U.S. patent application number 13/180589 was filed with the patent office on 2012-01-19 for pyrazolo[1,5a]pyrimidine derivatives as irak4 modulators.
Invention is credited to Nidhi Arora, Shaoqing Chen, Johannes Cornelius Hermann, Adreas Kuglstatter, Sharada Shenvi Labadie, Clara Jeou Jen Lin, Matthew C. Lucas, Amy Geraldine Moore, Eva Papp, Francisco Xavier Talamas, Jutta Wanner, Yansheng Zhai.
Application Number | 20120015962 13/180589 |
Document ID | / |
Family ID | 45467432 |
Filed Date | 2012-01-19 |
United States Patent
Application |
20120015962 |
Kind Code |
A1 |
Arora; Nidhi ; et
al. |
January 19, 2012 |
PYRAZOLO[1,5a]PYRIMIDINE DERIVATIVES AS IRAK4 MODULATORS
Abstract
Compounds of the formula I or II: ##STR00001## wherein X, m, Ar,
R.sup.1 and R.sup.2 are as defined herein. The subject compounds
are useful for treatment of IRAK-mediated conditions.
Inventors: |
Arora; Nidhi; (Cupertino,
CA) ; Chen; Shaoqing; (Bridgewater, NJ) ;
Hermann; Johannes Cornelius; (Jersey City, NJ) ;
Kuglstatter; Adreas; (Montclair, NJ) ; Labadie;
Sharada Shenvi; (Sunnyvale, CA) ; Lin; Clara Jeou
Jen; (Palo Alto, CA) ; Lucas; Matthew C.;
(Verona, NJ) ; Moore; Amy Geraldine; (Mountain
View, CA) ; Papp; Eva; (Palo Alto, CA) ;
Talamas; Francisco Xavier; (Livingston, NJ) ; Wanner;
Jutta; (Montclair, NJ) ; Zhai; Yansheng;
(Nutley, NJ) |
Family ID: |
45467432 |
Appl. No.: |
13/180589 |
Filed: |
July 12, 2011 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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61363855 |
Jul 13, 2010 |
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61485145 |
May 12, 2011 |
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Current U.S.
Class: |
514/259.3 ;
514/260.1; 514/301; 544/278; 544/281; 546/114 |
Current CPC
Class: |
C07D 495/04 20130101;
A61P 37/06 20180101; A61P 17/06 20180101; A61P 1/00 20180101; A61P
37/02 20180101; A61P 31/04 20180101; A61P 31/00 20180101; A61P
31/12 20180101; A61P 1/16 20180101; A61P 13/12 20180101; A61P 11/06
20180101; A61P 37/08 20180101; A61P 11/08 20180101; A61P 19/02
20180101; A61P 43/00 20180101; A61P 15/00 20180101; A61P 11/00
20180101; C07D 487/04 20130101; A61P 29/00 20180101; A61P 1/12
20180101 |
Class at
Publication: |
514/259.3 ;
544/281; 544/278; 546/114; 514/260.1; 514/301 |
International
Class: |
A61K 31/519 20060101
A61K031/519; C07D 495/04 20060101 C07D495/04; A61P 19/02 20060101
A61P019/02; A61P 11/00 20060101 A61P011/00; A61P 11/06 20060101
A61P011/06; A61P 11/08 20060101 A61P011/08; C07D 487/04 20060101
C07D487/04; A61K 31/4365 20060101 A61K031/4365 |
Claims
1. A compound of formula I or formula II: ##STR00286## or a
pharmaceutically acceptable salt thereof, wherein: X is N or CH m
is 1 or 2; Ar is: optionally substituted aryl; or optionally
substituted heteroaryl; R.sup.1 is: hydrogen; C.sub.1-6alkyl;
C.sub.1-6alkoxy; hydroxy; hydroxy-C.sub.1-6alkyl;
C.sub.1-6alkyl-amino; amino-C.sub.1-6alkyl;
amino-C.sub.1-6alkyl-amino; hydroxy-C.sub.1-6alkylamino
C.sub.3-6cycloalkylamino; amino-C.sub.3-6cycloalkylamino;
amino-C.sub.3-6heterocycloalkylamino; aminocarbonyl; halo;
hydroxy-C.sub.1-6alkyl; or hydroxy-C.sub.1-6alkoxy; and R.sup.2 is:
hydrogen; or C.sub.1-6alkyl.
2. The compound of claim 1, wherein R.sup.2 is hydrogen.
3. The compound of claim 1, wherein m is 1.
4. The compound of claim 1, wherein Ar is substituted phenyl.
5. The compound of claim 1, wherein Ar is phenyl substituted one,
two or three times with a group or groups independently selected
from: halo; C.sub.1-6alkyl; halo-C.sub.1-6alkyl; C.sub.1-6alkenyl;
C.sub.1-6alkoxy; halo-C.sub.1-6alkoxy; hydroxy-C.sub.1-6alkyl;
hydroxy-C.sub.1-6alkylamino; C.sub.1-6alkyl-amino; hydroxy; amino;
amino-C.sub.1-6alkyl; aminocarbonyl; hydroxy-C.sub.1-6alkoxy;
hydroxy-C.sub.1-6alkenyl; C.sub.1-6alkoxy-C.sub.1-6alkoxy;
C.sub.1-6alkylsulfonyl; C.sub.1-6alkylsulfanyl; piperidinyl wherein
the piperidinyl moiety is optionally substituted with hydroxy,
amino, amino-C.sub.1-6alkyl, hydroxy-C.sub.1-6alkyl or
aminocarbonyl; phenylaminocarbonyl; hydroxy-C.sub.1-6alkylamino;
cyclohexyloxy wherein the cyclohexyl moiety thereof is optionally
substituted with hydroxy, amino, amino-C.sub.1-6alkyl or
hydroxy-C.sub.1-6alkyl; cyclopentyloxy wherein the cyclopentyl
moiety thereof is optionally substituted with hydroxy, amino,
amino-C.sub.1-6alkyl or hydroxy-C.sub.1-6alkyl; piperidinyloxy
wherein the piperidinyl moiety thereof is optionally substituted
with hydroxy, amino, amino-C.sub.1-6alkyl, hydroxy-C.sub.1-6alkyl
or aminocarbonyl; phenyl wherein the phenyl moiety is optionally
substituted with amino, hydroxy, amino-C.sub.1-6alkyl,
hydroxy-C.sub.1-6alkyl or aminocarbonyl; pyrrolidinyl wherein the
pyrrolidinyl moiety is optionally substituted with hydroxy, amino,
amino-C.sub.1-6alkyl, hydroxy-C.sub.1-6alkyl or aminocarbonyl;
pyrrolidinyloxy wherein the pyrrolidinyl moiety is optionally
substituted with hydroxy, amino, amino-C.sub.1-6alkyl,
hydroxy-C.sub.1-6alkyl or aminocarbonyl; piperazinyl wherein the
piperazinyl moiety is optionally substituted with C.sub.1-6alkyl;
oxazol-C.sub.1-6alkoxy wherein the oxazol moiety thereof is
optionally substituted with C.sub.1-6alkyl; morpholinyl;
hydroxy-C.sub.1-6alkylaminocarbonyl; C.sub.3-6cycloalkyl; azepanyl
wherein the azepanyl moiety is optionally substituted with hydroxy,
amino, amino-C.sub.1-6alkyl, hydroxy-C.sub.1-6alkyl or
aminocarbonyl; benzyl wherein the phenyl moiety thereof is
optionally substituted with amino, hydroxy, amino-C.sub.1-6alkyl,
hydroxy-C.sub.1-6alkyl or aminocarbonyl;
C.sub.1-6alkoxycarbonyl-C.sub.1-6alkoxy; and
C.sub.1-6alkylcarbonylamino.
6. The compound of claim 1, wherein Ar is phenyl substituted once
with halo and once with a group selected from: halo;
C.sub.1-6alkyl; halo-C.sub.1-6alkyl; C.sub.1-6alkenyl;
C.sub.1-6alkoxy; halo-C.sub.1-6alkoxy; hydroxy-C.sub.1-6alkyl;
hydroxy-C.sub.1-6alkylamino; C.sub.1-6alkyl-amino; hydroxy; amino;
amino-C.sub.1-6alkyl; aminocarbonyl; hydroxy-C.sub.1-6alkoxy;
hydroxy-C.sub.1-6alkenyl; C.sub.1-6alkoxy-C.sub.1-6alkoxy;
C.sub.1-6alkylsulfonyl; C.sub.1-6alkylsulfanyl; piperidinyl wherein
the piperidinyl moiety is optionally substituted with hydroxy,
amino, amino-C.sub.1-6alkyl, hydroxy-C.sub.1-6alkyl or
aminocarbonyl; phenylaminocarbonyl; hydroxy-C.sub.1-6alkylamino;
cyclohexyloxy wherein the cyclohexyl moiety thereof is optionally
substituted with hydroxy, amino, amino-C.sub.1-6alkyl or
hydroxy-C.sub.1-6alkyl; cyclopentyloxy wherein the cyclopentyl
moiety thereof is optionally substituted with hydroxy, amino,
amino-C.sub.1-6alkyl or hydroxy-C.sub.1-6alkyl; piperidinyloxy
wherein the piperidinyl moiety thereof is optionally substituted
with hydroxy, amino, amino-C.sub.1-6alkyl, hydroxy-C.sub.1-6alkyl
or aminocarbonyl; phenyl wherein the phenyl moiety is optionally
substituted with amino, hydroxy, amino-C.sub.1-6alkyl,
hydroxy-C.sub.1-6alkyl or aminocarbonyl; pyrrolidinyl wherein the
pyrrolidinyl moiety is optionally substituted with hydroxy, amino,
amino-C.sub.1-6alkyl, hydroxy-C.sub.1-6alkyl or aminocarbonyl;
pyrrolidinyloxy wherein the pyrrolidinyl moiety is optionally
substituted with hydroxy, amino, amino-C.sub.1-6alkyl,
hydroxy-C.sub.1-6alkyl or aminocarbonyl; piperazinyl wherein the
piperazinyl moiety is optionally substituted with C.sub.1-6alkyl;
oxazol-C.sub.1-6alkoxy wherein the oxazol moiety thereof is
optionally substituted with C.sub.1-6alkyl; morpholinyl;
hydroxy-C.sub.1-6alkylaminocarbonyl; C.sub.3-6cycloalkyl; azepanyl
wherein the azepanyl moiety is optionally substituted with hydroxy,
amino, amino-C.sub.1-6alkyl, hydroxy-C.sub.1-6alkyl or
aminocarbonyl; benzyl wherein the phenyl moiety thereof is
optionally substituted with amino, hydroxy, amino-C.sub.1-6alkyl,
hydroxy-C.sub.1-6alkyl or aminocarbonyl;
C.sub.1-6alkoxycarbonyl-C.sub.1-6alkoxy; and
C.sub.1-6alkylcarbonylamino.
7. The compound of claim 1, wherein Ar is substituted aryl selected
from: 2-(4-aminomethyl-piperidin-1-yl)-5-chloro-phenyl;
2-(4-aminomethyl-piperidin-1-yl)-4-phenylcarbamoyl-phenyl;
5-chloro-2-[4-(1-hydroxy-ethyl)-piperidin-1-yl]-phenyl;
5-chloro-2-(4-hydroxymethyl-piperidin-1-yl)-phenyl;
5-chloro-2-(4-hydroxy-cyclohexyloxy)-phenyl;
5-chloro-2-piperidin-1-yl-phenyl;
2-(4-aminomethyl-piperidin-1-yl)-5-chloro-phenyl;
2-[4-(1-amino-ethyl)-piperidin-1-yl]-5-chloro-phenyl;
2-(4-carbamoyl-piperidin-1-yl)-5-chloro-phenyl;
5-chloro-2-[3-(1-hydroxy-ethyl)-pyrrolidin-1-yl]-phenyl;
4'-aminomethyl-4-chloro-biphenyl-2-yl; 5-chloro-2-methoxy-phenyl;
3-amino-2-(4-aminomethyl-piperidin-1-yl)-phenyl;
3-amino-2-piperidin-1-yl-phenyl;
5-hydroxymethyl-2-piperidin-1-yl-phenyl;
4-chloro-4'-hydroxymethyl-biphenyl-2-yl;
5-chloro-2-isopropoxy-phenyl;
5-chloro-2-(3-hydroxymethyl-cyclopentyloxy)-phenyl;
5-chloro-2-pyrrolidin-1-yl-phenyl;
5-chloro-2-(3-hydroxy-cyclopentyloxy)-phenyl;
5-chloro-2-(3-hydroxy-propoxy)-phenyl;
5-chloro-2-(4-hydroxy-butoxy; 2-methoxy-4-phenylcarbamoyl-phenyl;
5-chloro-2-(3-hydroxy-piperidin-1-yl)-phenyl;
5-chloro-2-(piperidin-4-yloxy)-phenyl;
4-chloro-4'-hydroxy-biphenyl-2-yl;
5-chloro-2-(3-hydroxy-pyrrolidin-1-yl)-phenyl;
5-chloro-2-(3,4-dihydroxy-butoxy;
5-chloro-2-(4-methyl-piperazin-1-yl)-phenyl;
5-chloro-2-(oxazol-5-ylmethoxy)-phenyl;
5-chloro-2-morpholin-4-yl-phenyl; 4-chloro-biphenyl-2-yl;
2-(3-aminomethyl-pyrrolidin-1-yl)-5-chloro-phenyl;
5-chloro-2-(3-hydroxy-cyclohexyloxy)-phenyl;
4-(3-hydroxy-propylcarbamoyl)-2-methoxy-phenyl;
5-chloro-2-(3-hydroxymethyl-pyrrolidin-1-yl)-phenyl;
5-chloro-2-difluoromethoxy-phenyl; 5-chloro-2-dimethylamino-phenyl;
2-(3-amino-pyrrolidin-1-yl)-5-chloro-phenyl;
5-chloro-2-methylsulfanyl-phenyl; 5-chloro-2-cyclohexyl-phenyl;
3-(2-hydroxy-ethylamino)-2-piperidin-1-yl-phenyl;
5-chloro-2-(4-methyl-oxazol-5-ylmethoxy)-phenyl; biphenyl-2-yl;
5-chloro-2-(3-hydroxy-1,1-dimethyl-propoxy)-phenyl;
2-(4-amino-cyclohexyloxy)-5-chloro-phenyl;
2-azepan-1-yl-5-chloro-phenyl;
4-(2-hydroxy-ethylcarbamoyl)-2-methoxy-phenyl;
4-hydroxy-cyclohexyloxy)-phenyl;
5-chloro-2-(2-methoxy-ethoxy)-phenyl;
4-chloro-3'-hydroxy-biphenyl-2-yl; 5-bromo-2-methoxy-phenyl;
5-chloro-2-[(2-hydroxy-ethyl)-methyl-amino]-phenyl;
5-chloro-2-(4-hydroxy-phenoxy)-phenyl;
4-carbamoyl-2-methoxy-phenyl; 5-chloro-2-isobutoxy-phenyl;
5-chloro-2-(2,3-dihydroxy-propoxy)-phenyl;
5-chloro-2-(3-methoxy-propoxy)-phenyl;
5-chloro-2-(3-hydroxymethyl-piperidin-1-yl)-phenyl;
5-chloro-2-(3-hydroxy-benzyloxy; 5-chloro-2,4-dimethoxy-phenyl;
2-methoxy-5-vinyl-phenyl;
3-(3-hydroxy-propylamino)-2-piperidin-1-yl-phenyl5-chloro-2-(4-hydroxy-bu-
tyl)-phenyl; 2-[3-(1-amino-ethyl)-pyrrolidin-1-yl]-5-chloro-phenyl;
5-chloro-2-[(3-hydroxy-propyl)-methyl-amino]-phenyl;
5-chloro-2-(4-methylaminomethyl-piperidin-1-yl)-phenyl;
5-(3-hydroxy-propenyl)-2-methoxy-phenyl; 5-chloro-2-ethyl-phenyl;
4-methanesulfonyl-2-methoxy-phenyl;
5-chloro-2-(3-hydroxy-phenoxy)-phenyl; 2,4-dimethoxy-phenyl;
5-fluoro-2-methoxy-phenyl; 5-chloro-2-phenoxy-phenyl;
5-(3-hydroxy-propyl)-2-methoxy-phenyl5-chloro-2-(2-hydroxymethyl-piperidi-
n-1-yl)-phenyl;
5-chloro-2-(4-dimethylaminomethyl-piperidin-1-yl)-phenyl;
3-methoxy-biphenyl-4-yl; 5-ethyl-2-methoxy-phenyl;
5-methoxy-2-methyl-biphenyl-4-yl; 2-methoxy-3,5-dimethyl-phenyl;
4-dimethylcarbamoyl-2-methoxy-pheny;
5-acetylamino-2-methoxy-phenyl;
5-chloro-2-methoxy-4-phenylcarbamoyl-phenyl; and
4-hydroxymethyl-2-methoxy-phenyl;
3-(3-hydroxy-cyclopentyloxy)-naphthalen-2-yl;
3-(3-hydroxy-propoxy)-naphthalen-2-yl;
7-hydroxymethyl-3-methoxy-naphthalen-2-yl;
3-(4-hydroxy-cyclohexyloxy)-naphthalen-2-yl; and
3-methoxy-naphthalen-2-yl.
8. The compound of claim 1, wherein Ar is substituted phenyl
selected from: 2-(4-aminomethyl-piperidin-1-yl)-5-chloro-phenyl;
2-(4-aminomethyl-piperidin-1-yl)-4-phenylcarbamoyl-phenyl;
5-chloro-2-[4-(1-hydroxy-ethyl)-piperidin-1-yl]-phenyl;
5-chloro-2-(4-hydroxymethyl-piperidin-1-yl)-phenyl;
5-chloro-2-(4-hydroxy-cyclohexyloxy)-phenyl;
5-chloro-2-piperidin-1-yl-phenyl;
2-(4-aminomethyl-piperidin-1-yl)-5-chloro-phenyl;
2-[4-(1-amino-ethyl)-piperidin-1-yl]-5-chloro-phenyl;
2-(4-carbamoyl-piperidin-1-yl)-5-chloro-phenyl;
5-chloro-2-[3-(1-hydroxy-ethyl)-pyrrolidin-1-yl]-phenyl;
4'-aminomethyl-4-chloro-biphenyl-2-yl; 5-chloro-2-methoxy-phenyl;
3-amino-2-(4-aminomethyl-piperidin-1-yl)-phenyl;
3-amino-2-piperidin-1-yl-phenyl;
5-hydroxymethyl-2-piperidin-1-yl-phenyl;
4-chloro-4'-hydroxymethyl-biphenyl-2-yl;
5-chloro-2-isopropoxy-phenyl;
5-chloro-2-(3-hydroxymethyl-cyclopentyloxy)-phenyl;
5-chloro-2-pyrrolidin-1-yl-phenyl;
5-chloro-2-(3-hydroxy-cyclopentyloxy)-phenyl;
5-chloro-2-(3-hydroxy-propoxy)-phenyl;
5-chloro-2-(4-hydroxy-butoxy; 2-methoxy-4-phenylcarbamoyl-phenyl;
5-chloro-2-(3-hydroxy-piperidin-1-yl)-phenyl;
5-chloro-2-(piperidin-4-yloxy)-phenyl;
4-chloro-4'-hydroxy-biphenyl-2-yl;
5-chloro-2-(3-hydroxy-pyrrolidin-1-yl)-phenyl;
5-chloro-2-(3,4-dihydroxy-butoxy;
5-chloro-2-(4-methyl-piperazin-1-yl)-phenyl;
5-chloro-2-(oxazol-5-ylmethoxy)-phenyl;
5-chloro-2-morpholin-4-yl-phenyl; 4-chloro-biphenyl-2-yl;
2-(3-aminomethyl-pyrrolidin-1-yl)-5-chloro-phenyl;
5-chloro-2-(3-hydroxy-cyclohexyloxy)-phenyl;
4-(3-hydroxy-propylcarbamoyl)-2-methoxy-phenyl;
5-chloro-2-(3-hydroxymethyl-pyrrolidin-1-yl)-phenyl;
5-chloro-2-difluoromethoxy-phenyl; 5-chloro-2-dimethylamino-phenyl;
2-(3-amino-pyrrolidin-1-yl)-5-chloro-phenyl;
5-chloro-2-methylsulfanyl-phenyl; 5-chloro-2-cyclohexyl-phenyl;
3-(2-hydroxy-ethylamino)-2-piperidin-1-yl-phenyl;
5-chloro-2-(4-methyl-oxazol-5-ylmethoxy)-phenyl; biphenyl-2-yl;
5-chloro-2-(3-hydroxy-1,1-dimethyl-propoxy)-phenyl;
2-(4-amino-cyclohexyloxy)-5-chloro-phenyl;
2-azepan-1-yl-5-chloro-phenyl;
4-(2-hydroxy-ethylcarbamoyl)-2-methoxy-phenyl;
4-hydroxy-cyclohexyloxy)-phenyl;
5-chloro-2-(2-methoxy-ethoxy)-phenyl;
4-chloro-3'-hydroxy-biphenyl-2-yl; 5-bromo-2-methoxy-phenyl;
5-chloro-2-[(2-hydroxy-ethyl)-methyl-amino]-phenyl;
5-chloro-2-(4-hydroxy-phenoxy)-phenyl;
4-carbamoyl-2-methoxy-phenyl; 5-chloro-2-isobutoxy-phenyl;
5-chloro-2-(2,3-dihydroxy-propoxy)-phenyl;
5-chloro-2-(3-methoxy-propoxy)-phenyl;
5-chloro-2-(3-hydroxymethyl-piperidin-1-yl)-phenyl;
5-chloro-2-(3-hydroxy-benzyloxy; 5-chloro-2,4-dimethoxy-phenyl;
2-methoxy-5-vinyl-phenyl;
3-(3-hydroxy-propylamino)-2-piperidin-1-yl-phenyl5-chloro-2-(4-hydroxy-bu-
tyl)-phenyl; 2-[3-(1-amino-ethyl)-pyrrolidin-1-yl]-5-chloro-phenyl;
5-chloro-2-[(3-hydroxy-propyl)-methyl-amino]-phenyl;
5-chloro-2-(4-methylaminomethyl-piperidin-1-yl)-phenyl;
5-(3-hydroxy-propenyl)-2-methoxy-phenyl; 5-chloro-2-ethyl-phenyl;
4-methanesulfonyl-2-methoxy-phenyl;
5-chloro-2-(3-hydroxy-phenoxy)-phenyl; 2,4-dimethoxy-phenyl;
5-fluoro-2-methoxy-phenyl; 5-chloro-2-phenoxy-phenyl;
5-(3-hydroxy-propyl)-2-methoxy-phenyl5-chloro-2-(2-hydroxymethyl-piperidi-
n-1-yl)-phenyl; and
5-chloro-2-(4-dimethylaminomethyl-piperidin-1-yl)-phenyl.
9. The compound of claim 1, wherein Ar is optionally substituted
heteroaryl.
10. The compound of claim 1, wherein Ar is heteroaryl selected
from: pyridinyl; benzo[1,3]dioxolyl; quinolinyl;
2-oxo-2,3-dihydro-indolyl; indolyl; benzimidazolyl; or indazolyl;
each optionally substituted once or twice with a group or groups
independently selected from: halo; C.sub.1-6alkyl;
halo-C.sub.1-6alkyl; C.sub.1-6alkenyl; C.sub.1-6alkoxy;
halo-C.sub.1-6alkoxy; hydroxy-C.sub.1-6alkyl;
hydroxy-C.sub.1-6alkylamino; C.sub.1-6alkyl-amino; hydroxy; amino;
amino-C.sub.1-6alkyl; aminocarbonyl; hydroxy-C.sub.1-6alkoxy;
hydroxy-C.sub.1-6alkenyl; C.sub.1-6alkoxy-C.sub.1-6alkoxy;
C.sub.1-6alkylsulfonyl; C.sub.1-6alkylsulfanyl; piperidinyl wherein
the piperidinyl moiety is optionally substituted with hydroxy,
amino, amino-C.sub.1-6alkyl, hydroxy-C.sub.1-6alkyl or
aminocarbonyl; phenylaminocarbonyl; hydroxy-C.sub.1-6alkylamino;
cyclohexyloxy wherein the cyclohexyl moiety thereof is optionally
substituted with hydroxy, amino, amino-C.sub.1-6alkyl or
hydroxy-C.sub.1-6alkyl; cyclopentyloxy wherein the cyclopentyl
moiety thereof is optionally substituted with hydroxy, amino,
amino-C.sub.1-6alkyl or hydroxy-C.sub.1-6alkyl; piperidinyloxy
wherein the piperidinyl moiety thereof is optionally substituted
with hydroxy, amino, amino-C.sub.1-6alkyl, hydroxy-C.sub.1-6alkyl
or aminocarbonyl; phenyl wherein the phenyl moiety is optionally
substituted with amino, hydroxy, amino-C.sub.1-6alkyl,
hydroxy-C.sub.1-6alkyl or aminocarbonyl; pyrrolidinyl wherein the
pyrrolidinyl moiety is optionally substituted with hydroxy, amino,
amino-C.sub.1-6alkyl, hydroxy-C.sub.1-6alkyl or aminocarbonyl;
pyrrolidinyloxy wherein the pyrrolidinyl moiety is optionally
substituted with hydroxy, amino, amino-C.sub.1-6alkyl,
hydroxy-C.sub.1-6alkyl or aminocarbonyl; piperazinyl wherein the
piperazinyl moiety is optionally substituted with C.sub.1-6alkyl;
oxazol-C.sub.1-6alkoxy wherein the oxazol moiety thereof is
optionally substituted with C.sub.1-6alkyl; morpholinyl;
hydroxy-C.sub.1-6alkylaminocarbonyl; C.sub.3-6cycloalkyl; azepanyl
wherein the azepanyl moiety is optionally substituted with hydroxy,
amino, amino-C.sub.1-6alkyl, hydroxy-C.sub.1-6alkyl or
aminocarbonyl; benzyl wherein the phenyl moiety thereof is
optionally substituted with amino, hydroxy, amino-C.sub.1-6alkyl,
hydroxy-C.sub.1-6alkyl or aminocarbonyl;
C.sub.1-6alkoxycarbonyl-C.sub.1-6alkoxy; and
C.sub.1-6alkylcarbonylamino.
11. The compound of claim 1, wherein Ar is quinolinyl optionally
substituted once or twice with a group or groups independently
selected from: C.sub.1-6alkyl; C.sub.1-6alkoxy;
hydroxy-C.sub.1-6alkoxy; hydroxy-C.sub.1-6alkylamino;
amino-C.sub.1-6alkoxy; cyclohexyloxy wherein the cyclohexyl moiety
thereof is optionally substituted with hydroxy, amino,
amino-C.sub.1-6alkyl or hydroxy-C.sub.1-6alkyl; piperidinyl wherein
the piperidinyl moiety is optionally substituted with hydroxy,
amino, amino-C.sub.1-6alkyl, hydroxy-C.sub.1-6alkyl or
aminocarbonyl; piperidinyloxy wherein the piperidinyl moiety
thereof is optionally substituted with hydroxy, amino,
amino-C.sub.1-6alkyl, hydroxy-C.sub.1-6alkyl or aminocarbonyl;
cyclopentyloxy wherein the cyclopentyl moiety thereof is optionally
substituted with hydroxy, amino, amino-C.sub.1-6alkyl or
hydroxy-C.sub.1-6alkyl; and pyrrolidinyloxy wherein the
pyrrolidinyl moiety is optionally substituted with hydroxy, amino,
amino-C.sub.1-6alkyl, hydroxy-C.sub.1-6alkyl or aminocarbonyl.
12. The compound of claim 1, wherein Ar is Ar is quinolin-6-yl
substituted at the 7-position, and optionally substituted at the
2-position, with a group or groups independently selected from:
C.sub.1-6alkyl; C.sub.1-6alkoxy; hydroxy-C.sub.1-6alkoxy;
hydroxy-C.sub.1-6alkylamino; amino-C.sub.1-6alkoxy; cyclohexyloxy
wherein the cyclohexyl moiety thereof is optionally substituted
with hydroxy, amino, amino-C.sub.1-6alkyl or
hydroxy-C.sub.1-6alkyl; piperidinyl wherein the piperidinyl moiety
is optionally substituted with hydroxy, amino,
amino-C.sub.1-6alkyl, hydroxy-C.sub.1-6alkyl or aminocarbonyl;
piperidinyloxy wherein the piperidinyl moiety thereof is optionally
substituted with hydroxy, amino, amino-C.sub.1-6alkyl,
hydroxy-C.sub.1-6alkyl or aminocarbonyl; cyclopentyloxy wherein the
cyclopentyl moiety thereof is optionally substituted with hydroxy,
amino, amino-C.sub.1-6alkyl or hydroxy-C.sub.1-6alkyl; and
pyrrolidinyloxy wherein the pyrrolidinyl moiety is optionally
substituted with hydroxy, amino, amino-C.sub.1-6alkyl,
hydroxy-C.sub.1-6alkyl or aminocarbonyl.
13. The compound of claim 1, wherein Ar is heteroaryl selected
from: 7-(4-aminomethyl-piperidin-1-yl)-quinolin-6-yl;
2-(2-hydroxy-ethylamino)-7-methoxy-quinolin-6-yl;
7-(4-hydroxy-cyclohexyloxy)-quinolin-6-yl; 7-methoxy-quinolin-6-yl;
7-piperidin-1-yl-quinolin-6-yl;
7-(3-hydroxy-cyclopentyloxy)-quinolin-6-yl;
7-(3-hydroxy-1-methyl-butoxy)-quinolin-6-yl;
7-(3-hydroxy-butoxy)-quinolin-6-yl;
7-(piperidin-4-yloxy)-quinolin-6-yl;
7-(3-hydroxy-1,1-dimethyl-propoxy)-quinolin-6-yl;
7-(3-amino-propoxy)-quinolin-6-yl;
7-(3-hydroxy-cyclopentyloxy)-quinolin-6-yl;
7-(piperidin-4-yloxy)-quinolin-6-yl;
7-(3-hydroxy-propoxy)-quinolin-6-yl;
7-(pyrrolidin-3-yloxy)-quinolin-6-yl;
7-(4-hydroxymethyl-piperidin-1-yl)-quinolin-6-yl;
7-(4-aminomethyl-piperidin-1-yl)-quinolin-6-yl; quinolin-6-yl;
5-(4-hydroxymethyl-piperidin-1-yl)-2-oxo-2,3-dihydro-1H-indol-6-yl;
5-(4-hydroxymethyl-phenyl)-2-methyl-1H-indol-6-yl;
2-oxo-5-piperidin-1-yl-2,3-dihydro-1H-indol-6-yl;
6-methoxy-1H-indazol-5-yl; 5-methoxy-2-methyl-1H-indol-6-yl;
5-methoxy-1H-indol-6-yl; or
1-(3-hydroxy-propyl)-1H-benzoimidazol-2-yl.
14. The compound of claim 1, wherein each R.sup.1 is independently:
hydrogen; C.sub.1-6alkyl; C.sub.1-6alkoxy; hydroxy;
hydroxy-C.sub.1-6alkyl; C.sub.1-6alkyl-amino; amino-C.sub.1-6alkyl;
amino-C.sub.1-6alkyl-amino; hydroxy-C.sub.1-6alkylamino;
C.sub.3-6cycloalkylamino; halo; or aminocarbonyl.
15. The compound of claim 1, wherein each R.sup.1 is independently:
hydrogen; hydroxy; 2-amino-ethyl)-methyl-amino; 2-amino-ethylamino;
methy; methoxy; 2-hydroxy-ethyl)-methyl-amino; hydroxymethyl;
2-hydroxy-1-methyl-ethylamino; 2-cyclopropylamino;
2-hydroxy-ethylamino; 2,3-dihydroxy-propylamino;
3-amino-propylamino; aminocarbonyl;
2-hydroxy-ethyl)-isopropyl-amino; bromo; isobutylamino;
isopropyl-methyl-amino; 3-hydroxy-propylamino;
1-hydroxymethyl-propylamino; 2-hydroxy-ethyl;
2-acetylamino-ethylamino; 3-hydroxy-propyl; or isopropyl-amino.
16. The compound of claim 1, wherein said compound is of formula Ia
or IIa: ##STR00287## wherein: R.sup.3 and R.sup.4 each
independently is: halo; C.sub.1-6alkyl; halo-C.sub.1-6alkyl;
C.sub.1-6alkenyl; C.sub.1-6alkoxy; halo-C.sub.1-6alkoxy;
hydroxy-C.sub.1-6alkyl; hydroxy-C.sub.1-6alkylamino;
C.sub.1-6alkyl-amino; hydroxy; amino; amino-C.sub.1-6alkyl;
aminocarbonyl; hydroxy-C.sub.1-6alkoxy; hydroxy-C.sub.1-6alkenyl;
C.sub.1-6alkoxy-C.sub.1-6alkoxy; C.sub.1-6alkylsulfonyl;
C.sub.1-6alkylsulfanyl; piperidinyl wherein the piperidinyl moiety
is optionally substituted with hydroxy, amino,
amino-C.sub.1-6alkyl, hydroxy-C.sub.1-6alkyl or aminocarbonyl;
phenylaminocarbonyl; hydroxy-C.sub.1-6alkylamino; cyclohexyloxy
wherein the cyclohexyl moiety thereof is optionally substituted
with hydroxy, amino, amino-C.sub.1-6alkyl or
hydroxy-C.sub.1-6alkyl; cyclopentyloxy wherein the cyclopentyl
moiety thereof is optionally substituted with hydroxy, amino,
amino-C.sub.1-6alkyl or hydroxy-C.sub.1-6alkyl; piperidinyloxy
wherein the piperidinyl moiety thereof is optionally substituted
with hydroxy, amino, amino-C.sub.1-6alkyl, hydroxy-C.sub.1-6alkyl
or aminocarbonyl; phenyl wherein the phenyl moiety is optionally
substituted with amino, hydroxy, amino-C.sub.1-6alkyl,
hydroxy-C.sub.1-6alkyl or aminocarbonyl; pyrrolidinyl wherein the
pyrrolidinyl moiety is optionally substituted with hydroxy, amino,
amino-C.sub.1-6alkyl, hydroxy-C.sub.1-6alkyl or aminocarbonyl;
pyrrolidinyloxy wherein the pyrrolidinyl moiety is optionally
substituted with hydroxy, amino, amino-C.sub.1-6alkyl,
hydroxy-C.sub.1-6alkyl or aminocarbonyl; piperazinyl wherein the
piperazinyl moiety is optionally substituted with C.sub.1-6alkyl;
oxazol-C.sub.1-6alkoxy wherein the oxazol moiety thereof is
optionally substituted with C.sub.1-6alkyl; morpholinyl;
hydroxy-C.sub.1-6alkylaminocarbonyl; C.sub.3-6cycloalkyl; azepanyl
wherein the azepanyl moiety is optionally substituted with hydroxy,
amino, amino-C.sub.1-6alkyl, hydroxy-C.sub.1-6alkyl or
aminocarbonyl; benzyl wherein the phenyl moiety thereof is
optionally substituted with amino, hydroxy, amino-C.sub.1-6alkyl,
hydroxy-C.sub.1-6alkyl or aminocarbonyl;
C.sub.1-6alkoxycarbonyl-C.sub.1-6alkoxy; or
C.sub.1-6alkylcarbonylamino; and R.sup.1 is as recited in claim
1.
17. The compound of claim 16, wherein R.sup.4 is halo.
18. The compound of claim 1, wherein said compound is of formula Ib
or IIb: ##STR00288## wherein: R.sup.5 and R.sup.6 each
independently is: hydrogen; halo; C.sub.1-6alkyl;
halo-C.sub.1-6alkyl; C.sub.1-6alkenyl; C.sub.1-6alkoxy;
halo-C.sub.1-6alkoxy; hydroxy-C.sub.1-6alkyl;
hydroxy-C.sub.1-6alkylamino; C.sub.1-6alkyl-amino; hydroxy; amino;
amino-C.sub.1-6alkyl; aminocarbonyl; hydroxy-C.sub.1-6alkoxy;
hydroxy-C.sub.1-6alkenyl; C.sub.1-6alkoxy-C.sub.1-6alkoxy;
C.sub.1-6alkylsulfonyl; C.sub.1-6alkylsulfanyl; piperidinyl wherein
the piperidinyl moiety is optionally substituted with hydroxy,
amino, amino-C.sub.1-6alkyl, hydroxy-C.sub.1-6alkyl or
aminocarbonyl; phenylaminocarbonyl; hydroxy-C.sub.1-6alkylamino;
cyclohexyloxy wherein the cyclohexyl moiety thereof is optionally
substituted with hydroxy, amino, amino-C.sub.1-6alkyl or
hydroxy-C.sub.1-6alkyl; cyclopentyloxy wherein the cyclopentyl
moiety thereof is optionally substituted with hydroxy, amino,
amino-C.sub.1-6alkyl or hydroxy-C.sub.1-6alkyl; piperidinyloxy
wherein the piperidinyl moiety thereof is optionally substituted
with hydroxy, amino, amino-C.sub.1-6alkyl, hydroxy-C.sub.1-6alkyl
or aminocarbonyl; phenyl wherein the phenyl moiety is optionally
substituted with amino, hydroxy, amino-C.sub.1-6alkyl,
hydroxy-C.sub.1-6alkyl or aminocarbonyl; pyrrolidinyl wherein the
pyrrolidinyl moiety is optionally substituted with hydroxy, amino,
amino-C.sub.1-6alkyl, hydroxy-C.sub.1-6alkyl or aminocarbonyl;
pyrrolidinyloxy wherein the pyrrolidinyl moiety is optionally
substituted with hydroxy, amino, amino-C.sub.1-6alkyl,
hydroxy-C.sub.1-6alkyl or aminocarbonyl; piperazinyl wherein the
piperazinyl moiety is optionally substituted with C.sub.1-6alkyl;
oxazol-C.sub.1-6alkoxy wherein the oxazol moiety thereof is
optionally substituted with C.sub.1-6alkyl; morpholinyl;
hydroxy-C.sub.1-6alkylaminocarbonyl; C.sub.3-6cycloalkyl; azepanyl
wherein the azepanyl moiety is optionally substituted with hydroxy,
amino, amino-C.sub.1-6alkyl, hydroxy-C.sub.1-6alkyl or
aminocarbonyl; benzyl wherein the phenyl moiety thereof is
optionally substituted with amino, hydroxy, amino-C.sub.1-6alkyl,
hydroxy-C.sub.1-6alkyl or aminocarbonyl;
C.sub.1-6alkoxycarbonyl-C.sub.1-6alkoxy; or
C.sub.1-6alkylcarbonylamino; and R.sup.1 is as recited in claim
1.
19. A composition comprising: (a) a pharmaceutically acceptable
carrier; and (b) the compound of claim 1.
20. A method for treating arthritis, said method comprising
administering to a subject in need thereof an effective amount of
the compound of claim 1.
21. A method for treating a respiratory disorder selected from
chronic obstructive pulmonary disorder (COPD), asthma, and
bronchospasm, said method comprising administering to a subject in
need thereof an effective amount of the compound of claim 1.
22. A method for treating a disease or condition mediated by or
otherwise associated with an IRAK receptor, the method comprising
administering to a subject in need thereof an effective amount of
the compound of claim 1.
23. A method for treating a disease or condition mediated by or
otherwise associated with an SYK receptor, the method comprising
administering to a subject in need thereof an effective amount of
the compound of claim 1.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is entitled to the benefit of U.S.
provisional patent application Ser. No. 61/363,855 filed on Jul.
13, 2010 and U.S. provisional patent application Ser. No.
61/485,145 filed on May 12, 2011, the disclosures of which are
incorporated herein by reference.
FIELD OF THE INVENTION
[0002] This invention pertains to compounds useful for treatment of
autoimmune and inflammatory diseases associated with Interleukin-1
Receptor Associated Kinase (IRAK), and more particularly compounds
that modulate the function of IRAK-1 and/or IRAK-4.
BACKGROUND OF THE INVENTION
[0003] TIR-domain containing cell surface receptors such as the
Toll-like receptors and the IL-1 and IL-18 receptors play critical
roles in innate immunity and have been implicated in the
pathogenesis of autoimmunity. TLRs, for example, recognize
pathogenic or endogenous ligands and provide a requisite signal for
dendritic cell maturation and antigen presentation to T cells (13).
Similarly, the proteins that mediate signaling from these receptors
have also been shown to play important roles in the pathogenesis of
autoimmune disorders. For example mice deficient in MyD88, an
adaptor protein that directly interacts with the TIR domain are
more susceptible to bacterial, fungal and parasitic infections. In
addition, MyD88 deficient mice are resistant to experimental
autoimmune encephalomyelitis (EAE) and streptococcal cell
wall-induced arthritis (7, 11, 18).
[0004] The Interleukin-1 Receptor Associated Kinase (IRAK) family
is comprised of four family members IRAK-1, IRAK-2, IRAK-3/M, and
IRAK-4. These proteins are characterized by a typical N-terminal
death domain that mediates interaction with MyD88-family adaptor
proteins and a centrally located kinase domain. Whereas IRAK-1 and
IRAK-4 have kinase activity, IRAK-2 and IRAK-3/M are catalytically
inactive. Upon activation of their upstream cognate receptors,
IRAK-4 is thought to phosphorylate IRAK-1 resulting in the
activation and autophosphorylation of IRAK-1 and subsequent
phosphorylation of downstream substrates. The hyperphosphorylation
of IRAK-1 directs its dissociation from the receptor complex and
its eventual ubiquitylation and proteasomal degradation.
Phosphorylation of downstream substrates such as Pellino-2
ultimately leads to the activation of the MAPKs such as p38 and
c-Jun N-terminal kinase (JNK) and NF-kB followed by production of
pro-inflammatory cytokines, chemokines, and destructive enzymes (8,
10, 22).
[0005] The role of IRAK-1 and IRAK-4 in innate immunity and in the
pathogenesis of autoimmune diseases is emerging. Patients with
destabilizing or null mutations in IRAK-4 demonstrate defects in
TLR signaling and the production of pro-inflammatory cytokines such
as IL-1 and TNF (2, 3, 5, 17), as well as antiviral cytokines such
as IFN.alpha. and IFN.beta. (27). These patients demonstrate an
increased susceptibility to gram-positive bacterial infections
although they are generally resistant to gram-negative bacterial,
viral, and fungal infections. Similarly, IRAK-4 deficient mice have
defects in TLR- and IL-1-mediated cytokine production and increased
susceptibility to infection. IRAK-1 deficient mice demonstrated a
loss of responsiveness to lipopolysaccharides (LPS), IL-1, IL-18 as
well as impaired Th1 development (9). These mice were resistant to
experimental autoimmune encephalomyelitis, exhibiting little or no
CNS inflammation.
[0006] Accordingly, compounds that modulate the function of IRAK-1
and/or IRAK-4 represent an attractive approach to the development
of therapeutic agents for the treatment of inflammatory, cell
proliferative and immune-related conditions and diseases associated
with IRAK-mediated signal transduction, such as rheumatoid
arthritis, inflammatory bowel disease, multiple sclerosis,
diabetes, obesity, allergic disease, psoriasis, asthma, graft
rejection, cancer and sepsis.
[0007] Activation of SYK tyrosine kinase is an important in the
signally pathways following the activation of mast cells (J. A.
Taylor et al., Molec. and Cell Biol., 1995, 15, 4149). SYK kinase
activation and activity is considered for Fc epsilon RI
(high-affinity IgE receptor)-mediated release of mediators from
mast cells Inhibitors of SYK kinase can thus block the release of
allergic and pro-inflammatory mediators and cytokines, and are
potentially useful for treatment of inflammatory and allergic
disorders such as asthma, chronic obstructive pulmonary disease
(COPD), adult respiratory distress syndrome (ARDS), ulcerative
colitis, Crohn's disease, bronchitis, conjunctivitis, psoriasis,
scleroderma, urticaria, dermatitis and allergic rhinitis.
SUMMARY OF THE INVENTION
[0008] The invention provides compounds of the formula I or formula
II:
##STR00002##
or a pharmaceutically acceptable salt thereof, wherein:
[0009] X is N or CH
[0010] m is 1 or 2;
[0011] Ar is: [0012] optionally substituted aryl; or [0013]
optionally substituted heteroaryl;
[0014] R.sup.1 is: [0015] hydrogen; [0016] C.sub.1-6alkyl; [0017]
C.sub.1-6alkoxy; [0018] hydroxy; [0019] hydroxy-C.sub.1-6alkyl;
[0020] C.sub.1-6alkyl-amino; [0021] amino-C.sub.1-6alkyl; [0022]
amino-C.sub.1-6alkyl-amino; [0023] hydroxy-C.sub.1-6alkylamino
[0024] C.sub.3-6cycloalkylamino; [0025]
amino-C.sub.3-6cycloalkylamino; [0026]
amino-C.sub.3-6heterocycloalkylamino; [0027] aminocarbonyl; [0028]
halo; [0029] hydroxy-C.sub.1-6alkyl; or [0030]
hydroxy-C.sub.1-6alkoxy; and
[0031] R.sup.2 is: [0032] hydrogen; or [0033] C.sub.1-6alkyl.
[0034] The invention also provides and pharmaceutical compositions
comprising the compounds, methods of using the compounds, and
methods of preparing the compounds.
DETAILED DESCRIPTION OF THE INVENTION
Definitions
[0035] Unless otherwise stated, the following terms used in this
application, including the specification and claims, have the
definitions given below. It must be noted that, as used in the
specification and the appended claims, the singular forms "a",
"an," and "the" include plural referents unless the context clearly
dictates otherwise.
[0036] "Alkyl" means the monovalent linear or branched saturated
hydrocarbon moiety, consisting solely of carbon and hydrogen atoms,
having from one to twelve carbon atoms. "Lower alkyl" refers to an
alkyl group of one to six carbon atoms, i.e. C.sub.1-C.sub.6alkyl.
Examples of alkyl groups include, but are not limited to, methyl,
ethyl, propyl, isopropyl, isobutyl, sec-butyl, tert-butyl, pentyl,
n-hexyl, octyl, dodecyl, and the like.
[0037] "Alkenyl" means a linear monovalent hydrocarbon radical of
two to six carbon atoms or a branched monovalent hydrocarbon
radical of three to six carbon atoms, containing at least one
double bond, e.g., ethenyl, propenyl, and the like.
[0038] "Alkynyl" means a linear monovalent hydrocarbon radical of
two to six carbon atoms or a branched monovalent hydrocarbon
radical of three to six carbon atoms, containing at least one
triple bond, e.g., ethynyl, propynyl, and the like.
[0039] "Alkylene" means a linear saturated divalent hydrocarbon
radical of one to six carbon atoms or a branched saturated divalent
hydrocarbon radical of three to six carbon atoms, e.g., methylene,
ethylene, 2,2-dimethylethylene, propylene, 2-methylpropylene,
butylene, pentylene, and the like.
[0040] "Alkoxy" and "alkyloxy", which may be used interchangeably,
mean a moiety of the formula --OR, wherein R is an alkyl moiety as
defined herein. Examples of alkoxy moieties include, but are not
limited to, methoxy, ethoxy, isopropoxy, and the like.
[0041] "Alkoxyalkyl" means a moiety of the formula
R.sup.a--O--R.sup.b--, where R.sup.a is alkyl and R.sup.b is
alkylene as defined herein. Exemplary alkoxyalkyl groups include,
by way of example, 2-methoxyethyl, 3-methoxypropyl,
1-methyl-2-methoxyethyl, 1-(2-methoxyethyl)-3-methoxypropyl, and
1-(2-methoxyethyl)-3-methoxypropyl.
[0042] "Alkoxyalkoxy" means a group of the formula --O--R--R'
wherein R is alkylene and R' is alkoxy as defined herein.
[0043] "Alkylcarbonyl" means a moiety of the formula --C(O)--R,
wherein R is alkyl as defined herein.
[0044] "Alkoxycarbonyl" means a group of the formula --C(O)--R
wherein R is alkoxy as defined herein.
[0045] "Alkylcarbonylalkyl" means a group of the formula
--R--C(O)--R wherein R is alkylene and
[0046] R' is alkyl as defined herein.
[0047] "Alkoxycarbonylalkyl" means a group of the formula
--R--C(O)--R wherein R is alkylene and R' is alkoxy as defined
herein.
[0048] "Alkoxycarbonylalkoxy" means a group of the formula
--O--R--C(O)--R' wherein R is alkylene and R' is alkoxy as defined
herein.
[0049] "Alkylcarbonylamino" means a group of the formula
--NRR'--C(O)--R'' wherein R is hydrogen or alkyl, R' is alkylene
and R'' is alkyl as defined herein.
[0050] "Hydroxycarbonylalkoxy" means a group of the formula
--O--R--C(O)--OH wherein R is alkylene as defined herein.
[0051] "Alkylaminocarbonylalkoxy" means a group of the formula
--O--R--C(O)--NHR' wherein R is alkylene and R' is alkyl as defined
herein.
[0052] "Dialkylaminocarbonylalkoxy" means a group of the formula
--O--R--C(O)--NR'R'' wherein R is alkylene and R' and R'' are alkyl
as defined herein.
[0053] "Alkylaminoalkoxy" means a group of the formula --O--R--NHR'
wherein R is alkylene and R' is alkyl as defined herein.
[0054] "Dialkylaminoalkoxy" means a group of the formula
--O--R--NR'R' wherein R is alkylene and R' and R'' are alkyl as
defined herein.
[0055] "Alkylsulfonyl" means a moiety of the formula --SO.sub.2--R,
wherein R is alkyl as defined herein.
[0056] "Alkylsulfonylalkyl" means a moiety of the formula
--R'--SO.sub.2--R'' where R' is alkylene and R'' is alkyl as
defined herein.
[0057] "Alkylsulfonylalkoxy" means a group of the formula
--O--R--SO.sub.2--R' wherein R is alkylene and R' is alkyl as
defined herein.
[0058] "Amino" means a moiety of the formula --NRR' wherein R and
R' each independently is hydrogen or alkyl as defined herein.
"Amino" thus includes "alkylamino" (where one of R and R' is alkyl
and the other is hydrogen) and "dialkylamino" (where R and R' are
both alkyl.
[0059] "Hydroxyalkylamino" means a moiety of the formula --NRR'
wherein R and R' is hydrogen or alkyl and R' is hydroxyalkyl as
defined herein.
[0060] "Aminocarbonyl" means a group of the formula --C(O)--R
wherein R is amino as defined herein.
[0061] "Alkoxyamino" means a moiety of the formula --NR--OR'
wherein R is hydrogen or alkyl and R' is alkyl as defined
herein.
[0062] "Alkylsulfanyl" means a moiety of the formula --SR wherein R
is alkyl as defined herein.
[0063] "Aminoalkyl" means a group --R--R' wherein R' is amino and R
is alkylene as defined herein. "Aminoalkyl" includes aminomethyl,
aminoethyl, 1-aminopropyl, 2-aminopropyl, and the like. The amino
moiety of "aminoalkyl" may be substituted once or twice with alkyl
to provide "alkylaminoalkyl" and "dialkylaminoalkyl" respectively.
"Alkylaminoalkyl" includes methylaminomethyl, methylaminoethyl,
methylaminopropyl, ethylaminoethyl and the like.
[0064] "Dialkylaminoalkyl" includes dimethylaminomethyl,
dimethylaminoethyl, dimethylaminopropyl,
N-methyl-N-ethylaminoethyl, and the like.
[0065] "Aminoalkoxy" means a group --OR--R' wherein R' is amino and
R is alkylene as defined herein.
[0066] "Alkylsulfonylamido" means a moiety of the formula
--NR'SO.sub.2--R wherein R is alkyl and R' is hydrogen or
alkyl.
[0067] "Aminocarbonyloxyalkyl" or "carbamylalkyl" means a group of
the formula --R--O--C(O)--NR'R'' wherein R is alkylene and R', R''
each independently is hydrogen or alkyl as defined herein.
[0068] "Alkynylalkoxy" means a group of the formula --O--R--R'
wherein R is alkylene and R' is alkynyl as defined herein.
[0069] "Aryl" means a monovalent cyclic aromatic hydrocarbon moiety
consisting of a mono-, bi- or tricyclic aromatic ring. The aryl
group can be optionally substituted as defined herein. Examples of
aryl moieties include, but are not limited to, phenyl, naphthyl,
phenanthryl, fluorenyl, indenyl, pentalenyl, azulenyl, oxydiphenyl,
biphenyl, methylenediphenyl, aminodiphenyl, diphenylsulfidyl,
diphenylsulfonyl, diphenylisopropylidenyl, benzodioxanyl,
benzofuranyl, benzodioxylyl, benzopyranyl, benzoxazinyl,
benzoxazinonyl, benzopiperadinyl, benzopiperazinyl,
benzopyrrolidinyl, benzomorpholinyl, methylenedioxyphenyl,
ethylenedioxyphenyl, and the like, including partially hydrogenated
derivatives thereof, each being optionally substituted.
[0070] "Arylalkyl" and "Aralkyl", which may be used
interchangeably, mean a radical-R.sup.aR.sup.b where R.sup.a is an
alkylene group and R.sup.b is an aryl group as defined herein;
e.g., phenylalkyls such as benzyl, phenylethyl,
3-(3-chlorophenyl)-2-methylpentyl, and the like are examples of
arylalkyl.
[0071] "Arylsulfonyl" means a group of the formula --SO.sub.2--R
wherein R is aryl as defined herein.
[0072] "Aryloxy" means a group of the formula --O--R wherein R is
aryl as defined herein.
[0073] "Aralkyloxy" means a group of the formula --O--R--R''
wherein R is alkylene and R' is aryl as defined herein.
[0074] "Carboxy" or "hydroxycarbonyl", which may be used
interchangeably, means a group of the formula --C(O)--OH.
[0075] "Cyanoalkyl" means a moiety of the formula --R'--R'', where
R' is alkylene as defined herein and R'' is cyano or nitrile.
[0076] "Cycloalkyl" means a monovalent saturated carbocyclic moiety
consisting of mono- or bicyclic rings. Preferred cycloalkyl are
unsubstituted or substituted with alkyl. Cycloalkyl can optionally
be substituted with one or more substituents, wherein each
substituent is independently hydroxy, alkyl, alkoxy, halo,
haloalkyl, amino, monoalkylamino, or dialkylamino, unless otherwise
specifically indicated. Examples of cycloalkyl moieties include,
but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl, cycloheptyl, and the like, including partially
unsaturated (cycloalkenyl) derivatives thereof.
[0077] "Cycloalkylalkyl" means a moiety of the formula --R'--R'',
where R' is alkylene and R'' is cycloalkyl as defined herein.
[0078] "Cycloalkylalkoxy" means a group of the formula --O--R--R'
wherein R is alkylene and R' is cycloalkyl as defined herein.
[0079] "Heteroalkyl" means an alkyl radical as defined herein
wherein one, two or three hydrogen atoms have been replaced with a
substituent independently selected from the group consisting of
--OR.sup.a, --NR.sup.bR.sup.c and --S(O)--R.sup.d (where n is an
integer from 0 to 2), with the understanding that the point of
attachment of the heteroalkyl radical is through a carbon atom,
wherein R.sup.a is hydrogen, acyl, alkyl, cycloalkyl, or
cycloalkylalkyl; R.sup.b and R.sup.c are independently of each
other hydrogen, acyl, alkyl, cycloalkyl, or cycloalkylalkyl; and
when n is 0, R.sup.d is hydrogen, alkyl, cycloalkyl, or
cycloalkylalkyl, and when n is 1 or 2, R.sup.d is alkyl,
cycloalkyl, cycloalkylalkyl, amino, acylamino, monoalkylamino, or
dialkylamino. Representative examples include, but are not limited
to, 2-hydroxyethyl, 3-hydroxypropyl,
2-hydroxy-1-hydroxymethylethyl, 2,3-dihydroxypropyl,
1-hydroxymethylethyl, 3-hydroxybutyl, 2,3-dihydroxybutyl,
2-hydroxy-1-methylpropyl, 2-aminoethyl, 3-aminopropyl,
2-methylsulfonylethyl, aminosulfonylmethyl, aminosulfonylethyl,
aminosulfonylpropyl, methylaminosulfonylmethyl,
methylaminosulfonylethyl, methylaminosulfonylpropyl, and the
like.
[0080] "Heteroaryl" means a monocyclic or bicyclic radical of 5 to
12 ring atoms having at least one aromatic ring containing one,
two, or three ring heteroatoms selected from N, O, or S, the
remaining ring atoms being C, with the understanding that the
attachment point of the heteroaryl radical will be on an aromatic
ring. The heteroaryl ring may be optionally substituted as defined
herein. Examples of heteroaryl moieties include, but are not
limited to, optionally substituted imidazolyl, oxazolyl,
isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl,
pyrazinyl, thienyl, benzothienyl, thiophenyl, furanyl, pyranyl,
pyridyl, pyrrolyl, pyrazolyl, pyrimidyl, quinolinyl, isoquinolinyl,
benzofuryl, benzothiophenyl, benzothiopyranyl, benzimidazolyl,
benzooxazolyl, benzooxadiazolyl, benzothiazolyl, benzothiadiazolyl,
benzopyranyl, indolyl, isoindolyl, triazolyl, triazinyl,
quinoxalinyl, purinyl, quinazolinyl, quinolizinyl, naphthyridinyl,
pteridinyl, carbazolyl, azepinyl, diazepinyl, acridinyl and the
like, including partially hydrogenated derivatives thereof, each
optionally substituted.
[0081] "Heteroarylalkyl" or "heteroaralkyl" means a group of the
formula --R--R' wherein R is alkylene and R' is heteroaryl as
defined herein.
[0082] "Heteroarylsulfonyl" means a group of the formula
--SO.sub.2--R wherein R is heteroaryl as defined herein.
[0083] "Heteroaryloxy" means a group of the formula --O--R wherein
R is heteroaryl as defined herein.
[0084] "Heteroaralkyloxy" means a group of the formula --O--R--R''
wherein R is alkylene and R' is heteroaryl as defined herein.
[0085] The terms "halo", "halogen" and "halide", which may be used
interchangeably, refer to a substituent fluoro, chloro, bromo, or
iodo.
[0086] "Haloalkyl" means alkyl as defined herein in which one or
more hydrogen has been replaced with same or different halogen.
Exemplary haloalkyls include --CH.sub.2Cl, --CH.sub.2CF.sub.3,
--CH.sub.2CCl.sub.3, perfluoroalkyl (e.g., --CF.sub.3), and the
like.
[0087] "Haloalkoxy" means a moiety of the formula --OR, wherein R
is a haloalkyl moiety as defined herein. An exemplary haloalkoxy is
difluoromethoxy.
[0088] "Heterocycloamino" means a saturated ring wherein at least
one ring atom is N, NH or N-alkyl and the remaining ring atoms form
an alkylene group.
[0089] "Heterocyclyl" means a monovalent saturated moiety,
consisting of one to three rings, incorporating one, two, or three
or four heteroatoms (chosen from nitrogen, oxygen or sulfur). The
heterocyclyl ring may be optionally substituted as defined herein.
Examples of heterocyclyl moieties include, but are not limited to,
optionally substituted piperidinyl, piperazinyl, homopiperazinyl,
azepinyl, pyrrolidinyl, pyrazolidinyl, imidazolinyl,
imidazolidinyl, pyridinyl, pyridazinyl, pyrimidinyl, oxazolidinyl,
isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl,
quinuclidinyl, quinolinyl, isoquinolinyl, benzimidazolyl,
thiadiazolylidinyl, benzothiazolidinyl, benzoazolylidinyl,
dihydrofuryl, tetrahydrofuryl, dihydropyranyl, tetrahydropyranyl,
thiamorpholinyl, thiamorpholinylsulfoxide, thiamorpholinylsulfone,
dihydroquinolinyl, dihydrisoquinolinyl, tetrahydroquinolinyl,
tetrahydrisoquinolinyl, and the like.
[0090] "Heterocyclylalkyl" means a moiety of the formula --R--R'
wherein R is alkylene and R' is heterocyclyl as defined herein.
[0091] "Heterocyclyloxy" means a moiety of the formula --OR wherein
R is heterocyclyl as defined herein.
[0092] "Heterocyclylalkoxy" means a moiety of the formula --OR--R'
wherein R is alkylene and
[0093] R' is heterocyclyl as defined herein.
[0094] "Hydroxyalkoxy" means a moiety of the formula --OR wherein R
is hydroxyalkyl as defined herein.
[0095] "Hydroxyalkenyl" means a moiety of the formula --R--OH
wherein R is alkenyl as defined herein.
[0096] "Hydroxyalkylamino" means a moiety of the formula --NR--R'
wherein R is hydrogen or alkyl and R' is hydroxyalkyl as defined
herein.
[0097] "Hydroxyalkylaminocarbonyl" means a moiety of the formula
--C(O)NR--R' wherein R is hydrogen or alkyl and R' is hydroxyalkyl
as defined herein.
[0098] "Hydroxyalkylaminoalkyl" means a moiety of the formula
--R--NR'--R'' wherein R is alkylene, R' is hydrogen or alkyl, and
R'' is hydroxyalkyl as defined herein.
[0099] "Hydroxycarbonylalkyl" or "carboxyalkyl" means a group of
the formula --R--(CO)--OH where R is alkylene as defined
herein.
[0100] "Hydroxycarbonylalkoxy" means a group of the formula
--O--R--C(O)--OH wherein R is alkylene as defined herein.
[0101] "Hydroxyalkyloxycarbonylalkyl" or
"hydroxyalkoxycarbonylalkyl" means a group of the formula
--R--C(O)--O--R--OH wherein each R is alkylene and may be the same
or different.
[0102] "Hydroxyalkyl" means an alkyl moiety as defined herein,
substituted with one or more, such as one, two or three hydroxy
groups, provided that the same carbon atom does not carry more than
one hydroxy group. Representative examples include, but are not
limited to, hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl,
3-hydroxypropyl, 1-(hydroxymethyl)-2-methylpropyl, 2-hydroxybutyl,
3-hydroxybutyl, 4-hydroxybutyl, 2,3-dihydroxypropyl,
2-hydroxy-1-hydroxymethylethyl, 2,3-dihydroxybutyl,
3,4-dihydroxybutyl and 2-(hydroxymethyl)-3-hydroxypropyl
[0103] "Hydroxycycloalkyl" means a cycloalkyl moiety as defined
herein wherein one, two or three hydrogen atoms in the cycloalkyl
radical have been replaced with a hydroxy substituent.
Representative examples include, but are not limited to, 2-, 3-, or
4-hydroxycyclohexyl, and the like.
[0104] "Alkoxy hydroxyalkyl" and "hydroxy alkoxyalkyl", which may
be used interchangeably, means an alkyl as defined herein that is
substituted at least once with hydroxy and at least once with
alkoxy. "Alkoxy hydroxyalkyl" and "hydroxy alkoxyalkyl" thus
encompass, for example, 2-hydroxy-3-methoxy-propan-1-yl and the
like.
[0105] "Phenylaminocarbonyl" means a group of the formula
--C(O)--NR--R' wherein R is hydrogen or alkyl as defined herein and
R' is phenyl.
[0106] "Urea" or "ureido" means a group of the formula
--NR'--C(O)--NR''R''' wherein R', R'' and
[0107] R''' each independently is hydrogen or alkyl.
[0108] "Carbamate" means a group of the formula --O--C(O)--NR'R''
wherein R' and R'' each independently is hydrogen or alkyl.
[0109] "Carboxy" means a group of the formula --O--C(O)--OH.
[0110] "Sulfonamido" means a group of the formula
--SO.sub.2--NR'R'' wherein R', R'' and R''' each independently is
hydrogen or alkyl.
[0111] "Optionally substituted", when used in association with
"aryl", phenyl", "heteroaryl", "cycloalkyl" or "heterocyclyl" means
an aryl, phenyl, heteroaryl, cycloalkyl or heterocyclyl which is
optionally substituted independently with one to four substituents,
preferably one or two substituents selected from alkyl, cycloalkyl,
cycloalkylalkyl, heteroalkyl, hydroxyalkyl, halo, nitro, cyano,
hydroxy, alkoxy, amino, acylamino, mono-alkylamino, di-alkylamino,
haloalkyl, haloalkoxy, heteroalkyl, --COR, --SO.sub.2R (where R is
hydrogen, alkyl, phenyl or phenylalkyl), --(CR'R'').sub.n--COOR
(where n is an integer from 0 to 5, R' and R'' are independently
hydrogen or alkyl, and R is hydrogen, alkyl, cycloalkyl,
cycloalkylalkyl, phenyl or phenylalkyl), or
--(CR'R'').sub.n--CONR.sup.aR.sup.b (where n is an integer from 0
to 5, R' and R'' are independently hydrogen or alkyl, and R.sup.a
and R.sup.b are, independently of each other, hydrogen, alkyl,
cycloalkyl, cycloalkylalkyl, phenyl or phenylalkyl). Certain
preferred optional substituents for "aryl", phenyl", "heteroaryl",
"cycloalkyl" or "heterocyclyl" include alkyl, halo, haloalkyl,
alkoxy, cyano, amino and alkylsulfonyl. More preferred substituents
are methyl, fluoro, chloro, trifluoromethyl, methoxy, amino and
methanesulfonyl.
[0112] "Leaving group" means the group with the meaning
conventionally associated with it in synthetic organic chemistry,
i.e., an atom or group displaceable under substitution reaction
conditions. Examples of leaving groups include, but are not limited
to, halogen, alkane- or arylenesulfonyloxy, such as
methanesulfonyloxy, ethanesulfonyloxy, thiomethyl,
benzenesulfonyloxy, tosyloxy, and thienyloxy, dihalophosphinoyloxy,
optionally substituted benzyloxy, isopropyloxy, acyloxy, and the
like.
[0113] "Modulator" means a molecule that interacts with a target.
The interactions include, but are not limited to, agonist,
antagonist, and the like, as defined herein.
[0114] "Optional" or "optionally" means that the subsequently
described event or circumstance may but need not occur, and that
the description includes instances where the event or circumstance
occurs and instances in which it does not.
[0115] "Disease" and "Disease state" means any disease, condition,
symptom, disorder or indication.
[0116] "Inert organic solvent" or "inert solvent" means the solvent
is inert under the conditions of the reaction being described in
conjunction therewith, including for example, benzene, toluene,
acetonitrile, tetrahydrofuran, N,N-dimethylformamide, chloroform,
methylene chloride or dichloromethane, dichloroethane, diethyl
ether, ethyl acetate, acetone, methyl ethyl ketone, methanol,
ethanol, propanol, isopropanol, tert-butanol, dioxane, pyridine,
and the like. Unless specified to the contrary, the solvents used
in the reactions of the present invention are inert solvents.
[0117] "Pharmaceutically acceptable" means that which is useful in
preparing a pharmaceutical composition that is generally safe,
non-toxic, and neither biologically nor otherwise undesirable and
includes that which is acceptable for veterinary as well as human
pharmaceutical use.
[0118] "Pharmaceutically acceptable salts" of a compound means
salts that are pharmaceutically acceptable, as defined herein, and
that possess the desired pharmacological activity of the parent
compound. Such salts include:
[0119] acid addition salts formed with inorganic acids such as
hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,
phosphoric acid, and the like; or formed with organic acids such as
acetic acid, benzenesulfonic acid, benzoic, camphorsulfonic acid,
citric acid, ethanesulfonic acid, fumaric acid, glucoheptonic acid,
gluconic acid, glutamic acid, glycolic acid, hydroxynaphtoic acid,
2-hydroxyethanesulfonic acid, lactic acid, maleic acid, malic acid,
malonic acid, mandelic acid, methanesulfonic acid, muconic acid,
2-naphthalenesulfonic acid, propionic acid, salicylic acid,
succinic acid, tartaric acid, p-toluenesulfonic acid,
trimethylacetic acid, and the like; or
[0120] salts formed when an acidic proton present in the parent
compound either is replaced by a metal ion, e.g., an alkali metal
ion, an alkaline earth ion, or an aluminum ion; or coordinates with
an organic or inorganic base. Acceptable organic bases include
diethanolamine, ethanolamine, N-methylglucamine, triethanolamine,
tromethamine, and the like. Acceptable inorganic bases include
aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium
carbonate and sodium hydroxide.
[0121] The preferred pharmaceutically acceptable salts are the
salts formed from acetic acid, hydrochloric acid, sulphuric acid,
methanesulfonic acid, maleic acid, phosphoric acid, tartaric acid,
citric acid, sodium, potassium, calcium, zinc, and magnesium.
[0122] It should be understood that all references to
pharmaceutically acceptable salts include solvent addition forms
(solvates) or crystal forms (polymorphs) as defined herein, of the
same acid addition salt.
[0123] "Protective group" or "protecting group" means the group
which selectively blocks one reactive site in a multifunctional
compound such that a chemical reaction can be carried out
selectively at another unprotected reactive site in the meaning
conventionally associated with it in synthetic chemistry. Certain
processes of this invention rely upon the protective groups to
block reactive nitrogen and/or oxygen atoms present in the
reactants. For example, the terms "amino-protecting group" and
"nitrogen protecting group" are used interchangeably herein and
refer to those organic groups intended to protect the nitrogen atom
against undesirable reactions during synthetic procedures.
Exemplary nitrogen protecting groups include, but are not limited
to, trifluoroacetyl, acetamido, benzyl (Bn), benzyloxycarbonyl
(carbobenzyloxy, CBZ), p-methoxybenzyloxycarbonyl,
p-nitrobenzyloxycarbonyl, tert-butoxycarbonyl (BOC), and the like.
The artisan in the art will know how to chose a group for the ease
of removal and for the ability to withstand the following
reactions.
[0124] "Solvates" means solvent additions forms that contain either
stoichiometric or non stoichiometric amounts of solvent. Some
compounds have a tendency to trap a fixed molar ratio of solvent
molecules in the crystalline solid state, thus forming a solvate.
If the solvent is water the solvate formed is a hydrate, when the
solvent is alcohol, the solvate formed is an alcoholate. Hydrates
are formed by the combination of one or more molecules of water
with one of the substances in which the water retains its molecular
state as H.sub.2O, such combination being able to form one or more
hydrate.
[0125] "Subject" means mammals and non-mammals. Mammals means any
member of the mammalia class including, but not limited to, humans;
non-human primates such as chimpanzees and other apes and monkey
species; farm animals such as cattle, horses, sheep, goats, and
swine; domestic animals such as rabbits, dogs, and cats; laboratory
animals including rodents, such as rats, mice, and guinea pigs; and
the like. Examples of non-mammals include, but are not limited to,
birds, and the like. The term "subject" does not denote a
particular age or sex.
[0126] "Inflammatory disease" means disease states or indications
that are accompanied by inflammatory, allergic, and/or
proliferative processes and can include:
(i) Lung diseases: chronic, obstructive lung diseases of any
genesis, particularly bronchial asthma and chronic obstructive
pulmonary disease (COPD); adult respiratory distress syndrome
(ARDS); bronchiectasis; bronchitis of various genesis; all forms of
restrictive lung diseases, particularly allergic alveolitis; all
forms of lung edema, particularly toxic lung edema; all forms of
interstitial lung diseases of any genesis, e.g., radiation
pneumonitis; and sarcoidosis and granulomatoses, particularly Boeck
disease. (ii) Rheumatic diseases or autoimmune diseases or joint
diseases: all forms of rheumatic diseases, especially rheumatoid
arthritis, acute rheumatic fever, and polymyalgia rheumatica;
reactive arthritis; rheumatic soft tissue diseases; inflammatory
soft tissue diseases of other genesis; arthritic symptoms in
degenerative joint diseases (arthroses); traumatic arthritis;
collagenoses of any genesis, e.g., systemic lupus erythematosus,
scleroderma, polymyositis, dermatomyositis, Sjogren syndrome, Still
disease, and Felty syndrome; (iii) Allergic diseases: all forms of
allergic reactions, e.g., angioneurotic edema, hay fever, insect
bites, allergic reactions to drugs, blood derivatives, contrast
agents, etc., anaphylactic shock (anaphylaxis), urticaria,
angioneurotic edema, and contact dermatitis; (iv) Vasculitis
diseases: panarteritis nodosa, polyarteritis nodosa, arteritis
temporalis, Wegner granulomatosis, giant cell arthritis, and
erythema nodosum; (v) Dermatological diseases: atopic dermatitis,
particularly in children; psoriasis; pityriasis rubra pilaris;
erythematous diseases triggered by various noxa, e.g., rays,
chemicals, burns, etc.; bullous dermatoses; diseases of the
lichenoid complex; pruritus (e.g., of allergic genesis); seborrheic
dermatitis; rosacea; pemphigus vulgaris; erythema multiforme
exudativum; balanitis; vulvitis; hair loss, such as occurs in
alopecia greata; and cutaneous T cell lymphomas; (vi) Renal
diseases: nephrotic syndrome; and all types of nephritis, e.g.,
glomerulonephritis; (vii) Hepatic diseases: acute liver cell
disintegration; acute hepatitis of various genesis, e.g., viral,
toxic, drug-induced; and chronically aggressive and/or chronically
intermittent hepatitis; (viii) Gastrointestinal diseases:
inflammatory bowel diseases, e.g., regional enteritis (Crohn
disease), colitis ulcerosa; gastritis; peptic esophagitis
(refluxoesophagitis); and gastroenteritis of other genesis, e.g.,
nontropical sprue; (ix) Proctological diseases: anal eczema;
fissures; hemorrhoids; and idiopathic proctitis; (x) Eye diseases:
allergic keratitis, uveitis, or iritis; conjunctivitis;
blepharitis; neuritis nervi optici; choroiditis; and sympathetic
ophthalmia; (xi) Diseases of the ear, nose, and throat (ENT) area:
allergic rhinitis or hay fever; otitis externa, e.g., caused by
contact eczema, infection, etc.; and otitis media; (xii)
Neurological diseases: brain edema, particularly tumor-related
brain edema; multiple sclerosis; acute encephalomyelitis;
meningitis; acute spinal cord injury; stroke; and various forms of
seizures, e.g., nodding spasms; (xiii) Blood diseases: acquired
hemolytic anemia; and idiopathic thrombocytopenia; (xiv) Tumor
diseases: acute lymphatic leukemia; malignant lymphoma;
lymphogranulomatoses; lymphosarcoma; extensive metastases,
particularly in mammary, bronchial, and prostatic carcinoma; (xv)
Endocrine diseases: endocrine ophthalmopathy; endocrine
orbitopathia; thyrotoxic crisis; Thyroiditis de Quervain; Hashimoto
thyroiditis; Morbus Basedow; granulomatous thyroiditis; struma
lymphomatosa; and Grave disease; (xvi) Organ and tissue
transplantations and graft-versus-host diseases; (xvii) Severe
states of shock, e.g., septic shock, anaphylactic shock, and
systemic inflammatory response syndrome (SIRS); (xviii)
Substitution therapy in: congenital primary adrenal insufficiency,
e.g., adrenogenital syndrome; acquired primary adrenal
insufficiency, e.g., Addison disease, autoimmune adrenalitis,
post-infection, tumors, metastases, etc.; congenital secondary
adrenal insufficiency, e.g., congenital hypopituitarism; and
acquired secondary adrenal insufficiency, e.g., post-infection,
tumors, metastases, etc.; (xix) Pain of inflammatory genesis, e.g.,
lumbago; and (xx) Various other disease-states or conditions
including type I diabetes (insulin-dependent diabetes),
osteoarthritis, Guillain-Barre syndrome, restenosis following
percutaneous transluminal coronary angioplasty, Alzheimer disease,
acute and chronic pain, atherosclerosis, reperfusion injury, bone
resorption diseases, congestive heart failure, myocardial
infarction, thermal injury, multiple organ injury secondary to
trauma, acute purulent meningitis, necrotizing enterocolitis and
syndromes associated with hemodialysis, leukopheresis, and
granulocyte transfusion.
[0127] "Arthritis" means diseases or conditions damage to joints of
the body and pain associated with such joint damage. Arthritis
includes rheumatoid arthritis, osteoarthritis, psoriatic arthritis,
septic arthritis and gouty arthritis.
[0128] "Pain" includes, without limitation, inflammatory pain;
surgical pain; visceral pain; dental pain; premenstrual pain;
central pain; pain due to burns; migraine or cluster headaches;
nerve injury; neuritis; neuralgias; poisoning; ischemic injury;
interstitial cystitis; cancer pain; viral, parasitic or bacterial
infection; post-traumatic injury; or pain associated with irritable
bowel syndrome.
[0129] "Therapeutically effective amount" means an amount of a
compound that, when administered to a subject for treating a
disease state, is sufficient to effect such treatment for the
disease state. The "therapeutically effective amount" will vary
depending on the compound, disease state being treated, the
severity or the disease treated, the age and relative health of the
subject, the route and form of administration, the judgment of the
attending medical or veterinary practitioner, and other
factors.
[0130] The terms "those defined above" and "those defined herein"
when referring to a variable incorporates by reference the broad
definition of the variable as well as preferred, more preferred and
most preferred definitions, if any.
[0131] "Treating" or "treatment" of a disease state includes, inter
alia, inhibiting the disease state, i.e., arresting the development
of the disease state or its clinical symptoms, and/or relieving the
disease state, i.e., causing temporary or permanent regression of
the disease state or its clinical symptoms.
[0132] The terms "treating", "contacting", and "reacting" when
referring to a chemical reaction means adding or mixing two or more
reagents under appropriate conditions to produce the indicated
and/or the desired product. It should be appreciated that the
reaction which produces the indicated and/or the desired product
may not necessarily result directly from the combination of two
reagents which were initially added, i.e., there may be one or more
intermediates which are produced in the mixture which ultimately
leads to the formation of the indicated and/or the desired
product.
Nomenclature and Structures
[0133] In general, the nomenclature used in this application is
based on AUTONOM.TM. v.4.0, a Beilstein Institute computerized
system for the generation of IUPAC systematic nomenclature.
Chemical structures shown herein were prepared using ISIS.RTM.
version 2.2. Any open valency appearing on a carbon, oxygen sulfur
or nitrogen atom in the structures herein indicates the presence of
a hydrogen atom unless indicated otherwise. Where a
nitrogen-containing heteroaryl ring is shown with an open valency
on a nitrogen atom, and variables such as R.sup.a, R.sup.b or
R.sup.c are shown on the heteroaryl ring, such variables may be
bound or joined to the open valency nitrogen. Where a chiral center
exists in a structure but no specific stereochemistry is shown for
the chiral center, both enantiomers associated with the chiral
center are encompassed by the structure. Where a structure shown
herein may exist in multiple tautomeric forms, all such tautomers
are encompassed by the structure. The atoms represented in the
structures herein are intended to encompass all naturally occurring
isotopes of such atoms. Thus, for example, the hydrogen atoms
represented herein are meant to include deuterium and tritium, and
the carbon atoms are meant to include C.sup.13 and C.sup.14
isotopes.
[0134] All patents and publications identified herein are
incorporated herein by reference in their entirety.
Compounds of the Invention
[0135] The invention provides compounds of the formula I or formula
II:
##STR00003##
or a pharmaceutically acceptable salt thereof, wherein:
[0136] X is N or CH
[0137] m is 1 or 2;
[0138] Ar is: [0139] optionally substituted aryl; or [0140]
optionally substituted heteroaryl;
[0141] R.sup.1 is: [0142] hydrogen; [0143] C.sub.1-6alkyl; [0144]
C.sub.1-6alkoxy; [0145] hydroxy; [0146] hydroxy-C.sub.1-6alkyl;
[0147] C.sub.1-6alkyl-amino; [0148] amino-C.sub.1-6alkyl; [0149]
amino-C.sub.1-6alkyl-amino; [0150] hydroxy-C.sub.1-6alkylamino
[0151] C.sub.3-6cycloalkylamino; [0152]
amino-C.sub.3-6cycloalkylamino; [0153]
amino-C.sub.3-6heterocycloalkylamino; [0154] aminocarbonyl; [0155]
halo; [0156] hydroxy-C.sub.1-6alkyl; or [0157]
hydroxy-C.sub.1-6alkoxy; and
[0158] R.sup.2 is: [0159] hydrogen; or [0160] C.sub.1-6alkyl.
[0161] In certain embodiments the compounds of the invention are of
formula I.
[0162] In certain embodiments the compounds of the invention are of
formula II.
[0163] In certain embodiments of formula II, X is N.
[0164] In certain embodiments of formula II, X is CH.
[0165] In certain embodiments of formula I or formula II, R.sup.2
is hydrogen.
[0166] In certain embodiments of formula I or formula II, m is
1.
[0167] In certain embodiments of formula I or formula II, m is
2.
[0168] In certain embodiments of formula I or formula II, Ar is
optionally substituted aryl.
[0169] In certain embodiments of formula I or formula II, Ar is
optionally substituted phenyl or optionally substituted
naphthyl.
[0170] In certain embodiments of formula I or formula II, Ar is
substituted phenyl.
[0171] In certain embodiments of formula I or formula II, Ar is
substituted naphthyl.
[0172] In certain embodiments of formula I or formula II, Ar is
phenyl substituted one, two or three times with a group or groups
independently selected from: halo; C.sub.1-6alkyl;
halo-C.sub.1-6alkyl; C.sub.1-6alkenyl; C.sub.1-6alkoxy;
halo-C.sub.1-6alkoxy; hydroxy-C.sub.1-6alkyl;
hydroxy-C.sub.1-6alkylamino; C.sub.1-6alkyl-amino; hydroxy; amino;
amino-C.sub.1-6alkyl; aminocarbonyl; hydroxy-C.sub.1-6alkoxy;
hydroxy-C.sub.1-6alkenyl; C.sub.1-6alkoxy-C.sub.1-6alkoxy;
C.sub.1-6alkylsulfonyl; C.sub.1-6alkylsulfanyl; piperidinyl wherein
the piperidinyl moiety is optionally substituted with hydroxy,
amino, amino-C.sub.1-6alkyl, hydroxy-C.sub.1-6alkyl or
aminocarbonyl; phenylaminocarbonyl; hydroxy-C.sub.1-6alkylamino;
cyclohexyloxy wherein the cyclohexyl moiety thereof is optionally
substituted with hydroxy, amino, amino-C.sub.1-6alkyl or
hydroxy-C.sub.1-6alkyl; cyclopentyloxy wherein the cyclopentyl
moiety thereof is optionally substituted with hydroxy, amino,
amino-C.sub.1-6alkyl or hydroxy-C.sub.1-6alkyl; piperidinyloxy
wherein the piperidinyl moiety thereof is optionally substituted
with hydroxy, amino, amino-C.sub.1-6alkyl, hydroxy-C.sub.1-6alkyl
or aminocarbonyl; phenyl wherein the phenyl moiety is optionally
substituted with amino, hydroxy, amino-C.sub.1-6alkyl,
hydroxy-C.sub.1-6alkyl or aminocarbonyl; pyrrolidinyl wherein the
pyrrolidinyl moiety is optionally substituted with hydroxy, amino,
amino-C.sub.1-6alkyl, hydroxy-C.sub.1-6alkyl or aminocarbonyl;
pyrrolidinyloxy wherein the pyrrolidinyl moiety is optionally
substituted with hydroxy, amino, amino-C.sub.1-6alkyl,
hydroxy-C.sub.1-6alkyl or aminocarbonyl; piperazinyl wherein the
piperazinyl moiety is optionally substituted with C.sub.1-6alkyl;
oxazol-C.sub.1-6alkoxy wherein the oxazol moiety thereof is
optionally substituted with C.sub.1-6alkyl; morpholinyl;
hydroxy-C.sub.1-6alkylaminocarbonyl; C.sub.3-6cycloalkyl; azepanyl
wherein the azepanyl moiety is optionally substituted with hydroxy,
amino, amino-C.sub.1-6alkyl, hydroxy-C.sub.1-6alkyl or
aminocarbonyl; benzyl wherein the phenyl moiety thereof is
optionally substituted with amino, hydroxy, amino-C.sub.1-6alkyl,
hydroxy-C.sub.1-6alkyl or aminocarbonyl;
C.sub.1-6alkoxycarbonyl-C.sub.1-6alkoxy; and
C.sub.1-6alkylcarbonylamino.
[0173] In certain embodiments of formula I or formula II, Ar is
phenyl substituted once or twice with a group or groups
independently selected from: halo; C.sub.1-6alkyl;
halo-C.sub.1-6alkyl; C.sub.1-6alkenyl; C.sub.1-6alkoxy;
halo-C.sub.1-6alkoxy; hydroxy-C.sub.1-6alkyl;
hydroxy-C.sub.1-6alkylamino; C.sub.1-6alkyl-amino; hydroxy; amino;
amino-C.sub.1-6alkyl; aminocarbonyl; hydroxy-C.sub.1-6alkoxy;
hydroxy-C.sub.1-6alkenyl; C.sub.1-6alkoxy-C.sub.1-6alkoxy;
C.sub.1-6alkylsulfonyl; C.sub.1-6alkylsulfanyl; piperidinyl wherein
the piperidinyl moiety is optionally substituted with hydroxy,
amino, amino-C.sub.1-6alkyl, hydroxy-C.sub.1-6alkyl or
aminocarbonyl; phenylaminocarbonyl; hydroxy-C.sub.1-6alkylamino;
cyclohexyloxy wherein the cyclohexyl moiety thereof is optionally
substituted with hydroxy, amino, amino-C.sub.1-6alkyl or
hydroxy-C.sub.1-6alkyl; cyclopentyloxy wherein the cyclopentyl
moiety thereof is optionally substituted with hydroxy, amino,
amino-C.sub.1-6alkyl or hydroxy-C.sub.1-6alkyl; piperidinyloxy
wherein the piperidinyl moiety thereof is optionally substituted
with hydroxy, amino, amino-C.sub.1-6alkyl, hydroxy-C.sub.1-6alkyl
or aminocarbonyl; phenyl wherein the phenyl moiety is optionally
substituted with amino, hydroxy, amino-C.sub.1-6alkyl,
hydroxy-C.sub.1-6alkyl or aminocarbonyl; pyrrolidinyl wherein the
pyrrolidinyl moiety is optionally substituted with hydroxy, amino,
amino-C.sub.1-6alkyl, hydroxy-C.sub.1-6alkyl or aminocarbonyl;
pyrrolidinyloxy wherein the pyrrolidinyl moiety is optionally
substituted with hydroxy, amino, amino-C.sub.1-6alkyl,
hydroxy-C.sub.1-6alkyl or aminocarbonyl; piperazinyl wherein the
piperazinyl moiety is optionally substituted with C.sub.1-6alkyl;
oxazol-C.sub.1-6alkoxy wherein the oxazol moiety thereof is
optionally substituted with C.sub.1-6alkyl; morpholinyl;
hydroxy-C.sub.1-6alkylaminocarbonyl; C.sub.3-6cycloalkyl; azepanyl
wherein the azepanyl moiety is optionally substituted with hydroxy,
amino, amino-C.sub.1-6alkyl, hydroxy-C.sub.1-6alkyl or
aminocarbonyl; benzyl wherein the phenyl moiety thereof is
optionally substituted with amino, hydroxy, amino-C.sub.1-6alkyl,
hydroxy-C.sub.1-6alkyl or aminocarbonyl;
C.sub.1-6alkoxycarbonyl-C.sub.1-6alkoxy; and
C.sub.1-6alkylcarbonylamino.
[0174] In certain embodiments of formula I or formula II, Ar is
phenyl substituted once with halo and once with a group selected
from: halo; C.sub.1-6alkyl; halo-C.sub.1-6alkyl; C.sub.1-6alkenyl;
C.sub.1-6alkoxy; halo-C.sub.1-6alkoxy; hydroxy-C.sub.1-6alkyl;
hydroxy-C.sub.1-6alkylamino; C.sub.1-6alkyl-amino; hydroxy; amino;
amino-C.sub.1-6alkyl; aminocarbonyl; hydroxy-C.sub.1-6alkoxy;
hydroxy-C.sub.1-6alkenyl; C.sub.1-6alkoxy-C.sub.1-6alkoxy;
C.sub.1-6alkylsulfonyl; C.sub.1-6alkylsulfanyl; piperidinyl wherein
the piperidinyl moiety is optionally substituted with hydroxy,
amino, amino-C.sub.1-6alkyl, hydroxy-C.sub.1-6alkyl or
aminocarbonyl; phenylaminocarbonyl; hydroxy-C.sub.1-6alkylamino;
cyclohexyloxy wherein the cyclohexyl moiety thereof is optionally
substituted with hydroxy, amino, amino-C.sub.1-6alkyl or
hydroxy-C.sub.1-6alkyl; cyclopentyloxy wherein the cyclopentyl
moiety thereof is optionally substituted with hydroxy, amino,
amino-C.sub.1-6alkyl or hydroxy-C.sub.1-6alkyl; piperidinyloxy
wherein the piperidinyl moiety thereof is optionally substituted
with hydroxy, amino, amino-C.sub.1-6alkyl, hydroxy-C.sub.1-6alkyl
or aminocarbonyl; phenyl wherein the phenyl moiety is optionally
substituted with amino, hydroxy, amino-C.sub.1-6alkyl,
hydroxy-C.sub.1-6alkyl or aminocarbonyl; pyrrolidinyl wherein the
pyrrolidinyl moiety is optionally substituted with hydroxy, amino,
amino-C.sub.1-6alkyl, hydroxy-C.sub.1-6alkyl or aminocarbonyl;
pyrrolidinyloxy wherein the pyrrolidinyl moiety is optionally
substituted with hydroxy, amino, amino-C.sub.1-6alkyl,
hydroxy-C.sub.1-6alkyl or aminocarbonyl; piperazinyl wherein the
piperazinyl moiety is optionally substituted with C.sub.1-6alkyl;
oxazol-C.sub.1-6alkoxy wherein the oxazol moiety thereof is
optionally substituted with C.sub.1-6alkyl; morpholinyl;
hydroxy-C.sub.1-6alkylaminocarbonyl; C.sub.3-6cycloalkyl; azepanyl
wherein the azepanyl moiety is optionally substituted with hydroxy,
amino, amino-C.sub.1-6alkyl, hydroxy-C.sub.1-6alkyl or
aminocarbonyl; benzyl wherein the phenyl moiety thereof is
optionally substituted with amino, hydroxy, amino-C.sub.1-6alkyl,
hydroxy-C.sub.1-6alkyl or aminocarbonyl;
C.sub.1-6alkoxycarbonyl-C.sub.1-6alkoxy; and
C.sub.1-6alkylcarbonylamino.
[0175] In certain embodiments of formula I or formula II, Ar is
substituted aryl selected from:
2-(4-aminomethyl-piperidin-1-yl)-5-chloro-phenyl;
2-(4-aminomethyl-piperidin-1-yl)-4-phenylcarbamoyl-phenyl;
5-chloro-2-[4-(1-hydroxy-ethyl)-piperidin-1-yl]-phenyl;
5-chloro-2-(4-hydroxymethyl-piperidin-1-yl)-phenyl;
5-chloro-2-(4-hydroxy-cyclohexyloxy)-phenyl;
5-chloro-2-piperidin-1-yl-phenyl;
2-(4-aminomethyl-piperidin-1-yl)-5-chloro-phenyl;
2-[4-(1-amino-ethyl)-piperidin-1-yl]-5-chloro-phenyl;
2-(4-carbamoyl-piperidin-1-yl)-5-chloro-phenyl;
5-chloro-2-[3-(1-hydroxy-ethyl)-pyrrolidin-1-yl]-phenyl;
4'-aminomethyl-4-chloro-biphenyl-2-yl; 5-chloro-2-methoxy-phenyl;
3-amino-2-(4-aminomethyl-piperidin-1-yl)-phenyl;
3-amino-2-piperidin-1-yl-phenyl;
5-hydroxymethyl-2-piperidin-1-yl-phenyl;
4-chloro-4'-hydroxymethyl-biphenyl-2-yl;
5-chloro-2-isopropoxy-phenyl;
5-chloro-2-(3-hydroxymethyl-cyclopentyloxy)-phenyl;
5-chloro-2-pyrrolidin-1-yl-phenyl;
5-chloro-2-(3-hydroxy-cyclopentyloxy)-phenyl;
5-chloro-2-(3-hydroxy-propoxy)-phenyl;
5-chloro-2-(4-hydroxy-butoxy; 2-methoxy-4-phenylcarbamoyl-phenyl;
5-chloro-2-(3-hydroxy-piperidin-1-yl)-phenyl;
5-chloro-2-(piperidin-4-yloxy)-phenyl;
4-chloro-4'-hydroxy-biphenyl-2-yl;
5-chloro-2-(3-hydroxy-pyrrolidin-1-yl)-phenyl;
5-chloro-2-(3,4-dihydroxy-butoxy;
5-chloro-2-(4-methyl-piperazin-1-yl)-phenyl;
5-chloro-2-(oxazol-5-ylmethoxy)-phenyl;
5-chloro-2-morpholin-4-yl-phenyl; 4-chloro-biphenyl-2-yl;
2-(3-aminomethyl-pyrrolidin-1-yl)-5-chloro-phenyl;
5-chloro-2-(3-hydroxy-cyclohexyloxy)-phenyl;
4-(3-hydroxy-propylcarbamoyl)-2-methoxy-phenyl;
5-chloro-2-(3-hydroxymethyl-pyrrolidin-1-yl)-phenyl;
5-chloro-2-difluoromethoxy-phenyl; 5-chloro-2-dimethylamino-phenyl;
2-(3-amino-pyrrolidin-1-yl)-5-chloro-phenyl;
5-chloro-2-methylsulfanyl-phenyl; 5-chloro-2-cyclohexyl-phenyl;
3-(2-hydroxy-ethylamino)-2-piperidin-1-yl-phenyl;
5-chloro-2-(4-methyl-oxazol-5-ylmethoxy)-phenyl; biphenyl-2-yl;
5-chloro-2-(3-hydroxy-1,1-dimethyl-propoxy)-phenyl;
2-(4-amino-cyclohexyloxy)-5-chloro-phenyl;
2-azepan-1-yl-5-chloro-phenyl;
4-(2-hydroxy-ethylcarbamoyl)-2-methoxy-phenyl;
4-hydroxy-cyclohexyloxy)-phenyl;
5-chloro-2-(2-methoxy-ethoxy)-phenyl;
4-chloro-3'-hydroxy-biphenyl-2-yl; 5-bromo-2-methoxy-phenyl;
5-chloro-2-[(2-hydroxy-ethyl)-methyl-amino]-phenyl;
5-chloro-2-(4-hydroxy-phenoxy)-phenyl;
4-carbamoyl-2-methoxy-phenyl; 5-chloro-2-isobutoxy-phenyl;
5-chloro-2-(2,3-dihydroxy-propoxy)-phenyl;
5-chloro-2-(3-methoxy-propoxy)-phenyl;
5-chloro-2-(3-hydroxymethyl-piperidin-1-yl)-phenyl;
5-chloro-2-(3-hydroxy-benzyloxy; 5-chloro-2,4-dimethoxy-phenyl;
2-methoxy-5-vinyl-phenyl;
3-(3-hydroxy-propylamino)-2-piperidin-1-yl-phenyl5-chloro-2-(4-hydroxy-bu-
tyl)-phenyl; 2-[3-(1-amino-ethyl)-pyrrolidin-1-yl]-5-chloro-phenyl;
5-chloro-2-[(3-hydroxy-propyl)-methyl-amino]-phenyl;
5-chloro-2-(4-methylaminomethyl-piperidin-1-yl)-phenyl;
5-(3-hydroxy-propenyl)-2-methoxy-phenyl; 5-chloro-2-ethyl-phenyl;
4-methanesulfonyl-2-methoxy-phenyl;
5-chloro-2-(3-hydroxy-phenoxy)-phenyl; 2,4-dimethoxy-phenyl;
5-fluoro-2-methoxy-phenyl; 5-chloro-2-phenoxy-phenyl;
5-(3-hydroxy-propyl)-2-methoxy-phenyl5-chloro-2-(2-hydroxymethyl-piperidi-
n-1-yl)-phenyl;
5-chloro-2-(4-dimethylaminomethyl-piperidin-1-yl)-phenyl;
3-methoxy-biphenyl-4-yl; 5-ethyl-2-methoxy-phenyl;
5-methoxy-2-methyl-biphenyl-4-yl; 2-methoxy-3,5-dimethyl-phenyl;
4-dimethylcarbamoyl-2-methoxy-pheny;
5-acetylamino-2-methoxy-phenyl;
5-chloro-2-methoxy-4-phenylcarbamoyl-phenyl; and
4-hydroxymethyl-2-methoxy-phenyl;
3-(3-hydroxy-cyclopentyloxy)-naphthalen-2-yl;
3-(3-hydroxy-propoxy)-naphthalen-2-yl;
7-hydroxymethyl-3-methoxy-naphthalen-2-yl;
3-(4-hydroxy-cyclohexyloxy)-naphthalen-2-yl; and
3-methoxy-naphthalen-2-yl.
[0176] In certain embodiments of formula I or formula II, Ar is
substituted phenyl selected from:
2-(4-aminomethyl-piperidin-1-yl)-5-chloro-phenyl;
2-(4-aminomethyl-piperidin-1-yl)-4-phenylcarbamoyl-phenyl;
5-chloro-2-[4-(1-hydroxy-ethyl)-piperidin-1-yl]-phenyl;
5-chloro-2-(4-hydroxymethyl-piperidin-1-yl)-phenyl;
5-chloro-2-(4-hydroxy-cyclohexyloxy)-phenyl;
5-chloro-2-piperidin-1-yl-phenyl;
2-(4-aminomethyl-piperidin-1-yl)-5-chloro-phenyl;
2-[4-(1-amino-ethyl)-piperidin-1-yl]-5-chloro-phenyl;
2-(4-carbamoyl-piperidin-1-yl)-5-chloro-phenyl;
5-chloro-2-[3-(1-hydroxy-ethyl)-pyrrolidin-1-yl]-phenyl;
4'-aminomethyl-4-chloro-biphenyl-2-yl; 5-chloro-2-methoxy-phenyl;
3-amino-2-(4-aminomethyl-piperidin-1-yl)-phenyl;
3-amino-2-piperidin-1-yl-phenyl;
5-hydroxymethyl-2-piperidin-1-yl-phenyl;
4-chloro-4'-hydroxymethyl-biphenyl-2-yl;
5-chloro-2-isopropoxy-phenyl;
5-chloro-2-(3-hydroxymethyl-cyclopentyloxy)-phenyl;
5-chloro-2-pyrrolidin-1-yl-phenyl;
5-chloro-2-(3-hydroxy-cyclopentyloxy)-phenyl;
5-chloro-2-(3-hydroxy-propoxy)-phenyl;
5-chloro-2-(4-hydroxy-butoxy; 2-methoxy-4-phenylcarbamoyl-phenyl;
5-chloro-2-(3-hydroxy-piperidin-1-yl)-phenyl;
5-chloro-2-(piperidin-4-yloxy)-phenyl;
4-chloro-4'-hydroxy-biphenyl-2-yl;
5-chloro-2-(3-hydroxy-pyrrolidin-1-yl)-phenyl;
5-chloro-2-(3,4-dihydroxy-butoxy;
5-chloro-2-(4-methyl-piperazin-1-yl)-phenyl;
5-chloro-2-(oxazol-5-ylmethoxy)-phenyl;
5-chloro-2-morpholin-4-yl-phenyl; 4-chloro-biphenyl-2-yl;
2-(3-aminomethyl-pyrrolidin-1-yl)-5-chloro-phenyl;
5-chloro-2-(3-hydroxy-cyclohexyloxy)-phenyl;
4-(3-hydroxy-propylcarbamoyl)-2-methoxy-phenyl;
5-chloro-2-(3-hydroxymethyl-pyrrolidin-1-yl)-phenyl;
5-chloro-2-difluoromethoxy-phenyl; 5-chloro-2-dimethylamino-phenyl;
2-(3-amino-pyrrolidin-1-yl)-5-chloro-phenyl;
5-chloro-2-methylsulfanyl-phenyl; 5-chloro-2-cyclohexyl-phenyl;
3-(2-hydroxy-ethylamino)-2-piperidin-1-yl-phenyl;
5-chloro-2-(4-methyl-oxazol-5-ylmethoxy)-phenyl; biphenyl-2-yl;
5-chloro-2-(3-hydroxy-1,1-dimethyl-propoxy)-phenyl;
2-(4-amino-cyclohexyloxy)-5-chloro-phenyl;
2-azepan-1-yl-5-chloro-phenyl;
4-(2-hydroxy-ethylcarbamoyl)-2-methoxy-phenyl;
4-hydroxy-cyclohexyloxy)-phenyl;
5-chloro-2-(2-methoxy-ethoxy)-phenyl;
4-chloro-3'-hydroxy-biphenyl-2-yl; 5-bromo-2-methoxy-phenyl;
5-chloro-2-[(2-hydroxy-ethyl)-methyl-amino]-phenyl;
5-chloro-2-(4-hydroxy-phenoxy)-phenyl;
4-carbamoyl-2-methoxy-phenyl; 5-chloro-2-isobutoxy-phenyl;
5-chloro-2-(2,3-dihydroxy-propoxy)-phenyl;
5-chloro-2-(3-methoxy-propoxy)-phenyl;
5-chloro-2-(3-hydroxymethyl-piperidin-1-yl)-phenyl;
5-chloro-2-(3-hydroxy-benzyloxy; 5-chloro-2,4-dimethoxy-phenyl;
2-methoxy-5-vinyl-phenyl;
3-(3-hydroxy-propylamino)-2-piperidin-1-yl-phenyl5-chloro-2-(4-hydroxy-bu-
tyl)-phenyl; 2-[3-(1-amino-ethyl)-pyrrolidin-1-yl]-5-chloro-phenyl;
5-chloro-2-[(3-hydroxy-propyl)-methyl-amino]-phenyl;
5-chloro-2-(4-methylaminomethyl-piperidin-1-yl)-phenyl;
5-(3-hydroxy-propenyl)-2-methoxy-phenyl; 5-chloro-2-ethyl-phenyl;
4-methanesulfonyl-2-methoxy-phenyl;
5-chloro-2-(3-hydroxy-phenoxy)-phenyl; 2,4-dimethoxy-phenyl;
5-fluoro-2-methoxy-phenyl; 5-chloro-2-phenoxy-phenyl;
5-(3-hydroxy-propyl)-2-methoxy-phenyls-chloro-2-(2-hydroxymethyl-piperidi-
n-1-yl)-phenyl; and
5-chloro-2-(4-dimethylaminomethyl-piperidin-1-yl)-phenyl.
[0177] In certain embodiments of formula I or formula II, Ar is
substituted naphthyl selected from:
3-(3-hydroxy-cyclopentyloxy)-naphthalen-2-yl;
3-(3-hydroxy-propoxy)-naphthalen-2-yl;
7-hydroxymethyl-3-methoxy-naphthalen-2-yl;
3-(4-hydroxy-cyclohexyloxy)-naphthalen-2-yl; and
3-methoxy-naphthalen-2-yl.
[0178] In certain embodiments of formula I or formula II, Ar is
2-(4-aminomethyl-piperidin-1-yl)-5-chloro-phenyl.
[0179] In certain embodiments of formula I or formula II, Ar is
2-(4-aminomethyl-piperidin-1-yl)-4-phenylcarbamoyl-phenyl.
[0180] In certain embodiments of formula I or formula II, Ar is
5-chloro-2-[4-(1-hydroxy-ethyl)-piperidin-1-yl]-phenyl.
[0181] In certain embodiments of formula I or formula II, Ar is
5-chloro-2-(4-hydroxymethyl-piperidin-1-yl)-phenyl.
[0182] In certain embodiments of formula I or formula II, Ar is
5-chloro-2-(4-hydroxy-cyclohexyloxy)-phenyl.
[0183] In certain embodiments of formula I or formula II, Ar is
5-chloro-2-piperidin-1-yl-phenyl.
[0184] In certain embodiments of formula I or formula II, Ar is
2-(4-aminomethyl-piperidin-1-yl)-5-chloro-phenyl.
[0185] In certain embodiments of formula I or formula II, Ar is
2-[4-(1-amino-ethyl)-piperidin-1-yl]-5-chloro-phenyl.
[0186] In certain embodiments of formula I or formula II, Ar is
2-(4-carbamoyl-piperidin-1-yl)-5-chloro-phenyl.
[0187] In certain embodiments of formula I or formula II, Ar is
5-chloro-2-[3-(1-hydroxy-ethyl)-pyrrolidin-1-yl]-phenyl.
[0188] In certain embodiments of formula I or formula II, Ar is
4'-aminomethyl-4-chloro-biphenyl-2-yl.
[0189] In certain embodiments of formula I or formula II, Ar is
5-chloro-2-methoxy-phenyl.
[0190] In certain embodiments of formula I or formula II, Ar is
3-amino-2-(4-aminomethyl-piperidin-1-yl)-phenyl.
[0191] In certain embodiments of formula I or formula II, Ar is
3-amino-2-piperidin-1-yl-phenyl.
[0192] In certain embodiments of formula I or formula II, Ar is
5-hydroxymethyl-2-piperidin-1-yl-phenyl.
[0193] In certain embodiments of formula I or formula II, Ar is
3-(3-hydroxy-cyclopentyloxy)-naphthalen-2-yl.
[0194] In certain embodiments of formula I or formula II, Ar is
4-chloro-4'-hydroxymethyl-biphenyl-2-yl.
[0195] In certain embodiments of formula I or formula II, Ar is
5-chloro-2-isopropoxy-phenyl.
[0196] In certain embodiments of formula I or formula II, Ar is
5-chloro-2-(3-hydroxymethyl-cyclopentyloxy)-phenyl.
[0197] In certain embodiments of formula I or formula II, Ar is
5-chloro-2-pyrrolidin-1-yl-phenyl.
[0198] In certain embodiments of formula I or formula II, Ar is
3-(3-hydroxy-propoxy)-naphthalen-2-yl.
[0199] In certain embodiments of formula I or formula II, Ar is
7-hydroxymethyl-3-methoxy-naphthalen-2-yl.
[0200] In certain embodiments of formula I or formula II, Ar is
5-chloro-2-(3-hydroxy-cyclopentyloxy)-phenyl.
[0201] In certain embodiments of formula I or formula II, Ar is
5-chloro-2-(3-hydroxy-propoxy)-phenyl.
[0202] In certain embodiments of formula I or formula II, Ar is
3-(4-hydroxy-cyclohexyloxy)-naphthalen-2-yl.
[0203] In certain embodiments of formula I or formula II, Ar is
5-chloro-2-(4-hydroxy-butoxy.
[0204] In certain embodiments of formula I or formula II, Ar is
2-methoxy-4-phenylcarbamoyl-phenyl.
[0205] In certain embodiments of formula I or formula II, Ar is
5-chloro-2-(3-hydroxy-piperidin-1-yl)-phenyl.
[0206] In certain embodiments of formula I or formula II, Ar is
5-chloro-2-(piperidin-4-yloxy)-phenyl.
[0207] In certain embodiments of formula I or formula II, Ar is
4-chloro-4'-hydroxy-biphenyl-2-yl.
[0208] In certain embodiments of formula I or formula II, Ar is
5-chloro-2-(3-hydroxy-pyrrolidin-1-yl)-phenyl.
[0209] In certain embodiments of formula I or formula II, Ar is
5-chloro-2-(3,4-dihydroxy-butoxy.
[0210] In certain embodiments of formula I or formula II, Ar is
5-chloro-2-(4-methyl-piperazin-1-yl)-phenyl.
[0211] In certain embodiments of formula I or formula II, Ar is
5-chloro-2-(oxazol-5-ylmethoxy)-phenyl.
[0212] In certain embodiments of formula I or formula II, Ar is
5-chloro-2-morpholin-4-yl-phenyl.
[0213] In certain embodiments of formula I or formula II, Ar is
4-chloro-biphenyl-2-yl.
[0214] In certain embodiments of formula I or formula II, Ar is
2-(3-aminomethyl-pyrrolidin-1-yl)-5-chloro-phenyl.
[0215] In certain embodiments of formula I or formula II, Ar is
5-chloro-2-(3-hydroxy-cyclohexyloxy)-phenyl.
[0216] In certain embodiments of formula I or formula II, Ar is
3-methoxy-naphthalen-2-yl.
[0217] In certain embodiments of formula I or formula II, Ar is
4-(3-hydroxy-propylcarbamoyl)-2-methoxy-phenyl.
[0218] In certain embodiments of formula I or formula II, Ar is
5-chloro-2-(3-hydroxymethyl-pyrrolidin-1-yl)-phenyl.
[0219] In certain embodiments of formula I or formula II, Ar is
5-chloro-2-difluoromethoxy-phenyl.
[0220] In certain embodiments of formula I or formula II, Ar is
5-chloro-2-dimethylamino-phenyl.
[0221] In certain embodiments of formula I or formula II, Ar is
2-(3-amino-pyrrolidin-1-yl)-5-chloro-phenyl.
[0222] In certain embodiments of formula I or formula II, Ar is
5-chloro-2-methylsulfanyl-phenyl.
[0223] In certain embodiments of formula I or formula II, Ar is
5-chloro-2-cyclohexyl-phenyl. In certain embodiments of formula I
or formula II, Ar is
3-(2-hydroxy-ethylamino)-2-piperidin-1-yl-phenyl.
[0224] In certain embodiments of formula I or formula II, Ar is
5-chloro-2-(4-methyl-oxazol-5-ylmethoxy)-phenyl.
[0225] In certain embodiments of formula I or formula II, Ar is
biphenyl-2-yl.
[0226] In certain embodiments of formula I or formula II, Ar is
5-chloro-2-(3-hydroxy-1,1-dimethyl-propoxy)-phenyl.
[0227] In certain embodiments of formula I or formula II, Ar is
2-(4-amino-cyclohexyloxy)-5-chloro-phenyl.
[0228] In certain embodiments of formula I or formula II, Ar is
2-azepan-1-yl-5-chloro-phenyl.
[0229] In certain embodiments of formula I or formula II, Ar is
4-(2-hydroxy-ethylcarbamoyl)-2-methoxy-phenyl.
[0230] In certain embodiments of formula I or formula II, Ar is
4-hydroxy-cyclohexyloxy)-phenyl.
[0231] In certain embodiments of formula I or formula II, Ar is
5-chloro-2-(2-methoxy-ethoxy)-phenyl.
[0232] In certain embodiments of formula I or formula II, Ar is
4-chloro-3'-hydroxy-biphenyl-2-yl.
[0233] In certain embodiments of formula I or formula II, Ar is
5-bromo-2-methoxy-phenyl.
[0234] In certain embodiments of formula I or formula II, Ar is
5-chloro-2-[(2-hydroxy-ethyl)-methyl-amino]-phenyl.
[0235] In certain embodiments of formula I or formula II, Ar is
5-chloro-2-(4-hydroxy-phenoxy)-phenyl.
[0236] In certain embodiments of formula I or formula II, Ar is
4-carbamoyl-2-methoxy-phenyl.
[0237] In certain embodiments of formula I or formula II, Ar is
5-chloro-2-isobutoxy-phenyl.
[0238] In certain embodiments of formula I or formula II, Ar is
5-chloro-2-(2,3-dihydroxy-propoxy)-phenyl.
[0239] In certain embodiments of formula I or formula II, Ar is
5-chloro-2-(3-methoxy-propoxy)-phenyl.
[0240] In certain embodiments of formula I or formula II, Ar is
5-chloro-2-(3-hydroxymethyl-piperidin-1-yl)-phenyl.
[0241] In certain embodiments of formula I or formula II, Ar is
5-chloro-2-(3-hydroxy-benzyloxy.
[0242] In certain embodiments of formula I or formula II, Ar is
5-chloro-2,4-dimethoxy-phenyl.
[0243] In certain embodiments of formula I or formula II, Ar is
2-methoxy-5-vinyl-phenyl.
[0244] In certain embodiments of formula I or formula II, Ar is
3-(3-hydroxy-propylamino)-2-piperidin-1-yl-phenyl.
[0245] In certain embodiments of formula I or formula II, Ar is
5-chloro-2-(4-hydroxy-butyl)-phenyl.
[0246] In certain embodiments of formula I or formula II, Ar is
2-[3-(1-amino-ethyl)-pyrrolidin-1-yl]-5-chloro-phenyl.
[0247] In certain embodiments of formula I or formula II, Ar is
5-chloro-2-[(3-hydroxy-propyl)-methyl-amino]-phenyl.
[0248] In certain embodiments of formula I or formula II, Ar is
5-chloro-2-(4-methylaminomethyl-piperidin-1-yl)-phenyl.
[0249] In certain embodiments of formula I or formula II, Ar is
5-(3-hydroxy-propenyl)-2-methoxy-phenyl.
[0250] In certain embodiments of formula I or formula II, Ar is
5-chloro-2-ethyl-phenyl.
[0251] In certain embodiments of formula I or formula II, Ar is
4-methanesulfonyl-2-methoxy-phenyl.
[0252] In certain embodiments of formula I or formula II, Ar is
5-chloro-2-(3-hydroxy-phenoxy)-phenyl.
[0253] In certain embodiments of formula I or formula II, Ar is
2,4-dimethoxy-phenyl.
[0254] In certain embodiments of formula I or formula II, Ar is
5-fluoro-2-methoxy-phenyl.
[0255] In certain embodiments of formula I or formula II, Ar is
5-chloro-2-phenoxy-phenyl.
[0256] In certain embodiments of formula I or formula II, Ar is
5-(3-hydroxy-propyl)-2-methoxy-phenyl.
[0257] In certain embodiments of formula I or formula II, Ar is
5-chloro-2-(2-hydroxymethyl-piperidin-1-yl)-phenyl.
[0258] In certain embodiments of formula I or formula II, Ar is
5-chloro-2-(4-dimethylaminomethyl-piperidin-1-yl)-phenyl.
[0259] In certain embodiments of formula I or formula II, Ar is
3-methoxy-biphenyl-4-yl.
[0260] In certain embodiments of formula I or formula II, Ar is
5-ethyl-2-methoxy-phenyl.
[0261] In certain embodiments of formula I or formula II, Ar is
5-methoxy-2-methyl-biphenyl-4-yl.
[0262] In certain embodiments of formula I or formula II, Ar is
2-methoxy-3,5-dimethyl-phenyl.
[0263] In certain embodiments of formula I or formula II, Ar is
4-dimethylcarbamoyl-2-methoxy-phenyl.
[0264] In certain embodiments of formula I or formula II, Ar is
5-acetylamino-2-methoxy-phenyl.
[0265] In certain embodiments of formula I or formula II, Ar is
5-chloro-2-methoxy-4-phenylcarbamoyl-phenyl.
[0266] In certain embodiments of formula I or formula II, Ar is
4-hydroxymethyl-2-methoxy-phenyl.
[0267] In certain embodiments of formula I or formula II, Ar is
optionally substituted heteroaryl.
[0268] In certain embodiments of formula I or formula II, Ar is
heteroaryl selected from: pyridinyl; benzo[1,3]dioxolyl;
quinolinyl; 2-oxo-2,3-dihydro-indolyl; indolyl; benzimidazolyl; or
indazolyl; each optionally substituted once or twice with a group
or groups independently selected from: halo; C.sub.1-6alkyl;
halo-C.sub.1-6alkyl; C.sub.1-6alkenyl; C.sub.1-6alkoxy;
halo-C.sub.1-6alkoxy; hydroxy-C.sub.1-6alkyl;
hydroxy-C.sub.1-6alkylamino; C.sub.1-6alkyl-amino; hydroxy; amino;
amino-C.sub.1-6alkyl; aminocarbonyl; hydroxy-C.sub.1-6alkoxy;
hydroxy-C.sub.1-6alkenyl; C.sub.1-6alkoxy-C.sub.1-6alkoxy;
C.sub.1-6alkylsulfonyl; C.sub.1-6alkylsulfanyl; piperidinyl wherein
the piperidinyl moiety is optionally substituted with hydroxy,
amino, amino-C.sub.1-6alkyl, hydroxy-C.sub.1-6alkyl or
aminocarbonyl; phenylaminocarbonyl; hydroxy-C.sub.1-6alkylamino;
cyclohexyloxy wherein the cyclohexyl moiety thereof is optionally
substituted with hydroxy, amino, amino-C.sub.1-6alkyl or
hydroxy-C.sub.1-6alkyl; cyclopentyloxy wherein the cyclopentyl
moiety thereof is optionally substituted with hydroxy, amino,
amino-C.sub.1-6alkyl or hydroxy-C.sub.1-6alkyl; piperidinyloxy
wherein the piperidinyl moiety thereof is optionally substituted
with hydroxy, amino, amino-C.sub.1-6alkyl, hydroxy-C.sub.1-6alkyl
or aminocarbonyl; phenyl wherein the phenyl moiety is optionally
substituted with amino, hydroxy, amino-C.sub.1-6alkyl,
hydroxy-C.sub.1-6alkyl or aminocarbonyl; pyrrolidinyl wherein the
pyrrolidinyl moiety is optionally substituted with hydroxy, amino,
amino-C.sub.1-6alkyl, hydroxy-C.sub.1-6alkyl or aminocarbonyl;
pyrrolidinyloxy wherein the pyrrolidinyl moiety is optionally
substituted with hydroxy, amino, amino-C.sub.1-6alkyl,
hydroxy-C.sub.1-6alkyl or aminocarbonyl; piperazinyl wherein the
piperazinyl moiety is optionally substituted with C.sub.1-6alkyl;
oxazol-C.sub.1-6alkoxy wherein the oxazol moiety thereof is
optionally substituted with C.sub.1-6alkyl; morpholinyl;
hydroxy-C.sub.1-6alkylaminocarbonyl; C.sub.3-6cycloalkyl; azepanyl
wherein the azepanyl moiety is optionally substituted with hydroxy,
amino, amino-C.sub.1-6alkyl, hydroxy-C.sub.1-6alkyl or
aminocarbonyl; benzyl wherein the phenyl moiety thereof is
optionally substituted with amino, hydroxy, amino-C.sub.1-6alkyl,
hydroxy-C.sub.1-6alkyl or aminocarbonyl;
C.sub.1-6alkoxycarbonyl-C.sub.1-6alkoxy; and
C.sub.1-6alkylcarbonylamino.
[0269] In certain embodiments of formula I or formula II, Ar is
heteroaryl selected from: quinolinyl; 2-oxo-2,3-dihydro-indolyl;
indolyl; benzimidazolyl; or indazolyl; each optionally substituted
once or twice with a group or groups independently selected from:
halo; C.sub.1-6alkyl; halo-C.sub.1-6alkyl; C.sub.1-6alkenyl;
C.sub.1-6alkoxy; halo-C.sub.1-6alkoxy; hydroxy-C.sub.1-6alkyl;
hydroxy-C.sub.1-6alkylamino; C.sub.1-6alkyl-amino; hydroxy; amino;
amino-C.sub.1-6alkyl; aminocarbonyl; hydroxy-C.sub.1-6alkoxy;
hydroxy-C.sub.1-6alkenyl; C.sub.1-6alkoxy-C.sub.1-6alkoxy;
C.sub.1-6alkylsulfonyl; C.sub.1-6alkylsulfanyl; piperidinyl wherein
the piperidinyl moiety is optionally substituted with hydroxy,
amino, amino-C.sub.1-6alkyl, hydroxy-C.sub.1-6alkyl or
aminocarbonyl; phenylaminocarbonyl; hydroxy-C.sub.1-6alkylamino;
cyclohexyloxy wherein the cyclohexyl moiety thereof is optionally
substituted with hydroxy, amino, amino-C.sub.1-6alkyl or
hydroxy-C.sub.1-6alkyl; cyclopentyloxy wherein the cyclopentyl
moiety thereof is optionally substituted with hydroxy, amino,
amino-C.sub.1-6alkyl or hydroxy-C.sub.1-6alkyl; piperidinyloxy
wherein the piperidinyl moiety thereof is optionally substituted
with hydroxy, amino, amino-C.sub.1-6alkyl, hydroxy-C.sub.1-6alkyl
or aminocarbonyl; phenyl wherein the phenyl moiety is optionally
substituted with amino, hydroxy, amino-C.sub.1-6alkyl,
hydroxy-C.sub.1-6alkyl or aminocarbonyl; pyrrolidinyl wherein the
pyrrolidinyl moiety is optionally substituted with hydroxy, amino,
amino-C.sub.1-6alkyl, hydroxy-C.sub.1-6alkyl or aminocarbonyl;
pyrrolidinyloxy wherein the pyrrolidinyl moiety is optionally
substituted with hydroxy, amino, amino-C.sub.1-6alkyl,
hydroxy-C.sub.1-6alkyl or aminocarbonyl; piperazinyl wherein the
piperazinyl moiety is optionally substituted with C.sub.1-6alkyl;
oxazol-C.sub.1-6alkoxy wherein the oxazol moiety thereof is
optionally substituted with C.sub.1-6alkyl; morpholinyl;
hydroxy-C.sub.1-6alkylaminocarbonyl; C.sub.3-6cycloalkyl; azepanyl
wherein the azepanyl moiety is optionally substituted with hydroxy,
amino, amino-C.sub.1-6alkyl, hydroxy-C.sub.1-6alkyl or
aminocarbonyl; benzyl wherein the phenyl moiety thereof is
optionally substituted with amino, hydroxy, amino-C.sub.1-6alkyl,
hydroxy-C.sub.1-6alkyl or aminocarbonyl;
C.sub.1-6alkoxycarbonyl-C.sub.1-6alkoxy; and
C.sub.1-6alkylcarbonylamino.
[0270] In certain embodiments of formula I or formula II, Ar is
heteroaryl selected from: quinolinyl; 2-oxo-2,3-dihydro-indolyl;
indolyl; benzimidazolyl; or indazolyl; each optionally substituted
once or twice with a group or groups independently selected from:
C.sub.1-6alkyl; C.sub.1-6alkoxy; hydroxy-C.sub.1-6alkoxy;
hydroxy-C.sub.1-6alkylamino; amino-C.sub.1-6alkoxy; cyclohexyloxy
wherein the cyclohexyl moiety thereof is optionally substituted
with hydroxy, amino, amino-C.sub.1-6alkyl or
hydroxy-C.sub.1-6alkyl; piperidinyl wherein the piperidinyl moiety
is optionally substituted with hydroxy, amino,
amino-C.sub.1-6alkyl, hydroxy-C.sub.1-6alkyl or aminocarbonyl;
piperidinyloxy wherein the piperidinyl moiety thereof is optionally
substituted with hydroxy, amino, amino-C.sub.1-6alkyl,
hydroxy-C.sub.1-6alkyl or aminocarbonyl; cyclopentyloxy wherein the
cyclopentyl moiety thereof is optionally substituted with hydroxy,
amino, amino-C.sub.1-6alkyl or hydroxy-C.sub.1-6alkyl; and
pyrrolidinyloxy wherein the pyrrolidinyl moiety is optionally
substituted with hydroxy, amino, amino-C.sub.1-6alkyl,
hydroxy-C.sub.1-6alkyl or aminocarbonyl.
[0271] In certain embodiments of formula I or formula II, Ar is
heteroaryl selected from: quinolinyl; 2-oxo-2,3-dihydro-indolyl;
indolyl; benzimidazolyl; or indazolyl, each substituted once or
twice with a group or groups independently selected from:
C.sub.1-6alkyl; C.sub.1-6alkoxy; hydroxy-C.sub.1-6alkoxy;
hydroxy-C.sub.1-6alkylamino; amino-C.sub.1-6alkoxy; cyclohexyloxy
wherein the cyclohexyl moiety thereof is optionally substituted
with hydroxy, amino, amino-C.sub.1-6alkyl or
hydroxy-C.sub.1-6alkyl; piperidinyl wherein the piperidinyl moiety
is optionally substituted with hydroxy, amino,
amino-C.sub.1-6alkyl, hydroxy-C.sub.1-6alkyl or aminocarbonyl;
piperidinyloxy wherein the piperidinyl moiety thereof is optionally
substituted with hydroxy, amino, amino-C.sub.1-6alkyl,
hydroxy-C.sub.1-6alkyl or aminocarbonyl; cyclopentyloxy wherein the
cyclopentyl moiety thereof is optionally substituted with hydroxy,
amino, amino-C.sub.1-6alkyl or hydroxy-C.sub.1-6alkyl; and
pyrrolidinyloxy wherein the pyrrolidinyl moiety is optionally
substituted with hydroxy, amino, amino-C.sub.1-6alkyl,
hydroxy-C.sub.1-6alkyl or aminocarbonyl.
[0272] In certain embodiments of formula I or formula II, Ar is
quinolinyl optionally substituted once or twice with a group or
groups independently selected from: C.sub.1-6alkyl;
C.sub.1-6alkoxy; hydroxy-C.sub.1-6alkoxy;
hydroxy-C.sub.1-6alkylamino; amino-C.sub.1-6alkoxy; cyclohexyloxy
wherein the cyclohexyl moiety thereof is optionally substituted
with hydroxy, amino, amino-C.sub.1-6alkyl or
hydroxy-C.sub.1-6alkyl; piperidinyl wherein the piperidinyl moiety
is optionally substituted with hydroxy, amino,
amino-C.sub.1-6alkyl, hydroxy-C.sub.1-6alkyl or aminocarbonyl;
piperidinyloxy wherein the piperidinyl moiety thereof is optionally
substituted with hydroxy, amino, amino-C.sub.1-6alkyl,
hydroxy-C.sub.1-6alkyl or aminocarbonyl; cyclopentyloxy wherein the
cyclopentyl moiety thereof is optionally substituted with hydroxy,
amino, amino-C.sub.1-6alkyl or hydroxy-C.sub.1-6alkyl; and
pyrrolidinyloxy wherein the pyrrolidinyl moiety is optionally
substituted with hydroxy, amino, amino-C.sub.1-6alkyl,
hydroxy-C.sub.1-6alkyl or aminocarbonyl.
[0273] In certain embodiments of formula I or formula II, Ar is
2-oxo-2,3-dihydro-indolyl optionally substituted once or twice with
a group or groups independently selected from: C.sub.1-6alkyl;
C.sub.1-6alkoxy; hydroxy-C.sub.1-6alkoxy;
hydroxy-C.sub.1-6alkylamino; amino-C.sub.1-6alkoxy; cyclohexyloxy
wherein the cyclohexyl moiety thereof is optionally substituted
with hydroxy, amino, amino-C.sub.1-6alkyl or
hydroxy-C.sub.1-6alkyl; piperidinyl wherein the piperidinyl moiety
is optionally substituted with hydroxy, amino,
amino-C.sub.1-6alkyl, hydroxy-C.sub.1-6alkyl or aminocarbonyl;
piperidinyloxy wherein the piperidinyl moiety thereof is optionally
substituted with hydroxy, amino, amino-C.sub.1-6alkyl,
hydroxy-C.sub.1-6alkyl or aminocarbonyl; cyclopentyloxy wherein the
cyclopentyl moiety thereof is optionally substituted with hydroxy,
amino, amino-C.sub.1-6alkyl or hydroxy-C.sub.1-6alkyl; and
pyrrolidinyloxy wherein the pyrrolidinyl moiety is optionally
substituted with hydroxy, amino, amino-C.sub.1-6alkyl,
hydroxy-C.sub.1-6alkyl or aminocarbonyl.
[0274] In certain embodiments of formula I or formula II, Ar is
indolyl optionally substituted once or twice with a group or groups
independently selected from: C.sub.1-6alkyl; C.sub.1-6alkoxy;
hydroxy-C.sub.1-6alkoxy; hydroxy-C.sub.1-6alkylamino;
amino-C.sub.1-6alkoxy; cyclohexyloxy wherein the cyclohexyl moiety
thereof is optionally substituted with hydroxy, amino,
amino-C.sub.1-6alkyl or hydroxy-C.sub.1-6alkyl; piperidinyl wherein
the piperidinyl moiety is optionally substituted with hydroxy,
amino, amino-C.sub.1-6alkyl, hydroxy-C.sub.1-6alkyl or
aminocarbonyl; piperidinyloxy wherein the piperidinyl moiety
thereof is optionally substituted with hydroxy, amino,
amino-C.sub.1-6alkyl, hydroxy-C.sub.1-6alkyl or aminocarbonyl;
cyclopentyloxy wherein the cyclopentyl moiety thereof is optionally
substituted with hydroxy, amino, amino-C.sub.1-6alkyl or
hydroxy-C.sub.1-6alkyl; and pyrrolidinyloxy wherein the
pyrrolidinyl moiety is optionally substituted with hydroxy, amino,
amino-C.sub.1-6alkyl, hydroxy-C.sub.1-6alkyl or aminocarbonyl.
[0275] In certain embodiments of formula I or formula II, Ar is
indazolyl optionally substituted once or twice with a group or
groups independently selected from: C.sub.1-6alkyl;
C.sub.1-6alkoxy; hydroxy-C.sub.1-6alkoxy;
hydroxy-C.sub.1-6alkylamino; amino-C.sub.1-6alkoxy; cyclohexyloxy
wherein the cyclohexyl moiety thereof is optionally substituted
with hydroxy, amino, amino-C.sub.1-6alkyl or
hydroxy-C.sub.1-6alkyl; piperidinyl wherein the piperidinyl moiety
is optionally substituted with hydroxy, amino,
amino-C.sub.1-6alkyl, hydroxy-C.sub.1-6alkyl or aminocarbonyl;
piperidinyloxy wherein the piperidinyl moiety thereof is optionally
substituted with hydroxy, amino, amino-C.sub.1-6alkyl,
hydroxy-C.sub.1-6alkyl or aminocarbonyl; cyclopentyloxy wherein the
cyclopentyl moiety thereof is optionally substituted with hydroxy,
amino, amino-C.sub.1-6alkyl or hydroxy-C.sub.1-6alkyl; and
pyrrolidinyloxy wherein the pyrrolidinyl moiety is optionally
substituted with hydroxy, amino, amino-C.sub.1-6alkyl,
hydroxy-C.sub.1-6alkyl or aminocarbonyl.
[0276] In certain embodiments of formula I or formula II, Ar is
benzimidazolyl optionally substituted once or twice with a group or
groups independently selected from: C.sub.1-6alkyl;
C.sub.1-6alkoxy; hydroxy-C.sub.1-6alkoxy;
hydroxy-C.sub.1-6alkylamino; amino-C.sub.1-6alkoxy; cyclohexyloxy
wherein the cyclohexyl moiety thereof is optionally substituted
with hydroxy, amino, amino-C.sub.1-6alkyl or
hydroxy-C.sub.1-6alkyl; piperidinyl wherein the piperidinyl moiety
is optionally substituted with hydroxy, amino,
amino-C.sub.1-6alkyl, hydroxy-C.sub.1-6alkyl or aminocarbonyl;
piperidinyloxy wherein the piperidinyl moiety thereof is optionally
substituted with hydroxy, amino, amino-C.sub.1-6alkyl,
hydroxy-C.sub.1-6alkyl or aminocarbonyl; cyclopentyloxy wherein the
cyclopentyl moiety thereof is optionally substituted with hydroxy,
amino, amino-C.sub.1-6alkyl or hydroxy-C.sub.1-6alkyl; and
pyrrolidinyloxy wherein the pyrrolidinyl moiety is optionally
substituted with hydroxy, amino, amino-C.sub.1-6alkyl,
hydroxy-C.sub.1-6alkyl or aminocarbonyl.
[0277] In certain embodiments of formula I or formula II, Ar is
quinolin-6-yl substituted once or twice with a group or groups
independently selected from: C.sub.1-6alkyl; C.sub.1-6alkoxy;
hydroxy-C.sub.1-6alkoxy; hydroxy-C.sub.1-6alkylamino;
amino-C.sub.1-6alkoxy; cyclohexyloxy wherein the cyclohexyl moiety
thereof is optionally substituted with hydroxy, amino,
amino-C.sub.1-6alkyl or hydroxy-C.sub.1-6alkyl; piperidinyl wherein
the piperidinyl moiety is optionally substituted with hydroxy,
amino, amino-C.sub.1-6alkyl, hydroxy-C.sub.1-6alkyl or
aminocarbonyl; piperidinyloxy wherein the piperidinyl moiety
thereof is optionally substituted with hydroxy, amino,
amino-C.sub.1-6alkyl, hydroxy-C.sub.1-6alkyl or aminocarbonyl;
cyclopentyloxy wherein the cyclopentyl moiety thereof is optionally
substituted with hydroxy, amino, amino-C.sub.1-6alkyl or
hydroxy-C.sub.1-6alkyl; and pyrrolidinyloxy wherein the
pyrrolidinyl moiety is optionally substituted with hydroxy, amino,
amino-C.sub.1-6alkyl, hydroxy-C.sub.1-6alkyl or aminocarbonyl.
[0278] In certain embodiments of formula I or formula II, Ar is
quinolin-6-yl substituted at the 7-position, and optionally
substituted at the 2-position, with a group or groups independently
selected from: C.sub.1-6alkyl; C.sub.1-6alkoxy;
hydroxy-C.sub.1-6alkoxy; hydroxy-C.sub.1-6alkylamino;
amino-C.sub.1-6alkoxy; cyclohexyloxy wherein the cyclohexyl moiety
thereof is optionally substituted with hydroxy, amino,
amino-C.sub.1-6alkyl or hydroxy-C.sub.1-6alkyl; piperidinyl wherein
the piperidinyl moiety is optionally substituted with hydroxy,
amino, amino-C.sub.1-6alkyl, hydroxy-C.sub.1-6alkyl or
aminocarbonyl; piperidinyloxy wherein the piperidinyl moiety
thereof is optionally substituted with hydroxy, amino,
amino-C.sub.1-6alkyl, hydroxy-C.sub.1-6alkyl or aminocarbonyl;
cyclopentyloxy wherein the cyclopentyl moiety thereof is optionally
substituted with hydroxy, amino, amino-C.sub.1-6alkyl or
hydroxy-C.sub.1-6alkyl; and pyrrolidinyloxy wherein the
pyrrolidinyl moiety is optionally substituted with hydroxy, amino,
amino-C.sub.1-6alkyl, hydroxy-C.sub.1-6alkyl or aminocarbonyl.
[0279] In certain embodiments of formula I or formula II, Ar is
heteroaryl selected from:
7-(4-aminomethyl-piperidin-1-yl)-quinolin-6-yl;
2-(2-hydroxy-ethylamino)-7-methoxy-quinolin-6-yl;
7-(4-hydroxy-cyclohexyloxy)-quinolin-6-yl; 7-methoxy-quinolin-6-yl;
7-piperidin-1-yl-quinolin-6-yl;
7-(3-hydroxy-cyclopentyloxy)-quinolin-6-yl;
7-(3-hydroxy-1-methyl-butoxy)-quinolin-6-yl;
7-(3-hydroxy-butoxy)-quinolin-6-yl;
7-(piperidin-4-yloxy)-quinolin-6-yl;
7-(3-hydroxy-1,1-dimethyl-propoxy)-quinolin-6-yl;
7-(3-amino-propoxy)-quinolin-6-yl;
7-(3-hydroxy-cyclopentyloxy)-quinolin-6-yl;
7-(piperidin-4-yloxy)-quinolin-6-yl;
7-(3-hydroxy-propoxy)-quinolin-6-yl;
7-(pyrrolidin-3-yloxy)-quinolin-6-yl;
7-(4-hydroxymethyl-piperidin-1-yl)-quinolin-6-yl;
7-(4-aminomethyl-piperidin-1-yl)-quinolin-6-yl; quinolin-6-yl;
5-(4-hydroxymethyl-piperidin-1-yl)-2-oxo-2,3-dihydro-1H-indol-6-yl;
5-(4-hydroxymethyl-phenyl)-2-methyl-1H-indol-6-yl;
2-oxo-5-piperidin-1-yl-2,3-dihydro-1H-indol-6-yl;
6-methoxy-1H-indazol-5-yl; 5-methoxy-2-methyl-1H-indol-6-yl;
5-methoxy-1H-indol-6-yl; or
1-(3-hydroxy-propyl)-1H-benzoimidazol-2-yl.
[0280] In certain embodiments of formula I or formula II, Ar is
heteroaryl selected from:
7-(4-aminomethyl-piperidin-1-yl)-quinolin-6-yl;
2-(2-hydroxy-ethylamino)-7-methoxy-quinolin-6-yl;
7-(4-hydroxy-cyclohexyloxy)-quinolin-6-yl; 7-methoxy-quinolin-6-yl;
7-piperidin-1-yl-quinolin-6-yl;
7-(3-hydroxy-cyclopentyloxy)-quinolin-6-yl;
7-(3-hydroxy-1-methyl-butoxy)-quinolin-6-yl;
7-(3-hydroxy-butoxy)-quinolin-6-yl;
7-(piperidin-4-yloxy)-quinolin-6-yl;
7-(3-hydroxy-1,1-dimethyl-propoxy)-quinolin-6-yl;
7-(3-amino-propoxy)-quinolin-6-yl;
7-(3-hydroxy-cyclopentyloxy)-quinolin-6-yl;
7-(piperidin-4-yloxy)-quinolin-6-yl;
7-(3-hydroxy-propoxy)-quinolin-6-yl;
7-(pyrrolidin-3-yloxy)-quinolin-6-yl;
7-(4-hydroxymethyl-piperidin-1-yl)-quinolin-6-yl;
7-(4-aminomethyl-piperidin-1-yl)-quinolin-6-yl;
5-(4-hydroxymethyl-piperidin-1-yl)-2-oxo-2,3-dihydro-1H-indol-6-yl;
5-(4-hydroxymethyl-phenyl)-2-methyl-1H-indol-6-yl;
2-oxo-5-piperidin-1-yl-2,3-dihydro-1H-indol-6-yl;
6-methoxy-1H-indazol-5-yl; 5-methoxy-2-methyl-1H-indol-6-yl;
5-methoxy-1H-indol-6-yl; or
1-(3-hydroxy-propyl)-1H-benzoimidazol-2-yl.
[0281] In certain embodiments of formula I or formula II, Ar is
quinolinyl selected from:
7-(4-aminomethyl-piperidin-1-yl)-quinolin-6-yl;
2-(2-hydroxy-ethylamino)-7-methoxy-quinolin-6-yl;
7-(4-hydroxy-cyclohexyloxy)-quinolin-6-yl; 7-methoxy-quinolin-6-yl;
7-piperidin-1-yl-quinolin-6-yl;
7-(3-hydroxy-cyclopentyloxy)-quinolin-6-yl;
7-(3-hydroxy-1-methyl-butoxy)-quinolin-6-yl;
7-(3-hydroxy-butoxy)-quinolin-6-yl;
7-(piperidin-4-yloxy)-quinolin-6-yl;
7-(3-hydroxy-1,1-dimethyl-propoxy)-quinolin-6-yl;
7-(3-amino-propoxy)-quinolin-6-yl;
7-(3-hydroxy-cyclopentyloxy)-quinolin-6-yl;
7-(piperidin-4-yloxy)-quinolin-6-yl;
7-(3-hydroxy-propoxy)-quinolin-6-yl;
7-(pyrrolidin-3-yloxy)-quinolin-6-yl;
7-(4-hydroxymethyl-piperidin-1-yl)-quinolin-6-yl;
7-(4-aminomethyl-piperidin-1-yl)-quinolin-6-yl; and
quinolin-6-yl.
[0282] In certain embodiments of formula I or formula II, Ar is
quinolinyl selected from:
7-(4-aminomethyl-piperidin-1-yl)-quinolin-6-yl;
2-(2-hydroxy-ethylamino)-7-methoxy-quinolin-6-yl;
7-(4-hydroxy-cyclohexyloxy)-quinolin-6-yl; 7-methoxy-quinolin-6-yl;
7-piperidin-1-yl-quinolin-6-yl;
7-(3-hydroxy-cyclopentyloxy)-quinolin-6-yl;
7-(3-hydroxy-1-methyl-butoxy)-quinolin-6-yl;
7-(3-hydroxy-butoxy)-quinolin-6-yl;
7-(piperidin-4-yloxy)-quinolin-6-yl;
7-(3-hydroxy-1,1-dimethyl-propoxy)-quinolin-6-yl;
7-(3-amino-propoxy)-quinolin-6-yl;
7-(3-hydroxy-cyclopentyloxy)-quinolin-6-yl;
7-(piperidin-4-yloxy)-quinolin-6-yl;
7-(3-hydroxy-propoxy)-quinolin-6-yl;
7-(pyrrolidin-3-yloxy)-quinolin-6-yl;
7-(4-hydroxymethyl-piperidin-1-yl)-quinolin-6-yl; and
7-(4-aminomethyl-piperidin-1-yl)-quinolin-6-yl.
[0283] In certain embodiments of formula I or formula II, each
R.sup.1 is independently: hydrogen;
[0284] C.sub.1-6alkyl; C.sub.1-6alkoxy; hydroxy;
hydroxy-C.sub.1-6alkyl; C.sub.1-6alkyl-amino; amino-C.sub.1-6alkyl;
amino-C.sub.1-6alkyl-amino; hydroxy-C.sub.1-6alkylamino;
C.sub.3-6cycloalkylamino; halo; or aminocarbonyl.
[0285] In certain embodiments of formula I or formula II, R.sup.1
is hydrogen.
[0286] In certain embodiments of formula I or formula II, R.sup.1
is C.sub.1-6alkyl.
[0287] In certain embodiments of formula I or formula II, R.sup.1
is C.sub.1-6alkoxy.
[0288] In certain embodiments of formula I or formula II, R.sup.1
is hydroxy.
[0289] In certain embodiments of formula I or formula II, R.sup.1
is hydroxy-C.sub.1-6alkyl.
[0290] In certain embodiments of formula I or formula II, R.sup.1
is C.sub.1-6alkyl-amino.
[0291] In certain embodiments of formula I or formula II, R.sup.1
is amino-C.sub.1-6alkyl.
[0292] In certain embodiments of formula I or formula II, R.sup.1
is amino-C.sub.1-6alkyl-amino.
[0293] In certain embodiments of formula I or formula II, R.sup.1
is hydroxy-C.sub.1-6alkylamino.
[0294] In certain embodiments of formula I or formula II, R.sup.1
is C.sub.3-6cycloalkylamino.
[0295] In certain embodiments of formula I or formula II, R.sup.1
is aminocarbonyl.
[0296] In certain embodiments of formula I or formula II, R.sup.1
is halo.
[0297] In certain embodiments of formula I or formula II, R.sup.1
is hydroxy-C.sub.1-6alkyl.
[0298] In certain embodiments of formula I or formula II, R.sup.1
is hydroxy-C.sub.1-6alkoxy.
[0299] In certain embodiments of formula I or formula II, R.sup.1
is: hydrogen; hydroxy; 2-amino-ethyl)-methyl-amino;
2-amino-ethylamino; methy; methoxy; 2-hydroxy-ethyl)-methyl-amino;
hydroxymethyl; 2-hydroxy-1-methyl-ethylamino; 2-cyclopropylamino;
2-hydroxy-ethylamino; 2,3-dihydroxy-propylamino;
3-amino-propylamino; aminocarbonyl;
2-hydroxy-ethyl)-isopropyl-amino; bromo; isobutylamino;
isopropyl-methyl-amino; 3-hydroxy-propylamino;
1-hydroxymethyl-propylamino; 2-hydroxy-ethyl;
2-acetylamino-ethylamino; 3-hydroxy-propyl; or isopropyl-amino.
[0300] In certain embodiments of formula I or formula II, R.sup.1
is hydroxy.
[0301] In certain embodiments of formula I or formula II, R.sup.1
is 2-amino-ethyl)-methyl-amino.
[0302] In certain embodiments of formula I or formula II, R.sup.1
is 2-amino-ethylamino.
[0303] In certain embodiments of formula I or formula II, R.sup.1
is methyl.
[0304] In certain embodiments of formula I or formula II, R.sup.1
is methoxy.
[0305] In certain embodiments of formula I or formula II, R.sup.1
is 2-hydroxy-ethyl)-methyl-amino.
[0306] In certain embodiments of formula I or formula II, R.sup.1
is hydroxymethyl.
[0307] In certain embodiments of formula I or formula II, R.sup.1
is 2-hydroxy-1-methyl-ethylamino.
[0308] In certain embodiments of formula I or formula II, R.sup.1
is 2-cyclopropylamino.
[0309] In certain embodiments of formula I or formula II, R.sup.1
is 2-hydroxy-ethylamino.
[0310] In certain embodiments of formula I or formula II, R.sup.1
is 2,3-dihydroxy-propylamino.
[0311] In certain embodiments of formula I or formula II, R.sup.1
is 3-amino-propylamino.
[0312] In certain embodiments of formula I or formula II, R.sup.1
is aminocarbonyl.
[0313] In certain embodiments of formula I or formula II, R.sup.1
is 2-hydroxy-ethyl)-isopropyl-amino.
[0314] In certain embodiments of formula I or formula II, R.sup.1
is bromo.
[0315] In certain embodiments of formula I or formula II, R.sup.1
is isobutylamino.
[0316] In certain embodiments of formula I or formula II, R.sup.1
is isopropyl-methyl-amino.
[0317] In certain embodiments of formula I or formula II, R.sup.1
is 3-hydroxy-propylamino.
[0318] In certain embodiments of formula I or formula II, R.sup.1
is 1-hydroxymethyl-propylamino.
[0319] In certain embodiments of formula I or formula II, R.sup.1
is 2-hydroxy-ethyl.
[0320] In certain embodiments of formula I or formula II, R.sup.1
is 2-acetylamino-ethylamino.
[0321] In certain embodiments of formula I or formula II, R.sup.1
is 3-hydroxy-propyl.
[0322] In certain embodiments of formula I or formula II, R.sup.1
is isopropyl-amino.
[0323] In certain embodiments, the compounds of formula I and II
may respectively be of formulas Ia or IIa:
##STR00004##
[0324] wherein:
[0325] R.sup.3 and R.sup.4 each independently is: halo;
C.sub.1-6alkyl; halo-C.sub.1-6alkyl; C.sub.1-6alkenyl;
C.sub.1-6alkoxy; halo-C.sub.1-6alkoxy; hydroxy-C.sub.1-6alkyl;
hydroxy-C.sub.1-6alkylamino; C.sub.1-6alkyl-amino; hydroxy; amino;
amino-C.sub.1-6alkyl; aminocarbonyl; hydroxy-C.sub.1-6alkoxy;
hydroxy-C.sub.1-6alkenyl; C.sub.1-6alkoxy-C.sub.1-6alkoxy;
C.sub.1-6alkylsulfonyl; C.sub.1-6alkylsulfanyl; piperidinyl wherein
the piperidinyl moiety is optionally substituted with hydroxy,
amino, amino-C.sub.1-6alkyl, hydroxy-C.sub.1-6alkyl or
aminocarbonyl; phenylaminocarbonyl; hydroxy-C.sub.1-6alkylamino;
cyclohexyloxy wherein the cyclohexyl moiety thereof is optionally
substituted with hydroxy, amino, amino-C.sub.1-6alkyl or
hydroxy-C.sub.1-6alkyl; cyclopentyloxy wherein the cyclopentyl
moiety thereof is optionally substituted with hydroxy, amino,
amino-C.sub.1-6alkyl or hydroxy-C.sub.1-6alkyl; piperidinyloxy
wherein the piperidinyl moiety thereof is optionally substituted
with hydroxy, amino, amino-C.sub.1-6alkyl, hydroxy-C.sub.1-6alkyl
or aminocarbonyl; phenyl wherein the phenyl moiety is optionally
substituted with amino, hydroxy, amino-C.sub.1-6alkyl,
hydroxy-C.sub.1-6alkyl or aminocarbonyl; pyrrolidinyl wherein the
pyrrolidinyl moiety is optionally substituted with hydroxy, amino,
amino-C.sub.1-6alkyl, hydroxy-C.sub.1-6alkyl or aminocarbonyl;
pyrrolidinyloxy wherein the pyrrolidinyl moiety is optionally
substituted with hydroxy, amino, amino-C.sub.1-6alkyl,
hydroxy-C.sub.1-6alkyl or aminocarbonyl; piperazinyl wherein the
piperazinyl moiety is optionally substituted with C.sub.1-6alkyl;
oxazol-C.sub.1-6alkoxy wherein the oxazol moiety thereof is
optionally substituted with C.sub.1-6alkyl; morpholinyl;
hydroxy-C.sub.1-6alkylaminocarbonyl; C.sub.3-6cycloalkyl; azepanyl
wherein the azepanyl moiety is optionally substituted with hydroxy,
amino, amino-C.sub.1-6alkyl, hydroxy-C.sub.1-6alkyl or
aminocarbonyl; benzyl wherein the phenyl moiety thereof is
optionally substituted with amino, hydroxy, amino-C.sub.1-6alkyl,
hydroxy-C.sub.1-6alkyl or aminocarbonyl;
C.sub.1-6alkoxycarbonyl-C.sub.1-6alkoxy; or
C.sub.1-6alkylcarbonylamino; and
[0326] R.sup.1 is as defined herein.
[0327] In certain embodiments of formula Ia or formula IIa, R.sup.4
is halo.
[0328] In certain embodiments of formula Ia or formula IIa, R.sup.4
is chloro.
[0329] In certain embodiments of formula Ia or formula IIa, R.sup.3
is halo.
[0330] In certain embodiments of formula Ia or formula IIa, R.sup.3
is C.sub.1-6alkyl.
[0331] In certain embodiments of formula Ia or formula IIa, R.sup.3
is halo-C.sub.1-6alkyl.
[0332] In certain embodiments of formula Ia or formula IIa, R.sup.3
is C.sub.1-6alkenyl.
[0333] In certain embodiments of formula Ia or formula IIa, R.sup.3
is C.sub.1-6alkoxy.
[0334] In certain embodiments of formula Ia or formula IIa, R.sup.3
is halo-C.sub.1-6alkoxy.
[0335] In certain embodiments of formula Ia or formula IIa, R.sup.3
is hydroxy-C.sub.1-6alkyl.
[0336] In certain embodiments of formula Ia or formula IIa, R.sup.3
is hydroxy-C.sub.1-6alkylamino.
[0337] In certain embodiments of formula Ia or formula IIa, R.sup.3
is C.sub.1-6alkyl-amino.
[0338] In certain embodiments of formula Ia or formula IIa, R.sup.3
is hydroxylamino.
[0339] In certain embodiments of formula Ia or formula IIa, R.sup.3
is amino-C.sub.1-6alkyl.
[0340] In certain embodiments of formula Ia or formula IIa, R.sup.3
is aminocarbonyl.
[0341] In certain embodiments of formula Ia or formula IIa, R.sup.3
is hydroxy-C.sub.1-6alkoxy.
[0342] In certain embodiments of formula Ia or formula IIa, R.sup.3
is hydroxy-C.sub.1-6alkenyl.
[0343] In certain embodiments of formula Ia or formula IIa, R.sup.3
is C.sub.1-6alkoxy-C.sub.1-6alkoxy.
[0344] In certain embodiments of formula Ia or formula IIa, R.sup.3
is C.sub.1-6alkylsulfonyl.
[0345] In certain embodiments of formula Ia or formula IIa, R.sup.3
is C.sub.1-6alkylsulfanyl.
[0346] In certain embodiments of formula Ia or formula IIa, R.sup.3
is piperidinyl wherein the piperidinyl moiety is optionally
substituted with hydroxy, amino, amino-C.sub.1-6alkyl,
hydroxy-C.sub.1-6alkyl or aminocarbonyl.
[0347] In certain embodiments of formula Ia or formula IIa, R.sup.3
is phenylaminocarbonyl.
[0348] In certain embodiments of formula Ia or formula IIa, R.sup.3
is hydroxy-C.sub.1-6alkylamino.
[0349] In certain embodiments of formula Ia or formula IIa, R.sup.3
is cyclohexyloxy wherein the cyclohexyl moiety thereof is
optionally substituted with hydroxy, amino, amino-C.sub.1-6alkyl or
hydroxy-C.sub.1-6alkyl.
[0350] In certain embodiments of formula Ia or formula IIa, R.sup.3
is cyclopentyloxy wherein the cyclopentyl moiety thereof is
optionally substituted with hydroxy, amino, amino-C.sub.1-6alkyl or
hydroxy-C.sub.1-6alkyl.
[0351] In certain embodiments of formula Ia or formula IIa, R.sup.3
is piperidinyloxy wherein the piperidinyl moiety thereof is
optionally substituted with hydroxy, amino, amino-C.sub.1-6alkyl,
hydroxy-C.sub.1-6alkyl or aminocarbonyl.
[0352] In certain embodiments of formula Ia or formula IIa, R.sup.3
is phenyl wherein the phenyl moiety is optionally substituted with
amino, hydroxy, amino-C.sub.1-6alkyl, hydroxy-C.sub.1-6alkyl or
aminocarbonyl.
[0353] In certain embodiments of formula Ia or formula IIa, R.sup.3
is pyrrolidinyl wherein the pyrrolidinyl moiety is optionally
substituted with hydroxy, amino, amino-C.sub.1-6alkyl,
hydroxy-C.sub.1-6alkyl or aminocarbonyl.
[0354] In certain embodiments of formula Ia or formula IIa, R.sup.3
is pyrrolidinyloxy wherein the pyrrolidinyl moiety is optionally
substituted with hydroxy, amino, amino-C.sub.1-6alkyl,
hydroxy-C.sub.1-6alkyl or aminocarbonyl.
[0355] In certain embodiments of formula Ia or formula IIa, R.sup.3
is piperazinyl wherein the piperazinyl moiety is optionally
substituted with C.sub.1-6alkyl.
[0356] In certain embodiments of formula Ia or formula IIa, R.sup.3
is oxazol-C.sub.1-6alkoxy wherein the oxazol moiety thereof is
optionally substituted with C.sub.1-6alkyl.
[0357] In certain embodiments of formula Ia or formula IIa, R.sup.3
is morpholinyl.
[0358] In certain embodiments of formula Ia or formula IIa, R.sup.3
is hydroxy-C.sub.1-6alkylaminocarbonyl.
[0359] In certain embodiments of formula Ia or formula IIa, R.sup.3
is C.sub.3-6cycloalkyl.
[0360] In certain embodiments of formula Ia or formula IIa, R.sup.3
is azepanyl wherein the azepanyl moiety is optionally substituted
with hydroxy, amino, amino-C.sub.1-6alkyl, hydroxy-C.sub.1-6alkyl
or aminocarbonyl.
[0361] In certain embodiments of formula Ia or formula IIa, R.sup.3
is benzyl wherein the phenyl moiety thereof is optionally
substituted with amino, hydroxy, amino-C.sub.1-6alkyl,
hydroxy-C.sub.1-6alkyl or aminocarbonyl.
[0362] In certain embodiments of formula Ia or formula IIa, R.sup.3
is C.sub.1-6alkoxycarbonyl-C.sub.1-6alkoxy.
[0363] In certain embodiments of formula Ia or formula IIa, R.sup.3
is C.sub.1-6alkylcarbonylamino. In certain embodiments, the
compounds of formula I and II may respectively be of formulas Ib or
IIb:
##STR00005##
[0364] wherein:
[0365] R.sup.5 and R.sup.6 each independently is: hydrogen; halo;
C.sub.1-6alkyl; halo-C.sub.1-6alkyl; C.sub.1-6alkenyl;
C.sub.1-6alkoxy; halo-C.sub.1-6alkoxy; hydroxy-C.sub.1-6alkyl;
hydroxy-C.sub.1-6alkylamino; C.sub.1-6alkyl-amino; hydroxy; amino;
amino-C.sub.1-6alkyl; aminocarbonyl; hydroxy-C.sub.1-6alkoxy;
hydroxy-C.sub.1-6alkenyl; C.sub.1-6alkoxy-C.sub.1-6alkoxy;
C.sub.1-6alkylsulfonyl; C.sub.1-6alkylsulfanyl; piperidinyl wherein
the piperidinyl moiety is optionally substituted with hydroxy,
amino, amino-C.sub.1-6alkyl, hydroxy-C.sub.1-6alkyl or
aminocarbonyl; phenylaminocarbonyl; hydroxy-C.sub.1-6alkylamino;
cyclohexyloxy wherein the cyclohexyl moiety thereof is optionally
substituted with hydroxy, amino, amino-C.sub.1-6alkyl or
hydroxy-C.sub.1-6alkyl; cyclopentyloxy wherein the cyclopentyl
moiety thereof is optionally substituted with hydroxy, amino,
amino-C.sub.1-6alkyl or hydroxy-C.sub.1-6alkyl; piperidinyloxy
wherein the piperidinyl moiety thereof is optionally substituted
with hydroxy, amino, amino-C.sub.1-6alkyl, hydroxy-C.sub.1-6alkyl
or aminocarbonyl; phenyl wherein the phenyl moiety is optionally
substituted with amino, hydroxy, amino-C.sub.1-6alkyl,
hydroxy-C.sub.1-6alkyl or aminocarbonyl; pyrrolidinyl wherein the
pyrrolidinyl moiety is optionally substituted with hydroxy, amino,
amino-C.sub.1-6alkyl, hydroxy-C.sub.1-6alkyl or aminocarbonyl;
pyrrolidinyloxy wherein the pyrrolidinyl moiety is optionally
substituted with hydroxy, amino, amino-C.sub.1-6alkyl,
hydroxy-C.sub.1-6alkyl or aminocarbonyl; piperazinyl wherein the
piperazinyl moiety is optionally substituted with C.sub.1-6alkyl;
oxazol-C.sub.1-6alkoxy wherein the oxazol moiety thereof is
optionally substituted with C.sub.1-6alkyl; morpholinyl;
hydroxy-C.sub.1-6alkylaminocarbonyl; C.sub.3-6cycloalkyl; azepanyl
wherein the azepanyl moiety is optionally substituted with hydroxy,
amino, amino-C.sub.1-6alkyl, hydroxy-C.sub.1-6alkyl or
aminocarbonyl; benzyl wherein the phenyl moiety thereof is
optionally substituted with amino, hydroxy, amino-C.sub.1-6alkyl,
hydroxy-C.sub.1-6alkyl or aminocarbonyl;
C.sub.1-6alkoxycarbonyl-C.sub.1-6alkoxy; or
C.sub.1-6alkylcarbonylamino; and
[0366] R.sup.1 is as defined herein.
[0367] In certain embodiments of formula Ib or formula IIb, R.sup.5
and R.sup.6 each independently is: halo; C.sub.1-6alkyl;
halo-C.sub.1-6alkyl; C.sub.1-6alkenyl; C.sub.1-6alkoxy;
halo-C.sub.1-6alkoxy; hydroxy-C.sub.1-6alkyl;
hydroxy-C.sub.1-6alkylamino; C.sub.1-6alkyl-amino; hydroxy; amino;
amino-C.sub.1-6alkyl; aminocarbonyl; hydroxy-C.sub.1-6alkoxy;
hydroxy-C.sub.1-6alkenyl; C.sub.1-6alkoxy-C.sub.1-6alkoxy;
C.sub.1-6alkylsulfonyl; C.sub.1-6alkylsulfanyl; piperidinyl wherein
the piperidinyl moiety is optionally substituted with hydroxy,
amino, amino-C.sub.1-6alkyl, hydroxy-C.sub.1-6alkyl or
aminocarbonyl; phenylaminocarbonyl; hydroxy-C.sub.1-6alkylamino;
cyclohexyloxy wherein the cyclohexyl moiety thereof is optionally
substituted with hydroxy, amino, amino-C.sub.1-6alkyl or
hydroxy-C.sub.1-6alkyl; cyclopentyloxy wherein the cyclopentyl
moiety thereof is optionally substituted with hydroxy, amino,
amino-C.sub.1-6alkyl or hydroxy-C.sub.1-6alkyl; piperidinyloxy
wherein the piperidinyl moiety thereof is optionally substituted
with hydroxy, amino, amino-C.sub.1-6alkyl, hydroxy-C.sub.1-6alkyl
or aminocarbonyl; phenyl wherein the phenyl moiety is optionally
substituted with amino, hydroxy, amino-C.sub.1-6alkyl,
hydroxy-C.sub.1-6alkyl or aminocarbonyl; pyrrolidinyl wherein the
pyrrolidinyl moiety is optionally substituted with hydroxy, amino,
amino-C.sub.1-6alkyl, hydroxy-C.sub.1-6alkyl or aminocarbonyl;
pyrrolidinyloxy wherein the pyrrolidinyl moiety is optionally
substituted with hydroxy, amino, amino-C.sub.1-6alkyl,
hydroxy-C.sub.1-6alkyl or aminocarbonyl; piperazinyl wherein the
piperazinyl moiety is optionally substituted with C.sub.1-6alkyl;
oxazol-C.sub.1-6alkoxy wherein the oxazol moiety thereof is
optionally substituted with C.sub.1-6alkyl; morpholinyl;
hydroxy-C.sub.1-6alkylaminocarbonyl; C.sub.3-6cycloalkyl; azepanyl
wherein the azepanyl moiety is optionally substituted with hydroxy,
amino, amino-C.sub.1-6alkyl, hydroxy-C.sub.1-6alkyl or
aminocarbonyl; benzyl wherein the phenyl moiety thereof is
optionally substituted with amino, hydroxy, amino-C.sub.1-6alkyl,
hydroxy-C.sub.1-6alkyl or aminocarbonyl;
C.sub.1-6alkoxycarbonyl-C.sub.1-6alkoxy; or
C.sub.1-6alkylcarbonylamino.
[0368] In certain embodiments of formula Ib or formula IIb, R.sup.5
is hydrogen.
[0369] In certain embodiments of formula Ia or formula IIa, R.sup.5
is halo.
[0370] In certain embodiments of formula Ia or formula IIa, R.sup.5
is C.sub.1-6alkyl.
[0371] In certain embodiments of formula Ia or formula IIa, R.sup.5
is halo-C.sub.1-6alkyl.
[0372] In certain embodiments of formula Ia or formula IIa, R.sup.5
is C.sub.1-6alkenyl.
[0373] In certain embodiments of formula Ia or formula IIa, R.sup.5
is C.sub.1-6alkoxy.
[0374] In certain embodiments of formula Ia or formula IIa, R.sup.5
is halo-C.sub.1-6alkoxy.
[0375] In certain embodiments of formula Ia or formula IIa, R.sup.5
is hydroxy-C.sub.1-6alkyl.
[0376] In certain embodiments of formula Ia or formula IIa, R.sup.5
is hydroxy-C.sub.1-6alkylamino.
[0377] In certain embodiments of formula Ia or formula IIa, R.sup.5
is C.sub.1-6alkyl-amino.
[0378] In certain embodiments of formula Ia or formula IIa, R.sup.5
is hydroxylamino.
[0379] In certain embodiments of formula Ia or formula IIa, R.sup.5
is amino-C.sub.1-6alkyl.
[0380] In certain embodiments of formula Ia or formula IIa, R.sup.5
is aminocarbonyl.
[0381] In certain embodiments of formula Ia or formula IIa, R.sup.5
is hydroxy-C.sub.1-6alkoxy.
[0382] In certain embodiments of formula Ia or formula IIa, R.sup.5
is hydroxy-C.sub.1-6alkenyl.
[0383] In certain embodiments of formula Ia or formula IIa, R.sup.5
is C.sub.1-6alkoxy-C.sub.1-6alkoxy.
[0384] In certain embodiments of formula Ia or formula IIa, R.sup.5
is C.sub.1-6alkylsulfonyl.
[0385] In certain embodiments of formula Ia or formula IIa, R.sup.5
is C.sub.1-6alkylsulfanyl.
[0386] In certain embodiments of formula Ia or formula IIa, R.sup.5
is piperidinyl wherein the piperidinyl moiety is optionally
substituted with hydroxy, amino, amino-C.sub.1-6alkyl,
hydroxy-C.sub.1-6alkyl or aminocarbonyl.
[0387] In certain embodiments of formula Ia or formula IIa, R.sup.5
is phenylaminocarbonyl.
[0388] In certain embodiments of formula Ia or formula IIa, R.sup.5
is hydroxy-C.sub.1-6alkylamino.
[0389] In certain embodiments of formula Ia or formula IIa, R.sup.5
is cyclohexyloxy wherein the cyclohexyl moiety thereof is
optionally substituted with hydroxy, amino, amino-C.sub.1-6alkyl or
hydroxy-C.sub.1-6alkyl.
[0390] In certain embodiments of formula Ia or formula IIa, R.sup.5
is cyclopentyloxy wherein the cyclopentyl moiety thereof is
optionally substituted with hydroxy, amino, amino-C.sub.1-6alkyl or
hydroxy-C.sub.1-6alkyl.
[0391] In certain embodiments of formula Ia or formula IIa, R.sup.5
is piperidinyloxy wherein the piperidinyl moiety thereof is
optionally substituted with hydroxy, amino, amino-C.sub.1-6alkyl,
hydroxy-C.sub.1-6alkyl or aminocarbonyl.
[0392] In certain embodiments of formula Ia or formula IIa, R.sup.5
is phenyl wherein the phenyl moiety is optionally substituted with
amino, hydroxy, amino-C.sub.1-6alkyl, hydroxy-C.sub.1-6alkyl or
aminocarbonyl.
[0393] In certain embodiments of formula Ia or formula IIa, R.sup.5
is pyrrolidinyl wherein the pyrrolidinyl moiety is optionally
substituted with hydroxy, amino, amino-C.sub.1-6alkyl,
hydroxy-C.sub.1-6alkyl or aminocarbonyl.
[0394] In certain embodiments of formula Ia or formula IIa, R.sup.5
is pyrrolidinyloxy wherein the pyrrolidinyl moiety is optionally
substituted with hydroxy, amino, amino-C.sub.1-6alkyl,
hydroxy-C.sub.1-6alkyl or aminocarbonyl.
[0395] In certain embodiments of formula Ia or formula IIa, R.sup.5
is piperazinyl wherein the piperazinyl moiety is optionally
substituted with C.sub.1-6alkyl.
[0396] In certain embodiments of formula Ia or formula IIa, R.sup.5
is oxazol-C.sub.1-6alkoxy wherein the oxazol moiety thereof is
optionally substituted with C.sub.1-6alkyl.
[0397] In certain embodiments of formula Ia or formula IIa, R.sup.5
is morpholinyl.
[0398] In certain embodiments of formula Ia or formula IIa, R.sup.5
is hydroxy-C.sub.1-6alkylaminocarbonyl.
[0399] In certain embodiments of formula Ia or formula IIa, R.sup.5
is C.sub.3-6cycloalkyl.
[0400] In certain embodiments of formula Ia or formula IIa, R.sup.5
is azepanyl wherein the azepanyl moiety is optionally substituted
with hydroxy, amino, amino-C.sub.1-6alkyl, hydroxy-C.sub.1-6alkyl
or aminocarbonyl.
[0401] In certain embodiments of formula Ia or formula IIa, R.sup.5
is benzyl wherein the phenyl moiety thereof is optionally
substituted with amino, hydroxy, amino-C.sub.1-6alkyl,
hydroxy-C.sub.1-6alkyl or aminocarbonyl.
[0402] In certain embodiments of formula Ia or formula IIa, R.sup.5
is C.sub.1-6alkoxycarbonyl-C.sub.1-6alkoxy.
[0403] In certain embodiments of formula Ia or formula IIa, R.sup.5
is C.sub.1-6alkylcarbonylamino.
[0404] In certain embodiments of formula Ib or formula IIb, R.sup.6
is hydrogen.
[0405] In certain embodiments of formula Ia or formula IIa, R.sup.6
is halo.
[0406] In certain embodiments of formula Ia or formula IIa, R.sup.6
is C.sub.1-6alkyl.
[0407] In certain embodiments of formula Ia or formula IIa, R.sup.6
is halo-C.sub.1-6alkyl.
[0408] In certain embodiments of formula Ia or formula IIa, R.sup.6
is C.sub.1-6alkenyl.
[0409] In certain embodiments of formula Ia or formula IIa, R.sup.6
is C.sub.1-6alkoxy.
[0410] In certain embodiments of formula Ia or formula IIa, R.sup.6
is halo-C.sub.1-6alkoxy.
[0411] In certain embodiments of formula Ia or formula IIa, R.sup.6
is hydroxy-C.sub.1-6alkyl.
[0412] In certain embodiments of formula Ia or formula IIa, R.sup.6
is hydroxy-C.sub.1-6alkylamino.
[0413] In certain embodiments of formula Ia or formula IIa, R.sup.6
is C.sub.1-6alkyl-amino.
[0414] In certain embodiments of formula Ia or formula IIa, R.sup.6
is hydroxylamino.
[0415] In certain embodiments of formula Ia or formula IIa, R.sup.6
is amino-C.sub.1-6alkyl.
[0416] In certain embodiments of formula Ia or formula IIa, R.sup.6
is aminocarbonyl.
[0417] In certain embodiments of formula Ia or formula IIa, R.sup.6
is hydroxy-C.sub.1-6alkoxy.
[0418] In certain embodiments of formula Ia or formula IIa, R.sup.6
is hydroxy-C.sub.1-6alkenyl.
[0419] In certain embodiments of formula Ia or formula IIa, R.sup.6
is C.sub.1-6alkoxy-C.sub.1-6alkoxy.
[0420] In certain embodiments of formula Ia or formula IIa, R.sup.6
is C.sub.1-6alkylsulfonyl.
[0421] In certain embodiments of formula Ia or formula IIa, R.sup.6
is C.sub.1-6alkylsulfanyl.
[0422] In certain embodiments of formula Ia or formula IIa, R.sup.6
is piperidinyl wherein the piperidinyl moiety is optionally
substituted with hydroxy, amino, amino-C.sub.1-6alkyl,
hydroxy-C.sub.1-6alkyl or aminocarbonyl.
[0423] In certain embodiments of formula Ia or formula IIa, R.sup.6
is phenylaminocarbonyl.
[0424] In certain embodiments of formula Ia or formula IIa, R.sup.6
is hydroxy-C.sub.1-6alkylamino.
[0425] In certain embodiments of formula Ia or formula IIa, R.sup.6
is cyclohexyloxy wherein the cyclohexyl moiety thereof is
optionally substituted with hydroxy, amino, amino-C.sub.1-6alkyl or
hydroxy-C.sub.1-6alkyl.
[0426] In certain embodiments of formula Ia or formula IIa, R.sup.6
is cyclopentyloxy wherein the cyclopentyl moiety thereof is
optionally substituted with hydroxy, amino, amino-C.sub.1-6alkyl or
hydroxy-C.sub.1-6alkyl.
[0427] In certain embodiments of formula Ia or formula IIa, R.sup.6
is piperidinyloxy wherein the piperidinyl moiety thereof is
optionally substituted with hydroxy, amino, amino-C.sub.1-6alkyl,
hydroxy-C.sub.1-6alkyl or aminocarbonyl.
[0428] In certain embodiments of formula Ia or formula IIa, R.sup.6
is phenyl wherein the phenyl moiety is optionally substituted with
amino, hydroxy, amino-C.sub.1-6alkyl, hydroxy-C.sub.1-6alkyl or
aminocarbonyl.
[0429] In certain embodiments of formula Ia or formula IIa, R.sup.6
is pyrrolidinyl wherein the pyrrolidinyl moiety is optionally
substituted with hydroxy, amino, amino-C.sub.1-6alkyl,
hydroxy-C.sub.1-6alkyl or aminocarbonyl.
[0430] In certain embodiments of formula Ia or formula IIa, R.sup.6
is pyrrolidinyloxy wherein the pyrrolidinyl moiety is optionally
substituted with hydroxy, amino, amino-C.sub.1-6alkyl,
hydroxy-C.sub.1-6alkyl or aminocarbonyl.
[0431] In certain embodiments of formula Ia or formula IIa, R.sup.6
is piperazinyl wherein the piperazinyl moiety is optionally
substituted with C.sub.1-6alkyl.
[0432] In certain embodiments of formula Ia or formula IIa, R.sup.6
is oxazol-C.sub.1-6alkoxy wherein the oxazol moiety thereof is
optionally substituted with C.sub.1-6alkyl.
[0433] In certain embodiments of formula Ia or formula IIa, R.sup.6
is morpholinyl.
[0434] In certain embodiments of formula Ia or formula IIa, R.sup.6
is hydroxy-C.sub.1-6alkylaminocarbonyl.
[0435] In certain embodiments of formula Ia or formula IIa, R.sup.6
is C.sub.3-6cycloalkyl.
[0436] In certain embodiments of formula Ia or formula IIa, R.sup.6
is azepanyl wherein the azepanyl moiety is optionally substituted
with hydroxy, amino, amino-C.sub.1-6alkyl, hydroxy-C.sub.1-6alkyl
or aminocarbonyl.
[0437] In certain embodiments of formula Ia or formula IIa, R.sup.6
is benzyl wherein the phenyl moiety thereof is optionally
substituted with amino, hydroxy, amino-C.sub.1-6alkyl,
hydroxy-C.sub.1-6alkyl or aminocarbonyl.
[0438] In certain embodiments of formula Ia or formula IIa, R.sup.6
is C.sub.1-6alkoxycarbonyl-C.sub.1-6alkoxy.
[0439] In certain embodiments of formula Ia or formula IIa, R.sup.6
is C.sub.1-6alkylcarbonylamino.
[0440] Where any of R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5 and
R.sup.6 is alkyl or contains an alkyl moiety, such alkyl is
preferably lower alkyl, i.e. C.sub.1-C.sub.6alkyl, and in many
embodiments is C.sub.1-C.sub.4alkyl.
[0441] The invention provides compounds of the formula I' or
formula II':
##STR00006##
or pharmaceutically acceptable salts thereof, wherein:
[0442] X is N or CH
[0443] m is 1 or 2;
[0444] Ar is: [0445] optionally substituted aryl; or [0446]
optionally substituted heteroaryl;
[0447] R.sup.1 is: [0448] hydrogen; [0449] C.sub.1-6alkyl; [0450]
C.sub.1-6alkoxy; [0451] hydroxy; [0452] hydroxy-C.sub.1-6alkyl;
[0453] C.sub.1-6alkyl-amino; [0454] amino-C.sub.1-6alkyl; [0455]
amino-C.sub.1-6alkyl-amino; [0456] hydroxy-C.sub.1-6alkylamino
[0457] C.sub.3-6cycloalkylamino; [0458] aminocarbonyl; [0459] halo;
[0460] hydroxy-C.sub.1-6alkyl; or [0461] hydroxy-C.sub.1-6alkoxy;
and
[0462] R.sup.2 is: [0463] hydrogen; or [0464] C.sub.1-6alkyl.
[0465] The invention also provides methods for treating a disease
or condition mediated by or otherwise associated with an IRAK
receptor, the method comprising administering to a subject in need
thereof an effective amount of a compound of the invention.
[0466] The invention also provides methods for treating a disease
or condition mediated by or otherwise associated with an SYK
receptor, the method comprising administering to a subject in need
thereof an effective amount of a compound of the invention.
[0467] The disease may be an inflammatory disease such as
arthritis, and more particularly rheumatoid arthritis,
osteoarthritis, psoriasis, allergic dermatitis, asthma, chronic
obstructive pulmonary disease, airways hyper-responsiveness, septic
shock, glomerulonephritis, irritable bowel disease, and Crohn's
disease.
[0468] The disease may be a pain condition, such as inflammatory
pain; surgical pain; visceral pain; dental pain; premenstrual pain;
central pain; pain due to burns; migraine or cluster headaches;
nerve injury; neuritis; neuralgias; poisoning; ischemic injury;
interstitial cystitis; cancer pain; viral, parasitic or bacterial
infection; post-traumatic injury; or pain associated with irritable
bowel syndrome.
[0469] The disease may be a respiratory disorder, such as chronic
obstructive pulmonary disorder (COPD), asthma, or bronchospasm, or
a gastrointestinal (GI) disorder such as Irritable Bowel Syndrome
(IBS), Inflammatory Bowel Disease (IBD), biliary colic and other
biliary disorders, renal colic, diarrhea-dominant IBS, pain
associated with GI distension.
[0470] Representative compounds in accordance with the methods of
the invention are shown in Table 1 with reference to the
experimental examples below, together with IC.sub.50 values
(micromolar) for IRAK1, IRAK4 and SYK for selected compounds.
TABLE-US-00001 IRAK IRAK # Structure Chemical Name 4 1 SYK Ex. 1
##STR00007## 6-Hydroxy- pyrazolo[1,5- alpha]pyrimidine-3-
carboxylic acid [2- (4-aminomethyl- piperidin-1-yl)-5-
chloro-phenyl]-amide 0.001 0.055 14 2 ##STR00008## Pyrazolo[1,5-
alpha]pyrimidine-3- carboxylic acid [7- (4-aminomethyl-
piperidin-1-yl)- quinolin-6-yl]-amide 0.002 15 3 ##STR00009##
Pyrazolo[1,5- alpha]pyrimidine-3- carboxylic acid [2- (2-hydroxy-
ethylamino)-7- methoxy-quinolin- 6-yl]-amide 0.003 1 4 ##STR00010##
Pyrazolo[1,5- alpha]pyrimidine-3- carboxylic acid [2-
(4-aminomethyl- piperidin-1-yl)-4- phenylcarbamoyl- phenyl]-amide
0.004 0.45 15 5 ##STR00011## Pyrazolo[1,5- alpha]pyrimidine-3-
carboxylic acid {5- chloro-2-[4-(1- hydroxy-ethyl)-
piperidin-1-yl]- phenyl}-amide 0.005 0.97 5 6 ##STR00012##
Thieno[3,2- d]pyrimidine-7- carboxylic acid [7- (4-hydroxy-
cyclohexyloxy)- quinolin-6-yl]- amide 0.007 0.07 5 7 ##STR00013##
2-[(2-Amino- ethyl)-methyl- amino]-thieno[3,2- d]pyrimidine-7-
carboxylic acid (7- methoxy-quinolin- 6-yl)-amide 0.008 0.9825 0.41
12 8 ##STR00014## Pyrazolo[1,5- alpha]pyrimidine-3- carboxylic acid
(7- piperidin-1-yl- quinolin-6-yl)- amide 0.008 1 9 ##STR00015##
6-Hydroxy- pyrazolo[1,5- alpha]pyrimidine-3- carboxylic acid (7-
methoxy-quinolin- 6-yl)-amide 0.009 0.20 14 10 ##STR00016##
Thieno[3,2- d]pyrimidine-7- carboxylic acid [2- (2-hydroxy-
ethylamino)-7- methoxy-quinolin- 6-yl]-amide 0.010 0.20 1 11
##STR00017## 2-(2-Amino- ethylamino)- thieno[3,2- d]pyrimidine-7-
carboxylic acid (7- methoxy-quinolin- 6-yl)-amide 0.010 0.712 0.017
12 12 ##STR00018## Thieno[3,2- d]pyrimidine-7- carboxylic acid [7-
(4-hydroxy- cyclohexyloxy)- quinolin-6-yl]- amide 0.011 0.168 5 13
##STR00019## Thieno[3,2- d]pyrimidine-7- carboxylic acid (7-
piperidin-1-y1- quinolin-6-yl)- amide 0.012 1 14 ##STR00020##
Thieno[3,2- d]pyrimidine-7- carboxylic acid [7- (4-aminomethyl-
piperidin-1-yl)- quinolin-6-yl]- amide hydrochloride 0.012 0.85 15
15 ##STR00021## Thieno[3,2- d]pyrimidine-7- carboxylic acid [7-
(3-hydroxy- cyclopentyloxy)- quinolin-6-yl]- amide hydrochloride
0.015 0.246 5 16 ##STR00022## 6-Hydroxy- pyrazolo[1,5-
alpha]pyrimidine-3- carboxylic acid [5- chloro-2-(4- hydroxymethyl-
piperidin-1-yl)- phenyl]-amide 0.018 0.836 14 17 ##STR00023##
Thieno[3,2- d]pyrimidine-7- carboxylic acid (7- methoxy-quinolin-
6-yl)-amide 0.018 0.622 1 18 ##STR00024## 6-Hydroxy- pyrazolo[1,5-
alpha]pyrimidine-3- carboxylic acid [5- chloro-2-(4- hydroxy-
cyclohexyloxy)- phenyl]-amide 0.023 0.163 5 19 ##STR00025##
Thieno[3,2- d]pyrimidine-7- carboxylic acid [7- (4-hydroxy-
cyclohexyloxy)- quinolin-6-yl]-amide 0.024 0.123 5 20 ##STR00026##
6-Hydroxy- pyrazolo[1,5- alpha]pyrimidine-3- carboxylic acid (5-
chloro-2-piperidin- 1-yl-phenyl)-amide 0.024 0.644 20 21
##STR00027## Thieno[3,2- d]pyrimidine-7- carboxylic acid [7-
(3-hydroxy-1- methyl-butoxy)- quinolin-6-yl]- amide 0.024 0.76
0.449 5 22 ##STR00028## 6-Methyl- pyrazolo[1,5- alpha]pyrimidine-3-
carboxylic acid [5- chloro-2-(4- hydroxymethyl- piperidin-1-yl)-
phenyl]-amide 0.028 1 23 ##STR00029## Pyrazolo[1,5-
alpha]pyrimidine-3- carboxylic acid [7- (4-hydroxy- cyclohexyloxy)-
quinolin-6-yl]- amide 0.029 0.103 5 24 ##STR00030## 2-[(2-Hydroxy-
ethyl)-methyl- amino]-thieno[3,2- d]pyrimidine-7- carboxylic acid
(7- methoxy-quinolin- 6-yl)-amide 0.029 0.3 12 25 ##STR00031##
Pyrazolo[1,{tilde over (5)}alpha] pyrimidine-3- carboxylic acid [2-
(4-aminomethyl- piperidin-1-yl)-5- chloro-phenyl]- amide 0.031 0.92
11 26 ##STR00032## 2-Isopropylamino- thieno[3,2- d]pyrimidine-7-
carboxylic acid (7- methoxy-quinolin- 6-yl)-amide 0.031 0.463 0.725
12 27 ##STR00033## 2-Isopropylamino- thieno[3,2- d]pyrimidine-7-
carboxylic acid (7- methoxy-quinolin- 6-yl)-amide 0.031 12 28
##STR00034## Thieno[3,2- d]pyrimidine-7- carboxylic acid [7-
(3-hydroxy- butoxy)-quinolin-6- yl]-amide 0.033 1 29 ##STR00035##
6-Methoxy- pyrazolo[1,{tilde over (5)}alpha]py- rimidine-3-
carboxylic acid [5- chloro-2-(4- hydroxymethyl- piperidin-1-yl)-
phenyl]-amide 0.033 1 30 ##STR00036## 6-Hydroxymethyl-
thieno[3,{tilde over (2)}beta]py- ridine-3-carboxylic acid
(7-methoxy- quinolin-6-yl)- amide 0.035 0.746 13 31 ##STR00037##
Pyrazolo[1,{tilde over (5)}alpha]py- rimidine-3- carboxylic acid
[2- (4-aminomethyl- piperidin-1-yl)-5- chloro-phenyl]-amide 0.037
11 32 ##STR00038## Pyrazolo[1,5- alpha]pyrimidine-3- carboxylic
acid [7- (piperidin-4-yloxy)- quinolin-6-yl]- amide hydrochloride
0.040 15 33 ##STR00039## Pyrazolo[1,{tilde over (5)}alpha]
pyrimidine-3- carboxylic acid (7- methoxy-quinolin- 6-yl)-amide
0.043 1 34 ##STR00040## Pyrazolo[1,5- alpha]pyrimidine-3-
carboxylic acid [5- (4-hydroxymethyl- piperidin-1-yl)-2-
oxo-2,3-dihydro- 1H-indol-6-yl]-amide 0.049 0.478 1 35 ##STR00041##
Thieno[3,2- d]pyrimidine-7- carboxylic acid [7- (3-hydroxy-1,1-
dimethyl-propoxy)- quinolin-6-yl]- amide hydrochloride 0.049 0.364
1 36 ##STR00042## Pyrazolo[1,5- alpha]pyrimidine-3- carboxylic acid
[5- (4-hydroxymethyl- phenyl)-2-methyl- 1H-indol-6-yl]- amide 0.052
1 37 ##STR00043## 6-Hydroxy- pyrazolo[1,5- alpha]pyrimidine-3-
carboxylic acid [5- chloro-2-(4- dimethylaminomethyl-
piperidin-1-yl)- phenyl]-amide 0.053 0.307 21 38 ##STR00044##
Pyrazolo[1,{tilde over (5)}alpha] pyrimidine-3- carboxylic acid {2-
[4-(1-amino-ethyl)- piperidin-1-yl]-5- chloro-phenyl}-amide 0.053
15 39 ##STR00045## 2-(2-Hydroxy-1- methyl- ethylamino)- thieno[3,2-
d]pyrimidine-7- carboxylic acid (7- methoxy-quinolin- 6-yl)-amide
0.063 0.492 12 40 ##STR00046## Pyrazolo[1,5- alpha]pyrimidine-3-
carboxylic acid [2- (4-carbamoyl- piperidin-1-yl)-5-
chloro-phenyl]- amide 0.069 0.5 1 41 ##STR00047## Thieno[3,2-
beta]pyridine-3- carboxylic acid [2- (4-aminomethyl-
piperidin-1-yl)-5- chloro-phenyl]- amide 0.070 11 42 ##STR00048##
Pyrazolo[1,5- alpha]pyrimidine-3- carboxylic acid [5- chloro-2-(4-
hydroxymethyl- piperidin-1-yl)- phenyl]-amide 0.072 1 43
##STR00049## 2- Cyclopropylamino- thieno[3,2- d]pyrimidine-7-
carboxylic acid (7- methoxy-quinolin- 6-yl)-amide 0.074 0.575 0.81
12 44 ##STR00050## Pyrazolo[1,{tilde over (5)}alpha] pyrimidine-3-
carboxylic acid {5- chloro-2-[3-(1- hydroxy-ethyl)-
pyrrolidin-1-yl]- phenyl}-amide 0.076 0.897 1 45 ##STR00051##
2-(2-Hydroxy- ethylamino)- thieno[3,2- d]pyrimidine-7- carboxylic
acid (7- methoxy-quinolin- 6-yl)-amide 0.076 0.216 12 46
##STR00052## Pyrazolo[1,{tilde over (5)}alpha] pyrimidine-3-
carboxylic acid (4'- aminomethyl-4- chloro-biphenyl-2- yl)-amide
0.081 15 47 ##STR00053## 2-(2,3-Dihydroxy- propylamino)-
thieno[3,2- d]pyrimidine-7- carboxylic acid (7- methoxy-quinolin-
6-yl)-amide 0.082 0.608 12 48 ##STR00054## Pyrazolo[1,5-
alpha]pyrimidine-3- carboxylic acid (2- oxo-5-piperidin-1-
yl-2,3-dihydro-1H- indol-6-yl)-amide 0.098 1 49 ##STR00055##
Thieno[3,2- d]pyrimidine-7- carboxylic acid [5- chloro-2-(4-
hydroxymethyl- piperidin-1-yl)- phenyl]-amide 0.100 0.70 1 50
##STR00056## 2-(3-Amino- propylamino)- thieno[3,2- d]pyrimidine-7-
carboxylic acid (7- methoxy-quinolin- 6-yl)-amide 0.101 12 51
##STR00057## Thieno[3,2- d]pyrimidine-7- carboxylic acid [7-
(3-amino-propoxy)- quinolin-6-yl]- amide 0.103 0.529 0.376 15 52
##STR00058## Pyrazolo[1,5- alpha]pyrimidine- 3,6-dicarboxylic acid
6-amide 3-{[5- chloro-2-(4- hydroxy- cyclohexyloxy)- phenyl]-amide}
0.107 5 53 ##STR00059## 2-(2-Amino- ethylamino)- thieno[3,2-
d]pyrimidine-7- carboxylic acid (5- chloro-2-methoxy-
phenyl)-amide} 0.107 0.813 0.35 12 54 ##STR00060## Thieno[3,2-
d]pyrimidine-7- carboxylic acid [7- (3-hydroxy- cyclopentyloxy)-
quinolin-6-yl]- amide hydrochloride 0.122 0.5 5 55 ##STR00061##
Pyrazolo[1,5- alpha]pyrimidine-3- carboxylic acid [3- (4-hydroxy-
cyclohexyloxy)- naphthalen-2-yl]- amide 0.124 0.817 0.628 1 56
##STR00062## Thieno[3,2- d]pyrimidine-7- carboxylic acid [7-
(piperidin-4-yloxy)- quinolin-6-yl]-amide hydrochloride 0.125 15 57
##STR00063## 2-[(2-Hydroxy- ethyl)-isopropyl- amino]-thieno[3,2-
d]pyrimidine-7- carboxylic acid (7- methoxy-quinolin- 6-yl)-amide
0.127 12 58 ##STR00064## Thieno[3,2- d]pyrimidine-7- carboxylic
acid [7- (3-hydroxy- propoxy)-quinolin- 6-yl]-amide 0.131 5 59
##STR00065## Pyrazolo[1,5- alpha]pyrimidine-3- carboxylic acid [3-
amino-2-(4- aminomethyl- piperidin-1-yl)- phenyl]-amide 0.133 15 60
##STR00066## Pyrazolo[1,5- alpha]pyrimidine-3- carboxylic acid [5-
chloro-2-(4- hydroxy-piperidin- 1-yl)-phenyl]-amide 0.136 1 61
##STR00067## 6-Bromo- pyrazolo[1,5- alpha]pyrimidine-3- carboxylic
acid [5- chloro-2-(4- hydroxy- cyclohexyloxy)- phenyl]-amide 0.137
5 62 ##STR00068## Thieno[3,2- d]pyrimidine-7- carboxylic acid [5-
chloro-2-(4- hydroxy- cyclohexyloxy)- phenyl]-amide 0.149 0.126 1
63 ##STR00069## Pyrazolo[1,5- alpha]pyrimidine-3- carboxylic acid
(3- amino-2-piperidin- 1-yl-phenyl)-amide 0.156 1 64 ##STR00070##
Thieno[3,2- d]pyrimidine-7- carboxylic acid [2- (4-aminomethyl-
piperidin-1-yl)-5- chloro-phenyl]-amide 0.167 0.80 11 65
##STR00071## Pyrazolo[1,5- alpha]pyrimidine-3- carboxylic acid [3-
(3-hydroxy- cyclopentyloxy)- naphthalen-2-yl]- amide 0.177 1 66
##STR00072## Pyrazolo[1,5- alpha]pyrimidine-3- carboxylic acid (5-
hydroxymethyl-2- piperidin-1-yl- phenyl)-amide 0.199 1 67
##STR00073## Pyrazolo[1,5- alpha]pyrimidine- 3,6-dicarboxylic acid
6-amide 3-{[5- chloro-2-(4-hydroxy- cyclohexyloxy)- phenyl]-amide}
0.203 6 68 ##STR00074## Pyrazolo[1,5- alpha]pyrimidine-3-
carboxylic acid (4- chloro-4'- hydroxymethyl- biphenyl-2-yl)- amide
0.218 1 69 ##STR00075## Pyrazolo[1,5- alpha]pyrimidine-3-
carboxylic acid (6- methoxy-1H- indazol-5-yl)-amide 0.231 1 70
##STR00076## Pyrazolo[1,{tilde over (5)}alpha] pyrimidine-3-
carboxylic acid [2- (4-amino-piperidin- 1-yl)-5-chloro-
phenyl]-amide 0.251 15 71 ##STR00077## 6-Methoxy- pyrazolo[1,5-
alpha]pyrimidine-3- carboxylic acid [2- (4-aminomethyl-
piperidin-1-yl)-5- chloro-phenyl]- amide 0.254 11 72 ##STR00078##
Pyrazolo[1,5- alpha]pyrimidine-3- carboxylic acid (5-
methoxy-2-methyl- 1H-indol-6-yl)- amide 0.255 1 73 ##STR00079##
2-Isobutylamino- thieno[3,2- d]pyrimidine-7- carboxylic
acid (7- methoxy-quinolin- 6-yl)-amide 0.271 12 74 ##STR00080##
Thieno[3,2- d]pyrimidine-7- carboxylic acid (5- chloro-2-
isopropoxy- phenyl)-amide 0.290 1 75 ##STR00081## 2-(2-Hydroxy-
ethylamino)- thieno[3,2- d]pyrimidine-7- carboxylic acid
quinolin-6-ylamide 0.300 12 76 ##STR00082## 6-Methoxy-
pyrazolo[1,5- a]pyrimidine-3- carboxylic acid [5- chloro-2-(4-
hydroxy- cyclohexyloxy)- phenyl]-amide 0.301 5 77 ##STR00083##
Pyrazolo[1,5- alpha]pyrimidine-3- carboxylic acid [5- chloro-2-(3-
hydroxymethyl- cyclopentyloxy)- phenyl]-amide 0.306 1 78
##STR00084## Pyrazolo[1,5- alpha]pyrimidine-3- carboxylic acid (5-
chloro-2-pyrrolidin- 1-yl-phenyl)-amide 0.312 1 79 ##STR00085##
Pyrazolo[1,5- alpha]pyrimidine-3- carboxylic acid (5-
chloro-2-piperidin- 1-yl-phenyl)-amide 0.314 1 80 ##STR00086##
Pyrazolo[1,5- alpha]pyrimidine-3- carboxylic acid [3- (3-hydroxy-
propoxy)- naphthalen-2-yl]- amide 0.327 1 81 ##STR00087##
Thieno[3,2- d]pyrimidine-7- carboxylic acid [5- chloro-2-(4-
hydroxy- cyclohexyloxy)- phenyl]-amide 0.338 0.60 1 82 ##STR00088##
Pyrazolo[1,5- alpha]pyrimidine-3- carboxylic acid (7-
hydroxymethyl-3- methoxy- naphthalen-2-yl)- amide 0.358 1 83
##STR00089## Pyrazolo[1,5- alpha]pyrimidine-3- carboxylic acid [5-
chloro-2-(3- hydroxy- cyclopentyloxy)- phenyl]-amide 0.361 0.656 1
84 ##STR00090## Pyrazolo[1,5- alpha]pyrimidine-3- carboxylic acid
[5- chloro-2-(3- hydroxy-propoxy)- phenyl]-amide 0.430 5 85
##STR00091## 2-(Isopropyl- methyl-amino)- thieno[3,2-
d]pyrimidine-7- carboxylic acid (7- methoxy-quinolin- 6-yl)-amide
0.432 12 86 ##STR00092## 2-[(2-Amino- ethyl)-methyl-
amino]-thieno[3,2- d]pyrimidine-7- carboxylic acid (5-
chloro-2-methoxy- phenyl)-amide 0.436 12 87 ##STR00093##
Pyrazolo[1,5- alpha]pyrimidine-3- carboxylic acid [5- chloro-2-(4-
hydroxy-butoxy)- phenyl]-amide 0.437 1 88 ##STR00094## Thieno[3,2-
d]pyrimidine-7- carboxylic acid [7- (pyrrolidin-3-
yloxy)-quinolin-6- yl]-amide hydrochloride 0.455 15 89 ##STR00095##
Pyrazolo[1,5- alpha]pyrimidine-3- carboxylic acid (2- methoxy-4-
phenylcarbamoyl- phenyl)-amide 0.455 1 90 ##STR00096##
Pyrazolo[1,5- alpha]pyrimidine-3- carboxylic acid [5- chloro-2-(4-
hydroxy- cyclohexyloxy)- phenyl]-amide 0.459 0.806 1 91
##STR00097## Pyrazolo[1,5- alpha]pyrimidine-3- carboxylic acid [5-
chloro-2-(3- hydroxy-piperidin- 1-yl)-phenyl]-amide 0.474 1 92
##STR00098## Pyrazolo[1,5- alpha]pyrimidine-3- carboxylic acid [5-
chloro-2-(piperidin- 4-yloxy)-phenyl]- amide hydrochloride 0.476 15
93 ##STR00099## Thieno[3,2- d]pyrimidine-7- carboxylic acid [5-
chloro-2-(piperidin- 4-yloxy)-phenyl]- amide trifluoro-acetic acid
0.476 0.93 11 94 ##STR00100## Pyrazolo[1,5- alpha]pyrimidine-3-
carboxylic acid (4- chloro-4'-hydroxy- biphenyl-2-yl)- amide 0.477
5 95 ##STR00101## Pyrazolo[1,5- alpha]pyrimidine-3- carboxylic acid
[5- chloro-2-(3- hydroxy-pyrrolidin- 1-yl)-phenyl]-amide 0.493 1 96
##STR00102## Pyrazolo[1,5- alpha]pyrimidine-3- carboxylic acid [5-
chloro-2-(3,4- dihydroxy-butoxy)- phenyl]-amide 0.506 18 97
##STR00103## Pyrazolo[1,5- alpha]pyrimidine-3- carboxylic acid [5-
chloro-2-(4-methyl- piperazin-1-yl)- phenyl]-amide 0.512 1 98
##STR00104## Pyrazolo[1,5- alpha]pyrimidine-3- carboxylic acid [5-
chloro-2-(oxazol-5- ylmethoxy)- phenyl]-amide 0.516 16 99
##STR00105## Pyrazolo[1,5- alpha]pyrimidine-3- carboxylic acid (5-
chloro-2- morpholin-4-yl- phenyl)-amide 0.523 1 100 ##STR00106##
Pyrazolo[1,5- alpha]pyrimidine-3- carboxylic acid (4-
chloro-biphenyl-2- yl)-amide 0.534 1 101 ##STR00107## Pyrazolo[1,5-
alpha]pyrimidine-3- carboxylic acid [2- (3-aminomethyl-
pyrrolidin-1-yl)-5- chloro-phenyl]- amide 0.564 11 102 ##STR00108##
Thieno[3,2- d]pyrimidine-7- carboxylic acid (5- methoxy-1H-indol-
6-yl)-amide 0.596 1 103 ##STR00109## Pyrazolo[1,5-
alpha]pyrimidine-3- carboxylic acid [5- chloro-2-(3- hydroxy-
cyclohexyloxy)- phenyl]-amide 0.605 1 104 ##STR00110##
Pyrazolo[1,5- alpha]pyrimidine-3- carboxylic acid (3- methoxy-
naphthalen-2-yl)- amide 0.613 1 105 ##STR00111## Pyrazolo[1,5-
alpha]pyrimidine-3- carboxlic acid [4- (3-hydroxy-
propylcarbamoyl)- 2-methoxy-phenyl]- amide 0.640 5 106 ##STR00112##
Pyrazolo[1,5- alpha]pyrimidine-3- carboxylic acid [5- chloro-2-(3-
hydroxymethyl- pyrrolidin-1-yl)- phenyl]-amide 0.650 1 107
##STR00113## Pyrazolo[1,5- alpha]pyrimidine-3- carboxylic acid (5-
chloro-2- difluoromethoxy- phenyl)-amide 0.717 1 108 ##STR00114##
Pyrazolo[1,5- alpha]pyrimidine-3- carboxylic acid (5- chloro-2-
dimethylamino- phenyl)-amide 0.739 1 109 ##STR00115## Pyrazolo[1,5-
alpha]pyrimidine-3- carboxylic acid [2- (3-amino-
pyrrolidin-1-yl)-5- chloro-phenyl]- amide 0.766 19 110 ##STR00116##
Pyrazolo[1,5- alpha]pyrimidine-3- carboxylic acid (5-
methoxy-1H-indol- 6-yl)-amide 0.787 1 111 ##STR00117##
Pyrazolo[1,5- alpha]pyrimidine-3- carboxylic acid (5- chloro-2-
methylsulfanyl- phenyl)-amide 0.798 1 112 ##STR00118##
Pyrazolo[1,5- alpha]pyrimidine-3- carboxylic acid (5- chloro-2-
cyclohexyl- phenyl)-amide 0.799 1 113 ##STR00119## Thieno[3,2-
d]pyrimidine-7- carboxylic acid [4- (3-hydroxy- propylcarbamoyl)-
2-methoxy-phenyl]- amide 0.833 5 114 ##STR00120## Pyrazolo[1,{tilde
over (5)}alpha] pyrimidine-3- carboxylic acid [3- (2-hydroxy-
ethylamino)-2- piperidin-1-yl- phenyl]-amide 1.029 1 115
##STR00121## Thieno[3,2- d]pyrimidine-7- carboxylic acid [5-
chloro-2-(4-methyl- oxazol-5- ylmethoxy)- phenyl]-amide 1.050 1 116
##STR00122## Pyrazolo[1,5- alpha]pyrimidine-3- carboxylic acid
biphenyl-2-ylamide 1.224 1 117 ##STR00123## Thieno[3,2-
d]pyrimidine-7- carboxylic acid [5- chloro-2-(3- hydroxy-1,1-
dimethyl-propoxy)- phenyl]-amide 1.459 1 118 ##STR00124##
Thieno[3,2- d]pyrimidine-7- carboxylic acid [2- (4-amino-
cyclohexyloxy)-5- chloro-phenyl]- amide 1.471 15 119 ##STR00125##
Pyrazolo[1,5- alpha]pyrimidine-3- carboxylic acid (2-
azepan-1-yl-5- chloro-phenyl)- amide 1.503 1 120 ##STR00126##
Thieno[3,2- d]pyrimidine-7- carboxylic acid [5- chloro-2-(3-
hydroxy- cyclopentyloxy)- phenyl]-amide 1.521 5 121 ##STR00127##
Pyrazolo[1,5- alpha]pyrimidine-3- carboxylic acid [5-
chloro-2-(4-methyl- oxazol-5- ylmethoxy)- phenyl]-amide 1.553 1 122
##STR00128## Thieno[3,2- d]pyrimidine-7- carboxylic acid [4-
(2-hydroxy- ethylcarbamoyl)-2- methoxy-phenyl]- amide 1.619 5 123
##STR00129## Pyrazolo[1,5- alpha]pyrimidine-3- carboxylic acid (5-
chloro-2-methoxy- phenyl)-amide 1.633 1 124 ##STR00130##
Pyrazolo[1,5- alpha]pyrimidine-3- carboxylic acid [5- chloro-2-(2-
methoxy-ethoxy)- phenyl]-amide 1.710 1 125 ##STR00131##
Pyrazolo[1,5- alpha]pyrimidine-3- carboxylic acid (4-
chloro-3'-hydroxy- biphenyl-2-yl)- amide 2.047 5 126 ##STR00132##
2-(3-Hydroxy- propylamino)- thieno[3,2- d]pyrimidine-7- carboxylic
acid (5- chloro-2-methoxy- phenyl)-amide 2.062 12 127 ##STR00133##
Pyrazolo[1,5- alpha]pyrimidine-3- carboxylic acid (5-
bromo-2-methoxy- phenyl)-amide 2.144 1 128 ##STR00134## Thieno[3,2-
d]pyrimidine-7- carboxylic acid (5- chloro-2-methoxy- phenyl)-amide
2.200 1 129 ##STR00135## Pyrazolo[1,5- alpha]pyrimidine-3-
carboxylic acid {5- chloro-2-[(2- hydroxy-ethyl)- methyl-amino]-
phenyl}-amide 2.203 1 130 ##STR00136## Pyrazolo[1,5-
alpha]pyrimidine-3- carboxylic acid [5- chloro-2-(4-
hydroxy-phenoxy)- phenyl]-amide 2.221 1 131 ##STR00137## 2-(1-
Hydroxymethyl- propylamino)- thieno[3,2- d]pyrimidine-7- carboxylic
acid (5- chloro-2-methoxy- phenyl)-amide 2.226 12 132 ##STR00138##
2-(2-Hydroxy- ethylamino)- thieno[3,2- d]pyrimidine-7- carboxylic
acid (5- chloro-2-methoxy- phenyl)-amide 2.237 12 133 ##STR00139##
6-Hydroxymethyl- pyrazolo[1,5- alpha]pyrimidine-3- carboxylic acid
[5- chloro-2-(4- hydroxy- cyclohexyloxy)- phenyl]-amide 2.253 6 134
##STR00140## Pyrazolo[1,5- alpha]pyrimidine-3- carboxylic acid (4-
carbamoyl-2- methoxy-phenyl)- amide 2.256 3 135 ##STR00141##
Pyrazolo[1,5- alpha]pyrimidine-3- carboxylic acid (5-
chloro-2-isobutoxy- phenyl)-amide 2.280 1 136 ##STR00142##
Thieno[3,2- d]pyrimidine-7- carboxylic acid [1- (3-hydroxy-
propyl)-1H- benzoimidazol-2- yl]-amide 2.310 1 137 ##STR00143##
Pyrazolo[1,5- alpha]pyrimidine-3- carboxylic acid [5-
chloro-2-(2,3- dihydroxy- propoxy)-phenyl]- amide 2.311 18 138
##STR00144## Pyrazolo[1,5- alpha]pyrimidine-3- carboxylic acid [5-
chloro-2-(3- methoxy-propoxy)- phenyl]-amide 2.419 1 139
##STR00145## Thieno[3,2- d]pyrimidine-7- carboxylic acid [5-
chloro-2-(3- hydroxy-propoxy)- phenyl]-amide 2.452 5 140
##STR00146## Pyrazolo[1,5- alpha]pyrimidine-3- carboxylic acid [5-
chloro-2-(3- hydroxymethyl- piperidin-1-yl)- phenyl]-amide 2.465 1
141 ##STR00147## Pyrazolo[1,5- alpha]pyrimidine-3- carboxylic acid
[5- chloro-2-(3- hydroxy- benzyloxy)- phenyl]-amide 2.626 7 142
##STR00148## Pyrazolo[1,5- alpha]pyrimidine-3- carboxylic acid (5-
chloro-2,4- dimethoxy-phenyl)- amide 2.738 1 143 ##STR00149##
Pyrazolo[1,5- alpha]pyrimidine-3- carboxylic acid (2-
methoxy-5-vinyl- phenyl)-amide 2.748 1 144 ##STR00150##
Pyrazolo[1,5- alpha]pyrimidine-3- carboxylic acid [3- (3-hydroxy-
propylamino)-2- piperidin-1-yl- phenyl]-amide 2.849 1 145
##STR00151## Pyrazolo[1,5- alpha]pyrimidine-3- carboxylic acid [5-
chloro-2-(4- hydroxy-butyl)- phenyl]-amide 2.949 1 146 ##STR00152##
Pyrazolo[1,5- alpha]pyrimidine-3- carboxylic acid [4- (2-hydroxy-
ethylcarbamoyl)-2- methoxy-phenyl]- amide 2.961 5 147 ##STR00153##
6-(2-Hydroxy- ethyl)-pyrazolo[1,5- alpha]pyrimidine-3- carboxylic
acid [5- chloro-2-(4- hydroxy- cyclohexyloxy)- phenyl]-amide 3.045
5 148 ##STR00154## Pyrazolo[1,5- alpha]pyrimidine-3- carboxylic
acid {2- [3-(1-amino-ethyl)- pyrrolidin-1-yl]-5-
chloro-phenyl}-amide hydrochloride 3.083 15 149 ##STR00155##
Pyrazolo[1,5- alpha]pyrimidine-3- carboxylic acid {5- chloro-2-[(3-
hydroxy-propyl)- methyl-amino]- phenyl}-amide 3.395 1 150
##STR00156## Thieno[3,2- beta]pyridine-3- carboxylic acid (5-
chloro-2-methoxy- phenyl)-amide 3.461 1 151 ##STR00157##
Thieno[3,2- d]pyrimidine-7- carboxylic acid [5- chloro-2-(4-
methylaminomethyl- piperidin-1-yl)- phenyl]-amide 3.545 8 152
##STR00158## Pyrazolo[1,5- alpha]pyrimidine-3- carboxylic acid [5-
(3-hydroxy- propenyl)-2- methoxy-phenyl]- amide 3.698 10 153
##STR00159## Pyrazolo[1,5- alpha]pyrimidine-3- carboxylic acid (2-
methoxy-5-methyl- phenyl)-amide 3.769 1 154 ##STR00160##
Pyrazolo[1,5- alpha]pyrimidine-3- carboxylic acid (5-
chloro-2-ethyl- phenyl)-amide 3.796 1
155 ##STR00161## Pyrazolo[1,5- alpha]pyrimidine-3- carboxylic acid
(4- methanesulfonyl-2- methoxy-phenyl)- amide 4.011 1 156
##STR00162## Pyrazolo[1,5- alpha]pyrimidine-3- carboxylic acid [5-
chloro-2-(3- hydroxy-phenoxy)- phenyl]-amide 4.047 1 157
##STR00163## 2-[(2-Hydroxy- ethyl)-methyl- amino]-thieno[3,2-
d]pyrimidine-7- carboxylic acid (5- chloro-2-methoxy- phenyl)-amide
4.133 12 158 ##STR00164## Pyrazolo[1,5- alpha]pyrimidine-3-
carboxylic acid (2,4-dimethoxy- phenyl)-amide 4.169 1 159
##STR00165## Pyrazolo[1,5- alpha]pyrimidine-3- carboxylic acid (5-
fluoro-2-methoxy- phenyl)-amide 4.302 1 160 ##STR00166##
{4-Chloro-2- [(pyrazolo[1,5- alpha]pyrimidine-3- carbonyl)-amino]-
phenoxy}-acetic acid methyl ester 4.305 2 161 ##STR00167##
Pyrazolo[1,5- alpha]pyrimidine-3- carboxylic acid (5-
chloro-2-phenoxy- phenyl)-amide 4.647 1 162 ##STR00168##
5-(2-Hydroxy- ethylamino)- thieno[3,2- beta]pyridine-3- carboxylic
acid (5- chloro-2-methoxy- phenyl)-amide 4.655 12 163 ##STR00169##
Pyrazolo[1,5- alpha]pyrimidine-3- carboxylic acid [5-
chloro-2-(2,3- dihydroxy- propoxy)-phenyl]- amide 4.664 18 164
##STR00170## Pyrazolo[1,5- alpha]pyrimidine-3- carboxylic acid [5-
chloro-2-(2- hydroxymethyl- piperidin-1-yl)- phenyl]-amide 4.848 1
165 ##STR00171## Pyrazolo[1,5- alpha]pyrimidine-3- carboxylic acid
(3- methoxy-biphenyl- 4-yl)-amide 5.205 1 166 ##STR00172##
Pyrazolo[1,5- alpha]pyrimidine-3- carboxylic acid (5-
ethyl-2-methoxy- phenyl)-amide 5.885 1 167 ##STR00173##
Pyrazolo[1,5- alpha]pyrimidine-3- carboxylic acid (5-
methoxy-2-methyl- biphenyl-4-yl)-amide 5.941 1 168 ##STR00174##
Pyrazolo[1,5- alpha]pyrimidine-3- carboxylic acid (2- methoxy-3,5-
dimethyl-phenyl)- amide 6.516 1 169 ##STR00175## Thieno[3,2-
d]pyrimidine-7- carboxylic acid (2- methoxy-phenyl)- amide 6.559 1
170 ##STR00176## 5-Methyl- pyrazolo[1,5- alpha]pyrimidine-3-
carboxylic acid [5- chloro-2-(4- hydroxy- cyclohexyloxy)-
phenyl]-amide 6.561 9 171 ##STR00177## Pyrazolo[1,5-
alpha]pyrimidine-3- carboxylic acid (2- methoxy-phenyl)- amide
7.337 1 172 ##STR00178## Pyrazolo[1,5- alpha]pyrimidine-3-
carboxylic acid (4- dimethylcarbamoyl- 2-methoxy-phenyl)- amide
7.651 1 173 ##STR00179## Pyrazolo[1,5- alpha]pyrimidine-3-
carboxylic acid (5- acetylamino-2- methoxy-phenyl)- amide 7.697 1
174 ##STR00180## Pyrazolo[1,5- alpha]pyrimidine-3- carboxylic acid
(5- chloro-2-methoxy- 4- phenylcarbamoyl- phenyl)-amide 7.915 1 175
##STR00181## 2-(2-Acetylamino- ethylamino)- thieno[3,2-
d]pyrimidine-7- carboxylic acid-(5- chloro-2-methoxy- phenyl)-amide
8.087 12 176 ##STR00182## Pyrazolo[1,5- alpha]pyrimidine-3-
carboxylic acid [5- (3-hydroxy- propyl)-2-methoxy- phenyl]-amide
8.361 1 177 ##STR00183## Pyrazolo[1,5- alpha]pyrimidine-3-
carboxylic acid (4- hydroxymethyl-2- methoxy-phenyl)- amide 8.673 5
178 ##STR00184## 6-(3-Hydroxy- propyl)- pyrazolo[1,5-
alpha]pyrimidine-3- carboxylic acid [5- chloro-2-(4- hydroxy-
cyclohexyloxy)- phenyl]-amide 9.417 1 179 ##STR00185##
Pyrazolo[1,5- alpha]pyrimidine-3- carboxylic acid [5- chloro-2-(2-
hydroxy-ethoxy)- phenyl]-amide 5 5 180 ##STR00186## Pyrazolo[1,5-
alpha]pyrimidine-3- carboxylic acid [5- chloro-2-(4-
methylaminomethyl- piperidin-1-yl)- phenyl]-amide 8 181
##STR00187## Pyrazolo[1,5- alpha]pyrimidine-3- carboxylic acid [7-
(4-hydroxymethyl- piperidin-1-yl)- quinolin-6-yl]-amide 1 182
##STR00188## Thieno[3,2- beta]pyridine-3- carboxylic acid [7-
(4-aminomethyl- piperidin-1-yl)- quinolin-6-yl]-amide 11 183
##STR00189## 6-Hydroxy- pyrazolo[1,5- alpha]pyrimidine-3-
carboxylic acid [7- (4-aminomethyl- piperidin-1-yl)-
quinolin-6-yl]- amide hydrochloride 14 184 ##STR00190##
2-((1R,2S)-2- Amino- cyclohexylamino)- thieno[3,2- d]pyrimidine-7-
carboxylic acid quinolin-8-ylamide 22 185 ##STR00191##
2-((1R,2S)-2- Amino- cyclohexylamino)- thieno[3,2- d]pyrimidine-7-
carboxylic acid benzo[1,3]dioxol-5- ylamide 23 186 ##STR00192##
2-((1R,2S)-2- Amino- cyclohexylamino)- thieno[3,2- d]pyrimidine-7-
carboxylic acid (3,4-dimethoxy- phenyl)-amide 24 187 ##STR00193##
2-((1S,2R)-2- Amino- cyclohexylamino)- thieno[3,2- d]pyrimidine-7-
carboxylic acid (1- methyl-1H- benzoimidazol-4- yl)-amide 25 188
##STR00194## 2-((1S,2R)-2- Amino- cyclohexylamino)- thieno[3,2-
d]pyrimidine-7- carboxylic acid (2,4-dimethoxy- phenyl)-amide 26
189 ##STR00195## 2-((1S,2R)-2- Amino- cyclohexylamino)- thieno[3,2-
d]pyrimidine-7- carboxylic acid (5,6-dimethoxy- pyridin-2-yl)-amide
27 190 ##STR00196## 2-((1S,2R)-2- Amino- cyclohexylamino)-
thieno[3,2- d]pyrimidine-7- carboxylic acid (3,4,5-trimethoxy-
phenyl)-amide 28 191 ##STR00197## 2-((1S,2R)-2- Amino-
cyclohexylamino)- thieno[3,2- d]pyrimidine-7- carboxylic acid
quinolin-6-ylamide 29 192 ##STR00198## 2-((3R,4R)-3-
Amino-tetrahydro- pyran-4-ylamino)- thieno[3,2- d]pyrimidine-7-
carboxylic acid (7- methoxy-quinolin- 6-yl)-amide 193 ##STR00199##
2-((1R,2S)-2- Amino- cyclopentylamino)- thieno[3,2- d]pyrimidine-7-
carboxylic acid (7- methoxy-quinolin- 6-yl)-amide
Synthesis
[0471] Compounds of the present invention can be made by a variety
of methods depicted in the illustrative synthetic reaction schemes
shown and described below.
[0472] The starting materials and reagents used in preparing these
compounds generally are either available from commercial suppliers,
such as Aldrich Chemical Co., or are prepared by methods known to
those skilled in the art following procedures set forth in
references such as Fieser and Fieser's Reagents for Organic
Synthesis; Wiley & Sons: New York, 1991, Volumes 1-15; Rodd's
Chemistry of Carbon Compounds, Elsevier Science Publishers, 1989,
Volumes 1-5 and Supplementals; and Organic Reactions, Wiley &
Sons: New York, 1991, Volumes 1-40. The following synthetic
reaction schemes are merely illustrative of some methods by which
the compounds of the present invention can be synthesized, and
various modifications to these synthetic reaction schemes can be
made and will be suggested to one skilled in the art having
referred to the disclosure contained in this application.
[0473] The starting materials and the intermediates of the
synthetic reaction schemes can be isolated and purified if desired
using conventional techniques, including but not limited to,
filtration, distillation, crystallization, chromatography, and the
like. Such materials can be characterized using conventional means,
including physical constants and spectral data.
[0474] Unless specified to the contrary, the reactions described
herein preferably are conducted under an inert atmosphere at
atmospheric pressure at a reaction temperature range of from about
-78.degree. C. to about 150.degree. C., more preferably from about
0.degree. C. to about 125.degree. C., and most preferably and
conveniently at about room (or ambient) temperature, e.g., about
20.degree. C.
[0475] Scheme A below illustrates one synthetic procedure usable to
prepare specific compounds of formula I, wherein R is lower alkyl
and may be the same or different in each occurrence, and Ar and
R.sup.1 and R.sup.2 are as defined herein.
##STR00200##
[0476] In step A of Scheme A, a cyclization reaction is carried out
wherein aminopyrazole ester a is reacted with aminoenal compound b
in the presence of base to afford pyrazolopyrimidine ester compound
c. The reaction may be carried out under polar aprotic solvent
conditions in the presence of sodium hydride. In step B,
pyrazolopyrimidine ester c is hydrolyzed to yield the corresponding
pyrazolopyrimidine carboxylic acid d. In step C, an amide coupling
reaction is carried out by reaction of compound d with aryl amine e
to provide pyrazolopyrimidine amide compound f, which is a compound
of formula I in accordance with the invention. Amide coupling in
step C may be carried out by forming an acid chloride intermediate
by treatment of compound d with thionyl chloride, or may be
effected using carbodiimides or other amide coupling reagents.
[0477] Scheme B below illustrates another procedure for preparation
of the compounds of the invention, wherein R is lower alkyl and Ar
and R.sup.1 and R.sup.2 are as defined herein.
##STR00201##
[0478] In step A of Scheme B, a cyclization reaction is carried out
wherein thienyl ester g is treated with formamide to afford
oxo-thienopyrimidine compound h. Compound h is treated with
phosphorus oxychloride or like chlorinating reagent in step B to
provide chloro-thienopyrimidine compound i. In step C,
chloro-thienopyrimidine compound undergoes reductive dechlorination
by hydrogenation in the presence of catalyst to form
thienopyrimidine compound j. A first oxidation is carried out in
step D wherein the methyl group of thienopyrimidine compound j is
oxidized to an aldehyde, thus affording thienopyrimidine
carboxaldehyde compound k. In step E a second oxidation reaction is
carried out on thienopyrimidine carboxaldehyde compound k give
thienopyrimidine carboxylic acid compound m. The oxidation of step
E may utilize, for example, sulfamic acid in the presence of sodium
chlorite. In step F, compound m is treated with aryl amine e in an
amide coupling reaction to afford thienopyrimidine amide compound
n, which is a compound of formula II in accordance with the
invention. Various amide coupling reagents as described above for
Scheme A may be used in this step.
[0479] Many variations on the procedure of Scheme A and Scheme B
are possible and will suggest themselves to those skilled in the
art. Specific details for producing compounds of the invention are
described in the Examples section below.
Utility
[0480] The compounds of the invention are usable for the treatment
of a wide range of inflammatory diseases and conditions such as
arthritis, including but not limited to, rheumatoid arthritis,
spondyloarthropathies, gouty arthritis, osteoarthritis, systemic
lupus erythematosus and juvenile arthritis, osteoarthritis, gouty
arthritis and other arthritic conditions. The subject compounds
would be useful for the treatment of pulmonary disorders or lung
inflammation, including adult respiratory distress syndrome,
pulmonary sarcoidosis, asthma, silicosis, bronchospasm and chronic
pulmonary inflammatory diseases, including chronic obstructive
pulmonary disorder (COPD). The subject compounds may further be
useful for treatment of inflammatory bowel disease, multiple
sclerosis, diabetes, obesity, allergic disease, psoriasis, asthma,
graft rejection, cancer and sepsis.
Administration and Pharmaceutical Composition
[0481] The invention includes pharmaceutical compositions
comprising at least one compound of the present invention, or an
individual isomer, racemic or non-racemic mixture of isomers or a
pharmaceutically acceptable salt or solvate thereof, together with
at least one pharmaceutically acceptable carrier, and optionally
other therapeutic and/or prophylactic ingredients.
[0482] In general, the compounds of the invention will be
administered in a therapeutically effective amount by any of the
accepted modes of administration for agents that serve similar
utilities. Suitable dosage ranges are typically 1-500 mg daily,
preferably 1-100 mg daily, and most preferably 1-30 mg daily,
depending upon numerous factors such as the severity of the disease
to be treated, the age and relative health of the subject, the
potency of the compound used, the route and form of administration,
the indication towards which the administration is directed, and
the preferences and experience of the medical practitioner
involved. One of ordinary skill in the art of treating such
diseases will be able, without undue experimentation and in
reliance upon personal knowledge and the disclosure of this
application, to ascertain a therapeutically effective amount of the
compounds of the present invention for a given disease.
[0483] Compounds of the invention may be administered as
pharmaceutical formulations including those suitable for oral
(including buccal and sub-lingual), rectal, nasal, topical,
pulmonary, vaginal, or parenteral (including intramuscular,
intraarterial, intrathecal, subcutaneous and intravenous)
administration or in a form suitable for administration by
inhalation or insufflation. The preferred manner of administration
is generally oral using a convenient daily dosage regimen which can
be adjusted according to the degree of affliction.
[0484] A compound or compounds of the invention, together with one
or more conventional adjuvants, carriers, or diluents, may be
placed into the form of pharmaceutical compositions and unit
dosages. The pharmaceutical compositions and unit dosage forms may
be comprised of conventional ingredients in conventional
proportions, with or without additional active compounds or
principles, and the unit dosage forms may contain any suitable
effective amount of the active ingredient commensurate with the
intended daily dosage range to be employed. The pharmaceutical
compositions may be employed as solids, such as tablets or filled
capsules, semisolids, powders, sustained release formulations, or
liquids such as solutions, suspensions, emulsions, elixirs, or
filled capsules for oral use; or in the form of suppositories for
rectal or vaginal administration; or in the form of sterile
injectable solutions for parenteral use. Formulations containing
about one (1) milligram of active ingredient or, more broadly,
about 0.01 to about one hundred (100) milligrams, per tablet, are
accordingly suitable representative unit dosage forms.
[0485] The compounds of the invention may be formulated in a wide
variety of oral administration dosage forms. The pharmaceutical
compositions and dosage forms may comprise a compound or compounds
of the present invention or pharmaceutically acceptable salts
thereof as the active component. The pharmaceutically acceptable
carriers may be either solid or liquid. Solid form preparations
include powders, tablets, pills, capsules, cachets, suppositories,
and dispersible granules. A solid carrier may be one or more
substances which may also act as diluents, flavoring agents,
solubilizers, lubricants, suspending agents, binders,
preservatives, tablet disintegrating agents, or an encapsulating
material. In powders, the carrier generally is a finely divided
solid which is a mixture with the finely divided active component.
In tablets, the active component generally is mixed with the
carrier having the necessary binding capacity in suitable
proportions and compacted in the shape and size desired. The
powders and tablets preferably contain from about one (1) to about
seventy (70) percent of the active compound. Suitable carriers
include but are not limited to magnesium carbonate, magnesium
stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin,
tragacanth, methylcellulose, sodium carboxymethylcellulose, a low
melting wax, cocoa butter, and the like. The term "preparation" is
intended to include the formulation of the active compound with
encapsulating material as carrier, providing a capsule in which the
active component, with or without carriers, is surrounded by a
carrier, which is in association with it. Similarly, cachets and
lozenges are included. Tablets, powders, capsules, pills, cachets,
and lozenges may be as solid forms suitable for oral
administration.
[0486] Other forms suitable for oral administration include liquid
form preparations including emulsions, syrups, elixirs, aqueous
solutions, aqueous suspensions, or solid form preparations which
are intended to be converted shortly before use to liquid form
preparations. Emulsions may be prepared in solutions, for example,
in aqueous propylene glycol solutions or may contain emulsifying
agents, for example, such as lecithin, sorbitan monooleate, or
acacia. Aqueous solutions can be prepared by dissolving the active
component in water and adding suitable colorants, flavors,
stabilizers, and thickening agents. Aqueous suspensions can be
prepared by dispersing the finely divided active component in water
with viscous material, such as natural or synthetic gums, resins,
methylcellulose, sodium carboxymethylcellulose, and other well
known suspending agents. Solid form preparations include solutions,
suspensions, and emulsions, and may contain, in addition to the
active component, colorants, flavors, stabilizers, buffers,
artificial and natural sweeteners, dispersants, thickeners,
solubilizing agents, and the like.
[0487] The compounds of the invention may be formulated for
parenteral administration (e.g., by injection, for example bolus
injection or continuous infusion) and may be presented in unit dose
form in ampoules, pre-filled syringes, small volume infusion or in
multi-dose containers with an added preservative. The compositions
may take such forms as suspensions, solutions, or emulsions in oily
or aqueous vehicles, for example solutions in aqueous polyethylene
glycol. Examples of oily or nonaqueous carriers, diluents, solvents
or vehicles include propylene glycol, polyethylene glycol,
vegetable oils (e.g., olive oil), and injectable organic esters
(e.g., ethyl oleate), and may contain formulatory agents such as
preserving, wetting, emulsifying or suspending, stabilizing and/or
dispersing agents. Alternatively, the active ingredient may be in
powder form, obtained by aseptic isolation of sterile solid or by
lyophilization from solution for constitution before use with a
suitable vehicle, e.g., sterile, pyrogen-free water.
[0488] The compounds of the invention may be formulated for topical
administration to the epidermis as ointments, creams or lotions, or
as a transdermal patch. Ointments and creams may, for example, be
formulated with an aqueous or oily base with the addition of
suitable thickening and/or gelling agents. Lotions may be
formulated with an aqueous or oily base and will in general also
containing one or more emulsifying agents, stabilizing agents,
dispersing agents, suspending agents, thickening agents, or
coloring agents. Formulations suitable for topical administration
in the mouth include lozenges comprising active agents in a
flavored base, usually sucrose and acacia or tragacanth; pastilles
comprising the active ingredient in an inert base such as gelatin
and glycerin or sucrose and acacia; and mouthwashes comprising the
active ingredient in a suitable liquid carrier.
[0489] The compounds of the invention may be formulated for
administration as suppositories. A low melting wax, such as a
mixture of fatty acid glycerides or cocoa butter is first melted
and the active component is dispersed homogeneously, for example,
by stirring. The molten homogeneous mixture is then poured into
convenient sized molds, allowed to cool, and to solidify.
[0490] The compounds of the invention may be formulated for vaginal
administration. Pessaries, tampons, creams, gels, pastes, foams or
sprays containing in addition to the active ingredient such
carriers as are known in the art to be appropriate.
[0491] The subject compounds may be formulated for nasal
administration. The solutions or suspensions are applied directly
to the nasal cavity by conventional means, for example, with a
dropper, pipette or spray. The formulations may be provided in a
single or multidose form. In the latter case of a dropper or
pipette, this may be achieved by the patient administering an
appropriate, predetermined volume of the solution or suspension. In
the case of a spray, this may be achieved for example by means of a
metering atomizing spray pump.
[0492] The compounds of the invention may be formulated for aerosol
administration, particularly to the respiratory tract and including
intranasal administration. The compound will generally have a small
particle size for example of the order of five (5) microns or less.
Such a particle size may be obtained by means known in the art, for
example by micronization. The active ingredient is provided in a
pressurized pack with a suitable propellant such as a
chlorofluorocarbon (CFC), for example, dichlorodifluoromethane,
trichlorofluoromethane, or dichlorotetrafluoroethane, or carbon
dioxide or other suitable gas. The aerosol may conveniently also
contain a surfactant such as lecithin. The dose of drug may be
controlled by a metered valve. Alternatively the active ingredients
may be provided in a form of a dry powder, for example a powder mix
of the compound in a suitable powder base such as lactose, starch,
starch derivatives such as hydroxypropylmethyl cellulose and
polyvinylpyrrolidine (PVP). The powder carrier will form a gel in
the nasal cavity. The powder composition may be presented in unit
dose form for example in capsules or cartridges of e.g., gelatin or
blister packs from which the powder may be administered by means of
an inhaler.
[0493] When desired, formulations can be prepared with enteric
coatings adapted for sustained or controlled release administration
of the active ingredient. For example, the compounds of the present
invention can be formulated in transdermal or subcutaneous drug
delivery devices. These delivery systems are advantageous when
sustained release of the compound is necessary and when patient
compliance with a treatment regimen is crucial. Compounds in
transdermal delivery systems are frequently attached to an
skin-adhesive solid support. The compound of interest can also be
combined with a penetration enhancer, e.g., Azone
(1-dodecylazacycloheptan-2-one). Sustained release delivery systems
are inserted subcutaneously into the subdermal layer by surgery or
injection. The subdermal implants encapsulate the compound in a
lipid soluble membrane, e.g., silicone rubber, or a biodegradable
polymer, e.g., polylactic acid.
[0494] The pharmaceutical preparations are preferably in unit
dosage forms. In such form, the preparation is subdivided into unit
doses containing appropriate quantities of the active component.
The unit dosage form can be a packaged preparation, the package
containing discrete quantities of preparation, such as packeted
tablets, capsules, and powders in vials or ampoules. Also, the unit
dosage form can be a capsule, tablet, cachet, or lozenge itself, or
it can be the appropriate number of any of these in packaged
form.
[0495] Other suitable pharmaceutical carriers and their
formulations are described in Remington: The Science and Practice
of Pharmacy 1995, edited by E. W. Martin, Mack Publishing Company,
19th edition, Easton, Pa. Representative pharmaceutical
formulations containing a compound of the present invention are
described below.
EXAMPLES
[0496] The following preparations and examples are given to enable
those skilled in the art to more clearly understand and to practice
the present invention. They should not be considered as limiting
the scope of the invention, but merely as being illustrative and
representative thereof.
[0497] Unless otherwise stated, all temperatures including melting
points (i.e., MP) are in degrees Celsius (.degree. C.). It should
be appreciated that the reaction which produces the indicated
and/or the desired product may not necessarily result directly from
the combination of two reagents which were initially added, i.e.,
there may be one or more intermediates which are produced in the
mixture which ultimately leads to the formation of the indicated
and/or the desired product. The following abbreviations may be used
in the Preparations and Examples.
LIST OF ABBREVIATIONS
TABLE-US-00002 [0498] AcOH Acetic acid AIBN
2,2'-Azobis(2-methylpropionitrile) Atm. Atmosphere (BOC).sub.2O
di-tert-Butyl dicarbonate DCM Dichloromethane/Methylene chloride
DIAD Diisopropyl azodicarboxylate DIPEA Diisopropylethylamine DMAP
4-Dimethylaminopyridine DME 1,2-Dimethoxyethane DMF
N,N-Dimethylformamide DMSO Dimethyl sulfoxide Et.sub.2O Diethyl
ether EtOH Ethanol/Ethyl alcohol EtOAc Ethyl acetate HBTU
O-Benzotriazol-1-yl-N,N,N',N'-tetramethyluronium
hexafluorophosphate HOBT 1-Hydroxybenzotriazole HPLC High pressure
liquid chromatography i-PrOH Isopropanol/isopropyl alcohol MeOH
Methanol/Methyl alcohol MW Microwaves NBS N-Bromosuccinimide NMP
1-Methyl-2-pyrrolidinone PSI Pound per square inch RT Room
temperature TBDMS tert-Butyldimethylsilyl TFA Trifluoroacetic acid
THF Tetrahydrofuran TLC Thin layer chromatography
Preparation 1: Synthesis of
6-Formyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
[0499] The synthesis of
6-formyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid was carried
out according to the process shown in Scheme 1.
##STR00202##
[0500] A mixture of 3-aminopyrazole-4-carboxylic acid (100 mg,
0.787 mmol) and 2-dimethylaminomethylene-malonaldehyde (Synthesis
1989 (11), 856-860) (100 mg, 0.787 mmol) in aqueous hydrochloric
acid (6 M, 2 mL) was stirred at room temperature for 30 minutes;
the resulting mixture was heated at 90.degree. C. for 2 hours and
was then stirred at room temperature for 64 hours. The solid formed
was collected by filtration, washed twice with water, methanol and
diethyl ether, dried in a vacuum oven to give 75 mg (50% yield) of
6-formyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid as a light
brown solid without further purifications.
Preparation 2: Synthesis of
2-[4-(tert-Butyl-dimethyl-silanyloxy)-cyclohexyloxy]-5-chloro-phenylamine
[0501] The synthesis of
2-[4-(tert-butyl-dimethyl-silanyloxy)-cyclohexyloxy]-5-chloro-phenylamine
was carried out according to the process shown in Scheme 2.
##STR00203##
Step A: synthesis of
4-(tert-butyl-dimethyl-silanyloxy)-cyclohexanol
[0502] A solution of tert-butyldimethylsilyl chloride (1.5 g, 9.9
mmol) in anhydrous N,N-dimethylformamide (5 mL) was added,
dropwise, at 0.degree. C., to a solution of 1,4-cyclohexanediol
(1.0 g, 8.6 mmol) and imidazole (1.5 g, 22.0 mmol) in anhydrous
tetrahydrofuran (5 mL). After completion of the addition brine was
added and the resulting mixture was extracted 3 times with ethyl
acetate. The combined organic extracts were washed with water and
brine, dried over anhydrous sodium sulfate, filtered and evaporated
under reduced pressure. The crude residue was purified on a silica
gel plug (hexane/EtOAc, 80/20) to afford 1.3 g (66% yield) of
4-(tert-butyl-dimethyl-silanyloxy)-cyclohexanol as a colorless
oil.
Step B: synthesis of
tert-butyl-[4-(4-chloro-2-nitro-phenoxy)-cyclohexyloxy]-dimethyl-silane
[0503] A solution of diisopropylazadicarboxylate (1.65 g, 8.16
mmol) in anhydrous tetrahydrofuran (5 mL) was added, dropwise, at
0.degree. C., to a solution of 4-chloro-2-nitrophenol (0.75 g, 4.32
mmol), 4-(tert-butyl-dimethyl-silanyloxy)-cyclohexanol (1.2 g, 5.21
mmol) and triphenylphosphine (2.27 g, 8.65 mmol) in anhydrous
tetrahydrofuran (10 mL). The resulting mixture was stirred at
0.degree. C. for 1 hour and at room temperature overnight. The
reaction mixture was then sonicated for 20 minutes at room
temperature and for 30 minutes at 40.degree. C. and then was
stirred at room temperature for 24 hours. The solvent was
evaporated under reduced pressure and the residue was partitioned
between ethyl acetate and an aqueous solution of sodium bicarbonate
(5%), the organic layer was separated and the aqueous layer was
extracted 3 times with ethyl acetate. The combined organic extracts
were washed with brine, dried over anhydrous sodium sulfate,
filtered and evaporated under reduced pressure. The yellow oily
residue was purified on a silica gel plug (hexane/EtOAc, from 99/1
to 90/10) to give a yellow oil. This material was dissolved in a
mixture of ethyl acetate and hexane (1/1) and the resulting
solution was washed twice with an aqueous solution of sodium
hydroxide (3 M) and once with brine, dried over anhydrous sodium
sulfate, filtered and evaporated under reduced pressure to give
1.28 g (79% yield) of
tert-butyl-[4-(4-chloro-2-nitro-phenoxy)-cyclohexyloxy]-dimethyl-silane
as a light yellow oil.
Step C: synthesis of
2-[4-(tert-butyl-dimethyl-silanyloxy)-cyclohexyloxy]-5-chloro-phenylamine
[0504] Stannous chloride (3.2 g, 16.98 mmol) was added to a
solution of
tert-butyl-[4-(4-chloro-2-nitro-phenoxy)-cyclohexyloxy]-dimethyl-silane
(1.28 g, 3.32 mmol) in a mixture of ethanol and ethyl acetate (1/1,
40 mL) and the resulting mixture was stirred at room temperature
for 24 hours. Ice and an aqueous solution of sodium bicarbonate
(5%, 150 mL) were added and the solid formed was filtered, washed
with ethyl acetate and discarded. The layers of the filtrate were
separated and the aqueous layer was extracted 3 times with ethyl
acetate. The combined organic extracts were washed with brine,
dried over anhydrous sodium sulfate, filtered through a CELITE.TM.
pad and evaporated under reduced pressure. The yellow oily residue
was purified by flash chromatography (EtOAc/hexane, from 5/95 to
80/20) to give 0.5 g (42% yield) of
2-[4-(tert-butyl-dimethyl-silanyloxy)-cyclohexyloxy]-5-chloro-phenylamine
as a yellow oil and 803 mg (16% yield) of
4-(2-amino-4-chloro-phenoxy)-cyclohexanol.
[0505] Utilizing the appropriate starting materials and the above
described procedure the following compounds were prepared: [0506]
cis-2-[4-(tert-butyl-dimethyl-silanyloxy)-cyclohexyloxy]-5-chloro-phenyla-
mine; [0507]
trans-2-[4-(tert-butyl-dimethyl-silanyloxy)-cyclohexyloxy]-5-chloro-pheny-
lamine; [0508]
2-[3-(tert-butyl-dimethyl-silanyloxy)-cyclopentyloxy]-5-chloro-phenylamin-
e; [0509] 3-(6-amino-quinolin-7-yloxy)-3-methyl-butan-1-ol (Step B
and Step C); [0510]
3-(2-amino-4-chloro-phenoxy)-3-methyl-butan-1-ol (Step B and Step
C); [0511] 5-chloro-2-cyclohexyloxy-phenylamine (Step B and Step
C); [0512] 5-chloro-2-isopropoxy-phenylamine (Step B and Step C);
[0513]
5-chloro-2-((S)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-phenylamine
(Step B and Step C); [0514]
5-chloro-2-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-phenylamine
(Step B and Step C); [0515]
[3-(2-amino-4-chloro-phenoxy)-cyclopentyl]-methanol (Step B and
Step C); [0516] 3-(2-amino-4-chloro-phenoxy)-cyclohexanol (Step B
and Step C); [0517] 1-(2-amino-4-chloro-phenyl)-pyrrolidin-3-ol
(Step B and Step C); [0518]
2-[3-(tert-butyl-dimethyl-silanyloxy)-propoxy]-5-chloro-phenylamine;
[0519]
2-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-5-chloro-phenylamine-
; [0520] [4-(2-amino-4-chloro-phenoxy)-cyclohexyl]-carbamic acid
tert-butyl ester (Step B and Step C); [0521]
5-chloro-2-[2-(2,2-dimethyl-[1,3]dioxolan-4-yl)-ethoxy]-phenylamine
(Step B and Step C); and [0522] 4-(2-amino-phenoxy)-cyclohexanol
(Step B and Step C).
Preparation 3: Synthesis of 4-Amino-3-methoxy-benzoic acid methyl
ester
[0523] The synthesis of 4-amino-3-methoxy-benzoic acid methyl ester
was carried out according to the process shown in Scheme 3.
##STR00204##
Step A: synthesis of 3-methoxy-4-nitro-benzoic acid methyl
ester
[0524] Boron trifluoride diethyl etherate (2 mL, 16.3 mmol) was
added to a suspension of 3-methoxy-4-nitrobenzoic acid (1.0 g, 5.07
mmol) in anhydrous methanol (15 mL) and the resulting mixture was
heated at reflux for 24 hours. The solvent was evaporated under
reduced pressure and the residue was partitioned between water and
dichloromethane; the aqueous layer was extracted 3 times with
dichloromethane. The combined organic extracts were dried over
anhydrous sodium sulfate, filtered and evaporated under reduced
pressure. The residue was purified over a silica gel plug
(EtOAc/hexane from 40/60 to 50/50) to give 1.09 g of
3-methoxy-4-nitro-benzoic acid methyl ester as a pale yellow
solid.
Step B: synthesis of 4-amino-3-methoxy-benzoic acid methyl
ester
[0525] Palladium on carbon (10%, catalytic amount) was added to a
solution of 3-methoxy-4-nitro-benzoic acid methyl ester (1.08 g,
5.11 mmol) in a mixture of methanol (40 mL) and dichloromethane (a
few drops). The resulting mixture was stirred under nitrogen
atmosphere (balloon pressure) overnight. The catalyst was filtered
off on a CELITE.TM. pad and the solvent was evaporated to give
0.929 g of 4-amino-3-methoxy-benzoic acid methyl ester as a yellow
solid.
[0526] Utilizing the above described procedure and the appropriate
starting materials 3-methoxy-4-nitro-N-phenyl-benzamide was reduced
to give 4-amino-3-methoxy-N-phenyl-benzamide.
Preparation 4: Synthesis of
4-(tert-Butyl-dimethyl-silanyloxymethyl)-2-methoxy-phenylamine
[0527] The synthesis of
4-(tert-butyl-dimethyl-silanyloxymethyl)-2-methoxy-phenylamine was
carried out according to the process shown in Scheme 4.
##STR00205##
Step A: synthesis of
tert-butyl-(3-methoxy-4-nitro-benzyloxy)-dimethyl-silane
[0528] tert-Butyldimethylsilyl chloride (0.9 g, 5.97 mmol) was
added to a solution of 2-methoxy-4-nitrobenzylalcohol (1.0 g, 5.46
mmol) and imidazole (0.9 g, 13.2 mmol) in anhydrous dichloromethane
(15 mL) and the resulting mixture was stirred at room temperature
overnight. The reaction mixture was then partitioned between water
and dichloromethane, the organic layer was separated and the
aqueous layer was extracted 3 times with dichloromethane. The
combined organic extracts were dried over anhydrous sodium sulfate,
filtered and evaporated under reduced pressure. The crude residue
was purified on a silica gel plug (hexane/EtOAc, 80/20) to afford
1.58 g (97% yield) of
tert-butyl-(3-methoxy-4-nitro-benzyloxy)-dimethyl-silane as a light
yellow solid.
Step B: synthesis of
4-(tert-butyl-dimethyl-silanyloxymethyl)-2-methoxy-phenylamine
[0529] tert-Butyl-(3-methoxy-4-nitro-benzyloxy)-dimethyl-silane was
reduced by hydrogenation as described in Preparation 3, Step B, to
give
4-(tert-butyl-dimethyl-silanyloxymethyl)-2-methoxy-phenylamine.
Preparation 5: Synthesis of 3-Methoxy-biphenyl-4-ylamine
[0530] The synthesis of 3-methoxy-biphenyl-4-ylamine was carried
out according to the process shown in Scheme 5.
##STR00206##
Step A: synthesis of 3-methoxy-4-nitro-biphenyl
[0531] A solution of potassium methoxyde (0.56 g, 7.98 mmol) in
anhydrous methanol (5 mL) was added at 0.degree. C. to a mixture of
5-chloro-2-nitroanisole (0.5 g, 2.66 mmol), phenylboronic acid
(0.42 g, 3.44 mmol), bis(dibenzylideneacetone)palladium (47 mg,
0.082 mmol), 1,3-bis(2,6-diisopropylphenyl)imidazolium chloride (35
mg, 0.082 mmol) and tetrabutylammonium bromide (86 mg, 0.267 mmol)
in anhydrous toluene (20 mL). The reaction mixture was stirred at
60.degree. C. for 24 hours, and then was partitioned between ethyl
acetate and water. The organic layer was separated and washed with
brine, dried over anhydrous sodium sulfate, filtered and evaporated
under reduced pressure. The crude residue was purified on a silica
gel plug (EtOAc/hexane, 20/80) to give 0.7 g of
3-methoxy-4-nitro-biphenyl as a yellow oil.
Step B: synthesis of 3-methoxy-biphenyl-4-ylamine
[0532] 3-Methoxy-4-nitro-biphenyl was reduced by hydrogenation as
described in Preparation 3, Step B, to give
3-methoxy-biphenyl-4-ylamine.
[0533] 4-Chloro-biphenyl-2-ylamine was synthesized utilizing the
appropriate starting materials and the above described procedure,
the reduction step was conducted in presence of stannous chloride
as described in Preparation 9, Step D.
Preparation 6: Synthesis of
6-Carbamoyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
[0534] The synthesis of
6-carbamoyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid was carried
out according to the process shown in Scheme 6.
##STR00207##
Step A: synthesis of 6-cyano-pyrazolo[1,5-a]pyrimidine-3-carboxylic
acid ethyl ester
[0535] Sodium hydride (60% dispersion in mineral oil, 0.52 g, 13.0
mmol) was added, at 0.degree. C., to a mixture of
3-amino-1H-pyrazole-4-carboxylic acid ethyl ester (0.9 g, 5.8 mmol)
and 3-dimethylamino-2-formyl-acrylonitrile (0.72 g, 5.8 mmol) in
anhydrous tetrahydrofuran (30 mL) and the reaction mixture was
stirred overnight while warming up to room temperature. Ice-water
was added and the resulting mixture was partitioned between water
and ethyl acetate; the organic layer was separated and the aqueous
layer was extracted 3 times with ethyl acetate. The combined
organic extracts were washed with brine, dried over anhydrous
sodium sulfate, filtered and evaporated. The yellow crude residue
was purified twice on a silica gel plug (EtOAc/hexane) to afford
0.4 g (32% yield) of 6-cyano-pyrazolo[1,5-a]pyrimidine-3-carboxylic
acid ethyl ester.
Step B: synthesis of
6-carbamoyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
[0536] An aqueous solution of sodium hydroxide (10%, 5 mL) was
added to a suspension of
6-cyano-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid ethyl ester
(0.35 mg, 1.62 mmol) in ethanol (5 mL) and the reaction mixture was
heated at 60.degree. C. for 5 hours. Ice-water was added and the
resulting mixture was acidified until pH<1 by addition of an
aqueous solution of hydrochloric acid (3 M). The solid which
crashed out was collected by filtration, washed twice with water,
methanol and diethyl ether, dried under reduced pressure to afford
0.25 g (75% yield) of
6-carbamoyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid.
Preparation 7: Synthesis of 2-Methoxy-benzene-1,3-diamine
[0537] The synthesis 2-methoxy-benzene-1,3-diamine was carried out
according to the process shown in Scheme 7.
##STR00208##
Step A: synthesis of 2-methoxy-1,3-dinitro-benzene
[0538] A solution of sodium methoxyde in methanol (25%, 2.25 mL)
was added to a suspension of 2-chloro-2,3-dinitrobenzene (3.26 g)
in anhydrous methanol (30 mL) and the resulting mixture was stirred
at room temperature overnight. The light yellow solid formed was
collected by filtration to give 1.59 g of
2-methoxy-1,3-dinitro-benzene without further purifications.
Step B: synthesis of 2-methoxy-benzene-1,3-diamine
[0539] A mixture of 2-methoxy-1,3-dinitro-benzene (1.49 g) and
palladium on carbon (10%, 150 mg) in ethanol (75 mL) was stirred
under hydrogen atmosphere (1 atm.) overnight. The catalyst was
filtered off on a CELITE.TM. pad and the filter cake was washed
with ethanol. The filtrate was evaporated under reduced pressure to
afford 1.1 g of 2-methoxy-benzene-1,3-diamine as a light yellow
solid without further purifications.
Preparation 8: Synthesis of
3-(3-Amino-2-piperidin-1-yl-phenylamino)-propan-1-ol
[0540] The synthesis
3-(3-amino-2-piperidin-1-yl-phenylamino)-propan-1-ol was carried
out according to the process shown in Scheme 8.
##STR00209##
Step A: synthesis of 1-(2,6-dinitro-phenyl)-piperidine
[0541] Piperidine (1.96 mL, 19.75 mmol) was added to a solution of
2-chloro-2,3-dinitrobenzene (2.0 g, 9.87 mmol) in anhydrous
dichloromethane (80 mL) and the reaction mixture was stirred for 2
hours. The solvent was evaporated under reduced pressure and the
orange solid residue was washed with water to give after drying
2.31 g of 1-(2,6-dinitro-phenyl)-piperidine as a light orange solid
without further purifications.
Step B: synthesis of 2-piperidin-1-yl-benzene-1,3-diamine
[0542] A mixture of 1-(2,6-dinitro-phenyl)-piperidine (2.31 g) and
palladium on carbon (10%, 230 mg) in ethanol (80 mL) was stirred
under hydrogen atmosphere (1 atm.), at room temperature, for 40
hours. The catalyst was filtered off on a CELITE.TM. pad. The
filtrate was evaporated under reduced pressure and the residue was
purified by flash chromatography (hexane/EtOAc, 80/20) to afford
1.29 g of 2-piperidin-1-yl-benzene-1,3-diamine as an orange solid
without further purifications.
[0543] Utilizing the above described procedure and the appropriate
starting materials, the following compounds were prepared: [0544]
[1-(2,6-diamino-phenyl)-piperidin-4-ylmethyl]-carbamic acid
tert-butyl ester; and [0545]
5-chloro-2-piperidin-1-yl-phenylamine.
Step C: synthesis of
3-(3-amino-2-piperidin-1-yl-phenylamino)-propan-1-ol
[0546] To a solution of 2-piperidin-1-yl-benzene-1,3-diamine (300
mg, 1.57 mmol) in N,N-dimethylformamide (4 mL) was added sodium
hydride (60% suspension in mineral oil, 63 mg, 1.57 mmol) followed
by 3-bromo-1-propanol (0.14 mL, 1.57 mmol) and the reaction mixture
was stirred at 60.degree. C. overnight. The resulting mixture was
then extracted with ethyl acetate (150 mL) and the organic layer
was washed twice with water (80 mL) and once with brine (80 mL),
dried over anhydrous sodium sulfate, filtered and evaporated under
reduced pressure. The crude residue was purified by flash
chromatography (hexane/EtOAc, 60/40) to give 22 mg of
3-(3-amino-2-piperidin-1-yl-phenylamino)-propan-1-ol.
[0547] 2-(3-Amino-2-piperidin-1-yl-phenylamino)-ethanol was
prepared utilizing the above described procedure and the
appropriate starting materials.
Preparation 9: Synthesis of
4-Amino-2-chloro-5-methoxy-N-phenyl-benzamide
[0548] The synthesis 4-amino-2-chloro-5-methoxy-N-phenyl-benzamide
was carried out according to the process shown in Scheme 9.
##STR00210##
Step A: synthesis of
1-chloro-4-methoxy-2-methyl-5-nitro-benzene
[0549] A solution of (trimethylsilyl)diazomethane (2.0 M in hexane,
13.3 mL, 26.6 mmol) was added to a mixture of
4-chloro-5-methyl-2-nitro-phenol (1.0 g, 5.33 mmol) and
diisopropylethylamine (1.04 mL, 6.13 mmol) in a mixture of
anhydrous methanol and anhydrous acetonitrile (1/1, 50 mL) and the
reaction mixture was stirred for 1 hour. Glacial acetic acid (5
drops) was then added and the resulting mixture was evaporated
under reduced pressure. The residue was partitioned between diethyl
ether (100 mL) and water (50 mL); the organic layer was separated,
dried over anhydrous sodium sulfate, filtered and evaporated under
reduced pressure to afford 1.07 g of
1-chloro-4-methoxy-2-methyl-5-nitro-benzene as a light orange solid
without further purifications.
[0550] 2-Methoxy-1,5-dimethyl-3-nitro-benzene was prepared
utilizing the above described procedure and the appropriate
starting materials.
Step B: synthesis of 2-chloro-5-methoxy-4-nitro-benzoic acid
[0551] A suspension of 1-chloro-4-methoxy-2-methyl-5-nitro-benzene
(1.05 g, 5.21 mmol) in a mixture of pyridine and water (1/2, 15 mL)
was heated to 97.degree. C. and then potassium permanganate (4.53
g, 28.64 mmol) was added. The reaction mixture was heated at
100.degree. C. for 4 hours; a second aliquot of the mixture
pyridine/water (1/1, 10 mL) was added and was followed by potassium
permanganate (1 g); the resulting mixture was heated to 100.degree.
C. overnight. The hot reaction mixture was filtered through a
CELITE.TM. pad, the filter cake was washed with hot water and the
filtrate was acidified, until pH 1, by addition of an aqueous
solution of hydrochloric acid (6 M). The resulting mixture was
extracted with ethyl acetate; the organic layer was dried over
anhydrous sodium sulfate, filtered and evaporated under reduced
pressure. The light yellow solid residue (903 mg) was washed twice
with a small aliquot of dichloromethane to give
2-chloro-5-methoxy-4-nitro-benzoic acid as an off-white solid
without further purifications.
Step C: synthesis of
2-chloro-5-methoxy-4-nitro-N-phenyl-benzamide
[0552] To a solution of 2-chloro-5-methoxy-4-nitro-benzoic acid
(200 mg, 0.86 mmol) in acetonitrile (10 mL) was added HBTU (327 mg,
0.86 mmol) followed by aniline (0.08 mL, 0.86 mmol) and
diisopropylethylamine (0.56 mL, 3.20 mmol) and the resulting
mixture was stirred at room temperature overnight. The reaction
mixture was then heated at 60.degree. C. for 24 hours and
concentrated under reduced pressure. The residue was partitioned
between ethyl acetate (50 mL) and water (50 mL); the organic layer
was separated and washed with water (50 mL) and brine (50 mL),
dried over anhydrous sodium sulfate, filtered and evaporated under
reduced pressure. The crude residue was purified by flash
chromatography (hexane/EtOAc, 75/25) to give 182 mg of
2-chloro-5-methoxy-4-nitro-N-phenyl-benzamide as a light yellow
solid.
Step D: synthesis of
4-amino-2-chloro-5-methoxy-N-phenyl-benzamide
[0553] Stannous chloride (334 mg, 1.76 mmol) was added to a
solution of 2-chloro-5-methoxy-4-nitro-N-phenyl-benzamide (180 mg,
0.59 mmol) in a mixture of ethyl acetate and ethanol (1/1, 8 mL)
and the reaction mixture was stirred at room temperature overnight.
The resulting mixture was partitioned between ethyl acetate (50 mL)
and an aqueous solution of potassium carbonate (5%, 30 mL); the
organic layer was separated, washed with brine (30 mL), dried over
anhydrous sodium sulfate, filtered and evaporate under reduced
pressure. The crude residue was purified by flash chromatography
(hexane/EtOAc, 70/30) to give 82 mf of
4-amino-2-chloro-5-methoxy-N-phenyl-benzamide as an off-white
solid.
Preparation 10: Synthesis of
4-Amino-3-methoxy-N,N-dimethyl-benzamide
[0554] The synthesis of 4-amino-3-methoxy-N,N-dimethyl-benzamide
was carried out according to the process shown in Scheme 10.
##STR00211##
Step A: synthesis of 3-methoxy-N,N-dimethyl-4-nitro-benzamide
[0555] N,N-Dimethylphosphoramidodichloridate (1.8 mL, 15.22 mmol)
was added to a solution of 3-methoxy-4-nitrobenzoic acid (300 mg,
1.52 mmol) in anhydrous 1,2-dimethoxyethane (15 mL) and the
resulting mixture was heated at reflux for 110 hours ca. The
reaction mixture was then cooled and poured into ice-water (50 mL);
the resulting mixture was extracted with diethyl ether (50 mL), the
organic layer was separated and the aqueous layer was extracted
with dichloromethane (50 mL). The combined organic extracts were
concentrated under reduced pressure; the residue was dissolved in
dichloromethane and washed with water (30 mL), dried over anhydrous
sodium sulfate, filtered and evaporated under reduced pressure. The
tan liquid residue was purified by flash chromatography (DCM/MeOH,
98/2) to give 185 mg of 3-methoxy-N,N-dimethyl-4-nitro-benzamide as
a yellow oil.
Step B: synthesis of 4-amino-3-methoxy-N,N-dimethyl-benzamide
[0556] A mixture of 3-methoxy-N,N-dimethyl-4-nitro-benzamide (185
mg) and palladium on carbon (10%, 20 mg) in ethanol (6 mL) was
stirred under hydrogen atmosphere (balloon pressure), at room
temperature, overnight. The reaction mixture was filtered on a
CELITE.TM. pad and the filtrate was concentrated under reduced
pressure. The crude residue was purified by flash chromatography
(DCM/MeOH, 98/2) to afford 60 mg of
4-amino-3-methoxy-N,N-dimethyl-benzamide.
[0557] 2-Methoxy-1,5-dimethyl-3-nitro-benzene was reduced utilizing
the above described procedure to give
2-methoxy-3,5-dimethyl-phenylamine.
Preparation 11: Synthesis of
6-chloro-thieno[2,3-b]pyridine-3-carboxylic acid
[0558] The synthesis of 6-chloro-thieno[2,3-b]pyridine-3-carboxylic
acid was carried out according to the process shown in Scheme
11.
##STR00212##
Step A: synthesis of
3-methyl-4H-thieno[3,2-b]pyridine-5,7-dione
[0559] Ethyl malonyl chloride (4.29 g, 28 mmol) was added to a
solution of methyl 3-amino-4-methylthiophene-2-carboxylate (4 g, 23
mmol) and triethylamine (4.2 mL, 30 mmol) in dichloromethane (50
mL) and the resulting mixture was stirred for 30 minutes. The
reaction mixture was diluted with dichloromethane, washed with
water and brine, dried over anhydrous sodium sulfate, filtered and
evaporated under reduced pressure. To the oily residue was added a
freshly prepared ethanolic solution of sodium ethoxyde (0.5 g in 25
mL of EtOH) and the reaction mixture was heated at reflux
overnight. The solvent was evaporated under reduced pressure and
water (50 mL) was added to the residue, followed by sodium
hydroxide (1.5 g). The resulting mixture was heated at reflux
overnight, then was cooled and acidified by addition of an aqueous
solution of hydrochloric acid (6 M). The solid formed was collected
by filtration, washed with water and dried under reduced pressure
to afford 2.0 g of 3-methyl-4H-thieno[3,2-b]pyridine-5,7-dione.
Step B: synthesis of
5,7-dichloro-3-methyl-thieno[3,2-b]pyridine
[0560] A mixture of 3-methyl-4H-thieno[3,2-b]pyridine-5,7-dione
(0.8 g) and phosphorus oxychloride (2.5 mL) was heated to
180.degree. C. in a microwave reactor for 15 minutes. The cooled
reaction mixture was poured into a mixture of ice-water and ethyl
acetate, the organic layer was separated, washed with brine, dried
over anhydrous sodium sulfate, filtered and evaporated under
reduced pressure. The crude residue was purified by flash
chromatography (DCM) to give
5,7-dichloro-3-methyl-thieno[3,2-b]pyridine.
Step C: synthesis of 5-chloro-3-methyl-thieno[3,2-b]pyridine
[0561] A mixture of 5,7-dichloro-3-methyl-thieno[3,2-b]pyridine
(1.2 g), palladium hydroxide on carbon (20%, 600 mg) and sodium
acetate (1.0 g) in ethyl acetate (50 mL) was shaken in a Parr
apparatus under hydrogen atmosphere (55 PSI) for 62 hours. The
resulting mixture was filtered on a CELITE.TM. pad, the filter cake
was washed with dichloromethane and the filtrate was evaporated
under reduced pressure. The crude residue was purified by flash
chromatography (acetone/hexane) to afford 0.4 g of
5-chloro-3-methyl-thieno[3,2-b]pyridine and 0.2 g of
3-methyl-thieno[3,2-b]pyridine.
Step D: synthesis of
5-chloro-thieno[3,2-b]pyridine-3-carbaldehyde
[0562] A mixture of 5-chloro-3-methyl-thieno[3,2-b]pyridine (0.5 g,
2.7 mmol), N-bromosuccinimide (0.48 g, 2.7 mmol) and benzoyl
peroxide (50 mg) in carbon tetrachloride (3 mL) was heated at
100.degree. C. in a microwave reactor for 15 minutes. The
supernatant was decanted and evaporated under reduced pressure, the
residue was suspended in toluene (3 mL) and pyridine-N-oxide (0.5
g) was added, followed by sodium bicarbonate (0.4 g) and
diisopropylethylamine (3 drops). The reaction mixture was heated at
150.degree. C. in a microwave reactor for 5 minutes, was then
diluted with ethyl acetate, washed with water and brine, dried over
anhydrous sodium sulfate, filtered and evaporated under reduced
pressure. The crude residue was purified by flash chromatography
(EtOAc/hexane, 20/80) to give 150 mg of
5-chloro-thieno[3,2-b]pyridine-3-carbaldehyde.
Step E: synthesis of 6-chloro-thieno[2,3-b]pyridine-3-carboxylic
acid
[0563] Sulfamic acid (150 mg) was added to a solution of
5-chloro-thieno[3,2-b]pyridine-3-carbaldehyde (150 mg, 0.76 mmol)
in a mixture of tetrahydrofuran, tert-butanol and water (1/1/1, 6
mL). A solution of sodium chlorite (100 mg) and potassium
dihydrogen phosphate (300 mg) in water (2 mL) was then added and
the resulting mixture was stirred for 30 minutes. The reaction
mixture was then concentrated under reduced pressure to the remove
the volatiles, the solid formed was collected by filtration, washed
with water and ethyl acetate, dried in a vacuum oven to give 70 mg
of 6-chloro-thieno[2,3-b]pyridine-3-carboxylic acid without further
purifications.
Preparation 12: Synthesis of thieno[3,2-d]pyrimidine-7-carboxylic
acid
[0564] The synthesis of thieno[3,2-d]pyrimidine-7-carboxylic acid
was carried out according to the process shown in Scheme 12.
##STR00213##
Step A: synthesis of 7-methyl-3H-thieno[3,2-d]pyrimidin-4-one
[0565] A mixture of 3-amino-4-methyl-thiophene-2-carboxylic acid
methyl ester (3.0 g) and formamide (50 mL) was heated to
150.degree. C. overnight. The reaction mixture was then cooled and
diluted with water. The solid formed was collected by filtration,
washed with water and dried under reduced pressure to give 2.1 g of
7-methyl-3H-thieno[3,2-d]pyrimidin-4-one without further
purifications.
Step B: synthesis of 4-chloro-7-methyl-thieno[3,2-d]pyrimidine
[0566] A suspension of 7-methyl-3H-thieno[3,2-d]pyrimidin-4-one
(2.1 g) in phosphorus oxychloride (10 mL) was heated at 100.degree.
C. for 1 hour. The reaction mixture was then cooled and poured into
a mixture of ice-water and ethyl acetate. The organic layer was
separated, washed with brine, dried over anhydrous sodium sulfate,
filtered and evaporated under reduced pressure. The crude residue
was purified by flash chromatography (DCM) to afford 2.0 g of
4-chloro-7-methyl-thieno[3,2-d]pyrimidine.
Step C: synthesis of 7-methyl-thieno[3,2-d]pyrimidine
[0567] A mixture of 4-chloro-7-methyl-thieno[3,2-d]pyrimidine (2
g), palladium hydroxide on carbon (20%, 1 g) and sodium acetate (2
g) in a mixture of ethyl acetate and isopropanol (5/1, 30 mL) was
shaken in a Parr apparatus under hydrogen atmosphere (50 PSI)
overnight. The resulting mixture was filtered on a CELITE.TM. pad,
the filter cake was washed with dichloromethane and the filtrate
was evaporated under reduced pressure. The crude residue was
purified by flash chromatography (acetone/DCM, 3/97) to afford 1 g
of 7-methyl-thieno[3,2-d]pyrimidine.
Step D: synthesis of thieno[3,2-d]pyrimidine-7-carbaldehyde
[0568] A mixture of 7-methyl-thieno[3,2-d]pyrimidine (1.2 g) and
N-bromosuccinimide (2.9 g) in carbon tetrachloride (50 mL) was
heated at reflux for 1 hour. The reaction mixture was then cooled,
the solid formed was filtered off and the filtrate was concentrated
under reduced pressure. The residue was suspended in water (10 mL)
and the suspension was heated at reflux for 1 hour. The resulting
mixture was basified by addition of a saturated aqueous solution of
sodium bicarbonate and extracted twice with dichloromethane (100
mL). The combined organic layers were washed with brine, dried over
anhydrous sodium sulfate, filtered and evaporated under reduced
pressure. The solid residue was triturated with ethyl acetate and
hexane and then collected by filtration to give 0.8 g of
thieno[3,2-d]pyrimidine-7-carbaldehyde.
Step E: synthesis of thieno[3,2-d]pyrimidine-7-carboxylic acid
[0569] Thieno[3,2-d]pyrimidine-7-carbaldehyde was oxidized using
the procedure described in Preparation 11, Step E, to give the
corresponding carboxylic acid.
Preparation 13: Synthesis of
2-Chloro-thieno[3,2-d]pyrimidine-7-carboxylic acid
[0570] The synthesis of
2-chloro-thieno[3,2-d]pyrimidine-7-carboxylic acid was carried out
according to the process shown in Scheme 13.
##STR00214##
Step A: synthesis of
7-methyl-1H-thieno[3,2-d]pyrimidine-2,4-dione
[0571] Trichloroacetyl isocyanate (2.0 g) was added to a solution
of methyl 3-amino-4-methylthiophene-2-carboxylate (1.3 g) in
acetonitrile (10 mL) and the resulting mixture was stirred for 15
minutes. The solid, which crashed out, was collected by filtration
and suspended in methanol (5 mL), a solution of ammonia in methanol
(7 M, 5 mL) was then added and the resulting mixture was heated at
70.degree. C. for 15 minutes. The reaction mixture was cooled, the
solid formed was collected by filtration, dried under reduced
pressure to give 0.8 g of
7-methyl-1H-thieno[3,2-d]pyrimidine-2,4-dione.
Step B: synthesis of
2,4-dichloro-7-methyl-thieno[3,2-d]pyrimidine
[0572] A mixture of 7-methyl-1H-thieno[3,2-d]pyrimidine-2,4-dione
(2.8 g) and phosphorus oxychloride (5 mL) was split in 2 portions
and both portions were heated at 180.degree. C. in a microwave
reactor for 15 minutes. The combined reaction mixtures were cooled
and partitioned between ice-water and ethyl acetate. The organic
layer was separated, washed with water and brine, dried over
anhydrous sodium sulfate, filtered and evaporated under reduced
pressure. The crude residue was triturated with hexane and the
solid was collected by filtration to afford 2.5 g of
2,4-dichloro-7-methyl-thieno[3,2-d]pyrimidine.
Step C: synthesis of 2-chloro-7-methyl-thieno[3,2-d]pyrimidine
[0573] A mixture of 2,4-dichloro-7-methyl-thieno[3,2-d]pyrimidine
(2.5 g), palladium hydroxide on carbon (20%, 0.5 g) and sodium
acetate (2.0 g) in a mixture of ethyl acetate (40 mL) and isopropyl
alcohol (5 mL) was shaken in a Parr apparatus under hydrogen
atmosphere (50 PSI) overnight. The reaction mixture was filtered on
a CELITE.TM. pad and the filtrate was evaporated under reduced
pressure. The crude residue was purified by flash chromatography
(DCM) to give 1.8 g of
2-chloro-7-methyl-thieno[3,2-d]pyrimidine.
Step D: synthesis of
2-chloro-thieno[3,2-d]pyrimidine-7-carbaldehyde
[0574] A mixture of 2-chloro-7-methyl-thieno[3,2-d]pyrimidine (1.8
g), N-bromosuccinimide (1.8 g), 2,2'-azobis(2-methylpropionitrile)
(0.1 g) in carbon tetrachloride (50 mL) was heated at reflux for 1
hour. The resulting mixture was cooled, the solid was filtered off
and the filtrate was evaporated under reduced pressure. The residue
was dissolved in acetonitrile (20 mL) and diisopropylethylamine
(2.0 mL) was added, followed by pyridine-N-oxide (3 g) and the
resulting mixture was heated at 100.degree. C. for 30 minutes. The
reaction mixture was cooled, diluted with ethyl acetate, washed
with water and brine, dried over anhydrous sodium sulfate, filtered
and evaporated under reduced pressure. The crude residue was
purified by flash chromatography (hexane/EtOAc) to afford 0.25 g of
2-chloro-thieno[3,2-d]pyrimidine-7-carbaldehyde and 1 g of
2-chloro-7-methyl-thieno[3,2-d]pyrimidine starting material.
Step E: synthesis of 2-chloro-thieno[3,2-d]pyrimidine-7-carboxylic
acid
[0575] To a solution of
2-chloro-thieno[3,2-d]pyrimidine-7-carbaldehyde (0.6 g) in a
mixture of tert-butanol/tertrahydrofuran/water (1/1/1, 45 mL) was
added sulfamic acid (1.0 g) followed by a solution of sodium
chlorite (0.9 g) and potassium dihydrogen phosphate (3.0 g) in
water (10 mL) and the resulting mixture was stirred for 1 hour. The
reaction mixture was then diluted with ethyl acetate; the organic
layer was separated and washed with brine, dried over anhydrous
sodium sulfate, filtered and evaporated under reduced pressure. The
residue was triturated with ethyl acetate and the solid was
collected by filtration to give 0.5 g of
2-chloro-thieno[3,2-d]pyrimidine-7-carboxylic acid.
Preparation 14: Synthesis of
5-Methyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
[0576] The synthesis of
5-methyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid was carried
out according to the process shown in Scheme 14.
##STR00215##
[0577] A mixture of ethyl 3-amino-4-pyrazolecarboxylate (1.0 g, 6.4
mmol) and acetylacetaldehyde dimethyl acetal (1.7 g, 13 mmol) in
toluene (5 mL) was heated at reflux overnight. The resulting
mixture was cooled and purified by flash chromatography
(hexane/ethyl acetate) to obtain 0.7 g of the ester. The ester was
then dissolved in a mixture of methanol and water (1/1, 10 mL) and
sodium hydroxide (0.7 g) and heated at reflux overnight. The
reaction mixture was cooled, neutralized with an aqueous solution
of hydrochloric acid (6 M) to pH 7 and extracted with ethyl
acetate. The organic layer was separated, washed with brine, dried
over anhydrous sodium sulfate, filtered and evaporated under
reduced pressure to afford
5-methyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid without
further purifications.
Preparation 15: Synthesis of
7-Methyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
[0578] The synthesis of
7-methyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid was carried
out according to the process shown in Scheme 15.
##STR00216##
[0579] A mixture of ethyl 3-amino-4-pyrazolecarboxylate (250 mg),
acetylacetaldehyde dimethyl acetale (200 .mu.L) and concentrated
hydrochloric acid (0.5 mL) was heated at 60.degree. C. for 15
minutes. The resulting mixture was cooled and the solid which
crashed out was collected by filtration, washed with ethyl acetate
and dried in a vacuum oven to give 200 mg of
7-methyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid.
Preparation 16: Synthesis of
(E)-3-(4-Methoxy-3-nitro-phenyl)-acrylic acid methyl ester
[0580] The synthesis of (E)-3-(4-methoxy-3-nitro-phenyl)-acrylic
acid methyl ester was carried out according to the process shown in
Scheme 16.
##STR00217##
Step A: synthesis of (E)-3-(4-methoxy-3-nitro-phenyl)-acrylic acid
methyl ester
[0581] A mixture of 4-methoxy-3-nitrobenzaldehyde (1.5 g, 8.2 mmol)
and methyl (triphenylphosphoranylidene)acetate (4.4 g, 13 mmol) in
tetrahydrofuran (30 mL) was heated at reflux overnight. The
reaction mixture was cooled and evaporated under reduced pressure;
the crude residue was purified by flash chromatography
(acetone/hexane, 20/80) to afford 0.5 g of
(E)-3-(4-methoxy-3-nitro-phenyl)-acrylic acid methyl ester.
Step B: synthesis of (E)-3-(3-amino-4-methoxy-phenyl)-acrylic acid
methyl ester
[0582] To a solution of (E)-3-(4-methoxy-3-nitro-phenyl)-acrylic
acid methyl ester (0.5 g) in dichloromethane (5 mL) was added zinc
dust (2 g), followed by acetic acid (1 mL) and the resulting
mixture was stirred at room temperature for 30 minutes. The solid
was filtered off and washed with dichloromethane. The filtrate was
evaporated under reduced pressure and the residue was purified by
flash chromatography (DCM/acetone, 95/5) to give
(E)-3-(3-amino-4-methoxy-phenyl)-acrylic acid methyl ester.
Step C: synthesis of
(E)-3-(3-amino-4-methoxy-phenyl)-prop-2-en-1-ol
[0583] A solution of lithium aluminum hydride (1 M in THF, 4 mL)
was added at 0.degree. C. to a solution of
(E)-3-(3-amino-4-methoxy-phenyl)-acrylic acid methyl ester (400 mg)
in tetrahydrofuran (10 mL) and the resulting mixture was stirred
for 15 minutes. The reaction mixture was then quenched by addition
of a saturated aqueous solution of ammonium chloride, the resulting
mixture was filtered and the filter cake was washed with ethyl
acetate. The filtrate was separated and the organic layer was dried
over anhydrous sodium sulfate, filtered and evaporated under
reduced pressure to afford 90 mg of
(E)-3-(3-amino-4-methoxy-phenyl)-prop-2-en-1-ol without further
purifications.
Step D: synthesis of 3-(3-amino-4-methoxy-phenyl)-propan-1-ol
[0584] A mixture of (E)-3-(3-amino-4-methoxy-phenyl)-prop-2-en-1-ol
(250 mg) and palladium hydroxide on carbon (20%, 50 mg) in ethyl
acetate (10 mL) was stirred under hydrogen atmosphere (balloon
pressure) overnight. The resulting mixture was filtered over a
CELITE.TM. pad, the filter cake was washed with dichloromethane and
the filtrate was evaporated under reduced pressure to give 100 mg
of 3-(3-amino-4-methoxy-phenyl)-propan-1-ol without further
purifications.
Preparation 17: Synthesis of 5-Ethyl-2-methoxy-phenylamine
[0585] The synthesis of 5-ethyl-2-methoxy-phenylamine was carried
out according to the process shown in Scheme 17.
##STR00218##
Step A: synthesis of 1-methoxy-2-nitro-4-vinyl-benzene
[0586] To a solution of 4-methoxy-3-nitrobenzaldehyde (0.6 g) in
tetrahydrofuran (10 mL) was added sodium hydride (50% suspension in
mineral oil, 0.5 g) followed by methyltriphenylphosphonium bromide
(1.8 g) and the resulting mixture was heated at reflux for 1 hour.
The reaction mixture was cooled, diluted with water, extracted with
brine, dried over anhydrous sodium sulfate, filtered and evaporated
under reduced pressure. The crude residue was purified by flash
chromatography (hexane/EtOAc, 90/10) to give 150 mg of
1-methoxy-2-nitro-4-vinyl-benzene.
Step B: synthesis of 5-ethyl-2-methoxy-phenylamine
[0587] A mixture of 1-methoxy-2-nitro-4-vinyl-benzene (150 mg) and
palladium on carbon (10%, 25 mg) in ethyl acetate (10 mL) was
stirred under hydrogen atmosphere (balloon pressure) at room
temperature overnight. The reaction mixture was filtered on a
CELITE.TM. pad and the filtrate was evaporated to give
5-ethyl-2-methoxy-phenylamine without further purifications.
Preparation 18: Synthesis of 2-Methoxy-5-vinyl-phenylamine
[0588] The synthesis of 2-methoxy-5-vinyl-phenylamine was carried
out according to the process shown in Scheme 18.
##STR00219##
[0589] To a solution of 1-methoxy-2-nitro-4-vinyl-benzene (100 mg)
in dichloromethane (2 mL) was added zinc dust (large excess),
followed by acetic acid (0.5 mL) and the resulting mixture was
stirred at room temperature for 30 minutes. The solid was filtered,
washed with dichloromethane and discarded. The filtrate was
evaporated under reduced pressure and the residue was purified by
flash chromatography (hexane/EtOAc, 90/10) to give 50 mg of
2-methoxy-5-vinyl-phenylamine.
Preparation 19: Synthesis of
[1-(2-Amino-4-chloro-phenyl)-piperidin-4-yl]methanol
[0590] The synthesis of
[1-(2-amino-4-chloro-phenyl)-piperidin-4-yl]-methanol was carried
out according to the process shown in Scheme 19.
##STR00220##
Step A: synthesis of
[1-(4-chloro-2-nitro-phenyl)-piperidin-4-yl]methanol
[0591] A mixture of 2,5-dichloronitrobenzene (0.7 g),
4-piperidinemethanol (0.6 g) and potassium carbonate (1 g) in
N,N-dimethylformamide (10 mL) was heated at 80.degree. C. for 1
hour. The reaction mixture was cooled, diluted with water and
extracted with ethyl acetate. The combined organic extracts were
washed with water and brine, dried over anhydrous sodium sulfate,
filtered and evaporated under reduced pressure. The crude residue
was purified by flash chromatography (DCM/Acetone, 90/10) to afford
0.8 g of [1-(4-chloro-2-nitro-phenyl)-piperidin-4-yl]-methanol.
Step B: synthesis of
[1-(2-amino-4-chloro-phenyl)-piperidin-4-yl]methanol
[0592] [1-(4-Chloro-2-nitro-phenyl)-piperidin-4-yl]-methanol (200
mg) was reduced following the procedure described in Preparation
16, Step B, to afford 90 mg of
[1-(2-amino-4-chloro-phenyl)-piperidin-4-yl]-methanol.
[0593] Utilizing the above described procedure and the appropriate
starting materials, the following compounds were prepared: [0594]
[1-(2-amino-4-chloro-phenyl)-piperidin-4-ylmethyl]-carbamic acid
tert-butyl ester; [0595]
1-(2-amino-4-chloro-phenyl)-piperidine-4-carboxylic acid amide;
[0596] [1-(2-amino-4-chloro-phenyl)-piperidin-3-yl]-methanol;
[0597] 2-azepan-1-yl-5-chloro-phenylamine; [0598]
(3-amino-4-piperidin-1-yl-phenyl)-methanol; [0599]
5-chloro-2-pyrrolidin-1-yl-phenylamine; [0600]
[1-(2-amino-4-chloro-phenyl)-pyrrolidin-3-yl]-methanol; [0601]
5-chloro-2-(4-methyl-piperazin-1-yl)-phenylamine; [0602]
4-(2-amino-4-chloro-phenoxy)-piperidine-1-carboxylic acid
tert-butyl ester; [0603]
2-[4-(tert-butyl-dimethyl-silanyloxymethyl)-piperidin-1-yl]-5-chloro-phen-
ylamine; [0604] 5-chloro-2-piperidin-1-yl-phenylamine; [0605]
2-[(2-amino-4-chloro-phenyl)-methyl-amino]-ethanol; [0606]
1-(2-amino-4-chloro-phenyl)-piperidin-4-ol; [0607]
1-(2-amino-4-chloro-phenyl)-piperidin-3-ol; [0608]
[1-(2-amino-4-chloro-phenyl)-piperidin-2-yl]-methanol; [0609]
3-[(2-amino-4-chloro-phenyl)-methyl-amino]-propan-1-ol; and [0610]
1-[1-(2-amino-4-chloro-phenyl)-pyrrolidin-3-yl]-ethanol.
Preparation 20: Synthesis of
3-(2-Amino-4-chloro-phenoxy)-cyclopentanecarboxylic acid ethyl
ester
[0611] The synthesis of
3-(2-amino-4-chloro-phenoxy)-cyclopentanecarboxylic acid ethyl
ester was carried out according to the process shown in Scheme
20.
##STR00221##
Step A: synthesis of
3-(4-chloro-2-nitro-phenoxy)-cyclopentanecarboxylic acid ethyl
ester
[0612] A mixture of 1,4-dichloro-2-nitro-benzene (190 mg, 1.1
mmol), 3-hydroxy-cyclopentanecarboxylic acid ethyl ester (180 mg,
1.14 mmol), triphenylphosphine (448 mg) and DIAD (345 mg) in
dichloromethane (10 mL) was stirred at room temperature overnight.
The reaction mixture was then evaporated under reduced pressure and
the crude residue was purified by flash chromatography to afford
280 mg of 3-(4-chloro-2-nitro-phenoxy)-cyclopentanecarboxylic acid
ethyl ester.
Step B: synthesis of
3-(2-amino-4-chloro-phenoxy)-cyclopentanecarboxylic acid ethyl
ester
[0613] To a solution of
3-(4-chloro-2-nitro-phenoxy)-cyclopentanecarboxylic acid ethyl
ester (280 mg) in dichloromethane (20 mL) was added zinc dust (2 g)
followed by glacial acetic acid (1 mL) and the resulting mixture
was stirred at room temperature for 20 minutes. The solid was
filtered, washed with dichloromethane and discarded. The filtrate
was evaporated under reduced pressure and the residue was purified
by flash chromatography (hexane/acetone, 80/20) to afford 200 mg of
3-(2-amino-4-chloro-phenoxy)-cyclopentanecarboxylic acid ethyl
ester.
[0614] 1-Methoxy-naphthalen-2-ylamine was prepared utilizing the
above described procedure and the appropriate starting
materials.
Preparation 21: Synthesis of
Pyrrolo[2,1-f][1,2,4]triazine-7-carboxylic acid
[0615] The synthesis of pyrrolo[2,1-f][1,2,4]triazine-7-carboxylic
acid was carried out according to the process shown in Scheme
21.
##STR00222##
Step A: synthesis of 1H-pyrrole-2,5-dicarboxylic acid 2-ethyl ester
5-methyl ester
[0616] To a solution of 5-formyl-1H-pyrrole-2-carboxylic acid ethyl
ester (1 g, 6 mmol) in a mixture of
tert-butanol/tertrahydrofuran/water (1/1/1, 60 mL) was added
sulfamic acid (1.0 g, 9 mmol) and the resulting mixture was stirred
for 10 minutes. A solution of sodium chlorite (0.76 g, 8.4 mmol)
and potassium dihydrogen phosphate (1.6 g, 12 mmol) in water (5 mL)
was then added and the reaction mixture was stirred for 30 minutes.
The resulting mixture was then extracted with ethyl acetate and the
organic extracts were washed with water and brine, dried over
anhydrous sodium sulfate, filtered and evaporated under reduced
pressure. The residue was dissolved in dichloromethane (20 mL) and
a solution of trimetisilidiazomethane (2 M in hexane, 5 mL) was
added; the resulting mixture was stirred until the gas evolution
ceased. Glacial acetic acid (a few drops) was added and the
resulting mixture was evaporated under reduced pressure. The
residue was purified by flash chromatography (hexane/EtOAc, 85/15)
to give 0.7 g of 1H-pyrrole-2,5-dicarboxylic acid 2-ethyl ester
5-methyl ester.
Step B: synthesis of 1-amino-1H-pyrrole-2,5-dicarboxylic acid
2-ethyl ester 5-methyl ester
[0617] Sodium hydride (60% suspension in mineral oil, 90 mg) was
added to a solution of 1H-pyrrole-2,5-dicarboxylic acid 2-ethyl
ester 5-methyl ester (100 mg) in N,N-dimethylformamide (2 mL) and
the resulting mixture was stirred for 5 minutes.
2,4,6-Trimethyl-benzenesulfonylhydroxylamine (prepared from 0.5 g
of mesitilene oxamate as described in JOC 1973, 1239) was then
added and the mixture was stirred for 5 minutes. The reaction
mixture was then quenched by addition of water and the resulting
mixture was extracted with ethyl acetate. The combined organic
layers were washed with water and brine, dried over anhydrous
sodium sulfate, filtered and evaporated under reduced pressure. The
crude residue was purified by flash chromatography (hexane/EtOAc,
90/10) to afford 100 mg of 1-amino-1H-pyrrole-2,5-dicarboxylic acid
2-ethyl ester 5-methyl ester.
Step C: synthesis of
4-oxo-3,4-dihydro-pyrrolo[2,1-f][1,2,4]triazine-7-carboxylic acid
ethyl ester
[0618] A mixture of 1-amino-1H-pyrrole-2,5-dicarboxylic acid
2-ethyl ester 5-methyl ester (140 mg) and formamide (1 mL) was
stirred at 140.degree. C. overnight. The reaction mixture was then
cooled and diluted with water, the solid which crashed out was
collected by filtration and dried under vacuum to give 60 mg of
4-oxo-3,4-dihydro-pyrrolo[2,1-f][1,2,4]triazine-7-carboxylic acid
ethyl ester.
Step D: synthesis of
4-chloro-pyrrolo[2,1-f][1,2,4]triazine-7-carboxylic acid ethyl
ester
[0619] A mixture of
4-oxo-3,4-dihydro-pyrrolo[2,1-f][1,2,4]triazine-7-carboxylic acid
ethyl ester (300 mg) and phosphorus oxychloride (1 mL) was heated
at 160.degree. C. for 15 minutes in a microwave reactor. The
resulting mixture was cooled and poured into a mixture of ice-water
and ethyl acetate. The organic layer was separated, washed with
brine, dried over anhydrous sodium sulfate, filtered and evaporated
under reduced pressure. The residue was purified by flash
chromatography (hexane/EtOAc, 90/10) to afford 120 mg of
4-chloro-pyrrolo[2,1-f][1,2,4]triazine-7-carboxylic acid ethyl
ester containing
4-chloro-pyrrolo[2,1-f][1,2,4]triazine-7-carbonitrile.
Step E: synthesis of pyrrolo[2,1-f][1,2,4]triazine-7-carboxylic
acid ethyl ester
[0620] A mixture of
4-chloro-pyrrolo[2,1-f][1,2,4]triazine-7-carboxylic acid ethyl
ester (120 mg), palladium hydroxide on carbon (20%, 40 mg) and
sodium acetate (600 mg) in a mixture of ethyl acetate and
isopropanol (5/1, 12 mL) was stirred at room temperature under
hydrogen atmosphere (balloon pressure) overnight. The resulting
mixture was filtered and a CELITE.TM. pad, the filtrate was
evaporated under reduced pressure. The crude residue was purified
by flash chromatography to give 45 mg of
pyrrolo[2,1-f][1,2,4]triazine-7-carboxylic acid ethyl ester.
Step F: synthesis of pyrrolo[2,1-f][1,2,4]triazine-7-carboxylic
acid
[0621] A mixture of pyrrolo[2,1-f][1,2,4]triazine-7-carboxylic acid
ethyl ester (40 mg) and an aqueous solution of sodium hydroxide (6
M, 1 mL) in a mixture of tetrahydrofuran and methanol (1/1, 1 mL)
was heated at 70.degree. C. for 1 hour. The reaction mixture was
then cooled, acidified by addition of an aqueous solution of
hydrochloric acid (6 M) and evaporated under reduced pressure. The
residue was dissolved in a mixture of dichloromethane and water
(10/1, 5.5 mL), the organic layer was separated, dried over
anhydrous sodium sulfate, filtered and evaporated under reduced
pressure to give 15 mg of
pyrrolo[2,1-f][1,2,4]triazine-7-carboxylic acid.
Preparation 22: Synthesis of
6-Amino-5-piperidin-1-yl-1,3-dihydro-indol-2-one
[0622] The synthesis of
6-amino-5-piperidin-1-yl-1,3-dihydro-indol-2-one was carried out
according to the process shown in Scheme 22.
##STR00223##
Step A: synthesis of 2-(5-chloro-2,4-dinitro-phenyl)-malonic acid
tert-butyl ester ethyl ester
[0623] Sodium hydride (60% suspension in mineral oil, 1.60 mmol)
was added to a mixture of tert-butyl ethyl malonate (300 mg) in
1-methyl-2-pyrrolidinone (3 mL) and was followed by
1,5-dichloro-2,4-dinitrobenzene (0.45 g). The reaction mixture was
stirred for 15 minutes and was then quenched by addition of a
diluted aqueous solution of hydrochloric acid. The resulting
mixture was extracted with ethyl acetate; the combined organic
extracts were washed with brine, dried over anhydrous sodium
sulfate, filtered and evaporated under reduced pressure. The
residue was purified by flash chromatography (EtOAc/hexane, 5/95 to
15/85) to give 0.4 g of 2-(5-chloro-2,4-dinitro-phenyl)-malonic
acid tert-butyl ester ethyl ester.
Step B: synthesis of (5-chloro-2,4-dinitro-phenyl)-acetic acid
ethyl ester
[0624] A solution of 2-(5-chloro-2,4-dinitro-phenyl)-malonic acid
tert-butyl ester ethyl ester (0.4 g) in a mixture of
dichloromethane (3 mL) and trifluoroacetic acid (0.5 mL) was heated
at 70.degree. C. for 30 minutes in a sealed tube. The reaction
mixture was then evaporated under reduced pressure and the residue
was purified by flash chromatography (EtOac/hexane, 10/90) to
afford 150 mg of (5-chloro-2,4-dinitro-phenyl)-acetic acid ethyl
ester.
Step C: synthesis of
6-amino-5-piperidin-1-yl-1,3-dihydro-indol-2-one
[0625] Piperidine (120 mg) was added to a solution of
(5-chloro-2,4-dinitro-phenyl)-acetic acid ethyl ester (150 mg) in
dichloromethane (5 mL) and the resulting mixture was stirred at
room temperature for 10 minutes. Glacial acetic acid (0.3 mL) and
zinc dust (1 scoop) were added and the reaction mixture was stirred
at room temperature for 20 minutes. The resulting mixture was
filtered through a CELITE.TM. pad, the filter cake was washed with
dichloromethane and the filtrate was evaporated under reduced
pressure. The residue was then diluted with ethyl acetate, washed
with brine, dried over anhydrous sodium sulfate, filtered and
evaporated under reduced pressure to give
(2,4-diamino-5-piperidin-1-yl-phenyl)-acetic acid ethyl ester. This
material was dissolved in toluene (2.5 mL) and heated at
150.degree. C. in a microwave reactor for 10 minutes. The reaction
mixture was then cooled, evaporated under reduced pressure and the
residue was purified by flash chromatography (DCM/MeOH, 95/5) to
give 30 mg of 6-amino-5-piperidin-1-yl-1,3-dihydro-indol-2-one.
MS=232 [M+H].sup.+.
[0626]
6-Amino-5-(4-hydroxymethyl-piperidin-1-yl)-1,3-dihydro-indol-2-one
was prepared following the above described procedure and utilizing
the appropriate starting materials.
Preparation 23: Synthesis of
[4-(6-Amino-2-methyl-1H-indol-5-yl)-phenyl]-methanol
[0627] The synthesis of
[4-(6-amino-2-methyl-1H-indol-5-yl)-phenyl]-methanol was carried
out according to the process shown in Scheme 23.
##STR00224##
Step A: synthesis of
(5'-methyl-2',4'-dinitro-biphenyl-4-yl)-methanol
[0628] A mixture of 5-chloro-2,4-dinitrotoluene (1.0 g),
4-(hydroxymethyl)phenylboronic acid (0.84 g),
bis(triphenylphosphine)palladium(II) chloride (150 mg) and
potassium carbonate (2.0 g) in a mixture of 1,4-dioxane and water
(10/1, 11 mL) was heated at 170.degree. C. in a microwave reactor
for 10 minutes. The reaction mixture was then cooled and diluted
with ethyl acetate. The organic layer was washed with water and
brine, dried over anhydrous sodium sulfate, filtered and evaporated
under reduced pressure. The crude residue was purified by flash
chromatography (acetone/DCM, 3/97) to give 0.6 g of
(5'-methyl-2',4'-dinitro-biphenyl-4-yl)-methanol.
Step B: synthesis of
1-(4'-hydroxymethyl-4,6-dinitro-biphenyl-3-yl)-propan-2-one
[0629] A solution of
(5'-methyl-2',4'-dinitro-biphenyl-4-yl)-methanol (0.6 g) in
N,N-dimethylacetamide dimethylacetal (5 mL) was heated at
100.degree. C. for 2 hour. The reaction mixture was then cooled,
diluted with ethyl acetate, washed with a diluted aqueous solution
of hydrochloric acid, water and brine, dried over anhydrous sodium
sulfate, filtered and evaporated under reduced pressure. The crude
residue was purified by flash chromatography (acetone/DCM, 3/97) to
afford
1-(4'-hydroxymethyl-4,6-dinitro-biphenyl-3-yl)-propan-2-one.
Step C: synthesis of
[4-(6-amino-2-methyl-1H-indol-5-yl)-phenyl]-methanol
[0630] A mixture of
1-(4'-hydroxymethyl-4,6-dinitro-biphenyl-3-yl)-propan-2-one (200
mg) and palladium on carbon (10%, 80 mg) in ethyl acetate was
shaken in a Parr apparatus under hydrogen atmosphere (50 PSI)
overnight. The reaction mixture was then filtered on a CELITE.TM.
pad, the filtrate was evaporated under reduced pressure and the
crude residue was purified by flash chromatography to afford
[4-(2-methyl-6-nitro-1H-indol-5-yl)-phenyl]-methanol and
[4-(6-hydroxyamino-2-methyl-1H-indol-5-yl)-phenyl]-methanol. The
two products were combined and dissolved in dichloromethane (5 mL).
Zinc dust (a large excess) and glacial acetic acid (1 mL) were
added and the resulting mixture was heated at 70.degree. C. for 30
minutes. The reaction mixture was then filtered on a CELITE.TM.
pad, the filter cake was washed with ethyl acetate. The filtrate
was washed with brine, dried over anhydrous sodium sulfate,
filtered and evaporated under reduced pressure. The crude residue
was purified by flash chromatography (MeOH/DCM, 5/95) to give 55 mg
of [4-(6-amino-2-methyl-1H-indol-5-yl)-phenyl]-methanol. MS=253
[M+H].sup.+.
Preparation 24: Synthesis of Thieno[3,2-b]pyridine-3,6-dicarboxylic
acid 6-ethyl ester
[0631] The synthesis of thieno[3,2-b]pyridine-3,6-dicarboxylic acid
6-ethyl ester was carried out according to the process shown in
Scheme 24.
##STR00225##
Step A: synthesis of 3-methyl-thieno[3,2-b]pyridine-6-carboxylic
acid ethyl ester
[0632] A mixture of
3-methyl-7-oxo-4,7-dihydro-thieno[3,2-b]pyridine-6-carboxylic acid
ethyl ester (WO 2003/059878 A2) (1.0 g) and phosphorus oxychloride
(3 mL) was heated at 150.degree. C. for 15 minutes in a microwave
reactor. The reaction mixture was then cooled and poured into a
mixture of ice-water and ethyl acetate. The resulting mixture was
stirred for 10 minutes; the organic layer was separated, washed
twice with water (50 mL) and with brine, dried over anhydrous
sodium sulfate, filtered and evaporated under reduced pressure. To
the solid residue dissolved in a mixture of ethyl acetate and
isopropanol (10/1, 55 mL) sodium acetate trihydrate (2.0 g) and
palladium hydroxide on carbon (20%, 0.3 g) were added and the
resulting mixture was shaken in a Parr apparatus under hydrogen
atmosphere (50 PSI) overnight. The reaction mixture was then
filtered on a CELITE.TM. pad, the filtrate was evaporated under
reduced pressure and the crude residue was purified by flash
chromatography (EtOAc/hexane, 10/90) to afford 0.78 g of
3-methyl-thieno[3,2-b]pyridine-6-carboxylic acid ethyl ester.
Step B: synthesis of 3-formyl-thieno[3,2-b]pyridine-6-carboxylic
acid ethyl ester
[0633] To a solution of 3-methyl-thieno[3,2-b]pyridine-6-carboxylic
acid ethyl ester (1.2 g) in carbon tetrachloride (50 mL) was added
N-bromosuccinimide (2.4 g) followed by AIBN (50 mg) and the
resulting mixture was heated at reflux for 4 hours. The reaction
mixture was cooled; the solids were removed by filtrations and
copiously washed with carbon tetrachloride. The filtrate was
evaporated under reduced pressure, the residue was dissolved in
dimethyl sulfoxide (20 mL) and the resulting mixture was heated at
80.degree. C. for 1 hour. The reaction mixture was cooled, diluted
with water, basified by addition of a saturated aqueous solution of
sodium bicarbonate and extracted with ethyl acetate. The combined
organic layers were washed with brine, dried over anhydrous sodium
sulfate, filtered and evaporated under reduced pressure. The
residue was purified by flash chromatography (acetone/DCM, 5/95) to
give 0.8 g of 3-formyl-thieno[3,2-b]pyridine-6-carboxylic acid
ethyl ester.
Step C: synthesis of thieno[3,2-b]pyridine-3,6-dicarboxylic acid
6-ethyl ester
[0634] A mixture of 3-formyl-thieno[3,2-b]pyridine-6-carboxylic
acid ethyl ester (0.8 g, 3.4 mmol) and sulfamic acid (0.66 g, 6.8
mmol) in a mixture of tert-butanol/tetrahydrofuran/water (1/1/1, 60
mL) was stirred for 20 minutes. A solution of sodium chlorite (0.55
g, 6 mmol) and potassium dihydrogen phosphate (1.36 g, 10 mmol) in
water (5 mL) was added and the resulting yellow solution was
stirred for 20 minutes. The reaction mixture was diluted with water
and ethyl acetate, the solid formed was collected by filtration,
washed with water and dried in a vacuum oven at 60.degree. C. The
filtrate was extracted with ethyl acetate; the organic layer was
washed with brine, dried over anhydrous sodium sulfate, filtered
and evaporated under reduced pressure to afford combined with the
solid previously collected 0.5 g of
thieno[3,2-b]pyridine-3,6-dicarboxylic acid 6-ethyl ester.
Preparation 25: Synthesis of 5-Chloro-2-ethyl-phenylamine
[0635] The synthesis of 5-chloro-2-ethyl-phenylamine was carried
out according to the process shown in Scheme 25.
##STR00226##
Step A: synthesis of N-(4-ethyl-phenyl)-acetamide
[0636] Acetic anhydride (4.3 mL, 45.45 mmol) was added to a mixture
of 4-ethylaniline (5.0 g, 41.32 mmol) and pyridine (20 mL) and the
resulting mixture was stirred at room temperature overnight. The
reaction mixture was partitioned between dichloromethane and an
aqueous solution of hydrochloric acid. The organic layer was
separated, dried over anhydrous sodium sulfate, filtered and
evaporated under reduced pressure to give 6.857 g of
N-(4-ethyl-phenyl)-acetamide as a brown solid without further
purifications.
Step B: synthesis of N-(4-ethyl-3-nitro-phenyl)-acetamide
[0637] To concentrate sulfuric acid (8 mL) was added portionwise
N-(4-ethyl-phenyl)-acetamide (2.0 g, 12.27 mmol) and the mixture
was cooled to -15.degree. C., fuming nitric acid (0.505 mL, 12.27
mmol) was then added dropwise. The reaction mixture was stirred at
a temperature ranging between -20 and -10.degree. C. for 75
minutes. The reaction mixture was then poured into ice, neutralized
by addition of sodium carbonate and extracted twice with diethyl
ether. The combined organic extracts were dried over anhydrous
sodium sulfate, filtered and evaporated under reduced pressure. The
crude residue was purified by flash chromatography (hexane/EtOAc,
100/0 to 70/30) to give 2.231 g (88% yield) of
N-(4-ethyl-3-nitro-phenyl)-acetamide.
Step C: synthesis of 4-ethyl-3-nitro-phenylamine
[0638] A mixture of N-(4-ethyl-3-nitro-phenyl)-acetamide (1.0 g)
and concentrated hydrochloric acid (5 mL) was heated at reflux for
4 hours. The reaction mixture was then cooled, basified by addition
of sodium hydroxide and extracted twice with diethyl ether. The
combined organic extracts were dried over anhydrous sodium sulfate,
filtered and evaporated under reduced pressure to afford 0.601 g of
4-ethyl-3-nitro-phenylamine without further purifications. MS=167
[M+H].sup.+.
Step D: synthesis of 4-chloro-1-ethyl-2-nitro-benzene (page
32042-86)
[0639] A solution of sodium nitrite (0.11 g, 1.32 mmol) in water (1
mL) was added, dropwise, at 0.degree. C., to a suspension of
4-ethyl-3-nitro-phenylamine (80%, 0.25 g, 1.20 mmol) in a mixture
of concentrated hydrochloric acid (2 mL) and water (4 mL). The
reaction mixture was stirred at 0.degree. C. for 5 minutes and then
urea (15 mg, 0.24 mmol) was added. The resulting mixture was
stirred for 10 minutes and then was poured into a suspension of
cuprous chloride (0.18 g, 1.8 mmol) in a mixture of concentrated
hydrochloric acid (1.5 mL) and water (0.6 mL) at 80.degree. C. The
reaction mixture was stirred at 80.degree. C. for 2 hours and then
was extracted with ethyl acetate. The organic extracts were washed
with an aqueous solution of sodium hydroxide (1 M) and water, dried
over anhydrous sodium sulfate, filtered and evaporated under
reduced pressure to give 200 mg (90% yield) of
4-chloro-1-ethyl-2-nitro-benzene as an oil.
[0640] 4-Chloro-1-(4-methoxy-butyl)-2-nitro-benzene was prepared
utilizing the above described procedure and the appropriate
starting materials.
Step E: synthesis of 5-chloro-2-ethyl-phenylamine
[0641] To a solution of 4-chloro-1-ethyl-2-nitro-benzene (0.57 g,
3.08 mmol) in a mixture of ethyl acetate and ethanol (1/1, 30 mL)
was added stannous chloride (1.7 g, 9.24 mmol) and the resulting
mixture was stirred at room temperature overnight. The reaction
mixture was then poured into water and basified by addition of
potassium carbonate until pH>10. The resulting mixture was
extracted with dichloromethane; the organic extracts were dried
over anhydrous sodium sulfate, filtered and evaporated under
reduced pressure. The crude residue was purified by flash
chromatography to afford 0.503 g of 5-chloro-2-ethyl-phenylamine as
a brown oil.
Preparation 26: Synthesis of
(7-Amino-6-methoxy-naphthalen-2-yl)-methanol
[0642] The synthesis of
(7-amino-6-methoxy-naphthalen-2-yl)-methanol was carried out
according to the process shown in Scheme 26.
##STR00227## ##STR00228##
Step A: synthesis of 7-bromo-3-methoxy-naphthalene-2-carboxylic
acid methyl ester
[0643] A mixture of 7-bromo-3-hydroxy-naphthalene-2-carboxylic acid
(J. Med. Chem. 1990, 33(1), 171) (5.3 g, 19.85 mmol), potassium
carbonate (13.7 g, 99.25 mmol) and dimethylsulfate (3.8 mL, 45.66
mmol) in acetone (50 mL) was heated at reflux for 3.5 hours. The
reaction mixture was then filtered; the filtrate was treated with
water (5 mL) and the resulting mixture was stirred for 10 minutes.
The reaction mixture was concentrated under reduced pressure; the
residue was dissolved in dichloromethane, dried over anhydrous
sodium sulfate, filtered and evaporated under reduced pressure to
afford 5.946 g of 7-bromo-3-methoxy-naphthalene-2-carboxylic acid
methyl ester without further purifications.
Step B: synthesis of 7-bromo-3-methoxy-naphthalene-2-carboxylic
acid
[0644] A solution of sodium hydroxide (1.6 g, 40 mmol) in water (30
mL) was added to a solution of
7-bromo-3-methoxy-naphthalene-2-carboxylic acid methyl ester (5.9
g, 20 mmol) in ethanol (100 mL) and the resulting mixture was
heated at reflux for 2 hours. The reaction mixture was then cooled
and concentrated under reduced pressure. The residue was acidified
until pH 3 ca. by addition of an aqueous solution of hydrochloric
acid. The resulting mixture was extracted twice with
dichloromethane and the combined organic extracts were dried over
anhydrous sodium sulfate, filtered and evaporated under reduced
pressure to give 5.329 g of
7-bromo-3-methoxy-naphthalene-2-carboxylic acid as a cream colored
solid.
Step C: synthesis of 7-bromo-3-methoxy-naphthalen-2-ylamine
[0645] A mixture of 7-bromo-3-methoxy-naphthalene-2-carboxylic acid
(1.0 g, 3.56 mmol) and thionyl chloride (5 mL) was heated at reflux
for 2 hours. The reaction mixture was evaporated under reduced
pressure and the residue was dissolved in acetone (30 mL). To this
solution was added, dropwise, a solution of sodium azide (0.23 g)
in water (0.5 mL) and the resulting mixture was stirred for 15
minutes at room temperature. Water (100 mL) was added and the
resulting mixture was extracted twice with benzene (50 mL). The
combined organic extracts were dried over anhydrous sodium sulfate,
filtered and heated to reflux for 1 hour. An aqueous solution of
potassium hydroxide (50%, 100 mL) was then added and the resulting
mixture was heated at reflux for 1 hour. The reaction mixture was
cooled, the organic layer was separated and the aqueous layer was
extracted twice with dichloromethane. The combined organic extracts
were dried over anhydrous sodium sulfate, filtered and evaporated
under reduced pressure. The crude residue was purified by flash
chromatography (hexane/EtOAc) to give 0.678 g of
7-bromo-3-methoxy-naphthalen-2-ylamine as a cream colored
solid.
Step D: synthesis of
N-(7-bromo-3-methoxy-naphthalen-2-yl)-acetamide
[0646] A mixture of 7-bromo-3-methoxy-naphthalen-2-ylamine (2.2 g,
8.76 mmol), acetic anhydride (1.4 g, 13.14 mmol) and pyridine (20
mL) was stirred at room temperature for 3 hours. Water (300 mL) was
added and the solid precipitate was collected by filtration and
copiously washed with water. The solid residue was dissolved in
dichloromethane, dried over anhydrous sodium sulfate, filtered and
evaporated under reduced pressure to give 2.569 g of
N-(7-bromo-3-methoxy-naphthalen-2-yl)-acetamide as a light pink
solid.
Step E: synthesis of
N-(7-cyano-3-methoxy-naphthalen-2-yl)-acetamide
[0647] To a solution of
N-(7-bromo-3-methoxy-naphthalen-2-yl)-acetamide (1.2 g, 4.0 mmol)
in a previously degassed mixture of water and N,N-dimethylformamide
(3/1, 40 mL) was added zinc cyanide (0.28 g, 2.4 mmol) followed by
tris(dibenzylideneacetone)dipalladium(0) (0.18 g, 0.22 mmol) and
1,1'-bis(diphenylphosphino)ferrocene (0.27 g, 0.48 mmol) and the
resulting mixture was heated at 120.degree. C. overnight. The
reaction mixture was poured into water and extracted with ethyl
acetate. The organic extracts were washed 3 times with water, dried
over anhydrous sodium sulfate, filtered and evaporated under
reduced pressure. The crude residue was purified by flash
chromatography (hexane/EtOAc) to afford 0.621 g of
N-(7-cyano-3-methoxy-naphthalen-2-yl)-acetamide as a cream colored
solid. MS=241 [M+H].sup.+.
Step F: synthesis of 7-amino-6-methoxy-naphthalene-2-carboxylic
acid
[0648] Sodium hydroxide (0.17 g, 4.17 mmol) was added to a
suspension of N-(7-cyano-3-methoxy-naphthalen-2-yl)-acetamide (0.2
g, 0.83 mmol) in ethylene glycol (2 mL) and the resulting mixture
was heated at reflux (195.degree. C.) overnight. The reaction
mixture was then cooled, water was added and the pH was adjusted to
4. The precipitate was collected by filtration and dried to give
0.156 g of 7-amino-6-methoxy-naphthalene-2-carboxylic acid as a
brown solid. MS=218 [M+H].sup.+.
Step G: synthesis of
(7-amino-6-methoxy-naphthalen-2-yl)-methanol
[0649] Borane tetrahydrofuran complex (1 mL, 0.92 mmol) was added,
at 0.degree. C., to a suspension of
7-amino-6-methoxy-naphthalene-2-carboxylic acid (0.1 g, 0.46 mmol)
in anhydrous tetrahydrofuran (2 mL) and the resulting mixture was
stirred at room temperature overnight. The reaction mixture was
quenched by addition of methanol and then was stirred for 2 hours
at room temperature. The resulting mixture was concentrated under
reduced pressure, partitioned between dichloromethane and a
saturated aqueous solution of sodium bicarbonate. The organic layer
was separated, dried over anhydrous sodium sulfate, filtered and
evaporated under reduced pressure to afford
(7-amino-6-methoxy-naphthalen-2-yl)-methanol without further
purifications. MS=204 [M+H].sup.+.
Preparation 27: Synthesis of
1-(4-Methoxy-butyl)-4-nitro-benzene
[0650] The synthesis of 1-(4-methoxy-butyl)-4-nitro-benzene was
carried out according to the process shown in Scheme 27.
##STR00229##
[0651] 4-(4-Nitrophenyl)-1-butanol (2 g, 10.26 mmol) was added,
dropwise, to a suspension of sodium hydride (60% dispersion in
mineral oil, 0.49 g, 12.30 mmol) in anhydrous tetrahydrofuran and
the resulting mixture was stirred at room temperature for 10
minutes. Methyl iodide (2 mL) was added and the resulting mixture
was stirred for 62 hours. The reaction mixture was evaporated under
reduced pressure; the residue was partitioned between
dichloromethane and water. The organic layer was separated, dried
over anhydrous sodium sulfate, filtered and evaporated under
reduced pressure. The residue was purified by flash chromatography
(EtOAc/hexane, 1/1) to give 1.996 g of
1-(4-methoxy-butyl)-4-nitro-benzene as an oil.
Preparation 28: Synthesis of
4-(4-Chloro-2-nitro-phenyl)-butan-1-ol
[0652] The synthesis of 4-(4-chloro-2-nitro-phenyl)-butan-1-ol was
carried out according to the process shown in Scheme 33.
##STR00230##
[0653] Boron tribromide (1.24 g, 4.925 mmol) was added to a cooled
mixture of 4-chloro-1-(4-methoxy-butyl)-2-nitro-benzene (0.2 g,
0.995 mmol) in dichloromethane (10 mL) and the resulting mixture
was stirred at room temperature overnight. The reaction mixture was
extracted with ethyl acetate and the organic extracts were dried
over anhydrous sodium sulfate, filtered and evaporated under
reduced pressure to give 80 mg of
4-(4-chloro-2-nitro-phenyl)-butan-1-ol as an oil without further
purifications.
Preparation 29: Synthesis of 7-Methoxy-quinolin-6-ylamine
[0654] The synthesis of 7-methoxy-quinolin-6-ylamine was carried
out according to the process shown in Scheme 29.
##STR00231##
Step A: synthesis of acetic acid 3-acetylamino-phenyl ester
[0655] Acetic anhydride (53 mL, 572.0 mmol) was slowly added to a
mixture of 3-aminophenol (25 g, 225.0 mmol) and
4-dimethylaminopyridine (catalytic quantity) in pyridine (100 mL)
at 0.degree. C. and the reaction mixture was stirred at room
temperature for 62 hours. Water (1 L) was added and the resulting
mixture was extracted with ethyl acetate. The organic extracts were
washed with an aqueous solution of hydrochloric acid, a saturated
aqueous solution of sodium bicarbonate and water, dried over
anhydrous sodium sulfate, filtered and evaporated under reduced
pressure to give 21.79 g of acetic acid 3-acetylamino-phenyl ester
as a solid without further purifications. A second batch (2.978 g)
of this material crashed out of the aqueous layer upon standing and
was collected by filtration.
Step B: synthesis of acetic acid 5-acetylamino-2-nitro-phenyl
ester
[0656] Acetic acid 3-acetylamino-phenyl ester (21.7 g, 112.4 mmol)
was added portionwise, at -15.degree. C., to fuming nitric acid
(109 mL) maintaining the temperature below -10.degree. C. The
reaction mixture was stirred at -10.degree. C. for 3 hours and then
was poured into ice. The resulting mixture was extracted 3 times
with ethyl acetate and the combined organic extracts were washed
with brine, dried over anhydrous sodium sulfate, filtered and
evaporated under reduced pressure. The crude residue was purified
by flash chromatography (EtOAc/hexane, 1/1) to afford 20.608 g (77%
yield) of acetic acid 5-acetylamino-2-nitro-phenyl ester as a cream
colored solid.
Step C: synthesis of N-(3-hydroxy-4-nitro-phenyl)-acetamide
[0657] A mixture of acetic acid 5-acetylamino-2-nitro-phenyl ester
(20.5 g, 85.77 mmol) and potassium carbonate (26 g, 188.4 mmol) in
methanol (200 mL) was stirred at room temperature for 3 hours. The
reaction mixture was concentrated under reduced pressure, water
(250 mL) was added and the resulting mixture was acidified by
addition of concentrated hydrochloric acid. The solid which crushed
out was triturated, collected by filtration, washed with water and
dried under vacuum to afford
N-(3-hydroxy-4-nitro-phenyl)-acetamide.
Step D: synthesis of N-(3-methoxy-4-nitro-phenyl)-acetamide
[0658] To a solution of N-(3-hydroxy-4-nitro-phenyl)-acetamide (2
g, 10.15 mmol) in anhydrous N,N-dimethylormamide (5 mL) was added
potassium carbonate (2.6 g, 18.88 mmol) followed by methyl iodide
(0.71 mL, 11.16 mmol) and the reaction mixture was stirred at room
temperature for 1 hour. A second aliquot of methyl iodide (0.15 mL)
was then added and the resulting mixture was stirred for 1 hour.
Ethyl acetate (100 mL) and brine (100 mL) were added, the organic
layer was separated, washed twice with water, dried over anhydrous
sodium sulfate, filtered and evaporated under reduced pressure to
give N-(3-methoxy-4-nitro-phenyl)-acetamide.
Step E: synthesis of 3-methoxy-4-nitro-phenylamine
[0659] A mixture of N-(3-methoxy-4-nitro-phenyl)-acetamide (16.6 g,
78.67 mmol) and an aqueous solution of hydrochloric acid (1.5 M,
200 mL) was refluxed until a clear solution was obtained. The
reaction mixture was basified by addition of an aqueous solution of
potassium carbonate and then was extracted four times with
dichloromethane (200 mL); the combined organic extracts were dried
over anhydrous sodium sulfate, filtered and evaporated under
reduced pressure to give 13.56 g (quantitative yield) of
3-methoxy-4-nitro-phenylamine as a yellow solid. MS=169
[M+H].sup.+.
Step F: synthesis of 7-methoxy-6-nitro-quinoline
[0660] To a mixture of 3-methoxy-4-nitro-phenylamine (13.4 g, 80.0
mmol), arsenic pentoxide (11.0 g, 48.0 mmol) and glycerol (33 mL,
216.0 mmol) at 100.degree. C., was added, dropwise, concentrated
sulfuric acid (4.7 mL, 88.0 mmol). The reaction mixture was then
heated at a temperature ranging between 150 and 160.degree. C. for
2 hours and then was cooled. Water (200 mL) was added and the
resulting mixture was extracted four times with ethyl acetate. The
combined organic extracts were dried over anhydrous sodium sulfate,
filtered and evaporated under reduced pressure. The crude residue
was purified by flash chromatography (EtOAc) to give 9.00 g (61%
yield) of 7-methoxy-6-nitro-quinoline as an orange solid.
Step G: synthesis of 7-methoxy-quinolin-6-ylamine
[0661] A mixture of 7-methoxy-6-nitro-quinoline (5 g, 24.0 mmol),
iron powder (9.8 g, 172 mmol) and ammonium chloride (9.1 g, 172
mmol) in a mixture of ethanol and water (3/1, 160 mL) was heated at
reflux overnight. The resulting mixture was filtered through a
CELITE.TM. pad, the filtrate was evaporated under reduced pressure
and the residue was partitioned between water and ethyl acetate.
The organic layer was separated, dried over anhydrous sodium
sulfate, filtered and evaporated under reduced pressure. The
residue was purified by flash chromatography (EtOAc) to afford
3.551 g of 7-methoxy-quinolin-6-ylamine as a grey solid.
Preparation 30: Synthesis of
N.sup.2-[2-(tert-Butyl-dimethyl-silanyloxy)-ethyl]-7-methoxy-quinoline-2,-
6-diamine
[0662] The synthesis of
N.sup.2-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-7-methoxy-quinoline-2,-
6-diamine was carried out according to the process shown in Scheme
30.
##STR00232## ##STR00233##
Step A: synthesis of
(E)-3-ethoxy-N-(3-methoxy-4-nitro-phenyl)-acrylamide
[0663] Thionyl chloride (1 mL) was added to 3,3-diethoxy-propionic
acid (Eur. J. Org. Chem. 2001, 2041) (0.20 g, 1.10 mmol) and the
resulting mixture was heated at 80.degree. C. for 1 hour. The
reaction mixture was then evaporated under reduced pressure and the
residue was dissolved in dichloromethane (2 mL). The resulting
solution was added to a mixture of 3-methoxy-4-nitro-phenylamine
(0.13 g, 0.77 mmol) and pyridine (0.12 g, 1.54 mmol) in
dichloromethane (5 mL) at 0.degree. C. The reaction mixture was
stirred at room temperature overnight and then the pH was then
neutralized by addition of an aqueous solution of hydrochloric acid
(6 M). The resulting mixture was extracted twice with ethyl acetate
and the combined organic extracts were washed with water, dried
over anhydrous sodium sulfate, filtered and evaporated under
reduced pressure to give 225 mg of
(E)-3-ethoxy-N-(3-methoxy-4-nitro-phenyl)-acrylamide as an orange
solid.
Step B: synthesis of 7-methoxy-6-nitro-1H-quinolin-2-one
[0664] Concentrated sulfuric acid (1 mL) was added to
(E)-3-ethoxy-N-(3-methoxy-4-nitro-phenyl)-acrylamide (225 mg) with
cooling and the resulting mixture was stirred at room temperature
for 1.5 hours. The reaction mixture was then poured into ice-water
and stirred for 1 hour. The solid which crushed out was collected
by filtration and dried under vacuum to give 142 mg of
7-methoxy-6-nitro-1H-quinolin-2-one as a brown solid. MS=221
[M+H].sup.+.
Step C: synthesis of 2-chloro-7-methoxy-6-nitro-quinoline
[0665] A mixture of 7-methoxy-6-nitro-1H-quinolin-2-one (0.13 g)
and phosphorus oxychloride (1 mL) was heated at 110.degree. C. for
2 hours. The resulting mixture was then cooled and poured into ice.
The solid which formed was collected by filtration and dried under
vacuum to afford 0.119 g of 2-chloro-7-methoxy-6-nitro-quinoline as
a brown solid.
Step D: synthesis of
2-(7-methoxy-6-nitro-quinolin-2-ylamino)-ethanol
[0666] A mixture of 2-chloro-7-methoxy-6-nitro-quinoline (0.1 g,
0.42 mmol) and 2-aminoethanol (38 .mu.L, 0.63 mmol) in anhydrous
1,4-dioxane (5 mL) was heated at 90.degree. C. overnight. A second
aliquot of 2-aminoethanol (38 .mu.L, 0.63 mmol) was added and the
resulting mixture was heated at 90.degree. C. overnight. The
reaction mixture was then concentrated under reduced pressure, the
residue was washed with water, dried over anhydrous sodium sulfate,
filtered and evaporated under reduced pressure to give 70 mg of
2-(7-methoxy-6-nitro-quinolin-2-ylamino)-ethanol as a solid without
further purifications. MS=264 [M+H].sup.+.
Step E: synthesis of
2-(6-amino-7-methoxy-quinolin-2-ylamino)-ethanol
[0667] A mixture of
2-(7-methoxy-6-nitro-quinolin-2-ylamino)-ethanol (0.5 g, 1.90
mmol), iron powder (0.32 g, 5.70 mmol) and ammonium chloride (0.32
g, 5.70 mmol) in a mixture of ethanol and water (3/1, 16 mL) was
heated at reflux for 2 hours. The reaction mixture was then
filtered through a CELITE.TM. pad, the filtrate was evaporated
under reduced pressure and the residue was triturated ten times
with a mixture of dichloromethane and methanol (9/1, 50 mL). The
residue was concentrated under reduced pressure to afford 0.425 g
of 2-(6-amino-7-methoxy-quinolin-2-ylamino)-ethanol as a brown
solid.
Step F: synthesis of
N.sup.2-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-7-methoxy-quinoline-2,-
6-diamine
[0668] A mixture of
2-(6-amino-7-methoxy-quinolin-2-ylamino)-ethanol (0.4 g, 1.72
mmol), tert-butyldimethylchlorosilane (0.8 g, 5.15 mmol) and
imidazole (0.4 g, 5.15 mmol) in dichloromethane (20 mL) was stirred
at room temperature for 62 hours. The resulting mixture was washed
with water and the organic layer was separated, dried over
anhydrous sodium sulfate, filtered and evaporated under reduced
pressure. The crude residue was purified by flash chromatography
(EtOAc/hexane, 3/7) to afford 206 mg of
N.sup.2-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-7-methoxy-quinoline-2,-
6-diamine as a brown oil. MS=348 [M+H].sup.+.
Preparation 31: Synthesis of
(2'-Amino-4'-chloro-biphenyl-4-yl)-methanol
[0669] The synthesis of (2'-amino-4'-chloro-biphenyl-4-yl)-methanol
was carried out according to the process shown in Scheme 31.
##STR00234##
Step A: synthesis of
(4'-chloro-2'-nitro-biphenyl-4-yl)-methanol
[0670] Nitrogen was bubbled through a mixture of
1-bromo-4-chloro-2-nitro-benzene (1.25 g, 5.3 mmol),
bis(triphenylphosphine)palladium(II) chloride (90 mg, 0.13 mmol)
and potassium phosphate tribasic (4.2 g, 19.7 mmol) in anhydrous
1,2-dimethoxyethane (30 mL) for 15 minutes. A solution of
4-(hydroxymethyl)phenylboronic acid (0.8 g, 5.3 mmol) in anhydrous
1,2-dimethoxyethane (1.5 mL) was added and the resulting mixture
was heated at 80.degree. C. overnight. The reaction mixture was
then poured into water and extracted twice with ethyl acetate. The
combined organic extracts were dried over anhydrous sodium sulfate,
filtered and evaporated under reduced pressure. The crude residue
was purified by flash chromatography (hexane/EtOAc, 70/30) to give
0.367 g of (4'-chloro-2'-nitro-biphenyl-4-yl)-methanol as a
solid.
Step B: synthesis of
(2'-amino-4'-chloro-biphenyl-4-yl)-methanol
[0671] (4'-Chloro-2'-nitro-biphenyl-4-yl)-methanol was reduced
utilizing the procedure described in Preparation 9, Step D.
[0672] Utilizing the above described procedure and the appropriate
starting materials, the following compounds were prepared: [0673]
(2'-amino-4'-chloro-biphenyl-3-yl)-methanol; and [0674]
(2'-amino-4'-chloro-biphenyl-4-ylmethyl)-carbamic acid tert-butyl
ester.
Preparation 32: Synthesis of
6-(3-Hydroxy-propyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic
acid
[0675] The synthesis of
6-(3-hydroxy-propyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
was carried out according to the process shown in Scheme 32.
##STR00235##
Step A: synthesis of
6-(3-hydroxy-propyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
ethyl ester
[0676] Sodium hydride (60% suspension in mineral oil, 350 mg, 8.78
mmol) was added, at 0.degree. C., to a solution of
5-amino-1H-pyrazole-4-carboxylic acid ethyl ester (1.4 g, 8.9 mmol)
and 5,6-dihydro-4H-pyran-3-carbaldehyde (0.5 g, 4.5 mmol) in
anhydrous N,N-dimethylformamide (10 mL) and the resulting mixture
was stirred, at 0.degree. C., for 30 minutes. The reaction mixture
was stirred at room temperature overnight and then heated at
50.degree. C. for 2 hours. The resulting mixture was partitioned
between water and ethyl acetate and the organic layer was
separated, dried over anhydrous sodium sulfate, filtered and
evaporated under reduced pressure. The crude residue was purified
by flash chromatography to afford 0.24 g of
6-(3-hydroxy-propyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
ethyl ester as a white solid. MS=250 [M+H].sup.+.
Step B: synthesis of
6-(3-hydroxy-propyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic
acid
[0677] A mixture of
6-(3-hydroxy-propyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
ethyl ester (5 mg) and an aqueous solution of sodium hydroxide (5
drops) was stirred at room temperature for 16 hours. The reaction
mixture was then acidified by addition of an aqueous solution of
hydrochloric acid (3 M). The precipitate was collected by
filtration to give
6-(3-hydroxy-propyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid.
MS=222 [M+H].sup.+.
Preparation 33: Synthesis of
6-Benzyloxy-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
[0678] The synthesis of
6-benzyloxy-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid was carried
out according to the process shown in Scheme 33.
##STR00236##
[0679] To solution of oxalyl chloride (0.6 mL, 6.87 mmol) in
anhydrous dichloromethane (15 mL), cooled at -78.degree. C., was
added, dropwise, a solution of anhydrous dimethyl sulfoxide (1.2
mL, 16.5 mmol) in dichloromethane (2 mL) and the resulting mixture
was stirred for 10 minutes at -78.degree. C. A solution of
2-benzyloxy-1,3-propanediol (0.5 g, 2.75 mmol) in dichloromethane
(2 mL) was then added dropwise at -78.degree. C. and the reaction
mixture was stirred for 15 minutes. Triethylamine (4.6 mL, 33 mmol)
was then added dropwise at -78.degree. C. and the resulting mixture
was stirred for 1 hour. The cold bath was removed and an aqueous
solution of hydrochloric acid (6 M, 6 mL, 36 mmol) was added,
followed by 5-amino-1H-pyrazole-4-carboxylic acid (0.35 g, 2.75
mmol) and the reaction mixture was heated at 70.degree. C. for 1
hour. The solid formed was collected by filtration, washed with
water and dried under vacuum. The solid residue (0.53 g) was then
washed with dichloromethane to give 65 mg (9% yield) of
6-benzyloxy-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid. MS=270
[M+H].sup.+.
Preparation 34: Synthesis of
5-chloro-2-(3-methoxy-propoxy)-phenylamine
[0680] The synthesis of 5-chloro-2-(3-methoxy-propoxy)-phenylamine
was carried out according to the process shown in Scheme 34.
##STR00237##
Step A: synthesis of
4-chloro-1-(3-methoxy-propoxy)-2-nitro-benzene
[0681] Sodium hydride (60% suspension in mineral oil, 0.15 g, 3.75
mmol) was added, at room temperature, to a solution of
4-chloro-2-nitrophenol (0.5 g, 2.88 mmol) in anhydrous
N,N-dimethylformamide (15 mL) and the resulting mixture was stirred
for 5 minutes. 1-Bromo-3-methoxy-propane (0.485 g, 3.17 mmol) was
then added and the reaction mixture was heated at 80.degree. C. for
62 hours. The resulting mixture was partitioned between an aqueous
solution of sodium hydroxide (3 M) and ethyl acetate, the organic
layer was separated, washed twice with an aqueous solution of
sodium hydroxide (3 M) and once with brine, dried over anhydrous
sodium sulfate, filtered and evaporated under reduced pressure. The
crude residue was purified by flash chromatography (hexane/EtOAc,
90/10 to 50/50) to give 0.455 g (64% yield) of
4-chloro-1-(3-methoxy-propoxy)-2-nitro-benzene as a yellow
solid.
Step B: synthesis of 5-chloro-2-(3-methoxy-propoxy)-phenylamine
[0682] Stannous chloride (1.04 g, 5.49 mmol) was added to a
solution of 4-chloro-1-(3-methoxy-propoxy)-2-nitro-benzene (0.448
g, 1.82 mmol) in a mixture of ethanol and ethyl acetate (1/1, 20
mL) and the resulting mixture was stirred at room temperature
overnight. More stannous chloride (0.76 g, 4 mmol) was added and
the reaction mixture was stirred for 1 day. The resulting mixture
was partitioned between an aqueous solution of sodium bicarbonate
(5%) and ethyl acetate, the aqueous solution was separated and
extracted twice with ethyl acetate, the combined organic extracts
were washed with brine, dried over anhydrous sodium sulfate,
filtered and evaporated under reduced pressure. The yellow oily
residue was purified by flash chromatography (hexane/EtOAc, 80/20
to 60/40) to give 0.29 g (74% yield) of
5-chloro-2-(3-methoxy-propoxy)-phenylamine as a yellow oil.
[0683] The following compounds were prepared utilizing the above
described procedure and the appropriate starting materials: [0684]
5-chloro-2-(2-methoxy-ethoxy)-phenylamine; and [0685]
5-chloro-2-isobutoxy-phenylamine.
Preparation 35: Synthesis of
4-(2-Amino-4-chloro-phenoxy)-piperidine-1-carboxylic acid
tert-butyl ester
[0686] The synthesis of
4-(2-amino-4-chloro-phenoxy)-piperidine-1-carboxylic acid
tert-butyl ester was carried out according to the process shown in
Scheme 35.
##STR00238##
Step A: synthesis of
4-(4-chloro-2-nitro-phenoxy)-piperidine-1-carboxylic acid
tert-butyl ester
[0687] A solution of diisopropylazodicarboxylate (3.4 mL, 17.55
mmol) in anhydrous tetrahydrofuran (5 mL) was added, at 0.degree.
C., to a solution of 4-chloro-2-nitrophenol (2.0 g, 11.52 mmol),
1-BOC-4-hydroxypiperidine (3.48 g, 17.3 mmol) and
triphenylphosphine (4.6 g, 17.5 mmol) in anhydrous tetrahydrofuran
(25 mL) and the resulting mixture was stirred at 0.degree. C. for 1
hour. Then the reaction mixture was stirred at room temperature for
24 hours; the residue was partitioned between water and ethyl
acetate. The organic layer was separated and the aqueous layer was
extracted twice with ethyl acetate; the combined organic extracts
were washed with brine, dried over anhydrous sodium sulfate,
filtered and evaporated under reduced pressure. The crude residue
was purified by flash chromatography (hexane/EtOAc, 90/10 to 70/30)
to give an oily residue which was washed with hexane to afford 6.5
g of an off-white solid material. This solid residue was repurified
by flash chromatography to give 3.61 g (88% yield) of
4-(4-chloro-2-nitro-phenoxy)-piperidine-1-carboxylic acid
tert-butyl ester as a white solid.
Step B: synthesis of
4-(2-amino-4-chloro-phenoxy)-piperidine-1-carboxylic acid
tert-butyl ester
[0688] 4-(4-Chloro-2-nitro-phenoxy)-piperidine-1-carboxylic acid
tert-butyl ester was reduced following the procedure described in
Preparation 37, Step E, to afford
4-(2-amino-4-chloro-phenoxy)-piperidine-1-carboxylic acid
tert-butyl ester as a light yellow oil in 76% yield. [0689]
4-(6-amino-quinolin-7-yloxy)-butan-2-ol; [0690]
4-(2-amino-4-chloro-phenoxy)-phenol; and [0691]
3-(2-amino-4-chloro-phenoxy)-phenol.
Preparation 36: Synthesis of
3'-(tert-Butyl-dimethyl-silanyloxy)-4-chloro-biphenyl-2-ylamine
[0692] Utilizing the above described procedure and the appropriate
starting materials the following compounds were prepared:
[0693] The synthesis of
3'-(tert-butyl-dimethyl-silanyloxy)-4-chloro-biphenyl-2-ylamine was
carried out according to the process shown in Scheme 36.
##STR00239##
Step A: synthesis of
tert-butyl-(4'-chloro-2'-nitro-biphenyl-3-yloxy)-dimethyl-silane
[0694] tert-Butyldimethylchlorosilane (0.82 g, 5.44 mmol) was added
at room temperature to a solution of
4'-chloro-2'-nitro-biphenyl-3-ol (1.05 g, 4.21 mmol) and imidazole
(0.58, 8.52 mmol) in anhydrous N,N-dimethylformamide (30 mL) and
the resulting mixture was stirred at room temperature for 4 days.
The reaction mixture was then partitioned between water and ethyl
acetate, the organic layer was separated and the aqueous layer was
extracted twice with ethyl acetate. The combined organic extracts
were washed with water and brine, dried over anhydrous sodium
sulfate, filtered and evaporated under reduced pressure. The crude
residue was purified on a silica gel plug (hexane/EtOAc, 90/10) to
give 1.43 g (94% yield) of
tert-butyl-(4'-chloro-2'-nitro-biphenyl-3-yloxy)-dimethyl-silane as
a yellow oil.
Step B: synthesis of
3'-(tert-butyl-dimethyl-silanyloxy)-4-chloro-biphenyl-2-ylamine
[0695]
tert-Butyl-(4'-chloro-2'-nitro-biphenyl-3-yloxy)-dimethyl-silane
was reduced following the procedure described in Preparation 37,
Step E, to afford
3'-(tert-butyl-dimethyl-silanyloxy)-4-chloro-biphenyl-2-ylamine in
88% yield as a colorless oil.
[0696]
4'-(tert-Butyl-dimethyl-silanyloxy)-4-chloro-biphenyl-2-ylamine was
prepared following the above described procedure and utilizing the
appropriate starting materials.
Preparation 37: Synthesis of
[1-(2-Amino-5-phenylcarbamoyl-phenyl)-piperidin-4-ylmethyl]-carbamic
acid tert-butyl ester
[0697] The synthesis of
[1-(2-amino-5-phenylcarbamoyl-phenyl)-piperidin-4-ylmethyl]-carbamic
acid tert-butyl ester was carried out according to the process
shown in Scheme 37.
##STR00240##
Step A: synthesis of 2-chloro-4-methyl-1-nitro-benzene
[0698] Concentrated nitric acid (16 mL) was slowly added, at
0.degree. C., to a solution of 3-chlorotoluene (3 mL, 25.4 mmol)
and concentrated sulfuric acid (6 mL) in glacial acetic acid (20
mL) and the resulting mixture was stirred for 24 hours allowing the
temperature to rise until room temperature. The reaction mixture
was then poured into ice-water and partitioned between water and
diethyl ether. The aqueous phase was separated and extracted twice
with diethyl ether; the combined organic extracts were washed with
water and brine, dried over anhydrous sodium sulfate, filtered and
evaporated under reduced pressure. The yellow oily residue was
purified on a silica gel plug and twice by flash chromatography to
give 1.22 g (14% yield) of 2-chloro-4-methyl-1-nitro-benzene as a
yellow oil and 3.39 g (39% yield) of
4-chloro-2-methyl-1-nitro-benzene.
Step B: synthesis of 3-chloro-4-nitro-benzoic acid
[0699] 2-Chloro-4-methyl-1-nitro-benzene (1.2 g, 6.99 mmol) in a
mixture of water and pyridine (2/1, 30 mL) was heated at 90.degree.
C. then potassium permanganate (5.2 g, 32.9 mmol) was added in 4
portions at intervals of 1.5 hours. The reaction mixture was heated
at 90.degree. C. for 8 hours and then more potassium permanganate
(2 g) was added and the resulting mixture was stirred at 90.degree.
C. overnight. More potassium permanganate (2 g) was added and the
resulting mixture was stirred at 90.degree. C. for 1 hour, the
solid was filtered off on a CELITE.TM. pad. Water (50 mL) was added
to the filtrate; the resulting mixture was acidified until pH<2
and was extracted 3 times with ethyl acetate. The combined organic
extracts were washed with water and brine, dried over anhydrous
sodium sulfate, filtered and evaporated under reduced pressure to
give 1.19 g (84% yield) of 3-chloro-4-nitro-benzoic acid as a light
yellow solid without further purifications
Step C: synthesis of 3-chloro-4-nitro-N-phenyl-benzamide
[0700] Diisopropylethylamine (0.65 mL, 3.7 mmol) was added to a
mixture of 3-chloro-4-nitro-benzoic acid (0.2 g, 0.992 mmol),
aniline (0.1 mL, 1.1 mmol) and HBTU (0.42 g, 1.1 mmol) in
acetonitrile (20 mL) and the reaction mixture was stirred at
80.degree. C. for 8 hours and then at room temperature for 62
hours. The resulting mixture was then partitioned between water and
ethyl acetate, the organic layer was separated and the aqueous
layer was extracted twice with ethyl acetate. The combined organic
extracts were washed with brine, dried over anhydrous sodium
sulfate, filtered and evaporated under reduced pressure. The crude
residue was purified on a silica gel plug (hexane/EtOAc, 80/20) to
afford 135 mg (49% yield) of 3-chloro-4-nitro-N-phenyl-benzamide as
a yellow solid.
Step D: synthesis of
[1-(2-nitro-5-phenylcarbamoyl-phenyl)-piperidin-4-ylmethyl]-carbamic
acid tert-butyl ester
[0701] To a solution of 3-chloro-4-nitro-N-phenyl-benzamide (0.13
g, 0.47 mmol) in N,N-dimethylformamide (10 mL) were added
piperidin-4-ylmethyl-carbamic acid tert-butyl ester (0.12 g, 0.56
mmol) and potassium carbonate (0.1 g, 0.72 mmol) and the resulting
mixture was heated at 50.degree. C. overnight. The reaction mixture
was then heated at 80.degree. C. for 8 hours; then more
piperidin-4-ylmethyl-carbamic acid tert-butyl ester (0.33 mmol) and
potassium carbonate (0.14 g, 1 mmol) were added and the resulting
mixture was heated at 85.degree. C. overnight. The reaction mixture
was partitioned between water and ethyl acetate, the organic layer
was separated and the aqueous layer was extracted twice with ethyl
acetate. The combined organic extracts were washed with water and
brine, dried over anhydrous sodium sulfate, filtered and evaporated
under reduced pressure. The crude residue was purified on a silica
gel plug (hexane/EtOAc, 20/80 to 40/60) to give 0.13 g, (61% yield)
of
[1-(2-nitro-5-phenylcarbamoyl-phenyl)-piperidin-4-ylmethyl]-carbamic
acid tert-butyl ester as on orange colored solid.
Step E: synthesis of
[1-(2-amino-5-phenylcarbamoyl-phenyl)-piperidin-4-ylmethyl]-carbamic
acid tert-butyl ester
[0702] To a solution of
[1-(2-nitro-5-phenylcarbamoyl-phenyl)-piperidin-4-ylmethyl]-carbamic
acid tert-butyl ester (0.13 g, 0.286 mmol) in a mixture of ethanol
(8 mL), ethyl acetate (3 mL) and water (3 mL) were added ammonium
chloride (0.12 g, 7.6 mmol) and iron powder (0.12 g, 7.5 mmol) and
the resulting mixture was heated at 80.degree. C. for 4 hours. The
reaction mixture was filtered through a CELITE.TM. pad, the filter
cake was washed with ethyl acetate. The filtrate was washed with
and aqueous solution of sodium bicarbonate (5%) and with brine,
dried over anhydrous sodium sulfate, filtered and evaporated under
reduced pressure to afford 0.12 g (quantitative yield) of
[1-(2-amino-5-phenylcarbamoyl-phenyl)-piperidin-4-ylmethyl]-carbamic
acid tert-butyl ester as light yellow foam.
Preparation 38: Synthesis of
7-[4-(tert-Butyl-dimethyl-silanyloxy)-cyclohexyloxy]-quinolin-6-ylamine
[0703] The synthesis of
7-[4-(tert-butyl-dimethyl-silanyloxy)-cyclohexyloxy]-quinolin-6-ylamine
was carried out according to the process shown in Scheme 38.
##STR00241##
Step A: synthesis of 6-nitro-quinolin-7-ol
[0704] A mixture of 7-methoxy-6-nitro-quinoline (1.5 g, 7.35 mmol)
and pyridine hydrochloride (2.6 g, 22.58 mmol) was heated at
150.degree. C. for ca. 5 hours. The residue was dissolved in an
aqueous solution of sodium hydroxide (3 M) and extracted twice with
ethyl acetate. The combined organic extract were washed twice with
an aqueous solution of sodium hydroxide (3 M) and then discarded.
The combined aqueous layers were neutralized (pH 7) by addition of
concentrated hydrochloric acid and extracted 4 times with ethyl
acetate. The combined organic extracts were dried over anhydrous
sodium sulfate, filtered and evaporated under reduced pressure. The
yellow solid residue was purified on a silica gel plug to give 1.29
g (69% yield) of 6-nitro-quinolin-7-ol as a yellow solid.
Step B: synthesis of
7-[4-(tert-butyl-dimethyl-silanyloxy)-cyclohexyloxy]-6-nitro-quinoline
[0705]
7-[4-(tert-Butyl-dimethyl-silanyloxy)-cyclohexyloxy]-6-nitro-quinol-
ine was synthesized following the procedure described in
Preparation 2, Step B.
Step C: synthesis of
7-[4-(tert-butyl-dimethyl-silanyloxy)-cyclohexyloxy]-quinolin-6-ylamine
[0706]
7-[4-(tert-Butyl-dimethyl-silanyloxy)-cyclohexyloxy]-6-nitro-quinol-
ine was reduced as described in Preparation 37, Step E, to afford
7-[4-(tert-butyl-dimethyl-silanyloxy)-cyclohexyloxy]-quinolin-6-ylamine
in 31% yield.
[0707] Utilizing the above described procedure and the appropriate
strating materials, the following compounds were prepared: [0708]
7-[3-(tert-butyl-dimethyl-silanyloxy)-cyclopentyloxy]-quinolin-6-ylamine;
[0709]
7-[3-(tert-butyl-dimethyl-silanyloxy)-1-methyl-butoxy]-quinolin-6--
ylamine; [0710]
7-[3-(tert-butyl-dimethyl-silanyloxy)-propoxy]-quinolin-6-ylamine;
[0711] [3-(6-amino-quinolin-7-yloxy)-propyl]-carbamic acid
tert-butyl ester; [0712]
3-(6-amino-quinolin-7-yloxy)-pyrrolidine-1-carboxylic acid
tert-butyl ester;
-trans-7-[4-(tert-butyl-diphenyl-silanyloxy)-cyclohexyloxy]-quinolin-6-yl-
amine, (4-(trans-tert-butyl-diphenyl-silanyloxy)-cyclohexanol and
cis-tert-butyl-diphenyl-silanyloxy)-cyclohexanol were prepared as
described in Preparation 2, Step A, and were separated by
flash-chromatography (EtOAc/hexane, 1/1)); and [0713]
cis-7-[4-(tert-butyl-diphenyl-silanyloxy)-cyclohexyloxy]-quinolin-6-ylami-
ne.
Preparation 39: Synthesis of
4-Amino-N-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-3-methoxy-benzamide
[0714] The synthesis
4-amino-N-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-3-methoxy-benzamide
was carried out according to the process shown in Scheme 39.
##STR00242##
Step A: synthesis of
N-(2-hydroxy-ethyl)-3-methoxy-4-nitro-benzamide
[0715] A suspension of 3-methoxy-4-nitro-benzoic acid (1.5 g, 7.61
mmol) in thionyl chloride (20 mL) and N,N-dimethylformamide (2
drops) was heated at reflux for 2 hours. The solvent was then
evaporated under reduced pressure to give a light yellow solid. A
portion of this residue (3.8 mmol) was dissolved in acetone
(previously dried over anhydrous sodium sulfate) (20 mL) and cooled
in an ice bath. Then a solution of ethylendiamine (0.46 mL, 7.62
mmol) in water (10 mL) was added at 0.degree. C. and the resulting
mixture was stirred at room temperature for 30 minutes. The
reaction mixture was partitioned between water and ethyl acetate;
the aqueous phase was separated and extracted twice with ethyl
acetate. The combined organic extracts were washed with brine,
dried over anhydrous sodium sulfate, filtered and evaporated under
reduced pressure. The crude residue was purified on a silica gel
plug (EtOAc/MeOH, 100/0 to 98/2) to afford 0.42 g (46% 2 steps
yield) of N-(2-hydroxy-ethyl)-3-methoxy-4-nitro-benzamide.
Step B: synthesis of
N-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-3-methoxy-4-nitro-benzamide
[0716]
N-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-3-methoxy-4-nitro-benz-
amide was synthesized, utilizing the appropriate starting
materials, as described in Preparation 36, Step A, and was obtained
in quantitative yield as a pale yellow solid.
Step C: synthesis of
4-amino-N-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-3-methoxy-benzamide
[0717]
N-[2-(tert-Butyl-dimethyl-silanyloxy)-ethyl]-3-methoxy-4-nitro-benz-
amide was reduced, utilizing the appropriate starting materials, as
described in Preparation 37, Step E, to afford
4-amino-N-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-3-methoxy-benzamide
as a colorless oil in 91% yield.
[0718]
4-Amino-N-[3-(tert-butyl-dimethyl-silanyloxy)-propyl]-3-methoxy-ben-
zamide was prepared utilizing the above described procedure and the
appropriate starting materials.
Preparation 40: Synthesis of
2-[3-(tert-Butyl-dimethyl-silanyloxy)-propoxy]-5-chloro-phenylamine
[0719] The synthesis
2-[3-(tert-butyl-dimethyl-silanyloxy)-propoxy]-5-chloro-phenylamine
was carried out according to the process shown in Scheme 40.
##STR00243##
Step A: synthesis of 3-(4-chloro-2-nitro-phenoxy)-propan-1-ol
[0720] 3-(4-Chloro-2-nitro-phenoxy)-propan-1-ol was synthesized,
utilizing the appropriate starting materials, following the
procedure described in Preparation 2, Step B, and was obtained as a
yellow oil in 48% yield.
Step B: synthesis of
tert-butyl-[3-(4-chloro-2-nitro-phenoxy)-propoxy]-dimethyl-silane
[0721]
tert-Butyl-[3-(4-chloro-2-nitro-phenoxy)-propoxy]-dimethyl-silane
was synthesized, utilizing the appropriate starting materials, as
described in Preparation 36, Step A, and was obtained in 82% yield
as a yellow oil.
Step C: synthesis of 3-(2-amino-4-chloro-phenoxy)-propan-1-ol
[0722] To a solution of
tert-butyl-[3-(4-chloro-2-nitro-phenoxy)-propoxy]-dimethyl-silane
(0.37 g, 1.07 mmol), in a mixture of ethanol (10 mL) and water (3
mL), were added ammonium chloride (0.3 g, 5.37 mmol) and iron
powder (0.3 g, 5.6 mmol) and the resulting mixture was heated at
80.degree. C. overnight. The solid was filtered through a
CELITE.TM. pad, the filter cake was washed with ethyl acetate. The
filtrate was washed with water and brine, dried over anhydrous
sodium sulfate, filtered and evaporated under reduced pressure. The
crude residue was purified on a silica gel plug to give 0.188 g
(87% yield) of 3-(2-amino-4-chloro-phenoxy)-propan-1-ol as a yellow
oil.
Step D: synthesis of
2-[3-(tert-butyl-dimethyl-silanyloxy)-propoxy]-5-chloro-phenylamine
[0723]
2-[3-(tert-Butyl-dimethyl-silanyloxy)-propoxy]-5-chloro-phenylamine
was synthesized, utilizing the appropriate starting materials, as
described in Preparation 36, Step A.
Preparation 41: Synthesis of
[1-(6-Amino-quinolin-7-yl)-piperidin-4-ylmethyl]-carbamic acid
tert-butyl ester
[0724] The synthesis of
[1-(6-amino-quinolin-7-yl)-piperidin-4-ylmethyl]-carbamic acid
tert-butyl ester was carried out according to the process shown in
Scheme 41.
##STR00244##
Step A: synthesis of N-(3-chloro-4-nitro-phenyl)-acetamide
[0725] Fuming nitric acid (150 mL) was slowly added, at -50.degree.
C., over a period of 50 minutes to N-(3-chloro-phenyl)-acetamide
(45 g). The reaction mixture was allowed to warm up to -20.degree.
C. and then was poured into ice-water. The solid formed was
collected by filtration, washed with water, and dried under reduced
pressure. The residue was washed with dichloromethane and dried
under reduced pressure to afford 14 g of
N-(3-chloro-4-nitro-phenyl)-acetamide as a light pink solid.
Step B: synthesis of 3-chloro-4-nitro-phenylamine
[0726] A mixture of N-(3-chloro-4-nitro-phenyl)-acetamide (18.55 g,
86.4 mmol) and an aqueous solution of hydrochloric acid (6 M, 120
mL) was heated at reflux for 2 hours. The resulting mixture was
cooled and poured into water (800 mL); the yellow solid which
crushed out was collected by filtration, washed with water and
dried under reduced pressure to give 5 g of
3-chloro-4-nitro-phenylamine. The water layer was basified until pH
8 by addition of potassium carbonate and then was extracted with
dichloromethane. The organic layer was dried over anhydrous sodium
sulfate, filtered and evaporated under reduced pressure to give 7.2
g of 3-chloro-4-nitro-phenylamine.
Step C: synthesis of 7-chloro-6-nitro-quinoline
[0727] To a mixture of 3-chloro-4-nitro-phenylamine (10.6 g, 61.4
mmol), arsenic pentoxide (8.79 g, 38.2 mmol) and glycerol (26 mL,
172.1 mmol) at 100.degree. C., was added, dropwise, concentrated
sulfuric acid (10.5 mL, 197.6 mmol). The reaction mixture was
heated at 150.degree. C. for 2 hours and then was cooled at
80.degree. C. Water (300 mL) was added and the resulting mixture
was extracted 3 times with ethyl acetate. The combined organic
extracts were dried over anhydrous sodium sulfate, filtered and
evaporated under reduced pressure to give 8.7 g of a brown solid
residue. A portion (2.7 g) of this crude material was purified by
flash chromatography (DCM) to afford 974 mg of
7-chloro-6-nitro-quinoline as a light yellow solid and 1.108 g of
5-chloro-6-nitro-quinoline.
Step D: synthesis of
[1-(6-nitro-quinolin-7-yl)-piperidin-4-ylmethyl]-carbamic acid
tert-butyl ester
[0728] To a solution of 7-chloro-6-nitro-quinoline (974 mg, 4.67
mmol) in N,N-dimethylformamide (25 mL) were added potassium
carbonate (1.93 g, 14.01 mmol) and piperidin-4-ylmethyl-carbamic
acid tert-butyl ester (1.00 g, 4.67 mmol) and the resulting mixture
was heated at 100.degree. C. overnight. The reaction mixture was
cooled and partitioned between water (500 mL) and ethyl acetate
(300 mL). The organic layer was separated, washed twice with water
(500 mL), dried over anhydrous sodium sulfate, filtered and
evaporated under reduced pressure. The crude residue was purified
twice by flash chromatography to afford 415 mg of
[1-(6-nitro-quinolin-7-yl)-piperidin-4-ylmethyl]-carbamic acid
tert-butyl ester as an orange solid.
Step E: synthesis of
[1-(6-amino-quinolin-7-yl)-piperidin-4-ylmethyl]-carbamic acid
tert-butyl ester
[0729] [1-(6-Nitro-quinolin-7-yl)-piperidin-4-ylmethyl]-carbamic
acid tert-butyl ester was reduced as described in Preparation 37,
Step E, to give
[1-(6-amino-quinolin-7-yl)-piperidin-4-ylmethyl]-carbamic acid
tert-butyl ester as a light yellow solid in 93% yield.
[0730] Utilizing the above described procedure and the appropriate
strating materials, the following compounds were prepared: [0731]
7-piperidin-1-yl-quinolin-6-ylamine; [0732]
[1-(2-amino-4-chloro-phenyl)-pyrrolidin-3-ylmethyl]-carbamic acid
tert-butyl ester (Step D and Step E); [0733]
[1-(2-amino-4-chloro-phenyl)-piperidin-4-ylmethyl]-carbamic acid
tert-butyl ester (Step D and Step E); and [0734]
[1-(6-amino-quinolin-7-yl)-piperidin-4-yl]-methanol (Step D and
Step E).
Preparation 42: Synthesis of
3-(2-Amino-4-chloro-phenoxy)-propan-1-ol
[0735] The synthesis of 3-(2-amino-4-chloro-phenoxy)-propan-1-ol
was carried out according to the process shown in Scheme 42.
##STR00245##
Step A: synthesis of
2-[3-(tert-butyl-dimethyl-silanyloxy)-propoxy]-5-chloro-phenylamine
[0736]
2-[3-(tert-Butyl-dimethyl-silanyloxy)-propoxy]-5-chloro-phenylamine
was synthesized, utilizing the appropriate starting materials, as
described in Preparation 2, Step B, and was obtained as a light
yellow oil in 71% yield.
Step B: synthesis of 3-(2-amino-4-chloro-phenoxy)-propan-1-ol
[0737]
2-[3-(tert-butyl-dimethyl-silanyloxy)-propoxy]-5-chloro-phenylamine
was reduced as described in Preparation 34, Step B, to afford
3-(2-amino-4-chloro-phenoxy)-propan-1-ol as a yellow oil in 42%
yield.
Preparation 43: Synthesis of
5-Chloro-2-(2-triisopropylsilanyl-oxazol-5-ylmethoxy)-phenylamine
[0738] The synthesis of
5-chloro-2-(2-triisopropylsilanyl-oxazol-5-ylmethoxy)-phenylamine
was carried out according to the process shown in Scheme 43.
##STR00246##
Step A: synthesis of
5-(4-chloro-2-nitro-phenoxymethyl)-2-triisopropylsilanyl-oxazole
[0739] Sodiumboron hydride (200 mg, 5.5 mmol) was added to a
solution of 2-triisopropylsilyl-oxazole-5-carboxaldehyde (0.7 g,
2.7 mmol) in a mixture of methanol and tetrahydrofuran (1/1, mL)
and the resulting mixture was stirred at room temperature for 20
minutes. The reaction mixture was then diluted with ethyl acetate,
washed with water and brine, dried over anhydrous sodium sulfate,
filtered and evaporated under reduced pressure to give
(2-triisopropylsilanyl-oxazol-5-yl)-methanol without further
purifications. This material was treated with
4-chloro-2-nitro-phenol as described in Preparation 20, Step A, to
give 0.7 g of
5-(4-chloro-2-nitro-phenoxymethyl)-2-triisopropylsilanyl-oxazole-
.
Step B: synthesis of
5-chloro-2-(2-triisopropylsilanyl-oxazol-5-ylmethoxy)-phenylamine
[0740]
5-(4-Chloro-2-nitro-phenoxymethyl)-2-triisopropylsilanyl-oxazole
was reduced utilizing zinc dust as described in Preparation 20,
Step B, to give 100 mg of
5-chloro-2-(2-triisopropylsilanyl-oxazol-5-ylmethoxy)-phenylamine.
Preparation 44: Synthesis of
3-[4-(tert-Butyl-dimethyl-silanyloxy)-cyclohexyloxy]-naphthalen-2-ylamine
[0741] The synthesis of
3-[4-(tert-butyl-dimethyl-silanyloxy)-cyclohexyloxy]-naphthalen-2-ylamine
was carried out according to the process shown in Scheme 44.
##STR00247##
Step A: synthesis of (3-hydroxy-naphthalen-2-yl)-carbamic acid
tert-butyl ester
[0742] Di-tert-butyldicarbonate (1.37 g, 6.28 mmol) was added to a
solution of 3-amino-2-naphthol (0.5 g, 3.14 mmol) in
tetrahydrofuran (15 mL) and the resulting mixture was stirred at
room temperature for 62 hours. The reaction mixture was then
partitioned between water and ethyl acetate; the aqueous layer was
separated and extracted twice with ethyl acetate. The combined
organic extracts were washed with brine, dried over anhydrous
sodium sulfate, filtered and evaporated under reduced pressure. The
crude residue was purified on a silica gel plug (hexane/EtOAc,
80/20) to give a brown solid which was washed twice with hexane to
give 0.69 g (85% yield) of (3-hydroxy-naphthalen-2-yl)-carbamic
acid tert-butyl ester as a gray solid.
Step B: synthesis of
[3-(4-hydroxy-cyclohexyloxy)-naphthalen-2-yl]-carbamic acid
tert-butyl ester
[0743] [3-(4-Hydroxy-cyclohexyloxy)-naphthalen-2-yl]-carbamic acid
tert-butyl ester (colorless oil) was synthesized (68% yield)
following the procedure described in Preparation 2, Step B.
Step C: synthesis of
4-(3-amino-naphthalen-2-yloxy)-cyclohexanol
[0744] A mixture of
[3-(4-hydroxy-cyclohexyloxy)-naphthalen-2-yl]-carbamic acid
tert-butyl ester (0.15 g, 0.58 mmol) and trifluoroacetic acid (0.2
mL) in dichloromethane (5 mL) was stirred at room temperature for
16 hours. The reaction mixture was basified by addition of an
aqueous solution of sodium hydroxide and was extracted twice with
dichloromethane. The combined organic extracts were dried over
anhydrous sodium sulfate, filtered and evaporated under reduced
pressure. The crude residue was purified by flash chromatography
(hexane/EtOAc, 75/25) to give 38 mg of
4-(3-amino-naphthalen-2-yloxy)-cyclohexanol and 66 mg of
trifluoro-acetic acid 4-(3-amino-naphthalen-2-yloxy)-cyclohexyl
ester. The trifluoroacetate was treated with a solution of sodium
hydroxide (11 mg) in ethanol (2 mL) and water and the resulting
mixture was stirred at room temperature overnight. The reaction
mixture was concentrated and the residue was partitioned between
water and dichloromethane, the organic layer was dried over
anhydrous sodium sulfate, filtered and evaporated under reduced
pressure to afford additional 40 mg of
4-(3-amino-naphthalen-2-yloxy)-cyclohexanol.
[0745] Utilizing the above described procedure and the appropriate
starting materials, the following compounds were prepared: [0746]
3-(3-amino-naphthalen-2-yloxy)-propan-1-ol; and [0747]
3-(3-amino-naphthalen-2-yloxy)-cyclopentanol.
Preparation 45: Synthesis of
[3-(2-Amino-4-chloro-phenoxy)-cyclopentyl]-methanol
[0748] The synthesis of
[3-(2-amino-4-chloro-phenoxy)-cyclopentyl]-methanol was carried out
according to the process shown in Scheme 45.
##STR00248##
[0749] A solution of lithium aluminum hydride (1 M, 3 mL) was added
to a cooled (0.degree. C.) solution of
3-(2-amino-4-chloro-phenoxy)-cyclopentanecarboxylic acid ethyl
ester (0.2 g) in tetrahydrofuran (5 mL) and the resulting mixture
was stirred for 30 minutes. The reaction mixture was then quenched
by addition of a saturated aqueous solution of ammonium chloride
and filtered. The filter cake was washed with ethyl acetate and the
filtrate was dried over anhydrous sodium sulfate, filtered and
evaporated under reduced pressure to give 180 mg of
[3-(2-amino-4-chloro-phenoxy)-cyclopentyl]-methanol without further
purifications.
Preparation 46: Synthesis of 6-Methoxy-1H-indazol-5-ylamine
[0750] The synthesis of 6-methoxy-1H-indazol-5-ylamine was carried
out according to the process shown in Scheme 46.
##STR00249##
Step A: synthesis of N-(5-methoxy-2-methyl-phenyl)-acetamide
[0751] Acetic anhydride (5.6 g, 54.66 mmol) was added to a solution
of 5-methoxy-2-methyl-phenylamine (5.0 g, 36.44 mmol) in pyridine
(30 mL) and the resulting mixture was stirred at room temperature
overnight. Water was added and the pH was adjusted to 5 by addition
of an aqueous solution of hydrochloric acid (3 M). The resulting
mixture was extracted with dichloromethane; the organic layer was
separated and washed with a saturated aqueous solution of sodium
bicarbonate and with brine, dried over anhydrous sodium sulfate,
filtered and evaporated under reduced pressure to afford 5.93 g of
N-(5-methoxy-2-methyl-phenyl)-acetamide as a white solid without
further purifications.
Step B: synthesis of
N-(5-methoxy-2-methyl-4-nitro-phenyl)-acetamide
[0752] Nitric acid (70%, 2.5 mL, 25.14 mmol) was added, dropwise,
at a temperature ranging between 5 and 10.degree. C., to a mixture
of N-(5-methoxy-2-methyl-phenyl)-acetamide (3.0 g, 16.76 mmol) and
concentrated sulfuric acid (10 mL) in glacial acetic acid (20 mL)
and the resulting mixture was stirred for 3 hours. The reaction
mixture was poured into ice-water and the solid formed was
collected by filtration. The residue was dissolved in
dichloromethane, dried over anhydrous sodium sulfate, filtered and
evaporated under reduced pressure to give 2.135 g of
N-(5-methoxy-2-methyl-4-nitro-phenyl)-acetamide as an off-white
solid.
Step C: synthesis of 6-methoxy-5-nitro-1H-indazole
[0753] To a mixture of
N-(5-methoxy-2-methyl-4-nitro-phenyl)-acetamide (0.5 g, 2.23 mmol),
potassium carbonate (0.26 g, 2.68 mmol), glacial acetic acid (0.15
mL, 2.68 mmol) and acetic anhydride (0.42 mL, 4.46 mmol) in
chloroform (20 mL) was added, dropwise, at 40.degree. C., isoamyl
nitrile (0.6 mL, 4.46 mmol) and the resulting mixture was heated at
60.degree. C. overnight. The reaction mixture was then basified by
addition of a saturated aqueous solution of sodium bicarbonate and
extracted twice with dichloromethane. The combined organic extracts
were dried over anhydrous sodium sulfate, filtered and evaporated
under reduced pressure. To the residue was added a mixture of an
aqueous solution of hydrochloric acid (3 M, 10 mL) and methanol (10
mL) and the resulting mixture was heated at 80.degree. C. for 2
hours. The reaction mixture was cooled, basified by addition of a
saturated aqueous solution of sodium bicarbonate and extracted with
dichloromethane. The organic extracts were dried over anhydrous
sodium sulfate, filtered and evaporated under reduced pressure. The
crude residue was purified by flash chromatography (EtOAc/hexane,
0/100 to 70/30) to afford 169 mg of 6-methoxy-5-nitro-1H-indazole
as orange solid.
Step D: synthesis of 6-methoxy-1H-indazol-5-ylamine
[0754] To a mixture of 6-methoxy-5-nitro-1H-indazole (0.16 g, 0.83
mmol), an aqueous solution of hydrochloric acid (6 M, 5 mL) and
concentrated hydrochloric acid (2 mL) was added, in portions, at
0.degree. C., stannous chloride (0.31 g, 1.66 mmol) and the
resulting mixture was warmed up to room temperature. The reaction
mixture was stirred at room temperature for 4 hours and then was
quenched by addition of a saturated aqueous solution of sodium
bicarbonate. The resulting mixture was extracted with
dichloromethane; the organic extracts were dried over anhydrous
sodium sulfate, filtered and evaporated under reduced pressure. The
crude residue was triturated with dichloromethane to give a 2/1
mixture of 6-methoxy-1H-indazol-5-ylamine and
3-chloro-6-methoxy-1H-indazol-5-ylamine.
Preparation 47: Synthesis of
6-[2-(tert-Butyl-dimethyl-silanyloxy)-ethyl]-pyrazolo[1,5-a]pyrimidine-3--
carboxylic acid
[0755] The synthesis of
6-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-pyrazolo[1,5-a]pyrimidine-3--
carboxylic acid was carried out according to the process shown in
Scheme 47.
##STR00250##
Step A: synthesis of
6-(2-hydroxy-ethyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
[0756] To a cooled (0.degree. C.) solution of
3-diethoxymethyl-2-ethoxy-tetrahydro-furan (prepared accordingly to
WO2005/095317) (350 mg, 1.61 mmol) in dichloromethane (2 mL) was
added an aqueous solution of hydrochloric acid (6 M, 2 mL) followed
by 5-amino-1H-pyrazole-4-carboxylic acid (250 mg, 1.97 mmol) and
the resulting mixture was gradually heated at 70.degree. C. for 1
hour. The organic solvent evaporated while heating and the solid
formed was collected by filtration of the aqueous layer to give 50
mg of 5-amino-1H-pyrazole-4-carboxylic acid residual. The filtrate
was repeatedly triturated with diethyl ether, decanted and
lyophilized to give
6-(2-hydroxy-ethyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic
acid.
Step B: synthesis of
6-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-pyrazolo[1,5-a]pyrimidine-3--
carboxylic acid
[0757] 6-(2-Hydroxy-ethyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic
acid was protected following the procedure described in Preparation
2, Step A.
Preparation 48: Synthesis of
6-methyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
[0758] The synthesis of
6-methyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid was carried
out according to the process shown in Scheme 48.
##STR00251##
[0759] A suspension of 5-amino-1H-pyrazole-4-carboxylic acid (271
mg, 2.1 mmol) and 1,1,3,3-tetraethoxy-2-methyl-propane (prepared
accordingly to the procedure described in JACS 126(7), 2004, 2194)
(0.5 g, 2.1 mmol) in an aqueous solution of hydrochloric acid (6 M,
1.3 mL) was heated at 95.degree. C. in a sealed tube. The solid
material completely dissolved when the temperature reached
82.degree. C. and then a solid precipitate crushed out of solution,
stirring was continued for 5 minutes. The resulting mixture was
cooled to room temperature and the solid was collected by
filtration, rinsed with water and dried in vacuum oven to afford
305.1 mg (81% yield) of
6-methyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid.
Preparation 49: Synthesis of
6-Methoxy-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
[0760] The synthesis of
6-methoxy-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid was carried
out according to the process shown in Scheme 49.
##STR00252##
[0761] To a solution of oxalyl chloride (6.9 mL) in dichloromethane
(65 mL), cooled at -78.degree. C., was added, dropwise, a solution
of dimethyl sulfoxide (13 mL) in dichloromethane (16 mL) and the
resulting mixture was stirred for 10 minutes. A solution of
2-O-methyl-glycerol (3.3 g, 31.5 mmol) in dichloromethane (16 mL)
was then added dropwise and the reaction mixture was stirred for 15
minutes. Triethylamine (52 mL) was then added dropwise and the
resulting mixture was stirred for 1 hour. The reaction mixture was
warmed up to room temperature and an aqueous solution of
hydrochloric acid (6 M, 35 mL) was added followed by
5-amino-1H-pyrazole-4-carboxylic acid (4 g, 31.5 mmol) and the
resulting mixture was heated to 95.degree. C. over 20 minutes, the
temperature was maintained at 95.degree. C. for 20 minutes. The
resulting mixture was cooled to room temperature and stored at room
temperature for 24 hours and at 4.degree. C. for 62 hours. The
solid formed was collected by filtration and dried in a vacuum oven
to afford 1.087 g (18% yield) of
6-methoxy-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid.
Preparation 50: Synthesis of
6-Bromo-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
[0762] The synthesis of
6-bromo-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid was carried out
according to the process shown in Scheme 50.
##STR00253##
[0763] A suspension of 5-amino-1H-pyrazole-4-carboxylic acid (1 g,
7.8 mmol) and 2-bromomalonaldehyde (1.2 g, 7.8 mmol) in an aqueous
solution of hydrochloric acid (6 M, 20 mL) was heated at 95.degree.
C. for 15 minutes. The resulting mixture was cooled to room
temperature and the solid formed was collected by filtration,
rinsed with water and dried in vacuum oven to give
6-bromo-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid.
Preparation 51: Synthesis of 1-pyrrolidin-3-yl-ethanol
trifluoroacetate
[0764] The synthesis of 1-pyrrolidin-3-yl-ethanol trifluoroacetate
was carried out according to the process shown in Scheme 51.
##STR00254##
[0765] A solution of methylmagnesium iodide (3.0 M in Et.sub.2O, 10
mL, 30 mmol) was added, under nitrogen atmosphere, to a solution of
3-formyl-pyrrolidine-1-carboxylic acid tert-butyl ester (2 g, 10.0
mmol) in tetrahydrofuran (15 mL) at 0.degree. C. and the resulting
mixture was stirred at room temperature for 1 hour. A second
aliquot of tetrahydrofuran (55 mL) was then added. The reaction
mixture was quenched by addition of a saturated aqueous solution of
ammonium chloride until dissolution of the solids. The volatiles
were evaporated under reduced pressure and the residue was
extracted twice with dichloromethane. The combined organic extracts
were washed with a saturated aqueous solution of sodium
bicarbonate, dried over anhydrous sodium sulfate, filtered and
evaporated under reduced pressure to give 2.149 of
3-(1-hydroxy-ethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester.
To a portion of this material (875 mg, 4.1 mmol) was added a
solution of trifluoroacetic acid (5% in DCM, 10 mL) and the
resulting mixture was stirred at room temperature for 30 minutes.
The reaction mixture was then evaporated under reduced pressure to
give 1-pyrrolidin-3-yl-ethanol trifluoroacetate which was used
without further purifications.
Preparation 52: Synthesis of
{1-[1-(2-amino-4-chloro-phenyl)-pyrrolidin-3-yl]-ethyl}-carbamic
acid tert-butyl ester
[0766] The synthesis of
{1-[1-(2-amino-4-chloro-phenyl)-pyrrolidin-3-yl]-ethyl}-carbamic
acid tert-butyl ester was carried out according to the process
shown in Scheme 52.
##STR00255##
Step A: synthesis of methanesulfonic acid
1-[1-(4-chloro-2-nitro-phenyl)-pyrrolidin-3-yl]-ethyl ester
[0767] A mixture of
1-[1-(2-amino-4-chloro-phenyl)-pyrrolidin-3-yl]-ethanol (320.7 mg,
1.2 mmol), triethylamine (0.5 mL) and p-toluenesulfonylchloride
(272 mg) in dichloromethae (15 mL) was stirred, under nitrogen
atmosphere, at room temperature, for 62 hours.
4-Dimethylaminopyridine (catalytic quantity) was then added and the
reaction mixture was heated at reflux for 3 hours. The resulting
mixture was evaporated under reduced pressure; the residue was
dissolved in pyridine and more p-toluenesulfonylchloride (272 mg)
was added. The reaction mixture was stirred at room temperature
overnight and then was evaporated under reduced pressure. The
residue was diluted with water and extracted 3 times with ethyl
acetate. The combined organic extracts were washed with brine,
dried over anhydrous sodium sulfate, filtered and evaporated under
reduced pressure. To a solution of this material in dichloromethane
(15 mL) was added triethylamine (0.5 mL) followed by
methanesulfonylchloride (0.26 mL) and the resulting mixture was
stirred, under nitrogen atmosphere, at room temperature, for 2
hours. The reaction mixture was washed twice with water and the
aqueous layer was extracted 3 times with dichloromethane. The
combined organic extracts were washed with brine, dried over
anhydrous sodium sulfate, filtered and evaporated under reduced
pressure. The crude residue was purified by flash chromatography
(hexane/EtOAc, 90/10 to 50/50) to afford 285.9 mg of
methanesulfonic acid
1-[1-(4-chloro-2-nitro-phenyl)-pyrrolidin-3-yl]-ethyl ester and
55.2 mg of toluene-4-sulfonic acid
1-[1-(4-chloro-2-nitro-phenyl)-pyrrolidin-3-yl]-ethyl ester.
Step B: synthesis of
3-(1-Azido-ethyl)-1-(4-chloro-2-nitro-phenyl)-pyrrolidine
[0768] A mixture of methanesulfonic acid
1-[1-(4-chloro-2-nitro-phenyl)-pyrrolidin-3-yl]-ethyl ester (285.9
mg), toluene-4-sulfonic acid
1-[1-(4-chloro-2-nitro-phenyl)-pyrrolidin-3-yl]-ethyl ester (55.2
mg) and sodium azide (185 mg) in N,N-dimethylformamide (ca. 5 mL)
was heated at 80.degree. C. overnight. The reaction mixture was
cooled, diluted with water and extracted 3 times with ethyl
acetate. The combined organic extracts were washed with brine,
dried over anhydrous sodium sulfate, filtered and evaporated under
reduced pressure. The crude residue was purified by flash
chromatography (hexane/EtOAc, 90/10) to give 214 mg (76% yield) of
3-(1-azido-ethyl)-1-(4-chloro-2-nitro-phenyl)-pyrrolidine.
Step C: synthesis of
1-[1-(4-chloro-2-nitro-phenyl)-pyrrolidin-3-yl]-ethylamine
[0769] A mixture of
3-(1-azido-ethyl)-1-(4-chloro-2-nitro-phenyl)-pyrrolidine (214 mg,
0.7 mmol), triphenylphosphine (500 mg) and water (0.171 mL) in
tetrahydrofuran (20 mL) was heated at 50.degree. C. overnight. The
resulting mixture was evaporated under reduced pressure; the
residue was diluted with ethyl acetate, washed twice with water and
once with brine, dried over anhydrous sodium sulfate, filtered and
evaporated under reduced pressure. The crude residue was purified
by flash chromatography (DCM/MeOH) to give 127 mg (65% yield) of
1-[1-(4-chloro-2-nitro-phenyl)-pyrrolidin-3-yl]-ethylamine.
Step D: synthesis of
{1-[1-(4-Chloro-2-nitro-phenyl)-pyrrolidin-3-yl]-ethyl}-carbamic
acid tert-butyl ester
[0770] To a mixture of
1-[1-(4-chloro-2-nitro-phenyl)-pyrrolidin-3-yl]-ethylamine (127 mg,
0.47 mmol) in dichloromethane (ca. 5 mL) cooled at 0.degree. C. was
added di-tert-butyl-dicarbonate (113 mg) and the resulting mixture
was stirred for 30 minutes at 0.degree. C. The reaction mixture was
then warmed up to room temperature and stirred for 2.5 hours. The
resulting mixture was washed with a saturated aqueous solution of
sodium bicarbonate and with brine, dried over anhydrous sodium
sulfate, filtered and evaporated under reduced pressure. The crude
residue was purified by flash chromatography (hexane/EtOAc, 90/10
to 50/50) to give 146 mg (84% yield) of
{1-[1-(4-chloro-2-nitro-phenyl)-pyrrolidin-3-yl]-ethyl}-carbamic
acid tert-butyl ester.
Step E: synthesis of
{1-[1-(2-amino-4-chloro-phenyl)-pyrrolidin-3-yl]-ethyl}-carbamic
acid tert-butyl ester
[0771]
{1-[1-(4-Chloro-2-nitro-phenyl)-pyrrolidin-3-yl]-ethyl}-carbamic
acid tert-butyl ester was reduced following the procedure described
in Preparation 20, Step B, to give
{1-[1-(2-amino-4-chloro-phenyl)-pyrrolidin-3-yl]-ethyl}-carbamic
acid tert-butyl ester in quantitative yield.
Example 1
Synthesis of Pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
[5-chloro-2-(4-hydroxy-cyclohexyloxy)-phenyl]-amide
[0772] The synthesis of pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
[5-chloro-2-(4-hydroxy-cyclohexyloxy)-phenyl]-amide was carried out
according to the process shown in Scheme 53.
##STR00256##
[0773] Diisopropylethylamine (0.35 mL, 2.01 mmol) was added at room
temperature to a suspension of
4-(2-amino-4-chloro-phenoxy)-cyclohexanol (127 mg, 0.525 mmol),
pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (85 mg, 0.521 mmol) and
HBTU (0.21 g, 0.55 mmol) in anhydrous acetonitrile (15 mL) and the
resulting solution was heated at 80.degree. C. overnight. The
resulting mixture was partitioned between ethyl acetate and an
aqueous solution of sodium bicarbonate (5%). The aqueous layer was
extracted 3 times with ethyl acetate and the combined organic
extracts were washed with brine, dried over anhydrous sodium
sulfate, filtered and evaporated under reduced pressure. The brown
oily residue was purified on a silica gel plug and by flash
chromatography (DCM/MeOH/NH.sub.4OH) to give a pale yellow solid
which was washed with dichloromethane and methanol to give 75 mg
(38% yield) of pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
[5-chloro-2-(4-hydroxy-cyclohexyloxy)-phenyl]-amide as a white
powder. MS=387 [M+H].sup.+.
[0774] In a similar manner, utilizing the appropriate starting
materials, the following compounds were prepared: [0775]
3-methoxy-4-[(pyrazolo[1,5-a]pyrimidine-3-carbonyl)-amino]-benzoic
acid methyl ester; [0776] pyrazolo[1,5-a]pyrimidine-3-carboxylic
acid
[4-(tert-butyl-dimethyl-silanyloxymethyl)-2-methoxy-phenyl]-amide;
[0777] 6-formyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
{2-[4-(tert-butyl-dimethyl-silanyloxy)-cyclohexyloxy]-5-chloro-phenyl}-am-
ide; [0778] pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
(3-methoxy-biphenyl-4-yl)-amide (light yellow solid); MS=345
[M+H].sup.+; [0779] pyrazolo[1,5-a]pyrimidine-3,6-dicarboxylic acid
6-amide
3-({2-[4-(tert-butyl-dimethyl-silanyloxy)-cyclohexyloxy]-5-chloro-phenyl}-
-amide); [0780] 3-methoxy-4-nitro-N-phenyl-benzamide; [0781]
pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
(2-methoxy-4-phenylcarbamoyl-phenyl)-amide (light yellow
crystalline solid); MS=388 [M+H].sup.+; [0782]
pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
(3-amino-2-methoxy-phenyl)-amide (light yellow powder); MS=284
[M+H].sup.+; [0783] pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
[3-(3-hydroxy-propylamino)-2-piperidin-1-yl-phenyl]-amide (light
yellow powder); MS=395 [M+H].sup.+; [0784]
pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
[3-(2-hydroxy-ethylamino)-2-piperidin-1-yl-phenyl]-amide (light
yellow powder); MS=381 [M+H].sup.+; [0785]
pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
(5-chloro-2-methoxy-4-phenylcarbamoyl-phenyl)-amide (white powder);
MS=422 [M+H].sup.+; [0786] pyrazolo[1,5-a]pyrimidine-3-carboxylic
acid (4-dimethylcarbamoyl-2-methoxy-phenyl)-amide (white powder);
MS=340 [M+H].sup.+; [0787] pyrazolo[1,5-a]pyrimidine-3-carboxylic
acid (2-methoxy-3,5-dimethyl-phenyl)-amide (light yellow powder);
MS=297 [M+H].sup.+; [0788]
5-methyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
{2-[4-(tert-butyl-dimethyl-silanyloxy)-cyclohexyloxy]-5-chloro-phenyl}-am-
ide; [0789] 7-methyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
{2-[4-(tert-butyl-dimethyl-silanyloxy)-cyclohexyloxy]-5-chloro-phenyl}-am-
ide; [0790] pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
[5-(3-hydroxy-propyl)-2-methoxy-phenyl]-amide (light brown
crystalline solid); MS=327 [M+H].sup.+; MP=189.7-190.2.degree. C.;
[0791] pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
(2-methoxy-5-vinyl-phenyl)-amide (light yellow solid); MS=295
[M+H].sup.+; [0792] pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
(5-ethyl-2-methoxy-phenyl)-amide (pink powder); MS=297 [M+H].sup.+;
[0793] pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
[5-chloro-2-(4-hydroxymethyl-piperidin-1-yl)-phenyl]-amide
(off-white solid); MS=386 [M+H].sup.+; [0794]
(1-{4-chloro-2-[(pyrazolo[1,5-a]pyrimidine-3-carbonyl)-amino]-phenyl}-pip-
eridin-4-ylmethyl)-carbamic acid tert-butyl ester; [0795]
pyrrolo[2,1-f][1,2,4]triazine-7-carboxylic acid
[5-chloro-2-(4-hydroxy-cyclohexyloxy)-phenyl]-amide (off-white
solid); MS=386 [M+H].sup.+; [0796]
2-chloro-thieno[3,2-d]pyrimidine-7-carboxylic acid
(7-methoxy-quinolin-6-yl)-amide; [0797]
pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
(2-oxo-5-piperidin-1-yl-2,3-dihydro-1H-indol-6-yl)-amide (black
solid); MS=377 [M+H].sup.+; [0798]
pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
(5-methoxy-2-methyl-1H-indol-6-yl)-amide (yellow solid); MS=322
[M+H].sup.+; [0799]
3-(7-methoxy-quinolin-6-ylcarbamoyl)-thieno[3,2-b]pyridine-6-carboxylic
acid ethyl ester; [0800] thieno[3,2-d]pyrimidine-7-carboxylic acid
[2-(2-hydroxy-ethylamino)-7-methoxy-quinolin-6-yl]-amide
hydrochloride (the hydrochloride salt was generated utilizing HCl
in Et.sub.2O) (yellow powder); MS=396 [M+H].sup.+;
MP=265.1-269.9.degree. C.; [0801]
4-{4-chloro-2-[(pyrazolo[1,5-a]pyrimidine-3-carbonyl)-amino]-phenoxy}-pip-
eridine-1-carboxylic acid tert-butyl ester; [0802]
pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
[3'-(tert-butyl-dimethyl-silanyloxy)-4-chloro-biphenyl-2-yl]-amide;
[0803]
(1-{5-phenylcarbamoyl-2-[(pyrazolo[1,5-a]pyrimidine-3-carbonyl)-am-
ino]-phenyl}-piperidin-4-ylmethyl)-carbamic acid tert-butyl ester;
[0804] pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
{7-[4-(tert-butyl-dimethyl-silanyloxy)-cyclohexyloxy]-quinolin-6-yl}-amid-
e; [0805]
(1-{2-amino-6-[(pyrazolo[1,5-a]pyrimidine-3-carbonyl)-amino]-phe-
nyl}-piperidin-4-ylmethyl)-carbamic acid tert-butyl ester; [0806]
pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
[5-chloro-2-(4-hydroxy-butoxy)-phenyl]-amide (white powder); MS=361
[M+H].sup.+; [0807] pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
(3-amino-2-piperidin-1-yl-phenyl)-amide (off-white powder); MS=337
[M+H].sup.+; [0808] pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
(4-chloro-biphenyl-2-yl)-amide (light yellow powder); MS=349
[M+H].sup.+; [0809] pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
(7-piperidin-1-yl-quinolin-6-yl)-amide hydrochloride (orange
powder) (the hydrochloride salt was prepared adding 3 equivalents
of HCl in Et.sub.2O to a solution of the free base in a mixture 1/1
of dichloromethane and methanol); MS=373 [M+H].sup.+;
MP=285-287.degree. C.; [0810]
pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
(2-methoxy-phenyl)-amide (light yellow powder); MS=268 [M].sup.+;
[0811] pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
(2,4-dimethoxy-phenyl)-amide (light yellow powder); MS=298
[M].sup.+; [0812] pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
(2-methoxy-4-methyl-phenyl)-amide (light yellow powder); MS=283
[M+H].sup.+; [0813] pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
(5-chloro-2-fluoro-phenyl)-amide (light yellow powder); MS=291
[M+H].sup.+; [0814] pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
(2-methoxy-5-methyl-phenyl)-amide (light yellow solid); MS=283
[M+H].sup.+; [0815] pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
(5-fluoro-2-methoxy-phenyl)-amide (light yellow powder); MS=287
[M+H].sup.+; [0816] pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
[5-chloro-2-(3-methoxy-propoxy)-phenyl]-amide (off-white powder);
MS=361 [M+H].sup.+; [0817] pyrazolo[1,5-a]pyrimidine-3-carboxylic
acid (5-methoxy-2-methyl-biphenyl-4-yl)-amide (light yellow
powder); MS=359 [M+H].sup.+; [0818]
pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
(2,5-dimethoxy-phenyl)-amide (light yellow crystalline solid);
MS=299 [M+H].sup.+; [0819] pyrazolo[1,5-a]pyrimidine-3-carboxylic
acid (7-methoxy-quinolin-6-yl)-amide (off-white powder); MS=320
[M+H].sup.+; MP=256-257.3.degree. C.; [0820]
pyrazolo[1,5-a]pyridine-3-carboxylic acid
(5-chloro-2-piperidin-1-yl-phenyl)-amide (white crystalline solid);
MS=355 [M+H].sup.+; MP=186.4-188.5.degree. C.; [0821]
pyrazolo[1,5-a]pyridine-3-carboxylic acid
(7-methoxy-quinolin-6-yl)-amide hydrochloride (yellow powder) (the
hydrochloride salt was prepared adding 3 equivalents of HCl in
Et.sub.2O to a solution of the free base in a mixture 1/1 of
dichloromethane and methanol); MS=319 [M+H].sup.+; [0822]
cis-thieno[3,2-d]pyrimidine-7-carboxylic acid
[5-chloro-2-(4-hydroxy-cyclohexyloxy)-phenyl]-amide (light yellow
powder); MS=404 [M+H].sup.+; [0823]
trans-thieno[3,2-d]pyrimidine-7-carboxylic acid
[5-chloro-2-(4-hydroxy-cyclohexyloxy)-phenyl]-amide (yellow
powder); MS=404 [M+H].sup.+; [0824]
pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
{4-[2-(tert-butyl-dimethyl-silanyloxy)-ethylcarbamoyl]-2-methoxy-phenyl}--
amide; [0825] thieno[3,2-d]pyrimidine-7-carboxylic acid
{4-[2-(tert-butyl-dimethyl-silanyloxy)-ethylcarbamoyl]-2-methoxy-phenyl}--
amide; [0826] thieno[3,2-d]pyrimidine-7-carboxylic acid
{4-[3-(tert-butyl-dimethyl-silanyloxy)-propylcarbamoyl]-2-methoxy-phenyl}-
-amide; [0827] pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
{4-[3-(tert-butyl-dimethyl-silanyloxy)-propylcarbamoyl]-2-methoxy-phenyl}-
-amide; [0828]
(1-{4-chloro-2-[(pyrazolo[1,5-a]pyrimidine-3-carbonyl)-amino]-phenyl}-pip-
eridin-4-yl)-carbamic acid tert-butyl ester; [0829]
pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
[2-(4-carbamoyl-piperidin-1-yl)-5-chloro-phenyl]-amide (off-white
powder); MS=399 [M+H].sup.+; [0830]
{4'-chloro-2'-[(pyrazolo[1,5-a]pyrimidine-3-carbonyl)-amino]-biphenyl-4-y-
lmethyl}-carbamic acid tert-butyl ester; [0831]
pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
[3-(3-hydroxy-cyclopentyloxy)-naphthalen-2-yl]-amide (off-white
solid); MS=389 [M+H].sup.+; [0832]
pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
(1-methoxy-naphthalen-2-yl)-amide (off-white solid); MS=319
[M+H].sup.+; [0833] pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
[5-(4-hydroxymethyl-piperidin-1-yl)-2-oxo-2,3-dihydro-1H-indol-6-yl]-amid-
e (black solid); MS=407 [M+H].sup.+; [0834]
pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
(5-bromo-2-methoxy-phenyl)-amide (light brown powder); MS=347
[M+H].sup.+; [0835] pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
biphenyl-2-ylamide (light yellow powder); MS=315 [M+H].sup.+;
[0836] pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
(5-chloro-2-morpholin-4-yl-phenyl)-amide (white powder); MS=358
[M+H].sup.+; [0837] pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
(5-chloro-2-methylsulfanyl-phenyl)-amide (light yellow needles);
MS=319 [M+H].sup.+; [0838]
(1-{6-[(pyrazolo[1,5-a]pyrimidine-3-carbonyl)-amino]-quinolin-7-yl}-piper-
idin-4-ylmethyl)-carbamic acid tert-butyl ester; [0839]
thieno[3,2-d]pyrimidine-7-carboxylic acid
(7-piperidin-1-yl-quinolin-6-yl)-amide (light yellow powder);
MS=390 [M+H].sup.+; MP=234.0-236.0.degree. C.; [0840]
thieno[3,2-d]pyrimidine-7-carboxylic acid
[7-(3-hydroxy-1,1-dimethyl-propoxy)-quinolin-6-yl]-amide
hydrochloride (the hydrochloride salt was generated utilizing HCl
in Et.sub.2O) (light yellow powder); MS=400 [M+H].sup.+;
MP>300.degree. C.; [0841] thieno[3,2-d]pyrimidine-7-carboxylic
acid [7-(3-hydroxy-butoxy)-quinolin-6-yl]-amide (light yellow
powder); MS=395 [M+H].sup.+; MP=256.0-257.0.degree. C.; [0842]
thieno[3,2-d]pyrimidine-7-carboxylic acid
[5-chloro-2-(3-hydroxy-1,1-dimethyl-propoxy)-phenyl]-amide (yellow
waxy solid); MS=392 [M+H].sup.+; MP=52.0-54.0.degree. C.; [0843]
thieno[3,2-d]pyrimidine-7-carboxylic acid
(5-chloro-2-cyclohexyloxy-phenyl)-amide (white powder); MS=388
[M+H].sup.+; MP=153.4-155.7.degree. C.; [0844]
thieno[3,2-d]pyrimidine-7-carboxylic acid
(5-chloro-2-isopropoxy-phenyl)-amide (white powder); MS=348
[M+H].sup.+; MP=149.6-150.6.degree. C.; [0845]
pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
[2-(2-hydroxy-ethylamino)-7-methoxy-quinolin-6-yl]-amide (light
brown powder); MS=379 [M+H].sup.+; MP=261.3-264.8.degree. C.;
[0846] pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
[5-chloro-2-(3-hydroxymethyl-pyrrolidin-1-yl)-phenyl]-amide (yellow
powder); MS=372 [M+H].sup.+; MP=174.4-175.9.degree. C.; [0847]
pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
[7-(4-hydroxymethyl-piperidin-1-yl)-quinolin-6-yl]-amide (light
yellow powder); MS=403 [M+H].sup.+; MP=247.7-249.0.degree. C.;
[0848] pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
[3-(3-hydroxy-propoxy)-naphthalen-2-yl]-amide (light brown solid);
MS=363 [M+H].sup.+; MP=227.7-230.2.degree. C.; [0849]
pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
[3-(4-hydroxy-cyclohexyloxy)-naphthalen-2-yl]-amide (light brown
solid); MS=403 [M+H].sup.+; [0850]
pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
[5-chloro-2-(3-hydroxy-cyclopentyloxy)-phenyl]-amide (light brown
powder); MS=373 [M+H].sup.+; MP=256.9-258.4.degree. C.; [0851]
pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
[5-chloro-2-(3-hydroxymethyl-cyclopentyloxy)-phenyl]-amide
(off-white solid); MS=387 [M+H].sup.+; [0852]
pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
[5-chloro-2-(3-hydroxy-cyclohexyloxy)-phenyl]-amide (off-white
solid); MS=387 [M+H].sup.+; [0853]
thieno[3,2-d]pyrimidine-7-carboxylic acid
(5-chloro-2-methoxy-phenyl)-amide (orange crystalline solid);
MS=320 [M+H].sup.+; MP=213.1-214.0.degree. C.; [0854]
pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
[5-chloro-2-(3-hydroxymethyl-piperidin-1-yl)-phenyl]-amide (dark
brown solid); MS=386 [M+H].sup.+; [0855]
pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
(2-azepan-1-yl-5-chloro-phenyl)-amide (pink solid); MS=370
[M+H].sup.+; [0856] pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
(5-hydroxymethyl-2-piperidin-1-yl-phenyl)-amide (light yellow
solid); MS=352 [M+H].sup.+; MP=196.6-197.9.degree. C.; [0857]
thieno[3,2-d]pyrimidine-7-carboxylic acid
[5-chloro-2-(4-hydroxymethyl-piperidin-1-yl)-phenyl]-amide
(off-white solid); MS=403 [M+H].sup.+; [0858]
thieno[3,2-d]pyrimidine-7-carboxylic acid (2-methoxy-phenyl)-amide
(orange solid); MS=286 [M+H].sup.+; [0859]
thieno[3,2-b]pyridine-3-carboxylic acid
(5-chloro-2-methoxy-phenyl)-amide (light yellow powder); MS=319
[M+H].sup.+; [0860] pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
(5-chloro-2-pyrrolidin-1-yl-phenyl)-amide (crystalline off-white
solid); MS=342 [M+H].sup.+; [0861]
pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
[5-(4-hydroxymethyl-phenyl)-2-methyl-1H-indol-6-yl]-amide (orange
semisolid); MS=398 [M+H].sup.+; [0862]
pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
(5-methoxy-1H-indol-6-yl)-amide (light green powder); MS=308
[M+H].sup.+; [0863] thieno[3,2-d]pyrimidine-7-carboxylic acid
(5-methoxy-1H-indol-6-yl)-amide (light green powder); MS=325
[M+H].sup.+; [0864] pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
[5-chloro-2-(4-methyl-piperazin-1-yl)-phenyl]-amide (off-white
solid); MS=371 [M+H].sup.+; [0865]
pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
[5-chloro-2-(4-methyl-oxazol-5-ylmethoxy)-phenyl]-amide (off-white
solid); MS=384 [M+H].sup.+; MP=240.9-242.5.degree. C.; [0866]
thieno[3,2-d]pyrimidine-7-carboxylic acid
[5-chloro-2-(4-methyl-oxazol-5-ylmethoxy)-phenyl]-amide (light
brown crystalline solid); MS=401 [M+H].sup.+;
MP=233.3-234.3.degree. C.; [0867]
pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
[5-chloro-2-(3-hydroxy-pyrrolidin-1-yl)-phenyl]-amide (off-white
solid); MS=358 [M+H].sup.+; [0868]
(1-{6-[(thieno[3,2-b]pyridine-3-carbonyl)-amino]-quinolin-7-yl}-piperidin-
-4-ylmethyl)-carbamic acid tert-butyl ester; [0869]
pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
{5-chloro-2-[3-(2,2,2-trifluoro-acetylamino)-pyrrolidin-1-yl]-phenyl}-ami-
de; [0870] pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
(5-chloro-2-methoxy-phenyl)-amide (crystalline off-white solid);
MS=303 [M+H].sup.+; [0871] pyrazolo[1,5-a]pyrimidine-3-carboxylic
acid
{2-[3-(tert-butyl-dimethyl-silanyloxy)-propoxy]-5-chloro-phenyl}-amide;
[0872] pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
{2-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-5-chloro-phenyl}-amide;
[0873] pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
[5-chloro-2-(2-methoxy-ethoxy)-phenyl]-amide (off-white solid);
MS=347 [M+H].sup.+; [0874] pyrazolo[1,5-a]pyrimidine-3-carboxylic
acid (5-chloro-2-ethyl-phenyl)-amide (off-white powder); MS=301
[M+H].sup.+; [0875] pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
(5-chloro-2-isobutoxy-phenyl)-amide (off-white powder); MS=345
[M+H].sup.+; [0876] pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
[5-chloro-2-(4-hydroxy-butyl)-phenyl]-amide (white powder); MS=345
[M+H].sup.+; [0877] pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
(5-chloro-2-cyclohexyl-phenyl)-amide (white powder); MS=355
[M+H].sup.+; [0878] pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
(4-chloro-4'-hydroxymethyl-biphenyl-2-yl)-amide (off-white powder);
MS=379 [M+H].sup.+; [0879] pyrazolo[1,5-a]pyrimidine-3-carboxylic
acid (7-hydroxymethyl-3-methoxy-naphthalen-2-yl)-amide (off-white
powder); MS=349 [M+H]
.sup.+; [0880] pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
(4-methanesulfonyl-2-methoxy-phenyl)-amide (off-white powder)
(4-methanesulfonyl-2-methoxy-phenylamine was prepared accordingly
to the procedure reported in Eur. J. Med. Chem. 37, 2002, 461);
MS=347 [M+H].sup.+; [0881] pyrazolo[1,5-a]pyrimidine-3-carboxylic
acid (6-methoxy-1H-indazol-5-yl)-amide (yellow powder); MS=309
[M+H].sup.+; [0882] thieno[3,2-d]pyrimidine-7-carboxylic acid
(7-methoxy-quinolin-6-yl)-amide (off-white powder); MS=337
[M+H].sup.+; MP=249.0-252.2.degree. C.; [0883]
cis-thieno[3,2-d]pyrimidine-7-carboxylic acid
{7-[4-(tert-butyl-diphenyl-silanyloxy)-cyclohexyloxy]-quinolin-6-yl}-amid-
e; [0884]
3-{6-[(thieno[3,2-d]pyrimidine-7-carbonyl)-amino]-quinolin-7-ylo-
xy}-pyrrolidine-1-carboxylic acid tert-butyl ester; [0885]
(3-{6-[(thieno[3,2-d]pyrimidine-7-carbonyl)-amino]-quinolin-7-yloxy}-prop-
yl)-carbamic acid tert-butyl ester; [0886]
thieno[3,2-d]pyrimidine-7-carboxylic acid
{7-[3-(tert-butyl-dimethyl-silanyloxy)-propoxy]-quinolin-6-yl}-amide;
[0887]
4-{6-[(thieno[3,2-d]pyrimidine-7-carbonyl)-amino]-quinolin-7-yloxy-
}-piperidine-1-carboxylic acid tert-butyl ester; [0888]
(1-{6-[(thieno[3,2-d]pyrimidine-7-carbonyl)-amino]-quinolin-7-yl}-piperid-
in-4-ylmethyl)-carbamic acid tert-butyl ester; [0889]
(1-{6-[(pyrazolo[1,5-a]pyrimidine-3-carbonyl)-amino]-quinolin-7-yl}-piper-
idin-4-ylmethyl)-carbamic acid tert-butyl ester; [0890]
thieno[3,2-d]pyrimidine-7-carboxylic acid
{7-[4-(tert-butyl-dimethyl-silanyloxy)-cyclohexyloxy]-quinolin-6-yl}-amid-
e; [0891]
(4-{4-chloro-2-[(thieno[3,2-d]pyrimidine-7-carbonyl)-amino]-phen-
oxy}-cyclohexyl)-carbamic acid tert-butyl ester; [0892]
4-{6-[(pyrazolo[1,5-a]pyrimidine-3-carbonyl)-amino]-quinolin-7-yloxy}-pip-
eridine-1-carboxylic acid tert-butyl ester; [0893]
6-(3-hydroxy-propyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
[5-chloro-2-(4-hydroxy-cyclohexyloxy)-phenyl]-amide (off-white
powder); MS=445 [M+H].sup.+; MP=236.7-237.7.degree. C.; [0894]
6-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-pyrazolo[1,5-a]pyrimidine-3--
carboxylic acid
{2-[4-(tert-butyl-dimethyl-silanyloxy)-cyclohexyloxy]-5-chloro-phenyl}-am-
ide; [0895] pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
(2-{4-[1-(tert-butyl-dimethyl-silanyloxy)-ethyl]-piperidin-1-yl}-5-chloro-
-phenyl)-amide (1-piperidin-4-yl-ethanol was prepared accordingly
to the procedure described in WO2005/080394); [0896]
[1-(1-{4-chloro-2-[(pyrazolo[1,5-a]pyrimidine-3-carbonyl)-amino]-phenyl}--
piperidin-4-yl)-ethyl]-carbamic acid tert-butyl ester
(1-piperidin-4-yl-ethylamine was prepared accordingly to the
procedure described in WO2005/080394); [0897]
pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
(5-acetylamino-2-methoxy-phenyl)-amide (light brown powder); MS=326
[M+H].sup.+; MP=232.3-233.8.degree. C.; [0898]
pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
(3-methoxy-naphthalen-2-yl)-amide (light yellow powder); MS=319
[M+H].sup.+; MP=202.3-205.0.degree. C.; [0899]
pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
(5-chloro-2,4-dimethoxy-phenyl)-amide (light brown powder); MS=333
[M+H].sup.+; MP=243.0-247.0.degree. C.; [0900]
pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
(5-chloro-2-phenoxy-phenyl)-amide (white powder); MS=365
[M+H].sup.+; MP=184.5-186.0.degree. C.; [0901]
pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
(5-chloro-2-piperidin-1-yl-phenyl)-amide (light yellow powder);
MS=356 [M+H].sup.+; MP=171.2-172.5.degree. C.; [0902]
pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
{5-chloro-2-[(2-hydroxy-ethyl)-methyl-amino]-phenyl}-amide
(off-white powder); MS=346 [M+H].sup.+; MP=150.2-151.7.degree. C.;
[0903] pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
(5-chloro-2-dimethylamino-phenyl)-amide (off-white powder); MS=316
[M+H].sup.+; MP=179.8-180.6.degree. C.; [0904]
pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
[5-chloro-2-(4-hydroxy-piperidin-1-yl)-phenyl]-amide (off-white
powder); MS=372 [M+H].sup.+; MP=130.7-132.0.degree. C.; [0905]
pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
[5-chloro-2-(3-hydroxy-piperidin-1-yl)-phenyl]-amide (off-white
powder); MS=372 [M+H].sup.+; MP=185.7-186.9.degree. C.; [0906]
pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
[5-chloro-2-(2-hydroxymethyl-piperidin-1-yl)-phenyl]-amide
(off-white powder); MS=386 [M+H].sup.+; MP=232.0-235.0.degree. C.;
[0907] pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
[5-chloro-2-(4-hydroxy-phenoxy)-phenyl]-amide (white powder);
MS=381 [M+H].sup.+; MP=284.7-285.4.degree. C.; [0908]
pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
[5-chloro-2-(3-hydroxy-phenoxy)-phenyl]-amide (off-white powder);
MS=381 [M+H].sup.+; MP=245.3-247.0.degree. C.; [0909]
(1-{4-chloro-2-[(pyrazolo[1,5-a]pyrimidine-3-carbonyl)-amino]-phenyl}-pip-
eridin-4-ylmethyl)-carbamic acid tert-butyl ester; [0910]
pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
{5-chloro-2-[(3-hydroxy-propyl)-methyl-amino]-phenyl}-amide (white
powder); MS=360 [M+H].sup.+; [0911]
6-methyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
[5-chloro-2-(4-hydroxymethyl-piperidin-1-yl)-phenyl]-amide
(off-white powder); MS=400 [M+H].sup.+; [0912]
6-methoxy-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
{2-[4-(tert-butyl-dimethyl-silanyloxy)-cyclohexyloxy]-5-chloro-phenyl}-am-
ide; [0913] 6-bromo-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
{2-[4-(tert-butyl-dimethyl-silanyloxy)-cyclohexyloxy]-5-chloro-phenyl}-am-
ide; [0914] imidazo[1,2-a]pyridine-8-carboxylic acid
{2-[4-(tert-butyl-dimethyl-silanyloxy)-cyclohexyloxy]-5-chloro-phenyl}-am-
ide; [0915] 6-methoxy-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
(5-chloro-2-piperidin-1-yl-phenyl)-amide; [0916]
[1,2,4]triazolo[4,3-a]pyridine-8-carboxylic acid
{2-[4-(tert-butyl-dimethyl-silanyloxy)-cyclohexyloxy]-5-chloro-phenyl}-am-
ide; [0917] 6-methoxy-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
[5-chloro-2-(4-hydroxymethyl-piperidin-1-yl)-phenyl]-amide (white
solid); MS=416 [M+H].sup.+; MP=257.5-258.3.degree. C.; [0918]
(1-{4-chloro-2-[(6-methoxy-pyrazolo[1,5-a]pyrimidine-3-carbonyl)-amino]-p-
henyl}-piperidin-4-ylmethyl)-carbamic acid tert-butyl ester; [0919]
(1-{4-chloro-2-[(6-methoxy-pyrazolo[1,5-a]pyrimidine-3-carbonyl)-amino]-p-
henyl}-piperidin-4-ylmethyl)-carbamic acid tert-butyl ester; [0920]
pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
{5-chloro-2-[3-(1-hydroxy-ethyl)-pyrrolidin-1-yl]-phenyl}-amide
(light yellow solid); MS=386 [M+H].sup.+; MP=175.5-175.9.degree.
C.; [0921] pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
(5-chloro-2-difluoromethoxy-phenyl)-amide (white solid); MS=339
[M+H].sup.+; MP=228.0-230.5.degree. C.; [0922]
[1-(1-{4-chloro-2-[(pyrazolo[1,5-a]pyrimidine-3-carbonyl)-amino]-phenyl}--
pyrrolidin-3-yl)-ethyl]-carbamic acid tert-butyl ester; [0923]
thieno[3,2-d]pyrimidine-7-carboxylic acid
[1-(3-hydroxy-propyl)-1H-benzoimidazol-2-yl]-amide (yellow
foam)(3-(2-amino-benzoimidazol-1-yl)-propan-1-ol was prepared
accordingly to the procedure described in WO03/030902 A1); MS=354
[M+H].sup.+; and [0924] thieno[3,2-d]pyrimidine-7-carboxylic acid
{7-[4-(tert-butyl-dimethyl-silanyloxy)-cyclohexyloxy]-quinolin-6-yl}-amid-
e.
Example 2
Synthesis of
{4-Chloro-2-[(pyrazolo[1,5-a]pyrimidine-3-carbonyl)-amino]-phenoxy}-aceti-
c acid methyl ester
[0925] The synthesis of
{4-chloro-2-[(pyrazolo[1,5-a]pyrimidine-3-carbonyl)-amino]-phenoxy}-aceti-
c acid methyl ester was carried out according to the process shown
in Scheme 54.
##STR00257##
Step A: synthesis of pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
(5-chloro-2-hydroxy-phenyl)-amide
[0926] Pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (0.5 g, 3.06
mmol) was suspended in thionyl chloride (25 mL) and the resulting
mixture was heated at 85.degree. C. for 1.5 hours. The volatiles
were then evaporated under high vacuum and the residue was
suspended in pyridine (25 mL). 2-Amino-4-chlorophenol (0.46 g, 3.2
mmol) was added and the resulting mixture was heated at reflux
overnight. The volatiles were then evaporated under high vacuum,
water and dichloromethane were added to the residue and the mixture
was evaporated under reduced pressure. The solid residue was washed
with a mixture of dichloromethane and methanol (96/4) to give 0.588
g (67% yield) of pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
(5-chloro-2-hydroxy-phenyl)-amide in mixture with
pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
4-chloro-2-[(pyrazolo[1,5-a]pyrimidine-3-carbonyl)-amino]-phenyl
ester.
Step B: synthesis of
{4-chloro-2-[(pyrazolo[1,5-a]pyrimidine-3-carbonyl)-amino]-phenoxy}-aceti-
c acid methyl ester
[0927] To a solution of pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
(5-chloro-2-hydroxy-phenyl)-amide (200 mg, 0.693 mmol) in anhydrous
N,N-dimethylformamide (15 mL), was added potassium carbonate (1.0
g, 7.2 mmol) followed by methyl bromoacetate (0.2 mL, 2.11 mmol)
and the resulting mixture was heated at 60.degree. C. for 6 hours.
The reaction mixture was cooled to room temperature and partitioned
between water and ethyl acetate; the organic layer was separated
and washed with water and brine, dried over anhydrous sodium
sulfate, filtered and evaporated under reduced pressure. The crude
residue was purified twice by flash chromatography
(DCM/MeOH/NH.sub.4OH and hexane/EtOAc) to give 80 mg of a brown
solid. This material was washed with acetonitrile, diethyl ether
and ethyl acetate to afford 28 mg of
{4-chloro-2-[(pyrazolo[1,5-a]pyrimidine-3-carbonyl)-amino]-phenoxy}-aceti-
c acid methyl ester as a light pink powder. MS=361 [M+H].sup.+.
[0928] Pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
[2-(3-hydroxy-benzyloxy)-phenyl]-amide was prepared utilizing the
above described procedure and the appropriate starting
materials.
Example 3
Synthesis of Pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
(4-carbamoyl-2-methoxy-phenyl)-amide
[0929] The synthesis of pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
(4-carbamoyl-2-methoxy-phenyl)-amide was carried out according to
the process shown in Scheme 55.
##STR00258##
[0930] A mixture of
3-methoxy-4-[(pyrazolo[1,5-a]pyrimidine-3-carbonyl)-amino]-benzoic
acid methyl ester (5 mg) and an aqueous solution of ammonium
hydroxide (concentrated, 1 mL) and a mixture of
3-methoxy-4-[(pyrazolo[1,5-a]pyrimidine-3-carbonyl)-amino]-benzoic
acid methyl ester (5 mg) and a solution of ammonia (2 M in MeOH, 1
mL) were stirred at room temperature for 2 days. The two mixtures
were then combined and dimethyl sulfoxide (1 mL) was added followed
by acetonitrile (1 mL). A solution of ammonia (2 M in MeOH, 1 mL)
and an aqueous solution of ammonium hydroxide (concentrated, 2 mL)
were then added and the resulting mixture was heated to 50.degree.
C. for 24 hours. A second portion of
3-methoxy-4-[(pyrazolo[1,5-a]pyrimidine-3-carbonyl)-amino]-benzoic
acid methyl ester (35 mg) was added followed by dimethyl sulfoxide
(5 mL), acetonitrile (5 mL), a solution of ammonia (2 M in MeOH, 5
mL) and an aqueous solution of ammonium hydroxide (concentrated, 5
mL) and the resulting mixture was heated to 85.degree. C. for 3
days. The white precipitate which formed was collected by
filtration, washed with water, methanol and diethyl ether to afford
after drying 15 mg (35% yield) of
pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
(4-carbamoyl-2-methoxy-phenyl)-amide as light yellow solid. MS=312
[M+H].sup.+.
Example 4
Synthesis of Pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
(2-methoxy-4-methoxymethyl-phenyl)-amide
[0931] The synthesis of pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
(2-methoxy-4-methoxymethyl-phenyl)-amide was carried out according
to the process shown in Scheme 56.
##STR00259##
[0932] A solution of hydrochloric acid (1 M in Et.sub.2O, 2 mL) was
added to a solution of pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
[4-(tert-butyl-dimethyl-silanyloxymethyl)-2-methoxy-phenyl]-amide
(160 mg, 0.388 mmol) in dichloromethane (20 mL) and the resulting
mixture was stirred at room temperature for 10 minutes. A second
aliquot of solution of hydrochloric acid (1 M in Et.sub.2O, 2 mL)
was added and the reaction mixture was stirred for 1 hour. The
resulting mixture was evaporated under reduced pressure and the
yellow solid residue was washed with hexane, ethyl acetate, diethyl
ether and dichloromethane. The solid and the filtrate were then
combined and partitioned between dichloromethane and aqueous
solution of sodium bicarbonate (5%). The organic layer was
separated and the aqueous layer was extracted 3 times with
dichloromethane. The combined organic extracts were washed with
brine, dried over anhydrous sodium sulfate, filtered and evaporated
under reduced pressure. The yellow solid residue was purified by
flash chromatography (DCM/MeOH/NH.sub.4OH) to give 80 mg of
pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
(2-methoxy-4-methoxymethyl-phenyl)-amide and 40 mg of
pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
(4-hydroxymethyl-2-methoxy-phenyl)-amide.
Pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
(2-methoxy-4-methoxymethyl-phenyl)-amide compound was repurified by
preparative TLC (DCM/MeOH/NH.sub.4OH) and was washed with diethyl
ether and hexane to give, after drying in a vacuum oven, 64 mg of
as a white solid. MS=313 [M+H].sup.+.
Example 5
Synthesis of Pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
(4-hydroxymethyl-2-methoxy-phenyl)-amide
[0933] The synthesis of pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
(4-hydroxymethyl-2-methoxy-phenyl)-amide was carried out according
to the process shown in Scheme 57.
##STR00260##
[0934] A solution of hydrochloric acid (1 M in Et.sub.2O, 3 mL) was
added to a solution of pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
[4-(tert-butyl-dimethyl-silanyloxymethyl)-2-methoxy-phenyl]-amide
(150 mg, 0.364 mmol) in dichloromethane (20 mL) and the resulting
mixture was stirred at room temperature for 2 hours. Ice and water
were then added and the pH of the mixture was neutralized by
addition of an aqueous solution of sodium hydroxide (5%). The
resulting mixture was extracted 3 times with dichloromethane. The
combined organic extracts were washed with brine, dried over
anhydrous sodium sulfate, filtered and evaporated under reduced
pressure. The crude residue was purified by flash chromatography
and by preparative TLC to give a yellow solid which was washed with
water, methanol, dichloromethane, hexane and diethyl ether to give
after drying pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
(4-hydroxymethyl-2-methoxy-phenyl)-amide as a light yellow solid.
MS=299 [M+H].sup.+.
[0935] Utilizing the above described procedure and the appropriate
starting materials, the following compounds were prepared: [0936]
pyrazolo[1,5-a]pyrimidine-3,6-dicarboxylic acid 6-amide
3-{[5-chloro-2-(4-hydroxy-cyclohexyloxy)-phenyl]-amide} (yellow
powder); MS=430 [M+H].sup.+; [0937]
pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
(4-chloro-3'-hydroxy-biphenyl-2-yl)-amide (off-white powder);
MS=365 [M+H].sup.+; [0938] pyrazolo[1,5-a]pyrimidine-3-carboxylic
acid [7-(4-hydroxy-cyclohexyloxy)-quinolin-6-yl]-amide (white
powder); MS=404 [M+H].sup.+; MP=273.8-275.1.degree. C.; [0939]
pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
(4-chloro-4'-hydroxy-biphenyl-2-yl)-amide (light yellow powder);
MS=365 [M+H].sup.+; [0940]
pyrazolo[1,5-a]pyrimidine-3,6-dicarboxylic acid 6-amide
3-{[5-chloro-2-(4-cis-hydroxy-cyclohexyloxy)-phenyl]-amide} (yellow
powder); MS=430 [M+H].sup.+; [0941]
thieno[3,2-d]pyrimidine-7-carboxylic acid
[7-((1R,3R)-3-hydroxy-cyclopentyloxy)-quinolin-6-yl]-amide
hydrochloride (light yellow powder); MS=407 [M+H].sup.+; [0942]
thieno[3,2-d]pyrimidine-7-carboxylic acid
[7-((1R,3S)-3-hydroxy-cyclopentyloxy)-quinolin-6-yl]-amide
hydrochloride salt (light yellow powder); MS=407 [M+H].sup.+;
[0943] thieno[3,2-d]pyrimidine-7-carboxylic acid
[7-(3-hydroxy-1-methyl-butoxy)-quinolin-6-yl]-amide
bishydrochloride salt (off-white powder); MS=409 [M+H].sup.+;
[0944] thieno[3,2-d]pyrimidine-7-carboxylic acid
[5-chloro-2-(3-hydroxy-cyclopentyloxy)-phenyl]-amide hydrochloride
salt (yellow powder); MS=390 [M+H].sup.+; MP=220.0-221.5.degree.
C.; [0945] thieno[3,2-d]pyrimidine-7-carboxylic acid
[5-chloro-2-(3-hydroxy-propoxy)-phenyl]-amide hydrochloride salt
(yellow powder); MS=364 [M+H].sup.+; MP=215.5-218.0.degree. C.;
[0946] pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
[4-(2-hydroxy-ethylcarbamoyl)-2-methoxy-phenyl]-amide (brown
powder); MS=356 [M+H].sup.+; MP=267.5-268.5.degree. C.; [0947]
thieno[3,2-d]pyrimidine-7-carboxylic acid
[4-(2-hydroxy-ethylcarbamoyl)-2-methoxy-phenyl]-amide hydrochloride
(yellow powder); MS=373 [M+H].sup.+; MP=223-226.degree. C.; [0948]
thieno[3,2-d]pyrimidine-7-carboxylic acid
[4-(3-hydroxy-propylcarbamoyl)-2-methoxy-phenyl]-amide (white
powder); MS=387 [M+H].sup.+; MP=229.3-229.8.degree. C.; [0949]
pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
[4-(3-hydroxy-propylcarbamoyl)-2-methoxy-phenyl]-amide (white
powder); MS=370 [M+H].sup.+; MP=230.8-232.3.degree. C.; [0950]
pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
[5-chloro-2-(3-hydroxy-propoxy)-phenyl]-amide (white powder);
MS=347 [M+H].sup.+; [0951] pyrazolo[1,5-a]pyrimidine-3-carboxylic
acid [5-chloro-2-(2-hydroxy-ethoxy)-phenyl]-amide (white powder);
MS=333 [M+H].sup.+; [0952] thieno[3,2-d]pyrimidine-7-carboxylic
acid [7-(4-hydroxy-cyclohexyloxy)-quinolin-6-yl]-amide (off-white
powder); MS=421 [M+H].sup.+; [0953]
thieno[3,2-d]pyrimidine-7-carboxylic acid
[7-(3-hydroxy-propoxy)-quinolin-6-yl]-amide hydrochloride (yellow
crystalline solid); MS=381 [M+H].sup.+; MP=269.9-271.0.degree. C.;
[0954] cis-thieno[3,2-d]pyrimidine-7-carboxylic acid
[7-(4-hydroxy-cyclohexyloxy)-quinolin-6-yl]-amide hydrochloride
(white powder); MS=421 [M+H].sup.+; MP=281.1-283.6.degree. C.;
[0955] 6-(2-hydroxy-ethyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic
acid [5-chloro-2-(4-hydroxy-cyclohexyloxy)-phenyl]-amide (light
yellow powder); MS=431 [M+H].sup.+; [0956]
pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
{5-chloro-2-[4-(1-hydroxy-ethyl)-piperidin-1-yl]-phenyl}-amide
(off-white powder); MS=400 [M+H].sup.+; MP=180.6-181.8.degree. C.;
[0957] 6-methoxy-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
[5-chloro-2-(4-hydroxy-cyclohexyloxy)-phenyl]-amide (off-white
solid); MS=417 [M+H].sup.+; MP=258.9-260.7.degree. C.; [0958]
6-bromo-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
[5-chloro-2-(4-hydroxy-cyclohexyloxy)-phenyl]-amide (off-white
solid); MS=465 [M+H].sup.+; MP=289.4-290.8.degree. C.; [0959]
[1,2,4]triazolo[4,3-a]pyridine-8-carboxylic acid
[5-chloro-2-(4-hydroxy-cyclohexyloxy)-phenyl]-amide (yellow solid);
MS=387 [M+H].sup.+; MP=216.3-217.3.degree. C.; [0960]
6-hydroxy-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
[5-chloro-2-(4-hydroxy-cyclohexyloxy)-phenyl]-amide (yellow solid);
MS=403 [M+H].sup.+; and [0961] thieno[3,2-d]pyrimidine-7-carboxylic
acid [7-(4-hydroxy-cyclohexyloxy)-quinolin-6-yl]-amide
hydrochloride (off-white powder); MS=421 [M+H].sup.+.
Example 6
Synthesis of 6-hydroxymethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic
acid [5-chloro-2-(4-hydroxy-cyclohexyloxy)-phenyl]-amide
[0962] The synthesis of
6-hydroxymethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
[5-chloro-2-(4-hydroxy-cyclohexyloxy)-phenyl]-amide was carried out
according to the process shown in Scheme 58.
##STR00261##
Step A: synthesis of
6-hydroxymethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
{2-[4-(tert-butyl-dimethyl-silanyloxy)-cyclohexyloxy]-5-chloro-phenyl}-am-
ide
[0963] Sodium borohydride (30 mg, 0.079 mmol) was added to a
solution of 6-formyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
{2-[4-(tert-butyl-dimethyl-silanyloxy)-cyclohexyloxy]-5-chloro-phenyl}-am-
ide (20 mg, 0.038 mmol) in a mixture of tetrahydrofuran (1.5 mL)
and water (0.1 mL) and the resulting mixture was stirred at room
temperature for 2.5 hours. The solvent was evaporated under reduced
pressure to give
6-hydroxymethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
{2-[4-(tert-butyl-dimethyl-silanyloxy)-cyclohexyloxy]-5-chloro-phenyl}-am-
ide as an oily residue.
Step B: synthesis of
6-hydroxymethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
[5-chloro-2-(4-hydroxy-cyclohexyloxy)-phenyl]-amide
[0964] 6-Hydroxymethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
{2-[4-(tert-butyl-dimethyl-silanyloxy)-cyclohexyloxy]-5-chloro-phenyl}-am-
ide was deprotected as described in Example 5 to give
6-hydroxymethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
[5-chloro-2-(4-hydroxy-cyclohexyloxy)-phenyl]-amide as a yellow
powder. MS=417 [M+H].sup.+.
Example 7
Synthesis of Pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
[5-chloro-2-(3-hydroxy-benzyloxy)-phenyl]-amide
[0965] The synthesis of pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
[5-chloro-2-(3-hydroxy-benzyloxy)-phenyl]-amide was carried out
according to the process shown in Scheme 59.
##STR00262##
[0966] An aqueous solution of sodium hydroxide (2 M, 0.14 mL, 0.28
mmol) was added to a suspension of
pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
[2-(3-hydroxy-benzyloxy)-phenyl]-amide (70 mg, 0.14 mmol) in a
mixture of ethanol and water (1/1, 6 mL) and the resulting mixture
was stirred at room temperature for 1 hour. The reaction mixture
was heated at 60.degree. C. for 1.5 hours, and then was evaporated
under reduced pressure. The residue was acidified (pH 5) by
addition of an aqueous solution of hydrochloric acid (1 M) and was
extracted with dichloromethane (50 mL). The organic layer was
separated, dried over anhydrous sodium sulfate, filtered and
evaporated under reduced pressure. The crude residue was purified
by preparative TLC (DCM/MeOH, 96/4) to afford
pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
[5-chloro-2-(3-hydroxy-benzyloxy)-phenyl]-amide as a white solid.
MS=395.
Example 8
Synthesis of Thieno[3,2-d]pyrimidine-7-carboxylic acid
[5-chloro-2-(4-methylaminomethyl-piperidin-1-yl)-phenyl]-amide
[0967] The synthesis of thieno[3,2-d]pyrimidine-7-carboxylic acid
[5-chloro-2-(4-methylaminomethyl-piperidin-1-yl)-phenyl]-amide was
carried out according to the process shown in Scheme 60.
##STR00263##
[0968] To a suspension of thieno[3,2-d]pyrimidine-7-carboxylic acid
[2-(4-aminomethyl-piperidin-1-yl)-5-chloro-phenyl]-amide (70 mg,
0.17 mmol) in water (1 mL) was added formic acid (22 .mu.L, 0.59
mmol) followed by formaldehyde (36% water solution, 0.4 mL) and the
resulting mixture was stirred at room temperature overnight. The
reaction mixture was basified by addition of an aqueous solution of
sodium hydroxide (2 M) until pH 14 and was then extracted with
dichloromethane. The organic layer was separated, dried over
anhydrous sodium sulfate, filtered and evaporated under reduced
pressure. The crude residue was purified several times by
preparative TLC (DCM/MeOH+NH.sub.4OH, 93/7+0.5) to give 25 mg of
thieno[3,2-d]pyrimidine-7-carboxylic acid
[5-chloro-2-(4-methylaminomethyl-piperidin-1-yl)-phenyl]-amide as a
light yellow solid; MS=416 [M+H].sup.+; MP=190.0-193.3.degree. C.;
and 3 mg of thieno[3,2-d]pyrimidine-7-carboxylic acid
[5-chloro-2-(4-dimethylaminomethyl-piperidin-1-yl)-phenyl]-amide as
a white powder; MS=430 [M+H].sup.+.
[0969] Utilizing the above described procedure and the appropriate
starting materials, the following compounds were prepared: [0970]
pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
[5-chloro-2-(4-dimethylaminomethyl-piperidin-1-yl)-phenyl]-amide
(white powder); MS=413 [M+H].sup.+; and [0971]
pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
[5-chloro-2-(4-methylaminomethyl-piperidin-1-yl)-phenyl]-amide
(light yellow powder); MS=399 [M+H].sup.+; MP=139.0-146.5.degree.
C.
Example 9
Synthesis of 7-Methyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
[5-chloro-2-(4-hydroxy-cyclohexyloxy)-phenyl]-amide
[0972] The synthesis of
7-methyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
[5-chloro-2-(4-hydroxy-cyclohexyloxy)-phenyl]-amide was carried out
according to the process shown in Scheme 61.
##STR00264##
[0973] Hydrochloric acid (concentrated, 5 drops) was added to a
solution of 7-methyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
{2-[4-(tert-butyl-dimethyl-silanyloxy)-cyclohexyloxy]-5-chloro-phenyl}-am-
ide (ca. 0.22 mmol) in methanol (3 mL) and the resulting mixture
was heated at 80.degree. C. for 30 minutes. The resulting mixture
was cooled, basified by addition of an aqueous solution of sodium
hydroxide (4 M, few drops) and evaporated under reduced pressure.
The crude residue was purified by flash chromatography to give 28
mg of 7-methyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
[5-chloro-2-(4-hydroxy-cyclohexyloxy)-phenyl]-amide (off-white
solid). MS=401 [M+H].sup.+.
[0974] 5-Methyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
[5-chloro-2-(4-hydroxy-cyclohexyloxy)-phenyl]-amide (white solid)
was prepared utilizing the above described procedure and the
appropriate starting materials; MS=401 [M+H].sup.+;
MP=179-182.degree. C.
Example 10
Synthesis of Pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
[5-((E)-3-hydroxy-propenyl)-2-methoxy-phenyl]-amide
[0975] The synthesis of pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
[5-((E)-3-hydroxy-propenyl)-2-methoxy-phenyl]-amide was carried out
according to the process shown in Scheme 62.
##STR00265##
[0976] A mixture of diisopropylethylamine (0.25 mL),
(E)-3-(3-amino-4-methoxy-phenyl)-prop-2-en-1-ol (90 mg),
pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (65 mg), HOBT (85 mg)
and HBTU (0.20 g) in anhydrous acetonitrile (5 mL) was heated to
80.degree. C. overnight. The resulting mixture was evaporated under
reduced pressure and the residue was partitioned between ethyl
acetate and water. The organic layer was separated, washed with
brine, dried over anhydrous sodium sulfate, filtered and evaporated
under reduced pressure. The crude residue was purified by flash
chromatography (MeOH/EtOAc, 3/97) to give an oil. This residue was
triturated with ethyl acetate to give, upon standing for 1 hour, 20
mg of (E)-3-(3-amino-4-methoxy-phenyl)-prop-2-en-1-ol as a light
brown solid which was collected by filtration. MS=325
[M+H].sup.+.
Example 11
Synthesis of Pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
[2-(4-aminomethyl-piperidin-1-yl)-5-chloro-phenyl]-amide
[0977] The synthesis of pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
[2-(4-aminomethyl-piperidin-1-yl)-5-chloro-phenyl]-amide was
carried out according to the process shown in Scheme 63.
##STR00266##
[0978] Trifluoroacetic acid (1 mL) was added to a solution of
(1-{4-chloro-2-[(pyrazolo[1,5-a]pyrimidine-3-carbonyl)-amino]-phenyl}-pip-
eridin-4-ylmethyl)-carbamic acid tert-butyl ester (80 mg) in
dichloromethane (2 mL) and the reaction mixture was stirred at room
temperature for 2 hours. The resulting mixture was evaporated under
reduced pressure and the residue was dissolved in dichloremethane,
carbonate resin (2.8 mmol/g, 200 mg) was added and the mixture was
stirred overnight. The solid was filtered off and the filtrate was
evaporated under reduced pressure, the residue was purified by
flash chromatography (DCM/MeOH/NH.sub.4OH) to give 40 mg of a foam.
This material was triturated with a mixture of ethyl acetate and
hexane (1/1), the solid was collected by filtration, dissolved in a
mixture of dichloromethane and methanol and the mixture was
evaporated under reduced pressure to give 20 mg of
pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
[2-(4-aminomethyl-piperidin-1-yl)-5-chloro-phenyl]-amide as a light
yellow foam. MS=385 [M+H].sup.+.
[0979] The following compounds were prepared utilizing the above
described procedure and the appropriate starting materials: [0980]
pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
[2-(3-aminomethyl-pyrrolidin-1-yl)-5-chloro-phenyl]-amide (light
yellow waxy solid) (the trifluorocetate salt was neutralized by
treatment with an aqueous solution of sodium hydroxide (2 M));
MS=371 [M+H].sup.+; [0981] thieno[3,2-d]pyrimidine-7-carboxylic
acid [2-(4-aminomethyl-piperidin-1-yl)-5-chloro-phenyl]-amide
(orange foam); MS=403 [M+H].sup.+; [0982]
thieno[3,2-b]pyridine-3-carboxylic acid
[2-(4-aminomethyl-piperidin-1-yl)-5-chloro-phenyl]-amide (pink
foam); MS=401 [M+H].sup.+; [0983]
thieno[3,2-d]pyrimidine-7-carboxylic acid
[5-chloro-2-(piperidin-4-yloxy)-phenyl]-amide trifluoroacetate
(off-white solid); MS=389 [M+H].sup.+; MP>300.degree. C.; [0984]
thieno[3,2-b]pyridine-3-carboxylic acid
[7-(4-aminomethyl-piperidin-1-yl)-quinolin-6-yl]-amide (off-white
solid); MS=418 [M+H].sup.+; [0985]
pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
[2-(4-aminomethyl-piperidin-1-yl)-5-chloro-phenyl]-amide
trifluoroacetate (white solid); MS=385 [M+H].sup.+;
MP=110.0-112.1.degree. C.; and [0986]
6-methoxy-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
[2-(4-aminomethyl-piperidin-1-yl)-5-chloro-phenyl]-amide (light
yellow solid); MS=415 [M+H].sup.+; MP=210.0-214.4.degree. C.
Example 12
Synthesis of 2-Isopropylamino-thieno[3,2-d]pyrimidine-7-carboxylic
acid (7-methoxy-quinolin-6-yl)-amide
[0987] The synthesis of
2-isopropylamino-thieno[3,2-d]pyrimidine-7-carboxylic acid
(7-methoxy-quinolin-6-yl)-amide was carried out according to the
process shown in Scheme 64.
[0988] A mixture of 2-chloro-thieno[3,2-d]pyrimidine-7-carboxylic
acid (7-methoxy-quinolin-6-yl)-amide (200 mg) and isopropylamine
(200 .mu.L) in 1,4-dioxane (5 mL) was heated at 100.degree. C. for
20 hours. The reaction mixture was then cooled and the solid which
crushed out was collected by filtration, washed with water and
ethyl acetate. The filtrate was washed with water and brine, dried
over anhydrous sodium sulfate, filtered and evaporated under
reduced pressure. The crude residue was purified by flash
chromatography (Acetone/DCM) to give combined with the previously
obtained solid 137 mg of
2-isopropylamino-thieno[3,2-d]pyrimidine-7-carboxylic acid
(7-methoxy-quinolin-6-yl)-amide after drying under vacuum at
60.degree. C. MS=394 [M+H].sup.+; MP=221.4-222.7.degree. C.
[0989] Utilizing the above described procedure and the appropriate
starting materials, the following compounds were prepared: [0990]
5-(2-hydroxy-ethylamino)-thieno[3,2-b]pyridine-3-carboxylic acid
(5-chloro-2-methoxy-phenyl)-amide (orange semisolid); MS=378
[M+H].sup.+; [0991]
2-(2-hydroxy-ethylamino)-thieno[3,2-d]pyrimidine-7-carboxylic acid
(5-chloro-2-methoxy-phenyl)-amide (yellow powder); MS=379
[M+H].sup.+; [0992]
2-(3-hydroxy-propylamino)-thieno[3,2-d]pyrimidine-7-carboxylic acid
(5-chloro-2-methoxy-phenyl)-amide (light yellow powder); MS=393
[M+H].sup.+; MP=178.0-181.0.degree. C.; [0993]
2-(2-hydroxy-ethylamino)-thieno[3,2-d]pyrimidine-7-carboxylic acid
quinolin-6-ylamide (light yellow solid); MS=366 [M+H].sup.+;
MP>300.degree. C.; [0994]
2-[(2-hydroxy-ethyl)-methyl-amino]-thieno[3,2-d]pyrimidine-7-carboxylic
acid (5-chloro-2-methoxy-phenyl)-amide (yellow solid); MS=393
[M+H].sup.+; MP=185.0-188.0.degree. C.; [0995]
2-(2-hydroxy-ethylamino)-thieno[3,2-d]pyrimidine-7-carboxylic acid
(7-methoxy-quinolin-6-yl)-amide (light yellow solid); MS=396
[M+H].sup.+; MP=227.0-229.0.degree. C.; [0996]
2-((S)-1-hydroxymethyl-propylamino)-thieno[3,2-d]pyrimidine-7-carboxylic
acid (5-chloro-2-methoxy-phenyl)-amide (light yellow solid); MS=407
[M+H].sup.+; MP=195.5-197.0.degree. C.; [0997]
2-[(2-hydroxy-ethyl)-methyl-amino]-thieno[3,2-d]pyrimidine-7-carboxylic
acid (7-methoxy-quinolin-6-yl)-amide (light yellow powder); MS=410
[M+H].sup.+; MP=205.0-207.0.degree. C.; [0998]
2-cyclopropylamino-thieno[3,2-d]pyrimidine-7-carboxylic acid
(7-methoxy-quinolin-6-yl)-amide (yellow solid); MS=392 [M+H].sup.+;
MP=256.6-260.1.degree. C.; [0999]
2-[(2-hydroxy-ethyl)-isopropyl-amino]-thieno[3,2-d]pyrimidine-7-carboxyli-
c acid (7-methoxy-quinolin-6-yl)-amide (light yellow solid); MS=438
[M+H].sup.+; [1000]
2-(2,3-dihydroxy-propylamino)-thieno[3,2-d]pyrimidine-7-carboxylic
acid (7-methoxy-quinolin-6-yl)-amide (purple solid); MS=426
[M+H].sup.+; [1001]
2-isopropylamino-thieno[3,2-d]pyrimidine-7-carboxylic acid
(7-methoxy-quinolin-6-yl)-amide (yellow solid); MS=394 [M+H].sup.+;
[1002]
2-(isopropyl-methyl-amino)-thieno[3,2-d]pyrimidine-7-carboxylic
acid (7-methoxy-quinolin-6-yl)-amide (off-white solid); MS=408
[M+H].sup.+; [1003]
2-isobutylamino-thieno[3,2-d]pyrimidine-7-carboxylic acid
(7-methoxy-quinolin-6-yl)-amide (yellow solid); MS=408 [M+H].sup.+;
MP=194.4-198.9.degree. C.; [1004]
2-isopropylamino-thieno[3,2-d]pyrimidine-7-carboxylic acid
[5-chloro-2-(4-hydroxy-cyclohexyloxy)-phenyl]-amide (off-white
solid); MS=460 [M].sup.+; MP=112.9-113.9.degree. C.; [1005]
2-((R)-2-hydroxy-1-methyl-ethylamino)-thieno[3,2-d]pyrimidine-7-carboxyli-
c acid (7-methoxy-quinolin-6-yl)-amide (light yellow solid); MS=410
[M+H].sup.+; [1006]
2-(2-amino-ethylamino)-thieno[3,2-d]pyrimidine-7-carboxylic acid
(5-chloro-2-methoxy-phenyl)-amide (white solid); MS=378
[M+H].sup.+; [1007]
2-(2-acetylamino-ethylamino)-thieno[3,2-d]pyrimidine-7-carboxylic
acid (5-chloro-2-methoxy-phenyl)-amide (light yellow solid); MS=420
[M+H].sup.+; MP=238.0-240.9.degree. C.; [1008]
2-[(2-amino-ethyl)-methyl-amino]-thieno[3,2-d]pyrimidine-7-carboxylic
acid (5-chloro-2-methoxy-phenyl)-amide (off-white solid); MS=392
[M+H].sup.+; MP=144.0-147.6.degree. C.; [1009]
2-[(2-amino-ethyl)-methyl-amino]-thieno[3,2-d]pyrimidine-7-carboxylic
acid (7-methoxy-quinolin-6-yl)-amide (light brown solid); MS=409
[M+H].sup.+; MP=195.0-197.0.degree. C.; [1010]
2-(3-amino-propylamino)-thieno[3,2-d]pyrimidine-7-carboxylic acid
(7-methoxy-quinolin-6-yl)-amide (off-white solid); MS=409
[M+H].sup.+; and [1011]
2-(2-amino-ethylamino)-thieno[3,2-d]pyrimidine-7-carboxylic acid
(7-methoxy-quinolin-6-yl)-amide (orange solid); MS=395
[M+H].sup.+.
Example 13
Synthesis of 6-Hydroxymethyl-thieno[3,2-b]pyridine-3-carboxylic
acid (7-methoxy-quinolin-6-yl)-amide
[1012] The synthesis of
6-hydroxymethyl-thieno[3,2-b]pyridine-3-carboxylic acid
(7-methoxy-quinolin-6-yl)-amide was carried out according to the
process shown in Scheme 65.
##STR00267##
[1013] A solution of lithium aluminum hydride (3.5 M in toluene,
0.1 mL) was added to a suspension of
3-(7-methoxy-quinolin-6-ylcarbamoyl)-thieno[3,2-b]pyridine-6-carboxylic
acid ethyl ester (30 mg) in tetrahydrofuran (2 mL) and the
resulting orange solution was stirred for 10 minutes. The reaction
mixture was then quenched by addition of a saturated aqueous
solution of ammonium chloride. The resulting mixture was filtered
through a CELITE.TM. pad and the filter cake was washed with ethyl
acetate. The filtrate was separated and the organic layer was dried
over anhydrous sodium sulfate, filtered and evaporated under
reduced pressure. The crude residue was purified by flash
chromatography (DCM/MeOH, 97/3) to give 8 mg of
6-hydroxymethyl-thieno[3,2-b]pyridine-3-carboxylic acid
(7-methoxy-quinolin-6-yl)-amide as an off-white solid. MS=365
[M+H].sup.+.
Example 14
Synthesis of 6-Hydroxy-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
[7-(4-aminomethyl-piperidin-1-yl)-quinolin-6-yl]-amide
hydrochloride
[1014] The synthesis of
6-hydroxy-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
[7-(4-aminomethyl-piperidin-1-yl)-quinolin-6-yl]-amide
hydrochloride was carried out according to the process shown in
Scheme 66.
##STR00268## ##STR00269##
Step A: synthesis of
(1-{6-[(6-benzyloxy-pyrazolo[1,5-a]pyrimidine-3-carbonyl)-amino]-quinolin-
-7-yl}-piperidin-4-ylmethyl)-carbamic acid tert-butyl ester
[1015] Thionyl chloride (0.27 mL, 3.7 mmol) was added to
6-benzyloxy-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (0.25 g,
0.94 mmol) at room temperature and the resulting mixture was
stirred until a clear solution was obtained. The reaction mixture
was concentrated under reduced pressure, to the residue was added
dichloromethane (10 mL) followed by a solution of
[1-(6-amino-quinolin-7-yl)-piperidin-4-ylmethyl]-carbamic acid
tert-butyl ester (0.33 g, 0.94 mmol) and diisopropylethylamine
(0.16 mL, 0.94 mmol) in dichloromethane (2 mL) at 0.degree. C. and
the resulting mixture was stirred at room temperature overnight.
The reaction mixture was heated at 60.degree. C. for 6 hours and
then was partitioned between water and dichloromethane. The organic
layer was separated, dried over anhydrous sodium sulfate, filtered
and evaporated under reduced pressure. The residue was purified by
flash chromatography (EtOAc/hexane, 1/1) to afford 0.420 g of
(1-{6-[(6-benzyloxy-pyrazolo[1,5-a]pyrimidine-3-carbonyl)-amino]-quinolin-
-7-yl}-piperidin-4-ylmethyl)-carbamic acid tert-butyl ester as a
solid.
Step B: synthesis of
(1-{6-[(6-hydroxy-pyrazolo[1,5-a]pyrimidine-3-carbonyl)-amino]-quinolin-7-
-yl}-piperidin-4-ylmethyl)-carbamic acid tert-butyl ester
[1016] A mixture of
(1-{6-[(6-benzyloxy-pyrazolo[1,5-a]pyrimidine-3-carbonyl)-amino]-quinolin-
-7-yl}-piperidin-4-ylmethyl)-carbamic acid tert-butyl ester (0.4 g)
and palladium on carbon (10%, 50 mg) in ethanol (20 mL) was stirred
under hydrogen atmosphere (balloon pressure) for 2 days. The
resulting mixture was filtered over a CELITE.TM. pad and the
filtrate was evaporated under reduced pressure. The crude residue
was purified by flash chromatography to afford 0.220 g of
(1-{6-[(6-hydroxy-pyrazolo[1,5-a]pyrimidine-3-carbonyl)-amino]-quinolin-7-
-yl}-piperidin-4-ylmethyl)-carbamic acid tert-butyl ester as a
yellow solid.
[1017] Utilizing the above described procedure and the appropriate
starting materials, the following compounds were prepared: [1018]
6-hydroxy-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
(7-methoxy-quinolin-6-yl)-amide (light yellow powder); MS=336
[M+H].sup.+; MP=265-268.degree. C.; and [1019]
6-hydroxy-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
[5-chloro-2-(4-hydroxymethyl-piperidin-1-yl)-phenyl]-amide
(off-white powder); MS=402 [M+H].sup.+.
Step C: synthesis of
6-hydroxy-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
[7-(4-aminomethyl-piperidin-1-yl)-quinolin-6-yl]-amide
hydrochloride
[1020] A solution of hydrochloric acid (1 M in Et.sub.2O, 5 mL) was
added to a solution of
(1-{6-[(6-hydroxy-pyrazolo[1,5-a]pyrimidine-3-carbonyl)-amino]-quinolin-7-
-yl}-piperidin-4-ylmethyl)-carbamic acid tert-butyl ester (0.22 g)
in a mixture of dichloromethane and methanol (1/1, 10 mL) and the
resulting mixture was stirred at room temperature overnight. The
solid formed was collected by filtration, washed with ethanol and
dried under reduced pressure to give 224 mg of
6-hydroxy-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
[7-(4-aminomethyl-piperidin-1-yl)-quinolin-6-yl]-amide
hydrochloride as a light yellow powder. MS=418 [M+H].sup.+;
MP>300.degree. C.
[1021] 6-Hydroxy-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
[2-(4-aminomethyl-piperidin-1-yl)-5-chloro-phenyl]-amide
bishydrochloride (white powder) was prepared utilizing the above
described procedure and the appropriate starting materials; Step A
was performed as described in Example 1. MS=401 [M+H].sup.+;
MP=285.0-288.0.degree. C.
Example 15
Synthesis of Pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
[5-chloro-2-(piperidin-4-yloxy)-phenyl]-amide hydrochloride
[1022] The synthesis of pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
[5-chloro-2-(piperidin-4-yloxy)-phenyl]-amide hydrochloride was
carried out according to the process shown in Scheme 67.
##STR00270##
[1023] A solution of hydrochloric acid (1 M in E.sub.2O, 10 mL) was
added, at room temperature, to a solution of
4-{4-chloro-2-[(pyrazolo[1,5-a]pyrimidine-3-carbonyl)-amino]-phenoxy}-pip-
eridine-1-carboxylic acid tert-butyl ester (0.2 g, 0.424 mmol) in
dichloromethane (5 mL) and the resulting mixture was stirred at
room temperature for 60 hours. The solid formed was collected by
filtration and washed once with dichloromethane, 3 times with
methanol, once again with dichloromethane and once with hexane,
then was dried in a vacuum oven at 60.degree. C. to afford 125 mg
(72% yield) of pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
[5-chloro-2-(piperidin-4-yloxy)-phenyl]-amide hydrochloride salt as
an off-white solid. MS=372 [M+H].sup.+.
[1024] Utilizing the above described procedure and the appropriate
starting materials, the following compounds were prepared: [1025]
pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
[2-(4-aminomethyl-piperidin-1-yl)-4-phenylcarbamoyl-phenyl]-amide
bishydrochloride (light yellow powder); MS=470 [M+H].sup.+; [1026]
pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
[3-amino-2-(4-aminomethyl-piperidin-1-yl)-phenyl]-amide
trihydrochloride (off-white powder); MS=366 [M+H].sup.+; [1027]
pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
[2-(4-amino-piperidin-1-yl)-5-chloro-phenyl]-amide (off-white
powder); MS=371 [M+H].sup.+; MP=213.5-232.4.degree. C.; [1028]
pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
(4'-aminomethyl-4-chloro-biphenyl-2-yl)-amide hydrochloride (white
powder); MS=378 [M+H].sup.+; MP=286.1-288.7.degree. C.; [1029]
pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
[7-(4-aminomethyl-piperidin-1-yl)-quinolin-6-yl]-amide bis
hydrochloride (light yellow powder); MS=402 [M+H].sup.+;
MP=197.0-198.0.degree. C.; [1030]
thieno[3,2-d]pyrimidine-7-carboxylic acid
[7-(4-aminomethyl-piperidin-1-yl)-quinolin-6-yl]-amide
hydrochloride (yellow powder); MS=419 [M+H].sup.+;
MP=255.9-260.0.degree. C.; [1031]
thieno[3,2-d]pyrimidine-7-carboxylic acid
[7-(piperidin-4-yloxy)-quinolin-6-yl]-amide hydrochloride (white
powder); MS=406 [M+H].sup.+; MP>300.degree. C.; [1032]
thieno[3,2-d]pyrimidine-7-carboxylic acid
[7-(3-amino-propoxy)-quinolin-6-yl]-amide hydrochloride (white
powder); MS=380 [M+H].sup.+; MP=234.0-237.0.degree. C.; [1033]
thieno[3,2-d]pyrimidine-7-carboxylic acid
[7-(pyrrolidin-3-yloxy)-quinolin-6-yl]-amide hydrochloride (white
powder); MS=392 [M+H].sup.+; MP>300.degree. C.; [1034]
thieno[3,2-d]pyrimidine-7-carboxylic acid
[2-(4-amino-cyclohexyloxy)-5-chloro-phenyl]-amide hydrochloride
(off-white powder); MS=403 [M+H].sup.+; MP=284.9-288.1.degree. C.;
[1035] pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
[7-(piperidin-4-yloxy)-quinolin-6-yl]-amide (off-white powder);
MS=389 [M+H].sup.+; MP>300.degree. C.; [1036]
pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
{2-[4-(1-amino-ethyl)-piperidin-1-yl]-5-chloro-phenyl}-amide (white
powder); MS=399 [M+H].sup.+; MP=178.8-179.7.degree. C.; and [1037]
pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
{2-[3-(1-amino-ethyl)-pyrrolidin-1-yl]-5-chloro-phenyl}-amide
(orange solid); MS=385 [M+H].sup.+; MP=228.0-229.0.degree. C.
Example 16
Synthesis of Pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
[5-chloro-2-(oxazol-5-ylmethoxy)-phenyl]-amide
[1038] The synthesis of pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
[5-chloro-2-(oxazol-5-ylmethoxy)-phenyl]-amide was carried out
according to the process shown in Scheme 68.
##STR00271##
[1039]
5-Chloro-2-(2-triisopropylsilanyl-oxazol-5-ylmethoxy)-phenylamine
was coupled with pyrazolo[1,5-a]pyrimidine-3-carboxylic acid in
presence of HBTU as described in Example 1. The product was
deprotected by heating with an aqueous solution of sodium hydroxide
in methanol for 2 hours. The reaction mixture was cooled; the solid
formed was collected by filtration and washed with water. The crude
residue was purified by flash chromatography to give 18 mg of
pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
[5-chloro-2-(oxazol-5-ylmethoxy)-phenyl]-amide as an off-white
solid. MS=370 [M+H].sup.+.
Example 17
Synthesis of Thieno[3,2-d]pyrimidine-7-carboxylic acid amide
[1040] The synthesis of thieno[3,2-d]pyrimidine-7-carboxylic acid
amide was carried out according to the process shown in Scheme
69.
##STR00272##
Step A: synthesis of thieno[3,2-d]pyrimidine-7-carboxylic acid
methyl ester
[1041] Trimethylsilyldiazomethane (2 M in hexane, 1 mL) was added
to a suspension of thieno[3,2-d]pyrimidine-7-carboxylic acid (50
mg) in a mixture of dichloromethane and methanol (95/5, 1 mL) and
the resulting mixture was stirred at room temperature for 1 hour.
The reaction mixture was then evaporated under reduced pressure and
the crude residue was purified by flash chromatography (DCM/MeOH,
97/3) to give 40 mg of thieno[3,2-d]pyrimidine-7-carboxylic acid
methyl ester.
Step B: synthesis of thieno[3,2-d]pyrimidine-7-carboxylic acid
amide
[1042] Ammonium hydroxide (concentrated, 2 mL) was added to a
solution of thieno[3,2-d]pyrimidine-7-carboxylic acid methyl ester
(40 mg) in 1,4-dioxane (2 mL) and the resulting mixture was heated
in a sealed tube at 100.degree. C. overnight. The reaction mixture
was then cooled and extracted with ethyl acetate. The combined
organic extracts were dried over anhydrous sodium sulfate, filtered
and evaporated under reduced pressure. The crude residue was
purified by flash chromatography (DCM/MeOH, 95/5) to give 12 mg of
thieno[3,2-d]pyrimidine-7-carboxylic acid amide as a light brown
solid. MS=180 [M+H].sup.+.
Example 18
Synthesis of Pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
[5-chloro-2-((R)-2,3-dihydroxy-propoxy)-phenyl]-amide
[1043] The synthesis of pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
[5-chloro-2-((R)-2,3-dihydroxy-propoxy)-phenyl]-amide was carried
out according to the process shown in Scheme 70.
##STR00273##
[1044] A mixture of pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
[5-chloro-2-((S)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-phenyl]-amide
(40 mg) and an aqueous solution of hydrochloric acid (2 M, 5 mL) in
tetrahydrofuran (5 mL) was heated at 70.degree. C. for 15 minutes.
The resulting mixture was cooled and the solid formed was collected
by filtration, washed with a diluted aqueous solution of sodium
hydroxide and with water, dried in a vacuum oven to give 30 mg of
pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
[5-chloro-2-((R)-2,3-dihydroxy-propoxy)-phenyl]-amide as a white
solid. MS=362 [M].sup.+.
[1045] Utilizing the above described procedure and the appropriate
starting materials, the following compounds were prepared: [1046]
pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
[5-chloro-2-((S)-2,3-dihydroxy-propoxy)-phenyl]-amide (off-white
solid); MS=362 [M].sup.+; and [1047]
pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
[5-chloro-2-(3,4-dihydroxy-butoxy)-phenyl]-amide (white powder);
MS=377 [M+H].sup.+; MP=223.0-224.5.degree. C.
Example 19
Synthesis of Pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
[2-(3-amino-pyrrolidin-1-yl)-5-chloro-phenyl]-amide
[1048] The synthesis of pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
[2-(3-amino-pyrrolidin-1-yl)-5-chloro-phenyl]-amide was carried out
according to the process shown in Scheme 71.
##STR00274##
[1049] A mixture of pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
{5-chloro-2-[3-(2,2,2-trifluoro-acetylamino)-pyrrolidin-1-yl]-phenyl}-ami-
de (50 mg), methanol (2 mL) and an aqueous solution of sodium
hydroxide (4 M, 1 mL) was heated at 60.degree. C. for 1 hour. The
resulting mixture was cooled, diluted with ethyl acetate, washed
with water and brine, dried over anhydrous sodium sulfate, filtered
and evaporated under reduced pressure to afford 30 mg of
pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
[2-(3-amino-pyrrolidin-1-yl)-5-chloro-phenyl]-amide (light yellow
foam) without further purifications. MS=356 [M].sup.+.
Example 20
Synthesis of 6-Hydroxy-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
(5-chloro-2-piperidin-1-yl-phenyl)-amide
[1050] The synthesis of
6-hydroxy-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
(5-chloro-2-piperidin-1-yl-phenyl)-amide was carried out according
to the process shown in Scheme 72.
##STR00275##
[1051] A mixture of
6-methoxy-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
(5-chloro-2-piperidin-1-yl-phenyl)-amide (100 mg) and sodium
methanethiolate (45 mg) in N,N-dimethylformamide (ca. 2 mL) was
heated in a sealed tube at 160.degree. C. for 48 hours. The
resulting mixture was evaporated under reduced pressure and the
residue was dissolved in a mixture of chloroform and methanol,
absorbed onto silica gel and purified by flash chromatography
(DCM/MeOH/AcOH) to give 25.4 mg (26% yield) of
6-hydroxy-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
(5-chloro-2-piperidin-1-yl-phenyl)-amide as a yellow solid. MS=372
[M+H].sup.+; MP>300.degree. C.
[1052] 6-Hydroxy-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
{2-[4-(tert-butyl-dimethyl-silanyloxy)-cyclohexyloxy]-5-chloro-phenyl}-am-
ide was synthesized utilizing the above described procedure and the
appropriate starting materials.
Example 21
Synthesis of 6-hydroxy-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
[5-chloro-2-(4-dimethylaminomethyl-piperidin-1-yl)-phenyl]-amide
[1053] The synthesis of
6-hydroxy-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
[5-chloro-2-(4-dimethylaminomethyl-piperidin-1-yl)-phenyl]-amide
was carried out according to the process shown in Scheme 73.
##STR00276##
[1054] A mixture of
1-{4-chloro-2-[(6-methoxy-pyrazolo[1,5-a]pyrimidine-3-carbonyl)-amino]-ph-
enyl}-piperidin-4-ylmethyl)-carbamic acid tert-butyl ester (120 mg,
0.23 mmol) and sodium methanethiolate (164 mg) in
N,N-dimethylformamide (ca. 3 mL) was heated in a sealed tube at
220.degree. C. in a microwave reactor for 20 minutes. The resulting
mixture was evaporated under reduced pressure and the residue was
dissolved in a mixture of dichloromethane and methanol, absorbed
onto silica gel and purified by flash chromatography (DCM/MeOH) to
give 32.0 mg of 6-hydroxy-pyrazolo[1,5-a]pyrimidine-3-carboxylic
acid
[5-chloro-2-(4-dimethylaminomethyl-piperidin-1-yl)-phenyl]-amide as
a brown solid. MS=429 [M+H].sup.+.
2-Chloro-thieno[3,2-d]pyrimidine-7-carboxylic acid
##STR00277##
[1055] Step A
[1056] To a solution of 15.0 g (87.6 mmole) of methyl
3-amino-4-methylthiophene-2-carboxylate in 437 mL of acetic acid
and 45 mL of water was added 21.6 g (263 mmole) of potassium
cyanate in 71 mL of water via additional funnel. The mixture was
stirred at room temperature for over night. 75 percent of the
solvent was removed. Precipitation was observed and filtered. 450
mL of 6% aqueous sodium hydroxide was added. The mixture was
refluxed at 130 degrees for 4 hours, then cooled down and acidified
with 60 ml of 12N hydrochloric acid to pH of 6. Precipitation was
observed, filtered, washed with water and dried in high vacuum for
over night to give 10.55 g of
7-methylthieno[3,2-d]pyrimidine-2,4(1H,3H)-dione as a white
solid.
Step B
[1057] A mixture of 10.0 g (54.9 mmole)
7-methylthienol[3,2-d]pyrimidine-2,4(1H,3H)-dione and 140 mL of
phosphorus oxychloride was refluxed for over night, then
concentrated under reduced pressure. The residue was slowly added
into ice water, and extracted three times with ethyl acetate. The
organic layer was washed with brine, dried over anhydrous sodium
sulfate, filtered and concentrated under reduced pressure. The
residue was purified by silica gel chromatography, eluting with
hexanes-ethyl acetate (gradient 100:0-80:20) to give 9.5 g of
2,4-dichloro-7-methyl-thienol[3,2-d]pyrimidine as a yellow
solid.
Step C
[1058] To a solution of 4.8 g (21.9 mmole)
2,4-dichloro-7-methyl-thienol[3,2-d]pyrimidine in 80 mL of ethyl
acetate and 10 mL of isopropanol was added 3.95 g (48.2 mmole) of
sodium acetate and 0.97 g (6.91 mmole) of palladium hydroxide. The
mixture was place on Parr Shaker at 45 psi hydrogen for over night.
The reaction was filtered through celite cake, washed with
dichloromethane and removed under reduced pressure. The residue was
purified by silica gel chromatography, eluting with hexanes-ethyl
acetate (gradient 100:0-75:25) to give 4.28 g of
2-chloro-7-methyl-thienol[3,2-d]pyrimidine as a white solid.
Step D
[1059] To a solution of 2.00 g (10.8 mmole)
2-chloro-7-methyl-2-chloro-thienol[3,2-d]pyrimidine in 72 mL of
anhydrous carbon tetrachloride was added 1.99 g (11.2 mmole) of
N-bromosuccinimide and 0.142 g (0.867 mmole) of
2,2'-azobis(2-methylpropionitrile) respectively. The mixture was
heated to reflux for 8 hours, cooled down, filtered and
concentrated under reduced pressure to yield 4.23 g of
7-bromomethyl-2-chloro-thienol[3,2-d]pyrimidine as a yellow oil,
which was used for next step.
Step E
[1060] To a solution of 2.85 g (10.8 mmole)
7-bromomethyl-2-chloro-thienol[3,2-d]pyrimidine in 72 mL of
anhydrous acetonitrile was added 2.83 mL (16.2 mmole) of
N,N-diisopropylethylamine and 3.59 g (37.8 mmole) of
pyridine-N-oxide respectively. The mixture was heated to 100
degrees for over night. Water and ethyl acetate were added to the
reaction mixture. The aqueous layer was washed with ethyl acetate.
The organic layer was washed with brine, dried over anhydrous
sodium sulfate, filtered and concentrated under reduced pressure.
The residue was purified by silica gel chromatography, eluting with
hexanes-ethyl acetate (gradient 100:0-60:40) to give 0.640 g of
2-chloro-thieno[3,2-d]pyrimidine-7-carbaldehyde as a yellow
solid.
Step F
[1061] To a suspension of 0.640 g (3.22 mmole)
2-chloro-thieno[3,2-d]pyrimidine-7-carbaldehyde in 20 mL of
tetrahydrofuran, 10 mL of tert-butanol and 10 mL of water was added
1.25 g (12.9 mmole) of sulfamic acid. A solution of 0.729 g (8.06
mmole) sodium chlorite and 3.33 g (24.5 mmole) of potassium
dihydrogen phosphate in 24 mL of water was slowly added via
additional funnel. The reaction mixture was stirred at room
temperature for over night. Water and ethyl acetate were added,
separated. Aqueous layer was washed with ethyl acetate. Organic
layer was washed with brine, dried over anhydrous sodium sulfate,
filtered and concentrated under reduced pressure. The solid residue
was dried in high vacuum for over night to give 0.660 g of
2-chloro-thieno[3,2-d]pyrimidine-7-carboxylic acid as a yellow
solid. MH+/Z=215
Example 22
2-(cis-2-Amino-cyclohexylamino)-thieno[3,2-d]pyrimidine-7-carboxylic
acid quinolin-8-ylamide
##STR00278##
[1062] Step A
[1063] To a solution of 0.050 g (0.235 mmole) of
2-chloro-thieno[3,2-d]pyrimidine-7-carboxylic acid, 0.034 g (0.235
mmole) of 8-aminoquinoline and 0.12 ml (0.7 mmole) of
diisopropylethylamine and 2 mL of dimethylformamide was added 0.12
g (0.28 mmole) of
O-(benzotriazol-1-yl)-N,N,N',N'-bis(tetramethylene)uronium
hexafluorophosphate. The mixture was stirred at room temperature
for 3 hours. Aqueous sodium carbonate was added, extracted with
CH.sub.2Cl.sub.2, organic layer was washed with sodium carbonate,
brine, dried over anhydrous Na.sub.2SO.sub.4, filtered and
concentrated to give 80 mg of a mixture of
2-chloro-thieno[3,2-d]pyrimidine-7-carboxylic acid
quinolin-8-ylamide and
2-(benzotriazol-1-yloxy)-thieno[3,2-d]pyrimidine-7-carboxylic acid
quinolin-8-ylamide as a slight yellow solid, which was used for the
next step without further purification.
Step B
[1064] A suspension of the mixture of 80 mg of
2-chloro-thieno[3,2-d]pyrimidine-7-carboxylic acid
quinolin-8-ylamide and
2-(benzotriazol-1-yloxy)-thieno[3,2-d]pyrimidine-7-carboxylic acid
quinolin-8-ylamide and 0.17 g (1.41 mmole) of
cis-1,2-diaminocyclohexane (from step a) in Dioxane (3 mL) was
stirred at 60.degree. C. for overnight. The reaction were cooled
down and diluted with CH.sub.2Cl.sub.2, washed with aqueous
Na.sub.2CO.sub.3, brine, dried over anhydrous Na.sub.2SO.sub.4,
concentrated and purified by flash chromatography (silica gel, 40
g, 0% to 30% MeOH (0.7 N) in CH.sub.2Cl.sub.2) to 40 mg of
2-(cis-2-amino-cyclohexylamino)-thieno[3,2-d]pyrimidine-7-carboxylic
acid quinolin-8-ylamide as light yellow solid. MH+/Z=419.
Example 23
2-(cis-2-Amino-cyclohexylamino)-thieno[3,2-d]pyrimidine-7-carboxylic
acid benzo[1,3]dioxol-5-ylamide
##STR00279##
[1065] Step A
[1066] To a solution of 0.050 g (0.235 mmole) of
2-chloro-thieno[3,2-d]pyrimidine-7-carboxylic acid, 0.032 g (0.235
mmole) of 3,4-(methylenedioxy)aniline and 0.12 ml (0.7 mmole) of
diisopropylethylamine and 2 mL of dimethylformamide was added 0.12
g (0.28 mmole) of
O-(benzotriazol-1-yl)-N,N,N',N'-bis(tetramethylene)uronium
hexafluorophosphate. The mixture was stirred at room temperature
for 3 hours. Aqueous sodium carbonate was added, extracted with
CH.sub.2Cl.sub.2, organic layer was washed with sodium carbonate,
brine, dried over anhydrous Na.sub.2SO.sub.4, filtered and
concentrated to give 80 mg of a mixture of
2-Chloro-thieno[3,2-d]pyrimidine-7-carboxylic acid
benzo[1,3]dioxol-5-ylamide and
2-(Benzotriazol-1-yloxy)-thieno[3,2-d]pyrimidine-7-carboxylic acid
benzo[1,3]dioxol-5-ylamide as a slight yellow solid, which was used
for the next step without further purification.
Step B
[1067] A suspension of the mixture of 80 mg of
2-Chloro-thieno[3,2-d]pyrimidine-7-carboxylic acid
benzo[1,3]dioxol-5-ylamide and
2-(Benzotriazol-1-yloxy)-thieno[3,2-d]pyrimidine-7-carboxylic acid
benzo[1,3]dioxol-5-ylamide (from step a) and 0.17 g (1.41 mmole) of
cis-1,2-diaminocyclohexane in Dioxane (3 mL) was stirred at
60.degree. C. for overnight. The reaction were cooled down and
diluted with CH.sub.2Cl.sub.2, washed with aqueous
Na.sub.2CO.sub.3, brine, dried over anhydrous Na.sub.2SO.sub.4,
concentrated and purified by flash chromatography (silica gel, 40
g, 0% to 30% MeOH (0.7 N) in CH.sub.2Cl.sub.2) to 40 mg of
2-(cis-2-Amino-cyclohexylamino)-thieno[3,2-d]pyrimidine-7-carboxylic
acid benzo[1,3]dioxol-5-ylamide as light yellow solid.
MH+/Z=412.
Example 24
2-(cis-2-Amino-cyclohexylamino)-thieno[3,2-d]pyrimidine-7-carboxylic
acid (3,4-dimethoxy-phenyl)-amide
##STR00280##
[1068] Step A
[1069] To a solution of 0.050 g (0.235 mmole) of
2-chloro-thieno[3,2-d]pyrimidine-7-carboxylic acid, 0.032 g (0.235
mmole) of 3,4-dimethoxyaniline and 0.12 ml (0.7 mmole) of
diisopropylethylamine and 2 ml of dimethylformamide was added 0.12
g (0.28 mmole) of
O-(benzotriazol-1-yl)-N,N,N',N'-bis(tetramethylene)uronium
hexafluorophosphate. The mixture was stirred at room temperature
for 3 hours. Aqueous sodium carbonate was added, extracted with
CH.sub.2Cl.sub.2, organic layer was washed with sodium carbonate,
brine, dried over anhydrous Na.sub.2SO.sub.4, filtered and
concentrated to give 85 mg of a mixture of
2-Chloro-thieno[3,2-d]pyrimidine-7-carboxylic acid
(3,4-dimethoxy-phenyl)-amide and
2-(Benzotriazol-1-yloxy)-thieno[3,2-d]pyrimidine-7-carboxylic acid
(3,4-dimethoxy-phenyl)-amide as a slight yellow solid, which was
used for the next step without further purification.
Step B
[1070] A suspension of the mixture of 85 mg of
2-Chloro-thieno[3,2-d]pyrimidine-7-carboxylic acid
(3,4-dimethoxy-phenyl)-amide and
2-(Benzotriazol-1-yloxy)-thieno[3,2-d]pyrimidine-7-carboxylic acid
(3,4-dimethoxy-phenyl)-amide (from step a) and 0.17 g (1.41 mmole)
of cis-1,2-diaminocyclohexane in Dioxane (3 mL) was stirred at
60.degree. C. for overnight. The reaction were cooled down and
diluted with CH.sub.2Cl.sub.2, washed with aqueous
Na.sub.2CO.sub.3, brine, dried over anhydrous Na.sub.2SO.sub.4,
concentrated and purified by flash chromatography (silica gel, 40
g, 0% to 30% MeOH (0.7 N) in CH.sub.2Cl.sub.2) to 50 mg of
2-(cis-2-Amino-cyclohexylamino)-thieno[3,2-d]pyrimidine-7-carboxylic
acid (3,4-dimethoxy-phenyl)-amide as light yellow solid.
MH+/Z=428.
Example 25
2-(cis-2-amino-cyclohexylamino)-thieno[3,2-d]pyrimidine-7-carboxylic
acid (1-methyl-1H-benzoimidazol-4-yl)-amide
##STR00281##
[1071] Step A
[1072] To a solution of 0.050 g (0.233 mmole)
2-chloro-thieno[3,2-d]pyrimidine-7-carboxylic acid, 0.0686 g (0.466
mmole) of 1-methyl-1H-benzol[d]imidazol-4-amine, 0.122 mL (0.699
mmole) of N,N-diisopropylethylamine and 1.55 mL of
dimethylformamide was added 0.111 g (0.256 mmole) of
O-(benzotriazol-1-yl)-N,N,N',N'-bis(tetramethylene)uronium
hexafluorophosphate. The mixture was stirred at room temperature
for overnight. Water and dichloromethane were added. The aqueous
layer was washed three times with dichloromethane. The combined
organic layer was washed with aqueous sodium carbonate, brine,
dried over anhydrous sodium sulfate, filtered and concentrated
under reduced pressure. Purification by silica gel chromatography,
eluting with hexanes-ethyl acetate (gradient 50:50-0:100) gave
0.042 g of 2-chloro-thieno[3,2-d]pyrimidine-7-carboxylic acid
(1-methyl-1H-benzoimidazol-4-yl)-amide as a yellow solid.
Step B
[1073] To a solution of 0.041 g (0.119 mmole)
2-chloro-thieno[3,2-d]pyrimidine-7-carboxylic
acid(1-methyl-1H-benzoimidazol-4-yl)-amide in 1.19 mL of dioxane
was added 0.082 g (0.716 mmole) of cis-cyclohexane-1,2-diamine. The
mixture was heated at 100 degrees for over night. Water and
dichloromethane were added, separated. The aqueous layer was washed
with dichloromethane twice. The organic layer was washed with
aqueous sodium carbonate, brine, dried over anhydrous sodium
sulfate, filtered and concentrated under reduced pressure.
Purification by silica gel chromatography, eluting with
dichloromethane-0.7 N ammonia solution in methanol (gradient
100:0-90:10) gave 0.019 g of
2-(cis-2-amino-cyclohexylamino)-thieno[3,2-d]pyrimidine-7-carboxylic
acid (1-methyl-1H-benzoimidazol-4-yl)-amide as a light yellow
solid. MH+/Z=422
Example 26
2-(cis-2-amino-cyclohexylamino)-thieno[3,2-d]pyrimidine-7-carboxylic
acid (2,4-dimethoxy-phenyl)-amide
##STR00282##
[1074] Step A
[1075] To a solution of 0.050 g (0.233 mmole)
2-chloro-thieno[3,2-d]pyrimidine-7-carboxylic acid, 0.0714 g (0.466
mmole) of 1-methyl-1H-benzol[d]imidazol-4-amine, 0.122 mL (0.699
mmole) of N,N-diisopropylethylamine and 1.55 mL of
dimethylformamide was added 0.111 g (0.256 mmole) of
O-(benzotriazol-1-yl)-N,N,N',N'-bis(tetramethylene)uronium
hexafluorophosphate. The mixture was stirred at room temperature
for over night. Water and dichloromethane were added. The aqueous
layer was washed three times with dichloromethane. The combined
organic layer was washed with aqueous sodium carbonate, brine,
dried over anhydrous sodium sulfate, filtered and concentrated
under reduced pressure. Purification by silica gel chromatography,
eluting with hexanes-ethyl acetate (gradient 100:0-60:40) gave
0.050 g of 2-chloro-thieno[3,2-d]pyrimidine-7-carboxylic
acid(2,4-dimethoxy-phenyl)-amide as a yellow solid.
Step B
[1076] To a solution of 0.047 g (0.134 mmole)
2-chloro-thieno[3,2-d]pyrimidine-7-carboxylic
acid(2,4-dimethoxy-phenyl)-amide in 1.34 mL of dioxane was added
0.0967 mL (0.806 mmole) of (cis-cyclohexane-1,2-diamine. The
mixture was heated at 100 degrees for over night. Dichloromethane
was added and washed with aqueous sodium bicarbonate. The aqueous
layer was washed twice with dichloromethane. The organic layer was
washed with brine, dried over anhydrous sodium sulfate, filtered
and concentrated under reduced pressure. Purification by silica gel
chromatography, eluting with dichloromethane-0.7 N ammonia solution
in methanol (gradient 100:0-90:10) gave 0.052 g of
2-(cis-2-amino-cyclohexylamino)-thieno[3,2-d]pyrimidine-7-carboxylic
acid (2,4-dimethoxy-phenyl)-amide as a yellow solid. MH+/Z=428
Example 27
2-(cis-2-amino-cyclohexylamino)-thieno[3,2-d]pyrimidine-7-carboxylic
acid (5,6-dimethoxy-pyridin-2-yl)-amide
##STR00283##
[1077] Step A
[1078] To a solution of 0.050 g (0.233 mmole)
2-chloro-thieno[3,2-d]pyrimidine-7-carboxylic acid, 0.0718 g (0.466
mmole) of 5,6-dimethoxypyridin-2-amine, 0.122 mL (0.699 mmole) of
N,N-diisopropylethylamine and 1.55 ml of dimethylformamide was
added 0.111 g (0.256 mmole) of
O-(benzotriazol-1-yl)-N,N,N',N'-bis(tetramethylene)uronium
hexafluorophosphate. The mixture was stirred at room temperature
for over night. Water and dichloromethane were added. The aqueous
layer was washed three times with dichloromethane. The combined
organic layer was washed with aqueous sodium carbonate, brine,
dried over anhydrous sodium sulfate, filtered and concentrated
under reduced pressure. The residue was dried in high vacuum to
give 2-chloro-thieno[3,2-d]pyrimidine-7-carboxylic acid
(5,6-dimethoxy-pyridin-2-yl)-amide as a black solid.
Step B
[1079] To a solution of 0.0817 g (0.233 mmole)
2-chloro-thieno[3,2-d]pyrimidine-7-carboxylic acid
(5,6-dimethoxy-pyridin-2-yl)-amide in 2.33 mL of dioxane was added
0.168 mL (1.4 mmole) of cis-cyclohexane-1,2-diamine. The mixture
was heated at 100 degrees for over night. Water and dichloromethane
were added, separated. The aqueous layer was washed with
dichloromethane twice. The organic layer was washed with aqueous
sodium carbonate, brine, dried over anhydrous sodium sulfate,
filtered and concentrated under reduced pressure. Purification by
silica gel chromatography, eluting with dichloromethane-0.7 N
ammonia solution in methanol (gradient 100:0-90:10) gave 0.048 g of
2-(cis-2-amino-cyclohexylamino)-thieno[3,2-d]pyrimidine-7-carboxylic
acid (5,6-dimethoxy-pyridin-2-yl)-amide as a light yellow solid.
MH+/Z=429.
Example 28
2-(cis-2-amino-cyclohexylamino)-thieno[3,2-d]pyrimidine-7-carboxylic
acid (3,4,5-trimethoxy-phenyl)-amide
##STR00284##
[1080] Step A
[1081] To a solution of 0.050 g (0.233 mmole)
2-chloro-thieno[3,2-d]pyrimidine-7-carboxylic acid, 0.0854 g (0.466
mmole) of 3,4,5-trimethoxyaniline, 0.122 mL (0.699 mmole) of
N,N-diisopropylethylamine and 1.55 mL of dimethylformamide was
added 0.111 g (0.256 mmole) of
O-(benzotriazol-1-yl)-N,N,N',N'-bis(tetramethylene)uronium
hexafluorophosphate. The mixture was stirred at room temperature
for 2 hours. Water and dichloromethane were added. The aqueous
layer was washed three times with dichloromethane. The combined
organic layer was washed with aqueous sodium carbonate, brine,
dried over anhydrous sodium sulfate, filtered and concentrated
under reduced pressure. The residue was dried in high vacuum to
give 2-chloro-thieno[3,2-d]pyrimidine-7-carboxylic acid
(3,4,5-trimethoxy-phenyl)-amide as a yellow solid
Step B
[1082] To a solution of 0.0885 g (0.233 mmole)
2-chloro-thieno[3,2-d]pyrimidine-7-carboxylic acid
(3,4,5-trimethoxy-phenyl)-amide in 2.33 mL of dioxane was added
0.168 mL (1.4 mmole) of cis-cyclohexane-1,2-diamine. The mixture
was heated at 100 degrees for over night. Water and dichloromethane
were added, separated. The aqueous layer was washed with
dichloromethane twice. The organic layer was washed with aqueous
sodium carbonate, brine, dried over anhydrous sodium sulfate,
filtered and concentrated under reduced pressure. Purification by
silica gel chromatography, eluting with dichloromethane-0.7 N
ammonia solution in methanol (gradient 100:0-90:10) gave 0.064 g of
2-(cis-2-amino-cyclohexylamino)-thieno[3,2-d]pyrimidine-7-carboxylic
acid (3,4,5-trimethoxy-phenyl)-amide as a light yellow solid.
MH+/Z=458.
Example 29
2-(cis-2-amino-cyclohexylamino)-thieno[3,2-d]pyrimidine-7-carboxylic
acid quinolin-6-ylamide
##STR00285##
[1083] Step A
[1084] To a solution of 0.050 g (0.233 mmole)
2-chloro-thieno[3,2-d]pyrimidine-7-carboxylic acid, 0.0672 g (0.466
mmole) of quinolin-6-amine, 0.122 mL (0.699 mmole) of
N,N-diisopropylethylamine and 1.55 mL of dimethylformamide was
added 0.111 g (0.256 mmole) of
O-(benzotriazol-1-yl)-N,N,N',N'-bis(tetramethylene)uronium
hexafluorophosphate. The mixture was stirred at room temperature
for 2 hours. Water and dichloromethane were added. The aqueous
layer was washed three times with dichloromethane. The combined
organic layer was washed with aqueous sodium carbonate, brine,
dried over anhydrous sodium sulfate, filtered and concentrated
under reduced pressure. The residue was dried in high vacuum to
give 2-chloro-thieno[3,2-d]pyrimidine-7-carboxylic acid
quinolin-6-ylamide as a yellow-greenish solid
Step B
[1085] To a solution of 0.0794 g (0.233 mmole)
2-chloro-thieno[3,2-d]pyrimidine-7-carboxylic acid
quinolin-6-ylamide in 2.33 mL of dioxane was added 0.168 mL (1.4
mmole) of cis-cyclohexane-1,2-diamine. The mixture was heated at
100 degrees for 2 hours. Water and dichloromethane were added,
separated. The aqueous layer was washed with dichloromethane twice.
The organic layer was washed with aqueous sodium carbonate, brine,
dried over anhydrous sodium sulfate, filtered and concentrated
under reduced pressure. Purification by silica gel chromatography,
eluting with dichloromethane-0.7 N ammonia solution in methanol
(gradient 100:0-90:10) gave 0.054 g of
2-(cis-2-amino-cyclohexylamino)-thieno[3,2-d]pyrimidine-7-carboxylic
acid quinolin-6-ylamide as a light yellow solid. MH+/Z=419.
Example 30
Formulations
[1086] Pharmaceutical preparations for delivery by various routes
are formulated as shown in the following Tables. "Active
ingredient" or "Active compound" as used in the Tables means one or
more of the Compounds of Formula I.
Composition for Oral Administration
TABLE-US-00003 [1087] Ingredient % wt./wt. Active ingredient 20.0%
Lactose 79.5% Magnesium stearate 0.5%
[1088] The ingredients are mixed and dispensed into capsules
containing about 100 mg each; one capsule would approximate a total
daily dosage.
Composition for Oral Administration
TABLE-US-00004 [1089] Ingredient % wt./wt. Active ingredient 20.0%
Magnesium stearate 0.5% Crosscarmellose sodium 2.0% Lactose 76.5%
PVP (polyvinylpyrrolidine) 1.0%
[1090] The ingredients are combined and granulated using a solvent
such as methanol. The formulation is then dried and formed into
tablets (containing about 20 mg of active compound) with an
appropriate tablet machine.
Composition for Oral Administration
TABLE-US-00005 [1091] Ingredient Amount Active compound 1.0 g
Fumaric acid 0.5 g Sodium chloride 2.0 g Methyl paraben 0.15 g
Propyl paraben 0.05 g Granulated sugar 25.5 g Sorbitol (70%
solution) 12.85 g Veegum K (Vanderbilt Co.) 1.0 g Flavoring 0.035
ml Colorings 0.5 mg Distilled water q.s. to 100 ml
[1092] The ingredients are mixed to form a suspension for oral
administration.
Parenteral Formulation
TABLE-US-00006 [1093] Ingredient % wt./wt. Active ingredient 0.25 g
Sodium Chloride qs to make isotonic Water for injection 100 ml
[1094] The active ingredient is dissolved in a portion of the water
for injection. A sufficient quantity of sodium chloride is then
added with stirring to make the solution isotonic. The solution is
made up to weight with the remainder of the water for injection,
filtered through a 0.2 micron membrane filter and packaged under
sterile conditions.
Suppository Formulation
TABLE-US-00007 [1095] Ingredient % wt./wt. Active ingredient 1.0%
Polyethylene glycol 1000 74.5% Polyethylene glycol 4000 24.5%
[1096] The ingredients are melted together and mixed on a steam
bath, and poured into molds containing 2.5 g total weight.
Topical Formulation
TABLE-US-00008 [1097] Ingredients Grams Active compound 0.2-2 Span
60 2 Tween 60 2 Mineral oil 5 Petrolatum 10 Methyl paraben 0.15
Propyl paraben 0.05 BHA (butylated hydroxy anisole) 0.01 Water q.s.
100
[1098] All of the ingredients, except water, are combined and
heated to about 60.degree. C. with stirring. A sufficient quantity
of water at about 60.degree. C. is then added with vigorous
stirring to emulsify the ingredients, and water then added q.s.
about 100 g.
Nasal Spray Formulations
[1099] Several aqueous suspensions containing from about 0.025-0.5
percent active compound are prepared as nasal spray formulations.
The formulations optionally contain inactive ingredients such as,
for example, microcrystalline cellulose, sodium
carboxymethylcellulose, dextrose, and the like. Hydrochloric acid
may be added to adjust pH. The nasal spray formulations may be
delivered via a nasal spray metered pump typically delivering about
50-100 microliters of formulation per actuation. A typical dosing
schedule is 2-4 sprays every 4-12 hours.
Example 31
In Vitro IRAK-1 and IRAK-4 Assay
[1100] Purified recombinant IRAK-4 protein was incubated with 250
uM synthetic peptide (KKARFSRFAGSSPSQSSMVAR) in 30 ul of kinase
buffer including (20 mM MOPS pH7.2, 25 mM beta glycerol phosphate,
5 mM EGTA, 1 mM sodium orthovanadate, 1 mM DTT, 50 uM ATP, 20 mM
MgCl.sub.2, 10 uCi .gamma.-.sup.33P, 0.1% BSA) for the indicated
time. For purified recombinant IRAK-1 protein kinase assay, 50 uM
ATP was used. A 25 ul aliquot of the reaction mixture was
transferred on to p81 phosphocellulose squares (Upstate
Biotechnology, Lake Placid, N.Y.). The assay squares were washed
three times with 0.75% phosphoric acid and once with acetone.
Enzyme activity was measured by determining the bound radioactivity
by liquid scintillation counting.
Example 32
In Vitro SYK Kinase Assay
[1101] Spleen tyrosine kinase (SYK) is a tyrosine kinase that plays
an important role in B cell signal transduction. SYK activity is
measured by phosphorylation of a peptide substrate
(Biotin-EPEGDYEEVLE) with [gamma-.sup.33P] ATP. The enzyme reaction
was conducted at 20 uM ATP with 0.05 uCi [gamma-.sup.33P] ATP (2
uCi for 40 ul assay) and 10 uM peptide substrate at final volume of
40 ul in buffer containing 50 mM Hepes, pH 7.2, 1 mM
dithiothreitol, 10 mM MgCl.sub.2,100 uM Na.sub.3VO.sub.4, 0.1% BSA
and 10% DMSO. The enzyme assay was carried out with human full
length SYK in the presence or absence of ten compound
concentrations. SYK and compound were pre-incubated for 10 minutes.
Then, the enzymatic reaction was initiated by addition of ATP and
peptide substrate. The reaction mixture was incubated at room
temperature for 30 minutes. At the end of incubation, the reaction
was terminated by transferring 25 ul of the reaction mixture to 100
ul of 10% streptavidin slurry containing 100 mM EDTA. The reaction
product was captured on the affinity resin and sequentially washed
on a filtration plate (Millipore, MABVNOB50) with 2M NaCl, 2M M
NaCl in 1% phosphoric acid and water to remove free radio
nucleotide. Then the incorporation of .sup.33P into peptide
substrate was quantified on a microplate scintillation counter.
Compound inhibition potency on SYK was measured by IC.sub.50 value
generated from ten concentration inhibition curve fitted into the
3-parameter model: %
inhibition=Maximum/(1+(IC.sub.50/[Inhibitor]).sup.slope). Data were
analyzed on Microsoft Excel for parameter estimation.
[1102] While the present invention has been described with
reference to the specific embodiments thereof, it should be
understood by those skilled in the art that various changes may be
made and equivalents may be substituted without departing from the
true spirit and scope of the invention. In addition, many
modifications may be made to adapt a particular situation,
material, composition of matter, process, process step or steps, to
the objective spirit and scope of the present invention. All such
modifications are intended to be within the scope of the claims
appended hereto.
* * * * *