U.S. patent application number 16/438135 was filed with the patent office on 2019-10-24 for 5-chloro-2-difluoromethoxyphenyl pyrazolopyrimidine compounds,compositions and methods of use thereof.
This patent application is currently assigned to Genentech, Inc.. The applicant listed for this patent is Genentech, Inc.. Invention is credited to Yun-Xing Cheng, Simon Charles Goodacre, Terry Kellar, Wei Li, Rohan Mendonca, Nicholas Charles Ray, Po-wai Yuen, Mark Edward Zak.
Application Number | 20190322661 16/438135 |
Document ID | / |
Family ID | 53276096 |
Filed Date | 2019-10-24 |
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United States Patent
Application |
20190322661 |
Kind Code |
A1 |
Zak; Mark Edward ; et
al. |
October 24, 2019 |
5-CHLORO-2-DIFLUOROMETHOXYPHENYL PYRAZOLOPYRIMIDINE
COMPOUNDS,COMPOSITIONS AND METHODS OF USE THEREOF
Abstract
Compounds of Formula (00A) and methods of use as Janus kinase
inhibitors are described herein.
Inventors: |
Zak; Mark Edward; (San
Mateo, CA) ; Ray; Nicholas Charles; (Harlow Essex,
GB) ; Goodacre; Simon Charles; (Harlow Essex, GB)
; Mendonca; Rohan; (Pleasanton, CA) ; Kellar;
Terry; (Burlingame, CA) ; Cheng; Yun-Xing;
(Beijing, CN) ; Li; Wei; (Beijing, CN) ;
Yuen; Po-wai; (Ann Arbor, MI) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Genentech, Inc. |
South San Francisco |
CA |
US |
|
|
Assignee: |
Genentech, Inc.
South San Francisco
CA
|
Family ID: |
53276096 |
Appl. No.: |
16/438135 |
Filed: |
June 11, 2019 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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15820515 |
Nov 22, 2017 |
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16438135 |
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15424536 |
Feb 3, 2017 |
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15820515 |
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15139164 |
Apr 26, 2016 |
9604984 |
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15424536 |
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14720323 |
May 22, 2015 |
9346815 |
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15139164 |
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62130098 |
Mar 9, 2015 |
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62101234 |
Jan 8, 2015 |
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62002547 |
May 23, 2014 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 31/519 20130101;
C07D 519/00 20130101; C07D 403/14 20130101; C07D 471/04 20130101;
C07D 487/04 20130101; A61P 11/06 20180101 |
International
Class: |
C07D 471/04 20060101
C07D471/04; C07D 487/04 20060101 C07D487/04; C07D 403/14 20060101
C07D403/14; A61K 31/519 20060101 A61K031/519; C07D 519/00 20060101
C07D519/00; A61P 11/06 20060101 A61P011/06 |
Foreign Application Data
Date |
Code |
Application Number |
Apr 22, 2015 |
CN |
PCT/CN2015/077176 |
Claims
1. A compound of Formula (00A): ##STR00729## and stereoisomers and
salts thereof, wherein: R.sup.00 is H or CH.sub.3; R.sup.01 is H or
NH.sub.2; R.sup.0 is H or NH.sub.2; and Ring Q is either (i) or
(ii): (i) ##STR00730## (ii) ##STR00731## wherein: t.sup.1 and
t.sup.2 are each independently 0 or 1; X.sup.A and X.sup.B are
independently selected from the group consisting of H,
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.4 alkenyl, --NR.sup.aR.sup.b,
C.sub.2-C.sub.5 alkynyl, 3-6-membered cycloalkyl, 6-10 membered
aryl, 3-11 membered heterocycloalkyl, 5-6 membered
heterocycloalkenyl, and 5-10 membered heteroaryl; wherein when
either of X.sup.A and X.sup.B are independently C.sub.1-C.sub.6
alkyl, C.sub.2-C.sub.4 alkenyl, C.sub.2-C.sub.5 alkynyl,
3-6-membered cycloalkyl, 6-10 membered aryl, 3-11 membered
heterocycloalkyl, 5-6 membered heterocycloalkenyl, and 5-10
membered heteroaryl, each of X.sup.A and X.sup.B is independently
optionally substituted by Y.sup.1, wherein Y.sup.1 is selected
from: (a) C.sub.1-C.sub.6 alkyl optionally substituted by T.sup.1,
wherein T.sup.1 is selected from the group consisting of OH, halo,
CN, imino, 3-6 membered cycloalkyl, 3-11 membered heterocycloalkyl,
3-11 membered heterocycloalkenyl, 5-10 membered heteroaryl,
--O--(C.sub.1-C.sub.6 alkyl), C(O)OH, oxetan-3-ylmethyl,
--C(O)O--(C.sub.1-C.sub.6 alkyl), --S--(C.sub.1-C.sub.6 alkyl),
--SO.sub.2--(C.sub.1-C.sub.6 alkyl), --NR.sup.aR.sup.b,
--N(+)R.sup.aR.sup.bR.sup.c wherein R.sup.c is methyl,
--C(O)NR.sup.aR.sup.b, -(2-oxoindolin-1-yl), --OC(O)-3-6 membered
cycloalkyl, and phenyl, wherein each alkyl, cycloalkyl,
heterocycloalkyl, heterocycloalkenyl, heteroaryl, and phenyl of Ti
is optionally substituted by OH, --C(O)O--(C.sub.1-C.sub.6 alkyl),
C.sub.1-C.sub.6 alkyl, halo, CN, oxo, --(C.sub.1-C.sub.6
alkyl)CONR.sup.aR.sup.b, --NR.sup.aR.sup.b, phenyl, or
--O--(C.sub.1-C.sub.6 alkyl) optionally substituted by OH; (b) 3-11
membered heterocycloalkyl, --(C.sub.1-C.sub.6 alkylene)-3-11
membered heterocycloalkyl, --C(O)-3-11 membered heterocycloalkyl,
--(C.sub.1-C.sub.6 alkylene)C(O)-3-11 membered heterocycloalkyl, or
--OC(O)-4-6 membered heterocycloalkyl; wherein the heterocycloalkyl
is optionally substituted by OH, halo, CN, C.sub.1-C.sub.6 alkyl,
--(C.sub.1-C.sub.6 alkylene)-CF.sub.3, oxo,
--C(O)--(C.sub.1-C.sub.6 alkyl), --C(O)O--(C.sub.1-C.sub.6 alkyl),
--C(O)O--(C.sub.1-C.sub.6 alkylene)-phenyl,
--SO.sub.2--(C.sub.1-C.sub.6 alkyl), --C(O)NR.sup.aR.sup.b,
--NR.sup.aR.sup.b, --(C.sub.1-C.sub.6 alkylene)-phenyl, or
--C(O)-4-6 membered heterocycloalkyl optionally substituted by
--NR.sup.aR.sup.b; (c) N(+)(AA).sub.3, wherein each AA is
independently C.sub.1-C.sub.6 alkyl optionally substituted by
phenyl; (d) 3-6 membered cycloalkyl optionally substituted by OH,
halo, NR.sup.aR.sup.b, or CN; (e) CN, halo, or oxo; (f)
--C(O)--(C.sub.1-C.sub.6 alkyl), --C(O)OH,
--C(O)O--(C.sub.1-C.sub.6 alkylene)-phenyl,
--SO.sub.2--(C.sub.1-C.sub.6 alkyl), --C(O)NR.sup.aR.sup.b, or
--C(O)-4-6 membered heterocycloalkyl optionally substituted by
--(C.sub.1-C.sub.6 alkyl) or --NR.sup.aR.sup.b, or
--C(O)O--(C.sub.1-C.sub.6 alkyl) optionally substituted by OH,
NR.sup.aR.sup.b, or 3-11 membered heterocycloalkyl wherein said
heterocycloalkyl is optionally substituted by C.sub.1-C.sub.6
alkyl; (g) OH, --O-phenyl, or --O--(C.sub.1-C.sub.6 alkyl), wherein
the alkyl is optionally substituted by OH or --NR.sup.aR.sup.b; (h)
phenyl optionally substituted by OH, halo, C.sub.1-C.sub.6 alkyl,
CF.sub.3, or CN; (i) 5-6 membered heteroaryl optionally substituted
by OH, halo, C.sub.1-C.sub.6 alkyl, CF.sub.3, CN, or 3-11 membered
heterocycloalkyl optionally substituted by C.sub.1-C.sub.6 alkyl or
3-11 membered heterocycloalkyl; (j) isoindolin-2-yl optionally
substituted by halo; (k) --NR.sup.aR.sup.b, and (l)
--O--CH.sub.2C(O)-3-11 membered heterocycloalkyl; wherein R.sup.a
and R.sup.b are independently selected from: (a) H, (b)
C.sub.1-C.sub.6 alkyl optionally substituted by OH, halo, CN,
--C(O)OH, --C(O)O--(C.sub.1-C.sub.6alkyl), --C(O)O-(3-11 membered
heterocycloalkyl), --C(O)O--(C.sub.1-C.sub.6
alkyl)-S--(C.sub.1-C.sub.6 alkyl), --S--(C.sub.1-C.sub.6 alkyl),
naphthylenyl, --NR.sup.azR.sup.bz, --C(O)NR.sup.azR.sup.bz, oxo,
--O--(C.sub.1-C.sub.6 alkyl), 5-6 membered heteroaryl optionally
substituted by C.sub.1-C.sub.6 alkyl or halo, or
benzo[1,3]dioxol-2-yl, or 3-11 membered heterocycloalkenyl
optionally substituted by oxo; (c) --(C.sub.1-C.sub.6 alkylene)-3-6
membered cycloalkyl wherein the alkylene is optionally substituted
by OH, halo, or CN; (d) --(C.sub.1-C.sub.6 alkylene)-phenyl wherein
alkylene is optionally substituted by halo and the phenyl is
optionally substituted by OH, halo, CF.sub.3, C.sub.1-C.sub.6
alkyl, --O--(C.sub.1-C.sub.6 alkyl), --S--(C.sub.1-C.sub.6 alkyl,
or --O-phenyl; (e) --(C.sub.1-C.sub.6 alkylene)-4-6 membered
heterocycloalkyl wherein the heterocycloalkyl is optionally
substituted by halo, oxo, or C.sub.1-C.sub.6 alkyl; (f)
--(C.sub.1-C.sub.6 alkylene)-O-phenyl wherein the phenyl is
optionally substituted by halo, C.sub.1-C.sub.6 alkyl, or
--O-phenyl; (g) --(C.sub.1-C.sub.6 alkyl).sub.3-6 membered
cycloalkyl optionally substituted by OH, halo, CN, or
C.sub.1-C.sub.6 alkyl optionally substituted by OH or CN; (h)
C.sub.2-C.sub.5 alkenyl; (i) 4-6 membered heterocycloalkyl
optionally substituted by halo, (j) --(C.sub.1-C.sub.6
alkylene)-3-6 membered cycloalkyl substituted by hydroxymethyl, (k)
phenyl, (l) --C(O)(C.sub.1-C.sub.6 alkyl), (m)
--C(O)O(C.sub.1-C.sub.6 alkyl), (n) --C(O)O(3-6 membered
cycloalkyl), and (o) --C(O)-phenyl, wherein R.sup.az and R.sup.bz
are each independently selected from (a) H, (b) C.sub.1-C.sub.6
alkyl optionally substituted by OH, halo, CN, --C(O)OH,
--C(O)O--(C.sub.1-C.sub.6alkyl), --C(O)O-(3-11 membered
heterocycloalkyl), --C(O)O--(C.sub.1-C.sub.6
alkyl)-S--(C.sub.1-C.sub.6 alkyl), --S--(C.sub.1-C.sub.6 alkyl),
naphthylenyl, -oxo, --O--(C.sub.1-C.sub.6 alkyl), 5-6 membered
heteroaryl optionally substituted by C.sub.1-C.sub.6 alkyl or halo,
or benzo[1,3]dioxol-2-yl, or 3-11 membered heterocycloalkenyl
optionally substituted by oxo; (c) --(C.sub.1-C.sub.6 alkylene)-3-6
membered cycloalkyl wherein the alkylene is optionally substituted
by OH, halo, or CN; (d) --(C.sub.1-C.sub.6 alkylene)-phenyl wherein
alkylene is optionally substituted by halo and the phenyl is
optionally substituted by OH, halo, CF.sub.3, C.sub.1-C.sub.6
alkyl, --O--(C.sub.1-C.sub.6 alkyl), --S--(C.sub.1-C.sub.6 alkyl,
or --O-phenyl; (e) --(C.sub.1-C.sub.6 alkylene)-4-6 membered
heterocycloalkyl wherein the heterocycloalkyl is optionally
substituted by halo, oxo, or C.sub.1-C.sub.6 alkyl; (f)
--(C.sub.1-C.sub.6 alkylene)-O-phenyl wherein the phenyl is
optionally substituted by halo, C.sub.1-C.sub.6 alkyl, or
--O-phenyl; (g) --(C.sub.1-C.sub.6 alkyl).sub.3-6 membered
cycloalkyl optionally substituted by OH, halo, CN, or
C.sub.1-C.sub.6 alkyl optionally substituted by OH or CN; (h)
C.sub.2-C.sub.5 alkenyl; (i) 4-6 membered heterocycloalkyl
optionally substituted by halo, (j) --(C.sub.1-C.sub.6
alkylene)-3-6 membered cycloalkyl substituted by hydroxymethyl, (k)
phenyl, (l) --C(O)(C.sub.1-C.sub.6 alkyl), (m)
--C(O)O(C.sub.1-C.sub.6 alkyl), (n) --C(O)O(3-6 membered
cycloalkyl), and (o) --C(O)-phenyl, with the following provisos:
when R.sup.0, R.sup.00, and R.sup.01 are each H and Ring Q is
##STR00732## where t.sup.1 is 0, then X.sup.A is not methyl,
2-methylpropan-2-ol, or tetrahydropyranyl.
2. The compound of claim 1, further defined as a compound of
Formula (II): ##STR00733## wherein: w is 0 or 1; R.sup.0b is H or
NH.sub.2; R.sup.1b is selected from the group consisting of a. H,
b. C.sub.1-C.sub.6 alkyl optionally substituted by OH, halo, CN,
--O--(C.sub.1-C.sub.6 alkyl), naphthylenyl, 5-6 membered
heteroaryl, or --C(O)NR.sup.vR.sup.w, wherein R.sup.v and R.sup.w
are independently H or C.sub.1-C.sub.6 alkyl optionally substituted
by halo, c. --(C.sub.1-C.sub.6 alkylene)-3-6 membered cycloalkyl
wherein the cycloalkyl is optionally substituted by CN, d.
--(C.sub.1-C.sub.6 alkylene)-phenyl wherein the alkyl is optionally
substituted by halo and wherein the phenyl is optionally
substituted by OH, halo, CF.sub.3, C.sub.1-C.sub.6 alkyl,
--O--(C.sub.1-C.sub.6 alkyl) or --O-phenyl, e. --(C.sub.1-C.sub.6
alkylene)-4-6 membered heterocycloalkyl wherein the
heterocycloalkyl is optionally substituted by halo or
C.sub.1-C.sub.6 alkyl, f. --(C.sub.1-C.sub.6 alkylene)-O-phenyl
wherein the phenyl is optionally substituted by halo or
C.sub.1-C.sub.6 alkyl, or g. 3-6 membered cycloalkyl; R.sup.2b is
selected from the group consisting of H, C.sub.1-C.sub.6 alkyl
optionally substituted by halo, or C.sub.2-C.sub.5 alkenyl; or
R.sup.1b and R.sup.2b together form a 3-11 membered
heterocycloalkyl optionally substituted by OH; R.sup.3b is absent
or methyl, wherein when R.sup.3b is methyl, the nitrogen to which
it is attached is N+ and w is 1; R.sup.4b is a bond or
C.sub.1-C.sub.6 alkylene; R.sup.5b is selected from the group
consisting of H, OH, and phenyl; and Ring F is a 3-7 membered
heterocycloalkyl wherein p.sup.1b is 0, 1 or 2 and p.sup.2b is 0, 1
or 2; wherein w is equal to 1 only when R.sup.3b is methyl.
3. The compound of claim 1, further defined as a compound of
Formula (Ia) or Formula (Ib): ##STR00734## wherein: R.sup.a is H or
NH.sub.2; R.sup.1a is bound to a nitrogen atom of Ring A in (Ia) or
is bound to a carbon atom of Ring B in (Ib), and is selected from
the group consisting of: a. H, b. C.sub.1-C.sub.6 alkyl optionally
substituted by OH, halo, --O--(C.sub.1-C.sub.6 alkyl),
--SO.sub.2--(C.sub.1-C.sub.6 alkyl), -(2-oxoindolin-1-yl),
--OC(O)-3-6 membered cycloalkyl, --OC(O)-4-6 membered
heterocycloalkyl, or phenyl; c. --(C.sub.1-C.sub.6
alkylene)-O--(C.sub.1-C.sub.6 alkylene)-phenyl wherein the phenyl
is optionally substituted by halo; d. --(C.sub.1-C.sub.6
alkylene)-3-6 membered cycloalkyl wherein the cycloalkyl is
optionally substituted by halo, OH, or CN; e. --(C.sub.1-C.sub.6
alkylene)-4-6 membered heterocycloalkyl, wherein the
heterocycloalkyl is optionally substituted by oxo, C.sub.1-C.sub.6
alkyl, --C(O)--(C.sub.1-C.sub.6 alkyl), --C(O)O--(C.sub.1-C.sub.6
alkyl), --SO.sub.2--(C.sub.1-C.sub.6 alkyl), --C(O)-4-6 membered
heterocycloalkyl, or --C(O)N(C.sub.1-C.sub.6 alkyl)(C.sub.1-C.sub.6
alkyl); f. --C(O)O--(C.sub.1-C.sub.6 alkylene)-OH; and g.
--C(O)O--(C.sub.1-C.sub.6 alkylene)-phenyl; h. --NR.sup.aR.sup.b,
wherein R.sup.a and R.sup.b are independently selected from the
group consisting of H and C.sub.1-C.sub.6 alkyl optionally
substituted by OH, halo, CN, phenyl, and 3-7 membered
heterocycloalkyl; R.sup.2a is selected from the group consisting of
H, C.sub.1-C.sub.6 alkyl optionally substituted by OH, and phenyl;
R.sup.3a is selected from the group consisting of H,
C.sub.1-C.sub.6 alkyl optionally substituted by OH, and phenyl;
Ring A is a 3-7 membered heterocycloalkyl; and Ring B is a 3-7
membered heterocycloalkyl or a 3-7 membered heterocyclyalkenyl,
wherein p.sup.1a is 0, 1 or 2 and p.sup.2a is 0, 1 or 2, provided
that Ring A and Ring B together form a 6-11 membered bicyclic
heterocycloalkyl.
4. The compound of claim 1, further defined as a compound of
Formula (III): ##STR00735## wherein: R.sup.0c is H or NH.sub.2;
R.sup.3 is (i) or (ii): (i) ##STR00736## wherein: R.sup.1c is
selected from the group consisting of H, C.sub.1-C.sub.6 alkyl,
--(C.sub.1-C.sub.6 alkyl)-phenyl, --C(O)--(C.sub.1-C.sub.6 alkyl),
--C(O)-phenyl, and 4-6 membered heterocycloalkyl; R.sup.2c is H or
C.sub.1-C.sub.6 alkyl; and R.sup.3c is a bond or C.sub.1-C.sub.6
alkylene optionally substituted by oxo; or R.sup.1c and R.sup.2c
together form a 3-11 membered heterocycloalkyl optionally
substituted by C.sub.1-C.sub.6 alkyl, oxo, or --(C.sub.1-C.sub.6
alkylene)-phenyl; or R.sup.1c and R.sup.3c together form a 3-7
membered heterocycloalkyl; (ii) H; C.sub.1-C.sub.6 alkyl optionally
substituted by OH, --SO.sub.2--(C.sub.1-C.sub.6 alkyl), phenyl, or
--O--(C.sub.1-C.sub.6 alkylene)-phenyl; --(C.sub.1-C.sub.6
alkylene)-C(O)O(C.sub.1-C.sub.6 alkyl); or 4-6 membered
heterocycloalkyl optionally substituted by --C(O)(C.sub.1-C.sub.6
alkyl); and Ring G is a 3-7 membered heterocycloalkyl wherein
p.sup.1c is 0, 1 or 2 and p.sup.2c is 0, 1 or 2.
5. The compound of claim 1, further defined as a compound of
Formula (IV): ##STR00737## wherein: R.sup.0d is H or NH.sub.2;
R.sup.1d is 3-11 membered heterocycloalkyl or --C(O)-3-11 membered
heterocycloalkyl, wherein the heterocycloalkyl is optionally
substituted C.sub.1-C.sub.6 alkyl, CF.sub.3, or fluoro, or R.sup.1d
is --(C.sub.1-C.sub.6 alkylene)-NR.sup.vR.sup.w, wherein R.sup.v
and R.sup.w are independently H or C.sub.1-C.sub.6 alkyl optionally
substituted by halo.
6. The compound of claim 1, further defined as a compound of
Formula (V): ##STR00738## wherein: R.sup.0e is H or NH.sub.2;
R.sup.1e is selected from the group consisting of a. H, b.
C.sub.1-C.sub.6 alkyl optionally substituted by halo, CN, or
phenyl, c. --(C.sub.1-C.sub.6 alkylene)-3-6 membered cycloalkyl
wherein the cycloalkyl is optionally substituted by CN, d.
--(C.sub.1-C.sub.6 alkylene)-4-6 membered heterocycloalkyl wherein
the heterocycloalkyl is optionally substituted by C.sub.1-C.sub.6
alkyl; R.sup.2e is H or C.sub.1-C.sub.6 alkyl; or R.sup.1e and
R.sup.2e together form a 3-11 membered heterocycloalkyl optionally
substituted by halo or --NR.sup.vR.sup.w, wherein R.sup.v and
R.sup.w are independently H or C.sub.1-C.sub.6 alkyl optionally
substituted by halo; R.sup.3e is a bond or C.sub.1-C.sub.6 alkylene
optionally substituted by oxo; and Ring H is a 3-7 membered
heterocycloalkyl wherein p.sup.1e is 0, 1 or 2 and p.sup.2e is 0, 1
or 2.
7. The compound of claim 1, further defined as a compound of
Formula (VI): ##STR00739## wherein: R.sup.0f is H or NH.sub.2;
R.sup.1f is selected from the group consisting of C.sub.1-C.sub.6
alkyl optionally substituted by halo, 3-6 membered cycloalkyl, or
phenyl; and Ring J is a 6-7 membered heterocycloalkyl wherein
p.sup.1f is 1 or 2 and p.sup.2f is 1 or 2.
8. The compound of claim 1, further defined as a compound of
Formula (VII): ##STR00740## wherein: R.sup.0g is H or NH.sub.2;
R.sup.1g is selected from the group consisting of C.sub.1-C.sub.6
alkyl; R.sup.2g is selected from the group consisting of
C.sub.1-C.sub.6 alkyl.
9. The compound of claim 1, further defined as a compound of
Formula (VIII): ##STR00741## wherein: R.sup.1h is selected from the
group consisting of H and C.sub.1-C.sub.6 alkyl optionally
substituted by CN, 3-6 membered cycloalkyl, or 4-6 membered
heterocycloalkylene-C(O)O--(C.sub.1-C.sub.6 alkylene)-phenyl; Ring
C is 3-7 membered cycloalkyl or 3-7 membered heterocycloalkyl; and
Ring D is a 3-7 membered heterocycloalkyl substituted at the sole
nitrogen by R.sup.1h; and provided Rings C and D together form a
3-11 membered spiro heterocycloalkyl.
10. The compound of claim 1, further defined as a compound of
Formula (IX): ##STR00742## wherein: R.sup.0j is H or NH.sub.2;
R.sup.3j is selected from the group consisting of H and
C.sub.1-C.sub.6 alkyl optionally substituted by OH, 3-6 membered
cycloalkyl, --O--(C.sub.1-C.sub.6 alkyl), --O--(C.sub.1-C.sub.6
alkyl)-OH, --SO.sub.2--(C.sub.1-C.sub.6 alkyl) and phenyl, wherein
the phenyl is optionally substituted by CN; R.sup.4j is selected
from the group consisting of H and C.sub.1-C.sub.6 alkyl optionally
substituted by OH; or R.sup.3j and R.sup.4j together form a
4-6-membered heterocycloalkyl; R.sup.5j is selected from the group
consisting of H and C.sub.1-C.sub.6 alkyl; and Ring K is a 6-7
membered heterocycloalkyl wherein p.sup.1j is 1 or 2 and p.sup.2j
is 1 or 2.
11. The compound of claim 1, further defined as a compound of
Formula (X): ##STR00743## wherein: R.sup.0k is H or NH.sub.2;
R.sup.1k is selected from the group consisting of a. H, b.
C.sub.1-C.sub.6 alkyl optionally substituted by halo, CN, or
phenyl, c. --(C.sub.1-C.sub.6 alkylene)-3-6 membered cycloalkyl
wherein the cycloalkyl is optionally substituted by CN, d.
--(C.sub.1-C.sub.6 alkylene)-4-6 membered heterocycloalkyl wherein
the heterocycloalkyl is optionally substituted by C.sub.1-C.sub.6
alkyl; R.sup.2k is selected from the group consisting of H and
C.sub.1-C.sub.6 alkyl; or R.sup.1k and R.sup.2k together form a
3-11 membered heterocycloalkyl optionally substituted by halo;
C.sub.1-C.sub.6 alkyl optionally substituted by OH; or
--NR.sup.vR.sup.w, wherein R.sup.v and R.sup.w are independently H
or C.sub.1-C.sub.6 alkyl optionally substituted by halo; and
R.sup.3k is a bond, methylene, or --C(.dbd.O)--.
12. The compound of claim 1, wherein X.sup.A and X.sup.B are
independently selected from the group consisting of 3-6-membered
cycloalkyl, 6-10 membered aryl, 5-6 membered heterocycloalkenyl,
and 5-10 membered heteroaryl, wherein each of X.sup.A and X.sup.B
are independently optionally substituted by Y.sup.1.
13. The compound of claim 1, wherein either X.sup.A or X.sup.B is a
3-11 membered heterocycloalkyl optionally substituted by
Y.sup.1.
14. The compound of claim 1, wherein Ring Q is (i).
15. The compound of claim 1, wherein Ring Q is (ii).
16. A pharmaceutical composition comprising a compound of claim 1
and a pharmaceutically acceptable carrier, diluent or
excipient.
17. A method of preventing, treating or lessening the severity of a
disease or condition responsive to the inhibition of a Janus kinase
activity in a patient, comprising administering to the patient a
therapeutically effective amount of a compound of claim 1.
18. The method of claim 17, wherein the disease or condition is
asthma.
19. The method of claim 17, wherein the Janus kinase is JAK1.
20. A kit, comprising the pharmaceutical composition of claim 1,
and printed instructions for administration of the pharmaceutical
composition.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. application Ser.
No. 15/820,515 filed on Nov. 22, 2017, which is a continuation of
U.S. application Ser. No. 15/424,536, filed Feb. 3, 2017, which is
a continuation of U.S. application Ser. No. 15/139,164, filed Apr.
26, 2016, now issued as U.S. Pat. No. 9,604,984, which is a
continuation of U.S. application Ser. No. 14/720,323, filed May 22,
2015, now issued as U.S. Pat. No. 9,346,815, which claims the
benefit of: U.S. Provisional Application No. 62/130,098, filed Mar.
9, 2015, now expired; U.S. Provisional Application No. 62/101,234,
filed Jan. 8, 2015, now expired; U.S. Provisional Application No.
62/002,547, filed May 23, 2014, now expired; and International
Application No. PCT/CN2015/077176, filed Apr. 22, 2015, each of
which is incorporated herein by reference in its entirety.
FIELD OF THE INVENTION
[0002] The field of the invention pertains to compounds of Formula
(00A), and subformulas thereof, which are inhibitors of a Janus
kinase, such as JAK1, as well as compositions containing these
compounds, and methods of use including, but not limited to,
diagnosis or treatment of patients suffering from a condition
responsive to the inhibition of a JAK kinase.
BACKGROUND OF INVENTION
[0003] Cytokine pathways mediate a broad range of biological
functions, including many aspects of inflammation and immunity.
Janus kinases (JAK), including JAK1, JAK2, JAK3 and TYK2, are
cytoplasmic protein kinases that associate with type I and type II
cytokine receptors and regulate cytokine signal transduction.
Cytokine engagement with cognate receptors triggers activation of
receptor associated JAKs and this leads to JAK-mediated tyrosine
phosphorylation of signal transducer and activator of transcription
(STAT) proteins and ultimately transcriptional activation of
specific gene sets (Schindler et al., 2007, J. Biol. Chem. 282:
20059-63). JAK1, JAK2 and TYK2 exhibit broad patterns of gene
expression, while JAK3 expression is limited to leukocytes.
Cytokine receptors are typically functional as heterodimers, and as
a result, more than one type of JAK kinase is usually associated
with cytokine receptor complexes. The specific JAKs associated with
different cytokine receptor complexes have been determined in many
cases through genetic studies and corroborated by other
experimental evidence.
[0004] Exemplary therapeutic benefits of the inhibition of JAK
enzymes are discussed, for example, in International Application
No. WO 2013/014567.
[0005] JAK1 was initially identified in a screen for novel kinases
(Wilks A. F., 1989, Proc. Natl. Acad. Sci. U.S.A. 86:1603-1607).
Genetic and biochemical studies have shown that JAK1 is
functionally and physically associated with the type I interferon
(e.g., IFNalpha), type II interferon (e.g., IFNgamma), and IL-2 and
IL-6 cytokine receptor complexes (Kisseleva et al., 2002, Gene
285:1-24; Levy et al., 2005, Nat. Rev. Mol. Cell Biol. 3:651-662;
O'Shea et al., 2002, Cell, 109 (suppl.): S121-S131). JAK1 knockout
mice die perinatally due to defects in LIF receptor signaling
(Kisseleva et al., 2002, Gene 285:1-24; O'Shea et al., 2002, Cell,
109 (suppl.): S121-S131). Characterization of tissues derived from
JAK1 knockout mice demonstrated critical roles for this kinase in
the IFN, IL-10, IL-2/IL-4 and IL-6 pathways. A humanized monoclonal
antibody targeting the IL-6 pathway (Tocilizumab) was approved by
the European Commission for the treatment of moderate-to-severe
rheumatoid arthritis (Scheinecker et al., 2009, Nat. Rev. Drug
Discov. 8:273-274).
[0006] CD4 T cells play an important role in asthma pathogenesis
through the production of TH2 cytokines within the lung, including
IL-4, IL-9 and IL-13 (Cohn et al., 2004, Annu. Rev. Immunol.
22:789-815). IL-4 and IL-13 induce increased mucus production,
recruitment of eosinophils to the lung, and increased production of
IgE (Kasaian et al., 2008, Biochem. Pharmacol. 76(2): 147-155).
IL-9 leads to mast cell activation, which exacerbates the asthma
symptoms (Kearley et al., 2011, Am. J. Resp. Crit. Care Med.,
183(7): 865-875). The IL-4R.alpha. chain activates JAK1 and binds
to either IL-4 or IL-13 when combined with the common gamma chain
or the IL-13R.alpha.1 chain respectively (Pernis et al., 2002, J.
Clin. Invest. 109(10):1279-1283). The common gamma chain can also
combine with IL-9R.alpha. to bind to IL-9, and IL-9R.alpha.
activates JAK1 as well (Demoulin et al., 1996, Mol. Cell Biol.
16(9):4710-4716). While the common gamma chain activates JAK3, it
has been shown that JAK1 is dominant over JAK3, and inhibition of
JAK1 is sufficient to inactivate signaling through the common gamma
chain despite JAK3 activity (Haan et al., 2011, Chem. Biol.
18(3):314-323). Inhibition of IL-4, IL-13 and IL-9 signaling by
blocking the JAK/STAT signaling pathway can alleviate asthmatic
symptoms in pre-clinical lung inflammation models (Mathew et al.,
2001, J. Exp. Med. 193(9): 1087-1096; Kudlacz et. al., 2008, Eur.
J. Pharmacol. 582(1-3): 154-161).
[0007] Biochemical and genetic studies have shown an association
between JAK2 and single-chain (e.g., EPO), IL-3 and interferon
gamma cytokine receptor families (Kisseleva et al., 2002, Gene
285:1-24; Levy et al., 2005, Nat. Rev. Mol. Cell Biol. 3:651-662;
O'Shea et al., 2002, Cell, 109 (suppl.): S121-S131). Consistent
with this, JAK2 knockout mice die of anemia (O'Shea et al., 2002,
Cell, 109 (suppl.): S121-S131).
[0008] Kinase activating mutations in JAK2 (e.g., JAK2 V617F) are
associated with myeloproliferative disorders in humans.
[0009] JAK3 associates exclusively with the gamma common cytokine
receptor chain, which is present in the IL-2, IL-4, IL-7, IL-9,
IL-15 and IL-21 cytokine receptor complexes. JAK3 is critical for
lymphoid cell development and proliferation and mutations in JAK3
result in severe combined immunodeficiency (SCID) (O'Shea et al.,
2002, Cell, 109 (suppl.): S121-S131). Based on its role in
regulating lymphocytes, JAK3 and JAK3-mediated pathways have been
targeted for immunosuppressive indications (e.g., transplantation
rejection and rheumatoid arthritis) (Baslund et al., 2005,
Arthritis & Rheumatism 52:2686-2692; Changelian et al., 2003,
Science 302: 875-878).
[0010] TYK2 associates with the type I interferon (e.g., IFNalpha),
IL-6, IL-10, IL-12 and IL-23 cytokine receptor complexes (Kisseleva
et al., 2002, Gene 285:1-24; Watford, W. T. & O'Shea, J. J.,
2006, Immunity 25:695-697). Consistent with this, primary cells
derived from a TYK2 deficient human are defective in type I
interferon, IL-6, IL-10, IL-12 and IL-23 signaling. A fully human
monoclonal antibody targeting the shared p40 subunit of the IL-12
and IL-23 cytokines (Ustekinumab) was recently approved by the
European Commission for the treatment of moderate-to-severe plaque
psoriasis (Krueger et al., 2007, N. Engl. J. Med. 356:580-92; Reich
et al., 2009, Nat. Rev. Drug Discov. 8:355-356). In addition, an
antibody targeting the IL-12 and IL-23 pathways underwent clinical
trials for treating Crohn's Disease (Mannon et al., 2004, N. Engl.
J. Med. 351:2069-79).
[0011] There exists a need in the art for additional or alternative
treatments of conditions mediated by JAK kinases, such as those
described above.
SUMMARY OF INVENTION
[0012] Provided herein are 5-chloro-2-difluoromethoxyphenyl
pyrazolopyrimidine compounds that inhibit one or more JAK
kinases.
[0013] Accordingly, one aspect of the invention includes a compound
of Formula (00A):
##STR00001##
and stereoisomers and salts thereof, wherein: R.sup.00 is H or
CH.sub.3; R.sup.01 is H or NH.sub.2; R.sup.0 is H or NH.sub.2; and
Ring Q is either (i) or (ii): [0014] (i)
[0014] ##STR00002## [0015] (ii)
##STR00003##
[0015] wherein: t.sup.1 and t.sup.2 are each independently 0 or 1;
X.sup.A and X.sup.B are independently selected from the group
consisting of H, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.4 alkenyl,
--NR.sup.aR.sup.b, C.sub.2-C.sub.5 alkynyl, 3-6-membered
cycloalkyl, 6-10 membered aryl, 3-11 membered heterocycloalkyl, 5-6
membered heterocycloalkenyl, and 5-10 membered heteroaryl; wherein
when either of X.sup.A and X.sup.B are independently
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.4 alkenyl, C.sub.2-C.sub.5
alkynyl, 3-6-membered cycloalkyl, 6-10 membered aryl, 3-11 membered
heterocycloalkyl, 5-6 membered heterocycloalkenyl, and 5-10
membered heteroaryl, each of X.sup.A and X.sup.B is independently
optionally substituted by Y.sup.1, wherein Y.sup.1 is selected
from: [0016] (a) C.sub.1-C.sub.6 alkyl optionally substituted by
T.sup.1, wherein T.sup.1 is selected from the group consisting of
OH, halo, CN, imino, 3-6 membered cycloalkyl, 3-11 membered
heterocycloalkyl, 3-11 membered heterocycloalkenyl, 5-10 membered
heteroaryl, --O--(C.sub.1-C.sub.6 alkyl), C(O)OH,
oxetan-3-ylmethyl, --C(O)O--(C.sub.1-C.sub.6 alkyl),
--S--(C.sub.1-C.sub.6 alkyl), --SO.sub.2--(C.sub.1-C.sub.6 alkyl),
--NR.sup.aR.sup.b, --N(+)R.sup.aR.sup.bR.sup.c wherein R.sup.c is
methyl, --C(O)NR.sup.aR.sup.b, -(2-oxoindolin-1-yl), --OC(O)-3-6
membered cycloalkyl, and phenyl, wherein each alkyl, cycloalkyl,
heterocycloalkyl, heterocycloalkenyl, heteroaryl, and phenyl of Ti
is optionally substituted by OH, --C(O)O--(C.sub.1-C.sub.6 alkyl),
C.sub.1-C.sub.6 alkyl, halo, CN, oxo, --(C.sub.1-C.sub.6
alkyl)CONR.sup.aR.sup.b, --NR.sup.aR.sup.b, phenyl, or
--O--(C.sub.1-C.sub.6 alkyl) optionally substituted by OH; [0017]
(b) 3-11 membered heterocycloalkyl, --(C.sub.1-C.sub.6
alkylene)-3-11 membered heterocycloalkyl, --C(O)-3-11 membered
heterocycloalkyl, --(C.sub.1-C.sub.6 alkylene)C(O)-3-11 membered
heterocycloalkyl, or --OC(O)-4-6 membered heterocycloalkyl; wherein
the heterocycloalkyl is optionally substituted by OH, halo, CN,
C.sub.1-C.sub.6 alkyl, --(C.sub.1-C.sub.6 alkylene)-CF.sub.3, oxo,
--C(O)--(C.sub.1-C.sub.6 alkyl), --C(O)O--(C.sub.1-C.sub.6 alkyl),
--C(O)O--(C.sub.1-C.sub.6 alkylene)-phenyl,
--SO.sub.2--(C.sub.1-C.sub.6 alkyl), --C(O)NR.sup.aR.sup.b,
--NR.sup.aR.sup.b, --(C.sub.1-C.sub.6 alkylene)-phenyl, or
--C(O)-4-6 membered heterocycloalkyl optionally substituted by
--NR.sup.aR.sup.b; (c) N(+)(AA).sub.3, wherein each AA is
independently C.sub.1-C.sub.6 alkyl optionally substituted by
phenyl; [0018] (d) 3-6 membered cycloalkyl optionally substituted
by OH, halo, NR.sup.aR.sup.b, or CN; (e) CN, halo, or oxo; [0019]
(f) --C(O)--(C.sub.1-C.sub.6 alkyl), --C(O)OH,
--C(O)O--(C.sub.1-C.sub.6 alkylene)-phenyl,
--SO.sub.2--(C.sub.1-C.sub.6 alkyl), --C(O)NR.sup.aR.sup.b, or
--C(O)-4-6 membered heterocycloalkyl optionally substituted by
--(C.sub.1-C.sub.6 alkyl) or --NR.sup.aR.sup.b, or
--C(O)O--(C.sub.1-C.sub.6 alkyl) optionally substituted by OH,
NR.sup.aR.sup.b, or 3-11 membered heterocycloalkyl wherein said
heterocycloalkyl is optionally substituted by C.sub.1-C.sub.6
alkyl; [0020] (g) OH, --O-phenyl, or --O--(C.sub.1-C.sub.6 alkyl),
wherein the alkyl is optionally substituted by OH or
--NR.sup.aR.sup.b; [0021] (h) phenyl optionally substituted by OH,
halo, C.sub.1-C.sub.6 alkyl, CF.sub.3, or CN; [0022] (i) 5-6
membered heteroaryl optionally substituted by OH, halo,
C.sub.1-C.sub.6 alkyl, CF.sub.3, CN, or 3-11 membered
heterocycloalkyl optionally substituted by C.sub.1-C.sub.6 alkyl or
3-11 membered heterocycloalkyl; [0023] (j) isoindolin-2-yl
optionally substituted by halo; [0024] (k) --NR.sup.aR.sup.b, and
[0025] (l) --O--CH.sub.2C(O)-3-11 membered heterocycloalkyl; [0026]
wherein R.sup.a and R.sup.b are independently selected from: [0027]
(a) H, [0028] (b) C.sub.1-C.sub.6 alkyl optionally substituted by
OH, halo, CN, --C(O)OH, --C(O)O--(C.sub.1-C.sub.6alkyl),
--C(O)O-(3-11 membered heterocycloalkyl), --C(O)O--(C.sub.1-C.sub.6
alkyl)-S--(C.sub.1-C.sub.6 alkyl), --S--(C.sub.1-C.sub.6 alkyl),
naphthylenyl, --NR.sup.azR.sup.bz, --C(O)NR.sup.azR.sup.bz, oxo,
--O--(C.sub.1-C.sub.6 alkyl), 5-6 membered heteroaryl optionally
substituted by C.sub.1-C.sub.6 alkyl or halo, or
benzo[1,3]dioxol-2-yl, or 3-11 membered heterocycloalkenyl
optionally substituted by oxo; [0029] (c) --(C.sub.1-C.sub.6
alkylene)-3-6 membered cycloalkyl wherein the alkylene is
optionally substituted by OH, halo, or CN; [0030] (d)
--(C.sub.1-C.sub.6 alkylene)-phenyl wherein alkylene is optionally
substituted by halo and the phenyl is optionally substituted by OH,
halo, CF.sub.3, C.sub.1-C.sub.6 alkyl, --O--(C.sub.1-C.sub.6
alkyl), --S--(C.sub.1-C.sub.6 alkyl, or --O-phenyl; [0031] (e)
--(C.sub.1-C.sub.6 alkylene)-4-6 membered heterocycloalkyl wherein
the heterocycloalkyl is optionally substituted by halo, oxo, or
C.sub.1-C.sub.6 alkyl; [0032] (f) --(C.sub.1-C.sub.6
alkylene)-O-phenyl wherein the phenyl is optionally substituted by
halo, C.sub.1-C.sub.6 alkyl, or --O-phenyl; [0033] (g)
--(C.sub.1-C.sub.6 alkyl)3-6 membered cycloalkyl optionally
substituted by OH, halo, CN, or C.sub.1-C.sub.6 alkyl optionally
substituted by OH or CN; [0034] (h) C.sub.2-C.sub.5 alkenyl; [0035]
(i) 4-6 membered heterocycloalkyl optionally substituted by halo,
[0036] (j) --(C.sub.1-C.sub.6 alkylene)-3-6 membered cycloalkyl
substituted by hydroxymethyl, [0037] (k) phenyl, [0038] (l)
--C(O)(C.sub.1-C.sub.6 alkyl), [0039] (m) --C(O)O(C.sub.1-C.sub.6
alkyl), [0040] (n) --C(O)O(3-6 membered cycloalkyl), and [0041] (o)
--C(O)-phenyl, wherein R.sup.az and R.sup.bz are each independently
selected from [0042] (a) H, [0043] (b) C.sub.1-C.sub.6 alkyl
optionally substituted by OH, halo, CN, --C(O)OH,
--C(O)O--(C.sub.1-C.sub.6alkyl), --C(O)O-(3-11 membered
heterocycloalkyl), --C(O)O--(C.sub.1-C.sub.6
alkyl)-S--(C.sub.1-C.sub.6 alkyl), --S--(C.sub.1-C.sub.6 alkyl),
naphthylenyl, -oxo, --O--(C.sub.1-C.sub.6 alkyl), 5-6 membered
heteroaryl optionally substituted by C.sub.1-C.sub.6 alkyl or halo,
or benzo[1,3]dioxol-2-yl, or 3-11 membered heterocycloalkenyl
optionally substituted by oxo; [0044] (c) --(C.sub.1-C.sub.6
alkylene)-3-6 membered cycloalkyl wherein the alkylene is
optionally substituted by OH, halo, or CN; [0045] (d)
--(C.sub.1-C.sub.6 alkylene)-phenyl wherein alkylene is optionally
substituted by halo and the phenyl is optionally substituted by OH,
halo, CF.sub.3, C.sub.1-C.sub.6 alkyl, --O--(C.sub.1-C.sub.6
alkyl), --S--(C.sub.1-C.sub.6 alkyl, or --O-phenyl; [0046] (e)
--(C.sub.1-C.sub.6 alkylene)-4-6 membered heterocycloalkyl wherein
the heterocycloalkyl is optionally substituted by halo, oxo, or
C.sub.1-C.sub.6 alkyl; [0047] (f) --(C.sub.1-C.sub.6
alkylene)-O-phenyl wherein the phenyl is optionally substituted by
halo, C.sub.1-C.sub.6 alkyl, or --O-phenyl; [0048] (g)
--(C.sub.1-C.sub.6 alkyl)3-6 membered cycloalkyl optionally
substituted by OH, halo, CN, or C.sub.1-C.sub.6 alkyl optionally
substituted by OH or CN; [0049] (h) C.sub.2-C.sub.5 alkenyl; [0050]
(i) 4-6 membered heterocycloalkyl optionally substituted by halo,
[0051] (j) --(C.sub.1-C.sub.6 alkylene)-3-6 membered cycloalkyl
substituted by hydroxymethyl, [0052] (k) phenyl, [0053] (l)
--C(O)(C.sub.1-C.sub.6 alkyl), [0054] (m) --C(O)O(C.sub.1-C.sub.6
alkyl), [0055] (n) --C(O)O(3-6 membered cycloalkyl), and [0056] (o)
--C(O)-phenyl, with the following provisos: when R.sup.0, R.sup.00,
and R.sup.01 are each H and Ring Q is
##STR00004##
[0056] where t.sup.1 is 0, then X.sup.A is not methyl,
2-methylpropan-2-ol, or tetrahydropyranyl; and, in some
embodiments, when Ring Q is (i) and t.sup.1 is 0, then X.sup.A
cannot be --NR.sup.aR.sup.b.
[0057] Further, another aspect of the invention includes a compound
of Formula (00A), further defined as a compound of Formula
(0A):
##STR00005##
and stereoisomers and salts thereof, wherein: R.sup.00 is H or
CH.sub.3; R.sup.01 is H or NH.sub.2; R.sup.0 is H or NH.sub.2; and
Ring Q is either (i) or (ii): [0058] (i)
[0058] ##STR00006## [0059] (ii)
##STR00007##
[0059] wherein: t.sup.1 and t.sup.2 are each independently 0 or 1;
X.sup.A and X.sup.B are independently selected from the group
consisting of H, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.4 alkenyl,
--NR.sup.aR.sup.b, C.sub.2-C.sub.5 alkynyl, 3-6-membered
cycloalkyl, 6-10 membered aryl, 3-11 membered heterocycloalkyl, 5-6
membered heterocycloalkenyl, and 5-10 membered heteroaryl; wherein
when either of X.sup.A and X.sup.B are independently
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.5 alkynyl, 3-6-membered
cycloalkyl, 6-10 membered aryl, 3-11 membered heterocycloalkyl, 5-6
membered heterocycloalkenyl, and 5-10 membered heteroaryl, each of
X.sup.A and X.sup.B are independently optionally substituted by
Y.sup.1, wherein Y.sup.1 is selected from: [0060] (a)
C.sub.1-C.sub.6 alkyl optionally substituted by T.sup.1, wherein
T.sup.1 is selected from the group consisting of OH, halo, CN,
imino, 3-6 membered cycloalkyl, 3-11 membered heterocycloalkyl,
3-11 membered heterocycloalkenyl, 5-10 membered heteroaryl,
--O--(C.sub.1-C.sub.6 alkyl), C(O)OH, oxetan-3-ylmethyl,
--C(O)O--(C.sub.1-C.sub.6 alkyl), --S--(C.sub.1-C.sub.6 alkyl),
--SO.sub.2--(C.sub.1-C.sub.6 alkyl), --NR.sup.aR.sup.b,
--N(+)R.sup.aR.sup.bR.sup.c wherein R.sup.c is methyl,
--C(O)NR.sup.aR.sup.b, -(2-oxoindolin-1-yl), --OC(O)-3-6 membered
cycloalkyl, and phenyl, wherein each alkyl, cycloalkyl,
heterocycloalkyl, heterocycloalkenyl, heteroaryl, and phenyl of Ti
is optionally substituted by OH, --C(O)O--(C.sub.1-C.sub.6 alkyl),
C.sub.1-C.sub.6 alkyl, halo, CN, oxo, --NR.sup.aR.sup.b, phenyl, or
--O--(C.sub.1-C.sub.6 alkyl) optionally substituted by OH; [0061]
(b) 3-11 membered heterocycloalkyl, --(C.sub.1-C.sub.6
alkylene)-3-11 membered heterocycloalkyl, --C(O)-3-11 membered
heterocycloalkyl, --(C.sub.1-C.sub.6 alkylene)C(O)-3-11 membered
heterocycloalkyl, or --OC(O)-4-6 membered heterocycloalkyl; wherein
the heterocycloalkyl is optionally substituted by OH, halo, CN,
C.sub.1-C.sub.6 alkyl, --(C.sub.1-C.sub.6 alkylene)-CF.sub.3, oxo,
--C(O)--(C.sub.1-C.sub.6 alkyl), --C(O)O--(C.sub.1-C.sub.6 alkyl),
--C(O)O--(C.sub.1-C.sub.6 alkylene)-phenyl,
--SO.sub.2--(C.sub.1-C.sub.6 alkyl), --C(O)NR.sup.aR.sup.b,
--NR.sup.aR.sup.b, --(C.sub.1-C.sub.6 alkylene)-phenyl, or
--C(O)-4-6 membered heterocycloalkyl optionally substituted by
--NR.sup.aR.sup.b; (c) N(+)(AA).sub.3, wherein each AA is
independently C.sub.1-C.sub.6 alkyl optionally substituted by
phenyl; [0062] (d) 3-6 membered cycloalkyl optionally substituted
by OH, halo, or CN; [0063] (e) CN, halo, or oxo; [0064] (f)
--C(O)--(C.sub.1-C.sub.6 alkyl), --C(O)OH,
--C(O)O--(C.sub.1-C.sub.6 alkylene)-phenyl,
--SO.sub.2--(C.sub.1-C.sub.6 alkyl), --C(O)NR.sup.aR.sup.b, or
--C(O)-4-6 membered heterocycloalkyl optionally substituted by
--NR.sup.aR.sup.b, or --C(O)O--(C.sub.1-C.sub.6 alkyl) optionally
substituted by OH, NR.sup.aR.sup.b, or 3-11 membered
heterocycloalkyl wherein said heterocycloalkyl is optionally
substituted by C.sub.1-C.sub.6 alkyl; [0065] (g) OH, --O-phenyl, or
--O--(C.sub.1-C.sub.6 alkyl), wherein the alkyl is optionally
substituted by OH or --NR.sup.aR.sup.b; [0066] (h) phenyl
optionally substituted by OH, halo, C.sub.1-C.sub.6 alkyl,
CF.sub.3, or CN; (i) 5-6 membered heteroaryl optionally substituted
by OH, halo, C.sub.1-C.sub.6 alkyl, CF.sub.3, or CN; [0067] (j)
isoindolin-2-yl optionally substituted by halo; and [0068] (k)
--NR.sup.aR.sup.b, [0069] wherein R.sup.a and R.sup.b are
independently selected from: [0070] (a) H, [0071] (b)
C.sub.1-C.sub.6 alkyl optionally substituted by OH, halo, CN,
--C(O)OH, --C(O)O--(C.sub.1-C.sub.6alkyl), --C(O)O-(3-11 membered
heterocycloalkyl), --C(O)O--(C.sub.1-C.sub.6
alkyl)-S--(C.sub.1-C.sub.6 alkyl), --S--(C.sub.1-C.sub.6 alkyl),
naphthylenyl, --NR.sup.azR.sup.bz, --C(O)NR.sup.azR.sup.bz, oxo,
--O--(C.sub.1-C.sub.6 alkyl), 5-6 membered heteroaryl optionally
substituted by C.sub.1-C.sub.6 alkyl or halo, or
benzo[1,3]dioxol-2-yl, or 3-11 membered heterocycloalkenyl
optionally substituted by oxo; [0072] (c) --(C.sub.1-C.sub.6
alkylene)-3-6 membered cycloalkyl wherein the alkylene is
optionally substituted by OH, halo, or CN; [0073] (d)
--(C.sub.1-C.sub.6 alkylene)-phenyl wherein alkylene is optionally
substituted by halo and the phenyl is optionally substituted by OH,
halo, CF.sub.3, C.sub.1-C.sub.6 alkyl, --O--(C.sub.1-C.sub.6
alkyl), --S--(C.sub.1-C.sub.6 alkyl, or --O-phenyl; [0074] (e)
--(C.sub.1-C.sub.6 alkylene)-4-6 membered heterocycloalkyl wherein
the heterocycloalkyl is optionally substituted by halo, oxo, or
C.sub.1-C.sub.6 alkyl; [0075] (f) --(C.sub.1-C.sub.6
alkylene)-O-phenyl wherein the phenyl is optionally substituted by
halo, C.sub.1-C.sub.6 alkyl, or --O-phenyl; [0076] (g) 3-6 membered
cycloalkyl optionally substituted by OH, halo, CN, or
C.sub.1-C.sub.6 alkyl optionally substituted by OH; [0077] (h)
C.sub.2-C.sub.5 alkenyl; [0078] (i) 4-6 membered heterocycloalkyl
optionally substituted by halo, (j) --(C.sub.1-C.sub.6
alkylene)-3-6 membered cycloalkyl substituted by hydroxymethyl,
[0079] (k) phenyl, [0080] (l) --C(O)(C.sub.1-C.sub.6 alkyl), [0081]
(m) --C(O)O(C.sub.1-C.sub.6 alkyl), [0082] (n) --C(O)O(3-6 membered
cycloalkyl), and [0083] (o) --C(O)-phenyl, wherein R.sup.az and
R.sup.bz are each independently selected from [0084] (a) H, [0085]
(b) C.sub.1-C.sub.6 alkyl optionally substituted by OH, halo, CN,
--C(O)OH, --C(O)O--(C.sub.1-C.sub.6alkyl), --C(O)O-(3-11 membered
heterocycloalkyl), --C(O)O--(C.sub.1-C.sub.6
alkyl)-S--(C.sub.1-C.sub.6 alkyl), --S--(C.sub.1-C.sub.6 alkyl),
naphthylenyl, -oxo, --O--(C.sub.1-C.sub.6 alkyl), 5-6 membered
heteroaryl optionally substituted by C.sub.1-C.sub.6 alkyl or halo,
or benzo[1,3]dioxol-2-yl, or 3-11 membered heterocycloalkenyl
optionally substituted by oxo; [0086] (c) --(C.sub.1-C.sub.6
alkylene)-3-6 membered cycloalkyl wherein the alkylene is
optionally substituted by OH, halo, or CN; [0087] (d)
--(C.sub.1-C.sub.6 alkylene)-phenyl wherein alkylene is optionally
substituted by halo and the phenyl is optionally substituted by OH,
halo, CF.sub.3, C.sub.1-C.sub.6 alkyl, --O--(C.sub.1-C.sub.6
alkyl), --S--(C.sub.1-C.sub.6 alkyl, or --O-phenyl; [0088] (e)
--(C.sub.1-C.sub.6 alkylene)-4-6 membered heterocycloalkyl wherein
the heterocycloalkyl is optionally substituted by halo, oxo, or
C.sub.1-C.sub.6 alkyl; [0089] (f) --(C.sub.1-C.sub.6
alkylene)-O-phenyl wherein the phenyl is optionally substituted by
halo, C.sub.1-C.sub.6 alkyl, or --O-phenyl; [0090] (g)
--(C.sub.1-C.sub.6 alkyl)3-6 membered cycloalkyl optionally
substituted by OH, halo, CN, or C.sub.1-C.sub.6 alkyl optionally
substituted by OH or CN; [0091] (h) C.sub.2-C.sub.5 alkenyl; [0092]
(i) 4-6 membered heterocycloalkyl optionally substituted by halo,
[0093] (j) --(C.sub.1-C.sub.6 alkylene)-3-6 membered cycloalkyl
substituted by hydroxymethyl, [0094] (k) phenyl, [0095] (l)
--C(O)(C.sub.1-C.sub.6 alkyl), [0096] (m) --C(O)O(C.sub.1-C.sub.6
alkyl), [0097] (n) --C(O)O(3-6 membered cycloalkyl), and [0098] (o)
--C(O)-phenyl, with the following provisos: when R.sup.0, R.sup.00,
and R.sup.01 are each H and Ring Q is
##STR00008##
[0098] where t.sup.1 is 0, then X.sup.A is not methyl,
2-methylpropan-2-ol, or tetrahydropyranyl; and, in some
embodiments, when Ring Q is (i) and t.sup.1 is 0, then X.sup.A
cannot be --NR.sup.aR.sup.b.
[0099] Another aspect of the invention includes a compound of
Formula (00A), further defined as a compound of Formula (A):
##STR00009##
and stereoisomers and salts thereof, wherein: R.sup.00 is H or
CH.sub.3; R.sup.01 is H or NH.sub.2; R.sup.0 is H or NH.sub.2; and
Ring Q is either (i) or (ii): [0100] (i)
[0100] ##STR00010## [0101] (ii)
##STR00011##
[0101] wherein: t.sup.1 and t.sup.2 are each independently 0 or 1;
X.sup.A and X.sup.B are independently selected from the group
consisting of H, C.sub.1-C.sub.6 alkyl, --NR.sup.aR.sup.b,
C.sub.2-C.sub.5 alkynyl, 3-6-membered cycloalkyl, 6-10 membered
aryl, 3-11 membered heterocycloalkyl, 5-6 membered
heterocycloalkenyl, and 5-10 membered heteroaryl; wherein when
either of X.sup.A and X.sup.B are independently C.sub.1-C.sub.6
alkyl, C.sub.2-C.sub.5 alkynyl, 3-6-membered cycloalkyl, 6-10
membered aryl, 3-11 membered heterocycloalkyl, 5-6 membered
heterocycloalkenyl, and 5-10 membered heteroaryl, each of X.sup.A
and X.sup.B are independently optionally substituted by Y.sup.1,
wherein Y.sup.1 is selected from: [0102] (a) C.sub.1-C.sub.6 alkyl
optionally substituted by T.sup.1, wherein T.sup.1 is selected from
the group consisting of OH, halo, CN, imino, 3-6 membered
cycloalkyl, --O--(C.sub.1-C.sub.6 alkyl), --C(O)O--(C.sub.1-C.sub.6
alkyl), --SO.sub.2--(C.sub.1-C.sub.6 alkyl), --NR.sup.aR.sup.b,
--N(+)R.sup.aR.sup.bR.sup.c wherein R.sup.c is methyl,
--C(O)NR.sup.aR.sup.b, -(2-oxoindolin-1-yl), --OC(O)-3-6 membered
cycloalkyl, and phenyl, wherein each alkyl, cycloalkyl, and phenyl
of T.sup.1 is optionally substituted by OH, C.sub.1-C.sub.6 alkyl,
halo, CN, oxo, --NR.sup.aR.sup.b, phenyl, or --O--(C.sub.1-C.sub.6
alkyl) optionally substituted by OH; [0103] (b) 3-11 membered
heterocycloalkyl, --(C.sub.1-C.sub.6 alkylene)-3-11 membered
heterocycloalkyl, --C(O)-3-11 membered heterocycloalkyl,
--(C.sub.1-C.sub.6 alkylene)C(O)-3-11 membered heterocycloalkyl, or
--OC(O)-4-6 membered heterocycloalkyl; wherein the heterocycloalkyl
is optionally substituted by OH, halo, CN, C.sub.1-C.sub.6 alkyl,
--(C.sub.1-C.sub.6 alkylene)-CF.sub.3, oxo,
--C(O)--(C.sub.1-C.sub.6 alkyl), --C(O)O--(C.sub.1-C.sub.6 alkyl),
--C(O)O--(C.sub.1-C.sub.6 alkylene)-phenyl,
--SO.sub.2--(C.sub.1-C.sub.6 alkyl), --C(O)NR.sup.aR.sup.b,
--NR.sup.aR.sup.b, --(C.sub.1-C.sub.6 alkylene)-phenyl, or
--C(O)-4-6 membered heterocycloalkyl optionally substituted by
--NR.sup.aR.sup.b; [0104] (c) N(+)(AA).sub.3, wherein each AA is
independently C.sub.1-C.sub.6 alkyl optionally substituted by
phenyl; [0105] (d) 3-6 membered cycloalkyl optionally substituted
by OH, halo, or CN; (e) CN, halo, or oxo; [0106] (f)
--C(O)--(C.sub.1-C.sub.6 alkyl), --C(O)O--(C.sub.1-C.sub.6 alkyl)
optionally substituted by OH, --C(O)OH, --C(O)O--(C.sub.1-C.sub.6
alkylene)-phenyl, --SO.sub.2--(C.sub.1-C.sub.6 alkyl),
--C(O)NR.sup.aR.sup.b, or --C(O)-4-6 membered heterocycloalkyl
optionally substituted by --NR.sup.aR.sup.b, [0107] (g) OH,
--O-phenyl, or --O--(C.sub.1-C.sub.6 alkyl), wherein the alkyl is
optionally substituted by OH or --NR.sup.aR.sup.b; [0108] (h)
phenyl optionally substituted by OH, halo, C.sub.1-C.sub.6 alkyl,
CF.sub.3, or CN; [0109] (i) 5-6 membered heteroaryl optionally
substituted by OH, halo, C.sub.1-C.sub.6 alkyl, CF.sub.3, or CN;
[0110] (j) isoindolin-2-yl optionally substituted by halo; and
[0111] (k) --NR.sup.aR.sup.b, [0112] wherein R.sup.a and R.sup.b
are independently selected from: [0113] (a) H, [0114] (b)
C.sub.1-C.sub.6 alkyl optionally substituted by OH, halo, CN,
naphthylenyl, --NR.sup.azR.sup.bz, --C(O)NR.sup.azR.sup.bz, oxo,
--O--(C.sub.1-C.sub.6 alkyl), phenyl, 5-6 membered heteroaryl
optionally substituted by C.sub.1-C.sub.6 alkyl or halo, or
benzo[1,3]dioxol-2-yl; [0115] (c) --(C.sub.1-C.sub.6 alkylene)-3-6
membered cycloalkyl wherein the alkylene is optionally substituted
by OH, halo, or CN; [0116] (d) --(C.sub.1-C.sub.6 alkylene)-phenyl
wherein alkylene is optionally substituted by halo and the phenyl
is optionally substituted by OH, halo, CF.sub.3, C.sub.1-C.sub.6
alkyl, --O--(C.sub.1-C.sub.6 alkyl), or --O-phenyl; [0117] (e)
--(C.sub.1-C.sub.6 alkylene)-4-6 membered heterocycloalkyl wherein
the heterocycloalkyl is optionally substituted by halo or
C.sub.1-C.sub.6 alkyl; [0118] (f) --(C.sub.1-C.sub.6
alkylene)-O-phenyl wherein the phenyl is optionally substituted by
halo, C.sub.1-C.sub.6 alkyl, or --O-phenyl; [0119] (g) 3-6 membered
cycloalkyl optionally substituted by OH, halo, CN, or
C.sub.1-C.sub.6 alkyl optionally substituted by OH; [0120] (h)
C.sub.2-C.sub.5 alkenyl; [0121] (i) 4-6 membered heterocycloalkyl
optionally substituted by halo, [0122] (j) --(C.sub.1-C.sub.6
alkylene)-3-6 membered cycloalkyl substituted by hydroxymethyl,
[0123] (k) phenyl, [0124] (l) --C(O)(C.sub.1-C.sub.6 alkyl), [0125]
(m) --C(O)O(C.sub.1-C.sub.6 alkyl), [0126] (n) --C(O)O(3-6 membered
cycloalkyl), and [0127] (o) --C(O)-phenyl, wherein R.sup.az and
R.sup.bz are each independently selected from [0128] (a) H, [0129]
(b) C.sub.1-C.sub.6 alkyl optionally substituted by OH, halo, CN,
--C(O)OH, --C(O)O--(C.sub.1-C.sub.6alkyl), --C(O)O-(3-11 membered
heterocycloalkyl), --C(O)O--(C.sub.1-C.sub.6
alkyl)-S--(C.sub.1-C.sub.6 alkyl), --S--(C.sub.1-C.sub.6 alkyl),
naphthylenyl, -oxo, --O--(C.sub.1-C.sub.6 alkyl), 5-6 membered
heteroaryl optionally substituted by C.sub.1-C.sub.6 alkyl or halo,
or benzo[1,3]dioxol-2-yl, or 3-11 membered heterocycloalkenyl
optionally substituted by oxo; [0130] (c) --(C.sub.1-C.sub.6
alkylene)-3-6 membered cycloalkyl wherein the alkylene is
optionally substituted by OH, halo, or CN; [0131] (d)
--(C.sub.1-C.sub.6 alkylene)-phenyl wherein alkylene is optionally
substituted by halo and the phenyl is optionally substituted by OH,
halo, CF.sub.3, C.sub.1-C.sub.6 alkyl, --O--(C.sub.1-C.sub.6
alkyl), --S--(C.sub.1-C.sub.6 alkyl, or --O-phenyl; [0132] (e)
--(C.sub.1-C.sub.6 alkylene)-4-6 membered heterocycloalkyl wherein
the heterocycloalkyl is optionally substituted by halo, oxo, or
C.sub.1-C.sub.6 alkyl; [0133] (f) --(C.sub.1-C.sub.6
alkylene)-O-phenyl wherein the phenyl is optionally substituted by
halo, C.sub.1-C.sub.6 alkyl, or --O-phenyl; [0134] (g)
--(C.sub.1-C.sub.6 alkyl)3-6 membered cycloalkyl optionally
substituted by OH, halo, CN, or C.sub.1-C.sub.6 alkyl optionally
substituted by OH or CN; [0135] (h) C.sub.2-C.sub.5 alkenyl; [0136]
(i) 4-6 membered heterocycloalkyl optionally substituted by halo,
[0137] (j) --(C.sub.1-C.sub.6 alkylene)-3-6 membered cycloalkyl
substituted by hydroxymethyl, [0138] (k) phenyl, [0139] (l)
--C(O)(C.sub.1-C.sub.6 alkyl), [0140] (m) --C(O)O(C.sub.1-C.sub.6
alkyl), [0141] (n) --C(O)O(3-6 membered cycloalkyl), and [0142] (o)
--C(O)-phenyl, with the following provisos: when R.sup.0, R.sup.00,
and R.sup.01 are each H and Ring Q is
##STR00012##
[0142] where t.sup.1 is 0, then X.sup.A is not methyl,
2-methylpropan-2-ol, or tetrahydropyranyl; and, in some
embodiments, when Ring Q is (i) and t.sup.1 is 0, then X.sup.A
cannot be --NR.sup.aR.sup.b.
[0143] Also provided are pharmaceutical compositions comprising a
5-chloro-2-difluoromethoxyphenyl pyrazolopyrimidine as described
herein, such as a compound of Formula (00A) and a pharmaceutically
acceptable carrier, dilient or excipient.
[0144] The present invention also provides, in some embodiments,
use of a 5-chloro-2-difluoromethoxyphenyl pyrazolopyrimidine
compound as described herein, such as a compound of Formula (00A),
in therapy, such as in the treatment of an inflammatory disease.
Also provided are uses of a 5-chloro-2-difluoromethoxyphenyl
pyrazolopyrimidine compound as described herein, such as a compound
of Formula (00A), for the preparation of a medicament for the
treatment of an inflammatory disease. Also provided is a method of
preventing, treating or lessening the severity of a disease or
condition responsive to the inhibition of a Janus kinase activity
in a patient, comprising administering to the patient a
therapeutically effective amount of a
5-chloro-2-difluoromethoxyphenyl pyrazolopyrimidine compound as
described herein, such as a compound of Formula (00A).
DESCRIPTION OF THE DRAWINGS
[0145] The foregoing aspects and many of the attendant advantages
will become more readily appreciated as the same become better
understood by reference to the following detailed description, when
taken in conjunction with the accompanying drawings, where:
[0146] FIG. 1 depicts a matched pair analysis of certain compounds
of the present invention containing either an OMe (i) or OCHF.sub.2
(ii) group at the indicated position.
DETAILED DESCRIPTION OF THE INVENTION
Definitions
[0147] "Halogen" or "halo" refers to F, Cl, Br or I. Additionally,
terms such as "haloalkyl," are meant to include monohaloalkyl and
polyhaloalkyl.
[0148] The term "alkyl" refers to a saturated linear or
branched-chain monovalent hydrocarbon radical, wherein the alkyl
radical may be optionally substituted. In one example, the alkyl
radical is one to eighteen carbon atoms (C.sub.1-C.sub.18). In
other examples, the alkyl radical is C.sub.0-C.sub.6,
C.sub.0-C.sub.5, C.sub.0-C.sub.3, C.sub.1-C.sub.12,
C.sub.1-C.sub.10, C.sub.1-C.sub.8, C.sub.1-C.sub.6,
C.sub.1-C.sub.5, C.sub.1-C.sub.4, or C.sub.1-C.sub.3. C.sub.0 alkyl
refers to a bond. Examples of alkyl groups include methyl (Me,
--CH.sub.3), ethyl (Et, --CH.sub.2CH.sub.3), 1-propyl (n-Pr,
n-propyl, --CH.sub.2CH.sub.2CH.sub.3), 2-propyl (i-Pr, i-propyl,
--CH(CH.sub.3).sub.2), 1-butyl (n-Bu, n-butyl,
--CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 2-methyl-1-propyl (i-Bu,
i-butyl, --CH.sub.2CH(CH.sub.3).sub.2), 2-butyl (s-Bu, s-butyl,
--CH(CH.sub.3)CH.sub.2CH.sub.3), 2-methyl-2-propyl (t-Bu, t-butyl,
--C(CH.sub.3).sub.3), 1-pentyl (n-pentyl,
--CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 2-pentyl
(--CH(CH.sub.3)CH.sub.2CH.sub.2CH.sub.3), 3-pentyl
(--CH(CH.sub.2CH.sub.3).sub.2), 2-methyl-2-butyl
(--C(CH.sub.3).sub.2CH.sub.2CH.sub.3), 3-methyl-2-butyl
(--CH(CH.sub.3)CH(CH.sub.3).sub.2), 3-methyl-1-butyl
(--CH.sub.2CH.sub.2CH(CH.sub.3).sub.2), 2-methyl-1-butyl
(--CH.sub.2CH(CH.sub.3)CH.sub.2CH.sub.3), 1-hexyl
(--CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 2-hexyl
(--CH(CH.sub.3)CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 3-hexyl
(--CH(CH.sub.2CH.sub.3)(CH.sub.2CH.sub.2CH.sub.3)),
2-methyl-2-pentyl (--C(CH.sub.3).sub.2CH.sub.2CH.sub.2CH.sub.3),
3-methyl-2-pentyl (--CH(CH.sub.3)CH(CH.sub.3)CH.sub.2CH.sub.3),
4-methyl-2-pentyl (--CH(CH.sub.3)CH.sub.2CH(CH.sub.3).sub.2),
3-methyl-3-pentyl (--C(CH.sub.3)(CH.sub.2CH.sub.3).sub.2),
2-methyl-3-pentyl (--CH(CH.sub.2CH.sub.3)CH(CH.sub.3).sub.2),
2,3-dimethyl-2-butyl (--C(CH.sub.3).sub.2CH(CH.sub.3).sub.2),
3,3-dimethyl-2-butyl (--CH(CH.sub.3)C(CH.sub.3).sub.3, 1-heptyl and
1-octyl. In some embodiments, substituents for "optionally
substituted alkyls" include one to four instances of F, Cl, Br, I,
OH, SH, CN, NH.sub.2, NHCH.sub.3, N(CH.sub.3).sub.2, NO.sub.2,
N.sub.3, C(O)CH.sub.3, COOH, CO.sub.2CH.sub.3, methyl, ethyl,
propyl, iso-propyl, butyl, isobutyl, cyclopropyl, methoxy, ethoxy,
propoxy, oxo, trifluoromethyl, difluoromethyl, sulfonylamino,
methanesulfonylamino, SO, SO.sub.2, phenyl, piperidinyl,
piperizinyl, and pyrimidinyl, wherein the alkyl, phenyl and
heterocyclic portions thereof may be optionally substituted, such
as by one to four instances of substituents selected from this same
list.
[0149] The term "alkenyl" refers to linear or branched-chain
monovalent hydrocarbon radical with at least one site of
unsaturation, i.e., a carbon-carbon double bond, wherein the
alkenyl radical may be optionally substituted, and includes
radicals having "cis" and "trans" orientations, or alternatively,
"E" and "Z" orientations. In one example, the alkenyl radical is
two to eighteen carbon atoms (C.sub.2-C.sub.18). In other examples,
the alkenyl radical is C.sub.2-C.sub.12, C.sub.2-C.sub.10,
C.sub.2-C.sub.8, C.sub.2-C.sub.6 or C.sub.2-C.sub.3. Examples
include, but are not limited to, ethenyl or vinyl
(--CH.dbd.CH.sub.2), prop-1-enyl (--CH.dbd.CHCH.sub.3), prop-2-enyl
(--CH.sub.2CH.dbd.CH.sub.2), 2-methylprop-1-enyl, but-1-enyl,
but-2-enyl, but-3-enyl, buta-1,3-dienyl, 2-methylbuta-1,3-diene,
hex-1-enyl, hex-2-enyl, hex-3-enyl, hex-4-enyl and hexa-1,3-dienyl.
In some embodiments, substituents for "optionally substituted
alkenyls" include one to four instances of F, Cl, Br, I, OH, SH,
CN, NH.sub.2, NHCH.sub.3, N(CH.sub.3).sub.2, NO.sub.2, N.sub.3,
C(O)CH.sub.3, COOH, CO.sub.2CH.sub.3, methyl, ethyl, propyl,
iso-propyl, butyl, isobutyl, cyclopropyl, methoxy, ethoxy, propoxy,
oxo, trifluoromethyl, difluoromethyl, sulfonylamino,
methanesulfonylamino, SO, SO.sub.2, phenyl, piperidinyl,
piperizinyl, and pyrimidinyl, wherein the alkyl, phenyl and
heterocyclic portions thereof may be optionally substituted, such
as by one to four instances of substituents selected from this same
list.
[0150] The term "alkynyl" refers to a linear or branched monovalent
hydrocarbon radical with at least one site of unsaturation, i.e., a
carbon-carbon, triple bond, wherein the alkynyl radical may be
optionally substituted. In one example, the alkynyl radical is two
to eighteen carbon atoms (C.sub.2-C.sub.18). In other examples, the
alkynyl radical is C.sub.2-C.sub.12, C.sub.2-C.sub.10,
C.sub.2-C.sub.8, C.sub.2-C.sub.6 or C.sub.2-C.sub.3. Examples
include, but are not limited to, ethynyl (--C.ident.CH),
prop-1-ynyl (--C.ident.CCH.sub.3), prop-2-ynyl (propargyl,
--CH.sub.2C.ident.CH), but-1-ynyl, but-2-ynyl and but-3-ynyl. In
some embodiments, substituents for "optionally substituted
alkynyls" include one to four instances of F, Cl, Br, I, OH, SH,
CN, NH.sub.2, NHCH.sub.3, N(CH.sub.3).sub.2, NO.sub.2, N.sub.3,
C(O)CH.sub.3, COOH, CO.sub.2CH.sub.3, methyl, ethyl, propyl,
iso-propyl, butyl, isobutyl, cyclopropyl, methoxy, ethoxy, propoxy,
oxo, trifluoromethyl, difluoromethyl, sulfonylamino,
methanesulfonylamino, SO, SO.sub.2, phenyl, piperidinyl,
piperizinyl, and pyrimidinyl, wherein the alkyl, phenyl and
heterocyclic portions thereof may be optionally substituted, such
as by one to four instances of substituents selected from this same
list.
[0151] "Alkylene" refers to a saturated, branched or straight chain
hydrocarbon group having two monovalent radical centers derived by
the removal of two hydrogen atoms from the same or two different
carbon atoms of a parent alkane. In one example, the divalent
alkylene group is one to eighteen carbon atoms (C.sub.1-C.sub.18).
In other examples, the divalent alkylene group is C.sub.0-C.sub.6,
C.sub.0-C.sub.5, C.sub.0-C.sub.3, C.sub.1-C.sub.12,
C.sub.1-C.sub.10, C.sub.1-C.sub.8, C.sub.1-C.sub.6,
C.sub.1-C.sub.5, C.sub.1-C.sub.4, or C.sub.1-C.sub.3. The group
C.sub.0 alkylene refers to a bond. Example alkylene groups include
methylene (--CH.sub.2--), 1,1-ethyl (--CH(CH.sub.3)--), (1,2-ethyl
(--CH.sub.2CH.sub.2--), 1,1-propyl (--CH(CH.sub.2CH.sub.3)--),
2,2-propyl (--C(CH.sub.3).sub.2--), 1,2-propyl
(--CH(CH.sub.3)CH.sub.2--), 1,3-propyl
(--CH.sub.2CH.sub.2CH.sub.2--), 1,1-dimethyleth-1,2-yl
(--C(CH.sub.3).sub.2CH.sub.2--), 1,4-butyl
(--CH.sub.2CH.sub.2CH.sub.2CH.sub.2--), and the like.
[0152] The term "heteroalkyl" refers to a straight or branched
chain monovalent hydrocarbon radical, consisting of the stated
number of carbon atoms, or, if none are stated, up to 18 carbon
atoms, and from one to five heteroatoms selected from the group
consisting of O, N, Si and S, and wherein the nitrogen and sulfur
atoms can optionally be oxidized and the nitrogen heteroatom can
optionally be quaternized. In some embodiments, the heteroatom is
selected from O, N and S, wherein the nitrogen and sulfur atoms can
optionally be oxidized and the nitrogen heteroatom can optionally
be quaternized. The heteroatom(s) can be placed at any interior
position of the heteroalkyl group, including the position at which
the alkyl group is attached to the remainder of the molecule (e.g.,
--O--CH.sub.2--CH.sub.3). Examples include
--CH.sub.2--CH.sub.2--O--CH.sub.3,
--CH.sub.2--CH.sub.2--NH--CH.sub.3,
--CH.sub.2--CH.sub.2--N(CH.sub.3)--CH.sub.3,
--CH.sub.2--S--CH.sub.2--CH.sub.3, --S(O)--CH.sub.3,
--CH.sub.2--CH.sub.2--S(O).sub.2--CH.sub.3, --Si(CH.sub.3).sub.3
and --CH.sub.2--CH.dbd.N--OCH.sub.3. Up to two heteroatoms can be
consecutive, such as, for example, --CH.sub.2--NH--OCH.sub.3 and
--CH.sub.2--O--Si(CH.sub.3).sub.3. Heteroalkyl groups can be
optionally substituted. In some embodiments, substituents for
"optionally substituted heteroalkyls" include one to four instances
of F, Cl, Br, I, OH, SH, CN, NH.sub.2, NHCH.sub.3,
N(CH.sub.3).sub.2, NO.sub.2, N.sub.3, C(O)CH.sub.3, COOH,
CO.sub.2CH.sub.3, methyl, ethyl, propyl, iso-propyl, butyl,
isobutyl, cyclopropyl, methoxy, ethoxy, propoxy, oxo,
trifluoromethyl, difluoromethyl, sulfonylamino,
methanesulfonylamino, SO, SO.sub.2, phenyl, piperidinyl,
piperizinyl, and pyrimidinyl, wherein the alkyl, phenyl and
heterocyclic portions thereof may be optionally substituted, such
as by one to four instances of substituents selected from this same
list.
[0153] "Amino" means primary (i.e., --NH.sub.2), secondary (i.e.,
--NRH), tertiary (i.e., --NRR) and quaternary (i.e., --N(+)RRR)
amines, that are optionally substituted, in which each R is the
same or different and selected from alkyl, cycloalkyl, aryl, and
heterocyclyl, wherein the alkyl, cycloalkyl, aryl and heterocyclyl
groups are as defined herein. Particular secondary and tertiary
amines are alkylamine, dialkylamine, arylamine, diarylamine,
aralkylamine and diaralkylamine, wherein the alkyl and aryl
portions can be optionally substituted. Particular secondary and
tertiary amines are methylamine, ethylamine, propylamine,
isopropylamine, phenylamine, benzylamine, dimethylamine,
diethylamine, dipropylamine and diisopropylamine. In some
embodiments, R groups of a quaternary amine are each independently
optionally substituted alkyl groups.
[0154] "Aryl" refers to a carbocyclic aromatic group, whether or
not fused to one or more groups, having the number of carbon atoms
designated, or if no number is designated, up to 14 carbon atoms.
One example includes aryl groups having 6-14 carbon atoms. Another
example includes aryl groups having 6-10 carbon atoms. Examples of
aryl groups include phenyl, naphthyl, biphenyl, phenanthrenyl,
naphthacenyl, 1,2,3,4-tetrahydronaphthalenyl, 1H-indenyl,
2,3-dihydro-1H-indenyl, and the like (see, e.g., Lang's Handbook of
Chemistry (Dean, J. A., ed.) 13.sup.th ed. Table 7-2 [1985]). A
particular aryl is phenyl. Substituted phenyl or substituted aryl
means a phenyl group or aryl group substituted with one, two,
three, four or five substituents, for example, 1-2, 1-3 or 1-4
substituents, such as chosen from groups specified herein (see
"optionally substituted" definition), such as F, Cl, Br, I, OH, SH,
CN, NH.sub.2, NHCH.sub.3, N(CH.sub.3).sub.2, NO.sub.2, N.sub.3,
C(O)CH.sub.3, COOH, CO.sub.2CH.sub.3, methyl, ethyl, propyl,
iso-propyl, butyl, isobutyl, cyclopropyl, methoxy, ethoxy, propoxy,
oxo, trifluoromethyl, difluoromethyl, sulfonylamino,
methanesulfonylamino, SO, SO.sub.2, phenyl, piperidinyl,
piperizinyl, and pyrimidinyl, wherein the alkyl, phenyl and
heterocyclic portions thereof may be optionally substituted, such
as by one to four instances of substituents selected from this same
list. Examples of the term "substituted phenyl" include a mono- or
di(halo)phenyl group such as 2-chlorophenyl, 2-bromophenyl,
4-chlorophenyl, 2,6-dichlorophenyl, 2,5-dichlorophenyl,
3,4-dichlorophenyl, 3-chlorophenyl, 3-bromophenyl, 4-bromophenyl,
3,4-dibromophenyl, 3-chloro-4-fluorophenyl, 2-fluorophenyl,
2,4-difluorophenyl and the like; a mono- or di(hydroxy)phenyl group
such as 4-hydroxyphenyl, 3-hydroxyphenyl, 2,4-dihydroxyphenyl, the
protected-hydroxy derivatives thereof and the like; a nitrophenyl
group such as 3- or 4-nitrophenyl; a cyanophenyl group, for
example, 4-cyanophenyl; a mono- or di(alkyl)phenyl group such as
4-methylphenyl, 2,4-dimethylphenyl, 2-methylphenyl,
4-(isopropyl)phenyl, 4-ethylphenyl, 3-(n-propyl)phenyl and the
like; a mono or di(alkoxy)phenyl group, for example,
3,4-dimethoxyphenyl, 3-methoxy-4-benzyloxyphenyl, 3-ethoxyphenyl,
4-(isopropoxy)phenyl, 4-(t-butoxy)phenyl, 3-ethoxy-4-methoxyphenyl
and the like; 3- or 4-trifluoromethylphenyl; a mono- or
dicarboxyphenyl or (protected carboxy)phenyl group such
4-carboxyphenyl, a mono- or di(hydroxymethyl)phenyl or (protected
hydroxymethyl)phenyl such as 3-(protected hydroxymethyl)phenyl or
3,4-di(hydroxymethyl)phenyl; a mono- or di(aminomethyl)phenyl or
(protected aminomethyl)phenyl such as 2-(aminomethyl)phenyl or
2,4-(protected aminomethyl)phenyl; or a mono- or di(N-(methyl
sulfonylamino))phenyl such as 3-(N-methyl sulfonylamino))phenyl.
Also, the term "substituted phenyl" represents disubstituted phenyl
groups where the substituents are different, for example,
3-methyl-4-hydroxyphenyl, 3-chloro-4-hydroxyphenyl,
2-methoxy-4-bromophenyl, 4-ethyl-2-hydroxyphenyl,
3-hydroxy-4-nitrophenyl, 2-hydroxy-4-chlorophenyl,
2-chloro-5-difluoromethoxy and the like, as well as trisubstituted
phenyl groups where the substituents are different, for example
3-methoxy-4-benzyloxy-6-methyl sulfonylamino,
3-methoxy-4-benzyloxy-6-phenyl sulfonylamino, and tetrasubstituted
phenyl groups where the substituents are different such as
3-methoxy-4-benzyloxy-5-methyl-6-phenyl sulfonylamino. In some
embodiments, a substituent of an aryl, such as phenyl, comprises an
amide. For example, an aryl (e.g., phenyl) substituent may be
--(CH.sub.2).sub.0-4CONR'R'', wherein R' and R'' each independently
refer to groups including, for example, hydrogen; unsubstituted
C.sub.1-C.sub.6 alkyl; C.sub.1-C.sub.6 alkyl substituted by
halogen, OH, CN, unsubstituted C.sub.1-C.sub.6 alkyl, unsubstituted
C.sub.1-C.sub.6 alkoxy, oxo or NR'R''; unsubstituted
C.sub.1-C.sub.6 heteroalkyl; C.sub.1-C.sub.6 heteroalkyl
substituted by halogen, OH, CN, unsubstituted C.sub.1-C.sub.6
alkyl, unsubstituted C.sub.1-C.sub.6 alkoxy, oxo or NR'R'';
unsubstituted C.sub.6-C.sub.10 aryl; C.sub.6-C.sub.10 aryl
substituted by halogen, OH, CN, unsubstituted C.sub.1-C.sub.6
alkyl, unsubstituted C.sub.1-C.sub.6 alkoxy, or NR'R'';
unsubstituted 3-11 membered heterocyclyl (e.g., 5-6 membered
heteroaryl containing 1 to 4 heteroatoms selected from O, N and S
or 4-11 membered heterocycloalkyl containing 1 to 4 heteroatoms
selected from O, N and S); and 3-11 membered heterocyclyl (e.g.,
5-6 membered heteroaryl containing 1 to 4 heteroatoms selected from
O, N and S or 4-11 membered heterocycloalkyl containing 1 to 4
heteroatoms selected from O, N and S) substituted by halogen, OH,
CN, unsubstituted C.sub.1-C.sub.6 alkyl, unsubstituted
C.sub.1-C.sub.6 alkoxy, oxo or NR'R''; or R' and R'' can be
combined with the nitrogen atom to form a 3-, 4-, 5-, 6-, or
7-membered ring wherein a ring atom is optionally substituted with
N, O or S and wherein the ring is optionally substituted with
halogen, OH, CN, unsubstituted C.sub.1-C.sub.6 alkyl, unsubstituted
C.sub.1-C.sub.6 alkoxy, oxo or NR'R''.
[0155] "Cycloalkyl" refers to a non-aromatic, saturated or
partially unsaturated hydrocarbon ring group wherein the cycloalkyl
group may be optionally substituted independently with one or more
substituents described herein. In one example, the cycloalkyl group
is 3 to 12 carbon atoms (C.sub.3-C.sub.12). In other examples,
cycloalkyl is C.sub.3-C.sub.8, C.sub.3-C.sub.10 or
C.sub.5-C.sub.10. In other examples, the cycloalkyl group, as a
monocycle, is C.sub.3-C.sub.8, C.sub.3-C.sub.6 or C.sub.5-C.sub.6.
In another example, the cycloalkyl group, as a bicycle, is
C.sub.7-C.sub.12. In another example, the cycloalkyl group, as a
spiro system, is C.sub.5-C.sub.12. Examples of monocyclic
cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl,
1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl,
cyclohexyl, perdeuteriocyclohexyl, 1-cyclohex-1-enyl,
1-cyclohex-2-enyl, 1-cyclohex-3-enyl, cyclohexadienyl, cycloheptyl,
cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl and cyclododecyl.
Exemplary arrangements of bicyclic cycloalkyls having 7 to 12 ring
atoms include, but are not limited to, [4,4], [4,5], [5,5], [5,6]
or [6,6] ring systems. Exemplary bridged bicyclic cycloalkyls
include, but are not limited to, bicyclo[2.2.1]heptane,
bicyclo[2.2.2]octane and bicyclo[3.2.2]nonane. Examples of spiro
cycloalkyl include, spiro[2.2]pentane, spiro[2.3]hexane,
spiro[2.4]heptane, spiro[2.5]octane and spiro[4.5]decane. In some
embodiments, substituents for "optionally substituted cycloalkyls"
include one to four instances of F, Cl, Br, I, OH, SH, CN,
NH.sub.2, NHCH.sub.3, N(CH.sub.3).sub.2, NO.sub.2, N.sub.3,
C(O)CH.sub.3, COOH, CO.sub.2CH.sub.3, methyl, ethyl, propyl,
iso-propyl, butyl, isobutyl, cyclopropyl, methoxy, ethoxy, propoxy,
oxo, trifluoromethyl, difluoromethyl, sulfonylamino,
methanesulfonyl amino, SO, SO.sub.2, phenyl, piperidinyl,
piperizinyl, and pyrimidinyl, wherein the alkyl, aryl and
heterocyclic portions thereof may be optionally substituted, such
as by one to four instances of substituents selected from this same
list. In some embodiments, a substituent of a cycloalkyl comprises
an amide. For example, a cycloalkyl substituent may be
--(CH.sub.2).sub.0-4CONR'R'', wherein R' and R'' each independently
refer to groups including, for example, hydrogen; unsubstituted
C.sub.1-C.sub.6 alkyl; C.sub.1-C.sub.6 alkyl substituted by
halogen, OH, CN, unsubstituted C.sub.1-C.sub.6 alkyl, unsubstituted
C.sub.1-C.sub.6 alkoxy, oxo or NR'R''; unsubstituted
C.sub.1-C.sub.6 heteroalkyl; C.sub.1-C.sub.6 heteroalkyl
substituted by halogen, OH, CN, unsubstituted C.sub.1-C.sub.6
alkyl, unsubstituted C.sub.1-C.sub.6 alkoxy, oxo or NR'R'';
unsubstituted C.sub.6-C.sub.10 aryl; C.sub.6-C.sub.10 aryl
substituted by halogen, OH, CN, unsubstituted C.sub.1-C.sub.6
alkyl, unsubstituted C.sub.1-C.sub.6 alkoxy, or NR'R'';
unsubstituted 3-11 membered heterocyclyl (e.g., 5-6 membered
heteroaryl containing 1 to 4 heteroatoms selected from O, N and S
or 4-11 membered heterocycloalkyl containing 1 to 4 heteroatoms
selected from O, N and S); and 3-11 membered heterocyclyl (e.g.,
5-6 membered heteroaryl containing 1 to 4 heteroatoms selected from
O, N and S or 4-11 membered heterocycloalkyl containing 1 to 4
heteroatoms selected from O, N and S) substituted by halogen, OH,
CN, unsubstituted C.sub.1-C.sub.6 alkyl, unsubstituted
C.sub.1-C.sub.6 alkoxy, oxo or NR'R''; or R' and R'' can be
combined with the nitrogen atom to form a 3-, 4-, 5-, 6-, or
7-membered ring wherein a ring atom is optionally substituted with
N, O or S and wherein the ring is optionally substituted with
halogen, OH, CN, unsubstituted C.sub.1-C.sub.6 alkyl, unsubstituted
C.sub.1-C.sub.6 alkoxy, oxo or NR'R''.
[0156] "Guanidine" or "guanidinyl" means the group --NH--C(NH)--NHR
in which R is hydrogen, alkyl, cycloalkyl, aryl or heterocyclyl,
wherein the alkyl, cycloalkyl, aryl and heterocyclyl groups are as
defined herein. A particular guanidine is the group
--NH--C(NH)--NH.sub.2.
[0157] "Heterocyclic group", "heterocyclic", "heterocycle",
"heterocyclyl", or "heterocyclo" are used interchangeably and refer
to any mono-, bi-, tricyclic or spiro, saturated or unsaturated,
aromatic (heteroaryl) or non-aromatic (e.g., heterocycloalkyl),
ring system, having 3 to 20 ring atoms, where the ring atoms are
carbon, and at least one atom in the ring or ring system is a
heteroatom selected from nitrogen, sulfur or oxygen. If any ring
atom of a cyclic system is a heteroatom, that system is a
heterocycle, regardless of the point of attachment of the cyclic
system to the rest of the molecule. In one example, heterocyclyl
includes 3-11 ring atoms ("members") and includes monocycles,
bicycles, tricycles and spiro ring systems, wherein the ring atoms
are carbon, where at least one atom in the ring or ring system is a
heteroatom selected from nitrogen, sulfur or oxygen. In one
example, heterocyclyl includes 1 to 4 heteroatoms. In one example,
heterocyclyl includes 1 to 3 heteroatoms. In another example,
heterocyclyl includes 3- to 7-membered monocycles having 1-2, 1-3
or 1-4 heteroatoms selected from nitrogen, sulfur or oxygen. In
another example, heterocyclyl includes 4- to 6-membered monocycles
having 1-2, 1-3 or 1-4 heteroatoms selected from nitrogen, sulfur
or oxygen. In another example, heterocyclyl includes 3-membered
monocycles. In another example, heterocyclyl includes 4-membered
monocycles. In another example, heterocyclyl includes 5-6 membered
monocycles, e.g., 5-6 membered heteroaryl. In another example,
heterocyclyl includes 3-11 membered heterocycloyalkyls, such as
4-11 membered heterocycloalkyls. In some embodiments, a
heterocycloalkyl includes at least one nitrogen. In one example,
the heterocyclyl group includes 0 to 3 double bonds. Any nitrogen
or sulfur heteroatom may optionally be oxidized (e.g., NO, SO,
SO.sub.2), and any nitrogen heteroatom may optionally be
quaternized (e.g., [NR.sub.4].sup.+Cl.sup.-,
[NR.sub.4].sup.+OH.sup.-). Example heterocycles are oxiranyl,
aziridinyl, thiiranyl, azetidinyl, oxetanyl, thietanyl,
1,2-dithietanyl, 1,3-dithietanyl, pyrrolidinyl,
dihydro-1H-pyrrolyl, dihydrofuranyl, tetrahydrofuranyl,
dihydrothienyl, tetrahydrothienyl, imidazolidinyl, piperidinyl,
piperazinyl, isoquinolinyl, tetrahydroisoquinolinyl, morpholinyl,
thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, dihydropyranyl,
tetrahydropyranyl, hexahydrothiopyranyl, hexahydropyrimidinyl,
oxazinanyl, thiazinanyl, thioxanyl, homopiperazinyl,
homopiperidinyl, azepanyl, oxepanyl, thiepanyl, oxazepinyl,
oxazepanyl, diazepanyl, 1,4-diazepanyl, diazepinyl, thiazepinyl,
thiazepanyl, tetrahydrothiopyranyl, oxazolidinyl, thiazolidinyl,
isothiazolidinyl, 1,1-dioxoisothiazolidinonyl, oxazolidinonyl,
imidazolidinonyl, 4,5,6,7-tetrahydro[2H]indazolyl,
tetrahydrobenzoimidazolyl, 4,5,6,7-tetrahydrobenzo[d]imidazolyl,
1,6-dihydroimidazol[4,5-d]pyrrolo[2,3-b]pyridinyl, thiazinyl,
oxazinyl, thiadiazinyl, oxadiazinyl, dithiazinyl, dioxazinyl,
oxathiazinyl, thiatriazinyl, oxatriazinyl, dithiadiazinyl,
imidazolinyl, dihydropyrimidyl, tetrahydropyrimidyl, 1-pyrrolinyl,
2-pyrrolinyl, 3-pyrrolinyl, indolinyl, thiapyranyl, 2H-pyranyl,
4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, pyrazolidinyl,
dithianyl, dithiolanyl, pyrimidinonyl, pyrimidindionyl,
pyrimidin-2,4-dionyl, piperazinonyl, piperazindionyl,
pyrazolidinylimidazolinyl, 3-azabicyclo[3.1.0]hexanyl,
3,6-diazabicyclo[3.1.1]heptanyl, 6-azabicyclo[3.1.1]heptanyl,
3-azabicyclo[3.1.1]heptanyl, 3-azabicyclo[4.1.0]heptanyl,
azabicyclo[2.2.2]hexanyl, 2-azabicyclo[3.2.1]octanyl,
8-azabicyclo[3.2.1]octanyl, 2-azabicyclo[2.2.2]octanyl,
8-azabicyclo[2.2.2]octanyl, 7-oxabicyclo[2.2.1]heptane,
azaspiro[3.5]nonanyl, azaspiro[2.5]octanyl, azaspiro[4.5]decanyl,
1-azaspiro[4.5]decan-2-only, azaspiro[5.5]undecanyl,
tetrahydroindolyl, octahydroindolyl, tetrahydroisoindolyl,
tetrahydroindazolyl, 1,1-dioxohexahydrothiopyranyl. Examples of
5-membered heterocycles containing a sulfur or oxygen atom and one
to three nitrogen atoms are thiazolyl, including thiazol-2-yl and
thiazol-2-yl N-oxide, thiadiazolyl, including 1,3,4-thiadiazol-5-yl
and 1,2,4-thiadiazol-5-yl, oxazolyl, for example oxazol-2-yl, and
oxadiazolyl, such as 1,3,4-oxadiazol-5-yl, and
1,2,4-oxadiazol-5-yl. Example 5-membered ring heterocycles
containing 2 to 4 nitrogen atoms include imidazolyl, such as
imidazol-2-yl; triazolyl, such as 1,3,4-triazol-5-yl;
1,2,3-triazol-5-yl, 1,2,4-triazol-5-yl, and tetrazolyl, such as
1H-tetrazol-5-yl. Example benzo-fused 5-membered heterocycles are
benzoxazol-2-yl, benzthiazol-2-yl and benzimidazol-2-yl. Example
6-membered heterocycles contain one to three nitrogen atoms and
optionally a sulfur or oxygen atom, for example pyridyl, such as
pyrid-2-yl, pyrid-3-yl, and pyrid-4-yl; pyrimidyl, such as
pyrimid-2-yl and pyrimid-4-yl; triazinyl, such as
1,3,4-triazin-2-yl and 1,3,5-triazin-4-yl; pyridazinyl, in
particular pyridazin-3-yl, and pyrazinyl. The pyridine N-oxides and
pyridazine N-oxides and the pyridyl, pyrimid-2-yl, pyrimid-4-yl,
pyridazinyl and the 1,3,4-triazin-2-yl groups, are other example
heterocycle groups. Heterocycles may be optionally substituted. For
example, substituents for "optionally substituted heterocycles"
include one to four instances of F, Cl, Br, I, OH, SH, CN,
NH.sub.2, NHCH.sub.3, N(CH.sub.3).sub.2, NO.sub.2, N.sub.3,
C(O)CH.sub.3, COOH, CO.sub.2CH.sub.3, methyl, ethyl, propyl,
iso-propyl, butyl, isobutyl, cyclopropyl, methoxy, ethoxy, propoxy,
oxo, trifluoromethyl, difluoromethyl, sulfonylamino,
methanesulfonyl amino, SO, SO.sub.2, phenyl, piperidinyl,
piperizinyl, and pyrimidinyl, wherein the alkyl, aryl and
heterocyclic portions thereof may be optionally substituted, such
as by one to four instances of substituents selected from this same
list. In some embodiments, a substituent of a heterocyclic group,
such as a heteroaryl or heterocycloalkyl, comprises an amide. For
example, a heterocyclic (e.g., heteroaryl or heterocycloalkyl)
substituent may be --(CH.sub.2).sub.0-4CONR'R'', wherein R' and R''
each independently refer to groups including, for example,
hydrogen; unsubstituted C.sub.1-C.sub.6 alkyl; C.sub.1-C.sub.6
alkyl substituted by halogen, OH, CN, unsubstituted C.sub.1-C.sub.6
alkyl, unsubstituted C.sub.1-C.sub.6 alkoxy, oxo or NR'R'';
unsubstituted C.sub.1-C.sub.6 heteroalkyl; C.sub.1-C.sub.6
heteroalkyl substituted by halogen, OH, CN, unsubstituted
C.sub.1-C.sub.6 alkyl, unsubstituted C.sub.1-C.sub.6 alkoxy, oxo or
NR'R''; unsubstituted C.sub.6-C.sub.10 aryl; C.sub.6-C.sub.10 aryl
substituted by halogen, OH, CN, unsubstituted C.sub.1-C.sub.6
alkyl, unsubstituted C.sub.1-C.sub.6 alkoxy, or NR'R'';
unsubstituted 3-11 membered heterocyclyl (e.g., 5-6 membered
heteroaryl containing 1 to 4 heteroatoms selected from O, N and S
or 4-11 membered heterocycloalkyl containing 1 to 4 heteroatoms
selected from O, N and S); and 3-11 membered heterocyclyl (e.g.,
5-6 membered heteroaryl containing 1 to 4 heteroatoms selected from
O, N and S or 4-11 membered heterocycloalkyl containing 1 to 4
heteroatoms selected from O, N and S) substituted by halogen, OH,
CN, unsubstituted C.sub.1-C.sub.6 alkyl, unsubstituted
C.sub.1-C.sub.6 alkoxy, oxo or NR'R''; or R' and R'' can be
combined with the nitrogen atom to form a 3-, 4-, 5-, 6-, or
7-membered ring wherein a ring atom is optionally substituted with
N, O or S and wherein the ring is optionally substituted with
halogen, OH, CN, unsubstituted C.sub.1-C.sub.6 alkyl, unsubstituted
C.sub.1-C.sub.6 alkoxy, oxo or NR'R''.
[0158] "Heteroaryl" refers to any mono-, bi-, or tricyclic ring
system where at least one ring is a 5- or 6-membered aromatic ring
containing from 1 to 4 heteroatoms selected from nitrogen, oxygen,
and sulfur, and in an example embodiment, at least one heteroatom
is nitrogen. See, for example, Lang's Handbook of Chemistry (Dean,
J. A., ed.) 13.sup.th ed. Table 7-2 [1985]. Included in the
definition are any bicyclic groups where any of the above
heteroaryl rings are fused to an aryl ring, wherein the aryl ring
or the heteroaryl ring is joined to the remainder of the molecule.
In one embodiment, heteroaryl includes 5-6 membered monocyclic
aromatic groups where one or more ring atoms is nitrogen, sulfur or
oxygen. Example heteroaryl groups include thienyl, furyl,
imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl,
isoxazolyl, triazolyl, thiadiazolyl, oxadiazolyl, tetrazolyl,
thiatriazolyl, oxatriazolyl, pyridyl, pyrimidyl, pyrazinyl,
pyridazinyl, triazinyl, tetrazinyl, tetrazolo[1,5-b]pyridazinyl,
imidazol[1,2-a]pyrimidinyl and purinyl, as well as benzo-fused
derivatives, for example benzoxazolyl, benzofuryl, benzothiazolyl,
benzothiadiazolyl, benzotriazolyl, benzoimidazolyl and indolyl.
Heteroaryl groups can be optionally substituted. In some
embodiments, substituents for "optionally substituted heteroaryls"
include one to four instances of F, Cl, Br, I, OH, SH, CN,
NH.sub.2, NHCH.sub.3, N(CH.sub.3).sub.2, NO.sub.2, N.sub.3,
C(O)CH.sub.3, COOH, CO.sub.2CH.sub.3, methyl, ethyl, propyl,
iso-propyl, butyl, isobutyl, cyclopropyl, methoxy, ethoxy, propoxy,
trifluoromethyl, difluoromethyl, sulfonylamino,
methanesulfonylamino, SO, SO.sub.2, phenyl, piperidinyl,
piperizinyl, and pyrimidinyl, wherein the alkyl, phenyl and
heterocyclic portions thereof may be optionally substituted, such
as by one to four instances of substituents selected from this same
list. In some embodiments, a substituent of a heteroaryl comprises
an amide. For example, a heteroaryl substituent may be
--(CH.sub.2).sub.0-4CONR'R'', wherein R' and R'' each independently
refer to groups including, for example, hydrogen; unsubstituted
C.sub.1-C.sub.6 alkyl; C.sub.1-C.sub.6 alkyl substituted by
halogen, OH, CN, unsubstituted C.sub.1-C.sub.6 alkyl, unsubstituted
C.sub.1-C.sub.6 alkoxy, oxo or NR'R''; unsubstituted
C.sub.1-C.sub.6 heteroalkyl; C.sub.1-C.sub.6 heteroalkyl
substituted by halogen, OH, CN, unsubstituted C.sub.1-C.sub.6
alkyl, unsubstituted C.sub.1-C.sub.6 alkoxy, oxo or NR'R'';
unsubstituted C.sub.6-C.sub.10 aryl; C.sub.6-C.sub.10 aryl
substituted by halogen, OH, CN, unsubstituted C.sub.1-C.sub.6
alkyl, unsubstituted C.sub.1-C.sub.6 alkoxy, or NR'R'';
unsubstituted 3-11 membered heterocyclyl (e.g., 5-6 membered
heteroaryl containing 1 to 4 heteroatoms selected from O, N and S
or 4-11 membered heterocycloalkyl containing 1 to 4 heteroatoms
selected from O, N and S); and 3-11 membered heterocyclyl (e.g.,
5-6 membered heteroaryl containing 1 to 4 heteroatoms selected from
O, N and S or 4-11 membered heterocycloalkyl containing 1 to 4
heteroatoms selected from O, N and S) substituted by halogen, OH,
CN, unsubstituted C.sub.1-C.sub.6 alkyl, unsubstituted
C.sub.1-C.sub.6 alkoxy, oxo or NR'R''; or R' and R'' can be
combined with the nitrogen atom to form a 3-, 4-, 5-, 6-, or
7-membered ring wherein a ring atom is optionally substituted with
N, O or S and wherein the ring is optionally substituted with
halogen, OH, CN, unsubstituted C.sub.1-C.sub.6 alkyl, unsubstituted
C.sub.1-C.sub.6 alkoxy, oxo or NR'R''.
[0159] In particular embodiments, a heterocyclyl group is attached
at a carbon atom of the heterocyclyl group. By way of example,
carbon bonded heterocyclyl groups include bonding arrangements at
position 2, 3, 4, 5, or 6 of a pyridine ring, position 3, 4, 5, or
6 of a pyridazine ring, position 2, 4, 5, or 6 of a pyrimidine
ring, position 2, 3, 5, or 6 of a pyrazine ring, position 2, 3, 4,
or 5 of a furan, tetrahydrofuran, thiofuran, thiophene, pyrrole or
tetrahydropyrrole ring, position 2, 4, or 5 of an oxazole,
imidazole or thiazole ring, position 3, 4, or 5 of an isoxazole,
pyrazole, or isothiazole ring, position 2 or 3 of an aziridine
ring, position 2, 3, or 4 of an azetidine ring, position 2, 3, 4,
5, 6, 7, or 8 of a quinoline ring or position 1, 3, 4, 5, 6, 7, or
8 of an isoquinoline ring.
[0160] In certain embodiments, the heterocyclyl group is
N-attached. By way of example, nitrogen bonded heterocyclyl or
heteroaryl groups include bonding arrangements at position 1 of an
aziridine, azetidine, pyrrole, pyrrolidine, 2-pyrroline,
3-pyrroline, imidazole, imidazolidine, 2-imidazoline,
3-imidazoline, pyrazole, pyrazoline, 2-pyrazoline, 3-pyrazoline,
piperidine, piperazine, indole, indoline, 1H-indazole, position 2
of a isoindole, or isoindoline, position 4 of a morpholine, and
position 9 of a carbazole, or .beta.-carboline.
[0161] The term "alkoxy" refers to a linear or branched monovalent
radical represented by the formula --OR in which R is alkyl, as
defined herein. Alkoxy groups include methoxy, ethoxy, propoxy,
isopropoxy, mono-, di- and tri-fluoromethoxy and cyclopropoxy.
[0162] "Acyl" means a carbonyl containing substituent represented
by the formula --C(O)--R in which R is hydrogen, alkyl, cycloalkyl,
aryl or heterocyclyl, wherein the alkyl, cycloalkyl, aryl and
heterocyclyl are as defined herein. Acyl groups include alkanoyl
(e.g., acetyl), aroyl (e.g., benzoyl), and heteroaroyl (e.g.,
pyridinoyl).
[0163] "Optionally substituted" unless otherwise specified means
that a group may be unsubstituted or substituted by one or more
(e.g., 0, 1, 2, 3, 4, or 5 or more, or any range derivable therein)
of the substituents listed for that group in which said
substituents may be the same or different. In an embodiment, an
optionally substituted group has 1 substituent. In another
embodiment an optionally substituted group has 2 substituents. In
another embodiment an optionally substituted group has 3
substituents. In another embodiment an optionally substituted group
has 4 substituents. In another embodiment an optionally substituted
group has 5 substituents.
[0164] Optional substituents for alkyl radicals, alone or as part
of another substituent (e.g., alkoxy), as well as alkylenyl,
alkenyl, alkynyl, heteroalkyl, heterocycloalkyl, and cycloalkyl,
also each alone or as part of another substituent, can be a variety
of groups, such as those described herein, as well as selected from
the group consisting of halogen; oxo; CN; NO; N.sub.3; --OR';
perfluoro-C.sub.1-C.sub.4 alkoxy; unsubstituted C.sub.3-C.sub.7
cycloalkyl; C.sub.3-C.sub.7 cycloalkyl substituted by halogen, OH,
CN, unsubstituted C.sub.1-C.sub.6 alkyl, unsubstituted
C.sub.1-C.sub.6 alkoxy, oxo or NR'R''; unsubstituted
C.sub.6-C.sub.10 aryl (e.g., phenyl); C.sub.6-C.sub.10 aryl
substituted by halogen, OH, CN, unsubstituted C.sub.1-C.sub.6
alkyl, unsubstituted C.sub.1-C.sub.6 alkoxy, or NR'R'';
unsubstituted 3-11 membered heterocyclyl (e.g., 5-6 membered
heteroaryl containing 1 to 4 heteroatoms selected from O, N and S
or 4-11 membered heterocycloalkyl containing 1 to 4 heteroatoms
selected from O, N and S); 3-11 membered heterocyclyl (e.g., 5-6
membered heteroaryl containing 1 to 4 heteroatoms selected from O,
N and S or 4-11 membered heterocycloalkyl containing 1 to 4
heteroatoms selected from O, N and S) substituted by halogen, OH,
CN, unsubstituted C.sub.1-C.sub.6 alkyl, unsubstituted
C.sub.1-C.sub.6 alkoxy, oxo or NR'R''; --NR'R''; --SR';
--SiR'R''R'''; --OC(O)R'; --C(O)R'; --CO.sub.2R'; --CONR'R'';
--OC(O)NR'R''; --NR''C(O)R'; --NR'''C(O)NR'R''; --NR''C(O).sub.2R';
--S(O).sub.2R'; --S(O).sub.2NR'R''; --NR'S(O).sub.2R''; --NR''
'S(O).sub.2NR'R''; amidinyl; guanidinyl; --(CH.sub.2).sub.1-4--OR';
--(CH.sub.2).sub.4--NR'R''; --(CH.sub.2).sub.1-4--SR';
--(CH.sub.2).sub.1-4--SiR'R''R'''; --(CH.sub.2).sub.1-4--OC(O)R';
--(CH.sub.2).sub.1-4--C(O)R'; --(CH.sub.2).sub.1-4--CO.sub.2R'; and
--(CH.sub.2).sub.1-4CONR'R'', or combinations thereof, in a number
ranging from zero to (2m'+1), where m' is the total number of
carbon atoms in such radical. R', R'' and R''' each independently
refer to groups including, for example, hydrogen; unsubstituted
C.sub.1-C.sub.6 alkyl; C.sub.1-C.sub.6 alkyl substituted by
halogen, OH, CN, unsubstituted C.sub.1-C.sub.6 alkyl, unsubstituted
C.sub.1-C.sub.6 alkoxy, oxo or NR'R''; unsubstituted
C.sub.1-C.sub.6 heteroalkyl; C.sub.1-C.sub.6 heteroalkyl
substituted by halogen, OH, CN, unsubstituted C.sub.1-C.sub.6
alkyl, unsubstituted C.sub.1-C.sub.6 alkoxy, oxo or NR'R'';
unsubstituted C.sub.6-C.sub.10 aryl; C.sub.6-C.sub.10 aryl
substituted by halogen, OH, CN, unsubstituted C.sub.1-C.sub.6
alkyl, unsubstituted C.sub.1-C.sub.6 alkoxy, or NR'R'';
unsubstituted 3-11 membered heterocyclyl (e.g., 5-6 membered
heteroaryl containing 1 to 4 heteroatoms selected from O, N and S
or 4-11 membered heterocycloalkyl containing 1 to 4 heteroatoms
selected from O, N and S); and 3-11 membered heterocyclyl (e.g.,
5-6 membered heteroaryl containing 1 to 4 heteroatoms selected from
O, N and S or 4-11 membered heterocycloalkyl containing 1 to 4
heteroatoms selected from O, N and S) substituted by halogen, OH,
CN, unsubstituted C.sub.1-C.sub.6 alkyl, unsubstituted
C.sub.1-C.sub.6 alkoxy, oxo or NR'R''. When R' and R'' are attached
to the same nitrogen atom, they can be combined with the nitrogen
atom to form a 3-, 4-, 5-, 6-, or 7-membered ring wherein a ring
atom is optionally substituted with N, O or S and wherein the ring
is optionally substituted with halogen, OH, CN, unsubstituted
C.sub.1-C.sub.6 alkyl, unsubstituted C.sub.1-C.sub.6 alkoxy, oxo or
NR'R''. For example, --NR'R'' is meant to include 1-pyrrolidinyl
and 4-morpholinyl.
[0165] Similarly, optional substituents for the aryl and heteroaryl
groups are varied. In some embodiments, substituents for aryl and
heteroaryl groups are selected from the group consisting of
halogen; CN; NO; N.sub.3; --OR'; perfluoro-C.sub.1-C.sub.4 alkoxy;
unsubstituted C.sub.3-C.sub.7 cycloalkyl; C.sub.3-C.sub.7
cycloalkyl substituted by halogen, OH, CN, unsubstituted
C.sub.1-C.sub.6 alkyl, unsubstituted C.sub.1-C.sub.6 alkoxy, oxo or
NR'R''; unsubstituted C.sub.6-C.sub.10 aryl (e.g., phenyl);
C.sub.6-C.sub.10 aryl substituted by halogen, OH, CN, unsubstituted
C.sub.1-C.sub.6 alkyl, unsubstituted C.sub.1-C.sub.6 alkoxy, or
NR'R''; unsubstituted 3-11 membered heterocyclyl (e.g., 5-6
membered heteroaryl containing 1 to 4 heteroatoms selected from O,
N and S or 4-11 membered heterocycloalkyl containing 1 to 4
heteroatoms selected from O, N and S); 3-11 membered heterocyclyl
(e.g., 5-6 membered heteroaryl containing 1 to 4 heteroatoms
selected from O, N and S or 4-11 membered heterocycloalkyl
containing 1 to 4 heteroatoms selected from O, N and S) substituted
by halogen, OH, CN, unsubstituted C.sub.1-C.sub.6 alkyl,
unsubstituted C.sub.1-C.sub.6 alkoxy, oxo or NR'R''; --NR'R'';
--SR'; --SiR'R''R'''; --OC(O)R'; --C(O)R'; --CO.sub.2R';
--CONR'R''; --OC(O)NR'R''; --NR''C(O)R'; --NR'''C(O)NR'R'';
--NR''C(O).sub.2R'; --S(O).sub.2R'; --S(O).sub.2NR'R'';
--NR'S(O).sub.2R''; --NR'''S(O).sub.2NR'R''; amidinyl; guanidinyl;
--(CH.sub.2).sub.1-4--OR'; --(CH.sub.2).sub.1-4--NR'R'';
--(CH.sub.2).sub.1-4--SR'; --(CH.sub.2).sub.1-4--SiR'R''R''';
--(CH.sub.2).sub.1-4--OC(O)R'; --(CH.sub.2).sub.1-4--C(O)R';
--(CH.sub.2).sub.1-4--CO.sub.2R'; and --(CH.sub.2).sub.1-4CONR'R'',
or combinations thereof, in a number ranging from zero to (2m'+1),
where m' is the total number of carbon atoms in such radical. R',
R'' and R''' each independently refer to groups including, for
example, hydrogen; unsubstituted C.sub.1-C.sub.6 alkyl;
C.sub.1-C.sub.6 alkyl substituted by halogen, OH, CN, unsubstituted
C.sub.1-C.sub.6 alkyl, unsubstituted C.sub.1-C.sub.6 alkoxy, oxo or
NR'R''; unsubstituted C.sub.1-C.sub.6 heteroalkyl; C.sub.1-C.sub.6
heteroalkyl substituted by halogen, OH, CN, unsubstituted
C.sub.1-C.sub.6 alkyl, unsubstituted C.sub.1-C.sub.6 alkoxy, oxo or
NR'R''; unsubstituted C.sub.6-C.sub.10 aryl; C.sub.6-C.sub.10 aryl
substituted by halogen, OH, CN, unsubstituted C.sub.1-C.sub.6
alkyl, unsubstituted C.sub.1-C.sub.6 alkoxy, or NR'R'';
unsubstituted 3-11 membered heterocyclyl (e.g., 5-6 membered
heteroaryl containing 1 to 4 heteroatoms selected from O, N and S
or 4-11 membered heterocycloalkyl containing 1 to 4 heteroatoms
selected from O, N and S); and 3-11 membered heterocyclyl (e.g.,
5-6 membered heteroaryl containing 1 to 4 heteroatoms selected from
O, N and S or 4-11 membered heterocycloalkyl containing 1 to 4
heteroatoms selected from O, N and S) substituted by halogen, OH,
CN, unsubstituted C.sub.1-C.sub.6 alkyl, unsubstituted
C.sub.1-C.sub.6 alkoxy, oxo or NR'R''. When R' and R'' are attached
to the same nitrogen atom, they can be combined with the nitrogen
atom to form a 3-, 4-, 5-, 6-, or 7-membered ring wherein a ring
atom is optionally substituted with N, O or S and wherein the ring
is optionally substituted with halogen, OH, CN, unsubstituted
C.sub.1-C.sub.6 alkyl, unsubstituted C.sub.1-C.sub.6 alkoxy, oxo or
NR'R''. For example, --NR'R'' is meant to include 1-pyrrolidinyl
and 4-morpholinyl.
[0166] The term "oxo" refers to .dbd.O or (.dbd.O).sub.2.
[0167] As used herein a wavy line "" that intersects a bond in a
chemical structure indicate the point of attachment of the atom to
which the wavy bond is connected in the chemical structure to the
remainder of a molecule, or to the remainder of a fragment of a
molecule. In some embodiments, an arrow together with an asterisk
is used in the manner of a wavy line to indicate a point of
attachment.
[0168] In certain embodiments, divalent groups are described
generically without specific bonding configurations. It is
understood that the generic description is meant to include both
bonding configurations, unless specified otherwise. For example, in
the group R.sup.1-R.sup.2-R.sup.3, if the group R.sup.2 is
described as --CH.sub.2C(O)--, then it is understood that this
group can be bonded both as R.sup.1--CH.sub.2C(O)--R.sup.3, and as
R.sup.1--C(O)CH.sub.2--R.sup.3, unless specified otherwise.
[0169] The phrase "pharmaceutically acceptable" refers to molecular
entities and compositions that do not produce an adverse, allergic
or other untoward reaction when administered to an animal, such as,
for example, a human, as appropriate.
[0170] Compounds of the present invention may be in the form of a
salt, such as a pharmaceutically acceptable salt. "Pharmaceutically
acceptable salts" include both acid and base addition salts.
"Pharmaceutically acceptable acid addition salt" refers to those
salts which retain the biological effectiveness and properties of
the free bases and which are not biologically or otherwise
undesirable, formed with inorganic acids such as hydrochloric acid,
hydrobromic acid, sulfuric acid, nitric acid, carbonic acid,
phosphoric acid and the like, and organic acids may be selected
from aliphatic, cycloaliphatic, aromatic, araliphatic,
heterocyclic, carboxylic, and sulfonic classes of organic acids
such as formic acid, acetic acid, propionic acid, glycolic acid,
gluconic acid, lactic acid, pyruvic acid, oxalic acid, malic acid,
maleic acid, maloneic acid, succinic acid, fumaric acid, tartaric
acid, citric acid, aspartic acid, ascorbic acid, glutamic acid,
anthranilic acid, benzoic acid, cinnamic acid, mandelic acid,
embonic acid, phenylacetic acid, methanesulfonic acid,
ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid,
salicyclic acid and the like.
[0171] "Pharmaceutically acceptable base addition salts" include
those derived from inorganic bases such as sodium, potassium,
lithium, ammonium, calcium, magnesium, iron, zinc, copper,
manganese, aluminum salts and the like. Particular base addition
salts are the ammonium, potassium, sodium, calcium and magnesium
salts. Salts derived from pharmaceutically acceptable organic
nontoxic bases include salts of primary, secondary, and tertiary
amines, substituted amines including naturally occurring
substituted amines, cyclic amines and basic ion exchange resins,
such as isopropylamine, trimethylamine, diethylamine,
triethylamine, tripropylamine, ethanolamine, 2-diethylaminoethanol,
tromethamine, dicyclohexylamine, lysine, arginine, histidine,
caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine,
glucosamine, methylglucamine, theobromine, purines, piperizine,
piperidine, N-ethylpiperidine, polyamine resins and the like.
Particular organic non-toxic bases include isopropylamine,
diethylamine, ethanolamine, tromethamine, dicyclohexylamine,
choline, and caffeine.
[0172] In some embodiments, a salt is selected from a
hydrochloride, hydrobromide, trifluoroacetate, sulphate, phosphate,
acetate, fumarate, maleate, tartrate, lactate, citrate, pyruvate,
succinate, oxalate, methanesulphonate, p-toluenesulphonate,
bisulphate, benzenesulphonate, ethanesulphonate, malonate,
xinafoate, ascorbate, oleate, nicotinate, saccharinate, adipate,
formate, glycolate, palmitate, L-lactate, D-lactate, aspartate,
malate, L-tartrate, D-tartrate, stearate, furoate (e.g., 2-furoate
or 3-furoate), napadisylate (naphthalene-1,5-disulfonate or
naphthalene-1-(sulfonic acid)-5-sulfonate), edisylate
(ethane-1,2-disulfonate or ethane-1-(sulfonic acid)-2-sulfonate),
isethionate (2-hydroxyethylsulfonate), 2-mesitylenesulphonate,
2-naphthalenesulphonate, 2,5-dichlorobenzenesulphonate,
D-mandelate, L-mandelate, cinnamate, benzoate, adipate, esylate,
malonate, mesitylate (2-mesitylenesulphonate), napsylate
(2-naphthalenesulfonate), camsylate (camphor-10-sulphonate, for
example (1S)-(+)-10-camphorsulfonic acid salt), glutamate,
glutarate, hippurate (2-(benzoylamino)acetate), orotate, xylate
(p-xylene-2-sulphonate), and pamoic
(2,2'-dihydroxy-1,1'-dinaphthylmethane-3,3'-dicarboxylate).
[0173] A "sterile" formulation is aseptic or free from all living
microorganisms and their spores.
[0174] "Stereoisomers" refer to compounds that have identical
chemical constitution, but differ with regard to the arrangement of
the atoms or groups in space. Stereoisomers include diastereomers,
enantiomers, conformers and the like.
[0175] "Chiral" refers to molecules which have the property of
non-superimposability of the mirror image partner, while the term
"achiral" refers to molecules which are superimposable on their
mirror image partner.
[0176] "Diastereomer" refers to a stereoisomer with two or more
centers of chirality and whose molecules are not mirror images of
one another. Diastereomers have different physical properties,
e.g., melting points, boiling points, spectral properties or
biological activities. Mixtures of diastereomers may separate under
high resolution analytical procedures such as electrophoresis and
chromatography such as HPLC.
[0177] "Enantiomers" refer to two stereoisomers of a compound which
are non-superimposable mirror images of one another.
[0178] Stereochemical definitions and conventions used herein
generally follow S. P. Parker, Ed., McGraw-Hill Dictionary of
Chemical Terms (1984) McGraw-Hill Book Company, New York; and
Eliel, E. and Wilen, S., "Stereochemistry of Organic Compounds",
John Wiley & Sons, Inc., New York, 1994. Many organic compounds
exist in optically active forms, i.e., they have the ability to
rotate the plane of plane-polarized light. In describing an
optically active compound, the prefixes D and L, or R and S, are
used to denote the absolute configuration of the molecule about its
chiral center(s). The prefixes d and 1 or (+) and (-) are employed
to designate the sign of rotation of plane-polarized light by the
compound, with (-) or 1 meaning that the compound is levorotatory.
A compound prefixed with (+) or d is dextrorotatory. For a given
chemical structure, these stereoisomers are identical except that
they are mirror images of one another. A specific stereoisomer may
also be referred to as an enantiomer, and a mixture of such isomers
is often called an enantiomeric mixture. A 50:50 mixture of
enantiomers is referred to as a racemic mixture or a racemate,
which may occur where there has been no stereoselection or
stereospecificity in a chemical reaction or process. The terms
"racemic mixture" and "racemate" refer to an equimolar mixture of
two enantiomeric species, devoid of optical activity.
[0179] The term "tautomer" or "tautomeric form" refers to
structural isomers of different energies which are interconvertible
via a low energy barrier. For example, proton tautomers (also known
as prototropic tautomers) include interconversions via migration of
a proton, such as keto-enol and imine-enamine isomerizations.
Valence tautomers include interconversions by reorganization of
some of the bonding electrons.
[0180] Certain compounds of the present invention can exist in
unsolvated forms as well as solvated forms, including hydrated
forms. A "solvate" refers to an association or complex of one or
more solvent molecules and a compound of the present invention.
Examples of solvents that form solvates include water, isopropanol,
ethanol, methanol, DMSO, ethyl acetate, acetic acid, and
ethanolamine. Certain compounds of the present invention can exist
in multiple crystalline or amorphous forms. In general, all
physical forms are intended to be within the scope of the present
invention. The term "hydrate" refers to the complex where the
solvent molecule is water.
[0181] A "metabolite" refers to a product produced through
metabolism in the body of a specified compound or salt thereof.
Such products can result, for example, from the oxidation,
reduction, hydrolysis, amidation, deamidation, esterification,
deesterification, enzymatic cleavage, and the like, of the
administered compound.
[0182] Metabolite products typically are identified by preparing a
radiolabelled (e.g., .sup.14C or .sup.3H) isotope of a compound of
the invention, administering it in a detectable dose (e.g., greater
than about 0.5 mg/kg) to an animal such as rat, mouse, guinea pig,
monkey, or to a human, allowing sufficient time for metabolism to
occur (typically about 30 seconds to 30 hours) and isolating its
conversion products from the urine, blood or other biological
samples. These products are easily isolated since they are labeled
(others are isolated by the use of antibodies capable of binding
epitopes surviving in the metabolite). The metabolite structures
are determined in conventional fashion, e.g., by MS, LC/MS or NMR
analysis. In general, analysis of metabolites is done in the same
way as conventional drug metabolism studies well known to those
skilled in the art. The metabolite products, so long as they are
not otherwise found in vivo, are useful in diagnostic assays for
therapeutic dosing of the compounds of the invention.
[0183] "Amino-protecting group" as used herein refers to a
derivative of the groups commonly employed to block or protect an
amino group while reactions are carried out on other functional
groups on the compound. Examples of such protecting groups include
carbamates, amides, alkyl and aryl groups, and imines, as well as
many N-heteroatom derivatives which can be removed to regenerate
the desired amine group. Particular amino protecting groups are Pmb
(p-Methoxybenzyl), Boc (tert-Butyloxycarbonyl), Fmoc
(9-Fluorenylmethyl oxycarb onyl) and Cbz (Carbobenzyloxy). Further
examples of these groups are found in T. W. Greene and P. G. M.
Wuts, "Protecting Groups in Organic Synthesis, 3.sup.rd ed., John
Wiley & Sons, Inc., 1999. The term "protected amino" refers to
an amino group substituted with one of the above amino-protecting
groups.
[0184] "Carboxy-protecting group" as used herein refers to those
groups that are stable to the conditions of subsequent reaction(s)
at other positions of the molecule, which may be removed at the
appropriate point without disrupting the remainder of the molecule,
to give the unprotected carboxy-group. Examples of carboxy
protecting groups include, ester groups and heterocyclyl groups.
Ester derivatives of the carboxylic acid group may be employed to
block or protect the carboxylic acid group while reactions are
carried out on other functional groups on the compound. Examples of
such ester groups include substituted arylalkyl, including
substituted benzyls, such as 4-nitrobenzyl, 4-methoxybenzyl,
3,4-dimethoxybenzyl, 2,4-dimethoxybenzyl, 2,4,6-trimethoxybenzyl,
2,4,6-trimethylbenzyl, pentamethylbenzyl, 3,4-methylenedioxybenzyl,
benzhydryl, 4,4'-dimethoxybenzhydryl,
2,2',4,4'-tetramethoxybenzhydryl, alkyl or substituted alkyl esters
such as methyl, ethyl, t-butyl allyl or t-amyl, triphenylmethyl
(trityl), 4-methoxytrityl, 4,4'-dimethoxytrityl,
4,4',4''-trimethoxytrityl, 2-phenylprop-2-yl, thioesters such as
t-butyl thioester, silyl esters such as trimethylsilyl,
t-butyldimethylsilyl esters, phenacyl, 2,2,2-trichloroethyl,
beta-(trimethylsilyl)ethyl, beta-(di(n-butyl)methylsilyl)ethyl,
p-toluenesulfonylethyl, 4-nitrobenzyl sulfonylethyl, allyl,
cinnamyl, 1-(trimethylsilylmethyl)prop-1-en-3-yl, and like
moieties. Another example of carboxy-protecting groups are
heterocyclyl groups such as 1,3-oxazolinyl. Further examples of
these groups are found in T. W. Greene and P. G. M. Wuts,
"Protecting Groups in Organic Synthesis, 3.sup.rd ed., John Wiley
& Sons, Inc., 1999. The term "protected carboxy" refers to a
carboxy group substituted with one of the above carboxy-protecting
groups.
[0185] "Hydroxy-protecting group" as used herein refers to a
derivative of the hydroxy group commonly employed to block or
protect the hydroxy group while reactions are carried out on other
functional groups on the compound. Examples of such protecting
groups include tetrahydropyranyloxy, benzoyl, acetoxy,
carbamoyloxy, benzyl, and silylethers (e.g., TBS, TBDPS) groups.
Further examples of these groups are found in T. W. Greene and P.
G. M. Wuts, "Protecting Groups in Organic Synthesis, 3.sup.rd ed.,
John Wiley & Sons, Inc., 1999. The term "protected hydroxy"
refers to a hydroxy group substituted with one of the above
hydroxy-protecting groups.
[0186] A "subject," "individual," or "patient" is a vertebrate. In
certain embodiments, the vertebrate is a mammal. Mammals include,
but are not limited to, farm animals (such as cows), sport animals,
pets (such as guinea pigs, cats, dogs, rabbits and horses),
primates, mice and rats. In certain embodiments, a mammal is a
human. In embodiments comprising administration of a compound of
Formula (00A), (0A), (A), (Ia), (Ib), (II), (III), (IV), (V), (VI),
(VII), (VIII), (IX), or (X), or a compound of Table 1 or of
Examples 1-468, to a patient, the patient is typically in need
thereof.
[0187] The term "Janus kinase" refers to JAK1, JAK2, JAK3 and TYK2
protein kinases. In some embodiments, a Janus kinase may be further
defined as one of JAK1, JAK2, JAK3 or TYK2. In any embodiment, any
one of JAK1, JAK2, JAK3 and TYK2 may be specifically excluded as a
Janus kinase. In some embodiments, a Janus kinase is JAK1. In some
embodiments, a Janus kinase is a combination of JAK1 and JAK2.
[0188] The terms "inhibiting" and "reducing," or any variation of
these terms, includes any measurable decrease or complete
inhibition to achieve a desired result. For example, there may be a
decrease of about, at most about, or at least about 5%, 10%, 15%,
20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%,
85%, 90%, 95%, 99%, or more, or any range derivable therein,
reduction of activity (e.g., JAK1 activity) compared to normal.
[0189] In some embodiments, a compound of Formula (00A), (0A), (A),
(Ia), (Ib), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), or
(X), or a compound of Table 1 or of Examples 1-468, is selective
for inhibition of JAK1 over JAK3 and TYK2. In some embodiments, a
compound of Formula (00A), (0A), (A), (Ia), (Ib), (II), (III),
(IV), (V), (VI), (VII), (VIII), (IX), or (X), or a compound of
Table 1 or of Examples 1-468, is selective for inhibition of JAK1
over JAK2, JAK3, or TYK2, or any combination of JAK2, JAK3, or
TYK2. In some embodiments, a compound of Formula (00A), (0A), (A),
(Ia), (Ib), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), or
(X), or a compound of Table 1 or of Examples 1-468, is selective
for inhibition of JAK1 and JAK2 over JAK3 and TYK2. In some
embodiments, a compound of Formula (00A), (0A), (A), (Ia), (Ib),
(II), (III), (IV), (V), (VI), (VII), (VIII), (IX), or (X), or a
compound of Table 1 or of Examples 1-468, is selective for
inhibition of JAK1 over JAK3. By "selective for inhibition" it is
meant that the compound is at least a 5%, 10%, 15%, 20%, 25%, 30%,
35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%,
99%, or more, or any range derivable therein, better inhibitor of a
particular Janus kinase (e.g., JAK1) activity compared to another
particular Janus kinase (e.g., JAK1) activity, or is at least a 2-,
3-, 4-, 5-, 10-, 25-, 50-, 100-, 250-, or 500-fold better inhibitor
of a particular Janus kinase (e.g., JAK1) activity compared to
another particular Janus kinase (e.g., JAK1) activity.
[0190] "Therapeutically effective amount" means an amount of a
compound of the present invention, such as a compound of Formula
(00A), (0A), (A), (Ia), (Ib), (II), (III), (IV), (V), (VI), (VII),
(VIII), (IX), or (X), or a compound of Table 1 or of Examples
1-468, that (i) treats or prevents the particular disease,
condition or disorder, or (ii) attenuates, ameliorates or
eliminates one or more symptoms of the particular disease,
condition, or disorder, and optionally (iii) prevents or delays the
onset of one or more symptoms of the particular disease, condition
or disorder described herein. In some embodiments, the
therapeutically effective amount is an amount sufficient to
decrease or alleviate the symptoms of an autoimmune or inflammatory
disease (e.g., asthma). In some embodiments, a therapeutically
effective amount is an amount of a chemical entity described herein
sufficient to significantly decrease the activity or number of
B-cells. In the case of cancer, the therapeutically effective
amount of the drug may reduce the number of cancer cells; reduce
the tumor size; inhibit (i.e., slow to some extent and preferably
stop) cancer cell infiltration into peripheral organs; inhibit
(i.e., slow to some extent and preferably stop) tumor metastasis;
inhibit, to some extent, tumor growth; or relieve to some extent
one or more of the symptoms associated with the cancer. To the
extent the drug may prevent growth or kill existing cancer cells,
it may be cytostatic or cytotoxic. For cancer therapy, efficacy
can, for example, be measured by assessing the time to disease
progression (TTP) or determining the response rate (RR).
[0191] "Treatment" (and variations such as "treat" or "treating")
refers to clinical intervention in an attempt to alter the natural
course of the individual or cell being treated, and can be
performed either for prophylaxis or during the course of clinical
pathology. Desirable effects of treatment include preventing
occurrence or recurrence of disease, alleviation of symptoms,
diminishment of any direct or indirect pathological consequences of
the disease, stabilized (i.e., not worsening) state of disease,
decreasing the rate of disease progression, amelioration or
palliation of the disease state, prolonging survival as compared to
expected survival if not receiving treatment and remission or
improved prognosis. In some embodiments, compounds of the
invention, such as a compound of Formula (00A), (0A), (A), (Ia),
(Ib), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), or (X), or
a compound of Table 1 or of Examples 1-468, are used to delay
development of a disease or disorder or to slow the progression of
a disease or disorder. Those in need of treatment include those
already with the condition or disorder as well as those prone to
have the condition or disorder, (for example, through a genetic
mutation) or those in which the condition or disorder is to be
prevented.
[0192] "Inflammatory disorder" refers to any disease, disorder or
syndrome in which an excessive or unregulated inflammatory response
leads to excessive inflammatory symptoms, host tissue damage, or
loss of tissue function. "Inflammatory disorder" also refers to a
pathological state mediated by influx of leukocytes or neutrophil
chemotaxis.
[0193] "Inflammation" refers to a localized, protective response
elicited by injury or destruction of tissues, which serves to
destroy, dilute, or wall off (sequester) both the injurious agent
and the injured tissue. Inflammation is notably associated with
influx of leukocytes or neutrophil chemotaxis. Inflammation can
result from infection with pathogenic organisms and viruses and
from noninfectious means such as trauma or reperfusion following
myocardial infarction or stroke, immune responses to foreign
antigens, and autoimmune responses. Accordingly, inflammatory
disorders amenable to treatment with a compound of the present
invention, such as a compound of Formula (00A), (0A), (A), (Ia),
(Ib), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), or (X), or
a compound of Table 1 or of Examples 1-468, encompass disorders
associated with reactions of the specific defense system as well as
with reactions of the nonspecific defense system.
[0194] "Specific defense system" refers to the component of the
immune system that reacts to the presence of specific antigens.
Examples of inflammation resulting from a response of the specific
defense system include the classical response to foreign antigens,
autoimmune diseases, and delayed type hypersensitivity responses
mediated by T-cells. Chronic inflammatory diseases, the rejection
of solid transplanted tissue and organs, e.g., kidney and bone
marrow transplants, and graft versus host disease (GVHD), are
further examples of inflammatory reactions of the specific defense
system.
[0195] The term "nonspecific defense system" refers to inflammatory
disorders that are mediated by leukocytes that are incapable of
immunological memory (e.g., granulocytes, and macrophages).
Examples of inflammation that result, at least in part, from a
reaction of the nonspecific defense system include inflammation
associated with conditions such as adult (acute) respiratory
distress syndrome (ARDS) or multiple organ injury syndromes;
reperfusion injury; acute glomerulonephritis; reactive arthritis;
dermatoses with acute inflammatory components; acute purulent
meningitis or other central nervous system inflammatory disorders
such as stroke; thermal injury; inflammatory bowel disease;
granulocyte transfusion associated syndromes; and cytokine-induced
toxicity.
[0196] "Autoimmune disease" refers to any group of disorders in
which tissue injury is associated with humoral or cell-mediated
responses to the body's own constituents. Non-limiting examples of
autoimmune diseases include rheumatoid arthritis, lupus and
multiple sclerosis.
[0197] "Allergic disease" as used herein refers to any symptoms,
tissue damage, or loss of tissue function resulting from allergy.
"Arthritic disease" as used herein refers to any disease that is
characterized by inflammatory lesions of the joints attributable to
a variety of etiologies. "Dermatitis" as used herein refers to any
of a large family of diseases of the skin that are characterized by
inflammation of the skin attributable to a variety of etiologies.
"Transplant rejection" as used herein refers to any immune reaction
directed against grafted tissue, such as organs or cells (e.g.,
bone marrow), characterized by a loss of function of the grafted
and surrounding tissues, pain, swelling, leukocytosis, and
thrombocytopenia. The therapeutic methods of the present invention
include methods for the treatment of disorders associated with
inflammatory cell activation.
[0198] "Inflammatory cell activation" refers to the induction by a
stimulus (including, but not limited to, cytokines, antigens or
auto-antibodies) of a proliferative cellular response, the
production of soluble mediators (including but not limited to
cytokines, oxygen radicals, enzymes, prostanoids, or vasoactive
amines), or cell surface expression of new or increased numbers of
mediators (including, but not limited to, major histocompatability
antigens or cell adhesion molecules) in inflammatory cells
(including but not limited to monocytes, macrophages, T
lymphocytes, B lymphocytes, granulocytes (i.e., polymorphonuclear
leukocytes such as neutrophils, basophils, and eosinophils), mast
cells, dendritic cells, Langerhans cells, and endothelial cells).
It will be appreciated by persons skilled in the art that the
activation of one or a combination of these phenotypes in these
cells can contribute to the initiation, perpetuation, or
exacerbation of an inflammatory disorder.
[0199] In some embodiments, inflammatory disorders which can be
treated according to the methods of this invention include, but are
not limited to, asthma, rhinitis (e.g., allergic rhinitis),
allergic airway syndrome, atopic dermatitis, bronchitis, rheumatoid
arthritis, psoriasis, contact dermatitis, chronic obstructive
pulmonary disease and delayed hypersensitivity reactions.
[0200] The terms "cancer" and "cancerous", "neoplasm", and "tumor"
and related terms refer to or describe the physiological condition
in mammals that is typically characterized by unregulated cell
growth. A "tumor" comprises one or more cancerous cells. Examples
of cancer include carcinoma, blastoma, sarcoma, seminoma,
glioblastoma, melanoma, leukemia, and myeloid or lymphoid
malignancies. More particular examples of such cancers include
squamous cell cancer (e.g., epithelial squamous cell cancer) and
lung cancer including small-cell lung cancer, non-small cell lung
cancer ("NSCLC"), adenocarcinoma of the lung and squamous carcinoma
of the lung. Other cancers include skin, keratoacanthoma,
follicular carcinoma, hairy cell leukemia, buccal cavity, pharynx
(oral), lip, tongue, mouth, salivary gland, esophageal, larynx,
hepatocellular, gastric, stomach, gastrointestinal, small
intestine, large intestine, pancreatic, cervical, ovarian, liver,
bladder, hepatoma, breast, colon, rectal, colorectal,
genitourinary, biliary passage, thyroid, papillary, hepatic,
endometrial, uterine, salivary gland, kidney or renal, prostate,
testis, vulval, peritoneum, anal, penile, bone, multiple myeloma,
B-cell lymphoma, central nervous system, brain, head and neck,
Hodgkin's, and associated metastases. Examples of neoplastic
disorders include myeloproliferative disorders, such as
polycythemia vera, essential thrombocytosis, myelofibrosis, such as
primary myelofibrosis, and chronic myelogenous leukemia (CML).
[0201] A "chemotherapeutic agent" is an agent useful in the
treatment of a given disorder, for example, cancer or inflammatory
disorders. Examples of chemotherapeutic agents are well-known in
the art and include examples such as those disclosed in U.S. Publ.
Appl. No. 2010/0048557, incorporated herein by reference.
Additionally, chemotherapeutic agents include pharmaceutically
acceptable salts, acids or derivatives of any of chemotherapeutic
agents, as well as combinations of two or more of them.
[0202] "Package insert" is used to refer to instructions
customarily included in commercial packages of therapeutic products
that contain information about the indications, usage, dosage,
administration, contraindications or warnings concerning the use of
such therapeutic products.
[0203] The terms "compound(s) of this invention," and "compound(s)
of the present invention" and the like, unless otherwise indicated,
include compounds of Formula (00A), (0A), (A), (Ia), (Ib), (II),
(III), (IV), (V), (VI), (VII), (VIII), (IX), or (X), or a compound
of Table 1 or of Examples 1-468, and stereoisomers (including
atropisomers), geometric isomers, tautomers, solvates, metabolites,
isotopes, salts (e.g., pharmaceutically acceptable salts), and
prodrugs thereof. In some embodiments, solvates, metabolites,
isotopes or prodrugs are excluded, or any combination thereof.
[0204] Unless otherwise stated, structures depicted herein are also
meant to include compounds that differ only in the presence of one
or more isotopically enriched atoms. Exemplary isotopes that can be
incorporated into compounds of the present invention, such as a
compound of Formula (00A), (0A), (A), (Ia), (Ib), (II), (III),
(IV), (V), (VI), (VII), (VIII), (IX), or (X), or a compound of
Table 1 or of Examples 1-468, include isotopes of hydrogen, carbon,
nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and
iodine, such as .sup.2H, .sup.3H, .sup.11C, .sup.13C, .sup.14C,
.sup.13N, .sup.15N, .sup.15O, .sup.17O, .sup.18O, .sup.32P,
.sup.33P, .sup.35S, .sup.18F, .sup.36Cl, .sup.123I, and .sup.125I,
respectively. Isotopically-labeled compounds (e.g., those labeled
with .sup.3H and .sup.14C) can be useful in compound or substrate
tissue distribution assays. Tritiated (i.e., .sup.3H) and carbon-14
(i.e., .sup.14C) isotopes can be useful for their ease of
preparation and detectability. Further, substitution with heavier
isotopes such as deuterium (i.e., .sup.2H) may afford certain
therapeutic advantages resulting from greater metabolic stability
(e.g., increased in vivo half-life or reduced dosage requirements).
In some embodiments, in compounds of Formula (00A), (0A), (A),
(Ia), (Ib), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), or
(X), or a compound of Table 1 or of Examples 1-468, one or more
hydrogen atoms are replaced by .sup.2H or .sup.3H, or one or more
carbon atoms are replaced by .sup.13C- or .sup.14C-enriched carbon.
Positron emitting isotopes such as .sup.15O, .sup.13N, .sup.11C,
and .sup.18F are useful for positron emission tomography (PET)
studies to examine substrate receptor occupancy. Isotopically
labeled compounds can generally be prepared by following procedures
analogous to those disclosed in the Schemes or in the Examples
herein, by substituting an isotopically labeled reagent for a
non-isotopically labeled reagent.
[0205] It is specifically contemplated that any limitation
discussed with respect to one embodiment of the invention may apply
to any other embodiment of the invention. Furthermore, any compound
or composition of the invention may be used in any method of the
invention, and any method of the invention may be used to produce
or to utilize any compound or composition of the invention.
[0206] The use of the term "or" is used to mean "and/or" unless
explicitly indicated to refer to alternatives only or the
alternative are mutually exclusive, although the disclosure
supports a definition that refers to only alternatives and
"and/or."
[0207] Throughout this application, the term "about" is used to
indicate that a value includes the standard deviation of error for
the device or method being employed to determine the value.
[0208] As used herein, "a" or "an" means one or more, unless
clearly indicated otherwise. As used herein, "another" means at
least a second or more.
[0209] Headings used herein are intended only for organizational
purposes.
Inhibitors of Janus Kinases
[0210] Accordingly, one aspect of the invention includes a compound
of Formula (00A):
##STR00013##
and stereoisomers and salts thereof, wherein: R.sup.00 is H or
CH.sub.3; R.sup.01 is H or NH.sub.2; R.sup.0 is H or NH.sub.2; and
Ring Q is either (i) or (ii): [0211] (i)
[0211] ##STR00014## [0212] (ii)
##STR00015##
[0212] wherein: t.sup.1 and t.sup.2 are each independently 0 or 1;
X.sup.A and X.sup.B are independently selected from the group
consisting of H, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.4 alkenyl,
--NR.sup.aR.sup.b, C.sub.2-C.sub.5 alkynyl, 3-6-membered
cycloalkyl, 6-10 membered aryl, 3-11 membered heterocycloalkyl, 5-6
membered heterocycloalkenyl, and 5-10 membered heteroaryl; wherein
when either of X.sup.A and X.sup.B are independently
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.4 alkenyl, C.sub.2-C.sub.5
alkynyl, 3-6-membered cycloalkyl, 6-10 membered aryl, 3-11 membered
heterocycloalkyl, 5-6 membered heterocycloalkenyl, and 5-10
membered heteroaryl, each of X.sup.A and X.sup.B is independently
optionally substituted by Y.sup.1, wherein Y.sup.1 is selected
from: [0213] (a) C.sub.1-C.sub.6 alkyl optionally substituted by
T.sup.1, wherein T.sup.1 is selected from the group consisting of
OH, halo, CN, imino, 3-6 membered cycloalkyl, 3-11 membered
heterocycloalkyl, 3-11 membered heterocycloalkenyl, 5-10 membered
heteroaryl, --O--(C.sub.1-C.sub.6 alkyl), C(O)OH,
oxetan-3-ylmethyl, --C(O)O--(C.sub.1-C.sub.6 alkyl),
--S--(C.sub.1-C.sub.6 alkyl), --SO.sub.2--(C.sub.1-C.sub.6 alkyl),
--NR.sup.aR.sup.b, --N(+)R.sup.aR.sup.bR.sup.c wherein R.sup.c is
methyl, --C(O)NR.sup.aR.sup.b, -(2-oxoindolin-1-yl), --OC(O)-3-6
membered cycloalkyl, and phenyl, wherein each alkyl, cycloalkyl,
heterocycloalkyl, heterocycloalkenyl, heteroaryl, and phenyl of Ti
is optionally substituted by OH, --C(O)O--(C.sub.1-C.sub.6 alkyl),
C.sub.1-C.sub.6 alkyl, halo, CN, oxo, --(C.sub.1-C.sub.6
alkyl)CONR.sup.aR.sup.b, --NR.sup.aR.sup.b, phenyl, or
--O--(C.sub.1-C.sub.6 alkyl) optionally substituted by OH; [0214]
(b) 3-11 membered heterocycloalkyl, --(C.sub.1-C.sub.6
alkylene)-3-11 membered heterocycloalkyl, --C(O)-3-11 membered
heterocycloalkyl, --(C.sub.1-C.sub.6 alkylene)C(O)-3-11 membered
heterocycloalkyl, or --OC(O)-4-6 membered heterocycloalkyl; wherein
the heterocycloalkyl is optionally substituted by OH, halo, CN,
C.sub.1-C.sub.6 alkyl, --(C.sub.1-C.sub.6 alkylene)-CF.sub.3, oxo,
--C(O)--(C.sub.1-C.sub.6 alkyl), --C(O)O--(C.sub.1-C.sub.6 alkyl),
--C(O)O--(C.sub.1-C.sub.6 alkylene)-phenyl,
--SO.sub.2--(C.sub.1-C.sub.6 alkyl), --C(O)NR.sup.aR.sup.b,
--NR.sup.aR.sup.b, --(C.sub.1-C.sub.6 alkylene)-phenyl, or
--C(O)-4-6 membered heterocycloalkyl optionally substituted by
--NR.sup.aR.sup.b; (c) N(+)(AA).sub.3, wherein each AA is
independently C.sub.1-C.sub.6 alkyl optionally substituted by
phenyl; [0215] (d) 3-6 membered cycloalkyl optionally substituted
by OH, halo, NR.sup.aR.sup.b, or CN; (e) CN, halo, or oxo; [0216]
(f) --C(O)--(C.sub.1-C.sub.6 alkyl), --C(O)OH,
--C(O)O--(C.sub.1-C.sub.6 alkylene)-phenyl,
--SO.sub.2--(C.sub.1-C.sub.6 alkyl), --C(O)NR.sup.aR.sup.b, or
--C(O)-4-6 membered heterocycloalkyl optionally substituted by
--(C.sub.1-C.sub.6 alkyl) or --NR.sup.aR.sup.b, or
--C(O)O--(C.sub.1-C.sub.6 alkyl) optionally substituted by OH,
NR.sup.aR.sup.b, or 3-11 membered heterocycloalkyl wherein said
heterocycloalkyl is optionally substituted by C.sub.1-C.sub.6
alkyl; [0217] (g) OH, --O-phenyl, or --O--(C.sub.1-C.sub.6 alkyl),
wherein the alkyl is optionally substituted by OH or
--NR.sup.aR.sup.b; [0218] (h) phenyl optionally substituted by OH,
halo, C.sub.1-C.sub.6 alkyl, CF.sub.3, or CN; (i) 5-6 membered
heteroaryl optionally substituted by OH, halo, C.sub.1-C.sub.6
alkyl, CF.sub.3, CN, or 3-11 membered heterocycloalkyl optionally
substituted by C.sub.1-C.sub.6 alkyl or 3-11 membered
heterocycloalkyl; [0219] (j) isoindolin-2-yl optionally substituted
by halo; [0220] (k) --NR.sup.aR.sup.b, and [0221] (l)
--O--CH.sub.2C(O)-3-11 membered heterocycloalkyl; [0222] wherein
R.sup.a and R.sup.b are independently selected from: [0223] (p) H,
[0224] (a) C.sub.1-C.sub.6 alkyl optionally substituted by OH,
halo, CN, --C(O)OH, --C(O)O--(C.sub.1-C.sub.6alkyl), --C(O)O-(3-11
membered heterocycloalkyl), --C(O)O--(C.sub.1-C.sub.6
alkyl)-S--(C.sub.1-C.sub.6 alkyl), --S--(C.sub.1-C.sub.6 alkyl),
naphthylenyl, --NR.sup.azR.sup.bz, --C(O)NR.sup.azR.sup.bz, oxo,
--O--(C.sub.1-C.sub.6 alkyl), 5-6 membered heteroaryl optionally
substituted by C.sub.1-C.sub.6 alkyl or halo, or
benzo[1,3]dioxol-2-yl, or 3-11 membered heterocycloalkenyl
optionally substituted by oxo; [0225] (b) --(C.sub.1-C.sub.6
alkylene)-3-6 membered cycloalkyl wherein the alkylene is
optionally substituted by OH, halo, or CN; [0226] (c)
--(C.sub.1-C.sub.6 alkylene)-phenyl wherein alkylene is optionally
substituted by halo and the phenyl is optionally substituted by OH,
halo, CF.sub.3, C.sub.1-C.sub.6 alkyl, --O--(C.sub.1-C.sub.6
alkyl), --S--(C.sub.1-C.sub.6 alkyl, or --O-phenyl; [0227] (d)
--(C.sub.1-C.sub.6 alkylene)-4-6 membered heterocycloalkyl wherein
the heterocycloalkyl is optionally substituted by halo, oxo, or
C.sub.1-C.sub.6 alkyl; [0228] (e) --(C.sub.1-C.sub.6
alkylene)-O-phenyl wherein the phenyl is optionally substituted by
halo, C.sub.1-C.sub.6 alkyl, or --O-phenyl; [0229] (f)
--(C.sub.1-C.sub.6 alkyl).sub.3-6 membered cycloalkyl optionally
substituted by OH, halo, CN, or C.sub.1-C.sub.6 alkyl optionally
substituted by OH or CN; [0230] (g) C.sub.2-C.sub.5 alkenyl; [0231]
(h) 4-6 membered heterocycloalkyl optionally substituted by halo,
[0232] (i) --(C.sub.1-C.sub.6 alkylene)-3-6 membered cycloalkyl
substituted by hydroxymethyl, [0233] (j) phenyl, [0234] (k)
--C(O)(C.sub.1-C.sub.6 alkyl), [0235] (l) --C(O)O(C.sub.1-C.sub.6
alkyl), [0236] (m) --C(O)O(3-6 membered cycloalkyl), and [0237] (n)
--C(O)-phenyl, wherein R.sup.az and R.sup.bz are each independently
selected from [0238] (a) H, [0239] (b) C.sub.1-C.sub.6 alkyl
optionally substituted by OH, halo, CN, --C(O)OH,
--C(O)O--(C.sub.1-C.sub.6alkyl), --C(O)O-(3-11 membered
heterocycloalkyl), --C(O)O--(C.sub.1-C.sub.6
alkyl)-S--(C.sub.1-C.sub.6 alkyl), --S--(C.sub.1-C.sub.6 alkyl),
naphthylenyl, -oxo, --O--(C.sub.1-C.sub.6 alkyl), 5-6 membered
heteroaryl optionally substituted by C.sub.1-C.sub.6 alkyl or halo,
or benzo[1,3]dioxol-2-yl, or 3-11 membered heterocycloalkenyl
optionally substituted by oxo; [0240] (c) --(C.sub.1-C.sub.6
alkylene)-3-6 membered cycloalkyl wherein the alkylene is
optionally substituted by OH, halo, or CN; [0241] (d)
--(C.sub.1-C.sub.6 alkylene)-phenyl wherein alkylene is optionally
substituted by halo and the phenyl is optionally substituted by OH,
halo, CF.sub.3, C.sub.1-C.sub.6 alkyl, --O--(C.sub.1-C.sub.6
alkyl), --S--(C.sub.1-C.sub.6 alkyl, or --O-phenyl; [0242] (e)
--(C.sub.1-C.sub.6 alkylene)-4-6 membered heterocycloalkyl wherein
the heterocycloalkyl is optionally substituted by halo, oxo, or
C.sub.1-C.sub.6 alkyl; [0243] (f) --(C.sub.1-C.sub.6
alkylene)-O-phenyl wherein the phenyl is optionally substituted by
halo, C.sub.1-C.sub.6 alkyl, or --O-phenyl; [0244] (g)
--(C.sub.1-C.sub.6 alkyl).sub.3-6 membered cycloalkyl optionally
substituted by OH, halo, CN, or C.sub.1-C.sub.6 alkyl optionally
substituted by OH or CN; [0245] (h) C.sub.2-C.sub.5 alkenyl; [0246]
(i) 4-6 membered heterocycloalkyl optionally substituted by halo,
[0247] (j) --(C.sub.1-C.sub.6 alkylene)-3-6 membered cycloalkyl
substituted by hydroxymethyl, [0248] (k) phenyl, [0249] (l)
--C(O)(C.sub.1-C.sub.6 alkyl), [0250] (m) --C(O)O(C.sub.1-C.sub.6
alkyl), [0251] (n) --C(O)O(3-6 membered cycloalkyl), and [0252] (o)
--C(O)-phenyl, with the following provisos: when R.sup.0, R.sup.00,
and R.sup.01 are each H and Ring Q is
##STR00016##
[0252] where t.sup.1 is 0, then X.sup.A is not methyl,
2-methylpropan-2-ol, or tetrahydropyranyl; and, in some
embodiments, when Ring Q is (i) and t.sup.1 is 0, then X.sup.A
cannot be --NR.sup.aR.sup.b.
[0253] Further, another aspect of the invention includes a compound
of Formula (00A), further defined as a compound of Formula
(0A):
##STR00017##
and stereoisomers and salts thereof, wherein: R.sup.00 is H or
CH.sub.3; R.sup.01 is H or NH.sub.2; R.sup.0 is H or NH.sub.2; and
Ring Q is either (i) or (ii): [0254] (i)
[0254] ##STR00018## [0255] (ii)
##STR00019##
[0255] wherein: t.sup.1 and t.sup.2 are each independently 0 or 1;
X.sup.A and X.sup.B are independently selected from the group
consisting of H, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.4 alkenyl,
--NR.sup.aR.sup.b, C.sub.2-C.sub.5 alkynyl, 3-6-membered
cycloalkyl, 6-10 membered aryl, 3-11 membered heterocycloalkyl, 5-6
membered heterocycloalkenyl, and 5-10 membered heteroaryl; wherein
when either of X.sup.A and X.sup.B are independently
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.5 alkynyl, 3-6-membered
cycloalkyl, 6-10 membered aryl, 3-11 membered heterocycloalkyl, 5-6
membered heterocycloalkenyl, and 5-10 membered heteroaryl, each of
X.sup.A and X.sup.B are independently optionally substituted by
Y.sup.1, wherein Y.sup.1 is selected from: [0256] (a)
C.sub.1-C.sub.6 alkyl optionally substituted by T.sup.1, wherein
T.sup.1 is selected from the group consisting of OH, halo, CN,
imino, 3-6 membered cycloalkyl, 3-11 membered heterocycloalkyl,
3-11 membered heterocycloalkenyl, 5-10 membered heteroaryl,
--O--(C.sub.1-C.sub.6 alkyl), C(O)OH, oxetan-3-ylmethyl,
--C(O)O--(C.sub.1-C.sub.6 alkyl), --S--(C.sub.1-C.sub.6 alkyl),
--SO.sub.2--(C.sub.1-C.sub.6 alkyl), --NR.sup.aR.sup.b,
--N(+)R.sup.aR.sup.bR.sup.c wherein R.sup.c is methyl,
--C(O)NR.sup.aR.sup.b, -(2-oxoindolin-1-yl), --OC(O)-3-6 membered
cycloalkyl, and phenyl, wherein each alkyl, cycloalkyl,
heterocycloalkyl, heterocycloalkenyl, heteroaryl, and phenyl of Ti
is optionally substituted by OH, --C(O)O--(C.sub.1-C.sub.6 alkyl),
C.sub.1-C.sub.6 alkyl, halo, CN, oxo, --NR.sup.aR.sup.b, phenyl, or
--O--(C.sub.1-C.sub.6 alkyl) optionally substituted by OH; [0257]
(b) 3-11 membered heterocycloalkyl, --(C.sub.1-C.sub.6
alkylene)-3-11 membered heterocycloalkyl, --C(O)-3-11 membered
heterocycloalkyl, --(C.sub.1-C.sub.6 alkylene)C(O)-3-11 membered
heterocycloalkyl, or --OC(O)-4-6 membered heterocycloalkyl; wherein
the heterocycloalkyl is optionally substituted by OH, halo, CN,
C.sub.1-C.sub.6 alkyl, --(C.sub.1-C.sub.6 alkylene)-CF.sub.3, oxo,
--C(O)--(C.sub.1-C.sub.6 alkyl), --C(O)O--(C.sub.1-C.sub.6 alkyl),
--C(O)O--(C.sub.1-C.sub.6 alkylene)-phenyl,
--SO.sub.2--(C.sub.1-C.sub.6 alkyl), --C(O)NR.sup.aR.sup.b,
--NR.sup.aR.sup.b, --(C.sub.1-C.sub.6 alkylene)-phenyl, or
--C(O)-4-6 membered heterocycloalkyl optionally substituted by
--NR.sup.aR.sup.b; (c) N(+)(AA).sub.3, wherein each AA is
independently C.sub.1-C.sub.6 alkyl optionally substituted by
phenyl; [0258] (d) 3-6 membered cycloalkyl optionally substituted
by OH, halo, or CN; [0259] (e) CN, halo, or oxo; [0260] (f)
--C(O)--(C.sub.1-C.sub.6 alkyl), --C(O)OH,
--C(O)O--(C.sub.1-C.sub.6 alkylene)-phenyl,
--SO.sub.2--(C.sub.1-C.sub.6 alkyl), --C(O)NR.sup.aR.sup.b, or
--C(O)-4-6 membered heterocycloalkyl optionally substituted by
--NR.sup.aR.sup.b, or --C(O)O--(C.sub.1-C.sub.6 alkyl) optionally
substituted by OH, NR.sup.aR.sup.b, or 3-11 membered
heterocycloalkyl wherein said heterocycloalkyl is optionally
substituted by C.sub.1-C.sub.6 alkyl; [0261] (g) OH, --O-phenyl, or
--O--(C.sub.1-C.sub.6 alkyl), wherein the alkyl is optionally
substituted by OH or --NR.sup.aR.sup.b; [0262] (h) phenyl
optionally substituted by OH, halo, C.sub.1-C.sub.6 alkyl,
CF.sub.3, or CN; [0263] (i) 5-6 membered heteroaryl optionally
substituted by OH, halo, C.sub.1-C.sub.6 alkyl, CF.sub.3, or CN;
[0264] (j) isoindolin-2-yl optionally substituted by halo; and
[0265] (k) --NR.sup.aR.sup.b, [0266] wherein R.sup.a and R.sup.b
are independently selected from: [0267] (a) H, [0268] (b)
C.sub.1-C.sub.6 alkyl optionally substituted by OH, halo, CN,
--C(O)OH, --C(O)O--(C.sub.1-C.sub.6alkyl), --C(O)O-(3-11 membered
heterocycloalkyl), --C(O)O--(C.sub.1-C.sub.6
alkyl)-S--(C.sub.1-C.sub.6 alkyl), --S--(C.sub.1-C.sub.6 alkyl),
naphthylenyl, --NR.sup.azR.sup.bz, --C(O)NR.sup.azR.sup.bz, oxo,
--O--(C.sub.1-C.sub.6 alkyl), 5-6 membered heteroaryl optionally
substituted by C.sub.1-C.sub.6 alkyl or halo, or
benzo[1,3]dioxol-2-yl, or 3-11 membered heterocycloalkenyl
optionally substituted by oxo; [0269] (c) --(C.sub.1-C.sub.6
alkylene)-3-6 membered cycloalkyl wherein the alkylene is
optionally substituted by OH, halo, or CN; [0270] (d)
--(C.sub.1-C.sub.6 alkylene)-phenyl wherein alkylene is optionally
substituted by halo and the phenyl is optionally substituted by OH,
halo, CF.sub.3, C.sub.1-C.sub.6 alkyl, --O--(C.sub.1-C.sub.6
alkyl), --S--(C.sub.1-C.sub.6 alkyl, or --O-phenyl; [0271] (e)
--(C.sub.1-C.sub.6 alkylene)-4-6 membered heterocycloalkyl wherein
the heterocycloalkyl is optionally substituted by halo, oxo, or
C.sub.1-C.sub.6 alkyl; [0272] (f) --(C.sub.1-C.sub.6
alkylene)-O-phenyl wherein the phenyl is optionally substituted by
halo, C.sub.1-C.sub.6 alkyl, or --O-phenyl; [0273] (g) 3-6 membered
cycloalkyl optionally substituted by OH, halo, CN, or
C.sub.1-C.sub.6 alkyl optionally substituted by OH; [0274] (h)
C.sub.2-C.sub.5 alkenyl; [0275] (i) 4-6 membered heterocycloalkyl
optionally substituted by halo, [0276] (j) --(C.sub.1-C.sub.6
alkylene)-3-6 membered cycloalkyl substituted by hydroxymethyl,
[0277] (k) phenyl, [0278] (l) --C(O)(C.sub.1-C.sub.6 alkyl), [0279]
(m) --C(O)O(C.sub.1-C.sub.6 alkyl), [0280] (n) --C(O)O(3-6 membered
cycloalkyl), and [0281] (o) --C(O)-phenyl, wherein R.sup.az and
R.sup.bz are each independently selected from [0282] (a) H, [0283]
(b) C.sub.1-C.sub.6 alkyl optionally substituted by OH, halo, CN,
--C(O)OH, --C(O)O--(C.sub.1-C.sub.6alkyl), --C(O)O-(3-11 membered
heterocycloalkyl), --C(O)O--(C.sub.1-C.sub.6
alkyl)-S--(C.sub.1-C.sub.6 alkyl), --S--(C.sub.1-C.sub.6 alkyl),
naphthylenyl, -oxo, --O--(C.sub.1-C.sub.6 alkyl), 5-6 membered
heteroaryl optionally substituted by C.sub.1-C.sub.6 alkyl or halo,
or benzo[1,3]dioxol-2-yl, or 3-11 membered heterocycloalkenyl
optionally substituted by oxo; [0284] (c) --(C.sub.1-C.sub.6
alkylene)-3-6 membered cycloalkyl wherein the alkylene is
optionally substituted by OH, halo, or CN; [0285] (d)
--(C.sub.1-C.sub.6 alkylene)-phenyl wherein alkylene is optionally
substituted by halo and the phenyl is optionally substituted by OH,
halo, CF.sub.3, C.sub.1-C.sub.6 alkyl, --O--(C.sub.1-C.sub.6
alkyl), --S--(C.sub.1-C.sub.6 alkyl, or --O-phenyl; [0286] (e)
--(C.sub.1-C.sub.6 alkylene)-4-6 membered heterocycloalkyl wherein
the heterocycloalkyl is optionally substituted by halo, oxo, or
C.sub.1-C.sub.6 alkyl; [0287] (f) --(C.sub.1-C.sub.6
alkylene)-O-phenyl wherein the phenyl is optionally substituted by
halo, C.sub.1-C.sub.6 alkyl, or --O-phenyl; [0288] (g)
--(C.sub.1-C.sub.6 alkyl).sub.3-6 membered cycloalkyl optionally
substituted by OH, halo, CN, or C.sub.1-C.sub.6 alkyl optionally
substituted by OH or CN; [0289] (h) C.sub.2-C.sub.5 alkenyl; [0290]
(i) 4-6 membered heterocycloalkyl optionally substituted by halo,
[0291] (j) --(C.sub.1-C.sub.6 alkylene)-3-6 membered cycloalkyl
substituted by hydroxymethyl, [0292] (k) phenyl, [0293] (l)
--C(O)(C.sub.1-C.sub.6 alkyl), [0294] (m) --C(O)O(C.sub.1-C.sub.6
alkyl), [0295] (n) --C(O)O(3-6 membered cycloalkyl), and [0296] (o)
--C(O)-phenyl, with the following provisos: when R.sup.0, R.sup.00,
and R.sup.01 are each H and Ring Q is
##STR00020##
[0296] where t.sup.1 is 0, then X.sup.A is not methyl,
2-methylpropan-2-ol, or tetrahydropyranyl; and, in some
embodiments, when Ring Q is (i) and t.sup.1 is 0, then X.sup.A
cannot be --NR.sup.aR.sup.b
[0297] In some embodiments of any formula herein, when Ring Q
is
##STR00021##
and t.sup.1 is 0, the pyrazole is not N-linked to a nitrogen of
X.sup.A.
[0298] Another aspect of the invention provides compounds of
Formula (00A), further defined as a compound of Formula (A):
##STR00022##
and stereoisomers and salts thereof, wherein:
[0299] R.sup.00 is H or CH.sub.3;
[0300] R.sup.01 is H or NH.sub.2;
[0301] R.sup.0 is H or NH.sub.2; and
[0302] Ring Q is either (i) or (ii): [0303] (i)
[0303] ##STR00023## [0304] (ii)
##STR00024##
[0305] wherein:
[0306] t.sup.1 and t.sup.2 are each independently 0 or 1;
[0307] X.sup.A and X.sup.B are independently selected from the
group consisting of H, C.sub.1-C.sub.6 alkyl, --NR.sup.aR.sup.b,
C.sub.2-C.sub.5 alkynyl, 3-6-membered cycloalkyl, 6-10 membered
aryl, 3-11 membered heterocycloalkyl, 5-6 membered
heterocycloalkenyl, and 5-10 membered heteroaryl;
[0308] wherein when either of X.sup.A and X.sup.B are independently
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.5 alkynyl, 3-6-membered
cycloalkyl, 6-10 membered aryl, 3-11 membered heterocycloalkyl, 5-6
membered heterocycloalkenyl, and 5-10 membered heteroaryl, each of
X.sup.A and X.sup.B are independently optionally substituted by
Y.sup.1, wherein Y.sup.1 is selected from: [0309] (a)
C.sub.1-C.sub.6 alkyl optionally substituted by T.sup.1, wherein
T.sup.1 is selected from the group consisting of OH, halo, CN,
imino, 3-6 membered cycloalkyl, --O--(C.sub.1-C.sub.6 alkyl),
--C(O)O--(C.sub.1-C.sub.6 alkyl), --SO.sub.2--(C.sub.1-C.sub.6
alkyl), --NR.sup.aR.sup.b, --N(+)R.sup.aR.sup.bR.sup.c wherein
R.sup.c is methyl, --C(O)NR.sup.aR.sup.b, -(2-oxoindolin-1-yl),
--OC(O)-3-6 membered cycloalkyl, and phenyl, [0310] wherein each
alkyl, cycloalkyl, and phenyl of Ti is optionally substituted by
OH, C.sub.1-C.sub.6 alkyl, halo, CN, oxo, --NR.sup.aR.sup.b,
phenyl, or --O--(C.sub.1-C.sub.6 alkyl) optionally substituted by
OH; [0311] (b) 3-11 membered heterocycloalkyl, --(C.sub.1-C.sub.6
alkylene)-3-11 membered heterocycloalkyl, --C(O)-3-11 membered
heterocycloalkyl, --(C.sub.1-C.sub.6 alkylene)C(O)-3-11 membered
heterocycloalkyl, or --OC(O)-4-6 membered heterocycloalkyl; [0312]
wherein heterocycloalkyl is optionally substituted by OH, halo, CN,
C.sub.1-C.sub.6 alkyl, --(C.sub.1-C.sub.6 alkylene)-CF.sub.3, oxo,
--C(O)--(C.sub.1-C.sub.6 alkyl), --C(O)O--(C.sub.1-C.sub.6 alkyl),
--C(O)O--(C.sub.1-C.sub.6 alkylene)-phenyl,
--SO.sub.2--(C.sub.1-C.sub.6 alkyl), --C(O)NR.sup.aR.sup.b,
--NR.sup.aR.sup.b, --(C.sub.1-C.sub.6 alkylene)-phenyl, or
--C(O)-4-6 membered heterocycloalkyl optionally substituted by
--NR.sup.aR.sup.b; [0313] (c) N(+)(AA).sub.3, wherein each AA is
independently C.sub.1-C.sub.6 alkyl optionally substituted by
phenyl; [0314] (d) 3-6 membered cycloalkyl optionally substituted
by OH, halo, or CN; [0315] (e) CN, halo, or oxo; [0316] (f)
--C(O)--(C.sub.1-C.sub.6 alkyl), --C(O)O--(C.sub.1-C.sub.6 alkyl)
optionally substituted by OH, --C(O)O--(C.sub.1-C.sub.6
alkylene)-phenyl, --SO.sub.2--(C.sub.1-C.sub.6 alkyl),
--C(O)NR.sup.aR.sup.b, or --C(O)-4-6 membered heterocycloalkyl
optionally substituted by --NR.sup.aR.sup.b, [0317] (g) OH,
--O-phenyl, or --O--(C.sub.1-C.sub.6 alkyl), wherein the alkyl is
optionally substituted by OH or --NR.sup.aR.sup.b; [0318] (h)
phenyl optionally substituted by OH, halo, C.sub.1-C.sub.6 alkyl,
CF.sub.3, or CN; [0319] (i) 5-6 membered heteroaryl optionally
substituted by OH, halo, C.sub.1-C.sub.6 alkyl, CF.sub.3, or CN;
[0320] (j) isoindolin-2-yl optionally substituted by halo; and
[0321] (k) --NR.sup.aR.sup.b, [0322] wherein R.sup.a and R.sup.b
are independently selected from: [0323] (a) H, [0324] (b)
C.sub.1-C.sub.6 alkyl optionally substituted by OH, halo, CN,
naphthylenyl, --NR.sup.azR.sup.bz, --C(O)NR.sup.azR.sup.bz, oxo,
--O--(C.sub.1-C.sub.6 alkyl), phenyl, 5-6 membered heteroaryl
optionally substituted by C.sub.1-C.sub.6 alkyl or halo, or
benzo[1,3]dioxol-2-yl; [0325] (c) --(C.sub.1-C.sub.6 alkylene)-3-6
membered cycloalkyl wherein the alkylene is optionally substituted
by OH, halo, or CN; [0326] (d) --(C.sub.1-C.sub.6 alkylene)-phenyl
wherein alkylene is optionally substituted by halo and the phenyl
is optionally substituted by OH, halo, CF.sub.3, C.sub.1-C.sub.6
alkyl, --O--(C.sub.1-C.sub.6 alkyl), or --O-phenyl; [0327] (e)
--(C.sub.1-C.sub.6 alkylene)-4-6 membered heterocycloalkyl wherein
the heterocycloalkyl is optionally substituted by halo or
C.sub.1-C.sub.6 alkyl; [0328] (f) --(C.sub.1-C.sub.6
alkylene)-O-phenyl wherein the phenyl is optionally substituted by
halo, C.sub.1-C.sub.6 alkyl, or --O-phenyl; [0329] (g) 3-6 membered
cycloalkyl optionally substituted by OH, halo, CN, or
C.sub.1-C.sub.6 alkyl optionally substituted by OH; [0330] (h)
C.sub.2-C.sub.5 alkenyl; [0331] (i) 4-6 membered heterocycloalkyl
optionally substituted by halo, [0332] (j) --(C.sub.1-C.sub.6
alkylene)-3-6 membered cycloalkyl substituted by hydroxymethyl,
[0333] (k) phenyl, [0334] (l) --C(O)(C.sub.1-C.sub.6 alkyl), [0335]
(m) --C(O)O(C.sub.1-C.sub.6 alkyl), [0336] (n) --C(O)O(3-6 membered
cycloalkyl), and [0337] (o) --C(O)-phenyl, wherein R.sup.az and
R.sup.bz are each independently selected from [0338] (a) H, [0339]
(b) C.sub.1-C.sub.6 alkyl optionally substituted by OH, halo, CN,
--C(O)OH, --C(O)O--(C.sub.1-C.sub.6alkyl), --C(O)O-(3-11 membered
heterocycloalkyl), --C(O)O--(C.sub.1-C.sub.6
alkyl)-S--(C.sub.1-C.sub.6 alkyl), --S--(C.sub.1-C.sub.6 alkyl),
naphthylenyl, -oxo, --O--(C.sub.1-C.sub.6 alkyl), 5-6 membered
heteroaryl optionally substituted by C.sub.1-C.sub.6 alkyl or halo,
or benzo[1,3]dioxol-2-yl, or 3-11 membered heterocycloalkenyl
optionally substituted by oxo; [0340] (c) --(C.sub.1-C.sub.6
alkylene)-3-6 membered cycloalkyl wherein the alkylene is
optionally substituted by OH, halo, or CN; [0341] (d)
--(C.sub.1-C.sub.6 alkylene)-phenyl wherein alkylene is optionally
substituted by halo and the phenyl is optionally substituted by OH,
halo, CF.sub.3, C.sub.1-C.sub.6 alkyl, --O--(C.sub.1-C.sub.6
alkyl), --S--(C.sub.1-C.sub.6 alkyl, or --O-phenyl; [0342] (e)
--(C.sub.1-C.sub.6 alkylene)-4-6 membered heterocycloalkyl wherein
the heterocycloalkyl is optionally substituted by halo, oxo, or
C.sub.1-C.sub.6 alkyl; [0343] (f) --(C.sub.1-C.sub.6
alkylene)-O-phenyl wherein the phenyl is optionally substituted by
halo, C.sub.1-C.sub.6 alkyl, or --O-phenyl; [0344] (g)
--(C.sub.1-C.sub.6 alkyl).sub.3-6 membered cycloalkyl optionally
substituted by OH, halo, CN, or C.sub.1-C.sub.6 alkyl optionally
substituted by OH or CN; [0345] (h) C.sub.2-C.sub.5 alkenyl; [0346]
(i) 4-6 membered heterocycloalkyl optionally substituted by halo,
[0347] (j) --(C.sub.1-C.sub.6 alkylene)-3-6 membered cycloalkyl
substituted by hydroxymethyl, [0348] (k) phenyl, [0349] (l)
--C(O)(C.sub.1-C.sub.6 alkyl), [0350] (m) --C(O)O(C.sub.1-C.sub.6
alkyl), [0351] (n) --C(O)O(3-6 membered cycloalkyl), and [0352] (o)
--C(O)-phenyl, with the following provisos:
[0353] when R.sup.0, R.sup.00, and R.sup.01 are each H and Ring Q
is
##STR00025##
where t.sup.1 is 0,
[0354] then X.sup.A is not methyl, 2-methylpropan-2-ol, or
tetrahydropyranyl; and, in some embodiments, when Ring Q is (i) and
t.sup.1 is 0, then X.sup.A cannot be --NR.sup.aR.sup.b.
[0355] In some embodiments, a compound of Formula (00A), (0A) or
(A) is further defined as a compound of Formula (II):
##STR00026##
wherein: [0356] w is 0 or 1; [0357] R.sup.0b is H or NH.sub.2;
[0358] R.sup.1b is selected from the group consisting of [0359] a.
H, [0360] b. C.sub.1-C.sub.6 alkyl optionally substituted by OH,
halo, CN, --O--(C.sub.1-C.sub.6 alkyl), naphthylenyl, 5-6 membered
heteroaryl, or --C(O)NR.sup.vR.sup.w, wherein R.sup.v and R.sup.w
are independently H or C.sub.1-C.sub.6 alkyl optionally substituted
by halo, [0361] c. --(C.sub.1-C.sub.6 alkylene)-3-6 membered
cycloalkyl wherein the cycloalkyl is optionally substituted by CN,
[0362] d. --(C.sub.1-C.sub.6 alkylene)-phenyl wherein the alkyl is
optionally substituted by halo and wherein the phenyl is optionally
substituted by OH, halo, CF.sub.3, C.sub.1-C.sub.6 alkyl,
--O--(C.sub.1-C.sub.6 alkyl) or --O-phenyl, [0363] e.
--(C.sub.1-C.sub.6 alkylene)-4-6 membered heterocycloalkyl wherein
the heterocycloalkyl is optionally substituted by halo or
C.sub.1-C.sub.6 alkyl, [0364] f. --(C.sub.1-C.sub.6
alkylene)-O-phenyl wherein the phenyl is optionally substituted by
halo or C.sub.1-C.sub.6 alkyl, or [0365] g. 3-6 membered
cycloalkyl;
[0366] R.sup.2b is selected from the group consisting of H,
C.sub.1-C.sub.6 alkyl optionally substituted by halo, or
C.sub.2-C.sub.5 alkenyl;
[0367] or R.sup.1b and R.sup.2b together form a 3-11 membered
heterocycloalkyl optionally substituted by OH;
[0368] R.sup.3b is absent or methyl, wherein when R.sup.3b is
methyl, the nitrogen to which it is attached is N+ and w is 1;
[0369] R.sup.4b is a bond or C.sub.1-C.sub.6 alkylene;
[0370] R.sup.5b is selected from the group consisting of H, OH, and
phenyl; and
[0371] Ring F is a 3-7 membered heterocycloalkyl wherein p.sup.1b
is 0, 1 or 2 and p.sup.2b is 0, 1 or 2;
[0372] wherein w is equal to 1 only when R.sup.3b is methyl.
[0373] In some embodiments, a compound of Formula (00A), (0A) or
(A) is further defined as a compound of Formula (Ia) or Formula
(Ib):
##STR00027##
wherein:
[0374] R.sup.0a is H or NH.sub.2;
[0375] R.sup.1a is bound to a nitrogen atom of Ring A in (Ia) or is
bound to a carbon atom of Ring B in (Ib), and is selected from the
group consisting of: [0376] a. H, [0377] b. C.sub.1-C.sub.6 alkyl
optionally substituted by OH, halo, --O--(C.sub.1-C.sub.6 alkyl),
--SO.sub.2--(C.sub.1-C.sub.6 alkyl), -(2-oxoindolin-1-yl),
--OC(O)-3-6 membered cycloalkyl, --OC(O)-4-6 membered
heterocycloalkyl, or phenyl; [0378] c. --(C.sub.1-C.sub.6
alkylene)-O--(C.sub.1-C.sub.6 alkylene)-phenyl wherein the phenyl
is optionally substituted by halo; [0379] d. --(C.sub.1-C.sub.6
alkylene)-3-6 membered cycloalkyl wherein the cycloalkyl is
optionally substituted by halo, OH, or CN; [0380] e.
--(C.sub.1-C.sub.6 alkylene)-4-6 membered heterocycloalkyl, wherein
the heterocycloalkyl is optionally substituted by oxo,
C.sub.1-C.sub.6 alkyl, --C(O)--(C.sub.1-C.sub.6 alkyl),
--C(O)O--(C.sub.1-C.sub.6 alkyl), --SO.sub.2--(C.sub.1-C.sub.6
alkyl), --C(O)-4-6 membered heterocycloalkyl, or
--C(O)N(C.sub.1-C.sub.6 alkyl)(C.sub.1-C.sub.6 alkyl); [0381] f.
4-6 membered heterocycloalkyl, wherein the heterocycloalkyl is
optionally substituted by oxo, C.sub.1-C.sub.6 alkyl,
--C(O)--(C.sub.1-C.sub.6 alkyl), --C(O)O--(C.sub.1-C.sub.6 alkyl),
--SO.sub.2--(C.sub.1-C.sub.6 alkyl), --C(O)-4-6 membered
heterocycloalkyl, or --C(O)N(C.sub.1-C.sub.6 alkyl)(C.sub.1-C.sub.6
alkyl); [0382] g. --C(O)O--(C.sub.1-C.sub.6 alkylene)-OH; and
[0383] h. --C(O)O--(C.sub.1-C.sub.6 alkylene)-phenyl; [0384] i.
--NR.sup.aR.sup.b, wherein R.sup.a and R.sup.b are independently
selected from the group consisting of H and C.sub.1-C.sub.6 alkyl
optionally substituted by OH, halo, CN, --C(O)OH, phenyl, and 3-7
membered heterocycloalkyl;
[0385] R.sup.2a is selected from the group consisting of H,
C.sub.1-C.sub.6 alkyl optionally substituted by OH, and phenyl;
[0386] R.sup.3a is selected from the group consisting of H,
C.sub.1-C.sub.6 alkyl optionally substituted by OH, and phenyl;
[0387] Ring A is a 3-7 membered heterocycloalkyl; and
[0388] Ring B is a 3-7 membered heterocycloalkyl or a 3-7 membered
heterocyclyalkenyl, wherein p.sup.1a is 0, 1 or 2 and p.sup.2a is
0, 1 or 2,
[0389] provided that Ring A and Ring B together form a 6-11
membered bicyclic heterocycloalkyl.
[0390] In some embodiments, a compound of Formula (00A), (0A) or
(A) is further defined as a compound of Formula (III):
##STR00028##
wherein:
[0391] R.sup.0c is H or NH.sub.2;
[0392] R.sup.3 is (i) or (ii):
[0393] (i)
##STR00029##
[0394] wherein: [0395] R.sup.1c is selected from the group
consisting of H, C.sub.1-C.sub.6 alkyl, --(C.sub.1-C.sub.6
alkyl)-phenyl, --C(O)--(C.sub.1-C.sub.6 alkyl), --C(O)-phenyl, and
4-6 membered heterocycloalkyl; [0396] R.sup.2c is H or
C.sub.1-C.sub.6 alkyl; and [0397] R.sup.3c is a bond or
C.sub.1-C.sub.6 alkylene optionally substituted by oxo; or [0398]
R.sup.1c and R.sup.2c together form a 3-11 membered
heterocycloalkyl optionally substituted by C.sub.1-C.sub.6 alkyl,
oxo, or --(C.sub.1-C.sub.6 alkylene)-phenyl; or [0399] R.sup.1c and
R.sup.3c together form a 3-7 membered heterocycloalkyl;
[0400] (ii) H; C.sub.1-C.sub.6 alkyl optionally substituted by OH,
--SO.sub.2--(C.sub.1-C.sub.6 alkyl), phenyl, or
--O--(C.sub.1-C.sub.6 alkylene)-phenyl; --(C.sub.1-C.sub.6
alkylene)-C(O)O(C.sub.1-C.sub.6 alkyl); or 4-6 membered
heterocycloalkyl optionally substituted by --C(O)(C.sub.1-C.sub.6
alkyl); and
[0401] Ring G is a 3-7 membered heterocycloalkyl wherein p.sup.1c
is 0, 1 or 2 and p.sup.2c is 0, 1 or 2.
[0402] In some embodiments, a compound of Formula (00A), (0A) or
(A) is further defined as a compound of Formula (IV):
##STR00030##
wherein:
[0403] R.sup.0d is H or NH.sub.2
[0404] R.sup.1d is 3-11 membered heterocycloalkyl or --C(O)-3-11
membered heterocycloalkyl, wherein the heterocycloalkyl is
optionally substituted C.sub.1-C.sub.6 alkyl, CF.sub.3, or fluoro,
or R.sup.1d is --(C.sub.1-C.sub.6 alkylene)-NR.sup.vR.sup.w,
wherein R.sup.v and R.sup.w are independently H or C.sub.1-C.sub.6
alkyl optionally substituted by halo.
[0405] In some embodiments, a compound of Formula (00A), (0A) or
(A) is further defined as a compound of Formula (V):
##STR00031##
wherein:
[0406] R.sup.0e is H or NH.sub.2;
[0407] R.sup.1e is selected from the group consisting of [0408] a.
H, [0409] b. C.sub.1-C.sub.6 alkyl optionally substituted by halo,
CN, or phenyl, [0410] c. --(C.sub.1-C.sub.6 alkylene)-3-6 membered
cycloalkyl wherein the cycloalkyl is optionally substituted by CN,
[0411] d. --(C.sub.1-C.sub.6 alkylene)-4-6 membered
heterocycloalkyl wherein the heterocycloalkyl is optionally
substituted by C.sub.1-C.sub.6 alkyl;
[0412] R.sup.2e is H or C.sub.1-C.sub.6 alkyl;
[0413] or R.sup.1e and R.sup.2e together form a 3-11 membered
heterocycloalkyl optionally substituted by halo or
--NR.sup.vR.sup.w, wherein R.sup.v and R.sup.w are independently H
or C.sub.1-C.sub.6 alkyl optionally substituted by halo;
[0414] R.sup.3e is a bond or C.sub.1-C.sub.6 alkylene optionally
substituted by oxo; and
[0415] Ring H is a 3-7 membered heterocycloalkyl wherein p.sup.1e
is 0, 1 or 2 and p.sup.2e is 0, 1 or 2.
[0416] In some embodiments, a compound of Formula (00A), (0A) or
(A) is further defined as a compound of Formula (VI):
##STR00032##
wherein:
[0417] R.sup.0f is H or NH.sub.2;
[0418] R.sup.1f is selected from the group consisting of
C.sub.1-C.sub.6 alkyl optionally substituted by halo, --C(O)OH,
oxetan-3-ylmethyl, 3-6 membered cycloalkyl, 3-11 membered
heterocycloalkyl, --S--(C.sub.1-C.sub.6 alkyl), 5-10 membered
heteroaryl or phenyl, or 3-11 membered heterocycloalkenyl
optionally substituted by oxo; and
[0419] Ring J is a 6-7 membered heterocycloalkyl wherein p.sup.1f
is 1 or 2 and p.sup.2f is 1 or 2.
[0420] In some embodiments, a compound of Formula (00A), (0A) or
(A) is further defined as a compound of Formula (VII):
##STR00033##
wherein:
[0421] R.sup.0g is H or NH.sub.2;
[0422] R.sup.1g is selected from the group consisting of
C.sub.1-C.sub.6 alkyl;
[0423] R.sup.2g is selected from the group consisting of
C.sub.1-C.sub.6 alkyl.
[0424] In some embodiments, a compound of Formula (00A), (0A) or
(A) is further defined as a compound of Formula (VIII):
##STR00034##
wherein:
[0425] R.sup.0h is H or NH.sub.2;
[0426] R.sup.1h is selected from the group consisting of H and
C.sub.1-C.sub.6 alkyl optionally substituted by CN, 3-6 membered
cycloalkyl, or 4-6 membered
heterocycloalkylene-C(O)O--(C.sub.1-C.sub.6 alkylene)-phenyl;
[0427] Ring C is 3-7 membered cycloalkyl or 3-7 membered
heterocycloalkyl; and
[0428] Ring D is a 3-7 membered heterocycloalkyl substituted at the
sole nitrogen by R.sup.1h; and
[0429] provided Rings C and D together form a 3-11 membered spiro
heterocycloalkyl.
[0430] In some embodiments, a compound of Formula (00A), (0A) or
(A) is further defined as a compound of Formula (IX):
##STR00035##
wherein:
[0431] R.sup.0j is H or NH.sub.2;
[0432] R.sup.3 is selected from the group consisting of H and
C.sub.1-C.sub.6 alkyl optionally substituted by OH, 3-6 membered
cycloalkyl, --O--(C.sub.1-C.sub.6 alkyl), --O--(C.sub.1-C.sub.6
alkyl)-OH, --SO.sub.2--(C.sub.1-C.sub.6 alkyl) and phenyl, wherein
the phenyl is optionally substituted by CN;
[0433] R.sup.4j is selected from the group consisting of H and
C.sub.1-C.sub.6 alkyl optionally substituted by OH;
[0434] or R.sup.3j and R.sup.4j together form a 4-6-membered
heterocycloalkyl;
[0435] R.sup.5 is selected from the group consisting of H and
C.sub.1-C.sub.6 alkyl; and
[0436] Ring K is a 6-7 membered heterocycloalkyl wherein p.sup.1j
is 1 or 2 and p.sup.2j is 1 or 2.
[0437] In some embodiments, a compound of Formula (00A), (0A) or
(A) is further defined as a compound of Formula (X):
##STR00036##
wherein:
[0438] R.sup.0k is H or NH.sub.2;
[0439] R.sup.1k is selected from the group consisting of [0440] a.
H, [0441] b. C.sub.1-C.sub.6 alkyl optionally substituted by halo,
CN, or phenyl, [0442] c. --(C.sub.1-C.sub.6 alkylene)-3-6 membered
cycloalkyl wherein the cycloalkyl is optionally substituted by CN,
[0443] d. --(C.sub.1-C.sub.6 alkylene)-4-6 membered
heterocycloalkyl wherein the heterocycloalkyl is optionally
substituted by C.sub.1-C.sub.6 alkyl;
[0444] R.sup.2k is selected from the group consisting of H and
C.sub.1-C.sub.6 alkyl;
[0445] or R.sup.1k and R.sup.2k together form a 3-11 membered
heterocycloalkyl optionally substituted by halo; C.sub.1-C.sub.6
alkyl optionally substituted by OH; or --NR.sup.vR.sup.w, wherein
R.sup.v and R'' are independently H or C.sub.1-C.sub.6 alkyl
optionally substituted by halo; and
[0446] R.sup.3k is a bond, methylene, or --C(.dbd.O)--.
[0447] In some embodiments, X.sup.A and X.sup.B are independently
selected from the group consisting of 3-6-membered cycloalkyl, 6-10
membered aryl, 5-6 membered heterocycloalkenyl, and 5-10 membered
heteroaryl, wherein each of X.sup.A and X.sup.B are independently
optionally substituted by Y.sup.1.
[0448] In some embodiments, either X.sup.A or X.sup.B is a 3-11
membered heterocycloalkyl optionally substituted by Y.sup.1.
[0449] In some embodiments, Ring Q is (i). In some embodiments Ring
Q is (ii).
[0450] In some embodiments, t.sup.1 is 0. In some embodiments,
t.sup.1 is 1.
[0451] In some embodiments, R.sup.0, R.sup.00 and R.sup.01 are each
H.
[0452] In some embodiments, R.sup.0 is NH.sub.2.
[0453] In some embodiments, Ring Q is (i), t.sup.1 is 0 or 1, and
R.sup.0, R.sup.00 and R.sup.01 are each H.
[0454] In some embodiments, Ring Q is (ii), t.sup.2 is 0 or 1, and
R.sup.0, R.sup.00 and R.sup.01 are each H.
[0455] In some embodiments, Ring Q is (i), t.sup.1 is 1, and
X.sup.A is NR.sup.aR.sup.b, wherein R.sup.a and R.sup.b are each
independently H, C.sub.1-C.sub.6 alkyl optionally substituted with
5-6 membered heteroaryl, or 3-6 membered cycloalkyl optionally
substituted by OH, halo, CN, or C.sub.1-C.sub.6 alkyl optionally
substituted by OH.
[0456] In some embodiments, Ring Q is (i), t.sup.1 is 0, and
X.sup.A is C.sub.1-C.sub.6 alkyl or 3-6 membered cycloalkyl,
wherein X.sup.A is optionally substituted by --NR.sup.aR.sup.b,
wherein R.sup.a and R.sup.b are independently H or C.sub.1-C.sub.6
alkyl.
[0457] In some embodiments, a compound is selected from Table 1 or
of Examples 1-468.
[0458] Also provided is a pharmaceutical composition comprising a
5-chloro-2-difluoromethoxyphenyl pyrazolopyrimidine compound as
described herein, such as a compound of Formula (00A), (0A) or (A),
or a subformula thereof, and a pharmaceutically acceptable carrier,
diluent or excipient.
[0459] Use of a 5-chloro-2-difluoromethoxyphenyl pyrazolopyrimidine
compound as described herein, such as a compound of Formula (00A),
(0A) or (A), or a subformula thereof, in therapy is also
provided.
[0460] Use of a 5-chloro-2-difluoromethoxyphenyl pyrazolopyrimidine
compound as described herein, such as a compound of Formula (00A),
(0A) or (A), or a subformula thereof, in the treatment of an
inflammatory disease, such as asthma, is also provided.
[0461] Use of a 5-chloro-2-difluoromethoxyphenyl pyrazolopyrimidine
compound as described herein, such as a compound of Formula (00A),
(0A) or (A), or a subformula thereof, for the preparation of a
medicament for the treatment of an inflammatory disease, such as
asthma, is also provided.
[0462] Also provided is a 5-chloro-2-difluoromethoxyphenyl
pyrazolopyrimidine compound as described herein, such as a compound
of Formula (00A), (0A) or (A), or a subformula thereof, for use in
the treatment of an inflammatory disease, such as asthma.
[0463] Also provided is a method of preventing, treating or
lessening the severity of a disease or condition responsive to the
inhibition of a Janus kinase activity in a patient, comprising
administering to the patient a therapeutically effective amount of
a 5-chloro-2-difluoromethoxyphenyl pyrazolopyrimidine compound as
described herein, such as a compound of Formula (00A), (0A) or (A),
or a subformula thereof. In some embodiments, the disease or
condition is asthma. In some embodiments, the Janus kinase is JAK1.
In some embodiments, a compound is administered via inhalation.
[0464] In some embodiments, such as a compound of Formula (00A),
(0A) or (A), R.sup.00 is H or CH.sub.3; R.sup.01 is H or NH.sub.2;
R.sup.0 is H or NH.sub.2; and Ring Q is either (i) or (ii): [0465]
(i)
##STR00037##
[0465] (ii)
##STR00038##
wherein t.sup.1 and t.sup.2 are each independently 0 or 1, and
X.sup.A and X.sup.B are each independently selected from the group
consisting of:
##STR00039## ##STR00040## ##STR00041## ##STR00042## ##STR00043##
##STR00044## ##STR00045## ##STR00046## ##STR00047## ##STR00048##
##STR00049## ##STR00050## ##STR00051## ##STR00052## ##STR00053##
##STR00054## ##STR00055## ##STR00056## ##STR00057## ##STR00058##
##STR00059## ##STR00060## ##STR00061##
##STR00062## ##STR00063## ##STR00064## ##STR00065## ##STR00066##
##STR00067## ##STR00068## ##STR00069## ##STR00070## ##STR00071##
##STR00072## ##STR00073## ##STR00074## ##STR00075## ##STR00076##
##STR00077## ##STR00078##
[0466] In some embodiments, such as a compound of Formula (00A),
(0A) or (A), R.sup.00 is H or CH.sub.3; R.sup.01 is H or NH.sub.2;
R.sup.0 is H or NH.sub.2; and Ring Q is either (i) or (ii): [0467]
(i)
##STR00079##
[0467] (ii)
##STR00080##
wherein t.sup.1 and t.sup.2 are each independently 0 or 1, and
X.sup.A and X.sup.B are each independently selected from the group
consisting of:
##STR00081## ##STR00082## ##STR00083## ##STR00084## ##STR00085##
##STR00086## ##STR00087## ##STR00088## ##STR00089## ##STR00090##
##STR00091## ##STR00092## ##STR00093## ##STR00094##
##STR00095## ##STR00096## ##STR00097## ##STR00098## ##STR00099##
##STR00100## ##STR00101## ##STR00102## ##STR00103## ##STR00104##
##STR00105##
[0468] In any embodiment herein, one or more compounds of WO
2011/003065 is/are excluded.
[0469] Also provided is a compound selected from Examples 1-468 or
Table 1, or any combination thereof. If any discrepancy exists
between a structure and its chemical name, the structure
prevails.
TABLE-US-00001 TABLE 1 Exemplary Compounds of the Present Invention
Ex. Structure Name 1 ##STR00106## N-[3-[5-chloro-2-
(difluoromethoxy)phenyl]- 1-(4-piperidyl)pyrazol-4-
yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 2 ##STR00107##
2-amino-N-[3-[5-chloro-2- (difluoromethoxy)phenyl]-
1-(4-piperidyl)pyrazol-4- yl]pyrazolo[1,5- a]pyrimidine-3-
carboxamide 3 ##STR00108## N-[1-[2-[(3aS,6aR)-2-
methyl-1,3,3a,4,6,6a- hexahydropyrrolo[3,4- c]pyrrol-5-yl]-2-oxo-
ethyl]-3-[5-chloro-2- (difluoromethoxy)phenyl]
pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 4
##STR00109## N-[1-[2-[(3aR,6aS)- 2,3,3a,4,6,6a-hexahydro-
1H-pyrrolo[3,4-c]pyrrol-5- yl]-2-oxo-ethyl]-3-[5- chloro-2-
(difluoromethoxy)phenyl] pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3-
carboxamide 5 ##STR00110## N-[1-[2-[(3aS,6aR)-2-
ethyl-1,3,3a,4,6,6a- hexahydropyrrolo[3,4- c]pyrrol-5-yl]-2-oxo-
ethyl]-3-[5-chloro-2- (difluoromethoxy)phenyl]
pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 6
##STR00111## N-[1-[2-[(3aS,6aR)-2- (cyclopropylmethyl)-
1,3,3a,4,6,6a- hexahydropyrrolo[3,4- c]pyrrol-5-yl]-2-oxo-
ethyl]-3-[5-chloro-2- (difluoromethoxy)phenyl]
pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 7
##STR00112## N-[1-[2-[(3aS,6aR)-2- methyl-1,3,3a,4,6,6a-
hexahydropyrrolo[3,4- c]pyrrol-5-yl]-2-oxo- ethyl]-3-[5-chloro-2-
(difluoromethoxy)phenyl] pyrazol-4-yl]-5-amino- pyrazolo[1,5-
a]pyrimidine-3- carboxamide 8 ##STR00113## N-[1-[2-[(3aR,6aS)-2-
methyl-1,3,3a,4,6,6a- hexahydropyrrolo[3,4- c]pyrrol-5-yl]-2-oxo-
ethyl]-3-[5-chloro-2- (difluoromethoxy)phenyl]
pyrazol-4-yl]-6-methyl- pyrazolo[1,5- a]pyrimidine-3- carboxamide 9
##STR00114## 2-amino-N-[3-[5-chloro-2- (difluoromethoxy)phenyl]-
1-[2-(2-methyl- 1,3,3a,4,6,6a- hexahydropyrrolo[3,4-
c]pyrrol-5-yl)-2-oxo- ethyl]pyrazol-4- yl]pyrazolo[1,5-
a]pyrimidine-3- carboxamide 10 ##STR00115## N-[1-[2-(2,3,3a,4,6,6a-
hexahydro-1H- pyrrolo[3,4-c]pyrrol-5-yl)- 2-oxo-ethyl]-3-[5-chloro-
2- (difluoromethoxy)phenyl] pyrazol-4-yl]-2-amino- pyrazolo[1,5-
a]pyrimidine-3- carboxamide 11 ##STR00116##
2-amino-N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[2-(2-ethyl-
1,3,3a,4,6,6a- hexahydropyrrolo[3,4- c]pyrrol-5-yl)-2-oxo-
ethyl]pyrazol-4- yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 12
##STR00117## N-[1-[2-[(3aS,6aR)-2- isopropyl-1,3,3a,4,6,6a-
hexahydropyrrolo[3,4- c]pyrrol-5-yl]-2-oxo- ethyl]-3-[5-chloro-2-
(difluoromethoxy)phenyl] pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3-
carboxamide 13 ##STR00118## N-[1-[2-[(3aS,6aR)-2-(2-
phenylethyl)-1,3,3a,4,6,6a- hexahydropyrrolo[3,4-
c]pyrrol-5-yl]-2-oxo- ethyl]-3-[5-chloro-2-
(difluoromethoxy)phenyl] pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3-
carboxamide 14 ##STR00119## N-[1-[2-[(3aR,6aS)-2-(3-
hydroxypropyl)- 1,3,3a,4,6,6a- hexahydropyrrolo[3,4-
c]pyrrol-5-yl]-2-oxo- ethyl]-3-[5-chloro-2-
(difluoromethoxy)phenyl] pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3-
carboxamide 15 ##STR00120## 3-hydroxypropyl (3aR,6aS)-2-[2-[3-[5-
chloro-2- (difluoromethoxy)phenyl]- 4-(pyrazolo[1,5-
a]pyrimidine-3- carbonylamino)pyrazol-1- yl]acetyl]-1,3,3a,4,6,6a-
hexahydropyrrolo[3,4- c]pyrrole-5-carboxylate 16 ##STR00121##
N-[1-[2-[(3aR,6aR)-2- methyl-3a-phenyl- 3,4,6,6a-tetrahydro-1H-
pyrrolo[3,4-c]pyrrol-5-yl]- 2-oxo-ethyl]-3-[5-chloro- 2-
(difluoromethoxy)phenyl] pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3-
carboxamide 17 ##STR00122## benzyl 4-[[(3aR,6aS)-5-[2-
[3-[5-chloro-2- (difluoromethoxy)phenyl]- 4-(pyrazolo[1,5-
a]pyrimidine-3- carbonylamino)pyrazol-1- yl]acetyl]-1,3,3a,4,6,6a-
hexahydropyrrolo[3,4- c]pyrrol-2- yl]methyl]piperidine-1-
carboxylate 18 ##STR00123## N-[1-[2-[(3aR,6aS)-2-[3-
(2-oxopyrrolidin-1- yl)propyl]-1,3,3a,4,6,6a- hexahydropyrrolo[3,4-
c]pyrrol-5-yl]-2-oxo- ethyl]-3-[5-chloro-2-
(difluoromethoxy)phenyl] pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3-
carboxamide 19 ##STR00124## N-[1-[2-[(3aR,6aS)-2-(3-
morpholinopropyl)- 1,3,3a,4,6,6a- hexahydropyrrolo[3,4-
c]pyrrol-5-yl]-2-oxo- ethyl]-3-[5-chloro-2-
(difluoromethoxy)phenyl] pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3-
carboxamide 20 ##STR00125## N-[1-[2-[(3aR,7aS)- 2,3,3a,4,5,6,7,7a-
octahydropyrrolo[3,2- c]pyridin-1-yl]-2-oxo- ethyl]-3-[5-chloro-2-
(difluoromethoxy)phenyl] pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3-
carboxamide 21 ##STR00126## N-[1-[2-[(3aS,7aR)- 1,2,3,3a,4,6,7,7a-
octahydropyrrolo[3,4- c]pyridin-5-yl]-2-oxo- ethyl]-3-[5-chloro-2-
(difluoromethoxy)phenyl] pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3-
carboxamide 22 ##STR00127## N-[1-[2-[(3aS,6aR)-2-[(1- acetyl-4-
piperidyl)methyl]- 1,3,3a,4,6,6a- hexahydropyrrolo[3,4-
c]pyrrol-5-yl]-2-oxo- ethyl]-3-[5-chloro-2-
(difluoromethoxy)phenyl] pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3-
carboxamide 23 ##STR00128## ethyl 4-[[(3aS,6aR)-5-[2-
[3-[5-chloro-2- (difluoromethoxy)phenyl]- 4-(pyrazolo[1,5-
a]pyrimidine-3- carbonylamino)pyrazol-1- yl]acetyl]-1,3,3a,4,6,6a-
hexahydropyrrolo[3,4- c]pyrrol-2- yl]methyl]piperidine-1-
carboxylate 24 ##STR00129## N-[1-[2-[(3aS,7aR)-5-
methyl-3,3a,4,6,7,7a- hexahydro-2H- pyrrolo[3,2-c]pyridin-1-
yl]-2-oxo-ethyl]-3-[5- chloro-2- (difluoromethoxy)phenyl]
pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 25
##STR00130## N-[1-[2-[(3aR,7aS)-2- methyl-3,3a,4,6,7,7a-
hexahydro-1H- pyrrolo[3,4-c]pyridin-5- yl]-2-oxo-ethyl]-3-[5-
chloro-2- (difluoromethoxy)phenyl] pyrazol-4-yl]pyrazolo[1,5-
a]pyrimidine-3- carboxamide 26 ##STR00131## N-[1-[2-[(3aR,6aS)-2-
(tetrahydropyran-4- ylmethyl)-1,3,3a,4,6,6a- hexahydropyrrolo[3,4-
c]pyrrol-5-yl]-2-oxo- ethyl]-3-[5-chloro-2-
(difluoromethoxy)phenyl] pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3-
carboxamide 27 ##STR00132## N-[1-[2-[(3aS,6aR)-2-(3-
methylsulfonylpropyl)- 1,3,3a,4,6,6a- hexahydropyrrolo[3,4-
c]pyrrol-5-yl]-2-oxo- ethyl]-3-[5-chloro-2-
(difluoromethoxy)phenyl] pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3-
carboxamide 28 ##STR00133## N-[1-[2-[(3aS,6aR)-2-
isobutyl-1,3,3a,4,6,6a- hexahydropyrrolo[3,4- c]pyrrol-5-yl]-2-oxo-
ethyl]-3-[5-chloro-2- (difluoromethoxy)phenyl]
pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 29
##STR00134## N-[3-[5-chloro-2- (difluoromethoxy)phenyl]-
1-[2-(1-methyl- 3,3a,4,6,7,7a-hexahydro- 2H-pyrrolo[3,2-c]pyridin-
5-yl)-2-oxo-ethyl]pyrazol- 4-yl]pyrazolo[1,5- a]pyrimidine-3-
carboxamide 30 ##STR00135## N-[3-[5-chloro-2-
(difluoromethoxy)phenyl]- 1-[2-(5-methyl- 3,3a,4,6,7,7a-hexahydro-
1H-pyrrolo[3,4-c]pyridin- 2-yl)-2-oxo-ethyl]pyrazol-
4-yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 31 ##STR00136##
N-[1-[2-[(3aS,6aR)-2-(2- methylsulfonylethyl)- 1,3,3a,4,6,6a-
hexahydropyrrolo[3,4- c]pyrrol-5-yl]-2-oxo- ethyl]-3-[5-chloro-2-
(difluoromethoxy)phenyl] pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3-
carboxamide 32 ##STR00137## N-[1-[2-[(3aS,6aR)-2-[3-
(2-oxooxazolidin-3- yl)propyl]-1,3,3a,4,6,6a- hexahydropyrrolo[3,4-
c]pyrrol-5-yl]-2-oxo- ethyl]-3-[5-chloro-2-
(difluoromethoxy)phenyl] pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3-
carboxamide 33 ##STR00138## N-[1-[2-[(3aR,6aS)-2- [(4,4-
difluorocyclohexyl) methyl]-1,3,3a,4,6,6a- hexahydropyrrolo[3,4-
c]pyrrol-5-yl]-2-oxo- ethyl]-3-[5-chloro-2-
(difluoromethoxy)phenyl] pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3-
carboxamide 34 ##STR00139## N-[1-[2-[(3aR,6aS)-2-[(1-
methylsulfonyl-4- piperidyl)methyl]- 1,3,3a,4,6,6a-
hexahydropyrrolo[3,4- c]pyrrol-5-yl]-2-oxo- ethyl]-3-[5-chloro-2-
(difluoromethoxy)phenyl] pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3-
carboxamide 35 ##STR00140## N-[1-[2-[(3aR,6aS)-2-[[1-
(tetrahydropyran-4- carbonyl)-4- piperidyl]methyl]- 1,3,3a,4,6,6a-
hexahydropyrrolo[3,4- c]pyrrol-5-yl]-2-oxo- ethyl]-3-[5-chloro-2-
(difluoromethoxy)phenyl] pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3-
carboxamide 36 ##STR00141## N-[1-[2-[(3aR,6aS)-2-[[1-
(dimethylcarbamoyl)-4- piperidyl]methyl]- 1,3,3a,4,6,6a-
hexahydropyrrolo[3,4- c]pyrrol-5-yl]-2-oxo- ethyl]-3-[5-chloro-2-
(difluoromethoxy)phenyl] pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3-
carboxamide 37 ##STR00142## N-[1-[2-[(3aS,4S,6R,6aR)-
6-(hydroxymethyl)-2- methyl-4-phenyl- 1,3,3a,4,6,6a-
hexahydropyrrolo[3,4- c]pyrrol-5-yl]-2-oxo- ethyl]-3-[5-chloro-2-
(difluoromethoxy)phenyl] pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3-
carboxamide 38 ##STR00143## N-[1-[2-[(3aR,6aS)-2-(3-
methoxypropyl)- 1,3,3a,4,6,6a- hexahydropyrrolo[3,4-
c]pyrrol-5-yl]-2-oxo- ethyl]-3-[5-chloro-2-
(difluoromethoxy)phenyl] pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3-
carboxamide 39 ##STR00144## N-[1-[2-[(3aR,6aS)-2-[(3-
methyloxetan-3- yl)methyl]-1,3,3a,4,6,6a- hexahydropyrrolo[3,4-
c]pyrrol-5-yl]-2-oxo- ethyl]-3-[5-chloro-2-
(difluoromethoxy)phenyl] pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3-
carboxamide 40 ##STR00145## N-[1-[2-[(3aR,6aS)-2-
(cyclobutylmethyl)- 1,3,3a,4,6,6a- hexahydropyrrolo[3,4-
c]pyrrol-5-yl]-2-oxo- ethyl]-3-[5-chloro-2-
(difluoromethoxy)phenyl] pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3-
carboxamide 41 ##STR00146## N-[1-[2-[(3aR,7aS)-1-
methyl-3,3a,4,6,7,7a- hexahydro-2H- pyrrolo[3,2-c]pyridin-5-
yl]-2-oxo-ethyl]-3-[5- chloro-2- (difluoromethoxy)phenyl]
pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 42
##STR00147## N-[1-[2-[(3aS,7aR)-1- methyl-3,3a,4,6,7,7a-
hexahydro-2H- pyrrolo[3,2-c]pyridin-5- yl]-2-oxo-ethyl]-3-[5-
chloro-2- (difluoromethoxy)phenyl] pyrazol-4-yl]pyrazolo[1,5-
a]pyrimidine-3- carboxamide 43 ##STR00148## N-[1-[2-[(3aS,6aS)-2-
methyl-3a-phenyl- 3,4,6,6a-tetrahydro-1H-
pyrrolo[3,4-c]pyrrol-5-yl]- 2-oxo-ethyl]-3-[5-chloro- 2-
(difluoromethoxy)phenyl] pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3-
carboxamide 44 ##STR00149## N-[1-[2-[(3aR,6aR)-2- methyl-3a-phenyl-
3,4,6,6a-tetrahydro-1H- pyrrolo[3,4-c]pyrrol-5-yl]-
2-oxo-ethyl]-3-[5-chloro- 2- (difluoromethoxy)phenyl]
pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 45
##STR00150## N-[1-[2-[(3aS,7aR)-5- methyl-3,3a,4,6,7,7a-
hexahydro-2H- pyrrolo[3,2-c]pyridin-1- yl]-2-oxo-ethyl]-3-[5-
chloro-2- (difluoromethoxy)phenyl] pyrazol-4-yl]pyrazolo[1,5-
a]pyrimidine-3- carboxamide 46 ##STR00151##
N-[1-[2-[(3aS,6aR)-2-[(1- hydroxycyclohexyl)methyl]- 1,3,3a,4,6,6a-
hexahydropyrrolo[3,4- c]pyrrol-5-yl]-2-oxo- ethyl]-3-[5-chloro-2-
(difluoromethoxy)phenyl] pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3-
carboxamide 47 ##STR00152## N-[1-[2-[(3aS,6aR)-2-[(1-
cyanocyclohexyl)methyl]- 1,3,3a,4,6,6a- hexahydropyrrolo[3,4-
c]pyrrol-5-yl]-2-oxo- ethyl]-3-[5-chloro-2-
(difluoromethoxy)phenyl] pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3-
carboxamide 48 ##STR00153## N-[1-[2-[(3aR,7aS)-5-
methyl-3,3a,4,6,7,7a- hexahydro-2H- pyrrolo[3,2-c]pyridin-1-
yl]-2-oxo-ethyl]-3-[5- chloro-2- (difluoromethoxy)phenyl]
pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 49
##STR00154## N-[1-[2-[(3aS,7aS)-5- methyl-3,3a,4,6,7,7a-
hexahydro-1H- pyrrolo[3,4-c]pyridin-2- yl]-2-oxo-ethyl]-3-[5-
chloro-2- (difluoromethoxy)phenyl] pyrazol-4-yl]pyrazolo[1,5-
a]pyrimidine-3- carboxamide 50 ##STR00155##
N-[1-[2-[(3aR,6aS)-2-(3- hydroxy-3-methyl-butyl)- 1,3,3a,4,6,6a-
hexahydropyrrolo[3,4- c]pyrrol-5-yl]-2-oxo- ethyl]-3-[5-chloro-2-
(difluoromethoxy)phenyl] pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3-
carboxamide
51 ##STR00156## 3-[(3aR,6aS)-5-[2-[3-[5- chloro-2-
(difluoromethoxy)phenyl]- 4-(pyrazolo[1,5- a]pyrimidine-3-
carbonylamino)pyrazol-1- yl]acetyl]-1,3,3a,4,6,6a-
hexahydropyrrolo[3,4- c]pyrrol-2-yl]propyl morpholine-4-carboxylate
52 ##STR00157## N-[1-[2-[(3aR,6aS)-2- (cyclohexylmethyl)-
1,3,3a,4,6,6a- hexahydropyrrolo[3,4- c]pyrrol-5-yl]-2-oxo-
ethyl]-3-[5-chloro-2- (difluoromethoxy)phenyl]
pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 53
##STR00158## N-[1-[2-[(3aR,7aR)-5- methyl-3,3a,4,6,7,7a-
hexahydro-1H- pyrrolo[3,4-c]pyridin-2- yl]-2-oxo-ethyl]-3-[5-
chloro-2- (difluoromethoxy)phenyl] pyrazol-4-yl]pyrazolo[1,5-
a]pyrimidine-3- carboxamide 54 ##STR00159##
N-[1-[2-[(3aR,6aS)-2-[3- (2-oxoindolin-1- yl)propyl]-1,3,3a,4,6,6a-
hexahydropyrrolo[3,4- c]pyrrol-5-yl]-2-oxo- ethyl]-3-[5-chloro-2-
(difluoromethoxy)phenyl] pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3-
carboxamide 55 ##STR00160## 3-[(3aS,6aR)-5-[2-[3-[5- chloro-2-
(difluoromethoxy)phenyl]- 4-(pyrazolo[1,5- a]pyrimidine-3-
carbonylamino)pyrazol-1- yl]acetyl]-1,3,3a,4,6,6a-
hexahydropyrrolo[3,4- c]pyrrol-2-yl]propyl cyclobutanecarboxylate
56 ##STR00161## 2-amino-N-[3-[5-chloro-2- (difluoromethoxy)phenyl]-
1-[2-(1-methyl- 3,3a,4,6,7,7a-hexahydro- 2H-pyrrolo[3,2-c]pyridin-
5-yl)-2-oxo-ethyl]pyrazol- 4-yl]pyrazolo[1,5- a]pyrimidine-3-
carboxamide 57 ##STR00162## N-[1-[2-[(3aS,6aR)-2-
(cyclopropylmethyl)- 1,3,3a,4,6,6a- hexahydropyrrolo[3,4-
c]pyrrol-5-yl]-2-oxo- ethyl]-3-[5-chloro-2-
(difluoromethoxy)phenyl] pyrazol-4-yl]-2-amino- pyrazolo[1,5-
a]pyrimidine-3- carboxamide 58 ##STR00163## N-[1-[2-[(3aS,6aR)-2-
[(4,4- difluorocyclohexyl)methyl]- 1,3,3a,4,6,6a-
hexahydropyrrolo[3,4- c]pyrrol-5-yl]-2-oxo- ethyl]-3-[5-chloro-2-
(difluoromethoxy)phenyl] pyrazol-4-yl]-2-amino- pyrazolo[1,5-
a]pyrimidine-3- carboxamide 59 ##STR00164## N-[1-[2-[(3aR,6aS)-2-
(2,2,2-trifluoroethyl)- 1,3,3a,4,6,6a- hexahydropyrrolo[3,4-
c]pyrrol-5-yl]-2-oxo- ethyl]-3-[5-chloro-2-
(difluoromethoxy)phenyl] pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3-
carboxamide 60 ##STR00165## N-[1-[2-[(3aR,6aS)-2-[2- [(4-
chlorophenyl)methoxy] ethyl]-1,3,3a,4,6,6a- hexahydropyrrolo[3,4-
c]pyrrol-5-yl]-2-oxo- ethyl]-3-[5-chloro-2-
(difluoromethoxy)phenyl] pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3-
carboxamide 61 ##STR00166## N-[1-[2-[(3aR,7aR)-5-
methyl-3,3a,4,6,7,7a- hexahydro-2H- pyrrolo[3,2-c]pyridin-1-
yl]-2-oxo-ethyl]-3-[5- chloro-2- (difluoromethoxy)phenyl]
pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 62
##STR00167## N-[1-[2-[(3aS,7aS)-5- methyl-3,3a,4,6,7,7a-
hexahydro-2H- pyrrolo[3,2-c]pyridin-1- yl]-2-oxo-ethyl]-3-[5-
chloro-2- (difluoromethoxy)phenyl] pyrazol-4-yl]pyrazolo[1,5-
a]pyrimidine-3- carboxamide 63 ##STR00168## N-[3-[5-chloro-2-
(difluoromethoxy)phenyl]- 1-[2-[4-[2- cyanoethyl(methyl)amino]-
1-piperidyl]-2-oxo- ethyl]pyrazol-4- yl]pyrazolo[1,5-
a]pyrimidine-3- carboxamide 64 ##STR00169## N-[3-[5-chloro-2-
(difluoromethoxy)phenyl]- 1-[2-[3- (dimethylamino)azetidin-
1-yl]-2-oxo-ethyl]pyrazol- 4-yl]pyrazolo[1,5- a]pyrimidine-3-
carboxamide 65 ##STR00170## N-[3-[5-chloro-2-
(difluoromethoxy)phenyl]- 1-[2-[3- (dimethylamino)pyrrolidin-
1-yl]-2-oxo- ethyl]pyrazol-4- yl]pyrazolo[1,5- a]pyrimidine-3-
carboxamide 66 ##STR00171## N-[1-[2-(4-amino-1-
piperidyl)-2-oxo-ethyl]-3- [5-chloro-2- (difluoromethoxy)phenyl]
pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 67
##STR00172## N-[3-[5-chloro-2- (difluoromethoxy)phenyl]-
1-[2-[4-(dimethylamino)- 1-piperidyl]-2-oxo- ethyl]pyrazol-4-
yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 68 ##STR00173##
N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[2-[4-[2-
methoxyethyl(methyl) amino]-1-piperidyl]-2-oxo- ethyl]pyrazol-4-
yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 69 ##STR00174##
N-[3-[5-chloro-2- (difluoromethoxy)phenyl]-
1-[2-oxo-2-(4-pyrrolidin- 1-yl-1- piperidyl)ethyl]pyrazol-4-
yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 70 ##STR00175##
N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[2-[4-
[(dimethylamino)methyl]- 1-piperidyl]-2-oxo- ethyl]pyrazol-4-
yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 71 ##STR00176##
N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[2-[(3R)-3-
[(dimethylamino)methyl]- 1-piperidyl]-2-oxo- ethyl]pyrazol-4-
yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 72 ##STR00177##
N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[2-[(3S)-3-
[(dimethylamino)methyl]- 1-piperidyl]-2-oxo- ethyl]pyrazol-4-
yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 73 ##STR00178##
N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[2-[4-[2-
(dimethylamino)ethoxy]- 1-piperidyl]-2-oxo- ethyl]pyrazol-4-
yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 74 ##STR00179##
N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[2-[4-
[(dimethylamino)methyl]- 4-hydroxy-1-piperidyl]-2-
oxo-ethyl]pyrazol-4- yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide
75 ##STR00180## 2-amino-N-[3-[5-chloro-2- (difluoromethoxy)phenyl]-
1-[2-[4-(ethylamino)-1- piperidyl]-2-oxo- ethyl]pyrazol-4-
yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 76 ##STR00181##
2-amino-N-[3-[5-chloro-2- (difluoromethoxy)phenyl]-
1-[2-[4-[(3R)-3- hydroxypyrrolidin-1-yl]-1- piperidyl]-2-oxo-
ethyl]pyrazol-4- yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 77
##STR00182## 2-amino-N-[3-[5-chloro-2- (difluoromethoxy)phenyl]-
1-[2-[4-[(3S)-3- hydroxypyrrolidin-1-yl]-1- piperidyl]-2-oxo-
ethyl]pyrazol-4- yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 78
##STR00183## 2-amino-N-[3-[5-chloro-2- (difluoromethoxy)phenyl]-
1-[2-[(2R)-2- [(dimethylamino)methyl] pyrrolidin-1-yl]-2-oxo-
ethyl]pyrazol-4- yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 79
##STR00184## 2-amino-N-[3-[5-chloro-2- (difluoromethoxy)phenyl]-
1-[2-[(2S)-2- [(dimethylamino)methyl] pyrrolidin-1-yl]-2-oxo-
ethyl]pyrazol-4- yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 80
##STR00185## N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[2-[4-
[(dimethylamino)methyl]- 4-phenyl-1-piperidyl]-2-
oxo-ethyl]pyrazol-4- yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide
81 ##STR00186## N-[1-[2-[(2S)-2- (aminomethyl)pyrrolidin-
1-yl]-2-oxo-ethyl]-3-[5- chloro-2- (difluoromethoxy)phenyl]
pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 82
##STR00187## 2-amino-N-[3-[5-chloro-2- (difluoromethoxy)phenyl]-
1-[2-[(3S)-3- [(dimethylamino)methyl]- 1-piperidyl]-2-oxo-
ethyl]pyrazol-4- yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 83
##STR00188## N-[3-[5-chloro-2- (difluoromethoxy)phenyl]-
1-[2-[4-(methylamino)-1- piperidyl]-2-oxo- ethyl]pyrazol-4-
yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 84 ##STR00189##
N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[2-[4-
(cyclobutylamino)-1- piperidyl]-2-oxo- ethyl]pyrazol-4-
yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 85 ##STR00190##
N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[2-[4-[methyl(2-
phenylethyl)amino]-1- piperidyl]-2-oxo- ethyl]pyrazol-4-
yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 86 ##STR00191##
N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[2-[4-[methyl-[2-(2-
pyridyl)ethyl]amino]-1- piperidyl]-2-oxo- ethyl]pyrazol-4-
yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 87 ##STR00192##
N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[2-[4-(2-
cyanoethylamino)-1- piperidyl]-2-oxo- ethyl]pyrazol-4-
yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 88 ##STR00193##
N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[2-[4-[[4-
(dimethylamino)-4-oxo- butyl]-methyl-amino]-1- piperidyl]-2-oxo-
ethyl]pyrazol-4- yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 89
##STR00194## N-[3-[5-chloro-2- (difluoromethoxy)phenyl]-
1-[2-oxo-2-[4-(2- phenylethylamino)-1- piperidyl]ethyl]pyrazol-4-
yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 90 ##STR00195##
N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[2-[4-[2-(4-
hydroxyphenyl)ethyl- methyl-amino]-1- piperidyl]-2-oxo-
ethyl]pyrazol-4- yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 91
##STR00196## N-[3-[5-chloro-2- (difluoromethoxy)phenyl]-
1-[2-[4-[2-(4- hydroxyphenyl)ethylamino]- 1-piperidyl]-2-oxo-
ethyl]pyrazol-4- yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 92
##STR00197## N-[3-[5-chloro-2- (difluoromethoxy)phenyl]-
1-[2-[4-[2-(4- chlorophenyl)ethylamino]- 1-piperidyl]-2-oxo-
ethyl]pyrazol-4- yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 93
##STR00198## N-[3-[5-chloro-2- (difluoromethoxy)phenyl]-
1-[2-oxo-2-[4-[2-[4- (trifluoromethyl)phenyl] ethylamino]-1-
piperidyl]ethyl]pyrazol-4- yl]pyrazolo[1,5- a]pyrimidine-3-
carboxamide 94 ##STR00199## N-[3-[5-chloro-2-
(difluoromethoxy)phenyl]- 1-[2-[4-[2-(4- chlorophenyl)ethyl-
methyl-amino]-1- piperidyl]-2-oxo- ethyl]pyrazol-4-
yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 95 ##STR00200##
N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[2-[4-[2-(4-
methoxyphenyl)ethyl- methyl-amino]-1- piperidyl]-2-oxo-
ethyl]pyrazol-4- yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 96
##STR00201## N-[3-[5-chloro-2- (difluoromethoxy)phenyl]-
1-[2-[4-[methyl-[(3- methyloxetan-3- yl)methyl]amino]-1-
piperidyl]-2-oxo- ethyl]pyrazol-4- yl]pyrazolo[1,5- a]pyrimidine-3-
carboxamide 97 ##STR00202## N-[3-[5-chloro-2-
(difluoromethoxy)phenyl]- 1-[2-[4-[methyl-[2-[4-
(trifluoromethyl)phenyl] ethyl]amino]-1-piperidyl]-2-
oxo-ethyl]pyrazol-4- yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide
98 ##STR00203## N-[1-[2-[4- [benzyl(methyl)amino]-1-
piperidyl]-2-oxo-ethyl]-3- [5-chloro-2- (difluoromethoxy)phenyl]
pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 99
##STR00204## N-[3-[5-chloro-2- (difluoromethoxy)phenyl]-
1-[2-[4-[methyl(2,2,2- trifluoroethyl)amino]-1- piperidyl]-2-oxo-
ethyl]pyrazol-4- yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 100
##STR00205## N-[3-[5-chloro-2- (difluoromethoxy)phenyl]-
1-[2-[4-[methyl(2- phenoxyethyl)amino]-1- piperidyl]-2-oxo-
ethyl]pyrazol-4- yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 101
##STR00206## N-[3-[5-chloro-2- (difluoromethoxy)phenyl]-
1-[2-[4-[2- cyclohexylethyl(methyl) amino]-1-piperidyl]-2-oxo-
ethyl]pyrazol-4- yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 102
##STR00207## N-[3-[5-chloro-2- (difluoromethoxy)phenyl]-
1-[2-[4-[(2,2-difluoro-2- phenyl-ethyl)-methyl-
amino]-1-piperidyl]-2- oxo-ethyl]pyrazol-4- yl]pyrazolo[1,5-
a]pyrimidine-3- carboxamide 103 ##STR00208## N-[3-[5-chloro-2-
(difluoromethoxy)phenyl]- 1-[2-oxo-2-[4-[2- phenylethyl(2,2,2-
trifluoroethyl)amino]-1- piperidyl]ethyl]pyrazol-4-
yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 104 ##STR00209##
N-[1-[2-[4-[2-(4- bromophenoxy)ethyl- methyl-amino]-1-
piperidyl]-2-oxo-ethyl]-3- [5-chloro-2- (difluoromethoxy)phenyl]
pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 105
##STR00210## N-[1-[2-[4-[2-(2- bromophenoxy)ethyl- methyl-amino]-1-
piperidyl]-2-oxo-ethyl]-3- [5-chloro-2- (difluoromethoxy)phenyl]
pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 106
##STR00211## N-[3-[5-chloro-2- (difluoromethoxy)phenyl]-
1-[2-[4-[2-(2- chlorophenoxy)ethyl- methyl-amino]-1-
piperidyl]-2-oxo- ethyl]pyrazol-4- yl]pyrazolo[1,5- a]pyrimidine-3-
carboxamide 107 ##STR00212## N-[3-[5-chloro-2-
(difluoromethoxy)phenyl]- 1-[2-[4-[2-(4- chlorophenoxy)ethyl-
methyl-amino]-1- piperidyl]-2-oxo- ethyl]pyrazol-4-
yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 108 ##STR00213##
N-[1-[2-[4-[butyl-[2-(4- methylphenoxy)ethyl]
amino]-1-piperidyl]-2-oxo- ethyl]-3-[5-chloro-2-
(difluoromethoxy)phenyl] pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3-
carboxamide 109 ##STR00214## N-[1-[2-[4-[allyl-[2-(4-
methylphenoxy)ethyl] amino]-1-piperidyl]-2-oxo-
ethyl]-3-[5-chloro-2- (difluoromethoxy)phenyl]
pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide
110 ##STR00215## N-[3-[5-chloro-2- (difluoromethoxy)phenyl]-
1-[2-[4-[methyl-[2-(4- methylphenoxy)ethyl]
amino]-1-piperidyl]-2-oxo- ethyl]pyrazol-4- yl]pyrazolo[1,5-
a]pyrimidine-3- carboxamide 111 ##STR00216## N-[3-[5-chloro-2-
(difluoromethoxy)phenyl]- 1-[2-[4-[(4,4-difluoro-1-
piperidyl)methyl]-4- phenyl-1-piperidyl]-2-oxo- ethyl]pyrazol-4-
yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 112 ##STR00217##
N-[1-[2-[4-[1,3- benzodioxol-2- ylmethyl(methyl)amino]-
1-piperidyl]-2-oxo-ethyl]- 3-[5-chloro-2- (difluoromethoxy)phenyl]
pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 113
##STR00218## N-[3-[5-chloro-2- (difluoromethoxy)phenyl]-
1-[2-[4-[methyl-[(3- phenoxyphenyl)methyl]
amino]-1-piperidyl]-2-oxo- ethyl]pyrazol-4- yl]pyrazolo[1,5-
a]pyrimidine-3- carboxamide 114 ##STR00219## N-[3-[5-chloro-2-
(difluoromethoxy)phenyl]- 1-[2-[4-[(1- cyanocyclohexyl)methyl-
methyl-amino]-1- piperidyl]-2-oxo- ethyl]pyrazol-4-
yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 115 ##STR00220##
N-[1-[2-[4-[butyl(2,2,2- trifluoroethyl)amino]-1-
piperidyl]-2-oxo-ethyl]-3- [5-chloro-2- (difluoromethoxy)phenyl]
pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 116
##STR00221## N-[1-[2-[4-[benzyl(2,2,2- trifluoroethyl)amino]-1-
piperidyl]-2-oxo-ethyl]-3- [5-chloro-2- (difluoromethoxy)phenyl]
pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 117
##STR00222## N-[3-[5-chloro-2- (difluoromethoxy)phenyl]-
1-[2-[4-[(3-methyloxetan- 3-yl)methyl-(3,3,3-
trifluoropropyl)amino]-1- piperidyl]-2-oxo- ethyl]pyrazol-4-
yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 118 ##STR00223##
N-[1-[2-[4-[benzyl(3,3,3- trifluoropropyl)amino]-1-
piperidyl]-2-oxo-ethyl]-3- [5-chloro-2- (difluoromethoxy)phenyl]
pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 119
##STR00224## N-[1-[2-[4-[(4- bromophenyl)methyl- methyl-amino]-1-
piperidyl]-2-oxo-ethyl]-3- [5-chloro-2- (difluoromethoxy)phenyl]
pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 120
##STR00225## N-[1-[2-[4-[(4-tert- butylphenyl)methyl-
methyl-amino]-1- piperidyl]-2-oxo-ethyl]-3- [5-chloro-2-
(difluoromethoxy)phenyl] pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3-
carboxamide 121 ##STR00226## N-[3-[5-chloro-2-
(difluoromethoxy)phenyl]- 1-[2-[4-[(3,4- dichiorophenyl)methy1-
methyl-amino]-1- piperidyl]-2-oxo- ethyl]pyrazol-4-
yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 122 ##STR00227##
N-[1-[2-[4-[(3- bromophenyl)methyl- methyl-amino]-1-
piperidyl]-2-oxo-ethyl]-3- [5-chloro-2- (difluoromethoxy)phenyl]
pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 123
##STR00228## N-[3-[5-chloro-2- (difluoromethoxy)phenyl]-
1-[2-[4-[methyl(3- phenylpropyl)amino]-1- piperidyl]-2-oxo-
ethyl]pyrazol-4- yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 124
##STR00229## [1-[2-[3-[5-chloro-2- (difluoromethoxy)phenyl]-
4-(pyrazolo[1,5- a]pyrimidine-3- carbonylamino)pyrazol-1-
yl]acetyl]-4-piperidyl]- dimethyl-(3- phenylpropyl)ammonium 125
##STR00230## N-[3-[5-chloro-2- (difluoromethoxy)phenyl]-
1-[2-[4-[(4- isopropoxyphenyl)methyl- methyl-amino]-1-
piperidyl]-2-oxo- ethyl]pyrazol-4- yl]pyrazolo[1,5- a]pyrimidine-3-
carboxamide 126 ##STR00231## N-[3-[5-chloro-2-
(difluoromethoxy)phenyl]- 1-[2-[4-[(4- chlorophenyl)methyl-
methyl-amino]-1- piperidyl]-2-oxo- ethyl]pyrazol-4-
yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 127 ##STR00232##
N-[1-[2-[4-[(4- butoxyphenyl)methyl- methyl-amino]-1-
piperidyl]-2-oxo-ethyl]-3- [5-chloro-2- (difluoromethoxy)phenyl]
pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 128
##STR00233## N-[3-[5-chloro-2- (difluoromethoxy)phenyl]-
1-[2-[4-[methyl-[[3- (trifluoromethyl)phenyl]
methyl]amino]-1-piperidyl]- 2-oxo-ethyl]pyrazol-4- yl]pyrazolo[1,5-
a]pyrimidine-3- carboxamide 129 ##STR00234## N-[3-[5-chloro-2-
(difluoromethoxy)phenyl]- 1-[2-[4-[(2,4- dimethylphenyl)methyl-
methyl-amino]-1- piperidyl]-2-oxo- ethyl]pyrazol-4-
yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 130 ##STR00235##
N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[2-[4-[methyl(2-
naphthylmethyl)amino]-1- piperidyl]-2-oxo- ethyl]pyrazol-4-
yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 131 ##STR00236##
N-[1-[2-[4-[(3-bromo-4- fluoro-phenyl)methyl- methyl-amino]-1-
piperidyl]-2-oxo-ethyl]-3- [5-chloro-2- (difluoromethoxy)phenyl]
pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 132
##STR00237## N-[3-[5-chloro-2- (difluoromethoxy)phenyl]-
1-[2-oxo-2-[4-[(2,2,2- trifluoro-1-phenyl- ethyl)amino]-1-
piperidyl]ethyl]pyrazol-4- yl]pyrazolo[1,5- a]pyrimidine-3-
carboxamide 133 ##STR00238## N-[1-[2-[4-[(1-benzyl-
2,2,2-trifluoro-ethyl)- methyl-amino]-1- piperidyl]-2-oxo-ethyl]-3-
[5-chloro-2- (difluoromethoxy)phenyl] pyrazol-4-yl]pyrazolo[1,5-
a]pyrimidine-3- carboxamide 134 ##STR00239## N-[3-[5-chloro-2-
(difluoromethoxy)phenyl]- 1-[2-[4-[2,2- difluoropropyl(methyl)
amino]-1-piperidyl]-2-oxo- ethyl]pyrazol-4- yl]pyrazolo[1,5-
a]pyrimidine-3- carboxamide 135 ##STR00240## N-[3-[5-chloro-2-
(difluoromethoxy)phenyl]- 1-[2-[4-(5- chloroisoindolin-2-yl)-1-
piperidyl]-2-oxo- ethyl]pyrazol-4- yl]pyrazolo[1,5- a]pyrimidine-3-
carboxamide 136 ##STR00241## 2-amino-N-[3-[5-chloro-2-
(difluoromethoxy)phenyl]- 1-[2-[3- (dimethylamino)pyrrolidin-
1-yl]-2-oxo- ethyl]pyrazol-4- yl]pyrazolo[1,5- a]pyrimidine-3-
carboxamide 137 ##STR00242## 2-amino-N-[3-[5-chloro-2-
(difluoromethoxy)phenyl]- 1-[2-[4-[2- (dimethylamino)ethoxy]-
1-piperidyl]-2-oxo- ethyl]pyrazol-4- yl]pyrazolo[1,5-
a]pyrimidine-3- carboxamide 138 ##STR00243##
2-amino-N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[2-[3-
(dimethylamino)azetidin- 1-yl]-2-oxo-ethyl]pyrazol-
4-yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 139 ##STR00244##
2-amino-N-[3-[5-chloro-2- (difluoromethoxy)phenyl]-
1-[2-[4-(dimethylamino)- 1-piperidyl]-2-oxo- ethyl]pyrazol-4-
yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 140 ##STR00245##
2-amino-N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[2-[4-[2-
hydroxyethyl(methyl) amino]-1-piperidyl]-2-oxo- ethyl]pyrazol-4-
yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 141 ##STR00246##
2-amino-N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[2-[4-[2-
methoxyethyl(methyl) amino]-1-piperidyl]-2-oxo- ethyl]pyrazol-4-
yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 142 ##STR00247##
N-[1-[1-(3- acetamidopropyl)-4- piperidyl]-3-[5-chloro-2-
(difluoromethoxy)phenyl] pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3-
carboxamide 143 ##STR00248## 2-amino-N-[3-[5-chloro-2-
(difluoromethoxy)phenyl]- 1-[1-[4-oxo-4-(1- piperidyl)butyl]-4-
piperidyl]pyrazol-4- yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide
144 ##STR00249## N-[1-[1-(1-acetyl-4- piperidyl)-4-piperidyl]-3-
[5-chloro-2- (difluoromethoxy)phenyl] pyrazol-4-y1]-2-amino-
pyrazolo[1,5- a]pyrimidine-3- carboxamide 145 ##STR00250##
2-amino-N-[1-[1-(3- benzamidopropyl)-4- piperidyl]-3-[5-chloro-2-
(difluoromethoxy)phenyl] pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3-
carboxamide 146 ##STR00251## 2-amino-N-[3-[5-chloro-2-
(difluoromethoxy)phenyl]- 1-[1-[3-(2-oxopyrrolidin- 1-yl)propyl]-4-
piperidyl]pyrazol-4- yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide
147 ##STR00252## 2-amino-N-[3-[5-chloro-2-
(difluoromethoxy)phenyl]- 1-[1-(4-morpholino-4-oxo-
butyl)-4-piperidyl]pyrazol- 4-yl]pyrazolo[1,5- a]pyrimidine-3-
carboxamide 148 ##STR00253## 2-amino-N-[3-[5-chloro-2-
(difluoromethoxy)phenyl]- 1-[1-[4-(dimethylamino)- 4-oxo-butyl]-4-
piperidyl]pyrazol-4- yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide
149 ##STR00254## 2-amino-N-[3-[5-chloro-2-
(difluoromethoxy)phenyl]- 1-[1-[4-(methylamino)-4- oxo-butyl]-4-
piperidyl]pyrazol-4- yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide
150 ##STR00255## N-[1-[1-(3- acetamidopropyl)-4-
piperidyl]-3-[5-chloro-2- (difluoromethoxy)phenyl]
pyrazol-4-yl]-2-amino- pyrazolo[1,5- a]pyrimidine-3- carboxamide
151 ##STR00256## 2-amino-N-[1-[1-[3- [benzoyl(methyl)amino]
propyl]-4-piperidyl]-3-[5- chloro-2- (difluoromethoxy)phenyl]
pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 152
##STR00257## N-[3-[5-chloro-2- (difluoromethoxy)phenyl]-
1-[1-[4-oxo-4- (tetrahydropyran-4- ylamino)butyl]-4-
piperidyl]pyrazol-4- yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide
153 ##STR00258## N-[3-[5-chloro-2- (difluoromethoxy)phenyl]-
1-[1-[4-(oxetan-3- ylamino)-4-oxo-butyl]-4- piperidyl]pyrazol-4-
yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 154 ##STR00259##
N-[3-[5-chloro-2- (difluoromethoxy)phenyl]-
1-[1-[3-(3-methyl-2-oxo- imidazolidin-1-yl)propyl]-
4-piperidyl]pyrazol-4- yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide
155 ##STR00260## N-[3-[5-chloro-2- (difluoromethoxy)phenyl]-
1-[1-[3-(2-oxopyrrolidin- 1-yl)propyl]-4- piperidyl]pyrazol-4-
yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 156 ##STR00261##
N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[1-[4-(ethylamino)-4-
oxo-butyl]-4- piperidyl]pyrazol-4- yl]pyrazolo[1,5- a]pyrimidine-3-
carboxamide 157 ##STR00262## N-[3-[5-chloro-2-
(difluoromethoxy)phenyl]- 1-[1-[2-(methylamino)-2- oxo-ethyl]-4-
piperidyl]pyrazol-4- yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide
158 ##STR00263## N-[3-[5-chloro-2- (difluoromethoxy)phenyl]-
1-[1-(3- morpholinopropyl)-4- piperidyl]pyrazol-4- yl]pyrazolo[1,5-
a]pyrimidine-3- carboxamide 159 ##STR00264## N-[3-[5-chloro-2-
(difluoromethoxy)phenyl]- 1-[1-(3- thiomorpholinopropyl)-4-
piperidyl]pyrazol-4- yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide
160 ##STR00265## N-[3-[5-chloro-2- (difluoromethoxy)phenyl]-
1-[1-[3-(methylamino)-3- oxo-propyl]-4- piperidyl]pyrazol-4-
yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 161 ##STR00266##
N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[1-[3-(1,1-dioxo-1,4-
thiazinan-4-yl)propyl]-4- piperidyl]pyrazol-4- yl]pyrazolo[1,5-
a]pyrimidine-3- carboxamide 162 ##STR00267## 2-amino-N-[1-[1-(4-
amino-4-oxo-butyl)-4- piperidyl]-3-[5-chloro-2-
(difluoromethoxy)phenyl] pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3-
carboxamide 163 ##STR00268## 2-amino-N-[3-[5-chloro-2-
(difluoromethoxy)phenyl]- 1-[1-[3-(2- oxoimidazolidin-1-
yl)propyl]-4- piperidyl]pyrazol-4- yl]pyrazolo[1,5- a]pyrimidine-3-
carboxamide 164 ##STR00269## 2-amino-N-[3-[5-chloro-2-
(difluoromethoxy)phenyl]- 1-[1-[3-(3-methyl-2-oxo-
imidazolidin-1-yl)propyl]- 4-piperidyl]pyrazol-4- yl]pyrazolo[1,5-
a]pyrimidine-3- carboxamide 165 ##STR00270## 2-amino-N-[1-[1-(3-
amino-3-oxo-propyl)-4- piperidyl]-3-[5-chloro-2-
(difluoromethoxy)phenyl] pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3-
carboxamide 166 ##STR00271## 2-amino-N-[1-[1-[3-(3- benzyl-2-oxo-
imidazolidin-1-yl)propyl]- 4-piperidyl]-3-[5-chloro-2-
(difluoromethoxy)phenyl] pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3-
carboxamide 167 ##STR00272## 2-amino-N-[1-[1-[4-
(benzylamino)-4-oxo- butyl]-4-piperidyl]-3-[5- chloro-2-
(difluoromethoxy)phenyl] pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3-
carboxamide 168 ##STR00273## N-[3-[5-chloro-2-
(difluoromethoxy)phenyl]- 1-[1-[4-(methylamino)-4- oxo-butyl]-4-
piperidyl]pyrazol-4- yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide
169 ##STR00274## N-[3-[5-chloro-2- (difluoromethoxy)phenyl]-
1-[1-(4-morpholino-4-oxo- butyl)-4-piperidyl]pyrazol-
4-yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 170 ##STR00275##
N-[1-[1-(4-amino-4-oxo- butyl)-4-piperidyl]-3-[5- chloro-2-
(difluoromethoxy)phenyl] pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3-
carboxamide 171 ##STR00276## 2-amino-N-[1-(azepan-4-
yl)-3-[5-chloro-2- (difluoromethoxy)phenyl]
pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3-
carboxamide 172 ##STR00277## 2-amino-N-[3-[5-chloro-2-
(difluoromethoxy)phenyl]- 1-(1-methylazepan-4- yl)pyrazol-4-
yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 173 ##STR00278##
N-[1-[1-[(1-acetyl-4- piperidyl)methyl]-4-
piperidyl]-3-[5-chloro-2- (difluoromethoxy)phenyl]
pyrazol-4-yl]-2-amino- pyrazolo[1,5- a]pyrimidine-3- carboxamide
174 ##STR00279## 2-amino-N-[3-[5-chloro-2-
(difluoromethoxy)phenyl]- 1-(1-isobutyl-4- piperidyl)pyrazol-4-
yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 175 ##STR00280## ethyl
4-[4-[4-[(2- aminopyrazolo[1,5- a]pyrimidine-3-
carbonyl)amino]-3-[5- chloro-2- (difluoromethoxy)phenyl]
pyrazol-1-yl]-1- piperidyl]butanoate 176 ##STR00281##
2-amino-N-[3-[5-chloro-2- (difluoromethoxy)phenyl]-
1-[1-(3-hydroxypropyl)-4- piperidyl]pyrazol-4- yl]pyrazolo[1,5-
a]pyrimidine-3- carboxamide 177 ##STR00282##
2-amino-N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[1-(3-
methylsulfonylpropyl)-4- piperidyl]pyrazol-4- yl]pyrazolo[1,5-
a]pyrimidine-3- carboxamide 178 ##STR00283##
2-amino-N-[1-(1-benzyl- 4-piperidyl)-3-[5-chloro-2-
(difluoromethoxy)phenyl] pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3-
carboxamide 179 ##STR00284## 2-amino-N-[3-[5-chloro-2-
(difluoromethoxy)phenyl]- 1-[1-(4-phenylbutyl)-4-
piperidyl]pyrazol-4- yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide
180 ##STR00285## 2-amino-N-[1-[1-(2- benzyloxyethyl)-4-
piperidyl]-3-[5-chloro-2- (difluoromethoxy)phenyl]
pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 181
##STR00286## 2-amino-N-[3-[5-chloro-2- (difluoromethoxy)phenyl]-
1-[1-[4-(2- phenylethoxy)butyl]-4- piperidyl]pyrazol-4-
yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 182 ##STR00287##
2-amino-N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[(3S)-1-
methylpyrrolidin-3- yl]pyrazol-4- yl]pyrazolo[1,5- a]pyrimidine-3-
carboxamide 183 ##STR00288## 2-amino-N-[3-[5-chloro-2-
(difluoromethoxy)phenyl]- 1-[(3R)-1- methylpyrrolidin-3-
yl]pyrazol-4- yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 184
##STR00289## 2-amino-N-[3-[5-chloro-2- (difluoromethoxy)phenyl]-
1-(1-methyl-4- piperidyl)pyrazol-4- yl]pyrazolo[1,5-
a]pyrimidine-3- carboxamide 185 ##STR00290##
2-amino-N-[3-[5-chloro-2- (difluoromethoxy)phenyl]-
1-[(3R)-pyrrolidin-3- yl]pyrazol-4- yl]pyrazolo[1,5-
a]pyrimidine-3- carboxamide 186 ##STR00291##
2-amino-N-[3-[5-chloro-2- (difluoromethoxy)phenyl]-
1-[(3S)-pyrrolidin-3- yl]pyrazol-4- yl]pyrazolo[1,5-
a]pyrimidine-3- carboxamide 187 ##STR00292## N-[3-[5-chloro-2-
(difluoromethoxy)phenyl]- 1-[4-[4-[(1- cyanocyclohexyl)methyl-
methyl-amino]piperidine- 1- carbonyl]phenyl]pyrazol-
4-yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 188 ##STR00293##
N-[4-[5-chloro-2- (difluoromethoxy)phenyl]- 2-[4-(dimethylamino)-1-
piperidyl]thiazol-5- yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide
189 ##STR00294## N-[4-[5-chloro-2- (difluoromethoxy)phenyl]-
2-[4-[2- cyanoethyl(methyl)amino]- 1-piperidyl]thiazol-5-
yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 190 ##STR00295##
N-[4-[5-chloro-2- (difluoromethoxy)phenyl]- 2-[4-
[(dimethylamino)methyl]- 1-piperidyl]thiazol-5- yl]pyrazolo[1,5-
a]pyrimidine-3- carboxamide 191 ##STR00296## N-[4-[5-chloro-2-
(difluoromethoxy)phenyl]- 2-[4-[2- (dimethylamino)ethyl]-1-
piperidyl]thiazol-5- yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide
192 ##STR00297## N-[4-[5-chloro-2- (difluoromethoxy)phenyl]-
2-[4-[methyl(2- phenylethyl)amino]-1- piperidyl]thiazol-5-
yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 193 ##STR00298##
N-[2-[4-[(4-amino-4-oxo- butyl)-methyl-amino]-1-
piperidyl]-4-[5-chloro-2- (difluoromethoxy)phenyl]
thiazol-5-yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 194
##STR00299## N-[4-[5-chloro-2- (difluoromethoxy)phenyl]-
2-[4-(3-fluoroazetidin-1- yl)-1-piperidyl]thiazol-5-
yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 195 ##STR00300##
N-[4-[5-chloro-2- (difluoromethoxy)phenyl]-
2-[3-(1-piperidyl)azetidin- 1-yl]thiazol-5- yl]pyrazolo[1,5-
a]pyrimidine-3- carboxamide 196 ##STR00301## N-[4-[5-chloro-2-
(difluoromethoxy)phenyl]- 2-[4-(3,3-difluoroazetidin-
1-yl)-1-piperidyl]thiazol- 5-yl]pyrazolo[1,5- a]pyrimidine-3-
carboxamide 197 ##STR00302## N-[4-[5-chloro-2-
(difluoromethoxy)phenyl]- 2-[4-[4- (dimethylamino)piperidine-
1-carbonyl]-1- piperidyl]thiazol-5- yl]pyrazolo[1,5-
a]pyrimidine-3- carboxamide 198 ##STR00303## N-[4-[5-chloro-2-
(difluoromethoxy)phenyl]- 2-[4-[methyl(2,2,2-
trifluoroethyl)amino]-1- piperidyl]thiazol-5- yl]pyrazolo[1,5-
a]pyrimidine-3- carboxamide 199 ##STR00304## N-[2-[4-
[butyl(methyl)amino]-1- piperidyl]-4-[5-chloro-2-
(difluoromethoxy)phenyl] thiazol-5-yl]pyrazolo[1,5- a]pyrimidine-3-
carboxamide 200 ##STR00305## N-[4-[5-chloro-2-
(difluoromethoxy)phenyl]- 2-[4-[methyl-[(3- methyloxetan-3-
yl)methyl]amino]-1- piperidyl]thiazol-5- yl]pyrazolo[1,5-
a]pyrimidine-3- carboxamide 201 ##STR00306## N-[2-[4-
[benzyl(methyl)amino]-1- piperidyl]-4-[5-chloro-2-
(difluoromethoxy)phenyl] thiazol-5-yl]pyrazolo[1,5- a]pyrimidine-3-
carboxamide 202 ##STR00307## N-[4-[5-chloro-2-
(difluoromethoxy)phenyl]- 2-[4-[4-[methyl(2,2,2-
trifluoroethyl)amino] piperidine-1-carbonyl]-1-
piperidyl]thiazol-5- yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide
203 ##STR00308## N-[4-[5-chloro-2- (difluoromethoxy)phenyl]-
2-[4-[(1- cyanocyclohexyl)methyl- methyl-amino]-1-
piperidyl]thiazol-5- yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide
204 ##STR00309## N-[4-[5-chloro-2- (difluoromethoxy)phenyl]-
2-[4-[4-[(1- cyanocyclohexyl)methyl- methyl-amino]piperidine-
1-carbonyl]-1- piperidyl]thiazol-5- yl]pyrazolo[1,5-
a]pyrimidine-3- carboxamide 205 ##STR00310## N-[4-[5-chloro-2-
(difluoromethoxy)phenyl]- 2-(4-methylpiperazin-1- yl)thiazol-5-
yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 206 ##STR00311##
N-[4-[5-chloro-2- (difluoromethoxy)phenyl]- 2-[4-(2-
phenylethyl)piperazin-1- yl]thiazol-5- yl]pyrazolo[1,5-
a]pyrimidine-3- carboxamide 207 ##STR00312## N-[4-[5-chloro-2-
(difluoromethoxy)phenyl]- 2-[4- (cyclopropylmethyl)
piperazin-1-yl]thiazol-5- yl]pyrazolo[1,5- a]pyrimidine-3-
carboxamide 208 ##STR00313## N-[4-[5-chloro-2-
(difluoromethoxy)phenyl]- 2-[4-(2,2,2- trifluoroethyl)piperazin-1-
yl]thiazol-5- yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 209
##STR00314## N-[4-[5-chloro-2- (difluoromethoxy)phenyl]- 2-[3-
(dimethylamino)prop-1- ynyl]thiazol-5- yl]pyrazolo[1,5-
a]pyrimidine-3- carboxamide 210 ##STR00315## N-[2-[3-
[butyl(methyl)amino]prop- 1-ynyl]-4-[5-chloro-2-
(difluoromethoxy)phenyl] thiazol-5-yl]pyrazolo[1,5- a]pyrimidine-3-
carboxamide 211 ##STR00316## N-[3-[5-chloro-2-
(difluoromethoxy)phenyl]- 1-[2-(7-methyl-2,7-
diazaspiro[3.4]octan-2-yl)- 2-oxo-ethyl]pyrazol-4- yl]pyrazolo[1,5-
a]pyrimidine-3- carboxamide 212 ##STR00317## N-[3-[5-chloro-2-
(difluoromethoxy)phenyl]- 1-[2-(7-methyl-2,7-
diazaspiro[4.4]nonan-2- yl)-2-oxo-ethyl]pyrazol-4- yl]pyrazolo[1,5-
a]pyrimidine-3- carboxamide 213 ##STR00318## N-[3-[5-chloro-2-
(difluoromethoxy)phenyl]- 1-[2-(9-methyl-1-oxa-4,9-
diazaspiro[5.5]undecan-4- yl)-2-oxo-ethyl]pyrazol-4-
yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 214 ##STR00319##
N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[2-(6-methyl-2,6-
diazaspiro[3.3]heptan-2- yl)-2-oxo-ethyl]pyrazol-4-
yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 215 ##STR00320##
2-amino-N-[3-[5-chloro-2- (difluoromethoxy)phenyl]-
1-[2-(9-methyl-1-oxa-4,9- diazaspiro[5.5]undecan-4-
yl)-2-oxo-ethyl]pyrazol-4- yl]pyrazolo[1,5- a]pyrimidine-3-
carboxamide 216 ##STR00321## N-[3-[5-chloro-2-
(difluoromethoxy)phenyl]- 1-[2-(7-methyl-2,7-
diazaspiro[3.5]nonan-2- yl)-2-oxo-ethyl]pyrazol-4- yl]pyrazolo[1,5-
a]pyrimidine-3- carboxamide 217 ##STR00322## N-[3-[5-chloro-2-
(difluoromethoxy)phenyl]- 1-[2-(2,7- diazaspiro[3.5]nonan-2-
yl)-2-oxo-ethyl]pyrazol-4- yl]pyrazolo[1,5- a]pyrimidine-3-
carboxamide 218 ##STR00323## N-[3-[5-chloro-2-
(difluoromethoxy)phenyl]- 1-[2-(2-methyl-2,7-
diazaspiro[3.5]nonan-7- yl)-2-oxo-ethyl]pyrazol-4- yl]pyrazolo[1,5-
a]pyrimidine-3- carboxamide 219 ##STR00324## N-[3-[5-chloro-2-
(difluoromethoxy)phenyl]- 1-[2-(2,6- diazaspiro[3.4]octan-6-yl)-
2-oxo-ethyl]pyrazol-4- yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide
220 ##STR00325## N-[3-[5-chloro-2- (difluoromethoxy)phenyl]-
1-[2-(2,7- diazaspiro[3.4]octan-2-yl)- 2-oxo-ethyl]pyrazol-4-
yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 221 ##STR00326##
N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[2-(2-methyl-2,6-
diazaspiro[3.4]octan-6-yl)- 2-oxo-ethyl]pyrazol-4- yl]pyrazolo[1,5-
a]pyrimidine-3- carboxamide 222 ##STR00327## N-[3-[5-chloro-2-
(difluoromethoxy)phenyl]- 1-[2-(8-methyl-2,8-
diazaspiro[4.5]decan-2- yl)-2-oxo-ethyl]pyrazol-4- yl]pyrazolo[1,5-
a]pyrimidine-3- carboxamide 223 ##STR00328## N-[3-[5-chloro-2-
(difluoromethoxy)phenyl]- 1-[2-(2,8- diazaspiro[4.5]decan-8-
yl)-2-oxo-ethyl]pyrazol-4- yl]pyrazolo[1,5- a]pyrimidine-3-
carboxamide 224 ##STR00329## N-[3-[5-chloro-2-
(difluoromethoxy)phenyl]- 1-[2-(2-methyl-2,8-
diazaspiro[4.5]decan-8- yl)-2-oxo-ethyl]pyrazol-4- yl]pyrazolo[1,5-
a]pyrimidine-3- carboxamide 225 ##STR00330## N-[3-[5-chloro-2-
(difluoromethoxy)phenyl]- 1-[2-(2-isobutyl-2,8-
diazaspiro[4.5]decan-8- yl)-2-oxo-ethyl]pyrazol-4- yl]pyrazolo[1,5-
a]pyrimidine-3- carboxamide 226 ##STR00331## benzyl 4-[[8-[2-[3-[5-
chloro-2- (difluoromethoxy)phenyl]- 4-(pyrazolo[1,5-
a]pyrimidine-3- carbonylamino)pyrazol-1- yl]acetyl]-2,8-
diazaspiro[4.5]decan-2- yl]methyl]piperidine-1- carboxylate 227
##STR00332## N-[3-[5-chloro-2- (difluoromethoxy)phenyl]-
1-[2-(4-methylpiperazin-1- yl)-2-oxo-ethyl]pyrazol-4-
yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 228 ##STR00333##
N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[2-[4-(2-
hydroxyethyl)piperazin-1- yl]-2-oxo-ethyl]pyrazol-4-
yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 229 ##STR00334##
N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[2-[4-(2-
methoxyethyl)piperazin-1- yl]-2-oxo-ethyl]pyrazol-4-
yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 230 ##STR00335##
N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[2-[4-(3-
hydroxypropyl)piperazin- 1-yl]-2-oxo-ethyl]pyrazol-
4-yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 231 ##STR00336##
N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[2-[4-[2-(2-
hydroxyethoxy)ethyl] piperazin-1-yl]-2-oxo- ethyl]pyrazol-4-
yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 232 ##STR00337##
N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[2-[4-(2-
methylsulfonylethyl) piperazin-1-yl]-2-oxo- ethyl]pyrazol-4-
yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 233 ##STR00338##
N-[3-[5-chloro-2- (difluoromethoxy)phenyl]-
1-[2-(4-ethylpiperazin-1- yl)-2-oxo-ethyl]pyrazol-4-
yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide
234 ##STR00339## N-[3-[5-chloro-2- (difluoromethoxy)phenyl]-
1-[2-[(3R)-3- (hydroxymethyl)-4- methyl-piperazin-1-yl]-2-
oxo-ethyl]pyrazol-4- yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide
235 ##STR00340## N-[3-[5-chloro-2- (difluoromethoxy)phenyl]-
1-[2-[(3S)-3- (hydroxymethyl)-4- methyl-piperazin-1-yl]-2-
oxo-ethyl]pyrazol-4- yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide
236 ##STR00341## N-[3-[5-chloro-2- (difluoromethoxy)phenyl]-
1-[2-oxo-2-(4- phenylpiperazin-1- yl)ethyl]pyrazol-4-
yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 237 ##STR00342##
N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[2-[4-(4-
cyanophenyl)piperazin-1- yl]-2-oxo-ethyl]pyrazol-4-
yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 238 ##STR00343##
N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[2-[4-[(4-
cyanophenyl)methyl] piperazin-1-yl]-2-oxo- ethyl]pyrazol-4-
yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 239 ##STR00344##
N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[2-(4-methyl-1,4-
diazepan-1-yl)-2-oxo- ethyl]pyrazol-4- yl]pyrazolo[1,5-
a]pyrimidine-3- carboxamide 240 ##STR00345## N-[3-[5-chloro-2-
(difluoromethoxy)phenyl]- 1-[2-[4-(2-hydroxyethyl)-
1,4-diazepan-1-yl]-2-oxo- ethyl]pyrazol-4- yl]pyrazolo[1,5-
a]pyrimidine-3- carboxamide 241 ##STR00346##
N-[1-[2-(1,3,4,6,7,8,9,9a- octahydropyrido[1,2-
a]pyrazin-2-yl)-2-oxo- ethyl]-3-[5-chloro-2-
(difluoromethoxy)phenyl] pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3-
carboxamide 242 ##STR00347## N-[3-[5-chloro-2-
(difluoromethoxy)phenyl]- 1-[2-[(1S,5R)-8-methyl- 3,8-
diazabicyclo[3.2.1]octan- 3-yl]-2-oxo-ethyl]pyrazol-
4-yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 243 ##STR00348##
2-amino-N-[3-[5-chloro-2- (difluoromethoxy)phenyl]-
1-[2-(4-methylpiperazin-1- yl)-2-oxo-ethyl]pyrazol-4-
yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 244 ##STR00349##
2-amino-N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[2-[4-(2-
hydroxyethyl)piperazin-1- yl]-2-oxo-ethyl]pyrazol-4-
yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 245 ##STR00350##
2-amino-N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[2-[4-(2-
methoxyethyl)piperazin-1- yl]-2-oxo-ethyl]pyrazol-4-
yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 246 ##STR00351##
2-amino-N-[3-[5-chloro-2- (difluoromethoxy)phenyl]-
1-[2-(4-methyl-1,4- diazepan-1-yl)-2-oxo- ethyl]pyrazol-4-
yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 247 ##STR00352##
2-amino-N-[3-[5-chloro-2- (difluoromethoxy)phenyl]-
1-[2-(4-ethylpiperazin-1- yl)-2-oxo-ethyl]pyrazol-4-
yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 248 ##STR00353##
2-amino-N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[2-[4-
(cyclopropylmethyl) piperazin-1-yl]-2-oxo- ethyl]pyrazol-4-
yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 249 ##STR00354##
2-amino-N-[3-[5-chloro-2- (difluoromethoxy)phenyl]-
1-(2-oxo-2-piperazin-1-yl- ethyl)pyrazol-4- yl]pyrazolo[1,5-
a]pyrimidine-3- carboxamide 250 ##STR00355##
2-amino-N-[3-[5-chloro-2- (difluoromethoxy)phenyl]-
1-[2-[(1S,4S)-5-methyl- 2,5- diazabicyclo[2.2.1]heptan-
2-yl]-2-oxo-ethyl]pyrazol- 4-yl]pyrazolo[1,5- a]pyrimidine-3-
carboxamide 251 ##STR00356## 2-amino-N-[3-[5-chloro-2-
(difluoromethoxy)phenyl]- 1-[2-[(3R,5S)-3,5-
dimethylpipeiazin-1-yl]-2- oxo-ethyl]pyrazol-4- yl]pyrazolo[1,5-
a]pyrimidine-3- carboxamide 252 ##STR00357##
2-amino-N-[3-[5-chloro-2- (difluoromethoxy)phenyl]-
1-[2-[(1R,4R)-5-methyl- 2,5- diazabicyclo[2.2.1]heptan-
2-yl]-2-oxo-ethyl]pyrazol- 4-yl]pyrazolo[1,5- a]pyrimidine-3-
carboxamide 253 ##STR00358## N-[4-[5-chloro-2-
(difluoromethoxy)phenyl]- 2-[4-[4- (dimethylamino)piperidine- 1-
carbonyl]phenyl]thiazol-5- yl]pyrazolo[1,5- a]pyrimidine-3-
carboxamide 254 ##STR00359## N-[4-[5-chloro-2-
(difluoromethoxy)phenyl]- 2-(4-pyridyl)thiazol-5- yl]pyrazolo[1,5-
a]pyrimidine-3- carboxamide 255 ##STR00360## N-[4-[5-chloro-2-
(difluoromethoxy)phenyl]- 2-[4- [(dimethylamino)methyl]
phenyl]thiazol-5- yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 256
##STR00361## N-[4-[5-chloro-2- (difluoromethoxy)phenyl]-
2-[4-[(3-fluoroazetidin-1- yl)methyl]phenyl]thiazol-
5-yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 257 ##STR00362##
N-[4-[5-chloro-2- (difluoromethoxy)phenyl]- 2-[4-[(3,3-
difluoroazetidin-1- yl)methyl]phenyl]thiazol- 5-yl]pyrazolo[1,5-
a]pyrimidine-3- carboxamide 258 ##STR00363## N-[4-[5-chloro-2-
(difluoromethoxy)phenyl]- 2-[4-(4-methylpiperazin-1-
yl)phenyl]thiazol-5- yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide
259 ##STR00364## N-[4-[5-chloro-2- (difluoromethoxy)phenyl]-
2-[4-(4-methylpiperazine- 1-carbonyl)phenyl]thiazol-
5-yl]pyrazol[1,5- a]pyrimidine-3- carboxamide 260 ##STR00365##
N-[4-[5-chloro-2- (difluoromethoxy)phenyl]-
2-[[4-(dimethylamino)-1- piperidyl]methyl]thiazol-
5-yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 261 ##STR00366##
N-[4-[5-chloro-2- (difluoromethoxy)phenyl]- 2-[[methyl(2-
phenylethyl)amino]methyl] thiazol-5-yl]pyrazolo[1,5-
a]pyrimidine-3- carboxamide 262 ##STR00367## N-[2-[[(3aR,6aS)-2-
methyl-1,3,3a,4,6,6a- hexahydropyrrolo[3,4-
c]pyrrol-5-yl]methyl]-4- [5-chloro-2- (difluoromethoxy)phenyl]
thiazol-5-yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 263
##STR00368## N-[4-[5-chloro-2- (difluoromethoxy)phenyl]- 2-(1-
piperidylmethyl)thiazol-5- yl]pyrazolo[1,5- a]pyrimidine-3-
carboxamide 264 ##STR00369## N-[2-[(3aR,6aS)-2-methyl-
1,3,3a,4,6,6a- hexahydropyrrolo[3,4- c]pyrrole-5-carbonyl]-4-
[5-chloro-2- (difluoromethoxy)phenyl] thiazol-5-yl]pyrazolo[1,5-
a]pyrimidine-3- carboxamide 265 ##STR00370## N-[4-[5-chloro-2-
(difluoromethoxy)phenyl]- 2-[4- (dimethylamino)piperidine-
1-carbonyl]thiazol-5- yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide
266 ##STR00371## 2-amino-N-[3-[5-chloro-2-
(difluoromethoxy)phenyl]- 1-[2-[4-(hydroxymethyl)-
1-piperidyl]-2-oxo- ethyl]pyrazol-4- yl]pyrazolo[1,5-
a]pyrimidine-3- carboxamide 267 ##STR00372## N-[3-[5-chloro-2-
(difluoromethoxy)phenyl]- 1-[2-[(2S)-2-(1,2-
dihydroxyethyl)pyrrolidin- 1-yl]-2-oxo-ethyl]pyrazol-
4-yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 268 ##STR00373##
N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[2-[(2S)-2-
(hydroxymethyl)pyrrolidin- 1-yl]-2-oxo- ethyl]pyrazol-4-
yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 269 ##STR00374##
N-[3-[5-chloro-2- (ditluoromethoxy)phenyl]-
1-[2-(3-hydroxy-3-methyl- pyrrolidin-1-yl)-2-oxo- ethyl]pyrazol-4-
yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 270 ##STR00375##
2-amino-N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[2-[(3S)-3-
hydroxypyrrolidin-1-yl]-2- oxo-ethyl]pyrazol-4- yl]pyrazolo[1,5-
a]pyrimidine-3- carboxamide 271 ##STR00376##
2-amino-N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[2-[(3R)-3-
hydroxypyrrolidin-1-yl]-2- oxo-ethyl]pyrazol-4- yl]pyrazolo[1,5-
a]pyrimidine-3- carboxamide 272 ##STR00377## N-[3-[5-chloro-2-
(difluoromethoxy)phenyl]- 1-[2-[4-hydroxy-4- (hydroxymethyl)-1-
piperidyl]-2-oxo- ethyl]pyrazol-4- yl]pyrazolo[1,5- a]pyrimidine-3-
carboxamide 273 ##STR00378## 2-amino-N-[3-[5-chloro-2-
(difluoromethoxy)phenyl]- 1-[2-[2- (hydroxymethyl)
morpholin-4-yl]-2-oxo- ethyl]pyrazol-4- yl]pyrazolo[1,5-
a]pyrimidine-3- carboxamide 274 ##STR00379## N-[3-[5-chloro-2-
(difluoromethoxy)phenyl]- 1-[2-[4-(hydroxymethyl)-
1-piperidyl]-2-oxo- ethyl]pyrazol-4- yl]pyrazolo[1,5-
a]pyrimidine-3- carboxamide 275 ##STR00380## N-[3-[5-chloro-2-
(difluoromethoxy)phenyl]- 1-[2-[4-(2- hydroxyethoxy)-1-
piperidyl]-2-oxo- ethyl]pyrazol-4- yl]pyrazolo[1,5- a]pyrimidine-3-
carboxamide 276 ##STR00381## N-[3-[5-chloro-2-
(difluoromethoxy)phenyl]- 1-[2-[4-hydroxy-4-(4-
pyridyl)-1-piperidyl]-2- oxo-ethyl]pyrazol-4- yl]pyrazolo[1,5-
a]pyrimidine-3- carboxamide 277 ##STR00382## N-[3-[5-chloro-2-
(difluoromethoxy)phenyl]- 1-[2-[2- (hydroxymethyl)
morpholin-4-yl]-2-oxo- ethyl]pyrazol-4- yl]pyrazolo[1,5-
a]pyrimidine-3- carboxamide 278 ##STR00383## N-[3-[5-chloro-2-
(difluoromethoxy)phenyl]- 1-[2-(4-hydroxy-1- piperidyl)-2-oxo-
ethyl]pyrazol-4- yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 279
##STR00384## 2-amino-N-[1-[2-(4- benzyl-4-hydroxy-1-
piperidyl)-2-oxo-ethyl]-3- [5-chloro-2- (difluoromethoxy)phenyl]
pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 280
##STR00385## N-[3-[5-chloro-2- (difluoromethoxy)phenyl]-
1-[2-(4-hydroxy-4-methyl- 1-piperidyl)-2-oxo- ethyl]pyrazol-4-
yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 281 ##STR00386##
N-[3-[5-chloro-2- (difluoromethoxy)phenyl]-
1-[2-(4-cyano-4-phenyl-1- piperidyl)-2-oxo- ethyl]pyrazol-4-
yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 282 ##STR00387##
2-amino-N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[2-(3,3-
difluoropyrrolidin-1-yl)-2- oxo-ethyl]pyrazol-4- yl]pyrazolo[1,5-
a]pyrimidine-3- carboxamide 283 ##STR00388##
2-amino-N-[3-[5-chloro-2- (difluoromethoxy)phenyl]-
1-[2-(4-cyano-4-phenyl-1- piperidyl)-2-oxo- ethyl]pyrazol-4-
yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 284 ##STR00389##
N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[2-(3,6-dihydro-2H-
pyridin-1-yl)-2-oxo- ethyl]pyrazol-4- yl]pyrazolo[1,5-
a]pyrimidine-3- carboxamide 285 ##STR00390##
2-amino-N-[3-[5-chloro-2- (difluoromethoxy)phenyl]-
1-[2-oxo-2-(4-phenoxy-1- piperidyl)ethyl]pyrazol-4-
yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 286 ##STR00391##
2-amino-N-[3-[5-chloro-2- (difluoromethoxy)phenyl]-
1-[2-(4-hydroxy-4-phenyl- 1-piperidyl)-2-oxo- ethyl]pyrazol-4-
yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 287 ##STR00392##
N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[2-(3,3-
difluoropyrrolidin-1-yl)-2- oxo-ethyl]pyrazol-4- yl]pyrazolo[1,5-
a]pyrimidine-3- carboxamide 288 ##STR00393## N-[3-[5-chloro-2-
(difluoromethoxy)phenyl]- 1-(2-morpholino-2-oxo- ethyl)pyrazol-4-
yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 289 ##STR00394##
N-[3-[5-chloro-2- (difluoromethoxy)phenyl]-
1-[2-(4-hydroxy-4-phenyl- 1-piperidyl)-2-oxo- ethyl]pyrazol-4-
yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 290 ##STR00395##
2-amino-N-[3-[5-chloro-2- (difluoromethoxy)phenyl]-
1-(2-morpholino-2-oxo- ethyl)pyrazol-4- yl]pyrazolo[1,5-
a]pyrimidine-3- carboxamide 291 ##STR00396## N-[3-[5-chloro-2-
(difluoromethoxy)phenyl]- 1-[2-[[1- (hydroxymethyl) cyclopropyl]
methylamino]-2-oxo- ethyl]pyrazol-4- yl]pyrazolo[1,5-
a]pyrimidine-3- carboxamide 292 ##STR00397## N-[3-[5-chloro-2-
(difluoromethoxy)phenyl]- hydroxycyclopentyl) methyl]pyrazol-4-
yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 293 ##STR00398##
N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[2-[[1-
(hydroxymethyl) cyclopropyl]-methyl- amino]-2-oxo- ethyl]pyrazol-4-
yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 294 ##STR00399##
N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[2-(2-
methoxyethylamino)ethyl] pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3-
carboxamide 295 ##STR00400## 2-amino-N-[1-(2-
aminoethyl)-3-[5-chloro- 2- (difluoromethoxy)phenyl]
pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide
296 ##STR00401## 2-amino-N-[3-[5-chloro-2-
(difluoromethoxy)phenyl]- 1-[(1S,3R)-3- (methylamino)cyclohexyl]
pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 297
##STR00402## 2-amino-N-[1-(3- aminocyclobutyl)-3-[5- chloro-2-
(difluoromethoxy)phenyl] pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3-
carboxamide 298 ##STR00403## 2-amino-N-[3-[5-chloro-2-
(difluoromethoxy)phenyl]- 1-[3- (methylamino)cyclobutyl]
pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 299
##STR00404## N-[3-[5-chloro-2- (difluoromethoxy)phenyl]-
1-[2-[ethyl-[(2-methyl-4- pyridyl)methyl]amino]-2-
oxo-ethyl]pyrazol-4- yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide
300 ##STR00405## N-[3-[5-chloro-2- (difluoromethoxy)phenyl]-
1-[2-[(2-chloro-4- pyridyl)methyl-ethyl- amino]-2-oxo-
ethyl]pyrazol-4- yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 301
##STR00406## N-[3-[5-chloro-2- (difluoromethoxy)phenyl]-
1-[2-[ethyl(3- pyridy1methyl)amino]-2- oxo-ethyl]pyrazol-4-
yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 302 ##STR00407##
N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[4-[4-
(dimethylamino)piperidine- 1- carbonyl]phenyl]pyrazol-
4-yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 303 ##STR00408##
N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[4-[4-[methyl(2,2,2-
trifluoroethyl)amino] piperidine-1- carbonyl]phenyl]pyrazol-
4-yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 304 ##STR00409##
N-[1-(3-amino-3-imino- propyl)-3-[5-chloro-2-
(difluoromethoxy)phenyl] pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3-
carboxamide 305 ##STR00410## N-[1-(4-amino-4-imino-
butyl)-3-[5-chloro-2- (difluoromethoxy)phenyl]
pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 306
##STR00411## ethyl 2-[2-[3-[5-chloro-2- (difluoromethoxy)phenyl]-
4-(pyrazolo[1,5- a]pyrimidine-3- carbonylamino)pyrazol-1-
yl]ethylamino]acetate 307 ##STR00412## cyclopentyl 2-[2-[3-[5-
chloro-2- (difluoromethoxy)phenyl]- 4-(pyrazolo[1,5-
a]pyrimidine-3- carbonylamino)pyrazol-1- yl]ethylamino]acetate 308
##STR00413## N-[3-[5-chloro-2- (difluoromethoxy)phenyl]-
1-[2-oxo-2-(1- piperidy1)ethyl]pyrazol-4- yl]pyrazolo[1,5-
a]pyrimidine-3- carboxamide 309 ##STR00414## ethyl
(2S)-2-amino-4-[3- [5-chloro-2- (difluoromethoxy)phenyl]-
4-(pyrazolo[1,5- a]pyrimidine-3- carbonylamino)pyrazol-1-
yl]butanoate 310 ##STR00415## 2-[4-(2-[3-[5-chloro-2-
(difluoromethoxy)phenyl]- 4-[pyrazolo[1,5- a]pyrimidine-3-amido]-
1H-pyrazol-1- yl]acetyl)piperazin-1- yl]acetic acid 311
##STR00416## 2-[[1-(2-[3-[5-chloro-2- (difluoromethoxy)phenyl]-
4-[pyrazolo[1,5- a]pyrimidine-3-amido]- 1H-pyrazol-1-
yl]ethyl)piperidin-4- yl]amino]acetic acid 312 ##STR00417##
N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-(2-[[2-
(methylsulfanyl)ethyl] amino]ethyl)-1H-pyrazol-4- yl]pyrazolo[1,5-
a]pyrimidine-3- carboxamide 313 ##STR00418## N-[1-[2-
(benzylamino)ethyl]-3-[5- chloro-2- (difluoromethoxy)phenyl]-
1H-pyrazol-4- yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 314
##STR00419## N-[3-[5-chloro-2- (difluoromethoxy)phenyl]-
1-[2-[(pyridin-2- ylmethyl)amino]ethyl]- 1H-pyrazol-4-
yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 315 ##STR00420##
N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[2-[(pyridin-4-
ylmethyl)amino]ethyl]- 1H-pyrazol-4- yl]pyrazolo[1,5-
a]pyrimidine-3- carboxamide 316 ##STR00421## N-[3-[5-chloro-2-
(difluoromethoxy)phenyl]- 1-[2-oxo-2-[4-(1-
phenylethyl)piperazin-1- yl]ethyl]-1H-pyrazol-4- yl]pyrazolo[1,5-
a]pyrimidine-3- carboxamide 317 ##STR00422## N-[3-[5-chloro-2-
(difluoromethoxy)phenyl]- 1-[2-[4-(2- methylpropyl)piperazin-1-
yl]-2-oxoethyl]-1H- pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3-
carboxamide 318 ##STR00423## N-[3-[5-chloro-2-
(difluoromethoxy)phenyl]- 1-(2-[4-[(3-methyloxetan-
3-yl)methyl]piperazin-1- yl]-2-oxoethyl)-1H-
pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 319
##STR00424## N-[3-[5-chloro-2- (difluoromethoxy)phenyl]-
1-[2-oxo-2-(4- propylpiperazin-1- yl)ethyl]-1H-pyrazol-4-
yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 320 ##STR00425##
N-[1-[2-(4- benzylpiperazin-1-yl)-2- oxoethyl]-3-[5-chloro-2-
(difluoromethoxy)phenyl]- 1H-pyrazol-4- yl]pyrazolo[1,5-
a]pyrimidine-3- carboxamide 321 ##STR00426## N-[3-[5-chloro-2-
(difluoromethoxy)phenyl]- 1-(2-[4-[2-(morpholin-4-
yl)ethyl]piperazin-1-yl]- 2-oxoethyl)-1H-pyrazol-4-
yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 322 ##STR00427##
methyl 2-[4-(2-[3-[5- chloro-2- (difluoromethoxy)
phenyl]-4-[pyrazolo[1,5- a]pyrimidine-3-amido]- 1H-pyrazol-1-
yl]acetyl)piperazin-1- yl]acetate 323 ##STR00428##
N-[3-[5-chloro-2- (difluoromethoxy)pyridin-
3-yl]-1-[(5-oxooxolan-2- yl)methyl]-1H-pyrazol-4- yl]pyrazolo[1,5-
a]pyrimidine-3- carboxamide 324 ##STR00429## N-[3-[5-chloro-2-
(difluoromethoxy)phenyl]- 1-[2-oxo-2-(piperazin-1-
yl)ethyl]-1H-pyrazol-4- yl]pyrazolo[1,5- a]pyrimidine-3-
carboxamide 325 ##STR00430## N-[3-[5-chloro-2-
(difluoromethoxy)phenyl]- 1-(2-[4- [(dimethylcarbamoyl)
methyl]piperazin-1-yl]-2- oxoethyl)-1H-pyrazol-4- yl]pyrazolo[1,5-
a]pyrimidine-3- carboxamide 326 ##STR00431## N-[3-[5-chloro-2-
(difluoromethoxy)phenyl]- 1-(2-[[(2- hydroxyphenyl)methyl]
amino]ethyl)-1H-pyrazol- 4-yl]pyrazolo[1,5- a]pyrimidine-3-
carboxamide 327 ##STR00432## N-[3-[5-chloro-2- (difluoromethoxy)
phenyl]-1-(2-[[(3- hydroxyphenyl)methyl] amino]ethyl)-1H-pyrazol-4-
yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 328 ##STR00433##
N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-(2-[[(4-
hydroxyphenyl)methyl] amino]ethyl)-1H-pyrazol-4- yl]pyrazolo[1,5-
a]pyrimidine-3- carboxamide 329 ##STR00434## methyl 2-[[1-(2-[3-[5-
chloro-2- (difluoromethoxy)phenyl]- 4-[pyrazolo[1,5-a]
pyrimidine-3-amido]-1H- pyrazol-1- yl]acetyl)piperidin-4-
yl]amino]acetate 330 ##STR00435## N-[3-[5-chloro-2-
(difluoromethoxy) phenyl]-1-[2-[4-(5- hydroxy-2-oxopiperidin-1-
yl)piperidin-1-yl]-2- oxoethyl]-1H-pyrazol-4- yl]pyrazolo[1,5-
a]pyrimidine-3- carboxamide 331 ##STR00436## methyl 3-[4-(2-[3-[5-
chloro-2- (difluoromethoxy)phenyl]- 4-[pyrazolo[1,5-
a]pyrimidine-3-amido]- 1H-pyrazol-1- yl]acetyl)piperazin-1-
yl]propanoate 332 ##STR00437## 3-[4-(2-[3-[5-chloro-2-
(difluoromethoxy)phenyl]- 4-[pyrazolo[1,5-a]
pyrimidine-3-amido]-1H- pyrazol-1- yl]acetyl)piperazin-1-
yl]propanoate 333 ##STR00438## methyl1-[2-[4-(2-[3-[5- chloro-2-
(difluoromethoxy)phenyl]- 4-[pyrazolo[1,5- a]pyrimidine-3-amido]-
1H-pyrazol-1- yl]acetyl)piperazin-1- yl]ethyl]piperidine-4-
carboxylate 334 ##STR00439## ethyl 1-[2-[4-(2-[3-[5- chloro-2-
(difluoromethoxy)phenyl]- 4-[pyrazolo[1,5-a]
pyrimidine-3-amido]-1H- pyrazol-1- yl]acetyl)piperazin-1-
yl]ethyl]piperidine-4- carboxylate 335 ##STR00440## methyl
1-[2-[4-(2-[3-[5- chloro-2- (difluoromethoxy)phenyl]-
4-[pyrazolo[1,5- a]pyrimidine-3-amido]- 1H-pyrazol-1-
yl]acetyl)piperazin-1- yl]ethyl]-4- methylpiperidine-4- carboxylate
336 ##STR00441## 2-(morpholin-4-yl)ethyl 1- (2-[3-[5-chloro-2-
(difluoromethoxy) phenyl]-4-[pyrazolo[1,5- a]pyrimidine-3-amido]-
1H-pyrazol-1- yl]acetyl)piperidine-4- carboxylate 337 ##STR00442##
ethyl 1-[2-[4-(2-[3-[5- chloro-2- (difluoromethoxy)phenyl]-
4-[pyrazolo[1,5- a]pyrimidine-3-amido]- 1H-pyrazol-1-
yl]acetyl)piperazin-1- yl]ethyl]-4- methylpiperidine-4- carboxylate
338 ##STR00443## 2-(dimethylamino)ethyl 1- (2-[3-[5-chloro-2-
(difluoromethoxy)phenyl]- 4-[pyrazolo[1,5- a]pyrimidine-3-amido]-
1H-pyrazol-1- yl]acetyl)piperidine-4- carboxylate 339 ##STR00444##
2-(morpholin-4-yl)ethyl 1- (2-[3-[5-chloro-2-
(difluoromethoxy)phenyl]- 4-[pyrazolo[1,5- a]pyrimidine-3-amido]-
1H-pyrazol-1-yl]acetyl)-4- methyIpiperidine-4- carboxylate 340
##STR00445## 2-(dimethylamino)ethyl 1- (2-[3-[5-chloro-2-
(difluoromethoxy) phenyl]-4-[pyrazolo[1,5- a]pyrimidine-3-amido]-
1H-pyrazol-1-yl]acetyl)-4- methylpiperidine-4- carboxylate 341
##STR00446## piperidin-4-ylmethyl 1-(2- [3-[5-chloro-2-
(difluoromethoxy)phenyl]- 4-[pyrazolo[1,5- a]pyrimidine-3-amido]-
1H-pyrazol-1- yl]acetyl)piperidine-4- carboxylate 342 ##STR00447##
1-(2-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 4-[pyrazolo[1,5-
a]pyrimidine-3-amido]- 1H-pyrazol-1- yl]acetyl)piperidine-4-
carboxylic acid 343 ##STR00448## 1-(2-[3-[5-chloro-2-
(difluoromethoxy)phenyl]- 4-[pyrazolo[1,5- a]pyrimidine-3-amido]-
1H-pyrazol-1-yl]acetyl)-4- methylpiperidine-4- carboxylic acid 344
##STR00449## N-[3-[5-chloro-2- (difluoromethoxy) phenyl]-1-[2-(4-
[methyl[(5-oxooxolan-2- yl)methyl]amino]piperidin-
1-yl)-2-oxoethyl]-1H- pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3-
carboxamide 345 ##STR00450## methyl 3-[[1-(2-[3-[5- chloro-2-
(difluoromethoxy)phenyl]- 4-[pyrazolo[1,5- a]pyrimidine-3-amido]-
1H-pyrazol-1- yl]acetyl)piperidin-4- yl](methyl)amino] propanoate
346 ##STR00451## N-[3-[5-chloro-2- (difluoromethoxy)phenyl]-
1-[2-([[4- (methylsulfanyl)phenyl] methyl]amino)ethyl]-1H-
pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 347
##STR00452## N-[3-[5-chloro-2- (difluoromethoxy)phenyl]-
1-[2-oxo-2-[4-(2-oxooxan- 4-yl)piperazin-1-yl]ethyl]- 1H-pyrazol-4-
yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 348 ##STR00453##
N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[2-[4-(morpholin-4-
ylmethyl)piperidin-1-yl]- 2-oxoethyl]-1H-pyrazol-4-
yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 349 ##STR00454##
N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[2-[4-(4-
methylpiperazin-1- yl)piperidin-1-yl]-2- oxoethyl]-1H-pyrazol-4-
yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 350 ##STR00455##
N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-(2-[4-[(4-
methylpiperazin-1- yl)methyl]piperidin-1-yl]-
2-oxoethyl)-1H-pyrazol-4- yl]pyrazolo[1,5- a]pyrimidine-3-
carboxamide 351 ##STR00456## N-[3-[5-chloro-2-
(difluoromethoxy)phenyl]- 1-(2-oxo-2-[4-[(5-oxo-2,5-
dihydrofuran-3- yl)methyl]piperazin-1- yl]ethyl)-1H-pyrazol-4-
yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 352 ##STR00457##
N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[2-(4-[methyl[(5-oxo-
2,5-dihydrofuran-3- yl)methyl]amino]piperidin-
1-yl)-2-oxoethyl]-1H- pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3-
carboxamide 353 ##STR00458## 3-[4-(2-[3-[5-chloro-2-
(difluoromethoxy)phenyl]- 4-[pyrazolo[1,5- a]pyrimidine-3-amido]-
1H-pyrazol-1- yl]acetyl)piperazin-1- yl]propanoic acid 354
##STR00459## tert-butyl (3R,4R)-4-[3-[5- chloro-2-
(difluoromethoxy)phenyl]- 4-[pyrazolo[1,5- a]pyrimidine-3-amido]-
1H-pyrazol-1-yl]-3- hydroxypiperidine-1- carboxylate 355
##STR00460## (3S,4S)-4-[3-[5-chloro-2- (difluoromethoxy)phenyl]-
4-[pyrazolo[1,5- a]pyrimidine-3-amido]- 1H-pyrazol-1-yl]-3-
hydroxypiperidine-1- carboxylate 356 ##STR00461##
(3R,4R)-3-[3-[5-chloro-2- (difluoromethoxy)phenyl]-
4-[pyrazolo[1,5- a]pyrimidine-3-amido]- 1H-pyrazol-1-yl]-4-
hydroxypiperidine-1- carboxylate 357 ##STR00462## tert-butyl
(3S,4S)-3-[3-[5- chloro-2- (difluoromethoxy)phenyl]-
4-[pyrazolo[1,5- a]pyrimidine-3-amido]- 1H-pyrazol-1-yl]-4-
hydroxypiperidine-1- carboxylate
358 ##STR00463## N-[3-[5-chloro-2- (difluoromethoxy)phenyl]-
1-[(3R,4R)-3- hydroxypiperidin-4-yl]- 1H-pyrazol-4-
yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 359 ##STR00464##
N-[3-[5-chloro-2- (difluoromethoxy) phenyl]-1-[(3S,4S)-3-
hydroxypiperidin-4-yl]- 1H-pyrazol-4- yl]pyrazolo[1,5-
a]pyrimidine-3- carboxamide 360 ##STR00465## N-[3-[5-chloro-2-
(difluoromethoxy)phenyl]- 1-[(3R,4R)-4- hydroxypiperidin-3-yl]-
1H-pyrazol-4- yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 361
##STR00466## N-[3-[5-chloro-2- (difluoromethoxy)phenyl]-
1-[(3S,4S)-4- hydroxypiperidin-3-yl]- 1H-pyrazol-4-
yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 362 ##STR00467## ethyl
2-[(2-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 4-[pyrazolo[1,5-
a]pyrimidine-3-amido]- 1H-pyrazol-1- yl]ethyl)(pyridin-3-
ylmethyl)amino]acetate 363 ##STR00468## 2-[(2-[3-[5-chloro-2-
(difluoromethoxy)phenyl]- 4-[pyrazolo[1,5- a]pyrimidine-3-amido]-
1H-pyrazol-1- yl]ethyl)(pyridin-3- ylmethyl)amino]acetic 364
##STR00469## ethyl2-[[1-(2-[3-[5- chloro-2-
(difluoromethoxy)phenyl]- 4-[pyrazolo[1,5- a]pyrimidine-3-amido]-
1H-pyrazol-1- yl]acetyl)piperidin-4- yl]amino]acetate 365
##STR00470## 2-[[1-(2-[3-[5-chloro-2- (difluoromethoxy)phenyl]-
4-[pyrazolo[1,5- a]pyrimidine-3-amido]- 1H-pyrazol-1-
yl]acetyl)piperidin-4- yl]amino]acetic acid 366 ##STR00471## ethyl
2-(4-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 4-[pyrazolo[1,5-
a]pyrimidine-3-amido]- 1H-pyrazol-1-yl]piperidin- 1-yl)acetate 367
##STR00472## N-[3-[5-chloro-2- (difluoromethoxy)phenyl]-
1-[2-[(1,3-oxazol-2- ylmethyl)amino]ethyl]- 1H-pyrazol-4-
yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 368 ##STR00473##
N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[2-[(pyridin-3-
ylmethyl)amino]ethyl]- 1H-pyrazol-4- yl]pyrazolo[1,5-
a]pyrimidine-3- carboxamide 369 ##STR00474## N-[3-[5-chloro-2-
(difluoromethoxy)phenyl]- 1-[(2S)-2- (methylamino)propyl]-1H-
pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 370
##STR00475## N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[(2S)-2-
(dimethylamino)propyl]- 1H-pyrazol-4- yl]pyrazolo[1,5-
a]pyrimidine-3- carboxamide 371 ##STR00476## N-[3-[5-chloro-2-
(difluoromethoxy)phenyl]- 1-[(2S)-2- (ethylamino)propyl]-1H-
pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 372
##STR00477## N-[3-[5-chloro-2- (difluoromethoxy)phenyl]-
1-(2-[4-[2- (methylsulfanyl)ethyl] piperazin-1-yl]-2- oxoethyl)-
1H-pyrazol-4- yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 373
##STR00478## N-[3-[5-chloro-2- (difluoromethoxy)phenyl]-
1-[2-oxo-2-[4-(propan-2- yl)piperazin-1-yl]ethyl]- 1H-pyrazol-4-
yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 374 ##STR00479##
N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[2-[4-
(cyclopropylmethyl) piperazin-1-yl]- 2-oxoethyl]-1H-
pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 375
##STR00480## N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-[2-(2,4-
dimethylpiperazin-1-yl)-2- oxoethyl]-1H-pyrazol-4- yl]pyrazolo[1,5-
a]pyrimidine-3- carboxamide 376 ##STR00481## N-[3-[5-chloro-2-
(difluoromethoxy)phenyl]- 1-[2-(3,4- dimethylpiperazin-1-yl)-2-
oxoethyl]-1H-pyrazol-4- yl]pyrazolo[1,5- a]pyrimidine-3-
carboxamide 377 ##STR00482## N-[3-[5-chloro-2-
(difluoromethoxy)phenyl]- 1-[2-oxo-2-(2,2,4- trimethylpiperazin-1-
yl)ethyl]-1H-pyrazol-4- yl]pyrazolo[1,5- a]pyrimidine-3-
carboxamide 378 ##STR00483## N-[3-[5-chloro-2-
(difluoromethoxy)phenyl]- 1-[2-oxo-2-(3,3,4- trimethylpiperazin-1-
yl)ethyl]-1H-pyrazol-4- yl]pyrazolo[1,5- a]pyrimidine-3-
carboxamide 379 ##STR00484## N-[3-[5-chloro-2-
(difluoromethoxy)phenyl]- 1-(2-[4-[2- (dimethylamino)ethyl]
piperazin-1-yl]-2- oxoethyl)- 1H-pyrazol-4- yl]pyrazolo[1,5-
a]pyrimidine-3- carboxamide 380 ##STR00485## N-[3-[5-chloro-2-
(difluoromethoxy)phenyl]- 1-[2-[4-(1,3-oxazol-2-
ylmethyl)piperazin-1-yl]- 2-oxoethyl]-1H-pyrazol-4-
yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 381 ##STR00486##
N-[3-[5-chloro-2- (difluoromethoxy)phenyl]- 1-(2-[[(5-oxooxolan-2-
yl)methyl]amino]ethyl)- 1H-pyrazol-4- yl]pyrazolo[1,5-
a]pyrimidine-3- carboxamide 382 ##STR00487## N-[3-[5-chloro-2-
(difluoromethoxy)phenyl]- 1-(2-oxo-2-[4-[(5- oxooxolan-2-
yl)methyl]piperazin-1- yl]ethyl)-1H-pyrazol-4- yl]pyrazolo[1,5-
a]pyrimidine-3- carboxamide 383 ##STR00488## N-[3-[5-chloro-2-
(difluoromethoxy)phenyl]- 1-(2-[4- [(methylcarbamoyl)methyl]
piperazin-1-yl]-2- oxoethyl)-1H-pyrazol-4- yl]pyrazolo[1,5-
a]pyrimidine-3- carboxamide 384 ##STR00489## N-[3-[5-chloro-2-
(difluoromethoxy)phenyl]- 1-(2-[[(1R)-1- phenylethyl]amino]ethyl)-
1H-pyrazol-4- yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 385
##STR00490## N-[3-[5-chloro-2- (difluoromethoxy)phenyl]-
1-(2-[[(1S)-1- phenylethyl]amino]ethyl)- 1H-pyrazol-4-
yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 386 ##STR00491##
methyl 2-[(2-[3-[5-chloro- 2- (difluoromethoxy)phenyl]-
4-[pyrazolo[1,5- a]pyrimidine-3-amido]- 1H-pyrazol-1-
yl]ethyl)amino]acetate 387 ##STR00492## methyl (2S)-2-amino-4-[3-
[5-chloro-2- (difluoromethoxy)phenyl]- 4-[pyrazolo[1,5-
a]pyrimidine-3-amido]- 1H-pyrazol-1-yl]butanoate 388 ##STR00493##
(1-methylpiperidin-4- yl)methyl 1-(2-[3-[5- chloro-2-
(difluoromethoxy)phenyl]- 4-[pyrazolo[1,5- a]pyrimidine-3-amido]-
1H-pyrazol-1- yl]acetyl)piperidine-4- carboxylate 389 ##STR00494##
(1-methylpiperidin-4- yl)methyl 1-(2-[3-[5- chloro-2-
(difluoromethoxy)phenyl]- 4-[pyrazolo[1,5- a]pyrimidine-3-amido]-
1H-pyrazol-1-yl]acetyl)-4- methylpiperidine-4- carboxylate 390
##STR00495## N-[3-[5-chloro-2- (difluoromethoxy)phenyl]-
1-(2-[methyl[(5- oxooxolan-2- yl)methyl]amino]ethyl)- 1H-pyrazol-4-
yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide 391 ##STR00496## ethyl
3-[[1-(2-[3-[5- chloro-2- (difluoromethoxy)phenyl]-
4-[pyrazolo[1,5- a]pyrimidine-3-amido]- 1H-pyrazol-1-
yl]acetyl)piperidin-4- yl](methyl)amino] propanoate 392
##STR00497## N-[3-[5-chloro-2- (difluoromethoxy)phenyl]-
1-[2-oxo-2-[4-(5- oxooxolan-3-yl)piperazin-
1-yl]ethyl]-1H-pyrazol-4- yl]pyrazolo[1,5- a]pyrimidine-3-
carboxamide 393 ##STR00498## N-[3-[5-chloro-2-
(difluoromethoxy)phenyl]- 1-[2-[4-(morpholin-4-
yl)piperidin-1-yl]-2- oxoethyl]-1H-pyrazol-4- yl]pyrazolo[1,5-
a]pyrimidine-3- carboxamide 394 ##STR00499## N-[3-[5-chloro-2-
(difluoromethoxy)phenyl]- 1-[(2E)-4-(morpholin-4-
yl)but-2-en-1-yl]-1H- pyrazol-4-yl]pyrazolo[1,5- a]pyrimidine-3-
carboxamide 395 ##STR00500## N-[3-[5-chloro-2-
(difluoromethoxy)phenyl]- 1-[(2E)-4-(4- methylpiperazin-1-yl)but-
2-en-1-yl]-1H-pyrazol-4- yl]pyrazolo[1,5- a]pyrimidine-3-
carboxamide 396 ##STR00501## 2-(methylthio)ethyl 2-(2-
(3-(5-chloro-2- (difluoromethoxy)phenyl)- 4-(pyrazolo[1,5-
a]pyrimidine-3- carboxamido)-1H-pyrazol- 1-yl)ethylamino)acetate
397 ##STR00502## ethyl 2-[4-(2-[3-[5-chloro- 2-
(difluoromethoxy)phenyl]- 4-[pyrazolo[1,5- a]pyrimidine-3-amido]-
1H-pyrazol-1- yl]acetyl)piperazin-1- yl]acetate 398 ##STR00503##
N-(3-(5-chloro-2- (difluoromethoxy)phenyl)- 1-(2-(4-(4-
methylpiperazine-1- carbonyl)piperidin-1-yl)-
2-oxoethyl)-1H-pyrazol-4- yl)pyrazolo[1,5- a]pyrimidine-3-
carboxamide 399 ##STR00504## N-(3-(5-chloro-2-
(difluoromethoxy)phenyl)- 1-(2-((S)-tetrahydrofuran-
3-ylamino)ethyl)-1H- pyrazol-4-yl)pyrazolo[1,5- a]pyrimidine-3-
carboxamide 400 ##STR00505## N-(3-(5-chloro-2-
(difluoromethoxy)phenyl)- 1-(2-(4-((2- (dimethylamino)-2-
oxoethyl)(methyl)amino) piperidin-1-yl)-2-oxoethyl)- 1H-pyrazol-4-
yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide 401 ##STR00506##
N-(3-(5-chloro-2- (difluoromethoxy)phenyl)- 1-(2-(4-(2-
(dimethylamino)-2- oxoethylamino)piperidin- 1-yl)-2-oxoethyl)-1H-
pyrazol-4-yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide 402
##STR00507## N-(3-(5-chloro-2- (difluoromethoxy)phenyl)-
1-(2-((R)-tetrahydrofuran- 3-ylamino)ethyl)-1H-
pyrazol-4-yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide 403
##STR00508## N-(3-(5-chloro-2- (difluoromethoxy)phenyl)-
1-(2-hydroxy-3- morpholinopropyl)-1H- pyrazol-4-yl)pyrazolo[1,5-
a]pyrimidine-3- carboxamide 404 ##STR00509## N-(3-(5-chloro-2-
(difluoromethoxy)phenyl)- 1-(3-(dimethylamino)-2-
hydroxypropyl)-1H- pyrazol-4-yl)pyrazolo[1,5- a]pyrimidine-3-
carboxamide 405 ##STR00510## N-(3-(5-chloro-2-
(difluoromethoxy)phenyl)- 1-(2-hydroxy-3-(piperidin-
1-yl)propyl)-1H-pyrazol- 4-yl)pyrazolo[1,5- a]pyrimidine-3-
carboxamide 406 ##STR00511## N-(3-(5-chloro-2-
(difluoromethoxy)phenyl)- 1-(2-(4-(2- cyanoethyl)piperazin-1-
yl)-2-oxoethyl)-1H- pyrazol-4-yl)pyrazolo[1,5- a]pyrimidine-3-
carboxamide 407 ##STR00512## N-(3-(5-chloro-2-
(difluoromethoxy)phenyl)- 1-(2-oxo-2-(4-(3- oxopiperazin-1-
yl)piperidin-1-yl)ethyl)- 1H-pyrazol-4- yl)pyrazolo[1,5-
a]pyrimidine-3- carboxamide 408 ##STR00513## N-(3-(5-chloro-2-
(difluoromethoxy)phenyl)- 1-(2-oxo-2-(4-(piperazine-
1-carbonyl)piperidin-1- yl)ethyl)-1H-pyrazol-4- yl)pyrazolo[1,5-
a]pyrimidine-3- carboxamide 409 ##STR00514## N-(3-(5-chloro-2-
(difluoromethoxy)phenyl)- 1-(2-(4-(3- cyanopyrrolidin-1-
yl)piperidin-1-yl)-2- oxoethyl)-1H-pyrazol-4- yl)pyrazolo[1,5-
a]pyrimidine-3- carboxamide 410 ##STR00515## N-(3-(5-chloro-2-
(difluoromethoxy)phenyl)- 1-(2-(4-methyl-4- morpholinopiperidin-1-
yl)-2-oxoethyl)-1H- pyrazol-4-yl)pyrazolo[1,5- a]pyrimidine-3-
carboxamide 411 ##STR00516## N-(3-(5-chloro-2-
(difluoromethoxy)phenyl)- 1-(3-(dimethylamino)-2-
oxopropyl)-1H-pyrazol-4- yl)pyrazolo[1,5- a]pyrimidine-3-
carboxamide 412 ##STR00517## N-(3-(5-chloro-2-
(difluoromethoxy)phenyl)- 1-(3-morpholino-2-
oxopropyl)-1H-pyrazol-4- yl)pyrazolo[1,5- a]pyrimidine-3-
carboxamide 413 ##STR00518## N-(3-(5-chloro-2-
(difluoromethoxy)phenyl)- 1-(2-(4-((2- cyanopropyl)(methyl)
amino)piperidin-1-yl)-2- oxoethyl)-1H-pyrazol-4- yl)pyrazolo[1,5-
a]pyrimidine-3- carboxamide 414 ##STR00519## N-(3-(5-chloro-2-
(difluoromethoxy)phenyl)- 1-(2-((S)-3-cyano-1,4'-
bipiperidin-1'-yl)-2- oxoethyl)-1H-pyrazol-4- yl)pyrazolo[1,5-
a]pyrimidine-3- carboxamide 415 ##STR00520## N-(3-(5-chloro-2-
(difluoromethoxy)phenyl)- 1-(2-(1-methylpiperidin-4-
ylidene)ethyl)-1H-pyrazol- 4-yl)pyrazolo[1,5- a]pyrimidine-3-
carboxamide 416 ##STR00521## N-(3-(5-chloro-2-
(difluoromethoxy)phenyl)- 1-(2-(4-(4-methyl-3- oxopiperazin-1-
yl)piperidin-1-yl)-2- oxoethyl)-1H-pyrazol-4- yl)pyrazolo[1,5-
a]pyrimidine-3- carboxamide 417 ##STR00522## N-(3-(5-chloro-2-
(difluoromethoxy)phenyl)- 1-(2-(2-oxopiperazin-1-
yl)ethyl)-1H-pyrazol-4- yl)pyrazolo[1,5- a]pyrimidine-3-
carboxamide 418 ##STR00523## N-(3-(5-chloro-2-
(difluoromethoxy)phenyl)- 1-(2-oxo-3-(piperidin-1-
yl)propyl)-1H-pyrazol-4- yl)pyrazolo[1,5- a]pyrimidine-3-
carboxamide 419 ##STR00524## N-(3-(5-chloro-2-
(difluoromethoxy)phenyl)- 1-(2-(4-(2- cyanopropylamino)
piperidin-1-yl)-2- oxoethyl)-1H- pyrazol-4-yl)pyrazolo[1,5-
a]pyrimidine-3- carboxamide 420 ##STR00525## N-(3-(5-chloro-2-
(difluoromethoxy)phenyl)-
1-(2-(4-((2- cyanoethyl)(methyl)amino) cyclohexylidene)ethyl)-
1H-pyrazol-4- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide 421
##STR00526## N-(3-(5-chloro-2- (difluoromethoxy)phenyl)-
1-(2-(4-(2- cyanoethylamino) cyclohexylidene)ethyl)- 1H-pyrazol-
4-yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide 422 ##STR00527##
N-(l-(2-(4- aminocyclohexylidene) ethyl)-3-(5-chloro-2-
(difluoromethoxy)phenyl)- 1H-pyrazol-4- yl)pyrazolo[1,5-
a]pyrimidine-3- carboxamide 423 ##STR00528## N-(3-(5-chloro-2-
(difluoromethoxy)phenyl)- 1-(2-(4-(((S)-2- (dimethylcarbamoyl)
pyrrolidin-1- yl)methyl)piperidin-1-yl)- 2-oxoethyl)-1H-pyrazol-4-
yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide 424 ##STR00529##
N-(3-(5-chloro-2- (difluoromethoxy)phenyl)- 1-(2-(4-((S)-2-
(dimethylcarbamoyl) pyrrolidin-1-yl) piperidin-1-yl)-
2-oxoethyl)-1H-pyrazol-4- yl)pyrazolo[1,5- a]pyrimidine-3-
carboxamide 425 ##STR00530## N-(3-(5-chloro-2-
(difluoromethoxy)phenyl)- 1-(2-(4-(((S)-2- (methylcarbamoyl)
pyrrolidin-1-yl) methyl)piperidin- 1-yl)-2-oxoethyl)-1H-
pyrazol-4-yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide 426
##STR00531## N-(3-(5-chloro-2- (difluoromethoxy)phenyl)-
1-(2-(4-((S)-2- (methylcarbamoyl) pyrrolidin-1-yl)
piperidin-1-yl)-2- oxoethyl)-1H-pyrazol-4- yl)pyrazolo[1,5-
a]pyrimidine-3- carboxamide 427 ##STR00532## N-(3-(5-chloro-2-
(difluoromethoxy)phenyl)- 1-(2-(4-((4-(2- (dimethylamino)-2-
oxoethyl)piperazin-1- yl)methyl)piperidin-1-yl)-
2-oxoethyl)-1H-pyrazol-4- yl)pyrazolo[1,5- a]pyrimidine-3-
carboxamide 428 ##STR00533## N-(3-(5-chloro-2-
(difluoromethoxy)phenyl)- 1-(2-(4-((1-(2- (dimethylamino)-2-
oxoethyl)piperidin-4- yl)methyl)piperazin-1-yl)-
2-oxoethyl)-1H-pyrazol-4- yl)pyrazolo[1,5- a]pyrimidine-3-
carboxamide 429 ##STR00534## N-(3-(5-chloro-2-
(difluoromethoxy)phenyl)- 1-(2-oxo-2-(4-(tetrahydro-
2H-pyran-4-yl)piperazin- 1-yl)ethyl)-1H-pyrazol-4- yl)pyrazolo[1,5-
a]pyrimidine-3- carboxamide 430 ##STR00535## N-(3-(5-chloro-2-
(difluoromethoxy)phenyl)- 1-(2-(1-methyl- hexahydropyrrolo[3,4-
b]pyrrol-5(1H)-yl)-2- oxoethyl)-1H-pyrazol-4- yl)pyrazolo[1,5-
a]pyrimidine-3- carboxamide 431 ##STR00536## N-(3-(5-chloro-2-
(difluoromethoxy)phenyl)- 1-(2-(4-((1- cyanocyclopropyl)(methyl)
amino)piperidin-1-yl)-2- oxoethyl)-1H-pyrazol-4- yl)pyrazolo[1,5-
a]pyrimidine-3- carboxamide 432 ##STR00537## N-(3-(5-chloro-2-
(difluoromethoxy)phenyl)- 1-(2-(4-(methyl((R)- tetrahydrofuran-3-
yl)amino)piperidin-1-yl)- 2-oxoethyl)-1H-pyrazol-4-
yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide 433 ##STR00538##
N-(1-(2-(4-(((1,3- dioxolan-2- yl)methyl)(methyl)amino)
piperidin-1-yl)-2- oxoethyl)-3-(5-chloro-2-
(difluoromethoxy)phenyl)- 1H-pyrazol-4- yl)pyrazolo[1,5-
a]pyrimidine-3- carboxamide 434 ##STR00539## N-(3-(5-chloro-2-
(difluoromethoxy)phenyl)- 1-(2-oxo-2-(4- thiomorpholinopiperidin-
1-yl)ethyl)-1H-pyrazol-4- yl)pyrazolo[1,5- a]pyrimidine-3-
carboxamide 435 ##STR00540## N-(3-(5-chloro-2-
(difluoromethoxy)phenyl)- 1-(2-(4-(((1- (cyanomethyl)cyclopropyl)
methyl)(methyl)amino) piperidin-1-yl)-2-oxoethyl)- 1H-pyrazol-4-
yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide 436 ##STR00541##
N-(3-(5-chloro-2- (difluoromethoxy)phenyl)- 1-(2-(4-(1-
cyanocyclopropylamino) piperidin-1-yl)-2-oxoethyl)- 1H-pyrazol-4-
yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide 437 ##STR00542##
N-(3-(5-chloro-2- (difluoromethoxy)phenyl)- 1-(2-oxo-2-(4-
(tetrahydrofuran-3- yl)piperazin-1-yl)ethyl)- 1H-pyrazol-4-
yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide 438 ##STR00543##
N-(3-(5-chloro-2- (difluoromethoxy)phenyl)- 1-(2-(4-(methyl((2-
methyl-1,3-dioxolan-2- yl)methyl)amino)piperidin-
1-yl)-2-oxoethyl)-1H- pyrazol-4-yl)pyrazolo[1,5- a]pyrimidine-3-
carboxamide 439 ##STR00544## N-(3-(5-chloro-2-
(difluoromethoxy)phenyl)- 1-(2- (octahydropyrrolo[3,4-
b]pyridin-6-yl)-2- oxoethyl)-1H-pyrazol-4- yl)pyrazolo[1,5-
a]pyrimidine-3- carboxamide 440 ##STR00545## N-(3-(5-chloro-2-
(difluoromethoxy)phenyl)- 1-(2-(1-methyl- octahydropyrrolo[3,4-
b]pyridin-6-yl)-2- oxoethyl)-1H-pyrazol-4- yl)pyrazolo[1,5-
a]pyrimidine-3- carboxamide 441 ##STR00546##
N-(1-(2-(4-(1,4-oxazepan- 4-yl)piperidin-1-yl)-2-
oxoethyl)-3-(5-chloro-2- (difluoromethoxy)phenyl)- 1H-pyrazol-4-
yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide 442 ##STR00547##
N-(3-(5-chloro-2- (difluoromethoxy)phenyl)- 1-(2-(4-(methyl((S)-
tetrahydrofuran-3- yl)amino)piperidin-1-yl)-
2-oxoethyl)-1H-pyrazol-4- yl)pyrazolo[1,5- a]pyrimidine-3-
carboxamide 443 ##STR00548## N-(3-(5-chloro-2-
(difluoromethoxy)phenyl)- 1-(2-oxo-2-(4- thiomorpholinopiperidin-
1-yl)ethyl)-1H-pyrazol-4- yl)pyrazolo[1,5- a]pyrimidine-3-
carboxamideoxide 444 ##STR00549## N-(3-(5-chloro-2-
(difluoromethoxy)phenyl)- 1-(2-((3aS,6aS)- hexahydropyrrolo[3,4-
b]pyrrol-5(1H)-yl)-2- oxoethyl)-1H-pyrazol-4- yl)pyrazolo[1,5-
a]pyrimidine-3- carboxamide 445 ##STR00550## N-(3-(5-chloro-2-
(difluoromethoxy)phenyl)- 1-(2-oxo-2-(4-(2- oxopiperazin-1-
yl)piperidin-1-yl)ethyl)- 1H-pyrazol-4- yl)pyrazolo[1,5-
a]pyrimidine-3- carboxamide 446 ##STR00551## N-(3-(5-chloro-2-
(difluoromethoxy)phenyl)- 1-(2-(4-(3-cyanoazetidin-
1-yl)piperidin-1-yl)-2- oxoethyl)-1H-pyrazol-4- yl)pyrazolo[1,5-
a]pyrimidine-3- carboxamide 447 ##STR00552##
N-(1-(2-(4-((1S,4S)-5-oxa- 2-aza- bicyclo[2.2.1]heptan-2-
yl)piperidin-1-yl)-2- oxoethyl)-3-(5-chloro-2-
(difluoromethoxy)phenyl)- 1H-pyrazol-4- yl)pyrazolo[1,5-
a]pyrimidine-3- carboxamide 448 ##STR00553## N-(3-(5-chloro-2-
(difluoromethoxy)phenyl)- 1-(2-(4-(4-methyl-2- oxopiperazin-1-
yl)piperidin-1-yl)-2- oxoethyl)-1H-pyrazol-4- yl)pyrazolo[1,5-
a]pyrimidine-3- carboxamide 449 ##STR00554## N-(3-(5-chloro-2-
(difluoromethoxy)phenyl)- 1-(2-(4-((R)-3- methylmorpholino)
piperidin-1-yl)-2- oxoethyl)-1H- pyrazol-4-yl)pyrazolo[1,5-
a]pyrimidine-3- carboxamide 450 ##STR00555##
N-(1-(2-(4-(6-oxa-3-aza- bicyclo[3.1.1]heptan-3-
yl)piperidin-1-yl)-2- oxoethyl)-3-(5-chloro-2-
(difluoromethoxy)phenyl)- 1H-pyrazol-4- yl)pyrazolo[1,5-
a]pyrimidine-3- carboxamide 451 ##STR00556## N-(3-(5-chloro-2-
(difluoromethoxy)phenyl)- 1-(2-(4-((S)-3- methylmorpholino)
piperidin-1-yl)-2- oxoethyl)-1H- pyrazol-4-yl)pyrazolo[1,5-
a]pyrimidine-3- carboxamide 452 ##STR00557## N-(3-(5-chloro-2-
(difluoromethoxy)phenyl)- 1-((1-(piperidin-4-yl)-1H-
1,2,3-triazol-4-yl)methyI)- 1H-pyrazol-4- yl)pyrazolo[1,5-
a]pyrimidine-3- carboxamide 453 ##STR00558## N-(3-(5-chloro-2-
(difluoromethoxy)phenyl)- 1-(2-(4-(2-morpholino-2-
oxoethoxy)piperidin-1-yl)- 2-oxoethyl)-1H-pyrazol-4-
yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide 454 ##STR00559##
N-(3-(5-chloro-2- (difluoromethoxy)phenyl)-
1-((1-(1-methylpiperidin- 4-yl)-1H-1,2,3-triazol-4-
yl)methyl)-1H-pyrazol-4- yl)pyrazolo[1,5- a]pyrimidine-3-
carboxamide 455 ##STR00560## N-(3-(5-chloro-2-
(difluoromethoxy)phenyl)- 1-((1-(1-(tetrahydrofuran-
3-yl)piperidin-4-yl)-1H- 1,2,3-triazol-4-yl)methyl)- 1H-pyrazol-4-
yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide 456 ##STR00561##
N-(3-(5-chloro-2- (difluoromethoxy)phenyl)- 1-(2-(4-(3-
cyanopropylamino) piperidin-1-yl)-2- oxoethyl)-1H-
pyrazol-4-yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide 457
##STR00562## N-(3-(5-chloro-2- (difluoromethoxy)phenyl)-
1-((1-(1-(tetrahydro-2H- pyran-4-yl)piperidin-4-yl)-
1H-1,2,3-triazol-4- yl)methyl)-1H-pyrazol-4- yl)pyrazolo[1,5-
a]pyrimidine-3- carboxamide 458 ##STR00563## N-(3-(5-chloro-2-
(difluoromethoxy)phenyl)- 1-(2-oxo-2-(4- ((tetrahydro-2H-pyran-4-
yl)methyl)piperazin-1- yl)ethyl)-1H-pyrazol-4- yl)pyrazolo[1,5-
a]pyrimidine-3- carboxamide 459 ##STR00564## N-(3-(5-chloro-2-
(difluoromethoxy)phenyl)- 1-(2-(4-(methyl(oxetan-3-
yl)amino)piperidin-1-yl)- 2-oxoethyl)-1H-pyrazol-4-
yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide 460 ##STR00565##
N-(3-(5-chloro-2- (difluoromethoxy)phenyl)- 1-(2-oxo-2-(4-(2-
thiomorpholinoethyl) piperazin-1-yl)ethyl)-1H-
pyrazol-4-yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide 461
##STR00566## N-(3-(5-chloro-2- (difluoromethoxy)phenyl)-
1-(2-(4-(3- cyanopropyl)piperazin-1- yl)-2-oxoethyl)-1H-
pyrazol-4-yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide 462
##STR00567## N-(3-(5-chloro-2- (difluoromethoxy)phenyl)-
1-(2-(4-cyano-1,4'- bipiperidin-1'-yl)-2- oxoethyl)-1H-pyrazol-4-
yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide 463 ##STR00568##
N-(3-(5-chloro-2- (difluoromethoxy)phenyl)- 1-(2-(4-(2,2-
difluoropropylamino) piperidin-1-yl)- 2-oxoethyl)-1H-
pyrazol-4-yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide 464
##STR00569## N-(3-(5-chloro-2- (difluoromethoxy)phenyl)-
1-(2-(4-((3- cyanopropyl)(methyl) amino)piperidin-1-yl)-2-
oxoethyl)-1H-pyrazol-4- yl)pyrazolo[1,5- a]pyrimidine-3-
carboxamide 465 ##STR00570## N-(3-(5-chloro-2-
(difluoromethoxy)phenyl)- 1-(2-(4-((2-cyano-2-
methylpropyl)(methyl) amino)piperidin-1-yl)-2-
oxoethyl)-1H-pyrazoI-4- yl)pyrazolo[1,5- a]pyrimidine-3-
carboxamide 466 ##STR00571## N-(3-(5-chloro-2-
(difluoromethoxy)phenyl)- 1-(2-(4-(2-cyano-2- methylpropylamino)
piperidin-1-yl)- 2-oxoethyl)-1H- pyrazol-4-yl)pyrazolo[1,5-
a]pyrimidine-3- carboxamide 467 ##STR00572## N-(3-(5-chloro-2-
(difluoromethoxy)phenyl)- 1-(2-(4-(((1- cyanocyclopropyl)methyl)
(methyl)amino)piperidin- 1-yl)-2-oxoethyl)-1H-
pyrazol-4-yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide 468
##STR00573## N-(3-(5-chloro-2- (difluoromethoxy)phenyl)-
1-(2-(4-(((1- cyanocyclopropyl)methyl) amino)piperidin-1-yl)-2-
oxoethyl)-1H-pyrazol-4- yl)pyrazolo[1,5- a]pyrimidine-3-
carboxamide
[0470] Compounds of the invention may contain one or more
asymmetric carbon atoms. Accordingly, the compounds may exist as
diastereomers, enantiomers or mixtures thereof. The syntheses of
the compounds may employ racemates, diastereomers or enantiomers as
starting materials or as intermediates. Mixtures of particular
diastereomeric compounds may be separated, or enriched in one or
more particular diastereomers, by chromatographic or
crystallization methods. Similarly, enantiomeric mixtures may be
separated, or enantiomerically enriched, using the same techniques
or others known in the art. Each of the asymmetric carbon or
nitrogen atoms may be in the R or S configuration and both of these
configurations are within the scope of the invention.
[0471] In the structures shown herein, where the stereochemistry of
any particular chiral atom is not specified, then all stereoisomers
are contemplated and included as the compounds of the invention.
Where stereochemistry is specified by a solid wedge or dashed line
representing a particular configuration, then that stereoisomer is
so specified and defined. Unless otherwise specified, if solid
wedges or dashed lines are used, relative stereochemistry is
intended.
[0472] Another aspect includes prodrugs of the compounds of the
present invention, such as a compound of Formula (00A), (0A), (A),
(Ia), (Ib), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), or
(X), or a compound of Table 1 or of Examples 1-468, including known
amino-protecting and carboxy-protecting groups which are released,
for example hydrolyzed, to yield the compound of the present
invention under physiologic conditions.
[0473] The term "prodrug" refers to a precursor or derivative form
of a pharmaceutically active substance that is less efficacious to
the patient compared to the parent drug and is capable of being
enzymatically or hydrolytically activated or converted into the
more active parent form. See, e.g., Wilman, "Prodrugs in Cancer
Chemotherapy" Biochemical Society Transactions, 14, pp. 375-382,
615th Meeting Belfast (1986) and Stella et al., "Prodrugs: A
Chemical Approach to Targeted Drug Delivery," Directed Drug
Delivery, Borchardt et al., (ed.), pp. 247-267, Humana Press
(1985). Prodrugs include, but are not limited to,
phosphate-containing prodrugs, thiophosphate-containing prodrugs,
sulfate-containing prodrugs, peptide-containing prodrugs, D-amino
acid-modified prodrugs, glycosylated prodrugs,
.beta.-lactam-containing prodrugs, optionally substituted
phenoxyacetamide-containing prodrugs or optionally substituted
phenylacetamide-containing prodrugs, and 5-fluorocytosine and
5-fluorouridine prodrugs.
[0474] A particular class of prodrugs are compounds in which a
nitrogen atom in an amino, amidino, aminoalkyleneamino,
iminoalkyleneamino or guanidino group is substituted with a hydroxy
group, an alkylcarbonyl (--CO--R) group, an alkoxycarbonyl
(--CO--OR), or an acyloxyalkyl-alkoxycarbonyl
(--CO--O--R--O--CO--R) group where R is a monovalent or divalent
group, for example alkyl, alkylene or aryl, or a group having the
Formula --C(O)--O--CP1P2-haloalkyl, where P1 and P2 are the same or
different and are hydrogen, alkyl, alkoxy, cyano, halogen, alkyl or
aryl. In a particular embodiment, the nitrogen atom is one of the
nitrogen atoms of the amidino group of the compounds of Formula
(00A), (0A) or (A) or a subformula thereof. Prodrugs may be
prepared by reacting a compound of the present invention, such as a
compound of Formula (00A), (0A), (A), (Ia), (Ib), (II), (III),
(IV), (V), (VI), (VII), (VIII), (IX), or (X), or a compound of
Table 1 or of Examples 1-468, with an activated group, such as acyl
groups, to bond, for example, a nitrogen atom in the compound to
the exemplary carbonyl of the activated acyl group. Examples of
activated carbonyl compounds are those containing a leaving group
bonded to the carbonyl group, and include, for example, acyl
halides, acyl amines, acyl pyridinium salts, acyl alkoxides, acyl
phenoxides such as p-nitrophenoxy acyl, dinitrophenoxy acyl,
fluorophenoxy acyl, and difluorophenoxy acyl. The reactions are
generally carried out in inert solvents at reduced temperatures
such as -78 to about 50.degree. C. The reactions may also be
carried out in the presence of an inorganic base, for example
potassium carbonate or sodium bicarbonate, or an organic base such
as an amine, including pyridine, trimethylamine, triethylamine,
triethanolamine, or the like.
[0475] Additional types of prodrugs are also encompassed. For
instance, a free carboxyl group of a compound of the invention,
such as a compound of Formula (00A), (0A), (A), (Ia), (Ib), (II),
(III), (IV), (V), (VI), (VII), (VIII), (IX), or (X), or suitable
free carboxyl-containing compound of Table 1 or of Examples 1-468,
can be derivatized as an amide or alkyl ester. As another example,
compounds of the present invention comprising free hydroxy groups
can be derivatized as prodrugs by converting the hydroxy group into
a group such as, but not limited to, a phosphate ester,
hemisuccinate, dimethylaminoacetate, or
phosphoryloxymethyloxycarbonyl group, as outlined in Fleisher, D.
et al., (1996) Improved oral drug delivery: solubility limitations
overcome by the use of prodrugs Advanced Drug Delivery Reviews,
19:115. Carbamate prodrugs of hydroxy and amino groups are also
included, as are carbonate prodrugs, sulfonate esters and sulfate
esters of hydroxy groups. Derivatization of hydroxy groups as
(acyloxy)methyl and (acyloxy)ethyl ethers, wherein the acyl group
can be an alkyl ester optionally substituted with groups including,
but not limited to, ether, amine and carboxylic acid
functionalities, or where the acyl group is an amino acid ester as
described above, are also encompassed. Prodrugs of this type are
described in J. Med. Chem., (1996), 39:10. More specific examples
include replacement of the hydrogen atom of the alcohol group with
a group such as (C.sub.1-C.sub.6)alkanoyloxymethyl,
1-((C.sub.1-C.sub.6)alkanoyloxy)ethyl,
1-methyl-1-((C.sub.1-C.sub.6)alkanoyloxy)ethyl,
(C.sub.1-C.sub.6)alkoxycarbonyloxymethyl,
N--(C.sub.1-C.sub.6)alkoxycarbonylaminomethyl, succinoyl,
(C.sub.1-C.sub.6)alkanoyl, alpha-amino(C.sub.1-C.sub.4)alkanoyl,
arylacyl and alpha-aminoacyl, or alpha-aminoacyl-alpha-aminoacyl,
where each alpha-aminoacyl group is independently selected from the
naturally occurring L-amino acids, P(O)(OH).sub.2,
--P(O)(O(C.sub.1-C.sub.6)alkyl).sub.2 or glycosyl (the radical
resulting from the removal of a hydroxyl group of the hemiacetal
form of a carbohydrate).
[0476] "Leaving group" refers to a portion of a first reactant in a
chemical reaction that is displaced from the first reactant in the
chemical reaction. Examples of leaving groups include, but are not
limited to, halogen atoms, alkoxy and sulfonyloxy groups. Example
sulfonyloxy groups include, but are not limited to,
alkylsulfonyloxy groups (for example methyl sulfonyloxy (mesylate
group) and trifluoromethylsulfonyloxy (triflate group)) and
arylsulfonyloxy groups (for example p-toluenesulfonyloxy (tosylate
group) and p-nitrosulfonyloxy (nosylate group)).
Synthesis of Janus Kinase Inhibitor Compounds
[0477] Compounds of the present invention may be synthesized by
synthetic routes described herein. In certain embodiments,
processes well-known in the chemical arts can be used, in addition
to, or in light of, the description contained herein. The starting
materials are generally available from commercial sources such as
Aldrich Chemicals (Milwaukee, Wis.) or are readily prepared using
methods well known to those skilled in the art (e.g., prepared by
methods generally described in Louis F. Fieser and Mary Fieser,
Reagents for Organic Synthesis, v. 1-19, Wiley, N.Y. (1967-1999
ed.), Beilsteins Handbuch der organischen Chemie, 4, Aufl. ed.
Springer-Verlag, Berlin, including supplements (also available via
the Beilstein online database)), or Comprehensive Heterocyclic
Chemistry, Editors Katrizky and Rees, Pergamon Press, 1984.
[0478] Compounds may be prepared singly or as compound libraries
comprising at least 2, for example 5 to 1,000 compounds, or 10 to
100 compounds. Libraries of compounds may be prepared by a
combinatorial `split and mix` approach or by multiple parallel
syntheses using either solution phase or solid phase chemistry, by
procedures known to those skilled in the art. Thus according to a
further aspect of the invention there is provided a compound
library comprising at least 2 compounds of the present invention,
such as a compound of Formula (00A), (0A), (A), (Ia), (Ib), (II),
(III), (IV), (V), (VI), (VII), (VIII), (IX), or (X), or a compound
of Table 1 or of Examples 1-468.
[0479] For illustrative purposes, reaction Schemes 1-26 depicted
below provide routes for synthesizing the compounds of the present
invention as well as key intermediates. For a more detailed
description of the individual reaction steps, see the Examples
section below. Those skilled in the art will appreciate that other
synthetic routes may be used. Although some specific starting
materials and reagents are depicted in the Schemes and discussed
below, other starting materials and reagents can be substituted to
provide a variety of derivatives or reaction conditions. In
addition, many of the compounds prepared by the methods described
below can be further modified in light of this disclosure using
conventional chemistry well known to those skilled in the art.
[0480] In the preparation of compounds of the present invention,
protection of remote functionality (e.g., primary or secondary
amine) of intermediates may be necessary. The need for such
protection will vary depending on the nature of the remote
functionality and the conditions of the preparation methods.
Suitable amino-protecting groups include acetyl, trifluoroacetyl,
benzyl, phenylsulfonyl, t-butoxycarbonyl (BOC), benzyloxycarbonyl
(CBz) and 9-fluorenylmethyleneoxycarbonyl (Fmoc). The need for such
protection is readily determined by one skilled in the art. For a
general description of protecting groups and their use, see T. W.
Greene, Protective Groups in Organic Synthesis, John Wiley &
Sons, New York, 1991.
[0481] Other conversions commonly used in the synthesis of
compounds of the present invention, and which can be carried out
using a variety of reagents and conditions, include the following:
[0482] (1) Reaction of a carboxylic acid with an amine to form an
amide. Such a transformation can be achieved using various reagents
known to those skilled in the art but a comprehensive review can be
found in Tetrahedron, 2005, 61, 10827-10852. [0483] (2) Reaction of
a primary or secondary amine with an aryl halide or pseudo halide,
e.g., a triflate, commonly known as a "Buchwald-Hartwig
cross-coupling," can be achieved using a variety of catalysts,
ligands and bases. A review of these methods is provided in
Comprehensive Organic Name Reactions and Reagents, 2010, 575-581.
[0484] (3) A palladium cross-coupling reaction between an aryl
halide and a vinyl boronic acid or boronate ester. This
transformation is a type of "Suzuki-Miyaura cross-coupling," a
class of reaction that has been thoroughly reviewed in Chemical
Reviews, 1995, 95(7), 2457-2483. [0485] (4) The hydrolysis of an
ester to give the corresponding carboxylic acid is well known to
those skilled in the art and conditions include: for methyl and
ethyl esters, the use of a strong aqueous base such as lithium,
sodium or potassium hydroxide or a strong aqueous mineral acid such
as HCl; for a tert-butyl ester, hydrolysis would be carried out
using acid, for example, HCl in dioxane or trifluoroacetic acid
(TFA) in dichloromethane (DCM).
[0486] Other exemplary transformations are discussed following the
Schemes below.
##STR00574##
[0487] Compounds of formula 6 can be synthesized as shown in
reaction Scheme 1. Trichloroacetonitrile can be reacted with
cyanoacetic acid ethyl ester to give compound 34. Compound 1 can be
condensed with hydrazine to give compound 2, which can then be
condensed with 1,1,3,3-tetramethoxypropane to give compound 3.
Amine 3 can be doubly Boc-protected to give compound 4, which can
then be hydrolyzed with lithium hydroxide to give carboxylic acid
5. Carboxylic acid 5 can then be coupled to various amines in the
presence of PyAOP, DIEA, and DMAP to give compounds of formula
6.
##STR00575##
[0488] A method for the synthesis of compounds of Formula 5 is
illustrated in Reaction Scheme 2. .alpha.-Bromoketones can be
generated from compound 1 with a reagent such as bromine.
Alkylation of di-tert-butyl iminodicarbonate with sodium hydride
and various .alpha.-bromoketones 2 generates compound 3. Compound 3
can be heated with DMFDMA to give compound 4. Cyclization of
compound 4 with hydrazine in ethanol provides pyrazole compound 5.
Coupling of compound 5 with pyrazolo[1,5-a]pyrimidine-3-carboxylic
acid in the presence of PyAOP, DIEA, and DMAP provides compounds of
Formula 6.
##STR00576##
[0489] An alternative method for the synthesis of compounds of
Formula 6 is described in Reaction Scheme 3. Alkylation of
potassium phthalimide with .alpha.-bromoketones 1 generates
compound 2. Condensation with DMFDMA yields compounds 3. Compound 3
may be cyclized with hydrazine to yield compound 4, which may then
be coupled with pyrazolo[1,5-a]pyrimidine-3-carboxylic acid under
amide formation conditions using HATU to provide compounds of
Formula 5. Alkylation of compound 5 with alkyl halides in the
presence of cesium carbonate gives compounds of Formula 6.
##STR00577##
[0490] Reaction Scheme 4 illustrates an alternate synthesis for
compounds of formula 5. Nitro-SEM pyrazole compound 1, prepared as
in Reaction Scheme 5, may be regioselectively deprotonated with
lithium hexamethyldisilazide at low temperature and quenched with
iodine to yield 2. The nitro group of compound 2 can be reduced in
the presence of iron and ammonium chloride, followed by Boc
protection to generate compound 3. Compound 3 may be coupled under
Suzuki conditions with aryl boronic acids or aryl boronates to
yield compounds 4. After cleavage of the Boc group with tin
tetrachloride, compounds of formula 5 are obtained.
##STR00578##
[0491] An alternate method for the synthesis of compounds of
Formula 6a and 6b is shown in Reaction Scheme 5. Commercially
available 4-nitro-1H-pyrazole may be protected with a
[.beta.-(trimethylsilyl)ethoxy]methyl (SEM) group by treatment with
sodium hydride and (2-(chloromethoxy)ethyl)trimethylsilane. The
resulting compound 1 can be arylated with aryl bromides or iodides
under palladium catalyzed conditions to generated
4-nitro-5-aryl-pyrazoles of formula 2. The nitro group of compounds
2 can be reduced in the presence of iron and ammonium chloride to
generate amino pyrazoles 3. Amide bond coupling with commercially
available pyrazolo[1,5-a]pyrimidine-3-carboxylic acid in the
presence of PyAOP, DIEA, and DMAP provides compounds 4. Removal of
the SEM protecting group by aqueous HCl in ethanol generates
compounds 5, which may be alkylated with alkyl halides in the
presence of a suitable base such as cesium carbonate or with
Michael acceptors to provide compounds of Formula 6a and 6b.
##STR00579##
[0492] An alternate method for the synthesis of compounds of
Formula 4a and 4b is shown in Reaction Scheme 6. Commercially
available 4-Nitro-1H-pyrazole can be reacted with alkyl bromides in
the presence of cesium carbonate at 55.degree. C. for 12 hours to
give compound 1. Compound 1 can be reacted with aryl bromides in
N,N-Dimethylacetamide in the presence of Palladium (II) acetate,
Di(1-adamntyl)-n-butylphosphine, potassium carbonate and
trimethylacetic acid to give compounds 2a and 2b. The ratio of
products 2a:2b varies depending on the substituent R1, but the
reaction generally favors formation of product 2b. Compounds 32a
and 32b can be reduced to compounds 3a and 3b in the presence of
iron and ammonium chloride in ethanol and water. Coupling of
compounds 3a and 3b with pyrazolo[1,5-a]pyrimidine-3-carboxylic
acid in the presence of PyAOP, DIEA, and DMAP can provide compounds
of Formula 4a and 4b.
##STR00580##
[0493] Amide bond coupling of 1 with
5-chloro-pyrazolo[1,5-a]pyrimidine-3-carbonyl chloride (prepared
according to the procedure in Journal of Medicinal Chemistry,
55(22), 10090-10107; 2012) in the presence of triethylamine
provides compounds of formula 2. Treatment of 2 with aqueous
ammonia generates compounds of formula 3. Removal of the SEM
protecting group by aqueous HCl in methanol generates compounds of
formula 4, which may be alkylated with alkyl halides in the
presence of a suitable base such as cesium carbonate or with
Michael acceptors to provide compounds of Formula 5a and 5b.
##STR00581##
[0494] A method for the synthesis of compounds of Formula 4a and 4b
is shown in Reaction Scheme 8. An amide bond coupling of compound 1
with commercially available
6-methyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid in the
presence of HATU and DIPEA provides compound 2. Removal of the SEM
protecting group by aqueous HCl in ethanol generates compounds 3,
which may be alkylated with alkyl halides in the presence of a
suitable base such as cesium carbonate or with Michael acceptors to
provide compounds of Formula 4a and 4b.
##STR00582##
[0495] Compounds of formula 4 can be synthesized as shown in
reaction Scheme 9. Pyrazole compound 1 (prepared as described
herein) may be alkylated with t-butyl-bromoacetate in the presence
of cesium carbonate to give intermediate 2. 2 may be treated with
trifluoroacetic acid to give acids 3, which may then be reacted
with primary or secondary amines in the presence of a coupling
reagent such as
N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium
hexafluorophosphate (HATU) to give compounds of formula 4.
##STR00583##
[0496] According to Scheme 10, compound 1 can be reacted with an
.alpha.-haloamide in the presence of a base such as cesium
carbonate and subsequently deprotected under aqueous acidic
conditions to give compounds of type 2. Compounds of type 2 can be
reacted with either primary or secondary amines under reductive
conditions to give compounds of type 4 and 3 respectively, using a
reducting agent for example sodium triacetoxyborohydride.
Intermediate 3 can be further elaborated by reaction with aldehydes
in the presence of an appropriate reducing agent such as sodium
triacetoxyborohydride to give compounds 4.
##STR00584##
Pyrazole compounds of the formula 1 may be elaborated via a copper
catalyzed coupling with for example a phenyl iodide containing a
secondary or tertiary amine sidechain to afford compound 2.
##STR00585## ##STR00586##
[0497] Treatment of compound 3 with thiourea in an appropriate
solvent such as ethanol with heating provides thiazole compound 4.
Aminothiazole 4 can be converted to the bromide 5 by treatment with
tBuONO, CuBr.sub.2 in a suitable solvent, for example acetonitrile.
Subsequent hydrolysis of compound 5 using an aqueous base such as
potassium hydroxide in a compatible solvent like ethanol will
afford acid (6). Compound 7 can be prepared by treatment of
compound 6 with diphenylphosphoryl azide (DPPA) in tert-butanol
followed by deprotection under acidic conditions. Activation of
pyrazolo[1,5-a]pyrimidine-3-carboxylic acid with thionyl chloride
in a solvent such as THF in the presence of a base like DIPEA and
susquent reaction with 7 to give compound 8. Demethylation of aryl
methylether 8 with for example BBr.sub.3 in DCM followed by
alkylation with sodium chlorodifluoroacetate and an appropriate
base and solvent combination such as cesium carbonate in DMF will
give compound 10.
##STR00587## ##STR00588##
[0498] Alternatively compounds of Formula 6 can be synthesized as
shown in Reaction Scheme 13. For example, compounds 1 can be
prepared by treatment of commercially available substituted
acetophenones with diethyl carbonate and subsequent bromination
using for example bromine in dioxane. Treatment of compounds 1 with
a suitably substituted thioamide or thiourea provides thiazole
compounds 2. Compounds 2 can be hydrolysed using an aqueous base
such as potassium hydroxide in a compatible solvent such as THF to
afford acid compounds 35. Compounds 4 can be prepared by treatment
of compounds 3 with diphenylphosphoryl azide (DPPA) in
tert-butanol. Deprotection of compounds 4 under acidic conditions
provides amino compounds 5. Compounds of formula 6 can prepared by
treatment of compounds 5 with pyrazolo[1,5-a]pyrimidine-3-carbonyl
chloride in pyridine.
##STR00589##
[0499] Compounds of type 1 can be reacted with suitable
nucleophiles such as appropriately mono-substituted cyclic
diamines, acetal containing cyclic amines and cyclic amines
containing a substituted second amino group can be achieved with
heating in a solvent such as DMA to give compounds 7, 2 and 6
respectively. Compounds of type 2 can be deprotected under aqueous
acidic conditions to provide structures of type 3. Compounds 3 can
be reductively aminated with mono or di-substituted amines, with
regards to the mono substituted amino products they can be further
elaborated via a reductively alkylated with a suitable aldehyde in
the presence of a reducing agent such as sodium cyanoborohydride
giving compounds of type 5.
##STR00590##
[0500] Compound 1 can undergo a Sonogashria reaction with an
N-substituted propargyl amine or propargyl alcohol to give
compounds 2 and 3 respectively in the presence of a palladium
source, a copper (i) halide and base in an appropriate solvent with
heating. For example, this could be a combination of
Pd(PPh.sub.3).sub.2Cl.sub.2, Cu(I)I, Et.sub.3N in THF. Alcohol 3
can be converted to the bromide 4 with CBr.sub.4, PPh.sub.3 in a
suitable solvent such as DCM. The bromide can be then displaced
with primary and secondary amines giving structures of type 5.
##STR00591##
[0501] As shown in Scheme 16, compounds of type 1 can be reacted
with 1,2-dibromo ethane to give alkyl bromides 2. Reaction of 2
with amine nucleophiles can produce structures of type 4.
##STR00592## ##STR00593##
[0502] As shown in Scheme 17, compounds of type 1 can be alkylated
with amine containing electrophiles to produce compounds 2.
Manipulation of functional groups on the pendant amine can produce
structures of type 3 and 4.
##STR00594##
[0503] As shown in Scheme 18, compounds of type 1 can be reacted
with allylic dihalides to produce compounds 2. Further reaction of
the pendant allylic halide with amine nucleophiles can produce
structures of type 4.
##STR00595##
[0504] As shown in Scheme 19, compounds of type 1 can be reacted
with substituted piperazines and an appropriate dehydrating agent
(such as HATU) to produce structures of type 4. Alternatively,
compounds of type 1 can be coupled with appropriately
mono-protected piperazines to produce compounds 2. Compounds 2 can
then be deprotected and further reacted with appropriate
electrophiles to produce structures of type 4.
##STR00596##
[0505] As shown in Scheme 20, compounds of type 1 can be reacted
with epoxides in the presence of a Lewis acid such as Yb(OTf).sub.3
to produce structures such as 2 and 3. Deprotection can then
produce structures of type 4 and 5.
##STR00597##
[0506] As shown in Scheme 21, compounds of type 1 can be reacted
with epoxides in the presence of a Lewis acid such as Yb(OTf).sub.3
to produce structures such as 2. The resulting alcohol can then be
oxidized to produce structures of type 3.
##STR00598##
[0507] As shown in Scheme 22, reaction of compounds of type 1 with
appropriate electrophiles in the presence of base, followed by
deprotection can produce structures such as 2. Further manipulation
of the reactive amine can then produce structures of type 3.
##STR00599##
[0508] As shown in Scheme 23, reaction of compounds of type 1 with
propargyl bromide or chloride in the presence of a base can produce
compounds of type 2. Reaction of 2 with azide compounds such as 3
in the presence of a copper halide and organic base, followed by
deprotection can lead to triazole compounds of type 4. Further
manipulation of the reactive amine can then produce structures of
type 5.
##STR00600##
As shown in Scheme 24, reaction of compounds of type 1 with a
2-(halomethyl)oxirane can produce compounds of type 2. Reaction of
compounds of type 2 with nucleophilic amines can lead to compounds
of type 3. Oxidation of 3 leads to compounds of type 4.
##STR00601##
As shown in Scheme 25, reaction of compounds of type 1 with
appropriate allylic alkylating reagents in the presense of base
leads to compounds of type 2. Deprotection of the amino protecting
group under acidic conditions, followed by reductive amination or
alkylation of the reactive amine leads to compounds of type 3.
##STR00602##
As shown in Scheme 26, reaction of compounds of type 1 with
appropriate allylic alkylating reagents leads to compounds of type
2. Removal of the ketal protecting group under acidic conditions,
followed by reaction of the liberated ketone with an amine under
reductive amination conditions leads to compounds of type 3. A
subsequent reductive amination or alkylation step produces
structures of type 3.
[0509] It will be appreciated that where appropriate functional
groups exist, compounds of various formulae or any intermediates
used in their preparation may be further derivatised by one or more
standard synthetic methods employing condensation, substitution,
oxidation, reduction, or cleavage reactions. Particular
substitution approaches include conventional alkylation, arylation,
heteroarylation, acylation, sulfonylation, halogenation, nitration,
formylation and coupling procedures.
[0510] In a further example, primary amine or secondary amine
groups may be converted into amide groups (--NHCOR' or --NRCOR') by
acylation. Acylation may be achieved by reaction with an
appropriate acid chloride in the presence of a base, such as
triethylamine, in a suitable solvent, such as dichloromethane, or
by reaction with an appropriate carboxylic acid in the presence of
a suitable coupling agent such HATU
(O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluorophosphate) in a suitable solvent such as dichloromethane.
Similarly, amine groups may be converted into sulphonamide groups
(--NHSO.sub.2R' or --NR''SO.sub.2R') groups by reaction with an
appropriate sulphonyl chloride in the presence of a suitable base,
such as triethylamine, in a suitable solvent such as
dichloromethane. Primary or secondary amine groups can be converted
into urea groups (--NHCONR'R'' or --NRCONR'R'') by reaction with an
appropriate isocyanate in the presence of a suitable base such as
triethylamine, in a suitable solvent, such as dichloromethane.
[0511] An amine (--NH.sub.2) may be obtained by reduction of a
nitro (--NO.sub.2) group, for example by catalytic hydrogenation,
using for example hydrogen in the presence of a metal catalyst, for
example palladium on a support such as carbon in a solvent such as
ethyl acetate or an alcohol e.g. methanol. Alternatively, the
transformation may be carried out by chemical reduction using for
example a metal, e.g. tin or iron, in the presence of an acid such
as hydrochloric acid.
[0512] In a further example, amine (--CH.sub.2NH.sub.2) groups may
be obtained by reduction of nitriles (--CN), for example by
catalytic hydrogenation using for example hydrogen in the presence
of a metal catalyst, for example palladium on a support such as
carbon, or Raney nickel, in a solvent such as an ether e.g. a
cyclic ether such as tetrahydrofuran, at an appropriate
temperature, for example from about -78.degree. C. to the reflux
temperature of the solvent.
[0513] In a further example, amine (--NH.sub.2) groups may be
obtained from carboxylic acid groups (--CO.sub.2H) by conversion to
the corresponding acyl azide (--CON.sub.3), Curtius rearrangement
and hydrolysis of the resultant isocyanate (--N.dbd.C.dbd.O).
[0514] Aldehyde groups (--CHO) may be converted to amine groups
(--CH.sub.2NR'R'')) by reductive amination employing an amine and a
borohydride, for example sodium triacetoxyborohydride or sodium
cyanoborohydride, in a solvent such as a halogenated hydrocarbon,
for example dichloromethane, or an alcohol such as ethanol, where
necessary in the presence of an acid such as acetic acid at around
ambient temperature.
[0515] In a further example, aldehyde groups may be converted into
alkenyl groups (--CH.dbd.CHR') by the use of a Wittig or
Wadsworth-Emmons reaction using an appropriate phosphorane or
phosphonate under standard conditions known to those skilled in the
art.
[0516] Aldehyde groups may be obtained by reduction of ester groups
(such as --CO.sub.2Et) or nitriles (--CN) using diisobutylaluminium
hydride in a suitable solvent such as toluene. Alternatively,
aldehyde groups may be obtained by the oxidation of alcohol groups
using any suitable oxidising agent known to those skilled in the
art.
[0517] Ester groups (--CO.sub.2R') may be converted into the
corresponding acid group (--CO.sub.2H) by acid- or base-catalused
hydrolysis, depending on the nature of R. If R is t-butyl,
acid-catalysed hydrolysis can be achieved for example by treatment
with an organic acid such as trifluoroacetic acid in an aqueous
solvent, or by treatment with an inorganic acid such as
hydrochloric acid in an aqueous solvent.
[0518] Carboxylic acid groups (--CO.sub.2H) may be converted into
amides (CONHR' or --CONR'R'') by reaction with an appropriate amine
in the presence of a suitable coupling agent, such as HATU, in a
suitable solvent such as dichloromethane.
[0519] In a further example, carboxylic acids may be homologated by
one carbon (i.e --CO.sub.2H to --CH.sub.2CO.sub.2H) by conversion
to the corresponding acid chloride (--COCl) followed by
Arndt-Eistert synthesis.
[0520] In a further example, --OH groups may be generated from the
corresponding ester (e.g. --CO.sub.2R'), or aldehyde (--CHO) by
reduction, using for example a complex metal hydride such as
lithium aluminium hydride in diethyl ether or tetrahydrofuran, or
sodium borohydride in a solvent such as methanol. Alternatively, an
alcohol may be prepared by reduction of the corresponding acid
(--CO.sub.2H), using for example lithium aluminium hydride in a
solvent such as tetrahydrofuran, or by using borane in a solvent
such as tetrahydrofuran.
[0521] Alcohol groups may be converted into leaving groups, such as
halogen atoms or sulfonyloxy groups such as an alkylsulfonyloxy,
e.g. trifluoromethylsulfonyloxy or arylsulfonyloxy, e.g.
p-toluenesulfonyloxy group using conditions known to those skilled
in the art. For example, an alcohol may be reacted with thioyl
chloride in a halogenated hydrocarbon (e.g. dichloromethane) to
yield the corresponding chloride. A base (e.g. triethylamine) may
also be used in the reaction.
[0522] In another example, alcohol, phenol or amide groups may be
alkylated by coupling a phenol or amide with an alcohol in a
solvent such as tetrahydrofuran in the presence of a phosphine,
e.g. triphenylphosphine and an activator such as diethyl-,
diisopropyl, or dimethylazodicarboxylate. Alternatively alkylation
may be achieved by deprotonation using a suitable base e.g. sodium
hydride followed by subsequent addition of an alkylating agent,
such as an alkyl halide.
[0523] Aromatic halogen substituents in the compounds may be
subjected to halogen-metal exchange by treatment with a base, for
example a lithium base such as n-butyl or t-butyl lithium,
optionally at a low temperature, e.g. around -78.degree. C., in a
solvent such as tetrahydrofuran, and then quenched with an
electrophile to introduce a desired substituent. Thus, for example,
a formyl group may be introduced by using N,N-dimethylformamide as
the electrophile. Aromatic halogen substituents may alternatively
be subjected to metal (e.g. palladium or copper) catalysed
reactions, to introduce, for example, acid, ester, cyano, amide,
aryl, heteraryl, alkenyl, alkynyl, thio- or amino substituents.
Suitable procedures which may be employed include those described
by Heck, Suzuki, Stille, Buchwald or Hartwig.
[0524] Aromatic halogen substituents may also undergo nucleophilic
displacement following reaction with an appropriate nucleophile
such as an amine or an alcohol. Advantageously, such a reaction may
be carried out at elevated temperature in the presence of microwave
irradiation.
Methods of Separation
[0525] In each of the exemplary Schemes it may be advantageous to
separate reaction products from one another or from starting
materials. The desired products of each step or series of steps is
separated or purified (hereinafter separated) to the desired degree
of homogeneity by the techniques common in the art. Typically such
separations involve multiphase extraction, crystallization or
trituration from a solvent or solvent mixture, distillation,
sublimation, or chromatography. Chromatography can involve any
number of methods including, for example: reverse-phase and normal
phase; size exclusion; ion exchange; supercritical fluid; high,
medium, and low pressure liquid chromatography methods and
apparatus; small scale analytical; simulated moving bed (SMB) and
preparative thin or thick layer chromatography, as well as
techniques of small scale thin layer and flash chromatography.
[0526] Another class of separation methods involves treatment of a
mixture with a reagent selected to bind to or render otherwise
separable a desired product, unreacted starting material, reaction
by product, or the like. Such reagents include adsorbents or
absorbents such as activated carbon, molecular sieves, ion exchange
media, or the like. Alternatively, the reagents can be acids in the
case of a basic material, bases in the case of an acidic material,
binding reagents such as antibodies, binding proteins, selective
chelators such as crown ethers, liquid/liquid ion extraction
reagents (LIX), or the like.
[0527] Selection of appropriate methods of separation depends on
the nature of the materials involved. Example separation methods
include boiling point, and molecular weight in distillation and
sublimation, presence or absence of polar functional groups in
chromatography, stability of materials in acidic and basic media in
multiphase extraction, and the like. One skilled in the art will
apply techniques most likely to achieve the desired separation.
[0528] Diastereomeric mixtures can be separated into their
individual diastereoisomers on the basis of their physical chemical
differences by methods well known to those skilled in the art, such
as by chromatography or fractional crystallization. Enantiomers can
be separated by converting the enantiomeric mixture into a
diastereomeric mixture by reaction with an appropriate optically
active compound (e.g., chiral auxiliary such as a chiral alcohol or
Mosher's acid chloride), separating the diastereoisomers and
converting (e.g., hydrolyzing) the individual diastereoisomers to
the corresponding pure enantiomers. Also, some of the compounds of
the present invention may be atropisomers (e.g., substituted
biaryls) and are considered as part of this invention. Enantiomers
can also be separated by use of a chiral HPLC column or
supercritical fluid chromatography.
[0529] A single stereoisomer, e.g., an enantiomer, substantially
free of its stereoisomer may be obtained by resolution of the
racemic mixture using a method such as formation of diastereomers
using optically active resolving agents (Eliel, E. and Wilen, S.,
Stereochemistry of Organic Compounds, John Wiley & Sons, Inc.,
New York, 1994; Lochmuller, C. H., J. Chromatogr., 113(3):283-302
(1975)). Racemic mixtures of chiral compounds of the invention can
be separated and isolated by any suitable method, including: (1)
formation of ionic, diastereomeric salts with chiral compounds and
separation by fractional crystallization or other methods, (2)
formation of diastereomeric compounds with chiral derivatizing
reagents, separation of the diastereomers, and conversion to the
pure stereoisomers, and (3) separation of the substantially pure or
enriched stereoisomers directly under chiral conditions. See: Drug
Stereochemistry, Analytical Methods and Pharmacology, Irving W.
Wainer, Ed., Marcel Dekker, Inc., New York (1993).
[0530] Diastereomeric salts can be formed by reaction of
enantiomerically pure chiral bases such as brucine, quinine,
ephedrine, strychnine, .alpha.-methyl-.beta.-phenylethylamine
(amphetamine), and the like with asymmetric compounds bearing
acidic functionality, such as carboxylic acid and sulfonic acid.
The diastereomeric salts may be induced to separate by fractional
crystallization or ionic chromatography. For separation of the
optical isomers of amino compounds, addition of chiral carboxylic
or sulfonic acids, such as camphorsulfonic acid, tartaric acid,
mandelic acid, or lactic acid can result in formation of the
diastereomeric salts.
[0531] Alternatively, the substrate to be resolved is reacted with
one enantiomer of a chiral compound to form a diastereomeric pair
(Eliel, E. and Wilen, S., Stereochemistry of Organic Compounds,
John Wiley & Sons, Inc., New York, 1994, p. 322).
Diastereomeric compounds can be formed by reacting asymmetric
compounds with enantiomerically pure chiral derivatizing reagents,
such as menthyl derivatives, followed by separation of the
diastereomers and hydrolysis to yield the pure or enriched
enantiomer. A method of determining optical purity involves making
chiral esters, such as a menthyl ester, e.g., (-) menthyl
chloroformate in the presence of base, or Mosher ester,
.alpha.-methoxy-.alpha.-(trifluoromethyl)phenyl acetate (Jacob, J.
Org. Chem. 47:4165 (1982)), of the racemic mixture, and analyzing
the NMR spectrum for the presence of the two atropisomeric
enantiomers or diastereomers. Stable diastereomers of atropisomeric
compounds can be separated and isolated by normal- and
reverse-phase chromatography following methods for separation of
atropisomeric naphthyl-isoquinolines (WO 96/15111, incorporated
herein by reference). By method (3), a racemic mixture of two
enantiomers can be separated by chromatography using a chiral
stationary phase (Chiral Liquid Chromatography W. J. Lough, Ed.,
Chapman and Hall, New York, (1989); Okamoto, J. of Chromatogr.
513:375-378 (1990)). Enriched or purified enantiomers can be
distinguished by methods used to distinguish other chiral molecules
with asymmetric carbon atoms, such as optical rotation and circular
dichroism. The absolute stereochemistry of chiral centers and
enatiomers can be determined by x-ray crystallography.
[0532] Positional isomers, for example E and Z forms, of compounds
of Formula (00A), (0A), (A), (Ia), (Ib), (II), (III), (IV), (V),
(VI), (VII), (VIII), (IX), or (X), and intermediates for their
synthesis, may be observed by characterization methods such as NMR
and analytical HPLC. For certain compounds where the energy barrier
for interconversion is sufficiently high, the E and Z isomers may
be separated, for example by preparatory HPLC.
Pharmaceutical Compositions and Administration
[0533] The compounds with which the invention is concerned are JAK
kinase inhibitors, such as JAK1 inhibitors, and are useful in the
treatment of several diseases, for example, inflammatory diseases,
such as asthma.
[0534] Accordingly, another embodiment provides pharmaceutical
compositions or medicaments containing a compound of the invention,
such as a compound of Formula (00A), (0A), (A), (Ia), (Ib), (II),
(III), (IV), (V), (VI), (VII), (VIII), (IX), or (X), or a compound
of Table 1 or of Examples 1-468, and a pharmaceutically acceptable
carrier, diluent or excipient, as well as methods of using the
compounds of the invention to prepare such compositions and
medicaments.
[0535] In one example, a compound of Formula (00A), (0A), (A),
(Ia), (Ib), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), or
(X), or a compound of Table 1 or of Examples 1-468, may be
formulated by mixing at ambient temperature at the appropriate pH,
and at the desired degree of purity, with physiologically
acceptable carriers, i.e., carriers that are non-toxic to
recipients at the dosages and concentrations employed into a
galenical administration form. The pH of the formulation depends
mainly on the particular use and the concentration of compound, but
typically ranges anywhere from about 3 to about 8. In one example,
a compound of Formula (00A), (0A), (A), (Ia), (Ib), (II), (III),
(IV), (V), (VI), (VII), (VIII), (IX), or (X), or a compound of
Table 1 or of Examples 1-468, is formulated in an acetate buffer,
at pH 5. In another embodiment, the compounds of the present
invention, such as a compound of Formula (00A), (0A), (A), (Ia),
(Ib), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), or (X), or
a compound of Table 1 or of Examples 1-468, are sterile. The
compound may be stored, for example, as a solid or amorphous
composition, as a lyophilized formulation or as an aqueous
solution.
[0536] Compositions are formulated, dosed, and administered in a
fashion consistent with good medical practice. Factors for
consideration in this context include the particular disorder being
treated, the particular mammal being treated, the clinical
condition of the individual patient, the cause of the disorder, the
site of delivery of the agent, the method of administration, the
scheduling of administration, and other factors known to medical
practitioners.
[0537] It will be understood that the specific dose level for any
particular patient will depend upon a variety of factors including
the activity of the specific compound employed, the age, body
weight, general health, sex, diet, time of administration, route of
administration, rate of excretion, drug combination and the
severity of the particular disease undergoing treatment. Optimum
dose levels and frequency of dosing will be determined by clinical
trial, as is required in the pharmaceutical art. In general, the
daily dose range for oral administration will lie within the range
of from about 0.001 mg to about 100 mg per kg body weight of a
human, often 0.01 mg to about 50 mg per kg, for example 0.1 to 10
mg per kg, in single or divided doses. In general, the daily dose
range for inhaled administration will lie within the range of from
about 0.1 .mu.g to about 1 mg per kg body weight of a human,
preferably 0.1 .mu.g to 50 .mu.g per kg, in single or divided
doses. On the other hand, it may be necessary to use dosages
outside these limits in some cases.
[0538] The compounds of the invention, such as a compound of
Formula (00A), (0A), (A), (Ia), (Ib), (II), (III), (IV), (V), (VI),
(VII), (VIII), (IX), or (X), or a compound of Table 1 or of
Examples 1-468, may be administered by any suitable means,
including oral, topical (including buccal and sublingual), rectal,
vaginal, transdermal, parenteral, subcutaneous, intraperitoneal,
intrapulmonary, intradermal, intrathecal, inhaled and epidural and
intranasal, and, if desired for local treatment, intralesional
administration. Parenteral infusions include intramuscular,
intravenous, intraarterial, intraperitoneal, or subcutaneous
administration. In some embodiments, inhaled administration is
employed.
[0539] The compounds of the present invention, such as a compound
of Formula (00A), (0A), (A), (Ia), (Ib), (II), (III), (IV), (V),
(VI), (VII), (VIII), (IX), or (X), or a compound of Table 1 or of
Examples 1-468, may be administered in any convenient
administrative form, e.g., tablets, powders, capsules, lozenges,
granules, solutions, dispersions, suspensions, syrups, sprays,
vapors, suppositories, gels, emulsions, patches, etc. Such
compositions may contain components conventional in pharmaceutical
preparations, e.g., diluents (e.g., glucose, lactose or mannitol),
carriers, pH modifiers, buffers, sweeteners, bulking agents,
stabilizing agents, surfactants, wetting agents, lubricating
agents, emulsifiers, suspending agents, preservatives,
antioxidants, opaquing agents, glidants, processing aids,
colorants, perfuming agents, flavoring agents, other known
additives as well as further active agents.
[0540] Suitable carriers and excipients are well known to those
skilled in the art and are described in detail in, e.g., Ansel,
Howard C., et al., Ansel's Pharmaceutical Dosage Forms and Drug
Delivery Systems. Philadelphia: Lippincott, Williams & Wilkins,
2004; Gennaro, Alfonso R., et al. Remington: The Science and
Practice of Pharmacy. Philadelphia: Lippincott, Williams &
Wilkins, 2000; and Rowe, Raymond C. Handbook of Pharmaceutical
Excipients. Chicago, Pharmaceutical Press, 2005. For example,
carriers include solvents, dispersion media, coatings, surfactants,
antioxidants, preservatives (e.g., antibacterial agents, antifungal
agents), isotonic agents, absorption delaying agents, salts,
preservatives, drugs, drug stabilizers, gels, binders, excipients,
disintegration agents, lubricants, sweetening agents, flavoring
agents, dyes, such like materials and combinations thereof, as
would be known to one of ordinary skill in the art (see, for
example, Remington's Pharmaceutical Sciences, pp 1289-1329, 1990).
Except insofar as any conventional carrier is incompatible with the
active ingredient, its use in the therapeutic or pharmaceutical
compositions is contemplated. Exemplary excipients include
dicalcium phosphate, mannitol, lactose, starch, magnesium stearate,
sodium saccharine, cellulose, magnesium carbonate or combinations
thereof. A pharmaceutical composition may comprise different types
of carriers or excipients depending on whether it is to be
administered in solid, liquid or aerosol form, and whether it need
to be sterile for such routes of administration.
[0541] For example, tablets and capsules for oral administration
may be in unit dose presentation form, and may contain conventional
excipients such as binding agents, for example syrup, acacia,
gelatin, sorbitol, tragacanth, or polyvinyl-pyrrolidone; fillers,
for example, lactose, sugar, maize-starch, calcium phosphate,
sorbitol or glycine; tabletting lubricant, for example, magnesium
stearate, talc, polyethylene glycol or silica; disintegrants, for
example, potato starch, or acceptable wetting agents such as sodium
lauryl sulfate. The tablets may be coated according to methods well
known in normal pharmaceutical practice. Oral liquid preparations
may be in the form of, for example, aqueous or oily suspensions,
solutions, emulsions, syrups or elixirs, or may be presented as a
dry product for reconstitution with water or other suitable vehicle
before use. Such liquid preparations may contain conventional
additives such as suspending agents, for example, sorbitol, syrup,
methyl cellulose, glucose syrup, gelatin hydrogenated edible fats;
emulsifying agents, for example, lecithin, sorbitan monooleate, or
acacia; non-aqueous vehicles (which may include edible oils), for
example, almond oil, fractionated coconut oil, oily esters such as
glycerine, propylene glycol, or ethyl alcohol; preservatives, for
example, methyl or propyl p-hydroxybenzoate or sorbic acid, and if
desired conventional flavoring or coloring agents.
[0542] For topical application to the skin, a compound may be made
up into a cream, lotion or ointment. Cream or ointment formulations
which may be used for the drug are conventional formulations well
known in the art, for example as described in standard textbooks of
pharmaceutics such as the British Pharmacopoeia.
[0543] Compounds of the invention, such as a compound of Formula
(00A), (0A), (A), (Ia), (Ib), (II), (III), (IV), (V), (VI), (VII),
(VIII), (IX), or (X), or a compound of Table 1 or of Examples
1-468, may also be formulated for inhalation, for example, as a
nasal spray, or dry powder or aerosol inhalers. For delivery by
inhalation, the compound is typically in the form of
microparticles, which can be prepared by a variety of techniques,
including spray-drying, freeze-drying and micronisation. Aerosol
generation can be carried out using, for example, pressure-driven
jet atomizers or ultrasonic atomizers, such as by using
propellant-driven metered aerosols or propellant-free
administration of micronized compounds from, for example,
inhalation capsules or other "dry powder" delivery systems.
[0544] By way of example, a composition of the invention may be
prepared as a suspension for delivery from a nebulizer or as an
aerosol in a liquid propellant, for example, for use in a
pressurized metered dose inhaler (PMDI). Propellants suitable for
use in a PMDI are known to the skilled person, and include CFC-12,
HFA-134a, HFA-227, HCFC-22 (CCl.sub.2F.sub.2) and HFA-152
(CH.sub.4F.sub.2 and isobutane).
[0545] In some embodiments, a composition of the invention is in
dry powder form, for delivery using a dry powder inhaler (DPI).
Many types of DPI are known.
[0546] Microparticles for delivery by administration may be
formulated with excipients that aid delivery and release. For
example, in a dry powder formulation, microparticles may be
formulated with large carrier particles that aid flow from the DPI
into the lung. Suitable carrier particles are known, and include
lactose particles; they may have a mass median aerodynamic diameter
of, for example, greater than 90 am.
[0547] In the case of an aerosol-based formulation, an example is:
[0548] Compound of the invention* 24 mg/canister [0549] Lecithin,
NF Liq. Conc. 1.2 mg/canister [0550] Trichlorofluoromethane, NF
4.025 g/canister [0551] Dichlorodifluoromethane, NF 12.15
g/canister. [0552] * Such as a compound of Formula (00A), (0A),
(A), (Ia), (Ib), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX),
or (X), or a compound of Table 1 or of Examples 1-468.
[0553] A compound, such as a compound of Formula (00A), (0A), (A),
(Ia), (Ib), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), or
(X), or a compound of Table 1 or of Examples 1-468, may be dosed as
described depending on the inhaler system used. In addition to the
compound, the administration forms may additionally contain
excipients as described above, or, for example, propellants (e.g.,
Frigen in the case of metered aerosols), surface-active substances,
emulsifiers, stabilizers, preservatives, flavorings, fillers (e.g.,
lactose in the case of powder inhalers) or, if appropriate, further
active compounds.
[0554] For the purposes of inhalation, a large number of systems
are available with which aerosols of optimum particle size can be
generated and administered, using an inhalation technique which is
appropriate for the patient. In addition to the use of adaptors
(spacers, expanders) and pear-shaped containers (e.g.,
Nebulator.RTM., Volumatic.RTM.), and automatic devices emitting a
puffer spray (Autohaler.RTM.), for metered aerosols, in the case of
powder inhalers in particular, a number of technical solutions are
available (e.g., Diskhaler.RTM., Rotadisk.RTM., Turbohaler.RTM. or
the inhalers, for example, as described in U.S. Pat. No. 5,263,475,
incorporated herein by reference). Additionally, compounds of the
invention, such as a compound of Formula (00A), (0A), (A), (Ia),
(Ib), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), or (X), or
a compound of Table 1 or of Examples 1-468, may be delivered in
multi-chamber devices thus allowing for delivery of combination
agents.
[0555] The compound, such as a compound of Formula (00A), (0A),
(A), (Ia), (Ib), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX),
or (X), or a compound of Table 1 or of Examples 1-468, may also be
administered parenterally in a sterile medium. Depending on the
vehicle and concentration used, the compound can either be
suspended or dissolved in the vehicle. Advantageously, adjuvants
such as a local anaesthetic, preservative or buffering agents can
be dissolved in the vehicle.
Targeted Inhaled Drug Delivery
[0556] Optimisation of drugs for delivery to the lung by topical
(inhaled) administration has been recently reviewed (Cooper, A. E.
et al. Curr. Drug Metab. 2012, 13, 457-473). Due to limitations in
the delivery device, the dose of an inhaled drug is likely to be
low (approximately <1 mg/day) in humans which necessitates
highly potent molecules. For compounds destined to be delivered via
dry powder inhalation there is also a requirement to be able to
generate crystalline forms of the compound that can be micronized
to 1-5 m in size. Additionally, the compound needs to maintain a
sufficient concentration in the lung over a given time period so as
to be able to exert a pharmacological effect of the desired
duration, and for pharmacological targets where systemic inhibition
of said target is undesired, to have a low systemic exposure. The
lung has an inherently high permeability to both large molecules
(proteins, peptides) as well as small molecules with concomitant
short lung half-lives, thus it is necessary to attenuate the lung
absorption rate through modification of one or more features of the
compounds: minimizing membrane permeability, reducing dissolution
rate, or introducing a degree of basicity into the compound to
enhance binding to the phospholipid-rich lung tissue or through
trapping in acidic sub-cellular compartments such as lysosomes (pH
5). Accordingly, in some embodiments, compounds of the present
invention exhibit one or more of these features.
Matched Pair Analysis
[0557] FIG. 1 depicts a matched pair analysis of certain compounds
of the present invention containing either an OMe (i) or OCHF.sub.2
(ii) group at the indicated position. Any two dots joined by a line
represent two compounds with identical R.sub.1 and R.sub.2 groups,
and differing only by an OMe or OCHF.sub.2 substitution at the
indicated position. FIG. 1 demonstrates that OCHF.sub.2 substituted
analogs (ii) are consistently more potent in the JAK1 biochemical
assay (described below) than the corresponding OMe analogs (i).
Methods of Treatment with and Uses of Janus Kinase Inhibitors
[0558] The compounds of the present invention, such as a compound
of Formula (00A), (0A), (A), (Ia), (Ib), (II), (III), (IV), (V),
(VI), (VII), (VIII), (IX), or (X), or a compound of Table 1 or of
Examples 1-468, inhibit the activity of a Janus kinase, such as
JAK1 kinase. For example, a compound of the present invention, such
as a compound of Formula (00A), (0A), (A), (Ia), (Ib), (II), (III),
(IV), (V), (VI), (VII), (VIII), (IX), or (X), or a compound of
Table 1 or of Examples 1-468, inhibits the phosphorylation of
signal transducers and activators of transcription (STATs) by JAK1
kinase as well as STAT mediated cytokine production. Compounds of
the present invention, such as a compound of Formula (00A), (0A),
(A), (Ia), (Ib), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX),
or (X), or a compound of Table 1 or of Examples 1-468, are useful
for inhibiting JAK1 kinase activity in cells through cytokine
pathways, such as IL-6, IL-15, IL-7, IL-2, IL-4, IL-9, IL-10,
IL-13, IL-21, G-CSF, IFNalpha, IFNbeta or IFNgamma pathways.
Accordingly, in one embodiment is provided a method of contacting a
cell with a compound of the present invention, such as a compound
of Formula (00A), (0A), (A), (Ia), (Ib), (II), (III), (IV), (V),
(VI), (VII), (VIII), (IX), or (X), or a compound of Table 1 or of
Examples 1-468, to inhibit a Janus kinase activity in the cell
(e.g., JAK1 activity).
[0559] The compounds of the present invention, such as compounds of
Formula (00A), (0A), (A), (Ia), (Ib), (II), (III), (IV), (V), (VI),
(VII), (VIII), (IX), or (X), or a compound of Table 1 or of
Examples 1-468, can be used for the treatment of immunological
disorders driven by aberrant IL-6, IL-15, IL-7, IL-2, IL-4, IL9,
IL-10, IL-13, IL-21, G-CSF, IFNalpha, IFNbeta or IFNgamma cytokine
signaling.
[0560] Accordingly, one embodiment includes compounds of the
present invention, such as a compound of Formula (00A), (0A), (A),
(Ia), (Ib), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), or
(X), or a compound of Table 1 or of Examples 1-468, for use in
therapy.
[0561] In some embodiments, there is provided use a compound of the
present invention, such as a compound of Formula (00A), (0A), (A),
(Ia), (Ib), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), or
(X), or a compound of Table 1 or of Examples 1-468, in the
treatment of an inflammatory disease. Further provided is use of a
compound of the present invention, such as a compound of Formula
(00A), (0A), (A), (Ia), (Ib), (II), (III), (IV), (V), (VI), (VII),
(VIII), (IX), or (X), or a compound of Table 1 or of Examples
1-468, for the preparation of a medicament for the treatment of an
inflammatory disease, such as asthma. Also provided is a compound
of the present invention, such as a compound of Formula (00A),
(0A), (A), (Ia), (Ib), (II), (III), (IV), (V), (VI), (VII), (VIII),
(IX), or (X), or a compound of Table 1 or of Examples 1-468, for
use in the treatment of an inflammatory disease, such as
asthma.
[0562] Another embodiment includes a method of preventing, treating
or lessening the severity of a disease or condition, such as
asthma, responsive to the inhibition of a Janus kinase activity,
such as JAK1 kinase activity, in a patient. The method can include
the step of administering to a patient a therapeutically effective
amount of a compound of the present invention, such as a compound
of Formula (00A), (0A), (A), (Ia), (Ib), (II), (III), (IV), (V),
(VI), (VII), (VIII), (IX), or (X), or a compound of Table 1 or of
Examples 1-468. In one embodiment, the disease or condition
responsive to the inhibition of a Janus kinase, such as JAK1
kinase, is asthma.
[0563] In one embodiment, the disease or condition is cancer,
stroke, diabetes, hepatomegaly, cardiovascular disease, multiple
sclerosis, Alzheimer's disease, cystic fibrosis, viral disease,
autoimmune diseases, atherosclerosis, restenosis, psoriasis,
rheumatoid arthritis, inflammatory bowel disease, asthma, allergic
disorders, inflammation, neurological disorders, a hormone-related
disease, conditions associated with organ transplantation (e.g.,
transplant rejection), immunodeficiency disorders, destructive bone
disorders, proliferative disorders, infectious diseases, conditions
associated with cell death, thrombin-induced platelet aggregation,
liver disease, pathologic immune conditions involving T cell
activation, CNS disorders or a myeloproliferative disorder.
[0564] In one embodiment, the inflammatory disease is rheumatoid
arthritis, psoriasis, asthma, inflammatory bowel disease, contact
dermatitis or delayed hypersensitivity reactions. In one
embodiment, the autoimmune disease is rheumatoid arthritis, lupus
or multiple sclerosis.
[0565] In one embodiment, the cancer is breast, ovary, cervix,
prostate, testis, penile, genitourinary tract, seminoma, esophagus,
larynx, gastric, stomach, gastrointestinal, skin, keratoacanthoma,
follicular carcinoma, melanoma, lung, small cell lung carcinoma,
non-small cell lung carcinoma (NSCLC), lung adenocarcinoma,
squamous carcinoma of the lung, colon, pancreas, thyroid,
papillary, bladder, liver, biliary passage, kidney, bone, myeloid
disorders, lymphoid disorders, hairy cells, buccal cavity and
pharynx (oral), lip, tongue, mouth, salivary gland, pharynx, small
intestine, colon, rectum, anal, renal, prostate, vulval, thyroid,
large intestine, endometrial, uterine, brain, central nervous
system, cancer of the peritoneum, hepatocellular cancer, head
cancer, neck cancer, Hodgkin's or leukemia.
[0566] In one embodiment, the disease is a myeloproliferative
disorder. In one embodiment, the myeloproliferative disorder is
polycythemia vera, essential thrombocytosis, myelofibrosis or
chronic myelogenous leukemia (CML).
[0567] Another embodiment includes the use of a compound of the
present invention, such as a compound of Formula (00A), (0A), (A),
(Ia), (Ib), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), or
(X), or a compound of Table 1 or of Examples 1-468, for the
manufacture of a medicament for the treatment of a disease
described herein (e.g., an inflammatory disorder, an immunological
disorder or cancer). In one embodiment, the invention provides a
method of treating a disease or condition as described herein e.g.,
an inflammatory disorder, an immunological disorder or cancer) by
targeting inhibition of a JAK kinase, such as JAK1.
Combination Therapy
[0568] The compounds of the present invention, such as a compound
of Formula (00A), (0A), (A), (Ia), (Ib), (II), (III), (IV), (V),
(VI), (VII), (VIII), (IX), or (X), or a compound of Table 1 or of
Examples 1-468, may be employed alone or in combination with other
agents for treatment. The second compound of a pharmaceutical
composition or dosing regimen typically has complementary
activities to the compound of this invention such that they do not
adversely affect each other. Such agents are suitably present in
combination in amounts that are effective for the purpose intended.
The compounds may be administered together in a unitary
pharmaceutical composition or separately and, when administered
separately this may occur simultaneously or sequentially. Such
sequential administration may be close or remote in time.
[0569] For example, other compounds may be combined with compounds
with which the invention is concerned for the prevention or
treatment of inflammatory diseases, such as asthma. Thus the
present invention is also concerned with pharmaceutical
compositions comprising a therapeutically effective amount of a
compound of the invention and one or more other therapeutic agents.
Suitable therapeutic agents for a combination therapy with
compounds of the invention include, but are not limited to: an
adenosine A2A receptor antagonist; an anti-infective; a
non-steroidal Glucocorticoid Receptor (GR Receptor) agonist; an
antioxidant; a .beta.2 adrenoceptor agonist; a CCR1 antagonist; a
chemokine antagonist (not CCR1); a corticosteroid; a CRTh2
antagonist; a DP1 antagonist; a formyl peptide receptor antagonist;
a histone deacetylase activator; a chloride channel hCLCA1 blocker;
an epithelial sodium channel blocker (ENAC blocker; an
inter-cellular adhesion molecule 1 blocker (ICAM blocker); an IKK2
inhibitor; a JNK inhibitor; a cyclooxygenase inhibitor (COX
inhibitor); a lipoxygenase inhibitor; a leukotriene receptor
antagonist; a dual .beta.2 adrenoceptor agonist/M3 receptor
antagonist (MABA compound); a MEK-1 inhibitor; a myeloperoxidase
inhibitor (MPO inhibitor); a muscarinic antagonist; a p38 MAPK
inhibitor; a phosphodiesterase PDE4 inhibitor; a
phosphatidylinositol 3-kinase .delta. inhibitor (PI3-kinase .delta.
inhibitor); a phosphatidylinositol 3-kinase .gamma. inhibitor
(PI3-kinase .gamma. inhibitor); a peroxisome proliferator activated
receptor agonist (PPAR.gamma. agonist); a protease inhibitor; a
retinoic acid receptor modulator (RAR .gamma. modulator); a statin;
a thromboxane antagonist; a TLR7 receptor agonist; or a
vasodilator.
[0570] In addition, compounds of the invention, such as a compound
of Formula (00A), (0A), (A), (Ia), (Ib), (II), (III), (IV), (V),
(VI), (VII), (VIII), (IX), or (X), or a compound of Table 1 or of
Examples 1-468, may be combined with: (1) corticosteroids, such as
alclometasone dipropionate, amelometasone, beclomethasone
dipropionate, budesonide, butixocort propionate, biclesonide,
blobetasol propionate, desisobutyrylciclesonide, dexamethasone,
dtiprednol dicloacetate, fluocinolone acetonide, fluticasone
furoate, fluticasone propionate, loteprednol etabonate (topical) or
mometasone furoate; (2) .beta.2-adrenoreceptor agonists such as
salbutamol, albuterol, terbutaline, fenoterol, bitolterol,
carbuterol, clenbuterol, pirbuterol, rimoterol, terbutaline,
tretoquinol, tulobuterol and long acting .beta.2-adrenoreceptor
agonists such as metaproterenol, isoproterenol, isoprenaline,
salmeterol, indacaterol, formoterol (including formoterol
fumarate), arformoterol, carmoterol, abediterol, vilanterol
trifenate, olodaterol; (3) corticosteroid/long acting 132 agonist
combination products such as salmeterol/fluticasone propionate
(Advair.RTM., also sold as Seretide.RTM.), formoterol/budesonide
(Symbicort.RTM.), formoterol/fluticasone propionate
(Flutiform.RTM.), formoterol/ciclesonide, formoterol/mometasone
furoate, indacaterol/mometasone furoate, vilanterol
trifenate/fluticasone furoate, or arformoterol/ciclesonide; (4)
anticholinergic agents, for example, muscarinic-3 (M3) receptor
antagonists such as ipratropium bromide, tiotropium bromide,
aclidinium (LAS-34273), glycopyrronium bromide, umeclidinium
bromide; (5) M3-anticholinergic/.beta.2-adrenoreceptor agonist
combination products such as vilanterol/umeclidinium (Anoro.RTM.
Ellipta.RTM.), olodaterol/tiotropium bromide, glycopyrronium
bromide/indacaterol (Ultibro.RTM., also sold as Xoterna.RTM.),
fenoterol hydrobromide/ipratropium bromide (Berodual.RTM.),
albuterol sulfate/ipratropium bromide (Combivent.RTM.), formoterol
fumarate/glycopyrrolate, or aclidinium bromide/formoterol (6) dual
pharmacology M3-anticholinergic/(32-adrenoreceptor agonists such as
batefenterol succinate, AZD-2115 or LAS-190792; (7) leukotriene
modulators, for example, leukotriene antagonists such as
montelukast, zafirulast or pranlukast or leukotriene biosynthesis
inhibitors such as zileuton, or LTB4 antagonists such as amelubant,
or FLAP inhibitors such as fiboflapon, GSK-2190915; (8)
phosphodiesterase-IV (PDE-IV) inhibitors (oral or inhaled), such as
roflumilast, cilomilast, oglemilast, rolipram, tetomilast,
AVE-8112, revamilast, CHF 6001; (9) antihistamines, for example,
selective histamine-1 (H1) receptor antagonists such as
fexofenadine, citirizine, loratidine or astemizole or dual H1/H3
receptor antagonists such as GSK 835726, or GSK 1004723; (10)
antitussive agents, such as codeine or dextramorphan; (11) a
mucolytic, for example, N-acetyl cysteine or fudostein; (12) a
expectorant/mucokinetic modulator, for example, ambroxol,
hypertonic solutions (e.g., saline or mannitol) or surfactant; (13)
a peptide mucolytic, for example, recombinant human
deoxyribonoclease I (dornase-alpha and rhDNase) or helicidin; (14)
antibiotics, for example azithromycin, tobramycin or aztreonam;
(15) non-selective COX-1/COX-2 inhibitors, such as ibuprofen or
ketoprofen; (16) COX-2 inhibitors, such as celecoxib and rofecoxib;
(17) VLA-4 antagonists, such as those described in WO97/03094 and
WO97/02289, each incorporated herein by reference; (18) TACE
inhibitors and TNF-.alpha. inhibitors, for example anti-TNF
monoclonal antibodies, such as Remicade.RTM. and CDP-870 and TNF
receptor immunoglobulin molecules, such as Enbrel.RTM.; (19)
inhibitors of matrix metalloprotease, for example MMP-12; (20)
human neutrophil elastase inhibitors, such as BAY-85-8501 or those
described in WO2005/026124, WO2003/053930 and WO06/082412, each
incorporated herein by reference; (21) A2b antagonists such as
those described in WO2002/42298, incorporated herein by reference;
(22) modulators of chemokine receptor function, for example
antagonists of CCR3 and CCR8; (23) compounds which modulate the
action of other prostanoid receptors, for example, a thromboxane
A.sub.2 antagonist; DP1 antagonists such as laropiprant or
asapiprant CRTH2 antagonists such as OC000459, fevipiprant, ADC
3680 or ARRY 502; (24) PPAR agonists including PPAR alpha agonists
(such as fenofibrate), PPAR delta agonists, PPAR gamma agonists
such as pioglitazone, rosiglitazone and balaglitazone; (25)
methylxanthines such as theophylline or aminophylline and
methylxanthine/corticosteroid combinations such as
theophylline/budesonide, theophylline/fluticasone propionate,
theophylline/ciclesonide, theophylline/mometasone furoate and
theophylline/beclometasone dipropionate; (26) A2a agonists such as
those described in EP1052264 and EP1241176; (27) CXCR2 or IL-8
antagonists such as AZD-5069, AZD-4721, danirixin; (28) IL-R
signalling modulators such as kineret and ACZ 885; (29) MCP-1
antagonists such as ABN-912; (30) a p38 MAPK inhibitor such as
BCT197, JNJ49095397, losmapimod or PH-797804; (31) TLR7 receptor
agonists such as AZD 8848; (32) PI3-kinase inhibitors such as
RV1729 or GSK2269557.
[0571] In some embodiments, the compounds of the present invention,
such as a compound of Formula (00A), (0A), (A), (Ia), (Ib), (II),
(III), (IV), (V), (VI), (VII), (VIII), (IX), or (X), or a compound
of Table 1 or of Examples 1-468, can be used in combination with
one or more additional drugs, for example anti-hyperproliferative,
anti-cancer, cytostatic, cytotoxic, anti-inflammatory or
chemotherapeutic agents, such as those agents disclosed in U.S.
Publ. Appl. No. 2010/0048557, incorporated herein by reference. A
compound of the present invention, such as a compound of Formula
(00A), (0A), (A), (Ia), (Ib), (II), (III), (IV), (V), (VI), (VII),
(VIII), (IX), or (X), or a compound of Table 1 or of Examples
1-468, can be also used in combination with radiation therapy or
surgery, as is known in the art.
Articles of Manufacture
[0572] Another embodiment includes an article of manufacture (e.g.,
a kit) for treating a disease or disorder responsive to the
inhibition of a Janus kinase, such as a JAK1 kinase. The kit can
comprise:
[0573] (a) a first pharmaceutical composition comprising a compound
of the present invention, such as a compound of Formula (00A),
(0A), (A), (Ia), (Ib), (II), (III), (IV), (V), (VI), (VII), (VIII),
(IX), or (X), or a compound of Table 1 or of Examples 1-468;
and
[0574] (b) instructions for use.
[0575] In another embodiment, the kit further comprises:
[0576] (c) a second pharmaceutical composition, such as a
pharmaceutical composition comprising an agent for treatment as
described above, such as an agent for treatment of an inflammatory
disorder, or a chemotherapeutic agent.
[0577] In one embodiment, the instructions describe the
simultaneous, sequential or separate administration of said first
and second pharmaceutical compositions to a patient in need
thereof.
[0578] In one embodiment, the first and second compositions are
contained in separate containers. In another embodiment, the first
and second compositions are contained in the same container.
[0579] Containers for use include, for example, bottles, vials,
syringes, blister pack, etc. The containers may be formed from a
variety of materials such as glass or plastic. The container
includes a compound of the present invention, such as a compound of
Formula (00A), (0A), (A), (Ia), (Ib), (II), (III), (IV), (V), (VI),
(VII), (VIII), (IX), or (X), or a compound of Table 1 or of
Examples 1-468, or composition thereof, which is effective for
treating the condition and may have a sterile access port (for
example the container may be an intravenous solution bag or a vial
having a stopper pierceable by a hypodermic injection needle). The
label or package insert indicates that the compound or composition
is used for treating the condition of choice, such as asthma or
cancer. In one embodiment, the label or package inserts indicates
that the compound or composition can be used to treat a disorder.
In addition, the label or package insert may indicate that the
patient to be treated is one having a disorder characterized by
overactive or irregular Janus kinase activity, such as overactive
or irregular JAK1 activity. The label or package insert may also
indicate that the compound or composition can be used to treat
other disorders.
[0580] Alternatively, or additionally, the kit may further comprise
a second (or third) container comprising a pharmaceutically
acceptable buffer, such as bacteriostatic water for injection
(BWFI), phosphate-buffered saline, Ringer's solution or dextrose
solution. It may further include other materials desirable from a
commercial and user standpoint, including other buffers, diluents,
filters, needles, and syringes.
[0581] In order to illustrate the invention, the following examples
are included. However, it is to be understood that these examples
do not limit the invention and are only meant to suggest a method
of practicing the invention. Persons skilled in the art will
recognize that the chemical reactions described may be readily
adapted to prepare other compounds of the present invention, and
alternative methods for preparing the compounds are within the
scope of this invention. For example, the synthesis of
non-exemplified compounds according to the invention may be
successfully performed by modifications apparent to those skilled
in the art, e.g., by appropriately protecting interfering groups,
by utilizing other suitable reagents known in the art other than
those described, or by making routine modifications of reaction
conditions. Alternatively, other reactions disclosed herein or
known in the art will be recognized as having applicability for
preparing other compounds of the invention.
EXAMPLES
[0582] Although the invention has been described and illustrated
with a certain degree of particularity, it is understood that the
present disclosure has been made only by way of example, and that
numerous changes in the combination and arrangement of parts can be
resorted to by those skilled in the art without departing from the
spirit and scope of the invention, as defined by the claims.
General Experimental Details:
[0583] All solvents and commercial reagents were used as received
unless otherwise stated. Where products were purified by
chromatography on silica this was carried out using either a glass
column manually packed with silica gel (Kieselgel 60, 220-440 mesh,
35-75 .mu.m) or an Isolute.RTM. SPE Si II cartridge. `Isolute SPE
Si cartridge` refers to a pre-packed polypropylene column
containing unbonded activated silica with irregular particles with
average size of 50 .mu.m and nominal 60A porosity. Where an
Isolute.RTM. SCX-2 cartridge was used, `Isolute.RTM. SCX-2
cartridge` refers to a pre-packed polypropylene column containing a
non-end-capped propylsulphonic acid functionalised silica strong
cation exchange sorbent.
Preparative HPLC Conditions
[0584] HPLC System 1: C18-reverse-phase column (250.times.21.2 mm
Gemini column with 5 .mu.m particle size), eluting with a gradient
of A: water+0.1% formic acid; B: acetonitrile+0.1% formic acid with
a flow rate typically 20 mL/min and a gradient increasing in B. UV
detection at 254 nm. Compounds were obtained as the formate salt
where stated.
[0585] HPLC System 2: Phenylhexyl reverse-phase column
(250.times.21.2 mm Gemini column with 5 .mu.m particle size),
eluting with a gradient of A: water+0.1% formic acid; B:
acetonitrile+0.1% formic acid with a flow rate typically 20 mL/min
and gradient of 1%/min increasing in B. UV detection at 254 nm.
Compounds were obtained as the formate salt where stated.
[0586] HPLC System 3: C18-reverse-phase end-capped column
(250.times.21.2 mm Gemini column with 5 .mu.m particle size),
eluting with a gradient of A: water+0.1% ammonia; B:
acetonitrile+0.1% ammonia with a flow rate typically 20 mL/min and
a gradient increasing in B. UV detection at 254 nm. Compounds were
obtained as the free base.
NMR Analytical Methods
[0587] .sup.1H NMR spectra were recorded at ambient temperature
using one of the following: [0588] i. Varian Unity Inova (400 MHz)
spectrometer with a 400 4NUC 5 mm probe. [0589] ii. Bruker Avance
DRX400 (400 MHz) spectrometer with a PABBO 5 mm probe. [0590] iii.
Varian Unity Inova (400 MHz) spectrometer with a 5 mm inverse
detection triple resonance probe. [0591] iv. Bruker Avance DRX (400
MHz) spectrometer with a 5 mm inverse detection triple resonance
TXI probe.
[0592] Chemical shifts are expressed in ppm relative to
tetramethylsilane.
LC-MS Analytical Methods
[0593] LC-MS information is provided in Table 2.
[0594] LC-MS Method 1: Waters Platform LC with a C18-reverse-phase
column (30.times.4.6 mm Phenomenex Luna 3 .mu.m particle size),
elution with A: water+0.1% formic acid; B: acetonitrile+0.1% formic
acid. Gradient:
TABLE-US-00002 Gradient - Time flow mL/min % A % B 0.00 2.0 95 5
0.50 2.0 95 5 4.50 2.0 5 95 5.50 2.0 5 95 6.00 2.0 95 5
[0595] Detection--MS, ELS, UV (100 .mu.l split to MS with in-line
UV detector)
[0596] MS ionisation method--Electrospray (positive and negative
ion)
[0597] LC-MS Method 2: Waters Micromass ZMD with a
C18-reverse-phase column (30.times.4.6 mm Phenomenex Luna 3 .mu.m
particle size), elution with A: water+0.1% formic acid; B:
acetonitrile+0.1% formic acid. Gradient:
TABLE-US-00003 Gradient - Time flow mL/min % A % B 0.00 2.0 95 5
0.50 2.0 95 5 4.50 2.0 5 95 5.50 2.0 5 95 6.00 2.0 95 5
[0598] Detection--MS, ELS, UV (100 .mu.l split to MS with in-line
UV detector)
[0599] MS ionisation method--Electrospray (positive and negative
ion)
[0600] LC-MS Method 3: VG Platform II quadrupole spectrometer with
a C18-reverse-phase column (30.times.4.6 mm Phenomenex Luna 3 .mu.m
particle size), elution with A: water+0.1% formic acid; B:
acetonitrile+0.1% formic acid. Gradient:
TABLE-US-00004 Gradient - Time flow mL/min % A % B 0.00 2.0 95 5
0.50 2.0 95 5 4.50 2.0 5 95 5.50 2.0 5 95 6.00 2.0 95 5
[0601] Detection--MS, ELS, UV (200 .mu.l/min split to the ESI
source with inline HP1050 DAD detection)
[0602] MS ionisation method--Electrospray (positive and negative
ion)
[0603] LC-MS Method 4: Finnigan AQA with a C18-reverse-phase column
(30.times.4.6 mm Phenomenex Luna 3 .mu.m particle size), elution
with A: water+0.1% formic acid; B: acetonitrile+0.1% formic acid.
Gradient:
TABLE-US-00005 Gradient - Time flow mL/min % A % B 0.00 2.0 95 5
0.50 2.0 95 5 4.50 2.0 5 95 5.50 2.0 5 95 6.00 2.0 95 5
[0604] Detection--MS, ELS, UV
[0605] MS ionisation method--Electrospray (positive ion)
[0606] LC-MS Method 5: Waters Micromass ZQ2000 quadrupole mass
spectrometer with a C18-reverse-phase column (100.times.2.1 mm
Acquity BEH C18 1.7.mu., Acquity BEH Shield RP18 1.7.mu., or
Acquity HSST3 1.8.mu.) maintained at 40.degree. C., elution with A:
water+0.1% formic acid; B: acetonitrile+0.1% formic acid.
Gradient:
TABLE-US-00006 Gradient - Time flow mL/min % A % B 0.00 0.4 95 5
0.40 0.4 95 5 6.00 0.4 5 95 6.80 0.4 5 95 7.00 0.4 95 5 8.00 0.4 95
5
[0607] Detection--MS, UV PDA
[0608] MS ionisation method--Electrospray (positive ion)
[0609] LC-MS Method 6: Waters Acquity UPLC with a C18-reverse-phase
column (100.times.2.1 mm Acquity BEH C18, 1.7 .mu.m particle size),
elution with solvent A: water+0.1% formic acid; solvent B:
acetonitrile+0.1% formic acid at 40.degree. C. Gradient:
TABLE-US-00007 Gradient - Time flow mL/min % A % B 0.00 0.4 95 5
0.40 0.4 95 5 6.00 0.4 5 95 6.80 0.4 5 95 8.00 0.4 95 5
[0610] Detection--UV (220 nm)
[0611] MS ionisation method--ESI.sup.+
[0612] LC-MS Method 7: SHIMADZU 20A HPLC with a C18-reverse-phase
column (30.times.2.1 mm Xtimate.TM.-C18, 3 .mu.m particle size),
elution with solvent A: water+0.038% trifluoroacetic acid; solvent
B: acetonitrile+0.02% trifluoroacetic acid. Gradient:
TABLE-US-00008 Gradient - Time flow mL/min % A % B 0.00 1.2 90 10
0.90 1.2 20 80 1.5 1.2 20 80 2.0 1.2 90 10
[0613] Detection--UV (220 nm)
[0614] MS ionisation method--ESI.sup.+
[0615] LC-MS Method 8: SHIMADZU 20A HPLC with a C18-reverse-phase
column (30.times.2.1 mm Xtimate.TM.-C18, 3 .mu.m particle size),
elution with solvent A: water+0.038% trifluoroacetic acid; solvent
B: acetonitrile+0.02% trifluoroacetic acid. Gradient:
TABLE-US-00009 Gradient - Time flow ml/min % A % B 0.00 1.2 90 10
1.35 1.2 20 80 2.25 1.2 20 80 2.75 1.2 90 10
[0616] Detection--UV (220 nm)
[0617] MS ionisation method--ESI.sup.+
[0618] LC-MS Method 9: SHIMADZU 20A HPLC with a C18-reverse-phase
column (30.times.2.1 mm Xtimate.TM.-C18, 3 .mu.m particle size),
elution with solvent A: water+0.038% trifluoroacetic acid; solvent
B: acetonitrile+0.02% trifluoroacetic acid. Gradient:
TABLE-US-00010 Gradient - Time flow mL/min % A % B 0.00 1.2 100 0
0.90 1.2 40 60 1.5 1.2 40 60 2.0 1.2 100 0
[0619] Detection--UV (220 nm)
[0620] MS ionisation method--ESI.sup.+
[0621] LC-MS Method 10: SHIMADZU 20A HPLC with a C18-reverse-phase
column (30.times.2.1 mm Xtimate.TM.-C18, 3 .mu.m particle size),
elution with solvent A: water+0.038% trifluoroacetic acid; solvent
B: acetonitrile+0.02% trifluoroacetic acid. Gradient:
TABLE-US-00011 Gradient - Time flow mL/min % A % B 0.00 0.8 100 0
6.0 0.8 40 60 6.5 0.8 40 60 7.0 0.8 100 0
[0622] Detection--UV (220 nm)
[0623] MS ionisation method--ESI.sup.+
[0624] LC-MS Method 11: Agilent 1200 HPLC with an Xtimate C18
column (3 um, 30.times.2.1 mm), elution with A: water+0.038%
trifluoroacetic acid; B: acetonitrile+0.02% trifluoroacetic
acid.
TABLE-US-00012 Gradient - Time flow mL/min % A % B 0.00 1.2 90 10
0.90 1.2 20 80 1.50 1.2 90 10 2.00 1.2 90 10
[0625] Detection--MS, UV (PDA detector)
[0626] MS ionisation method--Electrospray (positive ion)
[0627] LC-MS Method 12: Agilent 1200 HPLC with an Xtimate C18
column (3 um, 30.times.2.1 mm), elution with A: water+0.0.sup.38%
trifluoroacetic acid; B: acetonitrile+0.02% trifluoroacetic
acid.
TABLE-US-00013 Gradient - Time flow mL/min % A % B 0.00 1.2 100 0
0.90 1.2 40 60 1.50 1.2 100 0 2.00 1.2 100 0
[0628] Detection--MS, UV (PDA detector)
[0629] MS ionisation method--Electrospray (positive ion)
[0630] LC-MS Method 13: Agilent 1200 HPLC with an Xtimate C18
column (3 um, 30.times.2.1 mm), elution with A: water+0.0.sup.38%
trifluoroacetic acid; B: acetonitrile+0.02% trifluoroacetic
acid.
TABLE-US-00014 Gradient - Time flow mL/min % A % B 0.00 0.8 100 0
1.35 0.8 40 60 2.25 0.8 100 0 3.00 0.8 100 0
[0631] Detection--MS, UV (PDA detector)
[0632] MS ionisation method--Electrospray (positive ion)
[0633] LC-MS Method 14: SHIMADZU 20A HPLC with a C18-reverse-phase
column (50.times.2.0 mm Shim-pack XR-ODS, 1.6 .mu.m particle size),
elution with solvent A: water+0.05% trifluoroacetic acid; solvent
B: acetonitrile+0.05% trifluoroacetic acid. Gradient:
TABLE-US-00015 Gradient - Time flow ml/min % A % B 0.01 0.7 90 10
2.20 0.7 0 100 3.20 0.7 0 100 3.30 0.7 90 10
[0634] Detection--UV (254 nm)
[0635] MS ionisation method--ESI.sup.+
[0636] LC-MS Method 15: SHIMADZU 20A HPLC with a C18-reverse-phase
column (50.times.3.0 mm Shim-pack XR-ODS, 1.6 .mu.m particle size),
elution with solvent A: water+0.05% trifluoroacetic acid; solvent
B: acetonitrile+0.05% trifluoroacetic acid. Gradient:
TABLE-US-00016 Gradient - Time flow mL/min % A % B 0.01 1.0 95 5
3.00 1.0 20 80 3.80 1.0 20 80 3.90 1.0 95 5
[0637] Detection--UV (254 nm)
[0638] MS ionisation method--ESI.sup.+
[0639] LC-MS Method 16: SHIMADZU 20A HPLC with a C18-reverse-phase
column (50.times.3.0 mm Shim-pack XR-ODS, 2.2 .mu.m particle size),
elution with solvent A: water+0.05% trifluoroacetic acid; solvent
B: acetonitrile+0.05% trifluoroacetic acid. Gradient:
TABLE-US-00017 Gradient - Time flow mL/min % A % B 0.01 1.0 95 5
4.20 1.0 25 75 5.20 1.0 25 75 5.30 1.0 95 5
[0640] Detection--UV (254 nm)
[0641] MS ionisation method--ESI.sup.+
[0642] LC-MS Method 17: SHIMADZU 20A HPLC with a C18-reverse-phase
column (50.times.3.0 mm Shim-pack XR-ODS, 2.2 .mu.m particle size),
elution with solvent A: water+0.05% trifluoroacetic acid; solvent
B: acetonitrile+0.05% trifluoroacetic acid. Gradient:
TABLE-US-00018 Gradient - Time flow mL/min % A % B 0.01 1.0 95 5
2.20 1.0 0 100 3.20 1.0 0 100 3.30 1.0 95 5
[0643] Detection--UV (254 nm)
[0644] MS ionisation method--ESI.sup.+
[0645] LC-MS Method 18: SHIMADZU LCMS-2020 HPLC column
(150.times.4.6 mm Venusil XBP Silica, 5.0 .mu.m particle size),
elution with solvent A: Hexane; solvent B:Ethanol.
TABLE-US-00019 Gradient - Time flow mL/min % A % B 0.01 1.0 80 20
6.00 1.0 0 100 12.0 1.0 0 100
[0646] Detection--UV (254 nm)
[0647] MS ionisation method--ESI.sup.+
[0648] LC-MS Method 19: SHIMADZU 20A HPLC with a C18-reverse-phase
column (50.times.3 mm Xtimate.TM.-C18, 2.2 .mu.m particle size),
elution with solvent A: water+0.05% trifluoroacetic acid; solvent
B: acetonitrile+0.05% trifluoroacetic acid. Gradient:
TABLE-US-00020 Gradient - Time flow ml/min % A % B 0.00 1.0 95 5
2.00 1.0 0 100 3.10 1.0 0 100 3.30 1.0 95 5
[0649] Detection--UV (220 and 254 nm)
[0650] MS ionization method--Electrospray (positive ion)
[0651] LC-MS Methods 20: SHIMADZU 20A HPLC with a C18-reverse-phase
column (50.times.3 mm Xtimate.TM.-C18, 2.2 .mu.m particle size),
elution with solvent A: water+0.05% trifluoroacetic acid; solvent
B: acetonitrile+0.05% trifluoroacetic acid. Gradient:
TABLE-US-00021 Gradient - Time flow ml/min % A % B 0.00 1.0 95 5
2.00 1.0 0 100 3.20 1.0 0 100 3.30 1.0 95 5
[0652] Detection--UV (220 and 254 nm)
[0653] MS ionization method--Electrospray (positive ion)
[0654] LC-MS Method 21: SHIMADZU 20A HPLC with a C18-reverse-phase
column (50.times.3 mm Xtimate.TM.-C18, 2.2 .mu.m particle size),
elution with solvent A: water+0.05% trifluoroacetic acid; solvent
B: acetonitrile+0.05% trifluoroacetic acid. Gradient:
TABLE-US-00022 Gradient - Time flow ml/min % A % B 0.00 1.0 95 5
2.00 1.0 0 100 3.20 1.0 0 100 3.30 1.0 95 5
[0655] Detection--UV (220 and 254 nm)
[0656] MS ionization method--Electrospray (positive ion)
[0657] LC-MS Method 22: SHIMADZU 20A HPLC with a C18-reverse-phase
column (50.times.3 mm Xtimate.TM.-C18, 2.2 .mu.m particle size),
elution with solvent A: water+0.05% formic acid; solvent B:
acetonitrile+0.05% formic acid. Gradient:
TABLE-US-00023 Gradient - Time flow ml/min % A % B 0.00 1.0 95 5
1.20 1.0 0 100 2.20 1.0 0 100 2.30 1.0 95 5
[0658] Detection--UV (220 and 254 nm)
[0659] MS ionization method--Electrospray (positive ion)
[0660] LC-MS Method 23: SHIMADZU 20A HPLC with a C18-reverse-phase
column (50.times.3 mm Xtimate.TM.-C18, 2.2 .mu.m particle size),
elution with solvent A: water+0.1% formic acid; solvent B:
acetonitrile+0.05% formic acid. Gradient:
TABLE-US-00024 Gradient - Time flow ml/min % A % B 0.00 1.0 95 5
2.00 1.0 0 100 3.10 1.0 0 100 3.20 1.0 95 5
[0661] Detection--UV (220 and 254 nm)
[0662] MS ionization method--Electrospray (positive ion)
[0663] LC-MS Method 24: SHIMADZU 20A HPLC with a C18-reverse-phase
column (50.times.3 mm Xtimate.TM.-C18, 2.2 .mu.m particle size),
elution with solvent A: water+0.04% ammonium hydroxide; solvent B:
acetonitrile. Gradient:
TABLE-US-00025 Gradient - Time flow ml/min % A % B 0.00 1.2 95 5
1.20 1.2 0 100 2.20 1.2 0 100 2.30 1.2 95 5
[0664] Detection--UV (220 and 254 nm)
[0665] MS ionization method--Electrospray (positive ion)
[0666] LC-MS Method 25: SHIMADZU 20A HPLC with a C18-reverse-phase
column (30.times.2.1 mm Xtimate.TM.-C18, 3 .mu.m particle size),
elution with solvent A: water+0.05% trifluoroacetic acid; solvent
B: acetonitrile+0.05% trifluoroacetic acid. Gradient:
TABLE-US-00026 Gradient - Time flow ml/min % A % B 0.00 1.0 95 5
1.10 1.0 0 100 1.60 1.0 0 100 1.70 1.0 95 5
[0667] Detection--UV (220 and 254 nm)
[0668] MS ionization method--Electrospray (positive ion)
[0669] LC-MS Method 26: SHIMADZU 20A HPLC with a C18-reverse-phase
column (50.times.3.0 mm Xtimate.TM.-C18, 2.6 .mu.m particle size),
elution with solvent A: Water/0.1% formic acid; solvent B:
Acetonitrile/0.1% formic acid. Gradient:
TABLE-US-00027 Gradient - Time flow ml/min % A % B 0.00 1.5 90 10
2.00 1.5 0 100 2.70 1.5 0 100 2.8 1.5 90 10
[0670] Detection--UV (220 and 254 nm)
[0671] MS ionization method--Electrospray (positive ion)
[0672] LC-MS Method 27: SHIMADZU 20A HPLC with a C18-reverse-phase
column (50.times.2.1 mm Xtimate.TM.-C18, 2.7 .mu.m particle size),
elution with solvent A: Water/0.05% formic acid; solvent B:
Acetonitrile/0.1% formic acid:
TABLE-US-00028 Gradient - Time flow ml/min % A % B 0.00 1.0 95 5
2.00 1.0 5 95 2.70 1.0 5 95 2.8 1.0 95 5
[0673] Detection--UV (220 and 254 nm)
[0674] MS ionization method--Electrospray (positive ion)
[0675] LC-MS Method 28: SHIMADZU 20A HPLC with a C18-reverse-phase
column (50.times.3.0 mm Xtimate.TM.-C18, 2.5 .mu.m particle size),
elution with solvent A: Water/5 mM NH.sub.4HCO.sub.3; solvent B:
Acetonitrile:
TABLE-US-00029 Gradient - Time flow ml/min % A % B 0.00 1.5 90 10
2.10 1.5 5 95 2.70 1.5 5 95 3.0 1.5 95 5
[0676] Detection--UV (220 and 254 nm)
[0677] MS ionization method--Electrospray (positive ion)
[0678] LC-MS Methods 29: SHIMADZU LCMS-2020 C18 reverse-phase
column (50.times.3.0 mm, Shim-pack XR-ODS, 2.5 .mu.m particle
size), elution with solvent A: Water/0.05% TFA.sub.3; solvent B:
Acetonitrile/0.05% TFA:
TABLE-US-00030 Gradient - Time flow ml/min % A % B 0.00 1.0 95 5
2.20 1.0 5 95 3.20 1.0 5 95 3.30 1.0 95 5
[0679] Detection--UV (220 and 254 nm)
[0680] MS ionization method--Electrospray (positive ion)
[0681] LC-MS Methods 30: SHIMADZU LCMS-2020 C18 reverse-phase
column (50.times.2.1 mm, Shiseido CAPCELL CORE C18, 2.7 .mu.m
particle size), elution with solvent A: Water/0.05% TFA.sub.3;
solvent B: Acetonitrile/0.05% TFA:
TABLE-US-00031 Gradient - Time flow ml/min % A % B 0.00 1.0 95 5
2.0 1.0 5 95 2.75 1.0 5 95 2.80 1.0 95 5
[0682] Detection--UV (220 and 254 nm)
[0683] MS ionization method--Electrospray (positive ion)
[0684] LC-MS Methods 31: SHIMADZU LCMS-2020 C18 reverse-phase
column (50.times.2.1 mm, Waters BEH C18, 1.7 .mu.m particle size),
elution with solvent A: Water/0.1% TFA.sub.3; solvent B:
Acetonitrile/0.1% TFA:
TABLE-US-00032 Gradient - Time flow ml/min % A % B 0.00 0.7 90 10
3.50 0.7 5 95 4.60 0.7 5 95 4.70 0.7 90 10
[0685] Detection--UV (220 and 254 nm)
[0686] MS ionization method--Electrospray (positive ion)
[0687] LC-MS Methods 32: SHIMADZU LCMS-2020 C18 reverse-phase
column (50.times.3.0 mm, Gemini-NX 3.mu. C18 110A, 3.0 .mu.m
particle size), elution with solvent A: Water/6.5 mM
NH.sub.4HCO.sub.3 pH10; solvent B: Acetonitrile
TABLE-US-00033 Gradient - Time flow ml/min % A % B 0.00 1.2 95 5
0.50 1.2 95 5 2.20 1.2 5 95 3.00 1.2 5 95 3.20 1.2 90 10
[0688] Detection--UV (220 and 254 nm)
[0689] MS ionization method--Electrospray (positive ion)
[0690] LC-MS Methods 33: SHIMADZU LCMS-2020 C18 reverse-phase
column (50.times.2.1 mm, Waters BEH C18, 1.7 .mu.m particle size),
elution with solvent A: Water/0.05% TFA.sub.3; solvent B:
Acetonitrile/0.05% TFA:
TABLE-US-00034 Gradient - Time flow ml/min % A % B 0.00 0.7 95 5
2.00 0.7 5 95 2.60 0.7 5 95 2.70 0.7 95 5
[0691] Detection--UV (220 and 254 nm)
[0692] MS ionization method--Electrospray (positive ion)
[0693] LC-MS Methods 34: SHIMADZU LCMS-2020 C18 reverse-phase
column (50.times.2.1 mm, Waters BEH C18, 1.7 .mu.m particle size),
elution with solvent A: Water/0.05% TFA.sub.3; solvent B:
Acetonitrile/0.05% TFA:
TABLE-US-00035 Gradient - Time flow ml/min % A % B 0.00 0.7 95 5
4.00 0.7 20 80 5.00 0.7 20 80 5.20 0.7 95 5
[0694] Detection--UV (220 and 254 nm)
[0695] MS ionization method--Electrospray (positive ion)
[0696] LC-MS Methods 35: SHIMADZU LCMS-2020 C18 reverse-phase
column (50.times.3.0 mm, Shim-pack XR-ODS, 2.2 .mu.m particle
size), elution with solvent A: Water/0.05% TFA.sub.3; solvent B:
Acetonitrile/0.05% TFA:
TABLE-US-00036 Gradient - Time flow ml/min % A % B 0.00 1.0 95 5
3.20 1.0 40 60 3.80 1.0 0 100 4.70 1.0 0 100 4.80 1.0 95 5
[0697] Detection--UV (220 and 254 nm)
[0698] MS ionization method--Electrospray (positive ion)
[0699] LC-MS Methods 36: SHIMADZU 20A HPLC with a C18-reverse-phase
column (50.times.3.0 mm, Gemini-NX 3.mu. C18 110A, 3.0 .mu.m
particle size), elution with solvent A: Water/5 mM
NH.sub.4HCO.sub.3; solvent B: Acetonitrile:
TABLE-US-00037 Gradient - Time flow ml/min % A % B 0.00 1.2 90 10
4.00 1.2 40 60 5.20 1.2 40 60 5.30 1.2 90 10
[0700] Detection--UV (220 and 254 nm)
[0701] MS ionization method--Electrospray (positive ion)
[0702] LC/MS Methods 37: Agilent 10-min LCMS method:
[0703] Experiments performed on an Agilent 1100 HPLC coupled with
Agilent MSD mass spectrometer using ESI as ionization source. The
LC separation was using a Phenomenex XB-C18, 1.7 um, 50.times.2.1
mm column with a 0.4 ml/minute flow rate. Solvent A is water with
0.1% FA and solvent B is acetonitrile with 0.1% FA. The gradient
consisted with 2-98% solvent B over 7 min and hold 97% B for 1.5
min following equilibration for 1.5 min. LC column temperature is
40.degree. C. UV absorbance was collected at 220 nm and 254 nm and
mass spec full scan was applied to all experiments.
[0704] LC/MS Methods 38: Waters 10-min LCMS method:
[0705] Experiments performed on a Waters Acquity UPLC with Waters
LCT Premier XE mass spectrometer using ESI as ionization source.
The LC separation was using an Acquity UPLC BEH C18, 1.7 um,
2.1.times.50 mm column and a 0.6 ml/minute flow rate. Solvent A is
water with 0.050% TFA and solvent B is acetonitrile with 0.05% TFA
The gradient consisted of 2-980% solvent B over 7 min and hold 98%
B for 1.5 min following equilibration for 1.5 min. LC column
temperature is 40.degree. C. UV absorbance was collected at 220 nm
and 254 nm and mass spec full scan was applied to all
experiments.
[0706] LC/MS Methods 39: Shimadzu 5-min LCMS method:
[0707] Experiments performed on a Shimadzu LC with LC-30AD solvent
pump, SPD-M30A UV detector and 2020 MS using both ESI and APCI as
ionization source. The LC separation was using a Waters UPLC BEH
C18, 1.7 mm, 2.1.times.50 mm column and a 0.7 ml/minute flow rate.
Solvent A is water with 0.1% FA and solvent B is acetonitrile with
0.1% F A. The gradient consisted of 2-98% solvent B over 4.5 min
and hold 98% B for 0.5 min following equilibration for 0.5 min. LC
column temperature is 40.degree. C. UV absorbance was collected at
254 nm and mass spec full scan was applied to all experiments.
Preparative Mass Directed Automated Purification Conditions
[0708] MDAP Method 1: Agilent 1260 infinity purification system.
Agilent 6100 series single Quadrupole LC/MS. XSEELECT CSH Prep C18
5 .mu.m OBD, 30.times.150 mm, RT. Elution with solvent A: 0.1%
aqueous formic acid; solvent B: 0.1% formic acid in acetonitrile 60
ml/min. 10%-95%, 22 min, centred around a specific focused
gradient. Injection of a 20-60 mg/ml solution in DMSO (+optional
formic acid and water)
[0709] MDAP Method 2: Agilent 1260 infinity purification system.
Agilent 6100 series single Quadrupole LC/MS. XBridge Prep C18 5
.mu.m OBD, 30.times.150 mm, RT. Elution with solvent A: 0.1%
aqueous ammonia; solvent B: 0.1% ammonia in acetonitrile 60 ml/min.
10%-95%, 22 min, centred around a specific focused gradient.
Injection of a 20-60 mg/ml solution in DMSO (+optional formic acid
and water)
Abbreviations
[0710] CH.sub.3OD Deuterated Methanol [0711] CDCl.sub.3 Deuterated
Chloroform [0712] DCM Dichloromethane [0713] DIPEA
Diisopropylethylamine [0714] DMAP 4-Dimethylaminopyridine [0715]
DMF Dimethylformamide [0716] DMSO Dimethylsulfoxide [0717] DMSO-d6
Deuterated dimethylsulfoxide [0718] EtOAc Ethyl acetate [0719] EtOH
Ethanol [0720] HOAc Acetic acid [0721] g Gram [0722] HATU
(O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluorophosphate) [0723] HCl Hydrochloric acid [0724] IMS
Industrial methylated spirits [0725] L Litre [0726] MDAP Mass
directed automated purification [0727] MeOH Methanol [0728] mg
Milligram [0729] mL Millilitre [0730] SCX-2 Strong cation exchange
[0731] THF Tetrahydrofuran [0732] TFA Trifluoroacetic acid
Example A
##STR00603##
[0733] Pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
[3-(5-chloro-2-difluoromethoxyphenyl)-1H-pyrazol-4-yl]amide
[0734] To a solution of 2-bromo-4-chlorophenol (4.98 g, 24.0 mmol)
in DMF (25 mL) was added sodium chlorodifluoroacetate (8.42 g, 55.2
mmol), cesium carbonate (10.97 g, 33.67 mmol) and water (2.5 mL).
The reaction was stirred at 100.degree. C. for 16 hours. The
reaction mixture was partitioned between ethyl acetate and water,
the organic portion washed with brine, dried (MgSO.sub.4), and
evaporated. The crude product was purified by flash chromatography
on silica eluting with 0-20% EtOAc in heptanes to yield
2-bromo-4-chloro-1-(difluoromethoxy)benzene as a clear, colorless
oil (2.98 g, 48%). LCMS (ESI) no m/z signal; .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta.: (ppm) 7.90 (d, 1H), 7.54 (dd, 1H), 7.38 (d,
1H), 7.28 (t, 1H).
[0735] To a solution of
4-nitro-1-(2-trimethylsilanylethoxymethyl)-1H-pyrazole (preparation
described in WO2011003065) (46.5 g, 191 mmol) in DMA (350 mL) was
added 2-bromo-4-chloro-1-difluoromethoxybenzene (64.0 g, 248 mmol),
palladium (II) acetate (2.15 g, 9.6 mmol),
di-(adamantyl)-n-butylphosphine (5.0 g, 13.4 mmol), potassium
carbonate (79.2 g, 573 mmol) and trimethylacetic acid (5.27 g, 51.6
mmol). The mixture was degassed with nitrogen for 10 minutes then
heated at 130.degree. C. for 8 hours. The reaction mixture was
allowed to cool to room temperature, diluted with ethyl acetate and
washed with water and brine, dried (MgSO.sub.4), filtered and
evaporated. The resultant crude material was purified by flash
chromatography on silica eluting with 0-10% EtOAc in cyclohexane to
afford
5-(5-chloro-2-difluoromethoxyphenyl)-4-nitro-1-(2-trimethylsilanylethoxym-
ethyl)-1H-pyrazole (62.4 g, 78%). .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta.: (ppm) 8.24 (s, 1H), 7.52-7.53 (m, 2H), 6.39 (t, 1H),
5.29-5.30 (m, 2H), 3.63-3.64 (m, 2H), 0.90 (s, 9H).
[0736] To a solution of
5-(5-chloro-2-difluoromethoxyphenyl)-4-nitro-1-(2-trimethylsilanylethoxym-
ethyl)-1H-pyrazole (62 g, 148 mmol) in ethanol (600 mL) was added
water (200 mL), ammonium chloride (32 g, 590 mmol) and iron powder
(41 g, 740 mmol). The mixture was heated at 80.degree. C. for 2
hours then allowed to cool to room temperature. The residual solid
was removed by filtration through Celite.RTM.. The filtrate was
evaporated under reduced pressure, diluted with water and extracted
twice with DCM. The combined organic extracts were washed with
water and brine, dried (MgSO.sub.4) and evaporated to afford a dark
oil. The oil was purified by flash chromatography on silica eluting
with 0-25% EtOAc in DCM. Appropriate fractions were collected and
the solvent removed in-vacuo to afford
5-(5-chloro-2-difluoromethoxyphenyl)-1-(2-trimethylsilanyl-ethoxymethyl)--
1H-pyrazol-4-ylamine as a brown oil (30.8 g, 54%). .sup.1H NMR (400
MHz, CDCl.sub.3) .delta.: (ppm) 7.56 (d, 1H), 7.44 (dd, 1H), 7.34
(s, 1H), 7.30-7.25 (m, 1H), 6.37 (t, 1H), 5.29 (s, 2H), 3.56 (t,
2H), 0.88 (dd, 2H), 0.00 (s, 9H).
[0737] A solution of
5-(5-chloro-2-difluoromethoxyphenyl)-1-(2-trimethylsilanyl-ethoxymethyl)--
1H-pyrazol-4-ylamine (60.0 g, 154 mmol) in THF (100 mL) was added
dropwise over 30 minutes to an ice/water cooled mixture of
pyrazolo[1,5-a]pyrimidine-3-carbonyl chloride (27.8 g, 153 mmol),
and DIPEA (49.5 g, 383 mmol) in THF (300 mL). On complete addition
the mixture was left to stir at room temperature for 1 hour. The
solvent was evaporated and the residue diluted with 0.5 N aqueous
HCl and extracted with ethyl acetate. The combined organic extract
was passed through Celite.RTM. to remove the residual solid and the
filtrate washed with 1M aqueous K.sub.2CO.sub.3, water and brine,
dried (Na.sub.2SO.sub.4) and evaporated to give a red solid. The
solid was triturated with 10% diethyl ether in cyclohexane. The
solid was collected by filtration, washed with 1:1 diethyl ether in
cyclohexane and left to air dry to afford
pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
[5-(5-chloro-2-difluoromethoxyphenyl)-1-(2-trimethylsilanylethoxymethyl)--
1H-pyrazol-4-yl]amide as an off-white solid (59.2 g, 73%). .sup.1H
NMR (300 MHz, CDCl.sub.3): .delta. (ppm) 9.61 (s, 1H), 8.77-8.78
(m, 1H), 8.51 (dd, 1H), 8.36 (s, 1H), 7.65 (d, 1H), 7.52 (dd, 1H),
7.36 (d, 1H), 7.29 (s, 1H), 7.01 (dd, 1H), 6.42 (t, 1H), 5.39-5.41
(m, 2H), 3.60-3.64 (m, 2H), 0.87-0.89 (m, 2H), 0.09 (s, 9H).
[0738] A suspension of pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
[5-(5-chloro-2-difluoromethoxyphenyl)-1-(2-trimethylsilanylethoxymethyl)--
1H-pyrazol-4-yl] amide (59.0 g, 110 mmol) in methanol (420 mL) was
treated with 6N HCl (80 mL) and the mixture heated at 60.degree. C.
for 4 hours. The solvent was evaporated and the residue triturated
with water. The solid was collected by filtration, washed with
water and left to air dry. The solid was triturated with a minimum
volume of acetonitrile, collected by filtration, washed with
diethyl ether and dried at 60.degree. C. under high vacuum to
afford the title compound as a yellow solid (42.9 g, 96%). .sup.1H
NMR (400 MHz, DMSO-d.sub.6) .delta.: (ppm) 9.71 (s, 1H), 9.34 (dd,
1H), 8.68-8.69 (m, 1H), 8.66 (s, 1H), 8.25 (s, 1H), 7.62 (dd, 2H),
7.43-7.46 (m, 1H), 7.29 (dd, 1H), 7.23 (d, 1H).
Example B
##STR00604##
[0739] tert-Butyl
(3-((3-(5-chloro-2-(difluoromethoxy)phenyl)-1H-pyrazol-4-yl)carbamoyl)pyr-
azolo[1,5-a]pyrimidin-2-yl)carbamate
[0740] To a solution of compound
2-tert-butoxycarbonylamino-pyrazolo[1,5-a]pyrimidine-3-carboxylic
acid (2.78 g, 0.01 mol) in DMF (40 mL) was added DIPEA (3.9 g, 0.03
mol), HATU (3.8 g, 0.01 mol) and
5-(5-chloro-2-difluoromethoxyphenyl)-1H-pyrazol-4-ylamine (2.6 g,
0.01 mmol), and the reaction mixture was stirred at room
temperature overnight. The reaction mixture was poured into water
and the precipitate was collected to give the target compound as a
solid (4 g, 77%). LCMS (Method 7) [M+Na].sup.+=541.9, R.sub.T=1.20
min. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.: (ppm) 13.13 (s,
1H), 9.58 (s, 2H), 9.2 (dd, 1H, J=7.2, 1.6 Hz), 8.58 (d, 1H, J=2),
8.27 (s, 1H), 7.60 (m, 2H), 7.23-7.04 (m, 3H), 1.48 (s, 9H).
Example C
##STR00605##
[0741]
{3-(5-Chloro-2-difluoromethoxyphenyl)-4-[(pyrazolo[1,5-a]pyrimidine-
-3-carbonyl)amino]pyrazol-1-yl}acetic acid
[0742] A solution of pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
[3-(5-chloro-2-difluoromethoxyphenyl)-1H-pyrazol-4-yl]amide (42.0
g, 104 mmol) in DMF (400 mL) was treated with cesium carbonate
(37.2 g, 114 mmol) and tert-butyl-bromoacetate (22.3 g, 114 mmol)
and was left to stir at room temperature for 18 hours. The reaction
mixture was diluted with water and extracted twice with ethyl
acetate. The combined organic extract was washed with water and
brine, dried (Na.sub.2SO.sub.4), filtered and evaporated to afford
an orange solid. The resultant solid was triturated with diethyl
ether then recrystallised from acetone to afford a white solid
(33.2 g, 62%). The mother liquors were combined and evaporated to
afford an orange oil. The residual oil was purified by flash
chromatography on silica eluting with 0-50% EtOAc in DCM.
Appropriate fractions were combined and evaporated to afford a
white solid (12.3 g, 23%). Combined yield of
{3-(5-chloro-2-difluoromethoxyphenyl)-4-[(pyrazolo[1,5-a]pyrimidine-3-car-
bonyl)amino]pyrazol-1-yl}acetic acid tert-butyl ester (45.2 g,
85%). LCMS (Method 3) [M+H].sup.+=519.1, R.sub.T=3.72 min. .sup.1H
NMR (400 MHz, CDCl.sub.3) .delta.: (ppm) 9.86 (s, 1H), 8.75-8.76
(m, 2H), 8.56 (dd, 1H), 8.40 (s, 1H), 7.70 (d, 1H), 7.42 (dd, 1H),
6.99 (dd, 1H), 6.47 (t, 1H), 4.86 (s, 2H), 1.49 (s, 9H).
[0743] To a solution of
{3-(5-chloro-2-difluoromethoxyphenyl)-4-[(pyrazolo[1,5-a]pyrimidine-3-car-
bonyl)amino]pyrazol-1-yl}acetic acid tert-butyl ester (45.0 g, 86.7
mmol) in dichloromethane (350 mL) was added TFA (100 mL) and the
mixture left to stir at room temperature for 18 hours. The solvent
was evaporated and the resultant residue triturated with diethyl
ether. The resultant solid was collected by filtration, washed with
diethyl ether and left to air dry to afford the title compound as a
white solid (40.0 g, 99%). LCMS (Method 3) [M+H].sup.+=463.1,
R.sub.T=2.89 min. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.: (ppm)
9.86 (s, 1H), 8.78 (dd, 1H), 8.71 (s, 1H), 8.56 (dd, 1H), 8.40 (s,
1H), 7.70 (d, 1H), 7.42 (dd, 1H), 7.30 (s, 1H), 6.99 (dd, 1H), 6.47
(t, 1H), 4.86 (s, 2H), 1.49 (s, 9H).
Example D
##STR00606##
[0744]
[4-[(2-Amino-pyrazolo[1,5-a]pyrimidine-3-carbonyl)-amino]-3-(5-chlo-
ro-2-difluoromethoxy-phenyl)-pyrazol-1-yl]-acetic acid
[0745] A solution of tert-butyl
(3-((3-(5-chloro-2-(difluoromethoxy)phenyl)-1H-pyrazol-4-yl)carbamoyl)pyr-
azolo[1,5-a]pyrimidin-2-yl)carbamate (1.0 g, 1.92 mmol) in DMF (10
mL) was treated with cesium carbonate (0.69 g, 2.12 mmol) and
tert-butyl-bromoacetate (0.43 g, 2.12 mmol) and was left to stir at
room temperature for 2.5 hours. The reaction mixture was diluted
with water and the resultant precipitate was collected by
filtration. The resultant solid was purified by flash
chromatography on silica eluting with 0-70% EtOAc in cyclohexane.
Appropriate fractions were combined and evaporated to afford
[4-[(2-tert-butoxycarbonylamino-pyrazolo[1,5-a]pyrimidine-3-car- b
onyl)-amino]-3-(5-chloro-2-difluoromethoxy-phenyl)-pyrazol-1-yl]-acetic
acid tert-butyl ester as a white solid (0.91 g, 74%). LCMS (Method
3) [M+H].sup.+=633.9, R.sub.T=4.46 min. .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta.: (ppm) 9.78 (s, 1H), 9.70 (s, 1H), 8.76 (dd,
1H, J=1.8, 6.8 Hz), 8.47 (dd, 1H, J=1.8, 4.3 Hz), 8.34 (s, 1H),
7.69 (d, 1H, J=2.5 Hz), 7.41 (dd, 1H, J=2.7, 8.7 Hz), 7.28 (d, 1H,
J=8.8 Hz), 6.92 (dd, 1H, J=4.4, 6.9 Hz), 6.47 (t, 1H, J=74.0 Hz),
4.85 (s, 2H), 1.56 (s, 9H), 1.49 (s, 9H).
[0746] To a solution of
[4-[(2-tert-butoxycarbonylamino-pyrazolo[1,5-a]pyrimidine-3-carbonyl)-ami-
no]-3-(5-chloro-2-difluoromethoxy-phenyl)-pyrazol-1-yl]-acetic acid
tert-butyl ester (0.91 g, 1.43 mmol) in dichloromethane (7 mL) was
added TFA (15 mL) and the mixture left to stir at room temperature
for 6 hours. The solvent was evaporated and the resultant residue
azeotroped with dichlormethane/methanol to afford the title
compound as a pale yellow solid (0.66 g, 97%). LCMS (Method 3)
[M+H].sup.+=477.8, R.sub.T=2.95 min. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta.: (ppm) 13.15 (br s, 1H), 9.56 (s, 1H), 8.93
(dd, 1H, J=1.5, 6.8 Hz), 8.37-8.34 (m, 1H), 8.35 (s, 1H), 7.63 (dd,
1H, J=2.8, 8.8 Hz), 7.56 (d, 1H, J=2.8 Hz), 7.46 (d, 1H, J=8.9 Hz),
7.26 (t, 1H, J=73.4 Hz), 7.00 (dd, 1H, J=4.5, 6.8 Hz), 6.58 (br s,
2H), 5.05 (s, 2H).
Example E
##STR00607##
[0747] Pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
[2-bromo-4-(5-chloro-2-difluoromethoxy-phenyl)-thiazol-5-yl]-amide
[0748] Sodium hydride (60% dispersion in mineral oil, 2.17 g, 54.2
mmol) was added portionwise to a stirred solution of
1-(5-chloro-2-methoxy-phenyl)-ethanone (10.0 g, 54.2 mmol) in THF
(100 mL) at 0.degree. C. The mixture was then stirred for 10
minutes before addition of diethyl carbonate (7.68 g, 65.0 mmol)
and then for an additional 1 hour. The mixture was warmed to room
temperature for 2 hours and then heated to 65.degree. C. for 2
hours. Diethyl ether was added, the organics washed with water and
brine, then evaporated to dryness. The resultant residue was
purified by flash chromatography on silica gel (50 to 100%
dichloromethane in cyclohexane) to yield 3.41 g of ethyl
3-(5-chloro-2-methoxyphenyl)-3-oxopropanoate. LCMS (method 1)
[M+H].sup.+=257.2, R.sub.T=3.55 min. .sup.1H NMR (400 MHz,
CDCl.sub.3): .delta. (ppm) 7.59 (d, 1H), 7.38 (dd, 1H), 6.89 (d,
1H), 4.18 (q, 2H), 3.95 (s, 2H), 3.88 (s, 3H), 1.24 (t, 3H).
[0749] Bromine (0.70 mL, 13.6 mmol) was added to a solution of
ethyl 3-(5-chloro-2-methoxyphenyl)-3-oxopropanoate (3.39 g, 13.2
mmol) in dioxane (25 mL) and stirred for 1 hour. The reaction was
poured onto ice water, extracted with ethyl acetate, the organics
washed with water and brine and evaporated to dryness to give ethyl
2-bromo-3-(5-chloro-2-methoxyphenyl)-3-oxopropanoate. LCMS (method
1) [M+H].sup.+=337.2, R.sub.T=3.84 min.
[0750] A mixture of ethyl
2-bromo-3-(5-chloro-2-methoxyphenyl)-3-oxopropanoate (assumed to be
13.2 mmol) and thiourea (1.01 g, 13.3 mmol) in ethanol (25 mL) were
heated to reflux for 3 hours, then cooled to room temperature for
18 hours. The resultant solid was removed by filtration and the
filtrate evaporated under vacuum. DCM was added to the residue, the
organics washed with sodium hydrogen carbonate (sat. aq.), water
and brine, and evaporated to dryness. The residue was triturated
(DCM) to give ethyl
2-amino-4-(5-chloro-2-methoxyphenyl)thiazole-5-carboxylate (1.30 g,
31%) as a yellow solid. LCMS (method 1) [M+H].sup.+=313.2,
R.sub.T=3.15 min. .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta.
(ppm) 7.77 (s, br, 2H), 7.39 (dd, 1H), 7.22 (d, 1H), 7.05 (d, 1H),
4.00 (q, 2H), 3.70 (s, 3H), 1.04 (t, 3H).
[0751] Copper bromide (1.07 g, 4.79 mmol) in acetonitrile (20 mL)
was degassed with nitrogen and cooled to 0.degree. C. before
addition of tert-butyl nitrite (0.80 mL, 6.00 mmol), then a
suspension of ethyl
2-amino-4-(5-chloro-2-methoxyphenyl)thiazole-5-carboxylate (1.25 g,
3.99 mmol) in acetonitrile (20 mL) was added and stirred at room
temperature for 18 hours. The reaction was concentrated under
vacuum, ethyl acetate added, the organics washed with sodium
hydrogen carbonate (sat. aq.) and brine, then evaporated to dryness
to give ethyl
2-bromo-4-(5-chloro-2-methoxyphenyl)thiazole-5-carboxylate (1.40 g,
93%). LCMS (method 1) [M+H].sup.+=378.1, R.sub.T=4.26 min. .sup.1H
NMR (400 MHz, DMSO-d.sub.6): .delta. (ppm) 7.50 (dd, 1H), 7.42 (d,
1H), 7.14 (d, 1H), 4.16 (q, 2H), 3.73 (s, 3H), 1.12 (t, 3H).
[0752] A mixture of ethyl
2-bromo-4-(5-chloro-2-methoxyphenyl)thiazole-5-carboxylate (1.40 g,
3.72 mmol), potassium hydroxide (278 mg) in THF (40 mL) and water
(10 mL) was stirred for 20 hours at ambient temperature. The
mixture was treated with 1M HCl aq. (ca. 8 mL, 2 eq.), DCM was
added, and the organics separated and evaporated to dryness to give
2-bromo-4-(5-chloro-2-methoxyphenyl)thiazole-5-carboxylic acid
(1.23 g, 95%) as a yellow solid. LCMS (method 2) [M+H].sup.+=350.1,
R.sub.T=3.28 min. .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta.
(ppm) 7.47 (dd, 1H), 7.39 (d, 1H), 7.13 (d, 1H), 3.73 (s, 3H).
[0753] 2-bromo-4-(5-chloro-2-methoxyphenyl)thiazole-5-carboxylic
acid (1.22 g, 3.50 mmol), diphenylphosphoryl azide (963 mg, 3.50
mmol) and triethylamine (354 mg, 3.50 mmol) in tert-butanol (30 mL)
were stirred at 85.degree. C. for 4 hours. After cooling, the
reaction was partitioned between ethyl acetate and water, the
organics separated then washed with brine, and evaporated to
dryness. The resulting residues were purified by flash
chromatography on silica gel (50 to 100% dichloromethane in
cyclohexane) to yield tert-butyl
2-bromo-4-(5-chloro-2-methoxyphenyl)thiazol-5-ylcarbamate (970 mg,
66%). LCMS (method 1) [M+H-.sup.tBu].sup.+=364.8, R.sub.T=4.61 min.
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. (ppm) 7.43 (dd, 1H),
7.30 (d, 1H), 7.11 (d, 1H), 3.77 (s, 3H), 1.45 (s, 9H).
[0754] TFA (4.0 mL) was added to a solution of tert-butyl
2-bromo-4-(5-chloro-2-methoxyphenyl)thiazol-5-ylcarbamate (360 mg,
0.86 mmol) in DCM (10 mL) and water (3 drops). The reaction mixture
was stirred for 1.5 hours at room temperature and then evaporated
to dryness. The residue was taken up into DCM and washed with
sodium hydrogen carbonate (sat. aq.), water and brine, and
concentrated under vacuum to give
2-bromo-4-(5-chloro-2-methoxyphenyl)thiazol-5-amine as an orange
residue. LCMS (method 1) [M+H].sup.+=321.3, R.sub.T=3.63 min.
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. (ppm) 7.36 (d, 1H),
7.34-7.32 (m, 1H), 7.10 (d, 1H), 3.83 (s, 3H).
[0755] Using 2-bromo-4-(5-chloro-2-methoxyphenyl)thiazol-5-amine
and pyrazolo[1,5-a]pyrimidine-3-carbonyl chloride the title
compound was prepared following the synthetic procedures described
for pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
[3-(5-chloro-2-difluoromethoxyphenyl)-1H-pyrazol-4-yl]amide with
further purification by flash chromatography on silica gel (0 to
40% ethyl acetate in DCM) to give
N-(2-bromo-4-(5-chloro-2-methoxyphenyl)thiazol-5-yl)pyrazolo[1,5-a]pyrimi-
dine-3-carboxamide. LCMS (method 1) [M+H].sup.+=465.8, R.sub.T=4.01
min. .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 10.68 (s, br,
1H), 9.41 (dd, 1H), 8.78 (s, 1H), 8.76 (dd, 1H), 7.57 (dd, 1H),
7.50 (d, 1H), 7.37-7.34 (m, 2H), 3.81 (s, 3H).
[0756] To a solution of pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
[2-bromo-4-(5-chloro-2-methoxy-phenyl)-thiazol-5-yl]-amide (4.3 g,
9.3 mmol) in DCM (90 mL) at -78.degree. C. under an atmosphere of
N.sub.2 was added boron tribromide (1M in DCM, 45 mL, 45 mmol)
dropwise. The mixture was stirred at -78.degree. C. for 1 hour and
then allowed slowly to room temperature and stirred for a further
16 hours. The mixture was poured cautiously onto an aqueous
solution of sodium hydrogen carbonate, stirred for 15 mins,
filtered and the solid collected and dried to afford
pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
[2-bromo-4-(5-chloro-2-hydroxy-phenyl)-thiazol-5-yl]-amide as a
beige solid (6 g, >100%). LCMS (Method 3) [M+H].sup.+=450.1,
R.sub.T=3.71 min. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.:
15.96 (s, 1H), 9.18 (dd, 1H, J=1.6, 6.9 Hz), 8.70 (dd, 1H, J=1.8,
4.0 Hz), 8.59 (s, 1H), 7.80 (d, 1H, J=2.8 Hz), 7.15 (dd, 1H, J=4.0,
7.1 Hz), 7.05 (dd, 1H, J=2.8, 8.6 Hz), 6.77 (d, 1H, J=8.6 Hz).
[0757] To a solution of pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
[2-bromo-4-(5-chloro-2-hydroxy-phenyl)-thiazol-5-yl]-amide (1.1 g,
2.4 mmol) in DMF (20 mL) and water (2 mL) was added cesium
carbonate (1.1 g, 3.4 mmol) and then sodium chlorodifluoroacetate
(839 mg, 5.5 mmol). The mixture was stirred at 100.degree. C. for
16 hours before further cesium carbonate (2.2 g, 6.8 mmol) and
sodium chlorodifluoroacetate (1.7 g, 11 mmol) was added and
stirring continued at 100.degree. C. for 6 hours. The mixture was
allowed to cool to room temperature and partitioned between ethyl
acetate and water and the phases separated. The organic layer was
washed with brine. The combined aqueous layer was extracted with
ethyl acetate once and the combined organic layer dried
(Na.sub.2SO.sub.4), filtered and evaporated. The resultant residue
was purified by flash chromatography on silica eluting with 50%
ethyl acetate in cyclohexane to give the title compound as a yellow
solid (710 mg, 59%). LCMS (Method 3) [M+H].sup.+=500.1,
R.sub.T=3.97 min. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.:
10.84 (s, 1H), 9.42 (dd, 1H, J=1.6, 6.9 Hz), 8.79 (s, 1H), 8.66
(dd, 1H, J=1.6, 4.3 Hz), 7.76 (d, 1H, J=2.8 Hz), 7.51 (d, 1H, J=8.8
Hz), 7.36 (dd, 1H, J=4.2, 7.0 Hz), 7.22 (t, 1H, J=73.1 Hz).
Example 1
##STR00608##
[0758] Pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
[3-(5-chloro-2-difluoromethoxyphenyl)-1-piperidin-4-yl-1H-pyrazol-4-yl]am-
ide hydrochloride
[0759] Pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
[3-(5-chloro-2-difluoromethoxyphenyl)-1H-pyrazol-4-yl]amide (200
mg, 0.49 mmol) was dissolved in DMF (5 mL),
4-(toluene-4-sulfonyloxy)piperidine-1-carboxylic acid tert-butyl
ester (263 mg, 0.74 mmol) and cesium carbonate (240 mg, 0.74 mmol)
were added and the mixture heated at 90.degree. C. for 2 hours. The
mixture was allowed to cool to room temperature, diluted with water
and extracted with DCM (.times.3). The combined organic extract was
washed with brine, dried (Na.sub.2SO.sub.4), filtered and
evaporated. The resultant yellow oil was purified by flash
chromatography on silica eluting with 0-2% MeOH in DCM. The
appropriate fractions were collected and evaporated to afford
4-{3-(5-chloro-2-difluoromethoxyphenyl)-4-[(pyrazolo[1,5-a]pyrimidine-3-c-
arb onyl)amino]pyrazol-1-yl}piperidine-1-carboxylic acid tert-butyl
ester a yellow oil. The crude product was taken onto the next step
without further purification. LCMS (Method 4) [M+Na].sup.+=610.0;
R.sub.T=4.30 min.
[0760]
4-{3-(5-Chloro-2-difluoromethoxyphenyl)-4-[(pyrazolo[1,5-a]pyrimidi-
ne-3-carbonyl)amino]pyrazol-1-yl}piperidine-1-carboxylic acid
tert-butyl ester (600 mg, 0.97 mmol) was dissolved in DCM (3 mL)
and TFA (3 mL) was added. The mixture was allowed to stir at room
temperature for 30 minutes. The solvent was evaporated and the
residue was dissolved in MeOH and loaded onto an SCX-2 cartridge
which had been conditioned with MeOH. After flushing with MeOH, the
product was eluted with 2M ammonia in MeOH. Evaporation gave a
glass which was purified by HPLC (Method 3). Appropriate fractions
were combined and evaporated to afford an off-white solid. The
solid was dissolved in MeOH and 1.25M methanolic HCl (1 mL) was
added. The solvent was evaporated, azeotroped three times with
methanol and triturated with ethyl acetate to afford the title
compound as an off-white solid (144 mg, 28%). LCMS (Method 5)
[M+H].sup.+=488.0, R.sub.T=2.93 min. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta.: (ppm) 9.76 (s, 1H), 9.35 (dd, 1H, J=1.6, 7.0
Hz), 8.98 (d, 1H, J=9.9 Hz), 8.69 (dd, 1H, J=1.7, 4.3 Hz), 8.67 (s,
1H), 8.38 (s, 1H), 7.65-7.62 (m, 2H), 7.30 (dd, 1H, J=4.2, 7.2 Hz),
7.26 (t, 1H, J=73.6 Hz), 4.66-4.57 (m, 1H), 3.47-3.42 (m, 2H),
3.17-3.03 (m, 2H), 2.32-2.18 (m, 4H).
Example 2
##STR00609##
[0761] 2-Amino-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
[3-(5-chloro-2-difluoromethoxy-phenyl)-1-piperidin-4-yl-1H-pyrazol-4-yl]--
amide
[0762] The title compound was prepared from tert-butyl
(3-((3-(5-chloro-2-(difluoromethoxy)phenyl)-1H-pyrazol-4-yl)carbamoyl)pyr-
azolo[1,5-a]pyrimidin-2-yl) carbamate following the procedure
outlined in Example 1 to afford an amber solid. LCMS (Method 3)
[M+H].sup.+=503.3, R.sub.T=2.32 min. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta.: (ppm) 9.55 (s, 1H), 8.93 (dd, 1H, J=1.5, 6.8
Hz), 8.37 (dd, 1H, J=1.5, 4.5 Hz), 8.29 (s, 1H), 7.64-7.58 (m, 2H),
7.44 (d, 1H, J=8.7 Hz), 7.25 (t, 1H, J=73.5 Hz), 7.00 (dd, 1H,
J=4.5, 6.7 Hz), 6.57 (s, 2H), 4.33-4.22 (m, 1H), 3.07 (d, 2H,
J=12.6 Hz), 2.66-2.57 (m, 2H), 2.06-1.96 (m, 2H), 1.89-1.75 (m,
2H).
Example 3
##STR00610##
[0763] Cis-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
{3-(5-chloro-2-difluoromethoxyphenyl)1-[2-(5-methylhexahydropyrrolo[3,4-c-
]pyrrol-2-yl)-2-oxoethyl]-1H-pyrazol-4-yl}amide
[0764] A solution of
{3-(5-chloro-2-difluoromethoxyphenyl)-4-[(pyrazolo[1,5-a]pyrimidine-3-car-
bonyl)amino]pyrazol-1-yl}acetic acid (20.0 g, 43.2 mmol) in DMF
(150 mL) was treated with DIPEA (6.7 g, 5.2 mmol),
cis-2-methyloctahydropyrrolo[3,4-c]pyrrole (6.27 g, 49.7 mmol) and
HATU (18.9 g, 49.7 mmol) and the mixture left to stir at room
temperature for 1 hour. The reaction mixture was diluted with 0.5M
aqueous K.sub.2CO.sub.3 solution and extracted with ethyl acetate
(.times.2). The combined organic extract was washed with water
(.times.2) and brine, dried (Na.sub.2SO.sub.4) and evaporated to
afford a solid. The resultant solid was purified by flash
chromatography on silica eluting with 0-10% 2M NH.sub.3/MeOH in
DCM. Collecting appropriate fractions, followed by evaporation gave
the title compound as a cream solid (17.1 g, 69%). LCMS (Method 5)
[M+H].sup.+=570.9, R.sub.T=2.82. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta.: (ppm) 9.70 (s, 1H), 9.30 (dd, 1H, J=7.0, 1.6
Hz), 8.62-8.63 (m, 2H), 8.27 (s, 1H), 7.59 (dd, 1H, J=8.8, 2.7 Hz),
7.52 (d, 1H, J=2.7 Hz), 7.42 (d, 1H, J=8.8 Hz), 7.25 (dd, 1H,
J=7.0, 4.2 Hz), 7.11 (t, 1H, J=73.3 Hz), 5.07 (d, 2H, J=5.9 Hz),
3.69 (dd, 1H, J=10.8, 8.6 Hz), 3.56 (dd, 1H, J=12.2, 8.8 Hz), 3.36
(dd, 1H, J=10.8, 4.4 Hz), 3.22 (dd, 1H, J=12.3, 4.5 Hz), 2.45-2.46
(m, 3H), 2.37-2.39 (m, 3H), 2.17 (s, 3H).
Example 4
##STR00611##
[0765] Cis-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
{3-(5-chloro-2-difluoromethoxyphenyl)-1-[2-(hexahydropyrrolo[3,4-c]pyrrol-
-2-yl)-2-oxoethyl]-1H-pyrazol-4-yl}amide
[0766]
{3-(5-Chloro-2-difluoromethoxyphenyl)-4-[(pyrazolo[1,5-a]pyrimidine-
-3-carbonyl)amino]pyrazol-1-yl}acetic acid (3.35 g, 7.25 mmol) was
dissolved in DMF (30 mL) and HATU (2.85 g, 9.42 mmol) was added.
cis-hexahydropyrrolo[3,4-c]pyrrole-2-carboxylic acid tert-butyl
ester (2.0 g, 9.42 mmol) and DIPEA (1.63 mL, 9.42 mmol) were added
and the mixture was stirred at room temperature for 17 hours. The
volatiles were evaporated and the resultant residue azeotroped with
toluene. The solid was partitioned between water and DCM and the
organic layer was separated, dried (Na.sub.2SO.sub.4) and
evaporated. The residue was dissolved in DCM (10 mL) and TFA (10
mL) was added. The solution was stirred at room temperature for 4
hours and then evaporated. The residue was dissolved in MeOH and
loaded onto an SCX-2 cartridge which had been conditioned with
MeOH. After flushing with MeOH, the product was eluted with 2M
ammonia in MeOH. The solvent was evaporated and the product was
crystallised from MeOH/Et.sub.2O. The desired product was obtained
as an off-white solid (3.7 g, 90%). LCMS (Method 5)
[M+H].sup.+=556.9, R.sub.T=2.83 min. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta.: (ppm) 9.76 (s, 1H), 9.35 (dd, 1H, J=1.6, 7.0
Hz), 9.38-9.22 (m, 2H), 8.69 (dd, 2H, J=1.7, 4.2 Hz), 8.67 (s, 1H),
8.31 (s, 1H), 7.64 (dd, 1H, J=2.7, 8.8 Hz), 7.56 (d, 1H, J=2.6 Hz),
7.47 (d, 1H, J=8.8 Hz), 7.30 (dd, 2H, J=4.3, 7.0 Hz), 7.27 (t, 1H,
J=73.4 Hz), 5.15 (s, 2H), 3.80-3.67 (m, 2H), 3.65-3.53 (m, 2H),
3.49-3.32 (m, 3H), 3.16-2.94 (m, 4H).
Example 5
##STR00612##
[0767] Cis pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
{3-(5-chloro-2-difluoromethoxyphenyl)-1-[2-(5
ethyl-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-2-oxoethyl]-1H-pyrazol-4-yl}am-
ide hydrochloride
[0768] To a solution of cis-pyrazolo[1,5-a]pyrimidine-3-carboxylic
acid
{3-(5-chloro-2-difluoromethoxyphenyl)-1-[2-(hexahydropyrrolo[3,4-c]pyrrol-
-2-yl)-2-oxoethyl]-1H-pyrazol-4-yl}amide (100 mg, 0.18 mmol) in
acetonitrile (4 mL) was added potassium carbonate (37 mg, 0.27
mmol) and bromoethane (20 .mu.L, 0.27 mmol). The reaction was
heated at 50.degree. C. for 2 hours and then allowed to cool to
room temperature. The mixture was applied directly to an SCX-2
cartridge. Elution with 2M ammonia in MeOH gave the desired
product. The product was purified by HPLC (Method 1) and the pure
fractions were combined as passed through an SCX-2 cartridge.
Elution with 2M ammonia in MeOH gave the free base on evaporation
of the solvent. The solid was dissolved in 1.25M methanolic HCl and
then the volatiles were evaporated. The HCl salt was crystallised
from MeOH/Et.sub.2O and obtained as a white solid (32 mg, 40%).
LCMS (Method 5) [M+H].sup.+=585.0, R.sub.T=2.88 min. .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta.: (ppm) 10.44 (d, 1H, J=35.0 Hz),
9.79-9.74 (m, 1H), 9.35 (dd, 1H, J=1.3, 7.0 Hz), 8.69 (dd, 1H,
J=1.5, 4.2 Hz), 8.67 (s, 1H), 8.31 (d, 1H, J=3.8 Hz), 7.64 (dd, 1H,
J=2.5, 8.8 Hz), 7.57 (d, 1H, J=2.6 Hz), 7.47 (d, 1H, J=8.9 Hz),
7.30 (dd, 1H, J=4.3, 7.0 Hz), 7.27 (t, 1H, J=73.6 Hz), 5.22-5.10
(m, 2H), 3.43 (s, 12H), 3.84-2.77 (m, 12H), 1.29-1.19 (m, 3H).
Example 6
##STR00613##
[0769] Cis-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
{3-(5-chloro-2-difluoromethoxyphenyl)-1-[2-(5-cyclopropylmethylhexahydrop-
yrrolo[3,4-c]pyrrol-2-yl)-2-oxoethyl]-1H-pyrazol-4-yl}amide
[0770] To a solution of cis-pyrazolo[1,5-a]pyrimidine-3-carboxylic
acid
{3-(5-chloro-2-difluoromethoxyphenyl)-1-[2-(hexahydropyrrolo[3,4-c]pyrrol-
-2-yl)-2-oxoethyl]-1H-pyrazol-4-yl}amide (100 mg, 0.18 mmol) in
2,2,2-trifluoroethanol (3 mL) was added cyclopropanecarbaldehyde
(67 .mu.L, 0.90 mmol). After stirring at room temperature for 15
minutes, sodium borohydride (21 mg, 0.54 mmol) was added and the
reaction was heated at 90.degree. C. for 2 hours. MeOH was added to
quench the reaction and the mixture was loaded onto an SCX-2
cartridge which had been conditioned with MeOH. After flushing with
MeOH, the product was eluted with 2M ammonia in MeOH. Evaporation
gave a crude product which was purified by HPLC (Method 1). The
pure fractions loaded onto an SCX-2 cartridge which had been
conditioned with MeOH. After flushing with MeOH, the product was
eluted with 2M ammonia in MeOH. Evaporation gave the title compound
as a free base which was crystallised from MeOH/Et.sub.2O and
obtained as a yellow solid (55 mg, 50%). LCMS (Method 5)
[M+H].sup.+=611.1, R.sub.T=3.02 min. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta.: (ppm) 10.94-10.88 (m, 1H), 9.57-9.55 (m,
1H), 8.95-8.92 (m, 1H), 8.38-8.35 (m, 1H), 8.29-8.28 (m, 1H),
7.65-7.61 (m, 1H), 7.56-7.54 (m, 1H), 7.47 (d, 1H, J=8.9 Hz),
7.45-7.07 (m, 1H), 7.08 (d, 1H, J=1.9 Hz), 7.02-6.99 (m, 1H),
5.24-5.07 (m, 2H), 3.86-3.52 (m, 5H), 3.52-3.22 (m, 2H), 3.17-3.11
(m, 1H), 3.07-3.00 (m, 2H), 3.00-2.79 (m, 1H), 1.27-1.01 (m, 1H),
0.63-0.56 (m, 2H), 0.42-0.34 (m, 2H).
(Atropisomers Present)
Example 7
##STR00614##
[0771] 5-Amino-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
{3-(5-chloro-2-difluoromethoxy-phenyl)-1-[2-((3aR,6aS)-5-methyl-hexahydro-
-pyrrolo[3,4-c]pyrrol-2-yl)-2-oxo-ethyl]-1H-pyrazol-4-yl)}-amide
hydrochloride
[0772] A mixture of 5-chloro-pyrazolo[1,5-a]pyrimidine-3-carbonyl
chloride (500 mg, 2.3 mmol) (prepared according to the procedure in
Journal of Medicinal Chemistry, 55(22), 10090-10107; 2012) and
5-(5-chloro-2-difluoromethoxyphenyl)-1-(2-trimethylsilanyl-ethoxymethyl)--
1H-pyrazol-4-ylamine (868 mg, 2.3 mmol) were suspended in
triethylamine (0.35 mL, 2.5 mmol) and DCM (10 mL) and the mixture
was left to stir at room temperature for 2 hours. The reaction
mixture was diluted with dichloromethane and the resultant organic
layer was washed with saturated aqueous sodium hydrogen carbonate
solution, and brine, dried (Na.sub.2SO.sub.4) and evaporated to
afford an oil. The resultant oil was purified by flash
chromatography on silica eluting with 0-2% MeOH in DCM. Collecting
appropriate fractions, followed by evaporation gave
5-chloro-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
[5-(5-chloro-2-difluoromethoxy-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl-
)-1H-pyrazol-4-yl]-amide as a brown oil (1.19 g, 91%). .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta.: (ppm) 9.07 (s, 1H), 8.72 (s, 1H),
8.67 (d, 1H, J=7.3 Hz), 8.38 (s, 1H), 7.60 (d, 1H, J=2.3 Hz), 7.51
(dd, 1H, J=2.6, 8.8 Hz), 7.38 (d, 1H, J=8.9 Hz), 6.95 (d, 1H, J=7.2
Hz), 6.43 (t, 1H, J=72.8 Hz), 5.41 (d, 1H, J=10.9 Hz), 5.31 (d, 1H,
J=11.0 Hz), 3.76-3.49 (m, 2H), 1.27 (s, 1H), 0.94-0.84 (m, 2H),
0.00 (s, 9H).
[0773] 5-chloro-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
[5-(5-chloro-2-difluoromethoxy-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl-
)-1H-pyrazol-4-yl]-amide (756 mg, 1.32 mmol) was dissolved in THF
(10 mL) and concentrated aqueous ammonia (10 mL) added. The mixture
was heated at 50.degree. C. for 3 hours then allowed to cool to
ambient temperature. The solvent was evaporated and the residue
azeotroped with methanol (.times.2) to afford
5-amino-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
[5-(5-chloro-2-difluoromethoxy-phenyl)-1-(2-trimethyl
silanyl-ethoxymethyl)-1H-pyrazol-4-yl]-amide as a white solid (724
mg, 99%). LCMS (Method 4) [M+H].sup.+=549.9, R.sub.T=4.11 min.
[0774] A suspension of
5-amino-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
[5-(5-chloro-2-difluoromethoxy-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl-
)-1H-pyrazol-4-yl]-amide (720 mg, 1.31 mmol) in methanol (20 mL)
was treated with concentrated aqueous HCl (3 mL) and the mixture
heated at 80.degree. C. for 1 hour. The solvent was evaporated and
the residue azeotroped with methanol (.times.3). The resultant
solid was triturated with ethyl acetate, collected by filtration,
washed with ethyl acetate and diethyl ether and left to air dry.
The residual solid was purified by flash chromatography on silica
eluting with 0-12% 2M NH.sub.3/MeOH in DCM. Collecting appropriate
fractions, followed by evaporation gave
5-amino-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
[3-(5-chloro-2-difluoromethoxy-phenyl)-1H-pyrazol-4-yl]-amide as a
brown solid (378 mg, 69%). LCMS (Method 4) [M+H].sup.+=419.9,
R.sub.T=2.93
[0775] 5-Amino-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
[3-(5-chloro-2-difluoromethoxy-phenyl)-1H-pyrazol-4-yl]-amide was
converted to the title compound following the procedures outlined
in Example C and Example 1 to afford a white solid. LCMS (Method 5)
[M+H].sup.+=586.0, R.sub.T=2.58 min. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta.: (ppm) 9.76 (s, 1H), 9.35 (dd, 1H, J=1.6, 7.1
Hz), 9.38-9.21 (m, 2H), 8.69 (dd, 1H, J=1.7, 4.3 Hz), 8.67 (s, 1H),
8.31 (s, 1H), 7.64 (dd, 1H, J=2.7, 8.8 Hz), 7.56 (d, 1H, J=2.6 Hz),
7.48 (d, 1H, J=8.6 Hz), 7.30 (dd, 1H, J=4.3, 6.9 Hz), 7.27 (t, 1H,
J=73.3 Hz), 5.15 (s, 2H), 3.93-3.67 (m, 3H), 3.65-3.32 (m, 6H),
3.19-2.94 (m, 4H).
Example 8
##STR00615##
[0776] 6-Methyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
{3-(5-chloro-2-difluoromethoxy-phenyl)-1-[2-((3aR,6aS)-5-methyl-hexahydro-
-pyrrolo[3,4-c]pyrrol-2-yl)-2-oxo-ethyl]-1H-pyrazol-4-yl}-amide
hydrochloride
[0777] The title compound was prepared from commercially available
6-methyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid following the
procedure outlined above for Example B and Example 1 to afford a
white solid. LCMS (Method 5) [M+H].sup.+=585.0, R.sub.T=3.03 min.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.: (ppm) 10.74-10.49 (m,
1H), 9.70 (s, 1H), 9.21 (dd, 1H, J=1.1, 2.0 Hz), 8.60 (d, 1H, J=2.0
Hz), 8.58 (s, 1H), 8.31 (s, 1H), 7.65 (dd, 1H, J=2.7, 8.8 Hz), 7.55
(d, 1H, J=2.7 Hz), 7.49 (d, 1H, J=8.8 Hz), 7.28 (t, 1H, J=73.3 Hz),
5.19 (d, 1H, J=16.8 Hz), 5.13 (d, 1H, J=16.8 Hz), 3.94-2.88 (m,
10H), 2.82 (s, 3H), 2.39 (s, 3H).
##STR00616##
Pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
[3-(5-chloro-2-difluoromethoxy-phenyl)-1-(2-{4-[(2-cyano-ethyl)-methyl-am-
ino]-piperidin-1-yl}-2-oxo-ethyl)-1H-pyrazol-4-yl]-amide
[0778] A solution of pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
[3-(5-chloro-2-difluoromethoxy-phenyl)-1H-pyrazol-4-yl]-amide (32.0
g, 79.1 mmol) in DMF (400 mL) was treated with
2-chloro-1-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-ethanone (20.8 g,
94.9 mmol) and Cs.sub.2CO.sub.3 (51.5 g, 158.1 mmol) and the
mixture was stirred at room temperature for 19 hours. The reaction
was diluted with water (.about.1.6 L) and the resultant precipitate
was collected by filtration. The solid was washed with water dried
under reduced pressure to afford
pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
{3-(5-chloro-2-difluoromethoxy-phenyl)-1-[2-(1,4-dioxa-8-aza-spiro[4.5]de-
c-8-yl)-2-oxo-ethyl]-1H-pyrazol-4-yl}-amide as a beige solid (33.3
g, 72%). LCMS (Method 3) [M+H].sup.+=588.2, R.sub.T=3.02 min.
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta.: (ppm) 9.85 (s, 1H), 8.78
(dd, 1H, J=1.6, 6.9 Hz), 8.71 (s, 1H), 8.56 (dd, 1H, J=1.8, 4.0
Hz), 8.42 (s, 1H), 7.69 (d, 1H, J=2.5 Hz), 7.41 (dd, 1H, J=2.7, 8.7
Hz), 7.30-7.26 (m, 1H), 7.00 (dd, 1H, J=4.2, 6.9 Hz), 6.48 (t, 1H,
J=74.0 Hz), 5.06 (s, 2H), 4.00-3.95 (m, 4H), 3.74 (dd, 2H, J=5.8,
5.8 Hz), 3.61 (dd, 2H, J=5.8, 5.8 Hz), 1.74-1.64 (m, 4H).
[0779] A suspension of pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
{3-(5-chloro-2-difluoromethoxy-phenyl)-1-[2-(1,4-dioxa-8-aza-spiro[4.5]de-
c-8-yl)-2-oxo-ethyl]-1H-pyrazol-4-yl}-amide (46.7 g, 79.5 mmol) in
dioxane (280 mL) was cooled in an ice bath before being treated
with concentrated hydrochloric acid (210 mL) at a rate which
maintained an internal temperature below 22.degree. C. On complete
addition, the reaction was allowed to warm to room temperature and
stirred for 4 hours. The reaction was cooled in an ice bath,
diluted with ethyl acetate and water and the pH of the aqueous
phase adjusted to .about.8 by the portionwise addition of solid
Na.sub.2CO.sub.3. The mixture was extracted with ethyl acetate
(.times.4) and the combined organic extract was dried
(Na.sub.2CO.sub.3) and evaporated to afford
pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
{3-(5-chloro-2-difluoromethoxy-phenyl)-1-[2-oxo-2-(4-oxo-piperidin-1-yl)--
ethyl]-1H-pyrazol-4-yl}-amide.dioxane as a beige solid (48.8 g,
97%). LCMS (Method 3) [M+H].sup.+=544.2, R.sub.T=2.85 min. .sup.1H
NMR (400 MHz, CDCl.sub.3) .delta.: (ppm) 9.87 (s, 1H), 8.79 (dd,
1H, J=1.8, 7.0 Hz), 8.70 (s, 1H), 8.57 (dd, 1H, J=1.8, 4.0 Hz),
8.47 (s, 1H), 7.67 (d, 1H, J=2.8 Hz), 7.43 (dd, 1H, J=2.7, 8.7 Hz),
7.29 (d, 1H, J=8.8 Hz), 7.01 (dd, 1H, J=4.3, 7.0 Hz), 6.48 (t, 1H,
J=74.0 Hz), 5.14 (s, 2H), 3.93 (t, 2H, J=6.2 Hz), 3.85 (t, 2H,
J=6.2 Hz), 3.70 (s, 8H), 2.50 (t, 2H, J=6.2 Hz), 2.42 (t, 2H, J=6.1
Hz).
[0780] A solution of pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
{3-(5-chloro-2-difluoromethoxy-phenyl)-1-[2-oxo-2-(4-oxo-piperidin-1-yl)--
ethyl]-1H-pyrazol-4-yl}-amide.dioxane (36 g, 57.0 mmol) in DCM (500
mL) was treated with 3-amino-propionitrile (5.0 mL, 68.4 mmol) and
acetic acid (50 mL). The mixture was cooled in an ice bath before
the addition of sodium triacetoxyborohydride (18.1 g, 85.4 mmol)
portionwise. The reaction was allowed to warm to room temperature
and stirred for 1.5 hours. The mixture was diluted with methanol
and loaded onto a pad of Isolute.RTM. SCX-2 which had been
conditioned with MeOH. After flushing with MeOH, the product was
eluted with 2M ammonia in MeOH. The basic fractions were combined
and evaporated to afford pyrazolo[1,5-a]pyrimidine-3-carboxylic
acid
(3-(5-chloro-2-difluoromethoxy-phenyl)-1-{2-[4-(2-cyano-ethylamino)-piper-
idin-1-yl]-2-oxo-ethyl)}-1H-pyrazol-4-yl)-amide as a pale brown
solid (31.1 g, 91%). LCMS (Method 3) [M+H].sup.+=598.2,
R.sub.T=2.25 min. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.: (ppm)
9.84 (s, 1H), 8.78 (dd, 1H, J=1.6, 6.9 Hz), 8.69 (s, 1H), 8.58-8.55
(m, 1H), 8.40 (s, 1H), 7.68 (d, 1H, J=2.5 Hz), 7.41 (dd, 1H, J=2.7,
8.7 Hz), 7.28 (d, 1H, J=8.7 Hz), 7.28 (s, 1H), 7.00 (dd, 1H, J=4.2,
6.9 Hz), 6.50 (t, 1H, J=74.1 Hz), 5.08 (d, 1H, J=15.4 Hz), 5.02 (d,
1H, J=15.5 Hz), 4.37 (d, 1H, J=13.4 Hz), 3.88 (d, 1H, J=13.4 Hz),
3.22-3.12 (m, 1H), 3.02 (t, 1H, J=6.4 Hz), 2.98-2.86 (m, 2H),
2.82-2.72 (m, 1H), 2.52-2.46 (m, 2H), 1.96-1.83 (m, 2H), 1.36-1.20
(m, 2H).
[0781] A solution of pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
(3-(5-chloro-2-difluoromethoxy-phenyl)-1-{2-[4-(2-cyano-ethylamino)-piper-
idin-1-yl]-2-oxo-ethyl})-1H-pyrazol-4-yl)-amide (31.1 g, 52.0 mmol)
in DCM (500 mL) was treated with 37% aqueous formaldehyde solution
(21.3 mL, 286.2 mmol). On complete addition the reaction was cooled
in an ice bath before the addition of sodium triacetoxyborohydride
(44.1 g, 208.2 mmol) portionwise. The reaction mixture was warmed
to room temperature and stirred for 1.5 hours, after which, the
reaction was filtered and the filtrate diluted with methanol. The
mixture was diluted with methanol and loaded onto a pad of
Isolute.RTM. SCX-2 which had been conditioned with MeOH. After
flushing with MeOH, the product was eluted with 2M ammonia in MeOH.
The basic fractions were combined and evaporated. The resultant
residue was purified by flash column chromatography on silica
eluting with 0-10% 2M NH.sub.3/MeOH in DCM. Appropriate fractions
were combined and evaporated. The resultant residue was
recrystallized from ethyl acetate to afford the title compound as a
pale brown solid (30.7 g, 96%). LCMS (Method 5) [M+H].sup.+=612.2,
R.sub.T=2.84 min. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.:
(ppm) 9.75 (s, 1H), 9.34 (dd, 1H, J=7.0, 1.6 Hz), 8.70-8.67 (m,
1H), 8.68 (s, 1H), 8.32 (s, 1H), 7.63 (dd, 1H, J=8.8, 2.7 Hz), 7.56
(d, 1H, J=2.7 Hz), 7.47 (d, 1H, J=8.8 Hz), 7.29 (dd, 1H, J=7.0, 4.2
Hz), 7.26 (t, 1H, J=73.4 Hz), 5.22-5.24 (m, 2H), 4.38 (d, 1H,
J=12.9 Hz), 3.96 (d, 1H, J=13.5 Hz), 3.06 (t, 1H, J=12.7 Hz),
2.62-2.65 (m, 6H), 2.22 (s, 3H), 1.72 (d, 2H, J=11.9 Hz), 1.34-1.40
(m, 2H).
Example 142
##STR00617##
[0782] Pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
[1-[1-(3-acetylaminopropyl)piperidin-4-yl]-3-(5-chloro-2-difluoromethoxyp-
henyl)-1H-pyrazol-4-yl]amide hydrochloride
[0783] A mixture of pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
[3-(5-chloro-2-difluoromethoxyphenyl)-1-piperidin-4-yl-1H-pyrazol-4-yl]am-
ide (100 mg, 0.20 mmol), (3-bromo-propyl)-carbamic acid tert-butyl
ester (71 mg, 0.3 mmol) and potassium carbonate (45 mg, 0.32 mmol)
in DMF (2 mL) was heated at 60.degree. C. for 1.5 hours. The
reaction mixture was allowed to cool to ambient temperature,
diluted with water and extracted with dichloromethane. The organic
layer was separated, washed with brine, dried (Na.sub.2SO.sub.4)
and evaporated. The resultant residue was chromatographed on silica
eluting with dichloromethane on a gradient of 2M ammonia in
methanol (0-6%) to give
[3-(4-{3-(5-chloro-2-difluoromethoxyphenyl)-4-[(pyrazolo[1,5-a]pyrimidine-
-3-carbonyl)amino]pyrazol-1-yl}piperidin-1-yl)propyl]carbamic acid
tert-butyl ester as a yellow oil (131 mg, 100%). LCMS (Method 4)
[M+H].sup.+=675.0, R.sub.T=2.86 min.
[0784]
[3-(4-{3-(5-Chloro-2-difluoromethoxyphenyl)-4-[(pyrazolo[1,5-a]pyri-
midine-3-carbonyl)amino]pyrazol-1-yl}piperidin-1-yl)propyl]carbamic
acid tert-butyl ester (129 mg, 0.20 mmol) was dissolved in DCM (2
mL) and TFA (2 mL) was added. The reaction was stirred at room
temperature for 1 hour and then evaporated to dryness. The residue
was dissolved in MeOH and loaded onto an SCX-2 cartridge which had
been conditioned with MeOH. After flushing with MeOH, the product
was eluted with 2M ammonia in MeOH. Evaporation of the basic
fractions gave a residue which was dissolved in pyridine (2 mL).
Acetyl chloride (21 .mu.L, 0.30 mmol) was added and the solution
was allowed to stand at room temperature for 5 days. The volatiles
were evaporated and azeotroped with toluene. The residue was
dissolved in MeOH and loaded onto an SCX-2 cartridge which had been
conditioned with MeOH. After flushing with MeOH, the product was
eluted with 2M ammonia in MeOH. Evaporation gave a glassy solid
which was purified by HPLC (Method 3). The pure amine was dissolved
in MeOH and 1.25M methanolic HCl was added. The volatiles were
evaporated and the solid product was triturated with
EtOAc/Et.sub.2O to give the title compound as a white solid (40 mg,
32%). LCMS (Method 5) [M+H].sup.+=587.0, R.sub.T=2.91 min. .sup.1H
NMR (400 MHz, DMSO-d.sub.6) .delta.: (ppm) 9.89 (s, 1H), 9.76 (s,
1H), 9.35 (dd, 1H, J=1.5, 7.0 Hz), 8.69 (dd, 1H, J=1.6, 4.2 Hz),
8.67 (s, 1H), 8.39 (s, 1H), 8.04 (t, 1H, J=5.8 Hz), 7.67-7.61 (m,
2H), 7.46 (d, 2H, J=8.4 Hz), 7.31 (dd, 1H, J=4.2, 6.9 Hz), 7.26 (t,
1H, J=73.4 Hz), 4.64-4.54 (m, 1H), 3.64 (d, 2H, J=12.2 Hz),
3.21-3.01 (m, 6H), 2.40-2.29 (m, 4H), 1.84 (m, 5H).
Example 302
##STR00618##
[0785] Pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
{3-(5-chloro-2-difluoromethoxy-phenyl)-1-[4-(4-dimethylamino-piperidine-1-
-carbonyl)-phenyl]-1H-pyrazol-4-yl}-amide hydrochloride
[0786] A solution of 4-iodo-benzoyl chloride (4.72 g, 17.71 mmol)
in DCM (70 mL) at 0.degree. C. was treated with
dimethyl-piperidin-4-yl-amine (2.27 g, 17.71 mmol). The resultant
suspension was warmed to room temperature and stirred for 2.5
hours. The reaction mixture was diluted with 1M aqueous
Na.sub.2CO.sub.3 solution and the phases separated. The aqueous
phase was extracted twice with DCM and the combined organic phase
was dried (Na.sub.2SO.sub.4) and evaporated to afford
(4-dimethylamino-piperidin-1-yl)-(4-iodo-phenyl)-methanone as a
white solid (6.2 g, 98%). LCMS (Method 3) [M+H].sup.+=359.2,
R.sub.T=1.82 min.
[0787] A microwave vial was charged with
pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
[3-(5-chloro-2-difluoromethoxy-phenyl)-1H-pyrazol-4-yl]-amide (100
mg, 0.25 mmol),
(4-dimethylamino-piperidin-1-yl)-(4-iodo-phenyl)-methanone (107 mg,
0.30 mmol), copper (I) iodide (15 mg, 0.08 mmol), potassium
carbonate (73 mg, 0.53 mmol), trans-N,N'-dimethyl-1,2-cyclohexane
diamine (24 .mu.L, 0.15 mmol). The vessel was sealed and purged
with argon before the addition of toluene (1.0 mL). The reaction
mixture was stirred at 110.degree. C. for 18 hours. The reaction
was cooled to room temperature, diluted with water and the
resultant precipitate was collected by filtration, washed with
ethyl acetate and dried under reduced pressure. The resultant solid
was purified by MDAP (Method 1), the solid was taken up into a
mixture of MeOH/DCM and loaded onto an Isolute.RTM. SCX-2 cartridge
which had been conditioned with MeOH. The cartridge was washed with
MeOH then eluted with 2M NH.sub.3/MeOH. The basic fractions were
combined, evaporated and the resultant solid suspended in MeOH
before being treated with 1.25M HCl in MeOH. The suspension was
allowed to evaporate and the solid was triturated with ethyl
acetate, dried under reduced pressure giving the title compound as
a yellow solid (67 mg, 40%). LCMS (Method 5) [M+H].sup.+=635.2,
R.sub.T=3.27 min. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.:
(ppm) 9.88 (s, 1H), 9.38 (dd, 1H, J=7.1, 1.8 Hz), 9.04 (s, 1H),
8.71 (s, 1H), 8.70 (dd, 1H, J=4.3, 1.7 Hz), 8.04-7.99 (m, 2H), 7.79
(d, 1H, J=2.7 Hz), 7.72 (dd, 1H, J=8.8, 2.6 Hz), 7.63-7.57 (m, 2H),
7.53 (d, 1H, J=8.8 Hz), 7.33 (dd, 1H, J=7.0, 4.3 Hz), 7.31 (t, 1H,
J=73.1 Hz), 4.65 (brs, 1H), 2.98 (s, 2H), 2.67 (s, 6H), 2.14-1.82
(m, 2H), 1.69-1.54 (m, 2H).
Example 188
##STR00619##
[0788] Pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
[4-(5-chloro-2-difluoromethoxy-phenyl)-2-(4-dimethylamino-piperidin-1-yl)-
-thiazol-5-yl]-amide
[0789] Pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
[2-bromo-4-(5-chloro-2-difluoromethoxy-phenyl)-thiazol-5-yl]-amide
(100 mg, 0.2 mmol) and 4-dimethylaminopiperidine (128 mg, 1 mmol)
were dissolved in DMA (1 ml) and heated in a microwave at
160.degree. C. for 1 hour. The residue was dissolved in MeOH and
loaded onto an SCX-2 cartridge which had been conditioned with
MeOH. After flushing with MeOH, the product was eluted with 2M
ammonia in MeOH. The resulting yellow glass was purified by MDAP
(Method 1). Appropriate fractions were combined and evaporated to
afford a yellow solid. The residue was dissolved in MeOH and loaded
onto an SCX-2 cartridge which had been conditioned with MeOH. After
flushing with MeOH, the product was eluted with 2M ammonia in MeOH
to give the title compound as a yellow-orange solid (43 mg, 39%).
LCMS (Method 5) [M+H].sup.+=548.1, R.sub.T=3.20 min. .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta.: (ppm) 10.23 (s, 1H), 9.36 (dd, 1H,
J=1.6, 7.0 Hz), 8.68 (s, 1H), 8.63 (dd, 1H, J=1.6, 4.2 Hz), 7.66
(d, 1H, J=2.7 Hz), 7.59 (dd, 1H, J=2.6, 8.8 Hz), 7.41 (d, 1H, J=9.0
Hz), 7.31 (dd, 1H, J=4.2, 6.7 Hz), 7.18 (t, 1H, J=73.5 Hz), 3.93
(d, 2H, J=12.7 Hz), 3.02 (dd, 2H, J=10.3, 12.3 Hz), 3.05-2.95 (m,
1H), 2.40-2.26 (m, 6H), 1.92-1.89 (m, 2H), 1.58-1.47 (m, 2H).
Example 189
##STR00620##
[0790] Pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
(4-(5-chloro-2-difluoromethoxy-phenyl)-2-{4-[(2-cyano-ethyl)-methyl-amino-
]-piperidin-1-yl}-thiazol-5-yl)-amide
[0791] Pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
[2-bromo-4-(5-chloro-2-difluoromethoxy-phenyl)-thiazol-5-yl]-amide
(820 mg, 1.64 mmol) and 1,4 dioxa-8-azaspiro[4.5]decane (1.05 ml,
8.2 mmol) were dissolved in DMA (10 ml) and heated in a microwave
at 165.degree. C. for 1 hour. The reaction mixture partitioned
between ethyl acetate and water and the phases separated. The
organic layer was washed with brine. The combined aqueous layers
were extracted with ethyl acetate once and the organic layers
combined, dried (Na.sub.2SO.sub.4), filtered and the solvent
removed. The crude product was chromatographed on silica eluting
with 50-60% ethyl acetate in cyclohexane. Appropriate fractions
were combined and evaporated to afford
pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
[4-(5-chloro-2-difluoromethoxy-phenyl)-2-(1,4-dioxa-8-aza-spiro[4.5]-
dec-8-yl)-thiazol-5-yl]-amide as a yellow solid (541 mg, 59%). LCMS
(Method 3) [M+H].sup.+=563.3, R.sub.T=3.68 min. .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta.: (ppm) 10.26 (s, 1H), 9.37 (dd, 1H,
J=1.6, 6.9 Hz), 8.69 (s, 1H), 8.64 (dd, 1H, J=1.5, 4.4 Hz), 7.68
(d, 1H, J=2.5 Hz), 7.59 (dd, 1H, J=2.7, 8.7 Hz), 7.42 (d, 1H, J=8.5
Hz), 7.31 (dd, 1H, J=4.3, 7.0 Hz), 7.18 (t, 1H, J=73.8 Hz), 3.94
(s, 4H), 3.52 (dd, 4H, J=5.7, 5.7 Hz), 1.75 (dd, 4H, J=5.7, 5.7
Hz).
[0792]
[4-(5-chloro-2-difluoromethoxy-phenyl)-2-(1,4-dioxa-8-aza-spiro[4.5-
]dec-8-yl)-thiazol-5-yl]-amide (536 mg, 0.95 mmol) was dissolved in
dioxane (10 ml) and conc. hydrochloric acid (10 ml) and stirred at
room temperature for 3 hours. The mixture was cooled to 0.degree.
C. and basified to ca. pH 13 with 50% aqueous sodium hydroxide and
then partitioned between ethyl acetate and water and the phases
separated. The organic layer was washed with brine. The combined
aqueous layers were extracted with ethyl acetate once and the
organic layers combined, dried (Na.sub.2SO.sub.4), filtered and the
solvent removed to yield pyrazolo[1,5-a]pyrimidine-3-carboxylic
acid
[4-(5-chloro-2-difluoromethoxy-phenyl)-2-(4-oxo-piperidin-1-yl)-thiazol-5-
-yl]-amide as a yellow-orange solid (465 mg, 94%). LCMS (Method 3)
[M+H].sup.+=519.3, R.sub.T=3.39 min. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta.: (ppm) 10.30 (s, 1H), 9.38 (dd, 1H, J=1.5,
7.1 Hz), 8.70 (s, 1H), 8.65 (dd, 1H, J=1.4, 4.3 Hz), 7.70 (d, 1H,
J=2.5 Hz), 7.61 (dd, 1H, J=2.8, 8.8 Hz), 7.43 (d, 1H, J=9.2 Hz),
7.32 (dd, 1H, J=4.2, 7.1 Hz), 7.20 (t, 1H, J=74.0 Hz), 3.81 (dd,
4H, J=6.2, 6.2 Hz), 2.54 (d, 4H, J=6.1 Hz).
[0793] Pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
[4-(5-chloro-2-difluoromethoxy-phenyl)-2-(4-oxo-piperidin-1-yl)-thiazol-5-
-yl]-amide (90 mg, 0.17 mmol) was dissolved in DCM (2 ml) and
N-methyl-.beta.-alaninenitrile (20 .mu.l, 0.21 mmol), acetic acid
(200 .mu.l) and macroporous polymer supported cyanoborohydride (166
mg, 0.36 mmol) were successively added and stirred at room
temperature for 16 hours. The mixture was diluted with MeOH and
loaded onto an SCX-2 cartridge which had been conditioned with
MeOH. After flushing with MeOH, the product was eluted with 2M
ammonia in MeOH. The resulting yellow glass was purified by MDAP
(Method 1). Appropriate fractions were combined and evaporated to
afford a yellow glass. The residue was dissolved in MeOH and loaded
onto an SCX-2 cartridge which had been conditioned with MeOH. After
flushing with MeOH, the product was eluted with 2M ammonia in MeOH
to give the title compound as a yellow solid (46 mg, 46%). LCMS
(Method 5) [M+H].sup.+=587.2, R.sub.T=3.19 min. .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta.: (ppm) 10.23 (s, 1H), 9.36 (dd, 1H,
J=1.6, 7.0 Hz), 8.68 (s, 1H), 8.64 (dd, 1H, J=1.6, 4.3 Hz), 7.67
(d, 1H, J=2.6 Hz), 7.59 (dd, 1H, J=2.7, 8.9 Hz), 7.41 (d, 1H, J=8.6
Hz), 7.31 (dd, 1H, J=4.3, 7.1 Hz), 7.18 (t, 1H, J=73.9 Hz), 3.94
(d, 2H, J=12.8 Hz), 3.04-2.96 (m, 2H), 2.72-2.60 (m, 5H), 2.24 (s,
3H), 1.79 (d, 2H, J=10.9 Hz), 1.59-1.47 (m, 2H).
Example 205
##STR00621##
[0794] Pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
[4-(5-chloro-2-difluoromethoxy-phenyl)-2-(4-methyl-piperazin-1-yl)-thiazo-
l-5-yl]-amide
[0795] The title compound was prepared in an analogous manner to
pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
[4-(5-chloro-2-difluoromethoxy-phenyl)-2-(4-dimethylamino-piperidin-1-yl)-
-thiazol-5-yl]-amide to afford the title compound as a
yellow-orange solid. LCMS (Method 5) [M+H].sup.+=520.2,
R.sub.T=3.02 min. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.:
(ppm) 10.25 (s, 1H), 9.37 (dd, 1H, J=1.6, 7.0 Hz), 8.69 (s, 1H),
8.64 (dd, 1H, J=1.6, 4.3 Hz), 7.67 (d, 1H, J=2.6 Hz), 7.59 (dd, 1H,
J=2.7, 8.8 Hz), 7.42 (d, 1H, J=9.2 Hz), 7.31 (dd, 1H, J=4.2, 7.3
Hz), 7.18 (t, 1H, J=73.7 Hz), 3.41 (dd, 4H, J=4.9, 4.9 Hz),
2.48-2.42 (m, 4H), 2.24 (s, 3H).
##STR00622##
Pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
[4-(5-chloro-2-difluoromethoxy-phenyl)-2-(3-dimethylamino-prop-1-ynyl)-th-
iazol-5-yl]-amide
[0796] To a solution of pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
[2-bromo-4-(5-chloro-2-difluoromethoxy-phenyl)-thiazol-5-yl]-amide
(150 mg, 0.3 mmol), bis(triphenylphosphine)palladium(II) dichloride
(11 mg, 0.015 mmol), copper(I)iodide (5 mg, 0.024 mmol) in THF (1
mL) was added propargyl alcohol (35 .mu.L, 0.6 mmol) then
triethylamine (1 mL) under an atmosphere of nitrogen. The resultant
mixture was stirred at 50.degree. C. for 3 hours before being
cooled to room temperature. The mixture was partitioned between
ethyl acetate and water. The phases were separated and the organic
phase washed with brine, dried (Na.sub.2SO.sub.4) and evaporated.
The resultant residue was purified by flash column chromatography
on silica eluting with 80% ethyl acetate in cyclohexane to afford
pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
[4-(5-chloro-2-difluoromethoxy-phenyl)-2-(3-hydroxy-prop-1-ynyl)-thiazol--
5-yl]-amide as a yellow solid (112 mg, 78%). LCMS (Method 3)
[M+H].sup.+=476.2, R.sub.T=3.19 min.
[0797] To a suspension of pyrazolo[1,5-a]pyrimidine-3-carboxylic
acid
[4-(5-chloro-2-difluoromethoxy-phenyl)-2-(3-hydroxy-prop-1-ynyl)-thiazol--
5-yl]-amide (110 mg, 0.23 mmol) and triphenylphosphine (105 mg, 0.4
mmol) in DCM (3 mL) was added carbon tetrabromide (132 mg, 0.4
mmol) portionwise. The reaction was stirred at room temperature
before the addition of 2M methylamine in THF (1 mL). The resultant
mixture was stirred at room temperature for 3 hours. The mixture
was evaporated and the residue taken up into MeOH and loaded onto
an Isolute.RTM. SCX-2 cartridge which had been conditioned with
MeOH. The cartridge was washed with MeOH before being eluted with
2M NH.sub.3 in MeOH. The basic fractions were combined and
evaporated. The residue was purified by MDAP (Method 1), after
evaporation the material was taken up into MeCN and loaded onto an
Isolute.RTM. SCX-2 cartridge which had been conditioned with MeCN.
The cartridge was washed with MeCN before being eluted with 2M
NH.sub.3 in MeOH. The basic fractions were combined and evaporated,
giving the title compound as an orange solid (18 mg, 15%). LCMS
(Method 5) [M+H].sup.+=503.0, R.sub.T=3.16 min. .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta.: (ppm) 10.85 (s, 1H), 9.41 (dd, 1H,
J=7.1, 1.3 Hz), 8.79 (s, 1H), 8.63 (dd, 1H, J=4.4, 1.5 Hz), 7.76
(d, 1H, J=2.6 Hz), 7.72 (dd, 1H, J=8.8, 2.6 Hz), 7.52 (d, 1H, J=8.8
Hz), 7.36 (dd, 1H, J=7.0, 4.3 Hz), 7.19 (t, 1H, J=73.2 Hz), 3.61
(s, 2H), 2.29 (s, 6H).
Example 211
##STR00623##
[0798] Pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
{3-(5-chloro-2-difluoromethoxyphenyl)-1-[2-(6-methyl-2,6-diazaspiro[3.4]o-
ct-2-yl)-2-oxoethyl]-1H-pyrazol-4-yl}amide
[0799] Pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
{3-(5-chloro-2-difluoromethoxy-phenyl)-1-[2-(2,6-diazaspiro[3.4]oct-2-yl)-
-2-oxoethyl]-1H-pyrazol-4-yl}amide was prepared using a method
similar to that used in the synthesis of
pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
{3-(5-chloro-2-difluoromethoxy-phenyl)-1-[2-(hexahydro-pyrrolo[3,4-c]pyrr-
ol-2-yl)-2-oxoethyl]-1H-pyrazol-4-yl}amide. LCMS (Method 5)
[M+H].sup.+=556.9, R.sub.T=2.84 min.
[0800] Pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
{3-(5-chloro-2-difluoromethoxy-phenyl)-1-[2-(2,6-diaza-spiro[3.4]oct-2-yl-
)-2-oxoethyl]-1H-pyrazol-4-yl}amide (70 mg, 0.13 mmol) and
paraformaldehyde (19 mg, 0.63 mmol) were stirred in
2,2,2-trifluoroethanol for 15 minutes. Sodium borohydride (14 mg,
0.38 mmol) was added and the reaction mixture was heated at
90.degree. C. for 2 hours. The reaction mixture was allowed to cool
to room temperature and was quenched with MeOH. The mixture was
loaded onto an SCX-2 cartridge which had been conditioned with
MeOH. After flushing with MeOH, the product was eluted with 2M
ammonia in MeOH. Evaporation gave a crude product which was
purified by HPLC (Method 1). The pure fractions were loaded onto an
SCX-2 cartridge which had been conditioned with MeOH. After
flushing with MeOH, the product was eluted with 2M ammonia in MeOH.
Evaporation gave the free base 5 which was crystallised from
MeOH/Et.sub.2O. The title compound was obtained as a white solid
(28 mg, 39%). LCMS (Method 5) [M+H].sup.+=570.9, R.sub.T=2.86 min.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.: (ppm) 9.75 (s, 1H),
9.34 (dd, 1H, J=1.5, 7.0 Hz), 8.69-8.66 (m, 2H), 8.34 (s, 1H), 8.15
(s, 1H), 7.64 (dd, 1H, J=2.7, 8.9 Hz), 7.57 (d, 1H, J=2.7 Hz), 7.47
(d, 1H, J=8.8 Hz), 7.29 (dd, 2H, J=4.3, 7.1 Hz), 7.25 (t, 1H,
J=73.5 Hz), 4.94 (s, 2H), 4.04 (q, 2H, J=8.8 Hz), 3.90-3.81 (m,
2H), 2.69 (s, 2H), 2.27 (s, 3H), 2.03 (dd, 2H, J=6.8, 6.8 Hz).
Example 227
##STR00624##
[0801] Pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
{3-(5-chloro-2-difluoromethoxyphenyl)-1-[2-(4-methylpiperazin-1-yl)-2-oxo-
ethyl]-1H-pyrazol-4-yl}amide
[0802] The title compound was prepared in an analogous manner to
cis-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
{3-(5-chloro-2-difluoromethoxyphenyl)
1-[2-(5-methylhexahydropyrrolo[3,4-c]pyrrol-2-yl)-2-oxoethyl]-1H-pyrazol--
4-yl}amide using
{3-(5-chloro-2-difluoromethoxy-phenyl)-4-[(pyrazolo[1,5-a]pyrimidine-3-ca-
rbonyl)amino]pyrazol-1-yl}acetic acid and methyl piperazine to
afford the title compound as a pale yellow solid. LCMS (Method 5)
[M+H].sup.+=545.1, R.sub.T=2.89 min. .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta.: (ppm) 9.85 (s, 1H), 8.78 (dd, 1H, J=1.6, 7.0
Hz), 8.71 (s, 1H), 8.56 (dd, 1H, J=1.7, 4.1 Hz), 8.41 (s, 1H), 7.69
(d, 1H, J=2.6 Hz), 7.41 (dd, 1H, J=2.6, 8.7 Hz), 7.28 (d, 1H, J=9.1
Hz), 7.00 (dd, 1H, J=4.2, 7.0 Hz), 6.47 (t, 1H, J=74.1 Hz), 5.04
(s, 2H), 3.72-3.65 (m, 2H), 3.57 (dd, 2H, J=4.8, 4.8 Hz), 2.47-2.39
(m, 4H), 2.31 (s, 3H).
Example 233
##STR00625##
[0803] Pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
{3-(5-chloro-2-difluoromethoxy-phenyl)-1-[2-(4-ethyl-piperazin-1-yl)-2-ox-
o-ethyl]-1H-pyrazol-4-yl}-amide
[0804] The title compound was prepared in an analogous manner to
cis-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
{3-(5-chloro-2-difluoromethoxyphenyl)
1-[2-(5-methylhexahydropyrrolo[3,4-c]pyrrol-2-yl)-2-oxoethyl]-1H-pyrazol--
4-yl}amide using
{3-(5-chloro-2-difluoromethoxy-phenyl)-4-[(pyrazolo[1,5-a]pyrimidine-3-ca-
rbonyl)amino]pyrazol-1-yl}acetic acid and ethyl piperazine to
afford the title compound as a white solid. LCMS (Method 5)
[M+H].sup.+=559.1, R.sub.T=2.89 min. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta.: (ppm) 9.75 (s, 1H), 9.34 (dd, 1H, J=1.6, 7.0
Hz), 8.69-8.67 (m, 2H), 8.31 (s, 1H), 7.63 (dd, 1H, J=2.7, 8.8 Hz),
7.56 (d, 1H, J=2.6 Hz), 7.46 (d, 1H, J=9.0 Hz), 7.29 (dd, 1H,
J=4.2, 7.1 Hz), 7.25 (t, 1H, J=73.5 Hz), 5.23 (s, 2H), 3.50-3.49
(m, 4H), 2.41-2.32 (m, 6H), 1.02 (t, 3H, J=7.1 Hz).
Example 253
##STR00626##
[0805] Pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
{4-(5-chloro-2-difluoromethoxy-phenyl)-2-[4-(4-dimethylamino-piperidine-1-
-carbonyl)-phenyl]-thiazol-5-yl}-amide hydrochloride
[0806] Pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
[2-bromo-4-(5-chloro-2-difluoromethoxy-phenyl)-thiazol-5-yl]-amide
(100 mg, 0.2 mmol), 4-carboxybenzeneboronic acid (40 mg, 0.24
mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium
dichloromethane complex (16 mg, 0.02 mmol) and potassium carbonate
(110 mg, 0.8 mmol) were dissolved in dioxane (3.2 ml) and water
(0.8 ml) under an atmosphere of N.sub.2 and heated in a microwave
at 120.degree. C. for 30 mins. The mixture was partitioned between
ethyl acetate and water and the phases separated. The aqueous layer
was acidified with 1M HCl and the resulting precipitate was
filtered and the solid collected and dried.
[0807] The resultant residue was dissolved in DMF (2 ml) and DIPEA
(52 .mu.l, 0.3 mmol) and HATU (91 mg, 0.24 mmol) were added and
stirred at room temperature for 5 mins before the addition of
4-dimethylaminopiperidine (31 mg, 0.24 mmol). The resulting mixture
was stirred at room temperature for a further 16 hours. The mixture
was diluted with MeOH and loaded onto an SCX-2 cartridge which had
been conditioned with MeOH. After flushing with MeOH, the product
was eluted with 2M ammonia in MeOH. The resulting yellow glass was
purified by HPLC (MDAP, Method 1). Appropriate fractions were
combined and evaporated to afford an off-white solid. The residue
was dissolved in MeOH and loaded onto an SCX-2 cartridge which had
been conditioned with MeOH. After flushing with MeOH, the product
was eluted with 2M ammonia in MeOH to give the title compound as an
off-white solid (27 mg, 21%). LCMS (Method 5) [M+H].sup.+=652.3,
R.sub.T=3.35 min. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.:
(ppm) 10.82 (1H, s), 9.42 (1H, dd, J=1.4, 6.9 Hz), 8.80 (1H, s),
8.65 (1H, dd, J=1.4, 4.3 Hz), 8.03 (2H, d, J=8.2 Hz), 7.85 (1H, d,
J=2.6 Hz), 7.73 (1H, dd, J=2.7, 8.8 Hz), 7.56-7.51 (3H, m), 7.37
(1H, dd, J=4.3, 6.9 Hz), 7.25 (1H, t, J=73.5 Hz), 4.71-4.39 (m,
1H), 3.73-3.65 (1H, m), 3.52-3.41 (1H, m), 3.13-3.11 (1H, m),
2.89-2.88 (1H, m), 2.51 (s, 6H), 2.06-1.74 (2H, m), 1.49 (2H, dd,
J=7.6, 14.7 Hz).
##STR00627##
Pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
[4-(5-chloro-2-difluoromethoxy-phenyl)-2-(4-dimethyl
amino-piperidin-1-ylmethyl)-thiazol-5-yl]-amide
[0808] Pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
[2-bromo-4-(5-chloro-2-difluoromethoxy-phenyl)-thiazol-5-yl]-amide
(600 mg, 1.2 mmol), potassium vinyltrifluoroborate (177 mg, 1.32
mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium
dichloromethane complex (48 mg, 0.06 mmol) and DIPEA (627 .mu.l,
3.6 mmol) were dissolved in 2-propanol (9 ml) and water (4.5 ml)
under an atmosphere on N.sub.2 and heated in a microwave at
100.degree. C. for 40 mins. The mixture was partitioned between
ethyl acetate and water and the phases separated. The organic layer
was washed with brine, dried (Na.sub.2SO.sub.4), filtered and the
solvent removed.
[0809] The resulting residue was suspended in acetone (12 ml) and
water (1.2 ml), then potassium osmate dihydrate (25 mg, 0.06 mmol)
and N-methylmorpholine N-oxide (280 mg, 2.4 mmol) were added and
the mixture stirred vigorously at room temperature for 16 hours.
The reaction was quenched by the addition of solid sodium
metabisulfite (2 g), and then partitioned between ethyl acetate and
water and the phases separated. The organic layer was washed with
brine. The combined aqueous layers were extracted with ethyl
acetate once and the organic layers combined, dried
(Na.sub.2SO.sub.4), filtered and the solvent removed.
[0810] The resulting residue was dissolved in THF (15 ml) and water
(15 ml) and sodium periodate (514 mg, 2.4 mmol) was added and the
mixture was stirred vigorously at room temperature for 1.5 hours.
The reaction mixture partitioned between ethyl acetate and water
and the phases separated. The organic layer was washed with brine.
The combined aqueous layer was extracted with ethyl acetate once
and the organic layer combined, dried (Na.sub.2SO.sub.4), filtered
and the solvent removed to yield the title compound as an orange
solid (509 mg, 94%).
[0811] A portion of the resultant solid (100 mg, 0.22 mmol) was
dissolved in DCM (2 ml) and 4-dimethylaminopiperidine (33 mg, 0.26
mmol), acetic acid (200 .mu.l) and macroporous polymer supported
cyanoborohydride (216 mg, 0.44 mmol) were successively added and
stirred at room temperature for 16 hours. The mixture was diluted
with MeOH and loaded onto an SCX-2 cartridge which had been
conditioned with MeOH. After flushing with MeOH, the product was
eluted with 2M ammonia in MeOH. The resulting yellow glass was
purified by HPLC (MDAP, Method 1). Appropriate fractions were
combined and evaporated to afford a yellow glass. The residue was
dissolved in MeOH and loaded onto an SCX-2 cartridge which had been
conditioned with MeOH. After flushing with MeOH, the product was
eluted with 2M ammonia in MeOH to give the title compound as a pale
yellow solid (52 mg, 42%). LCMS (Method 5) [M+H].sup.+=562.1,
R.sub.T=2.56 min. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.:
(ppm) 10.59 (s, 1H), 9.39 (dd, 1H, J=1.6, 7.0 Hz), 8.75 (s, 1H),
8.62 (dd, 1H, J=1.6, 4.3 Hz), 7.48 (d, 1H, J=8.8 Hz), 7.34 (dd, 1H,
J=4.2, 7.0 Hz), 7.17 (t, 1H, J=73.4 Hz), 3.78 (s, 2H), 2.98 (d, 2H,
J=11.5 Hz), 2.19 (s, 6H), 2.17-2.08 (m, 3H), 1.79-1.72 (m, 2H),
1.50-1.38 (m, 2H).
Example 264
##STR00628##
[0812] Pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
[4-(5-chloro-2-difluoromethoxy-phenyl)-2-(5-methyl-hexahydro-pyrrolo[3,4--
c]pyrrole-2-carbonyl)-thiazol-5-yl]-amide
[0813] Pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
[2-bromo-4-(5-chloro-2-difluoromethoxy-phenyl)-thiazol-5-yl]-amide
(200 mg, 0.4 mmol), 2-methyl-octahydro-pyrrolo[3,4-c]pyrrole (70
mg, 0.56 mmol), Herrmann's catalyst (4.5 mg, 0.0048 mmol),
tri-tert-butyl phosphine hydrofluoroborate (3.5 mg, 0.011 mmol),
molybdenum hexacarbonyl (53 mg, 0.2 mmol) and DBU (40 .mu.l, 0.27
mmol) were dissolved in THF (2 ml) and heated in a microwave at
125.degree. C. for 15 mins. The residue was dissolved in MeOH and
loaded onto an SCX-2 cartridge which had been conditioned with
MeOH. After flushing with MeOH, the product was eluted with 2M
ammonia in MeOH. The resulting yellow glass was purified by HPLC
(MDAP, Method 1). Appropriate fractions were combined and
evaporated to afford a yellow solid. The residue was dissolved in
MeOH and loaded onto an SCX-2 cartridge which had been conditioned
with MeOH. After flushing with MeOH, the product was eluted with 2M
ammonia in MeOH to give the title compound as a pale yellow solid
(18 mg, 8%). LCMS (Method 5) [M+H].sup.+=574.1, R.sub.T=3.06 min.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.: (ppm) 10.88 (s, 1H),
9.42 (dd, 1H, J=1.6, 7.0 Hz), 8.81 (s, 1H), 8.61 (dd, 1H, J=1.5,
4.3 Hz), 7.84 (d, 1H, J=2.6 Hz), 7.73 (dd, 1H, J=2.6, 8.8 Hz), 7.54
(d, 1H, J=8.8 Hz), 7.36 (dd, 1H, J=4.3, 7.0 Hz), 7.22 (t, 1H,
J=73.1 Hz), 4.24 (dd, 1H, J=8.6, 12.3 Hz), 4.09 (dd, 1H, J=3.9,
12.3 Hz), 3.80 (dd, 1H, J=8.9, 12.6 Hz), 3.59-3.47 (m, 1H),
3.02-2.92 (m, 1H), 2.88-2.80 (m, 1H), 2.65-2.48 (m, 4H), 2.29 (s,
3H).
Example 297
##STR00629##
[0814] 2-Amino-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
[1-(3-amino-cyclobutyl)-3-(5-chloro-2-difluoromethoxy-phenyl)-1H-pyrazol--
4-yl]-amide
[0815] The title compound was prepared in an analogous manner to
2-amino-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
[3-(5-chloro-2-difluoromethoxy-phenyl)-1-piperidin-4-yl-1H-pyrazol-4-yl]--
amide using tert-butyl
(3-((3-(5-chloro-2-(difluoromethoxy)phenyl)-1H-pyrazol-4-yl)carbamoyl)pyr-
azolo[1,5-a]pyrimidin-2-yl) carbamate and trans-toluene-4-sulfonic
acid 3-tert-butoxycarbonylamino-cyclobutyl ester to afford the
title compound as a white solid. LCMS (Method 5) [M+H].sup.+=489.1,
R.sub.T=2.87 min. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.:
(ppm) 9.53 (s, 1H), 8.93 (dd, 1H, J=1.6, 6.8 Hz), 8.37-8.34 (m,
2H), 7.63-7.60 (m, 2H), 7.45 (d, 1H, J=7.2 Hz), 7.25 (t, 1H, J=72.6
Hz), 7.00 (dd, 1H, J=4.5, 6.5 Hz), 6.56 (s, 2H), 4.51-4.41 (m, 1H),
3.18-3.07 (m, 1H), 2.75-2.67 (m, 2H), 2.24-2.14 (m, 2H).
Example 304
##STR00630##
[0816]
N-[1-(2-carbamimidoylethyl)-3-[5-chloro-2-(difluoromethoxy)phenyl]--
1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide
[0817] A mixture of
N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]-
pyrimidine-3-carboxamide (500 mg, 1.24 mmol), 3-bromopropanenitrile
(412 mg, 3.08 mmol), Cs.sub.2CO.sub.3 (1.21 g, 3.70 mol) in
N,N-dimethylformamide (15 mL) was purged with a gentle flow of
nitrogen gas. The resulting mixture was stirred in a sealed tube at
65.degree. C. for 16 then poured into water (200 mL). The crude
product was collected by filtration and then purified by flash
chromatography on silica eluting with ethyl acetate/petroleum ether
(1:2). Appropriate fractions were collected and evaporated to
afford
N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-(2-cyanoethyl)-1H-pyrazol-4-y-
l]pyrazolo[1,5-a]pyrimidine-3-carboxamide as a light yellow solid
(320 mg, 57%). LCMS (Method 17) [M+H].sup.+=458.1, R.sub.T=1.67
min.
[0818] To a solution of
N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-(2-cyanoethyl)-1H-pyrazol-4-y-
l]pyrazolo[1,5-a]pyrimidine-3-carboxamide (200 mg, 0.44 mmol) and
methanol (280 mg, 8.74 mmol) in toluene (10 mL) was added acetyl
chloride (341 mg, 4.34 mmol) dropwise with stirring at 0.degree. C.
The resulting solution was stirred for 2 hours at room temperature.
To this was added a solution of concentrated ammonium hydroxide
(459 mg) in methanol (3 mL) dropwise with stirring at 0.degree. C.
The resulting solution was stirred overnight at room temperature
and concentrated under reduced pressure. The residue was purified
by flash chromatography on silica eluting with
dichloromethane/methanol (5/1). Appropriate fractions were
collected and concentrated to afford a white solid (130 mg), which
was further purified by high pH Prep-HPLC to afford N-[l
1-(2-carbamimidoylethyl)-3-[5-chloro-2-(difluoromethoxy)-phenyl]-1H-pyraz-
ol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide as a white solid
(36.8 mg). LCMS (Method 17) [M+H].sup.+=475.1 (Note: under method
17, decomposition products observed), LCMS (method 18) R.sub.T=6.52
min. .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta.: (ppm) 9.72 (s,
1H), 9.36 (dd, J=1.8, 7.2 Hz, 1H), 8.68-8.66 (m, 2H), 8.35 (s, 1H),
7.64-7.60 (m, 2H), 7.48-7.24 (m, 3H), 6.39 (s, 2H), 4.44 (t, J=7.2
Hz, 2H), 2.67 (t, J=7.2 Hz, 2H).
Example 306
##STR00631##
[0819] Ethyl
2-[(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidin-
e-3-amido]-1H-pyrazol-1-yl]ethyl)amino]acetate
[0820] A mixture of
N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]-
pyrimidine-3-carboxamide (3.00 g, 7.41 mmol), Cs.sub.2CO.sub.3
(9.90 g, 30.38 mmol), tetrahydrofuran (90 mL), 1,2-dibromoethane
(7.00 g, 37.26 mmol) was stirred at 70.degree. C. for 3 hours in an
oil bath. The mixture was allowed to cool to ambient temperature
then concentrated under reduced pressure. The residue was purified
by flash chromatography on silica eluting with ethyl
acetate/petroleum ether (1:1) to afford
N-[1-(2-bromoethyl)-3-[5-chloro-2-(difluoromethoxy)phenyl]-1H-pyrazol-4-y-
l]pyrazolo[1,5-a]-pyrimidine-3-carboxamide as a off-white solid
(2.2 g, 58%). TLC: R.sub.f=0.6; ethyl acetate/petroleum ether=1:1;
LCMS (Method 14) [M+H].sup.+=513.2, R.sub.T=1.03 min.
[0821] A mixture of
N-[1-(2-bromoethyl)-3-[5-chloro-2-(difluoromethoxy)-phenyl]-1H-pyrazol-4--
yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (200 mg, 0.39 mmol),
triethylamine (394 mg, 3.89 mmol), ethyl 2-aminoacetate
hydrochloride (271 mg, 1.94 mmol) in ethanol (20 mL) was stirred at
80.degree. C. for 24 hours then concentrated under reduced
pressure. The crude product was purified by high pH Prep-HPLC to
afford the title compound as an off-white solid (31.9 mg, 15%).
LCMS (Method 14) [M+H].sup.+=534.2, R.sub.T=1.13 min. .sup.1H NMR
(300 MHz, CD.sub.3OD-d.sub.4) .delta.: (ppm) 9.11 (dd, J=1.5, 7.0
Hz, 1H), 8.66-6.65 (m, 2H), 8.36 (s, 1H), 7.68 (d, J=2.4 Hz, 1H),
7.58 (dd, J=2.7, 8.7 Hz, 1H), 7.42 (d, J=8.7 Hz, 1H), 7.39 (dd,
J=4.5, 7.2 Hz, 1H), 6.55 (t, J=73.5 Hz, 1H), 4.35 (t, J=5.7 Hz,
2H), 4.17 (q, J=7.2 Hz, 2H), 3.41 (s, 2H), 3.15 (t, J=6.0 Hz, 2H),
1.25 (t, J=7.2 Hz, 3H).
Example 310
##STR00632##
[0822]
2-[4-(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]p-
yrimidine-3-amido]-1H-pyrazol-1-yl]acetyl)piperazin-1-yl]acetic
acid
[0823] Potassium hydroxide (200 mg, 3.56 mmol) in water (2 mL) was
added to a solution of ethyl
2-[4-(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimid-
ine-3-amido]-1H-pyrazol-1-yl]acetyl)piperazin-1-yl]acetate (200 mg,
0.32 mmol) in ethanol (20 mL), The resulting solution was stirred
at room temperature for 2 h and neutralized with 1 M HCl aqueous
solution until pH-7. The resultant solution was concentrated under
vacuum. The crude product was purified by Prep-HPLC with the
following conditions (Prep-HPLC-005): Column, XBridge Prep C18 OBD
Column, 5 um, 19*150 mm; mobile phase, water with 10 mmol NH4HCO3
and MeCN (30.0% up to 60.0% in 10 min, up to 95.0% in 1 min, hold
95.0% in 1 min, down to 30.0% in 2 min); Detector, UV 254/220 nm.
This resulted in 20.6 mg (11%) of
2-[4-(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimid-
ine-3-amido]-1H-pyrazol-1-yl]acetyl)piperazin-1-yl]acetic acid as a
white solid. LCMS (Method 26) [M+H].sup.+=589.2, R.sub.T=0.82 min.
.sup.1H NMR (400 MHz, CD.sub.3OD-d.sub.4) .delta.: (ppm) 9.10 (dd,
1H, J=1.6, 7.2 Hz), 8.66 (s, 1H), 8.65 (d, 1H, J=2.8 Hz), 8.38 (s,
1H), 7.69 (d, 1H, J=2.4 Hz), 7.57 (dd, 1H, J=2.4, 8.8 Hz), 7.42 (d,
1H, J=8.8 Hz), 7.21 (J=4.0, 6.8 Hz), 6.63 (t, 1H, J=73.6 Hz), 5.30
(s, 2H), 3.93-3.86 (m, 4H), 3.50 (s, 2H), 3.32-3.13 (m, 4H).
Example 311
##STR00633##
[0824]
2-[[1-(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]-
pyrimidine-3-amido]-1H-pyrazol-1-yl]ethyl)piperidin-4-yl]amino]acetic
acid
[0825] A mixture of t-butyl N-(piperidin-4-yl)carbamate (627 mg,
3.13 mmol) and
N-[1-(2-bromoethyl)-3-[5-chloro-2-(difluoromethoxy)phenyl]-1H-p-
yrazol-4-yl]pyrazolo[1,5-a]--pyrimidine-3-carboxamide (400 mg, 0.78
mmol) in DMF (5 mL) was stirred at 100.degree. C. for 5 h and
cooled to room temperature. Water (50 mL) was added. The
precipitates were collected by filtration and dried. This resulted
in 400 mg (81%) of tert-butyl N-[l
1-(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-
-3-amido]-1H-pyrazol-1-yl]ethyl)piperidin-4-yl]carbamate as a
yellow solid. LCMS (Method 21) [M+H].sup.+=631.1, R.sub.T=1.21
min.
[0826] Saturated HCl dioxane solution (15 mL) was added to
tert-butyl
N-[1-(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimid-
ine-3-amido]-1H-pyrazol-1-yl]ethyl)piperidin-4-yl]carbamate (400
mg, 0.63 mmol). The resulting solution was stirred at room
temperature overnight and concentrated under vacuum. The pH value
of the remaining solution was adjusted to 8-9 with saturated
aqueous Na.sub.2CO.sub.3. The resulting mixture was concentrated
under vacuum. The residue was purified by flash chromatography on
silica eluting with MeOH/DCM (1:1) to afford 330 mg (98%) of
N-[1-[2-(4-aminopiperidin-1-yl)ethyl]-3-[5-chloro-2-(difluoromet-
hoxy)phenyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide
as a yellow solid. LCMS (Method 28) [M+H].sup.+=531.1, R.sub.T=0.49
min.
[0827] Potassium carbonate (98 mg, 0.71 mmol) was added to a
solution of
N-[1-[2-(4-aminopiperidin-1-yl)ethyl]-3-[5-chloro-2-(difluoromethoxy)phen-
yl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (290
mg, 0.55 mmol) and tert-butyl 2-bromoacetate (96 mg, 0.49 mmol) in
DMF (5 mL). The resulting mixture was stirred at 50.degree. C.
overnight. The resulting mixture was concentrated under vacuum. The
residue was purified by flash chromatography on silica eluting with
15% MeOH in DCM to afford 150 mg (43%) of tert-butyl
2-[[1-(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimi-
dine-3-amido]-1H-pyrazol-1-yl]ethyl)piperidin-4-yl]amino]-acetate
as a yellow solid. LCMS (Method 24) [M+H].sup.+=645.2, R.sub.T=1.39
min.
[0828] A solution of tert-butyl ester from previous step (150 mg,
0.23 mmol) in DCM (2 mL) and TFA (2 mL) was stirred at room
temperature overnight. The resulting mixture was concentrated under
vacuum. The crude product was purified by Prep-HPLC with the
following conditions (Prep-HPLC-005): Column, XBridge Prep C18 OBD
Column, 5 um, 19*150 mm; mobile phase, water with 0.05% FA and MeCN
(20.0% up to 27.0% in 10 min, up to 95.0% in 1 min, hold 95.0% in 1
min, down to 20.0% in 2 min); Detector, UV 254/220 nm. This
resulted in 63.5 mg (43%) of the formic acid salt of
2-[[1-(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimi-
dine-3-amido]-1H-pyrazol-1-yl]ethyl)piperidin-4-yl]amino]acetic
acid as an off-white solid. LCMS (Method 25) [M+H].sup.+=589.1,
R.sub.T=0.85 min. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.:
(ppm) 9.73 (s, 1H), 9.34 (d, 1H, J=8.0 Hz), 8.79-8.65 (m, 2H),
8.46-8.35 (m, 1H), 7.64-6.98 (m, 5H), 4.30 (s, 2H), 3.10-2.82 (m,
5H), 2.54-2.53 (m, 2H), 2.17-1.93 (m, 4H), 1.58-1.45 (m, 2H).
Example 312
##STR00634##
[0829]
N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-(2-[[2-(methylsulfanyl)-
ethyl]amino]ethyl)-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide
[0830] 2-(Methylsulfanyl)ethan-1-amine (0.5 mL, 5.34 mmol) was
added to a solution of
N-[1-(2-bromoethyl)-3-[5-chloro-2-(difluoromethoxy)phenyl]-1H-pyrazol-4-y-
l]pyrazolo [1,5-a]pyrimidine-3-carboxamide (120 mg, 0.23 mmol) in
CH.sub.3CN (3 mL). The resulting solution was stirred at 80.degree.
C. for 2 h and concentrated under vacuum. The crude product was
purified by Prep-HPLC with the following conditions
(Prep-HPLC-005): Column, XBridge Prep C18 OBD Column, 5 um, 19*150
mm; mobile phase, water with 10 mmol NH.sub.4HCO.sub.3 and MeCN
(40.0% up to 57.0% in 10 min, up to 95.0% in 1 min, hold 95.0% in 1
min, down to 40.0% in 2 min); Detector, UV 254/220 nm. This
resulted in 58.2 mg (48%) of
N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-(2-[[2-(methylsulfanyl)ethyl]-
-amino]ethyl)-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide
as a yellow solid. LCMS (Method 20) [M+H].sup.+=522.2, R.sub.T=2.50
min. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.: (ppm) 9.73 (s,
1H), 9.34 (dd, 1H, J=1.6, 6.8 Hz), 8.67 (dd, 1H, J=1.6, 4.4 Hz),
8.67 (s, 1H), 8.36 (s, 1H), 7.68-7.61 (m, 2H), 7.46-7.44 (m, 1H),
7.28 (dd, 1H, J=4.4, 7.2 Hz), 7.06 (t, 1H, J=73.2 Hz), 4.23 (t, 2H,
J=6.4 Hz), 2.98 (t, 2H, J=6.0 Hz), 2.71 (t, 2H, J=6.8 Hz), 2.53 (t,
2H, J=6.8 Hz), 2.03 (s, 3H).
Example 313
##STR00635##
[0831]
N-[1-[2-(benzylamino)ethyl]-3-[5-chloro-2-(difluoromethoxy)phenyl]--
1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide
[0832] Using synthetic method analogous to that of
N-[3-[5-chloro-2-(difluoromethoxy)
phenyl]-1-(2-[[2-(methylsulfanyl)ethyl]amino]ethyl)-1H-pyrazol-4-yl]pyraz-
olo[1,5-a]pyrimidine-3-carboxamide, the title compound was prepared
from
N-[1-(2-bromoethyl)-3-[5-chloro-2-(difluoromethoxy)phenyl]-1H-pyrazol-4-y-
l]pyrazolo[1,5-a]pyrimidine-3-carboxamide and phenylmethanamine.
LCMS (Method 20) [M+H].sup.+=538.2, R.sub.T=2.70 min. .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta.: (ppm) 9.84 (s, 1H), 9.34 (dd, 1H,
J=1.6, 6.8 Hz), 8.67 (dd, 1H, J=1.6, 4.4 Hz), 8.67 (s, 1H), 8.37
(s, 1H), 7.64-7.59 (m, 2H), 7.46-7.42 (m, 1H), 7.32-7.19 (m, 6H),
7.06 (t, 1H, J=73.2 Hz), 4.25 (t, 2H, J=6.4 Hz), 3.73 (s, 2H), 2.93
(t, 2H, J=6.4 Hz).
Example 314
##STR00636##
[0833]
N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[2-[(pyridin-2-ylmethyl-
)amino]ethyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide
[0834] Using synthetic method analogous to that of
N-[3-[5-chloro-2-(difluoromethoxy)
phenyl]-1-(2-[[2-(methylsulfanyl)ethyl]amino]ethyl)-1H-pyrazol-4-yl]pyraz-
olo[1,5-a]pyrimidine-3-carboxamide, the title compound was prepared
from
N-[1-(2-bromoethyl)-3-[5-chloro-2-(difluoromethoxy)phenyl]-1H-pyrazol-4-y-
l]pyrazolo[1,5-a]pyrimidine-3-carboxamide and
pyridin-2-ylmethanamine. LCMS (Method 20) [M+H].sup.+=539.2,
R.sub.T=2.53 min. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.:
(ppm) 9.75 (s, 1H), 9.34 (dd, 1H, J=1.6, 6.8 Hz), 8.68 (dd, 1H,
J=1.6, 4.0 Hz), 8.67 (s, 1H), 8.49 (d, 1H, J=4.0 Hz), 8.37 (s, 1H),
7.72 (dd, 1H, J=1.6, 7.6 Hz), 7.70-7.61 (m, 2H), 7.46-7.06 (m, 5H),
4.27 (t, 2H, J=6.0 Hz), 3.83 (s, 2H), 2.98 (t, 2H, J=6.0 Hz).
Example 315
##STR00637##
[0835]
N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[2-[(pyridin-4-ylmethyl-
)amino]ethyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide
[0836] Using synthetic method analogous to that of
N-[3-[5-chloro-2-(difluoromethoxy)
phenyl]-1-(2-[[2-(methylsulfanyl)ethyl]amino]ethyl)-1H-pyrazol-4-yl]pyraz-
olo[1,5-a]pyrimidine-3-carboxamide, the title compound was prepared
from
N-[1-(2-bromoethyl)-3-[5-chloro-2-(difluoromethoxy)phenyl]-1H-pyrazol-4-y-
l]pyrazolo[1,5-a]pyrimidine-3-carboxamide and
pyridin-4-ylmethanamine. LCMS (Method 25) [M+H].sup.+=539.1,
R.sub.T=1.45 min. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.:
(ppm) 9.74 (s, 1H), 9.34 (dd, 1H, J=1.6, 6.8 Hz), 8.68 (dd, 1H,
J=1.6, 4.4 Hz), 8.45 (d, 2H, J=6.0 Hz), 8.38 (s, 1H), 7.64-7.59 (m,
2H), 7.44 (d, 1H, J=8.8 Hz), 7.32-7.28 (m, 3H), 7.07 (t, 1H, J=73.2
Hz), 4.26 (t, 2H, J=6.0 Hz), 3.76 (s, 2H), 2.93 (t, 2H, J=6.0
Hz).
##STR00638##
N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[2-oxo-2-[4-(1-phenylethyl)pi-
perazin-1-yl]ethyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamid-
e
[0837] To a solution of tert-butyl piperazine-1-carboxylate (1.00
g, 5.37 mmol) and 1-phenylethan-1-one (774 mg, 6.44 mmol) in
methanol (30 mL) was added NaBH.sub.3CN (511 mg, 8.13 mmol). The
resulting solution was stirred at 50.degree. C. overnight. Water
(50 mL) was added. Methanol was stripped off under vacuum. The
remaining solution was extracted with ethyl acetate (.times.2). The
organic layers were combined, washed with brine, dried over
anhydrous sodium sulfate and concentrated under vacuum. The residue
was purified by flash chromatography on silica gel column eluting
with ethyl acetate/petroleum ether (1:1). This resulted in 750 mg
(48%) of tert-butyl 4-(1-phenylethyl)piperazine-1-carboxylate as
yellow oil. LCMS (Method 20) [M+H].sup.+=291.1, R.sub.T=1.14
min.
[0838] A solution of tert-butyl
4-(1-phenylethyl)piperazine-1-carboxylate (750 mg, 2.58 mmol) and
saturated HCl dioxane solution (20 mL) was stirred at room
temperature for 3 h. The solids were collected by filtration and
dried. This resulted in 320 mg (55%) of 1-(1-phenylethyl)piperazine
hydrochloride as a white solid.
[0839] To a solution of
{3-(5-Chloro-2-difluoromethoxyphenyl)-4-[(pyrazolo[1,5-a]pyrimidine-3-car-
bonyl)amino]pyrazol-1-yl}acetic acid (100 mg) in DMF (4 mL) was
added 1-(1-phenylethyl)piperazine hydrochloride (47 mg, 0.21 mmol),
DIEA (67 mg, 0.52 mmol), HATU (79.2 mg, 0.21 mmol). The resulting
mixture was stirred at room temperature overnight and concentrated
under vacuum. The crude product was purified by Prep-HPLC with the
following conditions (Prep-HPLC-005): Column, XBridge Prep C18 OBD
Column, 5 um, 19* 150 mm; mobile phase, water with 10 mmol NH4HCO3
and MeCN (40.0% up to 65.0% in 10 min, up to 95.0% in 1 min, hold
95.0% in 1 min, down to 40.0% in 2 min); Detector, UV 254/220 nm.
This resulted in 31.3 mg (28%) of
N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[2-oxo-2-[4-(1-phenylethyl)pi-
perazin-1-yl]ethyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamid-
e as an off-white solid. LCMS (Method 21) [M+H].sup.+=635.0,
R.sub.T=1.56 min. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.:
(ppm) 9.74 (s, 1H), 9.34 (dd, 1H, J=1.6, 7.2 Hz), 8.67 (d, 1H,
J=4.8 Hz), 8.28 (s, 1H), 7.62 (dd, 1H, J=2.8, 8.8 Hz), 7.53 (d, 1H,
J=2.8 Hz), 7.45 (d, 1H, J=8.8 Hz), 7.35-7.26 (m, 6H), 7.07 (t, 1H,
J=73.2 Hz), 5.19 (s, 2H), 3.49-3.46 (m, 5H), 2.49-2.33 (m, 4H),
1.31 (d, 3H, J=6.4 Hz).
Example 317
##STR00639##
[0840]
N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[2-[4-(2-methylpropyl)p-
iperazin-1-yl]-2-oxoethyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-car-
boxamide
[0841] Using synthetic method analoguous to that of
N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[2-oxo-2-[4-(1-phenylethyl)pi-
perazin-1-yl]ethyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamid-
e, the title compound was prepared from
{3-(5-Chloro-2-difluoromethoxyphenyl)-4-[(pyrazolo[1,5-a]pyrimidine-3-car-
bonyl)amino]pyrazol-1-yl}acetic acid and
1-(2-methylpropyl)piperazine. LCMS (Method 25) [M+H].sup.+=587.1,
R.sub.T=1.80 min. .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta.:
(ppm) 9.75 (s, 1H), 9.33 (dd, 1H, J=1.8, 6.9 Hz), 8.68 (dd, 1H,
J=1.5, 3.9 Hz), 8.67 (s, 1H), 8.31 (s, 1H), 7.62 (dd, 1H, J=3.0,
8.7 Hz), 7.55 (d, 1H, J=2.7 Hz), 7.45 (d, 1H, J=9.0 Hz), 7.28 (dd,
1H, J=4.2, 7.2 Hz), 7.02 (t, 1H, J=73.2 Hz), 5.23 (s, 2H),
3.57-3.42 (m, 4H), 2.40-2.21 (m, 4H), 2.05 (d, 2H, J=7.2 Hz),
1.81-1.76 (m, 1H), 0.86 (d, 6H, J=6.3 Hz).
Example 318
##STR00640##
[0842]
N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-(2-[4-[(3-methyloxetan--
3-yl)methyl]piperazin-1-yl]-2-oxoethyl)-1H-pyrazol-4-yl]pyrazol[1,5-a]pyri-
midine-3-carboxamide
[0843] To a solution of 3-methyloxetane-3-carbaldehyde (17.2 mg,
0.17 mmol) and
N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[2-oxo-2-(piperazin-
-1-yl)ethyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide
(70 mg, 0.13 mmol) in methanol (5 mL) was added NaBH.sub.3CN (12.5
mg, 0.20 mmol). The resulting solution was stirred at room
temperature overnight. The reaction was then quenched by the
addition of 5 mL of water. The resulting mixture was concentrated
under vacuum. The residue was dissolved in ethyl acetate (30 mL),
washed with brine, dried and concentrated. The crude product was
purified by Prep-HPLC with the following conditions
(Prep-HPLC-005): Column, XBridge Prep C18 OBD Column, 5 um, 19*150
mm; mobile phase, water with 10 mmol NH.sub.4HCO.sub.3 and MeCN
(55.0% up to 65.0% in 10 min, up to 95.0% in 1 min, hold 95.0% in 1
min, down to 55.0% in 2 min); Detector, UV 254/220 nm. This
resulted in 39.8 mg (49%) of
N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-(2-[4-[(3-methyloxetan-3-yl)m-
ethyl]piperazin-1-yl]-2-oxoethyl)-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidin-
e-3-carboxamide. LCMS (Method 25) [M+H].sup.+=615.2, R.sub.T=0.93
min. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.: (ppm) 9.92 (s,
1H), 9.36-9.27 (m, 1H), 8.91-8.68 (m, 2H), 8.31 (s, 1H), 7.73-7.46
(m, 3H), 7.37-7.06 (m, 2H), 5.23 (s, 2H), 4.52-4.20 (m, 4H),
3.60-3.11 (m, 6H), 2.43-2.20 (m, 4H), 1.46 (s, 3H).
Example 319
##STR00641##
[0844]
N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[2-oxo-2-(4-propylpiper-
azin-1-yl)ethyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide
[0845] To a solution of 1-propylpiperazine dihydrobromide (60.4 mg,
0.21 mmol) and
{3-(5-Chloro-2-difluoromethoxyphenyl)-4-[(pyrazolo[1,5-a]pyrimi-
dine-3-carbonyl)amino]pyrazol-1-yl}acetic acid (100 mg) in DMF (2
mL) was added DIEA (112 mg, 0.866 mmol), HATU (79.2 mg, 0.21 mmol).
The resulting solution was stirred at room temperature overnight
and concentrated under vacuum. The crude product was purified by
Prep-HPLC with the following conditions (Prep-HPLC-005): Column,
XBridge Prep C18 OBD Column, 5 um, 19*150 mm; mobile phase, water
with 10 mmol NH4HCO3 and MeCN (50.0% up to 61.0% in 10 min, up to
95.0% in 1 min, hold 95.0% in 1 min, down to 50.0% in 2 min);
Detector, UV 254/220 nm. This resulted in 69.1 mg (70%) of
N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[2-oxo-2-(4-propylpiperazin-1-
-yl)ethyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide
as a white solid. LCMS (Method 20) [M+H].sup.+=573.2, R.sub.T=2.86
min. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.: (ppm) 9.76 (s,
1H), 9.34 (dd, 1H, J=1.6, 6.8 Hz), 8.68 (dd, 1H, J=1.6, 7.6 Hz),
8.67 (s, 1H), 8.31 (s, 1H), 7.62 (dd, 1H, J=2.4, 8.8 Hz), 7.55 (d,
1H, J=2.4 Hz), 7.45 (d, 1H, J=8.8 Hz), 7.28 (dd, 1H, J=4.4, 6.8
Hz), 7.08 (t, 1H, J=73.6 Hz), 5.23 (s, 2H), 3.48 (t, 4H, J=6.0 Hz),
2.40-2.34 (m, 4H), 2.24 (t, 2H, J=7.2 Hz), 1.48-1.41 (m, 2H), 0.85
(t, 3H, J=7.2 Hz).
Example 320
##STR00642##
[0846]
N-[1-[2-(4-benzylpiperazin-1-yl)-2-oxoethyl]-3-[5-chloro-2-(difluor-
omethoxy)phenyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide
[0847] To a solution of
2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-3--
amido]-1H-pyrazol-1-yl]acetic acid (100 mg, 0.17 mmol) in DMF (4
mL) and 1-benzylpiperazine (33.6 mg, 0.19 mmol) was added DIEA
(44.8 mg, 0.35 mmol), HATU (79.2 mg, 0.21 mmol). The resulting
solution was stirred at room temperature overnight. The resulting
mixture was concentrated under vacuum. The crude product was
purified by Prep-HPLC with the following conditions
(Prep-HPLC-005): Column, XBridge Prep C18 OBD Column, 5 um, 19*150
mm; mobile phase, water with 10 mmol NH.sub.4HCO.sub.3 and MeCN
(37.0% MeCN up to 50.0% in 10 min, up to 95.0% in 1 min, hold 95.0%
in 1 min, down to 37.0% in 2 min); Detector, UV 254/220 nm. This
resulted in 53.8 mg (50%) of
N-[1-[2-(4-benzylpiperazin-1-yl)-2-oxoethyl]-3-[5-chloro-2-(difluorometho-
xy)phenyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide
as an off-white solid. LCMS (Method 21) [M+H].sup.+=621.0,
R.sub.T=1.53 min. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.:
(ppm) 9.75 (s, 1H), 9.34 (dd, 1H, J=1.6, 7.2 Hz), 8.69-8.68 (m,
2H), 8.30 (s, 1H), 7.62 (dd, 1H, J=2.8, 8.8 Hz), 7.55 (d, 1H, J=2.8
Hz), 7.45 (d, 1H, J=8.8 Hz), 7.65-7.24 (m, 6H), 7.08 (t, 1H, J=73.2
Hz), 5.23 (m, 2H), 3.52-3.46 (m, 6H), 2.49-2.33 (m, 4H).
Example 321
##STR00643##
[0848]
N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-(2-[4-[2-(morpholin-4-y-
l)ethyl]piperazin-1-yl]-2-oxoethyl)-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimid-
ine-3-carboxamide
[0849] To a solution of
{3-(5-Chloro-2-difluoromethoxyphenyl)-4-[(pyrazolo[1,5-a]pyrimidine-3-car-
bonyl)amino]pyrazol-1-yl}acetic acid (100 mg) and
4-[2-(piperazin-1-yl)ethyl]morpholine (41 mg, 0.21 mmol) in DMF (5
mL) was added DIEA (45 mg, 0.35 mmol), HATU (79 mg, 0.21 mmol). The
resulting solution was stirred at room temperature for 3 h. The
resulting mixture was concentrated under vacuum. The crude product
was purified by Prep-HPLC with the following conditions
(Prep-HPLC-005): Column, XBridge Prep C18 OBD Column, 5 um, 19*150
mm; mobile phase, water with 10 mmol NH.sub.4HCO.sub.3 and MeCN
(37.0% MeCN up to 52.0% in 10 min, up to 95.0% in 1 min, hold 95.0%
in 1 min, down to 37.0% in 2 min); Detector, UV 254/220 nm. This
resulted in 62.0 mg (56%) of
N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-(2-[4-[2-(morpholin-4-yl)ethy-
l]piperazin-1-yl]-2-oxoethyl)-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3--
carboxamide as a white solid. LCMS (Method 20) [M+H].sup.+=644.2,
R.sub.T=2.34 min. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.:
(ppm) 9.76 (s, 1H), 9.34 (dd, 1H, J=1.6, 7.2 Hz), 8.68-8.67 (m,
2H), 8.31 (s, 1H), 7.63 (dd, 1H, J=2.8, 8.8 Hz), 7.55 (d, 1H, J=2.8
Hz), 7.46 (d, 1H, J=8.8 Hz), 7.28 (dd, 1H, J=4.4, 6.8 Hz), 7.09 (t,
1H, J=73.6 Hz), 5.23 (s, 2H), 3.54 (t, 4H, J=4.4 Hz), 3.50-3.46 (m,
4H), 2.49-2.39 (m, 12H).
Example 322
##STR00644##
[0850] methyl 2-[4-(2-[3-[5-chloro-2-(difluoromethoxy)
phenyl]-4-[pyrazolo[1,5-a]pyrimidine-3-amido]-1H-pyrazol-1-yl]acetyl)pipe-
razin-1-yl]acetate
[0851] To a solution of tert-butyl piperazine-1-carboxylate (5 g,
26.85 mmol) in DMF (50 mL) was added and Cs.sub.2CO.sub.3 (11 g,
33.76 mmol) and methyl 2-bromoacetate (3.4 g, 22.2 mmol). The
resulting mixture was stirred at room temperature for 6 h. Water
(50 mL) and DCM (100 mL) was added. Phases were separated. The
aqueous phase was extracted with DCM (100 mL). The combined organic
phases were washed with brine, dried over anhydrous sodium sulfate
and concentrated under vacuum. This resulted in 7.1 g (crude) of
tert-butyl 4-(2-methoxy-2-oxoethyl)piperazine-1-carboxylate as
yellow oil. LCMS (Method 27) [M+H].sup.+=259.2, R.sub.T=1.08
min.
[0852] A solution of tert-butyl
4-(2-methoxy-2-oxoethyl)piperazine-1-carboxylate (1.50 g, 5.81
mmol) and saturated HCl dioxane solution (20 mL) was stirred at
room temperature for 3 h. The solids were collected by filtration
and dried. This resulted in 950 mg (84%) of methyl
2-(piperazin-1-yl)acetate hydrochloride as a white solid.
[0853] To a solution of
{3-(5-Chloro-2-difluoromethoxyphenyl)-4-[(pyrazolo[1,5-a]pyrimidine-3-car-
bonyl)amino]pyrazol-1-yl}acetic acid (100 mg) in DMF (2 mL) was
added methyl 2-(piperazin-1-yl)acetate hydrochloride (41 mg, 0.21
mmol), DIEA (67.2 mg, 0.52 mmol), HATU (79.2 mg, 0.21 mmol). The
resulting solution was stirred at room temperature for 2 h and
concentrated under vacuum. The residue was passed through a short
pad of silica gel eluting with 10% MeOH in DCM. The crude product
was purified by Prep-HPLC with the following conditions
(Prep-HPLC-005): Column, XBridge Prep C18 OBD Column, 5 um, 19*150
mm; mobile phase, water with 10 mmol NH.sub.4HCO.sub.3 and MeCN
(40.0% up to 59.0% in 10 min, up to 95.0% in 1 min, hold 95.0% in 1
min, down to 40.0% in 2 min); Detector, UV 254/220 nm. This
resulted in 49.2 mg (47%) of methyl
2-[4-(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimid-
ine-3-amido]-1H-pyrazol-1-yl]acetyl)piperazin-1-yl]acetate as a
white solid. LCMS (Method 20) [M+H].sup.+=603.2, R.sub.T=2.83 min.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.: (ppm) 9.76 (s, 1H),
9.34 (dd, 1H, J=1.6, 7.2 Hz), 8.69-8.67 (m, 2H), 8.31 (s, 1H), 7.62
(dd, 1H, J=2.8, 8.8 Hz), 7.56 (d, 1H, J=2.4 Hz), 7.45 (d, 1H, J=8.8
Hz), 7.28 (dd, 1H, J=4.4, 7.2 Hz), 7.08 (t, 1H, J=73.2 Hz), 5.24
(s, 2H), 3.63 (s, 3H), 3.52-3.48 (m, 4H), 3.30 (s, 2H), 2.67-2.51
(m, 4H).
Example 323
##STR00645##
[0854]
N-[3-[5-chloro-2-(difluoromethoxy)pyridin-3-yl]-1-[(5-oxooxolan-2-y-
l)methyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide
[0855] A 8-mL microwave tube was charged with
N-[3-[5-chloro-2-(difluoromethoxy)
phenyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide
(150 mg, 0.37 mmol), 5-(chloromethyl)oxolan-2-one (74.6 mg, 0.55
mmol), Cs.sub.2CO.sub.3 (242 mg, 0.74 mmol) in DMF (2 mL). The
vessel was evacuated under vacuum and refilled with nitrogen 3
times. The final reaction mixture was irradiated with microwave
radiation at 120.degree. C. for 30 min. The resulting mixture was
concentrated under vacuum. The residue was passed through a short
pad of silica gel eluting with ethyl acetate. The crude product was
purified by Prep-HPLC with the following conditions
(Prep-HPLC-005): Column, XBridge Prep C18 OBD Column, 5 um, 19*150
mm; mobile phase, water with 0.05% FA and MeCN (39.0% up to 53.0%
in 10 min, up to 95.0% in 1 min, hold 95.0% in 1 min, down to 39.0%
in 2 min); Detector, UV 254/220 nm. This resulted in 35.8 mg (19%)
of
N-[3-[5-chloro-2-(difluoromethoxy)pyridin-3-yl]-1-[(5-oxooxolan-2-yl)meth-
yl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide as a
white solid. LCMS (Method 20) [M+H].sup.+=503.1, R.sub.T=1.65 min.
.sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta.: (ppm) 9.76 (s, 1H),
9.34 (dd, 1H, J=1.5, 6.9 Hz), 8.68-8.66 (m, 2H), 8.38 (s, 1H), 7.63
(dd, 1H, J=2.7, 8.7 Hz), 7.61 (d, 1H, J=2.7 Hz), 7.45 (d, 1H, J=8.7
Hz), 7.28 (dd, 1H, J=4.2, 6.9 Hz), 7.00 (t, 1H, J=73.2 Hz),
4.98-4.94 (m, 1H), 4.48 (d, 2H, J=5.1 Hz), 2.46-2.23 (m, 3H),
2.07-1.98 (m, 1H).
Example 324
##STR00646##
[0856]
N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[2-oxo-2-(piperazin-1-y-
l)ethyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide
[0857] To a solution of
{3-(5-Chloro-2-difluoromethoxyphenyl)-4-[(pyrazolo[1,5-a]pyrimidine-3-car-
bonyl)amino]pyrazol-1-yl}acetic acid (200 mg) in DMF (5 mL) was
added tert-butyl piperazine-1-carboxylate (77.5 mg, 0.42 mmol),
DIEA (89.6 mg, 0.69 mmol), HATU (158.3 mg, 0.42 mmol). The
resulting solution was stirred at room temperature for 3 h and
concentrated under vacuum. The residue was purified by flash
chromatography on silica gel eluting with 3% MeOH in DCM to afford
279 mg of tert-butyl
4-(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-
-3-amido]-1H-pyrazol-1-yl]acetyl)piperazine-1-carboxylate as a
yellow solid. LCMS (Method 22) [M+H].sup.+=631.4, R.sub.T=1.49
min.
[0858] A solution of tert-butyl
4-(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-
-3-amido]-1H-pyrazol-1-yl]acetyl)piperazine-1-carboxylate (279 mg,
0.44 mmol) and saturated HCl dioxane solution (10 mL) was stirred
at room temperature overnight. The reaction mixture was
concentrated under vacuum. The residue was redissolved in methanol
and neutralized with DIEA. The neutralized solution was
concentrated under vacuum. The crude product was purified by
Prep-HPLC with the following conditions (Prep-HPLC-005): Column,
XBridge Prep C18 OBD Column, 5 um, 19*150 mm; mobile phase, water
with 10 mmol NH.sub.4HCO.sub.3 and MeCN (35.0% MeCN up to 48.0% in
10 min, up to 95.0% in 1 min, hold 95.0% in 1 min, down to 35.0% in
2 min); Detector, UV 254/220 nm. This resulted in 95.6 mg (41%) of
N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[2-oxo-2-(piperazin-1-yl)e-
thyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide as a
white solid. LCMS (Method 20) [M+H].sup.+=531.2, R.sub.T=2.67 min.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.: (ppm) 9.76 (s, 1H),
9.34 (dd, 1H, J=1.6, 6.8 Hz), 8.69-8.67 (m, 2H), 8.30 (s, 1H), 7.62
(dd, 1H, J=2.8, 8.8 Hz), 7.55 (d, 1H, J=2.8 Hz), 7.45 (d, 1H, J=8.8
Hz), 7.28 (dd, 1H, J=4.4, 6.8 Hz), 7.08 (t, 1H, J=73.2 Hz), 5.22
(s, 2H), 3.47-3.41 (m, 4H), 2.73-2.67 (m, 4H).
Example 325
##STR00647##
[0859]
N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-(2-[4-[(dimethylcarbamo-
yl)methyl]piperazin-1-yl]-2-oxoethyl)-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrim-
idine-3-carboxamide
[0860] To a solution of tert-butyl piperazine-1-carboxylate (1 g,
5.37 mmol) in DMF (15 mL) was added Cs.sub.2CO.sub.3 (3.5 g, 10.74
mmol), 2-bromo-N,N-dimethylacetamide (1.80 g, 10.84 mmol). The
resulting mixture was stirred at room temperature overnight. Water
(40 mL) and EtOAc (100 mL) was added. Phases were separated. The
aqueous phase was extracted with EtOAc. The combined organic layers
were washed with brine, dried over anhydrous sodium sulfate and
concentrated under vacuum. The residue was purified by flash
chromatography on silica gel eluting with 3% MeOH in DCM. This
resulted in 880 mg (60%) of tert-butyl
4-[(dimethylcarbamoyl)methyl] piperazine-1-carboxylate as yellow
oil. TLC: R.sub.f=0.3; dichloromethane/methanol=1/10.
[0861] A solution of tert-butyl
4-[(dimethylcarbamoyl)methyl]piperazine-1-carboxylate (880 mg, 3.24
mmol) and saturated HCl dioxane solution (20 mL) was stirred at
room temperature overnight. The solids were collected by
filtration. This resulted in 450 mg (67%) of
N,N-dimethyl-2-(piperazin-1-yl)acetamide hydrochloride as a white
solid.
[0862] To a solution of
{3-(5-Chloro-2-difluoromethoxyphenyl)-4-[(pyrazolo[1,5-a]pyrimidine-3-car-
bonyl)amino]pyrazol-1-yl}acetic acid (100 mg) in DMF (4 mL) was
added N,N-dimethyl-2-(piperazin-1-yl)acetamide hydrochloride (72
mg, 0.35 mmol), DIEA (67.2 mg, 0.52 mmol), HATU (79.2 mg, 0.21
mmol). The resulting solution was stirred at room temperature
overnight and concentrated under vacuum. The crude product was
purified by Prep-HPLC with the following conditions
(Prep-HPLC-005): Column, XBridge Prep C18 OBD Column, 5 um, 19*150
mm; mobile phase, water with 0.05% FA and MeCN (27.0% up to 36.0%
in 10 min, up to 95.0% in 1 min, hold 95.0% in 1 min, down to 27.0%
in 2 min); Detector, UV 254/220 nm. This resulted in 73.4 mg (64%)
of the formic acid salt of
N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-(2-[4-[(dimethylcarbamoyl)
methyl]piperazin-1-yl]-2-oxoethyl)-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimid-
ine-3-carboxamide as a light yellow solid. LCMS (Method 20)
[M+H].sup.+=616.3, R.sub.T=2.41 min. .sup.1H NMR (400 MHz,
CD.sub.3OD-d.sub.4) .delta.: (ppm) 9.09 (dd, 1H, J=1.6, 7.2 Hz),
8.66-8.64 (m, 2H), 8.37 (s, 1H), 8.11 (s, 1H), 7.68 (d, 1H, J=2.8
Hz), 7.57 (dd, 1H, J=2.8, 8.8 Hz), 7.42 (d, 1H, J=8.8 Hz), 7.21
(dd, 1H, J=4.4, 7.2 Hz), 6.63 (t, 1H, J=73.6 Hz), 5.29 (s, 2H),
3.84-3.77 (m, 4H), 3.75 (s, 2H), 3.08 (s, 3H), 3.06-2.96 (m,
7H).
##STR00648##
N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-(2-[[(2-hydroxyphenyl)methyl]-
amino]ethyl)-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide
[0863] NaBH.sub.3CN (112 mg, 1.78 mmol) was added portionwise to a
solution of 2-hydroxybenzaldehyde (55 mg, 0.45 mmol) and
N-[1-(2-aminoethyl)-3-[5-chloro-2-(difluoromethoxy)phenyl]-1H-pyrazol-4-y-
l]pyrazolo[1,5-a]pyrimidine-3-carb oxamide (200 mg, 0.45 mmol) in
methanol (10 mL). The resulting solution was stirred at room
temperature overnight. The reaction was then quenched by the
addition of 0.5 mL of water. The resulting mixture was concentrated
under vacuum. The residue was passed through a short pad of silica
gel eluting with 3% MEOH in DCM. The crude product was purified by
Prep-HPLC with the following conditions (Prep-HPLC-005): Column,
XBridge Prep C.sub.18 OBD Column, 5 um, 19*150 mm; mobile phase,
water with 10 mmol NH.sub.4HCO.sub.3 and MeCN (38.0% up to 45.0% in
10 min, up to 95.0% in 1 min, hold 95.0% in 1 min, down to 38.0% in
2 min); Detector, UV 254/220 nm. This resulted in 28.8 mg (12%) of
N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-(2-[[(2-hydroxyphenyl)
methyl]amino]ethyl)-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxami-
de as a white solid. LCMS (Method 20) [M+H].sup.+=554.2,
R.sub.T=2.79 min. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.:
(ppm) 9.74 (s, 1H), 9.34 (dd, 1H, J=1.6, 7.2 Hz), 8.69-8.67 (m,
2H), 8.37 (s, 1H), 7.63 (dd, 1H, J=2.4, 8.0 Hz), 7.61 (d, 1H, J=2.8
Hz), 7.44 (d, 1H, J=8.8 Hz), 7.28 (dd, 1H, J=4.4, 7.2 Hz),
7.09-7.04 (m, 2H), 7.06 (t, 1H, J=73.6 Hz), 6.73-6.69 (m, 2H), 4.29
(t, 2H, J=6.0 Hz), 3.82 (s, 2H), 2.98 (t, 2H, J=6.0 Hz).
##STR00649##
N-[3-[5-chloro-2-(difluoromethoxy)
phenyl]-1-(2-[[(3-hydroxyphenyl)methyl]amino]ethyl)-1H-pyrazol-4-yl]pyraz-
olo[1,5-a]pyrimidine-3-carboxamide
[0864] NaBH.sub.3CN (28 mg, 0.45 mmol) was added to a solution of
N-[1-(2-aminoethyl)-3-[5-chloro-2-(difluoromethoxy)phenyl]-1H-pyrazol-4-y-
l]pyrazolo[1,5-a]pyrimidine-3-carboxamide (100 mg, 0.22 mmol) in
MeOH (10 mL) and 3-hydroxybenzaldehyde (55 mg, 0.45 mmol). The
resulting solution was stirred for at room temperature overnight.
The reaction was then quenched by the addition of 0.2 mL of water.
The resulting mixture was concentrated under vacuum. The residue
was passed through a short pad of silica gel eluting with 2.5% MeOH
in DCM. The crude product was purified by Prep-HPLC with the
following conditions (Prep-HPLC-005): Column, XBridge Prep C18 OBD
Column, 5 um, 19*150 mm; mobile phase, water with 0.05% FA and MeCN
(32.0% up to 36.0% in 10 min, up to 95.0% in 1 min, hold 95.0% in 1
min, down to 32.0% in 2 min); Detector, UV 254/220 nm. This
resulted in 25.7 mg (19%) of the formic acid salt of
N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-(2-[[(3-hydroxyphenyl)-methyl-
]amino]ethyl)-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide
formate as a white solid. LCMS (Method 20) [M+H].sup.+=554.2,
R.sub.T=1.58 min. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.:
(ppm) 9.37 (s, 1H), 9.34 (dd, 1H, J=1.6, 7.2 Hz), 8.68-8.67 (m,
2H), 8.37 (s, 1H), 7.61 (dd, 1H, J=2.4, 8.8 Hz), 7.60 (d, 1H, J=2.4
Hz), 7.44 (d, 1H, J=8.4 Hz), 7.28 (dd, 1H, J=4.4, 7.2 Hz), 7.05 (t,
1H, J=73.2 Hz), 7.10-7.06 (m, 1H), 6.74-6.72 (m, 2H), 6.60 (d, 1H,
J=7.2 Hz), 4.25 (t, 2H, J=6.0 Hz), 3.66 (s, 2H), 2.94 (t, 2H, J=6.0
Hz).
##STR00650##
N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-(2-[[(4-hydroxyphenyl)methyl]-
amino]ethyl)-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide
[0865] A solution of 4-hydroxybenzaldehyde (55 mg, 0.45 mmol) and
N-[1-(2-aminoethyl)-3-[5-chloro-2-(difluoromethoxy)phenyl]-1H-pyrazol-4-y-
l]pyrazolo[1,5-a]pyrimidine-3-carboxamide (100 mg, 0.22 mmol) in
THF (10 mL) was stirred at room temperature for 2 h and then
NaBH.sub.3CN (28 mg, 0.45 mmol) was added. The resulting solution
was stirred at room temperature overnight. The reaction was then
quenched by the addition of 0.1 mL of water. The resulting mixture
was concentrated under vacuum. The residue was passed through a
short pad of silica gel eluting with 3% MeOH in DCM. The crude
product was purified by Prep-HPLC with the following conditions
(Prep-HPLC-005): Column, XBridge Prep C18 OBD Column, 5 um, 19*150
mm; mobile phase, water with 0.05% FA and MeCN (34.0% MeCN up to
38.0% in 10 min, up to 95.0% in 1 min, hold 95.0% in 1 min, down to
34.0% in 2 min); Detector, UV 254/220 nm. This resulted in 31.4 mg
(23%) of the formic acid salt of
N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-(2-[[(4-hydroxyphenyl)methyl]-
amino]ethyl)-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide
as an off-white solid. LCMS (Method 20) [M+H].sup.+=554.2,
R.sub.T=1.58 min. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.:
(ppm) 9.74 (s, 1H), 9.34 (dd, 1H, J=1.6, 7.2 Hz), 8.69-8.67 (m,
2H), 8.37 (s, 1H), 7.62 (dd, 1H, J=2.8, 8.8 Hz), 7.60 (d, 1H, J=2.4
Hz), 7.44 (d, 1H, J=8.4 Hz), 7.28 (dd, 1H, J=4.4, 7.2 Hz), 7.10 (d,
2H, J=8.4 Hz), 7.06 (t, 1H, J=73.2 Hz), 6.68 (d, 2H, J=8.4 Hz),
4.25 (t, 2H, J=6.4 Hz), 3.63 (s, 2H), 2.95 (t, 2H, J=6.0 Hz).
##STR00651##
methyl
2-[[1-(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a-
] pyrimidine-3-amido]-1H-pyrazol-1-yl]acetyl)piperidin-4-yl]
amino]acetate formate
[0866] To a solution of
{3-(5-Chloro-2-difluoromethoxyphenyl)-4-[(pyrazolo[1,5-a]pyrimidine-3-car-
bonyl)amino]pyrazol-1-yl}acetic acid (500 mg) in DMF (10 mL) was
added tert-butyl N-(piperidin-4-yl)carbamate (208 mg, 1.04 mmol),
DIEA (224 mg, 1.73 mmol), HATU (395.9 mg, 1.04 mmol). The resulting
solution was stirred at room temperature overnight. Water (50 mL)
was added. The precipitates were collected by filtration and dried.
This resulted in 600 mg of tert-butyl
N-[1-(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimid-
ine-3-amido]-1H-pyrazol-1-yl]acetyl) piperidin-4-yl]carbamate as a
yellow crude solid. LCMS (Method 25) [M+H].sup.+=645.1,
R.sub.T=1.02 min.
[0867] A solution of the crude product from previous step (600 mg)
and saturated HCl dioxane solution (15 mL) was stirred at room
temperature overnight. The resulting solution was diluted with 100
mL of methanol and neutralized with saturated
aqueous.Na.sub.2CO.sub.3 and concentrated under vacuum. The residue
was passed through a short pad of silica gel eluting with 30% MeOH
in DCM. Collection of appropriate fractions and evaporation of
solvent afforded N-[l
1-[2-(4-aminopiperidin-1-yl)-2-oxoethyl]-3-[5-chloro-2-(difluoromethoxy)p-
henyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (520
mg) as a yellow solid. LCMS (Method 25) [M+H].sup.+=545.1,
R.sub.T=0.62 min.
[0868] Methyl 2-bromoacetate (30.74 mg, 0.20 mmol) was added to a
mixture of
N-[1-[2-(4-aminopiperidin-1-yl)-2-oxoethyl]-3-[5-chloro-2-(difluoromet-
hoxy)phenyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide
(100 mg, 0.18 mmol) in DMF (5 mL) and potassium carbonate (38.1 mg,
0.28 mmol). The resulting mixture was stirred at room temperature
overnight. Additional amount of methyl 2-bromoacetate (30.74 mg,
0.20 mmol) was added and the resulting solution was stirred at
60.degree. C. for 2 h. The resulting mixture was concentrated under
vacuum. The crude product was purified by Prep-HPLC with the
following conditions (Prep-HPLC-005): Column, XBridge Prep C18 OBD
Column, 5 um, 19*150 mm; mobile phase, water with 0.05% FA and MeCN
(25.0% MeCN up to 32.0% in 10 min, up to 95.0% in 1 min, hold 95.0%
in 1 min, down to 25.0% in 2 min); Detector, UV 254/220 nm. This
resulted in 68.9 mg (57%) of the formic acid salt of methyl
2-[[1-(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimi-
dine-3-amido]-1H-pyrazol-1-yl]acetyl)piperidin-4-yl]amino]-acetate
as an off-white solid. LCMS (Method 24) [M+H].sup.+=617.2,
R.sub.T=1.53 min. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.:
(ppm) 9.75 (s, 1H), 9.34 dd, 1H, J=1.6, 7.2 Hz), 8.69-8.67 (m, 2H),
8.30 (s, 1H), 7.62 (dd, 1H, J=2.4, 8.8 Hz), 7.55 (d, 1H, J=2.8 Hz),
7.45 (d, 1H, J=8.8 Hz), 7.28 (dd, 1H, J=4.0, 6.8 Hz), 7.08 (t, 1H,
J=73.2 Hz), 5.23-5.20 (m, 2H), 4.11-4.07 (m, 1H), 3.83-3.80 (m,
1H), 3.63 (s, 3H), 3.39-3.31 (m, 2H), 3.15-3.12 (m, 1H), 2.87-2.83
(m, 1H), 2.71-2.67 (m, 1H), 1.83-1.77 (m, 2H), 1.29-1.14 (m,
2H).
Example 330
##STR00652##
[0869] N-[3-[5-chloro-2-(difluoromethoxy)
phenyl]-1-[2-[4-(5-hydroxy-2-oxopiperidin-1-yl)piperidin-1-yl]-2-oxoethyl-
]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide
formate
[0870] DIEA (71 mg, 0.55 mmol) was added to a solution of
N-[1-[2-(4-aminopiperidin-1-yl)-2-oxoethyl]-3-[5-chloro-2-(difluoromethox-
y)phenyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide
(100 mg, 0.18 mmol) and (5-oxooxolan-2-yl)methyl
trifluoromethanesulfonate (69 mg, 0.28 mmol) in CH.sub.3CN (30 mL).
The resulting solution was stirred overnight at room temperature.
The resulting mixture was concentrated under vacuum. The crude
product was purified by Prep-HPLC with the following conditions
(Prep-HPLC-005): Column, XBridge Prep C.sub.18 OBD Column, 5 um,
19*150 mm; mobile phase, water with 0.05% FA and MeCN (38.0% up to
46.0% in 10 min, up to 95.0% in 1 min, hold 95.0% in 1 min, down to
38.0% in 2 min); Detector, UV 254/220 nm. This resulted in 41.6 mg
(33%) of N-[3-[5-chloro-2-(difluoromethoxy)
phenyl]-1-[2-[4-(5-hydroxy-2-oxopiperidin-1-yl)piperidin-1-yl]-2-oxoethyl-
]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide as an
off-white solid. LCMS (Method 25) [M+H].sup.+=643.2, R.sub.T=1.49
min. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.: (ppm) 9.75 (s,
1H), 9.35 (dd, 1H, J=1.6, 6.8 Hz), 8.69-8.68 (m, 2H), 8.32 (s, 1H),
7.63 (dd, 1H, J=2.8, 8.8 Hz), 7.56 (d, 1H, J=2.8 Hz), 7.46 (d, 1H,
J=8.8 Hz), 7.29 (dd, 1H, J=4.4, 7.2 Hz), 7.09 (t, 1H, J=73.2 Hz),
5.26-5.24 (m, 2H), 4.89 (br, 1H), 4.59-4.45 (m, 2H), 4.08-3.90 (m,
2H), 3.25-2.97 (m, 3H), 2.68-2.58 (m, 1H), 2.46-2.21 (m, 2H),
1.86-1.65 (m, 3H), 1.57-1.50 (m, 3H).
Example 331
##STR00653##
[0871] methyl
3-[4-(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimid-
ine-3-amido]-1H-pyrazol-1-yl]acetyl)piperazin-1-yl]propanoate
[0872] To a solution of tert-butyl piperazine-1-carboxylate (1 g,
5.37 mmol) in DMF (20 mL) was added Cs.sub.2CO.sub.3 (589 mg, 1.81
mmol) and methyl 3-bromopropanoate (744 mg, 4.46 mmol). The
resulting mixture was stirred at room temperature overnight. Water
(50 m) and EtOAc (50 mL) was added. Phases were separated. The
aqueous phase was extracted with EtOAc (50 mL). The organic layers
were combined, washed with brine, dried over anhydrous sodium
sulfate and concentrated under vacuum. The residue was purified by
flash chromatography on silica gel eluting with 3.5% MeOH in DCM.
Collection of appropriate fractions and evaporation of solvent
afforded tert-butyl
4-(3-methoxy-3-oxopropyl)piperazine-1-carboxylate (895 mg, 74%) as
yellow oil. TLC: R.sub.f=0.3; ethyl acetate/petroleum
ether=1/2.
[0873] A solution of tert-butyl
4-(3-methoxy-3-oxopropyl)piperazine-1-carboxylate (895 mg, 3.29
mmol) and saturated HCl dioxane solution (15 mL) was stirred at
room temperature overnight. The solids were collected by
filtration. This resulted in 710 mg of methyl
3-(piperazin-1-yl)propanoate hydrochloride as a white crude
solid.
[0874] To a solution of
{3-(5-Chloro-2-difluoromethoxyphenyl)-4-[(pyrazolo[1,5-a]pyrimidine-3-car-
bonyl)amino]pyrazol-1-yl}acetic acid (100 mg) in DMF (5 mL) was
added methyl 3-(piperazin-1-yl)propanoate hydrochloride (44 mg,
0.21 mmol), DIEA (90 mg, 0.70 mmol), HATU (79.2 mg, 0.21 mmol). The
resulting solution was stirred at room temperature for 4 h and
concentrated under vacuum. The crude product was purified by
Prep-HPLC with the following conditions (Prep-HPLC-005): Column,
XBridge Prep C18 OBD Column, 5 um, 19*150 mm; mobile phase, water
with 0.05% FA and MeCN (40.0% up to 51.0% in 10 min, up to 95.0% in
1 min, hold 95.0% in 1 min, down to 40.0% in 2 min); Detector, UV
254/220 nm. This resulted in 56.1 mg (49%) of the formic acid salt
of methyl
3-[4-(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimid-
ine-3-amido]-1H-pyrazol-1-yl]acetyl)piperazin-1-yl]propanoate as a
light yellow solid. LCMS (Method 25) [M+H].sup.+=617.1,
R.sub.T=1.51 min. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.:
(ppm) 9.76 (s, 1H), 9.34 (dd, 1H, J=1.6, 7.2 Hz), 8.68-8.67 (m,
2H), 8.31 (s, 1H), 7.62 (dd, 1H, J=2.8, 8.8 Hz), 7.55 (d, 1H, J=2.8
Hz), 7.45 (d, 1H, J=8.8 Hz), 7.28 (dd, 1H, J=4.4, 6.8 Hz), 7.08 (t,
1H, J=73.2 Hz), 5.23 (s, 2H), 3.60 (s, 3H), 3.49-3.41 (m, 4H), 2.59
(t, 2H, J=6.4 Hz), 2.51 (t, 2H, J=6.4 Hz), 2.39-2.33 (m, 4H).
Example 332
##STR00654##
[0875]
3-[4-(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]
pyrimidine-3-amido]-1H-pyrazol-1-yl]acetyl)piperazin-1-yl]propanoate
[0876] Using synthetic methods analoguous to that of methyl
3-[4-(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimid-
ine-3-amido]-1H-pyrazol-1-yl]acetyl)piperazin-1-yl]propanoate, the
title compound was prepared from ethyl 3-bromopropanoate. LCMS
(Method 28) [M+H].sup.+=631.2, R.sub.T=0.89 min. .sup.1H NMR (300
MHz, DMSO-d.sub.6) .delta.: (ppm) 9.76 (s, 1H), 9.34 (d, 1H, J=6.9
Hz), 8.69-8.67 (m, 2H), 8.30 (s, 1H), 7.62 (dd, 1H, J=2.7, 8.7 Hz),
7.55 (d, 1H, J=2.4 Hz), 7.45 (d, 1H, J=9.0 Hz), 7.28 (dd, 1H,
J=4.2, 6.9 Hz), 7.07 (t, 1H, J=72.9 Hz), 5.23 (s, 2H), 4.03 (q, 2H,
J=7.2 Hz), 3.59-3.47 (m, 4H), 2.61-2.59 (m, 2H), 2.50-2.33 (m, 6H),
1.16 (t, 3H, J=7.2 Hz).
Example 333
##STR00655##
[0877] methyl
1-[2-[4-(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyri-
midine-3-amido]-1H-pyrazol-1-yl]acetyl)piperazin-1-yl]ethyl]piperidine-4-c-
arboxylate
[0878] To a stirring solution of tert-butyl
4-(2-hydroxyethyl)piperazine-1-carboxylate (1.5 g, 6.51 mmol) and
DIEA (2.5 g, 19.34 mmol) in DCM (50 mL) was added MsCl (817 mg,
7.13 mmol) dropwise g at 0.degree. C. The resulting solution was
stirred for 1 h at room temperature. Water (100 mL) was added.
Phases were separated. The aqueous phase was extracted with
dichloromethane and the organic layers combined. The organic phases
were washed with brine, dried over anhydrous sodium sulfate and
concentrated under vacuum. This resulted in 1.8 g (crude) of
tert-butyl 4-[2-(methanesulfonyloxy)ethyl] piperazine-1-carboxylate
as light yellow oil.
[0879] To a solution of tert-butyl
4-[2-(methanesulfonyloxy)ethyl]piperazine-1-carboxylate (431 mg,
1.39 mmol) in DMF (5 mL) was added methyl piperidine-4-carboxylate
(300 mg, 2.095 mmol) and DIEA (361 mg, 2.79 mmol). The resulting
solution was stirred at room temperature overnight. The resulting
mixture was concentrated under vacuum. The residue was purified by
flash chromatography on silica gel eluting with 3% MeOH in DCM.
This resulted in 285 mg (57%) of tert-butyl
4-[2-[4-(methoxycarbonyl)piperidin-1-yl]ethyl]piperazine-1-carboxylate
as yellow oil. LCMS (Method 20) [M+H].sup.+=356.2, R.sub.T=0.99
min.
[0880] A solution of tert-butyl
4-[2-[4-(methoxycarbonyl)piperidin-1-yl]ethyl]piperazine-1-carboxylate
(285 mg, 0.80 mmol) and saturated HCl dioxane solution (15 mL) was
stirred at room temperature overnight. The resulting mixture was
concentrated under vacuum. This resulted in 205 mg (88%) of methyl
1-[2-(piperazin-1-yl)ethyl]piperidine-4-carboxylate hydrochloride
as a yellow solid. LCMS (Method 20) [M+H].sup.+=256.2, R.sub.T=0.44
min.
[0881] To a solution of
{3-(5-Chloro-2-difluoromethoxyphenyl)-4-[(pyrazolo[1,5-a]pyrimidine-3-car-
bonyl)amino]pyrazol-1-yl}acetic acid (150 mg, 0.32 mmol) in DMF (10
mL) was added methyl
1-[2-(piperazin-1-yl)ethyl]piperidine-4-carboxylate hydrochloride
(190 mg, 0.65 mmol), DIEA (126 mg, 0.97 mmol), HATU (148 mg, 0.39
mmol). The resulting solution was stirred at room temperature
overnight and concentrated under vacuum. The residue was passed
through a short pad of silica gel eluting with 4% MeOH in DCM. The
crude product was purified by Prep-HPLC with the following
conditions (Prep-HPLC-005): Column, XBridge Prep C18 OBD Column, 5
um, 19*150 mm; mobile phase, water with 0.05% FA and MeCN (22.0% up
to 31.0% in 10 min, up to 95.0% in 1 min, hold 95.0% in 1 min, down
to 22.0% in 2 min); Detector, UV 254/220 nm. This resulted in 96.5
mg (40%) of the formic acid salt of methyl
1-[2-[4-(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyri-
midine-3-amido]-1H-pyrazol-1-yl]acetyl)piperazin-1-yl]ethyl]
piperidine-4-carboxylate as a light yellow solid. LCMS (Method 24)
[M+H].sup.+=700.2, R.sub.T=2.21 min. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta.: (ppm) 9.75 (s, 1H), 9.34 (dd, 1H, J=1.6, 6.8
Hz), 8.69-8.68 (m, 2H), 8.30 (s, 1H), 7.62 (dd, 1H, J=2.8, 8.8 Hz),
7.55 (d, 1H, J=2.4 Hz), 7.46 (d, 1H, J=8.8 Hz), 7.28 (dd, 1H,
J=4.4, 6.8 Hz), 7.08 (t, 1H, J=73.2 Hz), 5.23 (s, 2H), 3.59 (s,
3H), 3.49-3.46 (m, 4H), 2.84-2.81 (m, 2H), 2.54-2.52 (m, 6H),
2.50-2.40 (m, 2H), 2.33-2.27 (m, 1H), 2.04-1.99 (m, 2H), 1.88-1.70
(m, 2H), 1.55-1.50 (m, 2H).
Example 334
##STR00656##
[0882] ethyl
1-[2-[4-(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]
pyrimidine-3-amido]-1H-pyrazol-1-yl]acetyl)piperazin-1-yl]ethyl]piperidin-
e-4-carboxylate
[0883] To a solution of tert-butyl
4-[2-(methanesulfonyloxy)ethyl]piperazine-1-carboxylate (392 mg,
1.27 mmol) in DMF (5 mL) was added DIEA (329 mg, 2.55 mmol) and
ethyl piperidine-4-carboxylate (300 mg, 1.91 mmol). The resulting
solution was stirred at room temperature overnight and concentrated
under vacuum. The residue was purified by flash chromatography on
silica gel eluting with 5% MeOH in DCM. This resulted in 310 mg
(66%) of tert-butyl
4-[2-[4-(ethoxycarbonyl)piperidin-1-yl]ethyl]piperazine-1-carboxylate
as a yellow solid. LCMS (Method 28) [M+H].sup.+=370.3, R.sub.T=0.50
min.
[0884] A mixture of tert-butyl
4-[2-[4-(ethoxycarbonyl)piperidin-1-yl]ethyl]piperazine-1-carboxylate
(310 mg, 0.84 mmol) and saturated HCl dioxane solution (15 mL) was
stirred at room temperature overnight. The resulting mixture was
concentrated under vacuum.
[0885] This resulted in 220 mg (86%) of ethyl
1-[2-(piperazin-1-yl)ethyl]piperidine-4-carboxylate hydrochloride
as a light yellow solid. LCMS (Method 28) [M+H].sup.+=270.3,
R.sub.T=0.89 min.
[0886] To a solution of
2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-3--
amido]-1H-pyrazol-1-yl]acetic acid (150 mg, 0.32 mmol) in DMF (10
mL) was added ethyl
1-[2-(piperazin-1-yl)ethyl]piperidine-4-carboxylate hydrochloride
(199 mg, 0.65 mmol), DIEA (126 mg, 0.97 mmol), HATU (148 mg, 0.39
mmol). The resulting solution was stirred at room temperature
overnight and concentrated under vacuum. The residue was passed
through a short pad of silica gel eluting with 3% MeOH in DCM. The
crude product was purified by Prep-HPLC with the following
conditions (Prep-HPLC-005): Column, XBridge Prep C18 OBD Column, 5
um, 19*150 mm; mobile phase, water with 0.05% FA and MeCN (18.0%
MeCN up to 27.0% in 10 min, up to 95.0% in 1 min, hold 95.0% in 1
min, down to 18.0% in 2 min); Detector, UV 254/220 nm. This
resulted in 66.1 mg (27%) of the formic acid salt of ethyl
1-[2-[4-(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyri-
midine-3-amido]-1H-pyrazol-1-yl]acetyl)piperazin-1-yl]ethyl]piperidine-4-c-
arboxylate. LCMS (Method 24) [M+H].sup.+=714.2, R.sub.T=2.42 min.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.: (ppm) 9.76 (s, 1H),
9.34 (dd, 1H, J=1.6, 6.8 Hz), 8.69-8.68 (m, 2H), 8.31 (s, 1H), 7.62
(dd, 1H, J=2.8, 8.8 Hz), 7.56 (d, 1H, J=2.4 Hz), 7.46 (d, 1H, J=8.8
Hz), 7.29 (dd, 1H, J=4.4, 6.8 Hz), 7.08 (t, 1H, J=73.2 Hz), 5.23
(m, 2H), 4.03 (q, 2H, J=6.8 Hz), 3.50-3.47 (m, 4H), 2.88-2.85 (m,
2H), 2.52-2.51 (m, 6H), 2.47-2.26 (m, 3H), 2.12-2.07 (m, 2H),
1.80-1.78 (m, 2H), 1.60-1.55 (m, 2H), 1.16 (t, 3H, J=7.2 Hz). Q
Example 335
##STR00657##
[0887] methyl
1-[2-[4-(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyri-
midine-3-amido]-1H-pyrazol-1-yl]acetyl)piperazin-1-yl]ethyl]-4-methylpiper-
idine-4-carboxylate formate
[0888] Using synthetic method analoguous to that of ethyl
1-[2-[4-(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyri-
midine-3-amido]-1H-pyrazol-1-yl]acetyl)piperazin-1-yl]ethyl]piperidine-4-c-
arboxylate, the title compound was prepared from methyl
4-methylpiperidine-4-carboxylate hydrochloride.
[0889] LCMS (Method 24) [M+H].sup.+=714.2, R.sub.T=1.94 min.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.: (ppm) 9.75 (s, 1H),
9.34 (dd, 1H, J=1.6, 6.8 Hz), 8.69-8.68 (m, 2H), 8.30 (s, 1H),
7.65-7.62 (dd, 1H, J=2.8, 8.8 Hz), 7.55 (d, 1H, J=2.8 Hz), 7.45 (d,
1H, J=8.8 Hz), 7.28 (dd, 1H, J=4.4, 6.8 Hz), 7.08 (t, 1H, J=73.6
Hz), 5.22 (s, 2H), 3.62 (s, 3H), 3.48-3.45 (m, 4H), 2.57-2.51 (m,
2H), 2.49-2.39 (m, 8H), 2.01-1.93 (m, 4H), 1.41-1.35 (m, 2H), 1.10
(s, 3H). .quadrature.
Example 336
##STR00658##
[0890] 2-(morpholin-4-yl)ethyl
1-(2-[3-[5-chloro-2-(difluoromethoxy)
phenyl]-4-[pyrazolo[1,5-a]pyrimidine-3-amido]-1H-pyrazol-1-yl]acetyl)pipe-
ridine-4-carboxylate
[0891] To a solution of
1-[(tert-butoxy)carbonyl]piperidine-4-carboxylic acid (1.00 g, 4.36
mmol) in DCM (15 mL) was added 2-(morpholin-4-yl)ethan-1-ol (858
mg, 6.54 mmol), EDC.HCl (1.00 g, 5.22 mmol),
4-dimethylaminopyridine (53.3 mg, 0.44 mmol). The resulting
solution was stirred at room temperature overnight. Water (30 mL)
and DCM (50 mL) was added. Phases were separated. The aqueous phase
was extracted with DCM and the organic layers combined. The
combined organic layers were washed with brine, dried over
anhydrous sodium sulfate and concentrated under vacuum. The residue
was purified by flash chromatography on silica gel eluting with
dichloromethane/ethyl acetate (2:3). This resulted in 1.4 g (crude)
of 1-tert-butyl
4-[2-(morpholin-4-yl)ethyl]piperidine-1,4-dicarboxylate as yellow
oil. TLC: R.sub.f=0.3; ethyl acetate.
[0892] A mixture of 1-tert-butyl 4-[2-(morpholin-4-yl)ethyl]
piperidine-1,4-dicarboxylate (1.4 g, 4.09 mmol) and saturated HCl
dioxane solution (20 mL) was stirred at room temperature overnight.
The resulting mixture was concentrated under vacuum. This resulted
in 1.2 g (crude) of 2-(morpholin-4-yl)ethyl
piperidine-4-carboxylate hydrochloride as yellow oil.
[0893] To a solution of
{3-(5-Chloro-2-difluoromethoxyphenyl)-4-[(pyrazolo[1,5-a]pyrimidine-3-car-
bonyl)amino]pyrazol-1-yl}acetic acid (150 mg, 0.26 mmol) in DMF (2
mL) was added 2-(morpholin-4-yl)ethyl piperidine-4-carboxylate
hydrochloride (140 mg, 0.50 mmol), DIEA (101 mg, 0.78 mmol), HATU
(119 mg, 0.31 mmol). The resulting solution was stirred at room
temperature overnight and concentrated under vacuum. The residue
was passed through a short pad of silica gel eluting with 10% MeOH
in DCM. The crude product was purified by Prep-HPLC with the
following conditions (Prep-HPLC-005): Column, XBridge Prep C18 OBD
Column, 5 um, 19*150 mm; mobile phase, water with 0.05% FA and MeCN
(31.0% MeCN up to 38.0% in 10 min, up to 95.0% in 1 min, hold 95.0%
in 1 min, down to 31.0% in 2 min); Detector, UV 254/220 nm. This
resulted in 35.6 mg (20%) of the formic acid salt of
2-(morpholin-4-yl)ethyl
1-(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-
-3-amido]-1H-pyrazol-1-yl]acetyl)piperidine-4-carboxylate as a
off-white solid. LCMS (Method 28) [M+H].sup.+=687.2, R.sub.T=0.86
min. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.: (ppm) 9.76 (s,
1H), 9.34 (dd, 1H, J=1.6, 7.2 Hz), 8.69-8.68 (m, 2H), 8.32 (s, 1H),
7.63 (dd, 1H, J=2.4, 8.8 Hz), 7.55 (d, 1H, J=2.8 Hz), 7.46 (d, 1H,
J=8.8 Hz), 7.29 (dd, 1H, J=4.4, 6.8 Hz), 7.08 (t, 1H, J=73.2 Hz),
5.27-5.22 (m, 2H), 4.20-4.15 (m, 3H), 3.89-3.82 (m, 1H), 3.58-3.55
(m, 4H), 3.26-3.17 (m, 1H), 2.89-2.78 (m, 1H), 2.69-2.59 (m, 1H),
2.53-2.51 (m, 2H), 2.40-2.32 (m, 4H), 1.91-1.80 (m, 2H), 1.69-1.41
(m, 2H).
Example 337
##STR00659##
[0894] ethyl
1-[2-[4-(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyri-
midine-3-amido]-1H-pyrazol-1-yl]acetyl)piperazin-1-yl]ethyl]-4-methylpiper-
idine-4-carboxylate formate
[0895] Using synthetic method analoguous to that of ethyl
1-[2-[4-(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyri-
midine-3-amido]-1H-pyrazol-1-yl]acetyl)piperazin-1-yl]ethyl]piperidine-4-c-
arboxylate, the title compound was prepared from ethyl
4-methylpiperidine-4-carboxylate hydrochloride. LCMS (Method 24)
[M+H].sup.+=728.2, R.sub.T=1.87 min. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta.: (ppm) 9.75 (s, 1H), 9.34 (dd, 1H, J=1.2, 6.8
Hz), 8.69-8.68 (m, 2H), 8.30 (s, 1H), 7.62 (dd, 1H, J=2.8, 8.8 Hz),
7.55 (d, 1H, J=2.8 Hz), 7.46 (d, 1H, J=8.8 Hz), 7.28 (dd, 1H,
J=4.4, 6.8 Hz), 7.08 (t, 1H, J=73.2 Hz), 5.22 (s, 2H), 4.06 (q, 2H,
J=7.2 Hz), 2.67-2.60 (m, 2H), 2.44-2.38 (m, 8H), 2.09-2.04 (m, 2H),
1.97-1.93 (m, 2H), 1.42-1.41 (m, 2H), 1.16 (t, 3H, J=7.2 Hz), 1.10
(s, 3H).
Example 338
##STR00660##
[0896] 2-(dimethylamino)ethyl
1-(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-
-3-amido]-1H-pyrazol-1-yl]acetyl)piperidine-4-carboxylate
[0897] Using synthetic method analoguous to that of
2-(morpholin-4-yl)ethyl
1-(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-
-3-amido]-1H-pyrazol-1-yl]acetyl)piperidine-4-carboxylate, the
title compound was prepared from 2-(dimethylamino)ethan-1-ol. LCMS
(Method 24) [M+H].sup.+=645.2, R.sub.T=2.97 min. .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta.: (ppm) 9.76 (s, 1H), 9.34 (dd, 1H,
J=1.6, 6.8 Hz), 8.68-8.67 (m, 2H), 8.31 (s, 1H), 7.62 (dd, 1H,
J=2.4, 8.8 Hz), 7.55 (d, 1H, J=2.4 Hz), 7.45 (d, 1H, J=8.8 Hz),
7.28 (dd, 1H, J=4.4, 7.2 Hz), 7.21 (t, J=73.1 Hz, 1H) 5.30-5.14 (m,
2H), 4.21-4.10 (m, 3H), 3.89-3.78 (m, 1H), 3.24-3.14 (m, 1H),
2.89-2.60 (m, 2H), 2.49-2.45 (m, 2H), 2.16 (s, 6H), 1.89-1.81 (m,
2H), 1.68-1.37 (m, 2H).
Example 339
##STR00661##
[0898] 2-(morpholin-4-yl)ethyl
1-(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-
-3-amido]-1H-pyrazol-1-yl]acetyl)-4-methylpiperidine-4-carboxylate
[0899] To a solution of
1-[(tert-butoxy)carbonyl]-4-methylpiperidine-4-carboxylic acid
(1.00 g, 4.11 mmol) in DCM (10 mL) was added
2-(morpholin-4-yl)ethan-1-ol (1.08 g, 8.23 mmol), HOBt (667 mg,
4.94 mmol). The mixture was stirred at room temperature for 2 hr,
then EDC.HCl (943 mg, 4.92 mmol) was added. The resulting solution
was stirred at room temperature overnight and diluted with 30 mL of
DCM. The resulting mixture was washed with water, brine, dried over
anhydrous sodium sulfate and concentrated under vacuum. The residue
was purified by flash chromatography on silica gel eluting with 4%
MeOH in DCM. This resulted in 800 mg (55%) of 1-tert-butyl
4-[2-(morpholin-4-yl)ethyl] 4-methylpiperidine-1,4-dicarboxylate as
yellow oil. LCMS (Method 28) [M+H].sup.+=357.2, R.sub.T=0.64
min.
[0900] A solution of 1-tert-butyl 4-[2-(morpholin-4-yl)ethyl]
4-methylpiperidine-1,4-dicarboxylate (800 mg, 2.24 mmol) and
saturated HCl dioxane solution (30 mL) was stirred at room
temperature overnight. The resulting mixture was concentrated under
vacuum. This resulted in 600 mg (crude) of 2-(morpholin-4-yl)ethyl
4-methylpiperidine-4-carboxylate hydrochloride as a white crude
solid. LCMS (Method 28) [M+H].sup.+=257.0, R.sub.T=0.86 min.
[0901] To a solution of
{3-(5-Chloro-2-difluoromethoxyphenyl)-4-[(pyrazolo[1,5-a]pyrimidine-3-car-
bonyl)amino]pyrazol-1-yl}acetic acid (100 mg) in DMF (3 mL) was
added 2-(morpholin-4-yl)ethyl 4-methylpiperidine-4-carboxylate
hydrochloride (76.2 mg, 0.26 mmol), DIEA (67.2 mg, 0.52 mmol), HATU
(79.2 mg, 0.21 mmol). The resulting solution was stirred at room
temperature overnight and concentrated under vacuum. The crude
product was purified by Prep-HPLC with the following conditions
(Prep-HPLC-005): Column, XBridge Prep C.sub.18 OBD Column, 5 um,
19*150 mm; mobile phase, water with 0.05% FA and MeCN (34.0% up to
38.0% in 10 min, up to 95.0% in 1 min, hold 95.0% in 1 min, down to
34.0% in 2 min); Detector, UV 254/220 nm. This resulted in 43.0 mg
(33%) of the formic acid salt of 2-(morpholin-4-yl)ethyl
1-(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-
-3-amido]-1H-pyrazol-1-yl]-acetyl)-4-methyl
piperidine-4-carboxylate. LCMS (Method 20) [M+H].sup.+=701.2,
R.sub.T=0.92 min. 1H NMR (400 MHz, DMSO-d6) .delta.: (ppm) 9.75 (s,
1H), 9.35 (dd, 1H, J=1.6, 7.2 Hz), 8.69-8.68 (m, 2H), 8.31 (s, 1H),
7.63 (dd, 1H, J=2.4, 8.8 Hz), 7.55 (d, 1H, J=2.8 Hz), 7.46 (d, 1H,
J=9.6 Hz), 7.29 (dd, 1H, J=4.4, 6.8 Hz), 7.09 (t, 1H, J=73.2 Hz),
5.23 (s, 2H), 4.21 (t, 2H, J=5.6 Hz), 4.02-3.98 (m, 1H), 3.77-3.74
(m, 1H), 3.53-3.51 (m, 4H), 3.27-3.22 (m, 1H), 3.00-2.94 (m, 1H),
2.55-2.52 (m, 2H), 2.49-2.39 (m, 4H), 2.04-1.97 (m, 2H), 1.18 (s,
3H).
Example 340
##STR00662##
[0902] 2-(dimethylamino)ethyl 1-(2-[3-[5-chloro-2-(difluoromethoxy)
phenyl]-4-[pyrazolo[1,5-a]pyrimidine-3-amido]-1H-pyrazol-1-yl]acetyl)-4-m-
ethylpiperidine-4-carboxylate
[0903] To a solution of
1-[(tert-butoxy)carbonyl]-4-methylpiperidine-4-carboxylic acid (1
g, 4.11 mmol) in DCM (10 mL) was added 2-(dimethylamino)ethan-1-ol
(733 mg, 8.22 mmol), HOBt (667 mg, 4.94 mmol). The mixture was
stirred at room temperature for 2 h, then EDC.HCl (943 mg, 4.92
mmol) was added. The resulting solution was stirred at room
temperature overnight and water (30 mL) was added. The resulting
solution was extracted with DCM (.times.2) and the organic layers
combined. The organic phase was washed with brine, dried over
anhydrous sodium sulfate and concentrated under vacuum. The residue
was purified by flash chromatography on silica gel eluting with 4%
MeOH in DCM. This resulted in 800 mg (62%) of 1-tert-butyl
4-[2-(dimethylamino)ethyl] 4-methylpiperidine-1,4-dicarboxylate as
yellow oil. TLC: R.sub.f=0.3; dichloromethane/methanol=10/1.
[0904] A mixture of 1-tert-butyl 4-[2-(dimethylamino)ethyl]
4-methylpiperidine-1,4-dicarboxylate (800 mg, 2.54 mmol) and
saturated HCl dioxane solution (20 mL) was stirred at room
temperature overnight. The resulting mixture was concentrated under
vacuum. This resulted in 340 mg (53%) of 2-(dimethylamino)ethyl
4-methylpiperidine-4-carboxylate hydrochloride as a white
solid.
[0905] To a solution of
{3-(5-Chloro-2-difluoromethoxyphenyl)-4-[(pyrazolo[1,5-a]pyrimidine-3-car-
bonyl)amino]pyrazol-1-yl}acetic acid (100 mg) in DMF (3 mL) was
added 2-(dimethylamino)ethyl 4-methylpiperidine-4-carboxylate
hydrochloride (87 mg, 0.35 mmol), DIEA (67.2 mg, 0.52 mmol), HATU
(79.2 mg, 0.21 mmol). The resulting solution was stirred at room
temperature overnight and concentrated under vacuum. The crude
product was purified by Prep-HPLC with the following conditions
(Prep-HPLC-005): Column, XBridge Prep C.sub.18 OBD Column, 5 um,
19*150 mm; mobile phase, water with 0.05% FA and MeCN (38.0% MeCN
up to 42.0% in 10 min, up to 95.0% in 1 min, hold 95.0% in 1 min,
down to 38.0% in 2 min); Detector, UV 254/220 nm. This resulted in
49.7 mg (41%) of the formic acid salt of 2-(dimethylamino)ethyl
1-(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-
-3-amido]-1H-pyrazol-1-yl]acetyl)-4-methylpiperidine-4-carboxylate.
LCMS (Method 28) [M+H].sup.+=659.2, R.sub.T=1.23 min. .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta.: (ppm) 9.76 (s, 1H), 9.35 (dd, 1H,
J=1.2, 7.2 Hz), 8.68-8.64 (m, 2H), 8.31 (s, 1H), 7.63 (dd, 1H,
J=2.8, 8.8 Hz), 7.55 (d, 1H, J=2.8 Hz), 7.46 (d, 1H, J=9.2 Hz),
7.29 (dd, 1H, J=4.4, 6.8 Hz), 7.09 (t, 1H, J=73.2 Hz), 5.23 (s,
2H), 4.16 (t, 2H, J=5.6 Hz), 3.97-3.93 (m, 1H), 3.75-3.71 (m, 1H),
3.25-3.20 (m, 1H), 3.00-2.94 (m, 1H), 2.48-2.47 (m, 2H), 2.33 (s,
6H), 2.16-1.95 (m, 2H), 1.49-1.44 (m, 2H), 1.18 (s, 3H).
##STR00663##
piperidin-4-ylmethyl
1-(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-
-3-amido]-1H-pyrazol-1-yl]acetyl)piperidine-4-carboxylate
[0906] To a solution of
1-(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-
-3-amido]-1H-pyrazol-1-yl]acetyl)piperidine-4-carboxylic acid (150
mg, 0.26 mmol) in DMF (5 mL) was added tert-butyl
4-(hydroxymethyl)piperidine-1-carboxylate (281 mg, 1.31 mmol),
4-dimethylaminopyridine (10 mg, 0.08 mmol), HATU (120 mg, 0.32
mmol). The resulting solution was stirred at room temperature
overnight. Then DIEA (68 mg, 0.53 mmol) was added. The resulting
solution was stirred for an additional 3 h at room temperature and
concentrated under vacuum. The residue was purified by flash
chromatography on silica gel eluting with 3% MeOH in DCM. This
resulted in 150 mg (74%) of
[1-[(tert-butoxy)carbonyl]piperidin-4-yl]methyl
1-(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-
-3-amido]-1H-pyrazol-1-yl]acetyl)piperidine-4-carboxylate as yellow
oil. LCMS (Method 28) [M+H].sup.+=771.2, R.sub.T=1.10 min.
[0907] A solution of
[1-[(tert-butoxy)carbonyl]piperidin-4-yl]methyl
1-(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-
-3-amido]-1H-pyrazol-1-yl]acetyl)piperidine-4-carboxylate (150 mg,
0.19 mmol) and saturated HCl dioxane solution (10 mL) was stirred
at room temperature overnight. The resulting mixture was
concentrated under vacuum. The resulting solution was diluted with
10 mL of methanol. The resulting mixture was concentrated under
vacuum. The crude product was purified by Prep-HPLC with the
following conditions (Prep-HPLC-005): Column, XBridge Prep C18 OBD
Column, 5 um, 19*150 mm; mobile phase, water with 0.05% FA and MeCN
(30.0% up to 33.0% in 10 min, up to 95.0% in 1 min, hold 95.0% in 1
min, down to 30.0% in 2 min); Detector, UV 254/220 nm. This
resulted in 82.3 mg (59%) of the formic acid salt of
piperidin-4-ylmethyl
1-(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-
-3-amido]-1H-pyrazol-1-yl]acetyl)piperidine-4-carboxylate as a
light yellow solid. LCMS (Method 20) [M+H].sup.+=671.3,
R.sub.T=1.58 min. .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta.:
(ppm) 9.76 (s, 1H), 9.33 (dd, 1H, J=1.2, 6.9 Hz), 8.68-8.67 (m,
2H), 8.31 (s, 1H), 7.62 (dd, 1H, J=2.7, 8.7 Hz), 7.55 (d, 1H, J=2.7
Hz), 7.45 (d, 1H, J=8.7 Hz), 7.28 (dd, 1H, J=4.5, 7.2 Hz), 7.01 (t,
1H, J=73.5), 5.25-5.23 (m, 2H), 4.24-4.19 (m, 1H), 3.93-3.85 (m,
3H), 2.83-2.80 (m, 1H), 2.72-2.64 (m, 3H), 1.92-1.87 (m, 3H),
1.71-1.67 (m, 3H), 1.59-1.48 (m, 1H), 1.44-1.23 (m, 2H).
Example 342
##STR00664##
[0908]
1-(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyri-
midine-3-amido]-1H-pyrazol-1-yl]acetyl)piperidine-4-carboxylic
acid
[0909] To a solution of
{3-(5-Chloro-2-difluoromethoxyphenyl)-4-[(pyrazolo[1,5-a]pyrimidine-3-car-
bonyl)amino]pyrazol-1-yl}acetic acid (500 mg, 1.08 mmol) in DMF (5
mL) was added methyl piperidine-4-carboxylate (232.1 mg, 1.62
mmol), DIEA (279.2 mg, 2.16 mmol), HATU (493.5 mg, 1.30 mmol). The
resulting solution was stirred at room temperature overnight. The
resulting mixture was concentrated under vacuum. The residue was
purified by flash chromatography on silica gel eluting with 3% MeOH
in DCM. This resulted in 500 mg (79%) of methyl
1-(2-[3-[5-chloro-2-(difluoromethoxy)
phenyl]-4-[pyrazolo[1,5-a]pyrimidine-3-amido]-1H-pyrazol-1-yl]acetyl)pipe-
ridine-4-carboxylate as yellow oil. LCMS (Method 25)
[M+H].sup.+=588.1, R.sub.T=0.87 min.
[0910] K.sub.2CO.sub.3 (500 mg, 3.59 mmol) in H.sub.2O (5 mL) was
added to methyl
1-(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyr-
imidine-3-amido]-1H-pyrazol-1-yl]acetyl)piperidine-4-carboxylate
(500 mg, 0.85 mmol) in methanol (10 mL). The resulting solution was
stirred at 50.degree. C. overnight and acidified with 1 N HCl to pH
2. The solids were collected by filtration. The crude product was
purified by Prep-HPLC with the following conditions
(Prep-HPLC-005): Column, XBridge Prep C18 OBD Column, 5 um, 19*150
mm; mobile phase, water with 0.05% FA and MeCN (30.0% MeCN up to
34.0% in 10 min, up to 95.0% in 1 min, hold 95.0% in 1 min, down to
30.0% in 2 min); Detector, UV 254/220 nm. This resulted in 390 mg
(80%) of
1-(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-
-3-amido]-1H-pyrazol-1-yl]-acetyl)piperidine-4-carboxylic acid as a
light yellow solid. LCMS (Method 28) [M+H].sup.+=574.1,
R.sub.T=1.11 min. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.:
(ppm) 12.34 (s, 1H), 9.76 (s, 1H), 9.34 (dd, 1H, J=1.6, 7.2 Hz),
8.69-8.67 (m, 2H), 8.31 (s, 1H), 7.62 (dd, 1H, J=2.8, 8.8 Hz), 7.55
(d, 1H, J=2.4 Hz), 7.46 (d, 1H, J=8.8 Hz), 7.28 (dd, 1H, J=4.4, 6.8
Hz), 7.08 (t, 1H, J=73.2 Hz), 5.29-5.19 (m, 2H), 4.28-4.18 (m, 1H),
3.87-3.84 (m, 1H), 3.19-3.13 (m, 1H), 2.83-2.77 (m, 1H), 1.86-1.85
(m, 2H), 1.60-1.57 (m, 1H), 1.43-1.41 (m, 2H).
Example 343
##STR00665##
[0911]
1-(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyri-
midine-3-amido]-1H-pyrazol-1-yl]acetyl)-4-methylpiperidine-4-carboxylic
acid
[0912] To a solution of
2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-3--
amido]-1H-pyrazol-1-yl]acetic acid (500 mg, 1.08 mmol) in DMF (4
mL) was added methyl 4-methylpiperidine-4-carboxylate (275 mg, 1.75
mmol), DIEA (419 mg, 3.24 mmol), HATU (494 mg, 1.30 mmol). The
resulting solution was stirred for 4 h at room temperature. The
resulting mixture was concentrated under vacuum. The residue was
purified by flash chromatography on silica gel eluting with 3% MEOH
in DCM. This resulted in 500 mg (77%) of methyl
1-(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-
-3-amido]-1H-pyrazol-1-yl]acetyl)-4-methylpiperidine-4-carboxylate
as yellow oil. LCMS (Method 25) [M+H].sup.+=602.1, R.sub.T=0.92
min.
[0913] To a solution of methyl
1-(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-
-3-amido]-1H-pyrazol-1-yl]acetyl)-4-methylpiperidine-4-carboxylate
(500 mg, 0.83 mmol) in methanol (10 mL) was added a solution of
potassium carbonate (700 mg, 5.06 mmol) in water (5 mL). The
resulting solution was stirred at 60.degree. C. overnight and
acidified with 1 N HCl to pH 2. The solids were collected by
filtration. The crude product was purified by Prep-HPLC with the
following conditions (Prep-HPLC-005): Column, XBridge Prep C18 OBD
Column, 5 um, 19*150 mm; mobile phase, water with 0.05% FA and MeCN
(30.0% MeCN up to 35.0% in 10 min, up to 95.0% in 1 min, hold 95.0%
in 1 min, down to 30.0% in 2 min); Detector, UV 254/220 nm. This
resulted in 26.6 mg of
1-(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-
-3-amido]-1H-pyrazol-1-yl]acetyl)-4-methylpiperidine-4-carboxylic
acid as a white solid. LCMS (Method 20) [M+H].sup.+=588.2,
R.sub.T=2.79 min. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.:
(ppm) 12.5 (br, 1H), 9.76 (s, 1H), 9.34 (d, 1H, J=6.8 Hz),
8.69-8.68 (m, 2H), 8.32 (s, 1H), 7.63 (dd, 1H, J=2.8, 8.8 Hz), 7.56
(d, 1H, J=2.8 Hz), 7.46 (d, 1H, J=8.8 Hz), 7.29 (dd, 1H, J=4.4, 7.2
Hz), 7.08 (t, 1H, J=73.2 Hz), 5.28-5.18 (m, 2H), 3.96-3.93 (m, 1H),
3.74-3.70 (m, 1H), 3.26-3.23 (m, 1H), 3.01-2.95 (m, 1H), 1.98-1.93
(m, 2H), 1.46-1.30 (m, 2H), 1.18 (s, 3H).
Example 344
##STR00666##
[0914] N-[3-[5-chloro-2-(difluoromethoxy)
phenyl]-1-[2-(4-[methyl[(5-oxooxolan-2-yl)methyl]amino]piperidin-1-yl)-2--
oxoethyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide
[0915] To a cold solution of 5-(hydroxymethyl)oxolan-2-one (100 mg,
0.86 mmol), DIEA (340 mg, 2.63 mmol) in DCM (5 mL) was added
Tf.sub.2O (247 mg, 0.88 mmol) at 0.degree. C. The resulting
solution was stirred at room temperature for 3 h and quenched with
saturated Na.sub.2CO.sub.3 solution. The resulting solution was
extracted with dichloromethane (.times.3) and the organic layers
combined. The combined organic layers were washed with brine.,
dried over anhydrous sodium sulfate and concentrated under vacuum.
This resulted in 180 mg (84%) of (5-oxooxolan-2-yl)methyl
trifluoromethanesulfonate as yellow oil.
[0916] To a solution of
N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[2-[4-(methylamino)piperidin--
1-yl]-2-oxoethyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide
(100 mg, 0.18 mmol) in CH.sub.3CN (5 mL) was added DIEA (70 mg,
0.54 mmol) and (5-oxooxolan-2-yl)methyl trifluoromethanesulfonate
(66.5 mg, 0.27 mmol). The resulting solution was stirred overnight
at room temperature. The crude product was purified by Prep-HPLC
with the following conditions (Prep-HPLC-005): Column, XBridge Prep
C18 OBD Column, 5 um, 19*150 mm; mobile phase, water with 0.05% FA
and MeCN (30.0% up to 36.0% in 10 min, up to 95.0% in 1 min, hold
95.0% in 1 min, down to 30.0% in 2 min); Detector, UV 254/220 nm.
This resulted in 37 mg (31%) of N-[3-[5-chloro-2-(difluoromethoxy)
phenyl]-1-[2-(4-[methyl[(5-oxooxolan-2-yl)methyl]amino]piperidin-1-yl)-2--
oxoethyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide
as a yellow solid. LCMS (Method 24) [M+H].sup.+=657.2, R.sub.T=1.68
min. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.: (ppm) 9.75 (s,
1H), 9.34 (dd, 1H, J=1.2, 7.2 Hz), 8.69-8.68 (m, 2H), 8.31 (s, 1H),
7.62 (dd, 1H, J=2.4, 8.8 Hz), 7.55 (d, 1H, J=2.8 Hz), 7.46 (d, 1H,
J=8.8 Hz), 7.29 (dd, 1H, J=4.0, 6.8 Hz), 7.09 (t, 1H, J=73.2 Hz),
5.24-5.17 (m, 2H), 4.58-4.54 (m, 1H), 4.41-4.38 (m, 1H), 3.98-3.95
(m, 1H), 3.16-3.03 (m, 1H), 2.69-2.55 (m, 4H), 2.46-2.44 (m, 2H),
2.26 (s, 3H), 2.24-2.16 (m, 1H), 1.88-1.83 (m, 1H), 1.79-1.71 (m,
2H), 1.48-1.44 (m, 1H), 1.29-1.21 (m, 1H).
Example 345
##STR00667##
[0917] methyl
3-[[1-(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimi-
dine-3-amido]-1H-pyrazol-1-yl]acetyl)piperidin-4-yl](methyl)amino]propanoa-
te
[0918] To a solution of tert-butyl 4-aminopiperidine-1-carboxylate
(1.00 g, 4.99 mmol) in CH.sub.3CN (20 mL) was added potassium
carbonate (1.38 g, 9.99 mmol) and methyl 3-bromopropanoate (3.34 g,
20.00 mmol). The resulting solution was heated to reflux for 20 h
and cooled to room temperature. Water (100 mL) and DCM (100 mL) was
added. Phases were separated. The aqueous phase was extracted with
DCM. The combined organic layers were washed with brine, dried over
anhydrous sodium sulfate and concentrated under vacuum. The residue
was purified by flash chromatography on silica gel eluting with 4%
MeOH in DCM. This resulted in 300 mg (21%) of tert-butyl
4-[(3-methoxy-3-oxopropyl)amino]piperidine-1-carboxylate as yellow
oil. LCMS (Method 20) [M+H].sup.+=287.0, R.sub.T=1.06 min.
[0919] To a solution of tert-butyl
4-[(3-methoxy-3-oxopropyl)amino]piperidine-1-carboxylate (300 mg,
1.05 mmol) in methanol (10 mL) was added polyformaldehyde (HCHO)n
(90 mg, 3.00 mmol). The reaction mixture was stirred at room
temperature for 6 hr, then NaBH.sub.3CN (130 mg, 2.07 mmol) was
added. The resulting solution was stirred at room temperature
overnight and quenched with water (0.5 mL). The resulting mixture
was concentrated under vacuum. The residue was purified by flash
chromatography on silica gel eluting with 4% MeOH in DCM. This
resulted in 300 mg (crude) of tert-butyl
4-[(3-methoxy-3-oxopropyl)(methyl)amino]piperidine-1-carboxylate as
yellow oil. LCMS (Method 20) [M+H].sup.+=301.0, R.sub.T=1.08
min.
[0920] A solution of tert-butyl
4-[(3-methoxy-3-oxopropyl)(methyl)amino]piperidine-1-carboxylate
(300 mg, 1.00 mmol) and saturated HCl dioxane solution (10 mL) was
stirred at room temperature overnight. The resulting mixture was
concentrated under vacuum. This resulted in 300 mg (crude) of
methyl 3-[methyl(piperidin-4-yl)amino]propanoate hydrochloride as a
white solid. LCMS (Method 20) [M+H].sup.+=201.0, R.sub.T=0.31
min.
[0921] To a solution of
{3-(5-Chloro-2-difluoromethoxyphenyl)-4-[(pyrazolo[1,5-a]pyrimidine-3-car-
bonyl)amino]pyrazol-1-yl}acetic acid trifluoroacetate (100 mg, 0.17
mmol) in DMF (3 mL) was added methyl
3-[methyl(piperidin-4-yl)amino]propanoate hydrochloride (62 mg,
0.26 mmol), DIEA (67.2 mg, 0.52 mmol), HATU (79.2 mg, 0.21 mmol).
The resulting solution was stirred at room temperature overnight
and concentrated under vacuum. The residue was passed through a
short pad of silica gel eluting with ethyl acetate/petroleum ether
(10:1). The crude product was purified by Prep-HPLC with the
following conditions (Prep-HPLC-005): Column, XBridge Prep C.sub.18
OBD Column, 5 um, 19*150 mm; mobile phase, water with 0.05% FA and
MeCN (37.0% up to 43.0% in 10 min, up to 95.0% in 1 min, hold 95.0%
in 1 min, down to 37.0% in 2 min); Detector, UV 254/220 nm. This
resulted in 45.2 mg (38%) of the formic acid salt of methyl
3-[[1-(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimi-
dine-3-amido]-1H-pyrazol-1-yl]acetyl)piperidin-4-yl](methyl)amino]propanoa-
te as an off-white solid. LCMS (Method 24) [M+H].sup.+=645.2,
R.sub.T=1.64 min. .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta.:
(ppm) 9.75 (s, 1H), 9.35 (dd, 1H, J=1.5, 6.9 Hz), 8.69-8.68 (m,
2H), 8.31 (s, 1H), 7.63 (dd, 1H, J=2.7, 8.7 Hz), 7.55 (d, 1H, J=2.7
Hz), 7.46 (d, 1H, J=8.7 Hz), 7.29 (dd, 1H, J=4.5, 7.2 Hz), 7.04 (t,
1H, J=73.2 Hz), 5.33-5.27 (m, 2H), 4.52-4.48 (m, 1H), 4.10-4.06 (m,
1H), 3.66 (s, 3H), 3.51-3.34 (m, 2H), 3.16-3.08 (m, 2H), 2.86-2.51
(m, 6H), 2.28-1.99 (m, 2H), 1.73-1.70 (m, 1H), 1.55-1.45 (m,
1H).
Example 346
##STR00668##
[0922]
N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[2-([[4-(methylsulfanyl-
)phenyl]methyl]amino)ethyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-ca-
rboxamide formate
[0923] To a solution of
N-[1-(2-aminoethyl)-3-[5-chloro-2-(difluoromethoxy)phenyl]-1H-pyrazol-4-y-
l]pyrazolo[1,5-a]pyrimidine-3-carboxamide (130 mg, 0.29 mmol) in
methanol (5 mL) was added 4-(methylsulfanyl)benzaldehyde (66.3 mg,
0.44 mmol). The mixture was stirred for 2 hr, then NaBH.sub.3CN
(27.5 mg, 0.44 mmol) was added. The resulting solution was stirred
at room temperature overnight and quenched with water (1 mL). The
resulting mixture was concentrated under vacuum. The crude product
was purified by Prep-HPLC with the following conditions
(Prep-HPLC-005): Column, XBridge Prep C18 OBD Column, 5 um, 19*150
mm; mobile phase, water with 0.05% FA and MeCN (30.0% up to 37.0%
in 10 min, up to 95.0% in 1 min, hold 95.0% in 1 min, down to 30.0%
in 2 min); Detector, UV 254/220 nm. This resulted in 39.6 mg (23%)
of the formic acid salt of
N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[2-([[4-(methylsulfanyl)pheny-
l]methyl]amino)-ethyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxa-
mide as a light yellow solid. LCMS (Method 20) [M+H].sup.+=584.2,
R.sub.T=2.23 min. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.:
(ppm) 9.74 (s, 1H), 9.34 (dd, 1H, J=1.6, 7.2 Hz), 8.69-8.67 (m,
2H), 8.37 (s, 1H), 7.61 (dd, 1H, J=2.8, 8.8 Hz), 7.59 (d, 1H, J=2.8
Hz), 7.44 (d, 1H, J=8.8 Hz), 7.31-7.27 (m, 3H), 7.18 (d, 2H, J=8.0
Hz), 7.07 (t, 1H, J=73.6 Hz), 4.25 (t, 2H, J=5.2 Hz), 3.70 (s, 2H),
2.95-2.92 (m, 2H), 2.50 (s, 3H).
Example 347
##STR00669##
[0924]
N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[2-oxo-2-[4-(2-oxooxan--
4-yl)piperazin-1-yl]ethyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-car-
boxamide
[0925] To a solution of tert-butyl piperazine-1-carboxylate (500
mg, 2.68 mmol) in MeOH (20 mL) was added 5,6-dihydro-2H-pyran-2-one
(530 mg, 5.40 mmol). The resulting solution was stirred at room
temperature for 20 h. The resulting mixture was concentrated under
vacuum. The residue was purified by flash chromatography on silica
gel eluting with 3% MeOH in DCM. This resulted in 550 mg (72%) of
tert-butyl 4-(2-oxooxan-4-yl)piperazine-1-carboxylate as yellow
oil. LCMS (Method 28) [M+H].sup.+=285.0, R.sub.T=0.53 min.
[0926] A mixture of tert-butyl
4-(2-oxooxan-4-yl)piperazine-1-carboxylate (550 mg, 1.93 mmol) and
saturated HCl dioxane solution (10 mL) was stirred overnight at
room temperature. The solids were collected by filtration. This
resulted in 335 mg (78%) of 4-(piperazin-1-yl)oxan-2-one
hydrochloride as a white solid.
[0927] To a solution of
{3-(5-Chloro-2-difluoromethoxyphenyl)-4-[(pyrazolo[1,5-a]pyrimidine-3-car-
bonyl)amino]pyrazol-1-yl}acetic acid trifluoroacetate (100 mg, 0.17
mmol) in DMF (3 mL) was added 4-(piperazin-1-yl)oxan-2-one
hydrochloride (76 mg, 0.34 mmol), DIEA (67.2 mg, 0.52 mmol), HATU
(79.2 mg, 0.21 mmol). The resulting solution was stirred at room
temperature overnight and concentrated under vacuum. The crude
product was purified by Prep-HPLC with the following conditions
(Prep-HPLC-005): Column, XBridge Prep C.sub.18 OBD Column, 5 um,
19*150 mm; mobile phase, water with 0.05% FA and MeCN (35.0% up to
39.0% in 10 min, up to 95.0% in 1 min, hold 95.0% in 1 min, down to
35.0% in 2 min); Detector, UV 254/220 nm. This resulted in 14.5 mg
(13%) of
N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[2-oxo-2-[4-(2-oxooxan-4-yl)p-
iperazin-1-yl]ethyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxami-
de as a white solid. LCMS (Method 28) [M+H].sup.+=629.1,
R.sub.T=1.44 min. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.:
(ppm) 9.76 (s, 1H), 9.34 (dd, 1H, J=2.0, 7.2 Hz), 8.69-8.68 (m,
2H), 8.31 (s, 1H), 7.62 (dd, 1H, J=2.8, 8.8 Hz), 7.55 (d, 1H, J=2.8
Hz), 7.45 (d, 1H, J=8.8 Hz), 7.28 (dd, 1H, J=4.4, 7.2 Hz), 7.08 (t,
1H, J=73.2 Hz), 5.24 (s, 2H), 4.35-4.29 (m, 1H), 4.19-4.16 (m, 1H),
3.50-3.32 (m, 6H), 3.02-2.99 (m, 1H), 2.69-2.51 (m, 4H), 2.08-1.98
(m, 1H), 1.77-1.75 (m, 1H).
Example 348
##STR00670##
[0928]
N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[2-[4-(morpholin-4-ylme-
thyl)piperidin-1-yl]-2-oxoethyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-
-3-carboxamide
[0929] To a solution of tert-butyl 4-formylpiperidine-1-carboxylate
(1.00 g, 4.69 mmol) in MeOH (10 mL) was added morpholine (613 mg,
7.04 mmol). The resulting mixture was stirred for 6 hr, then
NaBH.sub.3CN (444 mg, 7.07 mmol) was added. The resulting solution
was stirred at room temperature overnight and quenched with
H.sub.2O (1 mL). The resulting mixture was concentrated under
vacuum. The residue was purified by flash chromatography on silica
gel eluting with 3% MeOH in DCM. This resulted in 1.0 g (75%) of
tert-butyl 4-(morpholin-4-ylmethyl) piperidine-1-carboxylate as
yellow oil. LCMS (Method 25) [M+H].sup.+=285.0, R.sub.T=0.59
min.
[0930] A solution of tert-butyl
4-(morpholin-4-ylmethyl)piperidine-1-carboxylate (1.0 g, 3.52 mmol)
and saturated HCl dioxane solution (20 mL) was stirred at room
temperature overnight. This resulted in 660 mg (85%) of
4-(piperidin-4-ylmethyl)morpholine hydrochloride as a white solid.
LCMS (Method 20) [M+H].sup.+=185.0, R.sub.T=0.30 min.
[0931] To a solution of
{3-(5-Chloro-2-difluoromethoxyphenyl)-4-[(pyrazolo[1,5-a]pyrimidine-3-car-
bonyl)amino]pyrazol-1-yl}acetic acid (150 mg, 0.26 mmol) in DMF (2
mL) was added 4-(piperidin-4-ylmethyl)morpholine hydrochloride (69
mg, 0.31 mmol), DIEA (101.2 mg, 0.78 mmol), HATU (119.2 mg, 0.31
mmol). The resulting solution was stirred at room temperature
overnight. The resulting mixture was concentrated under vacuum. The
crude product was purified by Prep-HPLC with the following
conditions (Prep-HPLC-005): Column, XBridge Prep C18 OBD Column, 5
um, 19*150 mm; mobile phase, water with 10 mmol NH.sub.4HCO.sub.3
and MeCN (25.0% MeCN up to 36.0% in 10 min, up to 95.0% in 1 min,
hold 95.0% in 1 min, down to 25.0% in 2 min); Detector, UV 254/220
nm. This resulted in 61 mg (37%) of
N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[2-[4-(morpholin-4-ylmethyl)p-
iperidin-1-yl]-2-oxoethyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-car-
boxamide as a solid. LCMS (Method 20) [M+H].sup.+=629.2,
R.sub.T=1.55 min. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.:
(ppm) 9.75 (s, 1H), 9.34 (dd, 1H, J=1.6, 7.2 Hz), 8.69-8.68 (m,
2H), 8.30 (s, 1H), 7.62 (dd, 1H, J=2.8, 8.8 Hz), 7.55 (d, 1H,
J=2.4), 7.45 (d, 1H, J=8.8 Hz), 7.28 (dd, 1H, J=4.0, 6.8 Hz), 7.08
(t, 1H, J=73.2 Hz), 5.27-5.16 (m, 2H), 4.34-4.30 (m, 1H), 3.92-3.89
(m, 1H), 3.56 (t, 4H, J=4.2 Hz), 3.17-3.06 (m, 1H), 2.67-2.59 (m,
1H), 2.39-2.25 (m, 4H), 2.13-2.12 (m, 2H), 1.90-1.71 (m, 3H),
1.20-1.08 (m, 1H), 0.97-0.95 (m, 1H).
Example 349
##STR00671##
[0932]
N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[2-[4-(4-methylpiperazi-
n-1-yl)piperidin-1-yl]-2-oxoethyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidi-
ne-3-carboxamide
[0933] To a solution of tert-butyl 4-oxopiperidine-1-carboxylate
(1.00 g, 5.02 mmol) in MeOH (50 mL) was added 1-methylpiperazine
(1.0 g, 9.98 mmol) and AcOH (0.1 mL, 1.75 mmol). The reaction was
stirred 3 h and NaBH.sub.3CN (378 mg, 6.02 mmol) was added. The
resulting solution was stirred at room temperature for 12 h. The
reaction was then and quenched with saturated NH.sub.4Cl (2 mL).
The resulting mixture was concentrated under vacuum. The residue
was purified by flash chromatography on silica gel eluting with 8%
MeOH in DCM. This resulted in 800 mg (39%) of tert-butyl
4-(4-methylpiperazin-1-yl)piperidine-1-carboxylate as light yellow
oil. LCMS (Method 20) [M+H].sup.+=284.0, R.sub.T=0.97 min.
[0934] A solution of tert-butyl
4-(4-methylpiperazin-1-yl)piperazine-1-carboxylate (800 mg, 1.97
mmol) and saturated HCl dioxane solution (15 mL) was stirred at
room temperature for 3 h. The solids were collected by filtration
and dried. This resulted in 600 mg (83%) of
1-methyl-4-(piperazin-1-yl)piperazine hydrochloride as a white
solid. LCMS (Method 20) [M+H].sup.+=184.0, R.sub.T=0.32 min.
[0935] To a solution of
{3-(5-Chloro-2-difluoromethoxyphenyl)-4-[(pyrazolo[1,5-a]pyrimidine-3-car-
bonyl)amino]pyrazol-1-yl}acetic acid (200 mg, 0.35 mmol) in DMF (4
mL) was added 1-methyl-4-(piperidin-4-yl)piperazine hydrochloride
(170 mg, 0.77 mmol), DIEA (134.4 mg, 1.04 mmol), HATU (160 mg, 0.42
mmol). The resulting solution was stirred at room temperature
overnight. The resulting mixture was concentrated under vacuum. The
crude product was purified by Prep-HPLC with the following
conditions (Prep-HPLC-005): Column, XBridge Prep C18 OBD Column, 5
um, 19*150 mm; mobile phase, water with 0.05% FA and MeCN (25.0% up
to 34.0% in 10 min, up to 95.0% in 1 min, hold 95.0% in 1 min, down
to 25.0% in 2 min); Detector, UV 254/220 nm. This resulted in 74.3
mg (32%) of
N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[2-[4-(4-methylpiperazin-1-yl-
)piperidin-1-yl]-2-oxoethyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-c-
arboxamide formate as a off-white solid. LCMS (Method 20)
[M+H].sup.+=628.2, R.sub.T=2.20 min. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta.: (ppm) 9.76 (s, 1H), 9.36-9.34 (dd, 1H,
J=1.6, 7.2 Hz), 8.69-8.68 (m, 2H), 8.31 (s, 1H), 7.63 (dd, 1H,
J=2.4, 8.8 Hz), 7.55 (d, 1H, J=2.4 Hz), 7.46 (d, 1H, J=9.2 Hz),
7.29 (dd, 1H, J=4.0, 6.8 Hz), 7.09 (t, 1H, J=73.2 Hz), 5.25-5.21
(m, 2H), 4.36-4.29 (m, 1H), 3.98-3.79 (m, 1H), 3.10-3.00 (m, 1H),
2.69-2.51 (m, 1H), 2.49-2.32 (m, 8H), 2.18 (s, 3H), 1.91-1.86 (m,
2H), 1.47-1.41 (m, 1H), 1.39-1.25 (m, 1H).
Example 350
##STR00672##
[0936]
N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-(2-[4-[(4-methylpiperaz-
in-1-yl)methyl]piperidin-1-yl]-2-oxoethyl)-1H-pyrazol-4-yl]pyrazolo[1,5-a]-
pyrimidine-3-carboxamide
[0937] A solution of tert-butyl 4-formylpiperidine-1-carboxylate (1
g, 4.69 mmol) and 1-methylpiperazine (703 mg, 7.02 mmol) in
methanol (10 mL) was stirred for 6 h, then NaBH.sub.3CN (444 mg,
7.07 mmol) was added. The resulting solution was stirred at room
temperature overnight and quenched with water (1 mL). The resulting
mixture was concentrated under vacuum. The residue was purified by
flash chromatography on silica gel eluting with 5% MeOH in DCM.
This resulted in 1.1 g (79%) of tert-butyl
4-[(4-methylpiperazin-1-yl)methyl]piperidine-1-carboxylate as
yellow oil. LCMS (Method 28) [M+H].sup.+=298.0, R.sub.T=0.46
min.
[0938] A mixture of tert-butyl
4-[(4-methylpiperazin-1-yl)methyl]piperidine-1-carboxylate (1.1 g,
3.70 mmol,) and saturated HCl dioxane solution (20 mL) was stirred
at room temperature overnight. The solids were collected by
filtration. This resulted in 560 mg (65%) of
1-methyl-4-(piperidin-4-ylmethyl)piperazinehydrochloride as a white
solid. LCMS (Method 20) [M+H].sup.+=198.0, R.sub.T=0.32 min.
[0939] To a solution of
{3-(5-Chloro-2-difluoromethoxyphenyl)-4-[(pyrazolo[1,5-a]pyrimidine-3-car-
bonyl)amino]pyrazol-1-yl}acetic acid (100 mg) in DMF (2 mL) was
added 1-methyl-4-(piperidin-4-ylmethyl)piperazine hydrochloride (49
mg, 0.21 mmol), DIEA (67.2 mg, 0.52 mmol), HATU (79.2 mg, 0.21
mmol). The resulting solution was stirred at room temperature
overnight and concentrated under vacuum. The crude product was
purified by Prep-HPLC with the following conditions
(Prep-HPLC-005): Column, XBridge Prep C18 OBD Column, 5 um, 19*150
mm; mobile phase, water with 10 mmol NH.sub.4HCO.sub.3 and MeCN
(20.0% MeCN up to 30.0% in 10 min, up to 95.0% in 1 min, hold 95.0%
in 1 min, down to 20.0% in 2 min); Detector, UV 254/220 nm. This
resulted in 52.7 mg (47%) of
N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-(2-[4-[(4-methylpiperazin-1-y-
l)methyl]piperidin-1-yl]-2-oxoethyl)-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimi-
dine-3-carboxamide as an off-white solid. LCMS (Method 24)
[M+H].sup.+=642.2, R.sub.T=1.55 min. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta.: (ppm) 9.76 (s, 1H), 9.34 (dd, 1H, J=1.6, 7.2
Hz), 8.69-8.68 (m, 2H), 8.30 (s, 1H), 7.62 (dd, 1H, J=2.4, 8.8 Hz),
7.54 (d, 1H, J=2.8 Hz), 7.45 (d, 1H, J=8.8 Hz), 7.28 (dd, 1H,
J=4.4, 6.8 Hz), 7.08 (t, 1H, J=73.2 Hz), 5.26-5.16 (m, 2H),
4.37-4.30 (m, 1H), 3.93-3.87 (m, 1H), 3.11-3.05 (m, 1H), 2.67-2.59
(m, 1H), 2.49-2.23 (m, 8H), 2.16-2.12 (m, 5H), 1.83-1.71 (m, 3H),
1.10-1.07 (m, 1H), 0.97-0.88 (m, 1H).
Example 351
##STR00673##
[0940]
N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-(2-oxo-2-[4-[(5-oxo-2,5-
-dihydrofuran-3-yl)methyl]piperazin-1-yl]ethyl)-1H-pyrazol-4-yl]pyrazolo[1-
,5-a]pyrimidine-3-carboxamide
[0941] To a solution of
N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[2-oxo-2-(piperazin-1-yl)ethy-
l]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (100 mg,
0.19 mmol) in DMF (3 mL) was added DIEA (48.8 mg, 0.38 mmol),
4-(bromomethyl)-2,5-dihydrofuran-2-one (66.4 mg, 0.38 mmol). The
resulting solution was stirred at room temperature for 4 h and
concentrated under vacuum. The crude product was purified by
Prep-HPLC with the following conditions (Prep-HPLC-005): Column,
XBridge Prep C18 OBD Column, 5 um, 19*150 mm; mobile phase, water
with 0.05% FA and MeCN (34.0% up to 39.0% in 10 min, up to 95.0% in
1 min, hold 95.0% in 1 min, down to 34.0% in 2 min); Detector, UV
254/220 nm. This resulted in 53.4 mg (45%) of
N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-(2-oxo-2-[4-[(5-oxo-2,5-dihyd-
rofuran-3-yl)methyl]piperazin-1-yl]ethyl)-1H-pyrazol-4-yl]pyrazolo[1,5-a]p-
yrimidine-3-carboxamide as a light yellow solid. LCMS (Method 24)
[M+H].sup.+=627.1, R.sub.T=1.55 min. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta.: (ppm) 9.76 (s, 1H), 9.35 (d, 1H, J=6.8 Hz),
8.69-8.68 (m, 2H), 8.31 (s, 1H), 7.63 (dd, 1H, J=2.4, 8.8 Hz), 7.55
(d, 1H, J=2.4 Hz), 7.46 (d, 1H, J=9.2 Hz), 7.29 (dd, 1H, J=4.2, 7.0
Hz), 7.09 (t, 1H, J=73.2 Hz), 6.12 (s, 1H), 5.25 (s, 2H), 4.91 (s,
2H), 3.51 (t, 4H, J=5.4 Hz), 3.41 (s, 2H), 2.50-2.40 (m, 4H).
Example 352
##STR00674##
[0942]
N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[2-(4-[methyl[(5-oxo-2,-
5-dihydrofuran-3-yl)methyl]amino]piperidin-1-yl)-2-oxoethyl]-1H-pyrazol-4--
yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide
[0943] To a solution of
N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[2-[4-(methylamino)piperidin--
1-yl]-2-oxoethyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide
(100 mg, 0.18 mmol) in DMF (4 mL) was added DIEA (46 mg, 0.36
mmol), 4-(bromomethyl)-2,5-dihydrofuran-2-one (63 mg, 0.36 mmol).
The resulting solution was stirred at room temperature overnight.
The resulting mixture was concentrated under vacuum. The crude
product was purified by Prep-HPLC with the following conditions
(Prep-HPLC-005): Column, XBridge Prep C18 OBD Column, 5 um, 19*150
mm; mobile phase, water with 0.05% FA and MeCN (40.0% up to 48.0%
in 10 min, up to 95.0% in 1 min, hold 95.0% in 1 min, down to 40.0%
in 2 min); Detector, UV 254/220 nm. This resulted in 15.5 mg (13%)
of N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[2-(4-[methyl
[(5-oxo-2,5-dihydrofuran-3-yl)methyl]amino]piperidin-1-yl)-2-oxoethyl]-1H-
-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide as a white
solid. LCMS (Method 20) [M+H].sup.+=655.2, R.sub.T=1.91 min.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.: (ppm) 9.76 (s, 1H),
9.34 (dd, 1H, J=1.6, 7.2 Hz), 8.69-8.68 (m, 2H), 8.31 (s, 1H), 7.62
(dd, 1H, J=2.8, 8.8 Hz), 7.55 (d, 1H, J=2.8 Hz), 7.46 (d, 1H, J=9.2
Hz), 7.28 (dd, 1H, J=4.4, 7.2 Hz), 7.09 (t, 1H, J=73.2 Hz), 6.04
(s, 1H), 5.24-5.22 (m, 2H), 4.86 (d, 2H, J=1.2 Hz), 4.39-3.37 (m,
1H), 4.01-3.93 (m, 1H), 3.47 (s, 2H), 3.10-3.01 (m, 1H), 2.67-2.62
(m, 2H), 2.20 (s, 3H), 1.76-1.73 (m, 2H), 1.56-1.42 (m, 1H),
1.40-1.29 (m, 1H).
Example 353
##STR00675##
[0944]
3-[4-(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]p-
yrimidine-3-amido]-1H-pyrazol-1-yl]acetyl)piperazin-1-yl]propanoic
acid
[0945] To a solution of
{3-(5-Chloro-2-difluoromethoxyphenyl)-4-[(pyrazolo[1,5-a]pyrimidine-3-car-
bonyl)amino]pyrazol-1-yl}acetic acid (200 mg, 0.35 mmol) in DMF (4
mL) was added ethyl 3-(piperazin-1-yl)propanoate hydrochloride (90
mg, 0.40 mmol), DIEA (179.25 mg, 1.39 mmol), HATU (158.20 mg, 0.42
mmol). The resulting solution was stirred at room temperature for 6
h. The resulting mixture was concentrated under vacuum. The residue
was purified by flash chromatography on silica gel eluting with 10%
MeOH in DCM. This resulted in 270 mg (crude) of ethyl
3-[4-(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimid-
ine-3-amido]-1H-pyrazol-1-yl]acetyl)piperazin-1-yl]propanoate as a
yellow solid. LCMS (Method 28) [M+H].sup.+=631.2, R.sub.T=0.66
min.
[0946] To a solution of ethyl
3-[4-(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimid-
ine-3-amido]-1H-pyrazol-1-yl]acetyl)piperazin-1-yl]propanoate (270
mg, 0.43 mmol) in ethanol (10 mL) was added KOH (200 mg, 3.56 mmol)
and water (4 mL). The resulting solution was stirred at room
temperature for 1 h and neutralized with 1 N HCl solution. The
resulting mixture was concentrated under vacuum. The crude product
was purified by Prep-HPLC with the following conditions
(Prep-HPLC-005): Column, XBridge Prep C18 OBD Column, 5 um, 19*150
mm; mobile phase, water with 0.05% FA and MeCN (27.0% up to 35.0%
in 10 min, up to 95.0% in 1 min, hold 95.0% in 1 min, down to 27.0%
in 2 min); Detector, UV 254/220 nm. This resulted in 31.5 mg (11%)
of the formic acid salt of
3-[4-(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimid-
ine-3-amido]-1H-pyrazol-1-yl]-acetyl)piperazin-1-yl]propanoic acid
as a off-white solid. LCMS (Method 28) [M+H].sup.+=603.1,
R.sub.T=0.81 min. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.:
(ppm) 9.76 (s, 1H), 9.34 (dd, 1H, J=1.4, 7.0 Hz), 8.69-8.67 (m,
2H), 8.31 (s, 1H), 7.62 (dd, 1H, J=2.8, 8.8 Hz), 7.55 (d, 1H, J=2.4
Hz), 7.46 (d, 1H, J=8.4 Hz), 7.28 (dd, 1H, J=4.2, 7.0 Hz), 7.08 (t,
1H, J=73.6 Hz), 5.24 (s, 1H), 3.50-3.47 (m, 4H), 2.57 (t, 2H, J=7.2
Hz), 2.49-2.39 (m, 6H).
Example 354
##STR00676##
[0947] tert-butyl
(3R,4R)-4-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrim-
idine-3-amido]-1H-pyrazol-1-yl]-3-hydroxypiperidine-1-carboxylate
[0948] To a solution of
N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1H-pyrazol-4-yl]-pyrazolo[1,5-a-
]pyrimidine-3-carboxamide (600 mg, 1.482 mmol) in
1,2-dichloroethane (15 mL) was added Yb(OTf).sub.3 (300 mg, 0.484
mmol), tert-butyl 7-oxa-3-azabicyclo [4.1.0]heptane-3-carboxylate
(1.20 g, 6.02 mmol). The resulting mixture was stirred t at
65.degree. C. overnight and concentrated under vacuum. The residue
was purified by flash chromatography on silica gel eluting with
ethyl acetate/petroleum ether (4/1). The regioisomeric/enantiomeric
mixtures (500 mg) were separated by Chiral-Prep-HPLC with the
following conditions: Column, Phenomenex Lux 5u Cellulose-4.English
Pound.-AXIA Packed 250*21.2 mm, 5 um; mobile phase, Mobile Phase A:
Hexane, Mobile Phase B: Ethanol; Flow rate: 20 mL/min; Gradient: 35
B to 35 B in 28 min; RT 1:10; RT 2:13; Detector, 254/220 nm. 30 mg
product was obtained which Alpha (25 degree C., Hex:EtOH=60:40) to
give 31.3 mg (3.5%) of tert-butyl
(3R,4R)-4-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrim-
idine-3-amido]-1H-pyrazol-1-yl]-3-hydroxypiperidine-1-carboxylate
as a solid. (This single isomer is the first peak in Chiral-HPLC
with the above condition). LCMS (Method 20) [M+H].sup.+=604.3,
R.sub.T=2.08 min. .sup.1H NMR (300 MHz, CD.sub.3OD-d.sub.4)
.delta.: (ppm) 9.10 (dd, 1H, J=1.4, 6.9 Hz), 8.69-8.66 (m, 2H),
8.40 (s, 1H), 7.70 (d, 1H, J=2.4 Hz), 7.55 (dd, 1H, J=2.7, 8.7 Hz),
7.40 (d, 1H, J=8.7 Hz), 7.21 (dd, 1H, J=4.2, 6.9 Hz), 6.59 (t, 1H,
J=73.7 Hz), 4.37-4.03 (m, 4H), 3.03 (m, 1H), 2.15 (m, 1H), 1.59 (m,
2H), 1.52 (m, 9H).
Example 355
##STR00677##
[0949] tert-butyl (3
S,4S)-4-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimid-
ine-3-amido]-1H-pyrazol-1-yl]-3-hydroxypiperidine-1-carboxylate
[0950] (This single isomer is the second peak in Chiral-HPLC with
the above condition) to give 30.5 mg (3.5%) of tert-butyl
(3S,4S)-4-[3-[5-chloro-2-(difluoromethoxy)
phenyl]-4-[pyrazolo[1,5-a]pyrimidine-3-amido]-1H-pyrazol-1-yl]-3-hydroxyp-
iperidine-1-carboxylate as a solid. LCMS (Method 20)
[M+H].sup.+=604.3, R.sub.T=2.08 min. .sup.1H NMR (300 MHz,
CD.sub.3OD-d.sub.4) .delta.: (ppm) 9.10 (dd, 1H, J=1.2, 6.9 Hz),
8.69-8.66 (m, 2H), 8.40 (s, 1H), 7.71 (s, 1H), 7.55 (d, 1H, J=8.4
Hz), 7.40 (d, 1H, J=8.4 Hz), 7.26-7.22 (m, 1H), 6.59 (t, 1H, J=73.5
Hz), 4.37-4.03 (m, 4H), 3.03 (m, 1H), 2.15 (m, 1H), 1.59 (m, 2H),
1.52 (m, 9H).
##STR00678##
tert-butyl
(3R,4R)-3-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrim-
idine-3-amido]-1H-pyrazol-1-yl]-4-hydroxypiperidine-1-carboxylate
[0951] (This single isomer is the third peak in Chiral-HPLC with
the above condition) to give 24.8 mg (2.8%) of tert-butyl
(3R,4R)-3-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrim-
idine-3-amido]-1H-pyrazol-1-yl]-4-hydroxypiperidine-1-carboxylate
as a solid. LCMS (Method 20) [M+H].sup.+=604.3, R.sub.T=2.08 min.
.sup.1H NMR (300 MHz, CD.sub.3OD-d.sub.4) .delta.: (ppm) 9.10 (dd,
1H, J=1.2, 6.9 Hz), 8.69-8.65 (m, 2H), 8.38 (s, 1H), 7.69 (s, 1H),
7.55 (d, 1H, J=7.8 Hz), 7.39 (d, 1H, J=8.7 Hz), 7.25-7.22 (m, 1H),
6.83 (t, 1H, J=73.5 Hz), 4.38-4.35 (m, 1H), 4.25-4.15 (m, 2H),
4.01-3.93 (m, 1H), 2.97 (m, 1H), 2.77 (m, 1H), 2.17-2.13 (m, 2H),
1.53 (m, 9H).
Example 357
##STR00679##
[0952] tert-butyl (3
S,4S)-3-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimid-
ine-3-amido]-1H-pyrazol-1-yl]-4-hydroxypiperidine-1-carboxylate
[0953] (This single isomer is the fourth peak in Chiral-HPLC with
the above condition) to give 24.9 mg (2.8%) of tert-butyl
(3S,4S)-3-[3-[5-chloro-2-(difluoromethoxy)
phenyl]-4-[pyrazolo[1,5-a]pyrimidine-3-amido]-1H-pyrazol-1-yl]-4-hydroxyp-
iperidine-1-carboxylate as a solid. LCMS (Method 20)
[M+H].sup.+=604.3, R.sub.T=2.08 min. .sup.1H NMR (300 MHz,
CD.sub.3OD-d.sub.4) .delta.: (ppm) 9.10 (dd, 1H, J=1.2, 6.9 Hz),
8.69-8.65 (m, 2H), 8.38 (s, 1H), 7.69 (s, 1H), 7.55 (d, 1H, J=8.4
Hz), 7.42-7.39 (d, 1H, J=8.1 Hz), 7.25-7.22 (m, 1H), 6.58 (t, 1H,
J=73.5 Hz), 4.38-4.35 (m, 1H), 4.25-4.15 (m, 2H), 4.01-3.93 (m,
1H), 2.97 (m, 1H), 2.77 (m, 1H), 2.15-2.14 (m, 2H), 1.53 (m,
9H).
Example 358
##STR00680##
[0954]
N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[(3R,4R)-3-hydroxypiper-
idin-4-yl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide
(Assumed)
[0955] A mixture of the first peak from Example 357 chiral
separation (20 mg, 0.033 mmol) and saturated HCl dioxane solution
(4 m) was stirred at room temperature for 2 h. The resulting
mixture was concentrated under vacuum. This resulted in 18 mg
(100%) of
N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[(3R,4R)-3-hydroxypiperidin-4-
-yl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide
hydrochloride (assumed) as a solid. LCMS (Method 20)
[M+H].sup.+=504.2, R.sub.T=1.38 min. .sup.1H NMR (300 MHz,
CD.sub.3OD-d.sub.4) .delta.: (ppm) 9.10 (dd, 1H, J=1.5, 6.9 Hz),
8.67-8.65 (m, 2H), 8.44 (s, 1H), 7.71 (d, 1H, J 20=2.4 Hz), 7.56
(dd, 1H, J=2.5, 8.8 Hz), 7.40 (d, 1H, J=9 Hz), 7.21 (dd, 1H, J=4.4,
7.1 Hz), 6.85 (t, 1H, J=73.4 Hz), 4.45-4.43 (m, 1H), 4.28-4.23 (m,
1H), 3.77-3.50 (m, 4H), 2.32-2.27 (m, 1H), 1.91-1.86 (m, 1H).
##STR00681##
N-[3-[5-chloro-2-(difluoromethoxy) phenyl]-1-[(3 S,
4S)-3-hydroxypiperidin-4-yl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3--
carboxamide (Assumed)
[0956] A mixture of the second peak from Example 357 chiral
separation (Example 358) and saturated HCl dioxane solution (4 mL)
was stirred at room temperature for 2 h. The resulting mixture was
concentrated under vacuum. This resulted in 20 mg (86%) of
N-[3-[5-chloro-2-(difluoromethoxy)
phenyl]-1-[(3S,4S)-3-hydroxypiperidin-4-yl]-1H-pyrazol-4-yl]pyrazolo[1,5--
a]pyrimidine-3-carboxamide hydrochloride (assumed) as a yellow
solid. LCMS (Method 20) [M+H].sup.+=504.2, R.sub.T=1.71 min.
.sup.1H NMR (300 MHz, CD.sub.3OD-d.sub.4) .delta.: (ppm) 9.10 (d,
1H, J=6.9 Hz), 8.66-8.64 (m, 2H), 8.43 (s, 1H), 7.71 (d, 1H, J=2.7
Hz), 7.55 (dd, 1H, J=2.7, 8.7 Hz), 7.39 (d, 1H, J=9.0 Hz), 7.21
(dd, 1H, J=4.1, 6.9 Hz), 6.60 (t, 1H, J=73.4 Hz), 4.47-4.44 (m,
1H), 4.28-4.21 (m, 1H), 3.77-3.50 (m, 4H), 2.31-2.26 (m, 1H),
1.93-1.82 (m, 1H).
Example 360
##STR00682##
[0957]
N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[(3R,4R)-4-hydroxypiper-
idin-3-yl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide
(Assumed absolute)
[0958] A mixture of the third peak from Example 357 chiral
separation (Example 359) (20 mg, 0.033 mmol) and saturated HCl
dioxane solution was stirred room temperature for 2 h. The
resulting mixture was concentrated under vacuum. This resulted in
11.3 mg (63%) of
N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[(3R,4R)-4-hydroxypiperidin-3-
-yl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide
hydrochloride as a solid. LCMS (Method 20) [M+H].sup.+=504.2,
R.sub.T=1.38 min. .sup.1H NMR (300 MHz, CD.sub.3OD-d.sub.4)
.delta.: (ppm) 9.12 (d, 1H, J=6.0 Hz), 8.73-8.66 (m, 2H), 8.41 (s,
1H), 7.69 (d, 1H, J=1.5 Hz), 7.57 (dd, 1H, J=2.4, 8.7 Hz), 7.42 (d,
1H, J=5.7 Hz), 7.23 (dd, 1H, J=4.4, 7.1 Hz), 6.62 (t, 1H, J=73.4
Hz), 4.46-4.4.28 (m, 2H), 3.69-3.61 (m, 2H), 3.26 (m, 1H),
3.11-3.04 (m, 1H), 2.72-2.24 (m, 2H).
Example 361
##STR00683##
[0959] N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[(3 S,
4S)-4-hydroxypiperidin-3-yl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3--
carboxamide
[0960] A mixture of fourth peak from Example 357 (Example 360) (26
mg) and saturated HCl dioxane solution (4 mL) was stirred at room
temperature for 2 h. The resulting mixture was concentrated under
vacuum. This resulted in 22.4 mg (96%) of
N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[(3 S,4
S)-4-hydroxypiperidin-3-yl]-1H-pyrazol-4-yl]
pyrazolo[1,5-a]pyrimidine-3-carboxamide hydrochloride as a yellow
solid. LCMS (Method 20) [M+H].sup.+=504.2, R.sub.T=1.73 min.
.sup.1H NMR (300 MHz, CD.sub.3OD-d.sub.4) .delta.: (ppm) 9.08 (d,
1H, J=7.2 Hz), 8.64-8.63 (m, 2H), 8.37 (s, 1H), 7.65 (d, 1H, J=2.1
Hz), 7.53 (dd, 1H, J=2.1, 9.0 Hz), 7.37 (d, 1H, J=8.7 Hz), 7.19
(dd, 1H, J=4.8, 6.3 Hz), 6.58 (t, 1H, J=73.5 Hz), 4.39-4.4.27 (m,
2H), 3.74-3.40 (m, 2H), 3.31 (m, 1H), 3.07-3.00 (m, 1H), 2.44-2.43
(m, 2H).
##STR00684##
ethyl
2-[(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyr-
imidine-3-amido]-1H-pyrazol-1-yl]ethyl)(pyridin-3-ylmethyl)amino]acetate
[0961] To a solution of
N-[1-(2-bromoethyl)-3-[5-chloro-2-(difluoromethoxy)phenyl]-1H-pyrazol-4-y-
l]pyrazolo[1,5-a]pyrimidine-3-carboxamide (510 mg, 1.00 mmol) in
EtOH (30 mL) was added, triethylamine (1.01 g, 9.98 mmol) and ethyl
2-aminoacetate hydrochloride (681 mg, 4.88 mmol). The resulting
solution was stirred at 80.degree. C. for 24 h. The resulting
mixture was concentrated under vacuum. The residue was purified by
flash chromatography on silica gel eluting with 3% MeOH in DCM.
This resulted in 420 mg (79%) of ethyl
2-[(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidin-
e-3-amido]-1H-pyrazol-1-yl]ethyl)amino]acetate as light yellow oil.
LCMS (Method 20) [M+H].sup.+=534.0, R.sub.T=1.18 min.
[0962] To a solution of ethyl
2-[(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidin-
e-3-amido]-1H-pyrazol-1-yl]ethyl)amino]acetate (420 mg, 0.79 mmol)
in EtOH (30 mL) was added AcOH (0.1 mL, 1.75 mmol),
pyridine-3-carbaldehyde (126 mg, 1.18 mmol). The mixture was
stirred at room temperature for 3 h and NaBH.sub.3CN (99 mg, 1.58
mmol) was added. The resulting solution was stirred at 60.degree.
C. for 12 h. The solids were filtered out. The resulting mixture
was concentrated under vacuum. The residue was purified by flash
chromatography on silica gel eluting with 3% MeOH in DCM. The crude
product (100 mg) was purified by Flash-Prep-HPLC with the following
conditions (IntelFlash-2): Column, C18 silica gel; mobile phase,
CH.sub.3CN:H.sub.2O=5:95 increasing to CH.sub.3CN:H.sub.2O=24:40
within 12 min; Detector, UV 254 nm. 26 mg product was obtained.
This resulted in 25.6 mg (5%) of ethyl
2-[(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidin-
e-3-amido]-1H-pyrazol-1-yl]-ethyl)(pyridin-3-ylmethyl)amino]acetate
as an off-white solid. LCMS (Method 20) [M+H].sup.+=625.3,
R.sub.T=1.68 min. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.:
(ppm) 9.73 (s, 1H), 9.35 (d, 1H, J=6.8 Hz), 8.69-8.68 (m, 2H),
8.39-8.37 (m, 3H), 7.63-7.61 (m, 2H), 7.51 (s, 1H), 7.43 (d, 1H,
J=8.8 Hz), 7.31-7.25 (m, 2H), 7.04 (t, 1H, J=73.6 Hz), 4.30-4.27
(m, 2H), 4.07 (q, 2H, J=6.8 Hz), 3.82 (s, 2H), 3.44 (s, 2H),
3.15-3.11 (m, 2H), 1.17 (t, 3H, J=7.2 Hz).
Example 363
##STR00685##
[0963]
2-[(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyr-
imidine-3-amido]-1H-pyrazol-1-yl]ethyl)(pyridin-3-ylmethyl)amino]acetic
acid
[0964] A mixture of ethyl
2-[(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidin-
e-3-amido]-1H-pyrazol-1-yl]ethyl)(pyridin-3-ylmethyl)amino]acetate
(180 mg, 0.29 mmol), ethanol (10 mL) and 1 N sodium hydroxide (2
mL) was stirred at room temperature for 30 min. The mixture was
acidified with 1 HCl to pH 5. The resulting mixture was
concentrated under vacuum. The crude product (200 mg) was purified
by Flash-Prep-HPLC with the following conditions (IntelFlash-1):
Column, C18 silica gel; mobile phase, CH3CN:H2O=5:95 increasing to
CH.sub.3CN:H.sub.2O=24:40 within 12 min; Detector, UV 254 nm. 8.6
mg product was obtained. This resulted in 8.6 mg (5%) of
2-[(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]p-
yrimidine-3-amido]-1H-pyrazol-1-yl]ethyl)(pyridin-3-ylmethyl)amino]acetic
acid formate as a white solid. LCMS (Method 20) [M+H].sup.+=597.2,
R.sub.T=2.72 min. .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta.:
(ppm) 9.72 (s, 1H), 9.34 (d, 1H, J=7.2 Hz), 8.69-8.68 (m, 2H),
8.39-8.37 (m, 3H), 7.63-7.60 (m, 2H), 7.51 (d, 1H, J=2.1 Hz), 7.43
(d, 1H, J=9.0 Hz), 7.32-7.22 (m, 2H), 6.99 (t, 1H, J=73.2 Hz),
4.33-4.22 (m, 2H), 3.83 (s, 2H), 3.334 (s, 2H), 3.15-3.07 (m,
2H).
##STR00686##
ethyl
2-[[1-(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]-
pyrimidine-3-amido]-1H-pyrazol-1-yl]acetyl)piperidin-4-yl]
amino]acetate
[0965] To a solution of
{3-(5-Chloro-2-difluoromethoxyphenyl)-4-[(pyrazolo[1,5-a]pyrimidine-3-car-
bonyl)amino]pyrazol-1-yl}acetic acid (665 mg, 1.44 mmol) in DMF (7
mL) was added tert-butyl N-(piperidin-4-yl)carbamate (300 mg, 1.50
mmol), triethylamine (700 mg, 6.92 mmol), HATU (670 g, 2.78 mol).
The resulting solution was stirred at room temperature for 1.5 h.
EtOAc (100 mL) and water (50 mL) was added. Phases were separated.
The organic layer was, washed with brine, dried over anhydrous
sodium sulfate and concentrated under vacuum. The residue was
purified by flash chromatography on silica gel eluting with ethyl
acetate/hexane (1/1). This resulted in 600 mg (65%) of tert-butyl
N-[1-(2-[3-[5-chloro-2-(difluoromethoxy)
phenyl]-4-[pyrazolo[1,5-a]pyrimidine-3-amido]-1H-pyrazol-1-yl]acetyl)pipe-
ridin-4-yl]carbamate as a yellow solid. TLC: R.sub.f=0.3; ethyl
acetate/petroleum ether=1/1.
[0966] TFA (2.0 mL, 26.93 mmol) was added to a solution of
tert-butyl
N-[1-(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimid-
ine-3-amido]-1H-pyrazol-1-yl]acetyl)piperidin-4-yl]carbamate (600
mg, 0.93 mmol) in dichloromethane (8 mL). The resulting solution
was stirred room temperature for 2 h and concentrated under vacuum.
The residue was dissolved in ethyl acetate (100 mL), and saturated
NaHCO.sub.3 (50 mL) was added. Phases were separated. The organic
layer was washed with saturated NaHCO.sub.3, brine, dried over
anhydrous sodium sulfate and concentrated under vacuum. This
resulted in 450 mg (89%) of
N-[1-[2-(4-aminopiperidin-1-yl)-2-oxoethyl]-3-[5-chloro-2-(difluoromethox-
y)phenyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide
as a yellow solid. TLC: R.sub.f=0.3; MeOH/DCM=1/5.
[0967] To a solution of
N-[1-[2-(4-aminopiperidin-1-yl)-2-oxoethyl]-3-[5-chloro-2-(difluoromethox-
y)phenyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide
(126 mg, 0.24 mmol) in DMF (3 mL) was added potassium carbonate (76
mg, 0.55 mmol), ethyl 2-bromoacetate (0.03 mL, 0.27 mmol). The
resulting mixture was stirred at 25.degree. C. for 1 h and diluted
with 100 mL of ethyl acetate. Water (50 mL) was added. Phases were
separated. The organic phase was washed with brine, dried over
anhydrous sodium sulfate and concentrated under vacuum. The crude
product was purified by Flash-Prep-HPLC with the following
conditions (IntelFlash-1): Column: Xbridge C18, 19*150 mm, 5 um;
Mobile Phase A: Water/0.05% NH.sub.4HCO.sub.3, Mobile Phase B: ACN;
Flow rate: 30 mL/min; Gradient: 20% B to 85% B in 10 min; 254 nm.
This resulted in 29.3 mg (98%) of ethyl
2-[[1-(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimi-
dine-3-amido]-1H-pyrazol-1-yl]acetyl)piperidin-4-yl]amino]acetate
as a white solid. LCMS (Method 25) [M+H].sup.+=631.2, R.sub.T=1.89
min. .sup.1H NMR (400 MHz, CD.sub.3OD-d.sub.4) .delta.: (ppm) 8.98
(d, 1H, J=6.8 Hz), 8.53-8.52 (m, 2H), 8.25 (s, 1H), 7.58 (d, 1H,
J=2.4 Hz), 7.44 (dd, 1H, J=2.4, 8.8 Hz), 7.29 (d, 1H, J=8.8 Hz),
7.09 (dd, 1H, J=4.4, 6.8 Hz), 6.51 (t, 1H, J=73.6 Hz), 5.20-5.13
(m, 2H), 4.32 (d, 1H, J=13.2 Hz), 4.07 (q, 2H, J=7.2 Hz), 3.91 (d,
1H, J=13.2 Hz), 3.36 (s, 2H), 3.21-3.09 (m, 1H), 2.78-2.68 (m, 2H),
1.94-1.83 (m, 2H), 1.34-1.22 (m, 2H), 1.16 (t, 3H, J=7.2 Hz).
Example 365
##STR00687##
[0968]
2-[[1-(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]-
pyrimidine-3-amido]-1H-pyrazol-1-yl]acetyl)piperidin-4-yl]amino]acetic
acid
[0969] A mixture of ethyl
2-[[1-(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimi-
dine-3-amido]-1H-pyrazol-1-yl]acetyl)piperidin-4-yl]amino]-acetate
(200 mg, 0.32 mmol), KOH (100 mg, 1.78 mmol) in methanol (5 mL) was
stirred at 25.degree. C. for 12 h. The crude product was purified
by Flash-Prep-HPLC with the following conditions (IntelFlash-1):
Column: Xbridge C18, 19*150 mm, 5 um; Mobile Phase A: Water/0.05%
NH.sub.4HCO.sub.3, Mobile Phase B: ACN; Flow rate: 30 mL/min;
Gradient: 20% B to 85% B in 10 min; 254 nm. This resulted in 28.5
mg (15%) of
2-[[1-(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimi-
dine-3-amido]-1H-pyrazol-1-yl]-acetyl)piperidin-4-yl]amino]acetic
acid as a white solid. LCMS (Method 25) [M+H].sup.+=603.1,
R.sub.T=1.39 min. .sup.1H NMR (400 MHz, CD3OD-d.sub.4) .delta.:
(ppm) 8.98 (dd, 1H, J=1.2, 6.8 Hz), 8.54-8.53 (m, 2H), 8.24 (s,
1H), 7.57 (d, 1H, J=2.4 Hz), 7.45 (dd, 1H, J=2.8, 8.8 Hz), 7.30 (d,
1H, J=8.8 Hz), 7.09 (dd, 1H, J=4.4, 6.8 Hz), 6.70 (t, 1H, J=73.4
Hz), 5.23-5.10 (m, 2H), 4.54 (d, 1H, J=13.2 Hz), 4.05 (d, 1H,
J=13.6 Hz), 3.45 (s, 2H), 3.30-3.11 (m, 4H), 2.71-2.65 (m, 1H),
2.11-2.05 (m, 1H), 1.58-1.43 (m, 2H).
Example 366
##STR00688##
[0970] ethyl
2-(4-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-
-3-amido]-1H-pyrazol-1-yl]piperidin-1-yl)acetate
[0971] To a solution of tert-butyl
4-hydroxypiperidine-1-carboxylate (1 g, 4.97 mmol) in DCM (50 mL)
was added DIEA (2.00 g, 15.47 mmol), 4-dimethylaminopyridine (10
mg, 0.08 mmol) and MsCl (862 mg, 7.53 mmol). The resulting solution
was stirred at room temperature for 12 h, washed with water and
brine. The organic layer was dried over anhydrous sodium sulfate
and concentrated under vacuum. The residue was purified by flash
chromatography on silica gel eluting with ethyl acetate/petroleum
ether (1/1). This resulted in 860 mg (62%) of tert-butyl
4-(methanesulfonyloxy)piperidine-1-carboxylate as a light yellow
solid. LCMS (Method 20) [M+H].sup.+=224.0, R.sub.T=1.42 min.
[0972] To a solution of
N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]-
pyrimidine-3-carboxamide (500 mg, 1.24 mmol) in MeCN (50 mL) was
added Cs.sub.2CO.sub.3 (1.21 g, 3.71 mmol), tert-butyl
4-(methanesulfonyloxy)piperidine-1-carboxylate (828 mg, 2.96 mmol).
The resulting solution was stirred at 80.degree. C. for 18 h. The
solids were filtered out. The filtrate was concentrated under
vacuum. The residue was purified by flash chromatography on silica
gel eluting with 2% MeOH in DCM. This resulted in 1.1 g (crude) of
tert-butyl 4-[3-[5-chloro-2-(difluoromethoxy)
phenyl]-4-[pyrazolo[1,5-a]pyrimidine-3-amido]-1H-pyrazol-1-yl]piperidine--
1-carboxylate as a yellow solid. LCMS (Method 25)
[M+H].sup.+=588.0, R.sub.T=1.17 min.
[0973] A mixture of crude product from previous step tert-butyl
4-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-3--
amido]-1H-pyrazol-1-yl]-piperidine-1-carboxylate (1.1 g) and
saturated HCl dioxane solution (20 mL) was stirred at room
temperature for 8 h. The resulting mixture was concentrated under
vacuum. The residue was dissolved in ethanol (20 mL) and
neutralized with 2 N NaOH to pH-8. The resulting mixture was
concentrated under vacuum. The residue was purified by flash
chromatography on silica gel eluting with 15% MeOH in DCM. This
resulted in 320 mg (35%) of
N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-(piperidin-4-yl)-1H-pyrazol-4-
-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide as a yellow solid.
[0974] To a solution of
N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-(piperidin-4-yl)-1H-pyrazol-4-
-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (320 mg, 0.66 mmol) in
ethanol (20 mL) was added 50% ethyl 2-oxoacetate hydrate (268 mg,
1.31 mmol), AcOH (0.1 mL, 1.75 mmol) and NaBH.sub.3CN (83 mg, 1.32
mmol). The resulting solution was stirred at 60.degree. C. for 12 h
and concentrated under vacuum. The residue was passed through a
short pad of silica gel eluting with 2% MeOH in DCM. The crude
product (100 mg) was purified by Flash-Prep-HPLC with the following
conditions (IntelFlash-1): Column, silica gel; mobile phase,
CH.sub.3CN:H.sub.2O=5:95 increasing to CH.sub.3CN:H.sub.2O=55:75
within 12 min; Detector, UV 254 nm. 25.3 mg product was obtained.
This resulted in 25.3 mg (7%) of ethyl
2-(4-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-
-3-amido]-1H-pyrazol-1-yl]piperidin-1-yl)acetate as an off-white
solid. LCMS (Method 20) [M+H].sup.+=574.2, R.sub.T=2.70 min.
.sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta.: (ppm) 9.73 (s, 1H),
9.36 (s, 1H), 8.69-8.67 (m, 2H), 8.36 (s, 1H), 7.63-7.25 (m, 5H),
4.25-4.23 (m, 1H), 4.13-4.10 (m, 2H), 3.28-3.27 (m, 2H), 3.01-2.98
(m, 2H), 2.42-2.40 (m, 2H), 2.12-1.98 (m, 4H), 1.25-1.20 (m,
3H).
Example 367
##STR00689##
[0975]
N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[2-[(1,3-oxazol-2-ylmet-
hyl)amino]ethyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide
[0976] To a solution of
N-[1-(2-aminoethyl)-3-[5-chloro-2-(difluoromethoxy)phenyl]-1H-pyrazol-4-y-
l]pyrazolo[1,5-a]pyrimidine-3-carboxamide (100 mg, 0.22 mmol) in
MeOH (15 mL) was added 1,3-oxazole-2-carbaldehyde (21.7 mg, 0.22
mmol), followed by NaBH.sub.3CN (16 mg, 0.25 mmol). The resulting
solution was stirred at room temperature for 12 h. The resulting
mixture was concentrated under vacuum. The residue was passed
through a short pad of silica gel eluting with 5% MeOH in DCM. The
crude product was purified by Prep-HPLC with the following
conditions (2#-AnalyseHPLC-SHIMADZU(HPLC-10)): Column, XBridge
BEH130 Prep C18 OBD Column, 19� 100 mm 5 um 13 nm; mobile phase,
Water with 10 mM NH4CO3 and ACN (20% ACN up to 50% in 6 min);
Detector, UV 254/220 nm. 52.7 mg product was obtained. This
resulted in 52.7 mg (45%) of
N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[2-[(1,3-oxazol-2-yl-
methyl)amino]ethyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamid-
e as a light yellow solid. LCMS (Method 20) [M+H].sup.+=529.2,
R.sub.T=2.42 min. .sup.1H NMR (300 MHz, CD.sub.3OD-d.sub.4)
.delta.: (ppm) 9.08 (dd, 1H, J=1.7, 7.1 Hz), 8.66-8.63 (m, 2H),
8.34 (s, 1H), 7.87 (d, 1H, J=0.6 Hz), 7.67 (d, 1H, J=2.7 Hz), 7.53
(dd, 1H, J=2.4, 8.7 Hz), 7.38 (d, 1H, J=8.7 Hz), 7.19 (dd, 1H,
J=4.2, 7.2 Hz), 7.13 (d, 1H, J=0.6 Hz), 6.55 (t, 1H, J=73.5 Hz),
4.33 (t, 2H, J=6.0 Hz), 3.95 (s, 2H), 3.14 (t, 2H, J=6.0 Hz).
Example 368
##STR00690##
[0977]
N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[2-[(pyridin-3-ylmethyl-
)amino]ethyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide
[0978] A mixture of
N-[1-(2-bromoethyl)-3-[5-chloro-2-(difluoromethoxy)phenyl]-1H-pyrazol-4-y-
l]pyrazolo[1,5-a]pyrimidine-3-carboxamide (150 mg, 0.29 mmol) and
pyridin-3-ylmethanamine (158 mg, 1.46 mmol) in MeCN (3 mL) was
stirred at 70.degree. C. for 12 h. The resulting mixture was
concentrated under vacuum. The crude product was purified by
Flash-Prep-HPLC with the following conditions (IntelFlash-2):
Column, C.sub.18 silica gel; mobile phase, CH.sub.3CN:H.sub.2O=5:95
increasing to CH.sub.3CN:H.sub.2O=30:42 within 12 min; Detector, UV
254 nm. This resulted in 57.7 mg (37%) of
N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[2-[(pyridin-3-ylmethyl)amino-
]ethyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide as
a white solid. LCMS (Method 25) [M+H].sup.+=539.1, R.sub.T=0.87
min. .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta.: (ppm) 9.76 (s,
1H), 9.33 (dd, 1H, J=1.5, 6.9 Hz), 8.69-8.67 (m, 2H), 8.50 (d, 1H,
J=1.8 Hz), 8.41 (dd, 1H, J=1.5, 4.8 Hz), 8.38 (s, 1H), 7.73-7.70
(m, 1H), 7.61 (dd, 1H, J=2.7, 8.7 Hz), 7.59 (d, 1H, J=2.4 Hz), 7.43
(d, 1H, J=8.7 Hz), 7.33-7.28 (m, 2H), 6.99 (t, 1H, J=73.2 Hz), 4.24
(t, 2H, J=6.0 Hz), 3.75-3.72 (m, 2H), 3.01-2.94 (m, 2H), 2.27 (br,
1H).
##STR00691##
N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[(2S)-2-(methylamino)propyl]--
1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide
[0979] To a solution of (2S)-2-aminopropan-1-ol (1.0 g, 13.31 mmol)
in MeOH (30 mL) was added, 4-methoxybenzaldehyde (1.8 g, 13.22
mmol). NaBH.sub.3CN (600 mg) was then added. The resulting solution
was stirred at room temperature for 12 h. The solids were filtered
out. The resulting mixture was concentrated under vacuum. This
resulted in 2.1 g (crude) of
(2S)-2-[[(4-methoxyphenyl)methyl]amino]propan-1-ol as light yellow
oil. LCMS (Method 27) [M+H].sup.+=196.0, R.sub.T=0.95 min.
[0980] To a solution of
(2S)-2-[[(4-methoxyphenyl)methyl]amino]propan-1-ol (2.1 g, 10.75
mmol) and 37% formaldehyde (900 mg) in methanol (50 mL) was added
AcOH (0.1 mL, 1.75 mmol) and NaBH.sub.3CN (1.8 g, 28.64 mmol). The
resulting solution was stirred at room temperature for 5 h,
quenched with water (10 mL) and concentrated under vacuum. The
residue was dissolved in dichloromethane (100 mL), washed with
water and brine. The organic phase was dried over anhydrous sodium
sulfate and concentrated under vacuum. The residue was purified by
flash chromatography on silica gel eluting with 10% MeOH in DCM.
This resulted in 1.0 g (44%) of
(2S)-2-[[(4-methoxyphenyl)methyl](methyl)amino]propan-1-ol as
colorless oil. LCMS (Method 21) [M+H].sup.+=210.0, R.sub.T=0.92
min.
[0981] MsCl (250 mg, 2.18 mmol) was added dropwise to a stirring
solution of
(2S)-2-[[(4-methoxyphenyl)methyl](methyl)amino]propan-1-ol (400 mg,
1.91 mmol) and DIEA (516 mg, 3.99 mmol) in DCM (15 mL) at 0.degree.
C. The resulting solution was stirred at room temperature for 5 h
and quenched water (50 mL). Phases were separated. The aqueous
phase was extracted with DCM (.times.2) and the organic layers
combined. The organic phases were washed with brine, dried over
anhydrous sodium sulfate and concentrated under vacuum. This
resulted in 510 mg (crude) of
[(2S)-1-chloropropan-2-yl][(4-methoxyphenyl)methyl]methylamine as
light red oil. LCMS (Method 25) [M+H].sup.+=228.0, R.sub.T=0.55
min.
[0982] A 20-mL microwave vial was charged with
N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]-
-pyrimidine-3-carboxamide (400 mg, 0.99 mmol), Cs.sub.2CO.sub.3
(652 mg, 2.00 mmol), DMF (10 mL) and
[(2S)-1-chloropropan-2-yl][(4-methoxyphenyl)methyl]methylamine (454
mg, 1.99 mmol). The vessel was evacuated and refilled with nitrogen
3 times. The final reaction mixture was irradiated with microwave
radiation for 30 min at 120.degree. C. The reaction was then
quenched by the addition of 50 mL of water. The resulting solution
was extracted with dichloromethane (.times.2) and the organic
layers combined. and the organic layers were washed with brine,
dried over anhydrous sodium sulfate and concentrated under
vacuum.
[0983] The residue was purified by flash chromatography on silica
gel eluting with dichloromethane/ethyl acetate (1:1). This resulted
in 420 .mu.m of
N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[(2S)-2-[[(4-methoxy-
phenyl)methyl](methyl)amino]propyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimid-
ine-3-carboxamide and
N-[5-[5-chloro-2-(difluoromethoxy)phenyl]-1-[(2S)-2-[[(4-methoxyphenyl)me-
thyl](methyl)amino]propyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-car-
boxamide mixture. LCMS (Method 25) [M+H].sup.+=596.0, R.sub.T=0.81
min.
[0984] To the regioisomeric mixture from previous step (200 mg) in
CH.sub.3CN (20 mL) was added chloro(1-chloroethoxy)methanone (240
mg, 1.68 mmol). The resulting solution was stirred at 80.degree. C.
for 5 h. The resulting mixture was concentrated under vacuum and
dissolved with 20 mL of methanol. The resulting solution was
stirred at 80.degree. C. for 12 h and concentrated under vacuum.
The residue was passed through a short pad of silica gel eluting
with 5% MeOH in DCM. The crude product (120 mg) was purified by
Prep-HPLC with the following conditions (3#-Pre-HPLC-006(Waters)):
Column, XSelect CSH Prep C.sub.18 OBD Column, 5 um, 19*150 mm;
mobile phase, Water with 10 mmol NH4HCO3 and MeCN (26.0% MeCN up to
40.0% in 8 min); Detector, 254/220. Two fractions were obtained
with the major isomer (36.3 mg) as the title compound. LCMS (Method
20) [M+H].sup.+=476.2, R.sub.T=2.53 min. .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta.: (ppm) 9.73 (s, 1H), 9.33 (dd, 1H, J=1.2, 6.9
Hz), 8.68-8.66 (m, 2H), 8.33 (s, 1H), 7.65-7.61 (m, 2H), 7.43 (d,
1H, J=7.2 Hz), 7.27 (dd, 1H, J=4.5, 7.2 Hz), 6.97 (t, 1H, J=73.5
Hz), 4.11 (dd, 1H, J=6.3, 13.5 Hz), 4.01 (dd, 1H, J=6.0, 13.5 Hz),
2.97-2.91 (m, 1H), 2.29 (s, 3H), 1.76 (br, 1H), 0.95 (d, 3H, J=6.3
Hz).
Example 370
##STR00692##
[0985]
N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[(2S)-2-(dimethylamino)-
propyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide
[0986] To a solution of
N-[1-[(2S)-2-aminopropyl]-3-[5-chloro-2-(difluoromethoxy)
phenyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide
(170 mg, 0.37 mmol) in MeOH (15 mL) was added 37% formaldehyde
solution (16.6 mg, 0.55 mmol), NaBH.sub.3CN (23.3 mg, 0.37 mmol).
The resulting solution was stirred at room temperature for 12 h and
concentrated under vacuum. The residue was passed through a short
pad of silica gel eluting with 10% MeOH in DCM. The crude product
(80 mg) was purified by Prep-HPLC with the following conditions
(1#-Pre-HPLC-006(Waters)): Column, XSelect CSH Prep C18 OBD Column,
5 um, 19*150 mm; mobile phase, Water with 10 mM NH4CO3 and MeCN
(20.0% MeCN up to 35.0% in 8 min); Detector, 254/220. This resulted
in 29 mg (16%) of
N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[(2S)-2-(dimethylamino)propyl-
]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide as an
off-white solid. LCMS (Method 10) [M+H].sup.+=490.1, R.sub.T=0.84
min. .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta.: (ppm) 9.73 (s,
1H), 9.34 (dd, 1H, J=1.5, 6.9 Hz), 8.69-8.66 (m, 2H), 8.34 (s, 1H),
7.61 (dd, 1H, J=2.7, 8.7 Hz), 7.60 (d, 1H, J=2.1 Hz), 7.44 (d, 1H,
J=8.4 Hz), 7.28 (dd, 1H, J=4.5, 7.2 Hz), 6.99 (t, 1H, J=73.5 Hz),
4.22 (dd, 1H, J=7.2, 13.8 Hz), 4.02 (dd, 1H, J=6.9, 13.8 Hz),
3.20-3.18 (m, 1H), 2.22 (s, 6H), 0.88 (d, 3H, J=6.6 Hz).
Example 371
##STR00693##
[0987]
N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[(2S)-2-(ethylamino)pro-
pyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide
[0988] To a solution of
N-[1-[(2S)-2-aminopropyl]-3-[5-chloro-2-(difluoromethoxy)
phenyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide
(200 mg, 0.43 mmol) in EtOH (20 mL) was added acetaldehyde (48 mg,
40% aqueous solution) and NaBH.sub.3CN (32.7 mg, 0.52 mmol). The
resulting solution was stirred at room temperature for 12 h and
concentrated under vacuum. The residue was passed through a short
pad of silica gel eluting with 5% MeOH in DCM. The crude product
(60 mg) was purified by Prep-HPLC with the following conditions
(3#-Pre-HPLC-006(Waters)): Column, XSelect CSH Prep C18 OBD Column,
5 um, 19*150 mm; mobile phase, Water with 10 mM NH4CO3 and MeCN
(26.0% MeCN up to 40.0% in 8 min); Detector, 254/220. 24.2 mg
product was obtained. This resulted in 24.2 mg (11%) of
N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[(2S)-2-(ethylamino)propyl]-1-
H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide as a light
yellow solid. LCMS (Method 28) [M+H].sup.+=490.1, R.sub.T=0.86 min.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.: (ppm) 9.74 (s, 1H),
9.34 (dd, 1H, J=1.6, 7.2 Hz), 8.68-8.67 (m, 2H), 8.34 (s, 1H), 7.64
(d, 1H, J=2.1 Hz), 7.60 (dd, 1H, J=2.8, 8.4 Hz), 7.44 (d, 1H, J=8.4
Hz), 7.28 (dd, 1H, J=4.0, 7.2 Hz), 7.04 (t, 1H, J=73.2 Hz), 4.11
(dd, 1H, J=6.0, 13.6 Hz), 4.01 (dd, 1H, J=6.2, 13.6 Hz), 3.08-3.00
(m, 1H), 2.68-2.50 (m, 2H), 1.52 (br, 1H), 0.97 (t, 3H, J=7.0 Hz),
0.95 (d, 3H, J=6.4 Hz).
Example 372
##STR00694##
[0989]
N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-(2-[4-[2-(methylsulfany-
l)ethyl]piperazin-1-yl]-2-oxoethyl)-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimid-
ine-3-carboxamide
[0990] To a solution of tert-butyl piperazine-1-carboxylate (1.00
g, 5.37 mmol) in DMF (30 mL) was added
1-chloro-2-(methylsulfanyl)ethane (710 mg, 6.42 mmol),
Cs.sub.2CO.sub.3 (2.6 g, 7.98 mmol). The resulting mixture was
stirred at 50.degree. C. for 12 h. Water (50 mL) and EtOAc (30 mL)
was added. Phases were separated. The aqueous phase was extracted
with ethyl acetate (.times.2) and the organic layers combined. The
organic phases were washed with brine, dried over anhydrous sodium
sulfate and concentrated under vacuum. The residue was purified by
flash chromatography on silica gel eluting with ethyl
acetate/petroleum ether (1:2). This resulted in 180 mg (13%) of
tert-butyl 4-[2-(methylsulfanyl)ethyl] piperazine-1-carboxylate as
light yellow oil. LCMS (Method 25) [M+H].sup.+=261, R.sub.T=0.63
min.
[0991] A mixture of tert-butyl 4-[2-(methyl
sulfanyl)ethyl]piperazine-1-carboxylate (180 mg, 0.69 mmol) in DCM
(5 mL) and trifluoroacetic acid (10 mL) was stirred at room
temperature for 12 h. The resulting mixture was concentrated under
vacuum. The residue was dissolved in 5 mL of dioxane-HCl. The
resulting mixture was concentrated under vacuum. This resulted in
120 mg (88%) of 1-[2-(methylsulfanyl)ethyl]piperazine hydrochloride
as a light yellow solid. LCMS (Method 25) [M+H].sup.+=161.1,
R.sub.T=0.21 min.
[0992] To a solution of
{3-(5-Chloro-2-difluoromethoxyphenyl)-4-[(pyrazolo[1,5-a]pyrimidine-3-car-
bonyl)amino]pyrazol-1-yl}acetic acid (120 mg, 0.26 mmol) in DMF (10
mL) was added, 1-[2-(methylsulfanyl)ethyl]piperazine hydrochloride
(102 mg, 0.52 mmol), HATU (119 mg, 0.31 mmol), DIEA (168 mg, 1.30
mmol). The resulting solution was stirred at room temperature for
12 h. Water (50 mL) was added. The resulting solution was extracted
with DCM (.times.3) and the organic layers combined. The combined
organic layers were washed with brine, dried over sodium sulfate
and concentrated under vacuum. The crude product (150 mg) was
purified by Prep-HPLC with the following conditions
(1#-Pre-HPLC-006(Waters)): Column, XSelect CSH Prep C18 OBD Column,
5 um, 19*150 mm; mobile phase, Water with 10 mmol NH.sub.4HCO3 and
MeCN (20.0% MeCN up to 35.0% in 8 min); Detector, 254/220. This
resulted in 44.2 mg (28%) of
N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-(2-[4-[2-(methylsulfanyl)ethy-
l]-piperazin-1-yl]-2-oxoethyl)-1H-pyrazol-4-yl]-pyrazolo[1,5-a]pyrimidine--
3-carboxamide as a white solid. LCMS (Method 20) [M+H].sup.+=605.2,
R.sub.T=1.61 min. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.:
(ppm) 9.75 (s, 1H), 9.34 (dd, 1H, J=1.6, 7.2 Hz), 8.69-8.68 (m,
2H), 8.31 (s, 1H), 7.62 (dd, 1H, J=2.4, 8.8 Hz), 7.55 (d, 1H, J=2.4
Hz), 7.45 (d, 1H, J=8.8 Hz), 7.28 (dd, 1H, J=4.4, 6.8 Hz), 7.08 (t,
1H, J=73.2 Hz), 5.23 (s, 2H), 3.50-3.47 (m, 4H), 2.67-2.56 (m, 4H),
2.2.47-2.33 (m, 4H), 2.08 (s, 3H).
Example 373
##STR00695##
[0993]
N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[2-oxo-2-[4-(propan-2-y-
l)piperazin-1-yl]ethyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carbox-
amide
[0994] To a solution of
{3-(5-Chloro-2-difluoromethoxyphenyl)-4-[(pyrazolo[1,5-a]pyrimidine-3-car-
bonyl)amino]pyrazol-1-yl}acetic acid (150 mg, 0.32 mmol) in DMF (10
mL) was added DIEA (126 mg, 0.97 mmol), 1-(propan-2-yl)piperazine
(126 mg, 0.98 mmol) and HATU (185 mg, 0.49 mmol). The resulting
solution was stirred at room temperature overnight and concentrated
under vacuum. The crude product (200 mg) was purified by
Flash-Prep-HPLC with the following conditions (IntelFlash-1):
Column, C18 silica gel; mobile phase, CH3CN:H2O=5:95 increasing to
CH.sub.3CN:H.sub.2O=40:60 within 14 min; Detector, UV 254 nm. This
resulted in 51.6 mg (28%) of
N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[2-oxo-2-[4-(propan-2-yl)pipe-
razin-1-yl]ethyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide
as a white solid. LCMS (Method 20) [M+H].sup.+=573.2, R.sub.T=1.80
min. .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta.: (ppm) 9.76 (s,
1H), 9.34 (dd, 1H, J=1.2, 6.9 Hz), 8.69-8.67 (m, 2H), 8.31 (s, 1H),
7.62 (dd, 1H, J=2.7, 9.0 Hz), 7.55 (d, 1H, J=2.7 Hz), 7.45 (d, 1H,
J=8.7 Hz), 7.28 (dd, 1H, J=4.2, 6.9 Hz), 7.02 (t, 1H, J=73.2 Hz),
5.23 (s, 2H), 3.52-3.48 (m, 4H), 2.78-2.65 (m, 1H), 2.46-2.39 (m,
4H), 1.09-0.97 (d, 6H, J=6.6 Hz).
Example 374
##STR00696##
[0995]
N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[2-[4-(cyclopropylmethy-
l)piperazin-1-yl]-2-oxoethyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3--
carboxamide
[0996] To a solution of
{3-(5-Chloro-2-difluoromethoxyphenyl)-4-[(pyrazolo[1,5-a]pyrimidine-3-car-
bonyl)amino]pyrazol-1-yl}acetic acid (100 mg) in DMF (10 mL) was
added DIEA (83 mg, 0.64 mmol), 1-(cyclopropylmethyl)piperazine
(60.6 mg, 0.43 mmol) and HATU. The resulting solution was stirred
at room temperature overnight and concentrated under vacuum. The
crude product (120 mg) was purified by Flash-Prep-HPLC with the
following conditions (IntelFlash-1): Column, C.sub.18 silica gel;
mobile phase, CH.sub.3CN:H.sub.2O=5:95 increasing to
CH.sub.3CN:H.sub.2O=24:40 within 14 min; Detector, UV 254 nm. This
resulted in 47.6 mg (38%) of
N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[2-[4-(cyclopropylmethyl)pipe-
razin-1-yl]-2-oxoethyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carbox-
amide as a white solid. LCMS (Method 20) [M+H].sup.+=585.2,
R.sub.T=2.40 min. .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta.:
(ppm) 9.75 (s, 1H), 9.34 (dd, 1H, J=1.5, 6.9 Hz), 8.69-8.67 (m,
2H), 8.31 (s, 1H), 7.62 (dd, 1H, J=2.7, 8.7 Hz), 7.55 (d, 1H, J=2.7
Hz), 7.45 (d, 1H, J=8.7 Hz), 7.28 (dd, 1H, J=4.2, 6.9 Hz), 7.02 (t,
1H, J=73.2 Hz), 5.23 (s, 2H), 3.51-3.49 (m, 4H), 2.49-2.41 (m, 4H),
2.23-2.21 (m, 2H), 0.87-0.82 (m, 1H), 0.50-0.44 (m, 2H), 0.13-0.08
(m, 2H).
Example 375
##STR00697##
[0997]
N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[2-(2,4-dimethylpiperaz-
in-1-yl)-2-oxoethyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxami-
de
[0998] To a solution of tert-butyl 2-methylpiperazine-1-carboxylate
(500 mg, 2.50 mmol) in EtOH (20 mL) was added 37% formaldehyde
aqueous solution (405 mg) and AcOH (0.02 mL, 0.35 mmol). The
mixture was stirred for 2 hand NaBH.sub.3CN (315 mg, 5.01 mmol) was
added. The resulting solution was stirred at room temperature
overnight and concentrated under vacuum. The residue was purified
by flash chromatography on silica gel eluting with 4% MeOH in DCM.
This resulted in 430 mg (80%) of tert-butyl
2,4-dimethylpiperazine-1-carboxylate as colorless oil. LCMS (Method
25) [M+H].sup.+=215.0, R.sub.T=1.45 min.
[0999] A mixture of tert-butyl 2-methylpiperazine-1-carboxylate
(430 mg, 2.15 mmol), and saturated HCl dioxane solution (15 mL) was
stirred at room temperature for 2 h. The resulting mixture was
concentrated under vacuum. This resulted in 520 mg (crude) of
1,3-dimethylpiperazine hydrochloride as a light yellow solid. LCMS
(Method 24) [M+H].sup.+=115.0, R.sub.T=0.25 min.
[1000] To a solution of
{3-(5-Chloro-2-difluoromethoxyphenyl)-4-[(pyrazolo[1,5-a]pyrimidine-3-car-
bonyl)amino]pyrazol-1-yl}acetic acid (150 mg, 0.32 mmol) in DMF (10
mL) was added DIEA (209 mg, 1.62 mmol), 1,3-dimethylpiperazine
hydrochloride (146 mg, 0.97 mmol) and HATU (16 mg, 0.04 mmol). The
resulting solution was stirred at room temperature overnight. Water
(50 mL) and DCM (30 mL) was added. Phases were separated. The
aqueous phase was extracted with DCM and the organic layers
combined. The combined organic layers were washed with brine, dried
over sodium sulfate and concentrated under vacuum. The residue was
purified by Flash-Prep-HPLC with the following conditions
(IntelFlash-2): Column, C.sub.18 silica gel; mobile phase,
CH.sub.3CN:H.sub.2O=5:95 increasing to CH.sub.3CN:H.sub.2O=24:40
within 12 min; Detector, UV 254 nm. This resulted in 59.1 mg (33%)
of
N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[2-(2,4-dimethylpiperazin-1-y-
l)-2-oxoethyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide
as a yellow solid. LCMS (Method 25) [M+H].sup.+=559.2, R.sub.T=1.63
min. .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta.: (ppm) 9.75 (s,
1H), 9.34 (dd, 1H, J=1.5, 7.2 Hz), 8.69-8.67 (m, 2H), 8.34-8.31 (m,
1H), 7.62 (dd, 1H, J=2.7, 8.7 Hz), 7.55 (d, 1H, J=2.7 Hz), 7.45 (d,
1H, J=8.7 Hz), 7.28 (dd, 1H, J=4.2, 7.2 Hz), 7.02 (t, 1H, J=73.2
Hz), 5.31-5.11 (m, 2H), 4.52-4.47 (m, 0.5H), 4.20-4.11 (m, 1H),
3.78-3.69 (m, 0.5H), 3.32-3.21 (m, 0.5H), 2.97-2.83 (m, 0.5H), 2.75
(d, 1H, J=11.1 Hz), 2.63 (d, 1H, J=11.4 Hz), 2.20-1.71 (m, 5H),
1.38-1.12 (m, 3H).
##STR00698##
N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[2-(3,4-dimethylpiperazin-1-y-
l)-2-oxoethyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide
[1001] Using synthetic method analoguous that of
N-[3-[5-chloro-2-(difluoromethoxy)
phenyl]-1-[2-(2,4-dimethylpiperazin-1-yl)-2-oxoethyl]-1H-pyrazol-4-yl]pyr-
azolo[1,5-a]pyrimidine-3-carboxamide, the title compound was
prepared from tert-butyl 3-methylpiperazine-1-carboxylate. LCMS
(Method 20) [M+H].sup.+=559.2, R.sub.T=2.23 min. .sup.1H NMR (300
MHz, DMSO-d6) .delta.: (ppm) 9.75 (s, 1H), 9.34 (dd, 1H, J=1.5 Hz,
7.2 Hz), 8.69-8.67 (m, 2H), 8.31 (s, 1H), 7.62 (dd, 1H, J=2.7, 8.7
Hz), 7.55 (d, 1H, J=2.7 Hz), 7.45 (d, 1H, J=8.7 Hz), 7.28 (dd, 1H,
J=4.2, 6.9 Hz), 7.02 (t, 1H, J=73.2 Hz), 5.35-5.13 (m, 2H),
4.18-4.02 (m, 1H), 3.86-3.78 (m, 1H), 3.26-3.10 (m, 1H), 2.84-2.73
(m, 2H), 2.26-1.91 (m, 5H), 1.01 (d, 3H, J=6.0 Hz).
Example 377
##STR00699##
[1002]
N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[2-oxo-2-(2,2,4-trimeth-
ylpiperazin-1-yl)ethyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carbox-
amide
[1003] Using synthetic method analoguous to that of
N-[3-[5-chloro-2-(difluoromethoxy)
phenyl]-1-[2-(2,4-dimethylpiperazin-1-yl)-2-oxoethyl]-1H-pyrazol-4-yl]pyr-
azolo[1,5-a]pyrimidine-3-carboxamide, the title compound was
prepared from tert-butyl 2,2-dimethylpiperazine-1-carboxylate. LCMS
(Method 25) [M+H].sup.+=573.2, R.sub.T=0.97 min. .sup.1H NMR (300
MHz, DMSO-d.sub.6) .delta.: (ppm) 9.75 (s, 1H), 9.34 (dd, 1H,
J=1.2, 6.9 Hz), 8.69-8.68 (m, 2H), 8.27 (s, 1H), 7.62 (dd, 1H,
J=2.7, 8.7 Hz), 7.56 (d, 1H, J=2.4 Hz), 7.45 (d, 1H, J=8.7 Hz),
7.28 (dd, 1H, J=4.5, 6.9 Hz), 7.03 (t, 1H, 73.1 Hz), 5.17 (s, 2H),
3.48-3.42 (m, 2H), 2.28-2.22 (m, 2H), 2.17 (s, 3H), 2.08 (s, 2H),
1.39 (s, 6H).
Example 378
##STR00700##
[1004]
N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[2-oxo-2-(3,3,4-trimeth-
ylpiperazin-1-yl)ethyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carbox-
amide
[1005] Using synthetic method analoguous to that of
N-[3-[5-chloro-2-(difluoromethoxy)
phenyl]-1-[2-(2,4-dimethylpiperazin-1-yl)-2-oxoethyl]-1H-pyrazol-4-yl]pyr-
azolo[1,5-a]pyrimidine-3-carboxamide, the title compound was
prepared from tert-butyl 3,3-dimethylpiperazine-1-carboxylate. LCMS
(Method 20) [M+H].sup.+=573.2, R.sub.T=2.51 min. .sup.1H NMR (300
MHz, DMSO-d.sub.6) .delta.: (ppm) 9.76 (s, 1H), 9.34 (dd, 1H,
J=1.5, 7.2 Hz), 8.69-8.67 (m, 2H), 8.33 (s, 1H), 7.62 (dd, 1H,
J=2.7, 8.7 Hz), 7.55 (d, 1H, J=2.1 Hz), 7.45 (d, 1H, J=9.0 Hz),
7.28 (dd, 1H, J=4.2, 6.9 Hz), 7.02 (t, 1H, J=73.2 Hz), 5.26 (s,
1H), 5.17 (s, 1H), 3.51-3.48 (m, 2H), 3.22 (d, 2H, J=11.4 Hz),
2.45-2.36 (m, 2H), 2.13 (s, 3H), 0.99 (s, 3H), 0.92 (s, 3H).
##STR00701##
N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-(2-[4-[2-(dimethylamino)ethyl-
]piperazin-1-yl]-2-oxoethyl)-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-c-
arboxamide
[1006] To a solution of
2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]-pyrimidine-3-
-amido]-1H-pyrazol-1-yl]acetic acid (100 mg, 0.22 mmol) in DMF (10
mL) was added dimethyl[2-(piperazin-1-yl)ethyl]amine (68 mg, 0.43
mmol), DIEA (125 mg, 0.97 mmol) and HATU (123 mg, 0.32 mmol). The
resulting solution was stirred at room temperature overnight and
concentrated under vacuum. The crude product was purified by
Prep-HPLC with the following conditions
(2#-AnalyseHPLC-SHIMADZU(HPLC-10)): Column, XBridge BEH130 Prep C18
OBD Column, 19� 100 mm 5 um 13 nm; mobile phase, Water with 10 mM
NH4CO3 and ACN (15% ACN up to 40% in 6 min); Detector, UV 254/220
nm. This resulted in 79.1 mg (61%) of
N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-(2-[4-[2-(dimethylamino)ethyl-
]piperazin-1-yl]-2-oxoethyl)-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-c-
arboxamide as a light yellow solid. LCMS (Method 25)
[M+H].sup.+=602.2, R.sub.T=0.89 min. .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta.: (ppm) 9.75 (s, 1H), 9.34 (dd, 1H, J=1.7, 7.1
Hz), 8.69-8.67 (m, 2H), 8.30 (s, 1H), 7.62 (dd, 1H, J=2.7, 8.7 Hz),
7.55 (d, 1H, J=2.7 Hz), 7.45 (d, 1H, J=9.0 Hz), 7.28 (dd, 1H,
J=4.2, 6.9 Hz), 7.02 (t, 1H, J=73.2 Hz), 5.23 (s, 2H), 3.48-3.42
(m, 4H), 2.45-2.32 (m, 8H), 2.13 (s, 6H).
##STR00702##
N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[2-[4-(1,3-oxazol-2-ylmethyl)-
piperazin-1-yl]-2-oxoethyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-ca-
rboxamide
[1007] To a solution of tert-butyl piperazine-1-carboxylate (300
mg, 1.61 mmol) in MeOH (15 mL) was added 1,3-oxazole-2-carbaldehyde
(172 mg, 1.77 mmol), AcOH (0.01 mL, 0.17 mmol), and NaBH.sub.3CN
(152 mg, 2.42 mmol). The resulting solution was stirred at room
temperature overnight and concentrated under vacuum. The residue
was purified by flash chromatography on silica gel eluting with 5%
MEOH in DCM. This resulted in 480 mg (89%) of tert-butyl
4-(1,3-oxazol-2-ylmethyl) piperazine-1-carboxylate as colorless
oil. TLC: R.sub.f=0.4; MeOH/DCM=1/10.
[1008] A mixture of tert-butyl
4-(1,3-oxazol-2-ylmethyl)piperazine-1-carboxylate (480 mg, 1.44
mmol) saturated HCl dioxane solution (15 mL) was stirred at room
temperature for 3 h. This resulted in 300 mg (82%) of
1-(1,3-oxazol-2-ylmethyl)piperazine hydrochloride as a white solid.
LCMS (Method 20) [M+H].sup.+=168.0, R.sub.T=0.32 min.
[1009] To a solution of
2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]-pyrimidine-3-
-amido]-1H-pyrazol-1-yl]acetic acid (100 mg, 0.22 mmol) in DMF (10
mL) was added 1-(1,3-oxazol-2-ylmethyl)piperazine hydrochloride
(132 mg, 0.65 mmol), HATU (123 mg, 0.32 mmol), DIEA (139 mg, 1.08
mmol). The resulting solution was stirred at room temperature
overnight. Water (50 mL) and DCM (30 mL) was added.
[1010] Phases were separated. The aqueous phase was extracted with
DCM (.times.2) and the organic layers combined. The organic layers
were washed with brine, dried over Na.sub.2SO.sub.4 and
concentrated under vacuum. The crude product (150 mg) was purified
by Prep-HPLC with the following conditions
(2#-AnalyseHPLC-SHIMADZU(HPLC-10)): Column, XBridge BEH130 Prep C18
OBD Column, 19� 100 mm 5 um 13 nm; mobile phase, Water with 10 mM
NH4HCO3 and ACN (28% ACN up to 38% in 6 min); Detector, UV 254/220
nm. This resulted in 68.2 mg (52%) of
N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[2-[4-(1,3-oxazol-2-ylmethyl)-
piperazin-1-yl]-2-oxoethyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-ca-
rboxamide as an off-white solid. LCMS (Method 25)
[M+H].sup.+=612.1, R.sub.T=1.70 min. .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta.: (ppm) 9.75 (s, 1H), 9.34 (dd, 1H, J=1.7, 7.1
Hz), 8.69-8.67 (m, 2H), 8.30 (s, 1H), 8.09 (d, 1H, J=0.6 Hz), 7.62
(dd, 1H, J=2.7, 8.7 Hz), 7.55 (d, 1H, J=2.7 Hz), 7.45 (d, 1H, J=9.0
Hz), 7.28 (dd, 1H, J=4.2, 7.2 Hz), 7.18 (d, 1H, J=0.6 Hz), 7.01 (t,
1H, J=73.2 Hz), 5.23 (s, 2H), 3.76 (s, 2H), 3.54-3.48 (m, 4H),
2.45-2.42 (m, 4H).
Example 381
##STR00703##
[1011]
N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-(2-[[(5-oxooxolan-2-yl)-
methyl]amino]ethyl)-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamid-
e
[1012] Methanesulfonyl chloride (2.5 g, 21.8 mmol) was added
dropwise to a stirring solution of tert-butyl
N-(2-hydroxyethyl)carbamate (3.0 g, 18.61 mmol) and DIEA (7.2 g,
55.71 mmol) in DCM (50 mL) at 0.degree. C. The resulting solution
was stirred at room temperature for 8 h. The reaction was then
quenched by the addition of 100 mL of sodium bicarbonate. Phases
were separated. The aqueous phase was extracted with DCM (.times.2)
and the organic layers combined. The combined organic layers were
washed with brine, dried over anhydrous sodium sulfate and
concentrated under vacuum. The residue was purified by flash
chromatography on silica gel eluting with ethyl acetate/petroleum
ether (1:2). This resulted in 3.4 g (76%) of tert-butyl
N-[2-(methanesulfonyloxy)-ethyl]carbamate as a red solid. LCMS
(Method 25) [M+H].sup.+=225.0, R.sub.T=0.77 min.
[1013] To a solution of
N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]-
pyrimidine-3-carboxamide (1.00 g, 2.47 mmol) in CH.sub.3CN (30 mL)
was added Cs.sub.2CO.sub.3 (2.00 g, 6.14 mmol) and tert-butyl
N-[2-(methanesulfonyloxy)-ethyl]carbamate (1.20 g, 5.01 mmol). The
resulting solution was stirred at 70.degree. C. overnight. The
solids were filtered out. The filtrate was concentrated under
vacuum. The residue was purified by flash chromatography on silica
gel eluting with DCM/EtOAc (3:1). This resulted in 680 mg (50%) of
tert-butyl
N-(2-[3-[5-chloro-2-(difluoromethoxy)pyridin-3-yl]-4-[pyrazolo[1,5-a]pyri-
midine-3-amido]-1H-pyrazol-1-yl]ethyl)carbamate as yellow oil. LCMS
(Method 28) [M+H].sup.+=548.0, R.sub.T=1.33 min
[1014] A mixture of tert-butyl
N-(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-
-3-amido]-1H-pyrazol-1-yl]ethyl)carbamate (420 mg, 0.77 mmol) and
saturated HCl dioxane solution (10 mL) was stirred at room
temperature for 3 h. The resulting mixture was concentrated under
vacuum. The residue was dissolved in 15 mL of ethanol. The pH value
of the solution was adjusted to 8 with sodium hydroxide (2 mol/L).
The resulting mixture was concentrated under vacuum. The residue
was applied onto a silica gel column with dichloromethane/methanol
(85/15). This resulted in 260 mg (76%) of
N-[1-(2-aminoethyl)-3-[5-chloro-2-(difluoromethoxy)phenyl]-1H-py-
razol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide as a light
yellow solid. LCMS (Method 20) [M+H].sup.+=448.0, R.sub.T=0.76
min.
[1015] To a solution of
N-[1-(2-aminoethyl)-3-[5-chloro-2-(difluoromethoxy)phenyl]-1H-pyrazol-4-y-
l]pyrazolo[1,5-a]pyrimidine-3-carboxamide (200 mg, 0.45 mmol) in
CH3CN (20 mL) was added (5-oxooxolan-2-yl)methyl
trifluoromethanesulfonate (166 mg, 0.67 mmol) and DIEA (173 mg,
1.34 mmol). The resulting solution was stirred at room temperature
overnight and concentrated under vacuum. The residue was passed
through a short pad of silica gel eluting with 5% MeOH in DCM. The
crude product (100 mg) was purified by Prep-HPLC with the following
conditions (1#-Pre-HPLC-006(Waters)): Column, XSelect CSH Prep
C.sub.18 OBD Column, 5 um, 19*150 mm; mobile phase, Water with
0.05% FA and MeCN (24.0% MeCN up to 40.0% in 8 min); Detector,
254/220. 31.6 mg product was obtained. This resulted in 32 mg (12%)
of the formic acid salt of
N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-(2-[[(5-oxooxolan-2-y-
l)methyl]-amino]ethyl)-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxa-
mide as an off-white solid. LCMS (Method 28) [M+H].sup.+=546.1,
R.sub.T=0.82 min. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.:
(ppm) 9.76 (s, 1H), 9.34 (dd, 1H, J=1.6, 7.2 Hz), 8.68-8.66 (m,
2H), 8.31 (s, 1H), 7.64-7.62 (m, 2H), 7.44 (d, 1H, J=8.8 Hz), 7.28
(dd, 1H, J=4.4, 6.8 Hz), 7.06 (t, 1H, J=73.2 Hz), 4.56-4.53 (m,
1H), 4.23 (t, 2H, J=6.4 Hz), 3.01 (t, 2H, J=6.0 Hz), 2.77-2.75 (m,
2H), 2.48-2.44 (m, 2H), 2.19-2.16 (m, 1H), 1.92-1.88 (m, 1H).
Example 382
##STR00704##
[1016]
N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-(2-oxo-2-[4-[(5-oxooxol-
an-2-yl)methyl]piperazin-1-yl]ethyl)-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimi-
dine-3-carboxamide
[1017] Neat triflic anhydride Tf.sub.2O (486 mg, 1.72 mmol) was
added dropwise a solution of 5-(hydroxymethyl)oxolan-2-one (200 mg,
1.72 mmol) and DIEA (665 mg, 5.15 mmol) in DCM (20 mL) under
stirring at -5.degree. C. The resulting solution was stirred at
room temperature for 3 h and quenched by saturated NaHCO.sub.3
solution (50 mL). The resulting solution was extracted with DCM
(.times.2) and the organic layers combined. The combined organic
layers were washed with brine, dried over anhydrous sodium sulfate
and concentrated under vacuum. This resulted in 280 mg (crude) of
(5-oxooxolan-2-yl)methyl trifluoromethanesulfonate as a yellow
liquid. TLC: R.sub.f=0.5; ethyl acetate/petroleum ether=1/2.
[1018] To a solution of
N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[2-oxo-2-(piperazin-1-yl)ethy-
l]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (100 mg,
0.19 mmol) in CH.sub.3CN (15 mL) was added DIEA (73.03 mg, 0.57
mmol), and (5-oxooxolan-2-yl)methyl trifluoromethanesulfonate
(93.49 mg, 0.38 mmol). The resulting solution was stirred for 12 h
at room temperature for 3 h and concentrated under vacuum. The
crude product (180 mg) was purified by Prep-HPLC with the following
conditions (2#-AnalyseHPLC-SHIMADZU(HPLC-10)): Column, XBridge
BEH130 Prep C18 OBD Column, 19� 100 mm 5 um 13 nm; mobile phase,
Water with 10 mM NH.sub.4C03 and ACN (30% ACN up to 40% in 6 min);
Detector, UV 254/220 nm. 65 mg product was obtained. The residue
was applied onto a silica gel column with 5% MeOH in DCM. This
resulted in 29.5 mg of
N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-(2-oxo-2-[4-[(5-oxooxolan-2-y-
l)methyl]piperazin-1-yl]ethyl)-1H-pyrazol-4-yl]pyrazolo[1,5-a]-pyrimidine--
3-carboxamide as a white solid. LCMS (Method 28) [M+H].sup.+=629.1,
R.sub.T=0.81 min. .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta.:
(ppm) 9.76 (s, 1H), 9.34 (dd, 1H, J=1.5, 6.9 Hz), 8.69-8.67 (m,
2H), 8.31 (s, 1H), 7.62 (dd, 1H, J=2.7, 8.7 Hz), 7.55 (d, 1H, J=2.7
Hz), 7.45 (d, 1H, J=9.0 Hz), 7.28 (dd, 1H, J=4.2, 6.9 Hz), 7.02 (t,
1H, J=73.2 Hz), 5.24 (s, 2H), 4.71-4.66 (m, 1H), 3.50-3.33 (m, 4H),
2.58 (d, 2H, J=5.4 Hz), 2.60-2.46 (m, 6H), 2.48-2.42 (m, 4H),
2.30-2.21 (m, 1H), 1.90-1.83 (m, 1H).
Example 383
##STR00705##
[1019]
N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-(2-[4-[(methylcarbamoyl-
)methyl]piperazin-1-yl]-2-oxoethyl)-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimid-
ine-3-carboxamide
[1020] To a solution of
2-[4-[(tert-butoxy)carbonyl]piperazin-1-yl]acetic acid (500 mg,
2.05 mmol) in DMF (20 mL) was added methanamine hydrochloride (406
mg, 6.01 mmol), DIEA (793 mg, 6.14 mmol) and HATU (1.17 g, 3.08
mmol). The resulting solution was stirred for 12 h at room
temperature for 12 h. Water (50 mL) was added. The resulting
solution was extracted with DCM (.times.3) and the organic layers
combined. The combined organic layers were washed with brine, dried
over anhydrous sodium sulfate and concentrated under vacuum. The
residue was purified by flash chromatography on silica gel eluting
with 5% MeOH in DCM. This resulted in 500 mg of tert-butyl
4-[(methylcarbamoyl)methyl]piperazine-1-carboxylate as yellow oil.
LCMS (Method 25) [M+H].sup.+=258.0, R.sub.T=0.52 min.
[1021] A mixture of tert-butyl
4-[(methylcarbamoyl)methyl]piperazine-1-carboxylate (500 mg, 1.94
mmol) and saturated HCl dioxane solution was stirred at room
temperature for 3 h. The resulting solution was concentrated under
vacuum. This resulted in 300 mg (crude) of
N-methyl-2-(piperazin-1-yl)acetamide hydrochloride. LCMS (Method
20) [M+H].sup.+=158.0, R.sub.T=0.37 min.
[1022] To a solution of
{3-(5-Chloro-2-difluoromethoxyphenyl)-4-[(pyrazolo[1,5-a]pyrimidine-3-car-
bonyl)amino]pyrazol-1-yl}acetic acid (150 mg, 0.32 mmol) in DMF (10
mL) was added N-methyl-2-(piperazin-1-yl)acetamide hydrochloride
(125 mg, 0.65 mmol), HATU (185 mg, 0.49 mmol), DIEA (126 mg, 0.97
mmol). The resulting solution was stirred at room temperature for
12 h and concentrated under vacuum. The residue was passed through
a short pad of silica gel eluting with 8% MeOH in DCM. The crude
product (180 mg) was purified by Prep-HPLC with the following
conditions (3#-Pre-HPLC-006(Waters)): Column, XSelect CSH Prep C18
OBD Column, 5 um, 19*150 mm; mobile phase, Water with 10 mM NH4CO3
and MeCN (26.0% MeCN up to 40.0% in 8 min); Detector, 254/220. This
resulted in 73.9 mg (38%) of
N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-(2-[4-[(methylcarbamoyl)methy-
l]piperazin-1-yl]-2-oxoethyl)-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3--
carboxamide as a white solid. LCMS (Method 20) [M+H].sup.+=602.2,
R.sub.T=3.66 min. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.:
(ppm) 9.76 (s, 1H), 9.34 (dd, 1H, J=1.6, 6.8 Hz), 8.69-8.68 (m,
2H), 8.32 (s, 1H), 7.75 (q, 1H, J=4.8 Hz), 7.63 (dd, 1H, J=2.6, 8.6
Hz), 7.56 (d, 1H, J=2.8 Hz), 7.46 (d, 1H, J=8.8 Hz), 7.29 (dd, 1H,
J=4.4, 7.2 Hz), 7.08 (t, 1H, J=73.2 Hz), 5.24 (s, 2H), 3.54 (t, 4H,
J=5.0 Hz), 2.95 (s, 2H), 2.63 (d, 3H, J=4.8 Hz), 2.48-2.45 (m, 2H),
2.44-2.41 (m, 2H).
##STR00706##
N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-(2-[[(1R)-1-phenylethyl]amino-
]ethyl)-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide
[1023] A mixture of
N-[1-(2-bromoethyl)-3-[5-chloro-2-(difluoromethoxy)phenyl]-1H-pyrazol-4-y-
l]pyrazolo[1,5-a]pyrimidine-3-carboxamide (100 mg, 0.20 mmol) and
(1R)-1-phenylethan-1-amine (242 mg, 2.00 mmol) in MeCN (3 mL, 57.07
mmol) was stirred at 80.degree. C. for 12 h. The crude product (120
mg) was purified by Prep-HPLC with the following conditions
(2#-Analyse HPLC-SHIMADZU(HPLC-10)): Column, XBridge BEH130 Prep
C18 OBD Column, 19� 100 mm 5 um 13 nm; mobile phase, Water with 10
mM NH4CO3 and ACN (40% ACN up to 58% in 6 min); Detector, UV
254/220 nm. This resulted in 38 mg of
N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-(2-[[(1R)-1-phenylethyl]
amino]ethyl)-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide
as a off-white solid. LCMS (Method 25) [M+H].sup.+=552.1,
R.sub.T=1.16 min. .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta.:
(ppm) 9.72 (s, 1H), 9.34 (dd, 1H, J=1.5, 6.9 Hz), 8.69-8.67 (m,
2H), 8.34 (s, 1H), 7.60 (dd, 1H, J=2.7, 9.0 Hz), 7.55 (d, 1H, J=2.7
Hz), 7.43 (d, 1H, J=8.7 Hz), 7.31-7.17 (m, 6H), 6.98 (t, 1H, J=73.2
Hz), 4.18 (t, 2H, J=6.0 Hz), 3.70 (q, 1H, J=6.6 Hz), 2.83-2.73 (m,
2H), 1.22 (d, 3H, J=6.6 Hz).
##STR00707##
N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-(2-[[(1 S)-1-phenyl
ethyl]
amino]ethyl)-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide
[1024] Using synthetic method analoguous to that of
N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-(2-[[(1R)-1-phenyl
ethyl]
amino]ethyl)-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide,
the title compound was prepared from (1S)-1-phenylethan-1-amine.
LCMS (Method 25) [M+H].sup.+=552.1, R.sub.T=1.15 min. .sup.1H NMR
(300 MHz, DMSO-d.sub.6) .delta.: (ppm) 9.72 (s, 1H), 9.33 (dd, 1H,
J=1.5, 6.9 Hz), 8.69-8.67 (m, 2H), 8.34 (s, 1H), 7.60 (dd, 1H,
J=2.9, 8.9 Hz), 7.55 (d, 1H, J=2.7 Hz), 7.43 (d, 1H, J=8.7 Hz),
7.31-7.16 (m, 6H), 6.98 (t, 1H, J=73.2 Hz), 4.18 (t, 2H, J=6.0 Hz),
3.70 (q, 1H, J=6.6 Hz), 2.83-2.73 (m, 2H), 1.22 (d, 3H, J=6.6
Hz).
Example 386
##STR00708##
[1025] methyl
2-[(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidin-
e-3-amido]-1H-pyrazol-1-yl]ethyl)amino]acetate
[1026] Using synthetic method analoguous to that of
N-[3-[5-chloro-2-(difluoromethoxy)
phenyl]-1-(2-[[(1R)-1-phenylethyl]
amino]ethyl)-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide,
the title compound was prepared from methyl 2-aminoacetate
hydrochloride and DIEA. LCMS (Method 28) [M+H].sup.+=520.1,
R.sub.T=0.85 min. .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta.:
(ppm) 9.73 (s, 1H), 9.33 (dd, 1H, J=1.8, 6.9 Hz), 8.69-8.67 (m,
2H), 8.36 (s, 1H), 7.65-7.61 (m, 2H), 7.44 (d, 1H, J=9.3 Hz), 7.28
(dd, 1H, J=4.2, 7.2 Hz), 7.00 (t, 1H, J=73.5 Hz), 4.22 (t, 2H,
J=6.0 Hz), 3.62 (s, 3H), 3.37 (s, 2H), 2.98 (t, 2H, J=6.0 Hz), 2.27
(br, 1H).
Example 387
##STR00709##
[1027] methyl
(2S)-2-amino-4-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]-
pyrimidine-3-amido]-1H-pyrazol-1-yl]butanoate
[1028] To a solution of (2 S)-2-[[(tert-butoxy)carbonyl]
amino]-4-hydroxybutanoic acid (2.20 g, 10.03 mmol) in DCM (80 mL)
was added DIEA (2.58 g, 19.96 mmol), followed by TBDMS-Cl (1.65 g,
10.95 mmol) batchwise at 0.degree. C. The resulting solution was
stirred at room temperature for 12 h. Water (100 mL) was added.
Phases were separated. The aqueous phase was extracted with DCM
(.times.2) and the organic layers combined. The combined organic
layers were washed with brine, dried over anhydrous sodium sulfate
and concentrated under vacuum. The residue was purified by flash
chromatography on silica gel eluting with ethyl acetate/petroleum
ether (4:1). This resulted in 800 mg of (2
S)-2-[[(tert-butoxy)carbonyl] amino]-4-[(tert-butyl dimethyl
silyl)oxy]butanoic acid as light yellow oil. LCMS (Method 28)
[M+H].sup.+=275.0, R.sub.T=1.16 min.
[1029] To a solution of
(2S)-2-[[(tert-butoxy)carbonyl]amino]-4-[(tert-butyldimethylsilyl)oxy]but-
anoic acid (800 mg, 2.40 mmol) in DCM (30 mL) was added
4-dimethylaminopyridine (29 mg, 0.24 mmol), EDC.HCl (550 mg, 2.87
mmol) and methanol (5 mL). The resulting solution was stirred at
room temperature overnight and concentrated under vacuum. The
residue was purified by flash chromatography on silica gel eluting
with ethyl acetate/petroleum ether (1:4). This resulted in 600 mg
(72%) of methyl (2 S)-2-[[(tert-butoxy)carbonyl]
amino]-4-[(tert-butyldimethylsilyl)oxy]butanoate as light yellow
oil. LCMS (Method 25) [M+H].sup.+=348.0, R.sub.T=1.21 min.
[1030] A solution of methyl
2-[[(tert-butoxy)carbonyl]amino]-4-[(tert-butyldimethylsilyl)oxy]butanoat-
e (600 mg, 1.73 mmol) in THF (2 mL), water (2 mL) and AcOH (8 mL,
139.61 mmol, 80.90 equiv) was stirred at for 2 h. The reaction
mixture was neutralized with saturated sodium bicarbonate solution,
extracted with DCM (.times.3) and the organic layers combined. The
combined organic layers were washed with brine, dried over
anhydrous sodium sulfate and concentrated under vacuum. This
resulted in 400 mg of methyl 2-[[(tert-butoxy)carb onyl]
amino]-4-hydroxybutanoate as light yellow oil. LCMS (Method 28)
[M+H].sup.+=175, R.sub.T=0.65 min.
[1031] To a stirring solution of crude methyl
2-[[(tert-butoxy)carbonyl]amino]-4-hydroxybutanoate (400 mg,) in
DCM (20 mL) was added DIEA (387 mg, 2.99 mmol), followed by MsCl
(114 mg, 1.00 mmol) dropwise with stirring at 0.degree. C. The
resulting solution was stirred at room temperature for 3 h.
Saturated NaHCO.sub.3 (50 mL) was added. The resulting solution was
extracted with DCM (.times.2) and the organic layers combined. The
combined organic layers were washed with brine, dried over
anhydrous sodium sulfate and concentrated under vacuum. This
resulted in 510 mg (80%) of methyl 2-[[(tert-butoxy)carb onyl]
amino]-4-(methanesulfonyloxy) butanoate as yellow oil. LCMS (Method
25) [M+H].sup.+=212.0, R.sub.T=0.76 min.
[1032] To a solution of
N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]-
pyrimidine-3-carboxamide (200 mg, 0.49 mmol) in CH.sub.3CN (30 mL)
was added Cs.sub.2CO.sub.3 (326 mg, 1.00 mmol), and methyl
(2S)-2-[[(tert-butoxy)carbonyl]amino]-4-(methanesulfonyloxy)butanoate
(400 mg, crude). The resulting solution was stirred at room
temperature overnight. The solids were filtered out. The filtrate
was concentrated under vacuum. The residue was purified by flash
chromatography on silica gel eluting with dichloromethane/ethyl
acetate (70/30). This resulted in 280 mg (73%) of methyl
2-[[(tert-butoxy)carbonyl]amino]-4-[3-[5-chloro-2-(difluoromethoxy)phenyl-
]-4-[pyrazolo[1,5-a]pyrimidine-3-amido]-1H-pyrazol-1-yl]butanoate
as an off-white solid. LCMS (Method 25) [M+H].sup.+=620.0,
R.sub.T=0.98 min.
[1033] The mixture of methyl
(2S)-2-[[(tert-butoxy)carbonyl]amino]-4-[3-[5-chloro-2-(difluoromethoxy)p-
henyl]-4-[pyrazolo[1,5-a]pyrimidine-3-amido]-1H-pyrazol-1-yl]-butanoate
(280 mg), in DCM/TFA (15 mL, 2:1) was stirred at room temperature
overnight. The resulting mixture was concentrated under vacuum. The
crude product (200 mg) was purified by Prep-HPLC with the following
conditions (1#-Pre-HPLC-006(Waters)): Column, XSelect CSH Prep C18
OBD Column, 5 um, 19*150 mm; mobile phase, Water with 0.05% FA and
MeCN (24.0% MeCN up to 40.0% in 8 min); Detector, 254/220. 150 mg
product was obtained. This resulted in 148.4 mg (73%) of methyl
(2S)-2-amino-4-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]-
pyrimidine-3-amido]-1H-pyrazol-1-yl]butanoate formate as an
off-white solid. LCMS (Method 28) [M+H].sup.+=520.1, R.sub.T=0.82
min. .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta.: (ppm) 9.75 (s,
1H), 9.34 (dd, 1H, J=1.5, 6.9 Hz), 8.69-8.68 (m, 2H), 8.36 (s, 1H),
7.65-7.61 (m, 2H), 7.45 (d, 1H, J=8.4 Hz), 7.28 (dd, 1H, J=4.2, 7.2
Hz), 7.01 (t, 1H, J=73.2 Hz), 4.40-4.26 (m, 2H), 3.64 (s, 3H),
3.50-3.43 (m, 1H), 2.32-2.18 (m, 1H), 2.11-1.99 (m, 1H).
Example 388
##STR00710##
[1034] (1-methylpiperidin-4-yl)methyl
1-(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-
-3-amido]-1H-pyrazol-1-yl]acetyl)piperidine-4-carboxylate
[1035] To a solution of
1-[(tert-butoxy)carbonyl]piperidine-4-carboxylic acid (1.00 g, 4.36
mmol) in DCM (50 mL) was added (1-methylpiperidin-4-yl)methanol
(1.13 g, 8.75 mmol), EDC.HCl (1.0 g, 5.22 mmol),
4-dimethylaminopyridine (54 mg, 0.44 mmol), The resulting solution
was stirred at room temperature overnight. Water (50 mL) was added.
Phases were separated. The aqueous phase was extracted with DCM
(.times.2) and the organic layers combined. The organic layers were
dried over anhydrous sodium sulfate and concentrated under vacuum.
The residue was purified by flash chromatography on silica gel
eluting with 6% MeOH in DCM. This resulted in 1.2 g of 1-tert-butyl
4-(1-methylpiperidin-4-yl)methyl piperidine-1,4-dicarboxylate as
light yellow oil. LCMS (Method 28) [M+H].sup.+=341.0, R.sub.T=0.58
min.
[1036] A mixture of 1-tert-butyl 4-(1-methylpiperidin-4-yl)methyl
piperidine-1,4-dicarboxylate (1.2 g, 3.52 mmol) and saturated HCl
dioxane solution (15 mL) was stirred at room temperature overnight.
The resulting solution was concentrated under vacuum. This resulted
in 1.5 g (crude) of (1-methylpiperidin-4-yl)methyl
piperidine-4-carboxylate hydrochloride as a white solid. LCMS
(Method 25) [M+H].sup.+=241.0, R.sub.T=0.19 min.
[1037] To a solution of
{3-(5-Chloro-2-difluoromethoxyphenyl)-4-[(pyrazolo[1,5-a]pyrimidine-3-car-
bonyl)amino]pyrazol-1-yl}acetic acid (150 mg, 0.32 mmol) in DMF (10
mL) was added (1-methylpiperidin-4-yl)methyl
piperidine-4-carboxylate hydrochloride (178 mg, 0.64 mmol), DIEA
(126 mg, 0.97 mmol), HATU (160 mg, 0.42 mmol). The resulting
solution was stirred at room temperature overnight. Water (50 mL)
was added. The resulting solution was extracted with DCM (.times.3)
and the organic layers combined. The combined organic layers were
washed with brine, dried over anhydrous sodium sulfate and
concentrated under vacuum. The residue was passed through a short
pad of silica gel eluting with 8% MeOH in DCM. The crude product
(80 mg) was purified by Prep-HPLC with the following conditions
(3#-Pre-HPLC-006(Waters)): Column, XSelect CSH Prep C18 OBD Column,
5 um, 19*150 mm; mobile phase, Water with 0.05% FA and MeCN (32.0%
MeCN up to 50.0% in 8 min); Detector, 254/220. This resulted in 37
mg (16%) of the formic acid salt of (1-methylpiperidin-4-yl)methyl
1-(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-
-3-amido]-1H-pyrazol-1-yl]acetyl)piperidine-4-carboxylate as an
off-white solid. LCMS (Method 25) [M+H].sup.+=685.2, R.sub.T=1.05
min. .sup.1H NMR (400 MHz, DMSO-d6) .delta.: (ppm) 9.75 (s, 1H),
9.35 (dd, 1H, J=1.2, 6.8 Hz), 8.69-8.68 (m, 2H), 8.32 (s, 1H), 7.63
(dd, 1H, J=2.8, 8.8 Hz), 7.55 (d, 1H, J=2.4 Hz), 7.46 (d, 1H, J=8.8
Hz), 7.29 (dd, 1H, J=4.4, 7.2 Hz), 7.08 (t, 1H, J=73.2 Hz),
5.36-5.18 (m, 2H), 4.28-4.21 (m, 1H), 3.96-3.88 (m, 3H), 3.25-3.12
(m, 1H), 2.86-2.74 (m, 3H), 2.73-2.66 (m, 1H), 2.15 (s, 3H),
1.92-1.83 (m, 4H), 1.65-1.52 (m, 4H), 1.48-1.38 (m, 1H), 1.29-1.16
(m, 2H).
Example 389
##STR00711##
[1038] (1-methylpiperidin-4-yl)methyl
1-(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-
-3-amido]-1H-pyrazol-1-yl]acetyl)-4-methylpiperidine-4-carboxylate
[1039] Using synthetic method anaolguous to that of
(1-methylpiperidin-4-yl)methyl
1-(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-
-3-amido]-1H-pyrazol-1-yl]acetyl)piperidine-4-carboxylate, the
title compound was prepared from 1-[(tert-butoxy)carb
onyl]-4-methylpiperidine-4-carboxylic acid. LCMS (Method 28)
[M+H].sup.+=699.2, R.sub.T=0.95 min. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta.: (ppm) 9.75 (s, 1H), 9.34 (dd, 1H, J=1.6, 7.2
Hz), 8.69-8.68 (m, 2H), 8.31 (s, 1H), 7.63 (dd, 1H, J=2.4, 8.8 Hz),
7.55 (d, 1H, J=2.8 Hz), 7.46 (d, 1H, J=8.8 Hz), 7.29 (dd, 1H,
J=4.0, 6.8 Hz), 7.08 (t, 1H, J=73.2 Hz), 5.24 (s, 2H), 3.99-3.96
(m, 2H), 3.94-3.88 (m, 1H), 3.78-3.71 (m, 1H), 3.26-3.20 (m, 1H),
3.08-3.00 (m, 1H), 2.85-2.80 (m, 2H), 2.20 (s, 3H), 2.02-1.94 (m,
4H), 1.68-1.59 (m, 4H), 1.54-1.48 (m, 1H), 1.41-1.34 (m, 1H),
1.28-1.23 (m, 2H), 1.18 (s, 3H).
Example 390
##STR00712##
[1040]
N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-(2-[methyl[(5-oxooxolan-
-2-yl)methyl]amino]ethyl)-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carb-
oxamide
[1041] To a solution of
N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-(2-[[(5-oxooxolan-2-yl)methyl-
]amino]ethyl)-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide
(140 mg, 0.26 mmol) in MeOH (20 mL) was added 37% formaldehyde in
water (23 mg), followed by NaBH.sub.3CN (24.6 mg, 0.39 mmol). The
resulting solution was stirred at room temperature for 3 h. The
resulting mixture was concentrated under vacuum. The residue was
passed through a short pad of silica gel eluting with 8% MeOH in
DCM. The crude product (60 mg) was purified by Prep-HPLC with the
following conditions (1#-Pre-HPLC-006(Waters)): Column, XSelect CSH
Prep C18 OBD Column, 5 um, 19*150 mm; mobile phase, Water with
0.05% FA and MeCN (18.0% MeCN up to 36.0% in 8 min); Detector,
254/220. This resulted in 22.4 mg of the formic acid salt of
N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-(2-[methyl
[(5-oxooxolan-2-yl)methyl]amino]ethyl)-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyr-
imidine-3-carboxamide as a white solid. LCMS (Method 28)
[M+H].sup.+=560.2, R.sub.T=0.94 min. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta.: (ppm) 9.76 (s, 1H), 9.34 (dd, 1H, J=1.6, 7.2
Hz), 8.69-8.67 (m, 2H), 8.38 (s, 1H), 7.62 (dd, 1H, J=2.8, 8.8 Hz),
7.60 (d, 1H, J=2.4 Hz), 7.45 (d, 1H, J=8.8 Hz), 7.29 (dd, 1H,
J=4.0, 6.8 Hz), 7.08 (t, 1H, J=73.2 Hz), 4.59-4.55 (m, 1H),
4.30-4.27 (m, 2H), 2.94-2.88 (m, 2H), 2.62 (d, 2H, J=5.6 Hz),
2.44-2.41 (m, 2H), 2.32 (s, 3H), 2.14-2.11 (m, 1H), 1.83-1.77 (m,
1H).
Example 391
##STR00713##
[1042] ethyl
3-[[1-(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimi-
dine-3-amido]-1H-pyrazol-1-yl]acetyl)piperidin-4-yl](methyl)amino]propanoa-
te
[1043] To a solution of tert-butyl
4-(methylamino)piperidine-1-carboxylate (1.00 g, 4.67 mmol) in
ethanol (50 mL) was added AcOH (0.1 mL, 1.75 mmol) and ethyl
3-oxopropanoate (1.63 g, 14.04 mmol). The mixture was stirred at
room temperature for 5 h and NaBH.sub.3CN (882 mg, 14.04 mmol) was
added. The resulting solution was stirred at room temperature
overnight and concentrated under vacuum. The residue was purified
by flash chromatography on silica gel eluting with 4% MeOH in DCM.
This resulted in 580 mg of tert-butyl
4-[(3-ethoxy-3-oxopropyl)(methyl)amino]piperidine-1-carboxylate as
colorless oil. LCMS (Method 20) [M+H].sup.+=315.0, R.sub.T=1.14
min.
[1044] A mixture of tert-butyl
4-[(3-ethoxy-3-oxopropyl)(methyl)amino]piperidine-1-carboxylate
(580 mg, 1.84 mmol) and saturated HCl dioxane solution was stirred
at room temperature for 3 h. The resulting mixture was concentrated
under vacuum. The residue was triturated with EtOAc. The solids
were collected by filtration. This resulted in 200 mg (crude) of
ethyl 3-[methyl(piperidin-4-yl)amino]propanoate hydrochloride as an
off-white solid. LCMS (Method 20) [M+H].sup.+=215.0, R.sub.T=0.45
min.
[1045] To a solution of
{3-(5-Chloro-2-difluoromethoxyphenyl)-4-[(pyrazolo[1,5-a]pyrimidine-3-car-
bonyl)amino]pyrazol-1-yl}acetic acid (100 mg, 0.22 mmol) in DMF (10
mL) was added HATU (123 mg, 0.32 mmol), DIEA (83 mg, 0.64 mmol),
and ethyl 3-[methyl(piperidin-4-yl)amino]propanoate hydrochloride
(200 mg). The resulting solution was stirred at room temperature
overnight. Water (50 mL) was added. The resulting mixture was
extracted with DCM (.times.3) and the organic layers combined. The
combined organic layers were washed brine, dried over anhydrous
sodium sulfate and concentrated under vacuum. The crude product (82
mg) was purified by Prep-HPLC with the following conditions
(1#-Pre-HPLC-006(Waters)): Column, XSelect CSH Prep C18 OBD Column,
5 um, 19*150 mm; mobile phase, Water with 0.05% FA and MeCN (18.0%
MeCN up to 36.0% in 8 min); Detector, 254/220. 20.3 mg product was
obtained. This resulted in 20.3 mg (13%) of the formic acid salt of
ethyl
3-[[1-(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimi-
dine-3-amido]-1H-pyrazol-1-yl]acetyl)piperidin-4-yl](methyl)amino]propanoa-
te as an off-white solid. LCMS (Method 28) [M+H].sup.+=659.2,
R.sub.T=0.90 min. .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta.:
(ppm) 9.76 (s, 1H), 9.34 (dd, 1H, J=1.5, 7.2 Hz), 8.68-8.66 (m,
2H), 8.31 (s, 1H), 7.62 (dd, 1H, J=2.7, 8.7 Hz), 7.55 (d, 1H, J=2.4
Hz), 7.45 (d, 1H, J=8.7 Hz), 7.28 (dd, 1H, J=4.2, 7.2 Hz), 7.03 (t,
1H, J=73.2 Hz), 5.36-5.15 (m, 2H), 4.48-4.33 (m, 1H), 4.02 (q, 2H,
J=7.2 Hz), 4.00-3.96 (m, 1H), 3.18-3.00 (m, 1H), 2.89-2.80 (m, 3H),
2.68-2.54 (m, 3H), 2.31 (s, 3H), 1.85-1.76 (m, 2H), 1.61-1.25 (m,
2H), 1.19 (t, 3H, J=6.9 Hz).
Example 392
##STR00714##
[1046]
N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[2-oxo-2-[4-(5-oxooxola-
n-3-yl)piperazin-1-yl]ethyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-c-
arboxamide
[1047] A mixture of tert-butyl piperazine-1-carboxylate (1.0 g,
5.37 mmol), oxolane-2,4-dione (1.07 g, 10.69 mmol) and AcOH (0.2
mL) in THF (50 mL) was stirred at room temperature for 3 h.
NaBH.sub.3CN (508 mg, 8.08 mmol) was added. The resulting solution
was stirred at room temperature overnight. The resulting mixture
was concentrated under vacuum. The residue was passed through a
short pad of silica gel eluting with dichloromethane/ethyl acetate
(1/4). This resulted in 400 mg (28%) of tert-butyl
4-(5-oxooxolan-3-yl)piperazine-1-carboxylate as light yellow oil.
LCMS (Method 10) [M+H].sup.+=271.0, R.sub.T=0.56 min.
[1048] A mixture of tert-butyl
4-(5-oxooxolan-3-yl)piperazine-1-carboxylate (400 mg, 1.48 mmol)
and saturated HCl dioxane solution (15 mL) was stirred at room
temperature for 3 h. The solids were collected by filtration. This
resulted in 380 mg (crude) of 4-(piperazin-1-yl)oxolan-2-one
hydrochloride as a white solid. LCMS (Method 22) [M+H].sup.+=171.0,
R.sub.T=0.38 min.
[1049] To a solution of
{3-(5-Chloro-2-difluoromethoxyphenyl)-4-[(pyrazolo[1,5-a]pyrimidine-3-car-
bonyl)amino]pyrazol-1-yl}acetic acid (200 mg, 0.43 mmol) in DMF (10
mL) was added 4-(piperazin-1-yl)oxolan-2-one hydrochloride (250 mg,
1.21 mmol), HATU (247 mg, 0.65 mmol), DIEA (167 mg, 1.29 mmol).,
The resulting solution was stirred at room temperature overnight.
Water (50 mL) was added. The resulting solution was extracted with
DCM (.times.3) and the organic layers combined. The combined
organic layers were washed with brine, dried over anhydrous sodium
sulfate and concentrated under vacuum. The residue was passed
through a short pad of silica gel eluting with 8% MeOH in DCM. The
crude product (80 mg) was purified by Prep-HPLC with the following
conditions (1#-Pre-HPLC-006(Waters)): Column, XSelect CSH Prep C18
OBD Column, 5 um, 19*150 mm; mobile phase, Water with 0.05% FA and
MeCN (32.0% MeCN up to 60.0% in 10 min); Detector, 254/220. 37 mg
product was obtained. This resulted in 36.7 mg (14%) of
N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[2-oxo-2-[4-(5-oxooxolan-3-yl-
)piperazin-1-yl]ethyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxa-
mide as a white solid. LCMS (Method 28) [M+H].sup.+=615.0,
R.sub.T=0.99 min. .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta.:
(ppm) 9.76 (s, 1H), 9.34 (d, 1H, J=6.9 Hz), 8.69-8.67 (m, 2H), 8.30
(s, 1H), 7.62 (dd, 1H, J=2.4, 9.0 Hz), 7.56 (s, 1H), 7.45 (d, 1H,
J=8.7 Hz), 7.28 (dd, 1H, J=4.2, 6.9 Hz), 7.02 (t, 1H, J=73.2 Hz),
5.24 (s, 2H), 4.44-4.38 (m, 1H), 4.26-4.18 (m, 1H), 3.49 (t, 4H,
J=5.1 Hz), 3.40-3.37 (m, 1H), 2.78-2.68 (m, 1H), 2.60-2.55 (m, 1H),
2.47-2.35 (m, 4H).
Example 393
##STR00715##
[1050]
N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[2-[4-(morpholin-4-yl)p-
iperidin-1-yl]-2-oxoethyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-car-
boxamide
[1051] To a solution of
{3-(5-Chloro-2-difluoromethoxyphenyl)-4-[(pyrazolo[1,5-a]pyrimidine-3-car-
bonyl)amino]pyrazol-1-yl}acetic acid (100 mg) in DMF (2 mL) was
added HATU (100 mg, 0.26 mmol), DIEA (85 mg, 0.66 mmol), and
4-(piperidin-4-yl)morpholine hydrochloride (67 mg, 0.32 mmol). The
resulting solution was stirred at room temperature overnight. The
crude product (60 mg) was purified by Prep-HPLC with the following
conditions (1#-Pre-HPLC-006(Waters)): Column, XSelect CSH Prep C18
OBD Column, 5 um, 19*150 mm; mobile phase, Water with 10 mM
NH.sub.4CO.sub.3 and MeCN (20.0% MeCN up to 35.0% in 8 min);
Detector, 254/220. This resulted in 28.3 mg (21%) of
N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[2-[4-(morpholin-4-yl)piperid-
in-1-yl]-2-oxoethyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxami-
de as a yellow solid. LCMS (Method 20) [M+H].sup.+=615.2,
R.sub.T=1.84 min. .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta.:
(ppm) 9.75 (s, 1H), 9.34 (dd, 1H, J=1.5, 6.9 Hz), 8.69-8.67 (m,
2H), 8.31 (s, 1H), 7.62 (dd, 1H, J=2.7, 8.7 Hz), 7.55 (d, 1H, J=2.7
Hz), 7.45 (d, 1H, J=8.7 Hz), 7.28 (dd, 1H, J=4.2, 6.9 Hz), 7.02 (t,
1H, J=73.2 Hz), 5.24-5.21 (m, 2H), 4.42-4.31 (m, 1H), 4.02-3.95 (m,
1H), 3.55 (t, 4H, J=4.5 Hz), 3.16-3.02 (m, 1H), 2.78-2.64 (m, 1H),
2.49-2.45 (m, 5H), 1.90-1.76 (m, 2H), 1.54-1.21 (m, 2H).
Example 394
##STR00716##
[1052]
N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[(2E)-4-(morpholin-4-yl-
)but-2-en-1-yl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide
[1053] A mixture of
N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]-
pyrimidine-3-carboxamide (400 mg, 0.99 mmol),
(2E)-1,4-dichlorobut-2-ene (370 mg, 2.96 mmol) and cesium carbonate
(1 g, 3.07 mmol) was stirred at 65.degree. C. for 20 h. The
reaction mixture was cooled. The resulting solution was diluted
with ethyl acetate (100 mL), and washed H.sub.2O (.times.3). The
organic layer was dried over sodium sulfate and concentrated under
vacuum. The residue was purified by flash chromatography on silica
gel eluting with ethyl acetate/hexane (1:1). The appropriate
fractions were combined and concentrated under vacuum. This
resulted in 320 mg (66%) of
N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[(2E)-4-chlorobut-2-en-1-yl]--
1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide as a light
yellow solid. TLC: R.sub.f=0.4; ethyl acetate/petroleum
ether=1:1.
[1054] A solution of N-[3-[5-chloro-2-(difluoromethoxy)
phenyl]-1-[(2E)-4-chlorobut-2-en-1-yl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyr-
imidine-3-carboxamide (160 mg, 0.324 mmol) and morpholine (0.5 mL)
in DMF (4 mL) was stirred at room temperature for 2 h. The
resulting mixture was concentrated under vacuum. The crude product
(200 mg) was purified by Flash-Prep-HPLC with the following
conditions (IntelFlash-1): Column, silica gel; mobile phase,
CH.sub.3CN/H.sub.2O=20% increasing to CH.sub.3CN/H.sub.2O=50%
within 20 min; Detector, UV 254 nm. 35.4 mg product was obtained.
This resulted in 35.4 mg (20%) of
N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[(2E)-4-(morpholin-4-yl)but-2-
-en-1-yl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide
as a off-white solid. LCMS (Method 23) [M+H].sup.+=544.0,
R.sub.T=2.37 min. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.:
(ppm) 9.74 (s, 1H), 9.34 (dd, 1H, J=1.6, 6.8 Hz), 8.68-8.66 (m,
2H), 8.31 (s, 1H), 7.62 (dd, 1H, J=2.8, 8.8 Hz), 7.58 (d, 1H, J=2.8
Hz), 7.44 (d, 1H, J=8.8 Hz), 7.28 (dd, 1H, J=4.4, 6.8 Hz), 7.06 (t,
1H, J=73.2 Hz), 5.94-5.84 (m, 1H), 5.79-5.69 (m, 1H), 4.82 (d, 2H,
J=6.0 Hz), 3.56 (t, 4H, J=4.6 Hz), 2.96 (d, 2H, J=6.4 Hz),
2.40-2.30 (m, 4H).
Example 395
##STR00717##
[1055]
N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[(2E)-4-(4-methylpipera-
zin-1-yl)but-2-en-1-yl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carbox-
amide
[1056] Using synthetic method analoguous to that of
N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[(2E)-4-(morpholin-4-yl)but-2-
-en-1-yl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide,
the title compound was prepared from 1-methylpiperazine. LCMS
(Method 23) [M+H].sup.+=557.1, R.sub.T=1.76 min. .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta.: (ppm) 9.74 (s, 1H), 9.34 (d, 1H, J=5.2
Hz), 8.68-8.66 (m, 2H), 8.31 (s, 1H), 7.62 (d, 1H, J=8.8 Hz), 7.58
(d, 1H, J=2.4 Hz), 7.47 (d, 1H, J=8.8 Hz), 7.28 (dd, 1H, J=4.0, 6.8
Hz), 7.06 (t, 1H, J=73.2 Hz), 5.92-5.80 (m, 1H), 5.78-5.66 (m, 1H),
4.81 (d, 2H, J=6.0 Hz), 2.94 (d, 2H, J=6.4 Hz), 2.45-2.20 (m, 8H),
2.13 (s, 3H).
Example 396
##STR00718##
[1057] 2-(methylthio)ethyl
2-(2-(3-(5-chloro-2-(difluoromethoxy)phenyl)-4-(pyrazolo[1,5-a]pyrimidine-
-3-carboxamido)-1H-pyrazol-1-yl)ethylamino)acetate
[1058] To a solution of 2-(methylsulfanyl)ethan-1-ol (2.40 g, 26.04
mmol) in DMF (15 mL) was added 2-[(tert-butoxy)carbonyl]aminoacetic
acid (3.19 g, 18.21 mmol), HOBt (2.82 g, 20.87 mmol), EDC.HCl (3.99
g, 20.81 mmol) and DIEA (2 mL). The resulting solution was stirred
overnight at room temperature. The mixture was partitioned between
ethyl acetate and water. The organic layer was washed with brine,
dried over Na.sub.2SO.sub.4 and concentrated under vacuum. The
residue was purified by flash chromatography on silica gel eluting
with ethyl acetate/petroleum ether (3/1). This resulted in 2.00 g
(31%) of 2-(methylsulfanyl)ethyl
2-[[(tert-butoxy)carbonyl]amino]acetate as light yellow oil. LCMS
(Method 21): [M+H].sup.+=250, R.sub.T=1.37 min.
[1059] To a solution of 2-(methylsulfanyl)ethyl
2-[[(tert-butoxy)carbonyl] amino]acetate (2.00 g, 8.02 mmol) in
dioxane (5 mL) was added saturated HCl dioxane solution (10 mL) at
room temperature. The resulting solution was stirred at room
temperature for 2 h. The solids were collected by filtration. This
resulted in 1.2 g of 2-(methylsulfanyl)ethyl 2-aminoacetate HCl
salt as a white solid. LCMS (Method 25): [M+H].sup.+=150,
R.sub.T=0.28 min.
[1060] To a solution of 2-(methylsulfanyl)ethyl 2-aminoacetate HCl
salt (792 mg, 3.57 mmol) in CH.sub.3CN was added
N-[1-(2-bromoethyl)-3-[5-chloro-2-(difluoromethoxy)
phenyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide
(364 mg, 0.71 mmol) and DIEA (1.57 g, 12.15 mmol). The resulting
solution was stirred at 75.degree. C. overnight and concentrated
under vacuum. The crude product was purified by Prep-HPLC with the
following conditions conditions (2#-Waters 2767-2 (HPLC-08)):
Column, Xbridge Prep Phenyl, 5 um, 19.times.150 mm; mobile phase,
Water with 50 mmol ammonium bicarbonate and acetonitrile (10.0%
acetonitrile up to 33.0% in 2 min, up to 53.0% in 8 min, up to
100.0% in 1 min, down to 10.0% in 1 min); Detector, UV 220 nm. This
resulted in 53.1 mg (2%) of the formic acid salt of
2-(methylsulfanyl)ethyl
2-[(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidin-
e-3-amido]-1H-pyrazol-1-yl]ethyl)amino]acetate as light yellow oil.
LCMS (Method 20): [M+H].sup.+=580.15, R.sub.T=2.76 min. .sup.1H NMR
(300 MHz, DMSO-d.sub.6) .delta.: (ppm) 9.73 (s, 1H), 9.33 (dd, 1H,
J=1.5, 6.9 Hz), 8.67 (dd, 1H, J=1.5, 4.2 Hz), 8.66 (s, 1H), 8.36
(s, 1H), 7.65-7.61 (m, 2H), 7.44 (d, 1H, J=9.3 Hz), 7.23 (dd, 1H,
J=4.5, 7.2 Hz), 6.99 (t, 1H, J=73.5 Hz), 4.27-4.18 (m, 4H), 3.38
(s, 2H), 2.99 (t, 2H, J=6.0 Hz), 2.67 (t, 2H, J=6.6 Hz), 2.07 (s,
3H).
Example 397
##STR00719##
[1061] ethyl
2-[4-(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimid-
ine-3-amido]-1H-pyrazol-1-yl]acetyl)piperazin-1-yl]acetate
[1062] To a solution of ethyl 2-(piperazin-1-yl)acetate
hydrochloride (400 mg, 1.92 mmol) in DMF (10 mL) was added
{3-(5-Chloro-2-difluoromethoxyphenyl)-4-[(pyrazolo[1,5-a]pyrimidine-3-car-
bonyl)amino]pyrazol-1-yl}acetic acid (500 mg), DIEA (440 mg, 3.40
mmol), HATU (460 mg, 1.21 mmol). The resulting solution was stirred
at room temperature overnight and concentrated under vacuum. The
residue was purified by flash chromatography on silica eluting with
4.5% MeOH in DCM to afford 59.4 mg (11%) of ethyl
2-[4-(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimid-
ine-3-amido]-1H-pyrazol-1-yl]acetyl)piperazin-1-yl]acetate as a
white solid. LCMS (Method 20) [M+H].sup.+=617.2, R.sub.T=2.68 min.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.: (ppm) 9.75 (s, 1H),
9.34 (dd, 1H, J=1.6, 6.8 Hz), 8.69-8.67 (m, 2H), 8.31 (s, 1H), 7.62
(dd, 1H, J=2.4, 8.8 Hz), 7.56 (d, 1H, J=2.8 Hz), 7.45 (d, 1H, J=8.8
Hz), 7.28 (dd, 1H, J=4.4, 6.8 Hz), 7.07 (t, 1H, J=73.2 Hz), 5.24
(s, 2H), 4.07 (q, 2H, J=7.2 Hz), 3.52-3.49 (m, 4H), 3.28 (s, 2H),
3.17-3.16 (m, 1H), 2.59-2.50 (m, 4H), 1.18 (t, 3H, J=7.2 Hz).
Example 403
##STR00720##
[1063]
N-(3-(5-chloro-2-(difluoromethoxy)phenyl)-1-(2-hydroxy-3-morpholino-
propyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide
[1064] To a solution of
N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]-
pyrimidine-3-carboxamide (1.00 .mu.g, 2.47 mmol) in
N,N-dimethylformamide (10 mL), Cs.sub.2CO.sub.3 (970 mg, 2.977
mmol) was added and stirred for 10 minutes at room temperature.
Then 2-(chloromethyl)oxirane (2.28 g, 24.64 mmol) was added
dropwise at room temperature. The resulting mixture was stirred for
14 hour at room temperature and diluted with ethyl acetate (100
mL), washed with water and brine. The organic layer was dried over
anhydrous sodium sulfate and concentrated under vacuum. The residue
was purified by flash chromatography on silica gel eluting with
ethyl acetate/petroleum ether (60/40) to give 500 mg (44%) of
N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-(oxiran-2-ylmethyl)-1H-pyrazo-
l-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide as a light yellow
solid. LCMS (Method 24), [M+H].sup.+=461.1, R.sub.T=1.30 min.
[1065] To a solution of
N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-(oxiran-2-ylmethyl)-1H-pyrazo-
l-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (50 mg, 0.11 mmol)
in N,N-dimethylformamide (1 mL), DIEA (67 mg, 0.518 mmol) and
morpholine (14 mg, 0.161 mmol) was added at room temperature. The
resulting solution was stirred at 60.degree. C. overnight, cooled,
diluted with 30 mL of ethyl acetate, washed with 2.times.10 mL of
water and 2.times.10 mL of brine. The organic layer was dried over
anhydrous sodium sulfate and concentrated under vacuum. The residue
was purified by flash chromatography on silica gel eluting with
dichloromethane/methanol (95/5). This resulted in 50 mg of crude
product, which was purified by Flash-Prep-HPLC with the following
conditions (IntelFlash-1): Column: X Bridge C18, 19*150 mm, 5 um;
Mobile Phase A:Water/0.05% NH.sub.4HCO.sub.3, Mobile Phase B: ACN;
Flow rate: 20 mL/min; Gradient: 30% B to 70% B in 10 min; 254 nm to
obtain 40 mg (67%) of
N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[2-hydroxy-3-(morpholin-4-yl)-
propyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide as
a white solid. LCMS (Method 35) [M+H].sup.+=548.2, R.sub.T=2.28
min. .sup.1H-NMR (300 MHz, DMSO-d.sub.6): .delta. (ppm) 9.73 (s,
1H), 9.33 (dd, 1H, J=1.5, 7.2 Hz), 8.68-8.67 (m, 2H), 8.34 (s, 1H),
7.65 (d, 1H, J=2.7 Hz), 7.61 (s, 1H), 7.44 (d, 1H, J=8.7 Hz), 7.27
(dd, 1H, J=4.2, 6.9 Hz), 7.00 (t, 1H, J=73.5 Hz), 4.99 (d, 1H,
J=4.5 Hz), 4.31-4.28 (m, 1H), 4.13-4.07 (m, 2H), 3.56 (t, 4H, J=4.5
Hz), 2.42 (t, 4H, J=4.5 Hz), 2.32 (d, 2H, J=4.8 Hz).
Example 414
##STR00721##
[1066]
N-(3-(5-chloro-2-(difluoromethoxy)phenyl)-1-(2-oxo-3-(piperidin-1-y-
l)propyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide
[1067] To a stirring solution of oxalyl dichloride (0.46 mL, 0.923
mmol, 2 M) in dichloromethane (6 mL) at -78.degree. C., a solution
of DMSO (144 mg) in dichloromethane (1 mL) was added dropwise in 10
min. The mixture was stirred for an additional 10 minutes at this
temperature and a solution of
N-(3-(5-chloro-2-(difluoromethoxy)phenyl)-1-(2-hydroxy-3-morpholinopropyl-
)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (253 mg,
0.461 mmol) in 2 mL of dichloromethane was added dropwise at this
temperature. The mixture was stirred for another 30 min at this
temperature. Then DIEA (476 mg, 3.683 mmol) was added dropwise at
this temperature. The resulting solution was stirred for 0.5 h at
-78.degree. C. and then allowed warm to room temperature and
stirred for another 30 min. The resulting solution was diluted with
50 mL of ethyl acetate, washed with 2.times.20 mL of water and
2.times.20 mL of brine. The organic layer was dried over sodium
sulfate and concentrated under vacuum. The crude product (200 mg)
was purified by Flash-Prep-HPLC with the following conditions:
Column: X Bridge RP, 19*150 mm, 5 um; Mobile Phase A:Water/0.05%
NH.sub.4HCO.sub.3, Mobile Phase B: ACN; Flow rate: 30 mL/min;
Gradient: 25% B to 44% B in 10 min; 254 nm to give 108.6 mg (43%)
of
-(3-(5-chloro-2-(difluoromethoxy)phenyl)-1-(2-oxo-3-(piperidin-1-yl)pr-
opyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide as a
white solid. LCMS (Method 24) [M+H].sup.+=546.2, R.sub.T=1.68 min.
.sup.1H-NMR (300 MHz, CDCl.sub.3-d): .delta. (ppm) 9.89 (s, 1H),
8.77 (dd, 1H, J=1.5, 6.9 Hz), 8.72 (s, 1H), 8.55 (dd, 1H, J=1.5,
4.2 Hz), 8.40 (s, 1H), 7.68 (d, 1H, J=2.4 Hz), 7.42 (dd, 1H, J=2.4,
8.7 Hz), 7.28 (d, 1H, J=8.7 Hz), 6.99 (dd, 1H, J=4.2, 7.2 Hz), 6.47
(t, 1H, J=73.8 Hz), 5.07 (s, 1H), 3.76 (t, 4H, J=4.5 Hz), 3.26 (s,
2H), 2.56 (t, 4H, J=4.8 Hz).
Example 415
##STR00722##
[1068]
N-(3-(5-chloro-2-(difluoromethoxy)phenyl)-1-(2-(1-methylpiperidin-4-
-ylidene)ethyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide
[1069] To a mixture of
N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]-
pyrimidine-3-carboxamide (215.20 mg, 0.532 mmol), Cs.sub.2CO.sub.3
(694.8 mg, 2.132 mmol) in N,N-dimethylformamide (15 mL) was added
tert-butyl
4-[2-(methanesulfonyloxy)ethylidene]piperidine-1-carboxylate (650
mg, 2.128 mmol). The resulting mixture was stirred at 60.degree. C.
overnight, and concentrated under vacuum. The residue was purified
by flash chromatography on silica gel eluting with ethyl
acetate/petroleum ether (9/1). This resulted in 310 mg (95%) of
tert-butyl
4-(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-
-3-amido]-1H-pyrazol-1-yl]ethylidene)piperidine-1-carboxylate as
yellow oil. LCMS (Method 25) [M+H]=614.2, R.sub.T=1.11 min.
[1070] To a solution of tert-butyl
4-(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-
-3-amido]-1H-pyrazol-1-yl]ethylidene)piperidine-1-carboxylate (310
mg, 0.505 mmol) in dichloromethane (10 mL) was added
trifluoroacetic acid (6 mL) at room temperature. The resulting
solution was stirred for 5 h at room temperature and concentrated
under vacuum. The crude product was used without further
purification. LCMS (Method 25) [M+H].sup.+=514.1, R.sub.T=0.91
min.
[1071] An aqueous solution of 40% formaldehyde (210 mg) was added
to solution of
N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[2-(piperidin-4-ylidene)ethyl-
]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (360.00
mg, 0.700 mmol) in methanol (30 mL). The resulting solution was
stirred at ambient temperature for 2.5 h and NaBH.sub.3CN (44.02
mg, 0.700 mmol) was added. The resulting solution was stirred at
this temperature for 3 h and concentrated under vacuum. The residue
was applied onto a short pad of silica gel eluting with
dichloromethane/MeOH (10/1). The crude product (60 mg) was purified
by Flash-Prep-HPLC with the following conditions (IntelFlash-1):
Column, silica gel; mobile phase, ACN/10 mmol NH.sub.4HCO.sub.3=40%
increasing to ACN/10 mmol NH.sub.4HCO.sub.3=75% within 6 min;
Detector, UV 254 nm to obtain 4.3 mg (1%) of
N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[2-(1-methylpiperidin-4-ylide-
ne)ethyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide
as a light yellow solid. LCMS (Method 32): [M+H].sup.+=528.1,
R.sub.T=2.21 min. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.:
(ppm) 9.73 (s, 1H), 9.34 (dd, 1H, J=1.6, 6.8 Hz), 8.68-8.66 (m,
2H), 8.32 (s, 1H), 7.67-7.61 (m, 2H), 7.45 (d, 1H, J=8.4 Hz), 7.28
(dd, 1H, J=4.0, 6.8 Hz), 7.06 (t, 1H, J=73.2 Hz), 5.44 (t, 1H,
J=6.8 Hz), 4.27 (d, 2H, J=6.8 Hz), 2.81-2.68 (m, 2H), 2.52-2.50 (m,
2H), 2.50-2.42 (m, 2H), 2.19 (s, 3H), 2.12-2.04 (m, 2H).
Example 421
##STR00723##
[1072]
N-(3-(5-chloro-2-(difluoromethoxy)phenyl)-1-(2-(4-(2-cyanoethylamin-
o)cyclohexylidene)ethyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carbo-
xamide
[1073] Methanesulfonyl chloride (1.87 g, 16.325 mmol) was added
dropwise to a solution of
2-[1,4-dioxaspiro[4.5]decan-8-ylidene]ethan-1-ol (2.00 g, 10.86
mmol) and DIEA (4.21 g, 32.57 mmol) in dichloromethane (100 mL) at
room temperature. The resulting solution was stirred at room
temperature overnight and concentrated under vacuum. The residue
was purified by flash chromatography on silica gel eluting with
ethyl acetate/petroleum ether (1/9). This resulted in 1.95 g (68%)
of 2-[1,4-dioxaspiro[4.5]decan-8-ylidene]ethyl methanesulfonate as
off-white oil. TLC: R.sub.f=0.6; ethyl acetate/petroleum
ether=1/2.
[1074] To a solution of
N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]-
pyrimidine-3-carboxamide (1.50 .mu.g, 3.71 mmol) in
N,N-dimethylformamide (120 mL) was added Cs.sub.2CO.sub.3 (3.62 g,
11.11 mmol) and 2-[1,4-dioxaspiro[4.5]decan-8-ylidene]ethyl
methanesulfonate (1.94 g, 7.39 mmol) at room temperature. The
resulting solution was stirred for 4 h at room temperature and
concentrated under vacuum. The residue was purified by flash
chromatography on silica gel eluting with ethyl acetate/petroleum
ether (3/2) to give 1.59 g (75%) of
N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-(2-[1,4-dioxaspiro[4.5]decan--
8-ylidene]ethyl)-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide
as a light yellow solid. LCMS (Method 31) [M+H].sup.+=571.4,
R.sub.T=1.21 min.
[1075] Concentrated HCl aqueous solution (16 mL) was added to a
solution of
N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-(2-[1,4-dioxaspiro[4.5]dec-
an-8-ylidene]ethyl)-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamid-
e (1.59 g, 2.785 mmol) in 1,4-dioxane (160 mL). The resulting
solution was stirred at room temperature for 3 h and neutralized
with saturated sodium bicarbonate solution. The resulting mixture
was concentrated under vacuum. The residue was dissolved in
dichloromethane, washed with water, brine. The organic layer was
dried, and concentrated under vacuum. The residue was purified by
flash chromatography on silica gel eluting with ethyl
acetate/petroleum ether (3/2). This resulted in 930 mg (63%) of
N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[2-(4-oxocyclohexylidene)ethy-
l]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide as a
light yellow solid. LCMS (Method 25) [M+H].sup.+=527.1,
R.sub.T=0.94 min.
[1076] To solution of
N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[2-(4-oxocyclohexylidene)ethy-
l]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (300.0
mg, 0.569 mmol) in methanol (30 mL) was added 3-aminopropanenitrile
(199.5 mg, 2.85 mmol). The resulting solution was stirred at room
temperature for 3. Then NaBH.sub.3CN (71.56 mg, 1.14 mmol) was
added. The resulting solution was stirred at room temperature
overnight and concentrated under vacuum. The residue was applied
onto a short pad of silica gel eluting with ethyl acetate. The
crude product (60 mg) was purified by Flash-Prep-HPLC with the
following conditions (IntelFlash-1): Column, silica gel; mobile
phase, ACN/0.05% NH.sub.4HCO.sub.3=30% increasing to ACN/0.05%
NH.sub.4HCO.sub.3=55% within 8 min; Detector, UV 254 nm. 6.7 mg
product was obtained. This resulted in 6.7 mg (2%) of
N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-(2-[4-[(2-cyanoethyl)amino]cy-
clohexylidene]
ethyl)-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide as a
off-white solid. LCMS (Method 34) [M+H].sup.+=581.4, R.sub.T=2.44
min. .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta.: (ppm) 9.73 (s,
1H), 9.33 (dd, 1H, J=1.5, 6.9 Hz), 8.68-8.66 (m, 2H), 8.27 (s, 1H),
7.64-7.60 (m, 2H), 7.43 (d, 1H, J=8.1 Hz), 7.27 (dd, 1H, J=4.2, 6.9
Hz), 7.00 (t, 1H, J=73.5 Hz), 5.45 (t, 1H, J=6.9 Hz), 4.80 (d, 2H,
J=7.2 Hz), 2.79-2.72 (m, 3H), 2.71-2.57 (m, 5H), 2.10-1.97 (m, 2H),
1.94-1.86 (m, 2H), 1.23-1.16 (m, 2H).
Example 420
##STR00724##
[1077]
N-(3-(5-chloro-2-(difluoromethoxy)phenyl)-1-(2-(4-((2-cyanoethyl)(m-
ethyl)amino)cyclohexylidene)ethyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidi-
ne-3-carboxamide
[1078] To a solution of
N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-(2-[4-[(2-cyanoethyl)amino]cy-
clohexylidene]ethyl)-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxami-
de (140.0 mg, 0.241 mmol) in methanol (20 mL,) was added 40% HCHO
aqueous solution (75 mg, 0.96 mmol). The resulting solution was
stirred at room temperature overnight. Then NaBH.sub.3CN (15.14 mg,
0.241 mmol) was added. The resulting solution was stirred at room
temperature for 4 h and concentrated under vacuum. The residue was
purified by flash chromatography on silica gel eluting with
dichloromethane/MeOH (10/1). This resulted in 34.7 mg (24%) of
N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-(2-[4-[(2-cyanoethyl)(methyl)-
amino]cyclohexylidene]ethyl)-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-c-
arboxamide as a light yellow solid. LCMS (Method 33)
[M+H].sup.+=595.4, R.sub.T=1.43 min. .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta.: (ppm) 9.73 (s, 1H), 9.33 (dd, 1H, J=1.5, 6.9
Hz), 8.69-8.66 (m, 2H), 8.28 (s, 1H), 7.64-7.60 (m, 2H), 7.43 (d,
1H, J=8.4 Hz), 7.27 (dd, 1H, J=4.5, 7.5 Hz), 7.00 (t, 1H, J=73.5
Hz), 5.43 (t, 1H, J=7.2 Hz), 4.81 (d, 2H, J=6.9 Hz), 2.88-2.82 (m,
1H), 2.66-2.59 (m, 5H), 2.33-2.29 (m, 1H), 2.22 (s, 3H), 2.10-2.05
(m, 1H), 1.93-1.80 (m, 3H), 1.37-1.25 (m, 2H).
Example 452
##STR00725##
[1079]
N-(3-(5-chloro-2-(difluoromethoxy)phenyl)-1-((1-(piperidin-4-yl)-1H-
-1,2,3-triazol-4-yl)methyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-ca-
rboxamide
[1080] Sodium azide (246 mg, 2.79 mmol) was added to a solution of
tert-butyl 4-bromopiperidine-1-carboxylate (1.00 g, 3.79 mmol) and
sodium iodide (113 mg, 0.753 mmol) in N,N-dimethylformamide (20 mL)
at room temperature. The resulting solution was stirred at
60.degree. C. overnight, allowed cool to cool to room temperature.
Caution: the reaction should be conducted behind a blast shield.
The reaction was then quenched by the addition of 10 mL of
saturated sodium bicarbonate aqueous solution. The resulting
solution was extracted with 2.times.50 mL of ethyl acetate and the
organic layers combined and concentrated under vacuum. The residue
was applied onto a silica gel column with ethyl acetate/petroleum
ether (1/4). This resulted in 800 mg (93%) of tert-butyl
4-azidopiperidine-1-carboxylate as colorless oil. TLC: R.sub.f=0.6;
ethyl acetate/petroleum ether=1/4.
[1081] To a solution of
N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]-
pyrimidine-3-carboxamide (2 .mu.g, 4.941 mmol) in
N,N-dimethylformamide (50 mL) was added Cs.sub.2CO.sub.3 (3.23 g,
9.913 mmol) and 3-chloroprop-1-yne (720 mg, 9.663 mmol). The
resulting mixture was stirred at 50.degree. C. for 5 h and
concentrated under vacuum. The residue was purified by flash
chromatography on silica gel eluting with ethyl acetate. This
resulted in 1.74 g (80%) of
N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-(prop-2-yn-1-yl)-1H-pyrazol-4-
-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide as a light yellow
solid. LCMS (Method 23) [M+H].sup.+=443.0, R.sub.T=1.45 min.
[1082] To a solution of
N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-(prop-2-yn-1-yl)-1H-pyrazol-4-
-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (1.68 g, 3.794 mmol) in
N,N-dimethylformamide (40 mL) was added DIEA (980.6 mg, 7.587
mmol), CuI (143.7 mg, 0.755 mmol), tert-butyl
4-azidopiperidine-1-carboxylate (858.8 mg, 3.795 mmol). The
resulting solution was stirred at room temperature for 7 h and
concentrated under vacuum. The residue was purified by flash
chromatography on silica gel eluting with ethyl acetate. This
resulted in 1.98 g (78%) of tert-butyl
4-[4-([3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidin-
e-3-amido]-1H-pyrazol-1-yl]methyl)-1H-1,2,3-triazol-1-yl]piperidine-1-carb-
oxylate as a light yellow solid. LCMS (Method 24)
[M+H].sup.+=669.2, R.sub.T=1.34 min.
[1083] To a solution of tert-butyl
4-[4-([3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidin-
e-3-amido]-1H-pyrazol-1-yl]methyl)-1H-1,2,3-triazol-1-yl]piperidine-1-carb-
oxylate (1.98 g, 2.96 mmol) in methanol (30 mL) was added
concentrated HCl aqueous solution (15 mL). The resulting solution
was stirred for 5 h at room temperature. The resulting mixture was
concentrated under vacuum. This resulted in 1.85 g crude product,
which was sufficient for next step without further purification. A
small portion was purified for characterization and biological
submission. The crude product (100 mg) was purified by
Flash-Prep-HPLC with the following conditions (IntelFlash-1):
Column, silica gel; mobile phase, ACN/H.sub.2O (10 mmol
NH.sub.4HCO.sub.3)=18% increasing to ACN/H.sub.2O (10 mmol
NH.sub.4HCO.sub.3)=49% within 9 min; Detector, UV 254 nm. 42.1 mg
product was obtained. This resulted in 42.0 mg of
N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[[1-(piperidin-4-yl)-1H-1,2,3-
-triazol-4-yl]methyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxam-
ide as a light yellow solid. LCMS (Method 36) [M+H].sup.+=569.2,
R.sub.T=2.59 min. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.:
(ppm) 9.69 (s, 1H), 9.34 (d, 1H, J=6.4 Hz), 8.68-8.64 (m, 2H), 8.40
(s, 1H), 8.22 (s, 1H), 7.67-7.61 (m, 2H), 7.45 (d, 1H, J=8.4 Hz),
7.28 (dd, 1H, J=4.2, 7.0 Hz), 7.06 (t, 1H, J=73.4 Hz), 5.49 (s,
2H), 4.58-4.51 (m, 1H), 3.05-3.02 (m, 2H), 2.62-2.57 (m, 1H),
2.30-2.25 (br, 1H), 2.01-1.98 (m, 2H), 1.87-1.73 (m, 2H).
Example 457
##STR00726##
[1084]
N-(3-(5-chloro-2-(difluoromethoxy)phenyl)-1-((1-(1-(tetrahydro-2H-p-
yran-4-yl)piperidin-4-yl)-1H-1,2,3-triazol-4-yl)methyl)-1H-pyrazol-4-yl)py-
razolo[1,5-a]pyrimidine-3-carboxamide
[1085] To a solution of
N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[[1-(piperidin-4-yl)-1H-1,2,3-
-triazol-4-yl]methyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxam-
ide hydrochloride (200 mg, 0.330 mmol) in dichloromethane (30 mL)
was added oxan-4-one (264.9 mg, 2.646 mmol). The resulting solution
was stirred at room temperature overnight. Then NaBH(OAc).sub.3
(280.8 mg, 1.325 mmol) was added. The resulting solution was
stirred at room temperature for 6 h and concentrated under vacuum.
The residue was applied onto a silica gel column eluting with
DCM/MeOH (80:20). The crude product (150 mg) was purified by
Flash-Prep-HPLC with the following conditions (IntelFlash-1):
Column, silica gel; mobile phase, ACN/H.sub.2O (10 mmol
NH.sub.4HCO.sub.3)=20% increasing to ACN/H.sub.2O (10 mmol
NH.sub.4HCO.sub.3)=49% within 8 min; Detector, UV 254 nm. 56.9 mg
product was obtained. This resulted in 56.9 mg (26%) of
N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-([1-[1-(oxan-4-yl)piperidin-4-
-yl]-1H-1,2,3-triazol-4-yl]methyl)-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidi-
ne-3-carboxamide as a light yellow solid. LCMS (Method 20)
[M+H].sup.+=653.3, R.sub.T=1.74 min. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta.: (ppm) 9.73 (s, 1H), 9.34 (dd, 1H, J=1.6, 7.2
Hz), 8.67-8.66 (m, 2H), 8.39 (s, 1H), 8.26 (s, 1H), 7.65-7.62 (m,
2H), 7.44 (d, 1H, J=8.4 Hz), 7.28 (dd, 1H, J=4.0, 6.8 Hz), 7.06 (t,
1H, J=73.4 Hz), 5.48 (s, 2H), 4.58-4.45 (m, 1H), 3.90-3.87 (m, 2H),
3.32-3.25 (m, 2H), 3.04-2.98 (m, 2H), 2.51-2.33 (m, 1H), 2.30-2.24
(m, 2H), 2.09-2.06 (m, 2H), 1.99-1.91 (m, 2H), 1.70-1.67 ((m, 2H),
1.49-1.40 (m, 2H).
Example 468
##STR00727##
[1086]
N-(3-(5-chloro-2-(difluoromethoxy)phenyl)-1-(2-(4-(((1-cyanocyclopr-
opyl)methyl)amino)piperidin-1-yl)-2-oxoethyl)-1H-pyrazol-4-yl)pyrazolo[1,5-
-a]pyrimidine-3-carboxamide
[1087] To a solution of 1,4-dioxa-8-azaspiro[4,5]decane (9.80 g,
67.1 mmol) in dichloromethane (150 mL) under nitrogen was added
triethylamine (11.2 mL, 80.5 mmol.
[1088] This was then cooled to 0.degree. C. and to this was added
dropwise with stirring 2-chloroacetyl chloride (6.53 mL, 80.5 mmol)
in dichloromethane (50 mL) over 1 and a half hours. This was then
stirred overnight warming to room temperature in the process. The
reaction was then quenched by adding 1 N HCl (100 mL). This was
then extracted with ethyl acetate and the ethyl acetate layers were
dried with solid anhydrous magnesium sulfate powder, filtered and
concentrated to give
2-Chloro-1-(1,4-dioxa-8-azaspiro[4,5]decan-8-yl)ethan-1-one as a
brown oil (15.44 g). This was used without purification for the
next step.
[1089] To
N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1H-pyrazol-4-yl]pyrazo-
lo[1,5-a]pyrimidine-3-carboxamide (4.65 g, 11.5 mmol) and cesium
carbonate (10.08 g, 30.94 mmol) was added N,N-Dimethylformamide (40
mL) and stirred at room temperature for 5 minutes. To this was
added 2-Chloro-1-(1,4-dioxa-8-azaspiro[4,5]decan-8-yl)ethan-1-one
(5.34 g, 20.2 mmol) in N,N-Dimethylformamide (4.5 mL) and stirred
at room temperature for 3 and a half hours. LC/MS (method 31) shows
reaction complete. The reaction was then filtered and the filtrate
was concentrated under reduced pressure to give a red oil. This was
then dissolved in 30 mL dichloromethane and purified by ISCO using
a silica column and eluting with 0-100% Ethyl acetate in heptane in
5 minutes followed by 0-15% Methanol in dichloromethane to give
5.16 g (8.78 mmol) of
N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[2-(1,4-dioxa-8-azaspiro[4,5]-
decan-8-yl)-2-oxo-ethyl]pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxami-
de as a yellow foamy solid. LC/MS (method 39) [M+H].sup.+=589.2,
R.sub.T=1.91 min.
[1090] To a solution of
N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[2-(1,4-dioxa-8-azaspiro[4,5]-
decan-8-yl)-2-oxo-ethyl]pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxami-
de (1.01 g, 1.72 mmol) in acetone (20 mL) was added
p-toluenesulfonic acid (359 mg, 2.06 mmol) and refluxed for 6
hours. LC/MS (method 31) shows product and presence of minor
amounts of starting material. The reaction was cooled to room
temperature and quenched with water. This was then extracted with
ethyl acetate, dried with solid anhydrous magnesium sulfate powder
and filtered to give a red oil. This was then purified by ISCO with
a silica column and eluted with 0-15% methanol in dichloromethane
to afford 0.43 .mu.g (0.78 mmol) of
N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[2-oxo-2-(4-oxo-1-piperidyl)e-
thyl]pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide as a
foamy off white solid. LC/MS (method 39) [M+H].sup.+=544.1,
R.sub.T=1.91 min.
[1091] To a solution of
N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[2-oxo-2-(4-oxo-1-piperidyl)e-
thyl]pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (201.7 mg
0.38 mmol) in dichloromethane (1.0 mL) was added acetic acid (0.3
mL, 5.24 mmol). To this was then added
1-(aminomethyl)cyclopropanecarbonitrile (47.2 mg, 0.466 mmol). This
was then stirred at room temperature for 5 minutes. The reaction
was then cooled to 0.degree. C. and to this was added sodium
triacetyoxyborohydride (124.1 mg, 0.56 mmol) and stirred for 3
hours and let warm to room temperature in the process. LC/MS
(method 31) shows product as a major peak. The reaction was
quenched by adding 2 mL water followed by 10 mL saturated sodium
bicarbonate solution. This was the extracted with dichloromethane
and the organic layers were dried with solid anhydrous magnesium
sulfate powder, filtered and concentrated to give a white solid.
20.6 mg was then purified by reverse phase HPLC purification to
afford 10.2 mg of
N-(3-(5-chloro-2-(difluoromethoxy)phenyl)-1-(2-(4-(((1-cyanocyclopropyl)m-
ethyl)amino)piperidin-1-yl)-2-oxoethyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyr-
imidine-3-carboxamide. LC/MS (method 38) [M+H].sup.+=624.2,
R.sub.T=2.80 min. 1H NMR (400 MHz, DMSO-d6) 9.75 (s, 1H), 9.34 (dd,
J=7.0, 1.7 Hz, 1H), 8.68 (dd, J=4.3, 1.6 Hz, 1H), 8.67 (s, 1H),
8.30 (s, 1H), 7.63 (dd, J=8.8, 2.7 Hz, 1H), 7.56 (d, J=2.7 Hz, 1H),
7.46 (d, J=8.8 Hz, 1H), 7.29 (dd, J=7.0, 4.2 Hz, 1H), 7.25 (t,
J=73.0 Hz, 1H), 5.23 (d, J=4.7 Hz, 2H), 4.12 (d, J=12.7 Hz, 1H),
3.84 (d, J=13.7 Hz, 1H), 3.14 (t, J=11.9 Hz, 1H), 2.85 (t, J=11.9
Hz, 1H), 2.71-2.65 (m, 3H), 2.02 (s, 1H), 1.83 (t, J=16.2 Hz, 2H),
1.33-1.12 (m, 4H), 0.94 (m, 2H).
Enzymatic Assays
[1092] JAK Enzyme Assays were Carried Out as Follows:
[1093] The activity of the isolated recombinant JAK1 and JAK2
kinase domain was measured by monitoring phosphorylation of a
peptide derived from JAK3
(Val-Ala-Leu-Val-Asp-Gly-Tyr-Phe-Arg-Leu-Thr-Thr, fluorescently
labeled on the N-terminus with 5-carboxyfluorescein) using the
Caliper LabChip.RTM. technology (Caliper Life Sciences, Hopkinton,
Mass.). To determine inhibition constants (K.sub.i), compounds were
diluted serially in DMSO and added to 50 .mu.L kinase reactions
containing purified enzyme (1.5 nM JAK1, or 0.2 nM JAK2), 100 mM
HEPES buffer (pH 7.2), 0.015% Brij-35, 1.5 .mu.M peptide substrate,
ATP (25 .mu.M), 10 mM MgCl.sub.2, 4 mM DTT at a final DMSO
concentration of 2%. Reactions were incubated at 22.degree. C. in
384-well polypropylene 5 microtiter plates for 30 minutes and then
stopped by addition of 25 .mu.L of an EDTA containing solution (100
mM HEPES buffer (pH 7.2), 0.015% Brij-35, 150 mM EDTA), resulting
in a final EDTA concentration of 50 mM. After termination of the
kinase reaction, the proportion of phosphorylated product was
determined as a fraction of total peptide substrate using the
Caliper LabChip.RTM. 3000 according to the manufacturer's
specifications. K.sub.i values were then determined using the
Morrison tight binding model (Morrison, J. F., Biochim. Biophys.
Acta. 185:269-296 (1969); William, J. W. and Morrison, J. F., Meth.
Enzymol., 63:437-467 (1979)) modified for ATP-competitive
inhibition [K.sub.i=K.sub.i,app/(1+[ATP]/K.sub.m,app)].
JAK1 Pathway Assay in Cell Lines was Carried Out as Follows:
[1094] Inhibitor potency (EC.sub.50) was determined in cell-based
assays designed to measure JAK1 dependent STAT phosphorylation. As
noted above, inhibition of IL-4, IL-13, and IL-9 signaling by
blocking the Jak/Stat signaling pathway can alleviate asthmatic
symptoms in pre-clinical lung inflammation models (Mathew et al.,
2001, J Exp Med 193(9): 1087-1096; Kudlacz et. al., 2008, Eur J.
Pharmacol 582(1-3): 154-161).
[1095] In one assay approach, TF-1 human erythroleukemia cells
obtained from the American Type Culture Collection (ATCC; Manassas,
Va.) were used to measure JAK1-dependent STAT6 phosphorylation
downstream of IL-13 stimulation. Prior to use in the assays, TF-1
cells were starved of GM-CSF overnight in OptiMEM medium (Life
Technologies, Grand Island, N.Y.) supplemented with 0.5%
charcoal/dextran stripped fetal bovine serum (FBS), 0.1 mM
non-essential amino acids (NEAA), and 1 mM sodium pyruvate. The
assays were run in 384-well plates in serum-free OptiMEM medium
using 300,000 cells per well. In a second assay approach, BEAS-2B
human bronchial epithelial cells obtained from ATCC were plated at
100,000 cells per well of a 96-well plate one day prior to the
experiment. The BEAS-2B assay was run in complete growth medium
(bronchial epithelial basal medium plus bulletkit; Lonza; Basel,
Switzerland).
[1096] Test compounds were serially diluted 1:2 in DMSO and then
diluted 1:50 in medium just before use. Diluted compounds were
added to the cells, for a final DMSO concentration of 0.2%, and
incubated for 30 min (for the TF-1 assay) or 1 hr (for the BEAS-2B
assay) at 37.degree. C. Then, cells were stimulated with human
recombinant cytokine at their respective EC.sub.90 concentrations,
as previously determined for each individual lot. Cells were
stimulated with IL-13 (R&D Systems, Minneapolis, Minn.) for 15
min at 37.degree. C. The TF-1 cell reactions were stopped by the
direct addition of 10.times. lysis buffer (Cell Signaling
Technologies, Danvers, Mass.), whereas the BEAS-2B cell incubations
were halted by the removal of medium and addition of 1.times. lysis
buffer. The resultant samples were frozen in the plates at
-80.degree. C. Compound mediated inhibition of STAT6
phosphorylation was measured in the cell lysates using MesoScale
Discovery (MSD) technology (Gaithersburg, Md.). EC.sub.50 values
were determined as the concentration of compound required for 50%
inhibition of STAT phosphorylation relative to that measured for
the DMSO control.
[1097] Table 2 provides JAK1 K, JAK2 K, and IL-13-pSTAT6 IC.sub.50
information for the noted Examples of the indicated Tables as well
as LCMS (ESI) information.
TABLE-US-00038 TABLE 2 IL13- IL13- LCMS LCMS JAK1 JAK2 pSTAT6
pSTAT6 (ESI) m/z LCMS RT Ki Ki EC50_TF-1 EC50 Ex # [M + H]+ Method
(Min) (uM) (uM) (uM) (uM)_BEAS-2B 1 488.0 5 2.93 0.00162 0.00046
0.0211 2 503.3 5 2.32 0.00072 0.00019 0.0052 0.0195 3 570.9 5 2.82
0.00079 0.00081 0.0167 0.0324 4 556.9 5 2.83 0.00066 0.00080 0.5473
5 585.0 5 2.88 0.00084 0.00078 0.0111 6 611.1 5 3.02 0.00071
0.00075 0.0059 7 586.0 5 2.58 0.00110 0.00096 1.0402 8 585.0 5 3.03
0.09634 0.11951 0.7456 9 586.0 11 0.90 0.00071 0.00028 0.0156
0.5543 10 571.9 11 0.90 0.00065 0.00032 11 600.1 11 0.93 0.00105
0.00030 0.0118 12 599.1 5 2.96 0.00130 0.00117 0.0150 13 661.1 5
3.38 0.00073 0.00066 0.0220 14 615.0 5 2.86 0.00114 0.00113 0.3348
15 659.0 5 3.58 0.00053 0.00093 0.3345 16 647.0 5 3.24 0.00062
0.00056 0.0081 17 788.3 5 3.57 0.00071 0.00085 0.0809 18 682.1 5
2.91 0.00056 0.00056 0.2743 19 684.2 5 2.85 0.00072 0.00071 0.3792
20 570.9 5 2.87 0.00051 0.00121 0.3435 21 570.9 5 2.90 0.00047
0.00116 3.0382 22 696.1 5 2.87 0.00094 0.00095 0.1575 23 726.2 5
3.20 0.00070 0.00081 0.0086 24 584.9 5 2.88 0.00078 0.00202 0.0049
25 585.0 5 2.90 0.00066 0.00161 0.1214 26 655.1 5 2.93 0.00077
0.00094 0.0062 27 677.0 5 2.84 0.00046 0.00055 0.1444 28 613.1 5
3.06 0.00082 0.00084 0.0035 0.1770 29 584.9 5 2.85 0.00101 0.00176
0.0056 30 584.9 5 2.85 0.00070 0.00169 31 663.1 5 2.84 0.00037
0.00053 0.1024 32 684.4 5 2.87 0.00046 0.00050 0.0985 33 689.3 5
3.29 0.00066 0.00049 0.0062 0.0485 34 732.2 5 3.00 0.00047 0.00046
35 766.4 5 2.94 0.00051 0.00073 0.2346 36 725.3 5 2.99 0.00084
0.00062 0.0576 37 677.2 5 3.26 0.00110 0.00078 0.0118 38 629.2 5
2.94 0.00088 0.00078 0.0085 39 641.2 5 2.86 0.00055 0.00087 0.0066
40 625.2 5 3.13 0.00065 0.00061 0.0038 0.1280 41 585.2 5 2.86
0.00091 0.00147 0.0080 42 585.2 5 2.86 0.00069 0.00067 0.0031 43
647.2 5 3.24 0.00066 0.00036 0.0150 44 647.2 5 3.24 0.00054 0.00022
0.0067 45 585.2 5 2.87 0.00074 0.00178 0.0071 0.0245 46 669.3 5
3.14 0.00058 0.00070 0.0082 47 678.3 5 3.39 0.00033 0.00054 0.0110
48 585.2 5 2.87 0.00094 0.00185 0.0137 0.0594 49 585.2 5 2.86
0.00050 0.00096 0.0113 50 643.2 5 2.93 0.00099 0.00074 0.0320 51
728.3 5 2.99 0.00109 0.00106 0.0779 52 653.4 5 3.39 0.00065 0.00062
0.0054 0.0388 53 585.2 5 2.85 0.00061 0.00122 0.0109 54 730.4 5
3.23 0.00076 0.00067 0.0151 55 697.3 5 3.29 0.00085 0.00072 0.0210
56 600.1 5 2.90 0.00074 0.00026 0.0069 57 626.2 5 3.07 0.00059
0.00013 0.0150 58 704.2 5 3.34 0.00060 0.00033 0.0256 59 639.2 5
4.10 0.00050 0.00080 0.0037 60 725.2 5 3.62 0.00110 0.00070 0.0462
61 585.2 5 2.91 0.00023 0.00068 0.0275 0.0324 62 585.2 5 2.91
0.00207 0.00268 0.0558 0.0892 63 612.2 5 2.84 0.00034 0.00070
0.0057 0.0122 64 545.0 5 2.81 0.00066 0.00084 65 559.0 5 2.89
0.00054 0.00069 0.0094 66 545.0 5 2.84 0.00058 0.00178 0.0356
0.3345 67 573.0 5 2.88 0.00089 0.00187 0.0146 0.0715 68 617.0 5
2.98 0.00074 0.00168 0.0134 69 599.1 5 2.95 0.00086 0.00245 0.0204
70 587.0 5 2.94 0.00067 0.00238 0.0161 71 587.0 5 3.01 0.00106
0.00466 72 587.1 5 3.01 0.00117 0.00407 0.0072 73 617.1 5 3.01
0.00071 0.00171 74 603.1 5 2.87 0.00097 0.00242 0.0385 75 587.9 11
0.91 0.00066 0.00061 0.0787 76 630.2 11 0.89 0.00050 0.00052 77
630.2 11 0.88 0.00060 0.00051 0.2095 78 587.9 12 1.18 0.00208
0.00138 0.0524 79 587.9 12 1.18 0.00454 0.00211 0.1582 80 663.2 5
3.26 0.00043 0.00087 0.0049 81 545.1 5 2.92 0.00535 0.00324 0.2532
82 602.2 5 3.01 0.00117 0.00053 0.0087 83 559.2 5 2.84 0.00107
0.00159 0.0423 0.1425 84 599.2 5 3.02 0.00091 0.00147 0.0246 85
663.3 5 3.37 0.00086 0.00166 0.0153 0.1003 86 664.3 5 3.10 0.00072
0.00160 0.0252 87 598.2 5 2.97 0.00040 0.00073 0.0154 0.0140 88
672.2 5 3.03 0.00172 0.00191 0.2987 89 649.2 5 3.38 0.00088 0.00145
0.0227 90 679.3 5 3.12 0.00095 0.00131 0.0233 91 665.2 5 3.10
0.00075 0.00115 0.1487 92 683.2 5 3.50 0.00092 0.00203 0.0556 93
717.3 5 3.63 0.00128 0.00258 0.0959 94 697.3 5 3.57 0.00120 0.00207
0.0424 0.0931 95 693.3 5 3.38 0.00080 0.00260 0.0173 96 643.3 5
2.90 0.00063 0.00140 0.0041 97 731.3 5 3.70 0.00116 0.00197 0.1869
98 649.3 5 3.22 0.00079 0.00181 0.0038 0.0381 99 641.2 5 4.39
0.00040 0.00076 0.0017 0.0305 100 679.3 5 3.35 0.00084 0.00201
0.0054 101 669.3 5 3.63 0.00067 0.00177 0.0165 102 699.2 5 3.71
0.00062 0.00110 0.0085 0.0347 103 731.3 5 5.49 0.00398 0.00795
0.2649 104 757.2 5 3.65 0.00093 0.00211 0.0202 105 757.2 5 3.52
0.00145 0.00317 0.0500 106 713.3 5 3.48 0.00109 0.00229 0.0155 107
713.2 5 3.55 0.00097 0.00249 0.0176 108 735.4 5 3.81 0.00247
0.00366 0.0431 109 719.5 5 3.64 0.00322 0.00730 0.0429 110 693.5 5
3.51 0.00104 0.00203 0.0089 0.0875 111 739.4 5 4.00 0.00310 0.01061
0.2030 112 693.4 5 3.38 0.00045 0.00101 0.0963 113 741.4 5 3.74
0.00119 0.00215 0.0306 114 680.4 5 3.43 0.00052 0.00134 0.0153 115
683.3 5 5.43 0.00128 0.00248 0.0577 116 717.3 5 5.38 0.00376
0.00704 0.0233 117 725.4 5 3.97 0.00051 0.00113 0.0086 0.0546 118
731.4 5 4.01 0.00257 0.00445 0.1001 0.3030 119 727.2 5 3.45 0.00121
0.00051 0.0208 120 705.4 5 3.78 0.00030 0.00023 0.1179 121 717.3 5
3.56 0.00024 0.00031 0.1397 122 727.3 5 3.43 0.00027 0.00017 0.0249
123 677.3 5 3.49 0.00223 0.00163 0.0076 0.0487 124 691.3 5 3.48
0.00121 0.00290 0.0879 0.5355 125 707.4 5 3.55 0.00061 0.00220
0.0117 126 683.3 5 3.40 0.00063 0.00180 0.0149 127 721.4 5 3.80
0.00078 0.00244 0.0724 128 717.3 5 3.51 0.00112 0.00309 0.0425 129
677.3 5 3.46 0.00114 0.00333 0.0142 130 699.3 5 3.50 0.00110
0.00291 0.0323 131 745.3 5 3.46 0.00107 0.00268 0.0237 132 703.3 5
4.87 0.00057 0.00127 0.0031 0.0973 133 731.3 5 5.56 0.00651 0.00833
134 637.2 5 3.09 0.00033 0.00069 0.0023 0.0118 135 681.3 5 3.32
0.00052 0.00115 0.0269 136 574.0 12 1.18 0.00064 0.00025 0.0367 137
632.0 11 0.94 0.00053 0.00072 138 560.2 11 0.87 0.00052 0.00026 139
588.2 5 2.93 0.00078 0.00036 0.0402 140 617.9 11 0.88 0.00046
0.00039 0.0293 141 632.1 11 0.90 0.00068 0.00059 0.0150 142 587.0 5
2.91 0.00165 0.00038 0.0363 143 656.1 5 3.47 0.00076 0.00018 0.0204
144 628.0 7 0.98 0.00054 0.00017 0.0128 0.0213 145 664.0 9 1.26
0.00057 0.00016 0.0148 146 628.0 9 1.20 0.00045 0.00013 0.0039 147
658.0 9 1.19 0.00055 0.00014 0.0118 148 616.0 11 0.99 0.00064
0.00010 0.0094 149 601.9 13 1.75 0.00081 0.00020 0.0083 0.0198 150
602.0 11 0.98 0.00073 0.00017 0.0201 151 678.0 11 1.04 0.00200
0.00042 0.0938 152 657.3 5 3.03 0.00108 0.00019 0.0119 153 629.2 5
2.91 0.00155 0.00027 0.0365 154 628.3 5 3.06 0.00142 0.00023 0.0027
155 613.2 5 3.01 0.00156 0.00024 0.0051 156 601.2 5 3.05 0.00153
0.00019 0.0318 157 559.1 5 2.93 0.00132 0.00075 0.0092 158 615.3 5
2.47 0.00212 0.00026 0.0388 159 631.2 5 2.53 0.00232 0.00024 0.0578
160 573.3 5 2.90 0.00302 0.00039 0.0193 161 663.3 5 2.92 0.00123
0.00013 0.0223 162 588.1 5 2.93 0.00059 0.00018 0.0154 163 629.1 5
2.99 0.00069 0.00019 0.0073 164 643.1 5 3.13 0.00044 0.00006 0.0056
165 574.2 5 2.88 0.00038 0.00015 0.0069 166 719.4 5 3.60 0.00091
0.00026 0.0229 167 678.3 5 3.49 0.00053 0.00018 0.0197 168 587.3 5
3.03 0.00147 0.00029 0.0077 169 643.2 5 3.03 0.00116 0.00022 0.0068
170 573.3 5 2.86 0.00167 0.00025 0.0114 171 516.9 11 0.98 0.00072
0.00017 0.0219 172 530.9 11 0.99 0.00088 0.00015 0.0159 173 642.3 5
3.00 0.00058 0.00013 0.0048 174 559.1 5 3.27 0.00067 0.00009 0.0123
175 617.2 5 3.32 0.00078 0.00013 0.0134 176 561.2 5 2.96 0.00068
0.00012 0.0127 177 623.2 5 3.02 0.00045 0.00009 0.0150 178 593.2 5
3.43 0.00123 0.00043 0.0839 179 635.2 5 3.79 0.00304 0.00090 0.1302
180 637.3 5 3.65 0.00125 0.00035 0.0384 181 679.3 5 3.79 0.00199
0.00048 0.0956 182 502.9 12 1.23 0.00049 0.00020 0.0089 183 502.9
11 1.00 0.00049 0.00023 0.0068 184 547.3 11 1.00 0.00076 0.00018
0.0035 185 489.1 11 0.91 0.00059 0.00031 186 488.9 12 1.10 0.00071
0.00020 0.0123 187 742.4 5 3.94 0.00705 0.00903 188 548.1 5 3.20
0.00126 0.00084 0.0058 0.0349 189 587.2 5 3.19 0.00259 0.00161
0.0053 0.0200 190 562.1 5 3.18 0.00269 0.00202 0.0146 0.0098 191
576.1 5 3.29 0.00293 0.00292 0.0105 192 638.2 5 3.73 0.00500
0.00372 0.2723 193 619.1 5 3.03 0.00223 0.00146 0.0235 194 578.2 5
3.15 0.00228 0.00144 0.0174 195 560.1 5 3.07 0.00136 0.00086 0.0165
196 596.1 5 3.71 0.00174 0.00105 0.0174 197 586.3 5 3.10 0.00089
0.00086 0.0062 198 616.1 5 5.36 0.00272 0.00217 0.0291 199 590.3 5
3.51 0.00122 0.00107 0.0073 200 618.2 5 3.17 0.00124 0.00107 0.0059
0.0254 201 624.2 5 3.55 0.00505 0.00376 0.1837 202 727.4 5 4.89
0.00110 0.00182 0.0158 203 655.3 5 3.96 0.00548 0.00415 204 766.4 5
3.77 0.00200 0.00141 0.0079 0.1715 205 520.2 5 3.02 0.00080 0.00058
0.0044 0.0338 206 610.2 5 3.64 0.01404 0.00867 207 560.1 5 3.26
0.00101 0.00069 0.0236 208 588.0 5 5.29 0.00138 0.00108 0.0335 209
503.0 5 3.16 0.00078 0.00028 0.0074 0.0415 210 545.1 5 3.48 0.00016
0.00010 0.2397 211 570.9 5 2.86 0.00110 0.00138 0.0209 212 585.1 5
2.92 0.00091 0.00193 0.0306 213 615.2 5 2.97 0.00149 0.00234 214
556.9 5 2.82 0.00117 0.00129 215 630.2 12 1.12 0.00133 0.00126 216
585.0 5 2.87 0.00113 0.00182 0.0125 217 570.9 5 2.87 0.00107
0.00137 218 585.0 5 2.92 0.00101 0.00308 0.0756 219 556.9 5 2.87
0.00056 0.00128 1.0320 220 556.9 5 2.84 0.00122 0.00271 1.1706 221
570.9 5 2.88 0.00092 0.00168 0.1305 222 599.0 5 2.94 0.00054
0.00159 0.0289 223 584.9 5 2.94 0.00044 0.00072 0.1867 224 599.0 5
2.96 0.00056 0.00147 0.0193 225 641.3 5 3.15 0.00039 0.00129 0.0050
0.0423 226 816.4 5 3.59 0.00041 0.00111 0.0415 227 545.1 5 2.89
0.00055 0.00093 0.0036 0.0271 228 575.1 5 2.84 0.00047 0.00089
0.0111 0.0655 229 589.1 5 2.98 0.00038 0.00084 0.0033 0.0516 230
589.1 5 2.84 0.00061 0.00071 231 619.2 5 2.85 0.00054 0.00118 232
637.1 5 3.05 0.00074 0.00146 233 559.1 5 2.89 0.00078 0.00143
0.0100 0.0181 234 575.0 5 2.83 0.00058 0.00122 235 575.1 5 2.82
0.00058 0.00108 0.0213 0.1140 236 607.0 5 4.68 0.00041 0.00074 237
632.1 5 4.47 0.00032 0.00076 238 646.1 5 3.32 0.00045 0.00055
0.0218 239 559.1 5 2.87 0.00155 0.00238 0.0086 240 589.1 5 2.88
0.00100 0.00168 241 585.1 5 2.98 0.00087 0.00125 242 571.0 5 2.89
0.00095 0.00103
243 560.0 5 2.88 0.00049 0.00036 244 589.9 11 0.90 0.00049 0.00024
245 604.0 11 0.94 0.00035 0.00022 246 573.9 11 0.91 0.00108 0.00057
0.0488 247 574.1 11 0.91 0.00055 0.00030 248 600.2 11 0.94 0.00062
0.00039 249 545.9 12 1.09 0.00073 0.00044 0.0323 250 572.0 11 0.89
0.00139 0.00048 251 574.0 11 1.01 0.00083 0.00046 252 571.9 11 0.99
0.00081 0.00015 0.0430 253 652.3 5 3.35 0.00056 0.00041 0.0183 254
499.0 5 3.87 0.00163 0.00077 0.1174 255 555.1 5 3.39 0.00056
0.00040 0.0862 256 585.2 5 3.45 0.00131 0.00095 0.0920 257 603.1 5
4.28 0.00293 0.00210 1.0000 258 596.1 5 3.46 0.00117 0.00072 0.0710
259 624.2 5 3.29 0.00093 0.00056 0.0130 260 562.1 5 2.56 0.00774
0.00265 0.0685 261 569.1 5 3.62 0.01790 0.01024 262 560.1 5 2.85
0.00584 0.00173 0.0627 263 519.0 5 3.23 0.00150 0.00203 0.0192 264
574.1 5 3.06 0.00269 0.00238 0.0198 265 576.1 5 3.09 0.00363
0.00429 0.0228 266 575.2 5 3.64 0.00024 0.00010 0.0059 267 576.1 5
3.50 0.00066 0.00062 0.0358 268 546.1 5 3.68 0.00049 0.00046 0.0055
269 545.9 5 3.55 0.00033 0.00083 270 547.0 11 1.01 0.00024 0.00020
271 517.2 11 1.06 0.00021 0.00013 272 576.0 5 3.30 0.00033 0.00078
273 577.1 12 1.17 0.00049 0.00023 274 560.0 5 3.58 0.00034 0.00091
0.0032 0.0131 275 590.1 5 3.54 0.00031 0.00089 276 623.1 5 3.05
0.00023 0.00018 277 562.0 5 3.43 0.00051 0.00083 278 546.0 5 3.51
0.00024 0.00063 0.0050 279 651.2 12 1.35 0.00039 0.00022 280 560.0
5 3.69 0.00039 0.00081 0.0043 0.0215 281 631.0 5 4.75 0.00048
0.00045 0.0022 282 567.0 11 1.10 0.00017 0.00012 283 646.1 11 1.19
0.00055 0.00029 284 528.0 5 4.28 0.00015 0.00037 0.0016 0.0125 285
637.1 11 1.20 0.00061 0.00047 286 637.0 11 1.23 0.00054 0.00026 287
552.0 5 4.22 0.00035 0.00065 288 532.0 5 3.77 0.00058 0.00111
0.0028 0.0363 289 622.0 5 4.22 0.00030 0.00038 290 547.0 11 1.04
0.00024 0.00011 291 546.0 5 3.69 0.00054 0.00055 0.0036 0.0317 292
503.0 5 4.52 0.00039 0.00040 0.0014 0.0210 293 546.0 5 3.83 0.00029
0.00038 0.0030 0.0081 294 506.0 5 3.00 0.00089 0.00057 0.0062
0.0367 295 463.0 5 2.81 0.00049 0.00021 0.0055 0.0345 296 531.2 5
3.10 0.00026 0.00021 0.0056 0.0283 297 489.1 5 2.87 0.00032 0.00007
0.0071 0.0308 298 503.2 5 2.93 0.00052 0.00018 0.0044 0.0215 299
595.2 5 3.08 0.00038 0.00039 0.0041 0.0104 300 615.0 5 4.42 0.00028
0.00018 0.0040 0.0142 301 581.2 5 3.22 0.00033 0.00036 0.0034
0.0095 302 635.2 5 3.27 0.00060 0.00111 0.0162 303 703.3 5 5.09
0.00190 0.00328 0.0784 304 475.1 17 6.52 0.00078 0.00039 0.0059
0.0469 305 489.1 18 7.75 0.00061 0.00032 0.0109 0.0426 306 534.2 14
1.13 0.00115 0.00054 0.0062 0.0659 307 574.2 15 2.23 0.00145
0.00059 0.0061 0.0250 308 530.1 5 4.27 0.00024 0.00055 0.0015
0.0236 309 534.1 16 2.68 0.00134 0.00047 0.0163 0.0490 310 589.2 26
0.82 0.00052 0.00059 8.8300 311 589.1 25 0.85 0.00125 0.00073
2.6000 312 522.2 20 2.5 0.00040 0.00032 0.0719 313 538.2 20 2.7
0.00021 0.00021 0.0218 314 539.2 20 2.53 0.00062 0.00039 0.0995 315
539.1 25 1.45 0.00072 0.00040 0.0823 316 635 21 1.56 0.00048
0.00104 0.1420 317 587.1 25 1.8 0.00064 0.00116 0.0229 318 615.2 25
0.93 0.00056 0.00111 0.0283 319 573.2 20 2.86 0.00050 0.00086
0.0577 320 621 21 1.53 0.00031 0.00060 0.0473 321 644.2 20 2.34
0.00040 0.00090 0.0133 322 603.2 20 2.83 0.00031 0.00080 0.0411 323
503.1 20 1.65 0.00068 0.00033 0.0209 324 531.2 20 2.67 0.00095
0.00161 0.0566 325 616.3 20 2.41 0.00041 0.00103 0.0651 326 554.2
20 2.79 0.00021 0.00028 0.0070 327 554.2 20 1.58 0.00025 0.00020
0.0077 328 554.2 20 1.58 0.00021 0.00023 0.0102 329 617.2 24 1.53
0.00030 0.00076 0.0115 330 643.2 25 1.49 0.00039 0.00088 0.0343 331
617.1 25 1.51 0.00039 0.00077 0.0176 332 631.2 28 0.89 0.00049
0.00091 0.0692 333 700.2 24 2.21 0.00069 0.00196 0.0065 334 714.2
24 2.42 0.00069 0.00181 0.0061 335 714.2 24 1.94 0.00084 0.00222
0.0121 336 687.2 28 0.86 0.00049 0.00105 0.0145 337 728.2 24 1.87
0.00083 0.00252 0.0232 338 645.2 24 2.97 0.00036 0.00116 0.0177 339
701.2 20 0.92 0.00041 0.00101 0.0094 340 659.2 28 1.23 0.00044
0.00179 0.0090 341 671.3 20 1.58 0.00053 0.00262 0.5340 342 574.1
28 1.11 0.00019 0.00020 1.8100 343 588.2 20 2.79 344 657.2 24 1.68
0.00070 0.00190 0.0484 345 645.2 24 1.64 0.00059 0.00147 0.0166 346
584.2 20 2.23 0.00037 0.00031 0.1150 347 629.1 28 1.44 0.00039
0.00076 0.0307 348 629.2 20 1.55 0.00040 0.00102 0.0120 349 628.2
20 2.2 0.00055 0.00165 0.0155 350 642.2 24 1.55 0.00043 0.00142
0.0094 351 627.1 24 1.55 0.00046 0.00094 0.0365 352 655.2 20 1.91
0.00033 0.00075 0.0124 353 603.1 28 0.81 0.00032 0.00036 3.6100 354
604.3 20 2.08 0.00072 0.00105 0.0240 355 604.3 20 2.08 0.00332
0.00372 0.0678 356 604.3 20 2.08 0.00264 0.00237 0.0396 357 604.3
20 2.08 0.00122 0.00106 0.0216 358 504.2 20 1.38 0.00093 0.00066
0.0133 359 504.2 20 1.71 0.00385 0.00270 0.0309 360 504.2 20 1.38
0.00469 0.00170 0.0366 361 504.2 20 1.71 0.00294 0.00205 0.0273 362
625.3 20 1.68 0.00504 0.00327 363 597.2 20 2.72 0.00415 0