71 mmol)
under nitrogen. The reaction mixture was then stirred for 18 h at
RT. The reaction mixture was poured into water (100 mL) and
extracted with ethyl acetate (2.times.100 mL). The combined organic
layer was washed with brine, dried over anhydrous Na.sub.2SO.sub.4
and concentrated under reduced pressure. The crude compound was
purified by silica gel chromatography (12 g REDISEP.RTM. column,
eluting with 20% EtOAc in hexane). Fractions containing the product
were combined and evaporated to afford Intermediate 332A (2.1 g,
78% yield) as an oil. .sup.1H NMR (400 MHz, chloroform-d) .delta.
ppm 7.42-7.31 (m, 5H), 5.16 (s, 2H), 3.22-3.12 (m, 1H), 2.58-2.45
(m, 2H), 2.44-2.29 (m, 2H), 2.23 (s, 2H).
Intermediate 332B: Benzyl 3,3-difluorocyclopentanecarboxylate
##STR00566##
[0990] To a stirred ice-cooled solution of Intermediate 332A (0.2
g, 0.916 mmol) in anhydrous DCE (4 mL) was added DAST (0.303 mL,
2.291 mmol) under nitrogen. The reaction mixture was then allowed
to heat to 40.degree. C. and stir for 16 h. The reaction mixture
was quenched with an aq. solution of NaHCO.sub.3 at 0.degree. C.
and extracted with DCM (2.times.50 mL). The combined organic layer
was dried over anhydrous Na.sub.2SO.sub.4 and concentrated under
reduced pressure. The crude compound was purified by silica gel
chromatography (12 g REDISEP.RTM. column, eluting with 10% EtOAc in
hexanes). Fractions containing the product were combined and
evaporated to afford Intermediate 332B as a colorless oil (0.07 g,
30% yield). .sup.1H NMR (400 MHz, chloroform-d) .delta. ppm
7.41-7.31 (m, 5H), 5.15 (s, 2H), 3.05 (m, 1H), 2.49-2.33 (m, 2H),
2.26-2.00 (m, 4H).
Intermediate 332C: 3,3-Difluorocyclopentanecarboxylic acid
##STR00567##
[0992] To a stirred solution of Intermediate 332B (0.07 g, 0.291
mmol) in EtOAc (2 mL) was added 10% Pd/C (0.016 g, 0.015 mmol) and
the resulting mixture was stirred for 16 h under an atmosphere of
hydrogen (15 psi, balloon pressure). The reaction mixture was
filtered through a pad of CELITE.RTM. and the filter cake was
washed with EtOAc. The combined filtrate was concentrated under
reduced pressure to afford Intermediate 332C as a colorless oil
(0.035 g, 76% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
ppm 12.41 (br. s., 1H), 3.04-2.94 (m, 1H), 2.39-2.23 (m, 2H),
2.20-2.01 (m, 3H), 1.95-1.84 (m, 1H).
Compounds 332 and 333:
2-(3-Chloro-4-fluorophenyl)-N.sup.5-(3,3-difluorocyclopentyl)-6,7-dihydro-
pyrazolo[1,5-a]pyrazine-3,5(4H)-dicarboxamide
##STR00568##
[0994] A stirred solution of Intermediate 332C (32.6 mg, 0.217
mmol) in toluene (1 mL) at RT under nitrogen was added with TEA
(0.045 mL, 0.325 mmol) and DPPA (0.050 mL, 0.217 mmol) and heated
to 70.degree. C. for 2 h. The reaction mass was cooled to RT and to
it was added a solution of Intermediate 185B (30 mg, 0.108 mmol) in
THF (1 mL) and stirred at RT for 16 h. The reaction mass was
diluted with ethyl acetate (25 mL), washed with water and brine,
dried over anhydrous Na.sub.2SO.sub.4, filtered, and the filtrate
concentrated under reduced pressure. The individual isomers were
separated by preparative chiral SFC (Column: WHELK-O.RTM. 1 (R,R)
(250.times.4.6 mm), 5.mu. column, 5 Co-Solvent: 0.2% DEA, Column
Temperature: 24.4, Total Flow: 3 mL, CO.sub.2 Flow Rate: 2.1,
Co-Solvent Flow Rate: 0.9, Co-Solvent %: 30%, Back Pressure: 101
bar.
[0995] Compound 332: (retention time 4.6 min), (7 mg, 16%); MS(ES):
m/z=424.1 [M+H].sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
ppm 7.69-7.72 (m, 1H), 7.64 (dt, J=6.65, 1.95 Hz, 1H), 7.40-7.48
(m, 2H), 7.36 (br. s., 1H), 7.18 (br. s., 1H), 6.98 (d, J=7.03 Hz,
1H), 4.73 (s, 2H), 4.10-4.20 (m, 3H), 3.84 (t, J=5.52 Hz, 2H),
2.34-2.46 (m, 1H), 2.15-2.27 (m, 1H), 1.96-2.12 (m, 3H), 1.67-1.78
(m, 1H).
[0996] Compound 333: (retention time 4.92 min), (6 mg, 15%);
MS(ES): m/z=424.1 [M+H].sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. ppm 7.71 (t, J=1.76 Hz, 1H), 7.62-7.66 (m, 1H), 7.42-7.47
(m, 2H), 7.37 (br. s., 1H), 7.18 (br. s., 1H), 6.99 (d, J=15.56 Hz,
1H), 4.73 (s, 2H), 4.11-4.18 (m, 3H), 3.84 (t, J=5.52 Hz, 2H),
2.38-2.46 (m, 1H), 2.17-2.30 (m, 1H), 1.98-2.11 (m, 3H), 1.67-1.77
(m, 1H).
##STR00569##
Intermediate 334A:
N-(Dihydrofuran-3(2H)-ylidene)-2-methylpropane-2-sulfinamide
##STR00570##
[0998] To a stirred solution of dihydrofuran-3(2H)-one (0.901 mL,
11.62 mmol) in THF (20 mL) at RT under nitrogen was added
Ti(OEt).sub.4 (4.87 mL, 23.23 mmol), 2-methylpropane-2-sulfinamide
(1.549 g, 12.78 mmol) and the reaction mixture was stirred at
60.degree. C. for 8 h. The reaction mixture was quenched with a
saturated aq. solution of NaHCO.sub.3 with vigorous stirring. The
precipitate was filtered and washed with EtOAc and the aq. layer
was extracted with EtOAc. The combined organic layer was dried over
sodium sulfate, filtered and concentrated. The crude product was
purified by silica gel chromatography (40 g REDISEP.RTM. column,
eluting with 25% ethyl acetate in hexanes). Fractions containing
the product were combined and evaporated to afford Compound 334A as
a pale yellow liquid (700 mg, 32%). The crude compound was taken to
next step without purification.
Intermediate 334B:
N-(3-Cyanotetrahydrofuran-3-yl)-2-methylpropane-2-sulfinamide
##STR00571##
[1000] To a solution of Intermediate 334A (300 mg, 1.585 mmol) in
DCM (10 mL) at RT was added TMSCN (198 .mu.L, 1.477 mmol) dropwise,
followed by Ti(OEt).sub.4 (318 .mu.L, 1.426 mmol). The resulting
solution was stirred for 12 h. The reaction was quenched by pouring
it into a vigorously stirred saturated aq. solution of NaHCO.sub.3
(20 mL). The precipitate was filtered off and the aqueous layer was
extracted with EtOAc. The combined organic layers were dried over
sodium sulfate, filtered and concentrated. The crude compound was
triturated with diethyl ether to afford Intermediate 334B (150 mg,
44% yield) as a pale brown solid. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 6.48-6.36 (m, 1H), 4.05 (d, J=9.0 Hz,
1H), 3.87 (d, J=8.5 Hz, 3H), 2.49-2.33 (m, 2H), 1.21-1.10 (m,
9H).
Intermediate 334C: 3-Aminotetrahydrofuran-3-carbonitrile, HCl
##STR00572##
[1002] To a flask charged with Intermediate 334B (80 mg, 0.370
mmol) was added a 4 M solution of HCl in dioxane (925 .mu.l, 3.70
mmol) and the reaction mixture was stirred at RT for 2 h. The
reaction mixture was concentrated under vacuum and the crude
product triturated with diethyl ether to afford Intermediate 334C
as a pale yellow solid (40 mg, 72.8%). .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 9.18-9.06 (br. s., 2H), 4.18-4.06 (m,
1H), 4.04-3.86 (m, 3H), 2.72-2.57 (m, 1H), 2.47-2.32 (m, 1H).
Compound 334:
2-(3-Chloro-4-fluorophenyl)-N.sup.5-(3-cyanotetrahydrofuran-3-yl)-6,7-dih-
ydropyrazolo[1,5-a]pyrazine-3,5(4H)-dicarboxamide
##STR00573##
[1004] To a solution of Intermediate 334B (30.3 mg, 0.204 mmol) and
TEA (0.142 mL, 1.018 mmol) in THF (8 mL) was added triphosgene
(54.4 mg, 0.183 mmol) at 0.degree. C. and the reaction mixture was
stirred for 30 min at the same temperature. A solution of
Intermediate 185B (60 mg, 0.204 mmol) in THF (1 mL) was added and
the reaction mixture was stirred at RT for 12 h. The reaction
mixture was diluted with water and extracted with ethyl acetate
(3.times.15 mL). The combined organic layer was dried over sodium
sulfate, filtered and the filtrate concentrated. The crude product
was purified by preparative HPLC to afford Compound 334 as an
off-white solid (20.6 mg, 23%). HPLC retention time 7.12 and 7.33
min (Methods B and C respectively). MS(ES): m/z=433 [M+H].sup.+;
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 7.86 (dd, J=7.28,
2.26 Hz, 1H), 7.65-7.72 (m, 2H), 7.44-7.51 (m, 1H), 7.17-7.41 (m,
2H), 4.79 (s, 2H), 4.16-4.23 (m, 3H), 3.81-3.96 (m, 5H), 2.40-2.49
(m, 2H).
[1005] The Compounds shown in Table 40 have been prepared similar
to Compound 334 by coupling of in-situ generated isocyanate of 334B
with 199B.
TABLE-US-00042 TABLE 40 Ret Ex. Time HPLC No. Structure Name [M +
H].sup.+ (min.) Methods 335 ##STR00574## N.sup.5-(3-
Cyanotetrahydrofuran-3-yl)- 2-(3,4-dichlorophenyl)-6,7-
dihydropyrazolo[1,5-a] pyrazine-3,5(4H)- dicarboxamide 451 1.24
1.24 E L
##STR00575##
Intermediate 336A: (R)-Phenyl
(2-fluoro-3-hydroxy-3-methylbutyl)carbamate
##STR00576##
[1007] To a solution of (R)-4-amino-3-fluoro-2-methylbutan-2-ol
(100 mg, 0.825 mmol) in DCM (3 mL) was added phenyl chloroformate
(0.124 mL, 0.990 mmol) at 0.degree. C. followed by pyridine (0.100
mL, 1.238 mmol); the reaction mixture was stirred at RT for 12 h.
The reaction mixture was quenched with water and extracted with
ethyl acetate (3.times.10 mL). The combined organic layer was
washed with a 1.5 N aq. solution of HCl, dried over
Na.sub.2SO.sub.4, filtered and the filtrate evaporated under vacuum
to afford Intermediate 336A as a colorless liquid (130 mg, 65%).
The crude product was used in the subsequent transformation without
further purification. .sup.1H NMR (300 MHz, chloroform-d) .delta.
ppm 7.33-7.44 (m, 2H), 7.06-7.31 (m, 3H), 5.48 (bs, 1H), 4.30-4.56
(m, 1H), 3.73 (m, 1H), 3.33-3.51 (m, 1H), 1.91 (m, 1H), 1.32 (dd,
J=11.95, 1.23 Hz, 6H).
Compound 336:
(R)-2-(3-Chloro-4-fluorophenyl)-N.sup.5-(2-fluoro-3-hydroxy-3-methylbutyl-
)-6,7-dihydropyrazolo[1,5-a]pyrazine-3,5(4H)-dicarboxamide
##STR00577##
[1009] To a stirred solution of 185B (0.03 g, 0.102 mmol) in DMSO
(1 mL) was added Intermediate 336A (0.025 g, 0.102 mmol) and TEA
(0.043 mL, 0.305 mmol) under nitrogen and the reaction mixture was
stirred at RT for 12 h. The reaction mixture was diluted with ethyl
acetate (50 mL), washed with water, brine, dried over anhydrous
Na.sub.2SO.sub.4, filtered and the filtrate was concentrated. The
crude product was purified by preparative HPLC to afford Compound
336 as a pale yellow solid (9 mg, 20%). The HPLC Retention times
are 1.168 min and 1.209 min (Methods E and L respectively). MS(ES):
-m/z=442.2 [M+H].sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
ppm 7.85 (dd, J=7.28, 2.13 Hz, 1H), 7.68 (ddd, J=8.64, 4.82, 2.16
Hz, 1H), 7.46 (t, J=9.00 Hz, 1H), 7.40-7.20 (2bs, 2H), 7.11 (t,
J=5.40 Hz, 1H), 4.69-4.79 (m, 3H), 4.29-4.10 (dd, J=9.19, 1.85 Hz,
1H), 4.09-4.22 (m, 2H), 3.80-3.89 (m, 2H), 3.45-3.63 (m, 1H),
3.09-3.22 (m, 1H), 1.12 (dd, J=5.08, 1.13 Hz, 6H).
[1010] The Compounds shown in Table 41 have been prepared similar
to Compound 336 by coupling of 336A with 185B analogs.
TABLE-US-00043 TABLE 41 Ret Ex. Time HPLC No. Structure Name [M +
H].sup.+ (min.) Methods 337 ##STR00578## (R)-2-(3-Chlorophenyl)-
N.sup.5-(2-fluoro-3-hydroxy-3- methylbutyl)-6,7-
dihydropyrazolo[1,5-a] pyrazine-3,5(4H)- dicarboxamide 424.2 1.111
1.152 E L 338 ##STR00579## (R)-2-(3,4- Dichlorophenyl)-N.sup.5-(2-
fluoro-3-hydroxy-3- methylbutyl)-6,7- dihydropyrazolo[1,5-a]
pyrazine-3,5(4H)- dicarboxamide 458.2 1.247 1.230 E L
##STR00580##
Intermediate 339A: tert-Butyl
3-(3-carbamoyl-2-(3-chloro-4-fluorophenyl)-4,5,6,7-tetrahydropyrazolo[1,5-
-a]pyrazine-5-carboxamido)azetidine-1-carboxylate
##STR00581##
[1012] To a stirred solution of Intermediate
1-(tert-butoxycarbonyl)azetidine-3-carboxylic acid (273 mg, 1.47
mmol) in toluene (6 mL) was added TEA (0.472 ml, 3.39 mmol)
followed by DPPA (0.22 ml, 1.0 mmol) and the mixture was stirred at
90.degree. C. for 1 h. The reaction mixture was cooled to RT and a
solution of Intermediate 185B (200 mg, 0.679 mmol) in DMF (2 mL)
was added and stirring continued at RT for 16 h. The reaction was
quenched with a 10% aq. solution of NaHCO.sub.3, the organic layer
was separated, dried over sodium sulfate, and concentrated. The
crude product was purified by silica gel chromatography (4 g
REDISEP.RTM. column, eluting with 5% MeOH in CHCl.sub.3). Fractions
containing the product were combined and evaporated to afford
Intermediate 339A as a buff colored solid (250 mg, 75% yield)
MS(ES): m/z=493.
Intermediate 339B:
N.sup.5-(Azetidin-3-yl)-2-(3-chloro-4-fluorophenyl)-6,7-dihydropyrazolo[1-
,5-a]pyrazine-3,5(4H)-dicarboxamide
##STR00582##
[1014] To a stirred solution of Intermediate 339A (0.25 g, 0.50
mmol) in MeOH (5 mL) was added a 4M solution of HCl in dioxane (5
mL, 20 mmol). The resulting solution was allowed to stir at RT for
4 h. The reaction mixture was then concentrated and triturated with
diethyl ether to afford Intermediate 339B (0.2 g, 55%). MS(ES):
m/z=393 [M+H].sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
ppm 7.84 (dd, J=7.03, 2.01 Hz, 1H) 7.64-7.70 (m, 1H), 7.45 (q,
J=8.70 Hz, 1H), 7.18-7.39 (m, 2H), 6.61 (d, J=7.53 Hz, 1H), 5.53
(s, 1H), 4.73 (s, 2H), 4.13 (m, 1H), 3.97-4.04 (m, 2H), 3.83 (br.
s., 2H) 3.05-3.16 (m, 4H).
Compound 339:
2-(3-Chloro-4-fluorophenyl)-N.sup.5-(1-(2,2,2-trifluoroethyl)azetidin-3-y-
l)-6,7-dihydropyrazolo[1,5-a]pyrazine-3,5(4H)-dicarboxamide
##STR00583##
[1016] To a stirred solution of Intermediate 339B (100 mg, 0.255
mmol) in THF (10 mL) was added DIPEA (0.222 mL, 1.273 mmol)
followed by 2,2,2-trifluoroethyl trifluoromethanesulfonate (118 mg,
0.509 mmol) and stirred at RT for 16 h. The reaction mixture was
quenched with a 10% aqueous solution of NaHCO.sub.3 and extracted
with EtOAc (2.times.20 mL). The combined organic layer was dried
over Na.sub.2SO.sub.4, filtered and the filtrate evaporated. The
crude compound was purified by preparative HPLC to afford Compound
339 as an off-white solid (15 mg, 12%). HPLC retention times 10.73
min. and 11.90 min. (Methods C and D). MS(ES): m/z=475 [M+H].sup.+;
.sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. ppm 7.84 (dd, J=7.37,
2.08 Hz, 1H), 7.62-7.72 (m, 1H), 7.41-7.50 (m, 1H), 7.36 (br. s.,
1H), 7.27 (d, J=6.80 Hz, 1H), 7.18 (br. s., 1H), 4.73 (s, 2H)
4.19-4.31 (m, 1H), 4.06-4.17 (m, 2H), 3.84 (d, J=5.67 Hz, 2H),
3.57-3.69 (m, 2H), 3.09-3.23 (m, 4H).
##STR00584## ##STR00585##
Intermediate 340A: Diethyl
1-(2-((tert-butoxycarbonyl)amino)propyl)-3-iodo-1H-pyrazole-4,5-dicarboxy-
late
##STR00586##
[1018] To a stirred suspension of PPh.sub.3 (12.41 g, 47.3 mmol) in
THF (100 mL) was added DIAD (9.20 mL, 47.3 mmol) at -10.degree. C.
and allowed to stir at 0.degree. C. for 0.5 h. Intermediate 104C
(8.0 g, 23.66 mmol) was added as a solution in THF (10 mL) at
0.degree. C. and stirred at RT for 45 min. The reaction mixture was
cooled again to 0.degree. C. and tert-butyl
(1-hydroxypropan-2-yl)carbamate (5.39 g, 30.8 mmol) was added as a
solution in THF (10 mL) and the mixture was stirred at RT for 16 h.
The reaction mixture was diluted with ethyl acetate (100 mL),
washed with water and brine. The organic layer was dried over
Na.sub.2SO.sub.4, filtered and the filtrate concentrated under
reduced pressure. The crude compound was purified by silica gel
chromatography (40 g REDISEP.RTM. column, eluting with 15% EtOAc in
hexane). Fractions containing the product were combined and
evaporated to afford the Intermediate 340A as a brown liquid (7.0
g) contaminated with impurities arising from the coupling reagents.
MS(ES): m/z=496 [M+H].sup.+. The crude intermediate was taken to
the next step without further purification.
Intermediate 340B: Ethyl
2-iodo-6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxy-
late
##STR00587##
[1020] To a stirred solution of Intermediate 340A (7.0 g, 14.13
mmol) in 1,4-dioxane (10 mL) was added 4 M HCl in dioxane (25 mL,
100 mmol) and the solution was stirred at RT for 2 h. The reaction
mixture was concentrated and the residue was diluted with EtOAc (20
mL). The EtOAc solution was washed successively with water, a
saturated aq. solution of NaHCO.sub.3, and brine. The organic layer
was dried over Na.sub.2SO.sub.4, filtered and concentrated under
reduced pressure. The residue obtained was heated in a
ROTAVAPOR.RTM. at 60.degree. C. for 5 h. The solid product was
washed with ether to afford Intermediate 340B (4.0 g, 87%). MS(ES):
m/z=350 [M+H].sup.+; .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta.
ppm 8.49 (s, 1H), 4.27-4.49 (m, 1H), 4.11-4.26 (m, 2H), 4.03 (d,
J=11.71 Hz, 2H), 1.06-1.39 (m, 6H).
Intermediate 340C: Ethyl
2-iodo-6-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxylate
##STR00588##
[1022] To a solution of Intermediate 340B (4.0 g, 11.46 mmol) in
THF (40 mL) was added BH.sub.3.THF (40.1 mL, 80 mmol, 1M in THF)
and the reaction mixture was stirred at 70.degree. C. for 16 h.
Ethanol (10 mL) was added and the reaction mixture was heated to
reflux for 1 h. The reaction mixture was concentrated to afford
Intermediate 340C (1.9 g, 40% yield) as a pale brown liquid.
MS(ES): m/z=336 [M+H].sup.+. The crude compound was taken to the
next step without further purification.
Intermediate 340D: 5-tert-Butyl
3-ethyl2-iodo-6-methyl-6,7-dihydropyrazolo[1,5-a]pyrazine-3,5(4H)-dicarbo-
xylate
##STR00589##
[1024] To a stirred solution of Intermediate 340C (0.81 g, 2.417
mmol) in DCM (10 mL) was added TEA (0.404 mL, 2.90 mmol) followed
by Boc.sub.2O (0.617 mL, 2.66 mmol) and the resulting solution was
stirred at RT for 16 h. It was then diluted with DCM (10 mL) washed
with water and brine. The crude compound was purified by silica gel
chromatography (12 g REDISEP.RTM. column, eluting with 1% MeOH in
CHCl.sub.3). Fractions containing the product were combined and
evaporated to afford Intermediate 340D as a colorless semisolid
(0.7 g, 67%). MS(ES): m/z=435 [M+H].sup.+; .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 5.07 (d, J=18.57 Hz, 1H), 4.69 (br. s.,
1H), 4.39 (d, J=18.57 Hz, 1H), 4.06-4.28 (m, 4H), 1.45 (s, 9H),
1.23-1.34 (m, 3H), 1.08 (d, J=7.03 Hz, 3H).
Intermediate 340E:
5-(tert-Butoxycarbonyl)-2-iodo-6-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]-
pyrazine-3-carboxylic acid
##STR00590##
[1026] To a stirred solution of Intermediate 340D (0.85 g, 1.953
mmol) in EtOH (2.0 mL) was added a solution of NaOH (0.391 g, 9.76
mmol) in water (1.0 mL) and the resulting solution was stirred at
RT for 16 h. The reaction mixture was concentrated and the residue
was acidified by the addition of a 1N aq. solution of HCl (5 mL)
which was allowed to stir for 10 min. The generated precipitate was
filtered and dried to afford Intermediate 340E as a white solid
(0.65 g, 82%). MS(ES): m/z=408 [M+H].sup.+; .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta. ppm 5.05 (d, J=18.89 Hz, 1H), 4.67 (br. s.,
1H), 4.36 (d, J=18.13 Hz, 1H), 4.13-4.25 (m, 1H), 3.93-4.13 (m,
2H), 1.44 (s, 9H), 1.08 (t, J=6.99 Hz, 3H).
Intermediate 340F: tert-Butyl
3-carbamoyl-2-iodo-6-methyl-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carb-
oxylate
##STR00591##
[1028] To a stirred solution of Intermediate 340E (0.65 g, 1.596
mmol) in DMF (3.0 mL) was added NH.sub.4Cl (0.427 g, 7.98 mmol),
HATU (1.214 g, 3.19 mmol) and DIPEA (0.836 mL, 4.79 mmol) and the
resulting solution was allowed to stir at RT for 3 h. It was
diluted with ethyl acetate (10 mL), washed with water, brine, dried
over Na.sub.2SO.sub.4, filtered and the filtrate concentrated. The
crude compound was purified by silica gel chromatography (12 g
REDISEP.RTM. column, eluting with 2% MeOH in CHCl.sub.3). Fractions
containing the product were combined and evaporated to afford
Intermediate 340F as a colorless liquid (0.38 g, 59%). MS(ES):
m/z=407 [M+H].sup.+; .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta.
ppm 6.79-7.56 (m, 2H), 5.01 (d, J=18.51 Hz, 1H), 4.66 (br. s., 1H),
4.39 (d, J=18.13 Hz, 1H), 3.96-4.20 (m, 2H), 1.44 (s, 9H), 1.07 (d,
J=6.80 Hz, 3H).
Intermediate 340G: tert-Butyl
3-carbamoyl-2-iodo-6-methyl-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carb-
oxylate
##STR00592##
[1030] To a stirred suspension of Intermediate 340F (0.32 g, 0.788
mmol) in 1,4-dioxane (8.0 mL) was added
(3-chloro-4-fluorophenyl)boronic acid (0.179 g, 1.024 mmol),
K.sub.3PO.sub.4 (1.292 g, 2.58 mmol) and the contents of the flask
were purged with N.sub.2 for 10 min.
PdCl.sub.2(dppf)-CH.sub.2Cl.sub.2 (0.042 g, 0.052 mmol) was then
added and the reaction mixture was stirred at 80.degree. C. for 6
h. The reaction mixture was cooled to RT; diluted with ethyl
acetate (10 mL), washed with water, dried over Na.sub.2SO.sub.4,
filtered and the filtrate concentrated under reduced pressure. The
crude compound was purified by silica gel chromatography (12 g
REDISEP.RTM. column, eluting with 2% MeOH in CHCl.sub.3). Fractions
containing the product were combined and evaporated to afford
Intermediate 340G as a pale yellow solid (0.27 g, 84%). MS(ES):
m/z=408 [M+H].sup.+; .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta.
ppm 7.85-7.92 (m, 1H), 7.71 (ddd, J=8.69, 4.91, 2.27 Hz, 1H), 7.46
(d, J=17.75 Hz, 1H), 7.24-7.38 (m, 2H), 4.99 (d, J=17.75 Hz, 1H),
4.72 (br. s., 1H), 4.44 (d, J=17.75 Hz, 1H), 4.08-4.28 (m, 2H),
1.46 (s, 9H), 1.15 (s, 3H).
Intermediate 340H:
2-(3-Chloro-4-fluorophenyl)-6-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyr-
azine-3-carboxamide, TFA
##STR00593##
[1032] To a stirred solution of Intermediate 340G (0.09 g, 0.220
mmol) in DCM (3.0 mL) was added TFA (0.017 mL, 0.220 mmol) and the
resulting solution was stirred at RT for 2 h. It was then
concentrated and the residue was triturated with hexane to afford
Intermediate 340H as a white solid (0.1 g). MS(ES): m/z=308
(M+H].sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm
7.80-7.85 (m, 1H), 7.64-7.71 (m, 1H), 7.40-7.55 (m, 2H), 7.13-7.27
(m, 1H), 4.71 (d, J=16.06 Hz, 1H) 4.53 (dd, J=13.55, 4.02 Hz, 2H),
3.90-4.11 (m, 2H), 1.40 (d, J=6.53 Hz, 3H).
Compounds 340 and 341:
N.sup.5-(tert-Butyl)-2-(3-chloro-4-fluorophenyl)-6-methyl-6,7-dihydropyra-
zolo[1,5-a]pyrazine-3,5(4H)-dicarboxamide
##STR00594##
[1034] To a stirred suspension of Intermediate 340H (0.12 g, 0.284
mmol) in THF (3.0 mL) was added TEA (0.198 mL, 1.419 mmol) followed
by 2-isocyanato-2-methylpropane (0.028 g, 0.284 mmol) and the
resulting solution was stirred at RT for 2 h. The reaction mixture
was diluted with EtOAc (10 mL) washed successively with water, a
saturated aq. solution of NaHCO.sub.3 solution and brine. The
organic layer was dried over Na.sub.2SO.sub.4, filtered and the
filtrate concentrated under reduced pressure. The crude compound
was purified by silica gel chromatography (12 g REDISEP.RTM.
column, eluting with 2% MeOH in CHCl.sub.3) to afford the racemic
compound. The individual isomers were separated by preparative
Chiral SFC (Column: Lux cellulose-4 (250.times.4.6) mm, 5 .mu.m,
flow rate 4 mL/min, Mobile Phase A: CO.sub.2, Mobile Phase B: 0.3%
DEA in methanol, back pressure: 97 bar. Retention time: 1.95 min.
and 3.03 min. respectively for Compounds 340 and 341.
[1035] Compound 340: (24.5 mg, 20%, off-white solid); MS(ES):
m/z=408 [M+H].sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
ppm 7.87-7.92 (m, 1H), 7.68-7.77 (m, 1H), 7.46 (d, J=18.07 Hz, 1H),
7.21-7.39 (m, 2H), 6.18 (s, 1H), 5.04 (d, J=17.57 Hz, 1H),
4.70-4.80 (m, 1H), 4.31 (d, J=17.57 Hz, 1H), 3.99-4.19 (m, 2H),
1.21-1.39 (m, 9H), 1.06-1.16 (m, 3H).
[1036] Compound 341: (28 mg, 24%, off-white solid); MS(ES): m/z=408
[M+H].sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm
7.87-7.92 (m, 1H), 7.68-7.77 (m, 1H), 7.46 (d, J=18.07 Hz, 1H),
7.21-7.39 (m, 2H), 6.18 (s, 1H), 5.04 (d, J=17.57 Hz, 1H),
4.70-4.80 (m, 1H), 4.31 (d, J=17.57 Hz, 1H), 3.99-4.19 (m, 2H),
1.21-1.39 (m, 9H), 1.06-1.16 (m, 3H).
[1037] The Compounds shown in Table 42 have been prepared similar
to Compounds 340 and 341 by coupling of 340H with different
isocyanates.
TABLE-US-00044 TABLE 42 Ret Ex. Time HPLC No. Structure Name [M +
H].sup.+ (min.) Methods 342 ##STR00595##
2-(3-Chloro-4-fluorophenyl)- N.sup.5-(3,3-difluorocyclobutyl)-6-
methyl-6,7-dihydropyrazolo [1,5-a]pyrazine-3,5(4H)- dicarboxamide
442 1.61 N 343 ##STR00596## 2-(3-Chloro-4-fluorophenyl)-
N.sup.5-(3,3-difluorocyclobutyl)-6- methyl-6,7-dihydropyrazolo
[1,5-a]pyrazine-3,5(4H)- dicarboxamide 442 2.48 N 344 ##STR00597##
2-(3-Chloro-4-fluorophenyl)- N.sup.5-(3,3-difluoro-1-
methylcyclobutyl)-6-methyl- 6,7-dihydropyrazolo[1,5-a]
pyrazine-3,5(4H)- dicarboxamide 456 2.65 N 345 ##STR00598##
2-(3-Chloro-4-fluorophenyl)- N.sup.5-(3,3-difluoro-1-
methylcyclobutyl)-6-methyl- 6,7-dihydropyrazolo[1,5-a]
pyrazine-3,5(4H)- dicarboxamide 456 4.38 Q
##STR00599## ##STR00600##
Intermediate 346A: Diethyl
1-(2-((tert-butoxycarbonyl)amino)-3,3,3-trifluoropropyl)-3-iodo-1H-pyrazo-
le-4,5-dicarboxylate
##STR00601##
[1039] To a stirred solution of PPh.sub.3 (3.10 g, 11.83 mmol) in
THF (50 mL) was added DIAD (2.300 mL, 11.83 mmol) at 0.degree. C.
and the mixture stirred for 15 min prior to the addition of
Intermediate 104C (2 g, 5.92 mmol) in THF (10 mL) which was allowed
to stir for 15 min. A solution of tert-butyl
(1,1,1-trifluoro-3-hydroxypropan-2-yl)carbamate (1.763 g, 7.69
mmol) in THF (10 mL) was then added and the solution was stirred at
RT for 16 h. The reaction mixture was poured into water and
extracted with EtOAc (2.times.100 mL). The combined organic layer
was washed with brine, dried over anhydrous Na.sub.2SO.sub.4,
filtered and the filtrate concentrated under reduced pressure. The
crude compound was purified by silica gel chromatography (24 g
REDISEP.RTM. column, eluting with 10% EtOAc in hexanes). Fractions
containing the product were combined and evaporated to afford
Intermediate 346A (3 g, 88%) as an oil. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 7.94-7.84 (m, 1H), 4.87-4.80 (m, 1H),
4.79-4.67 (m, 1H), 4.40-4.31 (m, 3H), 4.30-4.21 (m, 2H), 1.33 (s,
9H), 1.30-1.25 (m, 6H).
Intermediate 346B: Ethyl
2-iodo-4-oxo-6-(trifluoromethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-
e-3-carboxylate
##STR00602##
[1041] Intermediate 346A (3 g, 5.46 mmol) was dissolved in 4 M HCl
in 1,4-dioxane (50 mL) and stirred at RT for 2 h. The volatiles
were removed under reduced pressure, and the crude residue was
dissolved in EtOAc (250 mL) and washed with an aq. solution of
NaHCO.sub.3, then dried over Na.sub.2SO.sub.4 and concentrated
under reduced pressure. The crude was dissolved in EtOH (25 mL) and
stirred at 60.degree. C. for 16 h. Ethanol was removed under
reduced pressure and the resulting residue was stirred with hexanes
for 15 min. The triturated solid was filtered and dried to afford
Intermediate 346B (0.96 g, 41.4%) as an off-white solid. MS(ES):
-m/z=404.0 [M+H].sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
ppm 9.34 (d, J=4.5 Hz, 1H), 4.84-4.73 (m, 2H), 4.71-4.60 (m, 1H),
4.34-4.20 (m, 2H), 1.32-1.23 (m, 3H).
Intermediate 346C: Ethyl
2-iodo-6-(trifluoromethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-ca-
rboxylate
##STR00603##
[1043] To a stirred solution of Intermediate 346B (0.1 g, 0.248
mmol) in THF (1 mL) was added BH.sub.3.DMS complex (0.236 mL, 2.481
mmol) under nitrogen and the reaction mixture was stirred at RT for
16 h. The reaction mixture was then cooled to 0.degree. C.,
quenched with methanol (1 mL) and stirred for 15 min at RT. The
volatiles were removed under reduced pressure and the crude
compound was purified by silica gel chromatography (12 g
REDISEP.RTM. column, eluting with 25% EtOAc in hexanes). Fractions
containing the product were combined and evaporated to afford
Intermediate 346C as a white solid (0.025 g, 25%). MS(ES):
-m/z=390.4 [M+H].sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
ppm 4.37-4.27 (m, 2H), 4.22 (q, J=7.4 Hz, 3H), 4.12-4.00 (m, 3H),
1.33-1.26 (m, 3H).
Intermediate 346D: 5-tert-Butyl 3-ethyl
2-iodo-6-(trifluoromethyl)-6,7-dihydropyrazolo[1,5-a]pyrazine-3,5(4H)-dic-
arboxylate
##STR00604##
[1045] To a stirred solution of Intermediate 346C (0.025 g, 0.064
mmol) in DCM (5 mL) was added TEA (0.027 mL, 0.193 mmol) and DMAP
(0.785 mg, 6.42 .mu.mol), followed by Boc.sub.2O (0.018 mL, 0.077
mmol) and the resulting solution was allowed to stir at RT for 12
h. The reaction mixture was then diluted with DCM (20 mL), washed
with water, dried over anhydrous Na.sub.2SO.sub.4, filtered and the
filtrate concentrated under reduced pressure. The crude compound
was purified by silica gel chromatography (12 g REDISEP.RTM.
column, eluting with 20% EtOAc in hexanes). Fractions containing
the product were combined and evaporated to afford Intermediate
346D as a white solid (0.025 g, 76%). MS(ES): m/z=490.4
[M+H].sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm
5.55-5.38 (m, 1H), 5.18-5.08 (m, 1H), 4.54 (br. s., 3H), 4.24 (d,
J=7.0 Hz, 2H), 1.48 (s, 9H), 1.31 (t, J=7.3 Hz, 3H).
Intermediate 346E:
5-(tert-Butoxycarbonyl)-2-iodo-6-(trifluoromethyl)-4,5,6,7-tetrahydropyra-
zolo[1,5-a]pyrazine-3-carboxylic acid
##STR00605##
[1047] To a solution of Intermediate 346D (0.22 g, 0.450 mmol) in
ethanol (2 mL) and water (2 mL) was added NaOH (0.036 g, 0.899
mmol) and the solution was stirred at RT for 16 h. The reaction
mixture was concentrated under reduced pressure and the pH of the
crude product was adjusted to 2 with an aqueous solution of 1.5N
HCl and extracted with EtOAc (2.times.20 mL). The combined organic
layer was dried over anhydrous Na.sub.2SO.sub.4, filtered and the
filtrate concentrated under reduced pressure to afford Intermediate
346E as a white solid (0.12 g, 55%). MS(ES): m/z=462.4 [M+H].sup.+;
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 12.4 (br, s., 1H),
5.55-5.38 (m, 1H), 5.18-5.08 (m, 1H), 4.54 (m, 3H), 1.48 (s,
9H).
Intermediate 346F: tert-Butyl
3-carbamoyl-2-iodo-6-(trifluoromethyl)-6,7-dihydropyrazolo[1,5-a]pyrazine-
-5(4H)-carboxylate
##STR00606##
[1049] To a solution of Intermediate 346E (0.12 g, 0.260 mmol) in
DMF (1 mL) was added NH.sub.4Cl (0.028 g, 0.520 mmol), HATU (0.099
g, 0.260 mmol) and DIPEA (0.136 mL, 0.781 mmol) under nitrogen and
the resulting solution was stirred at RT for 16 h. The reaction
mixture was poured into water and the aqueous layer was extracted
with EtOAc (2.times.25 mL). The combined organic layers were dried
over anhydrous Na.sub.2SO.sub.4 and concentrated under reduced
pressure. The crude compound was purified by silica gel
chromatography (12 g REDISEP.RTM. column, eluting with 3% MeOH in
CHCl.sub.3). Fractions containing the product were combined and
evaporated to afford Intermediate 346F as a white solid (0.07 g,
50%). MS(ES): m/z=460.9 [M+H].sup.+.
Intermediate 346G: tert-Butyl
3-carbamoyl-2-(3-chloro-4-fluorophenyl)-6-(trifluoromethyl)-6,7-dihydropy-
razolo[1,5-a]pyrazine-5 (4H)-carboxylate
##STR00607##
[1051] To a solution of Intermediate 346F (0.35 g, 0.761 mmol) and
(3-chloro-4-fluorophenyl)boronic acid (0.215 g, 0.837 mmol) in DMF
(2 mL) was added a solution of Na.sub.2CO.sub.3 (0.242 g, 2.282
mmol) in water (1 mL) and the reaction mixture was purged with
nitrogen for 5 min. Pd(PPh.sub.3).sub.4 (0.044 g, 0.038 mmol) was
then added and the reaction mixture was stirred at 100.degree. C.
for 18 h. The reaction mixture was cooled to RT and extracted with
EtOAc (2.times.50 mL). The combined organic layer was dried over
anhydrous Na.sub.2SO.sub.4, filtered and the filtrate concentrated
under reduced pressure. The crude compound was purified by silica
gel chromatography (12 g REDISEP.RTM. column, eluting with 5% MeOH
in CHCl.sub.3). Fractions containing the product were combined and
evaporated to afford Intermediate 346G as a white solid (0.25 g,
68%). MS(ES): m/z=464.5 [M+H].sup.+; .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 7.92-7.82 (m, 1H), 7.73-7.67 (m, 1H),
7.65-7.52 (m, 1H), 7.51-7.44 (m, 1H), 7.41-7.21 (m, 2H), 5.17-5.05
(m, 1H), 4.65-4.48 (m, 3H), 1.50 (s, 9H).
Intermediate 346H:
2-(3-Chloro-4-fluorophenyl)-6-(trifluoromethyl)-4,5,6,7-tetrahydropyrazol-
o[1,5-a]pyrazine-3-carboxamide.TFA
##STR00608##
[1053] To a solution of Intermediate 346G (0.3 g, 0.648 mmol) in
DCM (5 mL) was added TFA (0.499 mL, 6.48 mmol) under nitrogen and
the resulting solution was stirred at RT for 2 h. The volatiles
were removed under reduced pressure and the crude product was
triturated with diethyl ether to afford Intermediate 346H as a
white solid (0.21 g, 54%). MS(ES): m/z=363.4 [M+H].sup.+;
Compounds 346 and 347:
N.sup.5-(tert-Butyl)-2-(3-chloro-4-fluorophenyl)-6-(trifluoromethyl)-6,7--
dihydropyrazolo[1,5-a]pyrazine-3,5(4H)-dicarboxamide
##STR00609##
[1055] To a solution of Intermediate 346H (50 mg 0.10 mmol),
2-isocyanato-2-methylpropane (10.40 mg, 0.105 mmol) in THF (1 mL)
was added TEA (0.044 mL, 0.315 mmol) under nitrogen and the
resulting solution was stirred at 80.degree. C. for 16 h. The
reaction mixture was cooled to RT and concentrated under reduced
pressure. The crude material was dissolved in EtOAc (50 mL), washed
with water, brine, dried over anhydrous Na.sub.2SO.sub.4, filtered
and the filtrate concentrated under reduced pressure. The compound
was subjected to chiral separation using preparative SFC to afford
R and S enantiomers (Column: Lux cellulose-4 (250.times.4.6) mm, 5
.mu.m, flow rate 3 mL/min, Mobile Phase A: CO.sub.2, Mobile Phase
B: 0.3% DEA in methanol, back pressure: 100 bar. Retention times
2.61 min. and 5.05 min. respectively for Compounds 346 and 347.
[1056] Compound 346: (11.34 mg, 23%); MS(ES): m/z=462 [M+H].sup.+;
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 7.86 (dd, J=7.53,
2.01 Hz, 1H), 7.69 (ddd, J=8.66, 4.89, 2.01 Hz, 1H), 7.46 (t,
J=8.78 Hz, 1H), 7.40 (br. s., 1H), 7.29 (br. s., 1H), 6.47 (s, 1H),
5.63 (br. s., 1H), 5.10 (d, J=17.07 Hz, 1H), 4.46-4.55 (m, 3H),
1.31 (s, 9H).
[1057] Compound 347: (10.41 mg, 21%) MS(ES): m/z=462 [M+H].sup.+;
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 7.86 (dd, J=7.28,
2.26 Hz, 1H), 7.66-7.72 (m, 1H), 7.47 (d, J=9.04 Hz, 1H), 7.25-7.42
(m, 2H), 6.47 (s, 1H), 5.63 (d, J=4.52 Hz, 1H), 5.12 (s, 1H),
4.47-4.55 (m, 3H), 1.31 (s, 9H).
##STR00610## ##STR00611## ##STR00612##
Intermediate 348A:
tert-Butyl(1-cyclopropyl-2-hydroxyethyl)carbamate
##STR00613##
[1059] To a stirred solution of tert-butyl
(1-cyclopropyl-2-hydroxyethyl)carbamate (6.5 g, 64.3 mmol) in DCM
(10.0 mL) was added TEA (10.75 mL, 77 mmol), followed by Boc.sub.2O
(16.41 mL, 70.7 mmol) and the resulting solution was stirred at RT
for 16 h. The reaction mixture was concentrated and the residue was
extracted with DCM (50 mL). The organic layer was washed with
water, brine, dried over Na.sub.2SO.sub.4, filtered and the
filtrate concentrated under reduced pressure. The crude compound
was purified by silica gel chromatography (120 g REDISEP.RTM.
column, eluting with 20% EtOAc in hexanes). Fractions containing
the product were combined and evaporated to afford Intermediate
348A as a colorless liquid (6.2 g, 48%). .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 6.47 (d, J=7.03 Hz, 1H), 4.45-4.58 (m,
1H), 3.38-3.45 (m, 2H), 2.98 (br. s., 1H), 1.31-1.47 (m, 9H),
0.76-0.89 (m, 1H), 0.34-0.45 (m, 1H), 0.18-0.32 (m, 2H), 0.07-0.15
(m, 1H).
Intermediate 348B:
Diethyl1-(2-((tert-butoxycarbonyl)amino)-2-cyclopropylethyl)-3-iodo-1H-py-
razole-4,5-dicarboxylate
##STR00614##
[1061] To a stirred solution of PPh.sub.3 (15.52 g, 59.2 mmol) in
THF (40.0 mL) cooled to -10.degree. C. was added DIAD (11.50 mL,
59.2 mmol) and the resulting solution stirred at 0.degree. C. for
0.5 h. Intermediate 104C (10 g, 29.6 mmol) was added as a solution
in THF (10 mL) at 0.degree. C. and stirred at RT for 45 min. A
solution of Intermediate 348A (7.74 g, 38.5 mmol) in THF (10 mL) at
was added at 0.degree. C. and the reaction mixture was allowed to
stir at RT for 16 h. The reaction mixture was diluted with EtOAc
(50 mL) washed with water and brine. The organic layer was dried
over Na.sub.2SO.sub.4 and concentrated under reduced pressure. The
crude compound was purified by silica gel chromatography (120 g
REDISEP.RTM. column, eluting with 15% EtOAc in hexanes). Fractions
containing the product were combined and evaporated to afford
Intermediate 348B along with impurities arising from the coupling
reagents (8.01 g, 84%); the crude material was taken to the next
step without further purification. MS(ES): m/z=522 [M+H].sup.+.
Intermediate 348C: Ethyl
6-cyclopropyl-2-iodo-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-ca-
rboxylate
##STR00615##
[1063] To a stirred solution of Intermediate 348B (8.0 g, 15.34
mmol) in 1,4-dioxane (10.0 mL) was added 4 M HCl in dioxane (40.0
mL, 160 mmol) and the resulting solution stirred at RT for 2 h. The
reaction mixture was concentrated and diluted with EtOAc (50 mL).
The organic layer was washed successively with water, a saturated
aq. solution of NaHCO.sub.3, and brine, then dried over
Na.sub.2SO.sub.4, filtered and the filtrate concentrated under
reduced pressure. The residue obtained was heated in a
ROTAVAPOR.RTM. at 60.degree. C. for 5 h. The solid product was
triturated with diethyl ether to afford Intermediate 348C as an
off-white solid (1.6 g, 28%). MS(ES): m/z=376 [M+H].sup.+; .sup.1H
NMR (300 MHz, DMSO-d.sub.6) .delta. ppm 8.67 (d, J=2.27 Hz, 1H),
4.47 (dd, J=13.22, 4.53 Hz, 1H), 4.17-4.33 (m, 3H), 3.15 (d, J=9.07
Hz, 1H), 1.28 (s, 3H), 0.90 (d, J=8.69 Hz, 1H), 0.40-0.54 (m, 2H),
0.20-0.37 (m, 2H).
Intermediate 348D: Ethyl
6-cyclopropyl-2-iodo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxyl-
ate
##STR00616##
[1065] To a solution of Intermediate 348C (1.3 g, 3.47 mmol) in THF
(10 mL) was added BH.sub.3.THF (6.06 mL, 12.13 mmol, 1 M in THF)
and the resulting solution was stirred at 60.degree. C. for 16 h.
The reaction mixture was quenched with ethanol (10 mL) and heated
to reflux for 1 h. The reaction mixture was concentrated under
reduced pressure to afford crude Intermediate 348D (1.2 g), which
was taken to the next step without further purification. MS(ES):
m/z=362 [M+H].sup.+.
Intermediate 348E: 5-tert-Butyl 3-ethyl
6-cyclopropyl-2-iodo-6,7-dihydropyrazolo[1,5-a]pyrazine-3,5(4H)-dicarboxy-
late
##STR00617##
[1067] To a solution of Intermediate 348D (1.2 g, 3.32 mmol) in DCM
(10.0 mL) was added TEA (0.556 mL, 3.99 mmol), followed by
Boc.sub.2O (0.849 mL, 3.65 mmol) and the solution was stirred at RT
for 16 h. The reaction mixture was diluted with DCM (15 mL) and the
organic layer was washed with water, brine, dried over
Na.sub.2SO.sub.4, filtered and the filtrate concentrated. The crude
compound was purified by silica gel chromatography (24 g
REDISEP.RTM. column, eluting with 25% EtOAc in hexane). Fractions
containing the product were combined and evaporated to afford the
Intermediate 348E as a colorless semi-solid (0.85 g, 55%). MS(ES):
m/z=462 [M+H].sup.+; .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta.
ppm 5.13 (d, J=18.89 Hz, 1H), 4.48 (d, J=18.89 Hz, 1H), 4.13-4.31
(m, 4H), 3.84 (br. s., 1H), 1.38-1.47 (m, 9H), 1.31 (s, 3H),
0.84-0.96 (m, 1H), 0.46 (d, J=8.31 Hz, 2H), 0.38 (d, J=4.91 Hz,
2H).
Intermediate 348F:
5-(tert-Butoxycarbonyl)-6-cyclopropyl-2-iodo-4,5,6,7-tetrahydropyrazolo[1-
,5-a]pyrazine-3-carboxylic acid
##STR00618##
[1069] To a stirred solution of Intermediate 348E (0.85 g, 1.843
mmol) in ethanol (2 mL) and water (1 mL) was added NaOH (0.369 g,
9.21 mmol) and the resulting solution was stirred at RT for 10 h.
The reaction mixture was diluted with DCM (10 mL) and washed
successively with an aqueous solution of 1N HCl, water and brine.
The organic layer was then dried over Na.sub.2SO.sub.4, filtered
and the filtrate concentrated under reduced pressure to afford the
Intermediate 348F as an off-white solid (0.75 g, 94%). MS(ES):
m/z=434 [M+H].sup.+; .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta.
ppm 12.6 (br. s., 1H), 5.11 (d, J=18.89 Hz, 1H), 4.45 (d, J=18.51
Hz, 1H), 4.16-4.25 (m, 2H), 3.82 (br. s., 1H), 1.43 (s, 9H),
0.82-0.96 (m, 1H), 0.47 (d, J=7.93 Hz, 2H), 0.35 (dd, J=6.80, 4.91
Hz, 2H).
Intermediate 348G: tert-Butyl
3-carbamoyl-6-cyclopropyl-2-iodo-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-
-carboxylate
##STR00619##
[1071] To a stirred solution of Intermediate 348F (0.75 g, 1.731
mmol) in DMF (4.0 mL) was added NH.sub.4Cl (0.463 g, 8.66 mmol),
HATU (1.316 g, 3.46 mmol) and DIPEA (1.512 mL, 8.66 mmol) and the
resulting solution was stirred at RT for 16 h. The reaction mixture
was diluted with ethyl acetate (10 mL), washed with water and
brine. The organic layer was dried over Na.sub.2SO.sub.4, filtered
and the filtrate concentrated under reduced pressure. The crude
compound was purified by silica gel chromatography (24 g
REDISEP.RTM. column, eluting with 65% EtOAc in hexanes). Fractions
containing the product were combined and evaporated to afford
Intermediate 348G as a colorless liquid (0.51 g, 68%). MS(ES):
m/z=433 [M+H].sup.+; .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta.
ppm 6.83-7.50 (m, 2H), 5.07 (d, J=18.13 Hz, 1H), 4.50 (d, J=18.51
Hz, 1H), 4.20 (d, J=2.27 Hz, 2H), 3.84 (br. s., 1H), 1.43 (s, 9H),
0.89 (d, J=9.82 Hz, 1H), 0.47 (d, J=7.93 Hz, 2H), 0.27-0.40 (m,
2H).
Intermediate 348H: tert-Butyl
3-carbamoyl-2-(3-chloro-4-fluorophenyl)-6-cyclopropyl-6,7-dihydropyrazolo-
[1,5-a]pyrazine-5(4H)-carboxylate
##STR00620##
[1073] To a stirred suspension of Intermediate 348G (0.47 g, 1.087
mmol) in 1,4-dioxane (5 mL) was added K.sub.3PO.sub.4 (1.631 mL,
3.26 mmol), (3-chloro-4-fluorophenyl)boronic acid (0.246 g, 1.414
mmol) and the reaction mixture was purged with nitrogen for 10 min.
PdCl.sub.2(dppf)-CH.sub.2Cl.sub.2 (0.053 g, 0.065 mmol) was then
added and the reaction mixture was heated to 80.degree. C. and
stirred for 6 h. The reaction mixture was filtered through
CELITE.RTM. and the filtrate was diluted with ethyl acetate (10
mL), and washed with water and brine. The organic layer was dried
over Na.sub.2SO.sub.4, filtered and the filtrate concentrated under
reduced pressure. The crude compound was purified by silica gel
chromatography (12 g REDISEP.RTM. column, eluting with 2% MeOH in
CHCl.sub.3). Fractions containing the product were combined and
evaporated to afford Intermediate 348H as an off-white solid (0.4
g, 85%). MS(ES): m/z=435 [M+H].sup.+; .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta. ppm 7.85-7.95 (m, 1H), 7.66-7.77 (m, 1H),
7.47 (t, J=9.07 Hz, 1H), 7.20-7.39 (m, 2H), 5.05 (d, J=17.37 Hz,
1H), 4.55 (d, J=17.37 Hz, 1H), 4.24 (br. s., 2H), 3.89 (br. s.,
1H), 1.45 (s, 9H), 0.87-1.05 (m, 1H), 0.31-0.55 (m, 4H).
Intermediate 348I:
2-(3-Chloro-4-fluorophenyl)-6-cyclopropyl-4,5,6,7-tetrahydropyrazolo[1,5--
a]pyrazine-3-carboxamide
##STR00621##
[1075] To a stirred solution of Intermediate 348H (0.43 g, 0.989
mmol) in DCM (8.0 mL) was added TFA (4.0 mL, 51.9 mmol) and the
resulting solution was stirred at RT for 2 h. The reaction mixture
was concentrated and the residue was extracted with DCM (10 mL),
and washed successively with water, a saturated aq. NaHCO.sub.3
solution and brine. The organic layer was dried over
Na.sub.2SO.sub.4, filtered and the filtrate concentrated under
reduced pressure to afford Intermediate 348I as an off-white solid
(0.3 g, 67%). MS(ES): m/z=335 [M+H].sup.+; .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 7.80-7.91 (m, 1H), 7.64-7.70 (m, 1H),
7.35-7.50 (m, 1H), 7.02-7.29 (m, 2H), 4.12-4.25 (m, 2H), 3.93 (d,
J=16.56 Hz, 1H), 3.68-3.81 (m, 2H), 2.40 (br. s., 1H), 0.82-0.98
(m, 1H), 0.48 (d, J=8.03 Hz, 2H), 0.37 (d, J=5.02 Hz, 2H).
Compounds 348 and 349:
2-(3-Chloro-4-fluorophenyl)-6-cyclopropyl-N.sup.5-(3,3-difluoro-1-methylc-
yclobutyl)-6,7-dihydropyrazolo[1,5-a]pyrazine-3,5(4H)-dicarboxamide
##STR00622##
[1077] To a stirred solution of
3,3-difluoro-1-methylcyclobutanecarboxylic acid (0.047 g, 0.311
mmol) in toluene (2.0 mL) was added TEA (0.167 mL, 1.195 mmol),
followed by DPPA (0.104 mL, 0.478 mmol) and the reaction mixture
was stirred at 80.degree. C. for 1 h. The reaction mixture was
cooled to RT and to it was added a solution of Intermediate 348I
(0.08 g, 0.239 mmol) in THF (1.0 mL) and stirred at RT for 14 h.
The reaction mixture was diluted with EtOAc (10 mL), washed with
water and brine. The organic layer was dried over Na.sub.2SO.sub.4,
filtered and the filtrate concentrated under reduced pressure. The
crude compound was purified by silica gel chromatography (12 g
REDISEP.RTM. column, eluting with 1% MeOH in CHCl.sub.3) to afford
the racemic compound. The individual isomers were separated by
preparative Chiral SFC (Column: Lux cellulose-4 (250.times.4.6) mm,
5 .mu.m, flow rate 4 mL/min, Mobile Phase A: CO.sub.2, Mobile Phase
B: 0.2% DEA in methanol, back pressure: 100 bar. Retention time:
3.84 min. and 8.08 min. respectively for Compounds 348 and 349.
[1078] Compound 348: (20 mg, 16%, off-white solid); MS(ES): m/z=482
[M+H].sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm
7.86-7.93 (m, 1H), 7.66-7.75 (m, 1H), 7.42-7.49 (m, 1H), 7.28-7.41
(m, 2H), 7.07 (s, 1H), 5.06 (d, J=17.07 Hz, 1H), 4.51 (d, J=17.57
Hz, 1H), 4.15-4.26 (m, 2H), 3.97 (dd, J=9.29, 3.76 Hz, 1H),
2.75-2.91 (m, 2H), 2.54-2.64 (m, 2H), 1.43 (s, 3H), 0.92-1.26 (m,
1H), 0.30-0.55 (m, 4H).
[1079] Compound 349: (21 mg, 17%, off-white solid); MS(ES): m/z=482
[M+H].sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm
7.86-7.93 (m, 1H), 7.66-7.75 (m, 1H), 7.42-7.49 (m, 1H), 7.28-7.41
(m, 2H), 7.07 (s, 1H), 5.06 (d, J=17.07 Hz, 1H), 4.51 (d, J=17.57
Hz, 1H), 4.15-4.26 (m, 2H), 3.97 (dd, J=9.29, 3.76 Hz, 1H),
2.75-2.91 (m, 2H), 2.54-2.64 (m, 2H), 1.43 (s, 3H), 0.92-1.26 (m,
1H), 0.30-0.55 (m, 4H).
##STR00623## ##STR00624##
Intermediate 350A: Diethyl
1-((1-((tert-butoxycarbonyl)amino)cyclopropyl)methyl)-3-iodo-1H-pyrazole--
4,5-dicarboxylate
##STR00625##
[1081] To a stirred solution of PPh.sub.3 (15.52 g, 59.2 mmol) in
THF (80.0 mL) cooled to 0.degree. C. was added DIAD (11.50 mL, 59.2
mmol) and the resulting solution stirred at 0.degree. C. for 0.5 h.
Intermediate 104C (8.00 g, 23.66 mmol) was added as a solution in
THF (20 mL) at 0.degree. C. and stirred at RT for 45 min. A
solution of tert-butyl (1-(hydroxymethyl)cyclopropyl)carbamate
(5.32 g, 28.4 mmol) in THF (10 mL) at was added at 0.degree. C. and
the reaction mixture was allowed to stir at RT for 16 h. The
reaction mixture was diluted with water (250 mL) and extracted with
EtOAc (2.times.200 mL). The combined organic layer was washed with
brine dried over Na.sub.2SO.sub.4, filtered and concentrated. The
crude product was purified by silica gel chromatography (220 g
REDISEP.RTM. column, eluting with 20% EtOAc in hexane). Fractions
containing the product were combined and evaporated to afford
Intermediate 350A as a pale yellow liquid (10 g, 85%). MS(ES):
m/z=508 [M+H].sup.+; .sup.1H NMR (400 MHz, chloroform-d) .delta.
ppm 4.45 (s, 2H), 4.41-4.25 (m, 4H), 1.46 (s, 9H), 1.40-1.30 (m,
4H), 1.24 (s, 3H), 1.03-0.94 (m, 2H), 0.90-0.78 (m, 2H).
Intermediate 350B: Ethyl
2'-iodo-4'-oxo-5',7'-dihydro-4'H-spiro[cyclopropane-1,6'-pyrazolo[1,5-a]p-
yrazine]-3'-carboxylate
##STR00626##
[1083] To a stirred solution of Intermediate 350A (2.1 g, 4.14
mmol) in 1,4-dioxane (10.0 mL) was added 4 M HCl in dioxane (10 mL,
41 mmol) and the resulting solution stirred at RT for 1 h. The
reaction mixture was concentrated and diluted with EtOAc (50 mL).
The organic layer was washed successively with water, a saturated
aq. solution of NaHCO.sub.3, and brine, then dried over
Na.sub.2SO.sub.4, filtered and the filtrate concentrated under
reduced pressure. The residue obtained was heated in a
ROTAVAPOR.RTM. at 60.degree. C. for 5 h. The solid product was
triturated with diethyl ether to afford Intermediate 350B as a pale
yellow solid (1.1 g, 60%). MS(ES): m/z=362 [M+H].sup.+; .sup.1H NMR
(400 MHz, chloroform-d) .delta. ppm 6.93 (s, 1H), 4.41 (q, J=7.0
Hz, 2H), 4.26 (s, 2H), 1.41 (t, J=7.0 Hz, 3H), 1.11-0.85 (m,
4H).
Intermediate 350C: Ethyl
2'-iodo-5',7'-dihydro-4'H-spiro[cyclopropane-1,6'-pyrazolo[1,5-a]pyrazine-
]-3'-carboxylate
##STR00627##
[1085] To a solution of Intermediate 350B (1.1 g, 3.05 mmol) in THF
(10 mL) was added BH.sub.3.DMS (0.578 mL, 6.09 mmol, 2M) and the
resulting solution was stirred at 40.degree. C. for 18 h. The
reaction mixture was cooled to RT, quenched with ethanol (10 mL)
and heated to reflux for 1 h. Reaction mixture was concentrated
under reduced pressure. The crude product was purified by silica
gel chromatography (24 g REDISEP.RTM. column, eluting with 2% MeOH
in CHCl.sub.3). Fractions containing the product were combined and
evaporated to afford Intermediate 350C (0.7 g, 66%) as a gummy
solid. MS(ES): m/z=348 [M+H]+. .sup.1H NMR (400 MHz, chloroform-d)
.delta. ppm 4.41 (q, J=7.0 Hz, 2H), 3.92 (s, 1H), 1.38 (m, 4H),
1.36 (t, J=7.0 Hz, 3H), 0.90 (m, 2H), 0.68 (m, 2H).
Intermediate 350D: 5'-tert-Butyl 3'-ethyl
2'-iodo-4'H-spiro[cyclopropane-1,6'-pyrazolo[1,5-a]pyrazine]-3',5'(7'H)-d-
icarboxylate
##STR00628##
[1087] To a solution of Intermediate 350C (0.70 g, 2.016 mmol) in
DCM (10.0 mL) was added TEA (0.281 mL, 2.016 mmol), followed by
Boc.sub.2O (0.702 mL, 3.02 mmol) and the solution was stirred at RT
for 16 h. The reaction mixture was diluted with DCM (25 mL) and the
organic layer was washed with water, brine, dried over
Na.sub.2SO.sub.4, filtered and the filtrate concentrated. The crude
product was purified by silica gel chromatography (24 g
REDISEP.RTM. column, eluting with 30% EtOAc in petroleum ether).
Fractions containing the product were combined and evaporated to
afford Intermediate 350D as an off-white solid (0.6 g, 67%).
MS(ES): m/z=448 [M+H].sup.+; .sup.1H NMR (400 MHz, chloroform-d)
.delta. ppm 4.88 (br. s., 2H), 4.33 (q, J=7.0 Hz, 2H), 4.03 (br.
s., 2H), 1.48 (m, 9H), 1.41 (t, J=7.0 Hz, 3H), 1.17 (m, 2H),
0.97-0.85 (m, 2H).
Intermediate 350E:
5'-(tert-Butoxycarbonyl)-2'-iodo-5',7'-dihydro-4'H-spiro[cyclopropane-1,6-
'-pyrazolo[1,5-a]pyrazine]-3'-carboxylic acid
##STR00629##
[1089] To a stirred solution of Intermediate 350D (0.500 g, 1.118
mmol) in ethanol (10 mL) and water (1 mL) was added NaOH (0.369 g,
9.21 mmol) and the resulting solution was stirred at RT for 12 h.
The volatiles were removed under reduced pressure and the residue
was acidified with an aqueous solution of 1.5 N HCl. The solid
product separated was filtered through a Buchner funnel and dried
under vacuum to afford Intermediate 350E as a white solid (0.43 g,
90%). MS(ES): m/z=420 [M+H].sup.+; .sup.1H NMR (400 MHz,
chloroform-d) .delta. ppm 6.19 (br. s., 1H), 4.92 (br. s., 2H),
4.06 (br. s., 2H), 1.48 (s, 9H), 1.19 (br. s., 2H), 1.01-0.83 (m,
2H).
Intermediate 350F: tert-Butyl
3'-carbamoyl-2'-iodo-4'H-spiro[cyclopropane-1,6'-pyrazolo[1,5-a]pyrazine]-
-5'(7'H)-carboxylate
##STR00630##
[1091] To a stirred solution of Intermediate 350E (0.43 g, 1.026
mmol) in DMF (4 mL) was added NH.sub.4Cl (0.274 g, 5.13 mmol), HATU
(0.780 g, 2.051 mmol) and DIPEA (0.537 mL, 3.08 mmol) and the
resulting solution was stirred at RT for 16 h. The reaction mixture
was diluted with water (50 mL) and extracted with EtOAc (3.times.25
mL). The combined organic layer was washed with brine, dried over
Na.sub.2SO.sub.4, filtered and the filtrate concentrated. The
residue was triturated with diethyl ether, filtered and dried to
afford Intermediate 350F as an off-white solid (0.4 g, 89%).
MS(ES): m/z=419 [M+H].sup.+; .sup.1H NMR (400 MHz, chloroform-d)
.delta. ppm 6.56 (br. s., 1H), 5.54 (br. s., 1H), 4.96 (br. s.,
2H), 4.04 (br. s., 2H), 1.44 (s, 9H), 1.18 (m, 2H), 0.97-0.84 (m,
2H).
Intermediate 350G: tert-Butyl
3'-carbamoyl-2'-(3-chloro-4-fluorophenyl)-4'H-spiro[cyclopropane-1,6'-pyr-
azolo[1,5-a]pyrazine]-5'(7'H)-carboxylate
##STR00631##
[1093] To a stirred suspension of Intermediate 350F (0.400 g, 0.956
mmol) in 1,4-dioxane (5 mL) was added K.sub.3PO.sub.4 (0.500 g,
2.80 mmol), (3-chloro-4-fluorophenyl)boronic acid (0.250 g, 1.435
mmol) and the reaction mixture was purged with nitrogen for 10 min.
PdCl.sub.2(dppf)-CH.sub.2Cl.sub.2 (0.047 g, 0.057 mmol) was then
added and the reaction mixture was heated to 80.degree. C. and
stirred for 12 h. The reaction mixture was diluted with water (25
mL) and extracted with EtOAc (3.times.25 mL). The combined organic
layers were washed with brine, dried over Na.sub.2SO.sub.4,
filtered and the filtrate concentrated. The crude product was
purified by silica gel chromatography (24 g REDISEP.RTM. column,
eluting with 3% MeOH in CHCl.sub.3). Fractions containing the
product were combined and evaporated to afford Intermediate 350G as
a pale yellow solid (0.29 g, 70%). MS(ES): m/z=421 [M+H].sup.+;
.sup.1H NMR (400 MHz, chloroform-d) .delta. ppm 7.69 (dd, J=7.0,
2.3 Hz, 1H), 7.50 (ddd, J=8.5, 4.6, 2.1 Hz, 1H), 7.33-7.15 (m, 1H),
5.34 (br. s., 2H), 4.97 (br. s., 2H), 4.05 (br. s., 2H), 1.44 (s,
9H), 1.22-1.24 (m, 2H), 1.02-0.79 (m, 2H).
Intermediate 350H:
2'-(3-Chloro-4-fluorophenyl)-5',7'-dihydro-4'H-spiro[cyclopropane-1,6'-py-
razolo[1,5-a]pyrazine]-3'-carboxamide
##STR00632##
[1095] To a solution of Intermediate 350G (0.29 g, 0.689 mmol) in
DCM (5 mL) was added TFA (3 mL) and the resulting solution was
stirred at RT for 2 h. The volatiles were removed under reduced
pressure. The residue was basified with a 10% aqueous solution of
NaHCO.sub.3 and extracted with EtOAc (3.times.20 mL). The combined
organic layer was washed with brine, dried over Na.sub.2SO.sub.4,
filtered and the filtrate concentrated to afford Intermediate 350H
as a yellow solid (0.2 g, 85%). MS(ES): m/z=321 [M+H].sup.+;
.sup.1H NMR (300 MHz, chloroform-d) .delta. ppm 7.71 (dd, J=7.2,
2.3 Hz, 1H), 7.51 (ddd, J=8.3, 4.5, 2.3 Hz, 1H), 7.33-7.11 (m, 1H),
5.33 (br. s., 2H), 4.40 (s, 2H), 4.03 (s, 2H), 1.02-0.88 (m, 2H),
0.80-0.59 (m, 2H).
Compound 350:
N.sup.5'-(tert-Butyl)-2'-(3-chloro-4-fluorophenyl)-4'H-spiro[cyclopropane-
-1,6'-pyrazolo[1,5-a]pyrazine]-3',5'(7'H)-dicarboxamide
##STR00633##
[1097] To a solution of Intermediate 350H (30 mg, 0.094 mmol) in
THF (2 mL) was added TEA (0.026 mL, 0.187 mmol) and tert-butyl
isocyanate (0.022 mL, 0.187 mmol) and the resulting solution was
stirred at RT for 12 h. The reaction mixture was diluted with water
and extracted with EtOAc (3.times.20 mL). The combined organic
layer was washed with brine, dried over Na.sub.2SO.sub.4, filtered
and the filtrate concentrated. The crude product was purified by
preparative HPLC to afford Compound 350 as an off-white solid (10
mg, 25%). HPLC retention times 9.363 min. and 13.023 min. (Methods
A and F respectively). MS(ES): m/z=420 [M+H].sup.+; .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. ppm 7.85 (dd, J=7.31, 2.16 Hz, 1H),
7.68 (ddd, J=8.63, 4.80, 2.20 Hz, 1H), 7.45 (t, J=9 Hz, 1H), 7.30
(br.s, 1H), 7.16 (br.s, 1H), 4.78 (br.s, 2H), 4.10 (br.s, 2H), 1.26
(s, 9H), 1.09 (s, 4H).
##STR00634## ##STR00635##
Intermediate 351A: Diethyl
1-((3-(tert-butoxycarbonyl)-2,2-dimethyloxazolidin-4-yl)methyl)-3-iodo-1H-
-pyrazole-4,5-dicarboxylate
##STR00636##
[1099] To a stirred solution of triphenylphosphine (5.84 g, 22.25
mmol) in THF (20 mL) was added DIAD (4.50 g 22.25 mmol) dropwise at
0.degree. C. and the resulting solution was stirred for 15 min.
Intermediate 104C (3.0 g, 8.90 mmol) in THF (20 mL) was added
slowly at 0.degree. C. and stirred at room temperature for 45 min.
Intermediate tert-butyl
4-(hydroxymethyl)-2,2-dimethyloxazolidine-3-carboxylate (2.470 g,
10.68 mmol) in THF (20 mL) was added at 0.degree. C. and resulting
solution was stirred at room temperature overnight. The volatiles
were removed under reduced pressure and the crude compound was
purified by silica gel chromatography (40 g REDISEP.RTM. column,
eluting with 10-13% ethyl acetate in hexanes). Fractions containing
the product were combined and evaporated to afford Intermediate
351A (3.5 g, 58.5%) as a pale yellow oil. MS(ES): m/z=552
[M+H].sup.+; .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. ppm
4.53-4.18 (m, 6H), 3.96-3.82 (m, 2H), 1.50-1.21 (m, 21H).
Intermediate 351B: Ethyl
6-(hydroxymethyl)-2-iodo-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine--
3-carboxylate
##STR00637##
[1101] To a solution of Intermediate 351A (3.3 g, 5.99 mmol) in
dioxane (10 mL) was added 4 M HCl in dioxane (5 mL, 5.99 mmol) and
the resulting reaction mixture was stirred at RT for 3 h. The
reaction mixture was concentrated and the crude product was
basified with a 10% aqueous solution of sodium bicarbonate and
extracted with EtOAc (3.times.100 mL). The combined organic layer
was dried over sodium sulfate, filtered and concentrated slowly (2
to 3 h) using a rotary evaporator at 60.degree. C. to obtain
Intermediate 351B (1.6 g, 67.4%) as a white solid. MS(ES): m/z=366
[M+H].sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 8.43
(d, J=3.0 Hz, 1H), 5.14 (t, J=5.5 Hz, 1H), 4.46-4.41 (m, 1H),
4.37-4.30 (m, 1H), 4.25 (q, J=7.0 Hz, 2H), 3.84-3.75 (m, 1H),
3.54-3.47 (m, 1H), 3.36 (s, 1H), 1.28 (t, J=7.0 Hz, 3H).
Intermediate 351C: Ethyl
6-(((tert-butyldimethylsilyl)oxy)methyl)-2-iodo-4-oxo-4,5,6,7-tetrahydrop-
yrazolo[1,5-a]pyrazine-3-carboxylate
##STR00638##
[1103] To a solution of Intermediate 351B (1.2 g, 3.29 mmol) in DCM
(12 mL) was added imidazole (0.336 g, 4.93 mmol), TBDMS-Cl (0.644
g, 4.27 mmol), DMAP (0.028 g, 0.23 mmol) and the reaction mixture
was stirred at RT for 3 h. The reaction mixture was diluted with
water and extracted with DCM (3.times.40 mL). The combined organic
layer was washed with water, dried over sodium sulfate and
concentrated. The crude product obtained was purified by silica gel
chromatography (40 g REDISEP.RTM. column, eluting with 50% ethyl
acetate in hexanes). Fractions containing the product were combined
and evaporated to afford Intermediate 351C (1.1 g, 69%), MS(ES):
m/z=480.2 [M+H].sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
ppm 8.43 (d, J=4.0 Hz, 1H), 4.52-4.45 (m, 1H), 4.35 (dd, J=4.0,
13.6 Hz, 1H), 4.27-4.18 (m, 2H), 3.86-3.79 (m, 1H), 3.71 (dd,
J=4.0, 10.5 Hz, 1H), 3.55 (dd, J=6.0, 10.5 Hz, 1H), 1.27 (t, J=7.0
Hz, 3H), 0.81-0.75 (m, 9H), -0.02 (d, J=1.0 Hz, 6H).
Intermediate 351D: Ethyl
6-(((tert-butyldimethylsilyl)oxy)methyl)-2-iodo-4,5,6,7-tetrahydropyrazol-
o[1,5-a]pyrazine-3-carboxylate
##STR00639##
[1105] To a solution of Intermediate 351C (1.2 g, 2.503 mmol) in
THF (120 ml) was added neat borane dimethylsulfide complex (0.713
mL, 7.51 mmol) dropwise and the resulting solution was heated at
40.degree. C. for 36 h. The reaction mixture was cooled to room
temperature and ethanol (10 mL) was added dropwise. The reaction
mixture was stirred at 70.degree. C. for 1 h and concentrated to
afford Intermediate 351D as a white semi-solid (1.23 g, 95%), which
was taken to the next step without further purification. MS(ES):
m/z=466 [M+H].sup.+.
Intermediate 351E: Ethyl
6-(((tert-butyldimethylsilyl)oxy)methyl)-5-((4-cyanophenyl)carbamoyl)-2-i-
odo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxylate
##STR00640##
[1107] To a solution of Intermediate 351D (1.2 g, 2.58 mmol) in THF
(12 ml) was added 4-isocyanatobenzonitrile (0.446 g, 3.09 mmol) and
the solution was stirred at room temperature overnight. The
reaction mixture was concentrated and the crude product was
purified by silica gel chromatography (40 g REDISEP.RTM. column,
eluting with 16% EtOAc in hexanes). Fractions containing the
product were combined and evaporated to afford Intermediate 351E
(0.6 g, 38%) as a white solid. MS(ES): m/z=610 [M+H].sup.+; .sup.1H
NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 9.32 (s, 1H), 7.75-7.63 (m,
4H), 5.24 (d, J=18.6 Hz, 1H), 4.85-4.77 (m, 1H), 4.47 (d, J=18.6
Hz, 1H), 4.35 (d, J=2.5 Hz, 2H), 4.30-4.22 (m, 2H), 3.73-3.64 (m,
2H), 1.31 (t, J=7.0 Hz, 3H), 0.76-0.71 (m, 9H), -0.04 (m, 6H).
Intermediate 351F:
5-((4-Cyanophenyl)carbamoyl)-6-(hydroxymethyl)-2-iodo-4,5,6,7-tetrahydrop-
yrazolo[1,5-a]pyrazine-3-carboxylic acid
##STR00641##
[1109] To a solution of Intermediate 351E (0.7 g, 1.148 mmol) in
THF (10 mL) and water (5 ml) was added LiOH (0.083 g, 3.45 mmol)
and the reaction mass was stirred at RT for 24 h. The volatiles
were evaporated; the residue was diluted with water (10 mL) and
neutralized with an aqueous solution of 1.0 N HCl. The solid
product separated was filtered and dried to afford Intermediate
351F (0.4 g, 74%) as an off-white solid which was taken to the next
step without further purification. MS(ES): m/z=468 [M+H].sup.+;
.sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. ppm 12.35-12.80 (br,
1H), 9.33 (s, 1H), 7.69-7.74 (m, 2H), 7.62-7.68 (m, 2H), 5.20-5.30
(m, 1H), 5.10-5.19 (m, 1H), 4.72 (d, J=4.53 Hz, 1H), 4.46 (d,
J=18.51 Hz, 1H), 4.27-4.38 (m, 2H), 3.40-3.48 (m, 2H).
Intermediate 351G:
N.sup.5-(4-Cyanophenyl)-6-(hydroxymethyl)-2-iodo-6,7-dihydropyrazolo[1,5--
a]pyrazine-3,5(4H)-dicarboxamide
##STR00642##
[1111] To a solution of Intermediate 351F (0.12 g, 0.257 mmol) in
dry DMF (3 mL) was added HATU (0.195 g, 0.512 mmol),
diisopropylethylamine (224 .mu.L, 1.128 mmol) and ammonium chloride
(0.0687 g, 1.128 mmol) and the reaction mixture was stirred at room
temperature for 4 h. The reaction mixture was concentrated
completely to dryness and the crude was partitioned between ethyl
acetate and water. The organic layer was separated, washed with
brine, dried over Na.sub.2SO.sub.4, filtered and the filtrate
concentrated. The crude product was purified by silica gel
chromatography (12 g REDISEP.RTM. column, eluting with 3-5%
methanol in chloroform). Fractions containing the product were
combined to afford Intermediate 351G (0.08 g, 67%) as an off-white
solid. MS(ES): m/z=467 [M+H].sup.+; .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 9.29 (s, 1H), 7.69-7.74 (m, 2H),
7.63-7.69 (m, 2H), 7.37-7.48 (m, 1H), 6.93 (br. s., 1H), 5.22 (d,
J=18.07 Hz, 1H), 5.13 (t, J=5.27 Hz, 1H), 4.72 (d, J=4.52 Hz, 1H),
4.51 (d, J=18.57 Hz, 1H), 4.31-4.38 (m, 1H), 4.20-4.28 (m, 1H),
3.43 (t, J=6.02 Hz, 2H).
Compound 351:
2-(3-Chloro-4-fluorophenyl)-N.sup.5-(4-cyanophenyl)-6-(hydroxymethyl)-6,7-
-dihydropyrazolo[1,5-a]pyrazine-3,5(4H)-dicarboxamide
##STR00643##
[1113] A solution of Intermediate 351G (0.07 g, 0.15 mmol),
(3-chloro-4-fluorophenyl)boronic acid (0.0393 g, 0.225 mmol) and
K.sub.3PO.sub.4 (0.096, 0.45 mmol) in 1,4-dioxane (3 mL) and water
(0.5 mL) was degassed with nitrogen for 10 min.
PdCl.sub.2(dppf)-CH.sub.2Cl.sub.2 adduct (7.36 mg, 9.01 .mu.mol)
was added and the reaction mixture was stirred at 80.degree. C. for
12 h. The reaction mixture was concentrated and crude was
partitioned between ethyl acetate and water. The organic layer was
separated, washed with brine, dried over Na.sub.2SO.sub.4, filtered
and the filtrate concentrated. The crude was purified via
preparative HPLC to afford 351 as an off-white solid (20 mg, 30%).
HPLC retention times 8.10 min. and 7.95 min. (Methods A and B);
MS(ES): m/z=469 [M+H].sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. ppm 9.35 (br. s., 1H), 7.90 (dd, J=7.28, 2.26 Hz, 1H),
7.66-7.76 (m, 5H), 7.45-7.51 (m, 1H), 7.30-7.43 (m, 2H), 5.20 (d,
J=17.57 Hz, 2H), 4.80 (d, J=5.02 Hz, 1H), 4.54 (d, J=17.57 Hz, 1H),
4.36-4.42 (m, 1H), 4.24-4.31 (m, 1H), 3.50 (d, J=6.02 Hz, 2H).
##STR00644## ##STR00645##
Intermediate 352A: Diethyl
1-((3R,4S)-4-((tert-butoxycarbonyl)amino)tetrahydrofuran-3-yl)-3-iodo-1H--
pyrazole-4,5-dicarboxylate
##STR00646##
[1115] To a solution of PPh.sub.3 (2.72 g, 10.35 mmol) in THF (10
mL) at 0.degree. C. was added DIAD (2.013 mL, 10.35 mmol) dropwise
and stirred for 15 min. A solution of Intermediate 104C (1.4 g,
4.14 mmol) in THF (10 mL) was added to the above reaction mixture
and was stirred at 0.degree. C. for 45 min. A solution of
tert-butyl ((3S,4R)-4-hydroxytetrahydrofuran-3-yl)carbamate (1.683
g, 8.28 mmol) in THF (10 mL) was added dropwise at 0.degree. C. and
the reaction mixture was stirred at RT for 12 h. The reaction
mixture was then concentrated and the crude compound was purified
by silica gel chromatography (24 g REDISEP.RTM. column, eluting
with 30% EtOAc in hexanes). Fractions containing the product were
combined and evaporated to afford Intermediate 352A (1.7 g, 81%) as
a white solid. MS(ES): m/z=522 [M-H].sup.+; The crude product was
taken to the next step without further purification.
Intermediate 352B: (5aS,8aR)-Ethyl
2-iodo-4-oxo-4,5,5a,6,8,8a-hexahydrofuro[3,4-e]pyrazolo[1,5-a]pyrazine-3--
carboxylate
##STR00647##
[1117] To an ice cold solution of Intermediate 352A (6.0 g, 11.5
mmol) in dioxane (20 mL) was added a 4 M solution of HCl in dioxane
(100 mL, 11.47 mmol) and the reaction mixture was stirred at RT for
4 h. The reaction mixture was concentrated; the pH of the residue
was adjusted to 8 with a 10% aqueous solution of NaHCO.sub.3 and
the mixture was stirred at RT for 30 min. then was extracted with
EtOAc (3.times.100 mL). The combined organic layers were washed
with water, dried over Na.sub.2SO.sub.4, concentrated and kept
under vacuum at 60.degree. C. for 6 h to obtain Intermediate 352B
as an off-white solid (2.1 g, 48%). MS(ES): -m/z=378 [M+H].sup.+;
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 8.67 (d, J=3.5 Hz,
1H), 5.11-5.04 (m, 1H), 4.45 (dq, J=4.0, 6.5 Hz, 1H), 4.31-4.12 (m,
4H), 4.04-3.94 (m, 1H), 3.57 (dd, J=6.0, 9.0 Hz, 1H), 1.32-1.22 (m,
3H).
Intermediate 352C: (5aS,8aR)-Ethyl
2-iodo-4,5,5a,6,8,8a-hexahydrofuro[3,4-e]pyrazolo[1,5-a]pyrazine-3-carbox-
ylate
##STR00648##
[1119] To a stirred solution of Intermediate 352B (0.5 g, 1.33
mmol) in THF (1 mL) was added borane dimethyl sulfide complex
(0.378 mL, 3.98 mmol) and the reaction mixture was stirred at
40.degree. C. for 16 h. Additional quantity of borane dimethyl
sulfide complex (0.126 mL, 1.326 mmol) was added and the reaction
was stirred further for 16 h. The reaction was quenched by adding
ethanol (3 mL) and allowing the solution to heat to reflux for 2 h.
The reaction mixture was concentrated to afford crude Intermediate
352C as an off-white semi-solid which was taken as such for next
step without further purification.
Intermediate 352D: (5aS,8aR)-5-tert-Butyl 3-ethyl
2-iodo-5a,6,8,8a-tetrahydrofuro[3,4-e]pyrazolo[1,5-a]pyrazine-3,5(4H)-dic-
arboxylate
##STR00649##
[1121] To a stirred solution of Intermediate 352C (1.0 g, 2.75
mmol) in DCM (10 mL) was added TEA (1.151 mL, 8.26 mmol) and
stirred for 10 min., followed by the addition of Boc.sub.2O (0.767
mL, 3.30 mmol). The reaction mixture was allowed to stir at RT for
16 h., at which point it was diluted with water (50 mL) and
extracted with DCM (3.times.50 mL). The combined organic layers
were washed with water, dried over Na.sub.2SO.sub.4 and
concentrated. The crude compound was purified by silica gel
chromatography (12 g REDISEP.RTM. column, eluting with 50% EtOAc in
hexanes). Fractions containing the product were combined and
evaporated to afford Intermediate 352D (0.56, 44% yield) as an
off-white solid. MS(ES): -m/z=464 [M+H].sup.+; .sup.1H NMR (300
MHz, DMSO-d.sub.6) .delta. ppm 5.30 (d, J=18.5 Hz, 1H), 4.88 (dd,
J=3.0, 7.2 Hz, 1H), 4.51-4.36 (m, 1H), 4.33-4.14 (m, 2H), 4.13-4.00
(m, 1H), 3.98-3.86 (m, 1H), 3.82-3.71 (m, 1H), 1.49-1.39 (m, 9H),
1.35-1.25 (m, 3H).
Intermediate 352E:
(5aS,8aR)-5-(tert-Butoxycarbonyl)-2-iodo-4,5,5a,6,8,8a-hexahydrofuro[3,4--
e]pyrazolo[1,5-a]pyrazine-3-carboxylic acid
##STR00650##
[1123] To a stirred solution of Intermediate 352D (0.85 g, 1.835
mmol) in THF (5 mL) was added a solution of NaOH (0.220 g, 5.50
mmol) in water (4 mL) and the reaction mixture was heated to
70.degree. C. for 16 h. The reaction mixture was concentrated and
the pH of the residue was adjusted to 4-5 using an aqueous solution
of citric acid. The formed precipitate was filtered, washed with
n-hexanes and dried to afford Intermediate 352E (0.48 g, 51%) as an
off-white solid. MS(ES): -m/z=434 [M-H].sup.+; .sup.1H NMR (300
MHz, DMSO-d.sub.6) .delta. ppm 12.80-12.67 (m, 1H), 5.30 (d, J=18.5
Hz, 2H), 4.87 (dd, J=3.4, 6.8 Hz, 1H), 4.46-4.32 (m, 1H), 4.12-4.04
(m, 1H), 3.98-3.90 (m, 1H), 3.89-3.82 (m, 1H), 3.80-3.69 (m, 1H),
1.43 (s, 9H).
Intermediate 352F: (5aS,8aR)-tert-Butyl
3-carbamoyl-2-iodo-5a,6,8,8a-tetrahydrofuro[3,4-e]pyrazolo[1,5-a]pyrazine-
-5(4H)-carboxylate
##STR00651##
[1125] To a stirred solution of Intermediate 352E (0.480 g, 1.103
mmol) in DMF (10 mL) at RT was added DIPEA (0.963 mL, 5.51 mmol),
HATU (0.839 g, 2.206 mmol), and NH.sub.4Cl (0.295 g, 5.51 mmol).
After stirring for 12 h, the reaction mixture was diluted with
water and extracted with EtOAc (3.times.50 mL). The combined
organic layers were washed with water, dried over Na.sub.2SO.sub.4
and concentrated to afford Intermediate 352F (0.39 g, 74%) as a
pale yellow oil. MS(ES): m/z=435 [M+H].sup.+; .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta. ppm 7.95 (s, 2H), 5.30-5.13 (m, 2H), 4.86
(dd, J=3.4, 7.6 Hz, 1H), 4.38 (d, J=15.9 Hz, 1H), 4.14-4.03 (m,
1H), 3.98-3.82 (m, 2H), 3.75 (dd, J=6.6, 9.3 Hz, 1H), 1.43 (s,
9H).
Intermediate 352G: (5aS,8aR)-tert-Butyl
3-carbamoyl-2-(3-chloro-4-fluorophenyl)-5a,6,8,8a-tetrahydrofuro[3,4-e]py-
razolo[1,5-a]pyrazine-5(4H)-carboxylate
##STR00652##
[1127] To a stirred solution of Intermediate 352F (0.370 g, 0.852
mmol) and (3-chloro-4-fluorophenyl)boronic acid (0.297 g, 1.704
mmol) in dioxane (2 mL) was added a solution of K.sub.3PO.sub.4
(0.543 g, 2.56 mmol) in water (0.5 mL) and the reaction mixture was
purged with nitrogen for 10 min. PdCl.sub.2(dppf)CH.sub.2Cl.sub.2
(0.052 g, 0.064 mmol) was then added and the reaction mixture was
heated to 80.degree. C. and stirred for 16 h. The reaction mixture
was diluted with water and extracted with EtOAc (3.times.30 mL).
The combined organic layers were washed with water, dried over
Na.sub.2SO.sub.4 and concentrated. The crude compound was purified
by silica gel chromatography (12 g REDISEP.RTM. column, eluting
with 4% MeOH in CHCl.sub.3). Fractions containing the product were
combined and evaporated to afford Intermediate 352G (0.270 g, 54%)
as an off-white solid. MS(ES): m/z=437 [M+H].sup.+.
Intermediate 352H:
(5aS,8aR)-2-(3-Chloro-4-fluorophenyl)-4,5,5a,6,8,8a-hexahydrofuro[3,4-e]p-
yrazolo[1,5-a]pyrazine-3-carboxamide HCl
##STR00653##
[1129] To a stirred solution of Intermediate 352G (0.2 g, 0.458
mmol) in dioxane (1 mL) was added a solution of HCl in dioxane (2
mL, 8.0 mmol, 4 M). After stirring at RT for 2 h, the reaction
mixture was concentrated and the crude product was triturated with
hexanes to afford Intermediate 352H (0.17 g, 71%) as an off-white
solid. MS(ES): -m/z=337 [M+H].sup.+. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 7.90 (ddd, J=1.8, 7.5, 14.3 Hz, 1H),
7.80-7.68 (m, 2H), 7.54-7.47 (m, 1H), 7.38 (dd, J=8.3, 9.8 Hz, 1H),
5.10 (br. s., 1H), 4.63 (br. s., 1H), 4.56 (s, 2H), 4.20-3.98 (m,
4H), 3.57 (s, 1H).
Compound 352:
(5aS,8aR)-N.sup.5-(tert-Butyl)-2-(3-chloro-4-fluorophenyl)-5a,6,8,8a-tetr-
ahydrofuro[3,4-e]pyrazolo[1,5-a]pyrazine-3,5(4H)-dicarboxamide
##STR00654##
[1131] To a stirred solution of 352H (0.05 g, 0.148 mmol) in THF
was added 2-isocyanato-2-methylpropane (0.022 g, 0.223 mmol), TEA
(0.062 mL, 0.445 mmol) and the resulting solution was stirred at RT
for 16 h. Water (0.2 mL) was added and the reaction mixture was
concentrated. The crude product was further purified by preparative
HPLC to afford Compound 352 (8 mg, 12%) as an off-white solid. HPLC
retention times 1.37 min. and 1.46 min. (Methods E and L
respectively). MS(ES): m/z=436 [M+H].sup.+; .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 7.89 (dd, J=7.3, 2.3 Hz, 1H), 7.72 (ddd,
J=8.7, 4.9, 2.0 Hz, 1H), 7.49-7.44 (m, 1H), 7.42-7.31 (m, 2H), 6.41
(s, 1H), 5.36-5.29 (m, 1H), 5.16 (d, J=17.6 Hz, 1H), 4.79 (dd,
J=7.0, 3.5 Hz, 1H), 4.30 (d, J=17.1 Hz, 1H), 4.18 (d, J=10.0 Hz,
1H), 3.97-3.87 (m, 2H), 3.76-3.70 (m, 1H), 1.27 (s, 9H).
[1132] The Compounds shown in Table 43 have been prepared similar
to Compound 352 by coupling of 352H with different isocyanates.
TABLE-US-00045 TABLE 43 Ret Ex. Time HPLC No. Structure Name [M +
H].sup.+ (min.) Methods 353 ##STR00655## (5aS,8aR)-2-(3-Chloro-4-
fluorophenyl)-N.sup.5-(3,3- difluorocyclobutyl)-5a,6,8,8a-
tetrahydrofuro[3,4-e]pyrazolo [1,5-a]pyrazine-3,5(4H)-
dicarboxamide 470 1.39 1.46 E L 354 ##STR00656##
(5aS,8aR)-2-(3-Chloro-4- fluorophenyl)-N.sup.5-(3,3-difluoro-
1-methylcyclobutyl)-5a,6,8,8a- tetrahydrofuro[3,4-e]pyrazolo
[1,5-a]pyrazine-3,5(4H)- dicarboxamide 484 1.49 1.55 E L
##STR00657## ##STR00658## ##STR00659##
Intermediate A1A: tert-Butyl(2,3-dihydroxypropyl)carbamate
##STR00660##
[1134] The above Intermediate was synthesized according to a patent
literature procedure reported in U.S. Publication No. 2006/69156 A1
(2006).
[1135] To a solution of 3-aminopropane-1,2-diol (10.0 g, 110 mmol)
in MeOH (407 mL) was added Boc.sub.2O (35.9 g, 165 mmol) and TEA
(55 mL, 395 mmol) and the reaction mixture was heated at 50.degree.
C. for 20 min., followed by stirring at room temperature for 12 h.
The reaction was then concentrated under reduced pressure to
provide a residue. It was purified by silica gel chromatography
(330 g REDISEP.RTM. column, eluting with 5% MeOH in DCM). Fractions
containing the product were combined and evaporated to afford
Intermediate A1A (20.14 g, 96%) as a colorless oil. .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. ppm 6.61 (br. s., 1H), 4.63 (d,
J=4.9 Hz, 1H), 4.47 (t, J=5.6 Hz, 1H), 3.45 (d, J=5.6 Hz, 1H),
3.31-3.23 (m, 2H), 3.09-2.98 (m, 1H), 2.85 (d, J=6.6 Hz, 1H), 1.38
(s, 9H).
Intermediate A1B: tert-Butyl
(3-((tert-butyldimethylsilyl)oxy)-2-hydroxypropyl)carbamate
##STR00661##
[1137] The above Intermediate was synthesized according to a patent
literature procedure reported in U.S. Publication No. 2003/187026
A1 (2003).
[1138] To a solution of Intermediate A1A (20.14 g, 105 mmol) in DCM
(168 mL) were added TEA (17.62 mL, 126 mmol), TBSCl (18.00 g, 116
mmol) and DMAP (0.515 g, 4.21 mmol) and the reaction mixture was
stirred at room temperature for 16 h. The mixture was then diluted
with DCM (100 mL) and the organic layer was washed with water
(3.times.100 mL), brine, dried over anhydrous MgSO.sub.4, filtered
and the filtrate was concentrated under reduced pressure to provide
a crude residue. It was purified by silica gel chromatography (330
g REDISEP.RTM. column, eluting with a gradient of 0 to 30% EtOAc in
hexanes). Fractions containing the product were combined and
evaporated to afford Intermediate A1B (24.46 g, 76%) as a pale
yellow oil. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 6.58
(br. s., 1H), 4.69 (d, J=4.4 Hz, 1H), 3.55-3.42 (m, 3H), 1.37 (s,
9H), 0.92-0.82 (m, 9H).
Intermediate A1C: Ethyl 4-(3-chlorophenyl)-2,4-dioxobutanoate
##STR00662##
[1140] To an ice-cold solution of 1-(3-chlorophenyl)ethanone (16.79
mL, 129 mmol) and diethyl oxalate (18.05 mL, 136 mmol) in DMF (78.0
mL) was added, portionwise over 30 min., NaH (6.09 g, 155 mmol, 60%
dispersion in mineral oil) and the resultant mixture was stirred at
that temperature for 20 min. and then at room temperature for 16 h.
The reaction mixture was diluted with water and acidified to pH
.about.4-5 with 1N aq. HCl. The mixture was further diluted with
copious amounts of water. The aq. layer was extracted with EtOAc
(4.times.100 mL) and the combined organic layer was washed with
water, brine, dried over anhydrous MgSO.sub.4, filtered and the
filtrate was concentrated under reduced pressure to provide a crude
residue. It was purified by silica gel chromatography (220 g
REDISEP.RTM. column, eluting with a 0 to 15% EtOAc in hexanes).
Fractions containing the product were combined and evaporated to
afford Intermediate A1C (27.1 g, 84%) as a solid. MS(ES):
m/z=277.10 [M+Na].sup.+; .sup.1H NMR (400 MHz, chloroform-d)
.delta. ppm 7.99 (t, J=1.8 Hz, 1H), 7.95-7.86 (m, 1H), 7.60 (ddd,
J=8.0, 2.1, 1.0 Hz, 1H), 7.48 (t, J=7.9 Hz, 1H), 7.06 (s, 1H), 4.43
(q, J=7.3 Hz, 2H), 1.44 (t, J=7.2 Hz, 3H).
Intermediate A1D: Ethyl
3-(3-chlorophenyl)-1H-pyrazole-5-carboxylate
##STR00663##
[1142] To a suspension of Intermediate A1C (14.57 g, 57.2 mmol) in
EtOH (191 mL) was added hydrazine hydrate (5.57 mL, 57.2 mmol, 64%
solution) and the reaction mixture was stirred at room temperature
for 16 h. The reaction turned homogenous over time and then a solid
precipitated out. The thick precipitate was filtered off. The
filter cake was washed with a little EtOH to afford the product as
a white solid. The filtrate was rotavaped to dryness to afford the
crude product as a yellow solid. It was suspended in minimum amount
of EtOH or MeCN and filtered off to give more of the product. The
process of rotavaping the filtrate to dryness and suspending the
subsequent solid in EtOH or MeCN was repeated 2-3 more times to
provide more white product during each filtration cycle. The
combined solid was dried under vacuum for 3 h to afford
Intermediate A1D (10.9 g, 76%). MS(ES): m/z=273 [M+Na].sup.+;
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 13.91 (br. s., 1H),
7.97 (t, J=1.8 Hz, 1H), 7.86 (dt, J=7.8, 1.4 Hz, 1H), 7.55-7.33 (m,
4H), 4.34 (q, J=7.2 Hz, 2H), 1.34 (t, J=7.2 Hz, 3H).
Intermediate A1E: Ethyl
3-(3-chlorophenyl)-1-(2,2,3,3,11,11-hexamethyl-9-oxo-4,10-dioxa-8-aza-3-s-
iladodecan-6-yl)-1H-pyrazole-5-carboxylate
##STR00664##
[1144] To an ice-cold suspension of Intermediate A1D (7.0 g, 27.9
mmol) and PPh.sub.3 (10.99 g, 41.9 mmol) in THF (112 mL) was added
a solution of DIAD (8.57 mL, 41.9 mmol) in THF (15 mL). Soon the
reaction mixture turned homogenous. It was stirred at that
temperature for 30 min., followed by the addition of a solution of
Intermediate A1B (10.24 g, 33.5 mmol) in THF (15 mL). The resultant
reaction mixture was stirred at room temperature for 2 h and then
diluted with EtOAc (150 mL). The organic layer was washed with
brine, dried over anhydrous MgSO.sub.4, filtered and the filtrate
was concentrated under reduced pressure to provide a crude oil. It
was purified by silica gel chromatography (220 g REDISEP.RTM.
column, eluting with 0 to 15% EtOAc in hexanes). Fractions
containing the product were combined and evaporated to afford
Intermediate A1E (12.5 g, 83%) as a thick syrup. MS(ES): m/z=438.1
[M-Boc].sup.+; .sup.1H NMR (400 MHz, chloroform-d) .delta. ppm 7.97
(s, 1H), 7.91-7.83 (m, 1H), 7.53-7.37 (m, 3H), 7.01 (s, 1H), 5.54
(br. s., 1H), 4.32 (q, J=7.0 Hz, 2H), 3.94 (d, J=6.0 Hz, 2H), 3.48
(s, 1H), 3.39 (d, J=7.5 Hz, 1H), 1.41-1.29 (m, 12H), 0.74 (s,
9H).
Intermediate A1F: Ethyl
1-(1-amino-3-hydroxypropan-2-yl)-3-(3-chlorophenyl)-1H-pyrazole-5-carboxy-
late, 2 HCl
##STR00665##
[1146] To a solution of Intermediate A1E (21 g, 39 mmol) in
1,4-dioxane (156 mL) was added a solution of HCl (166 mL, 663 mmol,
4 M in 1,4-dioxane) and the reaction mixture was stirred at room
temperature for 6 h. The white precipitate that was generated was
filtered off and the filter cake was washed with a little dioxane.
The solid was dried under vacuum for 16 h to afford Intermediate
A1F as a bis HCl salt (11.9 g, 77%). MS(ES): m/z=324.0
[M+H].sup.+.
Intermediate A1G:
2-(3-Chlorophenyl)-7-(hydroxymethyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(-
5H)-one
##STR00666##
[1148] To a suspension of Intermediate A1F (5.23 g, 13.18 mmol) in
EtOH (132 mL) was added NH.sub.4OH (171 mL, 1318 mmol) and the
reaction mixture was stirred at RT for 16 h. Soon the mixture
became homogenous and a white precipitate formed overnight. The
solid was filtered off and the filtrate was concentrated under
reduced pressure to provide more product. The combined white solid
was dried overnight to afford Intermediate A1G (3.5 g, 96%).
MS(ES): m/z=278.0 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. ppm 8.22 (br. s., 1H), 7.94 (t, J=1.6 Hz, 1H), 7.86 (dt,
J=7.7, 1.3 Hz, 1H), 7.52-7.38 (m, 2H), 7.34 (s, 1H), 7.07 (br. s.,
1H), 5.29 (t, J=5.8 Hz, 1H), 4.54-4.42 (m, 1H), 3.86-3.71 (m, 3H),
3.65 (dt, J=13.4, 4.1 Hz, 1H).
Intermediate A1H:
7-(((tert-Butyldimethylsilyl)oxy)methyl)-2-(3-chlorophenyl)-6,7-dihydropy-
razolo[1,5-a]pyrazin-4(5H)-one
##STR00667##
[1150] To a solution of Intermediate A1G (4.365 g, 15.72 mmol) in
DMF (157 mL) was added imidazole (1.380 g, 20.28 mmol) and TBSCl
(2.84 g, 18.86 mmol) and the reaction mixture was stirred at room
temperature for 2 h. Most of the DMF was concentrated under reduced
pressure and the residue was diluted with water to generate a white
precipitate. This solid was filtered off and the filter cake was
dried under vacuum for 4 h to afford Intermediate A1H (5.1 g, 83%).
MS(ES): m/z=392.1 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. ppm 8.21 (br. s., 1H), 7.94 (t, J=1.6 Hz, 1H), 7.86 (dt,
J=7.5, 1.3 Hz, 1H), 7.52-7.37 (m, 2H), 7.35 (s, 1H), 4.58 (br. s.,
1H), 4.09-3.92 (m, 2H), 3.63 (s, 1H), 0.91-0.79 (m, 9H).
Intermediate A1I:
(2-(3-Chlorophenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-7-yl)methano-
l
##STR00668##
[1152] To a solution of Intermediate A1H (4.945 g, 12.61 mmol) in
THF (126 mL) was added, dropwise at -15.degree. C., a 1M solution
of LAH in THF (31.5 mL, 31.5 mmol) and the reaction mixture was
stirred at that temperature for 3 h. LC-MS shows mainly unreacted
starting material. Hence, more 1M LAH solution in THF (6.31 mL,
6.31 mmol, 0.5 equivalent) was added dropwise at -15.degree. C. and
the RM was allowed to gradually warm to room temperature and
stirred further for 16 h. The reaction mixture was carefully
quenched at -15.degree. C. with a sequential addition of H.sub.2O
(31.5 mL), NaOH (15% aq. solution, 31.5 mL) and H.sub.2O (92 mL).
The slurry was then allowed to stir at room temperature for
.about.30 min., followed by the addition of anhydrous MgSO.sub.4.
The mixture was stirred further for 15 min. and then the inorganics
were filtered off. The filter cake was washed with THF (150 mL).
The biphasic filtrate was concentrated under reduced pressure to
remove THF. The residual aq. layer was extracted with DCM
(3.times.50 mL). The combined organic layer was washed with brine,
dried over anhydrous MgSO.sub.4, filtered and concentrated under
reduced pressure to afford TBS cleaved Intermediate A1I (3.1 g,
93%) as a slightly impure yellow sticky solid. MS(ES): m/z=264.0
[M+H].sup.+.
Intermediate A1J:
7-(((tert-Butyldimethylsilyl)oxy)methyl)-2-(3-chlorophenyl)-4,5,6,7-tetra-
hydropyrazolo[1,5-a]pyrazine
##STR00669##
[1154] To a solution of Intermediate A1I (2.37 g, 8.97 mmol) in DCM
(90 mL) were added TBSCl (2.57 g, 17.05 mmol), DMAP (0.164 g, 1.346
mmol) and TEA (3.75 mL, 26.9 mmol) and the reaction mixture was
stirred at room temperature for 6 h. It was then diluted with a
saturated solution of aq. NaHCO.sub.3 and the two layers were
separated. The aq. layer was back-extracted with DCM (2.times.50
mL). The combined organic layer was washed with water, brine, dried
over anhydrous MgSO.sub.4, filtered and concentrated under reduced
pressure to give an oil. It was purified by silica gel
chromatography (120 g REDISEP.RTM. column, eluting with a gradient
of 40-65% EtOAc in hexanes). Fractions containing the product were
combined and evaporated to afford Intermediate A11 (3.194 g, 94%)
as a colorless oil. MS(ES): m/z=378.1 [M+H].sup.+.
Intermediate A1K: tert-Butyl
7-(((tert-butyldimethylsilyl)oxy)methyl)-2-(3-chlorophenyl)-6,7-dihydropy-
razolo[1,5-a]pyrazine-5(4H)-carboxylate
##STR00670##
[1156] To a solution of Intermediate A11 (3.194 g, 8.45 mmol) in
DCM (85 mL) were added Boc.sub.2O (2.213 g, 10.14 mmol), DMAP
(0.103 g, 0.845 mmol) and TEA (3.53 mL, 25.4 mmol) and the reaction
mixture was stirred at room temperature for 2 h. It was then
quenched with a saturated solution of aq. NaHCO.sub.3 and the two
layers were separated. The aq. layer was back-extracted with DCM
(2.times.50 mL). The combined organic layer was washed with brine,
dried, over anhydrous MgSO.sub.4, filtered and concentrated under
reduced pressure to give a solid. It was purified by silica gel
chromatography (120 g REDISEP.RTM. column, eluting with 20% EtOAc
in hexanes). Fractions containing the product were combined and
evaporated to afford Intermediate A1K (3.392 g, 84%) as an oil.
MS(ES): m/z=478.08 [M+H].sup.+.
Intermediate A1L: tert-Butyl
7-(((tert-butyldimethylsilyl)oxy)methyl)-2-(3-chlorophenyl)-3-iodo-6,7-di-
hydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate
##STR00671##
[1158] To a solution of Intermediate A1K (3.392 g, 7.09 mmol) in
DCM (37.8 mL) and MeOH (9.46 mL) was added NIS (7.66 g, 34.1 mmol)
and the reaction mixture was stirred at rt for 2 h. The solution
was then concentrated under reduced pressure to provide a solid. It
was purified by silica gel chromatography (120 g REDISEP.RTM.
column, eluting with a gradient of 10-15% EtOAc in hexanes).
Fractions containing the product were combined and evaporated to
afford Intermediate A1L (4.28 g, >99%) as a semi-solid. MS(ES):
m/z=604.08 [M+H].sup.+.
Intermediate A1M: tert-Butyl
7-(((tert-butyldimethylsilyl)oxy)methyl)-2-(3-chlorophenyl)-3-cyano-6,7-d-
ihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate
##STR00672##
[1160] To a solution of Intermediate A1L (1.0 g, 1.656 mmol) in DMF
(16.56 mL) was added CuCN (0.371 g, 4.14 mmol) and the reaction
mixture was heated in a sealed tube in an oil bath at 120.degree.
C. for 16 h. The inorganics were then filtered off and the filter
cake was washed with EtOAc. The combined filtrate was concentrated
under reduced pressure to give a crude residue. It was purified by
silica gel chromatography (80 g REDISEP.RTM. column, eluting with a
gradient of 10 to 15% EtOAc in hexanes). Fractions containing the
product were combined and evaporated to afford Intermediate A1M
(0.425 g, 51%) as an oil. MS(ES): m/z=504.08 [M+H].sup.+; .sup.1H
NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 7.90-7.78 (m, 2H),
7.69-7.50 (m, 2H), 4.88 (d, J=17.6 Hz, 1H), 4.71 (d, J=17.6 Hz,
1H), 4.48 (br. s., 1H), 4.13 (br. s., 1H), 4.00-3.91 (m, 2H), 3.81
(br. s., 1H), 1.53-1.43 (m, 9H), 0.88-0.77 (m, 9H).
Intermediate A1N: tert-Butyl
3-carbamoyl-2-(3-chlorophenyl)-7-(hydroxymethyl)-6,7-dihydropyrazolo[1,5--
a]pyrazine-5(4H)-carboxylate
##STR00673##
[1162] To a solution of Intermediate A1M (1.4 g, 2.78 mmol) in DMSO
(27 mL) was added a 5M solution of aq. KOH (2.78 mL, 13.91 mmol)
and H.sub.2O.sub.2 (5.68 mL, 55.7 mmol, 30% w/v in H.sub.2O) and
the reaction mixture was stirred at room temperature for 3 h. It
was then diluted with a lot of water and the aq. phase was
extracted with EtOAc (3.times.50 mL). The combined organic layer
was washed with water, brine, dried over anhydrous MgSO.sub.4,
filtered and concentrated under reduced pressure to give a crude
solid. It was purified by silica gel chromatography (80 g
REDISEP.RTM. column, eluting with 100% EtOAc). Fractions containing
the product were combined and evaporated to afford TBS cleaved
Intermediate A1N (0.95 g, 84%) as a white solid. MS(ES): m/z=407
[M+H].sup.+.
Intermediate A1O:
2-(3-Chlorophenyl)-7-(hydroxymethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyr-
azine-3-carboxamide
##STR00674##
[1164] To a solution of Intermediate A1N (0.17 g, 0.418 mmol) in
DCM (4.18 mL) was added TFA (0.644 mL, 8.36 mmol) and the reaction
mixture was stirred at room temperature for 1 h. The volatiles were
then evaporated under reduced pressure and the residue was basified
with saturated solution of aq. NaHCO.sub.3. The two layers were
separated and the aq. layer was extracted with DCM (3.times.10 mL).
The combined organic layer was washed with brine, dried over
anhydrous MgSO.sub.4, filtered and concentrated under reduced
pressure to give a crude solid. It was purified by silica gel
chromatography (25 g REDISEP.RTM. column, eluting with 35% MeOH in
DCM). Fractions containing the product were combined and evaporated
to afford Intermediate A1O (0.073 g, 57%) as a white solid. MS(ES):
m/z=307 [M+H].sup.+.
Compound A1:
2-(3-Chlorophenyl)-N.sup.5-(4-cyanophenyl)-7-(hydroxymethyl)-6,7-dihydrop-
yrazolo[1,5-a]pyrazine-3,5(4H)-dicarboxamide
##STR00675##
[1166] To a solution of Intermediate A1O (0.027 g, 0.088 mmol) in
DMF (1.76 mL) were added 4-isocyanatobenzonitrile (0.019 g, 0.132
mmol) and TEA (0.037 mL, 0.264 mmol) and the reaction mixture was
stirred at room temperature for 2 h. The mixture was then filtered
off and the filtrate was purified via preparative LC/MS. Fractions
containing the desired product were combined and evaporated to
afford Compound A1 (0.029 g, 70%). MS(ES): m/z=451 [M+H].sup.+;
HPLC Ret. Time 1.41 min. and 2.16 min. (HPLC Methods H and I);
.sup.1H NMR (600 MHz, DMSO-d.sub.6) .delta. ppm 7.77-7.69 (m, 3H),
7.69-7.60 (m, 3H), 7.50-7.40 (m, 2H), 7.38 (br. s., 1H), 7.23 (br.
s., 1H), 4.99-4.84 (m, 2H), 4.38-4.28 (m, 1H), 4.12-4.01 (m, 2H),
3.96-3.87 (m, 1H), 3.81 (dd, J=11.0, 7.3 Hz, 1H), 1.91 (s, 1H).
[1167] The Compounds described in Table 44 were synthesized
analogous to Compound A1 by reacting Intermediate A10 with
corresponding isocyanates.
TABLE-US-00046 TABLE 44 Ret Ex. Time HPLC No. Structure Name [M +
H].sup.+ (min.) Method A2 ##STR00676## N.sup.5-(tert-Butyl)-2-(3-
chlorophenyl)-7-(hydroxymethyl)- 6,7-dihydropyrazolo[1,5-a]
pyrazine-3,5(4H)-dicarboxamide 406.10 1.28 2.26 H I A3 ##STR00677##
2-(3-Chlorophenyl)-N.sup.5-(3,5- dichlorophenyl)-7-
(hydroxymethyl)-6,7- dihydropyrazolo[1,5-a]pyrazine-
3,5(4H)-dicarboxamide 495.90 2.29 2.70 H I
##STR00678##
Intermediate A4A: tert-Butyl
3-carbamoyl-2-(3-chlorophenyl)-7-(fluoromethyl)-6,7-dihydropyrazolo[1,5-a-
]pyrazine-5(4H)-carboxylate
##STR00679##
[1169] To a suspension of Intermediate A1N (0.15 g, 0.369 mmol) in
DCM (4.92 mL) cooled to -78.degree. C., was added DAST (0.073 mL,
0.553 mmol). Soon the reaction mixture turned homogenous. The
reaction was stirred at room temperature for 2 h. It was quenched
with a saturated solution of aq. NaHCO.sub.3. The organic layer was
separated and the aq. layer was extracted with DCM (3.times.10 mL).
The combined organic layer was washed with brine, dried over
anhydrous MgSO.sub.4, filtered and the filtrate concentrated under
reduced pressure to give an oil. It was purified by silica gel
chromatography (25 g
[1170] REDISEP.RTM. column, eluting with 55% EtOAc in hexanes).
Fractions containing the product were combined and evaporated to
afford Intermediate A4A (0.054 g, 35.8%) as a white solid. MS(ES):
m/z=409 [M+H].sup.+.
Intermediate A4B:
2-(3-Chlorophenyl)-7-(fluoromethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyra-
zine-3-carboxamide, 2 TFA
##STR00680##
[1172] To a solution of Intermediate A4A (0.054 g, 0.132 mmol) in
DCM (1.321 mL) was added TFA (0.102 mL, 1.321 mmol) and the
reaction mixture was stirred at room temperature for 1 h. It was
then concentrated under reduced pressure to provide a residue. The
residue was dried under vacuum to afford Intermediate A4B as the
bis TFA salt (0.071 g, >99%). MS(ES): m/z=309.0 [M+H].sup.+.
Compound A4:
2-(3-Chlorophenyl)-N.sup.5-(4-cyanophenyl)-7-(fluoromethyl)-6,7-dihydropy-
razolo[1,5-a]pyrazine-3,5(4H)-dicarboxamide
##STR00681##
[1174] To a solution of Intermediate A4B (0.035 g, 0.065 mmol) in
DMF (0.65 mL) was added 4-isocyanatobenzonitrile (0.019 g, 0.130
mmol) and DIPEA (0.057 mL, 0.326 mmol) and the reaction mixture was
stirred at room temperature for 1 h. The mixture was then filtered
off and the filtrate was purified via preparative LC/MS. Fractions
containing the desired product were combined and evaporated to
afford Compound A4 (0.017 g, 59%). MS(ES): m/z=453.30 [M+H].sup.+;
HPLC Ret. Time 1.44 min. and 2.31 min. (HPLC Methods H and I);
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. ppm 7.73 (d, J=7.6 Hz,
3H), 7.67 (d, J=8.5 Hz, 3H), 7.51-7.38 (m, 3H), 7.31 (br. s., 1H),
5.08 (d, J=5.8 Hz, 1H), 5.04-4.86 (m, 3H), 4.81 (d, J=7.9 Hz, 1H),
4.70 (br. s., 1H), 4.65 (br. s., 1H), 4.18 (d, J=10.1 Hz, 1H), 4.04
(dd, J=14.0, 6.4 Hz, 1H).
[1175] The Compound described in Table 45 was synthesized analogous
to Compound A4 by reacting Intermediate A4B with corresponding
isocyanate.
TABLE-US-00047 TABLE 45 Ret. Ex. Time HPLC No. Structure Name [M +
H].sup.+ (min.) Method A5 ##STR00682## N.sup.5-(tent-butyl)-2-(3-
chlorophenyl)-7- (fluoromethyl)-6,7- dihydropyrazolo[1,5-
a]pyrazine-3,5(4H)- dicarboxamide 408.08 1.41 2.36 H I
##STR00683##
Intermediate A6A: tert-Butyl
3-carbamoyl-2-(3-chlorophenyl)-7-formyl-6,7-dihydropyrazolo[1,5-a]pyrazin-
e-5(4H)-carboxylate
##STR00684##
[1177] To a suspension of Intermediate A1N (0.2 g, 0.492 mmol) in
DCM (4.92 mL) was added Dess-Martin periodinane (0.271 g, 0.639
mmol) and the reaction mixture was stirred at rt for 16 h. The
mixture was then quenched with a saturated solution of aq.
NaHCO.sub.3. The two layers were separated and the aq. layer was
extracted with DCM (2.times.10 mL). The combined organic layer was
washed with brine, dried over anhydrous MgSO.sub.4, filtered and
the filtrate was concentrated under reduced pressure to give an
oil. It was purified by silica gel chromatography (40 g
REDISEP.RTM. column, eluting with a gradient of 75% EtOAc in
hexanes to 100% EtOAc). Fractions containing the product were
combined and evaporated to afford Intermediate A6A (0.054 g, 35.8%)
as a white solid. MS(ES): m/z=409 [M+H].sup.+; .sup.1H NMR (400
MHz, chloroform-d) .delta. ppm 9.75 (s, 1H), 7.65-7.54 (m, 1H),
7.54-7.33 (m, 4H), 5.50 (br. s., 1H), 4.96 (d, J=16.8 Hz, 2H), 4.77
(br. s., 1H), 4.59 (d, J=16.1 Hz, 1H), 3.65 (d, J=12.3 Hz, 1H),
1.58-1.37 (m, 9H).
Intermediate A6B: tert-Butyl
3-carbamoyl-2-(3-chlorophenyl)-7-(difluoromethyl)-6,7-dihydropyrazolo[1,5-
-a]pyrazine-5(4H)-carboxylate
##STR00685##
[1179] To a solution of Intermediate A6A (0.105 g, 0.259 mmol) in
DCM (2.59 mL) at 0.degree. C. was added, DAST (0.103 mL, 0.778
mmol) and the reaction mixture was stirred at room temperature for
16 h. The reaction was then quenched with a saturated solution of
aq. NaHCO.sub.3. The two layers were separated and the aq. layer
was extracted with DCM (2.times.10 mL). The combined organic layer
was washed with brine, dried over anhydrous MgSO.sub.4, filtered
and the filtrate concentrated under reduced pressure to give an
oil. It was purified by silica gel chromatography (25 g
REDISEP.RTM. column, eluting with a gradient of 55 to 65% EtOAc in
hexanes). Fractions containing the product were combined and
evaporated to afford Intermediate A6B as a yellow solid. MS(ES):
m/z=427 [M+H].sup.+.
Intermediate A6C:
2-(3-Chlorophenyl)-7-(difluoromethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]py-
razine-3-carboxamide, 2 TFA
##STR00686##
[1181] Intermediate A6C was synthesized analogous to Intermediate
A4B (Scheme 58) by reacting Intermediate A6B with TFA. Intermediate
A6C (0.029 g, 20% from) was subjected to analoging as the bis TFA
salt. MS(ES): m/z=327 [M+H].sup.+.
Compound A6:
2-(3-Chlorophenyl)-N.sup.5-(4-cyanophenyl)-7-(difluoromethyl)-6,7-dihydro-
pyrazolo[1,5-a]pyrazine-3,5(4H)-dicarboxamide
##STR00687##
[1183] Compound A6 was synthesized analogous to Compound A4 by
reacting Intermediate A6C with 4-isocyanatobenzonitrile. MS(ES):
m/z=471.08 [M+H].sup.+; HPLC Ret. time 1.48 min. and 2.35 min.
(HPLC Methods H and I respectively); .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. ppm 7.96 (s, 1H), 7.78-7.70 (m, 3H), 7.67 (d,
J=8.5 Hz, 3H), 7.54-7.42 (m, 3H), 7.35 (br. s., 1H), 6.55 (br. s.,
1H), 5.16 (d, J=17.1 Hz, 1H), 4.93 (br. s., 1H), 4.82 (d, J=17.4
Hz, 1H), 4.50 (dd, J=14.3, 3.1 Hz, 1H), 3.93-3.79 (m, 1H).
##STR00688##
Intermediate A7A: tert-Butyl
3-carbamoyl-2-(3-chlorophenyl)-7-(((methylsulfonyl)oxy)methyl)-6,7-dihydr-
opyrazolo[1,5-a]pyrazine-5(4H)-carboxylate
##STR00689##
[1185] To an ice-cold suspension of Intermediate A1N (0.3 g, 0.737
mmol) in DCM (7.37 mL) was added TEA (0.123 mL, 0.885 mmol),
followed by a dropwise addition of methanesulfonyl chloride (0.063
mL, 0.811 mmol). The resultant homogenous reaction mixture was
stirred at room temperature for 2 h. The reaction was then quenched
with a saturated solution of aq. NaHCO.sub.3. The two layers were
separated and the aq. layer was extracted with DCM (2.times.10 mL).
The combined organic layer was washed with brine, dried over
anhydrous MgSO.sub.4, filtered and the filtrate was concentrated
under reduced pressure to give an oil. It was purified by silica
gel chromatography (40 g REDISEP.RTM. column, eluting with a
gradient of 75% to 85% EtOAc in hexanes). Fractions containing the
product were combined and evaporated to afford Intermediate A7A
(0.208 g, 58.2%) as a white foam. MS(ES): m/z=485 [M+H].sup.+.
Intermediate A7B: tert-Butyl
3-carbamoyl-2-(3-chlorophenyl)-7-methyl-6,7-dihydropyrazolo[1,5-a]pyrazin-
e-5(4H)-carboxylate
##STR00690##
[1187] To a solution of Intermediate A7A (0.08 g, 0.165 mmol) in
THF (3.30 mL) was added dropwise at room temperature, a 1M solution
of LiEt.sub.3BH in THF (1.650 mL, 1.650 mmol) and the reaction
mixture was stirred for 2 h. It was then carefully quenched with
water and extracted with DCM (3.times.10 mL). The combined organic
layer was washed with brine, dried over anhydrous MgSO.sub.4,
filtered and the filtrate concentrated under reduced pressure to
give an oil. It was purified by silica gel chromatography (25 g
REDISEP.RTM. column, eluting with a 50% EtOAc in hexanes).
Fractions containing the product were combined and evaporated to
afford Intermediate A7B (0.053 g, 81%) as a white foam. MS(ES):
m/z=391.1 [M+H].sup.+.
Intermediate A7C:
2-(3-Chlorophenyl)-7-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-c-
arboxamide, 2 TFA
##STR00691##
[1189] Intermediate A7C was synthesized analogous to Intermediate
A4B by reacting Intermediate A7B with TFA. Intermediate A7C (0.07
g, >99%) was subjected to analoging as the bis TFA salt. MS(ES):
m/z=291 [M+H].sup.+.
Compound A7:
2-(3-Chlorophenyl)-N5-(4-cyanophenyl)-7-methyl-6,7-dihydropyrazolo[1,5-a]-
pyrazine-3,5(4H)-dicarboxamide
##STR00692##
[1191] Compound A7 was synthesized analogous to Compound A4 by
reacting Intermediate A7C with 4-isocyanatobenzonitrile. MS(ES):
m/z=435.0 [M+H].sup.+; HPLC Ret. Time 1.48 min. and 2.41 min.
(Methods H and I respectively); .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. ppm 9.38 (s, 1H), 7.77-7.59 (m, 6H), 7.49-7.41 (m, 2H),
7.38 (br. s., 1H), 7.22 (br. s., 1H), 4.97 (d, J=17.1 Hz, 1H), 4.86
(d, J=17.1 Hz, 1H), 4.53-4.38 (m, 1H), 4.11 (dd, J=13.7, 3.7 Hz,
1H), 3.72 (dd, J=14.2, 6.9 Hz, 1H), 2.89 (s, 1H), 2.73 (s, 1H),
1.49 (d, J=6.4 Hz, 3H).
[1192] The Compound described in Table 46 was synthesized analogous
to Compound A7 by reacting Intermediate A7C with corresponding
isocyanate.
TABLE-US-00048 TABLE 46 Ret. Ex. Time HPLC No. Structure Name [M +
H].sup.+ (min.) Method A8 ##STR00693## N.sup.5-(tert-butyl)-2-(3-
chlorophenyl)-7- methyl-6,7- dihydropyrazolo[1,5-
a]pyrazine-3,5(4H)- dicarboxamide 390.0 1.41 2.41 H I
##STR00694## ##STR00695##
Intermediate A9A: Diethyl
1-(2,2,3,3,11,11-hexamethyl-9-oxo-4,10-dioxa-8-aza-3-siladodecan-6-yl)-3--
iodo-1H-pyrazole-4,5-dicarboxylate
##STR00696##
[1194] A solution of Intermediate 104C (1.0 g, 2.96 mmol),
Intermediate A1B (1.13 g, 3.70 mmol), triphenylphosphine (0.78 g,
2.96 mmol) and TEA (0.41 mL, 2.96 mmol) in THF (14.79 mL) was
cooled to 0.degree. C. and to it was added DTBAD (0.7 g, 2.96
mmol). The reaction mixture was then allowed to stir at room
temperature for 16 h and then diluted with water and EtOAc. The two
layers were separated and the aq. layer was extracted with EtOAc
(2.times.20 mL). The combined organic layer was washed with brine,
dried over anhydrous MgSO.sub.4, filtered and the filtrate was
concentrated to give an oil. It was purified by silica gel
chromatography (80 g REDISEP.RTM. column, eluting with a gradient
of 0 to 15% EtOAc in hexanes). Fractions containing the product
were combined and evaporated to afford Intermediate A9A (1.2 g,
65%) as a solid. MS(ES): m/z=648.1 [M+Na].sup.+.
Intermediate A9B: Ethyl
7-(hydroxymethyl)-2-iodo-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine--
3-carboxylate
##STR00697##
[1196] To a solution of Intermediate A9A (21.5 g, 34.4 mmol) in DCM
(344 mL) was added TFA (47.7 mL, 619 mmol) and the reaction mixture
was allowed to stir at room temperature for 48 h. The volatiles
were then concentrated under reduced pressure. The residue thus
obtained was directly taken up in EtOH (75 mL) and to it was added
ammonium hydroxide (581 mL, 447 mmol, 30% aq.). Soon a precipitate
generated. The stirring was continued for 1 h at room temperature.
The generated solid was filtered off. The filter cake was rinsed
with a small amount of EtOH. The combined filtrate was partially
evaporated under reduced pressure to generate more precipitate.
This solid was combined with the initial filter cake and air-dried
to afford Intermediate A9B (18 g, 71.6%) as a white solid. MS(ES):
m/z=365.8 [M+H].sup.+.
Intermediate A9C: Ethyl
7-(((tert-butyldimethylsilyl)oxy)methyl)-2-iodo-4-oxo-4,5,6,7-tetrahydrop-
yrazolo[1,5-a]pyrazine-3-carboxylate
##STR00698##
[1198] To a solution of Intermediate A9B (16.79 g, 46.0 mmol) in
DMF (230 mL) was added TBSCl (8.32 g, 55.2 mmol), followed by
imidazole (4.70 g, 69.0 mmol) and the reaction mixture was stirred
at room temperature for 1 h. The mixture was then concentrated to
dryness, the residue was diluted with water and extracted with DCM
(2.times.200 mL). The combined organic layer was washed with brine,
dried over anhydrous MgSO.sub.4, filtered and the filtrate was
concentrated to give an oil. It was purified by silica gel
chromatography (REDISEP.RTM. 330 g, eluting with a gradient of 10
to 55% EtOAc in hexanes). Fractions containing the product were
combined and evaporated to afford Intermediate A9C (16 g, 72.6%) as
a solid. MS(ES): m/z=479.9 [M+H].sup.+.
Intermediate A9D: 5-tert-Butyl 3-ethyl
7-(((tert-butyldimethylsilyl)oxy)methyl)-2-iodo-4-oxo-6,7-dihydropyrazolo-
[1,5-a]pyrazine-3,5(4H)-dicarboxylate
##STR00699##
[1200] To a solution of Intermediate A9C (11.74 g, 24.49 mmol) in
toluene (188 mL) was added DMAP (4.49 g, 36.7 mmol), followed by
Boc.sub.2O (6.41 g, 29.4 mmol) and the reaction mixture was heated
in an oil bath at 60.degree. C. for 1 h and then at room
temperature for 16 h. It was then concentrated to dryness to afford
a solid residue, which was purified by silica gel chromatography
(REDISEP.RTM. 220 g, eluting with a gradient of 5 to 25% EtOAc in
hexanes). Fractions containing the product were combined and
evaporated to afford Intermediate A9D (13.7 g, 96%) as a white
solid. MS(ES): m/z=580.1 [M+H].sup.+.
Intermediate A9E: 5-tert-Butyl 3-ethyl
7-(((tert-butyldimethylsilyl)oxy)methyl)-2-iodo-6,7-dihydropyrazolo[1,5-a-
]pyrazine-3,5(4H)-dicarboxylate
##STR00700##
[1202] To a -10.degree. C. solution of Intermediate A9D (1.0 g,
1.726 mmol) in THF (4.31 mL), SUPER-HYDRIDE.RTM. (2.07 mL, 2.071
mmol, 1M in THF) was added dropwise over 30 min., and the reaction
mixture was stirred at 0.degree. C. for 2 h. It was then quenched
with water and extracted with EtOAc (2.times.25 mL). The combined
organic layer was washed with brine, dried over anhydrous
MgSO.sub.4, filtered and the filtrate was concentrated to afford
the partially reduced intermediate as a foam. MS(ES): m/z=604.15
[M+Na].sup.+. It was used in the next step without further
purification.
[1203] To a -78.degree. C. solution of the above intermediate in
DCM (.about.8 mL) was added, triethylsilane (0.85 mL, 5.18 mmol),
followed by BF.sub.3.OEt.sub.2 (0.65 mL, 5.18 mmol) and the
reaction mixture was stirred at that temperature for 1 h.
Thereafter, more triethylsilane (0.852 mL, 5.18 mmol) and
BF.sub.3.OEt.sub.2 (0.656 mL, 5.18 mmol) were added and stirring
continued at -78.degree. C. for 3 h. The reaction was quenched with
a satd. aq. solution of NaHCO.sub.3, the two layers were separated
and the aq. layer was extracted with DCM (2.times.15 mL). The
combined organic layer was washed with brine, dried over anhydrous
MgSO.sub.4, filtered and the filtrate was concentrated to afford an
oil. It was purified by silica gel chromatography (80 g
REDISEP.RTM. column, eluting with a gradient of 5 to 15% EtOAc in
hexanes). Fractions containing the product were combined and
evaporated to afford Intermediate A9E (0.42 g, 43%) as a white
solid. MS(ES): m/z=566.15 [M+H].sup.+.
Intermediate A9F:
5-(tert-Butoxycarbonyl)-7-(hydroxymethyl)-2-iodo-4,5,6,7-tetrahydropyrazo-
lo[1,5-a]pyrazine-3-carboxylic acid
##STR00701##
[1205] To a solution of Intermediate A9E (10.0 g, 17.68 mmol) in
Ethanol (26.8 mL) and THF (53.6 mL) was added a suspension of LiOH
(6.05 g, 248 mmol) in water (17.86 mL) and the reaction mixture was
stirred at room temperature for 48 h. The volatiles were
concentrated under reduced pressure and the aq. residue was
extracted with Et.sub.2O. The Et.sub.2O layer was discarded and the
aq. layer was acidified with a 1N aqueous solution of HCl to pH=2.
It was then extracted with DCM (4.times.50 mL). The combined
organic layer was washed with brine, dried over anhydrous
MgSO.sub.4, filtered and the filtrate was concentrated to afford
Intermediate A9F (6.87 g, 92%) as a white solid, with the
concomitant loss of the TBS group. MS(ES): m/z=446.1 [M+Na]+.
Intermediate A9G: tert-Butyl
3-carbamoyl-7-(hydroxymethyl)-2-iodo-6,7-dihydropyrazolo[1,5-a]pyrazine-5-
(4H)-carboxylate
##STR00702##
[1207] To a solution of Intermediate A9F (6.87 g, 16.23 mmol) in
DMF (27.1 mL) was added DIPEA (11.34 mL, 64.9 mmol) and HATU (12.34
g, 32.5 mmol) and the mixture was stirred at room temperature for
30 min., followed by the addition of NH.sub.4Cl (3.47 g, 64.9
mmol). The resultant mixture was then continued stirring at room
temperature for 16 h. It was diluted with water (250 mL) and
extracted with DCM (3.times.70 mL). The combined organic layer was
washed with copious amounts of water, brine, dried over anhydrous
MgSO.sub.4, filtered and the filtrate was concentrated to afford an
oil. It was purified by silica gel chromatography (120 g
REDISEP.RTM. column, eluting with 5% EtOAc in hexanes). Fractions
containing the product were combined and evaporated to afford
Intermediate A9G (6.75 g, 98%) as a solid. MS(ES): m/z=423.1
[M+H].sup.+.
Intermediate A9H: tert-Butyl
3-carbamoyl-2-(3-chloro-4-fluorophenyl)-7-(hydroxymethyl)-6,7-dihydropyra-
zolo[1,5-a]pyrazine-5(4H)-carboxylate
##STR00703##
[1209] To a degassed solution of Intermediate A9G (5.1 g, 12.08
mmol) and (3-chloro-4-fluorophenyl)boronic acid (3.16 g, 18.12
mmol) in a 2M aqueous solution of K.sub.3PO.sub.4 (18.12 mL, 36.2
mmol) and 1,4-Dioxane (121 mL) was added PdCl.sub.2(dppf) (0.884 g,
1.208 mmol). The reaction mixture was degassed again for 5 min. and
then heated in a sealed tube in an oil bath at 85.degree. C. for 16
h. The mixture was concentrated under reduced pressure to near
dryness, the residue was partitioned between DCM and water, the two
layers were separated and the aq. layer was extracted with DCM
(2.times.40 mL). The combined organic layers were washed with
brine, dried over anhydrous MgSO.sub.4, filtered and the filtrate
was concentrated to afford an oil. It was purified by silica gel
chromatography (120 g REDISEP.RTM. column, eluting with a gradient
of 65 to 90% EtOAc in hexanes). Fractions containing the product
were combined and evaporated to afford Intermediate A9H (5.08 g,
>99%) as a pale brown solid. MS(ES): m/z=425.2 [M+H].sup.+.
Intermediate A9I: tert-Butyl
3-carbamoyl-2-(3-chloro-4-fluorophenyl)-7-(fluoromethyl)-6,7-dihydropyraz-
olo[1,5-a]pyrazine-5(4H)-carboxylate
##STR00704##
[1211] To a -78.degree. C. solution of Intermediate A9H (1.84 g,
4.33 mmol) in DCM (43.3 mL) was added DAST (0.57 mL, 4.33 mmol)
dropwise and then the reaction mixture was allowed to stir at room
temperature for 2 h. It was quenched with a satd. aq. solution of
NaHCO.sub.3, the organic layer was separated and the aq. layer was
extracted with DCM (2.times.20 mL). The combined organic layer was
washed with brine, dried over anhydrous MgSO.sub.4, filtered and
the filtrate was concentrated under reduced pressure to give a
solid. It was purified by silica gel chromatography (120 g
REDISEP.RTM. column, eluting with a gradient of 10 to 55% EtOAc in
hexanes). Fractions containing the product were combined and
evaporated to afford Intermediate A91 (0.56 g, 30.2%) as a white
solid. MS(ES): m/z=427.2 [M+H].sup.+.
Intermediate A9J:
2-(3-Chloro-4-fluorophenyl)-7-(fluoromethyl)-4,5,6,7-tetrahydropyrazolo[1-
,5-a]pyrazine-3-carboxamide
##STR00705##
[1213] To a solution of Intermediate A91 (0.2 g, 0.466 mmol) in DCM
(4.66 mL) was added TFA (0.72 mL, 9.32 mmol) and the reaction
mixture was stirred at room temperature for 2 h. The volatiles were
evaporated and the residue was basified with a satd. aq. solution
of NaHCO.sub.3 and extracted with a 5% solution of MeOH in DCM
(3.times.10 mL). The combined organic layer was washed with brine,
dried over anhydrous MgSO.sub.4, filtered and the filtrate was
concentrated under reduced pressure to give Intermediate A9J (0.15
g, 100%) as an off-white solid. MS(ES): m/z=327.2 [M+H].sup.+.
Compounds A9 and A10:
2-(3-Chloro-4-fluorophenyl)-N.sup.5-(3,3-difluoro-1-methylcyclobutyl)-7-(-
fluoromethyl)-6,7-dihydropyrazolo[1,5-a]pyrazine-3,5(4H)-dicarboxamide
##STR00706##
[1215] To a solution of 3,3-difluoro-1-methylcyclobutanecarboxylic
acid (0.029 g, 0.191 mmol) in toluene (2.040 mL) was added TEA
(0.085 mL, 0.612 mmol) and diphenyl phosphorazidate (0.043 mL,
0.191 mmol). This mixture was heated in an oil bath at 95.degree.
C. for 2 h. It was then cooled to room temperature and to it was
added a solution of Intermediate A9J (0.05 g, 0.153 mmol) in DMF
(1.02 mL). The resultant reaction mixture was stirred at room
temperature for 1 h. The volatiles were concentrated under reduced
pressure and the residue was purified by preparative HPLC to afford
a racemic mixture of A9 and A10. The individual enantiomers A9 and
A10 were separated by Chiral SFC purification using CHIRALPAK.RTM.
AD preparative column (21.times.250) mm, 10 .mu.m column, Solvent
A: 0.1% diethylamine in heptane, Solvent B: 100% EtOH, start % B:
30, isocratic, flow rate 15.0 mL/min for 20 min. UV monitored at
254 nm. Compound A9 (S)-isomer was eluted at 7.241 min. (14.3 mg,
100% ee, Yield=19.7%) and A10 (R)-isomer was eluted at 14.182 min.
(14.9 mg, 100% ee, Yield=20.5%). MS: m/z=473.9 [M+H].sup.+; HPLC
Ret. Time 1.594 min. and 2.865 min. (Methods H and I respectively);
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. ppm 7.90-7.83 (m, 1H),
7.75-7.64 (m, 1H), 7.48 (t, J=9.0 Hz, 1H), 7.41 (br. s., 1H), 7.28
(br. s., 1H), 7.20 (s, 1H), 5.01 (dd, J=9.9, 4.4 Hz, 1H), 4.96-4.89
(m, 1H), 4.86-4.67 (m, 3H), 4.58 (br. s., 1H), 4.53 (br. s., 1H),
4.01 (dd, J=13.9, 4.0 Hz, 1H), 3.87 (dd, J=14.5, 6.4 Hz, 1H),
2.89-2.78 (m, 2H), 2.65-2.53 (m, 3H), 1.44 (s, 3H).
##STR00707##
Intermediate A11C:
2-(3-Chloro-4-fluorophenyl)-7-(difluoromethyl)-4,5,6,7-tetrahydropyrazolo-
[1,5-a]pyrazine-3-carboxamide
##STR00708##
[1217] Intermediate A11C was synthesized from Intermediate A9H by
following the synthetic sequence shown in Scheme 59 for the
synthesis of Intermediate A6C. MS(ES): m/z=345.0.
Compounds A11 and A12:
2-(3-Chloro-4-fluorophenyl)-N.sup.5-cyclopentyl-7-(difluoromethyl)-6,7-di-
hydropyrazolo[1,5-a]pyrazine-3,5(4H)-dicarboxamide
##STR00709##
[1219] The racemic mixture of A11 and A12 was synthesized analogous
to Compounds A9 and A10 (Scheme 61) by reacting Intermediate A11C
with 3,3-difluoro-1-methylcyclobutanecarboxylic acid. The
individual enantiomers A11 and A12 were separated by chiral SFC
purification using CHIRALPAK.RTM. AS preparative column
(21.times.250) mm, 10 .mu.m column, Solvent A: 0.1% diethylamine in
heptane, Solvent B: 100% EtOH, start % B: 22, isocratic, flow rate
15.0 mL/min for 30 min. UV monitored at 254 nm. Compound A11
(S)-isomer was eluted at 8.523 min. (6.9 mg, 100% ee, Yield=10.44%)
and A12 (R)-isomer was eluted at 10.878 min. (7.2 mg, 100% ee,
Yield=10.89%). MS: m/z=454.5 [M-H].sup.+; HPLC Ret. Time 1.55 min.
and 2.45 min. (Methods H and I respectively); .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. ppm 7.86 (d, J=6.6 Hz, 1H), 7.70 (br. s.,
1H), 7.55-7.48 (m, 1H), 7.46 (d, J=14.3 Hz, 1H), 7.33 (br. s., 1H),
6.73 (d, J=7.0 Hz, 1H), 6.46 (br. s., 1H), 4.89 (d, J=17.6 Hz, 1H),
4.80 (br. s., 1H), 4.65 (d, J=17.2 Hz, 1H), 4.33-4.19 (m, 1H),
4.01-3.86 (m, 1H), 3.75 (d, J=12.8 Hz, 1H), 1.81 (d, J=5.9 Hz, 2H),
1.65 (br. s., 2H), 1.56-1.35 (m, 4H).
[1220] The Compounds described in Table 47 were synthesized
analogous to Compounds A11 and A12 by reacting Intermediate A11C
with the corresponding carboxylic acid.
TABLE-US-00049 TABLE 47 Ret. Ex. Time HPLC No. Structure Name [M +
H].sup.+ (min.) Method A13 ##STR00710## (S)-2-(3-Chloro-4-
fluorophenyl)-N.sup.5- (4,4- difluorocyclohexyl)-
7-(difluoromethyl)- 6,7- dihydropyrazolo[1,5- a]pyrazine-3,5(4H)-
dicarboxamide 506.5 1.57 2.44 H I A14 ##STR00711##
(R)-2-(3-Chloro-4- fluorophenyl)-N.sup.5- (4,4-
difluorocyclohexyl)- 7-(difluoromethyl)- 6,7- dihydropyrazolo[1,5-
a]pyrazine-3,5(4H)- dicarboxamide 506.5 1.63 2.44 H I
##STR00712##
Intermediate A15A: tert-Butyl
3-carbamoyl-2-(3-chloro-4-fluorophenyl)-7-(morpholinomethyl)-6,7-dihydrop-
yrazolo[1,5-a]pyrazine-5(4H)-carboxylate
##STR00713##
[1222] To a solution of Intermediate A11A (0.17 g, 0.402 mmol) in
DCM (5.36 mL) and MeOH (2.68 mL) was added morpholine (0.088 mL,
1.005 mmol), followed by sodium cyanoborohydride (0.076 g, 1.21
mmol) and glacial acetic acid (0.023 mL, 0.402 mmol). The reaction
mixture was stirred at room temperature for 8 h. It was quenched
with a satd. aq. solution of NaHCO.sub.3, the two layers were
separated and the aq. layer was extracted with DCM (2.times.10 mL).
The combined organic layer was washed with brine, dried over
anhydrous MgSO.sub.4, filtered and the filtrate was concentrated
under reduced pressure to afford an oil. It was purified by silica
gel chromatography (24 g REDISEP.RTM. column, eluting with a
gradient of 40 to 60% EtOAc in DCM). Fractions containing the
product were combined and evaporated to afford Intermediate A15A
(0.086 g, 43.3%) as an off-white foam. MS(ES): m/z=494.1
[M+H].sup.+.
Intermediate A15B:
2-(3-Chloro-4-fluorophenyl)-7-(morpholinomethyl)-4,5,6,7-tetrahydropyrazo-
lo[1,5-a]pyrazine-3-carboxamide, 2 TFA
##STR00714##
[1224] To a solution of Intermediate A15A (0.086 g, 0.174 mmol) in
DCM (1.74 mL) was added TFA (0.134 mL, 1.741 mmol) and the reaction
mixture was stirred at room temperature for 1 h. It was then
concentrated to dryness under reduced pressure to afford crude
Intermediate A15B (0.105 g, >99%) as the bis TFA salt. MS(ES):
m/z=394.0.
Compounds A15 and A16:
N.sup.5-(tert-Butyl)-2-(3-chloro-4-fluorophenyl)-7-(morpholinomethyl)-6,7-
-dihydropyrazolo[1,5-a]pyrazine-3,5(4H)-dicarboxamide
##STR00715##
[1226] A solution of Intermediate A15B (0.054 g, 0.087 mmol), DIPEA
(0.091 mL, 0.521 mmol) and 2-isocyanato-2-methylpropane (0.030 mL,
0.260 mmol) in DMF (0.87 mL) was stirred at room temperature for 1
h. The reaction mixture was purified by preparative HPLC to afford
a racemic mixture of A15 and A16. The individual enantiomers A15
and A16 were separated by Chiral SFC purification using
CHIRALCEL.RTM. OD preparative column (21.times.250) mm, 10 .mu.m
column, Solvent A: 0.1% diethylamine in heptane, Solvent B: 100%
EtOH, start % B: 7, isocratic, flow rate 15.0 mL/min for 53 min. UV
monitored at 254 nm. Compound A15 (S)-isomer was eluted at 42.08
min. (9.1 mg, 100% ee, Yield=21%) and A16 (R)-isomer was eluted at
35.463 min. (9.5 mg, 100% ee, Yield=22%). MS: m/z=493.2
[M+H].sup.+; HPLC Ret. Time 1.62 min. and 2.52 min. (Methods H and
I respectively); .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. ppm
7.84 (dd, J=7.2, 2.0 Hz, 1H), 7.73-7.63 (m, 1H), 7.47 (t, J=9.0 Hz,
1H), 7.36 (br. s., 1H), 7.24 (br. s., 1H), 6.05 (s, 1H), 4.98 (d,
J=17.2 Hz, 1H), 4.46 (d, J=16.9 Hz, 2H), 4.14 (d, J=16.9 Hz, 1H),
3.59-3.53 (m, 1H), 3.45-3.38 (m, 2H), 2.71 (d, J=4.0 Hz, 1H), 2.58
(d, J=18.0 Hz, 2H), 2.40 (d, J=5.5 Hz, 2H), 1.29 (s, 9H).
##STR00716## ##STR00717##
Intermediate A17A:
5-(tert-Butoxycarbonyl)-3-carbamoyl-2-(3-chloro-4-fluorophenyl)-4,5,6,7-t-
etrahydropyrazolo[1,5-a]pyrazine-7-carboxylic acid
##STR00718##
[1228] To a solution of Intermediate A9H (2.0 g, 4.71 mmol) in DMF
(47.1 mL) was added pyridinium dichromate (12.40 g, 33.0 mmol) and
the reaction mixture was stirred at room temperature for 48 h. It
was then diluted with water (250 mL) and extracted with EtOAc
(3.times.50 mL) The combined organic layer was washed with water,
brine, dried over anhydrous MgSO.sub.4, filtered and the filtrate
was concentrated under reduced pressure to afford crude
Intermediate A17A (1.47 g, 71.2%) as a brown solid. MS(ES):
m/z=439.3 [M+H].sup.+.
Intermediate A17B: 5-tert-Butyl 7-methyl
3-carbamoyl-2-(3-chloro-4-fluorophenyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-
e-5,7(4H)-dicarboxylate
##STR00719##
[1230] To a solution of crude Intermediate A17A (1.47 g, 3.35 mmol)
in DCM (16.75 mL) and MeOH (16.75 mL) was added TMS-diazomethane
(5.02 mL, 10.05 mmol, 2M solution in THF) and the reaction mixture
was stirred at room temperature for 2 h. The mixture was then
concentrated to dryness under reduced pressure. The residue was
purified by silica gel chromatography (40 g REDISEP.RTM. column,
eluting with a gradient of 45 to 55% EtOAc in hexanes). Fractions
containing the product were combined and evaporated to afford
Intermediate A17B (0.9 g, 59.4%) as a white amorphous solid.
MS(ES): m/z=451.3 [M-H].sup.+.
Intermediate A17C: tert-Butyl
3-carbamoyl-2-(3-chloro-4-fluorophenyl)-7-(2-hydroxypropan-2-yl)-6,7-dihy-
dropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate
##STR00720##
[1232] To a -78.degree. C. solution of Intermediate A17B (0.9 g,
1.990 mmol) in THF (19.90 mL), a solution of methylmagnesium
bromide (3.32 mL, 9.95 mmol, 3M in hexanes) was added dropwise. The
reaction mixture was gradually allowed to attain room temperature
and stirred for 16 h. It was quenched with a satd. aq. solution of
NH.sub.4Cl, the two layers were separated and the aq. layer was
extracted with EtOAc (2.times.60 mL). The combined organic layer
was washed with brine, dried over anhydrous MgSO.sub.4, filtered
and the filtrate was concentrated under reduced pressure to give an
oil. It was purified by silica gel chromatography (80 g
REDISEP.RTM. column, eluting with a gradient of 60 to 70% EtOAc in
DCM). Fractions containing the product were combined and evaporated
to afford Intermediate A17C (0.84 g, 93%) as a yellow solid. (ES):
m/z=453.08 [M-H].sup.+.
Intermediate A17D:
2-(3-Chloro-4-fluorophenyl)-7-(2-hydroxypropan-2-yl)-4,5,6,7-tetrahydropy-
razolo[1,5-a]pyrazine-3-carboxamide
##STR00721##
[1234] To a solution of Intermediate A17C (0.45 g, 0.994 mmol) in
DCM (10.0 mL) was added TFA (1.53 mL, 19.87 mmol) and the reaction
mixture was stirred at room temperature for 1 h. The volatiles were
concentrated under reduced pressure and the residue was neutralized
with a satd. aq. solution of NaHCO.sub.3, extracted with a 5%
solution of MeOH in DCM (3.times.20 mL). The combined organic layer
was washed with brine, dried over anhydrous MgSO.sub.4, filtered
and the filtrate was concentrated under reduced pressure to give
Intermediate A17D (0.34 g, 96%) as a solid. (ES): m/z=375.02
[M+Na].sup.+.
Compounds A17 and A18:
N.sup.5-(tert-Butyl)-2-(3-chloro-4-fluorophenyl)-7-(2-hydroxypropan-2-yl)-
-6,7-dihydropyrazolo[1,5-a]pyrazine-3,5(4H)-dicarboxamide
##STR00722##
[1236] A solution of Intermediate A17D (0.05 g, 0.142 mmol),
2-isocyanato-2-methylpropane (0.05 mL, 0.425 mmol) and DIPEA (0.09
mL, 0.5 mmol) in DMF (1.4 mL) was stirred at room temperature for 1
h. The reaction mixture was purified via preparative HPLC.
Fractions containing the desired product were combined and
evaporated to afford a racemic mixture of A17 and A18. Individual
enantiomers A17 and A18 were separated by chiral SFC separation
using CHIRALPAK.RTM. AD preparative column (21.times.250) mm, 10
.mu.m column, Solvent A: 0.1% diethylamine in heptane, Solvent B:
100% EtOH, start % B: 30, isocratic, flow rate 15.0 mL/min for 25
min. UV monitored at 254 nm. Compound A17 (S)-isomer was eluted at
5.011 min. (10.0 mg, 100% ee, Yield=16%) and A18 (R)-isomer was
eluted at 15.26 min. (12.5 mg, 100% ee, Yield=19.5%). MS: m/z=452.4
[M+H].sup.+; HPLC Ret. Time 1.50 min. and 2.49 min. (Methods H and
I respectively); .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. ppm
7.85 (d, J=5.5 Hz, 1H), 7.74-7.63 (m, 1H), 7.47 (t, J=9.0 Hz, 1H),
7.37 (br. s., 1H), 7.27 (br. s., 1H), 6.21 (s, 1H), 4.83 (d, J=16.9
Hz, 1H), 4.57 (d, J=17.6 Hz, 1H), 4.23-4.11 (m, 2H), 3.55 (d,
J=10.3 Hz, 1H), 1.33-1.26 (m, 13H), 1.23 (br. s., 1H), 0.97 (s,
3H).
[1237] The Compounds described in Table 48 were synthesized
analogous to Compounds A17 and A18 by reacting Intermediate A17D
with the corresponding carboxylic acid.
TABLE-US-00050 TABLE 48 Ret. Ex. Time HPLC No. Structure Name [M +
H].sup.+ (min.) Method A19 ##STR00723## (S)-2-(3-Chloro-4-
fluorophenyl)-N.sup.5- (3,3- difluorocyclobutyl)-
7-(2-hydroxypropan- 2-yl)-6,7- dihydropyrazolo[1,5-
a]pyrazine-3,5(4H)- dicarboxamide 486.4 1.40 2.35 H I A20
##STR00724## (R)-2-(3-Chloro-4- fluorophenyl)-N.sup.5- (3,3-
difluorocyclobutyl)- 7-(2-hydroxypropan- 2-yl)-6,7-
dihydropyrazolo[1,5- a]pyrazine-3,5(4H)- dicarboxamide 486.4 1.40
2.37 H I
##STR00725##
Intermediate A21A: tert-Butyl
3-carbamoyl-2-(3-chloro-4-fluorophenyl)-7-((difluoromethoxy)methyl)-6,7-d-
ihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate
##STR00726##
[1239] To a degassed mixture of Intermediate A9H (0.4 g, 0.942
mmol) and copper(I) iodide (0.054 g, 0.282 mmol) in acetonitrile
(9.42 mL) was added 2,2-difluoro-2-(fluorosulfonyl)acetic acid
(0.117 mL, 1.130 mmol) and the reaction mixture was heated in an
oil bath at 45-50.degree. C. for 16 h. It was then concentrated to
dryness and the residue was dissolved in EtOAc. The organic layer
was washed with water, brine, dried over anhydrous MgSO.sub.4,
filtered and the filtrate was concentrated under reduced pressure
to afford a crude solid. It was purified by silica gel
chromatography (24 g, Premium column, eluting with 35% EtOAc in
DCM). Fractions containing the product were combined and evaporated
to afford Intermediate A21A (0.06 g, 13.%) as a white solid.
MS(ES): m/z=475.04 [M+H].sup.+.
Intermediate A21B:
2-(3-Chloro-4-fluorophenyl)-7-((difluoromethoxy)methyl)-4,5,6,7-tetrahydr-
opyrazolo[1,5-a]pyrazine-3-carboxamide, 2 TFA
##STR00727##
[1241] To a solution of Intermediate A21A (0.06 g, 0.126 mmol) in
DCM (1.26 mL) was added TFA (0.195 mL, 2.53 mmol) and the reaction
mixture was stirred at room temperature for 1 h. It was then
concentrated to dryness to obtain crude Intermediate A21B (0.075 g,
>99%) as the bis TFA salt. MS(ES): m/z=375.0 [M+H].sup.+.
Compounds A21 and A22:
N.sup.5-(tert-Butyl)-2-(3-chloro-4-fluorophenyl)-7-((difluoromethoxy)meth-
yl)-6,7-dihydropyrazolo[1,5-a]pyrazine-3,5(4H)-dicarboxamide
##STR00728##
[1243] A solution of Intermediate A21B (0.076 g, 0.126 mmol),
2-isocyanato-2-methylpropane (0.043 mL, 0.38 mmol) and DIPEA (0.13
mL, 0.756 mmol) in DMF (1.26 mL) was stirred at room temperature
for 1 h. The reaction mixture was purified by preparative HPLC to
afford a racemic mixture of A21 and A22. The individual enantiomers
A21 and A22 were separated by chiral SFC purification using
CHIRALPAK.RTM. AD preparative column (21.times.250) mm, 10 .mu.m
column, Solvent A: 0.1% diethylamine in heptane, Solvent B: 100%
EtOH, start % B: 30, isocratic, flow rate 15.0 mL/min for 85 min.
UV monitored at 254 nm. Compound A21 (S)-isomer was eluted at 40.51
min. (2.6 mg, 100% ee, Yield=5.1%) and A22 (R)-isomer was eluted at
54.09 min. (2.9 mg, 100% ee, Yield=5.7%). MS: m/z=474.3
[M+H].sup.+; HPLC Ret. Time 1.71 min. and 2.54 min. (Methods H and
I respectively); .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. ppm
7.94-7.83 (m, 1H), 7.77-7.64 (m, 1H), 7.48 (t, J=9.0 Hz, 1H), 7.40
(br. s., 1H), 7.30 (br. s., 1H), 6.75 (s, 1H), 6.30 (s, 1H), 4.80
(d, J=16.9 Hz, 1H), 4.66 (d, J=16.9 Hz, 1H), 4.50 (br. s., 1H),
4.37-4.21 (m, 2H), 3.99 (dd, J=14.1, 3.9 Hz, 1H), 3.77 (dd, J=14.3,
6.6 Hz, 1H), 1.29 (s, 10H).
##STR00729##
Intermediate A23B:
2-(3-Chloro-4-fluorophenyl)-N.sup.7-cyclopropyl-4,5,6,7-tetrahydropyrazol-
o[1,5-a]pyrazine-3,7-dicarboxamide, 2 TFA
##STR00730##
[1245] A solution of Intermediate A17A (0.103 g, 0.235 mmol),
cyclopropanamine (0.033 mL, 0.469 mmol), HATU (0.178 g, 0.469 mmol)
and DIPEA (0.164 mL, 0.939 mmol) in DMF (2.0 mL) was stirred at
room temperature for 16 h. The reaction mixture was diluted with
water and extracted with EtOAc (2.times.10 mL). The combined
organic layer was washed with water, brine, dried over anhydrous
MgSO.sub.4, filtered and concentrated to afford the intermediate
amide A23A. (ES): m/z=478.1 [M+H].sup.+. It was subjected to the
deprotection of the Boc group without purification.
[1246] To a solution of intermediate cyclopropylamide A23A in DCM
(2 mL) was added TFA (0.362 mL, 4.69 mmol) and the reaction mixture
was stirred at room temperature for 1 h. The mixture was then
concentrated to dryness to afford crude Intermediate A23B (0.14 g,
>99%) as the bis TFA salt. MS(ES): m/z=378.0 [M+H].sup.+.
Compounds A23 and A24:
N.sup.5-(tert-Butyl)-2-(3-chloro-4-fluorophenyl)-N.sup.7-cyclopropyl-6,7--
dihydropyrazolo[1,5-a]pyrazine-3,5,7(4H)-tricarboxamide
##STR00731##
[1248] A solution of Intermediate A23B (0.06 g, 0.099 mmol),
2-isocyanato-2-methylpropane (0.034 mL, 0.297 mmol) and DIPEA
(0.104 mL, 0.594 mmol) in DMF (0.990 mL) was stirred at room
temperature for 1 h. The reaction mixture was purified via
preparative HPLC to afford a racemic mixture of A23 and A24.
Individual enantiomers A23 and A24 were separated by chiral SFC
separation using CHIRALPAK.RTM. AD preparative column
(21.times.250) mm, 10 .mu.m column, Solvent A: 0.1% diethylamine in
heptane, Solvent B: 100% EtOH, start % B: 30, isocratic, flow rate
15.0 mL/min for 25 min. UV monitored at 254 nm. Compound A23
(S)-isomer was eluted at 7.651 min. (2.0 mg, 100% ee, Yield=4.7%)
and A24 (R)-isomer was eluted at 14.88 min. (1.8 mg, 100% ee,
Yield=3.8%). MS(ES): m/z=477.3 [M+H].sup.+; HPLC Ret. Time 1.57
min. and 2.30 min. (Methods H and I respectively); .sup.1H NMR (500
MHz, DMSO-d.sub.6) .delta. ppm 8.45 (d, J=3.7 Hz, 1H), 7.82 (d,
J=7.3 Hz, 1H), 7.72-7.61 (m, 1H), 7.47 (t, J=8.8 Hz, 1H), 7.38 (br.
s., 1H), 7.28 (br. s., 1H), 6.17 (s, 1H), 4.83-4.73 (m, 2H), 4.00
(dd, J=14.1, 5.7 Hz, 1H), 3.87 (dd, J=14.1, 4.2 Hz, 1H), 3.52-3.45
(m, 1H), 3.44-3.39 (m, 2H), 2.69-2.59 (m, 1H), 1.30-1.23 (m,
11H).
##STR00732##
Intermediate A25C:
2-(3,4-Dichlorophenyl)-7-(fluoromethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]-
pyrazine-3-carboxamide
##STR00733##
[1250] Intermediate A25C was synthesized analogous to Intermediate
A9J by first coupling Intermediate A9G with
3,4-dichlorophenylboronic acid, followed by the synthetic sequence
described in Scheme 61. MS(ES): m/z=343.1 [M+H].sup.+.
Compounds A25 and A26:
N.sup.5-(4-Cyanophenyl)-2-(3,4-dichlorophenyl)-7-(fluoromethyl)-6,7-dihyd-
ropyrazolo[1,5-a]pyrazine-3,5(4H)-dicarboxamide
##STR00734##
[1252] A solution of Intermediate A25C (0.05 g, 0.146 mmol),
2-isocyanato-2-methylpropane (0.050 mL, 0.437 mmol) and DIPEA
(0.089 mL, 0.510 mmol) in DMF (2.91 mL) was stirred at room
temperature for 1 h. The reaction mixture was purified by
preparative HPLC to afford a racemic mixture of A25 and A26. The
individual enantiomers A25 and A26 were separated by Chiral SFC
purification using CHIRALPAK.RTM. IA preparative column
(30.times.250) mm, 5 .mu.m column, flow rate 70.0 mL/min for 16
min.; mobile phase: 40% MeOH in CO.sub.2. Temperature: 35.degree.
C., UV monitored at 265 nm, Back pressure: 150 bar. Compound A25
(S)-isomer was eluted at 9.23 min. (9.0 mg, 100% ee, Yield=14%) and
A26 (R)-isomer was eluted at 12.89 min. (8.3 mg, 100% ee,
Yield=13%). MS(ES): m/z=442.3 [M+H].sup.+; HPLC Ret. Time 1.61 min.
and 2.57 min. (Methods H and I respectively); .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. ppm 7.92 (s, 1H), 7.69 (s, 2H), 7.41 (br. s.,
1H), 7.35 (br. s., 1H), 6.28 (s, 1H), 5.03 (dd, J=9.9, 4.8 Hz, 1H),
4.94 (dd, J=9.7, 4.2 Hz, 1H), 4.81 (d, J=17.2 Hz, 2H), 4.73 (d,
J=7.0 Hz, 1H), 4.63 (d, J=17.2 Hz, 1H), 4.55 (br. s., 1H), 4.51
(br. s., 1H), 4.02 (dd, J=14.1, 4.2 Hz, 1H), 3.78 (dd, J=13.8, 7.2
Hz, 1H), 1.28 (s, 9H).
Compounds A27 and A28:
2-(3,4-Dichlorophenyl)-N.sup.5-(3,3-difluoro-1-methylcyclobutyl)-7-(fluor-
omethyl)-6,7-dihydropyrazolo[1,5-a]pyrazine-3,5(4H)-dicarboxamide
##STR00735##
[1254] A racemic mixture of Compounds A27 and A28 was synthesized
analogous to Compounds A9 and A10 (Scheme 61) by reacting
Intermediate A25C with 3,3-difluoro-1-methylcyclobutanecarboxylic
acid. The individual enantiomers A27 and A28 were separated by
chiral SFC purification using CHIRALPAK.RTM. AD preparative column
(21.times.250) mm, 10 .mu.m column, Solvent A: 0.1% diethylamine in
heptane, Solvent B: 100% EtOH, start % B: 20, isocratic, flow rate
15.0 mL/min for 20 min. UV monitored at 254 nm. Compound A27
(S)-isomer was eluted at 8.853 min. (5.5 mg, 100% ee, Yield=11.3%)
and A28 (R)-isomer was eluted at 10.996 min. (6.4 mg, 100% ee,
Yield=13.2%). MS(ES): m/z=489.9 [M+H].sup.+; HPLC Ret. Time 1.717
min. and 3.017 min. (H and I respectively); .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. ppm 7.92 (s, 1H), 7.73-7.65 (m, 2H), 7.43
(br. s., 1H), 7.36 (br. s., 1H), 7.21 (s, 1H), 5.02 (dd, J=9.7, 4.6
Hz, 1H), 4.93 (dd, J=10.3, 4.8 Hz, 1H), 4.86-4.67 (m, 3H), 4.59
(br. s., 1H), 4.54 (br. s., 1H), 4.01 (dd, J=14.1, 4.2 Hz, 1H),
3.95-3.81 (m, 1H), 2.90-2.80 (m, 2H), 2.65-2.54 (m, 2H), 1.44 (s,
3H).
[1255] The Compounds described in Table 49 were synthesized
analogous to Compounds A27 and A28 by reacting Intermediate A25C
with the corresponding carboxylic acid.
TABLE-US-00051 TABLE 49 Ret. Ex. Time HPLC No. Structure Name [M +
H].sup.+ (min.) Method A29 ##STR00736## (S)-2-(3,4-
dichlorophenyl)-N.sup.5- (3,3- difluorocyclobutyl)-
7-(fluoromethyl)- 6,7- dihydropyrazolo[1,5- a]pyrazine-3,5(4H)-
dicarboxamide 476.4 1.55 2.44 H I A30 ##STR00737## (R)-2-(3,4-
dichlorophenyl)-N.sup.5- (3,3- difluorocyclobutyl)-
7-(fluoromethyl)- 6,7- dihydropyrazolo[1,5- a]pyrazine-3,5(4H)-
dicarboxamide 476.3 1.57 2.46 H I
##STR00738##
Intermediate A31C:
2-(3,4-Dichlorophenyl)-7-(difluoromethyl)-4,5,6,7-tetrahydropyrazolo[1,5--
a]pyrazine-3-carboxamide
##STR00739##
[1257] Intermediate A31C was synthesized from Intermediate A25A
using a synthetic sequence analogous to the preparation of
Intermediate A6C (Scheme 59). MS(ES): m/z=361.2 [M+H].sup.+.
Compounds A31 and A32:
N.sup.5-(tert-Butyl)-2-(3,4-dichlorophenyl)-7-(difluoromethyl)-6,7-dihydr-
opyrazolo[1,5-a]pyrazine-3,5(4H)-dicarboxamide
##STR00740##
[1259] The racemic mixture of Compounds A31 and A32 was synthesized
analogous to Compounds A15 and A16 by reacting Intermediate A31C
with 2-isocyanato-2-methylpropane. The reaction mixture was
purified via preparative HPLC to afford a racemic mixture of A31
and A32. The individual enantiomers A31 and A32 were separated by
chiral SFC separation using CHIRALPAK.RTM. AD preparative column
(21.times.250) mm, 10 .mu.m column, Solvent A: 0.1% diethylamine in
heptane, Solvent B: 100% EtOH, start % B: 15, isocratic, flow rate
15.0 mL/min for 120 min. UV monitored at 254 nm. A31 (S)-isomer was
eluted at 12.428 min. (0.8 mg, 100% ee, Yield=1.1%) and A32
(R)-isomer was eluted at 21.622 min. (1.1 mg, 100% ee, Yield=1.6%).
MS(ES): m/z=460.4 [M+H].sup.+. HPLC Ret. Time 1.62 min. and 2.68
min. (Methods H and I respectively).
##STR00741##
Intermediate A33C:
2-(3,4-Dichlorophenyl)-7-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-
-3-carboxamide
##STR00742##
[1261] Intermediate A33C was synthesized from Intermediate A25A
using a synthetic sequence analogous to the preparation of
Intermediate A7C (Scheme 60). MS(ES): m/z=325.1 [M+H].sup.+.
Compounds A33 and A34:
N.sup.5-(tert-Butyl)-2-(3,4-dichlorophenyl)-7-methyl-6,7-dihydropyrazolo[-
1,5-a]pyrazine-3,5(4H)-dicarboxamide
##STR00743##
[1263] A solution of Intermediate A33C (0.05 g, 0.154 mmol),
2-isocyanato-2-methylpropane (0.045 mL, 0.384 mmol) and DIPEA (0.08
mL, 0.461 mmol) in DMF (1.54 mL) was stirred at room temperature
for 1 h. The residue was purified by preparative HPLC to afford a
racemic mixture of A33 and A34. The individual enantiomers A33 and
A34 were separated by Chiral SFC purification using CHIRALPAK.RTM.
AD preparative column (21.times.250) mm, 10 .mu.m column, Solvent
A: 0.1% diethylamine in heptane, Solvent B: 100% EtOH, start % B:
5.0, isocratic, flow rate 15.0 mL/min for 70 min. UV monitored at
254 nm. Compound A33 (S)-isomer was eluted at 44.01 min. (14.2 mg,
100% ee, Yield=21.8%) and A34 (R)-isomer was eluted at 33.14 min.
(14.6 mg, 100% ee, Yield=22.4%). MS(ES): m/z=424.3 [M+H].sup.+;
HPLC Ret. Time 1.64 min. and 2.61 min. (Methods H and I
respectively); .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. ppm 7.68
(s, 2H), 7.38 (br. s., 1H), 7.30 (br. s., 1H), 6.24 (s, 1H), 4.79
(d, J=16.9 Hz, 1H), 4.61 (d, J=16.9 Hz, 1H), 4.38-4.24 (m, 1H),
3.95 (dd, J=13.8, 3.5 Hz, 1H), 3.48 (dd, J=13.9, 7.3 Hz, 1H), 3.38
(d, J=4.8 Hz, 1H), 1.45 (d, J=6.2 Hz, 3H), 1.29 (s, 9H).
[1264] The Compounds described in Table 50 were synthesized
analogous to A33 and A34 by reacting Intermediate A33C with the
corresponding carboxylic acid.
TABLE-US-00052 TABLE 50 Ex. Synthetic Ret. Time HPLC No. Structure
Name method [M + H].sup.+ (min.) Method A35 ##STR00744##
(R)-2-(3,4- Dichlorophenyl)-N.sup.5- (3,3- difluorocyclobutyl)-
7-methyl-6,7- dihydropyrazolo[1,5- a]pyrazine-3,5(4H)-
dicarboxamide D 458.4 1.57, 2.52 H I A36 ##STR00745## (S)-2-(3,4-
Dichlorophenyl)-N.sup.5- (3,3- difluorocyclobutyl)- 7-methyl-6,7-
dihydropyrazolo[1,5- a]pyrazine-3,5(4H)- dicarboxamide D 458.4
1.57, 2.52 H I
##STR00746## ##STR00747##
Intermediate A37D:
2-(3,4-Dichlorophenyl)-7-(2-hydroxypropan-2-yl)-4,5,6,7-tetrahydropyrazol-
o[1,5-a]pyrazine-3-carboxamide
##STR00748##
[1266] Intermediate A37D was synthesized from Intermediate A25A by
using a synthetic sequence analogous to the preparation of
Intermediate A17D (Scheme 64). MS(ES): m/z=369.1 [M+H].sup.+.
Compounds A37 and A38:
N.sup.5-(tert-Butyl)-2-(3,4-dichlorophenyl)-7-(2-hydroxypropan-2-yl)-6,7--
dihydropyrazolo[1,5-a]pyrazine-3,5(4H)-dicarboxamide
##STR00749##
[1268] The racemic mixture of Compounds A37 and A38 was synthesized
analogous to Compounds A17 and A18 (Scheme 64) by reacting
Intermediate A37D with 2-isocyanato-2-methylpropane. The reaction
mixture was purified via preparative HPLC to afford a racemic
mixture of Compounds A37 and A38. The individual enantiomers A37
and A38 were separated by chiral SFC separation using
CHIRALPAK.RTM. AD preparative column (21.times.250) mm, 10 .mu.m
column, Solvent A: 0.1% diethylamine in heptane, Solvent B: 100%
EtOH, start % B: 30, isocratic, flow rate 15.0 mL/min for 25 min.
UV monitored at 254 nm. Compound A37 (S)-isomer was eluted at 5.078
min. (10.5 mg, 100% ee, Yield=16.6%) and A38 (R)-isomer was eluted
at 16.331 min. (13.4 mg, 100% ee, Yield=21.1%). MS(ES): m/z=468.3
[M+H].sup.+; HPLC Ret. Time 1.61 min. and 2.60 min. (Methods H and
I respectively); .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. ppm
7.89 (s, 1H), 7.71-7.62 (m, 2H), 7.38 (br. s., 1H), 7.34 (br. s.,
1H), 6.20 (s, 1H), 4.82 (d, J=17.2 Hz, 1H), 4.55 (d, J=17.2 Hz,
1H), 4.15 (d, J=3.7 Hz, 2H), 2.55 (s, 2H), 1.34-1.23 (m, 12H), 0.96
(s, 3H).
##STR00750## ##STR00751## ##STR00752## ##STR00753##
Intermediate A39A:
(Z)-1-(3-Chloro-4-fluorophenyl)-4,4-diethoxy-3-hydroxybut-2-en-1-one
##STR00754##
[1270] To a -78.degree. C. solution of
1-(3-chloro-4-fluorophenyl)ethanone (16.25 g, 94 mmol) and ethyl
2,2-diethoxyacetate (20.73 mL, 113 mmol) in THF (392 mL) was added,
dropwise, a solution of LDA (51.8 mL, 104 mmol, 2M in THF). The
resultant reaction mixture was gradually allowed to reach room
temperature and continued stirring for 16 h. The reaction was
carefully quenched with water and diluted with EtOAc. The two
layers were separated and the aq. layer was extracted with EtOAc
(2.times.150 mL). The combined organic layer was washed with brine,
dried over anhydrous MgSO.sub.4, filtered and the filtrate was
concentrated under reduced pressure to provide a crude oil. It was
purified by silica gel chromatography (1500 g Commodity column,
eluting with a 10% EtOAc in hexanes). Fractions containing the
product were combined and evaporated to afford Intermediate A39A
(9.97 g, 35%) as a solid. MS(ES): m/z=257 [M-OEt].sup.+.
Intermediate A39B:
3-(3-Chloro-4-fluorophenyl)-5-(diethoxymethyl)-1H-pyrazole
##STR00755##
[1272] To a solution of Intermediate A39A (19.37 g, 64.0 mmol) in
EtOH (128 mL) was added hydrazine hydrate (4.9 mL, 64.0 mmol, 64%
solution) and the reaction continued stirring at room temperature
for 2 h. Ethanol was concentrated under reduced pressure and the
residue was partitioned between water and EtOAc. The two layers
were separated and the aq. layer was extracted with EtOAc
(2.times.200 mL). The combined organic layer was washed with water,
brine, dried over anhydrous MgSO.sub.4, filtered and the filtrate
was concentrated under reduced pressure to provide a crude oil. It
was purified by silica gel chromatography (330 g REDISEP.RTM.
column, eluting with a gradient of 0 to 20% EtOAc in hexanes).
Fractions containing the product were combined and evaporated to
afford Intermediate A39B (17.08 g, 89%) as a bright yellow syrup
that later on solidified. MS(ES): m/z=253 [M-OEt]+; .sup.1H NMR
(400 MHz, chloroform-d) .delta. ppm 7.87 (dd, 2.3 Hz, 1H), 7.68
(ddd, J=8.5, 4.6, 2.1 Hz, 1H), 7.19 (t, J=8.7 Hz, 1H), 6.57 (s,
1H), 5.75 (s, 1H), 3.76-3.57 (m, 4H), 1.35-1.24 (m, 7H).
Intermediate A39C:
2-(3-(3-Chloro-4-fluorophenyl)-5-(diethoxymethyl)-1H-pyrazol-1-yl)acetoni-
trile
##STR00756##
[1274] To a 0.degree. C. solution of Intermediate A39B (1.21 g,
4.04 mmol) in DMF (10.22 mL) was added a solution of NHMDS (4.24
mL, 4.24 mmol, 1M in THF) and the reaction was continued stirring
at that temperature for 30 min., followed by the addition of
2-chloroacetonitrile (0.283 mL, 4.44 mmol). The resultant mixture
was stirred at room temperature for 16 h. It was quenched by the
addition of a satd. aq. solution of NH.sub.4Cl and the aq. layer
was extracted with EtOAc (3.times.25 mL). The combined organic
layer was washed with water, brine, dried over anhydrous
MgSO.sub.4, filtered, and the filtrate was concentrated under
reduced pressure to provide a crude oil. It was purified by silica
gel chromatography (120 g REDISEP.RTM. column, 20% EtOAc in
hexanes). Fractions containing the product were combined and
evaporated to afford A39C (1.0 g, 73.3%) as a white solid. MS(ES):
m/z=338.2 [M+H].sup.+.
Intermediate A39D:
1-(3-(3-Chloro-4-fluorophenyl)-5-(diethoxymethyl)-1H-pyrazol-1-yl)-3-hydr-
oxycyclobutanecarbonitrile
##STR00757##
[1276] To a -78.degree. C. solution of Intermediate A39C (0.5 g,
1.480 mmol) in THF (7.40 mL), a 1.6M solution of methyllithium
(0.925 mL, 1.480 mmol) was added dropwise and the reaction was
allowed to stir at that temperature for 1 h. Subsequently, a
solution of 2-(bromomethyl)oxirane (0.125 mL, 1.480 mmol) in THF (2
mL) was introduced dropwise. The reaction was allowed to stir at
-78.degree. C. for 1 h. Then, a solution of methylmagnesium bromide
(0.493 mL, 1.480 mmol, 3M in hexane) was added at -78.degree. C.
and the resultant reaction mixture was allowed to warm to room
temperature. After 16 h, the reaction was quenched with by adding a
satd. aq. solution of NH.sub.4Cl, the two layers were separated and
the aq. layer was extracted with EtOAc (2.times.20 mL). The
combined organic layer was washed with brine, dried over anhydrous
MgSO.sub.4, filtered and the filtrate was concentrated under
reduced pressure to provide a crude oil. It was purified by silica
gel chromatography (40 g REDISEP.RTM. column, eluting with a
gradient of 0 to 20% EtOAc in hexanes). Fractions containing the
product were combined and evaporated to afford Intermediate A39D
(0.197 g, 33.8%) as a solid. MS(ES): m/z=394.1 [M+H].sup.+.
Intermediate A39E:
1-(3-(3-Chloro-4-fluorophenyl)-5-(diethoxymethyl)-1H-pyrazol-1-yl)-3-oxoc-
yclobutanecarbonitrile
##STR00758##
[1278] To a solution of Intermediate A39D (4.6 g, 11.68 mmol) in
DCM (58.4 mL) was added Dess-Martin periodinane (7.43 g, 17.52
mmol) and the reaction mixture was stirred at room temperature for
2 h. It was then quenched with the addition of a satd. aq. solution
of NaHCO.sub.3 and satd. aq. solution of sodium sulfite. The two
layers were separated and the aq. layer was extracted with DCM
(2.times.70 mL), the combined organic layers was washed with brine,
dried over anhydrous MgSO.sub.4, filtered and the filtrate was
concentrated under reduced pressure to provide a crude oil. It was
purified by silica gel chromatography (220 g REDISEP.RTM. column,
eluting with a gradient of 0 to 15% EtOAc in hexanes). Fractions
containing the product were combined and evaporated to afford
Intermediate A39E (3.98 g, 87%) as a colorless syrup. MS(ES):
m/z=392.1 [M+H].sup.+.
Intermediate A39F:
1-(3-(3-Chloro-4-fluorophenyl)-5-(diethoxymethyl)-1H-pyrazol-1-yl)-3,3-di-
fluorocyclobutanecarbonitrile
##STR00759##
[1280] To a 0.degree. C. solution of Intermediate A39E (3.98 g,
10.16 mmol) in DCM (67.7 mL) was added DAST (4.03 mL, 30.5 mmol)
and the reaction mixture was stirred at room temperature for 18 h.
It was quenched with by adding satd. aq. solution of NaHCO.sub.3,
the two layers were separated and the aq. layer was extracted with
DCM (2.times.60 mL). The combined organic layer was washed with
brine, dried over anhydrous MgSO.sub.4, filtered and the filtrate
was concentrated under reduced pressure to provide a crude oil. It
was purified by silica gel chromatography (220 g REDISEP.RTM.
column, eluting with a gradient of 10 to 15% EtOAc in hexanes).
Fractions containing the product were combined and evaporated to
afford Intermediate A39F (3.075 g, 73.2%) as a pale yellow oil.
MS(ES): m/z=414.17 [M+H].sup.+.
Intermediate A39G:
(1-(3-(3-Chloro-4-fluorophenyl)-5-(diethoxymethyl)-1H-pyrazol-1-yl)-3,3-d-
ifluorocyclobutyl)methanamine
##STR00760##
[1282] To a 0.degree. C. suspension of Intermediate A39F (3.075 g,
7.43 mmol) and cobalt(II) chloride (2.96 g, 22.29 mmol) in MeOH
(74.3 mL) was slowly added NaBH.sub.4 (2.81 g, 74.3 mmol). The
reaction mixture instantly turned black and a vigorous gas
evolution was observed. The reaction was heated in an oil bath at
50.degree. C. for 4 h and then allowed to stir at room temperature
for 16 h. The reaction mixture was then filtered through a
CELITE.RTM. plug and the filtrate was concentrated under reduced
pressure to afford a residue. This residue was suspended in DCM and
filtered off. The filtrate was concentrated and purified by silica
gel chromatography (120 g REDISEP.RTM. column, eluting with a
gradient of 65 to 75% EtOAc in hexanes). Fractions containing the
product were combined and evaporated to afford Intermediate A39G
(1.1 g, 35.4%) as a colorless oil. .sup.1H NMR (400 MHz,
chloroform-d) .delta. ppm 7.86 (dd, J=7.2, 2.1 Hz, 1H), 7.65 (ddd,
J=8.6, 4.6, 2.1 Hz, 1H), 7.17 (t, J=8.7 Hz, 1H), 6.70 (s, 1H), 5.61
(s, 1H), 3.75-3.45 (m, 7H), 3.21 (s, 2H), 3.01 (ddd, J=15.4, 13.1,
4.9 Hz, 2H), 1.27 (t, J=7.0 Hz, 6H).
Intermediate A39H:
2'-(3-Chloro-4-fluorophenyl)-3,3-difluoro-6'H-spiro[cyclobutane-1,7'-pyra-
zolo[1,5-a]pyrazine]
##STR00761##
[1284] To a solution of Intermediate A39G (1.017 g, 2.434 mmol) in
THF (24.34 mL) was added a conc. aqueous solution of HCl (0.61 mL,
7.30 mmol). A precipitate formed and the reaction continued to stir
at room temperature for 2 h. The solvent was evaporated and the aq.
residue was basified with a satd. aq. solution of NaHCO.sub.3 and
extracted with EtOAc (3.times.25 mL). The combined organic layer
was washed with brine, dried over anhydrous MgSO.sub.4, filtered
and the filtrate was concentrated under reduced pressure to afford
crude Intermediate A39H (0.79 g, 100%) as a white solid. MS(ES):
m/z=326.0 [M+H].sup.+.
Intermediate A39I:
2'-(3-Chloro-4-fluorophenyl)-3,3-difluoro-5',6'-dihydro-4'H-spiro[cyclobu-
tane-1,7'-pyrazolo[1,5-a]pyrazine]
##STR00762##
[1286] To a solution of Intermediate A39H (0.79 g, 2.425 mmol) in
EtOH (24.25 mL) and THF (24.25 mL) was added NaBH.sub.4 (0.459 g,
12.13 mmol) at room temperature and the reaction mixture was
stirred for 16 h. It was diluted with water and extracted with DCM
(3.times.25 mL). The combined organic layer was washed with brine,
dried over anhydrous MgSO.sub.4, filtered and the filtrate was
concentrated under reduced pressure. It was purified by silica gel
chromatography (12 g REDISEP.RTM. column, eluting with a gradient
of 55 to 100% EtOAc in hexanes). Fractions containing the product
were combined and evaporated to afford Intermediate A39I (0.139 g,
17.49%) as a white solid. MS(ES): m/z=328.1 [M+H].sup.+.
Intermediate A39J: tert-Butyl
2'-(3-chloro-4-fluorophenyl)-3,3-difluoro-4'H-spiro[cyclobutane-1,7'-pyra-
zolo[1,5-a]pyrazine]-5'(6'H)-carboxylate
##STR00763##
[1288] To a solution of Intermediate A391 (0.137 g, 0.418 mmol) in
DCM (4.18 mL) was added TEA (0.175 mL, 1.254 mmol), DMAP (5.11 mg,
0.042 mmol) and Boc.sub.2O (0.109 g, 0.502 mmol) and the reaction
mixture was stirred for 16 h. It was quenched by adding satd. aq.
solution of NaHCO.sub.3, the two layers were separated and the aq.
layer was extracted with DCM (2.times.10 mL). The combined organic
layer was washed with brine, dried over anhydrous MgSO.sub.4,
filtered and the filtrate was concentrated under reduced pressure.
It was purified by silica gel chromatography (24 g REDISEP.RTM.
column, eluting with 21% EtOAc in hexanes). Fractions containing
the product were combined and evaporated to afford Intermediate
A39J (0.14 g, 78%) as a white solid. MS(ES): m/z=428.1
[M+H].sup.+.
Intermediate A39K: tert-Butyl
2'-(3-chloro-4-fluorophenyl)-3,3-difluoro-3'-iodo-4'H-spiro[cyclobutane-1-
,7'-pyrazolo[1,5-a]pyrazine]-5'(6'H)-carboxylate
##STR00764##
[1290] To a solution of Intermediate A39J (0.14 g, 0.327 mmol) in
DCM (2.62 mL) and MeOH (0.654 mL) was added NIS (0.221 g, 0.982
mmol) and the reaction mixture was continued stirring at room
temperature for 3 h. It was then concentrated under reduced
pressure and the residue was purified by silica gel chromatography
(24 g REDISEP.RTM. column, eluting with 18% EtOAc in hexanes).
Fractions containing the product were combined and evaporated to
afford Intermediate A39K (0.179 g, 100%) as a white foam. MS(ES):
m/z=554.0 [M+H].sup.+.
Intermediate A39L: tert-Butyl
2'-(3-chloro-4-fluorophenyl)-3'-cyano-3,3-difluoro-4'H-spiro[cyclobutane--
1,7'-pyrazolo[1,5-a]pyrazine]-5'(6'H)-carboxylate
##STR00765##
[1292] To a degassed solution of Intermediate A39K (0.148 g, 0.267
mmol) in DMF (5.35 mL) was added copper(I) cyanide (0.061 g, 0.668
mmol) and the mixture was degassed again for 5 min. with N.sub.2
and then heated in a sealed tube in an oil bath at 120.degree. C.
for 20 h. The reaction mixture was filtered and the filtrate
concentrated under reduced pressure to afford a crude residue,
which was purified by silica gel chromatography (12 g REDISEP.RTM.
column, eluting with 30% EtOAc in hexanes). Fractions containing
the product were combined and evaporated to afford Intermediate
A39L (0.095 g, 52.59%) as an off-white solid. MS(ES): m/z=478.3
[M+Na]+.
Intermediate A39M: tert-Butyl
3'-carbamoyl-2'-(3-chloro-4-fluorophenyl)-3,3-difluoro-4'H-spiro[cyclobut-
ane-1,7'-pyrazolo[1,5-a]pyrazine]-5'(6'H)-carboxylate
##STR00766##
[1294] To an ice-cold solution of Intermediate A39L (0.095 g, 0.210
mmol) in DMSO (2.1 mL) was added a 5M aq. solution of KOH (0.21 mL,
1.049 mmol), followed by the dropwise addition of a 30% aq.
solution of H.sub.2O.sub.2 (0.429 mL, 4.20 mmol). The reaction
mixture was stirred at room temperature for 1 h. It was then
diluted with water and extracted with EtOAc (2.times.10 mL). The
combined organic layer was washed with brine, dried over anhydrous
MgSO.sub.4, filtered and the filtrate was concentrated under
reduced pressure to give a yellow oil. It was purified by silica
gel chromatography (12 g REDISEP.RTM. column, eluting with 30%
EtOAc in DCM). Fractions containing the product were combined and
evaporated to afford Intermediate A39M (0.073 g, 73.9%) as a white
solid. MS(ES): m/z=471.1 [M+H].sup.+.
Intermediate A39N:
2'-(3-Chloro-4-fluorophenyl)-3,3-difluoro-5',6'-dihydro-4'H-spiro[cyclobu-
tane-1,7'-pyrazolo[1,5-a]pyrazine]-3'-carboxamide, TFA
##STR00767##
[1296] To a solution of Intermediate A39M (0.073 g, 0.155 mmol) in
DCM (1.55 mL) was added TFA (0.24 mL, 3.10 mmol) and the reaction
mixture was continued stirring at room temperature for 2 h. It was
then concentrated to dryness and the residue was dried under vacuum
for 20 min. to afford crude Intermediate A39N (0.073 g, >99%) as
the mono TFA salt.
Compound A39:
N.sup.5'-(tert-Butyl)-2'-(3-chloro-4-fluorophenyl)-3,3-difluoro-4'H-spiro-
[cyclobutane-1,7'-pyrazolo[1,5-a]pyrazine]-3',5'(6'H)-dicarboxamide
##STR00768##
[1298] To a solution of Intermediate A39N (0.037 g, 0.076 mmol) and
DIPEA (0.067 mL, 0.382 mmol) in DMF (0.763 mL) was added
2-isocyanato-2-methylpropane (0.018 mL, 0.153 mmol) and the
reaction mixture was continued stirring at room temperature for 2
h. It was then purified by preparative HPLC to afford Compound A39
(16 mg, 44.2%). MS(ES): m/z=470.4 [M+H].sup.+; HPLC Ret. Time 1.87
min. and 2.81 min. (HPLC Methods H and I); .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. ppm 7.83 (d, J=7.0 Hz, 1H), 7.66 (br. s.,
1H), 7.45 (t, J=9.0 Hz, 1H), 7.36 (br. s., 1H), 7.27 (br. s., 1H),
6.33 (s, 1H), 4.73 (s, 2H), 4.45-4.30 (m, 2H), 3.32 (d, J=13.6 Hz,
2H), 2.96 (t, J=11.9 Hz, 2H), 1.26 (s, 9H).
Compound A40:
2-(3-Chlorophenyl)-N.sup.5-(1-(trifluoromethyl)cyclopropyl)-6,7-dihydropy-
razolo[1,5-a]pyrazine-3,5(4H)-dicarboxamide
##STR00769##
[1300] To a solution of 1-(trifluoromethyl)cyclopropanamine (22.60
mg, 0.181 mmol) in THF (2 mL) at 0.degree. C. were added TEA (0.063
mL, 0.452 mmol) and triphosgene (20.11 mg, 0.068 mmol) in THF (2
mL). The suspension was stirred at 0.degree. C. for 30 min. Then a
solution of Intermediate 156E in DMF (1 mL) was added. The reaction
mixture was stirred at RT overnight. The reaction mixture was
quenched with MeOH and concentrated. The residue was dissolved in
DMF and purified by preparative HPLC. Fractions containing the
desired product were combined and dried under vacuum to afford
Compound A40 (29 mg, 75%). MS(ES): m/z=547 [M+H].sup.+; HPLC Ret.
Time 1.23 min. and 2.16 min. (HPLC Methods H and I); .sup.1H NMR
(500 MHz, DMSO-d.sub.6) .delta. ppm 7.56 (s, 1H), 7.49 (d, J=7.0
Hz, 1H), 7.34-7.18 (m, 3H), 7.04 (br. s., 1H), 4.60 (s, 2H),
4.06-3.92 (m, 2H), 3.77-3.65 (m, 2H), 1.13-0.97 (m, 2H), 0.93-0.88
(m., 2H).
[1301] The Compounds described in Table 51 were synthesized
analogous to Compound A40 using Intermediate 156E and corresponding
amines.
TABLE-US-00053 TABLE 51 Ret. Ex. Time HPLC No. Structure Name [M +
H].sup.+ (min.) Method A41 ##STR00770## 2-(3-Chlorophenyl)-
N.sup.5-(1,3-difluoro-2- (fluoromethyl)propan- 2-yl)-6,7-
dihydropyrazolo[1,5- a]pyrazine-3,5(4H)- dicarboxamide 430.1 1.44
2.12 H I A42 ##STR00771## 2-(3-Chlorophenyl)- N.sup.5-(1-
methylcyclopropyl)- 6,7- dihydropyrazolo[1,5- a]pyrazine-3,5(4H)-
dicarboxamide 374.2 1.50 2.23 H I A43 ##STR00772##
2-(3-Chlorophenyl)- N.sup.5-(1- cyanocyclobutyl)-6,7-
dihydropyrazolo[1,5- a]pyrazine-3,5(4H)- dicarboxamide 399.2 1.43
2.15 H I A44 ##STR00773## 2-(3-Chlorophenyl)- N.sup.5-(1-
methylcyclobutyl)- 6,7- dihydropyrazolo[1,5- a]pyrazine-3,5(4H)-
dicarboxamide 387.1 1.54 2.42 H I A45 ##STR00774##
2-(3-Chlorophenyl)- N.sup.5-(1- cyanocyclopropyl)- 6,7-
dihydropyrazolo[1,5- a]pyrazine-3,5(4H)- dicarboxamide 385.2 1.03
1.87 H I A46 ##STR00775## 2-(3-Chlorophenyl)- N.sup.5-(1-hydroxy-2-
methylpropan-2-yl)- 6,7- dihydropyrazolo[1,5- a]pyrazine-3,5(4H)-
dicarboxamide 392.5 1.05 2.01 H I A47 ##STR00776##
2-(3-Chlorophenyl)- N.sup.5-(1-methoxy-2- methylpropan-2-yl)- 6,7-
dihydropyrazolo[1,5- a]pyrazine-3,5(4H)- dicarboxamide 406.3 1.49
2.28 H I
[1302] The Compounds described in Table 52 were synthesized
analogous to Compound A40 using Intermediate 185B and corresponding
amines.
TABLE-US-00054 TABLE 52 Ret. Ex. Time HPLC No. Structure Name [M +
H].sup.+ (min.) Method A48 ##STR00777## 2-(3-Chloro-4-
fluorophenyl)-N.sup.5-(1- hydroxy-2- methylpropan-2-yl)- 6,7-
dihydropyrazolo[1,5- a]pyrazine-3,5(4H)- dicarboxamide 410.1 1.18
2.10 H I A49 ##STR00778## 2-(3-Chloro-4- fluorophenyl)-N.sup.5-
(1,3-difluoro-2- (fluoromethyl)propan- 2-yl)-6,7-
dihydropyrazolo[1,5- a]pyrazine-3,5(4H)- dicarboxamide 448.1 1.39
2.17 H I A50 ##STR00779## 2-(3-Chloro-4- fluorophenyl)-N.sup.5-(1-
cyanocyclopropyl)- 6,7- dihydropyrazolo[1,5- a]pyrazine-3,5(4H)-
dicarboxamide 479.1 1.56 2.36 H I
##STR00780## ##STR00781##
[1303] Intermediate A51A:
4-(Methoxycarbonyl)bicyclo[2.2.2]octane-1-carboxylic acid
##STR00782##
[1304] To a solution of dimethyl
bicyclo[2.2.2]octane-1,4-dicarboxylate (0.92 g, 4.07 mmol) in MeOH
(5 mL) was added LiOH (0.102 g, 4.27 mmol) in water (4 mL) at RT.
The reaction mixture was heated at 65.degree. C. for 6 h. It was
then cooled to RT and concentrated. The residue was acidified with
1N HCl to pH.about.2. The solid (presumed side product diacid) was
removed by filtration. The filtrate was extracted with EtOAc, and
the combined organic layer was washed with brine, dried over
Na.sub.2SO.sub.4, and filtered. The filtrate was concentrated to
afford Intermediate ASIA as a white solid, which was used for the
next step without further purification. MS(ES): m/z=213
[M+H].sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 12.11
(s, 1H), 3.66 (s, 3H), 1.78-1.58 (m, 12H).
Intermediate A51B: Methyl
4-fluorobicyclo[2.2.2]octane-1-carboxylate
##STR00783##
[1306] To a suspension of Intermediate ASIA (227 mg, 1.070 mmol) in
CH.sub.2Cl.sub.2 (4 mL) was added difluoroxenon (272 mg, 1.604
mmol). The suspension was stirred at RT overnight. The reaction
mixture was concentrated and the residue was purified by silica gel
chromatography (40 g REDISEP.RTM. column, eluting with 0-20% EtOAc
in hexane). Fractions containing the product were combined and
evaporated to afford Intermediate A51B (80 mg, 40.2%). .sup.1H NMR
(400 MHz, chloroform-d) .delta. ppm 3.66 (s, 3H), 2.05-1.94 (m,
6H), 1.90-1.79 (m, 6H).
Intermediate A51C: 4-Fluorobicyclo[2.2.2]octane-1-carboxylic
acid
##STR00784##
[1308] To a solution of Intermediate A51B (80 mg, 0.430 mmol) in
MeOH (2 mL) was added 1M solution of NaOH (1 mL, 1.00 mmol)
dropwise. The reaction mixture was stirred at RT overnight and
concentrated. The residue was acidified with 1N HCl to pH.about.2,
extracted with EtOAc. The combined organic layer was washed with
brine, dried over Na.sub.2SO.sub.4, and filtered. The filtrate was
concentrated to afford Intermediate A51C (66 mg, 89%) as a white
solid, which was used for the next step without further
purification. .sup.1H NMR (400 MHz, methanol-d.sub.4) .delta. ppm
2.10-1.95 (m, 6H), 1.90-1.78 (m, 6H).
Intermediate A51D: Methyl
4-bromobicyclo[2.2.2]octane-1-carboxylate
##STR00785##
[1310] To a solution of Intermediate ASIA (1.5 g, 7.07 mmol) in
CH.sub.2Cl.sub.2 was added mercury(II) oxide (2.60 g, 12.01 mmol).
The suspension was heated at reflux condition. To the reaction
mixture was added a solution of bromine (0.473 ml, 9.19 mmol) in
CH.sub.2Cl.sub.2 (5 mL) dropwise under refluxing. The reaction
mixture was heated at reflux for 1.5 h and cooled to RT. It was
passed through a pad of CELITE.RTM., washed with EtOAc. The
filtrate was concentrated. The residue was purified by silica gel
chromatography (40 g REDISEP.RTM. column, eluting with 0-30% EtOAc
in hexane. Fractions containing the product were combined and
evaporated to afford Intermediate A51D (1.2 g, 68.7%). .sup.1H NMR
(400 MHz, chloroform-d) .delta. ppm 3.65 (s, 3H), 2.35-2.19 (m,
6H), 2.04-1.90 (m, 6H).
Intermediate A51E: Methyl
4-phenylbicyclo[2.2.2]octane-1-carboxylate
##STR00786##
[1312] To a suspension of aluminum trichloride (809 mg, 6.07 mmol)
in benzene (4 mL, 1.214 mmol) at -10.degree. C. was added a
solution of Intermediate A51D (300 mg, 1.214 mmol) in benzene (2
mL) under nitrogen. The reaction mixture was gradually warmed up to
RT and stirred overnight. It was carefully poured into ice water,
extracted with EtOAc. The combined organic layer was washed with
brine, dried over Na.sub.2SO.sub.4, and filtered. The filtrate was
concentrated to afford Intermediate A51E (250 mg, 84%) as a tan
solid, which was used for the next step without further
purification. MS(ES): m/z=245 [M+H].sup.+; .sup.1H NMR (400 MHz,
chloroform-d) .delta. ppm 7.42-7.29 (m, 4H), 7.29-7.16 (m, 1H),
3.77-3.65 (s, 3H), 2.07-1.80 (m, 12H).
Intermediate A51F: Methyl
4-(4-bromophenyl)bicyclo[2.2.2]octane-1-carboxylate
##STR00787##
[1314] To a suspension of Intermediate A51E (330 mg, 1.351 mmol)
and silver trifluoroacetate (350 mg, 1.585 mmol) in CHCl.sub.3 (15
mL) was added Br.sub.2 (0.073 mL, 1.418 mmol) in CHCl.sub.3 (2 mL).
The reaction mixture was stirred at RT for 2 h. The reaction
mixture was passed through a pad of CELITE.RTM. and washed with
CH.sub.2Cl.sub.2. The filtrate was concentrated and the residue was
purified by silica gel chromatography (40 g REDISEP.RTM. column,
eluting with 0-30% EtOAc in hexane). Fractions containing the
product were combined and evaporated to afford Intermediate A51F
(310 mg, 71%). MS(ES): m/z=323 [M+H].sup.+; .sup.1H NMR (400 MHz,
chloroform-d) .delta. ppm 7.46-7.35 (m, J=8.5 Hz, 2H), 7.25-7.15
(m, J=8.5 Hz, 2H), 2.02-1.89 (m, 6H), 1.89-1.78 (m, 6H).
Intermediate A51G: Methyl
4-(4-cyanophenyl)bicyclo[2.2.2]octane-1-carboxylate
##STR00788##
[1316] To a microwave vial were added Intermediate A51F (101 mg,
0.312 mmol), dicyanozinc (55.0 mg, 0.469 mmol),
2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (25.7 mg, 0.062
mmol), DMF (3 mL), and two drops of water. Nitrogen was bubbled
into the reaction mixture for 2 min. To this mixture was added
tris(dibenzylideneacetone)dipalladium(0) (28.6 mg, 0.031 mmol) and
nitrogen was bubbled for another 2 min. The reaction mixture was
heated at 120.degree. C. in microwave for 1 h. The reaction mixture
was diluted with water and extracted with EtOAc. The combined
organic layer was washed with brine, dried over Na.sub.2SO.sub.4,
and filtered. The filtrate was concentrated. The crude product was
purified by silica gel chromatography (40 g REDISEP.RTM. column,
eluting with 0-20% EtOAc in hexane). Fractions containing the
product were combined and evaporated to afford Intermediate A51G
(70 mg, 83%). MS(ES): m/z=270 [M+H].sup.+; .sup.1H NMR (400 MHz,
chloroform-d) .delta. ppm 7.68-7.54 (m, J=8.5 Hz, 2H), 7.48-7.36
(m, J=8.8 Hz, 2H), 3.70 (s, 3H), 2.00-1.82 (m, 12H).
Intermediate A51H:
4-(4-Cyanophenyl)bicyclo[2.2.2]octane-1-carboxylic acid
##STR00789##
[1318] Intermediate A51H was prepared analogous to Intermediate
A51C by reacting Intermediate A51G with sodium hydroxide. (ES):
m/z=247 [M-H].sup.+; HPLC Ret. Time 1.59 min.
Intermediate A51I: Methyl
4-(hydroxymethyl)bicyclo[2.2.2]octane-1-carboxylate
##STR00790##
[1320] To a solution of Intermediate A51A (1.0531 g, 4.96 mmol) in
THF (40 mL) at 0.degree. C. were added TEA (1.729 mL, 12.40 mmol)
and ethyl carbonochloridate (1.131 g, 10.42 mmol) in THF (2 mL)
dropwise. The reaction mixture became a suspension (Et.sub.3N HCl
salt). The reaction mixture was stirred at 0.degree. C. for 30 min.
The suspension was filtered and washed with THF. The filtrate was
added to a suspension of sodium borohydride (0.751 g, 19.85 mmol)
in water (2 mL) at 0.degree. C. The reaction mixture was stirred at
RT for 1 h. The reaction mixture partitioned with EtOAc and water.
The organic layer was washed with brine, dried over
Na.sub.2SO.sub.4, and filtered. The filtrate was concentrated. The
residue was purified by silica gel chromatography (40 g
REDISEP.RTM. column, eluting with 10-50% EtOAc in hexane).
Fractions containing the product were combined and evaporated to
afford Intermediate A51I (0.9 g, 91%). (ES): m/z=199 [M+H].sup.+;
.sup.1H NMR (400 MHz, chloroform-d) .delta. ppm 3.66 (s, 3H), 3.30
(s, 2H), 1.91-1.73 (m, 6H), 1.52-1.41 (m, 6H).
Intermediate A51J: Methyl
4-(fluoromethyl)bicyclo[2.2.2]octane-1-carboxylate
##STR00791##
[1322] To a solution of Intermediate A51I (306 mg, 1.543 mmol) in
CH.sub.2Cl.sub.2 (5 mL) at -78.degree. C. under nitrogen was added
DAST (0.245 mL, 1.852 mmol). The reaction mixture was stirred at RT
for 3 h. The reaction mixture was cooled to 0.degree. C. and
carefully quenched with a saturated solution of NaHCO.sub.3. The
layers were separated. The aqueous layer was extracted with
CH.sub.2Cl.sub.2. The combined organic layer was washed with brine,
dried over Na.sub.2SO.sub.4, and filtered. The filtrate was
concentrated. The residue was purified by silica gel chromatography
(40 g REDISEP.RTM. column, eluting with 10-50% EtOAc in hexane).
Fractions containing the product were combined and evaporated to
afford Intermediate A51J (130 mg, 42%). .sup.1H NMR (400 MHz,
chloroform-d) .delta. ppm 3.66 (s, 3H), 2.15-1.95 (m, 4H),
1.94-1.22 (m, 10H).
Intermediate A51K:
4-(Fluoromethyl)bicyclo[2.2.2]octane-1-carboxylic acid
##STR00792##
[1324] To a solution of Intermediate A51J (70 mg, 0.353 mmol) in
MeOH was added 1M solution of NaOH (1 mL, 1.00 mmol). The reaction
mixture was stirred at RT overnight. It was concentrated. The
residue was diluted with water, acidified with 1N HCl to
pH.about.2, and extracted with EtOAc. The combined organic layer
was washed with brine, dried over Na.sub.2SO.sub.4, and filtered.
The filtrate was concentrated to afford Intermediate A51K as a
white solid, which was used for the next step without further
purification. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm
2.45-1.46 (m, 14H).
Intermediate A51L: Methyl
4-formylbicyclo[2.2.2]octane-1-carboxylate
##STR00793##
[1326] To a solution of Intermediate A51I (540 mg, 2.72 mmol) in
CH.sub.2Cl.sub.2 (20 mL) was added Dess-Martin periodinane (1502
mg, 3.54 mmol). The reaction mixture was stirred at RT overnight.
The reaction mixture was cooled to 0.degree. C. and carefully
quenched with a solution of NaHCO.sub.3. The layers were separated.
The aqueous layer was extracted with CH.sub.2Cl.sub.2. The combined
organic layer was washed with brine, dried over Na.sub.2SO.sub.4,
and filtered. The filtrate was concentrated. The residue was
purified by silica gel chromatography (40 g REDISEP.RTM. column,
eluting with 10-50% EtOAc in hexane). Fractions containing the
product were combined and evaporated to afford Intermediate A51L
(400 mg, 74.8%). (ES): m/z=199 [M+H].sup.+; .sup.1H NMR (400 MHz,
chloroform-d) .delta. ppm 9.48 (s, 1H), 3.68 (s, 3H), 1.94-1.78 (m,
6H), 1.78-1.61 (m, 6H).
Intermediate A51M: Methyl
4-(difluoromethyl)bicyclo[2.2.2]octane-1-carboxylate
##STR00794##
[1328] To a solution of Intermediate A51L (400 mg, 2.038 mmol) at
0.degree. C. in CH.sub.2Cl.sub.2 (8 mL) was added DAST (0.673 mL,
5.10 mmol). The reaction mixture was stirred at RT overnight. The
reaction mixture was cooled to 0.degree. C. and carefully quenched
with a solution of NaHCO.sub.3. The layers were separated. The
aqueous layer was extracted with CH.sub.2Cl.sub.2. The combined
organic layer was washed with brine, dried over Na.sub.2SO.sub.4,
and filtered. The filtrate was concentrated. The residue was
purified by silica gel chromatography (40 g REDISEP.RTM. column,
eluting with 0-20% EtOAc in hexane). Fractions containing the
product were combined and evaporated to afford Intermediate A51M
(280 mg, 62.9%). MS(ES): m/z=199 [M+H].sup.+; .sup.1H NMR (400 MHz,
chloroform-d) .delta. ppm 5.54-5.26 (m, 1H), 3.68 (s, 3H),
1.89-1.76 (m, 6H), 1.65-1.50 (m, 6H).
Intermediate A51N:
4-(Difluoromethyl)bicyclo[2.2.2]octane-1-carboxylic acid
##STR00795##
[1330] Intermediate A51N was prepared analogous to Intermediate
A51C by reacting Intermediate A51M with sodium hydroxide. (ES):
m/z=205 [M+H].sup.+.
##STR00796##
Intermediate A51O: Ethyl
2,2-difluoro-4-methoxybicyclo[2.2.2]octane-1-carboxylate
##STR00797##
[1332] Neat DEOXO-FLUOR.RTM. (1.956 mL, 10.61 mmol) was added to a
cold (0.degree. C.) solution of ethyl
4-methoxy-3-oxobicyclo[2.2.2]octane-1-carboxylate (1 g, 4.42 mmol)
in CH.sub.2Cl.sub.2, followed by addition of three drops of EtOH
(0.077 mL, 1.326 mmol). The reaction mixture was stirred at rt for
3 h and then heat at 60.degree. C. overnight. More DEOXO-FLUOR.RTM.
(1.956 ml, 10.61 mmol) was added and the reaction mixture was
heated at 60.degree. C. for another 16 h. It was carefully quenched
with a solution of NaHCO.sub.3 at 0.degree. C. The reaction mixture
was extracted with CH.sub.2Cl.sub.2. The combined organic layer was
washed with brine, dried over Na.sub.2SO.sub.4, and filtered. The
filtrate was concentrated. The residue was purified by silica gel
chromatography (40 g REDISEP.RTM. column, eluting with 10-55% EtOAc
in hexane). Fractions containing the product were combined and
evaporated to afford Intermediate A51T (600 mg, 55%). .sup.1H NMR
(400 MHz, chloroform-d) .delta. ppm 4.30-4.13 (m, 2H), 3.22 (s,
3H), 2.32-1.20 (m, 15H).
Intermediate A51P:
2,2-Difluoro-4-methoxybicyclo[2.2.2]octane-1-carboxylic acid
##STR00798##
[1334] Intermediate A51P was prepared analogous to Intermediate
A51C by reacting Intermediate A51O with sodium hydroxide. .sup.1H
NMR (400 MHz, chloroform-d) .delta. 3.22 (s, 3H), 2.32-1.20 (m,
15H).
Compound A51:
2-(3-Chloro-4-fluorophenyl)-N.sup.5-(4-(4-cyanophenyl)bicyclo[2.2.2]octan-
-1-yl)-6,7-dihydropyrazolo[1,5-a]pyrazine-3,5(4H)-dicarboxamide
##STR00799##
[1336] To a solution of Intermediate A51K (45 mg, 0.176 mmol) in
toluene (6 mL) were added TEA (0.11 mL, 0.75 mmol) and diphenyl
phosphorazidate (73 mg, 0.265 mmol). The reaction mixture was
heated at 90.degree. C. for 2 h and cooled to RT. A solution of
2-(3-chloro-4-fluorophenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-c-
arboxamide (25 mg, 0.085 mmol) in DMF (1 mL) was then added to the
above reaction mixture. The reaction mixture was stirred at RT
overnight and concentrated. The residue was purified by preparative
HPLC. Fractions containing the desired product were combined and
dried under vacuum to afford Compound A51 (24.5 mg, 54.7%). MS(ES):
m/z=547 [M+H].sup.+; HPLC Ret. Time 1.83 min. and 2.76 min. (HPLC
Methods H and I); .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. ppm
7.85 (d, J=7.0 Hz, 1H), 7.77-7.62 (m, 3H), 7.55 (d, J=8.4 Hz, 2H),
7.46 (t, J=9.0 Hz, 1H), 7.35 (br. s., 1H), 7.21 (br. s., 1H), 4.69
(s, 2H), 4.12 (t, J=5.1 Hz, 2H), 3.81 (t, J=5.1 Hz, 2H), 2.02-1.91
(m, 6H), 1.91-1.79 (m, 6H).
[1337] The Compounds described in Table 53 were synthesized
analogous to Compound A51 using
2-(3-chloro-4-fluorophenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-c-
arboxamide and corresponding acids.
TABLE-US-00055 TABLE 53 Ret. Ex. Time HPLC No. Structure Name [M +
H].sup.+ (min.) Method A52 ##STR00800##
2-(3-Chloro-4-fluorophenyl)-N.sup.5-(4-
(4-fluorophenyl)bicyclo[2.2.2]octan- 1-yl)-6,7-dihydropyrazolo[1,5-
a]pyrazine-3,5(4H)-dicarboxamide 540.4 1.93 2.91 H I A53
##STR00801## 2-(3-Chloro-4-fluorophenyl)-N.sup.5-(4-
phenylbicyclo[2.2.2]octan-1-yl)-6,7-
dihydropyrazolo[1,5-a]pyrazine- 3,5(4H)-dicarboxamide 522.5 2.90
1.92 H I A54 ##STR00802## 2-(3-Chloro-4-fluorophenyl)-N.sup.5-(4-
fluorobicyclo[2.2.2]octan-1-yl)-6,7-
dihydropyrazolo[1,5-a]pyrazine- 3,5(4H)-dicarboxamide 464.3 1.49
2.45 H I A55 ##STR00803## 2-(3-Chloro-4-fluorophenyl)-N.sup.5-(4-
(hydroxymethyl)bicyclo[2.2.2]octan- 1-yl)-6,7-dihydropyrazolo[1,5-
a]pyrazine-3,5(4H)-dicarboxamide 475.9 1.28 2.46 H I A56
##STR00804## 2-(3-Chloro-4-fluorophenyl)-N.sup.5-(4-
(fluoromethyl)bicyclo[2.2.2]octan-1- yl)-6,7-dihydropyrazolo[1,5-
a]pyrazine-3,5(4H)-dicarboxamide 478.3 1.49 2.50 H I A57
##STR00805## 2-(3-Chloro-4-fluorophenyl)-N.sup.5-(4-
(difluoromethyl)bicyclo[2.2.2]octan- 1-yl)-6,7-dihydropyrazolo[1,5-
a]pyrazine-3,5(4H)-dicarboxamide 496.3 1.58 2.55 H I A58
##STR00806## N.sup.5-(Bicyclo[2.2.2]octan-1-yl)-2-(3-
chloro-4-fluorophenyl)-6,7- dihydropyrazolo[1,5-a]pyrazine-
3,5(4H)-dicarboxamide 446.3 1.80 2.61 H I A59 ##STR00807##
2-(3-Chloro-4-fluorophenyl)-N.sup.5-(4-
methoxybicyclo[2.2.2]octan-1-yl)-
6,7-dihydropyrazolo[1,5-a]pyrazine- 3,5(4H)-dicarboxamide 476.3
1.48 2.12 H I A60 ##STR00808##
2-(3-Chloro-4-fluorophenyl)-N.sup.5-(4-
methoxy-2-oxobicyclo[2.2.2]octan- 1-yl)-6,7-dihydropyrazolo[1,5-
a]pyrazine-3,5(4H)-dicarboxamide 490.3 1.20 2.11 H I A61
##STR00809## 2-(3-Chloro-4-fluorophenyl)-N.sup.5- (2,2-difluoro-4-
methoxybicyclo[2.2.2]octan-1-yl)-
6,7-dihydropyrazolo[1,5-a]pyrazine- 3,5(4H)-dicarboxamide 512.3
2.31 1.64 H I A62 ##STR00810##
2-(3-Chloro-4-fluorophenyl)-N.sup.5-(4- (2-hydroxypropan-2-
yl)bicyclo[2.2.2]octan-1-yl)-6,7- dihydropyrazolo[1,5-a]pyrazine-
3,5(4H)-dicarboxamide 504.4 2.45 2.93 H I A63 ##STR00811##
2-(3-Chloro-4-fluorophenyl)-N.sup.5-(4-
methoxybicyclo[2.2.1]heptan-1-yl)-
6,7-dihydropyrazolo[1,5-a]pyrazine- 3,5(4H)-dicarboxamide 462.4
1.30 2.29 H I A64 ##STR00812##
N.sup.5-((1r,5r)-Bicyclo[3.3.1]nonan-1-
yl)-2-(3-chloro-4-fluorophenyl)-6,7-
dihydropyrazolo[1,5-a]pyrazine- 3,5(4H)-dicarboxamide 460.4 1.76
2.77 H I A65 ##STR00813## 2-(3-Chloro-4-fluorophenyl)-N.sup.5-
((3s,5s,7s)-3,5,7- trimethyladamantan-1-yl)-6,7-
dihydropyrazolo[1,5-a]pyrazine- 3,5(4H)-dicarboxamide 514.5 2.18
3.15 H I A66 ##STR00814## 2-(3-Chloro-4-fluorophenyl)-N.sup.5-(3-
hydroxy-7,7- dimethylbicyclo[2.2.1]heptan-1-yl)-
6,7-dihydropyrazolo[1,5-a]pyrazine- 3,5(4H)-dicarboxamide 490.2
1.50 2.47 H I A67 ##STR00815##
2-(3-Chloro-4-fluorophenyl)-N.sup.5-(3- fluoro-7,7-
dimethylbicyclo[2.2.1]heptan-1-yl)-
6,7-dihydropyrazolo[1,5-a]pyrazine- 3,5(4H)-dicarboxamide 492.2
1.74 2.66 H I A68 ##STR00816## 2-(3-Chloro-4-fluorophenyl)-N.sup.5-
((1r,3R,5S,7r)-3,5- dimethyladamantan-1-yl)-6,7-
dihydropyrazolo[1,5-a]pyrazine- 3,5(4H)-dicarboxamide 500.4 2.02
3.00 H I A69 ##STR00817## 2-(3-Chloro-4-fluorophenyl)-N.sup.5-
((lS,3R,5S,7R)-3-chloro-5- methyladamantan-1-yl)-6,7-
dihydropyrazolo[1,5-a]pyrazine- 3,5(4H)-dicarboxamide 506.4 1.77
2.74 H I A70 ##STR00818## N.sup.5-(4-Cyanocuban-1-yl)-2-(3-
chloro-4-fluorophenyl)-6,7- dihydropyrazolo[1,5-a]pyrazine-
3,5(4H)-dicarboxamide 465.22 1.30 2.22 H I A71 ##STR00819##
N.sup.5-(4-Fluorocuban-1-yl)-2-(3- chloro-4-fluorophenyl)-6,7-
dihydropyrazolo[1,5-a]pyrazine- 3,5(4H)-dicarboxamide 458.3 1.41
2.38 H I A72 ##STR00820## N.sup.5-(Cuban-1-yl)-2-(3-chloro-4-
fluorophenyl)-6,7- dihydropyrazolo[1,5-a]pyrazine-
3,5(4H)-dicarboxamide 440.3 1.43 2.51 H I A73 ##STR00821##
N.sup.5-(Bicyclo[2.2.1]heptan-1-yl)-2-(3-
chloro-4-fluorophenyl)-6,7- dihydropyrazolo[1,5-a]pyrazine-
3,5(4H)-dicarboxamide 432.2 1.58 2.54 H I
Compound A74:
2-(3-Chlorophenyl)-N.sup.5-(4-(4-cyanophenyl)bicyclo[2.2.2]octan-1-yl)-6,-
7-dihydropyrazolo[1,5-a]pyrazine-3,5(4H)-dicarboxamide
##STR00822##
[1339] To a solution of Intermediate A51K (45 mg, 0.176 mmol) in
toluene (6 mL) were added TEA (0.11 mL, 0.75 mmol) and diphenyl
phosphorazidate (73 mg, 0.265 mmol). The reaction mixture was
heated at 90.degree. C. for 2 h and cooled to rt. A solution of
2-(3-chlorophenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamid-
e (30 mg, 0.108 mmol) in DMF (1 mL) was then added to the above
reaction mixture. The reaction mixture was stirred at rt overnight
and concentrated. The residue was purified by preparative HPLC.
Fractions containing the desired product were combined and dried
under vacuum to afford Compound A74 (3.8 mg, 6.6%). MS(ES): m/z=529
[M+H].sup.+; HPLC Ret. Time 1.76 min. and 2.71 min. (HPLC Methods H
and I); .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. ppm 7.78-7.68
(m, 2H), 7.64 (d, J=7.0 Hz, 1H), 7.55 (d, J=8.4 Hz, 2H), 7.50-7.38
(m, 2H), 7.35 (br. s., 1H), 7.21 (br. s., 1H), 4.69 (s, 2H),
4.20-4.06 (m, 2H), 3.81 (d, J=5.1 Hz, 2H), 2.03-1.91 (m, 6H),
1.91-1.79 (m, 6H).
[1340] The Compounds described in Table 54 were synthesized
analogous to Compound A74 using
2-(3-chlorophenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamid-
e and corresponding acids.
TABLE-US-00056 TABLE 54 Ret. Ex. Time HPLC No. Structure Name [M +
H].sup.+ (min.) Method A75 ##STR00823##
2-(3-Chlorophenyl)-N.sup.5-(4- fluorobicyclo[2.2.2]octan-1-yl)-6,7-
dihydropyrazolo[1,5-a]pyrazine- 3,5(4H)-dicarboxamide 446.4 1.43
2.42 H I A76 ##STR00824## 2-(3-Chlorophenyl)-N.sup.5-(4-methoxy-
2-oxobicyclo[2.2.2]octan-1-yl)-6,7- dihydropyrazolo[1,5-a]pyrazine-
3,5(4H)-dicarboxamide 472.3 1.13 2.07 H I A77 ##STR00825##
2-(3-Chlorophenyl)-N.sup.5-(4- (difluoromethyl)bicyclo[2.2.2]octan-
1-yl)-6,7-dihydropyrazolo[1,5- a]pyrazine-3,5(4H)-dicarboxamide
478.3 1.54 2.52 H I A78 ##STR00826## 2-(3-Chlorophenyl)-N.sup.5-(4-
(fluoromethyl)bicyclo[2.2.2]octan- 1-yl)-6,7-dihydropyrazolo[1,5-
a]pyrazine-3,5(4H)-dicarboxamide 459.9 1.46 2.61 H I A79
##STR00827## N.sup.5-(Bicyclo[2.2.2]octan-1-yl)-2-(3-
chlorophenyl)-6,7- dihydropyrazolo[1,5-a]pyrazine-
3,5(4H)-dicarboxamide 428.3 1.77 2.59 H I A80 ##STR00828##
2-(3-Chlorophenyl)-N.sup.5-(4- methoxybicyclo[2.2.2]octan-1-yl)-
6,7-dihydropyrazolo[1,5-a]pyrazine- 3,5(4H)-dicarboxamide 458.3
1.44 2.25 H I A81 ##STR00829## 2-(3-Chlorophenyl)-N.sup.5-(2,2-
difluoro-4- methoxybicyclo[2.2.2]octan-1-yl)-
6,7-dihydropyrazolo[1,5-a]pyrazine- 3,5(4H)-dicarboxamide 494.3
1.69 2.24 H I A82 ##STR00830## 2-(3-Chlorophenyl)-N.sup.5-(4-
methoxybicyclo[2.2.1]heptan-1-yl)-
6,7-dihydropyrazolo[1,5-a]pyrazine- 3,5(4H)-dicarboxamide 444.4
1.24 2.23 H I A83 ##STR00831## 2-(3-Chlorophenyl)-N.sup.5-(4-
phenylbicyclo[2.2.2]octan-1-yl)-6,7-
dihydropyrazolo[1,5-a]pyrazine- 3,5(4H)-dicarboxamide 504.4 1.87
2.89 H I A84 ##STR00832## N.sup.5-((1r,5r)-Bicyclo[3.3.1]nonan-1-
yl)-2-(3-chlorophenyl)-6,7- dihydropyrazolo[1,5-a]pyrazine-
3,5(4H)-dicarboxamide 442.4 1.70 2.74 H I A85 ##STR00833##
2-(3-Chlorophenyl)-N.sup.5-((3s,5s,7s)-
3,5,7-trimethyladamantan-1-yl)-6,7- dihydropyrazolo[1,5-a]pyrazine-
3,5(4H)-dicarboxamide 496.5 1.95 3.07 H I A86 ##STR00834##
N.sup.5-(Cuban-1-yl)-2-(3- chlorophenyl)-6,7-
dihydropyrazolo[1,5-a]pyrazine- 3,5(4H)-dicarboxamide 422.3 1.66
2.43 H I A87 ##STR00835## N.sup.5-(4-Cyanocuban-1-yl)-2-(3-
chlorophenyl)-6,7- dihydropyrazolo[1,5-a]pyrazine-
3,5(4H)-dicarboxamide 447.21 1.25 2.15 H I A88 ##STR00836##
N.sup.5-(4-Fluorocuban-1-yl)-2-(3- chlorophenyl)-6,7-
dihydropyrazolo[1,5-a]pyrazine- 3,5(4H)-dicarboxamide 440.3 1.37
2.34 H I
[1341] The Compounds described in Table 55 were synthesized
analogous to Compound A51 using
2-(3,4-dichlorophenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carbox-
amide and corresponding acids.
TABLE-US-00057 TABLE 55 Ret. Ex. Time HPLC No. Structure Name [M +
H].sup.+ (min.) Method A89 ##STR00837##
2-(3,4-Dichlorophenyl)-N.sup.5-(4-(4-
fluorophenyl)bicyclo[2.2.2]octan- 1-yl)-6,7-dihydropyrazolo[1,5-
a]pyrazine-3,5(4H)- dicarboxamide 540.4 1.93 2.91 H I A90
##STR00838## N.sup.5-(4-(4- Cyanophenyl)bicyclo[2.2.2]octan-
1-yl)-2-(3,4-dichlorophenyl)-6,7- dihydropyrazolo[1,5-a]pyrazine-
3,5(4H)-dicarboxamide 556.4 2.02 3.00 H I A91 ##STR00839##
2-(3,4-Dichlorophenyl)-N.sup.5- ((3s,5s,7s)-3,5,7-
trimethyladamantan-1-yl)-6,7- dihydropyrazolo[1,5-a]pyrazine-
3,5(4H)-dicarboxamide 530.2 2.08 3.20 H I A92 ##STR00840##
2-(3,4-Dichlorophenyl)-N.sup.5- ((1r,3R,5S,7r)-3,5-
dimethyladamantan-1-yl)-6,7- dihydropyrazolo[1,5-a]pyrazine-
3,5(4H)-dicarboxamide 515.4 2.13 3.07 H I A93 ##STR00841##
N.sup.5-((1S,3R,5S,7R)-3-Chloro-5- methyladamantan-1-yl)-2-(3,4-
dichlorophenyl)-6,7- dihydropyrazolo[1,5-a]pyrazine-
3,5(4H)-dicarboxamide 522.1 1.94 2.92 H I
Compound A94:
N.sup.5-(4-(Difluoromethyl)bicyclo[2.2.2]octan-1-yl)-2-(3-fluorophenyl)-6-
,7-dihydropyrazolo[1,5-a]pyrazine-3,5(4H)-dicarboxamide
##STR00842##
[1343] Compound A94 were synthesized analogous to Compound A51
using
2-(3-fluorophenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamid-
e and 4-(difluoromethyl)bicyclo[2.2.2]octane-1-carboxylic acid.
MS(ES): m/z=462.3 [M+H].sup.+; HPLC Ret. Time 1.41 min. and 2.37
min. (HPLC Methods H and I); .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. ppm 7.59-7.39 (m, 3H), 7.34 (br. s., 1H), 7.25-7.08 (m,
2H), 6.24 (s, 1H), 5.68 (t, J=55 Hz t, 1H), 4.67 (s, 2H), 4.12 (t,
J=5.0 Hz, 2H), 3.79 (t, J=5.1 Hz, 2H), 1.94-1.77 (m, 6H), 1.62-1.49
(m, 6H).
Compound A95:
N.sup.5-(1,3-Difluoro-2-(fluoromethyl)propan-2-yl)-2-(3-fluorophenyl)-6,7-
-dihydropyrazolo[1,5-a]pyrazine-3,5(4H)-dicarboxamide
##STR00843##
[1345] Compound A95 were synthesized analogous to Compound A40
using
2-(3-fluorophenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamid-
e and 1,3-difluoro-2-(fluoromethyl)propan-2-amine. MS(ES):
m/z=414.3 [M+H].sup.+; HPLC Ret. Time 1.25 min. and 1.92 min. (HPLC
Methods H and I); .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. ppm
7.59-7.39 (m, 3H), 7.34 (br. s., 1H), 7.25-7.08 (m, 2H), 6.24 (s,
1H), 5.68 (t, J=55 Hz t, 1H), 4.67 (s, 2H), 4.12 (t, J=5.0 Hz, 2H),
3.79 (t, J=5.1 Hz, 2H), 1.94-1.77 (m, 6H), 1.62-1.49 (m, 6H).
##STR00844## ##STR00845## ##STR00846##
Intermediate A96B: Methyl
4-((tert-butoxycarbonyl)amino)-3-hydroxybutanoate
##STR00847##
[1347] To a suspension of 4-amino-3-hydroxybutanoic acid (17.8 g,
149 mmol) in MeOH (150 mL) and DMF (2 mL) at 0.degree. C. was added
SOCl.sub.2 (23.99 mL, 329 mmol) dropwise via a dropping funnel. The
reaction mixture gradually became a clear solution. It was stirred
at RT for 30 min. and then heated at 60.degree. C. for 2 h. It was
cooled to RT, concentrated, suspended in dioxane (150 mL), and
added to a saturated sodium bicarbonate solution (74.7 mL, 149
mmol). BOC-anhydride (41.6 mL, 179 mmol) was added and the reaction
mixture was stirred at RT for 16 h. The reaction mixture was
extracted with EtOAc. The combined organic layer was washed with
brine, dried over Na.sub.2SO.sub.4, and filtered. The filtrate was
concentrated. The crude product was purified by silica gel
chromatography (240 g REDISEP.RTM. column, eluting with 30-70%
EtOAc in hexane). Fractions containing the product were combined
and evaporated to afford Intermediate A96B (25 g, 71.7% for two
steps). .sup.1H NMR (400 MHz, chloroform-d) .delta. ppm 4.22-4.04
(m, 1H), 3.74 (s, 3H), 3.51 (d, J=7.5 Hz, 1H), 3.20-3.08 (m, 1H),
2.57-2.48 (m, 2H), 1.52-1.40 (m, 9H).
Intermediate A96C: tert-Butyl(2,4-dihydroxybutyl)carbamate
##STR00848##
[1349] To a solution of Intermediate A96B (25 g, 107 mmol) in
diethyl ether (200 mL) and MeOH (7.59 mL, 188 mmol) at 0.degree. C.
was added LiBH.sub.4 (3.50 g, 161 mmol) in portions carefully. The
reaction was stirred at RT for 1 h and heated at 60.degree. C. for
1 h. The reaction was carefully quenched with MeOH and
concentrated. The residue was diluted with a solution of saturated
NH.sub.4Cl and extracted with EtOAc. The combined organic layer was
washed with brine, dried over Na.sub.2SO.sub.4, and filtered. The
filtrate was concentrated to afford Intermediate A96C (19 g, 86%)
as an off-white solid. It was used for the next step without
further purification. .sup.1H NMR (400 MHz, chloroform-d) .delta.
ppm 4.03-3.77 (m, 3H), 3.30 (ddd, J=14.1, 6.1, 3.1 Hz, 1H),
3.22-3.03 (m, 1H), 1.78-1.65 (m, 2H), 1.46 (s, 9H).
Intermediate A96D: tert-Butyl
(4-((tert-butyldimethylsilyl)oxy)-2-hydroxybutyl)carbamate
##STR00849##
[1351] To a solution of A96C (10 g, 48.7 mmol) and TEA (2.55 mL,
18.30 mmol) in CH.sub.2Cl.sub.2 (80 mL) were added TBS-Cl (8.08 g,
53.6 mmol) and DMAP (0.060 g, 0.487 mmol). It was stirred at RT for
4 h. The reaction mixture was diluted with water and extracted with
EtOAc. The organic layer was washed with brine, dried over
Na.sub.2SO.sub.4, and filtered. The filtrate was concentrated. The
residue was purified by silica gel chromatography (240 g
REDISEP.RTM. column, eluting with 10-50% EtOAc in hexane).
Fractions containing the product were combined and evaporated to
afford Intermediate A96D (12 g, 77%). .sup.1H NMR (400 MHz,
chloroform-d) .delta. ppm 3.99-3.72 (m, 3H), 3.41-3.22 (m, 1H),
3.22-3.03 (m, 1H), 1.78-1.60 (m, 2H), 1.46 (s, 9H), 0.96-0.84 (m,
9H), 0.19-0.06 (m, 6H).
Intermediate A96F: Ethyl
3-(3-chloro-4-fluorophenyl)-1-(2,2,3,3,12,12-hexamethyl-10-oxo-4,11-dioxa-
-9-aza-3-silatridecan-7-yl)-1H-pyrazole-5-carboxylate
##STR00850##
[1353] To a solution of ethyl
3-(3-chloro-4-fluorophenyl)-1H-pyrazole-5-carboxylate (10.7 g, 40
mmol) in THF (100 mL) at 0.degree. C. were added Intermediate A96D
(15.25 g, 48 mmol), TEA (5.6 mL, 40 mmol), triphenylphosphine (10.5
g, 40 mmol), and DTBAD (9.17 g, 40 mmol). The reaction mixture was
stirred at RT for 2 h and concentrated. The residue was diluted
with water and EtOAc. The layers were separated. The aqueous layer
was extracted with EtOAc. The combined organic layer was washed
with brine, dried over Na.sub.2SO.sub.4, and filtered. The filtrate
was concentrated. The crude product was purified by silica gel
chromatography (330 g REDISEP.RTM. column, eluting with 10-40%
EtOAc in hexane). Fractions containing the product were combined
and evaporated to afford Intermediate A96F (16.5 g, 73%). MS(ES):
m/z=592.3 [M+Na].sup.+.
Intermediate A96G: Ethyl
1-(1-amino-4-hydroxybutan-2-yl)-3-(3-chloro-4-fluorophenyl)-1H-pyrazole-5-
-carboxylate bis HCl salt
##STR00851##
[1355] To a solution of Intermediate A96F in CH.sub.2Cl.sub.2 (120
mL) was added 4M HCl solution in dioxane (10.70 mL, 42.8 mmol). The
reaction mixture was stirred at RT overnight. The solid
Intermediate A96G was collected by filtration. It was used for the
next step without further purification. MS(ES): m/z=356.1
[M+H].sup.+.
Intermediate A96H:
2-(3-Chloro-4-fluorophenyl)-7-(2-hydroxyethyl)-6,7-dihydropyrazolo[1,5-a]-
pyrazin-4(5H)-one
##STR00852##
[1357] To a suspension of Intermediate A96G (4.20 g, 10.7 mmol) in
ethanol (80 mL) was added 30% water solution of ammonia (80 mL,
3697 mmol). It was stirred at RT for 2 h and concentrated. The
solid was collected by filtration, washed with water, and dried.
The crude product Intermediate A96H was used for the next step
without further purification. MS(ES): m/z=310.0 [M+H].sup.+;
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 8.27 (br. s., 1H),
8.07 (dd, J=7.3, 2.3 Hz, 1H), 7.89 (ddd, J=8.7, 4.8, 2.1 Hz, 1H),
7.48 (t, J=9.0 Hz, 1H), 7.34 (s, 1H), 4.74 (t, J=5.0 Hz, 1H),
4.67-4.47 (m, 1H), 3.79 (ddd, J=13.3, 4.4, 2.4 Hz, 1H), 3.66-3.55
(m, 2H), 3.50 (ddd, J=13.4, 5.6, 3.4 Hz, 1H), 2.17 (dd, J=13.8, 6.0
Hz, 1H), 2.03-1.81 (m, 1H).
Intermediate A96I:
7-(2-((tert-Butyldimethylsilyl)oxy)ethyl)-2-(3-chloro-4-fluorophenyl)-6,7-
-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one
##STR00853##
[1359] To a suspension of Intermediate A96H in CH.sub.2Cl.sub.2
(300 mL) and DMF (15 mL) were added TEA (10.80 mL, 77 mmol), TBS-Cl
(9.34 g, 62.0 mmol), and DMAP (0.316 g, 2.58 mmol). The suspension
was stirred at RT overnight. The reaction mixture was diluted with
water, extracted with CH.sub.2Cl.sub.2. The organic layer was
washed with brine, dried over Na.sub.2SO.sub.4, and filtered. The
filtrate was concentrated. The crude product was purified by silica
gel chromatography (330 g REDISEP.RTM. column, eluting with 0-40%
EtOAc in CH.sub.2Cl.sub.2). Fractions containing the product were
combined and evaporated to afford Intermediate A961 (17.8 g, 81%).
MS(ES): m/z=446.2 [M+Na].sup.+. .sup.1H NMR (400 MHz, chloroform-d)
.delta. ppm 7.91 (dd, J=7.2, 2.1 Hz, 1H), 7.66 (ddd, J=8.6, 4.6,
2.1 Hz, 1H), 7.27-7.10 (m, 2H), 6.25 (br. s., 1H), 4.78-4.51 (m,
1H), 4.02-3.79 (m, 3H), 3.72 (ddd, J=13.1, 5.5, 3.5 Hz, 1H),
2.47-2.23 (m, 1H), 2.23-1.96 (m, 1H), 1.00-0.88 (m, 9H), 0.18-0.05
(m, 6H).
Intermediate A96J: tert-Butyl
7-(2-((tert-butyldimethylsilyl)oxy)ethyl)-2-(3-chloro-4-fluorophenyl)-4-o-
xo-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate
##STR00854##
[1361] To a suspension of Intermediate A961 (13.64 g, 32.2 mmol) in
toluene (120 mL) were added DMAP (5.90 g, 48.3 mmol) and
BOC-anhydride (8.96 mL, 38.6 mmol). The reaction mixture was
stirred at RT for 1 h and it became a clear solution about 5 min.
after addition. The reaction mixture was concentrated and the
residue was purified by silica gel chromatography (240 g
REDISEP.RTM. column, eluting with 0-40% EtOAc in CH.sub.2Cl.sub.2).
Fractions containing the product were combined and evaporated to
afford Intermediate A96J (17.8 g, 81%). MS(ES): m/z=524.4
[M+H].sup.+; .sup.1H NMR (400 MHz, chloroform-d) .delta. 7.90 (dd,
J=7.0, 2.0 Hz, 1H), 7.66 (ddd, J=8.5, 4.6, 2.1 Hz, 1H), 7.29 (s,
1H), 7.25-7.03 (m, 2H), 4.84-4.63 (m, 1H), 4.38-4.18 (m, 2H),
4.05-3.79 (m, 2H), 2.51-2.24 (m, 1H), 2.03 (dtd, J=14.4, 7.2, 2.3
Hz, 1H), 1.61 (s, 9H), 0.95 (s, 9H), 0.14 (s, 3H), 0.12 (s,
3H).
Intermediate A96K: tert-Butyl
7-(2-((tert-butyldimethylsilyl)oxy)ethyl)-2-(3-chloro-4-fluorophenyl)-6,7-
-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate
##STR00855##
[1363] To a solution of Intermediate A96J (1.5 g, 2.86 mmol) in THF
(15 mL) was added 2M solution of BH.sub.3.Me.sub.2S in THF (4.29
mL, 8.59 mmol) dropwise at RT. The reaction mixture was heated to
reflux for 4 h and cooled to 0.degree. C. It was carefully quenched
with MeOH. The reaction mixture was concentrated. The residue was
diluted with a solution of NH.sub.4Cl, extracted with EtOAc. The
combined organic layer was washed with brine, dried over
Na.sub.2SO.sub.4, and filtered. The filtrate was concentrated to
afford Intermediate A96K (1.2 g, 82%), which was used for the next
step without further purification. MS(ES): m/z=510.3
[M+H].sup.+.
Intermediate A96L: tert-Butyl
7-(2-((tert-butyldimethylsilyl)oxy)ethyl)-2-(3-chloro-4-fluorophenyl)-3-i-
odo-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate
##STR00856##
[1365] To a solution of Intermediate A96K (3.53 g, 6.92 mmol) in
CH.sub.2Cl.sub.2 (25 mL) and MeOH (10 mL) was added NIS (1.868 g,
8.30 mmol). The reaction mixture was stirred at RT for 3 h and
concentrated. The residue was purified by silica gel chromatography
(80 g REDISEP.RTM. column, eluting with 0-25% EtOAc in hexane).
Fractions containing the product were combined and evaporated to
afford Intermediate A96L (3 g, 76%). MS(ES): m/z=636.2
[M+H].sup.+.
Intermediate A96M: tert-Butyl
7-(2-((tert-butyldimethylsilyl)oxy)ethyl)-2-(3-chloro-4-fluorophenyl)-3-c-
yano-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate
##STR00857##
[1367] To a solution of Intermediate A96L (3 g, 4.72 mmol) in DMF
(12 mL) was added copper (I) cyanide (1.056 g, 11.79 mmol). The
reaction mixture was heated at 120.degree. C. overnight. It was
cooled to RT, diluted with EtOAc, passed through a pad of
CELITE.RTM., washed with EtOAc. The filtrate was concentrated. The
residue was purified by silica gel chromatography (80 g
REDISEP.RTM. column, eluting with 0-35% EtOAc in hexane). Fractions
containing the product were combined and evaporated to afford
Intermediate A96M (1.2 g, 48%). MS(ES): m/z=557.2 [M+Na]+.
Intermediate A96N: tert-Butyl
3-carbamoyl-2-(3-chloro-4-fluorophenyl)-7-(2-hydroxyethyl)-6,7-dihydropyr-
azolo[1,5-a]pyrazine-5(4H)-carboxylate
##STR00858##
[1369] To a solution of Intermediate A96M (1.2 g, 2.242 mmol) in
ethanol (10 mL) and THF (10 mL) were added potassium hydroxide
(2.242 mL, 11.21 mmol) and 30% H.sub.2O.sub.2 (4.58 mL, 44.8 mmol).
The reaction mixture was stirred at RT for two days. It was
concentrated. The residue was extracted with EtOAc. The combined
organic layer was washed with brine, dried over Na.sub.2SO.sub.4,
filtered. The filtrate was concentrated. The crude Intermediate
A96N (820 mg, 83%). was used for the next step without further
purification. MS(ES): m/z=439.1 [M+1].sup.+.
Intermediate A96O:
2-(3-Chloro-4-fluorophenyl)-7-(2-hydroxyethyl)-4,5,6,7-tetrahydropyrazolo-
[1,5-a]pyrazine-3-carboxamide HCl salt
##STR00859##
[1371] To a solution of Intermediate A96N (95 mg, 0.216 mmol) in
MeOH (10 mL) was added 4M HCl solution in dioxane (0.5 mL, 2.00
mmol). The reaction mixture was stirred at RT for 4 h and
concentrated. The crude material Intermediate A96O was used for the
next step without further purification. MS(ES): m/z=339.1
[M+1].sup.+.
Compounds A96 and A97:
N.sup.5-(tert-Butyl)-2-(3-chloro-4-fluorophenyl)-7-(2-hydroxyethyl)-6,7-d-
ihydropyrazolo[1,5-a]pyrazine-3,5(4H)-dicarboxamide
##STR00860##
[1373] To a solution of Intermediate A96N (35 mg, 0.093 mmol) in
DMF (1 mL) were added Hunig's base (0.033 mL, 0.187 mmol) and
2-isocyanato-2-methylpropane (13.87 mg, 0.140 mmol). The reaction
mixture was stirred at RT for 2 h. It was purified by preparative
HPLC to afford racemate Compounds A96 and A97. The racemate was
further separated by chiral HPLC to give enantiomer A96 (Ret. Time
13.39 min, 8.6 mg, 21%) and enantiomer A97 (Ret. Time 16.87 min,
9.0 mg, 22%). Chiral HPLC Method: Column: CHIRALPAK.RTM. AD
21.times.250 mm, 10 .mu.m; Mobile Phase A: 0.1%
diethylamine/heptane; Mobile Phase B: ethanol; Gradient: hold at
12%-100% B over 31 minutes; Flow rate: 15 mL/min; MS(ES): m/z=438.5
[M+H].sup.+; HPLC Ret. Time 1.27 and 2.28 min. (HPLC Methods H and
I); .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. ppm 7.84 (d, J=7.0
Hz, 1H), 7.68 (br. s., 1H), 7.46 (t, J=9.0 Hz, 1H), 7.34 (br. s.,
1H), 7.23 (br. s., 1H), 6.30 (s, 1H), 4.95 (br. s., 1H), 4.84 (d,
J=16.9 Hz, 1H), 4.53 (d, J=17.2 Hz, 1H), 4.35 (d, J=4.4 Hz, 1H),
3.98-3.82 (m, 1H), 3.78-3.60 (m, 3H), 2.12 (dd, J=13.4, 5.7 Hz,
1H), 1.79 (d, J=5.9 Hz, 1H), 1.28 (s, 9H).
##STR00861##
Intermediate A98A: tert-Butyl
3-carbamoyl-2-(3-chloro-4-fluorophenyl)-7-(2-((methylsulfonyl)oxy)ethyl)--
6,7-dihydropyrazolo[1,5-a]pyrazine-5 (4H)-carboxylate
##STR00862##
[1375] To a solution of Intermediate A96N (500 mg, 1.139 mmol) in
CH.sub.2Cl.sub.2 (12 mL) at 0.degree. C. under nitrogen were added
TEA (0.206 mL, 1.481 mmol) and Ms-Cl (0.107 mL, 1.367 mmol). The
reaction mixture was stirred at 0.degree. C. for 1 h before it was
quenched with a saturated solution of NaHCO.sub.3 and extracted
with CH.sub.2Cl.sub.2. The combined organic layer was washed with
brine, dried over Na.sub.2SO.sub.4, and filtered. The filtrate was
concentrated. The crude product was purified by silica gel
chromatography (40 g REDISEP.RTM. column, eluting with 35-80% EtOAc
in hexane). Fractions containing the product were combined and
evaporated to afford Intermediate A98A (380 m g, 65%). MS(ES):
m/z=517.1 [M+H].sup.+; .sup.1H NMR (400 MHz, chloroform-d) .delta.
ppm 7.68 (dd, 2.0 Hz, 1H), 7.49 (ddd, J=8.5, 4.5, 2.3 Hz, 1H),
7.32-7.19 (m, 1H), 5.19 (d, J=16.8 Hz, 1H), 4.73 (d, J=18.8 Hz,
1H), 4.52 (t, J=6.0 Hz, 3H), 4.31-4.16 (m, 1H), 3.76-3.59 (m, 1H),
3.09 (s, 3H), 2.50-2.32 (m, 1H), 2.32-2.14 (m, 1H), 1.56-1.47 (m,
9H).
Intermediate A98B: tert-Butyl
3-carbamoyl-2-(3-chloro-4-fluorophenyl)-7-ethyl-6,7-dihydropyrazolo[1,5-a-
]pyrazine-5(4H)-carboxylate
##STR00863##
[1377] To a solution of tert-butyl
3-carbamoyl-2-(3-chloro-4-fluorophenyl)-7-(2-((methylsulfonyl)oxy)ethyl)--
6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate (200 mg, 0.387
mmol) in THF (6 mL) at 0.degree. C. under nitrogen was added 1M THF
solution of SUPER-HYDRIDE.RTM. (1.934 mL, 1.934 mmol). The reaction
mixture was stirred at RT for 1 h and quenched with water. It was
extracted with EtOAc. The combined organic layer was washed with
brine, dried over Na.sub.2SO.sub.4, and filtered. The filtrate was
concentrated. The crude product was purified by silica gel
chromatography (40 g REDISEP.RTM. column, eluting with 35-80% EtOAc
in hexane). Fractions containing the product were combined and
evaporated to afford Intermediate A98B (128 m g, 78%). MS(ES):
m/z=423.1 [M+H].sup.+.
Intermediate A98C:
2-(3-Chloro-4-fluorophenyl)-7-ethyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyra-
zine-3-carboxamide TFA salt
##STR00864##
[1379] To a solution of Intermediate A98B (160 mg, 0.378 mmol) in
CH.sub.2Cl.sub.2 (20 mL) was added TFA (2 mL, 26.0 mmol). The
reaction mixture was stirred at RT overnight and concentrated. The
crude Intermediate A97C as a TFA salt was used for the next step
without further purification. MS(ES): m/z=4323.1 [M+H].sup.+.
Compounds A98 and A99:
N.sup.5-(tert-Butyl)-2-(3-chloro-4-fluorophenyl)-7-ethyl-6,7-dihydropyraz-
olo[1,5-a]pyrazine-3,5(4H)-dicarboxamide
##STR00865##
[1381] To a solution of Intermediate A98C (40 mg, 0.092 mmol) in
DMF (1 mL) were added Hunig's base (0.064 mL, 0.366 mmol) and
2-isocyanato-2-methylpropane (13.62 mg, 0.137 mmol). The reaction
mixture was stirred at RT for 2 h. It was purified by preparative.
HPLC to afford racemate Compounds A98 and A99. The racemate was
further separated by chiral HPLC to give enantiomer A98 (Ret. Time
28.91 min, 12.1 mg, 31.3%) and enantiomer A99 (Ret. Time 32.84 min,
13.1 mg, 33.9%). Chiral HPLC Method: Column: CHIRALPAK.RTM. AD
21.times.250 mm, 10 .mu.m; Mobile Phase A: 0.1%
diethylamine/heptane; Mobile Phase B: ethanol; Gradient: hold at
15%-100% B over 40 minutes; Flow rate: 15 mL/min; MS(ES): m/z=422.5
[M+H].sup.+; HPLC Ret. Time 1.65 and 2.62 min (HPLC Methods H and
I); .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. ppm 7.85 (d, J=7.3
Hz, 1H), 7.69 (br. s., 1H), 7.46 (t, J=9.0 Hz, 1H), 7.35 (br. s.,
1H), 7.21 (br. s., 1H), 6.22 (s, 1H), 4.77 (d, J=17.2 Hz, 1H), 4.65
(d, J=16.9 Hz, 1H), 4.14 (d, J=3.7 Hz, 1H), 3.86-3.77 (m, 1H),
3.77-3.63 (m, 1H), 3.39-3.30 (m, 2H), 2.07-1.94 (m, 1H), 1.77-1.63
(m, 1H), 1.29 (s, 9H), 0.99 (t, J=7.5 Hz, 3H).
Intermediate A100A: tert-Butyl
3-carbamoyl-2-(3-chloro-4-fluorophenyl)-7-(2-methoxyethyl)-6,7-dihydropyr-
azolo[1,5-a]pyrazine-5(4H)-carboxylate
##STR00866##
[1383] To a solution of Intermediate A98A (170 mg, 0.329 mmol) in
MeOH (5 mL) was added 25% sodium methoxide solution in MeOH (426
mg, 1.973 mmol). The reaction mixture was stirred at RT overnight.
It was concentrated. The residue was diluted with water, extracted
with EtOAc. The combined organic layer was washed with brine, dried
over Na.sub.2SO.sub.4, and filtered. The filtrate was concentrated.
The crude product was purified by silica gel chromatography (40 g
REDISEP.RTM. column, eluting with 35-80% EtOAc in hexane).
Fractions containing the product were combined and evaporated to
afford Intermediate A100A (120 mg, 81%). MS(ES): m/z=453.1
[M+H].sup.+; .sup.1H NMR (400 MHz, chloroform-d) .delta. ppm
7.77-7.64 (m, 1H), 7.55-7.44 (m, 1H), 7.34-7.16 (m, 1H), 5.44-5.27
(m, 1H), 4.79 (d, J=17.8 Hz, 1H), 4.56-4.39 (m, 1H), 4.14-4.04 (m,
1H), 3.74 (dd, J=13.8, 3.8 Hz, 1H), 3.62 (t, J=6.1 Hz, 2H), 3.39
(s, 3H), 2.45-2.25 (m, 1H), 1.98 (ddt, J=14.3, 8.5, 5.8 Hz, 1H),
1.59-1.48 (m, 9H).
Intermediate A100B:
2-(3-Chloro-4-fluorophenyl)-7-(2-methoxyethyl)-4,5,6,7-tetrahydropyrazolo-
[1,5-a]pyrazine-3-carboxamide TFA salt
##STR00867##
[1385] To a solution of Intermediate A100A (120 mg, 0.265 mmol) in
CH.sub.2Cl.sub.2 (15 mL) was added TFA (1 mL, 12.98 mmol). The
reaction mixture was stirred at RT for 6 h and concentrated. The
crude Intermediate A100B as a TFA salt was used for the next step
without further purification. MS(ES): m/z=353.0 [M+H].sup.+.
Compounds A100 and A101:
N.sup.5-(tert-Butyl)-2-(3-chloro-4-fluorophenyl)-7-(2-methoxyethyl)-6,7-d-
ihydropyrazolo[1,5-a]pyrazine-3,5(4H)-dicarboxamide
##STR00868##
[1387] To a solution of Intermediate A100B (35 mg, 0.075 mmol) in
DMF (1 mL) were added Hunig's base (0.026 mL, 0.150 mmol) and
2-isocyanato-2-methylpropane (11.15 mg, 0.112 mmol). The reaction
mixture was stirred at RT for 2 h. It was purified by preparative
HPLC to afford racemate Compounds A100 and A101. The racemate was
further separated by chiral HPLC to give enantiomer A100 (Ret. Time
24.56 min, 9.7 mg, 28.6%) and enantiomer A101 (Ret. Time 30.65 min,
9.8 mg, 28.9%). Chiral HPLC Method: Column: CHIRALPAK.RTM. AD
21.times.250 mm, 10 .mu.m; Mobile Phase A: 0.1%
diethylamine/heptane; Mobile Phase B: ethanol; Gradient: hold at
12%-100% B over 40 minutes; Flow rate: 15 mL/min; MS(ES): m/z=452.5
[M+H].sup.+; HPLC Ret. Time 1.60 and 2.57 min (HPLC Methods H and
I); .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. ppm 7.85 (d, J=6.6
Hz, 1H), 7.68 (d, J=5.5 Hz, 1H), 7.46 (t, J=9.2 Hz, 1H), 7.35 (br.
s., 1H), 7.23 (br. s., 1H), 6.17 (s, 1H), 4.83 (d, J=16.9 Hz, 1H),
4.57 (d, J=16.9 Hz, 1H), 4.33 (d, J=4.4 Hz, 1H), 3.94-3.83 (m, 1H),
3.76-3.67 (m, 1H), 3.56 (q, J=5.6 Hz, 3H), 3.42-3.32 (m, 3H), 2.19
(dd, J=13.6, 5.9 Hz, 1H), 1.88 (dd, J=13.8, 7.9 Hz, 1H), 1.29 (s,
9H).
##STR00869##
Intermediate A102A: tert-Butyl
3-carbamoyl-2-(3-chloro-4-fluorophenyl)-7-(2-(tosyloxy)ethyl)-6,7-dihydro-
pyrazolo[1,5-a]pyrazine-5(4H)-carboxylate
##STR00870##
[1389] To a solution of Intermediate A96N (0.76 g, 1.732 mmol) in
CH.sub.2Cl.sub.2 (30 mL) were added TEA (0.483 mL, 3.46 mmol),
Ts-Cl (0.220 mL, 2.078 mmol), and DMAP (10.58 mg, 0.087 mmol). The
reaction mixture was stirred at RT overnight and concentrated. The
residue was purified by silica gel chromatography (40 g
REDISEP.RTM. column, eluting with 35-80% EtOAc in hexane).
Fractions containing the product were combined and evaporated to
afford Intermediate A102A (0.76 g, 76%). MS(ES): m/z=593.1
[M+H].sup.+; .sup.1H NMR (400 MHz, chloroform-d) .delta. ppm
7.85-7.78 (m, 2H), 7.64 (dd, J=7.0, 2.0 Hz, 1H), 7.46 (ddd, J=8.5,
4.5, 2.3 Hz, 1H), 7.39-7.18 (m, 3H), 5.12 (br. s., 1H), 4.73 (d,
J=18.6 Hz, 1H), 4.43 (br. s., 1H), 4.32 (t, J=6.3 Hz, 2H), 4.06
(dd, J=14.1, 3.5 Hz, 1H), 3.67 (d, J=12.0 Hz, 1H), 2.45 (s, 3H),
2.41-2.29 (m, 1H), 2.19-2.08 (m, 1H), 1.59-1.44 (m, 9H).
Intermediate A102B: tert-Butyl
3-carbamoyl-2-(3-chloro-4-fluorophenyl)-7-(2-fluoroethyl)-6,7-dihydropyra-
zolo[1,5-a]pyrazine-5(4H)-carboxylate
##STR00871##
[1391] To a solution of Intermediate A102A (260 mg, 0.438 mmol) in
THF (15 mL) at 0.degree. C. under nitrogen was added 1M THF
solution of tetrabutylammonium fluoride (0.526 mL, 0.526 mmol). The
reaction mixture was stirred at RT overnight. It was concentrated.
The residue was purified by silica gel chromatography (40 g
REDISEP.RTM. column, eluting with 35-80% EtOAc in hexane).
Fractions containing the product were combined and evaporated to
afford Intermediate A102B (140 mg, 72%). MS(ES): m/z=441.1
[M+H].sup.+.
Intermediate A102C:
2-(3-Chloro-4-fluorophenyl)-7-(2-fluoroethyl)-4,5,6,7-tetrahydropyrazolo[-
1,5-a]pyrazine-3-carboxamide TFA salt
##STR00872##
[1393] To a solution of afford Intermediate A102B (140 mg, 0.318
mmol) in CH.sub.2Cl.sub.2 (10 mL) was added TFA (1 mL, 12.98 mmol).
The reaction mixture was stirred at RT for 4 h and concentrated.
The crude Intermediate A102C was used for the next step without
further purification. MS(ES): m/z=341.1 [M+H].sup.+.
Compounds A102 and A103:
N.sup.5-(tert-Butyl)-2-(3-chloro-4-fluorophenyl)-7-(2-fluoroethyl)-6,7-di-
hydropyrazolo[1,5-a]pyrazine-3,5(4H)-dicarboxamide
##STR00873##
[1395] To a solution of Intermediate A102C (40 mg, 0.088 mmol) in
DMF (1 mL) were Hunig's base (0.030 mL, 0.173 mmol) and
2-isocyanato-2-methylpropane (13.08 mg, 0.132 mmol). The reaction
mixture was stirred at RT for 2 h. It was purified by preparative
HPLC to afford racemate Compounds A102 and A103. The racemate was
further separated by chiral HPLC to give enantiomer (A102 (Ret time
19.38 min, 8.5 mg, 22%) and enantiomer A103 (Ret time 25.82 min,
8.5 mg, 22%). Chiral HPLC Method: Column: CHIRALPAK.RTM. AD
21.times.250 mm, 10 .mu.m; Mobile Phase A: 0.1%
diethylamine/heptane; Mobile Phase B: ethanol; Gradient: hold at
13% B-100% B over 32 minutes; Flow rate: 15 mL/min; MS(ES):
m/z=440.5 [M+H].sup.+; HPLC Ret. Time 1.57 and 2.51 min (HPLC
Methods H and I); .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. ppm
7.85 (d, J=6.6 Hz, 1H), 7.69 (br. s., 1H), 7.47 (t, J=9.0 Hz, 1H),
7.36 (br. s., 1H), 7.24 (br. s., 1H), 6.23 (s, 1H), 4.85-4.71 (m,
2H), 4.71-4.61 (m, 2H), 4.38 (br. s., 1H), 3.81 (d, J=4.0 Hz, 2H),
3.39 (s, 4H), 2.42-2.21 (m, 1H), 2.21-1.98 (m, 1H), 1.28 (s,
9H).
Intermediate 104A: tert-Butyl
3-carbamoyl-2-(3-chloro-4-fluorophenyl)-7-(2-cyanoethyl)-6,7-dihydropyraz-
olo[1,5-a]pyrazine-5(4H)-carboxylate
##STR00874##
[1397] To a solution of Intermediate A102A (180 mg, 0.304 mmol) in
DMSO (2 mL) were added tetrabutylammonium iodide (11.21 mg, 0.030
mmol) and sodium cyanide (74.4 mg, 1.518 mmol). The reaction
mixture was heated at 85.degree. C. for 16 h and cooled to RT. The
reaction mixture was diluted with water, extracted with EtOAc. The
combined organic layer was washed with brine, dried over
Na.sub.2SO.sub.4, and filtered. The filtrate was concentrated. The
crude product was purified by silica gel chromatography (40 g
REDISEP.RTM. column, eluting with 35-80% EtOAc in hexane).
Fractions containing the product were combined and evaporated to
afford Intermediate A104A (80 mg, 59%). MS(ES): m/z=448.1
[M+H].sup.+.
Intermediate 104B:
2-(3-Chloro-4-fluorophenyl)-7-(2-cyanoethyl)-4,5,6,7-tetrahydropyrazolo[1-
,5-a]pyrazine-3-carboxamide TFA salt
##STR00875##
[1399] To a solution of Intermediate A104A (80 mg, 0.179 mmol) in
CH.sub.2Cl.sub.2 (10 mL) was added TFA (1 mL, 12.98 mmol). The
reaction mixture was stirred at RT for 4 h and concentrated. The
crude Intermediate A104B was used for the next step without further
purification. MS(ES): m/z=348.1 [M+H].sup.+.
Compounds A104 and A105:
N.sup.5-(tert-Butyl)-2-(3-chloro-4-fluorophenyl)-7-(2-cyanoethyl)-6,7-dih-
ydropyrazolo[1,5-a]pyrazine-3,5(4H)-dicarboxamide
##STR00876##
[1401] To a solution of Intermediate A104B (40 mg, 0.087 mmol) in
DMF (1 mL) were added Hunig's base (0.030 mL, 0.173 mmol) and
2-isocyanato-2-methylpropane (12.88 mg, 0.130 mmol). The reaction
mixture was stirred at RT for 2 h. It was purified by preparative
HPLC to afford racemate Compounds A104 and A105. The racemate was
further separated by chiral HPLC to give enantiomer A104 (Ret time
12.08 min, 9.2 mg, 24%) and enantiomer A105 (Ret time 15.60 min,
9.7 mg, 25%). Chiral HPLC Method: Column: CHIRALPAK.RTM. AD
21.times.250 mm, 10 pin; Mobile Phase A: 0.1% diethylamine/heptane;
Mobile Phase B: ethanol; Gradient: hold at 15%-100% B over 20
minutes; Flow rate: 15 mL/min; MS(ES): m/z=422.5 [M+H].sup.+; HPLC
Ret. Time 1.65 and 2.62 min (HPLC Methods H and I); .sup.1H NMR
(500 MHz, DMSO-d.sub.6) .delta. ppm 7.85 (d, J=7.3 Hz, 1H), 7.69
(br. s., 1H), 7.46 (t, J=9.0 Hz, 1H), 7.35 (br. s., 1H), 7.21 (br.
s., 1H), 6.22 (s, 1H), 4.77 (d, J=17.2 Hz, 1H), 4.65 (d, J=16.9 Hz,
1H), 4.14 (d, J=3.7 Hz, 1H), 3.86-3.77 (m, 1H), 3.77-3.63 (m, 1H),
3.39-3.30 (m, 2H), 2.07-1.94 (m, 1H), 1.77-1.63 (m, 1H), 1.29 (s,
9H), 0.99 (t, J=7.5 Hz, 3H).
##STR00877## ##STR00878## ##STR00879##
Intermediate A106A: Ethyl
3-(3-fluorophenyl)-1-(2,2,3,3,11,11-hexamethyl-9-oxo-4,10-dioxa-8-aza-3-s-
iladodecan-6-yl)-1H-pyrazole-5-carboxylate
##STR00880##
[1403] To a flask charged with triphenylphosphine (2.93 g, 11.16
mmol), sealed with a septum and purged with a dry atmosphere of
nitrogen, was added THF (20 mL) via syringe and the reaction
mixture was cooled to 0.degree. C. Next, DIAD (2.170 mL, 11.16
mmol) was added via syringe resulting in a thick milky yellow
solution. A solution of Intermediate A1A (3.28 g, 10.73 mmol) in
THF (5.0 mL) was added to the ice-cold solution. After 15 minutes,
pyrazole 4B (2.01 g, 8.58 mmol) was added as a solution in THF (5.0
mL). The reaction was then allowed to warm to RT. After 18 h, the
reaction mixture was diluted with EtOAc (150 mL). The organic layer
was washed with brine, dried over anhydrous Na.sub.2SO.sub.4,
filtered and concentrated under reduced pressure to provide a crude
oil. The crude reaction mixture was purified by silica gel
chromatography (220 g REDISEP.RTM. column, eluting with 0 to 15%
EtOAc in hexanes). Fractions containing the product were combined
and evaporated to afford Intermediate A106A (4.5 g, 80%) as a thick
syrup. MS(ES): m/z=522.09 [M+H].sup.+; .sup.1H NMR (400 MHz,
chloroform-d) .delta. ppm 7.49-7.60 (2H, m), 7.32-7.41 (1H, m),
7.12 (1H, s), 6.99-7.07 (1H, m), 5.52-5.64 (1H, m), 4.92-5.07 (1H,
m), 4.37 (2H, q, J=7.28 Hz), 3.97 (2H, d, J=6.53 Hz), 3.67-3.83
(2H, m), 1.37-1.50 (9H, m), 0.75-0.86 (9H, m), 0.04-0.11 (2H, m),
-0.12-0.00 (6H, m).
Intermediate A106B: Ethyl
1-(1-amino-3-hydroxypropan-2-yl)-3-(3-fluorophenyl)-1H-pyrazole-5-carboxy-
late
##STR00881##
[1405] To an ice-cooled solution of Intermediate A106A (4.35 g,
8.34 mmol) in DCM (50 mL) was added a 4M solution of HCl in
1,4-dioxane (12.5 mL, 50.0 mmol). The reaction mixture was allowed
to stir at RT for 2 h. The white precipitate that was generated was
filtered off and the filter cake was washed with diethyl ether. The
solid was dried under vacuum for 16 h to afford Intermediate A106B
as an HCl salt (2.56 g, >98%). MS(ES): m/z=308.0 [M+H].sup.+.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 8.04 (1H, br. s.),
7.72-7.80 (1H, m), 7.44-7.54 (1H, m), 7.13-7.23 (1H, m), 5.46-5.58
(1H, m), 5.24 (1H, br. s.), 4.35 (2H, q, J=7.11 Hz), 3.58-3.80 (3H,
m), 3.40 (1H, d, J=11.29 Hz), 1.31-1.40 (2H, m).
Intermediate A106C:
2-(3-Fluorophenyl)-7-(hydroxymethyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(-
5H)-one
##STR00882##
[1407] To a suspension of Intermediate A106B (2.56 g, 8.34 mmol) in
EtOH (50 mL) was added NH.sub.4OH (32.5 mL, 334 mmol, 40% wt).
After a few moments, the reaction mixture became homogeneous and
the solution was allowed to stir at RT for 16 h. The crude reaction
mixture was concentrated in vacuo and diluted with EtOAc. The
aqueous solution was neutralized to pH=7 using a 1.0 M aqueous
solution of HCl. The organic layer was separated and the aqueous
layer was extracted with EtOAc. The combined organic layers were
then washed with brine, dried over sodium sulfate, and concentrated
to afford Intermediate A106C (2.1 g, 96%) as a white solid. MS(ES):
m/z=261.97 [M+H].sup.+. NMR (400 MHz, chloroform-d) .delta. ppm
7.49-7.61 (2H, m), 7.36-7.45 (1H, m), 7.16-7.21 (1H, s), 7.06 (1H,
tdd, J=8.41, 8.41, 2.51, 1.00 Hz), 6.28 (1H, br. s.), 4.56-4.67
(1H, m), 4.07-4.23 (2H, m), 3.72-3.85 (2H, m), 3.14-3.37 (1H,
m).
Intermediate A106D:
7-(((tert-Butyldimethylsilyl)oxy)methyl)-2-(3-fluorophenyl)-6,7-dihydropy-
razolo[1,5-a]pyrazin-4(5H)-one
##STR00883##
[1409] To a solution of Intermediate A106C (11.5 g, 44.1 mmol) in
DMF (120 mL) was added imidazole (3.66 g, 53.8 mmol) and TBSCl
(7.64 g, 50.7 mmol) and the reaction mixture was stirred at RT for
14 h. The solution was concentrated and the crude material was
diluted with equal parts water and DCM (250 mL each). The organic
layer was separated and washed several more times with water before
being dried over sodium sulfate and concentrated to afford
Intermediate A106D (13.57 g, 82%) as a white solid. MS(ES):
m/z=375.95 [M+H].sup.+. .sup.1H NMR (400 MHz, chloroform-d) .delta.
ppm 7.52-7.63 (1H, m), 7.35-7.46 (1H, m), 7.13-7.20 (1H, m),
6.99-7.11 (1H, m), 6.01-6.25 (1H, m), 4.48-4.62 (1H, m), 4.10 (1H,
dd, J=10.04, 4.27 Hz), 3.84-4.03 (3H, m), 0.90-0.93 (9H, m),
0.07-0.12 (6H, m).
Intermediate A106E:
(2-(3-Fluorophenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-7-yl)methano-
l
##STR00884##
[1411] To a solution of Intermediate A106D (5.162 g, 13.75 mmol) in
THF (125 mL) cooled to -15.degree. C., was introduced a 1 M
solution of LAH in THF (38.5 mL, 38.5 mmol) dropwise. The reaction
mixture was allowed to gradually reach room temperature and stir
for an additional 18 h. The reaction mixture was carefully quenched
at -15.degree. C. with sequential addition of H.sub.2O (38.5 mL),
NaOH (15% aq. solution, 38.5 mL) and H.sub.2O (114 mL). The slurry
was then allowed to stir at RT for 30 minutes, followed by the
addition of anhydrous MgSO.sub.4. The mixture was allowed to stir
for 15 minutes and then the inorganics were filtered off. The
filter cake was washed with DCM (150 mL). The biphasic filtrate was
concentrated under reduced pressure to remove THF. The aqueous
layer was then extracted with DCM (3.times.50 mL). The combined
organic layers were washed with brine, dried over anhydrous
Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure
to afford Intermediate A106E (3.41 g, >98%) as a white sticky
solid. MS(ES): m/z=247.94 [M+H].sup.+. .sup.1H NMR (400 MHz,
chloroform-d) .delta. ppm 7.55 (1H, dt, J=7.84, 1.10 Hz), 7.48 (1H,
ddd, J=10.16, 2.51, 1.63 Hz), 7.31-7.40 (1H, m), 6.96-7.04 (1H, m),
6.32 (1H, s), 4.26-4.35 (1H, m), 4.07-4.15 (2H, m), 4.01-4.07 (1H,
m), 3.91-3.98 (1H, m), 3.41 (1H, dd, J=13.30, 4.77 Hz), 3.12 (1H,
dd, J=13.18, 7.15 Hz).
Intermediate A106F:
7-(((tert-Butyldimethylsilyl)oxy)methyl)-2-(3-fluorophenyl)-4,5,6,7-tetra-
hydropyrazolo[1,5-a]pyrazine
##STR00885##
[1413] To a flask charged with Intermediate A106E (3.41 g, 13.79
mmol) was added DMAP (0.084 g, 0.690 mmol) and triethylamine (2.307
mL, 16.55 mmol). The reaction mixture was dissolved in DCM (125 mL)
and finally TBSCl (2.286 g, 15.17 mmol) was added. The reaction
mixture was then allowed to stir at 22.degree. C. for 16 h after
which the mixture was diluted with a saturated aq. solution of
NaHCO.sub.3 and the two layers were separated. The aqueous phase
was extracted with DCM (2.times.50 mL). The combined organic layers
were washed with water, brine, dried over anhydrous
Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure
to afford a pale yellow oil. Crude Intermediate A106F (5.12 g, 92%)
was found to be 90% pure and carried forward to amine protection
with Boc-anhydride without further purification. MS(ES): m/z=361.94
[M+H].sup.+.
Intermediate A106G: tert-Butyl
7-(((tert-butyldimethylsilyl)oxy)methyl)-2-(3-fluorophenyl)-6,7-dihydropy-
razolo[1,5-a]pyrazine-5(4H)-carboxylate
##STR00886##
[1415] To a solution of Intermediate A106F (4.33 g, 11.98 mmol) in
DCM (100 mL) was added triethylamine (6.68 mL, 47.9 mmol) and DMAP
(0.073 g, 0.599 mmol). To the colorless solution was then added
di-tert-butyl dicarbonate (3.92 g, 17.97 mmol) resulting in gas
evolution. The reaction mixture was allowed to stir at 22.degree.
C. for 24 h prior to being quenched with a saturated aqueous
solution of NaHCO.sub.3. The layers were separated, and the aqueous
layer was extracted twice more with DCM. The combined organic
layers were washed with water, followed by brine, dried over sodium
sulfate, and concentrated in vacuo. The crude product was purified
by silica gel chromatography (120 g REDISEP.RTM. column, eluting
with 20% EtOAc in hexanes). Fractions containing the product were
combined and evaporated to afford Intermediate A106G (4.87 g, 88%)
as a colorless oil. MS(ES): m/z=461.77 [M+H].sup.+. .sup.1H NMR
(400 MHz, chloroform-d) .delta. ppm 7.45-7.58 (1H, m), 7.35 (1H,
td, J=8.03, 6.02 Hz), 6.95-7.05 (1H, m), 6.29-6.39 (1H, m),
4.55-4.79 (2H, m), 4.33 (1H, br. s.), 4.06-4.22 (2H, m), 3.74-4.03
(2H, m), 1.49-1.54 (9H, m), 0.83-0.95 (9H, m), -0.01-0.14 (6H,
m).
Intermediate A106H: tert-Butyl
7-(((tert-butyldimethylsilyl)oxy)methyl)-2-(3-fluorophenyl)-3-iodo-6,7-di-
hydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate
##STR00887##
[1417] To a solution of Intermediate A106G (4.87 g, 10.6 mmol) in
DCM (56 mL) and MeOH (14 mL) was added NIS (7.12 g, 31.6 mmol) and
the reaction mixture was allowed to stir at RT for 90 min. The
solution was then concentrated under reduced pressure to provide a
red oil. The crude reaction mixture was purified by silica gel
chromatography (120 g REDISEP.RTM. column, eluting with a gradient
of 0-30% EtOAc in hexanes). Fractions containing the product were
combined and evaporated to afford Intermediate A106H (5.70 g, 92%)
as a sticky solid. MS(ES): m/z=587.95 [M+H].sup.+. .sup.1H NMR (400
MHz, chloroform-d) .delta. ppm 7.65 (1H, dq, J=7.78, 0.84 Hz),
7.54-7.60 (1H, m), 7.36-7.44 (1H, m), 7.08 (1H, tdd, J=8.44, 8.44,
2.57, 0.88 Hz), 4.50-4.71 (1H, m), 4.41-4.49 (1H, m), 4.02-4.40
(3H, m), 3.83-3.99 (1H, m), 3.75-3.82 (1H, m), 1.53 (8H, s),
0.84-0.93 (10H, m), -0.01-0.15 (6H, m).
Intermediate A106I: tert-Butyl
7-(((tert-butyldimethylsilyl)oxy)methyl)-2-(3-fluorophenyl)-3-cyano-6,7-d-
ihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate
##STR00888##
[1419] To a flask charged with Intermediate A106H (3.84 g, 6.54
mmol) was added DMF (43.6 mL) and copper (I) cyanide (1.463 g,
16.34 mmol). The heterogeneous reaction mixture was equipped with a
reflux condenser and was heated to 100.degree. C. for 18 h. The
reaction mixture was cooled to RT and the solution was filtered
through a pad of CELITE.RTM.. The filter cake was washed with
EtOAc. The combined filtrate was concentrated under reduced
pressure to afford the crude reaction mixture as a dark green oil.
The product was purified by silica gel chromatography (80 g
REDISEP.RTM. column, eluting with a gradient of 5-30% EtOAc in
hexanes). Fractions containing the product were combined and
evaporated to afford Intermediate A1061 (1.441 g, 45%) as a white
solid. MS(ES): m/z=431.0 [M+H.sub.2O-OtBu].sup.+; .sup.1H NMR (400
MHz, chloroform-d) .delta. ppm 7.62-7.83 (2H, m), 7.39-7.51 (1H,
m), 7.08-7.19 (1H, m), 4.67-4.96 (2H, m), 4.34 (1H, br. s.),
3.84-4.19 (4H, m), 1.47-1.54 (9H, m), 0.79-0.91 (9H, m), -0.02-0.10
(6H, m).
Intermediate A106J: tert-Butyl
3-carbamoyl-2-(3-fluorophenyl)-7-(hydroxymethyl)-6,7-dihydropyrazolo[1,5--
a]pyrazine-5(4H)-carboxylate
##STR00889##
[1421] To an ice-cooled solution of Intermediate A1061 (1.44 g,
2.96 mmol) in DMSO (20 mL) was added a 5 M aq. solution of KOH
(2.96 mL, 14.8 mmol) and H.sub.2O.sub.2 (6.05 mL, 59.2 mmol, 30%
w/v in H.sub.2O) and the reaction mixture was stirred at 22.degree.
C. for 3 h. The reaction mixture was then partitioned between equal
parts water and EtOAc and the layers were separated. The aqueous
phase was extracted twice more with EtOAc. The combined organic
layers were washed with water, brine, dried over anhydrous
MgSO.sub.4, filtered and concentrated under reduced pressure to
afford a white solid. The crude reaction mixture was purified by
silica gel chromatography (120 g REDISEP.RTM. column, eluting with
a gradient from 75-100% EtOAc in hexanes). Fractions containing the
product were combined and evaporated to afford Intermediate A106J
(0.997 g, 52%) as a white solid contaminated with dimethyl sulfone.
MS(ES): m/z=412.96 [M+Na]+.
Intermediate A106K: tert-Butyl
3-carbamoyl-7-(fluoromethyl)-2-(3-fluorophenyl)-6,7-dihydropyrazolo[1,5-a-
]pyrazine-5(4H)-carboxylate
##STR00890##
[1423] A suspension of Intermediate A106J (131.5 mg, 0.337 mmol) in
DCM (5.5 mL) was allowed to cool to -78.degree. C. DAST (0.067 mL,
0.505 mmol) was added dropwise to the solution and was then allowed
to warm to RT. After stirring at 22.degree. C. for 1 h, the
reaction was quenched by the addition of a saturated aq. solution
of NaHCO.sub.3 at 0.degree. C. The two layers were separated and
the aqueous layer was extracted with DCM (3.times.10 mL). The
combined organic layers were washed with brine, dried over
anhydrous MgSO.sub.4, filtered and concentrated under reduced
pressure to afford an orange oil. The crude reaction mixture was
purified by silica gel chromatography (24 g REDISEP.RTM. column,
eluting with 75% EtOAc in hexanes). Fractions containing the
product were combined and evaporated to afford Intermediate A106K
(52.8 mg, 40%) as a white solid. MS(ES): m/z=393.0 [M+H].sup.+.
Compounds A106 and A107:
N.sup.5-(tert-Butyl)-7-(fluoromethyl)-2-(3-fluorophenyl)-6,7-dihydropyraz-
olo[1,5-a]pyrazine-3,5(4H)-dicarboxamide
##STR00891##
[1425] To a solution of Intermediate A106K (0.021 g, 0.054 mmol) in
DCM (1.5 mL) was added trifluoroacetic acid (0.041 mL, 0.537 mmol).
The reaction mixture was then allowed to stir at RT for 3 h prior
to the removal of the volatiles to afford the crude bis TFA
salt.
[1426] The TFA salt was then dissolved in DMF (1.0 mL) and treated
with DIPEA (0.047 mL, 0.269 mmol). The resulting mixture was
allowed to stir for 5 minutes prior to the addition of
2-isocyanato-2-methylpropane (0.012 mL, 0.105 mmol). The reaction
was allowed to stir for 2 h after which it was filtered and
purified via preparative HPLC. Fractions containing the desired
product were combined and evaporated to afford the racemic
compound. The compound was further purified through chiral
separation using preparative HPLC: CHIRALPAK.RTM. AD, 21.times.250
mm, 10 .mu.m column eluted with 70% heptane with 0.1% diethylamine:
30% EtOH at 15 mL/min. The first eluting enantiomer, rt=6.8 min:
(S)-A106 (0.0068 g, 65%) and the second eluting enantiomer, rt=12.6
min: (R)-A107 (0.0051 g, 48%) were thus separated. MS(ES),
m/z=392.2 [M+H].sup.+; HPLC Ret. Time 1.38 min. and 2.22 min. (HPLC
Methods H and I). .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. ppm
7.53 (d, J=7.7 Hz), 7.42-7.51 (2H, m), 7.39 (1H, br. s.), 7.17-7.23
(1H, m), 6.30 (1H, s), 4.90-5.05 (m, 1H), 4.70-4.85 (m, 2H), 4.62
(d, J=16.9 Hz, 1H), 4.03 (dd, J=13.8, 3.9 Hz, 1H), 3.76 (dd,
J=14.1, 7.2 Hz, 1H), 1.28 (s, 9H).
##STR00892##
Intermediate A108A: tert-Butyl
3-carbamoyl-2-(3-fluorophenyl)-7-(((methylsulfonyl)oxy)methyl)-6,7-dihydr-
opyrazolo[1,5-a]pyrazine-5(4H)-carboxylate
##STR00893##
[1428] To an ice-cold suspension of Intermediate A106J (148.2 mg,
0.380 mmol) in DCM (3.8 mL) was added triethylamine (0.063 mL,
0.456 mmol) followed by the dropwise addition of methanesulfonyl
chloride (0.032 mL, 0.418 mmol). The resultant homogeneous reaction
mixture was allowed to warm to RT and continue to stir for an
additional 2 h. The reaction was then quenched with a saturated aq.
solution of NaHCO.sub.3. The two layers were separated and the
aqueous layer was extracted with DCM (2.times.10 mL). The combined
organic layers were washed with brine, dried over anhydrous
MgSO.sub.4, filtered and the filtrate concentrated under reduced
pressure to afford a colorless oil. The crude reaction mixture was
purified by silica gel chromatography (24 g REDISEP.RTM. column,
eluting with a gradient of 60-85% EtOAc in hexanes). Fractions
containing the product were combined and evaporated to afford
Intermediate A108A (0.0948 g, 33%) as a white solid. MS(ES):
m/z=468.9 [M+H].sup.+.
Intermediate A108B: tert-Butyl
3-carbamoyl-2-(3-fluorophenyl)-7-methyl-6,7-dihydropyrazolo[1,5-a]pyrazin-
e-5(4H)-carboxylate
##STR00894##
[1430] To a solution of Intermediate A108A (0.0948 g, 0.202 mmol)
in THF (2.0 mL) at RT was added dropwise a 1M solution of
LiEt.sub.3BH in THF (2.02 mL, 2.02 mmol), and the reaction mixture
was stirred for 2 h. The reaction was then carefully quenched with
a saturated aq. solution of NaHCO.sub.3. The organic phase was
separated and the aqueous layer was extracted twice more with DCM.
The combined organic layers were washed with brine, dried over
sodium sulfate, and concentrated to provide a pale yellow oil. The
crude reaction mixture was purified by silica gel chromatography
(24 g REDISEP.RTM. column, eluting with a gradient of 50-90% EtOAc
in hexanes). Fractions containing the product were combined and
evaporated to afford Intermediate A108B (0.029 g, 81%) as a white
foam. MS(ES): m/z=375.08 [M+H].sup.+.
Compounds A108 and A109:
N.sup.5-(tert-Butyl)-2-(3-fluorophenyl)-7-methyl-6,7-dihydropyrazolo[1,5--
a]pyrazine-3,5(4H)-dicarboxamide
##STR00895##
[1432] Compounds A108 and A109 were synthesized analogous to
Compounds A106 and A107 by reacting deprotected A108B with
2-isocyanato-2-methylpropane. The compound was purified by
preparative HPLC and further purified through chiral separation
using preparative HPLC: CHIRALPAK.RTM. AD, 21.times.250 mm, 10
.mu.m column eluted with 85% heptane with 0.1% diethylamine: 15%
EtOH at 15 mL/min. The first eluting enantiomer, rt=10.0 min:
(R)-A108 (0.014 g, 45%) and the second eluting enantiomer, rt=18.0
min: (S)-A109 (0.0146 g, 47%) were thus separated. MS(ES):
m/z=374.2 [M+H].sup.+; HPLC Ret. Time 1.46 min and 2.26 min.
(Methods H and I respectively); .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. ppm 7.52 (1H, d, J=7.70 Hz), 7.39-7.49 (2H, m), 7.34 (1H,
br. s.), 7.12-7.23 (2H, m), 6.17-6.28 (1H, m), 4.78 (1H, d, J=16.87
Hz), 4.53-4.64 (1H, m), 4.23-4.35 (1H, m), 3.90-3.99 (1H, m), 3.47
(1H, dd, J=13.76, 7.15 Hz), 1.44 (3H, d, J=6.24 Hz), 1.22-1.32 (9H,
s).
##STR00896##
Compounds A110 and A111:
2-(3-Chlorophenyl)-N.sup.5-(3,3-difluorocyclobutyl)-7-methyl-6,7-dihydrop-
yrazolo[1,5-a]pyrazine-3,5(4H)-dicarboxamide
##STR00897##
[1434] To an ice-cold solution of triphosgene (0.069 g, 0.232 mmol)
in THF (5 mL) was added a solution of 3,3-difluorocyclobutanamine
(0.066 g, 0.619 mmol) and TEA (0.173 mL, 1.238 mmol) in THF (5 mL).
The reaction mixture was stirred at 0.degree. C. for 30 minutes,
followed by the addition of A7C (0.090 g, 0.310 mmol) and TEA
(0.173 mL, 1.238 mmol) in DMF (2.5 mL). The resulting mixture was
stirred at RT for 16 h and then concentrated under reduced
pressure. The crude material was purified via preparative HPLC.
Fractions containing the desired product were combined and dried
via centrifugal evaporation to obtain the racemic compound. The
compound was further purified through chiral separation using
preparative HPLC: CHIRALPAK.RTM. AD, 21.times.250 mm, 10 .mu.m
column eluted with 80% heptane with 0.1% diethylamine: 20% EtOH at
15 mL/min. The first eluting enantiomer, rt=20.2 min: (S)-A110 and
the second eluting enantiomer, rt=30.6 min: (R)-A111 were thus
separated. MS(ES), m/z=424 [M+H].sup.+; HPLC Ret. Time 1.41 min.
and 2.33 min. (Methods H and I respectively). .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 7.70 (s, 1H), 7.64 (d, J=7.0 Hz, 1H),
7.50-7.40 (m, 2H), 4.85-4.63 (m, 2H), 4.40-4.30 (m, 1H), 4.08-3.88
(m, 2H), 3.56 (dd, J=13.8, 6.8 Hz, 1H), 2.85 (d, J=4.4 Hz, 2H),
2.70-2.57 (m, 2H), 1.45 (d, J=6.2 Hz, 3H).
##STR00898##
Compounds A112 and A113:
2-(3-Chlorophenyl)-N.sup.5-(3,3-difluorocyclobutyl)-7-(fluoromethyl)-6,7--
dihydropyrazolo[1,5-a]pyrazine-3,5(4H)-dicarboxamide
##STR00899##
[1436] To an ice-cold solution of triphosgene (0.029 g, 0.097 mmol)
in THF (3 mL) was added a solution of 3,3-difluorocyclobutanamine
HCl (0.037 g, 0.259 mmol) and TEA (0.072 mL, 0.518 mmol) in THF (3
mL). The reaction mixture was stirred at 0.degree. C. for 30
minutes, followed by the addition of A9J (0.04 g, 0.130 mmol) and
TEA (0.072 mL, 0.518 mmol) as a solution in DMF (1.5 mL). The
resulting reaction mixture was stirred at RT for 16 h. It was
concentrated and the crude material was purified via preparative
HPLC. Fractions containing the desired product were combined and
dried via centrifugal evaporation to obtain the racemic compound.
The compound was further purified through chiral separation using
preparative HPLC: CHIRALPAK.RTM. AD, 21.times.250 mm, 10 .mu.m
column eluted with 80% heptane with 0.1% diethylamine: 20% EtOH at
15 mL/min. The first eluting enantiomer, rt=12.2 min: (S)-A112 and
the second eluting enantiomer, rt=22.5 min: (R)-A113 were thus
separated. MS(ES), m/z=442 [M+H].sup.+; HPLC Ret. Time 1.35 min.
and 2.26 min. (Methods H and I respectively). .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 7.71 (s, 1H), 7.65 (d, J=6.6 Hz, 1H),
7.50-7.42 (m, 2H), 5.05-4.89 (m, 1H), 4.82-4.69 (m, 2H), 4.63-4.51
(m, 1H), 4.08-3.97 (m, 2H), 3.88 (dd, J=14.3, 6.6 Hz, 1H), 3.39 (d,
J=3.7 Hz, 2H), 2.89-2.80 (m, 2H), 2.64 (br. s., 2H).
Intermediate (R)-A9H: (R)-tert-Butyl
3-carbamoyl-2-(3-chloro-4-fluorophenyl)-7-(hydroxymethyl)-6,7-dihydropyra-
zolo[1,5-a]pyrazine-5(4H)-carboxylate
##STR00900##
[1438] Intermediate (R)-A9H was prepared analogously to
Intermediate A1N as depicted in Scheme 57 substituting enantiopure
Intermediate (S)-A1A for racemic Intermediate A1A and substituting
Intermediate A96E for Intermediate A1D. The chiral amino alcohol
Intermediate (S)-A1A was derived from commercially available
(S)-3-aminopropane-1,2-diol through the same synthetic sequence
described in Scheme 57.
Compound A114:
(R)-2-(3-Chloro-4-fluorophenyl)-N.sup.5-(3,3-difluorocyclobutyl)-7-(fluor-
omethyl)-6,7-dihydropyrazolo[1,5-a]pyrazine-3,5(4H)-dicarboxamide
##STR00901##
[1440] Intermediate (R)-A9H was used in the asymmetric synthesis of
Compound (R)-A114 using the synthetic sequence outlined above for
related Compounds A112 and A113 in Scheme 80. MS(ES) m/z=460
[M+H].sup.+; Ret. Time=1.44 and 2.33 min. (Methods H and I
respectively). .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 7.84 (d,
J=7.3 Hz, 1H), 7.67 (br. s., 1H), 7.47 (t, J=9.2 Hz, 1H), 5.05-4.87
(m, 1H), 4.85-4.67 (m, 3H), 4.61-4.49 (m, 1H), 4.01 (d, J=11.7 Hz,
2H), 3.90 (s, 1H), 2.84 (br. s., 2H), 2.64 (br. s., 2H).
Compound A115:
(S)-2-(3-Chloro-4-fluorophenyl)-N.sup.5-(3,3-difluorocyclobutyl)-7-methyl-
-6,7-dihydropyrazolo[1,5-a]pyrazine-3,5(4H)-dicarboxamide
##STR00902##
[1442] Intermediate (R)-A9H was used in the asymmetric synthesis of
Compound (S)-A115 using the synthetic sequence outlined above for
related Compounds A110 and A111 in Scheme 79. MS(ES) m/z=442
[M+H].sup.+; Ret. Time=1.48 and 2.48 min. (Methods H and I
respectively). .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 7.84 (d,
J=7.3 Hz, 1H), 7.67 (d, J=5.1 Hz, 1H), 7.47 (t, J=8.8 Hz, 1H),
4.85-4.64 (m, 2H), 4.40-4.29 (m, 1H), 4.09-3.89 (m, 2H), 3.56 (dd,
J=13.8, 6.8 Hz, 1H), 3.37 (d, J=8.4 Hz, 1H), 2.84 (br. s., 1H),
2.63 (d, J=11.0 Hz, 2H), 1.44 (d, J=6.6 Hz, 3H).
##STR00903##
Compound A116:
(R)-2-(3-Chloro-4-fluorophenyl)-N.sup.5-(3,3-difluorocyclobutyl)-7-(hydro-
xymethyl)-6,7-dihydropyrazolo[1,5-a]pyrazine-3,5(4H)-dicarboxamide
##STR00904##
[1444] Intermediate (R)-A9H was used in the enantiospecific
preparation of Compound A116 as shown in Scheme 81 using a
synthetic sequence analogous to Compound A115. MS(ES) m/z=458
[M+H].sup.+; Ret. time=1.23 and 2.24 min. (Methods H and I
respectively); .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 7.85 (d,
J=6.6 Hz, 1H), 7.68 (br. s., 1H), 7.47 (t, J=9.0 Hz, 1H), 7.30-7.12
(m, 2H), 4.85-4.60 (m, 2H), 4.22 (br. s., 1H), 4.08-3.96 (m, 1H),
3.95-3.82 (m, 3H), 3.81-3.73 (m, 1H), 3.37 (br. s., 2H), 2.84 (br.
s., 2H), 2.71-2.56 (m, 2H).
##STR00905##
Intermediate A117A: 1-Amino-3,3-dimethylbutan-2-ol
##STR00906##
[1446] In a sealed pressure tube at RT was added
2-(tert-butyl)oxirane (1.0 g, 9.98 mmol) and ammonia in methanol
(7N) (4.28 mL, 30.0 mmol). The reaction vessel was sealed and
heated at 70.degree. C. for 4 h. The reaction mixture was cooled to
RT and concentrated and under reduced pressure. Crude Intermediate
A117A (0.968, 83% yield) was used as such without further
purification. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 3.15-2.88
(m, 1H), 2.66-2.46 (m, 1H), 2.42-2.21 (m, 1H), 0.88-0.73 (m,
9H).
Intermediate A117B: tert-Butyl
(2-hydroxy-3,3-dimethylbutyl)carbamate
##STR00907##
[1448] To a solution of Intermediate A117A (0.812 g, 6.93 mmol) in
DCM (20 mL) was added TEA (2.414 mL, 17.32 mmol), DMAP (0.042 g,
0.346 mmol) and di-tert-butyl dicarbonate (2.268 g, 10.39 mmol).
The reaction mixture was allowed to stir overnight at RT. The
reaction mixture was diluted with EtOAc (500 mL) and washed with
brine, dried (MgSO.sub.4) and concentrated. The crude product was
purified by silica gel chromatography (80 g REDISEP.RTM. column,
eluting with a gradient from 0-30% EtOAc in hexanes). Fractions
containing the product were combined and concentrated to afford
Intermediate A117B (1.2 g, 80% yield). .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 4.07-3.93 (m, 1H), 3.92-3.80 (m, 1H), 3.62
(dd, J=10.3, 7.8 Hz, 1H), 1.46 (s, 9H), 0.87 (s, 9H).
##STR00908##
Intermediate A117C: tert-Butyl
7-(tert-butyl)-3-carbamoyl-2-(3-chloro-4-fluorophenyl)-6,7-dihydropyrazol-
o[1,5-a]pyrazine-5(4H)-carboxylate
##STR00909##
[1450] Intermediate A117C was prepared using an analogous synthetic
strategy to that employed for the preparation of Intermediate A1N
(outlined in Scheme 57). Intermediate A117B was used in
substitution for Intermediate A1B in the initial Mitsunobu coupling
reaction. MS(ES) m/z=451 [M+H].sup.+.
Compounds A117 and A118:
N.sup.5-7-Di-tert-butyl-2-(3-chloro-4-fluorophenyl)-6,7-dihydropyrazolo[1-
,5-a]pyrazine-3,5(4H)-dicarboxamide
##STR00910##
[1452] To a solution of Intermediate A117C (0.305 g, 0.676 mmol)
DCM (20 mL) was added TFA (0.313 mL, 4.06 mmol) and the resulting
solution was allowed to stir at RT for 18 h. The reaction was then
concentrated under reduced pressure and the afforded crude bis TFA
salt Intermediate A117D (0.314 g, >98% yield) used in the
subsequent reaction with no purification. To a solution of
Intermediate A117D (0.05 g, 0.713 mmol) in DMF (2 mL) at RT under
nitrogen was added DIPEA (0.124 mL, 0.713 mmol) and
2-isocyanato-2-methylpropane (0.041 g, 0.413 mmol). The reaction
mixture was stirred for 1 h. The reaction mixture was filtered and
concentrated. The crude material was purified via preparative HPLC.
Fractions containing the desired product were combined and dried
via centrifugal evaporation to obtain the racemic product. The
compound was further purified through chiral separation using
preparative SFC: CHIRALPAK.RTM. AD, 30.times.250 mm, 5 .mu.m column
eluted with 10% EtOH in CO.sub.2 at 70 mL/min and 150 bar,
monitored by UV at 254 nm. The first eluting enantiomer, rt=9.3
min: (R)-A117 and the second eluting enantiomer, rt=11.2 min:
(S)-A118 were thus separated. MS(ES) m/z=450 [M+H].sup.+; Ret.
time=1.98 and 2.86 min. (Methods H and I respectively). .sup.1H NMR
(500 MHz, DMSO-d.sub.6) .delta. 7.86 (d, J=7.3 Hz, 1H), 7.77-7.63
(m, 6H), 5.19-4.72 (m, 2H), 4.60 (d, J=13.9 Hz, 1H), 4.18 (br. s.,
1H), 3.42 (s, 1H), 1.02 (s, 9H).
##STR00911##
Intermediate A119A: tert-Butyl
3-carbamoyl-2-(3-chloro-4-fluorophenyl)-7-isopropyl-6,7-dihydropyrazolo[1-
,5-a]pyrazine-5(4H)-carboxylate
##STR00912##
[1454] Intermediate A119A was prepared using an analogous synthetic
strategy to that employed for the preparation of Intermediate
A117C. An analogous amino alcohol to Intermediate A117B was
prepared commencing with 2-(iso-propyl)oxirane and used in
substitution for Intermediate A1B in the initial Mitsunobu coupling
reaction. MS(ES) m/z=437 [M+H].sup.+.
Compounds A119 and A120:
N.sup.5-(tert-Butyl)-2-(3-chloro-4-fluorophenyl)-7-isopropyl-6,7-dihydrop-
yrazolo[1,5-a]pyrazine-3,5(4H)-dicarboxamide
##STR00913##
[1456] Compounds A119 and A120 were prepared analogously to
Compounds A117 and A118 using Intermediate A119A. The racemic
compound obtained from preparative HPLC was further purified
through chiral separation using preparative HPLC: CHIRALPAK.RTM.
AD, 21.times.250 mm, 10 .mu.m column eluted with 80% heptane with
0.1% diethylamine: 20% EtOH at 15 mL/min The first eluting
enantiomer, rt=8.4 min: (R)-A119 and the second eluting enantiomer,
rt=15.5 min: (S)-A120 were thus separated. MS(ES) m/z=436
[M+H].sup.+; Ret. time=1.77 and 2.79 min. (Methods H and I
respectively). .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. ppm 7.85
(1H, d, J=6.60 Hz), 7.66-7.72 (1H, m), 7.41-7.49 (1H, m), 7.15-7.38
(2H, m), 6.08-6.21 (1H, m), 4.62-4.77 (2H, m), 4.08 (1H, d, J=4.77
Hz), 3.85-3.97 (1H, m), 3.61 (1H, dd, J=13.76, 3.85 Hz), 3.28-3.37
(1H, m), 2.29-2.43 (1H, m), 1.21-1.32 (9H, m), 0.99 (3H, d, J=6.97
Hz), 0.85 (3H, d, J=6.97 Hz).
##STR00914##
Compounds A121 and A122:
7-(tert-Butyl)-2-(3-chloro-4-fluorophenyl)-N5-(3,3-difluorocyclobutyl)-6,-
7-dihydropyrazolo[1,5-a]pyrazine-3,5(4H)-dicarboxamide
##STR00915##
[1458] To an ice-cooled stirred solution of triphosgene (0.023 g,
0.078 mmol) in THF (3 mL) was added a solution of
3,3-difluorocyclobutanamine, HCl (0.030 g, 0.208 mmol) and TEA
(0.085 mL, 0.607 mmol) in THF (3 mL) and DMF (0.5 mL). The reaction
mixture was stirred for 10 min. prior to the addition of a solution
of Intermediate A117D (0.035 g, 0.104 mmol) and TEA (0.085 mL,
0.607 mmol) in DMF (1.5 mL). The reaction mixture was allowed to
warm to RT and stir overnight. It was concentrated and the crude
material was purified via preparative HPLC. Fractions containing
the desired product were combined and dried via centrifugal
evaporation to obtain the racemic compound which was further
purified through chiral separation using preparative HPLC:
CHIRALPAK.RTM. AD, 21.times.250 mm, 10 .mu.m column eluted with 80%
heptane with 0.1% diethylamine: 20% EtOH at 15 mL/min The first
eluting enantiomer, rt=11.5 min: (R)-A121 and the second eluting
enantiomer, rt=21.9 min: (S)-A122 were thus separated. MS(ES)
m/z=484 [M+H].sup.+; Ret. time=1.81 and 2.80 min. (Methods H and I
respectively); .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. ppm 7.84
(1H, dd, J=6.97, 1.83 Hz), 7.62-7.72 (1H, m), 7.47 (1H, t, J=9.17
Hz), 7.22-7.43 (2H, m), 7.17 (1H, d, J=6.60 Hz), 4.86 (1H, d,
J=17.24 Hz), 4.59 (1H, d, J=17.24 Hz), 4.49 (1H, d, J=14.30 Hz),
3.97-4.11 (2H, m), 3.28 (1H, dd, J=14.12, 3.85 Hz), 2.76-2.90 (3H,
m), 2.57-2.70 (2H, m), 0.98 (9H, s).
##STR00916##
Compounds A123 and A124:
2-(3-Chloro-4-fluorophenyl)-N.sup.5-(3,3-difluorocyclobutyl)-7-isopropyl--
6,7-dihydropyrazolo[1,5-a]pyrazine-3,5(4H)-dicarboxamide
##STR00917##
[1460] Compounds A123 and A124 were prepared analogously to
Compounds A121 and A122 using Intermediate A119B. The racemic
compound obtained from preparative HPLC was further purified
through chiral separation using preparative HPLC: CHIRALPAK.RTM.
AD, 21.times.250 mm, 10 .mu.m column eluted with 80% heptane with
0.1% diethylamine: 20% EtOH at 15 mL/min The first eluting
enantiomer, rt=11.5 min: (R)-A123 and the second eluting
enantiomer, rt=21.9 min: (S)-A124 were thus separated. MS(ES)
m/z=484 [M+H].sup.+; Ret. time=1.61 and 2.69 min. (Methods H and I
respectively). .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. ppm 7.84
(1H, d, J=6.97 Hz), 7.64-7.71 (1H, m), 7.47 (1H, t, J=9.17 Hz),
7.23-7.41 (3H, m), 4.68-4.83 (2H, m), 4.11 (1H, d, J=4.77 Hz),
3.96-4.07 (2H, m), 3.64 (1H, dd, J=13.75, 3.48 Hz), 2.59-2.72 (2H,
m), 2.35 (1H, dd, J=13.39, 6.42 Hz), 0.95-1.02 (3H, m), 0.85 (3H,
d, J=6.60 Hz).
##STR00918## ##STR00919## ##STR00920## ##STR00921##
Intermediate A125:
1,1,1-Trifluoro-3-((4-methoxybenzyl)amino)propan-2-ol
##STR00922##
[1462] To a solution of 2-(trifluoromethyl)oxirane (2.00 g, 17.8
mmol) in iso-propanol (20 mL) in a pressure tube was added
(4-methoxyphenyl)methanamine (7.35 g, 53.5 mmol). The reaction
vessel was capped and heated at 80.degree. C. for 3 h. The reaction
mixture was concentrated and purified by silica gel chromatography
(80 g REDISEP.RTM. column, eluting with a gradient from 0-60% EtOAc
in hexanes). The required fractions were concentrated to obtain
Intermediate A125A (3.1 g, 70.6% yield) as a white solid. MS(ES)
m/z=287 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
7.29-7.17 (m, 2H), 6.87 (d, J=8.5 Hz, 2H), 6.25 (br. s., 1H), 4.04
(td, J=7.8, 3.3 Hz, 1H), 3.72 (s, 3H), 3.66 (d, J=1.8 Hz, 2H),
2.74-2.55 (m, 2H), 2.08 (br. s., 1H).
Intermediate A125B:
3-(3-Chloro-4-fluorophenyl)-1H-pyrazole-5-carboxylic acid
##STR00923##
[1464] To a solution of Intermediate A96E (5.0 g, 18.6 mmol) in
EtOH (10 mL) and THF (20 mL) at RT was added a solution of LiOH
(5.35 g, 223 mmol) in water (6.67 mL). The reaction mixture was
stirred at RT overnight. The reaction mixture was concentrated and
the resulting residue was dissolved in water (200 mL) and extracted
with ether. The organic layer was separated and the aqueous layer
was acidified to a pH of 2 using a conc. aq. solution of HCl. The
aqueous layer was extracted with EtOAc (3.times.200 mL). The
combined organic layers were washed with brine, dried (MgSO.sub.4)
and concentrated to obtain Intermediate A125B (3.02 g, 67.4%
yield). Product was used as such without further purification.
MS(ES) m/z=241 [M+H].sup.+.
Intermediate A125C:
3-(3-Chloro-4-fluorophenyl)-N-(4-methoxybenzyl)-N-(3,3,3-trifluoro-2-hydr-
oxypropyl)-1H-pyrazole-5-carboxamide
##STR00924##
[1466] To a solution of Intermediate A125B (0.8 g, 3.32 mmol) in
1,4-dioxane heated at 50.degree. C. was added CDI (0.593 g, 3.66
mmol). The reaction was heated for 30 min, and Intermediate A125A
(0.911 g, 3.66 mmol) was added. The reaction mixture was allowed to
stir for an additional 30 min. at 50.degree. C. The reaction
mixture was diluted with water once cooled to RT and was extracted
with EtOAc (3.times.100 mL). The combined organic layers were
washed with brine, dried (MgSO.sub.4), and concentrated. The
residue was purified by silica gel chromatography (80 g
REDISEP.RTM. column, eluting with a gradient from 0-30% EtOAc in
hexanes). Fractions containing the product were combined and
concentrated to afford Intermediate A125C (1.015 g, 64.7% yield).
MS(ES) m/z=472 [M+H].sup.+.
Intermediate A125D:
2-(3-Chloro-4-fluorophenyl)-5-(4-methoxybenzyl)-7-(trifluoromethyl)-6,7-d-
ihydropyrazolo[1,5-a]pyrazin-4(5H)-one
##STR00925##
[1468] To an ice-cold stirred solution of triphenylphosphine (0.733
g, 2.80 mmol) in THF (30 mL) was added DIAD (0.544 mL, 2.80 mmol)
resulting in a thick milky yellow solution. After 10 min. a
solution of Intermediate A125C (1.015 g, 2.151 mmol) in THF (5.0
mL) was added. The reaction was then allowed to warm to RT and stir
overnight. The reaction mixture was diluted with EtOAc (200 mL) and
washed with brine, dried (MgSO.sub.4) and concentrated in vacuo.
The crude yellow oil was purified by silica gel chromatography (80
g REDISEP.RTM. column, eluting with a gradient from 0-40% EtOAc in
hexanes). Fractions containing the product were combined and
concentrated to afford Intermediate A125D (0.614 g, 62.8% yield).
MS(ES) m/z=454 [M+H].sup.+. .sup.1H NMR (400 MHz, chloroform-d)
.delta. 7.88 (dd, J=7.0, 2.0 Hz, 1H), 7.66 (ddd, J=8.6, 4.6, 2.1
Hz, 1H), 7.31-7.14 (m, 4H), 6.94-6.85 (m, 2H), 5.01-4.89 (m, 1H),
4.72 (s, 2H), 4.06-3.96 (m, 1H), 3.85-3.74 (m, 4H).
Intermediate A125E:
2-(3-Chloro-4-fluorophenyl)-7-(trifluoromethyl)-6,7-dihydropyrazolo[1,5-a-
]pyrazin-4(5H)-one
##STR00926##
[1470] To a solution of Intermediate A125D (0.405 g, 0.892 mmol) in
acetonitrile (5 mL) and water (0.556 mL) at RT was added CAN (1.957
g, 3.57 mmol). The reaction mixture was allowed to stir at RT for
24 h. The reaction mixture was concentrated, the residue was
dissolved in methanol and purified by reverse phase preparative
HPLC using 30.times.100 mm XTERRA.RTM. column and 30-100% B, 18
minute gradient, 20 minute run. (Solvent A: 90% water, 10%
methanol, 0.1% TFA: Solvent B: 10% water, 90% methanol, 0.1% TFA).
Required fractions were concentrated to obtain Intermediate A125E
(0.1 g, 34% yield). MS(ES) m/z=334 [M+H].sup.+.
Intermediate A125F:
2-(3-Chloro-4-fluorophenyl)-7-(trifluoromethyl)-4,5,6,7-tetrahydropyrazol-
o[1,5-a]pyrazine
##STR00927##
[1472] To a solution of Intermediate A125E (0.1 g, 0.300 mmol) in
anhydrous THF (10 mL) at 0.degree. C. under nitrogen was added a
solution of LiAlH.sub.4 (0.180 mL, 0.360 mmol, 2M in THF). The
reaction mixture was allowed to warm to RT and stir for 4 hours.
The reaction mixture was cooled to 0.degree. C. and an additional
equivalent of LAH was added and the solution was warmed to RT and
stirred for 5 h. The reaction mixture was again cooled to 0.degree.
C. and quenched by slow addition of a saturated aq. solution of
Rochelle's salt. The solution was then extracted with EtOAc
(3.times.) and the combined organic layers were washed with brine,
dried (MgSO.sub.4) and concentrated. The crude residue was purified
by silica gel chromatography (24 g REDISEP.RTM. column, eluting
with a gradient from 0-80% EtOAc in hexanes). Fractions containing
the product were combined and concentrated to afford Intermediate
A125F (0.06 g, 63% yield, contaminated with 15% of the des-chloro
byproduct). MS(ES) m/z=320 [M+H].sup.+.
Intermediate A125G: tert-Butyl
2-(3-chloro-4-fluorophenyl)-7-(trifluoromethyl)-6,7-dihydropyrazolo[1,5-a-
]pyrazine-5(4H)-carboxylate
##STR00928##
[1474] To a solution of Intermediate A125F (0.06 g, 0.188 mmol) in
DCM (10 mL) was added TEA (0.065 mL, 0.469 mmol), DMAP (1.146 mg,
9.38 .mu.mol) and Boc.sub.2O (0.061 g, 0.282 mmol). The reaction
mixture was stirred overnight at RT. The reaction mixture was
diluted with EtOAc (300 mL) and washed with brine, dried
(MgSO.sub.4) and concentrated. The crude product was purified by
silica gel chromatography using (24 g REDISEP.RTM. column, eluting
with a gradient from 0-30% EtOAc in hexanes). Fractions containing
the product were combined and concentrated to afford Intermediate
A125G (0.055 g, 70% yield). MS(ES) m/z=420 [M+H].sup.+.
Intermediate A125H: tert-Butyl
2-(3-chloro-4-fluorophenyl)-3-iodo-7-(trifluoromethyl)-6,7-dihydropyrazol-
o[1,5-a]pyrazine-5(4H)-carboxylate
##STR00929##
[1476] To a solution of Intermediate A125G (0.055 g, 0.131 mmol) in
a 4:1 mixture of CH.sub.2Cl.sub.2 (10 mL) and MeOH (2.5 mL) was
added NIS (0.088 g, 0.393 mmol). The reaction mixture was stirred
at RT. After 90 min., another equivalent of NIS was added and the
resulting solution was stirred overnight at RT. The reaction
mixture was concentrated in vacuo affording the crude product as a
red oil. The product was purified by silica gel chromatography
using (24 g REDISEP.RTM. column, eluting with a gradient from 0-30%
EtOAc in hexanes). Fractions containing the product were combined
and concentrated to afford Intermediate A125H (0.059 g, 83% yield).
MS(ES) m/z=546 [M+H].sup.+.
Intermediate A125I: tert-Butyl
2-(3-chloro-4-fluorophenyl)-3-cyano-7-(trifluoromethyl)-6,7-dihydropyrazo-
lo[1,5-a]pyrazine-5(4H)-carboxylate
##STR00930##
[1478] To a solution of Intermediate A125H (0.115 g, 0.245 mmol) in
DMF (20 mL) was added CuCN (0.055 g, 0.613 mmol). The reaction
mixture was heated in a sealed tube to 120.degree. C. for 16 h. The
reaction mixture was filtered through a pad of CELITE.RTM., the
filter cake washed with EtOAc and the combined filtrate was
concentrated under reduced pressure. The crude product was purified
by silica gel chromatography (24 g REDISEP.RTM. column, eluting
with a gradient from 0-40% EtOAc in hexanes). Fractions containing
the product were combined and concentrated to afford Intermediate
A125I (0.075 g, 83% yield). MS(ES) m/z=369 [M+H].sup.+.
Intermediate A125J: tert-Butyl
3-carbamoyl-2-(3-chloro-4-fluorophenyl)-7-(trifluoromethyl)-6,7-dihydropy-
razolo[1,5-a]pyrazine-5(4H)-carboxylate
##STR00931##
[1480] To a solution of Intermediate A125I (0.061 g, 0.137 mmol) in
EtOH (10 mL) at RT was added a 5M aq. solution of KOH (0.137 mL,
0.686 mmol). The reaction mixture was cooled to 0.degree. C. and
hydrogen peroxide (0.280 mL, 2.74 mmol, 30% w/v in H.sub.2O) was
added dropwise. The reaction mixture was allowed to warm to RT and
stir overnight. The reaction mixture was concentrated and residue
was diluted with EtOAc. The solution was washed with water, brine,
dried (MgSO.sub.4) and concentrated. The crude product was purified
by silica gel chromatography (24 g REDISEP.RTM. column, eluting
with a gradient from 0-20% MeOH in DCM). The required fractions
were concentrated to obtain Intermediate A125J (0.046 g, 72%
yield). MS(ES) m/z=463 [M+H].sup.+.
Intermediate A125K:
2-(3-Chloro-4-fluorophenyl)-7-(trifluoromethyl)-4,5,6,7-tetrahydropyrazol-
o[1,5-a]pyrazine-3-carboxamide, TFA
##STR00932##
[1482] To a solution of Intermediate A125J (0.141 g, 0.305 mmol) in
DCM (10 mL) was added TFA (0.141 mL, 1.828 mmol). The reaction
mixture was stirred overnight at RT. The reaction mixture was
concentrated to obtain crude Intermediate A125K (0.145 g, 0.304
mmol, 100% yield) as the TFA salt. The product was used as such
without further purification. Yield was assumed to be quantitative.
MS(ES) m/z=363 [M+H].sup.+.
Compounds A125 and A126:
2-(3-Chloro-4-fluorophenyl)-N.sup.5-(3,3-difluorocyclobutyl)-7-(trifluoro-
methyl)-6,7-dihydropyrazolo[1,5-a]pyrazine-3,5(4H)-dicarboxamide
##STR00933##
[1484] To a stirred ice-cooled suspension of triphosgene (0.034 g,
0.114 mmol) in THF (3 mL) was added a solution of
3,3-difluorocyclobutanamine HCl (0.044 g, 0.303 mmol) and TEA
(0.085 mL, 0.607 mmol) in THF (3 mL) and DMF (0.5 mL). The reaction
mixture was stirred for 10 min. prior to the introduction of a
solution of A125K (0.055 g, 0.152 mmol) and TEA (0.085 mL, 0.607
mmol) in DMF (1.5 mL). The reaction mixture was warmed to RT and
stirred overnight. The reaction mixture was concentrated and
purified via preparative HPLC. Fractions containing the desired
product were combined and concentrated to obtain the product as a
racemate, purified via preparative HPLC. Fractions containing the
desired product were combined and dried via centrifugal evaporation
to obtain the racemic compound which was further purified through
chiral separation using preparative HPLC: CHIRALPAK.RTM. AD,
21.times.250 mm, 10 .mu.m column eluted with 80% heptane with 0.1%
diethylamine: 20% EtOH at 15 mL/min The first eluting enantiomer,
r.sub.t=22.1 min: (S)-A125 and the second eluting enantiomer,
r.sub.t=25.2 min: (R)-A126 were thus separated. MS(ES) m/z=496
[M+H].sup.+; Ret. time=1.66 and 2.35 min. (Methods H and I
respectively); .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 7.84 (d,
J=7.0 Hz, 1H), 7.69 (br. s., 1H), 7.33 (d, J=6.2 Hz, 1H), 5.44 (br.
s., 1H), 5.12 (d, J=17.2 Hz, 1H), 4.78-4.47 (m, 2H), 4.12-3.96 (m,
1H), 3.60 (d, J=15.0 Hz, 1H), 2.93-2.80 (m, 2H), 2.71-2.55 (m,
2H).
##STR00934##
Compounds A127 and A128:
N.sup.5-(tert-Butyl)-2-(3-chloro-4-fluorophenyl)-7-(trifluoromethyl)-6,7--
dihydropyrazolo[1,5-a]pyrazine-3,5(4H)-dicarboxamide
##STR00935##
[1486] To a solution of A125K (0.055 g, 0.152 mmol) in DMF (2 mL)
at RT under nitrogen was added DIPEA (0.132 mL, 0.758 mmol) and
2-isocyanato-2-methylpropane (0.030 g, 0.303 mmol). The reaction
mixture was stirred for 1 h and then filtered and concentrated. The
crude material was purified via preparative HPLC. Fractions
containing the desired product were combined and dried via
centrifugal evaporation to obtain the racemic compound which was
further purified through chiral separation using preparative HPLC:
CHIRALPAK.RTM. AD, 21.times.250 mm, 10 .mu.m column eluted with 80%
heptane with 0.1% diethylamine: 20% EtOH at 15 mL/min The first
eluting enantiomer, rt=15.2 min: (S)-A127 and the second eluting
enantiomer, r.sub.t=18.4 min: (R)-A128 were thus separated. MS(ES)
m/z=462 [M+H].sup.+; HPLC Ret. Time=1.71 and 3.02 min. (Methods H
and I respectively). .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta.
7.85 (d, J=7.3 Hz, 1H), 7.69 (br. s., 1H), 7.41 (br. s., 1H), 5.37
(br. s., 1H), 5.18 (d, J=17.2 Hz, 1H), 4.72 (d, J=14.7 Hz, 1H),
4.48 (d, J=17.2 Hz, 1H), 3.54 (d, J=15.4 Hz, 1H), 1.28 (s, 9H).
##STR00936## ##STR00937## ##STR00938##
Intermediate A129A: tert-Butyl
4-(3-chlorophenyl)-2,4-dioxobutanoate
##STR00939##
[1488] Under an atmosphere of nitrogen, a solution of
3'-chloroacetophenone (1.015 mL, 7.82 mmol) in anhydrous diethyl
ether (50 mL) was allowed to cool to -78.degree. C. for 15 minutes
prior to the slow addition of a 1.0 M solution of LHMDS (8.60 mL,
8.60 mmol) in THF. The enolate formation was allowed to stir for 45
minutes at -78.degree. C., after which di-tert-butyl oxalate (1.898
g, 9.38 mmol) was added as a single portion. The pale yellow
reaction mixture was allowed to warm to RT and stir for 18 hours.
The dark-green solution was then quenched with 50 mL of a 1.0 M aq.
solution of HCl. The two layers were separated and the aq. layer
was extracted twice more with EtOAc. The combined organic layers
were washed with brine, dried over anhydrous MgSO.sub.4, filtered
and the filtrate concentrated under reduced pressure to afford an
orange oil. The crude reaction mixture was purified by silica gel
chromatography (40 g REDISEP.RTM. column, eluting with a gradient
from 100% hexanes to 80:20 hexanes:EtOAc solution). Fractions
containing the product were combined and evaporated to afford
Intermediate A129A (2.17 g, 98%) as a yellow solid. .sup.1H NMR
(400 MHz, chloroform-d) .delta. ppm 7.94-7.99 (1H, m), 7.86 (1H,
dt, J=7.78, 1.38 Hz), 7.58 (1H, ddd, J=7.97, 2.20, 1.13 Hz),
7.43-7.49 (1H, m), 6.94-6.99 (1H, m), 1.58-1.63 (9H, m).
Intermediate A129B: tert-Butyl
3-(3-chlorophenyl)-1H-pyrazole-5-carboxylate
##STR00940##
[1490] To a solution of Intermediate A129A (2.17 g, 7.68 mmol) in
ethanol (80 mL) was added hydrazine hydrate (0.471 mL, 7.68 mmol,
80% wt). The solution was allowed to stir for 18 h at RT. There was
little conversion to the desired pyrazole so at this point acetic
acid (5 mL) was added and the reaction mixture was heated to
60.degree. C. for 24 h. The reaction mixture was diluted with EtOAc
(100 mL) and quenched by the addition of a saturated aq. solution
of NaHCO.sub.3. The organic layer was separated and washed with
brine (2.times.100 mL). The organic layer was dried over sodium
sulfate and concentrated in vacuo. The crude reaction mixture was
purified by silica gel chromatography (80 g REDISEP.RTM. column,
eluting with a gradient of 0-60% EtOAc in hexanes). Fractions
containing the product were combined and evaporated to afford
Intermediate A129B (1.82 g, 83%) as a yellow crystalline solid.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 13.70-14.15 (1H,
m), 7.93 (1H, t, J=1.76 Hz), 7.83 (1H, d, J=7.28 Hz), 7.22-7.53
(3H, m), 1.51-1.59 (9H, m).
Intermediate A129C: tert-Butyl
3-(3-chlorophenyl)-1-(cyanomethyl)-1H-pyrazole-5-carboxylate
##STR00941##
[1492] To a flask charged with an ice-cooled solution of
Intermediate A129B (1.82 g, 6.53 mmol) in DMF (15 mL) is added a
2.0 M solution of NHMDS in THF (3.43 mL, 6.86 mmol) dropwise. The
reaction mixture is allowed to stir for 5 minutes and the ice bath
was subsequently removed, chloroacetonitrile (0.456 mL, 7.19 mmol),
which had been freshly passed through a column of CELITE.RTM. and
sodium bicarbonate, was added to the reaction mixture. The reaction
was allowed to warm to 22.degree. C. and stir for an additional 18
h. The reaction was quenched by the addition of 1.0 mL of a
saturated aqueous solution of ammonium chloride. The reaction was
diluted with equal parts water and EtOAc and the resulting mixture
was allowed to stir vigorously for 15 min. The organic layer was
separated, dried over sodium sulfate, and concentrated in vacuo to
afford an orange solid. The crude reaction mixture was purified by
silica gel chromatography (80 g REDISEP.RTM. column, eluting with a
gradient of 0-50% EtOAc in hexanes). Fractions containing the
product were combined and evaporated to afford Intermediate A129C
(1.87 g, 90%) as a white solid. MS(ES): m/z=261.91
[M+H.sub.2O-OtBu].sup.+. .sup.1H NMR (400 MHz, chloroform-d)
.delta. ppm 7.78-7.83 (1H, m), 7.66-7.73 (1H, m), 7.31-7.40 (2H,
m), 7.08-7.15 (1H, m), 5.50-5.60 (2H, m), 1.59-1.69 (9H, m).
Intermediate A129D: tert-Butyl
3-(3-chlorophenyl)-1-(1-cyanocyclopropyl)-1H-pyrazole-5-carboxylate
##STR00942##
[1494] To an ice-cooled solution of Intermediate A129C (1.87 g,
5.88 mmol) and 1-bromo-2-chloroethane (0.844 mL, 7.36 mmol) in DMF
(20 mL) was added sodium hydride (0.588 g, 14.71 mmol) (60%
dispersion in mineral oil) portionwise. The orange cloudy solution
was allowed to slowly warm to RT over several hours. The reaction
was allowed to stir at RT for 16 h prior to quenching with the
addition of 10 mL of a saturated aq. solution of NH.sub.4Cl. The
mixture was then partitioned in equal parts water and EtOAc (250 mL
each) by vigorous stirring for 15 minutes. The organic layer was
separated, washed with brine, dried over sodium sulfate, and
concentrated in vacuo to afford an orange oil. The crude reaction
mixture was purified by silica gel chromatography (80 g
REDISEP.RTM. column eluting with a gradient of 0-50% EtOAc in
hexanes). Fractions containing the product were combined and
evaporated to afford Intermediate A129D (1.02 g, 50%) as a white
solid. MS(ES): m/z=287.96 [M+H.sub.2O-OtBu].sup.+. .sup.1H NMR (400
MHz, chloroform-d) .delta. ppm 7.78-7.82 (1H, m), 7.64-7.68 (1H,
m), 7.33-7.37 (2H, m), 7.11 (1H, s), 1.67 (9H, s), 1.64 (2H, s),
1.54-1.58 (2H, m).
Intermediate A129E: tert-Butyl
1-(1-(aminomethyl)cyclopropyl)-3-(3-chlorophenyl)-1H-pyrazole-5-carboxyla-
te
##STR00943##
[1496] To a solution of Intermediate A129D (0.211 g, 0.613 mmol) in
MeOH (15 mL) was added cobalt(II) chloride (0.239 g, 1.838 mmol).
The bright purple solution was allowed to cool to 0.degree. C.
prior to the slow and careful addition of sodium borohydride (0.232
g, 6.13 mmol). After stirring at 0.degree. C. for 10 minutes, the
reaction mixture was warmed to 50.degree. C. After stirring for two
h, the reaction was allowed to cool to RT and the heterogeneous
mixture is plugged through a fritted glass funnel packed with a
short pad of CELITE.RTM.. The filtrate was diluted with EtOAc and
100 mL of a 1.0 M solution of HCl. The acidic aqueous solution
dissolved all of the cobalt salts (color change from dark brown to
light pink). The pH of the aqueous layer was adjusted to pH=7 with
a 1.0 M aq. solution of NaOH. The organic layer was then separated
and the aqueous phase was extracted 3 times with EtOAc. The
combined organic phases were washed with a brine solution, dried
over sodium sulfate, and concentrated under vacuum to afford a
colorless oil, crude Intermediate A129E (0.213 g, 100%) as a white
foam. MS(ES): m/z=273.9 [M+H.sub.2O-OtBu].sup.+. .sup.1H NMR (400
MHz, chloroform-d) .delta. ppm 7.74-7.85 (1H, m), 7.59-7.69 (1H,
m), 7.21-7.34 (1H, m), 6.98-7.06 (1H, m), 3.06 (2H, s), 1.54-1.63
(9H, m), 1.29-1.42 (4H, m), 1.08-1.16 (2H, m).
Intermediate A129F:
2'-(3-Chlorophenyl)-5',6'-dihydro-4'H-spiro[cyclopropane-1,7'-pyrazolo[1,-
5-a]pyrazin]-4'-one
##STR00944##
[1498] To a solution of Intermediate A129E (0.213 g, 0.612 mmol) in
EtOH (5.0 mL) was added ammonium hydroxide (0.954 mL, 24.5 mmol, 40
wt %). The dark solution was allowed to stir at RT for 18 h. The
crude reaction mixture was concentrated under reduced pressure and
diluted with EtOAc. The aqueous solution was neutralized to pH=7
using a 1.0 M aq. solution of HCl. The organic layer was separated
and the aqueous layer was extracted twice more with EtOAc. The
combined organic layers was then washed with brine, dried over
sodium sulfate, and concentrated to afford Intermediate A129F
(0.118 g, 69%) as a white solid. MS(ES): m/z=273.9 [M+H].sup.+.
.sup.1H NMR (400 MHz, chloroform-d) .delta. ppm 7.80-7.84 (1H, m),
7.65 (1H, dt, J=7.34, 1.47 Hz), 7.28-7.37 (2H, m), 7.15-7.19 (1H,
m), 6.59 (1H, br. s.), 3.68-3.74 (2H, m), 1.71-1.77 (2H, m),
1.08-1.15 (2H, m).
Intermediate A129G:
2'-(3-Chlorophenyl)-5',6'-dihydro-4'H-spiro[cyclopropane-1,7'-pyrazolo[1,-
5-a]pyrazine]
##STR00945##
[1500] A solution of Intermediate A129F (0.166 g, 0.606 mmol) in
anhydrous THF (6.1 mL) placed under an atmosphere of N.sub.2 was
allowed to cool to -5.degree. C. A 1.0 M solution of LAH (1.456 mL,
1.456 mmol) in THF was added dropwise. The ice bath was removed
once the bubbling had subsided. The reaction was then allowed to
warm to RT and stir for an additional 18 h. The reaction mixture
was cooled to 0.degree. C. and carefully quenched with the
sequential addition of 1.5 mL of H.sub.2O, 1.5 mL of a 15% aq.
solution of NaOH, and 4.5 mL of H.sub.2O. The cooling bath was
removed and the biphasic mixture was allowed to stir at RT for 30
min. Anhydrous MgSO.sub.4 was added to the mixture and was stirred
for 15 min. The reaction mixture was then filtered through pad of
CELITE.RTM.. The filtrate was washed twice with DCM (2.times.20
mL). The organic layer of the filtrate was separated, the aqueous
layer was extracted with 2.times.50 mL of DCM. The combined organic
layers were washed with brine, dried over sodium sulfate, and
concentrated in vacuo to provide a pale green oil. The crude
reaction mixture was purified by silica gel chromatography (40 g
REDISEP.RTM. column, eluting with a gradient from 50-100% EtOAc in
hexanes). Fractions containing the product were combined and
evaporated to afford Intermediate A129G (0.115 g, 73%) as a white
solid. MS(ES): m/z=260.0 [M+H].sup.+.
Intermediate A129H: tert-Butyl
2'-(3-chlorophenyl)-4'H-spiro[cyclopropane-1,7'-pyrazolo[1,5-a]pyrazine]--
5'(6'H)-carboxylate
##STR00946##
[1502] To a 20 mL reaction vial, charged with a solution of
Intermediate A129G (0.175 g, 0.674 mmol) in DCM (4 mL) was added
triethylamine (0.376 mL, 2.70 mmol) and DMAP (4.12 mg, 0.034 mmol).
To the resulting homogeneous solution was added di-tert-butyl
dicarbonate (221 mg, 1.011 mmol). After stirring at RT for 16 h,
the reaction was quenched by the addition of 20 mL of a saturated
aq. solution of NaHCO.sub.3. The layers were separated, and the
aqueous layer was washed twice more with DCM. The combined organic
layers were washed with water, followed by brine, dried over sodium
sulfate, and concentrated in vacuo. The crude reaction mixture was
purified by silica gel chromatography (40 g REDISEP.RTM. column,
eluting with a gradient from 0 to 40% EtOAc in hexanes). Fractions
containing the product were combined and evaporated to afford
Intermediate A129H (0.240 g, 99%) as a colorless oil. MS(ES):
m/z=360.08 [M+H].sup.+. .sup.1H NMR (400 MHz, chloroform-d) .delta.
ppm 7.75 (1H, t, J=1.76 Hz), 7.61 (1H, d, J=7.53 Hz), 7.21-7.34
(2H, m), 6.35 (1H, s), 4.80 (2H, br. s.), 3.81 (2H, s), 1.63-1.69
(2H, m), 1.50-1.54 (9H, m), 0.95-1.08 (2H, m).
Intermediate A129I: tert-Butyl
2'-(3-chlorophenyl)-3'-iodo-4'H-spiro[cyclopropane-1,7'-pyrazolo[1,5-a]py-
razine]-5'(6'H)-carboxylate
##STR00947##
[1504] To a flask charged with a solution of Intermediate A129H
(241 mg, 0.670 mmol) in a 4:1 solution of DCM (5.4 mL) and MetOH
(1.4 mL), was added NIS (452 mg, 2.009 mmol) and the solution was
allowed to stir at 22.degree. C. After 1 h, the volatiles were
removed under reduced pressured and the red oil was purified by
silica gel chromatography (24 g REDISEP.RTM. column, eluting with a
gradient from 0-25% EtOAc in hexanes). Fractions containing the
product were combined and evaporated to afford Intermediate A129I
(0.270 g, 83%) as a white foam. MS(ES): m/z=485.8 [M+H].sup.+.
.sup.1H NMR (400 MHz, chloroform-d) .delta. ppm 7.78-7.82 (1H, m),
7.73 (1H, dt, J=6.59, 1.98 Hz), 7.32-7.37 (2H, m), 4.59-4.76 (2H,
m), 3.82 (2H, br. s.), 1.65 (2H, s), 1.52 (9H, s), 1.04 (2H, br.
s.).
Intermediate A129J: tert-Butyl
7'-(3-chlorophenyl)-8'-cyano-1'H-spiro[cyclopropane-1,4'-pyrrolo[1,2-a]py-
razine]-2'(3'H)-carboxylate
##STR00948##
[1506] To a flask charged with Intermediate A129I (267.4 mg, 0.550
mmol), was added Pd(Ph.sub.3P).sub.4 (63.6 mg, 0.055 mmol),
dicyanozinc (71.1 mg, 0.606 mmol), and zinc (7.20 mg, 0.110 mmol).
The flask was sealed with a septum and the contents were degassed
with N.sub.2 for 5 min. DMF (2.4 mL) was added and the yellow
solution was degassed for an additional 5 min. The reaction mixture
was then allowed to heat to 80.degree. C. After 2 h, the reaction
mixture was diluted with equal parts water and EtOAc. The organic
layer was separated and the aqueous phase was extracted (3.times.50
mL) with EtOAc. The combined organic layers were washed with brine,
dried over sodium sulfate, and concentrated in vacuo. The crude
reaction mixture was purified by silica gel chromatography (40 g
REDISEP.RTM. column, eluting with a gradient from 25-60% EtOAc in
hexanes). Fractions containing the product were combined and
evaporated to afford Intermediate A129J (0.186 g, 86%) as a white
solid. MS(ES): m/z=385.0 [M+H].sup.+. .sup.1H NMR (400 MHz,
chloroform-d) .delta. ppm 7.89 (1H, d, J=1.00 Hz), 7.81-7.86 (1H,
m), 7.29-7.40 (2H, m), 4.92 (2H, br. s.), 3.84 (2H, s), 1.66-1.71
(2H, m), 1.52 (9H, s), 1.10 (2H, d, J=2.51 Hz).
Intermediate A129K: tert-Butyl
8'-carbamoyl-7'-(3-chlorophenyl)-1'H-spiro[cyclopropane-1,4'-pyrrolo[1,2--
a]pyrazine]-2'(3'H)-carboxylate
##STR00949##
[1508] To a solution of Intermediate A129J (0.145 g, 0.377 mmol) in
DMSO (2 mL) at RT was added dropwise a 5 M aq. solution of KOH
(0.38 mL, 1.884 mmol) followed by a 30 wt % solution of
H.sub.2O.sub.2 (0.77 mL, 0.754 mmol). The reaction was allowed to
stir at 22.degree. C. for 3 h after which the mixture was
partitioned between equal parts EtOAc and water. The organic phase
was separated and the aqueous layer was extracted twice more with
EtOAc. The combined organic layers were washed with brine, dried
over anhydrous MgSO.sub.4, filtered and the filtrate concentrated
under reduced pressure to afford a white solid. The crude reaction
mixture was purified by silica gel chromatography (40 g
REDISEP.RTM. column, eluting with a gradient from 75-100% EtOAc in
hexanes). Fractions containing the product were combined and
evaporated to afford Intermediate A129K (0.117 g, 42%) as a white
solid. MS(ES): m/z=403.08 [M+H].sup.+. .sup.1H NMR (400 MHz,
chloroform-d) .delta. ppm 8.67 (2H, br. s.), 7.35-7.58 (4H, m),
5.31-6.03 (2H, m), 4.96-5.15 (2H, m), 3.82 (2H, s), 1.59-1.69 (2H,
m), 1.42-1.57 (9H, m), 0.94-1.17 (2H, m).
##STR00950##
Compound A129:
N.sup.5-(tert-Butyl)-2'-(3-chlorophenyl)-4'H-spiro[cyclopropane-1,7'-pyra-
zolo[1,5-a]pyrazine]-3',5'(6'H)-dicarboxamide
##STR00951##
[1510] Compound A129 was synthesized analogous to Compound A106 by
reacting deprotected A129K with 2-isocyanato-2-methylpropane. The
product was purified by preparative HPLC (0.0202 g, 50%): MS(ES):
m/z=402.2 [M+H].sup.+; HPLC Ret. Time 1.73 min and 2.62 min.
(Methods H and I respectively); .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. ppm 7.66 (1H, s), 7.55-7.63 (1H, m), 7.12-7.46 (4H, m),
6.22 (1H, s), 4.78 (2H, s), 3.82 (2H, s), 1.38-1.46 (2H, m),
1.23-1.32 (9H, m), 1.03-1.10 (2H, m).
[1511] The Compound described in Table 56 was synthesized analogous
to Compound A129 by reacting deprotected Intermediate A129K with
the corresponding carboxylic acid.
TABLE-US-00058 TABLE 56 Ret. Ex. Time HPLC No. Structure Name [M +
H].sup.+ (min.) Method A130 ##STR00952## 2'-(3-
Chlorophenyl)-N.sup.5'- (3,3- difluorocyclobutyl)- 4'H-
spiro[cyclopropane- 1,7'-pyrazolo[1,5- a]pyrazine]- 3',5'(6'H)-
dicarboxamide 436.4 1.54 2.60 H I
##STR00953## ##STR00954## ##STR00955##
Intermediate A131A: Ethyl
1-(cyanomethyl)-3-(3-fluorophenyl)-1H-pyrazole-5-carboxylate
##STR00956##
[1513] To an ice-cooled solution of Intermediate 4B (7.0 g, 29.9
mmol) in DMF (45 mL), is added dropwise a solution of LHMDS (31.4
mL, 31.4 mmol, 1M in THF). The reaction mixture is allowed to stir
for 5 min. and the ice bath is subsequently removed.
2-Chloroacetonitrile (2.482 g, 32.9 mmol) was added to the reaction
mixture. The reaction was allowed to warm to RT and stir for 18 h.
The reaction was quenched by the addition of 1.0 mL of a satd. aq.
solution of NH.sub.4Cl. The reaction was diluted with equal parts
water and EtOAc and the resulting mixture was allowed to stir
vigorously for 15 min. The organic layer was separated, dried over
sodium sulfate, and concentrated in vacuo. The crude reaction
mixture was purified by silica gel chromatography (120 g
REDISEP.RTM. column, eluting with a gradient from 0-40% EtOAc in
hexanes). Fractions containing the product were combined and
concentrated to afford Intermediate A131A (6.15 g, 75%) as a white
solid. MS(ES) m/z=274 [M+H].sup.+.
Intermediate A131B: Ethyl
1-(1-cyanocyclopropyl)-3-(3-fluorophenyl)-1H-pyrazole-5-carboxylate
##STR00957##
[1515] To an ice-cooled solution of Intermediate A131A (3.75 g,
13.72 mmol) and 1-bromo-2-chloroethane (2.362 g, 16.47 mmol) in DMF
(40 mL) was added NaH (1.372 g, 34.3 mmol) (60% dispersion in
mineral oil) portionwise. The orange cloudy solution was allowed to
slowly warm to RT and stir for 16 h. The reaction mixture was
quenched by the addition of 10 mL of saturated aq. solution of
NH.sub.4Cl. The mixture was partitioned in a mixture of water and
EtOAc. The organic layer was separated, washed with brine, dried
over sodium sulfate, and concentrated in vacuo. The crude orange
oil was purified by silica gel chromatography (80 g REDISEP.RTM.
column, eluting with a gradient from 0-40% EtOAc in hexanes).
Fractions containing the product were combined and concentrated to
afford Intermediate A131B (0.51 g, 12%) as a yellow solid. MS(ES)
m/z=300 [M+H].sup.+.
Intermediate A131C:
2'-(3-Fluorophenyl)-5',6'-dihydro-4'H-spiro[cyclopropane-1,7'-pyrazolo[1,-
5-a]pyrazin]-4'-one
##STR00958##
[1517] To an ice-cooled solution of Intermediate A131B (0.4 g,
1.336 mmol) and cobalt(II) chloride (0.521 g, 4.01 mmol) in MeOH
(50 mL) was slowly added sodium borohydride (0.506 g, 13.36 mmol).
The solution instantly turned black with vigorous gas evolution.
The reaction was heated to 50.degree. C. for 2 h. The reaction
mixture was filtered through CELITE.RTM. and the filtrate was
concentrated. The crude reaction mixture was purified by silica gel
chromatography (24 g REDISEP.RTM. column, eluting with a gradient
from 0-40% EtOAc in hexanes). Fractions containing the product were
combined and evaporated to afford Intermediate A131C (0.16 g, 47%).
MS(ES) m/z=258 [M+H].sup.+.
Intermediate A131D:
2'-(3-Fluorophenyl)-5',6'-dihydro-4'H-spiro[cyclopropane-1,7'-pyrazolo[1,-
5-a]pyrazine]
##STR00959##
[1519] To a stirred solution of Intermediate A131C (0.16 g, 0.622
mmol) in THF (10 mL) under an inert atmosphere of nitrogen at
-10.degree. C. was added dropwise a 1.0 M solution of LiAlH.sub.4
(1.866 mL, 1.866 mmol) in THF. The reaction was allowed to slowly
reach RT. The reaction mixture was allowed to stir overnight at RT
and then heated at 50.degree. C. for 4 h. The reaction was quenched
by slow addition of a saturated solution of Rochelle's salt at
0.degree. C. The mixture was diluted with DCM, the organic layer
was separated, and the aqueous layer was extracted with DCM
(2.times.100 mL). The combined organic layers were washed with
brine, dried (MgSO.sub.4) and concentrated to obtain Intermediate
A131D (0.14 g, 0.575 mmol, 93% yield) as an off-white solid. The
product was used as such without further purification. MS(ES)
m/z=244 [M+H].sup.+.
Intermediate A131E: tert-Butyl
2'-(3-fluorophenyl)-4'H-spiro[cyclopropane-1,7'-pyrazolo[1,5-a]pyrazine]--
5'(6'H)-carboxylate
##STR00960##
[1521] To a solution of Intermediate A131D (0.14 g, 0.575 mmol) in
MeOH (5 mL) was added TEA (0.289 mL, 2.072 mmol) and di-tert-butyl
dicarbonate (0.188 g, 0.863 mmol). The solution was allowed to stir
overnight at RT. It was concentrated and purified by silica gel
chromatography (24 g REDISEP.RTM. column, eluting with a gradient
from 0-30% EtOAc in hexanes). Fractions containing the product were
combined and concentrated to afford Intermediate A131E (0.156 g,
79% yield). MS(ES) m/z=344 [M+H].sup.+.
Intermediate A131F: tert-Butyl
2'-(3-fluorophenyl)-3'-iodo-4'H-spiro[cyclopropane-1,7'-pyrazolo[1,5-a]py-
razine]-5'(6'H)-carboxylate
##STR00961##
[1523] To a solution of Intermediate A131E (0.156 g, 0.454 mmol) in
a 4:1 solution of CH.sub.2Cl.sub.2 (5 mL) and MeOH (1.25 mL) was
added NIS (0.307 g, 1.363 mmol) and the reaction mixture was
allowed to stir at RT. After stirring for 90 min, the solution was
concentrated in vacuo affording the crude product as red oil. The
product was purified by silica gel chromatography (24 g
REDISEP.RTM. column, eluting with a gradient from 0-30% EtOAc in
hexanes). Fractions containing the product were combined and
concentrated to afford Intermediate A131F (0.14 g, 66% yield).
MS(ES) m/z=470 [M+H].sup.+.
Intermediate A131G: tert-Butyl
3'-cyano-2'-(3-fluorophenyl)-4'H-spiro[cyclopropane-1,7'-pyrazolo[1,5-a]p-
yrazine]-5'(6'H)-carboxylate
##STR00962##
[1525] To a solution of Intermediate A131F (0.14 g, 0.298 mmol) in
DMF (10 mL) was added copper cyanide (0.067 g, 0.746 mmol). The
reaction mixture was heated in a sealed tube to 120.degree. C. for
16 h. The reaction mixture was cooled to RT and filtered. The
filter cake was washed with EtOAc and the combined filtrate was
concentrated. The residue was purified by silica gel chromatography
(24 g REDISEP.RTM. column, eluting with a gradient from 0-40% EtOAc
in hexanes). Fractions containing the product were combined and
concentrated to afford Intermediate A131G (0.091 g, 83% yield).
MS(ES) m/z=369 [M+H].sup.+.
Intermediate A131H: tert-Butyl
3'-carbamoyl-2'-(3-fluorophenyl)-4'H-spiro[cyclopropane-1,7'-pyrazolo[1,5-
-a]pyrazine]-5'(6'H)-carboxylate
##STR00963##
[1527] To a solution of Intermediate A131G (0.091 g, 0.247 mmol) in
EtOH (20 mL) at RT was added KOH (0.247 mL, 1.235 mmol). The
reaction mixture was cooled to 0.degree. C. prior to the dropwise
addition of hydrogen peroxide (0.505 mL, 4.94 mmol, 30 wt %). The
reaction mixture was allowed to warm to RT and stir overnight. The
reaction mixture was concentrated and the residue was dissolved in
EtOAc. The organic phase was washed with water, brine, dried
(MgSO.sub.4) and concentrated. The residue was purified by silica
gel chromatography (12 g REDISEP.RTM. column, eluting with a
gradient from 0-20% MeOH in DCM). The required fractions were
concentrated to obtain Intermediate A131H (0.075 g, 79% yield).
MS(ES) m/z=387 [M+H].sup.+.
[1528] Intermediate A131I:
2'-(3-Fluorophenyl)-5',6'-dihydro-4'H-spiro[cyclopropane-1,7'-pyrazolo[1,-
5-a]pyrazine]-3'-carboxamide, TFA
##STR00964##
[1529] To a solution of Intermediate A131H (0.085 g, 0.220 mmol) in
DCM (5 mL) at RT was added TFA (0.085 mL, 1.100 mmol) and the
mixture was stirred overnight. The reaction mixture was
concentrated to obtain the TFA salt of Intermediate A1311 (0.063 g,
0.220 mmol, 100% yield). The crude product was used as such without
further purification. Yield was assumed to be quantitative. MS(ES)
m/z=287 [M+H].sup.+.
Compound A131:
N.sup.5'-(tert-Butyl)-2'-(3-fluorophenyl)-4'H-spiro[cyclopropane-1,7'-pyr-
azolo[1,5-a]pyrazine]-3',5'(6'H)-dicarboxamide
##STR00965##
[1531] To a solution of Intermediate A1311 (0.085 g, 0.297 mmol) in
DMF (2 mL) at RT under nitrogen was added DIPEA (0.259 mL, 1.484
mmol) and 2-isocyanato-2-methylpropane (0.059 g, 0.594 mmol). The
reaction mixture was stirred for 1 h. The crude material was
purified via preparative HPLC. Fractions containing the desired
product were combined and evaporated to obtain Compound A131 (27.2
mg, 23.7% yield). MS(ES) m/z=386 [M+H].sup.+; Ret. time=1.58 and
2.46 min. (Methods H and I respectively); .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 7.54-7.29 (m, 2H), 7.23-7.10 (m, 1H), 6.23
(s, 1H), 5.45 (s, 1H), 4.79 (s, 1H), 3.83 (s, 1H), 3.37 (d, J=7.3
Hz, 3H), 1.46-1.36 (m, 1H), 1.28 (s, 5H), 1.19 (s, 4H), 1.11-1.00
(m, 1H).
[1532] The Compounds described in Table 57 were prepared following
the synthetic sequence outlined in Scheme 91 substituting
Intermediate 4B with Intermediate A96E.
TABLE-US-00059 TABLE 57 Ret. Ex. Time HPLC No. Structure Name [M +
H].sup.+ (min.) Method A132 ##STR00966## N.sup.5-(tert-Butyl)-2'-
(3-chloro-4- fluorophenyl)-4'H- spiro[cyclopropane-
1,7'-pyrazolo[1,5- a]pyrazine]- 3',5'(6'H)- dicarboxamide 420.3
1.68 2.70 H I A133 ##STR00967## 2'-(3-Chloro-4-
fluorophenyl)-N.sup.5'- (3,3- difluorocyclobutyl)- 4'H-
spiro[cyclopropane- 1,7'-pyrazolo[1,5- a]pyrazine]- 3',5'(6'H)-
dicarboxamide 436.4 1.58 2.60 H I
##STR00968## ##STR00969##
Intermediate A134A: tert-Butyl
3-carbamoyl-7-formyl-2-iodo-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carb-
oxylate
##STR00970##
[1534] A solution of Intermediate A9G (0.421 g, 0.997 mmol) and
NaHCO.sub.3 (84 mg, 0.997 mmol) in anhydrous DCM (5.0 mL) was
allowed to cool to -30.degree. C. for several minutes prior to the
addition of Dess-Martin periodinane (0.508 g, 1.197 mmol). The
reaction was maintained at -30.degree. C. for 2 h after which the
temperature was allowed to gradually reach 22.degree. C. After
having stirred for 18 h, the reaction was diluted with DCM and a
saturated aq. solution of NaHCO.sub.3. The organic layer was
separated and the aqueous phase is extracted with DCM (3.times.10
mL). The combined organic layers were washed with brine, dried over
anhydrous MgSO.sub.4, filtered and the filtrate concentrated under
reduced pressure. The crude reaction mixture was purified by silica
gel chromatography (40 g REDISEP.RTM. column, eluting with a
gradient from 50-100% EtOAc in hexanes). Fractions containing the
product were combined and evaporated to afford Intermediate A134A
(0.200 g, 47%) as a white foam. MS(ES): m/z=364.9
[M+H.sub.2O-OtBu].sup.+. .sup.1H NMR (400 MHz, chloroform-d)
.delta. ppm 9.62-9.78 (1H, m), 5.81-6.83 (2H, m), 4.49-5.55 (4H,
m), 3.58 (1H, d, J=11.80 Hz), 1.39-1.50 (9H, m).
Intermediate A134B: tert-Butyl
3-carbamoyl-7,7-bis(hydroxymethyl)-2-iodo-6,7-dihydropyrazolo[1,5-a]pyraz-
ine-5(4H)-carboxylate
##STR00971##
[1536] To a solution of Intermediate A134A (0.200 g, 0.476 mmol) in
MeOH (4.0 mL) was added dropwise at RT an 85% aq. solution of KOH
(2.380 mL, 4.76 mmol) and a 37% w/w aq. solution of formaldehyde
(0.886 mL, 11.90 mmol) in MeOH (1 mL). The reaction was allowed to
stir at RT for 18 h after which the mixture was partitioned between
equal parts EtOAc and water. The organic phase was separated and
the aqueous layer was extracted twice more. The organic layers were
combined, dried over sodium sulfate, and concentrated to provide
the crude .beta.-hydroxy aldehyde Intermediate. The crude material
was dissolved in MeOH (2.0 mL) and treated with NaBH.sub.4 (0.036
g, 0.952 mmol). After stirring at RT for 1 h, the reaction mixture
was partitioned between equal parts water and EtOAc. The organic
layer was separated and the aqueous phase was extracted twice more
with EtOAc. The combined organic layers were dried over sodium
sulfate, filtered, and concentrated to provide a crude colorless
oil. The crude product was purified by silica gel chromatography
(40 g REDISEP.RTM. column, eluting with a gradient from 50-100%
EtOAc in hexanes). Fractions containing the product were combined
and evaporated to afford Intermediate A134B (0.096 g, 45%) as a
white solid. MS(ES): m/z=397.0 [M+H.sub.2O-OtBu].sup.+. .sup.1H NMR
(400 MHz, chloroform-d) .delta. ppm 6.29-6.87 (1H, m), 5.84-6.34
(1H, m), 4.85-5.03 (2H, m), 3.72-3.97 (5H, m), 3.58 (2H, br. s.),
1.42-1.52 (9H, m).
Intermediate A134C: tert-Butyl
3-carbamoyl-7-(hydroxymethyl)-2-iodo-7-((tosyloxy)methyl)-6,7-dihydropyra-
zolo[1,5-a]pyrazine-5 (4H)-carboxylate
##STR00972##
[1538] To a solution of Intermediate A134B (0.095 g, 0.210 mmol)
and dibutyltin oxide (0.0261 g, 0.105 mmol) in DCM (1.0 mL) was
added triethylamine (0.029 mL, 0.210 mmol) followed by
p-toluenesulfonyl chloride (0.040 g, 0.210 mmol). The reaction was
then allowed to stir at 22.degree. C. After 24 h, the reaction mass
was filtered and the filtrate was concentrated. The crude reaction
mixture was purified by silica gel chromatography (24 g
REDISEP.RTM. column, eluting with a gradient from 50-100% EtOAc in
hexanes). Fractions containing the product were combined and
evaporated to afford Intermediate A134C (0.033 g, 26%) as a white
foam. MS(ES): m/z=550.9 [M+H.sub.2O-OtBu].sup.+.
Intermediate A134D: tert-Butyl
3'-carbamoyl-2'-iodo-4'H-spiro[oxetane-3,7'-pyrazolo[1,5-a]pyrazine-5'(6'-
H)-carboxylate
##STR00973##
[1540] To an ice-cooled solution of Intermediate A134C (0.033 g,
0.054 mmol) in THF (1.0 mL) was added NaH (0.005 g, 0.136 mmol, 60%
dispersion in mineral oil). The reaction was allowed to stir at
0.degree. C. for 30 min. prior to heating the mixture to 50.degree.
C. for 1 h. The reaction was allowed to cool to RT, diluted with
EtOAc, and quenched with the addition of a saturated aq. solution
of NH.sub.4Cl. The organic layer was separated and the aqueous
phase was extracted twice with EtOAc. The combined organic phases
were dried over sodium sulfate and concentrated under reduced
pressure to afford an oil which was purified by silica gel
chromatography (12 g REDISEP.RTM. column, eluting with a gradient
from 50-100% EtOAc in hexanes). Fractions containing the product
were combined and evaporated to afford Intermediate A134D (0.018 g,
76%) as a white solid. MS(ES): m/z=379.0 [M+H.sub.2O-OtBu].sup.+.
.sup.1H NMR (400 MHz, chloroform-d) .delta. ppm 6.43-6.90 (1H, m),
5.38-5.70 (1H, m), 5.19-5.29 (2H, m), 4.87-4.99 (2H, m), 4.61 (2H,
d, J=6.78 Hz), 4.07-4.23 (2H, m), 1.41-1.55 (9H, m).
Intermediate A134E: tert-Butyl
3'-carbamoyl-2'-(3-chloro-4-fluorophenyl)-4'H-spiro[oxetane-3,7'-pyrazolo-
[1,5-a]pyrazine-5'(6'H)-carboxylate
##STR00974##
[1542] To a pressure vial equipped with a stir bar and charged with
Intermediate A134D (0.018 g, 0.041 mmol) was added
(3-chloro-4-fluorophenyl)boronic acid (10.8 mg, 0.062 mmol) and
PdCl.sub.2(dppf) (3.03 mg, 4.15 .mu.mol). The reaction vial was
capped and purged with dry N.sub.2 for 5 minutes. Anhydrous
1,4-dioxane (1.0 mL) and a 2M aq. solution of K.sub.3PO.sub.4
(0.062 mL, 0.124 mmol) were added. The resulting red slurry was
allowed to heat to 80.degree. C. for 18 h under a N.sub.2
atmosphere. The reaction was allowed to cool to RT and quenched by
the addition of 50 mL of water followed by dilution with DCM. The
organic phase was separated and the aqueous phase was extracted
twice more with additional DCM. The combined organic layers were
washed with a brine solution, dried over sodium sulfate, and
concentrated in vacuo to provide a colorless oil. The crude
reaction mixture is purified by silica gel chromatography (12 g
REDISEP.RTM. column, eluting with a 30-100% EtOAc in hexanes).
Fractions containing the product were combined and evaporated to
afford Intermediate A134E (0.017 g, 84%) as a white foam. MS(ES):
m/z=437.0 [M+H].sup.+.
Compound 134:
N.sup.5'-(tert-Butyl)-2'-(3-chloro-4-fluorophenyl)-4'H-spiro[oxetane-3,7'-
-pyrazolo[1,5-a]pyrazine]-3',5'(6'H)-dicarboxamide
##STR00975##
[1544] Compound A134 was synthesized analogous to Compound A106 by
reacting deprotected A134E with 2-isocyanato-2-methylpropane. The
product was purified by preparative HPLC. MS(ES): m/z=436.5
[M+H].sup.+; HPLC Ret. Time 1.43 min and 1.43 min. (Methods H and
I); .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. ppm 7.88-7.93 (1H,
m), 7.70-7.77 (1H, m), 7.49 (1H, t, J=8.99 Hz), 7.21-7.44 (2H, m),
6.46 (1H, d, J=15.77 Hz), 4.98-5.08 (2H, m), 4.60-4.71 (4H, m),
4.18 (2H, s), 1.23-1.31 (9H, s).
##STR00976## ##STR00977##
Intermediate A135A: tert-Butyl
3-carbamoyl-2-(3-chloro-4-fluorophenyl)-7,7-bis(hydroxymethyl)-6,7-dihydr-
opyrazolo[1,5-a]pyrazine-5(4H)-carboxylate
##STR00978##
[1546] To a solution of Intermediate A9H (0.425 g, 1.005 mmol) in
MeOH (5.0 mL) at RT was added dropwise an 85% aq. solution of KOH
(5.03 mL, 10.05 mmol) and a 37% w/w aq. solution of formaldehyde
(1.871 mL, 25.1 mmol) in MeOH (1 mL). The reaction was allowed to
stir at RT for 18 h after which the mixture was partitioned between
equal parts EtOAc and water. The organic phase was separated and
the aqueous layer was extracted twice more. The combined organic
layers were dried over sodium sulfate, and concentrated to provide
the crude .beta.-hydroxy aldehyde Intermediate. The crude material
was dissolved in MeOH (2.0 mL) and treated with NaBH.sub.4 (0.076
g, 2.010 mmol). After stirring at 22.degree. C. for 1 h, the
reaction mixture was partitioned in equal parts water and EtOAc.
The organic layer was separated and the aqueous phase was extracted
twice more with EtOAc. The combined organic layers were dried over
sodium sulfate, filtered, and concentrated to provide a crude
colorless oil. The crude product was purified by silica gel
chromatography (40 g REDISEP.RTM. column, eluting with a gradient
from 60-100% EtOAc in hexanes). Fractions containing the product
were combined and evaporated to afford Intermediate A135A (0.210 g,
46%) as a white solid. MS(ES): m/z=399.0 [M+H.sub.2O-OtBu].sup.+.
.sup.1H NMR (400 MHz, chloroform-d) .delta. ppm 7.64 (1H, ddd,
J=7.84, 7.09, 2.13 Hz), 7.40-7.52 (1H, m), 7.23-7.32 (2H, m),
5.33-5.61 (1H, m), 4.97 (2H, s), 4.70-4.82 (1H, m), 3.70-4.06 (6H,
m), 3.26-3.52 (2H, m), 1.50-1.56 (9H, m).
Intermediate A135B: tert-Butyl
3-carbamoyl-2-(3-chloro-4-fluorophenyl)-7,7-bis((tosyloxy)methyl)-6,7-dih-
ydropyrazolo[1,5-a]pyrazine-5 (4H)-carboxylate
##STR00979##
[1548] To an ice-cooled solution of Intermediate A135A (0.210 g,
0.462 mmol) in THF (5.0 mL) was added NaH (0.0739 g, 0.210 mmol,
60% dispersion in mineral oil) portionwise. After 10 minutes, a
solution of p-toluenesulfonyl chloride (0.264 g, 1.385 mmol) in THF
was added dropwise at 0.degree. C. The reaction was then allowed to
warm to 22.degree. C. After 18 h, the reaction was quenched at
0.degree. C. with a saturated aq. solution of NH.sub.4Cl and
diluted with EtOAc. The organic layer was separated and the aqueous
phase was extracted twice more with EtOAc. The combined organic
layers were dried over sodium sulfate, filtered, and concentrated
to afford a colorless oil. The crude reaction mixture is purified
by silica gel chromatography (40 g REDISEP.RTM. column, eluting
with a gradient from 40-100% EtOAc in hexanes) to separate the
bistosylate from the monotosylated product. Fractions containing
the product were combined and evaporated to afford Intermediate
A135B (0.183 g, 52%) as a white solid. MS(ES): m/z=707.2
[M+H.sub.2O-OtBu].sup.+.
Intermediate A135C: tert-Butyl
7-(azidomethyl)-3-carbamoyl-2-(3-chloro-4-fluorophenyl)-7-((tosyloxy)meth-
yl)-6,7-dihydropyrazolo[1,5-a]pyrazine-5 (4H)-carboxylate
##STR00980##
[1550] To a solution of Intermediate A135B (0.092 g, 0.121 mmol) in
DMF (2.0 mL) was added sodium azide (9.40 mg, 0.145 mmol). The
reaction was allowed to heat at 80.degree. C. for 18 h followed by
20 h at 100.degree. C. The mixture was allowed to cool to RT and
partitioned between equal parts EtOAc and water. The aqueous layer
was extracted twice more with EtOAc and the combined organic layers
are washed with brine, dried over sodium sulfate, filtered, and
concentrated to afford the crude material as a colorless oil. The
crude reaction mixture is purified by silica gel chromatography (40
g REDISEP.RTM. column, eluting with a gradient from 0-30% EtOAc in
hexanes) to separate the azide from the unreacted bistosylate.
Fractions containing the product were combined and evaporated to
afford Intermediate A135C (0.029 g, 38%) as a white solid. MS(ES):
m/z=578.1 [M+H.sub.2O-OtBu]+.
Intermediate A135D: tert-Butyl
1-acetyl-3'-carbamoyl-2'-(3-chloro-4-fluorophenyl)-4'H-spiro[azetidine-3,-
7'-pyrazolo[1,5-a]pyrazine-5'(6'H)-carboxylate
##STR00981##
[1552] To a flask equipped with a stir bar and charged with a
solution of Intermediate A135C (29 mg, 0.046 mmol) in THF was added
triphenylphosphine (13.20 mg, 0.050 mmol) and water (0.824 .mu.L,
0.046 mmol). After stirring for 18 h at 22.degree. C. there was
complete conversion to the intermediate iminophosphorane. The
hydrolysis of the iminophosphorane is accomplished by treating the
crude reaction mixture with NH.sub.4OH (0.030 mL, 0.229 mmol, 40 wt
%). After stirring at 22.degree. C. for 2 h, the reaction mixture
was allowed to heat to 40.degree. C. for 2 h after which the
volatiles were removed under reduced pressure. The intermediate
crude azetidine was then acylated without purification. The crude
oil was dissolved in DCM (0.50 mL) and treated with TEA (0.024 mL,
0.174 mmol) and a 1.0 M solution of acetyl chloride (0.065 mL,
0.065 mmol) in DCM. The reaction was allowed to stir at room
temperature for 1 h after which the reaction mixture was diluted
with equal parts EtOAc and water and the aqueous phase is extracted
twice more with EtOAc. The combined organic layers were dried over
sodium sulfate and concentrated under reduced pressure. The crude
reaction mixture is purified by silica gel chromatography (24 g
REDISEP.RTM. column, eluting with a gradient from 20-90% EtOAc in
hexanes). Fractions containing the product were combined and
evaporated to afford Intermediate A135D (0.0125 g, 48% over 3
steps) as a white solid. MS(ES): m/z=422.1
[M+H.sub.2O-OtBu].sup.+.
Compound A135:
1-Acetyl-N.sup.5'-(tert-butyl)-2'-(3-chloro-4-fluorophenyl)-4'H-spiro[aze-
tidine-3,7'-pyrazolo[1,5-a]pyrazine]-3',5'(6'H)-dicarboxamide
##STR00982##
[1554] Compound A135 was synthesized analogous to Compound A106 by
reacting deprotected A135D with 2-isocyanato-2-methylpropane. The
product was purified by preparative HPLC. MS(ES): m/z=476.9
[M+H].sup.+; HPLC Ret. Time 1.28 min and 2.27 min. (Methods H and I
respectively); .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. ppm 7.89
(1H, d, J=6.97 Hz), 7.64-7.77 (1H, m), 7.14-7.51 (3H, m), 6.33-6.43
(1H, m), 4.61-4.79 (2 H, m), 4.54 (1H, d, J=8.80 Hz), 4.19-4.35
(2H, m), 4.00-4.16 (3H, m), 1.80-1.92 (3H, m), 1.29 (9H, s).
##STR00983## ##STR00984##
Intermediate A136B: tert-Butyl
2-(3-chloro-4-fluorophenyl)-7-formyl-6,7-dihydropyrazolo[1,5-a]pyrazine-5-
(4H)-carboxylate
##STR00985##
[1556] To a flask charged with Intermediate A136A (0.358 g, 0.938
mmol) and sodium bicarbonate (79 mg, 0.938 mmol) was added
anhydrous DCM (6.0 mL). The reaction mixture was allowed to cool to
-30.degree. C. for several minutes prior to the addition of
Dess-Martin periodinane (0.477 g, 1.125 mmol). The reaction was
maintained at -30.degree. C. for 2 h before warming to 22.degree.
C. After 18 h, the reaction was diluted with DCM and a saturated
aq. solution of NaHCO.sub.3. The organic layer was separated and
the aqueous phase was extracted with DCM (3.times.10 mL). The
combined organic layers were washed with a saturated aq. solution
of NaHCO.sub.3, dried over anhydrous MgSO.sub.4, filtered and the
filtrate concentrated under reduced pressure to provide a yellow
foam. The crude reaction mixture was purified by silica gel
chromatography (80 g REDISEP.RTM. column, eluting with a gradient
from 0-50% EtOAc in hexanes). Fractions containing the product were
combined and evaporated to afford Intermediate A136B (0.311 g, 87%)
as a white solid. MS(ES): m/z=378.2 [M-H].sup.+. .sup.1H NMR (400
MHz, chloroform-d) .delta. ppm 9.73-9.82 (1H, m), 7.84 (1H, dd,
J=7.03, 2.01 Hz), 7.59-7.68 (1H, m), 7.14-7.22 (1H, m), 6.41-6.48
(1H, m), 4.62-5.16 (4H, m), 4.35-4.52 (2H, m), 3.64-3.78 (1H, m),
1.58 (9H, br. s.)
Intermediate A136C: tert-Butyl 3
2-(3-chloro-4-fluorophenyl)-7,7-bis(hydroxymethyl)-6,7-dihydropyrazolo[1,-
5-a]pyrazine-5(4H)-carboxylate
##STR00986##
[1558] To a solution of Intermediate A136B (0.311 g, 0.818 mmol) in
MeOH (5.0 mL) at RT was added dropwise an 85% aq. solution of KOH
(0.459 g, 8.18 mmol) and a 37% w/w aq. solution of formaldehyde
(1.523 mL, 20.45 mmol) in MeOH (1 mL). The reaction was allowed to
stir at RT for 18 h after which the mixture was partitioned between
equal parts EtOAc and water. The organic phase was separated and
the aqueous layer was extracted twice more. The combined organic
layers were dried over sodium sulfate, and concentrated to provide
the crude .beta.-hydroxy aldehyde intermediate. The crude material
was dissolved in MeOH (2.0 mL) and treated with NaBH.sub.4 (0.062
g, 1.636 mmol). After stirring at RT for 1 h, the reaction mixture
was partitioned between equal parts water and EtOAc. The organic
layer was separated and the aqueous phase was extracted twice more
with EtOAc. The combined organic layers were dried over sodium
sulfate, filtered, and concentrated to provide a colorless oil. The
crude product was purified by silica gel chromatography (40 g
REDISEP.RTM. column, eluting with a gradient from 0-60% EtOAc in
hexanes). Fractions containing the product were combined and
evaporated to afford Intermediate A136C (0.287 g, 77%) as a white
solid. MS(ES): m/z=412.3 [M+H].sup.+. .sup.1H NMR (400 MHz,
chloroform-d) .delta. ppm 7.78 (1H, dd, J=7.03, 2.26 Hz), 7.51-7.63
(1H, m), 7.11-7.21 (1H, m), 6.33 (1H, s), 4.67-4.78 (2H, m),
3.96-4.06 (2H, m), 3.73-3.94 (4H, m), 3.42-3.61 (1H, m), 1.52 (9H,
s).
Intermediate A136D: tert-Butyl
2-(3-chloro-4-fluorophenyl)-7,7-bis((tosyloxy)methyl)-6,7-dihydropyrazolo-
[1,5-a]pyrazine-5(4H)-carboxylate
##STR00987##
[1560] To an ice-cooled solution of Intermediate A136C (0.110 g,
0.267 mmol) in THF (2.0 mL) was added NaH (0.0427 g, 1.068 mmol,
60% dispersion in mineral oil) in small portions. After 10 minutes,
a solution of p-toluenesulfonyl chloride (0.153 g, 0.801 mmol) in
THF was introduced dropwise at 0.degree. C. The reaction was then
allowed to stir at 22.degree. C. After 18 h, the reaction was
quenched at 0.degree. C. with a saturated aq. solution of
NH.sub.4Cl and diluted with EtOAc. The organic layer was separated
and the aqueous phase was extracted twice more with EtOAc. The
combined organic layers were dried over MgSO.sub.4, filtered, and
concentrated to afford a pale yellow solid. The crude reaction
mixture was purified by preparative HPLC (70:30 solution of 95%
H.sub.2O:5% MeCN to 95% MeCN:5% H.sub.2O, 30 min isocratic) to
separate the desired bistosylate from the monotosylated byproduct.
Fractions containing the product were combined and evaporated to
afford Intermediate A136D (0.129 g, 67%) as a white solid. MS(ES):
m/z=720.2 [M+H].sup.+. .sup.1H NMR (400 MHz, chloroform-d) .delta.
ppm 7.55-7.70 (5H, m), 7.42 (1H, br. s.), 7.24 (4H, d, J=8.03 Hz),
7.11-7.18 (1H, m), 6.22-6.25 (1H, m), 4.54-4.74 (2H, m), 4.18-4.48
(4H, m), 3.97-4.11 (2H, m), 2.35-2.44 (6H, s), 1.49 (9H, br.
s.).
Intermediate A136E: tert-Butyl
2-(3-chloro-4-fluorophenyl)-7,7-bis(fluoromethyl)-6,7-dihydropyrazolo[1,5-
-a]pyrazine-5(4H)-carboxylate
##STR00988##
[1562] To a solution of Intermediate A136D (0.093 g, 0.129 mmol) in
THF (1.0 mL) was added a 1.0 M solution of tetrabutylammonium
fluoride (0.646 mL, 0.646 mmol) in THF and the mixture was allowed
to stir at 50.degree. C. After 18 h, the reaction was allowed to
cool to 22.degree. C. and diluted with equal parts EtOAc and water.
The organic layer was separated and the aqueous phase was extracted
twice more with additional EtOAc. The combined organic phases were
dried over sodium sulfate and concentrated under reduced pressure
to afford a colorless oil. The crude reaction mixture was purified
by silica gel chromatography (40 g REDISEP.RTM. column, eluting
with a gradient from 0-60% EtOAc in hexanes). Fractions containing
the product were combined and evaporated to afford Intermediate
A136E (0.0312 g, 58%) as a white solid. MS(ES): m/z=416.1
[M+H].sup.+. .sup.1H NMR (400 MHz, chloroform-d) .delta. 7.84 (1H,
dd, J=7.15, 2.13 Hz), 7.61 (1H, ddd, J=8.53, 4.64, 2.13 Hz),
7.12-7.21 (1H, m), 6.29-6.39 (1H, m), 4.92-5.02 (1H, m), 4.78-4.90
(2H, m), 4.66-4.76 (3H, m), 4.07-4.15 (2H, m), 1.46-1.55 (9H,
m).
Intermediate A136F: tert-Butyl
2-(3-chloro-4-fluorophenyl)-7,7-bis(fluoromethyl)-3-iodo-6,7-dihydropyraz-
olo[1,5-a]pyrazine-5(4H)-carboxylate
##STR00989##
[1564] To a solution of Intermediate A136E (0.031 g, 0.075 mmol) in
a 4:1 solution of DCM:MeOH (0.75 mL) was added NIS (0.0503 g, 0.224
mmol) and the mixture was allowed to stir at 22.degree. C. After 18
h, due to low reactivity, an additional 3 equivalents of NIS
(0.0503 g, 0.224 mmol) were added to the reaction mixture which was
then heated to 50.degree. C. for 4 h. The reaction was then allowed
to cool to RT and the volatiles were removed under reduced pressure
to afford a red oil. The crude reaction mixture was purified by
silica gel chromatography (24 g REDISEP.RTM. column, eluting with a
gradient from 0-40% EtOAc in hexanes). Fractions containing the
product were combined and evaporated to afford Intermediate A136F
(0.0394 g, 8%) as a white solid. MS(ES): m/z=542.0 [M+H].sup.+.
.sup.1H NMR (400 MHz, chloroform-d) .delta. 7.88 (1H, dd, J=7.15,
2.13 Hz), 7.70-7.77 (1H, m), 7.21 (1H, t, J=8.78 Hz), 4.94-5.01
(1H, m), 4.75-4.89 (2H, m), 4.52-4.71 (3H, m), 4.06-4.16 (2H, m),
1.51-1.56 (9H, m).
Intermediate A136G: tert-Butyl
2-(3-chloro-4-fluorophenyl)-3-cyano-7,7-bis(fluoromethyl)-6,7-dihydropyra-
zolo[1,5-a]pyrazine-5(4H)-carboxylate
##STR00990##
[1566] To a flask charged with Intermediate A136F (39 mg, 0.072
mmol) was added Pd(PPh.sub.3).sub.4 (8.32 mg, 7.20 .mu.mol), zinc
cyanide (9.30 mg, 0.079 mmol), and zinc (1.0 mg, 0.015 mmol). The
flask was fitted with a reflux condenser and was purged and
refilled with dry N.sub.2 in three cycles. The condenser was sealed
with a septum and the contents were degassed with dry N.sub.2 prior
to the addition of DMF (1.0 mL). The yellow reaction mixture was
then heated to 80.degree. C. After 24 h, the reaction mixture was
cooled to RT and diluted with equal parts water and EtOAc. The
organic layer was separated and the aqueous phase was extracted
twice more with EtOAc. The combined organic layers were washed with
brine, dried over sodium sulfate, filtered, and concentrated to
afford an oil. The crude reaction mixture was purified by silica
gel chromatography (24 g REDISEP.RTM. column, eluting with a
gradient from 0-60% EtOAc in hexanes). Fractions containing the
product were combined and concentrated under reduced pressure to
afford Intermediate A136G (0.0211 g, 46%) as a white solid. MS(ES):
m/z=439.3 [M-H].sup.-.
Intermediate A136H: tert-Butyl
3-carbamoyl-2-(3-chloro-4-fluorophenyl)-7,7-bis(fluoromethyl)-6,7-dihydro-
pyrazolo[1,5-c]pyrazine-5(4H)-carboxylate
##STR00991##
[1568] To a flask charged with a solution of Intermediate A136G (21
mg, 0.048 mmol) in DMSO (1.0 mL) was added a 5.0 M aq. solution of
KOH (0.048 mL, 0.239 mmol) and a 30 wt % solution of hydrogen
peroxide (0.098 mL, 0.957 mmol). The reaction was allowed to stir
at RT for 1 h after which it was diluted with equal parts water and
EtOAc. The organic layer was separated and the aqueous phase was
extracted twice more with EtOAc. The combined organic layers were
dried over sodium sulfate, filtered, and concentrated to afford a
pale yellow oil. The crude reaction mixture was purified by silica
gel chromatography (24 g REDISEP.RTM. column, eluting with a
gradient from 20-100% EtOAc in hexanes). Fractions containing the
product were combined and evaporated yielding Intermediate A136H
(0.011 g, 50%) as a white solid. MS(ES): m/z=403.0
[M+H.sub.2O-OtBu].sup.+.
Compound A136:
N.sup.5'-(tert-Butyl)-2-(3-chloro-4-fluorophenyl)-7,7-bis(fluoromethyl)-6-
,7-dihydropyrazolo[1,5-a]pyrazine]-3,5(4H)-dicarboxamide
##STR00992##
[1570] Compound A136 was synthesized analogous to Compound A106 by
reacting deprotected A136H with 2-isocyanato-2-methylpropane. The
product was purified by preparative LCMS. MS(ES): m/z=458.2
[M+H].sup.+; HPLC Ret. Time 1.63 min. and 2.60 min. (Methods H and
I); .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. ppm 7.84 (1H, d,
J=5.87 Hz), 7.64-7.71 (1H, m), 7.25-7.52 (3H, m), 6.29 (1H, s),
4.86-4.96 (1H, m), 4.73-4.86 (4H, m), 4.71 (1H, d, J=9.54 Hz), 3.99
(2H, s), 1.20-1.31 (9H, m).
##STR00993##
Intermediate A137D:
4-(Methoxycarbonyl)bicyclo[2.2.1]heptane-1-carboxylic acid
##STR00994##
[1572] Intermediate A137D was prepared following the synthetic
route described in Scheme 95. The experimental procedures described
in U.S. Publication No. 2007/0155738 (Jul. 5, 2007) were followed.
.sup.1H NMR (400 MHz, chloroform-d) .delta. ppm 9.29-12.86 (1H, m),
3.67-3.74 (1H, m), 2.06-2.15 (2H, m), 1.96 (1H, s), 1.65-1.79 (2H,
m).
Intermediate A137E: Methyl
4-fluorobicyclo[2.2.1]heptane-1-carboxylate
##STR00995##
[1574] Intermediate A137D was converted to the corresponding
fluoride Intermediate A137E as described in J. Org. Chem.,
57:2850-2855 (1992). .sup.1H NMR (400 MHz, chloroform-d) .delta.
ppm 3.30-3.82 (3H, m), 0.53-2.71 (10H, m).
Intermediate A137F: 4-Fluorobicyclo[2.2.1]heptane-1-carboxylic
acid
##STR00996##
[1576] To a solution of Intermediate A137E (0.049 g, 0.285 mmol) in
MeOH (2 mL) was introduced a 1.0 M aq. solution of NaOH (0.569 mL,
0.569 mmol). The reaction was allowed to stir at RT for 18 h. The
reaction was then diluted with equal parts EtOAc and a saturated
aq. solution of NaHCO.sub.3. The organic phase was separated and
the aqueous phase was acidified using a concentrated solution of
HCl until the pH was equal to 1. The acidic water layer was then
extracted with EtOAc (3.times.50 mL). The combined extracts were
dried over MgSO.sub.4 and concentrated under reduced pressure to
provide a crude white solid which was used without further
purification.
##STR00997##
Compound A137:
2-(3-Chloro-4-fluorophenyl)-N.sup.5-(4-fluorobicyclo[2.2.1]heptan-1-yl)-6-
,7-dihydropyrazolo[1,5-a]pyrazine-3,5(4H)-dicarboxamide
##STR00998##
[1578] Compound A137 was synthesized using a Curtius rearrangement
procedure as depicted in Scheme 96. To a solution of Intermediate
A137F (50 mg, 0.316 mmol) in toluene (1.0 mL) was added TEA (0.126
mL, 0.903 mmol), followed by diphenyl phosphorazidate (93 mg, 0.339
mmol). The reaction mixture was heated to 90.degree. C. for 2 h
after which it was allowed to cool to RT. Intermediate 185B (66.5
mg, 0.226 mmol), as a solution in DMF, was added to the reaction
mixture and the resulting solution was allowed to stir for 1 h. The
mixture was diluted with MeOH and concentrated to provide an oil.
The product was purified by preparative HPLC. MS(ES): m/z=450.3
[M+H].sup.+; HPLC Ret. Time 1.53 min. and 2.37 min. (Methods H and
I respectively); .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. ppm
7.84 (1H, dd, J=7.3, 1.8 Hz), 7.67 (1H, ddd, J=8.44, 4.77, 2.20
Hz), 7.46 (1H, t, J=8.99 Hz), 7.14-7.40 (2H, m), 6.91 (1H, s), 4.70
(2H, s), 4.08-4.17 (2H, m), 3.81 (2H, t, J=5.32 Hz), 1.70-2.06
(10H, m).
##STR00999##
Intermediate A138A: Methyl
4-(hydroxymethyl)bicyclo[2.2.1]heptane-1-carboxylate
##STR01000##
[1580] Intermediate A138A was prepared following the synthetic
route described in Scheme 97. The experimental procedures described
in Eur. J. Med. Chem., 46:5728-5735 (2011) were followed. A flask
charged with a solution of Intermediate A137D (316 mg, 1.594 mmol)
in THF (8 mL) was sealed with a septum and purged with dry N2. The
solution was cooled to 0.degree. C. prior to the dropwise addition
of a 2.0 M solution of borane-methyl sulfide complex (0.996 mL,
1.993 mmol) in THF. The reaction mixture was allowed to gradually
warm to RT. After 18 h, MeOH (5 mL) was added to the reaction and
the mixture was heated to reflux for 2 h. The solution was then
cooled to RT, concentrated under reduced pressure and diluted with
equal parts EtOAc and water. The organic phase was separated and
the aqueous phase was extracted twice more with EtOAc. The combined
organic layers were washed twice with a 1 N aq. solution of HCl,
dried over MgSO.sub.4, and concentrated to provide crude
Intermediate A138A (0.296 g, >98% yield) as a white solid.
.sup.1H NMR (400 MHz, chloroform-d) .delta. ppm 3.69-3.72 (2H, m),
3.68 (3H, s), 2.58-3.20 (2H, m), 2.08-2.11 (1H, m), 1.95-2.03 (2H,
m), 1.60-1.76 (5H, m), 1.57 (2H, s), 1.34-1.46 (3H, m).
Intermediate A138B: Methyl
4-(fluoromethyl)bicyclo[2.2.1]heptane-1-carboxylate
##STR01001##
[1582] A solution of Intermediate A138A (0.155 g, 0.841 mmol) in
DCM (5 mL), was cooled to -78.degree. C. DAST (0.111 mL, 0.841
mmol) was added and the reaction mixture was stirred at 22.degree.
C. for 1 h. The reaction mixture was quenched at 0.degree. C. by
the careful addition of a saturated aq. solution of NaHCO.sub.3.
The reaction mixture was diluted with DCM. The organic layer was
separated and the aqueous phase was extracted twice more with DCM.
The combined organic phases were dried over MgSO.sub.4 and
concentrated under reduced pressure. The crude reaction mixture was
purified by silica gel chromatography (24 g REDISEP.RTM. column,
eluting with a gradient from 0-30% EtOAc in hexanes). Fractions
containing the product were combined and concentrated affording
Intermediate A138B (0.047 g, 30% yield) as a white solid. .sup.1H
NMR (400 MHz, chloroform-d) .delta. ppm 3.72-3.90 (2H, m), 3.68
(3H, s), 1.93-2.05 (2H, m), 1.55-1.74 (7H, m), 1.34-1.48 (2H,
m).
Intermediate A138C:
4-(Fluoromethyl)bicyclo[2.2.1]heptane-1-carboxylic acid
##STR01002##
[1584] The carboxylic acid was prepared following the
saponification procedure to afford Intermediate A137F. The afforded
crude white solid was used in the Curtius rearrangement without
further purification.
Compound A138:
2-(3-Chloro-4-fluorophenyl)-N.sup.5-(4-(fluoromethyl)bicyclo[2.2.1]heptan-
-1-yl)-6,7-dihydropyrazolo[1,5-a]pyrazine-3,5(4H)-dicarboxamide
##STR01003##
[1586] Compound A138 was synthesized analogously to Compound A137
using a Curtius rearrangement procedure as depicted in Scheme 96
with Intermediate A138C. MS(ES): m/z=464.3 [M+H].sup.+; HPLC Ret.
Time 1.66 min. and 2.51 min. (Methods H and I); .sup.1H NMR (500
MHz, DMSO-d.sub.6) .delta. ppm 7.85 (1H, dd, J=7.34, 1.83 Hz), 7.68
(1H, ddd, J=8.53, 4.86, 2.02 Hz), 7.45 (1H, t, J=8.99 Hz),
7.15-7.40 (2H, m), 6.94 (1H, s), 5.97-6.28 (1H, m), 4.71 (2H, s),
4.12 (2H, t, J=5.14 Hz), 3.82 (2H, t, J=5.14 Hz), 1.65-1.92 (9H,
m), 1.35-1.48 (2H, m).
##STR01004##
Intermediate A139A: Methyl
4-formylbicyclo[2.2.1]heptane-1-carboxylate
##STR01005##
[1588] To a solution of Intermediate A138A (0.118 g, 0.640 mmol) in
DCM (5 mL) was added Dess-Martin periodinane (0.326 g, 0.769 mmol).
The reaction mixture was allowed to stir at RT for 18 h. The
reaction was diluted with equal parts DCM and a saturated aq.
solution of NaHCO.sub.3. The organic phase was separated and the
aqueous phase was extracted twice more with DCM. The combined
organic layers were dried over MgSO.sub.4, and concentrated to
provide a white solid. The crude reaction mixture was purified by
silica gel chromatography (24 g REDISEP.RTM. column, eluting with a
gradient from 0-15% EtOAc in hexanes). Fractions containing the
product were combined and evaporated yielding Intermediate A139A
(0.086 g, 74%) as a white solid. .sup.1H NMR (400 MHz,
chloroform-d) .delta. ppm 9.81-9.84 (1H, m), 3.70-3.73 (3H, m),
2.05-2.12 (4H, m), 1.85 (2H, s), 1.72-1.80 (2H, m), 1.49-1.62 (2H,
m).
Intermediate A139B: Methyl
4-(difluoromethyl)bicyclo[2.2.1]heptane-1-carboxylate
##STR01006##
[1590] A solution of Intermediate A139A (0.086 g, 0.472 mmol) in
DCM (5 mL) was cooled to 0.degree. C. prior to the dropwise
introduction of DAST (0.187 mL, 1.416 mmol). The reaction mixture
was stirred at 22.degree. C. for 18 hour. The reaction was quenched
by the addition of a saturated aqueous solution of sodium
bicarbonate. The organic layer was separated and the aqueous phase
was extracted twice more with DCM. The combined organic phases were
dried over magnesium sulfate and concentrated under reduced
pressure to afford Intermediate A139B (0.085 g, 88%) as a white
solid, which was used without further purification. .sup.1H NMR
(400 MHz, chloroform-d) .delta. ppm 5.66-6.00 (1H, m), 3.69 (3H,
s), 1.45-2.04 (10H, m).
Intermediate A139C:
4-(Difluoromethyl)bicyclo[2.2.1]heptane-1-carboxylic acid
##STR01007##
[1592] The carboxylic acid A139C was prepared following the
saponification procedure to afford Intermediate A137F. The afforded
crude white solid was used in the Curtius rearrangement without
further purification.
Compound A139:
2-(3-Chloro-4-fluorophenyl)-N.sup.5-(4-(difluoromethyl)bicyclo[2.2.1]hept-
an-1-yl)-6,7-dihydropyrazolo[1,5-a]pyrazine-3,5(4H)-dicarboxamide
##STR01008##
[1594] Compound A139 was synthesized using a Curtius rearrangement
procedure as depicted in Scheme 96 using Intermediate A139C.
MS(ES): m/z=482.3 [M+H].sup.+; HPLC Ret. Time 1.74 min. and 2.52
min. (Methods H and I); .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta.
ppm 7.85 (1H, dd, J=7.34, 1.83 Hz), 7.63-7.72 (1H, m), 7.45 (1H, t,
J=8.99 Hz), 7.15-7.41 (2H, m), 6.94 (1H, s), 5.97-6.26 (1H, m),
4.71 (2H, s), 4.12 (2H, t, J=5.14 Hz), 3.82 (2H, t, J=5.14 Hz),
1.64-1.93 (9H, m), 1.35-1.49 (2H, m).
##STR01009##
Intermediate A140B: Methyl
4-cyanobicyclo[2.2.1]heptane-1-carboxylate
##STR01010##
[1596] Intermediate A140B was prepared following the synthetic
route described in Scheme 99. The experimental procedures described
in U.S. Publication No. 2007/0155738 (Jul. 5, 2007) were
followed.
Intermediate A140C: 4-Cyanobicyclo[2.2.1]heptane-1-carboxylic
acid
##STR01011##
[1598] The carboxylic acid A140C was prepared following the
saponification procedure to afford Intermediate A137F. The afforded
crude white solid was used in the Curtius rearrangement without
further purification. .sup.1H NMR (400 MHz, chloroform-d) .delta.
ppm 2.04-2.15 (6H, m), 1.68-1.93 (4H, m).
Compound A140:
2-(3-Chloro-4-fluorophenyl)-N.sup.5-(4-cyanobicyclo[2.2.1]heptan-1-yl)-6,-
7-dihydropyrazolo[1,5-a]pyrazine-3,5(4H)-dicarboxamide
##STR01012##
[1600] Compound A140 was synthesized using a Curtius rearrangement
procedure as depicted in Scheme 96 using Intermediate A140C.
MS(ES): m/z=457.3 [M+H].sup.+; HPLC Ret. Time 1.43 min. and 2.20
min. (Methods H and I); .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta.
ppm 7.84 (1H, dd, J=7.15, 2.02 Hz), 7.67 (1H, ddd, J=8.53, 4.86,
2.02 Hz), 7.46 (1H, t, J=8.99 Hz), 7.13-7.41 (2H, m), 7.01 (1H, s),
4.68-4.75 (2H, m), 4.12 (2H, t, J=5.14 Hz), 3.77-3.86 (2H, m),
1.78-2.08 (8H, m), 1.65-1.76 (2H, m).
* * * * *