U.S. patent application number 10/326005 was filed with the patent office on 2003-12-11 for pyrrolopyrimidine a2b selective antagonist compounds, their synthesis and use.
Invention is credited to Castelhano, Arlindo, McKibben, Bryan, Steinig, Arno.
Application Number | 20030229067 10/326005 |
Document ID | / |
Family ID | 23346139 |
Filed Date | 2003-12-11 |
United States Patent
Application |
20030229067 |
Kind Code |
A1 |
Castelhano, Arlindo ; et
al. |
December 11, 2003 |
Pyrrolopyrimidine A2b selective antagonist compounds, their
synthesis and use
Abstract
The subject invention provides compounds having the structure: 1
wherein, R.sub.1 is a substituted or unsubstituted alkyl, wherein
the substituent is hydroxyl, dihydroxy, carboxyl,
--C(.dbd.O)NR.sub.aR.sub.b, --NR.sub.aR.sub.b,
--NR.sub.aC(.dbd.O)NR.sub.aR.sub.b, --NR.sub.aC(.dbd.O)OR.sub.a,
--OC(.dbd.O)NR.sub.aR.sub.b, or --NHC(.dbd.O)R.sub.a; R.sub.2 is
hydrogen or a substituted or unsubstituted alkyl, wherein the
substituent is hydroxyl, dihydroxy, carboxyl,
--C(.dbd.O)NR.sub.aR.sub.b, --NR.sub.aR.sub.b,
--NR.sub.aC(.dbd.O)NR.sub.aR.sub.b, --NR.sub.aC(.dbd.O)OR.sub.a,
--OC(.dbd.O)NR.sub.aR.sub.b, or --NHC(.dbd.O)R.sub.a, or R.sub.1,
R.sub.2 and N together form a substituted piperazine, substituted
azetidine ring, or a pyrrolidine ring substituted with
--(CH.sub.2).sub.2OH or --CH.sub.2C(.dbd.O)OH; R.sub.3 is a
substituted or unsubstituted phenyl or a 5-6 membered heteroaryl
ring, wherein the substituent is halogen, hydroxyl, cyano,
(C.sub.1-C.sub.15)alkyl, (C.sub.1-C.sub.15)alkoxy, or
--NR.sub.aR.sub.b; R.sub.4 is hydrogen or substituted or
unsubstituted (C.sub.1-C.sub.15)alkyl; R.sub.5 is
--(CH.sub.2).sub.mOR.sub.6, --CHNOR.sub.7,
--C(.dbd.O)NR.sub.8R.sub.9, --(CH.sub.2).sub.mC(.dbd.O)OR.sub.10,
--(CH.sub.2).sub.kC(.dbd.O)NR.sub.11R.sub.12; wherein R.sub.6 is a
substituted or unsubstituted (C.sub.1-C.sub.30)alkyl,
(C.sub.3-C.sub.10)cycloalkyl, or an aryl, heteroaryl or 4-8
membered heterocyclic ring; R.sub.7 is hydrogen, or a substituted
or unsubstituted (C.sub.1-C.sub.30)alkyl,
(C.sub.1-C.sub.30)alkylaryl; R.sub.8 and R.sub.9 are each
independently hydrogen, or a substituted or unsubstituted
(C.sub.1-C.sub.30)alkyl, (C.sub.1-C.sub.30)alkylaryl,
(C.sub.1-C.sub.30)alkylamino, (C.sub.1-C.sub.30)alkoxy, or a
saturated or unsaturated, monocyclic or bicyclic, carbocyclic or
heterocyclic ring, or R.sub.8, N, and R.sub.9 together form a
substituted or unsubstituted 4-8 membered heterocyclic ring;
R.sub.10 is hydrogen or a substituted or unsubstituted
(C.sub.1-C.sub.30)alkyl, (C.sub.3-C.sub.10)cycloalkyl, or an aryl,
heteroaryl or heterocyclic ring; R.sub.11, N and R.sub.12 together
form a 4-8 membered heterocyclic ring; R.sub.a and R.sub.b are each
independently hydrogen or alkyl; m is 0, 1, 2 or 3; and k is 1, 2
or 3, or a specific enantiomer thereof, or a specific tautomer
thereof, or a pharmaceutically acceptable salt thereof, and a
method for treating a disease associated with the A.sub.2b
adenosine receptor in a subject in need of such treatment
comprising administering to the subject a therapeutically effective
amount of the compounds of the invention.
Inventors: |
Castelhano, Arlindo; (New
City, NY) ; McKibben, Bryan; (Hopewell Junction,
NY) ; Steinig, Arno; (East Northport, NY) |
Correspondence
Address: |
Cooper and Dunham LLP
1185 Avenue of the Americas
New York
NY
10036
US
|
Family ID: |
23346139 |
Appl. No.: |
10/326005 |
Filed: |
December 20, 2002 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
60343443 |
Dec 20, 2001 |
|
|
|
Current U.S.
Class: |
514/210.21 ;
514/252.16; 514/265.1; 544/280 |
Current CPC
Class: |
A61P 27/02 20180101;
A61P 1/12 20180101; A61P 9/10 20180101; A61P 9/12 20180101; A61P
9/00 20180101; A61P 3/10 20180101; A61P 29/00 20180101; A61P 17/00
20180101; A61P 43/00 20180101; A61P 35/04 20180101; A61P 13/00
20180101; A61P 19/02 20180101; A61P 37/08 20180101; A61P 11/06
20180101; A61P 35/00 20180101; A61P 17/04 20180101; C07D 487/04
20130101; A61P 1/04 20180101 |
Class at
Publication: |
514/210.21 ;
544/280; 514/252.16; 514/265.1 |
International
Class: |
A61K 031/519; C07D
487/02 |
Claims
What is claimed is:
1. A compound having the structure: 371wherein, R.sub.1 is a
substituted or unsubstituted alkyl, wherein the substituent is
hydroxyl, dihydroxy, carboxyl, --C(.dbd.O)NR.sub.aR.sub.b,
--NR.sub.aR.sub.b, --NR.sub.aC(.dbd.O)NR.sub.aR.sub.b,
--NR.sub.aC(.dbd.O)OR.sub.a, --OC(.dbd.O)NR.sub.aR.sub.b, or
--NHC(.dbd.O)R.sub.a; R.sub.2 is hydrogen or a substituted or
unsubstituted alkyl, wherein the substituent is hydroxyl,
dihydroxy, carboxyl, --C(.dbd.O)NR.sub.aR.sub.b, --NR.sub.aR.sub.b,
--NR.sub.aC(.dbd.O)NR.sub.aR.sub.b, --NR.sub.aC(.dbd.O)OR.sub.a,
--OC(.dbd.O)NR.sub.aR.sub.b, or --NHC(.dbd.O)R.sub.a, or R.sub.1,
R.sub.2 and N together form a substituted piperazine, substituted
azetidine ring, or a pyrrolidine ring substituted with
--(CH.sub.2).sub.2OH or --CH.sub.2C(.dbd.O)OH; R.sub.3 is a
substituted or unsubstituted phenyl or a 5-6 membered heteroaryl
ring, wherein the substituent is halogen, hydroxyl, cyano,
(C.sub.1-C.sub.15)alkyl, (C.sub.1-C.sub.15)alkoxy, or
--NR.sub.aR.sub.b; R.sub.4 is hydrogen or substituted or
unsubstituted (C.sub.1-C.sub.15)alkyl; R.sub.5 is
--(CH.sub.2).sub.mOR.sub.6, --CHNOR.sub.7,
--C(.dbd.O)NR.sub.8R.sub.9, --(CH.sub.2).sub.mC(.dbd.O)OR.- sub.10,
--(CH.sub.2).sub.kC(.dbd.O)NR.sub.11R.sub.12; wherein R.sub.6 is a
substituted or unsubstituted (C.sub.1-C.sub.30)alkyl,
(C.sub.3-C.sub.10)cycloalkyl, or an aryl, heteroaryl or 4-8
membered heterocyclic ring; R.sub.7 is hydrogen, or a substituted
or unsubstituted (C.sub.1-C.sub.30)alkyl,
(C.sub.1-C.sub.30)alkylaryl; R.sub.8 and R.sub.9 are each
independently hydrogen, or a substituted or unsubstituted
(C.sub.1-C.sub.30)alkyl, (C.sub.1-C.sub.30)alkylaryl,
(C.sub.1-C.sub.30)alkylamino, (C.sub.1-C.sub.30)alkoxy, or a
saturated or unsaturated, monocyclic or bicyclic, carbocyclic or
heterocyclic ring, or R.sub.8, N, and R.sub.9 together form a
substituted or unsubstituted 4-8 membered heterocyclic ring;
R.sub.10 is hydrogen or a substituted or unsubstituted
(C.sub.1-C.sub.30)alkyl, (C.sub.3-C.sub.10)cycloalkyl, or an aryl,
heteroaryl or heterocyclic ring; R.sub.11, N and R.sub.12 together
form a 4-8 membered heterocyclic ring; R.sub.a and R.sub.b are each
independently hydrogen or alkyl; m is 0, 1, 2 or 3; and k is 1, 2
or 3, or a specific enantiomer thereof, or a specific tautomer
thereof, or a pharmaceutically acceptable salt thereof.
2. The compound of claim 1, wherein any heterocyclic or heteroaryl
ring, if present, is a piperazine, piperidine, pyrazine, pyridine,
pyrrolidine, pyrazole, pyrimidine, thiophene, imidazole, azetidine,
pyrrole, benzothiazole, benzodioxolane, dithiolane, oxathiine,
imidazolidine, quinoline, isoquinoline, dihydro-1H-isoquinoline,
dihydro-2H-pyridine, 1,3,4,9-tetrahydro-.beta.-carboline,
2,8-diazaspiro[4.5]decane, 2,5-diazabicyclo[2.2.1]heptane, or
[1,4]diazepane ring, dihydroisoquinoline, indole, isoindole,
triazaspiro[4.5]decane, morpholine, furan or an isothiazole
ring.
3. The compound of claim 1, having the structure: 372wherein,
R.sub.1 is hydrogen or methyl; R.sub.2 is
--(CH.sub.2).sub.2NHC(.dbd.O)CH.sub.3, --(CH.sub.2).sub.2OH,
--(CH.sub.2).sub.2NHC(.dbd.O)NHCH.sub.3, --CH.sub.2CH(CH.sub.3)OH,
--CH(CH.sub.2OH)CH.sub.2CH(CH.sub.3).sub.2, --CH(CH.sub.2OH).sub.2,
--CH(CH.sub.3)CH.sub.2OH, --CH(CH.sub.2OH)CH(CH.s- ub.3).sub.2,
--(CH.sub.2).sub.3OH, --(CH.sub.2).sub.2NH.sub.2,
--(CH.sub.2).sub.2NHC(.dbd.O)N(CH.sub.3).sub.2,
--(CH.sub.2).sub.2C(.dbd.- O)NH.sub.2, --CH.sub.2C(.dbd.O)NH.sub.2,
--CH.sub.3, --CH.sub.2CH(OH)CH.sub.2OH,
--CH.sub.2C(.dbd.O)(NC.sub.5H.sub.8[OCH.sub.3- ])(C.sub.6H.sub.4Cl)
or R.sub.1, R.sub.2 and N together form a pyrrolidine ring
substituted with --(CH.sub.2).sub.2OH or --CH.sub.2C(.dbd.O)OH, a
piperazine ring substituted with --C(.dbd.O)CH.sub.3, or an
azetidine ring substituted with --OH or CH.sub.2OH; R.sub.4 is
hydrogen, or methyl; and R.sub.5 is --CH.sub.2O(C.sub.6H.sub.5),
--CH.sub.2O(C.sub.6H.sub.4Cl)- , --CH.sub.2O(C.sub.6H.sub.4Br),
--CH.sub.2O(C.sub.6H.sub.4F), --CHNOCH.sub.2(C.sub.6H.sub.5),
--CH.sub.2O(C.sub.6H[OCH.sub.3]),
--CH.sub.2O(C.sub.6H.sub.4[CH.sub.3]), --CHNOC(CH.sub.3).sub.3,
--CH.sub.2O(C.sub.5H.sub.4N), --CH.sub.2(NC.sub.5H.sub.4[O]),
--CH.sub.2O(C.sub.6H.sub.4[NH.sub.2]),
--CH.sub.2O(C.sub.5H.sub.9N)SO.sub- .2(C.sub.6H.sub.5),
--CH.sub.2O(C.sub.5H.sub.9N)SO.sub.2CH.sub.2(C.sub.6H.- sub.5),
--CH.sub.2O(C.sub.6H.sub.4[NHC(.dbd.O)CH.sub.3]),
--CH.sub.2O(C.sub.5H.sub.9N)(CH.sub.2).sub.P(C.sub.6H.sub.5),
--CH.sub.2O(C.sub.5H.sub.9N)(CH.sub.2).sub.P(C.sub.6H.sub.4Br),
--CH.sub.2O(C.sub.5H.sub.9N)(CH.sub.2).sub.P(C.sub.6H.sub.4Cl),
--CH.sub.2O(C.sub.5H.sub.9N)(CH.sub.2).sub.P(C.sub.6H.sub.4[OCH.sub.3]),
--CH.sub.2O(C.sub.5H.sub.9N)(CH.sub.2).sub.P(C.sub.6H.sub.3FCl),
--CH.sub.2O(C.sub.5H.sub.9N)(CH.sub.2).sub.P(C.sub.6H4[CF.sub.3]),
--CH.sub.2O(CH.sub.2).sub.2CH(OH)(C.sub.6H.sub.5),
--CH.sub.2NOCH.sub.2(C.sub.6H.sub.5),
--CH.sub.2NOC(CH.sub.3).sub.3, --C(.dbd.O)(NC.sub.4H.sub.8O),
--C(.dbd.O)(NC.sub.4HgN)CH.sub.2CHCH(C.sub- .6H.sub.5),
--C(.dbd.O)(NC.sub.4H.sub.8N)(CH.sub.2).sub.P(C.sub.6H.sub.5),
--C(.dbd.O)(NC.sub.4H.sub.8N)(CH.sub.2).sub.2O(C.sub.6H.sub.4Cl),
--C(.dbd.O)(NC.sub.5H.sub.8[CN])(C.sub.6H.sub.5),
--C(.dbd.O)(NC.sub.4H.s- ub.8N)CH.sub.2C.sub.2(C.sub.6H.sub.5),
--C(.dbd.O)(NC.sub.4(CH.sub.3).sub.-
2N)(CH.sub.2).sub.P(C.sub.6H.sub.5),
--C(.dbd.O)(NC.sub.5H.sub.9)CH(OH)(C.- sub.6H.sub.4F),
--C(.dbd.O)(NC.sub.4(CH.sub.3).sub.2NH),
--C(.dbd.O)(NC.sub.5H.sub.8[CH.sub.3])(C.sub.6H.sub.5),
--C(.dbd.O)(NC.sub.4H.sub.8N)(C.sub.5H.sub.3N[CF.sub.3]),
--C(.dbd.O)(NC.sub.5H.sub.8[OCH.sub.3])(C.sub.6H.sub.4[C.sub.6H.sub.4Cl])-
, --C(.dbd.O)(NC.sub.5H.sub.8[OCH.sub.3])(C.sub.6H.sub.4Cl),
--C(.dbd.O)(NC.sub.5H.sub.8[OH])(C.sub.6H.sub.4Cl),
--C(.dbd.O)(NC.sub.5H.sub.8[OH])(C.sub.6H.sub.4[C.sub.6H.sub.4Cl]),
--C(.dbd.O)(NC.sub.5H.sub.8[OCH.sub.3])(C.sub.6H.sub.4F),
--C(.dbd.O)NH(C.sub.5H.sub.9N)(CH.sub.2).sub.P(C.sub.6H.sub.5),
--C(.dbd.O)(NC.sub.5H.sub.9)(CH.sub.2).sub.P(C.sub.6H.sub.5),
--C(O)(NC.sub.5H.sub.9)(NC.sub.4H.sub.8),
--C(.dbd.O)(NC.sub.4H.sub.8N)(C- H.sub.2).sub.P(C.sub.6H.sub.11),
--C (.dbd.O)(NC.sub.4H.sub.8N)(CH.sub.2).- sub.PCH(CH.sub.3).sub.2,
--C(.dbd.O)(NC.sub.5H.sub.9[NC.sub.5H.sub.10]),
--C(.dbd.O)(NC.sub.4H.sub.8N)(C.sub.5H.sub.9),
--C(O)(NC.sub.5H.sub.9)NH.- sub.2,
--C(.dbd.O)(NC.sub.5H.sub.8[C(.dbd.O)CH.sub.3])(C.sub.6H.sub.5),
--C(.dbd.O)(NC.sub.5H.sub.7)C.sub.2(C.sub.6H.sub.5),
--C(.dbd.O)(NC.sub.5H.sub.9)(C(CH.sub.3).sub.3,
--C(.dbd.O)(NC.sub.4H.sub- .8N)CH.sub.2C.sub.2(C.sub.6H[CN]),
--C(.dbd.O)(NC.sub.5H.sub.8[C(.dbd.O)OC- H.sub.3)(C.sub.6H.sub.5),
--C(.dbd.O)(NC.sub.5H.sub.8[C(.dbd.O)O(CH.sub.2)-
.sub.PCH.sub.3])(C.sub.6H.sub.5),
--C(.dbd.O)(NC.sub.5H.sub.8[C(.dbd.O)NH.- sub.2])(C.sub.6H.sub.5),
--C(.dbd.O)(NC.sub.5H.sub.8[C(.dbd.O)NHCH.sub.3])-
(C.sub.6H.sub.5),
--C(.dbd.O)(NC.sub.5H.sub.8[NHC(.dbd.O)CH.sub.3])(C.sub.-
6H.sub.5),
--C(.dbd.O)(NC.sub.5H.sub.8[C(.dbd.O)N(CH.sub.3).sub.2])(C.sub.-
6H.sub.5),
--C(.dbd.O)(NC.sub.5H.sub.8[C(.dbd.O)NHCH.sub.2(C.sub.6H.sub.5)-
])(C.sub.6H.sub.5),
--C(.dbd.O)(NC.sub.5H.sub.8[C(.dbd.O)NH(CH.sub.2).sub.-
PCH.sub.3])(C.sub.6H.sub.5), --C(.dbd.O)(NC.sub.5H.sub.8[C(.dbd.O)N
{(CH.sub.2).sub.PCH.sub.3}.sub.2])(C.sub.6H.sub.5),
--C(.dbd.O)(NC.sub.5H.sub.8[C(.dbd.O)(NC.sub.3H.sub.6)])(C.sub.6H.sub.5),
--C(.dbd.O)(NC.sub.5H.sub.8[C(.dbd.O)OC(CH.sub.3).sub.2])(C.sub.6H.sub.5)-
,
--C(.dbd.O)(NC.sub.5H.sub.8[C(.dbd.O)NH.sub.2])(NECH.sub.2CH.sub.3),
--C(.dbd.O)(NC.sub.5H.sub.8[OCH.sub.3])(C.sub.6H.sub.4[OCH.sub.3]),
--C(.dbd.O)(NC.sub.5H.sub.5[C(--O)NH.sub.2])(NC.sub.4H.sub.8),
--C(.dbd.O)(NC.sub.5H.sub.7)(C.sub.6H.sub.4[OCH.sub.3]),
--C(.dbd.O)(NC.sub.5H.sub.8[NH.sub.2])(C.sub.6H.sub.5),
--C(.dbd.O)(NC.sub.5H.sub.8[C(.dbd.O)H])(C.sub.6H.sub.5),
--C(.dbd.O)(NC.sub.5H.sub.8[OCH.sub.3])(CH.sub.2).sub.P(C.sub.6H.sub.5),
--C(.dbd.O)(NC.sub.5H.sub.8[OCH.sub.3])(C.sub.6H.sub.4[CH.sub.3]),
--C(.dbd.O)(NC.sub.5H.sub.8[(CH.sub.2).sub.POCH.sub.3])(C.sub.6H.sub.5),
--C(.dbd.O)NH(C.sub.4H.sub.7N)(CH.sub.2).sub.P(C.sub.6H.sub.5),
--C(.dbd.O)(NC.sub.4H.sub.8N)(CH.sub.2).sub.P(C.sub.6H.sub.4Cl),
--C(.dbd.O)(NC.sub.4H.sub.8N)(CH.sub.2).sub.P(C.sub.6H.sub.4[OCH.sub.3]),
--C(.dbd.O)NH(CH.sub.2).sub.P(C.sub.6H.sub.4[C.sub.2HSN.sub.2],
--C(.dbd.O)(NC.sub.4H.sub.8N)C(.dbd.O)(CH.sub.2).sub.P(C.sub.6H.sub.4Cl),
--C(.dbd.O)(NC.sub.5H.sub.9)(C.sub.3N.sub.2H.sub.2)(C.sub.6H.sub.4Cl),
--C(.dbd.O)(NC.sub.4H.sub.8N)CH.sub.2C(.dbd.O)N(CH.sub.3)(C.sub.6H.sub.5)-
,
--C(.dbd.O)(NC.sub.4H.sub.8N)C(.dbd.O)O(CH.sub.2).sub.P(C.sub.6H.sub.5),
--C(.dbd.O)(NC.sub.5H.sub.8[C.sub.2H.sub.3N.sub.2O])(C.sub.6H.sub.5),
--C(.dbd.O)(NC.sub.5H.sub.9)N(CH.sub.3)(CH.sub.2).sub.P(C.sub.6H.sub.5),
--C(.dbd.O)(NC.sub.5H.sub.9)NH(CH.sub.2).sub.P(C.sub.6H.sub.5),
--C(.dbd.O)(NC.sub.5H.sub.9)NH(CH.sub.2).sub.P(C.sub.6H.sub.4Cl),
--C(.dbd.O)(NC.sub.5H.sub.9)NH(CH.sub.2).sub.P(C.sub.3N.sub.2H.sub.3),
--C(.dbd.O)(NC.sub.5H.sub.9)NH(CH.sub.2).sub.P(C.sub.5H.sub.4N),
--C(.dbd.O)(NC.sub.5H.sub.9)NH(CH.sub.2).sub.P(C.sub.6H.sub.5),
--C(.dbd.O)(NC.sub.5H.sub.9)N(CH.sub.3)(CH.sub.2).sub.P(C.sub.6H.sub.5),
--C(.dbd.O)(NC.sub.5H.sub.9)NHCH(CH.sub.3)(C.sub.6H.sub.5),
--(CH.sub.2)PC(.dbd.O)(NC.sub.4H.sub.8N)(CH.sub.2).sub.P(C.sub.6H.sub.5),
--C(.dbd.O)NH(CH.sub.2).sub.P(C.sub.6H.sub.5),
--C(.dbd.O)NHCH[(CH.sub.2)-
.sub.POH].sub.2--C(.dbd.O)NH(CH.sub.2).sub.P(OH)(C.sub.6H.sub.10),
--C(.dbd.O)NH(CH.sub.2).sub.P(C.sub.6H.sub.4{O[C.sub.6H.sub.5]}),
--C(.dbd.O)(NC.sub.4H.sub.7)(CH.sub.2).sub.PNH(C.sub.6H.sub.5),
--C(.dbd.O)(NC.sub.4H.sub.8N)(CH.sub.2).sub.P(C.sub.6H.sub.4)CF.sub.3,
--C(.dbd.O)(NC.sub.4H.sub.8N)(CH.sub.2).sub.P(C.sub.6H.sub.4F),
--C(.dbd.O)(NC.sub.4H.sub.8N)(CH.sub.2).sub.P(C.sub.7O.sub.2H.sub.5),
--C(.dbd.O)(NC.sub.4H.sub.8N)(CH.sub.2).sub.P(C.sub.6H.sub.4)CH.sub.3,
--C(.dbd.O)(NC.sub.4H.sub.8N)(CH.sub.2).sub.P(C.sub.6 H.sub.5),
--C(.dbd.O)(NC.sub.4H.sub.8N)(CH.sub.2).sub.P(C.sub.6H.sub.3Cl.sub.2),
--C(.dbd.O)(NC.sub.5H.sub.8N)(CH.sub.2).sub.P(C.sub.6H.sub.5),
--C(.dbd.O)(NC.sub.4H.sub.8)(C.sub.6H.sub.4)NHC(.dbd.O)CH.sub.3,
--C(.dbd.O)(NC.sub.4H.sub.8N)(C.sub.6H.sub.4[CN]),
--C(.dbd.O)(NC.sub.4H.sub.8N)(C.sub.6H.sub.4[N(CH.sub.3)C(.dbd.O)CH.sub.3-
]),
--C(.dbd.O)(NC.sub.4H.sub.8N)(C.sub.6H.sub.3[(CH.sub.3).sub.2]),
--C(.dbd.O)(NC.sub.4H.sub.8N)(C.sub.6H.sub.4Cl),
--C(.dbd.O)(NC.sub.4H.su- b.8N)(C.sub.6H.sub.3[OCH.sub.3).sub.2]),
--C(.dbd.O)(NC.sub.4H.sub.8N)(C.s- ub.6H.sub.3Cl[(OCH.sub.3)]),
--C(.dbd.O)(NC.sub.5H.sub.9N)(CH.sub.2).sub.P- O(C.sub.6H.sub.4Cl),
--C(--O)(NC.sub.5H.sub.8N)(CH.sub.2).sub.P(C.sub.6H.s- ub.5),
--C(.dbd.O)(NC.sub.5H.sub.9)(CH.sub.2).sub.PO(C.sub.6H.sub.5),
--C(.dbd.O)(NC.sub.5H.sub.9)(CH.sub.2).sub.PO(C.sub.6H.sub.4[CN]),
--C(.dbd.O)(NC.sub.4H.sub.8N)(C.sub.6H.sub.4[NO.sub.2]),
--C(.dbd.O)(NC.sub.4H.sub.8N)(C.sub.6H.sub.4[C(.dbd.O)OCH.sub.3]),
--C(.dbd.O)(NC.sub.4H.sub.8N)(C.sub.6H.sub.4[CH.sub.3]),
--C(.dbd.O)(NC.sub.5H.sub.9)(CH.sub.2).sub.PO(C.sub.6H.sub.3Cl.sub.2),
--C(.dbd.O)(NC.sub.5H.sub.9)(CH.sub.2).sub.PO(C.sub.6H.sub.3[CN]),
--C(.dbd.O)(NC.sub.5H.sub.9[CN])(C.sub.6H.sub.4Cl),
--C(.dbd.O)(NC.sub.5H.sub.8N)(C.sub.6H.sub.4[C(.dbd.O)NH.sub.2]),
--C(.dbd.O)(NC.sub.5H.sub.8[CN])(C.sub.6H.sub.4[OCH.sub.3]),
--C(.dbd.O)(NC.sub.5H.sub.8[CN])(C.sub.6H.sub.4Cl),
--C(.dbd.O)(NC.sub.5H.sub.8N[C(.dbd.O)(NC.sub.4H.sub.8)])(C.sub.6H.sub.5)-
,
--C(.dbd.O)(NC.sub.5H.sub.5[C(.dbd.O)(NC.sub.5H.sub.10)])(C.sub.6H.sub.5-
),
--C(.dbd.O)(NC.sub.5H.sub.8[C(.dbd.O)(NC.sub.4H.sub.8O)])(C.sub.6H.sub.-
5),
--C(.dbd.O)(NC.sub.5H.sub.8[C(.dbd.O)NHC(CH.sub.3).sub.3])(C.sub.6H.su-
b.5),
--C(.dbd.O)(NC.sub.5H.sub.8[C(.dbd.O)(NC.sub.3H.sub.6)])(C.sub.6H.su-
b.5),
--C(.dbd.O)(NC.sub.5H.sub.8[CH(CH.sub.3).sub.2])(C.sub.6H.sub.5),
--C(.dbd.O)(NC.sub.4H.sub.8N)CH.sub.2C.sub.2(C.sub.4H.sub.3S),
--C(.dbd.O)(NC.sub.5H.sub.8[C(.dbd.O)OCH.sub.2(C.sub.4H.sub.7)])(C.sub.6H-
.sub.5), --C(.dbd.O)(NC.sub.5H.sub.8[OCH.sub.3])(C.sub.6H.sub.4Cl),
--C(.dbd.O)(NC.sub.5H.sub.8[OCH.sub.3])(C.sub.6H.sub.4[CF.sub.3]),
--C(.dbd.O)(NC.sub.5H.sub.8[OCH.sub.3])(C(CH.sub.3).sub.2),
--C(.dbd.O)(NC.sub.4H.sub.8N)(CH.sub.2).sub.P(C.sub.6H[CN]),
--C(.dbd.O)(NC.sub.5H.sub.8)(C.sub.6H.sub.5).sub.2--CH.sub.2O(CH.sub.2).s-
ub.PN(CH.sub.3)CH.sub.2CHCH(C.sub.6H.sub.5), or
--CH.sub.2O(CH.sub.2).sub.- PNH(CH.sub.2).sub.3(C.sub.6H.sub.5);
wherein p is 0, 1, 2, 3 or 4, or a specific enantiomer thereof, or
a specific tautomer thereof, or a pharmaceutically acceptable salt
thereof.
4. The compound of claim 1, having the structure: 373wherein,
R.sub.1, R.sub.2 and N together form a substituted azetidine or
piperazine ring; R.sub.4 is H; and R.sub.6 is a substituted or
unsubstituted aryl or heteroaryl ring.
5. The compound of claim 4, wherein R.sub.1, R.sub.2 and N together
form a substituted azetidine ring.
6. The compound of claim 4, wherein R.sub.1, R.sub.2 and N together
form a substituted piperazine ring.
7. The compound of claim 1, having the structure: 374wherein,
R.sub.6 is a substituted or unsubstituted aryl or heteroaryl ring;
and m is 0, 1, 2 or 3.
8. The compound of claim 9, wherein R.sub.4 is H.
9. The compound of claim 8, wherein R.sub.3 is substituted or
unsubstituted phenyl.
10. The compound of claim 9, wherein, R.sub.1 is
--(CH.sub.2).sub.2NHC(.db- d.O)CH.sub.3; R.sub.2 is hydrogen or
methyl; R.sub.4 is hydrogen or methyl; and R.sub.6 is substituted
or unsubstituted phenyl or pytidine.
11. The compound of claim 10, wherein R.sub.2 is H.
12. The compound of claim 11, wherein R.sub.6 is substituted
phenyl.
13. The compound of claim 1, having the structure: 375wherein,
R.sub.6 is a substituted or unsubstituted (C.sub.1-C.sub.30)alkyl
or (C.sub.3-C.sub.10)cycloalkyl; m is 0, 1, 2 or 3.
14. The compound of claim 13, wherein R.sub.4 is H;
15. The compound of claim 14, wherein R.sub.3 is substituted or
unsubstituted phenyl.
16. The compound of claim 15, wherein, R.sub.1 is
--(CH.sub.2).sub.2NHC(.d- bd.O)CH.sub.3; R.sub.2 is hydrogen or
methyl; R.sub.4 is hydrogen or methyl; and R.sub.6 is substituted
or unsubstituted cyclopentyl.
17. The compound of claim 16, wherein R.sub.2 is H.
18. The compound of claim 1, having the structure: 376wherein,
R.sub.6 is a substituted or unsubstituted 4-8 membered heterocyclic
ring; and m is 0, 1, 2 or 3.
19. The compound of claim 18, wherein R.sub.4 is H.
20. The compound of claim 19, wherein R.sub.3 is substituted or
unsubstituted phenyl;
21. The compound of claim 20, wherein, R.sub.1 is
--(CH.sub.2).sub.2NHC(.d- bd.O)CH.sub.3; R.sub.2 is hydrogen or
methyl; R.sub.4 is hydrogen or methyl; and R.sub.6 is substituted
or unsubstituted piperidine.
22. The compound of claim 21, wherein R.sub.2 is H.
23. The compound of claim 1, having the structure: 377wherein,
R.sub.7 is hydrogen, or a substituted or unsubstituted
(C.sub.1-C.sub.30)alkyl, (C.sub.1-C.sub.30)alkylaryl.
24. The compound of claim 23, wherein R.sub.3 is substituted or
unsubstituted phenyl.
25. The compound of claim 24, wherein R.sub.4 is hydrogen.
26. The compound of claim 1, having the structure: 378wherein,
R.sub.8, N, and R.sub.9 together form a substituted or
unsubstituted 4-8 membered heterocyclic ring.
27. The compound of claim 26, wherein R.sub.8NR.sub.9 together form
a substituted or unsubstituted azetidine, pyrrolidine, piperazine,
piperidine, morpholine, azocane, dihydro-1H-isoquinoline,
1,2,3,6-tetrahydropyridine, dihydro-2H-pyridine,
1,3,4,9-tetrahydro-.beta- .-carboline,
1,3,8-triazaspiro[4.5]decane, 2,8-diazaspiro[4.5]decane,
2,5-diazabicyclo[2.2.1]heptane, 1,4-dioxa-8-azaspiro[4.5]decane, or
[1.4]diazepane ring.
28. The compound of claim 27, wherein R.sub.8NR.sub.9 together form
a substituted or unsubstituted azetidine, pyrrolidine, piperazine,
piperidine or [1.4]diazepane ring.
29. The compound of claim 27, wherein the ring formed by
R.sub.8NR.sub.9 is substituted with one or more aryl, heteroaryl,
(C.sub.1-C.sub.30)alkyl- aryl, (C.sub.1-C.sub.30)alkylheteroaryl,
(C.sub.1-C.sub.30)alkenylaryl, (C.sub.1-C.sub.30)alkenylheteroaryl,
(C.sub.1-C.sub.30)alkynylaryl, or
(C.sub.1-C.sub.30)allynylheteroaryl moiety, which itself can be
substituted.
30. The compound of claim 26, wherein R.sub.3 is a substituted or
unsubstituted phenyl.
31. The compound of claim 30, wherein R.sub.1 is
--(CH.sub.2).sub.2NHC(.db- d.O)CH.sub.3; R.sub.2 is hydrogen or
methyl; and R.sub.4 is hydrogen or methyl.
32. The compound of claim 1, having the structure: 379wherein,
R.sub.8 and R.sub.9 are each independently hydrogen, or a
substituted or unsubstituted (C.sub.1-C.sub.30)alkyl,
(C.sub.1-C.sub.30)alkylaryl, (C.sub.1-C.sub.30)alkylamino,
(C.sub.1-C.sub.30)alkoxy, or a saturated or unsaturated, monocyclic
or bicyclic, carbocyclic or heterocyclic ring.
33. The compound of claim 32, wherein R.sub.8 or R.sub.9 is a
(C.sub.1-C.sub.30)alkyl substituted with one or more hydroxy,
dihydroxy or amino moiety.
34. The compound of claim 32, wherein R.sub.8 or R.sub.9 is a
substituted or unsubstituted pyrrolidine, piperidine,
bicycle[2.2.1]heptane, 2-oxoazepan, indane, or cyclopropylbenzene
ring.
35. The compound of claim 1, having the structure: 380wherein,
R.sub.10 is hydrogen or a substituted or unsubstituted
(C.sub.1-C.sub.30)alkyl, (C.sub.3-C.sub.10)cycloalkyl, or an aryl,
heteroaryl or heterocyclic ring.
36. The compound of claim 35, wherein R.sub.10 is a substituted or
unsubstituted piperidine ring.
37. The compound of claim 35, wherein R.sub.3 is a substituted or
unsubstitited phenyl.
38. The compound of claim 37, wherein R.sub.4 is hydrogen.
39. The compound of claim 38, wherein R.sub.1 is
--(CH.sub.2).sub.2NHC(.db- d.O)CH.sub.3;
40. The compound of claim 39, wherein R.sub.2 is hydrogen.
41. The compound of claim 35, having the structure: 381
42. The compound of claim 1, having the structure: 382wherein,
R.sub.11NR.sub.12 together form a substituted or unsubstituted 4-8
membered heterocyclic ring; and k is 1, 2 or 3.
43. The compound of claim 42, wherein R.sub.11NR.sub.12 together
form a substituted or unsubstituted azetidine, pyrrolidine,
piperazine, piperidine, morpholine, azocane,
dihydro-1H-isoquinoline, 1,2,3,6-tetrahydropyridine,
dihydro-2H-pyridine, 1,3,4,9-tetrahydro-.beta- .-carboline,
1,3,8-triazaspiro[4.5]decane, 2,8-diazaspiro[4.5]decane,
2,5-diazabicyclo[2.2.1]heptane, 1,4-dioxa-8-azaspiro[4.5]decane, or
[1.4]diazepane ring.
44. The compound of claim 43, wherein R.sub.11NR.sub.12 together
form a substituted or unsubstituted azetidine, pyrrolidine,
piperazine, piperidine or [1.4]diazepane ring.
45. The compound of claim 43, wherein the ring formed by
R.sub.11NR.sub.12 is substituted with one or more aryl, heteroaryl,
(C.sub.1-C.sub.30)alkyl- aryl, (C.sub.1-C.sub.30)alkylheteroaryl,
(C.sub.1-C.sub.30)alkenylaryl, (C.sub.1-C.sub.30)alkenylheteroaryl,
(C.sub.1-C.sub.30)alkynylaryl, or
(C.sub.1-C.sub.30)alkynylheteroaryl moieties, which itself can be
substituted.
46. The compound of claim 42, wherein R.sub.3 is a substituted or
unsubstituted phenyl.
47. The compound of claim 46, wherein R.sub.4 is hydrogen.
48. The compound of claim 47, wherein R.sub.1 is
--(CH.sub.2).sub.2NHC(.db- d.O)CH.sub.3.
49. The compound of claim 1, having the structure: 383wherein,
R.sub.11NR.sub.12 together form a substituted or unsubstituted 4-8
membered heterocyclic ring; and k is 1, 2 or 3.
50. The compound of claim 49, wherein R.sub.11NR.sub.12 together
form a substituted or unsubstituted azetidine, pyrroliaine,
piperazine, piperidine, morpholine, azocane,
dihydro-1H-isoquinoline, 1,2,3,6-tetrahydropyridine,
dihydro-2H-pyridine, 1,3,4,9-tetrahydro-.beta- .-carboline,
1,3,8-triazaspiro[4.5]decane, 2,8-diazaspiro[4.5]decane,
2,5-diazabicyclo[2.2.1]heptane, 1,4-dioxa-8-azaspiro[4.5]decane, or
[1.4]diazepane ring.
51. The compound of claim 50, wherein R.sub.11NR.sub.12 together
form a substituted or unsubstituted azetidine, pyrrolidine,
piperazine, piperidine or [1.4]diazepane ring.
52. The compound of claim 50, wherein the ring formed by
R.sub.11NR.sub.12 is substituted with one or more aryl, heteroaryl,
(C.sub.1-C.sub.30)alkyl- aryl, (C.sub.1-C.sub.30)alkylheteroaryl,
(C.sub.1-C.sub.30)alkenylaryl, (C.sub.1-C.sub.30)alkenylheteroaryl,
(C.sub.1-C.sub.30)alkynylaryl, or
(C.sub.1-C.sub.30)alkynylheteroaryl moiety.
53. The compound of claim 49, wherein R.sub.3 is a substituted or
unsubstituted phenyl.
54. The compound of claim 53, wherein R.sub.4 is hydrogen.
55. The compound of claim 54, wherein R.sub.1 is
--(CH.sub.2).sub.2NHC(.db- d.O)CH.sub.3.
56. A compound having the structure: 384wherein, R.sub.13 and
R.sub.14 are each independently a hydrogen atom or a substituted or
unsubstituted alkyl or alkylaryl moiety; or R.sub.13NR.sub.14
together form a substituted or unsubstituted 4 membered
heterocyclic ring, a substituted or unsubstituted 5 membered ring,
or a substituted or unsubstituted piperazine, wherein the
five-membered ring is substituted with --CH.sub.2C(.dbd.O)OH;
R.sub.15 is hydrogen or a substituted or unsubstituted alkyl; and
R.sub.16 is --CH.sub.2NR.sub.17, --CH.sub.2OR.sub.17,
--CH.sub.2CH.sub.2C(.dbd.O)OR.sub.17,
CH.sub.2CH.sub.2C(.dbd.O)NR.sub.18R.sub.19,
--C(.dbd.O)NR.sub.18R.sub.19, or --C(.dbd.O)OR.sub.17, wherein
R.sub.17, R.sub.18 and R.sub.19 are each independently a hydrogen
atom, a substituted or unsubstituted alkyl, aryl or alkylaryl
moiety, or R.sub.14NR.sub.15 together form a substituted or
unsubstituted 4 to 8 membered heterocyclic ring.
57. The compound of claim 56, wherein any alkyl is a straight chain
(C.sub.1-C.sub.30)alkyl or a branched chain
(C.sub.3-C.sub.30)alkyl.
58. The compound of claim 57, wherein any heterocyclic ring, if
present, is a substituted or unsubstituted morpholine, pyrrolidine,
piperazine, piperidine, azocane, dihydro-1H-isoquinoline,
dihydro-2H-pyridine, 1,3,4,9-tetrahydro-.beta.-carboline,
1,3,8-triazaspiro[4.5]decane, 2,8-diazaspiro[4.5]decane,
2,5-diazabicyclo[2.2.1]heptane, or [1,4]diazepane ring.
59. The compound of claim 7, wherein the compound is selected from
the group consisting of:
N-{2-[6-(4-Fluorophenoxymethyl)-2-phenyl-7H-pyrrolo[-
2,3-d]pyrimidin-4-ylamino]-ethyl}-acetamide;
N-{2-[6-(4-Methoxyphenoxymeth-
yl)-2-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino]-ethyl}-acetamide;
N-[2-(2-Phenyl-6-m-tolyloxymethyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-e-
thyl]-acetamide;
N-{2-[6-(3-Bromophenoxymethyl)-2-phenyl-7H-pyrrolo[2,3-d]-
pyrimidin-4-ylamino]-ethyl}-acetamide;
3-[4-(2-Acetylaminoethylamino)-2-ph-
enyl-7H-pyrrolo[2,3-d]pyrimidin-6-ylmethoxy]-benzoic acid methyl
ester;
N-{2-[6-(4-Chlorophenoxymethyl)-2-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-yla-
mino]-ethyl}-acetamide; and
N-{2-[6-(3-Methoxyphenoxymelhyl)-2-phenyl-7H-p-
yrrolo[2,3-d]pyrimidin-4-ylamino]-ethyl}-acetamide.
60. The compound of claim 18, wherein the compound is selected from
the group consisting of:
N-(2-{6-[1-(Benzenesulfonyl)piperidin-4-yloxymethyl]-
-2-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino}ethyl)acetamide;
N-{2-[6-(1-Phenethylpiperidin-4-yloxymethyl)-2-phenyl-7H-pyrrolo[2,3-d]py-
rimidin-4-ylamino]ethyl}acetamide;
N-[2-{6-[1-(3-Phenylpropyl)piperidin-4--
yloxymethyl]-2-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino}ethyl]acetamide-
;
N-(2-{6-[1-(4-Bromobenzyl)piperidin-4-yloxymethyl]-2-phenyl-7H-pyrrolo[2-
,3-d]pyrimidin-4-ylamino}ethyl)acetamide;
N-[2-(6-{1-[2-(2-Chlorophenyl)et-
hyl]piperidin-4-yloxymethyl}-2-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino-
)ethyl]acetamide;
N-[2-(6-{1-[2-(3-Chlorophenyl)ethyl]piperidin-4-yloxymet-
hyl}-2-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)ethyl]acetamide;
N-(2-{6-[1-(3-Chlorobenzyl)piperidin-4-yloxymethyl]-2-phenyl-7H-pyrrolo[2-
,3-d]pyrimidin-4-ylamino}ethyl)acetamide;
N-[2-(6-{1-[2-(4-Chlorophenyl)et-
hyl]piperidin-4-yloxymethyl}-2-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino-
)ethyl]acetamide;
N-[2-(6-{1-[2-(2-Methoxyphenyl)ethyl]piperidin-4-yloxyme-
thyl}-2-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)ethyl]acetamide;
N-[2-(6-{1-[2-(3-Methoxyphenyl)ethyl]piperidin-4-yloxymethyl}-2-phenyl-7H-
-pyrrolo[2,3-d]pyrimidin-4-4ylamino)ethyl]acetamide;
N-[2-(6-{1-[2-(4-Methoxyphenyl)ethyl]piperidin-4-yloxymethyl}-2-phenyl-7H-
-pyrrolo[2,3-d]pyrimidin-4-ylamino)ethyl]acetamide;
N-[2-(6-{1-[2-(4-Fluorophenyl)ethyl]piperidin-4-yloxymethyl}-2-phenyl-7H--
pyrrolo[2,3-d]pyrimidin-4-ylamino)ethyl]acetamide;
N-[2-(6-{1-[2-(2-Chloro-
-4-fluorophenyl)ethyl]piperidin-4-yloxymethyl}-2-phenyl-7H-pyrrolo[2,3-d]p-
yrimidin-4-ylamino)ethyl]acetamide;
N-[2-(6-{1-[2-(2-Chloro-6-fluorophenyl-
)ethyl]piperidin-4-yloxymethyl}-2-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylam-
ino)ethyl]acetamide;
N-[2-(6-{1-[2-(2-Trifluoromethylphenyl)ethyl]piperidi-
n-4-yloxymethyl}-2-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)ethyl]aceta-
mide; and
N-[2-(6-{1-[2-(2-Bromophenyl)ethyl]piperidin-4-yloxymethyl}-2-ph-
enyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)ethyl]acetamide.
61. The compound of claim 13, wherein the compound is
N-(2-(6-{2-[Methyl-(3-phenylallyl)amino]ethoxymethyl}-2-phenyl-7H-pyrrolo-
[2,3-d]pyrimidin-4-ylamino}ethyl]acetamide
62. The compound of claim 26, wherein the compound is selected from
the group consisting of:
N-(2-{2-Phenyl-6-[4-(3-phenylallyl)-piperazine-1-car-
bonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino}-ethyl)-acetamide;
N-{2-[6-(4-Hydroxy4-isopropylpiperidine-1-carbonyl)-2-phenyl-7H-pyrrolo[2-
,3-d]pyrimidin-4-ylamino]-ethyl}-acetamide;
N-(2-{2-Phenyl-6-[4-(3-phenylp-
ropyl)-piperazine-1-carhonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino}-ethyl)-
-acetamide;
N-{2-[6-(4-Phenethylpiperazine-1-carbonyl)-2-phenyl-7H-pyrrolo-
[2,3-d]pyrimidin-4-ylamino]-ethyl}-acetamide;
2-{2-Phenyl-6-[4-(3-phenylpr-
opyl)-piperazine-1-carbonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino}-acetami-
de;
N-[2-(6-{4-[2-(4-Chlorophenoxy)-ethyl]-piperazine-1-carbonyl}-2-phenyl-
-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-ethyl]-acetamide;
N-{2-[6-(4-Cyano-4-phenylpiperidine-1-carbonyl)-2-phenyl-7H-pyrrolo[2,3-d-
]pyrimidin-4-ylamino]-ethyl}-acetamide;
N-(2-{2-Phenyl-6-[4-(3-phenylprop--
2-ynyl)-piperazine-1-carbonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino}-ethyl-
)-acetamide;
N-(2-{6-[cis-3,5-Dimethyl4-(3-phenylpropyl)-piperazine-1-carb-
onyl]-2-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino}-ethyl)-acetamide;
N-{2-[6-(4,4-Diphenylpiperidine-1-carbonyl)-2-phenyl-7H-pyrrolo[2,3-d]pyr-
imidin-4-ylamino]-ethyl}-acetamide;
N-{2-[6-(3,3-Diphenylpiperidine-1-carb-
onyl)-2-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino]-ethyl}-acetamide;
N-{2-[6-(4-Methoxy4-phenylpiperidine-1-carbonyl)-2-phenyl-7H-pyrrolo[2,3--
d]pyrimidin-4-ylamino]-ethyl}-acetamide;
N-(2-{6-[trans-2,5-Dimethyl-4-(3--
phenylpropyl)-piperazine-1-carbonyl]-2-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-
-ylamino}-ethyl)-acetamide;
N-{2-[6-(trans-2,5-Dimethylpiperazine-1-carbon-
yl)-2-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino]-ethyl}-acetamide;
N-{2-[6-(4-Benzyl-cis-3,5-dimethylpiperazine-1-carbonyl)-2-phenyl-7H-pyrr-
olo[2,3-d]pyrimidin-4-ylamino]-ethyl}-acetamide;
N-{2-[6-(cis-3,5-Dimethyl-
4-phenethylpiperazine-1-carbonyl)-2-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl-
amino]-ethyl}-acetamide;
N-{2-[6-(3-Methyl-3-phenylpiperidine-1-carbonyl)--
2-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino]-ethyl}-acetamide;
N-(2-{2-Phenyl-6-[4-(5-trifluoromethylpyridin-2-yl)-piperazine-1-carbonyl-
]-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino}-ethyl)-acetamide;
N-(2-{6-[4-(2'-Chlorobiphenyl-2-yl)-4-methoxypiperidine-1-carbonyl]-2-phe-
nyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino}-ethyl)-acetamide;
N-(2-{6-[4-(2-Chlorophenyl).sub.4-methoxypiperidine-1-carbonyl]-2-phenyl--
7H-pyrrolo[2,3-d]pyrimidin-4-ylamino}-ethyl)-acetamide;
N-(2-{6-[4-(2-Chlorophenyl).sub.4-hydroxypiperidine-1-carbonyl]-2-phenyl--
7H-pyrrolo[2,3-d]pyrimidin-4-ylamino}-ethyl)-acetamide;
N-(2-{6-[4-(2'-Chlorobiphenyl-2-yl)-4-hydroxypiperidine-1-carbonyl]-2-phe-
nyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino}-ethyl)-acetamide;
N-(2-{6-[4-(4-Fluorophenyl)-4-methoxypiperidine-1-carbonyl]-2-phenyl-7H-p-
yrrolo[2,3-d]pyrimidin-4-ylamino}-ethyl)-acetamide;
N-(2-{2-Phenyl-6-[4-(4-phenylbutyl)-piperazine-1-carbonyl]-7H-pyrrolo[2,3-
-d]pyrimidin-4-ylamino}-ethyl)-acetamide;
N-(2-{2-Phenyl-6-[4-(3-phenylpro-
pyl)-piperidine-1-carbonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino}-ethyl)-a-
cetamide;
N-{2-[2-Phenyl-6-(4-pyrrolidin-1-yl-piperidine-1-carbonyl)-7H-py-
rrolo[2,3-d]pyrimidin-4-ylamino]-ethyl}-acetamide;
N-(2-{6-[4-(3-Cyclohexy-
lpropyl)-piperazine-1-carbonyl]-2-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylam-
ino}-ethyl)-acetamide;
N-(2-{6-[4-(4-Methylpentyl)-piperazine-1-carbonyl]--
2-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino}-ethyl)-acetamide;
N-{2-[6-([1,4']Bipiperidinyl-1'-carbonyl)-2-phenyl-7H-pyrrolo[2,3-d]pyrim-
idin-4-ylamino]-ethyl}-acetamide;
N-{2-[6-(4-Cyclopentylpiperazine-1-carbo-
nyl)-2-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino]-ethyl}-acetamide;
N-{2-[6-(4-Aminopiperidine-1-carbonyl)-2-phenyl-7H-pyrrolo[2,3-d]pyrimidi-
n-4-ylamino]-ethyl}-acetamide;
N-{2-[6-(4-Acetyl-4-phenylpiperidine-1-carb-
onyl)-2-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino]-ethyl}-acetamide;
N-(2-{6-[4-(2-Cyclohexylethyl)-piperazine-1-carbonyl]-2-phenyl-7H-pyrrolo-
[2,3-d]pyrimidin-4-ylamino}-ethyl)-acetamide;
N-{2-[2-Phenyl-6-(4-phenylet-
hynyl-3,6-dihydro-2H-pyridine-1-carbonyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yla-
mino]-ethyl}-acetamide;
N-{2-[6-(4-tert-Butylpiperidine-1-carbonyl)-2-phen-
yl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino]-ethyl}-acetamide;
N-{2-[6-(4-Phenethylpiperidine-1-carbonyl)-2-phenyl-7H-pyrrolo[2,3-d]pyri-
midin-4-ylamino]-ethyl}-acetamide;
N-[2-(6-{4-[3-(2-Cyanophenyl)-prop-2-yn-
yl]-piperazine-1-carbonyl}-2-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)--
ethyl]-acetamide;
N-[2-(6-{4-[3-(3-Cyanophenyl)-prop-2-ynyl]-piperazine-1--
carbonyl}-2-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-ethyl]-acetamide;
N-[2-(6-{4-[3-(4-Cyanophenyl)-prop-2-ynyl]-piperazine-1-carbonyl}-2-pheny-
l-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-ethyl]-acetamide;
1-[4-(2-Acetylaminoethylamino)-2-phenyl-7H-pyrrolo[2,3-d]pyrimidine-6-car-
bonyl]-4-phenylpiperidine-4-carboxylic acid methyl ester;
N-(2-{6-[4-(1-Hydroxyethyl)-4-phenylpiperidine-1-carbonyl]-2-phenyl-7H-py-
rrolo[2,3-d]pyrimidin-4-ylamino}-ethyl)-acetamide;
N-[2-(6-{4-[3-(4-Cyanop-
henyl)-propyl]-piperazine-1-carbonyl}-2-phenyl-7H-pyrrolo[2,3-d]pyrimidin--
4-ylamino)-ethyl]-acetamide;
1-[4-(2-Acetylaminoethylamino)-2-phenyl-7H-py-
rrolo[2,3-d]pyrimidine-6-carbonyl]-4-phenylpiperidine-4-carboxylic
acid ethyl ester;
1-[4-(2-Acetylaminoethylamino)-2-phenyl-7H-pyrrolo[2,3-d]pyr-
imidine-6-carbonyl]-4-phenylpiperidine-4-carboxylic acid amide;
1-[4-(2-Acetylaminoethylamino)-2-phenyl-7H-pyrrolo[2,3-d]pyrimidine-6-car-
bonyl]-4-phenylpiperidine-4-carboxylic acid methylamide;
1-[4-(2-Acetylaminoethylamino)-2-phenyl-7H-pyrrolo[2,3-d]pyrimidine-6-car-
bonyl]-4-phenylpiperidine-4-carboxylic acid dimethylamide;
1-[4-(2-Acetylaminoethylamino)-2-phenyl-7H-pyrrolo[2,3-d]pyrimidine-6-car-
bonyl]-4-phenylpiperidine-4-carboxylic acid benzylamide;
1-[4-(2-Acetylaminoethylamino)-2-phenyl-7H-pyrrolo[2,3-d]pyrimidine-6-car-
bonyl]-4-phenylpiperidine-4-carboxylic acid ethylamide;
1-[4-(2-Acetylaminoethylamino)-2-phenyl-7H-pyrrolo[2,3-d]pyrimidine-6-car-
bonyl]-4-phenylpiperidine-4-carboxylic acid diethylamide;
N-(2-{6-[4-(Azetidine-1-carbonyl)-4-phenylpiperidine-1-carbonyl]-2-phenyl-
-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino}-ethyl)-acetamide;
N-(2-{2-Phenyl-6-[4-phenyl-4-(pyrrolidine-1-carbonyl)-piperidine-1-carbon-
yl]-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino}-ethyl)-acetamide;
N-(2-{2-Phenyl-6-[4-phenyl-4-(piperidine-1-carbonyl)-piperidine-1-carbony-
l]-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino}-ethyl)-acetamide;
N-(2-{6-[4-(Morpholine-4-carbonyl)-4-phenylpiperidine-1-carbonyl]-2-pheny-
l-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino}-ethyl)-acetamide;
1-[4-(2-Acetylaminoethylamino)-2-phenyl-7H-pyrrolo[2,3-d]pyrimidine-6-car-
bonyl]-4-phenylpiperidine-4-carboxylic acid tert-butylamide;
N-{2-[6-(4-Isopropyl-4-phenylpiperidine-1-carbonyl)-2-phenyl-7H-pyrrolo[2-
,3-d]pyrimidin-4-ylamino]-ethyl}-acetamide;
N-(2-{2-Phenyl-6-[4-(3-thiophe-
n-2-yl-prop-2-ynyl)-piperazine-1-carbonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl-
amino}-ethyl)-acetamide;
1-[4-(2-Acetylaminoethylamino)-2-phenyl-7H-pyrrol-
o[2,3-d]pyrimidine-6-carbonyl]-4-phenylpiperidine-4-carboxylic acid
cyclobutylmethyl ester;
N-(2-{6-[4-(4-Chlorophenyl)-4-methoxypiperidine-1-
-carbonyl]-2-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino}-ethyl)-acetamide-
;
N-(2-{6-[4-Methoxy-4-(3-trifluoromethylphenyl)-piperidine-1-carbonyl]-2--
phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino}-ethyl)-acetamide;
N-{2-[6-(4-Isopropyl-4-methoxypiperidine-1-carbonyl)-2-pbenyl-7H-pyrrolo[-
2,3-d]pyrimidin-4-ylamino]-ethyl}-acetamide;
N-{2-[6-(4-Acetylamino-4-phen-
ylpiperidine-1-carbonyl)-2-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino]-et-
hyl}-acetamide;
1-[4-(2-Acetylaminoethylamino)-2-phenyl-7H-pyrrolo[2,3-d]p-
yrimidine-6-carbonyl]-4-phenylpiperidine-4-carboxylic acid
isopropyl ester;
1-[4-(2-Acetylaminoethylamino)-2-phenyl-7H-pyrrolo[2,3-d]pyrimidin-
e-6-carbonyl]-4-ethylaminopiperidine-4-carboxylic acid amide;
N-(2-{6-[4-Methoxy-4-(3-methoxyphenyl)-piperidine-1-carbonyl]-2-phenyl-7H-
-pyrrolo[2,3-d]pyrimidin-4-ylamino}-ethyl)-acetamide;
1-[4-(2-Acetylaminoethylamino)-2-phenyl-7H-pyrrolo[2,3-d]pyrimidine-6-car-
bonyl]-4-pyrrolidin-1-ylpiperidine-4-carboxylic acid amide;
N-(2-{6-[4-(2-Methoxyphenyl)-3,6-dihydro-2H-pyridine-1-carbonyl]-2-phenyl-
-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino}-ethyl)-acetamide;
N-{2-[6-(4-Amino-4-phenylpiperidine-1-carbonyl)-2-phenyl-7H-pyrrolo[2,3-d-
]pyrimidin-4-ylamino]-ethyl}-acetamide;
N-{2-[6-(4-Formyl-4-phenylpiperidi-
ne-1-carbonyl)-2-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino]-ethyl}-aceta-
mide;
N-{2-[6-(4-Benzyl4-methoxypiperidine-1-carbonyl)-2-phenyl-7H-pyrrolo-
[2,3-d]pyrimidin-4-ylamino]-ethyl}-acetamide;
N-{2-[6-(4-Methoxy-4-o-tolyl-
piperidine-1-carbonyl)-2-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino]-ethy-
l}-acetamide;
N-{2-[6-(4-Methoxymethyl-4-phenylpiperidine-1-carbonyl)-2-ph-
enyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino]-ethyl}-acetamide;
N-[2-(6-{4-[3-(2-Chlorophenyl)-propyl]-piperazine-1-carbonyl}-2-phenyl-7H-
-pyrrolo[2,3-d]pyrimidin-4-ylamino)-ethyl]-acetamide;
N-[2-(6-{4-[3-(3-Chlorophenyl)-propyl]-piperazine-1-carbonyl}-2-phenyl-7H-
-pyrrolo[2,3-d]pyrimidin-4-ylamino)-ethyl]-acetamide;
N-[2-(6-{4-[3-(4-Chlorophenyl)-propyl]-piperazine-1-carbonyl}-2-phenyl-7H-
-pyrrolo[2,3-d]pyrimidin-4-ylamino)-ethyl]-acetamide;
N-[2-(6-{4-[3-(2-Methoxyphenyl)-propyl]-piperazine-1-carbonyl}-2-phenyl-7-
H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-ethyl]-acetamide;
N-[2-(6-{4-[3-(3-Methoxyphenyl)-propyl]-piperazine-1-carbonyl}-2-phenyl-7-
H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-ethyl]-acetamide;
N-[2-(6-{4-[3-(4-Methoxyphenyl)-propyl]-piperazine-1-carbonyl}-2-phenyl-7-
H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-ethyl]-acetamide;
N-[2-(6-{4-[3-(4-Chlorophenyl)-propionyl]-piperazine-1-carbonyl}-2-phenyl-
-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-ethyl]-acetamide;
N-[2-(6-{4-[3-(3-Chlorophenyl)-propionyl]-piperazine-1-carbonyl}-2-phenyl-
-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-ethyl]-acetamide;
N-[2-(6-{4-[3-(2-Chlorophenyl)propionyl]-piperazine-1-carbonyl}-2-phenyl--
7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-ethyl]-acetamide;
N-[2-(6-{4-[5-(4-Chlorophenyl)-2H-pyrazol-3-yl]-piperidine-1-carbonyl}-2--
phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-ethyl]-acetamide;
2-{4-[4-(2-Acetylaminoethylamino)-2-phenyl-7H-pyrrolo[2,3-d]pyrimidine-6--
carbonyl]-piperazin-1-yl}-N-methyl-N-phenylacetamide;
4-[4-(2-Acetylaminoethylamino)-2-phenyl-7H-pyrrolo[2,3-d]pyrimidine-6-car-
bonyl]-piperazine-1-carboxylic acid benzyl ester;
N-{2-[6-(4-Oxo-1-phenyl-- 1,3,8-triazaspiro[4
.5]decane-8-carbonyl)-2-phenyl-7H-pyrrolo[2,3-d]pyrimi-
din-4-ylamino]-ethyl}-acetamide;
N-(2-{6-[4-(Methylphenethylamino)-piperid-
ine-1-carbonyl]-2-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino}-ethyl)-acet-
amide;
N-{2-[6-(4-Phenethylaminopiperidine-1-carbonyl)-2-phenyl-7H-pyrrolo-
[2,3-d]pyrimidin-4-ylamino]-ethyl}-acetamide;
N-[2-(6-{4-[2-(4-Chloropheny-
l)-ethylamino]-piperidine-1-carbonyl}-2-phenyl-7H-pyrrolo[2,3-d]pyrimidin--
4-ylamino)-ethyl]-acetamide;
N-[2-(6-{4-[2-(3H-Imidazol-4-yl)-ethylamino]--
piperidine-1-carbonyl}-2-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-ethy-
l]-acetamide;
N-(2-{2-Phenyl-6-[4-(2-pyridin-4-ylethylamino)-piperidine-1--
carbonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino}-ethyl)-acetamide;
N-(2-{2-Phenyl-6-[4-(2-pyridin-2-ylethylamino)-piperidine-1-carbonyl]-7H--
pyrrolo[2,3-d]pyrimidin-4-ylamino}-ethyl)-acetamide;
N-{2-[6-(4-Benzylaminopiperidine-1-carbonyl)-2-phenyl-7H-pyrrolo[2,3-d]-p-
yrimidin-4-ylamino]-ethyl}-acetamide;
N-(2-{6-[4-(Benzylmethylamino)-piper-
idine-1-carbonyl]-2-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino}-ethyl)-ac-
etamide;
N-[2-(2-Phenyl-6-{4-[(pyridin-4-ylmethyl)-amino]-piperidine-1-car-
bonyl}-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-ethyl]-acetamide;
N-(2-{2-Phenyl-6-[4-(2-pyridin-3-ylethylamino)-piperidine-1-carbonyl]-7H--
pyrrolo[2,3-d]pyrimidin-4-ylamino}-ethyl)-acetamide;
N-{2-[2-Phenyl-6-((S)-2-phenylaminomethylpyrrolidine-1-carbonyl)-7H-pyrro-
lo[2,3-d]pyrimidin-4-ylamino]-ethyl}-acetamide;
N-[2-(2-Phenyl-6-{4-[3-(4--
trifluoromethylphenyl)-propyl]-piperazine-1-carbonyl}-7H-pyrrolo[2,3-d]pyr-
imidin-4-ylamino)-ethyl]-acetamide;
N-[2-(6-{4-[3-(4-Fluorophenyl)-propyl]-
-piperazine-1-carbonyl}-2-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-eth-
yl]-acetamide;
N-(2-{6-[4-(3-Benzo[1,3]dioxol-5-yl-propyl)-piperazine-1-ca-
rbonyl]-2-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino}-ethyl)-acetamide;
N-(2-{2-Phenyl-6-[4-(3-p-tolylpropyl)-piperazine-1-carbonyl]-7H-pyrrolo[2-
,3-d]pyrimidin-4-ylamino}-ethyl)-acetamide;
N-[2-(6-{4-[3-(4-Bromophenyl)-- propyl]-piperazine-
-carbonyl}-2-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylami-
no)-ethyl]-acetamide;
N-[2-(6-{4-[3-(3,4-Dichlorophenyl)-propyl]-piperazin-
e-1-carbonyl}-2-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-ethyl]-acetam-
ide;
N-[2-(6-{4-[3-(2,4-Dichlorophenyl)-propyl]-piperazine-1-carbonyl}-2-p-
henyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-ethyl]-acetamide;
N-{2-[6-(4-Benzyl-[1,4]diazepane-1-carbonyl)-2-phenyl-7H-pyrrolo[2,3-d]py-
rimidin-4-ylamino]-ethyl}-acetamide;
N-{2-[6-(4-Phenethyl-[1,4]diazepane-1-
-carbonyl)-2-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino]-ethyl}-acetamide-
;
N-(2-{2-Phenyl-6-[4-(3-phenylpropyl)-[1,4]diazepane-1-carbonyl]-7H-pyrro-
lo[2,3-d]pyrimidin-4-ylamino}-ethyl)-acetamide;
N-(2-{6-[4-(4-Acetylaminop-
henyl)-piperazine-1-carbonyl]-2-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamin-
o}-ethyl)-acetamide;
N-(2-{6-[4-(2-Cyanophenyl)-piperazine-1-carbonyl]-2-p-
henyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino}-ethyl)-acetamide;
N-[2-(6-{4-[4-(Acetylmethylamino)-phenyl]-piperazine-1-carbonyl}-2-phenyl-
-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-ethyl]-acetamide;
N-(2-{6-[4-(2,6-Dimethylphenyl)-piperazine-1-carbonyl]-2-phenyl-7H-pyrrol-
o[2,3-d]pyrimidin-4-ylamino}-ethyl)-acetamide;
N-(2-{6-[4-(2-Chlorophenyl)-
-piperazine-1-carbonyl]-2-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino}-eth-
yl)-acetamide;
N-(2-{6-[4-(2,4-Dimethoxyphenyl)-piperazine-1-carbonyl]-2-p-
henyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino}-ethyl)-acetamide;
N-(2-{6-[4-(5-Chloro-2-methoxyphenyl)-piperazine-1-carbonyl]-2-phenyl-7H--
pyrrolo[2,3-d]pyrimidin-4-ylamino}-ethyl)-acetamide;
N-(2-{6-[4-(4-Chlorophenoxymethyl)-piperidine-1-carbonyl]-2-phenyl-7H-pyr-
rolo[2,3-d]pyrimidin-4-ylamino}-ethyl)-acetamide;
N-{2-[6-(5-Benzyl-2,5-di-
azabicyclo[2.2.1]heptane-2-carbonyl)-2-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-
-ylamino]-ethyl}-acetamide;
N-{2-[6-(4-Phenoxymethylpiperidine-1-carbonyl)-
-2-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino]-ethyl}-acetamide;
N-(2-{6-[4-(4-Cyanophenoxymethyl)-piperidine-1-carbonyl]-2-phenyl-7H-pyrr-
olo[2,3-d]pyrimidin-4-ylamino}-ethyl)-acetamide;
N-(2-{6-[4-(3-Cyanophenox-
ymethyl)-piperidine-1-carbonyl]-2-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylam-
ino}-ethyl)-acetamide;
N-(2-{6-[4-(2-Nitrophenyl)-piperazine-1-carbonyl]-2-
-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino}-ethyl)-acetamide;
2-{4-[4-(2-Acetylaminoethylamino)-2-phenyl-7H-pyrrolo[2,3-d]pyrimidine-6--
carbonyl]-piperazin-1-yl}-benzoic acid methyl ester;
N-{2-[2-Phenyl-6-(4-o-tolylpiperazine-1-carbonyl)-7H-pyrrolo[2,3-d]pyrimi-
din-4-ylamino]-ethyl}-acetamide;
N-(2-{6-[4-(3,4-Dichlorophenoxymethyl)-pi-
peridine-1-carbonyl]-2-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino}-ethyl)-
-acetamide;
N-(2-{6-[4-(2-Cyanophenoxymethyl)-piperidine-1-carbonyl]-2-phe-
nyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino}-ethyl)-acetamide;
N-(2-{6-[4-(2-Chlorophenyl)-4-cyanopiperidine-1-carbonyl]-2-phenyl-7H-pyr-
rolo[2,3-d]pyrimidin-4-ylamino}-ethyl)-acetamide;
2-{4-[4-(2-Acetylaminoet-
hylamino)-2-phenyl-7H-pyrrolo[2,3-d]pyrimidine-6-carbonyl]-piperazin-1-yl}-
-benzamide;
N-(2-{6-[4-Cyano-4-(2-methoxyphenyl)-piperidine-1-carbonyl]-2--
phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino}-ethyl)-acetamide;
N-(2-{6-[4-(3-Chlorophenyl)-4-cyanopiperidine-1-carbonyl]-2-phenyl-7H-pyr-
rolo[2,3-d]pyrimidin-4-ylamino}-ethyl)-acetamide;
N-(2-{6-[4-Cyano4-(3-met-
hoxyphenyl)-piperidine-1-carbonyl]-2-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-y-
lamino}-ethyl)-acetamide; and
N-(2-{6-[4-Cyano-4-(4-methoxyphenyl)-piperid-
ine-1-carbonyl]-2-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino}-ethyl)-acet-
amide.
63. The compound of claim 32, wherein the compound is selected from
the group consisting of:
4-(2-Acetylaminoethylamino)-2-phenyl-7H-pyrrolo[2,3--
d]pyrimidine-6-carboxylic acid (3-phenoxyphenyl)-amide;
4-(2-Acetylaminoethylamino)-2-phenyl-7H-pyrrolo[2,3-d]pyrimidine-6-carbox-
ylic acid (1-benzylpiperidin4-yl)-amide;
4-(2-Acetylaminoethylamino)-2-phe-
nyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid
(1-benzylpyrrolidin-3-yl- )-amide;
4-(2-Acetylaminoethylamino)-2-phenyl-7H-pyrrolo[2,3-d]pyrimidine--
6-carboxylic acid 4-[1,2,3]thiadiazol-4-yl-benzylamide;
4-(2-Acetylaminoethylamino)-2-phenyl-7H-pyrrolo[2,3-d]pyrimidine-6-carbox-
ylic acid benzylamide;
4-(2-Acetylaminoethylamino)-2-phenyl-7H-pyrrolo[2,3-
-d]pyrimidine-6-carboxylic acid
(2-hydroxy-1-hydroxymethylethyl)-amide;
4-(2-Acetylaminoethylamino)-2-phenyl-7H-pyrrolo[2,3-d]pyrimidine-6-carbox-
ylic acid (1-hydroxycyclohexylmethyl)-amide; and
4-(2-Acetylaminoethylamin-
o)-2-phenyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid
[2-(4-phenoxyphenyl)-ethyl]-amide.
64. The compound of claim 42, wherein the compound is
N-(2-{6-[3-(4-Benzylpiperazin-1-yl)-3-oxopropyl]-2-phenyl-7H-pyrrolo[2,3--
d]pyrimidin-4-ylamino}-ethyl)-acetamide.
65. A compound having the structure: 385wherein R.sub.3 is a
substituted or unsubstituted 4-10 membered aryl, heteroaryl or
heterocyclic ring; R.sub.20 is halogen or
--NH(CHR.sub.20').sub.nNHC(.dbd.O)CH.sub.3, where R.sub.20' is H,
OH, alkyl, hydroxyalkyl, cycloalkyl, heteroalkyl, or amino;
R.sub.21 is H or --C(.dbd.O)OH; R.sub.22 is H or SO.sub.2Ph; and n
is 2, 3, 4 or 5; wherein when R.sub.20 is
--NH(CHR.sub.20').sub.nNHC(.dbd- .O)CH.sub.3, R.sub.21 is
--C(.dbd.O)OH.
66. The compound of claim 65, wherein R.sub.3 is substituted or
unsubstituted phenyl.
67. The compound of claim 66, wherein R.sub.20 is Cl.
68. The compound of claim 67, wherein R.sub.22 is SO.sub.2Ph.
69. The compound of claim 68, wherein R.sub.21 is H.
70. The compound of claim 69, wherein R.sub.21 is
--C(.dbd.O)OH.
71. The compound of claim 67, wherein R.sub.20 is
--NH(CH.sub.2).sub.nNHC(- .dbd.O)CH.sub.3 and R.sub.21 is
--C(.dbd.O)OH.
72. The compound of claim 71, wherein R.sub.22 is H.
73. The compound of claim 71, wherein R.sub.22 is SO.sub.2Ph.
74. A method for treating a disease associated with the A.sub.2b
adenosine receptor in a subject in need of such treatment
comprising administering to the subject a therapeutically effective
amount of the compound of claim 1 so as to thereby treat the
disease associated with the A.sub.2b adenosine receptor in the
subject, wherein the disease associated with the A.sub.2b adenosine
receptor is asthma, urticaria, scleroderm arthritis, myocardial
infarction, myocardial reperfusion after ischemia, diabetic
retinopathy, retinopathy of prematurity, diabetes, diarrhea,
inflammatory bowel disease, proliferating tumor or is associated
with mast cell degranulation, vasodilation, hypertension,
hypersensitivity or the release of allergic mediators.
75. The method of claim 74, wherein the disease associated with the
A.sub.2b adenosine receptor is diabetes.
76. The method of claim 74, wherein the disease associated with the
A.sub.2b adenosine receptor is asthma.
77. The method of claim 74, wherein the disease associated with the
A.sub.2b adenosine receptor is associated with mast cell
degranulation.
78. The method of claim 74, wherein the disease associated with the
A.sub.2b adenosine receptor is a proliferating tumor.
79. A method for treating a disease associated with the A.sub.2b
adenosine receptor in a subject in need of such treatment
comprising administering to the subject a therapeutically effective
amount of the compound of claim 1 so as to thereby treat the
disease associated with the A.sub.2b adenosine receptor in the
subject, wherein the disease associated with the A.sub.2b adenosine
receptor is asthma, urticaria, scleroderm arthritis, myocardial
infarction, myocardial reperfusion after ischemia, diabetic
retinopathy, retinopathy of prematurity, diabetes, diarrhea,
inflammatory bowel disease, proliferating tumor or is associated
with mast cell degranulation, vasodilation, hypertension,
hypersensitivity or the release of allergic mediators.
80. A pharmaceutical composition comprising the compound of claim
1, 3, 4, 7, 13, 18, 23, 26, 32, 35, 42 or 49 and a pharmaceutically
acceptable carrier.
81. The pharmaceutical composition of claim 80, formulated for
oral, topical, parenteral or nasal administration.
82. A process for the manufacture of a pharmaceutical composition
comprising admixing the compound of claim 1, 3, 4, 7, 13, 18, 23,
26, 32, 35, 42 or 49 with a pharmaceutically acceptable
carrier.
83. An article of manufacture comprising packaging material; the
pharmaceutical composition of claim 80; and instructions for use of
the pharmaceutical composition in the treatment of a disease
associated with the A.sub.2b adenosine receptor.
84. A process of manufacturing a compound having the structure:
386wherein, R.sub.8 and R.sub.9 are each independently hydrogen, or
a substituted or unsubstituted (C.sub.1-C.sub.30)alkyl,
(C.sub.1-C.sub.30)alkylaryl, (C.sub.1-C.sub.30)alkylamino,
(C.sub.1-C.sub.30)alkoxy, or a saturated or unsaturated, monocyclic
or bicyclic, carbocyclic or heterocyclic ring, or R.sub.8, N, and
R.sub.9 together form a substituted or unsubstituted 4-8 membered
heterocyclic ring, comprising: (a) reacting 387 with PhSO.sub.2Cl
and a reducing agent in the presence of solvent to produce: 388(b)
reacting the product of step (a) with CO.sub.2 in the presence of
lithium diisopropylamide (LDA) and a solvent to produce: 389(c)
reacting the product of step (b) with 390 in the presence solvent
to produce: 391(d) reacting the product of step (c) with a
hydroxide base in solution to produce: 392(e) reacting the product
of step (d) with HNR.sub.7R.sub.8 in the presence of a base and a
coupling agent to produce the compound.
85. The process of claim 84, wherein the reducing agent in step (a)
is NaH and the solvent is dimethylformamide (DMF).
86. The process of claim 84, wherein the solvent in step (b) is
tetrahydrofuran (THF).
87. The process of claim 84, wherein the solvent in step (c) is
dimethyl sulfoxide (DMSO).
88. The process of claim 84, wherein the hydroxide base in step (d)
is sodium hydroxide.
89. The process of claim 84, wherein the base in step (e) is
triethylamine, the coupling agent is
O-(benzotriazol-1-yl)-N,N,N',N'-tetr- amethyluronium
tetrafluoroborate (TBTU), benzotriazol-1-yl-oxytripyrrolidi-
nophosphonium hexafluorophosphate, or
1-ethyl-3-(3-dimethylaminopropyl)-ca- rbodiimide (EDC) and
N-Hydroxybenzotriazole, and the solvent is DMF.
90. The process of claim 84, wherein the order of the steps is (a),
(b), (c), (e), then (d).
91. A compound produced by the process of claim 84.
92. Use of the compound of any one of claims 1-64 for manufacturing
a medicament useful for treating a disease associated with the
A.sub.2b adenosine receptor in a subject, wherein the disease
associated with the A.sub.2b adenosine receptor is asthma,
urticaria, scleroderm arthritis, myocardial infarction, myocardial
reperfusion after ischemia, diabetic retinopathy, retinopathy of
prematurity, diabetes, diarrhea, inflammatory bowel disease,
proliferating tumor, or is associated with mast cell degranulation,
vasodilation, hypertension, hypersensitivity or the release of
allergic mediators.
93. The use of claim 92, wherein the disease associated with the
A.sub.2b adenosine receptor is diabetes.
94. The use of claim 92, wherein the disease associated with the
A.sub.2b adenosine receptor is asthma.
95. The use of claim 92, whereinr the disease associated with the
A.sub.2b adenosine receptor is associated with mast cell
degranulation.
96. The use of claim 92, wherein the disease associated with the
A.sub.2b adenosine receptor is a proliferating tumor.
97. The compound of any one of claims 1, 2, 4-30, 32-46, 49-53, or
56-58, wherein any substituent, if present, is selected from
halogen, hydroxyl, carbonyl, straight chain
(C.sub.1-C.sub.30)alkyl, branched chain (C.sub.3-C.sub.30)alkyl,
(C.sub.3-C.sub.10)cycloalkyl, straight
chain(C.sub.1-C.sub.30)alkylcarbonyloxy, branched chain
(C.sub.3-C.sub.30)alkylcarbonyloxy, arylcarbonyloxy, straight
chain(C.sub.1-C.sub.30)alkoxycarbonyloxy, branched
chain(C.sub.3-C.sub.30)alkoxycarbonyloxy, aryloxycarbonyloxy,
carboxylate, straight chain(C.sub.1-C.sub.30)alkylcarbonyl,
branched chain (C.sub.3-C.sub.30)alkylcarbonyl, arylcarbonyl,
straight chain (C.sub.1-C.sub.30)alkoxycarbonyl, branched chain
(C.sub.3-C.sub.30)alkoxy- carbonyl, aminocarbonyl, straight chain
(C.sub.1-C.sub.30)alkylthiocarbony- l, branched chain
(C.sub.3-C.sub.30)alkylthiocarbonyl, straight chain
(C.sub.1-C.sub.30)alkylsulfonyl, branched chain
(C.sub.3-C.sub.30)alkylsu- lfonyl, straight chain
(C.sub.1-C.sub.30)alkoxyl, branched chain
(C.sub.1-C.sub.30)alkoxyl, phosphate, phosphonato, cyano, amino,
straight chain (C.sub.1-C.sub.30)alkylamino, branched chain
(C.sub.3-C.sub.30)alkylamino, straight chain
(C.sub.1-C.sub.30)dialkylami- no, branched chain
(C.sub.3-C.sub.30)dialkylamino, arylamino, diarylamino, straight
chain (C.sub.1-C.sub.30)alkylarylamino, branched chain
(C.sub.3-C.sub.30)alkylarylamino, acylamino, straight chain
(C.sub.1-C.sub.30)alkylcarbonylamino, branched chain
(C.sub.3-C.sub.30)alkylcarbonylamino, arylcarbonylamino, carbamoyl,
ureido, amidino, imino, sulfhydryl, straight chain
(C.sub.1-C.sub.30)alkylthio, branched chain
(C.sub.3-C.sub.30)alkylthio, arylthio, thiocarboxylate, sulfates,
sulfonato, sulfamoyl, sulfonamido, sulfonyl, benzenesulfonyl,
nitro, trifluoromethyl, azido,
6-methoxy-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxole,
3,4-dihydroxy-5-methoxytetrahydrofuran, 4-10 membered heterocyclyl,
straight chain (C.sub.1-C.sub.30)alkylaryl, branched chain
(C.sub.3-C.sub.30)alkylaryl, straight chain
(C.sub.1-C.sub.30)alkylhetero- aryl, branched chain
(C.sub.3-C.sub.30)alkylheteroaryl, (C.sub.1-C.sub.30)alkenylaryl,
(C.sub.1-C.sub.30)alkenylheteroaryl, (C.sub.1-C.sub.30)alkynylaryl,
(C.sub.1-C.sub.30)alkynylheteroaryl or an aromatic or 5-6 membered
heteroaromatic moiety, which substituent may be further substituted
by any of the above.
Description
[0001] This application claims the benefit of U.S. Provisional
Application No. 60/343,443, filed Dec. 20, 2001, the entire
contents of which are hereby incorporated by reference.
[0002] Throughout this application, various publications are
referenced by full citations. The disclosures of these publications
in their entireties are hereby incorporated by reference into this
application in order to more fully describe the state of the art as
known to those skilled therein as of the date of the invention
described and claimed herein.
BACKGROUND OF THE INVENTION
[0003] Adenosine is an ubiquitous modulator of numerous
physiological activities, particularly within the cardiovascular
and nervous systems. The effects of adenosine appear to be mediated
by specific cell surface receptor proteins. Adenosine modulates
diverse physiological functions including induction of sedation,
vasodilation, suppression of cardiac rate and contractility,
inhibition of platelet aggregability, stimulation of
gluconeogenesis and inhibition of lipolysis. In addition to its
effects on adenylate cyclase, adenosine has been shown to open
potassium channels, reduce flux through calcium channels, and
inhibit or stimulate phosphoinositide turnover through receptor-
mediated mechanisms (See for example, C. E. Muller and B. Stein
"Adenosine Receptor Antagonists: Structures and Potential
Therapeutic Applications," Current Pharmaceutical Design, 2:501
(1996) and C. E. Muller "A.sub.1-Adenosine Receptor Antagonists,"
Exp. Opin. Ther. Patents 7(5):419 (1997)).
[0004] Adenosine receptors belong to the superfamily of purine
receptors which are currently subdivided into P.sub.1 (adenosine)
and P.sub.2 (ATP, ADP, and other nucleotides) receptors. Four
receptor subtypes for the nucleoside adenosine have been cloned so
far from various species including humans. Two receptor subtypes
(A.sub.1 and A.sub.2a) exhibit affinity for adenosine in the
nanomolar range while two other known subtypes A.sub.2b and A.sub.3
are low-affinity receptors, with affinity for adenosine in the
low-micromolar range. A.sub.1 and A.sub.3 adenosine receptor
activation can lead to an inhibition of adenylate cyclase activity,
while A.sub.2a and A.sub.2b activation causes a stimulation of
adenylate cyclase.
[0005] A few A.sub.1 antagonists have been developed for the
treatment of cognitive disease, renal failure, and cardiac
arrhythmias. It has been suggested that A.sub.2a antagonists may be
beneficial for patients suffering from Morbus Parkinson
(Parkinson's disease). Particularly in view of the potential for
local delivery, adenosine receptor antagonists may be valuable for
treatment of allergic inflammation and asthma. Available
information (for example, Nyce & Metzger "DNA antisense Therapy
for Asthma in an Animal Model" Nature (1997) 385: 721-5)indicates
that in this pathophysiologic context, A.sub.1 antagonists may
block contraction of smooth muscle underlying respiratory
epithelia, while A.sub.2b or A.sub.3 receptor antagonists may block
mast cell degranulation, mitigating the release of histamine and
other inflammatory mediators. A.sub.2b receptors have been
discovered throughout the gastrointestinal tract, especially in the
colon and the intestinal epithelia. It has been suggested that
A.sub.2b receptors mediate cAMP response (Strohmeier et al., J.
Bio. Chem. (1995) 270:2387-94).
[0006] A.sub.2b receptors have also been implicated in wide variety
of physiological activities, thereby suggesting that treatment of
associated disorders can be effected by blocking the A.sub.2b
receptor. For example, A.sub.2b receptor sites play a role in the
degranulation of mast cells and hence in the treatment of asthma,
myocardial reperfusion injury, allergic reactions including but not
limited to rhinitis, poison ivy induced responses, urticaria,
scleroderm arthritis, other autoimmune diseases and inflammatory
bowel diseases (Gao, Z. et al., J. Biol. Chem. (1999),
274(9):5972-5980, Linden, J. et al., Life Sciences (1998),
62(17-18):1519-1524 and U.S. Pat. No. 6,117,878, issued Sep. 12,
2000). A.sub.2b receptors have also been shown to: inhibit the
growth of cardiac fibroblasts, thereby suggesting that they may
prevent cardiac remodeling associated with hypertension, myocardial
infarction and myocardial reperfusion after ischemia (Dubey, R. K.
et al., Hypertension (2001), 37:716-721), mediate the role of
adenosine in lymphocyte activation (Mirabet, M. et al., J. Cell.
Sci. (1999), 112(4):491-502), regulate vasodilation and growth
(Ralevic, V. and Burnstock, G., Pharmacol. Rev. (1998),
50(3):413-492, Corset, V. et al., Nature (2000), 407(6805):747-750,
and Haynes, J. Jr. et al., Am. J. Physiol. (1999),
276(6):H1877-83), participate in neural reflexes in the human gut
(Christofi, F. L. et al., J. Comp. Neurol. (2001), 439(1):46-64),
and regulate retinal angiogenesis--thereby suggesting the use of
A.sub.2b antagonists in treating diseases associated with abberant
neovascularization such as diabetic retinopathy and retinopathy of
prematurity (Grant, M. B. et al., Invest. Opthalmol. Vis. Sci.
(2001), 42(9):2068-2073). They are also involved in the modulation
of intestinal tone and secretion and neurotransmission and
neurosecretion (Feoktistov, I. and Biaggioni, I., Pharmacol. Rev.
(1997), 49(4):381-402).
[0007] A.sub.2b receptors are also coupled to Gs/Gq signaling which
has been shown to be involved in cellular transformations such as
cellular invasion (Faivre, K. et al., Molecular Pharmacology
(2001), 60:363-372 and Regnauld, K. et al., Oncogene (2002),
21(25):4020-403 1), thereby suggesting that treatment of cancer can
be effected with A.sub.2b antagonists.
[0008] Adenosine receptors have also been shown to exist on the
retinas of various mammalian species including bovine, porcine,
monkey, rat, guinea pig, mouse, rabbit and human (See, Blazynski et
al., Discrete Distributions of Adenosine Receptors in Mammalian
Retina, Journal of Neurochemistry, volume 54, pages 648-655 (1990);
Woods et al., Characterization of Adenosine A.sub.1-Receptor
Binding Sites in Bovine Retinal Membranes, Experimental Eve
Research, volume 53, pages 325-331 (1991); and Braas et al.,
Endogenous adenosine and adenosine receptors localized to ganglion
cells of the retina, Proceedings of the National Academy of
Science, volume 84, pages 3906-3910 (1987)). Recently, Williams
reported the observation of adenosine transport sites in a cultured
human retinal cell line (Williams et al., Nucleoside Transport
Sites in a Cultured Human Retinal Cell Line Established By SV-40 T
Antigen Gene, Current Eye Research, volume 13, pages 109-118
(1994)).
[0009] Compounds which regulate the uptake of adenosine have
previously been suggested as potential therapeutic agents for the
treatment of retinal and optic nerve head damage. In U.S. Pat. No.
5,780,450 to Shade, Shade discusses the use of adenosine uptake
inhibitors for treating eye disorders. Shade does not disclose the
use of specific A.sub.3 receptor inhibitors. The entire contents of
U.S. Pat. No. 5,780,450 are hereby incorporated herein by
reference.
[0010] Compounds specific to the adenosine A.sub.1, A.sub.2a and
A.sub.3 receptors and their uses thereof have been previously
disclosed in PCT International Publication Nos. WO 99/62518 and WO
01/39777 A1. The entire contents of PCT International Publication
Nos. WO 99/62518 and WO 01/39777 A1 are hereby incorporated herein
by reference.
[0011] Additional adenosine receptor antagonists are needed as
pharmacological tools and are of considerable interest as drugs for
the above-referenced disease states and/or conditions.
SUMMARY OF THE INVENTION
[0012] The subject invention provides compounds having the
structure: 2
[0013] wherein,
[0014] R.sub.1 is a substituted or unsubstituted alkyl, wherein the
substituent is hydroxyl, dihydroxy, carboxyl,
--C(.dbd.O)NR.sub.aR.sub.b, NR.sub.aR.sub.b,
NR.sub.aC(.dbd.O)NR.sub.aR.sub.b, --NR.sub.aC(.dbd.O)OR.sub.a,
--OC(.dbd.O)NR.sub.aR.sub.b, or --NHC(.dbd.O)R.sub.a;
[0015] R.sub.2 is hydrogen or a substituted or unsubstituted alkyl,
wherein the substituent is hydroxyl, dihydroxy, carboxyl,
--C(.dbd.O)NR.sub.aR.sub.b, --NR.sub.aR.sub.b,
--NR.sub.aC(.dbd.O)NR.sub.- aR.sub.b, --NR.sub.aC(.dbd.O)OR.sub.a,
--OC(.dbd.O)NR.sub.aR.sub.b, or --NHC(.dbd.O)R.sub.a, or
[0016] R.sub.1, R.sub.2 and N together form a substituted
piperazine, substituted azetidine ring, or a pyrrolidine ring
substituted with --(CH.sub.2).sub.2OH or --CH.sub.2C(.dbd.O)OH;
[0017] R.sub.3 is a substituted or unsubstituted phenyl or a 5-6
membered heteroaryl ring, wherein the substituent is halogen,
hydroxyl, cyano, (C.sub.1-C.sub.15)alkyl, (C.sub.1-C.sub.15)alkoxy,
or --NR.sub.aR.sub.b;
[0018] R.sub.4 is hydrogen or substituted or unsubstituted
(C.sub.1-C.sub.15)alkyl;
[0019] R.sub.5 is --(CH.sub.2).sub.mOR.sub.6, --CHNOR.sub.7,
--C(.dbd.O)NR.sub.8R.sub.9, (CH.sub.2).sub.mC(.dbd.O)OR.sub.10,
--(CH.sub.2).sub.kC(.dbd.O)NR.sub.11R.sub.12;
[0020] wherein R.sub.6 is a substituted or unsubstituted
(C.sub.1-C.sub.30)alkyl, (C.sub.3-C.sub.10)cycloalkyl, or an aryl,
heteroaryl or 4-8 membered heterocyclic ring;
[0021] R.sub.7 is hydrogen, or a substituted or unsubstituted
(C.sub.1-C.sub.30)alkyl, (C.sub.1-C.sub.30)alkylaryl;
[0022] R.sub.8 and R.sub.9 are each independently hydrogen, or a
substituted or unsubstituted (C.sub.1-C.sub.30)alkyl,
(C.sub.1-C.sub.30)alkylaryl, (C.sub.1-C.sub.30)alkylamino,
(C.sub.1-C.sub.30)alkoxy, or a saturated or unsaturated, monocyclic
or bicyclic, carbocyclic or heterocyclic ring, or
[0023] R.sub.8, N, and R.sub.9 together form a substituted or
unsubstituted 4-8 membered heterocyclic ring;
[0024] R.sub.10 is hydrogen or a substituted or unsubstituted
(C.sub.1-C.sub.30)alkyl, (C.sub.3-C.sub.10)cycloalkyl, or an aryl,
heteroaryl or heterocyclic ring;
[0025] R.sub.11, N and R.sub.12 together form a 4-8 membered
heterocyclic ring;
[0026] R.sub.a and R.sub.b are each independently hydrogen or
alkyl;
[0027] m is 0, 1, 2 or 3; and
[0028] k is 1, 2 or 3,
[0029] or a specific enantiomer thereof, or a specific tautomer
thereof, or a pharmaceutically acceptable salt thereof.
[0030] The subject invention also provides compounds having the
structure: 3
[0031] wherein
[0032] R.sub.3 is a substituted or unsubstituted 4-10 membered
aryl, heteroaryl or heterocyclic ring;
[0033] R.sub.20 is halogen or
--NH(CHR.sub.20').sub.nNHC(.dbd.O)CH.sub.3, where R.sub.20' is H,
OH, alkyl, hydroxyalkyl, cycloalkyl, heteroalkyl, or amino;
[0034] R.sub.21 is H or --C(.dbd.O)OH;
[0035] R.sub.22 is H or SO.sub.2Ph; and
[0036] n is 2, 3, 4 or 5;
[0037] wherein when R.sub.20 is
--NH(CHR.sub.20').sub.nNHC(.dbd.O)CH.sub.3- , R.sub.21 is
--C(.dbd.O)OH.
[0038] The subject invention also provides a method for treating a
disease associated with the A.sub.2b adenosine receptor in a
subject in need of such treatment comprising administering to the
subject a therapeutically effective amount of the compounds of
Structure I so as to thereby treat the disease associated with the
A.sub.2b adenosine receptor in the subject, wherein the disease
associated with the A.sub.2b adenosine receptor is asthma,
urticaria, scleroderm arthritis, myocardial infarction, myocardial
reperfusion after ischemia, diabetic retinopathy, retinopathy of
prematurity, diabetes, diarrhea, inflammatory bowel disease,
proliferating tumor or is associated with mast cell degranulation,
vasodilation, hypertension, hypersensitivity or the release of
allergic mediators.
DETAILED DESCRIPTION
[0039] The subject invention provides compounds having the
structure: 4
[0040] wherein,
[0041] R.sub.1 is a substituted or unsubstituted alkyl, wherein the
substituent is hydroxyl, dihydroxy, carboxyl,
--C(.dbd.O)NR.sub.aR.sub.b, --NR.sub.aR.sub.b,
--NR.sub.aC(.dbd.O)NR.sub.aR.sub.b, --NR.sub.aC(.dbd.O)OR.sub.a,
--OC(.dbd.O)NR.sub.aR.sub.b, or --NHC(.dbd.O)R.sub.a;
[0042] R.sub.2 is hydrogen or a substituted or unsubstituted alkyl,
wherein the substituent is hydroxyl, dihydroxy, carboxyl,
--C(.dbd.O)NR.sub.aR.sub.b, --NR.sub.aR.sub.b,
--NR.sub.aC(.dbd.O)NR.sub.- aR.sub.b, --NR.sub.aC(.dbd.O)OR.sub.a,
--OC(.dbd.O)NR.sub.aR.sub.b, or --NHC(.dbd.O)R.sub.a, or
[0043] R.sub.1, R.sub.2 and N together form a substituted
piperazine, substituted azetidine ring, or a pyrrolidine ring
substituted with --(CH.sub.2).sub.2OH or --CH.sub.2C(.dbd.O)OH;
[0044] R.sub.3 is a substituted or unsubstituted phenyl or a 5-6
membered heteroaryl ring, wherein the substituent is halogen,
hydroxyl, cyano, (C.sub.1-C.sub.15)alkyl, (C.sub.1-C.sub.15)alkoxy,
or --NR.sub.aR.sub.b;
[0045] R.sub.4 is hydrogen-or substituted or unsubstituted
(C.sub.1-C.sub.15)alkyl;
[0046] R.sub.5 is --(CH.sub.2).sub.mOR.sub.6, --CHNOR.sub.7,
--C(.dbd.O)NR.sub.8R.sub.9, --(CH.sub.2).sub.mC(.dbd.O)OR.sub.10,
--(CH.sub.2).sub.kC(.dbd.O)NR.sub.11R.sub.12;
[0047] wherein R.sub.6 is a substituted or unsubstituted
(C.sub.1-C.sub.30)alkyl, (C.sub.3-C.sub.10)cycloalkyl, or an aryl,
heteroaryl or 4-8 membered heterocyclic ring;
[0048] R.sub.7 is hydrogen, or a substituted or unsubstituted
(C.sub.1-C.sub.30)alkyl, (C.sub.1-C.sub.30)alkylaryl;
[0049] R.sub.8 and R.sub.9 are each independently hydrogen, or a
substituted or unsubstituted (C.sub.1-C.sub.30)alkyl,
(C.sub.1-C.sub.30)alkylaryl, (C.sub.1-C.sub.30)alkylamino,
(C.sub.1-C.sub.30)alkoxy, or a saturated or unsaturated, monocyclic
or bicyclic, carbocyclic or heterocyclic ring, or
[0050] R.sub.8, N, and R.sub.9 together form a substituted or
unsubstituted 4-8 membered heterocyclic ring;
[0051] R.sub.10 is hydrogen or a substituted or unsubstituted
(C.sub.1-C.sub.30)alkyl, (C.sub.3-C.sub.10)cycloalkyl, or an aryl,
heteroaryl or heterocyclic ring;
[0052] R.sub.11, N and R.sub.12 together form a 4-8 membered
heterocyclic ring;
[0053] R.sub.a and R.sub.b are each independently hydrogen or
alkyl;
[0054] m is 0, 1, 2 or 3; and
[0055] k is 1, 2 or 3,
[0056] or a specific enantiomer thereof, or a specific tautomer
thereof, or a pharmaceutically acceptable salt thereof.
[0057] In a further embodiment of the above compounds, wherein any
heterocyclic or heteroaryl ring, if present, is a piperazine,
piperidine, pyrazine, pyridine, pyrroiidine, pyrazole, pyrimidine,
thiophene, imidazole, azetidine, pyrrole, benzothiazole,
benzodioxolane, dithiolane, oxathiine, imidazolidine, quinoline,
isoquinoline, dihydro-1H-isoquinoline, dihydro-2H-pyridine,
1,3,4,9-tetrahydro-p-carbol- ine, 2,8-diazaspiro[4.5]decane,
2,5-diazabicyclo[2.2.1]heptane, or [1,4]diazepane ring,
dihydroisoquinoline, indole, isoindole, triazaspiro[4.5]decane,
morpholine, furan or an isothiazole ring
[0058] In a further embodiment of Structure I, the compounds have
the structure: 5
[0059] wherein,
[0060] R.sub.1 is hydrogen or methyl;
[0061] R.sub.2 is --(CH.sub.2).sub.2NHC(.dbd.O)CH.sub.3,
--(CH.sub.2).sub.2OH, --(CH.sub.2).sub.2NHC(.dbd.O)NHCH.sub.3,
--CH.sub.2CH(CH.sub.3)OH,
--CH(CH.sub.2OH)CH.sub.2CH(CH.sub.3).sub.2, --CH(CH.sub.2OH).sub.2,
--CH(CH.sub.3)CH.sub.2OH, --CH(CH.sub.2OH)CH(CH.s- ub.3).sub.2,
--(CH.sub.2).sub.3OH, --(CH.sub.2).sub.2NH.sub.2,
--(CH.sub.2).sub.2NHC(.dbd.O)N(CH.sub.3).sub.2,
--(CH.sub.2).sub.2C(.dbd.- O)NH.sub.2, --CH.sub.2C(.dbd.O)NH.sub.2,
--CH.sub.3, --CH.sub.2CH(OH)CH.sub.2OH,
--CH.sub.2C(.dbd.O)(NC.sub.5H.sub.8[OCH.sub.3- ])(C.sub.6H.sub.4Cl)
or
[0062] R.sub.1, R.sub.2 and N together form a pyrrolidine ring
substituted with --(CH.sub.2).sub.2OH or --CH.sub.2C(.dbd.O)OH, a
piperazine ring substituted with --C(.dbd.O)CH.sub.3, or an
azetidine ring substituted with --OH or CH.sub.2OH;
[0063] R.sub.4 is hydrogen, or methyl; and
[0064] R.sub.5 is --CH.sub.2O(C.sub.6H.sub.5),
--CH.sub.2O(C.sub.6H.sub.4C- l), --CH.sub.2O(C.sub.6H.sub.4Br),
--CH.sub.2O(C.sub.6H.sub.4F), --CHNOCH.sub.2(C.sub.6H.sub.5),
--CH.sub.2O(C.sub.6H.sub.4[OCH.sub.3]),
--CH.sub.2O(C.sub.6H.sub.4[CH.sub.3]), --CHNOC(CH.sub.3).sub.3,
--CH.sub.2O(C.sub.5H.sub.4N), --CH.sub.2(NC.sub.5H.sub.4[O]),
--CH.sub.2O(C.sub.6H.sub.4[NH.sub.2]),
--CH.sub.2O(C.sub.5H.sub.9N)SO.sub- .2(C.sub.6H.sub.5),
--CH.sub.2O(C.sub.5H.sub.9N)SO.sub.2CH.sub.2(C.sub.6H.- sub.5),
--CH.sub.2O(C.sub.6H.sub.4[NHC(.dbd.O)CH.sub.3]),
--CH.sub.2O(C.sub.5H.sub.9N)(CH.sub.2).sub.P(C.sub.6H.sub.5),
--CH.sub.2O(C.sub.5H.sub.9N)(CH.sub.2).sub.P(C.sub.6H.sub.4Br),
--CH.sub.2O(C.sub.5H.sub.9N)(CH.sub.2).sub.P(C.sub.6H.sub.4Cl),
--CH.sub.2O(C.sub.5H.sub.9N)(CH.sub.2).sub.P(C.sub.6H.sub.4[OCH.sub.3]),
--CH.sub.2O(C.sub.5H.sub.9N)(CH.sub.2).sub.P(C.sub.6H.sub.3FCl),
--CH.sub.2O(C.sub.5H.sub.9N)(CH.sub.2).sub.P(C6H4[CF.sub.3]),
--CH.sub.2O(CH.sub.2).sub.2CH(OH)(C.sub.6H.sub.5),
--CH.sub.2NOCH.sub.2(C.sub.6H.sub.5),
--CH.sub.2NOC(CH.sub.3).sub.3, --C(.dbd.O)(NC.sub.4H.sub.8O),
--C(.dbd.O)(NC.sub.4H.sub.8N)CH.sub.2CHCH(- C.sub.6H.sub.5),
--C(.dbd.O)(NC.sub.4H.sub.8N)(CH.sub.2).sub.P(C.sub.6H.su- b.5),
--C(.dbd.O)(NC.sub.4H.sub.8N)(CH.sub.2).sub.2O(C.sub.6H.sub.4Cl),
--C(.dbd.O)(NC.sub.5H.sub.8[CN])(C.sub.6H.sub.5),
--C(.dbd.O)(NC.sub.4H.s- ub.8N)CH.sub.2C.sub.2(C.sub.6H.sub.5),
--C(.dbd.O)(NC.sub.4(CH.sub.3).sub.-
2N)(CH.sub.2).sub.P(C.sub.6H.sub.5),
--C(.dbd.O)(NC.sub.5H.sub.9)CH(OH)(C.- sub.6H.sub.4F),
--C(.dbd.O)(NC.sub.4(CH.sub.3).sub.2NH),
--C(.dbd.O)(NC.sub.5H.sub.8[CH.sub.3])(C.sub.6H.sub.5),
--C(.dbd.O)(NC.sub.4H.sub.8N)(C.sub.5H.sub.3N[CF.sub.3]),
--C(.dbd.O)(NC.sub.5H.sub.8[OCH.sub.3])(C.sub.6H.sub.4[C.sub.6H.sub.4Cl])-
, --C(.dbd.O)(NC.sub.5H.sub.8[OCH.sub.3])(C.sub.6H.sub.4Cl),
--C(.dbd.O)(NC.sub.5H.sub.8[OH])(C.sub.6H.sub.4Cl),
--C(.dbd.O)(NC.sub.5H.sub.8[OH])(C.sub.6H.sub.4[C.sub.6H.sub.4Cl]),
--C(.dbd.O)(NC.sub.5H.sub.8[OCH.sub.3])(C.sub.6H.sub.4F),
--C(.dbd.O)NH(C.sub.5H.sub.9N)(CH.sub.2).sub.P(C.sub.6H.sub.5),
--C(.dbd.O)(NC.sub.5H.sub.9)(CH.sub.2).sub.P(C.sub.6H.sub.5),
--C(O)(NC.sub.5H.sub.9)(NC.sub.4H.sub.8),
--C(.dbd.O)(NC.sub.4H.sub.8N)(C- H.sub.2).sub.P(C.sub.6H.sub.11),
--C(.dbd.O)(NC.sub.4H.sub.8N)(CH.sub.2).s- ub.PCH(CH.sub.3).sub.2,
--C(.dbd.O)(NC.sub.5H.sub.9[NC.sub.5H.sub.10]),
--C(.dbd.O)(NC.sub.4H.sub.8N)(C.sub.5H.sub.9),
--C(O)(NC.sub.5H.sub.9)NH.- sub.2,
--C(.dbd.O)(NC.sub.5H.sub.8[C(.dbd.O)CH.sub.3])(C.sub.6H.sub.5),
--C(.dbd.O)(NC.sub.5H.sub.7)C.sub.2(C.sub.6H.sub.5),
--C(.dbd.O)(NC.sub.5H.sub.9)(C(CH.sub.3).sub.3,
--C(.dbd.O)(NC.sub.4H.sub- .8N)CH.sub.2C.sub.2(C.sub.6H[CN]),
--C(.dbd.O)(NC.sub.5H.sub.8[C(.dbd.O)OC- H.sub.3)(C.sub.6H.sub.5),
--C(.dbd.O)(NC.sub.5H.sub.8[C(.dbd.O)O(CH.sub.2)-
.sub.PCH.sub.3])(C.sub.6H.sub.5),
--C(.dbd.O)(NC.sub.5H.sub.8[C(.dbd.O)NH.- sub.2])(C.sub.6H.sub.5),
--C(.dbd.O)(NC.sub.5H.sub.8[C(.dbd.O)NHCH.sub.3])-
(C.sub.6H.sub.5),
--C(.dbd.O)(NCSH.sub.8[NHC(.dbd.O)CH.sub.3])(C.sub.6H.su- b.5),
--C(.dbd.O)(NC.sub.5H.sub.8[C(.dbd.O)N(CH.sub.3).sub.2])(C.sub.6H.su-
b.5),
--C(.dbd.O)(NC.sub.5H.sub.8[C(.dbd.O)NHCH.sub.2(C.sub.6H.sub.15))(C.-
sub.6H.sub.5),
--C(.dbd.O)(NC.sub.5H.sub.8[C(.dbd.O)NH(CH.sub.2).sub.PCH.s-
ub.3])(C.sub.6H.sub.5), --C(.dbd.O)(NC.sub.5H.sub.8[C(.dbd.O)N
{(CH.sub.2).sub.PCH.sub.3}.sub.2])(C.sub.6H.sub.5),
--C(.dbd.O)(NC.sub.5H.sub.8[C(.dbd.O)(NC.sub.3H.sub.6)])(C.sub.6H.sub.5),
--C(.dbd.O)(NC.sub.5H.sub.8[C(.dbd.O)OC(CH.sub.3).sub.2])(C.sub.6H.sub.5)-
,
--C(.dbd.O)(NC.sub.5H.sub.8[C(.dbd.O)NH.sub.2])(NHCH.sub.2CH.sub.3),
--C(.dbd.O)(NC.sub.5H.sub.8[OCH.sub.3])(C.sub.6H.sub.4[OCH.sub.3]),
--C(.dbd.O)(NC.sub.5H.sub.8[C(.dbd.O)NH.sub.2])(NC.sub.4H.sub.8),
--C(.dbd.O)(NC.sub.5H.sub.7)(C.sub.6H.sub.4[OCH.sub.3]),
--C(.dbd.O)(NC.sub.5H.sub.8[NH.sub.2])(C.sub.6H.sub.5),
--C(.dbd.O)(NC.sub.5H.sub.8[C(.dbd.O)H])(C.sub.6H.sub.5),
--C(.dbd.O)(NC.sub.5H.sub.8[OCH.sub.3])(CH.sub.2).sub.P(C.sub.6H.sub.5),
--C(.dbd.O)(NC.sub.5H.sub.8[OCH.sub.3])(C.sub.6H.sub.4[CH.sub.3]),
--C(.dbd.O)(NC.sub.5H.sub.8[(CH.sub.2)POCH.sub.3])(C.sub.6H.sub.5),
--C(.dbd.O)NH(C.sub.4H.sub.7N)(CH.sub.2).sub.P(C.sub.6H.sub.5),
--C(.dbd.O)(NC.sub.4H.sub.8N)(CH.sub.2).sub.P(C.sub.6H.sub.4Cl),
--C(.dbd.O)(NC.sub.4H.sub.8N)(CH.sub.2).sub.P(C.sub.6H.sub.4[OCH.sub.3]),
--C(.dbd.O)NH(CH.sub.2).sub.P(C.sub.6H.sub.4[C.sub.2HSN2],
--C(.dbd.O)(NC.sub.4H.sub.8N)C(.dbd.O)(CH.sub.2).sub.P(C.sub.6H.sub.4Cl),
--C(.dbd.O)(NC.sub.5H.sub.9)(C.sub.3N.sub.2H.sub.2)(C.sub.6H.sub.4Cl),
--C(.dbd.O)(NC.sub.4H.sub.8N)CH.sub.2C(.dbd.O)N(CH.sub.3)(C.sub.6H.sub.5)-
,
--C(.dbd.O)(NC.sub.4H.sub.8N)C(.dbd.O)O(CH.sub.2).sub.P(C.sub.6H.sub.5),
--C(.dbd.O)(NC.sub.5H.sub.8[C.sub.2H.sub.3N.sub.2O])(C.sub.6H.sub.5),
--C(.dbd.O)(NC.sub.5H.sub.9)N(CH.sub.3)(CH.sub.2).sub.P(C.sub.6H.sub.5),
--C(.dbd.O)(NC.sub.5H.sub.9)NH(CH.sub.2).sub.P(C.sub.6H.sub.5),
--C(.dbd.O)(NC.sub.5H.sub.9)NH(CH.sub.2).sub.P(C.sub.6H.sub.4Cl),
--C(.dbd.O)(NC.sub.5H.sub.9)NH(CH.sub.2).sub.P(C.sub.3N.sub.2H.sub.3),
--C(.dbd.O)(NC.sub.5H.sub.9)NH(CH.sub.2).sub.P(C.sub.5H.sub.4N),
--C(.dbd.O)(NC.sub.5H.sub.9)NH(CH.sub.2).sub.P(C.sub.6H.sub.5),
--C(.dbd.O)(NC.sub.5H.sub.9)N(CH.sub.3)(CH.sub.2).sub.P(C.sub.6H.sub.5),
--C(O)(NC.sub.5H.sub.9)NHCH(CH.sub.3)(C.sub.6H.sub.5),
--(CH.sub.2).sub.PC(.dbd.O)(NC.sub.4H.sub.5N)(CH.sub.2).sub.P(C.sub.6HS),
--C(.dbd.O)NH(CH.sub.2).sub.P(C.sub.6H.sub.5),
--C(--O)NHCH[(CH.sub.2).su-
b.POH].sub.2--C(.dbd.O)NH(CH.sub.2).sub.P(OH)(C.sub.6H.sub.10),
--C(.dbd.O)NH(CH.sub.2).sub.P(CH.sub.4{O[C.sub.6H.sub.5]}),
--C(.dbd.O)(NC.sub.4H.sub.7)(CH.sub.2).sub.PNH(C.sub.6H.sub.5),
--C(.dbd.O)(NC.sub.4H.sub.8N)(CH.sub.2).sub.P(C.sub.6H.sub.4)CF.sub.3,
--C(.dbd.O)(NC.sub.4H.sub.8N)(CH.sub.2).sub.P(C.sub.6H.sub.4F),
--C(.dbd.O)(NC.sub.4H.sub.8N)(CH.sub.2).sub.P(C.sub.7O.sub.2H.sub.5),
--C(.dbd.O)(NC.sub.4H.sub.8N)(CH.sub.2).sub.P(C.sub.6H.sub.4)CH.sub.3,
--C(.dbd.O)(NC.sub.4H.sub.8N)(CH.sub.2).sub.P(C.sub.6H.sub.4Br),
--C(.dbd.O)(NC.sub.4H.sub.8N)(CH.sub.2).sub.P(C.sub.6H.sub.3Cl.sub.2),
--C(.dbd.O)(NC.sub.5H.sub.10N)(CH.sub.2).sub.P(C.sub.6H.sub.5),
--C(.dbd.O)(NC.sub.4H.sub.8)(C.sub.6H.sub.4)NHC(.dbd.O)CH.sub.3,
--C(.dbd.O)(NC.sub.4H.sub.8N)(C.sub.6H.sub.4[CN]),
--C(.dbd.O)(NC.sub.4H.sub.8N)(C.sub.6H.sub.4[N(CH.sub.3)C(.dbd.O)CH.sub.3-
]),
--C(.dbd.O)(NC.sub.4H.sub.8N)(C.sub.6H.sub.3[(CH.sub.3).sub.2]),
--C(.dbd.O)(NC.sub.4H.sub.8N)(C.sub.6H.sub.4Cl),
--C(.dbd.O)(NC.sub.4H.su- b.8N)(C.sub.6H.sub.3[(OCH.sub.3).sub.2]),
--C(.dbd.O)(NC.sub.4H.sub.8N)(C.- sub.6H.sub.3Cl[(OCH.sub.3)]),
--C(.dbd.O)(NC.sub.5H.sub.9N)(CH.sub.2).sub.- PO(C.sub.6H.sub.4Cl),
--C(.dbd.O)(NC.sub.5H.sub.8N)(CH.sub.2).sub.P(C.sub.- 6H.sub.5),
--C(.dbd.O)(NC.sub.5H.sub.9)(CH.sub.2).sub.PO(C.sub.6H.sub.5),
--C(.dbd.O)(NC.sub.5H.sub.9)(CH.sub.2)PO(C.sub.6H.sub.4[CN]),
--C(.dbd.O)(NC.sub.4H.sub.8N)(C.sub.6H.sub.4[NO.sub.2]),
--C(.dbd.O)(NC.sub.4H.sub.8N)(C.sub.6H.sub.4[C(.dbd.O)OCH.sub.3]),
--C(.dbd.O)(NC.sub.4H.sub.8N)(C.sub.6H.sub.4[CH.sub.3]),
--C(.dbd.O)(NC.sub.5H.sub.9)(CH.sub.2).sub.PO(C.sub.6H.sub.3Cl.sub.2),
--C(.dbd.O)(NC.sub.5H.sub.9)(CH.sub.2).sub.PO(C.sub.6H.sub.3[CN]),
--C(.dbd.O)(NC.sub.5H.sub.9[CN])(C.sub.6H.sub.4Cl),
--C(.dbd.O)(NC.sub.5H.sub.8N)(C.sub.6H.sub.4[C(.dbd.O)NH.sub.2]),
--C(.dbd.O)(NC.sub.5H.sub.8[CN])(C.sub.6H.sub.4[OCH.sub.3]),
--C(.dbd.O)(NC.sub.5H.sub.8[CN])(C.sub.6H.sub.4Cl),
--C(.dbd.O)(NC.sub.5H.sub.8[C(.dbd.O)(NC.sub.4H.sub.8)])(C.sub.6H.sub.5),
--C(.dbd.O)(NC.sub.5H.sub.8[C(.dbd.O)(NC.sub.5H.sub.10)])(C.sub.6H.sub.5)-
,
--C(.dbd.O)(NC.sub.5H.sub.8[C(.dbd.O)(NC.sub.4H.sub.8O)])(C.sub.6H.sub.5-
),
--C(.dbd.O)(NC.sub.5H.sub.8[C(.dbd.O)NHC(CH.sub.3).sub.3])(C.sub.6H.sub-
.5),
--C(.dbd.O)(NC.sub.5H.sub.8[C(.dbd.O)(NC.sub.3H.sub.6)])(C.sub.6H.sub-
.5),
--C(.dbd.O)(NC.sub.5H.sub.8[CH(CH.sub.3).sub.2])(C.sub.6H.sub.5),
--C(.dbd.O)(NC.sub.4H.sub.8N)CH.sub.2C.sub.2(C.sub.4H.sub.3S),
--C(.dbd.O)(NC.sub.5H.sub.8[C(.dbd.O)OCH.sub.2(C.sub.4H.sub.7)])(C.sub.6H-
.sub.5), --C(.dbd.O)(NC.sub.5H.sub.8[OCH.sub.3])(C.sub.6H.sub.4Cl),
--C(.dbd.O)(NC.sub.5H.sub.8[OCH.sub.3])(C.sub.6H.sub.4[CF.sub.3]),
--C(.dbd.O)(NC.sub.5H.sub.8[OCH.sub.3])(C(CH.sub.3).sub.2),
--C(.dbd.O)(NC.sub.4H.sub.8N)(CH.sub.2).sub.P(C.sub.6H.sub.4[CN]),
--C(.dbd.O)(NC.sub.5H.sub.8)(C.sub.6H.sub.5).sub.2--CH.sub.2O(CH.sub.2).s-
ub.PN(CH.sub.3)CH.sub.2CHCH(C.sub.6H.sub.5), or
--CH.sub.2O(CH.sub.2).sub.-
PNH(CH.sub.2).sub.3(C.sub.6H.sub.5);
[0065] wherein p is 0, 1, 2, 3 or 4,
[0066] or a specific enantiomer thereof, or a specific tautomer
thereof, or a pharmaceutically acceptable salt thereof.
[0067] In a further embodiment, the subject invention provides
compounds having the structure: 6
[0068] wherein,
[0069] R.sub.1, R.sub.2 and N together form a substituted azetidine
or piperazine ring;
[0070] R.sub.4 is H; and
[0071] R.sub.6 is a substituted or unsubstituted aryl or heteroaryl
ring.
[0072] In one embodiment, R.sub.1, R.sub.2 and N together form a
substituted azetidine ring.
[0073] In another embodiment, R.sub.1, R.sub.2 and N together form
a substituted piperazine ring.
[0074] In another embodiment of Structure I, the subject invention
provides compounds having the structure: 7
[0075] wherein,
[0076] R.sub.6 is a substituted or unsubstituted aryl or heteroaryl
ring; and
[0077] m is 0, 1, 2 or 3.
[0078] In one embodiment, R.sub.4 is H.
[0079] In another embodiment, R.sub.3 is substituted or
unsubstituted phenyl.
[0080] In a further embodiment,
[0081] R.sub.1 is --(CH.sub.2).sub.2NHC(.dbd.O)CH.sub.3;
[0082] R.sub.2 is hydrogen or methyl;
[0083] R.sub.4 is hydrogen or methyl; and
[0084] R.sub.6 is substituted or unsubstituted phenyl or
pyridine.
[0085] In a further embodiment, R.sub.2 is H.
[0086] In a further embodiment, R.sub.6 is substituted phenyl.
[0087] In another embodiment, the compound is selected from the
group consisting of:
[0088]
N-{2-[6-(4-Fluorophenoxymethyl)-2-phenyl-7H-pyrrolo[2,3-d]pyrimidin-
-4-ylamino]-ethyl}-acetamide;
[0089]
N-{2-[6-(4-Methoxyphenoxymethyl)-2-phenyl-7H-pyrrolo[2,3-d]pyrimidi-
n-4-ylamino]-ethyl}-acetamide;
[0090]
N-[2-(2-Phenyl-6-rn-tolyloxymethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yla-
mino)-ethyl]-acetamide;
[0091]
N-{2-[6-(3-Bromophenoxymethyl)-2-phenyl-7H-pyrrolo[2,3-d]pyrimidin--
4-ylamino]-ethyl}-acetamide;
[0092]
3-[4-(2-Acetylaminoethylamino)-2-phenyl-7H-pyrrolo[2,3-d]pyrimidin--
6-ylmethoxy]-benzoic acid methyl ester;
[0093]
N-{2-[6-(4-Chlorophenoxymethyl)-2-phenyl-7H-pyrrolo[2,3-d]pyrimidin-
-4-ylamino]-ethyl}-acetamide; and
[0094]
N-{2-[6-(3-Methoxyphenoxymethyl)-2-phenyl-7H-pyrrolo[2,3-d]pyrimidi-
n-4-ylamino]-ethyl}-acetamide.
[0095] In a further embodiment of Structure I, the subject
invention provides compounds having the structure: 8
[0096] wherein,
[0097] R.sub.6 is a substituted or unsubstituted
(C.sub.1-C.sub.30)alkyl or (C.sub.3-C.sub.10)cycloalkyl;
[0098] m is 0, 1, 2 or 3.
[0099] In one embodiment, R.sub.4 is H;
[0100] In another embodiment, R.sub.3 is substituted or
unsubstituted phenyl;
[0101] In a further embodiment,
[0102] R.sub.1 is --(CH.sub.2).sub.2NHC(.dbd.O)CH.sub.3;
[0103] R.sub.2 is hydrogen or methyl;
[0104] R.sub.4 is hydrogen or methyl; and
[0105] R.sub.6 is substituted or unsubstituted cyclopentyl.
[0106] In a further embodiment, R.sub.2 is H.
[0107] In another embodiment, the compound is
N-(2-(6-{2-[Methyl-(3-phenyl-
allyl)amino]ethoxymethyl}-2-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino}et-
hyl]acetamide.
[0108] In a further embodiment of Structure I, the subject
invention provides compounds having the structure: 9
[0109] wherein,
[0110] R.sub.6 is a substituted or unsubstituted 4-8 membered
heterocyclic ring; and
[0111] m is 0, 1, 2 or 3.
[0112] In one embodiment, R.sub.4 is H.
[0113] In a further embodiment, R.sub.3 is substituted or
unsubstituted phenyl;
[0114] In a further embodiment,
[0115] R.sub.1 is --(CH.sub.2).sub.2NHC(.dbd.O)CH.sub.3;
[0116] R.sub.2 is hydrogen or methyl;
[0117] R.sub.4 is hydrogen or methyl; and
[0118] R.sub.6 is substituted or unsubstituted piperidine.
[0119] In a further embodiment, R.sub.2 is H.
[0120] In another embodiment, the compound is selected from the
group consisting of:
[0121]
N-(2-{6-[1-(Benzenesulfonyl)piperidin-4-yloxymethyl]-2-phenyl-7H-py-
rrolo[2,3-d]pyrimidin-4-ylamino}ethyl)acetamide;
[0122]
N-{2-[6-(1-Phenethylpiperidin-4-yloxymethyl)-2-phenyl-7H-pyrrolo[2,-
3-d]pyrimidin-4-ylamino]ethyl}acetamide;
[0123]
N-[2-{6-[1-(3-Phenylpropyl)piperidin-4-yloxymethyl]-2-phenyl-7H-pyr-
rolo[2,3-d]pyrimidin-4-ylamino}ethyl]acetamide;
[0124]
N-(2-{6-[1-(4-Bromobenzyl)piperidin-4-yloxymethyl]-2-phenyl-7H-pyrr-
olo[2,3-d]pyrimidin-4-ylamino}ethyl)acetamide;
[0125]
N-[2-(6-{1-[2-(2-Chlorophenyl)ethyl]piperidin-4-yloxymethyl}-2-phen-
yl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)ethyl]acetamide;
[0126]
N-[2-(6-{1-[2-(3-Chlorophenyl)ethyl]piperidin-4-yloxymethyl}-2-phen-
yl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)ethyl]acetamide;
[0127]
N-(2-{6-[1-(3-Chlorobenzyl)piperidin-4-yloxymethyl]-2-phenyl-7H-pyr-
rolo[2,3-d]pyrimidin-4-ylamino}ethyl)acetamide;
[0128]
N-[2-(6-{1-[2-(4-Chlorophenyl)ethyl]piperidin-4-yloxymethyl}-2-phen-
yl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)ethyl]acetamide;
[0129]
N-[2-(6-{1-[2-(2-Methoxyphenyl)ethyl]piperidin-4-yloxymethyl}-2-phe-
nyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)ethyl]acetamide;
[0130]
N-[2-(6-{1-[2-(3-Methoxyphenyl)ethyl]piperidin-4-yloxymethyl}-2-phe-
nyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)ethyl]acetamide;
[0131]
N-[2-(6-{1-[2-(4-Methoxyphenyl)ethyl]piperidin-4-yloxymethyl}-2-phe-
nyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)ethyl]acetamide;
[0132]
N-[2-(6-{1-[2-(4-Fluorophenyl)ethyl]piperidin-4-yloxymethyl}-2-phen-
yl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)ethyl]acetamide;
[0133]
N-[2-(6-{1-[2-(2-Chloro-4-fluorophenyl)ethyl]piperidin-4-yloxymethy-
l}-2-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)ethyl]acetamide;
[0134]
N-[2-(6-{1-[2-(2-Chloro-6-fluorophenyl)ethyl]piperldin-4-yloxymethy-
l}-2-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)ethyl]acetamide;
[0135]
N-[2-(6-{1-[2-(2-Trifluoromethylphenyl)ethyl]piperidin-4-yloxymethy-
l}-2-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)ethyl]acetamide;
and
[0136]
N-[2-(6-{1-[2-(2-Bromophenyl)ethyl]piperidin-4-yloxymethyl}-2-pheny-
l-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)ethyl]acetamide.
[0137] In a further embodiment of Structure I, the subject
invention provides compounds having the structure: 10
[0138] wherein,
[0139] R.sub.7 is hydrogen, or a substituted or unsubstituted
(C.sub.1-C.sub.30)alkyl, (C.sub.1-C.sub.30)alkylaryl.
[0140] In one embodiment, R.sub.3 is substituted or unsubstituted
phenyl.
[0141] In a further embodiment, R.sub.4 is hydrogen.
[0142] In a further embodiment of Structure I, the subject
invention provides compounds having the structure: 11
[0143] wherein,
[0144] R.sub.8, N, and R.sub.9 together form a substituted or
unsubstituted 4-8 membered heterocyclic ring.
[0145] In one embodiment, R.sub.8NR.sub.9 together form a
substituted or unsubstituted azetidine, pyrrolidine, piperazine,
piperidine, morpholine, azocane, dihydro-1H-isoquinoline,
1,2,3,6-tetrahydropyridine, dihydro-2H-pyridine,
1,3,4,9-tetrahydro-.beta.-carboline, 1,3,8-triazaspiro[4.5]decane,
2,8-diazaspiro[4.5]decane, 2,5-diazabicyclo[2.2.1]heptane,
1,4-dioxa-8-azaspiro[4.5]decane, or [1.4]diazepane ring.
[0146] In a further embodiment, R.sub.8NR.sub.9 together form a
substituted or unsubstituted azetidine, pyrrolidine, piperazine,
piperidine or [1.4]diazepane ring.
[0147] In another embodiment, the ring formed by R.sub.8NR.sub.9 is
substituted with one or more aryl, heteroaryl,
(C.sub.1-C.sub.30)alkylary- l, (C.sub.1-C.sub.30)alkylheteroaryl,
(C.sub.1-C.sub.30)alkenylaryl, (C.sub.1-C.sub.30)alkenylheteroaryl,
(C.sub.1-C.sub.30)alkynylaryl, or
(C.sub.1-C.sub.30)alkynylheteroaryl moiety, which itself can be
substituted.
[0148] In another embodiment, R.sub.3 is a substituted or
unsubstituted phenyl.
[0149] In a further embodiment,
[0150] R.sub.1 is --(CH.sub.2).sub.2NHC(.dbd.O)CH.sub.3;
[0151] R.sub.2 is hydrogen or methyl; and
[0152] R.sub.4 is hydrogen or methyl.
[0153] In another embodiment, the compound is selected from the
group consisting of:
[0154]
N-(2-{2-Phenyl-6-[4-(3-phenylallyl)-piperazine-1-carbonyl]-7H-pyrro-
lo[2,3-d]pyrimidin-4-ylamino}-ethyl)-acetamide;
[0155]
N-{2-[6-(4-Hydroxy-4-isopropylpiperidine-1-carbonyl)-2-phenyl-7H-py-
rrolo[2,3-d]pyrimidin-4-ylamino]-ethyl}-acetamide;
[0156]
N-(2-{2-Phenyl-6-[4-(3-phenylpropyl)-piperazine-1-carbonyl]-7H-pyrr-
olo[2,3-d]pyrimidin-4-ylamino}-ethyl)-acetamide;
[0157]
N-{2-[6-(4-Phenethylpiperazine-1-carbonyl)-2-phenyl-7H-pyrrolo[2,3--
d]pyrimidin-4-ylamino]-ethyl}-acetamide;
[0158]
2-{2-Phenyl-6-[4-(3-phenylpropyl)-piperazine-1-carbonyl]-7H-pyrrolo-
[2,3-d]pyrimidin-4-ylamino}-acetamide;
[0159]
N-[2-(6-{4-[2-(4-Chlorophenoxy)-ethyl]-piperazine-1-carbonyl}-2-phe-
nyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-ethyl]-acetamide;
[0160]
N-{2-[6-(4-Cyano-4-phenylpiperidine-1-carbonyl)-2-phenyl-7H-pyrrolo-
[2,3-d]pyrimidin-4-ylamino]-ethyl}-acetamide;
[0161]
N-(2-{2-Phenyl-6-[4-(3-phenylprop-2-ynyl)-piperazine-1-carbonyl]-7H-
-pyrrolo[2,3-d]pyrimidin-4-ylamino}-ethyl)-acetamide;
[0162]
N-(2-{6-[cis-3,5-Dimethyl-4-(3-phenylpropyl)-piperazine-1-carbonyl]-
-2-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino}-ethyl)-acetamide;
[0163]
N-{2-[6-(4,4-Diphenylpiperidine-1-carbonyl)-2-phenyl-7H-pyrrolo[2,3-
-d]pyrimidin-4-ylamino]-ethyl}-acetamide;
[0164]
N-{2-[6-(3,3-Diphenylpiperidine-1-carbonyl)-2-phenyl-7H-pyrrolo[2,3-
-d]pyrimidin-4-ylamino]-ethyl}-acetamide;
[0165]
N-{2-[6-(4-Methoxy-4-phenylpiperidine-1-carbonyl)-2-phenyl-7H-pyrro-
lo[2,3-d]pyrimidin-4-ylamino]-ethyl}-acetamide;
[0166]
N-(2-{6-[tranis-2,5-Dimethyl-4-(3-phenylpropyl)-piperazine-1-carbon-
yl]-2-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino}-ethyl)-acetamide;
[0167]
N-{2-[6-(trans-2,5-Dimethylpiperazine-1-carbonyl)-2-phenyl-7H-pyrro-
lo[2,3-d]pyrimidin-4-ylamino]-ethyl}-acetamide;
[0168]
N-{2-[6-(4-Benzyl-cis-3,5-dimethylpiperazine-1-carbonyl)-2-phenyl-7-
H-pyrrolo[2,3-d]pyrimidin-4-ylamino]-ethyl}-acetamide;
[0169]
N-{2-[6-(cis-3,5-Dimethyl-4-phenethylpiperazine-1-carbonyl)-2-pheny-
l-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino]-ethyl}-acetamide;
[0170]
N-{2-[6-(3-Methyl-3-phenylpiperidine-1-carbonyl)-2-phenyl-7H-pyrrol-
o[2,3-d]-pyrimidin-4-ylamino]-ethyl}-acetamide;
[0171]
N-(2-{2-Phenyl-6-[4-(5-trifluoromethylpyridin-2-yl)-pjperazine-1-ca-
rbonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino}-ethyl)-acetamide;
[0172]
N-(2-{6-[4-(2'-Chlorobiphenyl-2-yl)-4-methoxypiperidine-1-carbonyl]-
-2-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino}-ethyl)-acetamide;
[0173]
N-(2-{6-[4-(2-Chlorophenyl)-4-methoxypiperidine-1-carbonyl]-2-pheny-
l-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino}-ethyl)-acetamide;
[0174]
N-(2-{6-[4-(2-Chlorophenyl)-4-hydroxypiperidine-1-carbonyl]-2-pheny-
l-7H-pyrrolo[2,3--dlpyrimidin-4-ylamino}-ethyl)-acetamide;
[0175]
N-(2-{6-[4-(2'-Chlorobiphenyl-2-yl)-4-hydroxypiperidine-1-carbonyl]-
-2-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino}-ethyl)-acetamide;
[0176]
N-(2-{6-[4-(4-Fluorophenyl)-4-methoxypiperidine-1-carbonyl]-2-pheny-
l-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino}-ethyl)-acetamide;
[0177]
N-(2-{2-Phenyl-6-[4-(4-phenylbutyl)-piperazine-1-carbonyl]-7H-pyrro-
lo[2,3-d]pyrimidin-4-ylamino}-ethyl)-acetamide;
[0178]
N-(2-{2-Phenyl-6-[4-(3-phenylpropyl)-piperidine-1-carbonyl]-7H-pyrr-
olo[2,3-d]pyrimidin-4-ylamino}-ethyl)-acetamide;
[0179]
N-{2-[2-Phenyl-6-(4-pyrrolidin-1-yl-piperidine-1-carbonyl)-7H-pyrro-
lo[2,3-d]pyrimidin-4-ylamino]-ethyl}-acetamide;
[0180]
N-(2-{6-[4-(3-Cyclohexylpropyl)-piperazine-1-carbonyl]-2-phenyl-7H--
pyrrolo[2,3--dlpyrimidin-4-ylamino}-ethyl)-acetamide;
[0181]
N-(2-{6-[4-(4-Methylpentyl)-piperazine-1-carbonyl]-2-phenyl-7H-pyrr-
olo[2,3-d]pyrimidin-4-ylamino}-ethyl)-acetamide;
[0182]
N-{2-[6-([1,4']Bipiperidinyl-1'-carbonyl)-2-phenyl-7H-pyrrolo[2,3-d-
]pyrimidin-4-ylamino]-ethyl}-acetamide;
[0183]
N-{2-[6-(4-Cyclopentylpiperazine-1-carbonyl)-2-phenyl-7H-pyrrolo[2,-
3-d]pyrimidin-4-ylamino]-ethyl}-acetamide;
[0184]
N-{2-[6-(4-Aminopiperidine-1-carbonyl)-2-phenyl-7H-pyrrolo[2,3-d]py-
rimidin-4-ylamino]-ethyl}-acetamide;
[0185]
N-{2-[6-(4-Acetyl-4-phenylpiperidine-1-carbonyl)-2-phenyl-7H-pyrrol-
o[2,3-d]pyrimidin-4-ylamino]-ethyl}-acetamide;
[0186]
N-(2-{6-[4-(2-Cyclohexylethyl)-piperazine-1-carbonyl]-2-phenyl-7H-p-
yrrolo[2,3-d]pyrimidin-4-ylamino}-etbyl)-acetamide;
[0187]
N-{2-[2-Phenyl-6-(4-phenylethynyl-3,6-dihydro-2H-pyridine-1-carbony-
l)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino]-ethyl}-acetamide;
[0188]
N-{2-[6-(4-tert-Butylpiperidine-1-carbonyl)-2-phenyl-7H-pyrrolo[2,3-
-d]pyrimidin-4-ylamino]-ethyl}-acetamide;
[0189]
N-{2-[6-(4-Phenethylpiperidine-1-carbonyl)-2-phenyl-7H-pyrrolo[2,3--
d]pyrimidin-4-ylamino]-ethyl}-acetamide;
[0190]
N-[2-(6-{4-[3-(2-Cyanophenyl)-prop-2-ynyl]-piperazine-1-carbonyl}-2-
-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-ethyl]-acetamide;
[0191]
N-[2-(6-{4-[3-(3-Cyanophenyl)-prop-2-ynyl]-piperazine-1-carbonyl}-2-
-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-ethyl]-acetamide;
[0192]
N-[2-(6-{4-[3-(4-Cyanophenyl)-prop-2-ynyl]-piperazine-1-carbonyl}-2-
-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-ethyl]-acetamide;
[0193]
1-[4-(2-Acetylaminoethylamino)-2-phenyl-7H-pyrrolo[2,3-d]pyrimidine-
-6-carbonyl]-4-phenylpiperidine-4-carboxylic acid methyl ester;
[0194]
N-(2-{6-[4-(1-Hydroxyethyl)-4-phenylpiperidine-1-carbonyl]-2-phenyl-
-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino}-ethyl)-acetamide;
[0195]
N-[2-(6-{4-[3-(4-Cyanophenyl)-propyl]-piperazine-1-carbonyl}-2-phen-
yl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-ethyl]-acetamide;
[0196]
1-[4-(2-Acetylaminoethylamino)-2-phenyl-7H-pyrrolo[2,3-d]pyrimidine-
-6-carbonyl]-4-phenylpiperidine-4-carboxylic acid ethyl ester;
[0197]
1-[4-(2-Acetylaminoethylamino)-2-phenyl-7H-pyrrolo[2,3-d]pyrimidine-
-6-carbonyl]-4-phenylpiperidine-4-carboxylic acid amide;
[0198]
1-[4-(2-Acetylaminoethylamino)-2-phenyl-7H-pyrrolo[2,3-d]pyrimidine-
-6-carbonyl]-4-phenylpiperidine-4-carboxylic acid methylamide;
[0199]
1-[4-(2-Acetylaminoethylamino)-2-phenyl-7H-pyrrolo[2,3-d]pyrimidine-
-6-carbonyl]-4-phenylpiperidine-4-carboxylic acid
dimethylamide;
[0200]
1-[4-(2-Acetylaminoethylamino)-2-phenyl-7H-pyrrolo[2,3-d]pyrimidine-
-6-carbonyl]-4-phenylpiperidine-4-carboxylic acid benzylamide;
[0201]
1-[4-(2-Acetylaminoethylamino)-2-phenyl-7H-pyrrolo[2,3-d]pyrimidine-
-6-carbonyl]-4-phenylpiperidine-4-carboxylic acid ethylamide;
[0202]
1-[4-(2-Acetylaminoethylamino)-2-phenyl-7H-pyrrolo[2,3-d]pyrimidine-
-6-carbonyl]-4-phenylpiperidine-4-carboxylic acid diethylamide;
[0203]
N-(2-{6-[4-(Azetidine-1-carbonyl)-4-phenylpiperidine-1-carbonyl]-2--
phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino}-ethyl)-acetamide;
[0204]
N-(2-{2-Phenyl-6-[4-phenyl-4-(pyrrolidine-1-carbonyl)-piperidine-1--
carbonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino}-ethyl)-acetamide;
[0205]
N-(2-{2-Phenyl-6-[4-phenyl-4-(piperidine-1-carbonyl)-piperidine-1-c-
arbonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino}-ethyl)-acetamide;
[0206]
N-(2-{6-[4-(Morpholine-4-carbonyl)-4-phenylpiperidine-1-carbonyl]-2-
-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino}-ethyl)-acetamide;
[0207]
1-[4-(2-Acetylaminoethylamino)-2-phenyl-7H-pyrrolo[2,3-d]pyrimidine-
-6-carbonyl]-4-phenylpiperidine-4-carboxylic acid
tert-butylamide;
[0208]
N-{2-[6-(4-Isopropyl-4-phenylpiperidine-1-carbonyl)-2-phenyl-7H-pyr-
rolo[2,3-d]pyrimidin-4-ylamino]-ethyl}-acetamide;
[0209]
N-(2-{2-Phenyl-6-[4-(3-thiophen-2-yl-prop-2-ynyl)-piperazine-1-carb-
onyl]-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino}-ethyl)-acetamide;
[0210]
1-[4-(2-Acetylaminoethylamino)-2-phenyl-7H-pyrrolo[2,3-d]pyrimidine-
-6-carbonyl]-4-phenylpiperidine-4-carboxylic acid cyclobutylmethyl
ester;
[0211]
N-(2-{6-[4-(4-Chlorophenyl)-4-methoxypiperidine-1-carbonyl]-2-pheny-
l-7H- pyrrolo[2,3-d]pyrimidin-4-ylamino}-ethyl)-acetamide;
[0212]
N-(2-{6-[4-Methoxy-4-(3-trifluoromethylphenyl)-piperidine-1-carbony-
l]-2-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino}-ethyl)-acetamide;
[0213]
N-{2-[6-(4-Isopropyl-4-methoxypiperidine-1-carbonyl)-2-phenyl-7H-py-
rrolo[2,3-d]pyrimidin-4-ylamino]-ethyl}-acetamide;
[0214]
N-{2-[6-(4-Acetylamino4-phenylpiperidine-1-carbonyl)-2-phenyl-7H-py-
rrolo[2,3-d]pyrimidin-4-ylamino]-ethyl}-acetamide;
[0215]
1-[4-(2-Acetylaminoethylamino)-2-phenyl-7H-pyrrolo[2,3-d]pyrimidine-
-6-carbonyl]-4-phenylpiperidine-4-carboxylic acid isopropyl
ester;
[0216]
1-[4-(2-Acetylaminoethylamino)-2-phenyl-7H-pyrrolo[2,3-d]pyrimidine-
-6-carbonyl]-4-ethylaminopiperidine-4-carboxylic acid amide;
[0217]
N-(2-{6-[4-Methoxy-4-(3-methoxyphenyl)-piperidine-1-carbonyl]-2-phe-
nyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino}-ethyl)-acetamide;
[0218]
1-[4-(2-Acetylaminoetbylamino)-2-phenyl-7H-pyrrolo[2,3-d]pyrimidine-
-6-carbonyl]-4-pyrrolidin-1-ylpiperidine-4-carboxylic acid
amide;
[0219]
N-(2-{6-[4-(2-Methoxyphenyl)-3,6-dihydro-2H-pyridine-1-carbonyl]-2--
phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino}-ethyl)-acetamide;
[0220]
N-{2-[6-(4-Amino-4-phenylpiperidine-1-carbonyl)-2-phenyl-7H-pyrrolo-
[2,3-d]pyrimidin-4-ylamino]-ethyl}-acetamide;
[0221]
N-{2-[6-(4-Formyl-4-phenylpiperidine-1-carbonyl)-2-phenyl-7H-pyrrol-
o[2,3-d]pyrimidin-4-ylamino]-ethyl}-acetamide;
[0222]
N-{2-[6-(4-Benzyl-4-methoxypiperidine-1-carbonyl)-2-phenyl-7H-pyrro-
lo[2,3-d]pyrimidin-4-ylamino]-ethyl}-acetamilde;
[0223] N-{2-[6-(4-Methoxy-4-o-tolylpiperidine-
-carbonyl)-2-phenyl-7H-pyrr-
olo[2,3-d]pyrimidin-4-ylamino]-ethyl}-acetamide;
[0224]
N-{2-[6-(4-Methoxymethyl-4-phenylpiperidine-1-carbonyl)-2-phenyl-7H-
-pyrrolo[2,3-d]pyrimidin-4-ylamino]-ethyl}-acetamide;
[0225]
N-[2-(6-{4-[3-(2-Chlorophenyl)-propyl]-piperazine-1-carbonyl}-2-phe-
nyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-ethyl]-acetamide;
[0226]
N-[2-(6-{4-[3-(3-Chlorophenyl)-propyl]-piperazine-1-carbonyl}-2-phe-
nyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-ethyl]-acetamide;
[0227]
N-[2-(6-{4-[3-(4-Chlorophenyl)-propyl]-piperazine-1-carbonyl}-2-phe-
nyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-ethyl]-acetamide;
[0228]
N-[2-(6-{4-[3-(2-Methoxyphenyl)-propyl]-piperazine-1-carbonyl}-2-ph-
enyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-ethyl]-acetamide;
[0229]
N-[2-(6-{4-[3-(3-Methoxyphenyl)-propyl]-piperazine-1-carbonyl}-2-ph-
enyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-ethyl]-acetamide;
[0230]
N-[2-(6-{4-[3-(4-Methoxyphenyl)-propyl]-piperazine-1-carbonyl}-2-ph-
enyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-ethyl]-acetamide;
[0231]
N-[2-(6-{4-[3-(4-Chlorophenyl)-propionyl]-piperazine-1-carbonyl}-3--
2-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-ethyl]-acetamide;
[0232]
N-[2-(6-{4-[3-(3-Chlorophenyl)-propionyl]-piperazine-1-carbonyl}-2--
phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-ethyl]-acetamide;
[0233]
N-[2-(6-{4-[3-(2-Chlorophenyl)-propionyl]-piperazine-1-carbonyl}-2--
phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-ethyl]-acetamide;
[0234]
N-[2-(6-{4-[5-(4-Chlorophenyl)-2H-pyrazol-3-yl]-piperidine-1-carbon-
yl}-2-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-ethyl]-acetamide;
[0235]
2-{4-[4-(2-Acetylaminoethylamino)-2-phenyl-7H-pyrrolo[2,3-d]pyrimid-
ine-6-carbonyl]-piperazin-1-yl}-N-methyl-N-phenylacetamide;
[0236]
4-[4-(2-Acetylaminoethylamino)-2-phenyl-7H-pyrrolo[2,3-d]pyrimidine-
-6-carbonyl]-piperazine-1-carboxylic acid benzyl ester;
[0237]
N-{2-[6-(4-Oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carbonyl)-2--
phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino]-ethyl}-acetamide;
[0238]
N-(2-{6-[4-(Methylphenethylamino)-piperidine-1-carbonyl]-2-phenyl-7-
H-pyrrolo[2,3-d]pyrimidin-4-ylamino}-ethyl)-acetamide;
[0239]
N-{2-[6-(4-Phenethylaminopiperidine-1-carbonyl)-2-phenyl-7H-pyrrolo-
[2,3-d]pyrimidin-4-ylamino]-ethyl}-acetamide;
[0240]
N-[2-(6-{4-[2-(4-Chlorophenyl)-ethylamino]-piperidine-1-carbonyl}-2-
-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-ethyl]-acetamide;
[0241]
N-[2-(6-{4-[2-(3H-Imidazol-4-yl)-ethylamino]-piperidine-1-carbonyl}-
-2-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-ethyl]-acetamide;
[0242]
N-(2-{2-Phenyl-6-[4-(2-pyridin-4-ylethylamino)-piperidine-1-carbony-
l]-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino}-ethyl)-acetamide;
[0243]
N-(2-{2-Phenyl-6-[4-(2-pyridin-2-ylethylamino)-piperidine-1-carbony-
l]-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino}-ethyl)-acetamide;
[0244]
N-{2-[6-(4-Benzylaminopiperidine-1-carbonyl)-2-phenyl-7H-pyrrolo[2,-
3-d]pyrimidin-4-ylamino]-ethyl}-acetamide;
[0245]
N-(2-{6-[4-(Benzylmethylamino)-piperidine-1-carbonyl]-2-phenyl-7H-p-
yrrolo[2,3-d]pyrimidin-4-ylamino}-ethyl)-acetamide;
[0246]
N-[2-(2-Phenyl-6-{4-[(pyridin-4-ylmethyl)-amino]-piperidine-1-carbo-
nyl}-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-ethyl]-acetamide;
[0247]
N-(2-{2-Phenyl-6-[4-(2-pyridin-3-ylethylamino)-piperidine-1-carbony-
l]-7H-pyrrolo[2,3-d]pyrinmidin-4-ylamino}-ethyl)-acetamide;
[0248]
N-{2-[2-Phenyl-6-((S)-2-phenylaminomethylpyrrolidine-1-carbonyl)-7H-
-pyrrolo[2,3-d]pyrimidin-4-ylamino]-ethyl}-acetamide;
[0249]
N-[2-(2-Phenyl-6-{4-[3-(4-trifluoromethylphenyl)-propyl]-piperazine-
-1-carbonyl}-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-ethyl]-acetamide;
[0250]
N-[2-(6-{4-[3-(4-Fluorophenyl)-propyl]-piperazine-1-carbonyl}-2-phe-
nyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-ethyl]-acetamide;
[0251]
N-(2-{6-[4-(3-Benzo[1,3]dioxol-5-yl-propyl)-pipera-zine-1-carbonyl]-
-2-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino}-ethyl)-acetamide;
[0252]
N-(2-{2-Phenyl-6-[4-(3-p-tolylpropyl)-piperazine-1-carbonyl]-7H-pyr-
rolo[2,3-d]pyrimidin-4-ylamino}-ethyl)-acetamide;
[0253]
N-[2-(6-{4-[3-(4-Bromophenyl)-propyl]-piperazine-1-carbonyl}-2-phen-
yl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-iethyl]-acetamide;
[0254]
N-[2-(6-{4-[3-(3,4-Dichlorophenyl)-propyl]-piperazine-1-carbonyl}-2-
-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-ethyl]-acetamide;
[0255]
N-[2-(6-{4-[3-(2,4-Dichlorophenyl)-propyl]-piperazine-1-carbonyl}-2-
-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-ethyl]-acetamide;
[0256]
N-{2-[6-(4-Benzyl-[1,4]diazepane-1-carbonyl)-2-phenyl-7H-pyrrolo[2,-
3-d]pyrimidin-4-ylamino]-ethyl}-acetamide;
[0257]
N-{2-[6-(4-Phenethyl-[1,4]diazepane-1-carbonyl)-2-phenyl-7H-pyrrolo-
[2,3-d]pynimidin-4-ylamino]-ethyl}-acetamide;
[0258]
N-(2-{2-Phenyl-6-[4-(3-phenylpropyl)-[1,4]diazepane-1-carbonyl]-7H--
pyrrolo[2,3-d]pyrimidin-4-ylamino}-ethyl)-acetamide;
[0259]
N-(2-{6-[4-(4-Acetylaminophenyl)-piperazine-1-carbonyl]-2-phenyl-7H-
-pyrrolo[2,3-d]pyrimidin-4-ylamino}-ethyl)-acetamide;
[0260]
N-(2-{6-[4-(2-Cyanophenyl)-piperazine-1-carbonyl]-2-phenyl-7H-pyrro-
lo[2,3-d]pyrimidin-4-ylamino}-ethyl)-acetamide;
[0261]
N-[2-(6-{4-[4-(Acetylmethylamino)-phenyl]-piperazine-1-carbonyl}-2--
phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-ethyl]-acetamide;
[0262]
N-(2-{6-[4-(2,6-Dimethylphenyl)-piperazine-1-carbonyl]-2-phenyl-7H--
pyrrolo[2,3-d]pyrimidin-4-ylamino}-ethyl)-acetamide;
[0263]
N-(2-{6-[4-(2-Chlorophenyl)-piperazine-1-carbonyl]-2-phenyl-7H-pyrr-
olo[2,3-d]pyrimidin-4-ylamino}-ethyl)-acetamide;
[0264]
N-(2-{6-[4-(2,4-Dimethoxyphenyl)-piperazine-1-carbonyl]-2-phenyl-7H-
-pyrrolo[2,3-d]pyrimidin-4-ylamino}-ethyl)-acetamide;
[0265]
N-(2-{6-[4-(5-Chloro-2-methoxyphenyl)-piperazine-1-carbonyl]-2-phen-
yl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino}-ethyl)-acetamide;
[0266]
N-(2-{6-[4-(4-Chlorophenoxymethyl)-piperidine-1-carbonyl]-2-phenyl--
7H-pyrrolo[2,3-d]pyrimidin-4-ylamino}-ethyl)-acetamide;
[0267]
N-{2-[6-(5-Benzyl-2,5-diazabicyclo[2.2.1]heptane-2-carbonyl)-2-phen-
yl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino]-ethyl}-acetamide;
[0268]
N-{2-[6-(4-Phenoxymethylpiperidine-1-carbonyl)-2-phenyl-7H-pyrrolo[-
2,3-d]pyrimidin-4-ylamino]-ethyl}-acetamide;
[0269]
N-(2-{6-[4-(4-Cyanophenoxymethyl)-piperidine-1-carbonyl]-2-phenyl-7-
H-pyrrolo[2,3-d]pyrimidin-4-ylamino}-etyl)-acetamide;
[0270]
N-(2-{6-[4-(3-Cyanophenoxymethyl)-piperidine-1-carbonyl]-2-phenyl-7-
H-pyrrolo[2,3-d]pyrimidin-4-ylamino}-ethyl)-acetamide;
[0271]
N-(2-{6-[4-(2-Nitrophenyl)-piperazine-1-carbonyl]-2-phenyl-7H-pyrro-
lo[2,3-d]pyrimidin-4-ylamino}-ethyl)-acetamide;
[0272]
2-{4-[4-(2-Acetylaminoethylamino)-2-phenyl-7H-pyrrolo[2,3-d]pyrimid-
ine-6-carbonyl]-piperazin-1-yl}-benzoic acid methyl ester;
[0273]
N-{2-[2-Phenyl-6-(4-o-tolylpiperazine-1-carbonyl)-7H-pyrrolo[2,3-d]-
pyrimidin-4-ylamino]-ethyl}-acetamide;
[0274]
N-(2-{6-[4-(3,4-Dichlorophenoxymethyl)-piperidine-1-carbonyl]-2-phe-
nyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino}-ethyl)-acetamide;
[0275]
N-(2-{6-[4-(2-Cyanophenoxymethyl)-piperidine-1-carbonyl]-2-phenyl-7-
H-pyrrolo[2,3-d]pyrimidin-4-ylamino}-ethyl)-acetamide;
[0276]
N-(2-{6-[4-(2-Chlorophenyl)-4-cyanopiperidine-1-carbonyl]-2-phenyl--
7H-pyrrolo[2,3-d]pyrimidin-4-ylamino}-ethyl)-acetamide;
[0277]
2-{4-[4-(2-Acetylaminoethylamino)-2-phenyl-7H-pyrrolo[2,3-d]pyrimid-
ine-6-carbonyl]-piperazin-1-yl}-benzamide;
[0278]
N-(2-{6-[4-Cyano-4-(2-methoxyphenyl)-piperidine-1-carbonyl]-2-pheny-
l-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino}-ethyl)-acetamide;
[0279]
N-(2-{6-[4-(3-Chlorophenyl)-4-cyanopiperidine-1-carbonyl]-2-phenyl--
7H-pyrrolo[2,3-d]pyrimidin-4-ylamino}-ethyl)-acetamide;
[0280]
N-(2-{6-[4-Cyano-4-(3-methoxyphenyl)-piperidine-1-carbonyl]-2-pheny-
l-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino}-ethyl)-acetamide; and
[0281] N-(2-{6-[4-Cyano-4-(4-methoxyphenyl)-piperidine-
-carbonyl]-2-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino}-ethyl)-acetamid-
e.
[0282] In another embodiment of Structure I, the subject invention
provides compounds having the structure: 12
[0283] wherein,
[0284] R.sub.8 and R.sub.9 are each independently hydrogen, or a
substituted or unsubstituted (C.sub.1-C.sub.30)alkyl,
(C.sub.1-C.sub.30)alkylaryl, (C.sub.1-C.sub.30)alkylamino,
(C.sub.1-C.sub.30)alkoxy, or a saturated or unsaturated, monocyclic
or bicyclic, carbocyclic or heterocyclic ring.
[0285] In one embodiment, R.sub.8 or R.sub.9 is a
(C.sub.1-C.sub.30)alkyl substituted with one or more hydroxy,
dihydroxy or amino moiety.
[0286] In another embodiment, R.sub.8 or R.sub.9 is a substituted
or unsubstituted pyrrolidine, piperidine, bicycle[2.2.1]heptane,
2-oxoazepan, indane, or cyclopropylbenzene ring.
[0287] In another embodiment, the compound is selected from the
group consisting of:
[0288]
4-(2-Acetylaminoethylamino)-2-phenyl-7H-pyrrolo[2,3-d]pyrimidine-6--
carboxylic acid (3-phenoxyphenyl)-amide;
[0289]
4-(2-Acetylaminoethylamino)-2-phenyl-7H-pyrrolo[2,3-d]pyrimidine-6--
carboxylic acid (1-benzylpiperidin-4-yl)-amide;
[0290]
4-(2-Acetylaminoethylamino)-2-phenyl-7H-pyrrolo[2,3-d]pyrimidine-6--
carboxylic acid (1-benzylpyrrolidin-3-yl)-amide;
[0291]
4-(2-Acetylaminoethylamino)-2-phenyl-7H-pyrrolo[2,3-d]pyrimidine-6--
carboxylic acid 4-[1,2,3]thiadiazol-4-yl-benzylamide;
[0292] 4-(2-Acetyl
aminoethylamino)-2-phenyl-7H-pyrrolo[2,3-d]pyrimidine-6-
-carboxylic acid benzylamide;
[0293]
4-(2-Acetylaminoethylamino)-2-phenyl-7H-pyrrolo[2,3-d]pyrimidine-6--
carboxylic acid (2-hydroxy-1-hydroxymethylethyl)-amide;
[0294]
4-(2-Acetylaminoethylamino)-2-phenyl-7H-pyrrolo[2,3-d]pyrimidine-6--
carboxylic acid (1-hydroxycyclohexylmethyl)-amide; and
[0295]
4-(2-Acetylaminoethylamino)-2-phenyl-7H-pyrrolo[2,3-d]pyrimidine-6--
carboxylic acid [2-(4-phenoxyphenyl)-ethyl]-amide.
[0296] In another embodiment of Structure I, the subject invention
provides compounds having the structure: 13
[0297] wherein,
[0298] R.sub.10 is hydrogen or a substituted or unsubstituted
(C.sub.1-C.sub.30)alkyl, (C.sub.3-C.sub.10)cycloalkyl, or an aryl,
heteroaryl or heterocyclic ring.
[0299] In one embodiment, R.sub.10 is a substituted or
unsubstituted piperidine ring.
[0300] In another embodiment, R.sub.3 is a substituted or
unsubstituted phenyl.
[0301] In a further embodiment, R.sub.4 is hydrogen.
[0302] In a further embodiment, R.sub.1 is
--(CH.sub.2).sub.2NHC(.dbd.O)CH- .sub.3;
[0303] In a further embodiment, R.sub.2 is hydrogen.
[0304] In a further embodiment, the compound has the structure:
14
[0305] In a further embodiment of Structure I, the subject
invention provides compounds having the structure: 15
[0306] wherein,
[0307] R.sub.11NR.sub.12 together form a substituted or
unsubstituted 4-8 membered heterocyclic ring; and
[0308] k is 1, 2 or 3.
[0309] In one embodiment, R.sub.11NR.sub.12 together form a
substituted or unsubstituted azetidine, pyrrolidine, piperazine,
piperidine, morpholine, azocane, dihydro-1H-isoquinoline,
1,2,3,6-tetrahydropyridine, dihydro-2H-pyridine,
1,3,4,9-tetrahydro-p-carboline, 1,3,8-triazaspiro[4.5]decane,
2,8-diazaspiro[4.5]decane, 2,5-diazabicyclo[2.2.1]heptane,
1,4-dioxa-8-azaspiro[4.5]decane, or [1.4]diazepane ring.
[0310] In a further embodiment, R.sub.11NR.sub.12 together form a
substituted or unsubstituted azetidine, pyrrolidine, piperazine,
piperidine or [1.4]diazepane ring.
[0311] In another embodiment, the ring formed by R.sub.11NR.sub.12
is substituted with one or more aryl, heteroaryl,
(C.sub.1-C.sub.30)alkylary- l, (C.sub.1-C.sub.30)alkylheteroaryl,
(C.sub.1-C.sub.30)alkenylaryl, (C.sub.1-C.sub.30)alkenylheteroaryl,
(C.sub.1-C.sub.30)alkynylaryl, or
(C.sub.1-C.sub.30)alkynylheteroaryl moieties, which itself can be
substituted.
[0312] In another embodiment, R.sub.3 is a substituted or
unsubstituted phenyl.
[0313] In a further embodiment, R.sub.4 is hydrogen.
[0314] In a further embodiment, R.sub.1 is
--(CH.sub.2).sub.2NHC(.dbd.O)CH- .sub.3.
[0315] In another embodiment, the compound is
N-(2-{6-[3-(4-Benzylpiperazi-
n-1-yl)-3-oxopropyl]-2-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino}-ethyl)-
-acetamide.
[0316] 5. In a further embodiment of Structure I, the subject
invention provides compounds having the structure: 16
[0317] wherein,
[0318] R.sub.11NR.sub.12 together form a substituted or
unsubstituted 4-8 membered heterocyclic ring; and
[0319] k is 1, 2 or 3.
[0320] In one embodiment, R.sub.11NR.sub.12 together form a
substituted or unsubstituted azetidine, pyrrolidine, piperazine,
piperidine, morpholine, azocane, dihydro-1H-isoquinoline,
1,2,3,6-tetrahydropyridine, dihydro-2H-pyridine,
1,3,4,9-tetrahydro-p-carboline, 1,3,8-triazaspiro[4.5]decane,
2,8-diazaspiro[4.5]decane, 2,5-diazabicyclo[2.2.1]heptane,
1,4-dioxa-8-azaspiro[4.5]decane, or [1.4]diazepane ring.
[0321] In a further embodiment, R.sub.11NR.sub.12 together form a
substituted or unsubstituted azetidine, pyrrolidine, piperazine,
piperidine or [1.4]diazepane ring.
[0322] In another embodiment, the ring formed by R.sub.11NR.sub.12
is substituted with one or more aryl, heteroaryl,
(C.sub.1-C.sub.30)alkylary- l, (C.sub.1-C.sub.30)alkylheteroaryl,
(C.sub.1-C.sub.30)alkenylaryl, (C.sub.1-C.sub.30)alkenylheteroaryl,
(C.sub.1-C.sub.30)alkynylaryl, or
(C.sub.1-C.sub.30)alkynylheteroaryl moiety.
[0323] In another embodiment, R.sub.3 is a substituted or
unsubstituted phenyl.
[0324] In a further embodiment, R.sub.4 is hydrogen.
[0325] In a further embodiment, R.sub.1 is
--(CH.sub.2).sub.2NHC(.dbd.O)CH- .sub.3.
[0326] The subject invention also provides compounds having the
structure: 17
[0327] wherein,
[0328] R.sub.13 and R.sub.14 are each independently a hydrogen atom
or a substituted or unsubstituted alkyl or alkylaryl moiety;
[0329] or R.sub.13NR.sub.14 together form a substituted or
unsubstituted 4 membered heterocyclic ring, a substituted or
unsubstituted 5 membered ring, or a substituted or unsubstituted
piperazine, wherein the five-membered ring is substituted with
[0330] --CH.sub.2C(.dbd.O)OH;
[0331] R.sub.15 is hydrogen or a substituted or unsubstituted
alkyl; and
[0332] R.sub.16 is --CH.sub.2NR.sub.17, --CH.sub.2OR.sub.17,
--CH.sub.2CH.sub.2C(.dbd.O)OR.sub.17,
CH.sub.2CH.sub.2C(.dbd.O)NR.sub.18R- .sub.19,
--C(.dbd.O)NR.sub.18R.sub.19, or --C(.dbd.O)OR.sub.17, wherein
R.sub.17, R.sub.18 and R.sub.19 are each independently a hydrogen
atom, a substituted or unsubstituted alkyl, aryl or alkylaryl
moiety, or R.sub.14NR.sub.15 together form a substituted or
unsubstituted 4 to 8 membered heterocyclic ring.
[0333] In one embodiment, any alkyl is a straight chain
(C.sub.1-C.sub.30)alkyl or a branched chain
(C.sub.3-C.sub.30)alkyl.
[0334] In a further embodiment, any heterocyclic ring, if present,
is a substituted or unsubstituted morpholine, pyrrolidine,
piperazine, piperidine, azocane, dihydro-1H-isoquinoline,
dihydro-2H-pyridine, 1,3,4,9-tetrahydro-.beta.-carboline,
1,3,8-triazaspiro[4.5]decane, 2,8-diazaspiro[4.5]decane,
2,5-diazabicyclo[2.2.1]heptane, or [1,4]diazepane ring.
[0335] The subject invention also provides compounds having the
structure: 18
[0336] wherein
[0337] R.sub.3 is a substituted or unsubstituted 4-10 membered
aryl, heteroaryl or heterocyclic ring;
[0338] R.sub.20 is halogen or
--NH(CHR.sub.20').sub.nNHC(.dbd.O)CH.sub.3, where R.sub.20' is H,
OH, alkyl, hydroxyalkyl, cycloalkyl, heteroalkyl, or amino;
[0339] R.sub.21 is H or --C(.dbd.O)OH;
[0340] R.sub.22 is H or SO.sub.2Ph; and
[0341] n is 2, 3, 4 or 5;
[0342] wherein when R.sub.20 is
--NH(CHR.sub.20').sub.nNHC(.dbd.O)CH.sub.3- , R.sub.21 is
--C(.dbd.O)OH.
[0343] In one embodiment, R.sub.3 is substituted or unsubstituted
phenyl.
[0344] In a further embodiment, R.sub.20 is Cl.
[0345] In a further embodiment, R.sub.22 is SO.sub.2Ph.
[0346] In a further embodiment, R.sub.21 is H.
[0347] In a further embodiment, R.sub.21 is --C(.dbd.O)OH.
[0348] In another embodiment, R.sub.20 is
--NH(CH.sub.2).sub.nNHC(.dbd.O)C- H.sub.3 and R.sub.21 is
--C(.dbd.O)OH.
[0349] In a further embodiment, R.sub.22 is H.
[0350] In a further embodiment, R.sub.22 is SO.sub.2Ph.
[0351] The subject invention also provides a method for treating a
disease associated with the A.sub.2b adenosine receptor in a
subject in need of such treatment comprising administering to the
subject a therapeutically effective amount of the compounds of
Structure I so as to thereby treat the disease associated with the
A.sub.2b adenosine receptor in the subject, wherein the disease
associated with the A.sub.2b adenosine receptor is asthma,
urticaria, scleroderm arthritis, myocardial infarction, myocardial
reperfusion after ischemia, diabetic retinopathy, retinopathy of
prematurity, diabetes, diarrhea, inflammatory bowel disease,
proliferating tumor or is associated with mast cell degranulation,
vasodilation, hypertension, hypersensitivity or the release of
allergic mediators.
[0352] In one embodiment, the disease associated with the A.sub.2b
adenosine receptor is diabetes.
[0353] In another embodiment, the disease associated with the
A.sub.2b adenosine receptor is asthma.
[0354] In another embodiment, the disease associated with the
A.sub.2b adenosine receptor is associated with mast cell
degranulation.
[0355] In another embodiment, the disease associated with the
A.sub.2b adenosine receptor is a proliferating tumor.
[0356] The subject invention also provides a method for treating a
disease associated with the A.sub.2b adenosine receptor in a
subject in need of such treatment comprising administering to the
subject a therapeutically effective amount of the compound.of
Structure II so as to thereby treat the disease associated with the
A.sub.2b adenosine receptor in the subject, wherein the disease
associated with the A.sub.2b adenosine receptor is asthma,
urticaria, scleroderm arthritis, myocardial infarction, myocardial
reperfusion after ischemia, diabetic retinopathy, retinopathy of
prematurity, diabetes, diarrhea, inflammatory bowel disease,
proliferating tumor or is associated with mast cell degranulation,
vasodilation, hypertension, hypersensitivity or the release of
allergic mediators.
[0357] The subject invention also provides a pharmaceutical
composition comprising a compound of the invention and a
pharmaceutically acceptable carrier.
[0358] In one embodiment, the pharmaceutical composition is
formulated for oral, topical, parenteral or nasal
administration.
[0359] The subject invention also provides a process for the
manufacture of a pharmaceutical composition comprising admiking a
compound of the invention with a pharmaceutically acceptable
carrier.
[0360] The subject invention also provides an article of
manufacture comprising
[0361] packaging material;
[0362] the above pharmaceutical composition; and
[0363] instructions for use of the pharmaceutical composition in
the treatment of a disease associated with the A.sub.2b adenosine
receptor.
[0364] The subject invention also provides a process of
manufacturing a compound having the structure: 19
[0365] wherein,
[0366] R.sub.8 and R.sub.9 are each independently hydrogen, or a
substituted or unsubstituted (C.sub.1-C.sub.30)alkyl,
(C.sub.1-C.sub.30)alkylaryl, (C.sub.1-C.sub.30)alkylamino,
(C.sub.1-C.sub.30)alkoxy, or a saturated or unsaturated, monocyclic
or bicyclic, carbocyclic or heterocyclic ring, or
[0367] R.sub.8, N, and R.sub.9 together form a substituted or
unsubstituted 4-8 membered heterocyclic ring,
[0368] comprising:
[0369] (a) reacting 20
[0370] with PhSO.sub.2Cl and a reducing agent in the presence of
solvent to produce: 21
[0371] (b) reacting the product of step (a) with CO.sub.2 in the
presence of lithium diisopropylamide (LDA) and a solvent to
produce: 22
[0372] (c) reacting the product of step (b) with 23
[0373] in the presence solvent to produce: 24
[0374] (d) reacting the product of step (c) with a hydroxide base
and a coupling agent in solution to produce: 25
[0375] and
[0376] (e) reacting the product of step (d) with HNR.sub.7R.sub.8
in the presence of a base to produce the compound.
[0377] In one embodiment of the above process, the reducing agent
in step (a) is NaH and the solvent is dimethylformamide (DMF).
[0378] In another embodiment, the solvent in step (b) is
tetrahydrofuran (THF).
[0379] In another embodiment, the solvent in step (c) is dimethyl
sulfoxide (DMSO).
[0380] In another embodiment, the hydroxide base in step (d) is
sodium hydroxide.
[0381] In another embodiment, the base in step (e) is
triethylamine, the coupling agent is
O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
tetrafluoroborate (TBTU),
benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate,
or 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide (EDC) and
N-Hydroxybenzotriazole, and the solvent is DMF.
[0382] In another embodiment, the order of the steps is (a), (b),
(c), (e), then (d).
[0383] The subject invention also provides a compound produced by
the above process.
[0384] The subject invention also provides the use of a compound of
the invention for manufacturing a medicament useful for treating a
disease associated with the A.sub.2b adenosine receptor in a
subject, wherein the disease associated with the A.sub.2b adenosine
receptor is asthma, urticaria, scleroderm arthritis, myocardial
infarction, myocardial reperfusion after ischemia, diabetic
retinopathy, retinopathy of prematurity, diabetes, diarrhea,
inflammatory bowel disease, proliferating tumor, or is associated
with mast cell degranulation, vasodilation, hypertension,
hypersensitivity or the release of allergic mediators.
[0385] In one embodiment of the above use, the disease associated
with the A.sub.2b adenosine receptor is diabetes.
[0386] In another embodiment, the disease associated with the
A.sub.2b adenosine receptor is asthma.
[0387] In another embodiment, the disease associated with the
A.sub.2b adenosine receptor is associated with mast cell
degranulation.
[0388] In another embodiment, the disease associated with the
A.sub.2b adenosine receptor is a proliferating tumor.
[0389] The subject invention also provides any of the above
compounds, wherein any substituent, if present, is selected from
halogen, hydroxyl, carbonyl, straight chain
(C.sub.1-C.sub.30)alkyl, branched chain (C.sub.3-C.sub.30)alkyl,
(C.sub.3-C.sub.10)cycloalkyl, straight
chain(C.sub.1-C.sub.30)alkylcarbonyloxy, branched chain
(C.sub.3-C.sub.30)alkylcarbonyloxy, arylcarbonyloxy, straight
chain(C.sub.1-C.sub.30)alkoxycarbonyloxy, branched
chain(C.sub.3-C.sub.30)alkoxycarbonyloxy, aryloxycarbonyloxy,
carboxylate, straight chain(C.sub.1-C.sub.30)alkylcarbonyl,
branched chain (C.sub.3-C.sub.30)alkylcarbonyl, arylcarbonyl,
straight chain (C.sub.1-C.sub.30)alkoxycarbonyl, branched chain
(C.sub.3-C.sub.30)alkoxy- carbonyl, aminocarbonyl, straight chain
(C.sub.1-C.sub.30)alkylthiocarbony- l, branched chain
(C.sub.3-C.sub.30)alkylthiocarbonyl, straight chain
(C.sub.1-C.sub.30)alkylsulfonyl, branched chain
(C.sub.3-C.sub.30)alkylsu- lfonyl, straight chain
(C.sub.1-C.sub.30)alkoxyl, branched chain
(C.sub.1-C.sub.30)alkoxyl, phosphate, phosphonato, cyano, amino,
straight chain (C.sub.1-C.sub.30)alkylamino, branched chain
(C.sub.3-C.sub.30)alkylamino, straight chain
(C.sub.1-C.sub.30)dialkylami- no, branched chain
(C.sub.3-C.sub.30)dialkylamino, arylamino, diarylamino, straight
chain (C.sub.1-C.sub.30)alkylarylamino, branched chain
(C.sub.3-C.sub.30)alkylarylamino, acylamino, straight chain
(C.sub.1-C.sub.30)alkylcarbonylamino, branched chain
(C.sub.3-C.sub.30)alkylcarbonylamino, arylcarbonylamino, carbamoyl,
ureido, amidino, imino, sulfhydryl, straight chain
(C.sub.1-C.sub.30)alkylthio, branched chain
(C.sub.3-C.sub.30)alkylthio, arylthio, thiocarboxylate, sulfates,
sulfonato, sulfamoyl, sulfonamido, sulfonyl, benzenesulfonyl,
nitro, trifluoromethyl, azido,
6-methoxy-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxole,
3,4-dihydroxy-5-methoxytetrahydrofuran, 4-10 membered heterocyclyl,
straight chain (C.sub.1-C.sub.30)alkylaryl, branched chain
(C.sub.3-C.sub.30)alkylaryl, straight chain
(C.sub.1-C.sub.30)alkylhetero- aryl, branched chain
(C.sub.3-C.sub.30)alkylheteroaryl, (C.sub.1-C.sub.30)alkenylaryl,
(C.sub.1-C.sub.30)alkenylheteroaryl, (C.sub.1-C.sub.30)alkynylaryl,
(C.sub.1-C.sub.30)alkynylheteroaryl or an aromatic or 5-6 membered
heteroaromatic moiety,
[0390] which substituent may be further substituted by any of the
above.
[0391] The subject invention also includes the specific compounds
that are included by each of the above structures. The specific
compounds are described in the examples.
[0392] The number of carbons when represented as
"(C.sub.1-C.sub.30)" or "(C.sub.3-C.sub.30)" is intended to mean
any incremental whole number between 1 and 3 and 30, e.g. 1, 2, 3,
4, 5 . . . or 30.
[0393] The present invention is based on compounds which
selectively bind to adenosine A.sub.2b receptor, thereby treating a
disease associated with A.sub.2b adenosine receptor in a subject by
administering to the subject a therapeutically effective amount of
such compounds. The diseases to be treated are associated with, for
example, asthma, mast cell degranulation, myocardial reperfusion
injury, allergic reactions including but not limited to rhinitis,
poison ivy induced responses, urticaria, scleroderm arthritis,
autoimmune diseases, inflammatory bowel diseases, hypertension,
myocardial infarction, myocardial reperfusion after ischemia,
lymphocyte activation, vasodilation, growth, neural reflexes in the
human gut, retinal angiogenesis, abberant neovascularization such
as diabetic retinopathy and retinopathy of prematurity, modulation
of intestinal tone and secretion and neurotransmission and
neurosecretion.
[0394] A.sub.2b receptors have also been implicated in
hypersensitivity, hay fever, serum sickness, allergic vasculitis,
atopic dermatitis, dermatitis, eczema, idiopathic pulmonary
fibrosis, eosinophilic chlorecystitis, chronic airway inflammation,
hypereosinophilic syndromes, eosinophilic gastroenteritis, edema,
eosinophilic myocardial disease, episodic angioedema with
eosinophilia, ulcerative colitis, allergic granulomatosis,
carcinomatosis, eosinophilic granuloma, familial histiocytosis,
tumor, cardiac hypoxia, cerebral ischemia, diuresis, renal failure,
neurological disorder, mental disorder, cognitive disorder,
myocardial ischemia, bronchoconstriction, Crohn's disease, Grave's
disease, diabetes, multiple sclerosis, anaemia, psoriasis,
fertility disorders, lupus erthyematosus, brain arteriole diameter,
the release of allergic mediators, scleroderma, stroke, global
ischemia, central nervous system disorder, cardiovascular disorder,
renal disorder, inflammatory disorder, gastrointestinal disorder,
eye disorder, allergic disorder, respiratory disorder, or
immunological disorder.
[0395] The invention further pertains to methods for treating
A.sub.2b associated disorders in a mammal by administering to the
mammal a therapeutically effective amount of the compounds of the
present invention, such that treatment of the disorder in the
mammal occurs.
[0396] The invention further pertains to methods for treating
A.sub.2b associated disorders in a mammal by administering to the
mammal a therapeutically effective amount of the compounds of the
present invention, such that treatment of the disorder in the
mammal occurs.
[0397] The present invention also pertains to packaged
pharmaceutical compositions for treating A.sub.2b associated
disorders. The packaged pharmaceutical composition includes a
container holding a therapeutically effective amount of at least
one of the compounds of the present invention and instructions for
using the said compounds for treating an A.sub.2b associated
disease.
[0398] The compounds of this invention rqay advantageously be
selective A.sub.2b receptor antagonists.
[0399] In a particularly preferred embodiment, the compound is a
water soluble prodrug that is capable of being metabolized in vivo
to an active drug by, for example, esterase catalyzed
hydrolysis.
[0400] In yet another embodiment, the invention features a method
for inhibiting the activity of an adenosine receptor (e.g.,
A.sub.2b) in a cell, by contacting the cell with a compound of the
present invention (e.g., preferably, an adenosine receptor
antagonist).
[0401] The invention also features a pharmaceutical composition
comprising a compound of the present invention. Preferably, the
pharmaceutical preparation is an ophthalmic formulation (e.g., an
periocular, retrobulbar or intraocular injection formulation, a
systemic formulation, or a surgical irrigating solution).
[0402] The present invention pertains to methods for treating an
A.sub.2b associated disorder in a mammal. The methods include
administration of a therapeutically effective amount of the
compounds of the invention, described infra, to the mammal, such
that treatment of the A.sub.2b associated disorder in the mammal
occurs.
[0403] The language "treatment of an A.sub.2b associated disorder"
refers to treatment which includes a significant diminishment of at
least one symptom or effect of the disorder achieved with a
compound of the invention. Typically such disorders are associated
with an increase of adenosine within a host such that the host
often experiences physiological symptoms which include, but are not
limited to, urticaria, scleroderm arthritis, allergic rhinitis,
asthma, inflammatory bowel diseases, hypertension, diabetic
retinopathy and retinopathy of prematurity. (See for example, C. E.
Muller and B. Stein "Adenosine Receptor Antagonists: Structures and
Potential Therapeutic Applications," Current Pharmaceutical Design,
2:501 (1996) and C. E. Muller "A.sub.1-Adenosine Receptor
Antagonists," Exp. Opin. Ther. Patents 7(5):419 (1997) and I.
Feoktistove, R. Polosa, S. T. Holgate and I. Biaggioni "Adenosine
A.sub.2B receptors: a novel therapeutic target in asthma?" TiPS 19;
148 (1998)). The effects often associated with such symptoms
include, but are not limited to, fever, shortness of breath,
nausea, diarrhea, weakness, headache, and even death. In one
embodiment, the disorder includes those disease states which are
mediated by stimulation of adenosine receptors, e.g., A.sub.1,
A.sub.2a, A.sub.2b, A.sub.3, etc., such that calcium concentrations
in cells and/or activation of PLC (phospholipase C) is modulated.
In a preferred embodiment, the disorder is associated with
adenosine receptor(s), e.g., the compound of the invention acts as
an antagonist. Examples of suitable responsive states which can be
treated by the compounds of the invention, e.g., adenosine receptor
subtypes which mediate biological effects, include central nervous
system (CNS) effects, cardiovascular effects, renal effects,
respiratory effects, immunological effects, gastro-intestinal
effects and metabolic effects. The relative amount of adenosine in
a subject can be associated with the effects listed below; that is
increased levels of adenosine can trigger an effect, e.g., an
undesired physiological response, e.g., an asthmatic attack.
[0404] Immunological effects include mast cell degranulation
(A.sub.2b). Therapeutic applications of antagonists include
allergic and non allergic inflammation, e.g., release of histamine
and other inflammatory mediators.
[0405] Gastrointestinal effects include colonic, intestinal and
diarrheal disease, e.g., diarrheal disease associated with
intestinal inflammation (A.sub.2b).
[0406] The term "disease state" is intended to include those
conditions caused by or associated with unwanted levels of
adenosine, adenylyl cyclase activity, increased physiological
activity associated with aberrant stimulation of adenosine
receptors and/or an increase in cAMP. In one embodiment, the
disease state is, for example, asthma, chronic obstructive
pulmonary disease, allergic rhinitis, bronchitis, renal disorders,
gastrointestinal disorders, or eye disorders. Additional examples
include chronic bronchitis and cystic fibrosis. Suitable examples
of inflammatory diseases include non-lymphocytic leukemia,
myocardial ischaemia, angina, infarction, cerebrovascular ischemia,
intermittent claudication, critical limb ischemia, venous
hypertension, varicose veins, venous ulceration and
arteriosclerosis. Impaired reperfusion states include, for example,
any post-surgical trauma, such as reconstructive surgery,
thrombolysis or angioplasty.
[0407] This invention also provides a combination therapy for
glaucoma, comprising one of the compounds of the invention, and a
prostagladin agonist, beta-2 agonist, or a muscarinic
antagonist.
[0408] The language "treating an A.sub.2b associated disorder" or
"treating an A.sub.2b associated disease" is intended to include
changes in a disease state or condition, as described above, such
that physiological symptoms in a mammal can be significantly
diminished or minimized. The language also includes control,
prevention or inhibition of physiological symptoms or effects
associated with an aberrant amount of adenosine. In one preferred
embodiment, the control of the disease state or condition is such
that the disease state or condition is eradicated. In another
preferred embodiment, the control is selective such that aberrant
levels of adenosine receptor activity are controlled while other
physiologic systems and parameters are unaffected.
[0409] The language "therapeutically effective amount" of the
compounds of the invention, described infra, refers to that amount
of a therapeutic compound necessary or sufficient to perform its
intended function within a mammal, e.g., treat an A.sub.2b
associated disorder, or a disease state in a mammal. An effective
amount of the therapeutic compound can vary according to factors
such as the amount of the causative agent already present in the
mammal, the age, sex, and weight of the mammal, and the ability of
the therapeutic compounds of the present invention to affect the
A.sub.2b associated disorder in the mammal. One of ordinary skill
in the art would be able to study the aforementioned factors and
make a determination regarding the effective amount of the
therapeutic compound without undue experimentation. An in vitro or
in vivo assay also can be used to determine an "effective amount"
of the therapeutic compounds described infra. The ordinarily
skilled artisan would select an appropriate amount of the
therapeutic compound for use in the aforementioned assay or as a
therapeutic treatment.
[0410] A therapeutically effective amount preferably diminishes at
least one symptom or effect associated with the A.sub.2b associated
disorder being treated by at least about 20%, (more preferably by
at least about 40%, even more preferably by at least about 60%, and
still more preferably by at least about 80%) relative to untreated
subjects. Assays can be designed by one skilled in the art to
measure the diminishment of such symptoms and/or effects. Any art
recognized assay capable of measuring such parameters are intended
to be included as part of this invention. For example, if asthma is
the state being treated, then the volume of air expended from the
lungs of a subject can be measured before and after treatment for
measurement of increase in the volume using an art recognized
technique. Likewise, if inflammation is the state being treated,
then the area which is inflamed can be measured before and after
treatment for measurement of diminishment in the area inflamed
using an art recognized technique.
[0411] The term "cell" includes both prokaryotic and eukaryotic
cells.
[0412] The term "animal" includes any organism with adenosine
receptors. Examples of animals include yeast, mammals, reptiles,
and birds. It also includes transgenic animals.
[0413] The term "mammal" is art recognized and is intended to
include an animal, more preferably a warm-blooded animal, most
preferably cattle, sheep, pigs, horses, dogs, cats, rats, mice, and
humans. Mammals susceptible to A.sub.2b associated disorders
responsive state, inflammation, emphysema, asthma, central nervous
system conditions, or acute respiratory distress syndrome, for
example, are included as part of this invention.
[0414] In another aspect, the present invention pertains to methods
for modulating an adenosine receptor(s) in a mammal by
administering to the mammal a therapeutically effective amount of
the compounds of the invention, such that modulation of the
adenosine receptor in the mammal occurs. Suitable adenosine
receptors include the families of A.sub.1, A.sub.2, or A.sub.3 In a
preferred embodiment, the compound is an adenosine receptor
antagonist.
[0415] The language "modulating an adenosine receptor" is intended
to include those instances where a compound interacts with an
adenosine receptor(s), causing increased, decreased or abnormal
physiological activity associated with an adenosine receptor or
subsequent cascade effects resulting from the modulation of the
adenosine receptor. Physiological activities associated with
adenosine receptors include induction of sedation, vasodilation,
suppression of cardiac rate and contractility, inhibition of
platelet aggregbility, stimulation of gluconeogenesis, inhibition
of lipolysis, opening of potassium channels, reducing flux of
calcium channels, etc.
[0416] The terms "modulate", "modulating" and "modulation" are
intended to include preventing, eradicating, or inhibiting the
resulting increase of undesired physiological activity associated
with abnormal stimulation of an adenosine receptor, e.g., in the
context of the therapeutic methods of the invention. In another
embodiment, the term modulate includes antagonistic effects, e.g.,
diminishment of the activity or production of mediators of allergy
and allergic inflammation which results from the overstimulation of
adenosine receptor(s). For example, the therapeutic deazapurines of
the invention can interact with an adenosine receptor to inhibit,
for example, adenylate cyclase activity.
[0417] The language "condition characterized by aberrant adenosine
receptor activity" is intended to include those diseases, disorders
or conditions which are associated with aberrant stimulation of an
adenosine receptor, in that the stimulation of the receptor causes
a biochemical and or physiological chain of events that is directly
or indirectly associated with the disease, disorder or condition.
This stimulation of an adenosine receptor does not have to be the
sole causative agent of the disease, disorder or condition but
merely be responsible for causing some of the symptoms typically
associated with the disease, disorder, or condition being treated.
The aberrant stimulation of the receptor can be the sole factor or
at least one other agent can be involved in the state being
treated. Examples of conditions include those disease states listed
supra, and those symptoms manifested by the presence of increased
adenosine receptor activity.
[0418] The language "treating or treatment of a condition
characterized by aberrant adenosine receptor activity" is intended
to include the alleviation of or diminishment of at least one
symptom typically associated with the condition. The treatment also
includes alleviation or diminishment of more than one symptom.
Preferably, the treatment cures, e.g., substantially eliminates,
the symptoms associated with the condition.
[0419] The invention further pertains to a method for inhibiting
the activity of an adenosine receptor (e.g., an A.sub.2b adenosine
receptor) in a cell by contacting the cell with a compound of the
invention. Preferably, the compound is an antagonist of the
receptor.
[0420] In another embodiment, the invention relates to a
pharmaceutical composition containing a compound of the invention
and a pharmaceutically acceptable carrier.
[0421] The invention also pertains to a method for treating an
A.sub.2b associated disease in an animal, by administering to a
mammal a therapeutically effective amount of a compound of the
invention, such that treatment of the A.sub.2b associated disorder
occurs.
[0422] Advantageously, the disease state may be a disorder mediated
by adenosine. Examples of preferred disease states include: central
nervous system disorders, cardiovascular disorders, renal
disorders, inflammatory disorders, allergic disorders,
gastrointestinal disorders, eye disorders, and respiratory
disorders.
[0423] The term "alkyl" refers to the radical of saturated
aliphatic groups, including straight-chain alkyl groups,
branched-chain alkyl groups, cycloalkyl (alicyclic) groups, alkyl
substituted cycloalkyl groups, and cycloalkyl substituted alkyl
groups. In preferred embodiments, a straight chain or branched
chain alkyl has 30 or fewer carbon atoms in its backbone (e.g.,
C.sub.1-C.sub.30 for straight chain, C.sub.3-C.sub.30 for branched
chain), and more preferably 20 or fewer. Likewise, preferred
cycloalkyls have from 4-10 carbon atoms in their ring structure,
and more preferably have 5, 6 or 7 carbons in the ring
structure.
[0424] The term "substituted alkyls" refers to alkyl moieties
having substituents replacing a hydrogen on one or more carbons of
the hydrocarbon backbone. Such substituents can include, for
example, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy,
alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl,
alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, alkoxyl,
phosphate, phosphonato, phosphinato, cyano, amino (including alkyl
amino, dialkylamino, arylamino, diarylamino, and alkylarylamino),
acylamino (including alkylcarbonylamino, arylcarbonylamino,
carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio,
arylthio, thiocarboxylate, sulfates, sulfonato, sulfamoyl,
sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl,
alkylaryl, or an aromatic or heteroaromatic moiety. It will be
understood by those skilled in the art that the moieties
substituted on the hydrocarbon chain can themselves be substituted,
if appropriate. Cycloalkyls can be further substituted, e.g., with
the substituents described above. An "alkylaryl" moiety is an alkyl
substituted with an aryl (e.g., phenylmethyl (benzyl)). The term
"alkyl" also includes unsaturated aliphatic groups analogous in
length and possible substitution to the alkyls described above, but
that contain at least one double or triple bond respectively.
[0425] The term "aryl" as used herein, refers to the radical of
aryl groups, including 5- and 6-membered single-ring aromatic
groups that may include from zero to four heteroatoms, for example,
benzene, pyrrole, furan, thiophene, imidazole, benzoxazole,
benzothiazole, triazole, tetrazole, pyrazole, pyridine, pyrazine,
pyridazine and pyrimidine, and the like. Aryl groups also include
polycyclic fused aromatic groups such as naphthyl, quinolyl,
indolyl, and the like. Those aryl groups having heteroatoms in the
ring structure may also be referred to as "aryl heterocycles",
"heteroaryls" or "heteroaromatics". The aromatic ring can be
substituted at one or more ring positions with such substituents as
described above, as for example, halogen, hydroxyl, alkoxy,
alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy,
aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkoxycarbonyl,
aminocarbonyl, alkylthiocarbonyl, phosphate, phosphonato,
phosphinato, cyano, amino (including alkyl amino, dialkylamino,
arylamino, diarylamino, and alkylarylamino), acylamino (including
alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido),
amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate,
sulfates, sulfonato, sulfamoyl, sulfonamido, nitro,
trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an
aromatic or heteroaromatic moiety. Aryl groups can also be fused or
bridged with alicyclic or heterocyclic rings which are not aromatic
so as to form a polycycle (e.g., tetralin).
[0426] The terms "alkenyl" and "alkynyl" refer to unsaturated
aliphatic groups analogous in length and possible substitution to
the alkyls described above, but that contain at least one double or
triple bond respectively. For example, the invention contemplates
cyano and propargyl groups.
[0427] Unless the number of carbons is otherwise specified, "lower
alkyl" as used herein means an alkyl group, as defined above, but
having from one to ten carbons, more preferably from one to six
carbon atoms in its backbone structure, even more preferably one to
three carbon atoms in its backbone structure. Likewise, "lower
alkenyl" and "lower alkynyl" have similar chain lengths.
[0428] The terms "alkoxyalkyl", "polyaminoalkyl" and
"thioalkoxyalkyl" refer to alkyl groups, as described above, which
further include oxygen, nitrogen or sulfur atoms replacing one or
more carbons of the hydrocarbon backbone, e.g., oxygen, nitrogen or
sulfur atoms.
[0429] The terms "polycyclyl" or "polycyclic radical" refer to the
radical of two or more cyclic rings (e.g., cycloalkyls,
cycloalkenyls, cycloalkynyls, aryls and/or heterocyclyls) in which
two or more atoms are common to two adjoining rings, e.g., the
rings are "fused rings". Rings that are joined through non-adjacent
atoms are termed "bridged" rings. Each of the rings of the
polycycle can be substituted with such substituents as described
above, as for example, halogen, hydroxyl, alkylcarbonyloxy,
arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy,
carboxylate, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl,
alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato,
cyano, amino (including alkyl amino, dialkylamino, arylamino,
diarylamino, and alkylarylamino), acylamino (including
alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido),
amidino, imino, sulfbydryl, alkylthio, arylthio, thiocarboxylate,
sulfates, sulfonato, sulfamoyl, sulfonamido, nitro,
trifluoromethyl, cyano, azido, heterocyclyl, alkyl, alkylaryl, or
an aromatic or heteroaromatic moiety.
[0430] The term "heteroatom" as used herein means an atom of any
element other than carbon or hydrogen. Preferred heteroatoms are
nitrogen, oxygen, sulfur and phosphorus.
[0431] The term "heterocycle" or "heterocyclic system" as used
herein is intended to mean a stable 5, 6 or 7-membered monocyclic
or 7, 8, 9, 10 or 11- membered bicyclic heterocyclic ring which is
saturated or partially unsaturated.
[0432] The terms "carbocyclic" or "heterocyclic" further include
spiro compounds, which denote a bicyclic compound in which the two
rings have one atom in common and the atom may be carbon or a
heteroatom.
[0433] The term "amino acids" includes naturally and unnaturally
occurring amino acids found in proteins such as glycine, alanine,
valine, cysteine, leucine, isoleucine, serine, threonine,
methionine, glutamic acid, aspartic acid, glutamine, asparagine,
lysine, arginine, proline, histidine, phenylalanine, tyrosine, and
tryptophan. Amino acid analogs include amino acids with lengthened
or shortened side chains or variant side chains with appropriate
functional groups. Amino acids also include D and L stereoisomers
of an amino acid when the structure of the amino acid admits of
stereoisomeric forms. The term "dipeptide" includes two or more
amino acids linked together. Preferably, dipeptides are two amino
acids linked via a peptide linkage. Particularly preferred
dipeptides include, for example, alanine-alanine and
glycine-alanine.
[0434] It will be noted that the structure of some of the compounds
of this invention includes asymmetric carbon atoms and thus occur
as racemates and racemic mixtures, single enantiomers,
diastereomeric mixtures and individual diastereomers. All such
isomeric forms of these compounds are expressly included in this
invention. Each stereogenic carbon may be of the R or S
configuration. It is to be understood accordingly that the isomers
arising from such asymmetry (e.g., all enantiomers and
diastereomers) are included within the scope of this invention,
unless indicated otherwise. Such isomers can be obtained in
substantially pure form by classical separation techniques and by
stereochemically controlled synthesis.
[0435] The invention further pertains to pharmaceutical
compositions for treating A.sub.2b associated disorders in a
mammal. The pharmaceutical composition includes a therapeutically
effective amount of a. compound of the invention and a
pharmaceutically acceptable carrier. It is to be understood, that
all of the compounds described below are included for therapeutic
treatment. It is to be further understood that the compounds of the
invention can be used alone or in combination with other compounds
of the invention or in combination with additional therapeutic
compounds, such as antibiotics, antiinflammatories, or anticancer
agents, for example.
[0436] The term "antibiotic" is art recognized and is intended to
include those substances produced by growing microorganisms and
synthetic derivatives thereof, which eliminate or inhibit growth of
pathogens and are selectively toxic to the pathogen while producing
minimal or no deleterious effects upon the infected host subject.
Suitable examples of antibiotics include, but are not limited to,
the principle classes of aminoglycosides, cephalosporins,
chloramphenicols, fuscidic acids, macrolides, penicillins,
polymixins, tetracyclines and streptomycins.
[0437] The term "antuinflammatory" is art recognized and is
intended to include those agents which act on body mechanisms,
without directly antagonizing the causative agent of the
inflammation such as glucocorticoids, aspirin, ibuprofen, NSAIDS,
etc.
[0438] The term "anticancer agent" is art recognized and is
intended to include those agents which diminish, eradicate, or
prevent growth of cancer cells without, preferably, adversely
affecting other physiological functions. Representative examples
include cisplatin and cyclophosphamide.
[0439] The term "cancer" as used herein is intended to mean a
cellular malignancy whose unique trait--loss of normal
controls--results in unregulated growth, lack of differentiation,
and ability to invade local tissues and metastasize. The presence
of a cellular malignancy is often indicated by the presence of a
tumor. Local tissue invasion can result from local tumor pressure
on normal tissues that can lead to inflammation, or the tumor may
elaborate substances that lead to enzymatic destruction.
[0440] When the compounds of the present invention are administered
as pharmaceuticals, to humans and mammals, they can be given per se
or as a pharmaceutical composition containing, for example, 0.1 to
99.5% (more preferably, 0.5 to 90%) of active ingredient in
combination with a pharmaceutically acceptable carrier.
[0441] The phrase "pharmaceutically acceptable carrier" as used
herein means a pharmaceutically acceptable material, composition or
vehicle, such as a liquid or solid filler, diluent, excipient,
solvent or encapsulating material, involved in carrying or
transporting a compound(s) of the present invention within or to
the subject such that it can performs its intended function.
Typically, such compounds are carried or transported from one
organ, or portion of the body, to another organ, or portion of the
body. Each carrier must be "acceptable" in the sense of being
compatible with the other ingredients of the formulation and not
injurious to the patient. Some examples of materials which can
serve as pharmaceutically acceptable carriers include: sugars, such
as lactose, glucose and sucrose; starches, such as corn starch and
potato starch; cellulose, and its derivatives, such as sodium
carboxymethyl cellulose, ethyl cellulose and cellulose acetate;
powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa
butter and suppository waxes; oils, such as peanut oil, cottonseed
oil, safflower oil, sesame oil, olive oil, corn oil and soybean
oil; glycols, such as propylene glycol; polyols, such as glycerin,
sorbitol, mannitol and polyethylene glycol; esters, such as ethyl
oleate and ethyl laurate; agar; buffering agents, such as magnesium
hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water;
isotonic saline; Ringer's solution; ethyl alcohol; phosphate buffer
solutions; and other non-toxic compatible substances employed in
pharmaceutical formulations.
[0442] As set out above, certain embodiments of the present
compounds can contain a basic functional group, such as amino or
alkylamino, and are, thus, capable of forming pharmaceutically
acceptable salts with pharmaceutically acceptable acids. The term
"pharmaceutically acceptable salts" in this respect, refers to the
relatively non-toxic, inorganic and organic acid addition salts of
compounds of the present invention. These salts can be prepared in
situ during the final isolation and purification of the compounds
of the invention, or by separately reacting a purified compound of
the invention in its free base form with a suitable organic or
inorganic acid, and isolating the salt thus formed. Representative
salts include the hydrobromide, hydrochloride, sulfate, bisulfate,
phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate,
laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate,
fumarate, succinate, tartrate, napthylate, mesylate,
glucoheptonate, lactobionate, and laurylsulphonate salts and the
like. (See, e.g., Berge et al. (1977) "Pharmaceutical Salts", J.
Pharm. Sci. 66:1-19).
[0443] In other cases, the compounds of the present invention may
contain one or more acidic functional groups and, thus, are capable
of forming pharmaceutically acceptable salts with pharmaceutically
acceptable bases. The term "pharmaceutically acceptable salts" in
these instances refers to the relatively non-toxic, inorganic and
organic base addition salts of compounds of the present invention.
These salts can likewise be prepared in situ during the final
isolation and purification of the compounds, or by separately
reacting the purified compound in its free acid form with a
suitable base, such as the hydroxide, carbonate or bicarbonate of a
pharmaceutically acceptable metal cation, with ammonia, or with a
pharmaceutically acceptablesorganic primary, secondary or tertiary
amine. Representative alkali or alkaline earth salts include the
lithium, sodium, potassium, calcium, magnesium, and aluminum salts
and the like. Representative organic amines useful for the
formation of base addition salts include ethylamine, diethylamine,
ethylenediamine, ethanolamine, diethanolamine, piperazine and the
like.
[0444] The term "pharmaceutically acceptable esters" refers to the
relatively non-toxic, esterified products of the compounds of the
present invention. These esters can be prepared in situ during the
final isolation and purification of the compounds, or by separately
reacting the purified compound in its free acid form or hydroxyl
with a suitable esterifying agent. Carboxylic acids can be
converted into esters via treatment with an alcohol in the presence
of a catalyst. Hydroxyl containing derivatives can be converted
into esters via treatment with an esterifying agent such as
alkanoyl halides. The term is further intended to include lower
hydrocarbon groups capable of being solvated under physiological
conditions, e.g., alkyl esters, methyl, ethyl and propyl esters.
(See, for example, Berge et al., supra.)
[0445] The invention further contemplates the use of prodrugs which
are converted in vivo to the therapeutic compounds of the invention
(see, e.g., R.B. Silverman, 1992, "The Organic Chemistry of Drug
Design and Drug Action", Academic Press, Chapter 8). Such prodrugs
can be used to alter the biodistribution (e.g., to allow compounds
which would not typically enter the reactive site of the protease)
or the pharmacokinetics of the therapeutic compound. For example, a
carboxylic acid group, can be esterified, e.g., with a methyl group
or an ethyl group to yield an ester. When the ester is administered
to a subject, the ester is cleaved, enzymatically or
non-enzymatically, reductively or hydrolytically, to reveal the
anionic group. An anionic group can be esterified with moieties
(e.g., acyloxymethyl esters) which are cleaved to reveal an
intermediate compound which subsequently decomposes to yield the
active compound. In another embodiment, the prodrug is a reduced
form of a sulfate or sulfonate, e.g., a thiol, which is oxidized in
vivo to the therapeutic compound. Furthermore, an anionic moiety
can be esterified to a group which is actively transported in vivo,
or which is selectively taken up by target organs. The ester can be
selected to allow specific targeting of the therapeutic moieties to
particular reactive sites, as described below for carrier
moieties.
[0446] Wetting agents, emulsifiers and lubricants, such as sodium
lauryl sulfate and magnesium stearate, as well as coloring agents,
release agents, coating agents, sweetening, flavoring and perfuming
agents, preservatives and antioxidants can also be present in the
compositions.
[0447] Examples of pharmaceutically acceptable antioxidants
include: water soluble antioxidants, such as ascorbic acid,
cysteine hydrochloride, sodium bisulfate, sodium metabisulfite,
sodium sulfite and the like; oil-soluble antioxidants, such as
ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated
hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol,
and the like; and metal chelating agents, such as citric acid,
ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid,
phosphoric acid, and the like.
[0448] Formulations of the present invention include those suitable
for oral, nasal, topical, transdermal, buccal, sublingual, rectal,
vaginal and/or parenteral administration. The formulations may
conveniently be presented in unit dosage form and may be prepared
by any methods well known in the art of pharmacy. The amount of
active ingredient which can be combined with a carrier material to
produce a single dosage form will generally be that amount of the
compound which produces a therapeutic effect. Generally, out of one
hundred percent, this amount will range from about 1 percent to
about ninety-nine percent of active ingredient, preferably from
about 5 percent to about 70 percent, most preferably from about 10
percent to about 30 percent.
[0449] Methods of preparing these formulations or compositions
include the step of bringing into association a compound of the
present invention with the carrier and, optionally, one or more
accessory ingredients. In general, the formulations are prepared by
uniformly and intimately bringing into association a compound of
the present invention with liquid carriers, or finely divided solid
carriers, or both, and then, if necessary, shaping the product.
[0450] Formulations of the invention suitable for oral
administration may be in the form of capsules, cachets, pills,
tablets, lozenges (using a flavored basis, usually sucrose and
acacia or tragacanth), powders, granules, or as a solution or a
suspension in an aqueous or non-aqueous liquid, or as an
oil-in-water or water-in-oil liquid emulsion, or as an elixir or
syrup, or as pastilles (using an inert base, such as gelatin and
glycerin, or sucrose and acacia) and/or as mouth washes and the
like, each containing a predetermined amount of a compound of the
present invention as an active ingredient. A compound of the
present invention may also be administered as a bolus, electuary or
paste.
[0451] In solid dosage forms of the invention for oral
administration (capsules, tablets, pills, dragees, powders,
granules and the like), the active ingredient is mixed with one or
more pharmaceutically acceptable carriers, such as sodium citrate
or dicalcium phosphate, and/or any of the following: fillers or
extenders, such as starches, lactose, sucrose, glucose, mannitol,
and/or silicic acid; binders, such as, for example,
carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone,
sucrose and/or acacia; humectants, such as glycerol; disintegrating
agents, such as agar-agar, calcium carbonate, potato or tapioca
starch, alginic acid, certain silicates, and sodium carbonate;
solution retarding agents, such as paraffin; absorption
accelerators, such as quaternary ammonium compounds; wetting
agents, such as, for example, acetyl alcohol and glycerol
monostearate; absorbents, such as kaolin and bentonite clay;
lubricants, such a talc, calcium stearate, magnesium stearate,
solid polyethylene glycols, sodium lauryl sulfate, and mixtures
thereof, and coloring agents. In the case of capsules, tablets and
pills, the pharmaceutical compositions may also comprise buffering
agents. Solid compositions of a similar type may also be employed
as fillers in soft and hard-filled gelatin capsules using such
excipients as lactose or milk sugars, as well as high molecular
weight polyethylene glycols and the like.
[0452] A tablet may be made by compression or molding, optionally
with one or more accessory ingredients. Compressed tablets may be
prepared using binder (for example, gelatin or hydroxypropylmethyl
cellulose), lubricant, inert diluent, preservative, disintegrant
(for example, sodium starch glycolate or cross-linked sodium
carboxymethyl cellulose), surface-active or dispersing agent.
Molded tablets may be made by molding in a suitable machine a
mixture of the powdered compound moistened with an inert liquid
diluent.
[0453] The tablets, and other solid dosage forms of the
pharmaceutical compositions of the present invention, such as
dragees, capsules, pills and granules, may optionally be scored or
prepared with coatings and shells, such as enteric coatings and
other coatings well known in the pharmaceutical-formulating art.
They may also be formulated so as to provide slow or controlled
release of the active ingredient therein using, for example,
hydroxypropylmethyl cellulose in varying proportions to provide the
desired release profile, other polymer matrices, liposomes and/or
microspheres. They may be sterilized by, for example, filtration
through a bacteria-retaining filter, or by incorporating
sterilizing agents in the form of sterile solid compositions which
can be dissolved in sterile water, or some other sterile injectable
medium immediately before use. These compositions may also
optionally contain opacifying agents and may be of a composition
that they release the active ingredient(s) only, or preferentially,
in a certain portion of the gastrointestinal tract, optionally, in
a delayed manner. Examples of embedding compositions which can be
used include polymeric substances and waxes. The active ingredient
can also be in micro-encapsulated form, if appropriate, with one or
more of the above-described excipients.
[0454] Liquid dosage forms for oral administration of the compounds
of the invention include pharmaceutically acceptable emulsions,
microemulsions, solutions, suspensions, syrups and elixirs. In
addition to the active ingredient, the liquid dosage forms may
contain inert dilutents commonly used in the art, such as, for
example, water or other solvents, solubilizing agents and
emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl
carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate,
propylene glycol, 1,3-butylene glycol, oils (in particular,
cottonseed, groundnut, corn, germ, olive, castor and sesame oils),
glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty
acid esters of sorbitan, and mixtures thereof.
[0455] Besides inert dilutents, the oral compositions can also
include adjuvants such as wetting agents, emulsifying and
suspending agents, sweetening, flavoring, coloring, perfuming and
preservative agents.
[0456] Suspensions, in addition to the active compounds, may
contain suspending agents as, for example, ethoxylated isostearyl
alcohols, polyoxyethylene sorbitol and sorbitan esters,
microcrystalline cellulose, aluminum metahydroxide, bentonite,
agar-agar and tragacanth, and mixtures thereof.
[0457] Formulations of the pharmaceutical compositions of the
invention for rectal or vaginal administration may be presented as
a suppository, which may be prepared by mixing one or more
compounds of the invention with one or more suitable nonirritating
excipients or carriers comprising, for example, cocoa butter,
polyethylene glycol, a suppository wax or a salicylate, and which
is solid at room temperature, but liquid at body temperature and,
therefore, will melt in the rectum or vaginal cavity and release
the active compound.
[0458] Formulations of the present invention which are suitable for
vaginal administration also include pessaries, tampons, creams,
gels, pastes, foams or spray formulations containing such carriers
as are known in the art to be appropriate.
[0459] Dosage forms for the topical or transdermal administration
of a compound of this invention include powders, sprays, ointments,
pastes, creams, lotions, gels, solutions, patches and inhalants.
The active compound may be mixed under sterile conditions with a
pharmaceutically acceptable carrier, and with any preservatives,
buffers, or propellants which may be required.
[0460] The ointments, pastes, creams and gels rhay contain, in
addition to an active compound of this invention, excipients, such
as animal and vegetable fats, oils, waxes, paraffins, starch,
tragacanth, cellulose derivatives, polyethylene glycols, silicones,
bentonites, silicic acid, talc and zinc oxide, or mixtures
thereof.
[0461] Powders and sprays can contain, in addition to a compound of
this invention, excipients such as lactose, talc, silicic acid,
aluminum hydroxide, calcium silicates and polyamide powder, or
mixtures of these substances. Sprays can additionally contain
customary propellants, such as chlorofluorohydrocarbons and
volatile unsubstituted hydrocarbons, such as butane and
propane.
[0462] Transdermnal patches have the added advantage of providing
controlled delivery of a compound of the present invention to the
body. Such dosage forms can be made by dissolving or dispersing the
compound in the proper medium. Absorption enhancers can also be
used to increase the flux of the compound across the skin. The rate
of such flux can be controlled by either providing a rate
controlling membrane or dispersing the active compound in a polymer
matrix or gel.
[0463] Ophthalmic formulations, eye ointments, powders, solutions
and the like, are also contemplated as being within the scope of
this invention. Preferably, the pharmaceutical preparation is an
ophthalmic formulation (e.g., an periocular, retrobulbar or
intraocular injection formulation, a systemic formulation, or a
surgical irrigating solution).
[0464] The ophthalmic formulations of the present invention may
include one or more of the compounds of the invention and a
pharmaceutically acceptable vehicle. Various types of vehicles may
be used. The vehicles will generally be aqueous in nature. Aqueous
solutions are generally preferred, based on case of formulation, as
well as a patient's ability to easily administer such compositions
by means of instilling one to two drops of the solutions in the
affected eyes. However, the deazapurines of the present invention
may also be readily incorporated into other types of compositions,
such as suspensions, viscous or semi-viscous gels or other types of
solid or semi-solid compositions. The ophthalmic compositions of
the present invention may also include various other ingredients,
such as buffers, preservatives, co-solvents and viscosity building
agents.
[0465] An appropriate buffer system (e.g., sodium phosphate, sodium
acetate or sodium borate) may be added to prevent pH drift under
storage conditions.
[0466] Ophthalmic products are typically packaged in multidose
form. Preservatives are thus required to prevent microbial
contamination during use. Suitable preservatives include:
benzalkonium chloride, thimerosal, chlorobutanol, methyl paraben,
propyl paraben, phenylethyl alcohol, edetate disodium, sorbic acid,
polyquaternium-1, or other agents known to those skilled in the
art. Such preservatives are typically employed at a level of from
0.001 to 1.0% weight/volume ("% w/v").
[0467] When the compounds of the present invention are administered
during intraocular surgical procedures, such as through retrobulbar
or periocular injection and intraocular perfusion or injection, the
use of balanced salt irrigating solutions as vehicles are most
preferred. BSS.RTM. Sterile Irrigating Solution and BSS Plus.RTM.
Sterile Intraocular Irrigating Solution (Alcon Laboratories, Inc.,
Fort Worth, Tex., USA) are examples of physiologically balanced
intraocular irrigating solutions. The latter type of solution is
described in U.S. Pat. No. 4,550,022 (Garabedian, et al.), the
entire contents of which are hereby incorporated in the present
specification by reference. Retrobulbar and periocular injections
are known to those skilled in the art and are described in numerous
publications including, for example, Ophthalmic Surgery: Principles
of Practice, Ed., G. L. Spaeth. W. B. Sanders Co., Philadelphia,
Pa., U.S.A., pages 85-87 (1990).
[0468] As indicated above, use of the compounds of the present
invention to prevent or reduce damage to retinal and optic nerve
head tissues at the cellular level is a particularly important
aspect of one embodiment of the invention. Ophthalmic conditions
which may be treated include, but are not limited to, retinopathies
and damage associated with injuries to ophthalmic tissues, such as
ischemia reperfusion injuries. The compounds may be used for acute
treatment of temporary conditions, or may be administered
chronically, especially in the case of degenerative disease. The
compounds may also be used prophylactically, especially prior to
ocular surgery or noninvasive ophthalmic procedures, or other types
of surgery.
[0469] Pharmaceutical compositions of this invention suitable for
parenteral administration comprise one or more compounds of the
invention in combination with one or more pharmaceutically
acceptable sterile isotonic aqueous or nonaqueous solutions,
dispersions, suspensions or emulsions, or sterile powders which may
be reconstituted into sterile injectable solutions or dispersions
just prior to use, which may contain antioxidants, buffers,
bacteriostats, solutes which render the formulation isotonic with
the blood of the intended recipient or suspending or thickening
agents.
[0470] Examples of suitable aqueous and nonaqueous carriers which
may be employed in the pharmaceutical compositions of the invention
include water, ethanol, polyols (such as glycerol, propylene
glycol, polyethylene glycol, and the like), and suitable mixtures
thereof, vegetable oils, such as olive oil, and injectable organic
esters, such as ethyl oleate. Proper fluidity can be maintained,
for example, by the use of coating materials, such as lecithin, by
the maintenance of the required particle size in the case of
dispersions, and by the use of surfactants.
[0471] These compositions may also contain adjuvants such as
preservatives, wetting agents, emulsifying agents and dispersing
agents. Prevention of the action of microorganisms may be ensured
by the inclusion of various antibacterial and antifungal agents,
for example, paraben, chlorobutanol, phenol sorbic acid, and the
like. It may also be desirable to include isotonic agents, such as
sugars, sodium chloride, and the like into the compositions. In
addition, prolonged absorption of the injectable pharmaceutical
form may be brought about by the inclusion of agents which delay
absorption such as aluminum monostearate and gelatin.
[0472] In some cases, in order to prolong the effect of a drug, it
is desirable to slow the absorption of the drug from subcutaneous
or intramuscular injection. This may be accomplished by the use of
a liquid suspension of crystalline or amorphous material having
poor water solubility. The rate of absorption of the drug then
depends upon its rate of dissolution which, in turn, may depend
upon crystal size and crystalline form. Alternatively, delayed
absorption of a parenterally-administered drug form is accomplished
by dissolving or suspending the drug in an oil vehicle.
[0473] Injectable depot forms are made by forming microencapsule
matrices of the subject compounds in biodegradable polymers such as
polylactide-polyglycolide. Depending on the ratio of drug to
polymer, and the nature of the particular polymer employed, the
rate of drug release can be controlled. Examples of other
biodegradable polymers include poly(orthoesters) and
poly(anhydrides). Depot injectable formulations are also prepared
by entrapping the drug in liposomes or microemulsions which are
compatible with body tissue.
[0474] The preparations of the present invention may be given
orally, parenterally, topically, or rectally. They are of course
given by forms suitable for each administration route. For example,
they are administered in tablets or capsule form, by injection,
inhalation, eye lotion, ointment, suppository, etc. administration
by injection, infusion or inhalation; topical by lotion or
ointment; and rectal by suppositories. Oral administration is
preferred.
[0475] The phrases "parenteral administration" and "administered
parenterally" as used herein means modes of administration other
than enteral and topical administration, usually by injection, and
includes, without limitation, intravenous, intramuscular,
intraarterial, intrathecal, intracapsular, intraorbital,
intracardiac, intradermal, intraperitoneal, transtracheal,
subcutaneous, subcuticular, intraarticular, subcapsular,
subarachnoid, intraspinal and intrastemal injection and
infusion.
[0476] The phrases "systemic administration," "administered
systematically," "peripheral administration" and "administered
peripherally" as used herein mean the administration of a compound,
drug or other material other than directly into the central nervous
system, such that it enters the patient's system and, thus, is
subject to metabolism and other like processes, for example,
subcutaneous administration.
[0477] These compounds may be administered to humans and other
animals for therapy by any suitable route of administration,
including orally, nasally, as by, for example, a spray, rectally,
intravaginally, parenterally, intracisternally and topically, as by
powders, ointments or drops, including buccally and
sublingually.
[0478] Regardless of the route of administration selected, the
compounds of the present invention, which may be used in a suitable
hydrated form, and/or the pharmaceutical compositions of the
present invention, are formulated into pharmaceutically acceptable
dosage forms by conventional methods known to those of skill in the
art.
[0479] Actual dosage levels of the active ingredients in the
pharmaceutical compositions of this invention may be varied so as
to obtain an amount of the active ingredient which is effective to
achieve the desired therapeutic response for a particular patient,
composition, and mode of administration, without being toxic to the
patient.
[0480] The selected dosage level will depend upon a variety of
factors including the activity of the particular compound of the
present invention employed, or the ester, salt or amide thereof,
the route of administration, thetime of administration, the rate of
excretion of the particular compound being employed, the duration
of the treatment, other drugs, compounds and/or materials used in
combination with the particular compound employed, the age, sex,
weight, condition, general health and prior medical history of the
patient being treated, and like factors well known in the medical
arts.
[0481] A physician or veterinarian having ordinary skill in the art
can readily determine and prescribe the effective amount of the
pharmaceutical composition required. For example, the physician or
veterinarian could start doses of the compounds of the invention
employed in the pharmaceutical composition at levels lower than
that required in order to achieve the desired therapeutic effect
and gradually increase the dosage until the desired effect is
achieved.
[0482] In general, a suitable daily dose of a compound of the
invention will be that amount of the compound which is the lowest
dose effective to produce a therapeutic effect. Such an effective
dose will generally depend upon the factors described above.
Generally, intravenous and subcutaneous doses of the compounds of
this invention for a patient, when used for the indicated analgesic
effects, will range from about 0.0001 to about 200 mg per kilogram
of body weight per day, more preferably from about 0.01 to about
150 mg per kg per day, and still more preferably from about 0.2 to
about 140 mg per kg per day.
[0483] If desired, the effective daily dose of the active compound
may be administered as two, three, four, five, six or more
sub-doses administered separately at appropriate intervals
throughout the day, optionally, in unit dosage forms.
[0484] While it is possible for a compound of the present invention
to be administered alone, it is preferable to administer the
compound as a pharmaceutical composition.
[0485] The present invention also pertains to packaged
pharmaceutical compositions for treating A.sub.2b associated
disorders in a mammal. The packaged pharmaceutical compositions
include a container hoiding a therapeutically effective amount of
at least one compound of the invention, as described below, and
instructions for using the compound for treating the A.sub.2b
associated disorder in the mammal.
[0486] The compounds of the invention may comprise water-soluble
prodrugs which are described in WO 99/33815, International
Application No. PCT/US98/04595, filed Mar. 9, 1998 and published
Jul. 8, 1999. The entire content of WO 99/33815 is expressly
incorporated herein by reference. The water-soluble prodrugs are
metabolized in vivo to an active drug, e.g., by esterase catalyzed
hydrolysis.
[0487] In another aspect, the invention features a method for
treating damage to the eye of an animal(e.g., a human) by
administering to the animal an effective amount of the compounds of
the present invention. Preferably, the compound is an antagonist of
A.sub.2b adenosine receptors in cells of the animal. The damage is
to the retina or the optic nerve head and may be acute or chronic.
The damage may be the result of, for example, glaucoma, edema,
ischemia, hypoxia or trauma.
[0488] The invention further pertains to a method for inhibiting
the activity of an adenosine receptor (e.g., an A.sub.2b adenosine
receptor) in a cell by contacting the cell with a compound of the
invention. Preferably, the compound is an antagonist of the
receptor.
[0489] In another embodiment, the invention relates to a
pharmaceutical composition containing a compound of the invention
and a pharmaceutically acceptable carrier.
[0490] The invention also pertains to a method for treating an
A.sub.2b associated disease state in an animal, by administering to
a mammal a therapeutically effective amount of a compound of the
invention, such that treatment of disorder in the animal occurs.
Advantageously, the disease state may be a disorder mediated by
adenosine. Examples of preferred disease states include: central
nervous system disorders, cardiovascular disorders, renal
disorders, inflammatory disorders, allergic disorders,
gastrointestinal disorders, eye disorders, and respiratory
disorders.
[0491] The invention further pertains to pharmaceutical
compositions for treating an A.sub.2b associated disease state in a
mammal, e.g., respiratory disorders (e.g., asthma, bronchitis,
chronic obstructive pulmonary disorder, and allergic rhinitis),
renal disorders, gastrointestinal disorders, and eye disorders. The
pharmaceutical composition includes a therapeutically effective
amount of a compound of the invention, described below, and a
pharmaceutically acceptable carrier. It is to be understood, that
all of the compounds described below are included for therapeutic
treatment. It is to be further understood that the compounds of the
invention can be used alone or in combination with other compounds
of the invention or in combination with additional therapeutic
compounds, such as antibiotics, antuinflammatories, or anticancer
agents, for example.
[0492] As indicated above, use of the compounds of the invention to
prevent or reduce damage to retinal and optic nerve head tissues at
the cellular level is a particularly important aspect of one
embodiment of the invention. Ophthalmic conditions which may be
treated include, but are not limited to, retinopathies, macular
degeneration, ocular ischemia, glaucoma, and damage associated with
injuries to ophthalmic tissues, such as ischemia reperfusion
injuries, photochemical injuries, and injuries associated with
ocular surgery, particularly injuries to the retina or optic nerve
head by exposure to light or surgical instruments. The compounds
may also be used as an adjunct to ophthalmic surgery, such as by
vitreal or subconjunctival injection following ophthalmic surgery.
The compounds may be used for acute treatment of temporary
conditions, or may be administered chronically, especially in the
case of degenerative disease. The compounds may also be used
prophylactically, especially prior to ocular surgery or noninvasive
ophthalmic procedures, or other types of surgery.
[0493] The invention is further illustrated by the following
examples which in no way should be construed as being further
limiting. The contents of all references, pending patent
applications and published patent applications, cited throughout
this application, including those referenced in the background
section, are hereby incorporated by reference. It should be
understood that the models used throughout the examples are
accepted models and that the demonstration of efficacy in these
models is predictive of efficacy in humans.
[0494] The features and other details of the invention will now be
more particularly described and pointed out in the claims. It is to
be understood that the particular embodiments of the invention are
shown by way of illustration and not as limitations of the
invention. The principal features of this invention can be employed
in various embodiments without departing from the scope of the
invention.
[0495] This invention will be better understood from the
Experimental Details which follow. However, one skilled in the art
will readily appreciate that the specific. methods and results
discussed are merely illustrative of the invention as described
more fully in the claims which follow thereafter.
[0496] Experimental Details
[0497] General Information
[0498] LC/MS analysis was performed using a Gilson 215 autosampler
and Gilson 819 autoinjector, attached to a Hewlett Packard
HP110.
[0499] Mass spectra were obtained on a Micromass Platform II mass
spectrometer, using positive electrospray ionization.
[0500] LC analysis was undertaken at 254 nm using a UV detector.
Samples were eluted on a Phenomenex Luna C18(2) (5 microns,
4.6.times.150 mm) column using either a linear gradient of 15-99%
solvent A in solvent B over 10 minutes (method A, non-polar) or
5-100% solvent A in solvent B over 15 minutes (method B, polar).
The solvent A was 100% acetonitrile, solvent B was 0.01% formic
acid, which was observed to have no noticeable effect on sample
retention time, in water.
[0501] IR spectra were recorded on a Perkin-Elmer Spectrum 1000
FT-IR spectrometer as thin films using diffuse reflectance.
[0502] .sup.1H NMR and .sup.13C NMR spectra were recorded with
Varian instruments (400 MHz or 200 MHz for .sup.1H, 100.6 MHz or
50.3 MHz for .sup.13C) at ambient temperature with TMS or the
residual solvent peak as internal standards. The line positions or
multiplets are given in ppm (.delta.) and the coupling constants
(J) are given as absolute values in Hertz, while the signal
multiplicities are abbreviated as follows: s (singlet), d
(doublet), t (triplet), q (quartet), quint (quintet), m
(multiplet), mc (centered multiplet), br (broadened).
[0503] All melting points were determined with a MeI-Temp II
apparatus and are uncorrected. Elemental analyses were carried out
at Atlantic Microlab, Inc., Norcross, Ga.
[0504] Commercially available anhydrous solvents and HPLC-grade
solvents were used without further purification.
EXAMPLE 1
Synthesis of Non-Commercial 3,3- and 4,4-Disubstituted Piperidines
29
[0505] The syntheses of several 4,4-disubstituted piperidines 29
are shown in scheme 1. Boc-protected alcohols Boc-29 were prepared
from commercially available aminoalcohols 29.629.8, 29.10, and
29.18 by reaction with di-tert-butyl dicarbonate or from
N-Boc-4-pyridone (Boc-29.155) by addition of Grignard or
organolithium reagents. Methylation with methyl iodide and KHMDS
yielded the corresponding methyl ethers. Deprotection with HCl/MeOH
gave the methyl ether amine hydrochlorides, and/or, in some cases,
the corresponding 1,2,3,6-tetrahydropyridines. Alkylation of the
nitriles 35 with the protected nitrogen mustard 34 followed by Boc
removal with HCl in dioxane gave amines 29.237 and 29.240-29.244.
26
[0506] In addition, standard reactions with
4-acetyl-4-phenylpiperidine 29.76 (reduction and addition of
methyllithium) gave piperidines 29.93 and 29.102, respectively.
4-Alkyl-4-phenylpiperidines 29.108, 29.110, and 29.128 and
3,3-diphenylpiperidine (29.26) were synthesized by Friedel-Crafts
reactions using aluminium trichloride (see J. Med. Chem. 1998, 41,
5320-5333) or triflic acid (see J. Org. Chem. 1999, 64, 6702-6705),
respectively. Esters 29.92, 29.95, and 29.118 were prepared from
the acid 29.85 using the alcohol as solvent and H.sub.2SO.sub.4 as
acid catalyst.
[0507] 4-(2-Chlorophenyl)-4-hydroxypiperidine-1-carboxylic acid
tert-butyl ester (Boc-29.43), method A (I-Li exchange): To a
solution of 2-chloroiodobenzene (122 .mu.L, 0.999 mmol) in TIHF (10
mL), cooled by dry ice/acetone, was added nBuLi (2.5M in hexanes,
0.5 mL, 1.25 mmol). After 30 min, a solution of N-Boc-4-piperidone
(Boc-29.155) (225 mg, 1.13 mmol) in THF (1 mL) was added. After 1.5
h the cooling bath was removed, and after another 1.5 h the
reaction was quenched by adding sat. NaHCO.sub.3 solution and
water. The mixture was extracted with EtOAc (4.times.15 mL), the
combined organic layers were washed with 2N NaOH, water, and brine,
dried over MgSO.sub.4, filtered and concentrated. This material was
dissolved in MeOH (5 mL), NaBH.sub.4 (19 mg, 0.5 mmol) was added,
and the solution was stirred at ambient temperature for 1 h. The
solvent was evaporated, water was added, and the solution was
extracted with EtOAc (4.times.15 mL). The combined organic layers
were washed with water and brine, dried over MgSO.sub.4, filtered
and concentrated. The crude material was chromatographed on silica
gel, giving 180 mg of a mixture of Boc-29.43 (49%) and Boc-29.47
(7%). Boc-29.47: MS (ES): m/z 388.0/390.0 (20/7) [MH.sup.+].
.sup.1H NMR (CDCl.sub.3, 200 MHz): most peaks overlap with those of
the 2-chlorophenyl compound, .delta.=1.45 (s, 9H), 6.96-7.03 (m,
1H). t.sub.R (non-polar)=11.0 min.
[0508] Method B (I-Mg exchange): To a solution of
2-chlorojodobenzene (145 .mu.L, 1.19 mmol) in THF (3 mL), cooled to
-20 to -15.degree. C., was added iPrMgCl (2M in THF, 0.6 mL, 1.2
mmol). After 30 min, a solution of N-Boc-4-piperidone (Boc-29.155)
(203 mg, 1.02 mmol) in THF (2 mL) was added, and the reaction
mixture was stirred overnight, warming up to ambient temperature.
Sat. NH.sub.4Cl solution and water were added, and the solution was
extracted with EtOAc (3.times.15 mL). The combined organic layers
were washed with brine, dried over MgSO.sub.4, filtered and
concentrated. This material was dissolved in MeOH (10 mL),
NaBH.sub.4 (38 mg, 1 mmol) was added, and the solution was stirred
at ambient temperature for 1.5 h. The solvent was evaporated, water
was added, and the solution was extracted with EtOAc (3.times.15
mL). The combined organic layers were washed with water and brine,
dried over MgSO.sub.4, filtered and concentrated. The crude
material was chromatographed on silica gel, giving 168 mg (0.540
mmol, 53%) of Boc-29.43. Trituration of the slowly solidifying oil
with hexanes yielded 158 mg (0.507 mmol, 50%) of analytically pure
compound as colorless crystals, mp 126-127.degree. C. MS (ES): m/z
312.0/314.0 (10/3) [MH.sup.+]. .sup.1H NMR (CDCl.sub.3, 200 MHz):
.delta.=1.48 (s, 9H), 1.98 (brd, J=14.0 Hz, 2H), 2.24 (brdt, J=4.8,
12.8 Hz, 2H), 2.82 (s, 1H), 3.16 (brt, J=12.8 Hz, 2H), 4.04 (brd,
J=10.8 Hz, 2H), 7.15-7.29 (m, 2H), 7.31-7.41 (m, 1H), 7.50-7.56 (m,
11H). t.sub.R (non-polar)=9.9 min. C.sub.16H.sub.22ClNO.sub.3
(311.81): calcd. C 61.63, H 7.11, N 4.49, Cl 11.37; found C, 61.75;
H, 7.14; N, 4.42, Cl 11.50.
[0509] 4-Hydroxy-4-o-tolylpiperidine-1-carboxylic acid tert-butyl
ester: N-Boc-4-piperidone (Boc-29.155) (200 mg, 1.0 mmol) was
dissolved in 5 ml of anhydrous ethyl ether, cooled in dry
ice/acetone bath. 2-Tolylmagnesium bromide (550 .mu.l, 2M in ethyl
ether, 1.1 mmol) was added dropwise over 5 min. White precipitate
was formed. After 5 h, remove the dry ice/acetone bath and rise to
room temperature gradually. After 2 h, cooled in ice bath, 8 ml of
saturated NH.sub.4Cl and 2 ml of H.sub.2O were added. The organic
phase was separated and aqueous phase was extracted with 4.times.10
ml of Et.sub.2O. Combined with organic phase and washed with 8 ml
of H.sub.2O and 10 ml of brine, dried over MgSO.sub.4. Concentrated
and dried to obtain 361 mg of colorless oil. Separated by silica
gel to obtain 4f (229.7 mg, 79% yield) as colorless oil. .sup.1H
NMR (CDCl.sub.3, 200 MHz) .delta. 1.47 (s, 9H), 1.93 (m, 4H), 2.60
(s, 3H), 3.27 (t, 2H, J=13.0 Hz), 3.96 (d, 2H, J=12.2 Hz), 7.15 (m,
3H), 7.35(m, 1H).
[0510] 4-Methoxy-4-thiophen-2-ylpiperidine-1-carboxylic acid
tert-butyl ester: To a solution of N-Boc-4-piperidone (Boc-29.155)
(201 mg, 1.01 mmol) in THF (5 mL), cooled by dry ice/ acetone, was
added 2-thienyllithium (1M in THF, 1.5 mL, 1.5 mmol). After 50 min,
the cooling bath was removed; after additional 1 h, methyl iodide
(125 .mu.L, 2.01 mmol) was added, and the solution was stirred at
ambient temperature overnight. The solvent was evaporated, water
was added, and the mixture was extracted with EtOAc (4.times.15
mL). The combined organic layers were washed with water and brine,
dried over MgSO.sub.4, filtered and concentrated. The crude
material (acc. to .sup.1H NMR mixture of methyl ether and the
alcohol in a 1:2 ratio) was methylated according to the general
procedure, yielding 300 mg (1.01 mmol, 100% yield) of the title
compound as yellow oil. .sup.1H NMR (CDCl.sub.3, 200 MHz):
.delta.=1.46 (s, 9H), 1.93 (brdt, J=4.3, 12.6 Hz, 2H), 2.00 (brd,
J=12.8 Hz, 2H), 3.05 (s, 3H), 3.16 (brt, J=11.0 Hz, 2H), 3.84 (brd,
J=12.2 Hz, 2H), 6.93-7.00 (m, 2H), 7.25-7.31 (m, 1H).
[0511] 4-Cyclohexyl-4-hydroxypiperidine-1-carboxylic acid
tert-butyl ester: Prepared according to the procedure for
Boc-29.43. White solid, 37% yield of analytically pure material,
mp. 87-89.degree. C. C.sub.16H.sub.29NO.sub.3 (283.41):,calcd. C,
67.81; H, 10.31; N, 4.94; found C 67.89, H 10.31, N 4.94.
[0512] 4-(2-Fluorophenyl)-4-hydroxypiperidine-1-carboxylic acid
tert-butyl ester: Prepared according to method A of preparation of
Boc-29.43. White solid, 61% yield of analytically pure material,
mp. 109-110.degree. C. C.sub.16H.sub.22FNO.sub.3 (295.36): calcd. C
65.07, H 7.51, N 4.74; found C, 64.79; H, 7.45; N, 4.70.
[0513] 4-(2-Bromophenyl)-4-hydroxypiperidine-1-carboxylic acid
tert-butyl ester: Prepared according to method B of preparation of
Boc-29.43. MS (ES): m/z 356/358 [MH.sup.+].
[0514]
4'-Hydroxy-3-methyl-3',4',5',6'-tetrahydro-2'H-[2,4'bipyridinyl-1'--
carboxylic acid tert-butyl ester: Prepared according to method B of
preparation of Boc-29.43. .sup.1H NMR (CDCl.sub.3, 200 MHz):
.delta.=1.50 (s, 9H), 2.22-2.40 (m, 4H), 2.50 (s, 3H), 3.33 (brt,
J=12.8 Hz, 2H), 4.10 (brd, J=10.8 Hz, 2H), 7.17 (dd, J=4.7, 7.7 Hz,
1H), 7.50 (dd, J=1.2, 7.7 Hz, 1H), 8.37 (dd, J=1.2, 4.8 Hz,
1H).
[0515] General Procedure for the Boc-protection of aminoalcohols:
To a solution of the aminoalcohol (1.99 mmol) in CH.sub.2Cl.sub.2
(20 ml) are added Boc.sub.2O (440 mg, 2.02 mmol) and DMAP (5 mg,
0.04 mmol). After stirring at ambient temperature for 18 h, the
reaction mixture is concentrated and dried to obtain the
Boc-protected aminoalcohol, which is typically used directly in the
next step or purified by chromatography.
[0516] 4-Hydroxy-4-phenylpiperidine-1-carboxylic acid tert-butyl
ester (Boc-29.7): Prepared according to general procedure, 100%
yield. White solid, mp. 120-121.degree. C. .sup.1H NMR (CDCl.sub.3,
200 MHz): .delta.=1.48 (s, 9H), 1.65-1.80 (m, 2H), 2.00 (brdt,
J=4.7, 13.0 Hz, 2H), 3.24 (brt, J=11.7 Hz, 2H), 4.02 (brd, J=11.7
Hz, 2H), 7.21-7.41 (m, 3H), 7.44-7.52 (m, 2H).
[0517] 4-(4-Fluorophenyl)-4-hydroxypiperidine-1-carboxylic acid
tert-butyl ester (Boc-29.18): Prepared according to general
procedure, 86% yield. .sup.1H NMR (CDCl.sub.3, 200 MHz):
.delta.=1.48 (s, 9H), 1.65-1.80 (m, 2H), 1.97 (brdt, J=4.8,
12.4.Hz, 2H), 3.23 (brt, J=12.8 Hz, 2H), 4.03 (brd, J=12.8 Hz, 2H),
6.99-7.10 (m, 2H), 7.40-7.50 (m, 2H).
[0518] General Procedure for the methylation of alcohols: To a
solution of the alcohol (0.55 mmol) in dry THF (5 mL), cooled by
ice/water, is added KHMDS (0.5M solution in toluene, 1.6 mL, 0.80
mmol). After 30 min, methyl iodide (50 .mu.L, 0.80 mmol) is added.
A white precipitate appears almost immediately. The cooling bath is
then removed, and the reaction mixture is stirred at ambient
temperature. As judged by TLC, the reaction is usually complete
after 1 h; if the starting alcohol is still present, additional
KHMDS and methyl iodide are added to drive the reaction to
completion. For workup, sat. NaHCO.sub.3 sol. and water are added,
the mixture is extracted with CH.sub.2Cl.sub.2 (4.times.15 mL). The
combined organic layers are washed with brine, dried over
MgSO.sub.4, filtered and concentrated. The crude material can
typically be used directly in the next step or is purified by
chromatography.
[0519] 4-(2-Chlorophenyl)-4-methoxypiperidine-1-carboxylic acid
tert-butyl ester (Boc-29.42) and
4-(2'-chlorobiphenyl-2-yl)-4-methoxypiperidine-1-ca- rboxylic acid
tert-butyl ester (Boc-29.46): Synthesized from the mixture of
Boc-29.43 and Boc-29.47 according to the general procedure in 95%
yield. Boc-29.42: .sup.1H NMR (CDCl.sub.3, 200 MHz): .delta.=1.47
(s, 9H), 1.92 (m.sub.c, 2H), 2.38 (brd, J=13.8 Hz, 2H), 3.02 (s,
3H), 3.20 (brt, J=12.6 Hz, 2H), 3.99 (brd, J=10.2 Hz, 2H),
7.15-7.43 (m, 4H). Boc-29-46: .sup.1H NMR (CDCl.sub.3, 200 MHz):
most peaks-overlap with those of the 2-chlorophenyl compound.
.delta.=1.41 (s, 9H), 3.01 (s, 3H), 6.96-7.03 (m, 1H), 7.60-7.65
(m, 1H).
[0520] 4-Methoxy-4-phenylpiperidine-1-carboxylic acid tert-butyl
ester (Boc-29.27): Synthesized according to the general procedure
in 100% yield. IR (film): v=3059 cm.sup.-1, 2974, 2933, 2874, 1693,
1446, 1422, 1365, 1281, 1246, 1214, 1169, 1130, 1070, 1024, 893,
864, 761, 700. .sup.1H NMR (CDCl.sub.3, 200 MHz): .delta.=1.47 (s,
9H), 1.85 (brdt, J=2.2, 12.0 Hz, 2H), 2.03 (brd, J=12.6 Hz, 2H),
2.98 (s, 3H), 3.18 (brt, J=12.3 Hz, 2H), 3.97 (brd, J=11.0 Hz, 2H),
7.26-7.40 (m, 5H).
[0521] 4-(4-Fluorophenyl)-4-methoxypiperidine-1-carboxylic acid
tert-butyl ester (Boc-29.48): Synthesized according to the general
procedure in 70% yield. .sup.1H NMR (CDCl.sub.3, 200 MHz):
.delta.=1.47 (s, 9H), 1.81 (brdt, J=3.6, 13.2 Hz, 2H), 2.00 (brd,
J=12.2 Hz, 2H), 2.96 (s, 3H), 3.16 (brt, J=11.9 Hz, 2H), 3.97 (brd,
J=10.2 Hz, 2H), 7.00-7.10 (m, 2H), 7.30-7.40 (m, 2H).
[0522] General Procedure for the removal of Boc groups: Acetyl
chloride (1.5 mL, 21 mmol) is added dropwise into dry methanol (8
mL) at ambient temperature. After 10 min, this solution is added to
a solution of the Boc-protected amine (0.9 mmol), and the reaction
is stirred at ambient temperature. Upon complete consumption of
starting material as judged by TLC, the solvents are evaporated.
The residue (amine hydrochloride) is used directly for the amide
formation.
[0523] 4-(2-Chlorophenyl)-4-methoxypiperidine hydrochloride (29.42)
and 4-(2'-Chloro-biphenyl-2-yl)-4-methoxypiperidine hydrochloride
(29.46): General procedure was followed using the material derived
from the mixture of Boc-29.42 and Boc.29-46. Pale yellow foam, 100%
yield. 29.42: MS (ES): nimz 226.0/228.0 (22/8) [MH.sup.+],
194.0/196.0 (100/35) [MH.sup.+-MeOH]. .sup.1H NMR (CDCl.sub.3, 200
MHz): .delta.=2.2-2.5 (brs, 2H), 2.5-2.7 (brs, 2H), 2.99 (s, 3H),
3.42 (brs, 4H), 7.25-7.45 (m, 4H). t.sub.R (non-polar)=3.8 min.
29.46: MS (ES): m/z 302.0/304.0 (4/1) [MH.sup.+], 270.0/272.0
(100/35) [MH.sup.+-MeOH]. No distinct peaks irf the .sup.1H NMR.
t.sub.R (non-polar)=4.7 min.
[0524] 4-(2-Chlorophenyl)-piperidin-4-ol (29.43) and
4-(2'-chlorobiphenyl-2-yl)-piperidin-4-ol (29.47): A solution of
the mixture of amines Boc-29.43 and Boc-29.47 (34 mg, 0.11 mmol)
and H.sub.2SO.sub.4 (20 mg, 0.20 mmol) in methanol (3 mL) was
stirred at ambient temperature for 3.5 days. Sat. NaHCO.sub.3 was
added, and the mixture was extracted with CH.sub.2Cl.sub.2
(5.times.10 mL). The combined organic layers were dried over
MgSO.sub.4, filtered and concentrated to yield 12 mg (0.057 mmol,
52%) of 29.43, containing Z15% of the chlorobiphenyl piperidine
29.47. 29.43: .sup.1H NMR (CDCl.sub.3, 200 MHz): .delta.=1.90-2.10
(brm, 2H), 2.28 (brdt, J=4.4, 13.6 Hz, 2H), 2.8-3.1 (brm, 2H),
3.1-3.3 (brm, 2H), 7.15-7.45 (m, 3H), 7.55-7.61 (m, 2H). Only
distinguishable peak of 29.47: .sup.1H NMR (CDCl.sub.3, 200 MHz):
.delta.=6.98-7.16 (m, 1H).
[0525] 4-Methoxy-4-phenylpiperidine hydrochloride (29.27): General
procedure was followed, beige solid, 97% yield. .sup.1H NMR
(CDCl.sub.3, 200 MHz): .delta.=2.19 (brd, J=14.2 Hz, 2H), 2.24-2.44
(brn, 2H), 2.98 (s, 3H), 3.40 (brs, 4H), 7.27-7.44 (m, 5H), 9.6
(brs, 2H).
[0526] 4-(4-Fluorophenyl)-4-methoxypiperidine hydrochloride
(29.48): General procedure was followed, beige solid, 99% yield.
.sup.1H NMR (CDCl.sub.3, 200 MHz): .delta.=2.10-2.25 (brm, 2H),
2.25-2.45 (brm, 2H), 2.96 (s, 3H), 3.39 (brs, 4H), 7.00-7.15 (m,
2H), 7.25-7.38 (m, 2H), 9.6 (brs, 2H).
[0527] Following the general procedures for Boc-protection,
methylation, and deprotection, the following 7 piperidines were
prepared.
[0528] 4-(4-Chlorophenyl)-4-methoxypiperidine hydrochloride salt
(29.114): 44% yield. .sup.1H NMR (CDCl.sub.3, 200 MHz):
.delta.=2.21 (brs, 4H), 2.97 (s, 3H), 3.36 (brs, 4H), 7.35(m,
4H).
[0529] 4-Methoxy-4-(3-trifluoromethylphenyl)-piperidine
hydrochloride salt (29.115): 49% yield. .sup.1H NMR (CDCl.sub.3,
200 MHz): .delta.=1.99 (brs, 4H), 2.99 (s, 3H), 3.20 (brs, 2H),
3.99 (brs, 2H), 7.55(m, 4H).
[0530] 4-Isopropyl-4-methoxypiperidine hydrochloride salt (29.116):
18% yield. .sup.1H NMR (CDCl.sub.3, 200 MHz): .delta.=0.85 (d, 6H,
J=6.6 Hz), 1.54 (brs, 4H), 1.94 (m, 1H), 2.96 (brs, 2H), 3.20 (s,
3H), 3.87 (brs, 2H).
[0531] 4-Methoxy-4-(3-methoxyphenyl)-piperidine hydrochloride salt
(29.121): 42% yield. .sup.1H NMR (CD.sub.3OD, 200 MHz):
.delta.=2.25 (m, 4H), 2.99 (s, 3H), 3.31 (m, 4H), 3.80 (s, 3H),
6.96 (m, 31H), 7.32 (t, 1H, J=7.6 Hz).
[0532] 4-Benzyl-4-methoxypiperidine hydrochloride salt (29.129):
49% yield. .sup.1H NMR (CD.sub.3OD, 200 MHz): .delta.=1.89 (m, 4H),
2.86 (s, 2H), 3.14 (brs, 4H), 3.34 (brs, 2H), 3.37 (s, 3H), 7.22
(m, 5H).
[0533] 4-Methoxy-4-o-tolylpiperidine hydrochloride salt (29.130):
38% yield. .sup.1H NMR (CD.sub.3OD, 200 MHz): .delta.=2.12 (m, 2H),
2.48 (brs, 2H), 2.53 (s, 3H), 2.97 (s, 3H), 3.33 (brs, 4H), 7.20
(brs, 4H).
[0534] 4-Methoxymethyl-4-phenylpiperidine hydrochloride salt
(29.131): 64% yield. .sup.1H NMR (CD.sub.3OD, 200 MHz):
.delta.=2.20 (m, 2H), 2.48 (d, 2H, J=15.0 Hz), 2.93 (t, 2H, J=11.4
Hz), 3.24 (s, 3H), 3.31 (m, 4H), 7.28-7.43 (m, 5H).
[0535] 4-Methoxy4-(2-methoxyphenyl)-piperidine (29.124): Boc-29.70
was dissolved in 30 ml anhydrous MeOH and then 10 drops of conc.
H.sub.2SO.sub.4 was added. The whole mixture was reflux under
N.sub.2 overnight. After heating, triethylamine was added till
pH=7-8. Concentrated and then dissolved in 6 ml saturated
NaHCO.sub.3, extracted with 5.times.12 ml EtOAc, washed with
2.times.10 ml brine and dried over MgSO.sub.4. Filtered and
concentrated to obtain 5.1 mg (10%) of beige oil. This oil was used
for further reaction without purification.
[0536] Bis-(2-chloroethyl)-carbamic acid tert-butyl ester (34): To
a suspension of 33 (10.05 g, 56.3 mmol) and Boc.sub.2O (13.6 g,
62.3 mmol) in CH.sub.2Cl.sub.2 (70 mL), cooled by ice/water, was
added triethylamine (9.5 mL, 68.2 mmol). After 45 min, the cooling
bath was removed, and the reaction mixture was stirred at ambient
temperature overnight. Water (50 mL) was added, and the mixture was
extracted with ether:hexanes 1:1 (3.times.100 mL). The combined
organic layers were washed with water (2.times.) and brine, dried
over MgSO.sub.4 and concentrated to give a pale yellow liquid,
which was a 1:1 mixture of 34 and Boc.sub.2O. The reaction was
therefore repeated with this material twice, first with 5.89 g
(33.0 mmol) of 33 and 4.8 mL of NEt.sub.3 (34 mmol) and then with
2.5 g (14 mmol) of 33 and 2.3 mL of NEt.sub.3 (17 mmol). This gave
14.887 g (61.5 mmol, 99%) of the known amine 34 as pale yellow
liquid, pure by .sup.1H NMR and TLC. .sup.1H NMR (CDCl.sub.3, 200
MHz): .delta.=1.47 (s, 9H), 3.55-3.70 (brm, 8H).
[0537] 4-(2-Chlorophenyl)-4-cyanopiperidine-1-carboxylic acid
tert-butyl ester (Boc-29.237): To a suspension of NaH (60% oil
suspension, 7.37 g, 184.4 mmol) in DMF (110 mL), cooled by
ice/water, was added a solution of the nitrile 35.237 (9.782 g,
64.52 mmol) in DMF (20 mL) over 20 min. Hydrogen evolved, and the
reaction mixture turned yellow. After 30 min, a solution of the
chloroamine 34 (14.88 g, 61.45 mmol) in DMF (15 mL) was added.
After 15 min the cooling bath was removed, and the reaction mixture
was heated to 75.degree. C. (bath temperature) for 5.5 h. TLC
indicated the complete consumption of both starting materials. The
DMF was evaporated. Upon addition of water and ether (200 mL each)
a solid separated, which was filtered off, washed thoroughly with
ether and EtOAc, and dried, yielding 8.018 g (24.99 mmol, 41%) of
Boc-29.237. The layers of the combined filtrate and washings were
separated, and the aqueous layer was extracted with more ether
(2.times.150 mL). The combined organic layers were washed with 5%
HOAc, water, 1N NaOH, water, and brine and dried over MgSO.sub.4.
This solution was filtered through a pad of silica gel. Upon
concentration a solid precipitated, which was filtered off, washed
with ether and hexanes and dried, yielding 6.138 g (19.13 mmol,
31%) of Boc-29.237. The mother liquor was concentrated and the
residue purified by column chromatography on silica gel, yielding
2.885 g (8.99 mmol, 15%) of Boc-29.237. The total yield was 17.04 g
(53.12 mmol, 86%), mp 165-166.degree. C. .sup.1H NMR (CDCl.sub.3,
200 MHz): .delta.=1.48 (s, 9H), 2.00 (brdt, J=4.2, 13.0 Hz, 2H),
2.43-2.53 (m, 2H), 3.28 (brt, J=12.8 Hz, 2H), 4.28 (brd, J=13.2 Hz,
2H), 7.28-7.50 (m, 4H). C.sub.17H.sub.21ClN.sub.2O.sub.2 (320.82):
calcd. C 63.65, H 6.60, Cl 11.05, N 8.73; found C 63.82, H 6.61, Cl
10.90, N 8.72.
[0538] 4-(2-Chlorophenyl)-piperidine-4-carbonitrile hydrochloride
(29.237): A solution of HCl in dioxane (4M, 200 mL, 800 mmol) was
added to the Boc-protected amine Boc-29.237 (18.4 g, 57.4 mmol).
After 1.5 h the solvent was evaporated and the residue dried in
vacuo, giving 14.8 g (57.4 mmol, 100%) of 29.237, colorless solid,
mp 241-243.degree. C. (decomp.). MS (ES) 221 [MH.sup.+], t.sub.R
(method B)=8.15 min. .sup.1H NMR (CDCl.sub.3, 200 MHz):
.delta.=2.5-2.8 (brm, 4H), 3.4-3.6 (brm, 2H), 3.6-3.8 (brm, 2H),
7.33-7.39 (m, 3H), 7.48-7.53 (m, 1H), 10.01 (brs, 2H).
C.sub.12H.sub.14Cl.sub.2N.sub.2 (257.16): calcd. C 56.05, H 5.49,
Cl 27.57, N 10.89; found C 55.67, H 5.48, Cl 27.86, N 10.61.
[0539] The following compounds were prepared in a similar
manner:
[0540] 4-Cyano-4-(2-methoxyphenyl)-piperidine-1-carboxylic acid
tert-butyl ester (Boc-26.240): MS (ES) 217.0 [MH.sup.+-Boc],
t.sub.R (method A)=9.9 min.
[0541] 4-(3-Chlorophenyl)-4-cyanopiperidine-1-carboxylic acid
tert-butyl ester (Boc-26.241): MS (ES) 221.0 [MH.sup.+-Boc].
[0542] 4-Cyano-4-(3-methoxyphenyl)-piperidine-1-carboxylic acid
tert-butyl ester (Boc-26.242): MS (ES) 217.0 [MH.sup.+-Boc].
[0543] 4-(4-Chlorophenyl)-4-cyanopiperidine-1-carboxylic acid
tert-butyl ester (Boc-26.243): MS (ES) 221.0 [MH.sup.+-Boc],
t.sub.R (method A)=10.7 min.
[0544] 4-Cyano-4-(4-methoxyphenyl)-piperidine-1-carboxylic acid
tert-butyl ester (Boc-26.244): .sup.1H NMR (CDCl.sub.3, 200 MHz):
.delta.=1.48 (s, 9H), 1.90 (brdt, J=4.3, 12.8 Hz, 2H), 2.02-2.14
(m, 2H), 3.19 (brt, J=12.4 Hz, 2H), 3.81 (s, 3H), 4.28 (brd, J=13.6
Hz, 2H), 6.93 and 7.38 (AA'BB', 4H).
[0545] 4-(2-Methoxyphenyl)-piperidine-4-carbonitrile hydrochloride
(29.240): MS (ES) 217.07 [MH.sup.+], t.sub.R (method B)=7.70
min.
[0546] 4-(3-Chlorophenyl)-piperidine-4-carbonitrile hydrochloride
(29.241): MS (ES) 220.98 [MH.sup.+], t.sub.R (method B)=8.57
min.
[0547] 4-(3-Metboxyphenyl)-piperidine4-carbonitrile hydrochloride
(29.242): MS (ES) 217.02 [MH.sup.+], t.sub.R (method B)=7.28
min.
[0548] 4-(4-Chlorophenyl)-piperidine-4-carbonitrile hydrochloride
(29.243): MS (ES) 220.96 [MH.sup.+], t.sub.R (method B)=8.83
min.
[0549] 4-(4-Methoxyphenyl)-piperidine-4-carbonitrile hydrochloride
(29.244): MS (ES) 217.02 [MH.sup.+], t.sub.R (method B)=7.43
min.
[0550] General Procedure for Friedel-Crafts Reaction:
4-Isopropylpiperidin-4-ol 29.4 (62.4 mg, 0.436 mmol) and AlCl.sub.3
(178 mg, 3 eq.) was suspended in benzene (15 ml), refluxed under
argon for 24 h. the reaction mixture was poured into 20 ml of
ice-water, extracted with 5.times.10 ml of EtOAc, washed with
2.times.15 ml of brine, dried over MgSO.sub.4. After solvent
removed and purified by TLC, brownish oil 29.110 (25.3 mg, 29%) was
obtained. 29.128 and Bn-29.108 were prepared by the same
method.
[0551] 1-Benzyl-4-methyl-4-phenylpiperidine (Bn-29.108): .sup.1H
NMR (CDCl.sub.3, 200 MHz) .delta. 1.20 (m, 3H), 1.78 (m, 2H), 2.13
(m, 2H), 2.45 (m, 4H), 3.45 (s, 2H), 7.13-7.32 (m, 10H).
[0552] 4-Ethyl-4-phenylpiperidine (29.128): .sup.1H NMR
(CDCl.sub.3, 200 MHz) .delta. 0.56 (t, 3H, J=7.3 Hz), 1.58 (m, 2H),
1.87 (m, 2H), 2.19 (m, 2H), 3.03 (brs, 2H), 3.56 (brs, 2H),
7.10-7.37 (m, 5H).
[0553] 4-Isopropyl-4-phenylpiperidine (29.110): .sup.1H NMR
(CDCl.sub.3, 200 MHz) .delta. 1.12-1.20 (m, 2H), 1.27 (d, 6H),
1.41-1.63 (m, 3H), 2.28 (brs, 1H), 2.50 (t, 2H, J=11.2 Hz), 3.09
(d, 2H, J=12.2 Hz), 4.49 (s, 2H), 7.14-7.31 (m, 5H).
[0554] 4-Phenylpiperidine-4-carboxylic acid methyl ester (29.92):
After 29.85 (113 mg, 0.3 mmol) and methanol (50 ml) were combined
together, 2 drops of concentrated H.sub.2SO.sub.4 were added and
the solution was heated to reflux. After 14 h, the solvent was
removed and 2N NaOH was added till pH=13-14. Extracted with
3.times.10 ml of CH.sub.2Cl.sub.2, washed with 2.times.10 ml of
brine, dried over MgSO.sub.4. After solvent was removed, white
solid 29.92 (20 mg, 31% yield) was obtained. .sup.1HNMR
(CD.sub.3OD, 200 MHz): .delta.=1.92 (m, 2H), 2.52 (m, 2H), 2.78 (m,
2H), 3.02 (m, 2H), 3.65 (s, 3H), 7.20-7.42 (m, 5H).
[0555] 29.95 and 29.118 were prepared by the same method, using
ethanol and isopropanol, respectively, as solvents in place of
methanol.
[0556] 4-Phenylpiperidine-4-carboxylic acid ethyl ester (29.95):
25% yield. .sup.1H NMR (CD.sub.3OD, 200 MHz): .delta.=1.16 (t, 3H,
J=7 Hz), 1.91 (m, 2H), 2.52 (m, 2H), 2.80 (m, 2H), 3.03 (m, 2H),
4.11 (q, 2H, J=11.5 Hz), 7.20-7.41 (m, 5H).
[0557] 4-Phenylpiperidine-4-carboxylic acid isopropyl ester
(29.118): 12% yield. .sup.1H NMR (CDCl.sub.3, 200 MHz):
.delta.=1.17 (d, 6H, J=3.1 Hz), 2.23 (brs, 2H), 2.64 (brs, 2H),
3.01 (brs, 2H), 3.39 (brs, 2H), 5.03 (m, 1H), 7.27-7.34 (m,
5H).
EXAMPLE 2
Preparation of Non-Commercial 3- and 4-Monosubstituted Piperidines
29
[0558] 27
[0559] 4-(4-(4-Chlorophenoxy)-piperidine-1-carboxylic acid
tert-butyl ester (Boc-29.194) A solution of DIAD (11.4 mL; 55.0
mmol) in THF (15 mL) was added dropwise over 35 min to an ice-cold
solution of 4-hydroxypiperidine-1-carboxylic acid tert-butyl ester
(10.06 g; 50.0 mmol), 4-chlorophenol (5.1 mL; 50.4 mmol) and
triphenylphosphine (14.44 g; 55.1 mmol) in THF (40 mL). After 2.9
days at room temperature the solvent was removed on a rotary
evaporator leaving a viscous liquid; hexanes was added then
evaporated leaving a solid. Ether (25 mL), followed by hexanes (100
mL), was added and the solid was filtered and washed with hexanes.
The filtrate was concentrated on a rotary evaporator leaving a
golden, viscous liquid (19.6 g). The crude product was used as is.
ESIMS 311.9/313.8 (25/10) [MH.sup.+], 296.9/298.8 (100/34)
[MH.sup.+-C.sub.4H.sub.9+CH.sub.3CN], 255.9/257.8 (94/32)
[MH.sup.+-C.sub.4H.sub.9], 212.0/214.0 (13/5)
[MH.sup.+-C.sub.4H.sub.9--C- O.sub.2].
[0560] 4-(4-Chlorophenoxy)-piperidinium chloride (29.194):
Trifluoroacetic acid (40 mL) was added to crude carbamate
Boc-29.194 (18.6 g; 59.7 mmol) cooled in an ice-water bath. After 1
min the reaction was stirred at rt for 15 min, then concentrated on
a rotary evaporator. Ether (200 mL) was added and this washed with
3 M NaOH (3.times.50 mL) and water (50 mL). The product was
extracted into 1 M HCl (3.times.50 mL) and the aq phase was
basified with 3 M NaOH (60 mL). The free base was extracted into
DCM (1.times.50 mL then 2.times.25 mL), dried (MgSO.sub.4),
filtered and concentrated to an oil. The hydrochloride salt was
precipitated from a methanolic (6 mL) solution of the free base by
the dropwise addition of HCl in ether (200 mL of HCl-saturated
ether plus. 150 mL of ether). The salt was collected by filtration
and washed with ether (100 mL) giving an off- white solid (7.97 g;
68% from 4-hydroxypiperidine-1-carboxylic acid tert-butyl ester).
ESIMS (free base) 212.0/213.9 (100/35) [MH.sup.+].
[0561] 29.193 and 29.195-29.196 were prepared in the same way.
[0562] General Procedure for, benzyl ether formation: A solution of
4-(2-hydroxyethyl)-piperidine-1-carboxylic acid tert-butyl ester
(114.7 mg, 0.5 mmol) in T14F (2 ml) was added into NaH (13.2 mg,
1.l eq.) and THF (2 ml) suspension at rt and under N.sub.2. After
30 min a solution of benzyl bromide (65.4 .mu.l, 1.1 eq.) in THF (2
ml) was added. After 20 h, solvent was removed and poured into 10
ml of H.sub.2O, extracted with 3.times.10 ml of EtOAc, washed with
10 ml of H.sub.2O and 10 ml of brine, dried over MgSO.sub.4. After
solvent removed and purified by silica gel, Boc-29.84 was obtained
(75.5 mg, 47% yield). Into Boc-29.84, TFA (1 ml) was added and
stirred for 3 h. Excess TFA was removed and neutralized by 2N NaOH
till pH=13, dissolved in 8 ml of H.sub.2O, extracted with 5.times.8
ml of EtOAc, washed with 10 ml of brine, dried over MgSO.sub.4.
Remove solvent to obtain 29.84 (24.6 mg, 48% yield).
[0563] 29.96 was prepared by the same route.
[0564] 4-(2-Benzyloxyethyl)-piperidine-1-carboxylic acid tert-butyl
ester (Boc-29.84): .sup.1H NMR (CDCl.sub.3, 200 MHz) .delta. 1.13
(m, 2H), 1.45 (s, 9H), 1.59 (m, 5H), 2.67 (t, 2H, J=12.1 Hz), 3.50
(t, 2H, J=6 Hz), 4.09 (d, 2H, J=12.8 Hz), 4.49 (s, 2H), 7.26-7.35
(m, 5H).
[0565] 4-(2-Benzyloxyethyl)-piperidine (29.84): .sup.1H NMR
(CDCl.sub.3, 200 MHz) .delta. 1.15 (m, 2H), 1.58 (m, 5H), 2.60
(brs, 2H), 3.04 (brs, 2H), 3.51 (t, 2H, J=5.6 Hz), 4.49 (s, 2H),
7.26-7.34 (m, 5H).
[0566] 4-Benzyloxypiperidine-1-carboxylic acid tert-butyl ester
(Boc-29.96): 37% yield. .sup.1H NMR (CDCl.sub.3, 200 MHz) .delta.
1.45 (s, 9H), 1.90 (m, 2H), 1.84 (m, 2H), 3.10 (m, 2H), 3.56 (m,
1H), 3.77 (m, 1H), 4.55 (s, 2H), 7.25-7.35 (m, 5H).
[0567] 4-Benzyloxypiperidine (29.96): 54% yield. .sup.1H NMR
(CDCl.sub.3, 200 MHz) .delta. 1.42 (brs, 2H), 1.88 (brs, 2H), 2.56
(brs, 2H), 3.03 (brs, 2H), 3.41 (m, 1H), 4.55 (s, 2H), 7.25-7.35
(m, 5H).
[0568] General procedure for aryloxymethylpiperidines (J. Med.
Chenm, 1997, 40, 50-59)
[0569] Piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl
ester (Boc-29.151): 1 equiv. of ethyl isonipecotate was dissolved
in ethyl acetate (anhydrous) and cooled to 0.degree. C. in an
ice-bath. Then 1 equiv. of Boc anhydride was dissolved in ethyl
acetate and added dropwise to the stirring reaction mixture and
allowed to slowly reach room-temp and stirred overnight. Reaction
mixture was poured into water then washed with 1 portion of water,
0.1M HCl, sat'd sodium bicarb., and brine. This was dried with
sodium sulfate, filtered and concentrated which resulted in a
clear/colorless oil.
[0570] 4-Hydroxymethylpiperidine-1-carboxylic acid tert-butyl ester
(Boc-29.204): 1 equiv. of Boe-29.151 was dissolved in THF
(anhydrous) and taken down to 0.degree. C. in an ice-bath then 0.7
equiv. of LiAlH.sub.4 (1M in THF) was added dropwise to this
stirring solution and was stirred for 2 hours at 0.degree. C.
Reaction mixture was then quenched at 0.degree. C. with water and
2M sodium hydroxide and filtered through a fritted funnel and solid
was washed with ethyl acetate. The filtrate was washed with water,
brine, and dried. with sodium sulfate, filtered and
concentrated.
[0571] 4-Methanesulfonyloxymethylpiperidine-1-carboxylic acid
tert-butyl ester (39): 1 equiv. of Boc-29.204 was dissolved in DCM
(anhydrous) and 1.2 equiv of TEA was also added to the reaction
mixture and taken down to 0.degree. C. in an ice-bath. 1.1 equiv.
of methansulfonyl chloride was added to reaction mixture and slowly
allowed to reach room temp. The reaction mixture was partitioned
between chloroform and water and aqueous was washed 3 times with
chloroform. Chloroform washes were combined dried with sodium
sulfate, filtered, and concentrated resulting in a light
brown/yellow oil which turned to a light tan solid upon standing in
refrigerator.
[0572] 4-Aryloxymethylpiperidine-1-carboxylic acid tert-butyl
ester: 1.1 equiv. of appropriate phenol was dissolved in
DMF(anhydrous) and taken down to 0.degree. C. in a ice-bath then
1.0 equiv of NaH was added and allowed to stir at 0.degree. C. for
1 hour while slowly reaching room-temp. The mesylate 39 was
dissolved in a minimum of DMF (anhydrous) and dropwise added to the
reaction mixture and heated to 60.degree. C. in an oil-bath
overnight. The reaction mixture was concentrated via reduced
pressure then partitioned between ether and 0.5M sodium hydroxide.
The etherate was washed with 2 more portions of 0.5M sodium
hydroxide, 1 portion water, and 1 portion of brine dried with
sodium sulfate, filtered and concentrated resulting in an off-white
to white solid.
[0573] 4-Aryloxymethylpiperidines: 1 equiv of Boc-protected
aryloxymethylpiperidine was dissolved in 25-30 mL of 4M HCl in
dioxane and stirred for 2 hours at room temp. reactions were
complete by this time. Then reaction mixtures were concentrated and
dried via reduced pressure.
[0574] 4-Phenoxymethyl-piperidine-1-carboxylic acid tert-butyl
ester MS (ES)
[0575] 4-(4-Chlorophenoxymethyl)-piperidine-1-carboxylic acid
tert-butyl ester MS (ES) no ionization [MH.sup.+], t.sub.R (method
A)=12.1 min.
[0576] 4-(4-Cyanophenoxymethyl)-piperidine-1-carboxylic acid
tert-butyl ester MS (ES) no ionization [MH.sup.+] t.sub.R (method
A)=10.7 min.
[0577] 4-(3,4-Dichlorophenoxymethyl)-piperidine-1-carboxylic acid
tert-butyl ester MS (ES) no ionization [MH.sup.+], t.sub.R (method
A )=12.7 min.
[0578] 4-(3-Cyanophenoxymethyl)-piperidine-1-carboxylic acid
tert-butyl ester MS (ES) no ionization [MH.sup.+], t.sub.R (method
A)=10.9 min.
[0579] 4-(2-Cyanophenoxymiethyl)-piperidine-1-carboxylic acid
tert-butyl ester MS (ES) 316.89 [MH.sup.+], t.sub.R (method A)=10.1
min.
[0580] 4-Phenoxymethylpiperidine; hydrochloride MS (ES) 191.93
[MH.sup.+], t.sub.R (method A)=3.6 min.
[0581] 4-(4-Chlorophenoxymethyl)-piperidine; hydrochloride no ms
data
[0582] 4-(3,4-Dichlorophenoxymethyl)-piperidine; hydrochloride MS
(ES) 259.80 [MH.sup.+], t.sub.R (method A)=4.6 min.
[0583] 4-(Piperidin4-ylmethoxy)-benzonitrile; hydrochloride MS (ES)
216.93 [MH.sup.+], t.sub.R (method A)=3.2 min.
[0584] 3-(Piperidin-4-ylmethoxy)-benzonitrile; hydrochloride MS
(ES) 216.94 [MH.sup.+], t.sub.R (method A)=3.5 min.
[0585] 2-(Piperidin-4-ylmethoxy)-benzonitrile; hydrochloride MS
(ES) 217.0 [MH.sup.+], t.sub.R (method A)=8.3 min.
[0586] Phenyl ethers were synthesized from N-Boc-hydroxypiperidines
36 and 37 and the phenols by Mitsunobu reaction, and from
N-Boc-4-hydroxymethylpiperidine (Boc-29.204) via mesylate formation
and displacement with phenolates. Benzyl ethers were prepared by
alkylation with benzyl bromide. Benzyl piperidines 29.28, 29.29,
29.81, and 29.82 were prepared from the corresponding ketone by
reduction with TFA/Et.sub.3SiH (J. Med. Chem. 1992, 35,
4903-4910).
EXAMPLE 3
Preparation of Non-Commercial Piperazines and Homopiperazines
29
[0587] 28
[0588] Substituted (phenylpropyl)piperazines were prepared starting
from the commercially available aylpropionic acids 40, either by
formation of the acid chloride using thionyl chloride, reaction
with piperazine and reduction of the amide thus formed with LiAlH4
to the amine 29, or EDC coupling of the acid with monoprotected
piperazine followed by deprotection and reduction to the amine 29.
The latter sequence was also used for the preparation of
phenylpropylhomopiperazine (29.192). Further alkylarylpiperazines
were prepared from the mono-Boc-protected derivatives by reductive
amination with the appropriate aldehyde using NaBH(OAc).sub.3 as
reducing agent followed by deprotection HCl/MeOH, or by reductive
amination with 26.22 and 26.31. Homopiperazine 29.189 was prepared
from 41 by Buchwald-Hartwig coupling. The piperazinyl acetamides
29.200 and 29.206 were prepared in 4 or 5 steps, respectively, from
the nitrophenyl-piperazine 42.
[0589] In addition, 1-(2-methanesulfinylphenyl)-piperazine (29.238)
was prepared from the thiomethyl compound 29.228 by oxidation with
sodium periodate. SNAr of methyl 2-bromobenzoate with piperazine
gave the 2-piperazinyl benzoic ester 29.232. Its reaction with
ammonia yielded the 2-piperazinylbenzamide 29.239. Alkylation of
piperazine with propargyl bromide, (3-bromoprop-1-ynyl)-benzene,
and the mesylate of 4-phenyl-1-butanol gave 1-prop-2-ynylpiperazine
(29.83), 1-(3-phenylprop-2-ynyl)-piperazine (29.21), and
1-(4-phenylbutyl)-piperaz- ine (29.56), respectively.
[0590] General procedure for the reductive amination of
Boc-protected piperazines and homopiperazine with aldehydes
[0591] 4-(3-Chlorobenzyl)-piperazine-1-carboxylic acid tert-butyl
ester (20.24): To a solution of piperazine-1-carboxylic acid
tert-butyl ester (4.00 g, 21.5 mmol) in dry dichloroethane (70 mL)
are added 3-chlorobenzaldehyde (2.49 mL, 3.08 g, 21.9 mmol), HOAc
(2.58 mL, 2.71 g, 45.1 mmol) and NaBH(OAc).sub.3 (5.46 g, 25.8
mmol) at ambient temperature. After stirring at ambient temperature
for 3d, 2N NaOH (40 mL) is added, the layers are separated, and the
aqueous layer is extracted with CH.sub.2Cl.sub.2 (4.times.50 mL).
The combined organic extracts are washed with water (3.times.50 mL)
and brine (80 mL) and dried over MgSO.sub.4. The crude material is
purified by chromatography on silica gel, eluting with hexane:EtOAc
mixtures, yielding 5.83 g (18.8 mmol, 87%) of the title compound as
yellow oil. MS (ES): m/z 311.0/313.0(50/18) [MH.sup.+]. t.sub.R
(method A)=5.0 min.
[0592] 4-Benzyl-cis-3,5-dimethylpiperazine1-carboxylic acid
tert-butyl ester (20.16): The procedure for the corresponding
3-chlorobenzyl piperazine was used. The title compound was obtained
as yellow oil (34% yield) after chromatography on silica gel.
.sup.1H NMR (200 MHz, CDCl.sub.3) .delta. 7.40-7.18 (m, 5H),
3.90-3.80 (m, 2H), 3.81 (s, 2H), 2.72-2.50 (m, 4H), 1.45 (s, 9H),
1.04 (d, J=6.0 Hz, 6H).
[0593] 1-Benzyl-cis-2,6-dimethylpiperazine dihydrochloride (29.32):
Following the general procedure for Boc removal with HCl, the title
compound was obtained from
4-benzyl-cis-3,5-dimethylpiperazine-1-carboxyl- ic acid tert-butyl
ester as beige solid (quant.). MS (ES, free base): in/z 205.1 (100)
[MH.sup.+]. t.sub.R (method B, free base)=5.8 min.
[0594] 1-Prop-2-ynylpiperazine (29.83): Propargyl bromide (1.19 g,
10 mmol) and piperazine (8.61 g, 100 mmol) were dissolved in THF
(90 ml). Stir under N.sub.2 and reflux for 4 h. Remove solvent and
dissolve in 40 ml of H.sub.2O. Extracted with 4.times.40 ml of
EtOAc, washed with 2.times.15 ml of brine, dried over MgSO.sub.4.
After solvent was removed, brownish solid 29.83 (285 mg, 23% yield)
was obtained. .sup.1H NMR (CDCl.sub.3, 200 MHz): .delta.=2.28 (t,
1H, J=2.4 Hz), 2.56 (m, 4H), 2.92 (m, 4H), 3.30 (d, 2H, J=2.6
Hz).
[0595] 1-(3-Phenylprop-2-ynyl)-piperazine (29.21): To a solution of
piperazine (862 mg, 10.0 mmol) in THF (16 mL) is added
(3-bromoprop-1-ynyl)-benzene (245 mg, 1.26 mmol), and the reaction
mixture is stirred overnight. THF is evaporated,
water/Na.sub.2CO.sub.3 is added, the mixture is extracted with
Et.sub.2O (6.times.10 mL), the combined extracts are washed with
water, brine, dried over MgSO.sub.4, filtered, and concentrated.
The residue is purified by chromatography (silica gel,
MeOH/CH.sub.2Cl.sub.2), yielding 179 mg (0.892 mmol, 71%) of the
target compound. .sup.1H NMR (CDCl.sub.3, 200 MHz): .delta.=1.97
(s, 1H), 2.63 (m, 4H), 2.97 (m, 4H), 3.51 (s,-2H), 7.25-7.35 (m,
3H), 7.40-7.48 (m, 2H).
[0596] 1-[3-(4-Chlorophenyl)-allyl]-piperazine (29.135): .sup.1H
NMR (CDCl.sub.3, 200 MHz): .delta.=1.60 (brs, 1H), 1.79 (tt, J=7.6,
7.6 Hz, 2H), 2.28-2.50 (m, 6H), 2.60 (t, J=7.8 Hz, 2H), 2.85-2.94
(m, 4H), 7.08-7.15 (m, 2H), 7.20-7.27 (m, 2H).
[0597] 2-Piperazin-1-yl-benzoic acid methyl ester (29.232) (see J.
Med. Chem., 1978, 21(12), 1301-1306): 10 equiv of piperazine, 1
equiv of bromide starting material 10, and potassium carbonate were
dissolved in 1,4 dioxane and refluxed overnight then stirred at
room-temp for another day then reaction was worked up. The reaction
mixture was concentrated and partitioned between 2M NaOH and
chloroform. The aqueous fraction was washed 3 time with chloroform
and organic fractions were combined dried with sodium sulfate,
filtered, and concentrated which resulted in 8 g of a white solid
which contained large amounts of the piperazine starting material.
Therefore, material was washed again with water and neutralized
with 1M HCl and concentrated. This mixture was triturated with
chloroform/methanol and filtered through a fritted funnel. The
filtrate was once again washed with water and aqueous was extracted
4 times with chloroform. Chloroform fractions were combined dried
with sodium sulfate, filtered and concentrated with resulted in a
yellow oil (14% yield) and was used as crude for subsequent
reaction. MS (ES) 221 [MH.sup.+], t.sub.R (method A)=3.56 min.
[0598] 2-Piperazin-1-yl-benzamide (29.239): 1 equiv of 29.232 was
dissolved in MeOH (anhydrous) and cooled to 0.degree. C. in a
ice-bath in Parr bomb then ammonia gas was bubbled into mixture
until saturated. This mixture was then heated to 50.degree. C. in
an oil-bath overnight. Material was concentrated and purified by
silica column using 20%MeOH in CHCl.sub.3 as eluent which resulted
in an off-white solid (20% yield) and recovered starting material.
MS (ES) 206 [MH.sup.+], t.sub.R (method B)=4.14 min.
[0599] 1-(2-Methanesulfinylphenyl)-piperazine (29.238): 1 equiv of
29.228 was dissolved in acetonitrile/water and taken down to
0.degree. C. in an ice-bath. Then 1.5 equiv. of sodium periodate
was added in one portion to the first mixture and allowed stir at
room temp. overnight. Reaction mixture was partitioned between
chloroform and water and neutralized with sat'd sodium bicarbonate
and aqueous was washed with six portions of chloroform. Chloroform
washes were combined dried with sodium sulfate, filtered and
concentrated which resulted in a yellow solid, was used as crude
for the next step. MS (ES) 225 [MH.sup.+], t.sub.R (method A)=2.07
min.
[0600] 4-(4-Nitrophenyl)-piperazine-1-carboxylic acid tert-butyl
ester (43): 1 equiv of piperazine 42 was dissolved in DCM
(anhydrous) followed by 1.5 equiv. of TEA and taken down to
0.degree. C. in an ice-bath and then 1.25 equiv. of Boc anhydride
was added to the reaction mixture and allowed to stir for one hour.
The reaction mixture was washed with one portion of water, one
portion of sat'd sodium bicarbonate, dried with sodium sulfate
filtered and concentrated and resulted in a yellow solid. MS (ES)
307.9 [MH.sup.+].
[0601] 4-(4-Aminophenyl)-piperazine-1-carboxylic acid tert-butyl
ester (44): 1 equiv of 43 dissolved in methanol (anhydrous) and 10%
of 10% Pd/C was added under a hydrogen atmosphere and allowed to
stir overnight at room-temp. Reaction was filtered through a pad of
celite and concentrated to give a blue/purple oil. The oil was
brought up in DCM acidified using 1 M HCl and organic wash was
removed. The aqueous was neutralized with sat'd sodium bicarbonate
and washed 3 times with DCM, dried with sodium sulfate, filtered
and concentrated and resulted in a pale red oil, 72% yield. MS (ES)
277.8 [MH.sup.+].
[0602] 4-(4-Acetylaminophenyl)-piperazine-1-carboxylic acid
tert-butyl ester (Boc-29.200): 1 equiv. of 15 was dissolved in DCM
(anhydrous) and 1.5 equiv of TEA was added to reaction mixture and
taken down to 0.degree. C. in an ice-bath. To this mixture was
added 1.1 equiv of acetyl chloride and was allowed to reach
room-temp and stopped after 1 hour. The solvent was removed by
reduced pressure and was partitioned between DCM and water. The
aqueous was washed 3 times with DCM and all organic washes were
combined and dried with sodium sulfate, filtered and concentrated
which resulted in a light brown/tan solid (91%). MS (ES) 320.3
[MH.sup.+]
[0603] 4-[4-(Acetylmethylamino)-phenyl]-piperazine-1-carboxylic
acid tert-butyl ester (Boc-29.206): 1 equiv of Boc-29.200 was
dissolved in DMF (anhydrous) and taken to 0.degree. C. in an
ice-bath. Then 1.5 equiv of NaH was added to the reaction mixture
and was continued being stirred at 0.degree. C. for .+-.2 hour.
Then 1.2 equiv of methyl iodide was added to reaction mixture and
was stirred for an additional hour. The reaction was quenched with
water then aqueous was washed three times with ethyl acetate.
Organic fractions were combined dried with sodium sulfate, filtered
and concentrated and resulted in a light brown/tan solid (94%
yield). MS (ES) 334.2 [MH.sup.+].
[0604] N-Methyl-N-(4-piperazin-1-ylphenyl)-acetamide (29.206): 1
equiv of Boc-29.206 was dissolved in a 25% TFA in DCM solution and
stirred at room temp. under a nitrogen atmosphere and was allowed
to stir for 1 hour. Solvent was removed and crude mixture was
partitioned between DCM and sat'd sodium bicarbonate and aqueous
was washed 3 times with DCM. The organic washes were combined dried
with sodium sulfate, filtered and concentrated. The aqueous was
concentrated and triturated with DMC/MeOH. The organic was combined
with the previous organic washes and resulted in a pale yellow
solid (71% yield). MS (ES) 234.2 [MH.sup.+]
[0605] N-(4-Piperazin-1-ylphenyl)-acetamide (29.200): Following the
procedure for 29.206, 29.200 was prepared from Boc-29.200 in 87%
yield, pale yellow solid. MS (ES) 220.1 [MH.sup.+].
EXAMPLE 4
Synthesis of Intermediate 7
[0606] The key intermediate for pyrrolo[2,3-d]pyrimidines with
phenoxymethylene, alkoxymethylene or oxinme ether moieties at C-6
is the bromide 7, which is prepared in 6 steps from methyl
cyanoacetate and chloroacetone (scheme 4). The monoalkylation
product 2 is protected as 1,3-dioxolane, then the pyrimidine ring
is formed by reaction with a benzamidine. Cyclization of the
pyrrole ring occurs on reaction with aqueous HCl, and refluxing
with POCl.sub.3 yields the chloride 5. Boc-protection of the
pyrrole followed by radical bromination with NBS gives the bromide
7. 29
[0607] 2-Cyano-4-oxopentanoic acid methyl ester (1): To an
ice-cooled (0.degree. C.) solution of ethyl cyanoacetate (6.58 g,
58.1 mmol) in MeOH (20 mL) was slowly added a solution of NaOMe
(25% w/v; 58.1 mmol). After 10 min, chloroacetone (5 mL; 62.8 mmol)
was slowly added. After 4 h, the solvent was removed. The brown oil
was diluted the EtOAc (100 mL) and washed with H.sub.2O (100 mL).
The organic fraction was dried, filtered, and concentrated to a
brown oil (7.79 g; 79%). The oil was a mixture of methyl/ethyl
ester products (9/1), and was used without further purification.
.sup.1H NMR (200 MHz, CDCl.sub.3): .delta. 1.26 (t, J=7.1 Hz), 2.44
(s, 3H), 3.02 (dd, 1H, J=15.0, 7.0 Hz), 3.42 (dd, 1H, J=15.0, 7.1
Hz), 3.62 (s, 3H), 3.91 (dd, 1H, J=7.2, 7.0 Hz), 4.24 (q, J=7.2
Hz).
[0608] 2-Cyano-3-(2-methyl-[1,3]dioxolan-2-yl)-propionic acid
methyl ester (2) The procedure of Seela and Lupke was used..sup.1
Thus, protection of the ketone (1) (5.0 g, 32.2 mmol) with ethylene
glycol (4 mL, 64.4 mmol) in the presence of TsOH (100 mg) afforded
2 as an oil (5.2 g, 81.0%) after flash chromatography (SiO.sub.2;
3/7 EtOAc/Hex, R.sub.f 0.35). Still contains .about.5% ethyl ester:
.sup.1H NMR (200 MHz, CDCl.sub.3): .delta. 1.26 (t, J=7.1 Hz), 1.35
(s, 3H), 2.32 (dd, 1H, J=15.0, 7.0 Hz), 2.48 (dd, 1H, J=15.0, 7.1
Hz), 3.62 (dd, 11H, J=7.2, 7.0 Hz), 3.79 (s, 3H), 3.98 (s, 4H),
4.24 (q, J=7.2 Hz); MS (ES) 200.1 (M.sup.++1).
[0609]
6-Amino-5-(2-methyl-[1,3]dioxolan-2-ylmethyl)-2-phenylpyrimidin-4-o-
l (3):
[0610] A solution of acetal (2) (1 g, 5.02 mmol), benzamidine (786
mg, 5.02 mmol), and DBU (1.5 mL, 10.04 mmol) in dry DMF (15 mL) was
heated to 85.degree. C. for 15 h. The mixture was diluted with
CHCl.sub.3 (30 mL) and washed with 0.5 N NaOH (10 mL) and H.sub.2O
(20 mL). The organic fraction was dried, filtered and concentrated
to a brown oil. Flash chromatography (SiO.sub.2; 1/9
EtOAc/CH.sub.2Cl.sub.2, R.sub.f 0.35) was attempted, but material
crystalized on the column. The silica gel was washed with MeOH.
Fractions containing the product (3) were concentrated and used
without further purification (783 mg, 54.3%): .sup.1H NMR (200 MHz,
CDCl.sub.3): .delta. 1.38 (s, 3H), 3.60-3.15 (m, 2H), 3.98 (s, 4H),
5.24 (brs, 2H), 7.45 (m, 3H), 8.24 (m, 2H); MS (ES) 288.1
(M.sup.++1).
[0611] 6-Methyl-2-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-ol
hydrochloride (4):
[0612] A solution of acetal 3 (700 mg, 2.44 mmol) in 1 N HCl (40
mL) was stirred for 2 h at RT. The resulting slurry was filtered
yielding the HCl salt 4 as a tan solid (498 mg, 78.0%): .sup.1H NMR
(200 MHz, DMSO-d.sub.6): .delta. 2.25 (s, 3H), 6.17 (s, 1H), 7.45
(m, 3H), 8.05 (m, 2H), 11.78 (s, 1H); MS (ES) 226.1
(M.sup.++1).
[0613] 4-Chloro-6-methyl-2-phenyl-7H-pyrrolo[2,3-d]pyrimidine
hydrochloride (5):
[0614] A heterogeneous mixture of 4 (4.0 g, 17.76 mmol) and
phosphorus oxychloride (125 mL) was heated to reflux. After 14 h
the homogeneous solution was cooled to room temperature and
concentrated in vacuo yielding a black oil. Water was added to the
oil and the mixture was warmed. The resulting solid was filtered,
washed with water and dried at room temperature to yield 4.22 g of
a brown solid (97%). .sup.1H NMR (200 MHz, DMSO-d.sub.6): .delta.
2.43 (s, 3H), 6.31 (s, 1H), 7.49 (m, 3H), 8.34 (m, 2H).
[0615]
4-Chloro-6-methyl-2-phenylpyrrolo[2,3-d]pyrimidine-7-carboxylic
acid tert-butyl ester (6):
[0616] Di-tert-butyl dicarbonate (5.37 g, 24.6 mmol) and
dimethylaminopyridine (1.13 g, 9.2 mmol) were added to a solution
containing (5) (1.50 g, 6.15 mmol) and pyridine (30 mL).
[0617] After 20 h the reaction was concentrated and the residue was
partitioned between CH.sub.2Cl.sub.2 and water. The
CH.sub.2Cl.sub.2 layer was separated, dried over MgSO.sub.4,
filtered and concentrated to yield a black solid. Flash
chromatography (SiO.sub.2; 1/9 EtOAc/Hexanes, R.sub.f 0.40) yielded
1.70 g of a white solid (80%). mp=175-177.degree. C.; .sup.1H NMR
(200 MHz, CDCl.sub.3): .delta. 1.76 (s, 9H), 2.66 (s, 3H), 6.39 (s,
1H), 7.45 (m, 3H), 8.50 (m, 2H); MS (ES): 344.1 (M.sup.++1).
[0618]
6-Bromomethyl-4-chloro-2-phenylpyrrolo[2,3-d]pyrimidine-7-carboxyli-
c acid tert-butyl ester (7):
[0619] N-Bromosuccinimide (508 mg, 2.86 mmol) and AIBN (112 mg,
0.68 mmol) were added to a solution containing 6 (935 mg, 2.71
mmol) and CCl.sub.4 (50 mL). The solution was heated to reflux.
After 2 h the reaction was cooled to room temperature and
concentrated in vacuo to yield a white solid. Flash chromatography
(SiO.sub.2; 1/1 CH.sub.2Cl.sub.2/Hexanes, R.sub.f 0.30) yielded 960
mg of a white solid (84%). mp=155-157.degree. C.; .sup.1H NMR (200
MHz, CDCl.sub.3): .delta. 1.79 (s, 9H), 4.93 (s, 2H), 6.76 (s, 1H),
7.48 (m, 3H), 8.52 (m, 2H); MS (ES): 423.9 (M.sup.++1).
EXAMPLE 5
C-6 Phenoxymethylene Derivatives
[0620] The benzylic bromide in 7 is easily displaced with
phenoxides to give 8. Upon heating with amines in DMSO, the
chloride at C-4 is displaced and the Boc group is removed, yielding
the A.sub.2B antagonists 9.1-9.51 (scheme 5). 30
1TABLE 1 A.sub.2B antagonists 9.1-9.51. Comp. # Structure MW 9.1 31
401.47 9.2 32 448.96 9.3 33 470.96 9.4 34 470.96 9.5 35 424.89 9.6
36 424.89 9.7 37 450.97 9.8 38 476.97 9.9 39 462.94 9.10 40 461.96
9.11 41 419.46 9.12 42 431.50 9.13 43 435.92 9.14 44 402.46 9.15 45
420.90 9.16 46 435.92 9.17 47 415.50 9.18 48 480.37 9.19 49 459.51
9.20 50 522.01 9.21 51 622.13 9.22 52 582.06 9.23 53 402.46 9.24 54
435.92 9.25 55 416.49 9.26 56 431.50 9.27 57 416.49 9.28 58 458.52
9.29 59 394.86 9.30 60 450.97 9.31 61 408.89 9.32 62 408.89 9.33 63
424.89 9.34 64 450.93 9.35 65 505.02 9.36 66 462.98 9.37 67 408.89
9.38 68 408.89 9.39 69 408.89 9.40 70 436.95 9.41 71 436.95 9.42 72
470.96 9.43 73 470.96 9.44 74 448.96 9.45 75 493.01 9.46 76 451.96
9.47 77 393.88 9.48 78 464.96 9.49 79 461.96 9.50 80 406.88 9.51 81
449.94
[0621] General Procedure for Bromide Displacement with Phenols:
[0622]
4-Chloro-6-phenoxymethyl-2-phenyl-pyrrolo[2,3-d]pyrimidine-7-carbox-
ylic acid tert-butyl ester (8.1): Sodium phenoxide trihydrate (173
mg, 1.02 mmol) was added in one portion to a solution of bromide
(7) (410 mg, 0.97 mmol) dissolved in CH.sub.2Cl.sub.2 (5 mL) and
DMF (10 mL). After 2 h the reaction solution was partitioned
between CH.sub.2Cl.sub.2 and water. The water layer was extracted
with CH.sub.2Cl.sub.2. The combined CH.sub.2Cl.sub.2 layers were
washed with water, dried over MgSO.sub.4, filtered and concentrated
to yield a yellow solid. Flash chromatography (SiO.sub.2; 1/6
EtOAc/Hexanes, R.sub.f 0.30) yielded 210 mg of a white solid (50%).
.sup.1H NMR (200 MHz, CDCl.sub.3): .delta. 1.76 (s, 9H), 5.45 (s,
2H), 6.83 (s, 1H), 7.03 (m, 3H), 7.34 (m, 2H), 7.48 (m, 3H), 8.53
(m, 2H); MS (ES): 436.2 (M.sup.++1).
[0623] General Procedure for C-4 Chloride Displacement with
Amines:
[0624]
N-[2-(6-Phenoxymethyl-2-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino-
)-ethyl]-acetamide (9.1): A solution containing (8.1) (85 mg, 0.20
mmol), N-acetylethylene-diamine (201 mg, 1.95 mmol) and DMSO (3 mL)
was heated to 100.degree. C. After 1 h the temperature was raised
to 130.degree. C. After 3 h the reaction was cooled to room
temperature and partitioned between EtOAc and water. The water
layer was extracted with EtOAc (2.times.). The combined EtOAc
layers are washed with water, dried over MgSO.sub.4, filtered and
concentrated. Flash chromatography (SiO.sub.2; 1/10 EtOH/
CHCl.sub.3, R.sub.f 0.25) yielded 73 mg (93%) of a white foamy
solid, mp. 196-197.degree. C. .sup.1H NMR (200 MHz, DMSO-d.sub.6):
.delta. 1.79 (s, 3H), 3.36 (m, 2H), 3.61 (m, 2H), 5.12 (s, 2H),
6.59 (s, 1H), 6.89-7.09 (m, 3H), 7.20-7.50 (m, 5H), 7.57 (brt, 1H),
8.03 (brt, 1H), 8.39 (m, 2H), 11.81 (br s, 1H); MS (ES): 402.6
(MH.sup.+). t.sub.R (method A)=3.6 min.
[0625] The following compounds 9.2-9.51.were prepared in the same
manner:
[0626]
2-{1-[6-(3-Chlorophenoxymethyl)-2-phenyl-7H-pyrrolo[2,3-d]pyrimidin-
-4-yl]-pyrrolidin-2-yl}-ethanol (9.2): MS (ES): 449.0
(M.sup.++1).
[0627]
3-(S)-[6-(3-Chlorophenoxymethyl)-2-phenyl-7H-pyrrolo[2,3-d]pyrimidi-
n-4-ylamino]-1-phenylethanol (9.3): .sup.1H-NMR (200 MHz,
CDCl.sub.3): .delta. 8.27 (m, 2H), 7.35 (m, 8H), 7.06 (m, 1H), 6.87
(in, 1H), 6.51 (m, 2H), 6.23 (s, 1H), 5.67 (m, 1H), 5.06 (m, 1H),
4.52 (s, 2H), 4.20-4.00 (m, 1H), 3.90-3.60 (m, 1H). MS (ES): 471.0
(M.sup.++1).
[0628]
2-(R)-[6-(3-Chlorophenoxymethyl)-2-phenyl-7H-pyrrolo[2,3-d]pyrimidi-
n-4-ylamino]-1-phenylethanol (9.4): .sup.1H-NMR (200 MHz,
CDCl.sub.3): .delta. 8.27 (m, 2H), 7.32 (m, 8H), 7.06 (m, 1H), 6.88
(m, 1H), 6.54 (m, 2H), 6.23 (s, 1H), 5.66 (m, 1H), 5.07 (m, 1H),
4.56 (s, 2H), 4.20-4.00 (m, 1H), 3.90-3.70 (m, 1H). MS (ES): 471.0
(M.sup.++1).
[0629]
3-(S)-[6-(3-Chlorophenoxymethyl)-2-phenyl-7H-pyrrolo[2,3-d]pyrimidi-
n-4-ylamino]-propane-1,2-diol (9.5): .sup.1H-NMR (200 MHz,
CD.sub.3OD): .delta. 8.27 (m, 2H), 7.39 (m, 3H), 7.22 (dd, 1H,
J=8.2 Hz), 7.02 (m, 1H), 6.96-6.86 (m, 2H), 6.57 (s, 1H), 5.09 (s,
2H), 3.99-3.86 (m, 1H), 3.86-3.64 (m, 2H), 3.56 (d, 2H, J=5.2 Hz).
MS (ES): 425.0 (M.sup.++1).
[0630]
3-(R)-[6-(3-Chlorophenoxymethyl)-2-phenyl-7H-pyrrolo[2,3-d]pyrimidi-
n-4-ylamino]-propane-1,2-diol (9.6): .sup.1H-NMR (200 MHz,
CD.sub.3OD): .delta. 8.26 (m, 2H), 7.39 (m, 3H), 7.22 (dd, 1H,
J=8.2 Hz), 7.02 (m, 1H), 6.96-6.86 (m, 2H), 6.57 (s, 11H), 5.09 (s,
2H), 4.00-3.86 (m, 1H), 3.86-3.65 (m, 2H), 3.56 (d, 2H, J=5.3 Hz).
MS (ES): 425.0 (M.sup.++1).
[0631]
2-(R)-[6-(3-Chlorophenoxymethyl)-2-phenyl-7H-pyrrolo[2,3-d]pyrimidi-
n-4-ylamino]-4-methylpentan-1-ol (9.7): .sup.1H-NMR (200 MHz,
CDCl.sub.3): .delta. 8.27 (m, 2H), 7.38 (m, 3H), 7.10 (m, 1H), 6.90
(m, 1H), 6.54 (m, 2H), 6.37 (s, 1H), 5.30-5.10 (m, 1H), 4.71-4.45
(m, 2H), 4.00-3.85 (m, 1H), 3.80-3.65 (m, 1H), 1.89-1.65 (m, 1H),
1.65-1.50 (m, 1H), 1.01 (d, 3H,J=6.6 Hz), 0.97 (d, 3H,J=6.6 Hz). MS
(ES): 451.0 (M.sup.++1).
[0632]
{1-[6-(3-Chlorophenoxymethyl)-2-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-
-yl]-pyrrolidin-3-yl}-acetic acid methyl ester (9.8): .sup.1H-NMR
(200 MHz, CD.sub.3OD): .delta. 8.32 (m, 2H), 7.39 (m, 3H), 7.23
(dd, 1H, J=8.1 Hz), 7.02 (m, 11H), 6.92 (m, 2H), 6.58 (s, 1H), 5.06
(s, 2H), 4.10 (m, 1H), 3.93 (m, 1H), 3.72 (m, 1H), 3.69 (s, 3H),
3.38 (m, 1H), 2.64 (m, 1H), 2.49 (br d, 2H, J=6.2 Hz), 2.18 (m,
1H), 1.65 (m, 1H). MS (ES): 477.1 (M.sup.++1).
[0633]
{1-[6-(3-Chlorophenoxymethyl)-2-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-
-yl]-pyrrolidin-3-yl}-acetic acid (9.9): .sup.1H-NMR (200 MHz,
CD.sub.3OD): .delta. 8.32 (m, 2H), 7.40 (m, 31H), 7.25 (dd, 1H,
J=8.2 Hz), 7.07 (m, 1H), 6.95 (m, 2H), 6.69 (s, 11H), 5.14 (s, 2H),
4.25-4.15 (m, 1H), 4.12-3.99 (m, 1H), 3.92-3.78 (m, 1H), 3.38 (m,
1H), 2.64 (m, 1H), 2.49 (m, 2H), 2.18 (m, 1H), 1.65 (m, 1H). MS
(ES): 463.0 (M.sup.++1).
[0634]
2-{1-[6-(3-Chlorophenoxymethyl)-2-phenyl-7H-pyrrolo[2,3-d]pyrimidin-
-4-yl]-pyrrolidin-3-yl}-acetamide (9.10): .sup.1H-NMR (200 MHz,
CD.sub.3OD): .delta. 8.35 (m, 2H), 7.39 (m, 3H), 7.25 (dd, 1H,
J=8.0 Hz), 7.06 (m, 1H), 6.96 (m, 2H), 6.69 (s, 1H), 5.14 (s, 2H),
4.14 (dd, 1H, J=10.6 & 7.0 Hz), 4.02 (m, 1H), 3.83 (m, 1H),
3.53 (m, 1H), 2.72 (m, 1H), 2.42 (d, 2H, J=7.4 Hz), 2.26 (m, 1H),
1.69 (m, 1H). MS (ES): 462.2 (M.sup.++1).
[0635]
N-{2-[6-(4-Fluorophenoxymethyl)-2-phenyl-7H-pyrrolo[2,3-d]pyrimidin-
-4-ylamino]-ethyl}-acetamide (9.11): MS (ES) 420 (M.sup.++H);
t.sub.R (method A)=6.8 min.
[0636]
N-{2-[6-(4-Methoxyphenoxymethyl)-2-phenyl-7H-pyrrolo[2,3-d]pyrimidi-
n-4-ylamino]-ethyl}-acetamide (9.12): MS (ES) 432 (M.sup.+);
t.sub.R (method A)=6.4 min.
[0637]
N-{2-[6-(3-Chlorophenoxymethyl)-2-phenyl-7H-pyrrolo[2,3-d]pyrimidin-
-4-ylamino]-ethyl}-acetamide (9.13): MS (ES) 436 (M.sup.+); t.sub.R
(method A)=7.7 min.
[0638]
N-{2-[2-Phenyl-6-(pyridin-3-yloxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-
-4-ylamino]ethyl}-acetamide (9.14): MS (ES) 403 (M.sup.++H);
t.sub.R (method A)=3.8 min.
[0639]
{1-[6-(3-Chlorophenoxymethyl)-2-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-
-yl]-azetidin-3-yl}-methanol (9.15): MS (ES) 421 (M.sup.+); t.sub.R
(method A)=9.5 min.
[0640]
N-{2-[6-(2-Chlorophenoxymethyl)-2-phenyl-7H-pyrrolo[2,3-d]pyrimidin-
-4-ylamino]-ethyl}-acetamide (9.16): MS (ES) 436 (M.sup.+); t.sub.R
(method A)=8.6 min.
[0641]
N-[2-(2-Phenyl-6-m-tolyloxymethyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylam-
ino)-ethyl]-acetamide (9.17): MS (ES) 416 (M.sup.+); t.sub.R
(method A)=8.6 min.
[0642]
N-{2-[6-(3-Bromophenoxymethyl)-2-phenyl-7H-pyrrolo[2,3-d]pyrimidin--
4-ylamino]-ethyl}-acetamide (9.18): MS (ES) 480/482 (91/100)
[MH.sup.+]; t.sub.R (method B)=6.0 min.
[0643]
3-[4-(2-Acetylaminoethylamino)-2-phenyl-7H-pyrrolo[2,3-d]pyrimidin--
6-ylmethoxy]-benzoic acid methyl ester (9.19): yellow solid, mp.
80-85.degree. C. (decomp.); MS (ES) 459.9 [MH.sup.+]; t.sub.R
(method A)=6.8 min.
[0644]
[4-(2-Acetylaminoethylamino)-6-(3-chlorophenoxymethyl)-2-phenylpyrr-
olo[2,3-d]pyrimidin-7-yl]-acetic acid ethyl ester (9.20): MS (ES)
522 (M.sup.+); t.sub.R (method A)=10.6 min.
[0645]
N-{2-[6-(3-Chlorophenoxymethyl)-7-(6-methoxy-2,2-dimethyltetrahydro-
furo
[3,4-d][1,3]dioxol-4-ylmethyl)-2-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4--
ylamino]-ethyl}-acetamide (9.21): MS (ES) 622 (M.sup.+); t.sub.R
(method A)=11.3 min.
[0646]
N-{2-[6-(3-Chlorophenoxymethyl)-7-(3,4-dihydroxy-5-methoxytetrahydr-
ofuran-2-ylmethyl)-2-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino]-ethyl}-a-
cetamide (9.22): MS (ES) 582 (M.sup.+); t.sub.R (method A)=8.0
min.
[0647]
N-{2-[6-(2-Oxo-2H-pyridin-1-ylmethyl)-2-phenyl-7H-pyrrolo[2,3-d]pyr-
imidin-4-ylamino]-ethyl}-acetamide (9.23): .sup.1H NMR (200 MHz,
DMSO-d.sub.6): .delta. 1.78 (s, 3H), 3.32 (m, 2H), 3.59 (m, 2H),
5.14 (s, 2H), 6.27 (dd, 1H, J=6.6, 6.6 Hz), 6.34 (s, 11H), 6.43 (d,
1H, J=8.8 Hz), 7.44 (m, 5H), 7.76 (d, 1H,J=6.9 Hz), 8.00 (brt, 1H),
8.38 (m, 2H); MS (ES): 403.1 (M.sup.++1).
[0648]
N-{2-[6-(4-Chlorophenoxymethyl)-2-phenyl-7H-pyrrolo[2,3-d]pyrimidin-
-4-ylamino]-ethyl}-acetamide (9.24): .sup.1H NMR (200 MHz,
DMSO-d.sub.6): .delta. 1.79 (s, 3H), 3.56 (m, 2H), 3.61 (m, 2H),
5.13 (s, 2H), 6.60 (s, 1H), 7.05 (d, 2H, J=9.2 Hz), 7.34 (d, 2H,
J=9.2 Hz), 7.60 (m, 3H), 7.57 (brt, 1H), 8.03 (brt, 1H), 8.40 (m,
2H); MS (ES): 436.1 [MH.sup.+].
[0649]
1-Methyl-3-[2-(6-phenoxymethyl-2-phenyl-7H-pyrrolo[2,3-d]pyrimidin--
4-ylamino)-ethyl]-urea (9.25): .sup.1H NMR (200 MHz, CD.sub.3OD):
.delta. 2.64 (s, 3H), 3.51 (t, 2H, J=6.0 Hz), 3.82 (t, 2H, J=6.0
Hz), 5.19 (s, 2H), 6.60 (s,1H), 6.97 (dd, 11H, J=7.4 Hz), 7.06 (d,
2H, J=7.8 Hz), 7.32 (m, 2H), 7.44 (m, 3H), 8.39 (m, 2H); MS (ES):
416.9 (M.sup.++1); t.sub.R (method A)=6.1 min.
[0650]
N-{2-[6-(3-Methoxyphenoxymethyl)-2-phenyl-7H-pyrrolo[2,3-d]pyrimidi-
n-4-ylamino]-ethyl}-acetamide (9.26): .sup.1H NMR (200 MHz,
CDCl.sub.3): .delta. 1.75 (s, 3H), 3.56 (m, 2H), 3.75 (s, 3H), 3.87
(m, 2H), 4.88 (s, 2H), 5.80 (brs, 11H), 6.35 (d, 3H, J=6.2 Hz),
6.50 (d, 1H, J=6.6 Hz), 7.10 (d, 1H, J=7.2 Hz), 7.40 (m, 3H), 8.36
(m, 2H) 10.47 (brs, 1H); MS (ES): 432.0 (M.sup.++1).
[0651]
N-{2-[6-(3-Aminophenoxymethyl)-2-phenyl-7H-pyrrolo[2,3-d]pyrimidin--
4-ylamino]-ethyl}-acetamide (9.27): .sup.1H NMR (200 MHz,
CDCl.sub.3): .delta. 1.78 (s, 3H), 3.57 (m, 2H), 3.75 (s, 3H), 3.88
(m, 2H), 5.02 (s, 2H), 5.90 (brs, 1H), 6.20-6.60 (m, 4H), 7.04 (m,
2H), 7.44 (m, 3H), 8.38 (m, 2H) 9.45 (brs, 1H).
[0652]
N-{2-[6-(3-Acetylaminophenoxymethyl)-2-phenyl-7H-pyrrolo[2,3-d]pyri-
midin-4-ylamino]-ethyl}-acetamide (9.28): .sup.1H NMR (200 MHz,
CD.sub.3OD): .delta. 1.83 (s, 3H), 2.10 (s, 3H), 3.50 (t, 2H, J=6.0
Hz), 3.80 (t, 2H, J-=6.2 Hz), 5.14 (s, 2H), 6.55 (s, 1H), 6.76 (m,
1H), 7.02 (d, 1H, J=8.4 Hz), 7.20 (dd, 1H, J-=8.0, 8.0 Hz), 7.40
(m, 3H), 8.37 (m, 2H).
[0653]
2-[6-(3-Chlorophenoxymethyl)-2-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4--
ylamino]-ethanol (9.29): .sup.1H NMR (200 MHz, CD.sub.3OD): .delta.
3.15 (t, 2H, J=5.8 Hz), 3.55 (t, 2H, J=5.4 Hz), 5.17 (s, 2H), 6.59
(s, 1H), 7.00 (m, 2H), 7.08 (s, 1H), 7.26 (dd, 1H, J=8.4, 8.4 Hz)
7.42 (m, 3H), 8.34 (m, 2H); MS (ES): 395.0 (M.sup.++1); t.sub.R
(method A)=8.4 min.
[0654]
(2S)-2-[6-(3-Chlorophenoxymethyl)-2-phenyl-7H-pyrrolo[2,3-d]pyrimid-
in-4-ylamino]-4-methylpentan-1-ol (9.30): MS (ES): 451.0
(M.sup.++1); t.sub.R (method A)=10.5 min.
[0655]
(2R)-1-[6-(3-Chlorophenoxymethyl)-2-phenyl-7H-pyrrolo[2,3-d]pyrimid-
in-4-ylamino]-propan-2-ol (9.31): .sup.1H NMR (200 MHz,
CD.sub.3OD): .delta. 1.25 (d, 3H, J=6.2 Hz), 3.54-3.79 (m, 2H),
4.12 (m, 1H), 5.15 (s, 2H), 6.60 (s, 1H), 6.95 (m, 2H), 7.07 (dd,
1H, J=-7.8, 7.8 Hz), 7.42 (m, 3H), 8.32 (m, 2H); MS (ES): 409.0
(M.sup.++1); t.sub.R (method A)=8.7 min.
[0656]
(2S)-1-[6-(3-Chlorophenoxymethyl)-2-phenyl-7H-pyrrolo[2,3-d]pyrimid-
in-4-ylamino]-propan-2-ol (9.32): .sup.1H NMR (200 MHz,
CD.sub.3OD): .delta. 1.25 (d, 3H, J=6.2 Hz), 3.54-3.79 (m, 2H),
4.12 (m, 1H), 5.15 (s, 2H), 6.60 (s, 1H), 6.95 (m, 2H), 7.07 (dd,
1H, J=7.8, 7.8 Hz), 7.42 (m, 3H), 8.32 (m, 2H); MS (ES): 409.0
(M.sup.++1); t.sub.R (method A)=8.7 min.
[0657]
2-[6-(3-Chlorophenoxymethyl)-2-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4--
ylamino]-propane-1,3-diol (9.33): .sup.1H NMR (200 MHz,
CD.sub.3OD): .delta. 3.86 (d, 4H, J=5.8 Hz), 4.57 (t, 1H, J=5.4
Hz), 5.18 (s, 2H), 6.64 (s, 1H), 6.95 (m, 2H), 7.07 (dd, 1H, J=2.2,
2.2 Hz), 8.20 (dd, 1H, J=8.2, 8.2 Hz), 7.43 (m, 3H), 8.32 (m, 2H);
MS. (ES): 425.0 (M.sup.++1); t.sub.R (method A)=7.7 min.
[0658]
1-{2-[6-(3-Chlorophenoxymethyl)-2-phenyl-7H-pyrrolo[2,3-d]pyrimidin-
-4-ylamino]-ethyl}-3-methylurea (9.34): .sup.1H NMR (200 MHz,
CDCl.sub.3): .delta. 2.57 (d, 3H, J=4.8 Hz), 3.55 (m, 2H), 3.83 (m,
2H), 4.85 (s, 2H), 5.52 (brs, 1H), 6.00 (brs, 1H), 6.38 (s, 1H),
6.64 (m, 1H), 6.73 (dd, 1H, J=1.8, 1.8 Hz), 6.92 (d, 1H, J=8.8 Hz),
7.14 (dd, 1H, J=8.0, 8.0 Hz), 7.40 (m, 3H), 8.34 (m, 2H), 10.64
(brs, 1H); MS (ES): 451.0 (M.sup.++1); t.sub.R (method A)=8.0
min.
[0659]
2-{[6-(3-Chlorophenoxymethyl)-2-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-
-ylamino]-methyl}-piperidine-1-carboxylic acid methylamide (9.35):
.sup.1H NMR (200 MHz, CD.sub.3OD+DMSO-d.sub.6): .delta. 1.40-1.70
(m, 6H), 2.43 (s, 3H), 3.50-3.90 (m, 2H), 4.10 (m, 11H), 4.45 (m,
2H), 3.83 (m, 2H), 5.20 (s, 2H), 6.58 (s, 11H), 7.04 (m, 2H), 7.10
(dd, 11H, J=2.2, 2.2 Hz), 7.29 (dd, 1H, J=8.2, 8.2 Hz), 7.44 (m,
31H), 8.38 (m, 2H); MS (ES): 505.0 (M.sup.++1); t.sub.R (method
A)=9.7 min.
[0660]
trans-2-{[6-(3-Chlorophenoxymethyl)-2-phenyl-7H-pyrrolo[2,3-d]pyrim-
idin-4-ylamino]-methyl}-cyclohexanol (9.36): .sup.1H NMR (200 MHz,
CDCl.sub.3): .delta. 1.00-2.00 (m, 9H), 2.93 (m, 1H), 3.66 (m, 2H),
4.73 (d, 2H, J=2.8 Hz), 4.90 (brs, 1H), 6.00 (brs, 1H), 5.41 (brs,
1H), 6.37 (s, 1H), 6.57 (ddd, 1H, J=1.0, 2.6, 8.2 Hz), 6.66 (dd,
1H, J=2.6, 2.6 Hz), 6.93 (ddd, 1H, J=0.8, 1.8, 7.9 Hz), 7.13 (dd,
1H, J=8.0, 8.0 Hz), 7.38 (m, 3H), 8.23 (m, 2H), 11.23 (brs, 11H);
MS (ES) 463/465 (MH.sup.+); t.sub.R (method A)=10.0 min.
[0661]
(R)-2-[6-(3-Chlorophenoxymethyl)-2-phenyl-7H-pyrrolo[2,3-d]pyrimidi-
n-4-ylamino]-propan-1-ol (9.37): .sup.1H NMR(CDCl.sub.3, 200 MHz):
.delta. 1.36 (d, 3H, J=7 Hz), 1.44 (s, 1H), 3.71 (dd, 1H, J=7.2,
3.8 Hz), 3.90 (dd, 1H, J=8.2, 2.8 Hz), 4.44-4.67 (m, 3H), 5.17-5.35
(m, 1H), 6.32 (s, 1H), 6.42-6.57 (m, 2H), 6.76-6.94 (m, 2H),
7.00-7.14 (m, 1H), 7.29-7.44 (m, 3H), 8.14-8.32 (m, 2H); MS (ES)
409.0/411.1 (100/35) [MH.sup.+1; t.sub.R (method A)=8.9 min.
[0662]
(S)-2-[6-(3-Chlorophenoxymethyl)-2-phenyl-7H-pyrrolo[2,3-d]pyrimidi-
n-4-ylamino]-propan-1-ol (9.38): .sup.1H NMR(CDCl.sub.3, 200 MHz):
.delta. 1.37(d,3H, J=7 Hz), 1.44 (s,1H), 3.72 (dd, 1H, J=7.4, 3.6
Hz), 3.90 (dd, 1H, J=8, 3 Hz), 4.40-4.70 (m,3H), 5.28 (brd,1H,
J=5.4 Hz), 6.33 (s,11H), 6.43-6.60 (m,2H), 6.76-6.94 (m,2H),
7.02-7.14 (m,1H), 7.30-7.45 (m,3H), 8.14-8.32 (m,2H); MS (ES)
409/411 (100/35).[MH.sup.+]; t.sub.R (method A) 8.9 min.
[0663]
3-[6-(3-Chlorophenoxymethyl)-2-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4--
ylamino]-propan-1-ol (9.39): MS (ES) 409/411 [MH.sup.+]; t.sub.R
(method A)=8.4 min.
[0664]
(R)-2-[6-(3-Chlorophenoxymethyl)-2-phenyl-7H-pyrrolo[2,3-d]pyrimidi-
n-4-ylamino]-3-methyl-butan-1-ol (9.40): MS (ES) 437/439
[MH.sup.+]; t.sub.R (method A)=9.7 mm.
[0665]
(S)-2-[6-(3-Chlorophenoxymethyl)-2-phenyl-7H-pyrrolo[2,3-d]pyrimidi-
n-4-ylamino]-3-methyl-butan-1-ol (9.41): MS (ES) 437/439
[MH.sup.+]; t.sub.R (method A)=9.7 min.
[0666]
(R)-2-[6-(3-Chlorophenoxymethyl)-2-phenyl-7H-pyrrolo[2,3-d]pyrimidi-
n-4-ylamino]-2-phenylethanol (9.42): MS (ES) 471/473 [MH.sup.+];
t.sub.R (method A)=9.8 min.
[0667]
(S)-2-[6-(3-Chlorophenoxymethyl)-2-phenyl-7H-pyrrolo[2,3-d]pyrimidi-
n-4-ylamino]-2-phenylethanol (9.43): MS (ES) 471/473 [MH.sup.+];
t.sub.R (method A)=9.8 min.
[0668]
{1-[6-(3-Chlorophenoxymethyl)-2-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-
-yl]-piperidin-3-yl}-methanol (9.44): .sup.1H NMk (CDCl.sub.3, 200
MHz): .delta. 1.4-2.00 (m, 5H), 3.52 (d, 2H, J=7.6 Hz), 3.78-3.86
(m, 1H), 4.02-4.22 (m, 2H), 4.50 (dd, 2H, J=11.6, 3.2 Hz),
6.35-6.50 (m, 2H), 6.54 (brs, 1H), 6.83-6.94 (m, 1H), 7.05 (t, 1H,
J=8.2 Hz), 7.28-7.44 (m, 3H), 8.18-8.31 (m, 2H); MS (ES) 449/451
[MH.sup.+]; t.sub.R (method A)=10.3 min.
[0669]
N-{2-[6-(3-Chlorophenoxymethyl)-5-dimethylaminomethyl-2-phenyl-7H-p-
yrrolo[2,3-d]pyrimidin-4-ylamino]-ethyl}-acetamide (9.45): .sup.1H
NMR (CDCl.sub.3, 200 MHz): .delta. 1.61 (s, 3H), 2.30 (s, 6H),
3.43-3.60 (m, 4H), 3.74-3.93 (m, 2H), 4.53 (brs, 2H), 6.34-6.50 (m,
2H), 6.83-6.95 (m, 1H), 7.07 (t, 1H, J=8.4 Hz), 7.25-7.45 (m,3H),
7.53-7.71 (m, 1H), 8.22-8.40 (m, 2H), 9.57-9.78 (m, 11H); MS (ES)
493/495 [MH.sup.+]; t.sub.R (method A)=7.2 min.
[0670]
2-[6-(3-Chlorophenoxymethyl)-5-dimethylaminomethyl-2-phenyl-7H-pyrr-
olo[2,3-d]pyrimidin-4-ylamino]-ethanol (9.46): .sup.1H
NMR(CDCl.sub.3, 200 MHz): .delta. 2.29 (s, 6H), 3.50 (s, 2H),
3.71-3.84 (m, 2H), 3.85-3.97 (m, 2H), 4.44 (s, 2H), 6.33-6.49 (m,
2H), 6.83-6.95 (m, 1H), 7.07 (t, 1H, J=8.2 Hz), 7.20-7.42 (m, 4H),
8.18-8.31 (m, 2H), 9.77 (brs, 1H); MS (ES) 452/454 [MH.sup.+];
t.sub.R (method A)=7.0 min.
[0671]
N-[6-(3-Chlorophenoxymethyl)-2-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4--
yl]ethane-diamine (9.47): MS (ES): 394/396 [MH.sup.+].
[0672]
3-{2-[6-(3-Chlorophenoxymethyl)-2-phenyl-7H-pyrrolo[2,3-d]pyrimidin-
-4-ylamino]ethyl}-1,1-dimethylurea (9.48): To a solution of 9.47
(20 mg) and TEA (100 mg) in DCM (5 mL) and DMF (1 mL) was added
dropwise the solution of ClC(O)N(CH.sub.3).sub.2 (100 mg) in DCM (3
mL) at 0.degree. C. while stirring. After adding, the stirring was
continued for 2 h and the reaction mixture was washed with
saturated NaHCO.sub.3 aqueous solution twice, brine once, dried
over MgSO.sub.4, and then concentrated. The residue was purified by
preparative TLC (silica gel, EtOAc/Hexane=2/1), yielding an
off-white foam (7 mg, 31%). .sup.1H-NMR (200 MHz, CDCl.sub.3):
.delta. 2.70 (s, 6H), 3.55-3.68 (m, 2H), 3.82-3.94 (m, 2H), 4.82
(s, 2H), 5.40 (t, 1H, J=5.2 Hz), 6.30 (brs, 1H), 6.42 (s, 1H),
6.55-6.78 (m, 2H), 6.90-6.95 (m, 1H), 7.08-7.20 (m, 1H), 7.18-7.48
(m, 3H), 8.28-8.40 (m, 2H), 10.90 (brs, 11H); MS (ES): 465/467
[MH.sup.+].
[0673]
1-{4-[6-(3-Chlorophenoxymethyl)-2-phenyl-7H-pyrrolo[2,3-d]pyrimidin-
-4-yl]-piperazin-1-yl}-ethanone (9.49): .sup.1H NMR(CDCl.sub.3, 200
MHz): .delta. 2.18 (s, 3H), 3.61-3.77 (m, 2H), 3.77-3.90 (m, 2H),
4.00-4.10 (m, 2H), 4.10-4.20 (m, 2H), 4.62 (brs, 2H), 6.40-6.54 (m,
3H), 6.86-6.95 (m, 1H), 7.08 (t, 1H, J=8.2 Hz), 7.32-7.45 (m, 3H),
8.25-8.39 (m, 2H); MS (ES) 462/464 [MH.sup.+]; t.sub.R (method
A)=9.8 min.
[0674]
1-[6-(3-Chlorophenoxymethyl)-2-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4--
yl]azetidin-3-ol (9.50): MS (ES): 407/409 [MH.sup.+]; t.sub.R
(method A)=8.6 min.
[0675]
N-(2-{[6-(3-Chlorophenoxymethyl)-2-phenyl-7H-pyrrolo[2,3-d]pyrimidi-
n-4-yl]methylamino}ethyl)acetamide (9.51): MS (ES): 450/452
[MH.sup.+]; t.sub.R (method A) 8.5 mm.
EXAMPLE 6
C-6 Alkoxymethylene Derivatives
[0676] Alkoxymethylene derivatives are conveniently prepared by
silver-mediated displacement of the bromide in 7 with alcohols. A
series of piperidine sulfonamides 15 was prepared from the
intermediate 10 by Boc removal, C-4 chloride displacement, and
sulfonylation (scheme 6). 82
[0677] General Procedure for Silver-Mediated Bromide
Displacement:
[0678]
6-([-tert-Butoxycarbonylpiperidin4-yloxymethyl)-4-chloro-2-phenylpy-
rrolo[2,3-d]pyrimidine-7-carboxylic acid tert-butyl ester (10):
Bromide 7 (4.54 g, 10 mmol) and N-Boc-piperidin-4-ol (13.32 g) were
dissolved in DCM (120 mL) and treated with AgOTf (3.55 g) under
N.sub.2 at rt for 0.1 8 h. The solid in the reaction mixture was
removed by filtration and washed with DCM (2.times.20 mL). The
filtrate was washed with saturated NaHCO.sub.3 solution and brine,
dried over MgSO.sub.4, filtered and concentrated. The crude product
was purified by flash chromatography (silica gel, EtOAc/Hexane=1:2)
to give 4.339 g (82%) of the title compound as white solid.
.sup.1H-NMR (200 MHz, CDCl.sub.3): .delta. 1.45 (s, 9H), 1.50-1.65
(m, 2H), 1.70-1.98 (m, 11H), 3.30-3.50 (m, 2H), 3.70-3.90 (m, 3H),
4.95 (s, 2H), 6.70 (s, 1H), 7.46-7.49 (m, 3H), 8.49-8.53 (m,
2H).
[0679]
4-Chloro-2-phenyl-6-(piperidin-4-yloxymethyl)-7H-pyrrolo[2,3-d]pyri-
midine (11): Following the procedure to synthesize 14, 11 was
prepared in 29% yield.
[0680]
4-[2-Acetylaminoethylamino)-2-phenyl-7H-pyrrolo[2,3-d]pyrimidin-6-y-
lmethoxy]piperidine-1-carboxylic acid tert-butyl ester (12): Aryl
chloride 10 (1.3 g), DMSO (20 mL), N-acetylethylenediamine (3.0 g)
and NaHCO.sub.3 (2 g) were stirred and heated to 90.degree. C.
under nitrogen overnight. The reaction mixture is then cooled to
room temperature and diluted with water (60 ml). The resulted
slurry is extracted with EtOAc three times. The combined organic
layers was washed with saturated NaHCO.sub.3 solution and brine,
dried over MgSO.sub.4, filtered and concentrated to give 1.46 g
(97%) of a brown solid. .sup.1H-NMR (200 MHz, CDCl.sub.3): .delta.
1.44 (s, 9H), 1.50-1.64 (m, 2H), 1.80 (s, 2H), 1.82-1.92 (m, 2H),
2.84-3.08 (m, 3H), 3.18-3.42 (m, 4H), 3.45-3.70 (m, 4H), 3.78-3.95
(m, 3H), 4.46 (s, 2H), 5.76 (t, 1H, J=5.6 Hz), 6.25 (s, 2H), 7.19
(t, 1H, J-=6.2), 7.38-7.56 (m, 3H), 8.43-8.46 (m, 2H), 10.19 (brs,
11H); MS (ES): 509.0 [MH.sup.+].
[0681]
6-([-Bezenesulfonylpiperidin-4-yloxymethyl).sub.4-chloro-2-phenyl-7-
H-pyrrolo[2,3-d]pyrimidine (13.1): Following the procedure to
synthesize 15.3, 13.1 was prepared in 95% yield. .sup.1H-NMR (200
MHz, CDCl.sub.3): .delta. 1.50-1.70 (m, 2H), 1.70-1.90 (m, 2H),
2.75-2.90 (m, 2H), 3.03-3.36 (m, 3H), 4.45 (s, 2H), 6.40 (s, 1H),
7.30-7.70 (m, 6H), 7.71-7.77 (m, 2H), 8.01-8.06 (m, 2H), 10.08
(brs, 1H).
[0682]
6-(1-Benzylsulfonylpiperidin-4-yloxymethyl)-4-chloro-2-phenyl-7H-py-
rrolo[2,3-d]pyrimidine (13.2): Following the procedure to
synthesize 15.3, 13.2 was prepared in 83% yield. .sup.1H-NMR (200
MHz, CDCl.sub.3) .delta. 1.50-1.70 (m, 2H), 1.70-1.90 (m, 2H),
2.90-3.00 (m, 2H), 3.15-3.30 (m, 2H), 3.30-3.45 (m, 1H), 4.19 (s,
2H), 4.52 (s, 2H), 6.45 (s, 1H), 7.30-7.45 (m, 5H), 7.45-7.53 (m,
3H), 8.01-8.06 (m, 2H), 10.08 (brs, 1H).
[0683]
N-{2-[2-Phenyl-6-(piperidin-4-yloxymethyl]-7H-pyrrolo[2,3-d]pyrimid-
in-4-ylamino}ethyl)acetamide trifluoroacetic acid salt (14):
Compound 12 (0.23 g) was stirred in 5% TFA/DCM (4 mL). A white foam
(0.19 g) was obtained after drying in vacuo in quantitative yield.
.sup.1H-NMR (200 MHz, CDCl.sub.3): .delta. 1.63 (s, 3H), 1.66-2.00
(m, 2H), 2.78-3.00 (m, 2H), 3.00-3.20 (m, 2H), 3.30-3.48 (m, 2H),
3.50-3.60 (m, 1H), 3.63-3.75 (m, 2H), 4.13 (s, 2H), 6.30 (s, 1H),
7.20-7.40 (m, 3H), 8.13-8.17 (m, 2H); MS (ES): 408.8
[MH.sup.+].
[0684]
N-(2-{6-[1-(Benzenesulfonyl)piperidin4-yloxymethyl]-2-phenyl-7H-pyr-
rolo[2,3-d]pyrimidin-4-ylamino}ethyl)acetamide (15.1): Following
the general procedure for C-4 chloride displacement, 15.1 was
prepared from 13.1 in 37% yield. .sup.1H-NMR (200 MHz, CDCl.sub.3):
.delta. 1.45-1.59 (m, 2H), 1.67 (s, 3H), 2.75-2.87 (m, 2H),
3.03-3.26 (m, 4H), 3.27-3.35 (m, 11H), 3.57-3.62 (m, 2H), 3.83-3.92
(m, 2H), 4.36 (s, 2H), 5.74 (t, 1H, J=5.6 Hz), 6.22 (s, 1H), 6.96
(t, 1H, J=5.6 Hz), 7.40-7.54 (m, 3H), 7.55-7.62 (m, 3H), 7.68-7.72
(m, 2H), 8.37-8.45 (m, 2H), 10.09 (brs, 1H); MS (ES): 546.8
[MH.sup.+].
[0685]
N-(2-{6-[1-(Benzylsulfonyl)piperidin-4-yloxymethyl]-2-phenyl-7H-pyr-
rolo[2,3-d]pyrimidin-4-ylamino}ethyl)acetamide (15.2): Following
the general procedure for C-4 chloride displacement, 15.2 was
prepared from 13.2 in 68% yield. .sup.1H-NMR (200 MHz, CDCl.sub.3):
.delta. 1.41-1.51 (m, 2H), 1.57-1.67 (m, 2H), 1.84 (s, 3H),
2.17-2.95 (m, 2H), 3.11-3.23 (m, 2H), 3.27-3.32 (m, 1H), 3.59-3.64
(m, 2H), 3.85 (m, 2H), 4.14 (s, 2H), 4.41 (s, 2H), 6.18 (brs, 1H),
6.28 (s, 1H), 6.92 (t, 1H, J=5.0 Hz), 7.30-7.40 (m, 5H), 7.40-7.58
(m, 3H), 8.40-8.45 (m, 2H), 10.55 (brs, 1H); MS (ES): 562.7
[MH.sup.+].
[0686] N-(2-{6-11-(4-Cyanobenzenesulfonyl)piperidin4-yloxymethyll
-2-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino}ethyl)acetamide
(15.3): Amine 14 (62 mg) and NEt.sub.3 (00.1 mL) were stirred in
THF (6 mL) and DCM (6 mL) and cooled to 5.degree. C.
4-Cyanophenylsulfonyl chloride (30 mg) was added dropwise by
syringe, and stirring was continued at rt for 2 h, then the
reaction mixture was concentrated. The residue was redissolved in
DCM and washed with saturated NaHCO.sub.3, brine, and dried over
MgSO.sub.4. After removal of solvent, the crude product was
purified by preparative TLC (silica gel, DCM/MeOH=12/1) to give 16
mg (36%) of 15.3 as an off-white foam. .sup.1H-NMR (200 MHz,
CDCl.sub.3): .delta. 1.50-1.67 (m, 2H), 1.80 (s, 3H), 2.94-3.20 (m,
4H), 3.32-3.46 (m, 1H), 3.50-3.70 (m, 2H), 3.80-3.95 (m, 2H), 4.47
(s, 2H), 5.72 (brs, 1H), 6.22 (s, 1H), 6.81 (brs, 1H), 7.20-7.38
(m, 3H), 7.75-7.90 (m, 4H), 8.37-8.40 (m, 2H), 9.37 (brs, 1H); MS
(ES): 574.1 [MH.sup.+].
EXAMPLE 7
N-Alkylpiperidine Derivatives
[0687] N-Alkylpiperidine derivatives 17.1-17.19 were prepared by
alkylation of 11 and by reductive amination of 14 using
NaBH(OAc).sub.3 as reducing agent (scheme 7). 83
[0688] General Procedure for the Alkylation 11.fwdarw.16:
[0689] Compund 11 (49 mg), the alkyl bromide, and potassium
carbonate (100 mg) were stirred in anhydrous DMF under N.sub.2 at
rt for 3 h. The DMF was then removed in vacuo. The residue was
partitioned between DCM and water. The aqueous layer was separated
and extracted with DCM twice. The combined DCM layers were washed
with an aqueous saturated sodium bicarbonate solution and brine,
and dried over MgSO.sub.4. After removal of solvent, the crude
product was purified by TLC (silica gel, 100% EtOAc). The following
compounds were prepared in this manner:
[0690]
4-Chloro-2-phenyl-6-(1-benzylpiperidin-4-yloxymethyl)-7H-pyrrolo[2,-
3-d]pyrimidine (16.1): 57% yield.
[0691]
4-Chloro-2-phenyl-6-(1-phenethylpiperidin-4-yloxymethyl)-7H-pyrrolo-
[2,3-d]pyrimidine (16.2): 31% yield.
[0692]
4-Chloro-2-phenyl-6-11-(3-phenylpropyl]piperidin-4-yloxymethyl]-7H--
pyrrolo[2,3-d]pyrimidine (16.3): 55% yield.
[0693]
4-Chloro-2-phenyl-6-[1-(4-bromobenzyl)piperidin-4-yloxymethyl]-7H-p-
yrrolo[2,3-d]pyrimidine (16.4): 95% yield.
[0694]
N-{2-[6-(1-Benzylpiperidin-4-yloxymethyl)-2-phenyl-7H-pyrrolo[2,3-d-
]pyrimidin-4-ylamino]ethyl}acetamide (17.1): Following the general
procedure for C-4 chloride displacement, 17.1 was prepared from
16.1 in 5% yield. .sup.1H-NMR (200 MHz, CDCl.sub.3): .delta.
1.52-1.65 (m, 2H), 1.74-1.92 (m, 5H), 2.15-2.25 (m, 2H), 2.62-2.78
(m, 2H), 3.20-3.30 (m, 1H), 3.45 (s, 2H), 3.56-3.68 (m, 2H),
3.82-3.95 (m, 2H), 4.20 (s, 2H), 5.67 (t, 1H, J=5.4 Hz), 6.25 (s,
1H), 7.09 (brs, 1H), 7.20-7.38 (m, 5H), 7.42-7.48 (m, 3H),
8.38-8.43 (m, 2H), 9.34 (brs, 1H); MS (ES): 499.2 (M.sup.++1).
[0695]
N-{2-[6-(1-Phenethylpiperidin4-yloxymethyl)-2-phenyl-7H-pyrrolo[2,3-
-d]pyrimidin-4-ylamino]ethyl}acetamide (17.2): Following the
general procedure for C-4 chloride displacement, 17.2 was prepared
from 16.2 in 23% yield. .sup.1H-NMR (200 MHz, CDCl.sub.3): .delta.
1.41-1.58 (m, 2H), 1.57-1.67 (m, 2H), 1.77 (s, 3H), 1.80-2.00 (m,
2H), 2.16-2.26 (m, 2H), 2.53-2.61 (m, 2H), 2.76-2.84 (m, 4H),
3.34-3.42 (m, 1H), 3.57-3.63 (m, 2H), 3.86-3.94 (m, 2H), 4.60 (s,
2H), 5.57 (t, 1H, J=5.8 Hz), 6.25 (s, 11H), 7.06 (brs, 1H),
7.20-7.38 (m, 5H), 7.40-7.58 (m, 3H), 8.40-8.44 (m, 2H), 9.15 (brs,
1H); MS (ES): 513.0 (M.sup.++1).
[0696]
N-[2-{6-11-(3-Phenylpropyl)piperidin4-yloxymethyl]-2-phenyl-7H-pyrr-
olo[2,3-d]pyrimidin-4-ylamino}ethyl]acetamide (17.3): Following the
general procedure for C-4 chloride displacement, 17.3 was prepared
from 16.2 in 18% yield.
[0697] .sup.1H-NMR (200 MHz, CDCl.sub.3): .delta. 1.57-1.67 (m,
2H), 1.77 (s, 3H), 1.80-1.98 (m, 4H), 2.00-2.18 (m, 2H), 2.34 (t,
2H, J=7.6 Hz), 2.62 (t, 2H, J=8.4 Hz), 2.68-2.84 (m, 2H), 3.34-3.46
(m, 11H), 3.57-3.64 (m, 2H), 3.86-3.94 (m, 2H), 4.61 (s, 2H), 5.53
(t, 1H, J=5.4 Hz), 6.24 (s, 1H), 7.07 (brs, 1H), 7.20-7.38 (m, 5H),
7.40-7.58 (m, 3H), 8.40-8.44 (m, 2H), 8.97 (brs, 1H); MS (ES):
527.2 (M.sup.++1).
[0698]
N-(2-{6-[1-(4-Bromobenzyl)piperidin-4-yloxymethyl]-2-phenyl-7H-pyrr-
olo[2,3-d]pyrimidin-4-ylamino}ethyl)acetamide (17.4): Following the
general procedure for C-4 chloride displacement, 17.4 was prepared
from 16.4 in 32% yield. .sup.1H-NMR (200 MHz, CDCl.sub.3): .delta.
1.50-1.65 (m, 2H), 1.76-1.96 (m, 5H), 2.05-2.20 (m, 2H), 2.60-2.75
(m, 2H), 3.25-3.35 (m, 1H), 3.43 (s, 2H), 3.54-3.62 (m, 2H),
3.85-3.93 (m, 2H), 4.50 (s, 2H), 5.67 (t, 1H, J=5.4 Hz), 6.25 (s,
1H), 7.09 (brs, 1H), 7.21 (d, 2H, J=8.4 Hz), 7.40-7.51 (m, 5H),
8.39-8.44 (m, 2H), 9.70 (brs, 1H); MS (ES): 576.9 (M.sup.++1).
[0699]
2-[6-(1-Benzylpiperidin4-yloxymethyl)-2-phenyl-7H-pyrrolo[2,3-d]pyr-
imidin-4-ylamino]acetamide (17.5): Following the general procedure
for C-4 chloride displacement using glycinamide as amine, 17.5 was
prepared from 16.1 in 43% yield.
[0700] .sup.1H-NMR (200 MHz, CDCl.sub.3): .delta. 1.60-1.78 (m,
2H), 1.80-1.95 (m, 2H), 2.08-2.16 (m, 2H), 2.60-2.75 (m, 2H),
3.28-3.39 (m, 1H), 3.47 (s, 2H),4.38 (d, 2H, J=5.4 Hz), 4.57 (s,
2H), 5.50-5.70 (m, 2H), 6.25 (s, 1H), 6.47 (brs, 1H), 7.20-7.40 (m,
5H), 7.42-7.48 (m, 3H), 8.38-8.43 (m, 2H), 9.34 (brs, 1H).
[0701]
N-(2-{2-Phenyl-6-[-(3-phenylallyl)piperidin4-yloxymethyl]-7H-pyrrol-
o[2,3-d]pyrimidin-4-ylamino}ethyl]acetamide (17.6): Following the
procedure for the alkylation 11.fwdarw.16, 17.6 was prepared from
14 in 4% yield. .sup.1H-NMR (200 MHz, CDCl.sub.3) .delta. 1.57-1.76
(m, 2H), 1.78 (s, 3H), 1.82-2.00 (m, 2H), 2.74-2.92 (m, 2H),
3.20-3.38 (m, 2H), 3.40-3.50 (m, 1H), 3.52-3.64 (m, 2H), 3.82-3.94
(m, 2H), 4.56 (s, 2H), 5.29 (s, 2H), 5.69 (brs, 1H), 6.16-6.34 (m,
2H), 6.59 (d, 11H, J=15.4 Hz), 7.01 (brs, 1H), 7.30-7.40 (m, 5H),
7.40-7.50 (m, 3H), 8.39-8.44 (m, 2H), 9.40 (brs, 11H); MS (ES):
525.2 [MH.sup.+].
[0702]
N-[2-(6-{1-[2-(2-Chlorophenyl)ethyl]piperidin-4-yloxymethyl}-2-phen-
yl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)ethyl]acetamide (17.7):
Following the general procedure for C-4 chloride displacement, 17.7
was prepared in 70% yield. .sup.1H-NMR (200 MHz, CDCl.sub.3)
.delta. 1.48-1.67 (m, 2H), 1.70-1.90 (m, 5H), 2.23 (t, 2H, J=9.2
Hz), 2.50-2.61 (m, 2H), 2.78-2.94 (m, 4H), 3.18-3.26 (m, 1H),
3.54-3.60 (m, 2H), 3.83-3.91 (m, 2H), 4.44 (s, 2H), 5.73 (t, 1H,
J=6.0 Hz), 6.26 (s, 1H), 7.11-7.34 (m, 5H), 7.42-7.51 (m, 3H),
8.40-8.45 (m, 2H), 10.30 (brs, 1H); MS (ES): 546.8 (M.sup.++1).
[0703]
N-[2-(-6-{1-[2-(2-Chlorophenyl)ethyl]piperidine-4-yloxymethyl}-2-ph-
enyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)ethyl]acetamide
methanesulfonic acid salt (17.7.MsOH): 17.7 (315 mg) was dissolved
in methanol (5 mL) and cooled to 5.degree. C. Methanesulfonic acid
(57 mg) in methanol (5 mL) was added. The resulted solution was
then diluted with isopropyl ether (20 mL) and set in freezer
overnight. A white solid (82 mg) was obtained after filtration. The
mother liquid was concentrated in vacuo (bath temperature
10.degree. C.) to give a slightly brownish oil. The resulting oil
was stirred in anhydrous isopropyl ether for 1 h to give 246 mg of
a slightly brownish solid. The two batches of product were combined
and stirred in anhydrous ethyl ether to give 324 mg (88% yield) of
a slightly brownish solid, mp. 153-156.degree. C. .sup.1H-NMR (200
MHz, CD.sub.3OD) .delta. 1.80-2.18 (m, 5H), 2.20-2.40 (m, 2H),
2.65-2.90 (m, 5H), 3.20-3.60 (m 10H), 3.70-3.85 (m, 1H), 4.75 (s,
2H), 6.80 (brs, 1H), 7.25-7.40 (m, 2H), 7.40-7.51 (m, 2H),
7.60-7.80 (m, 3H), 8.16-8.35 (m, 2H); t.sub.R (method A)=11.15 min;
MS (ES): 546.9 [MH.sup.+].
[0704] General Procedure for Reductive Amination of 14:
[0705] Piperidine 14 (60 mg, 0.1 5 mmol), aldehyde (45 mg, 0.29
mmol), and NaBH(OAc).sub.3 (67 mg, 0.32 mmol) are stirred in MeOH
(6 mL) at rt overnight. The reaction mixture is filtered, and the
filtrate is directly charged onto a TLC plate and developed with
DCM/MeOH=4/1.
[0706] The amines 17.8-17.18 were prepared according to this
procedure.
[0707]
N-[2-(6-{1-[2-(3-Chlorophenyl)ethyl]piperidin-4-yloxymethyl}-2-phen-
yl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)ethyl)acetaniide (17.8):
10% yield. .sup.1H-NMR (200 MHz, CDCl.sub.3): .delta. 1.50-1.72 (m,
2H), 1.80 (s, 3H), 1.82-1.96 (m, 2H), 2.26-2.42 (m, 2H), 2.55-2.68
(m, 2H), 2.70-2.86 (m, 4H), 3.22-3.40 (m, 1H), 3.55-3.65 (m, 2H),
3.83-3.91 (m, 2H), 4.49 (s, 2H), 5.75 (t, 11H, J=6.0 Hz), 6.26 (s,
1H), 7.00-7.15 (m, 2H), 7.15-7.25 (m, 3H), 7.40-7.55 (m, 3H),
8.40-8.44 (m, 2H), 9.98 (brs, 1H); MS (ES): 546.80 (M.sup.++1).
[0708]
N-(2-{6-[1-(3-Chlorobenzyl)piperidin-4-yloxymethyl]-2-phenyl-7H-pyr-
rolo[2,3-d]pyrimidin-4-ylamino}ethyl)acetamide (17.9): 33% yield.
.sup.1H-NMR (200 MHz, CDCl.sub.3): .delta. 1.50-1.65 (m, 2H), 1.76
(s, 3H), 2.00-2.20 (m, 2H), 2.60-2.69 (m, 2H), 3.28-3.35 (m, 1H),
3.42 (s, 2H), 3.49-3.58 (m, 2H), 3.85-3.93 (m, 2H), 4.54 (s, 2H),
5.59 (t, 1H, J=5.8 Hz), 6.23 (s, 1H), 7.08 (t, 1H, J=5.8 Hz),
7.16-7.25 (m, 3H), 7.30 (s, 1H), 7.40-7.51 (m, 5H), 8.38-8.43 (m,
2H), 9.39 (brs, 1H); MS (ES): 532.8 (M.sup.++1).
[0709]
N-[2-(6-{1-[2-(4-Chlorophenyl)ethyl]piperidin-4-yloxymethyl}-2-phen-
yl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)ethyl]acetamide (17.10):
10% yield. .sup.1H-NMR (200 MHz, CDCl.sub.3) .delta. 1.50-1.72 (m,
2H), 1.78 (s, 3H), 1.82-1.96 (m, 2H), 2.16-2.30 (2H), 2.16-2.30 (m,
2H), 2.48-2.60 (m, 2H), 2.71-2.86 (m, 4H), 3.22-3.40 (m, 1H),
3.55-3.65 (m, 2H), 3.86-3.91 (m, 2H), 4.60 (s, 2H), 5.58 (t, 1H,
J=5.0 Hz), 6.24 (s, 1H), 7.03 (t, 1H, J=5.0 Hz), 7.13 (d, 2H, J=8.4
Hz), 7.26 (d, 2H, J=8.4 Hz), 7.43-7.51 (m, 3H), 8.38-8.43 (m, 2H),
9.11 (brs, 1H); MS (ES): 546.8 (M.sup.++1).
[0710]
N-[2-(6-{1-[2-(2-Methoxyphenyl)ethyl]piperidin-4-yloxymethyl}-2-phe-
nyl-7H-pyrrolo[[2,3-d]pyrimidin-4-ylamino)ethyl]acetamide (17.11):
18% yield. .sup.1H-NMR (200 MHz, CDCl.sub.3) .delta. 1.50-1.70 (m,
2H), 1.79 (s, 3H), 1.80-1.96 (m, 2H), 2.40-2.62 (m, 2H), 2.65-2.75
(m, 2H), 2.76-2.86 (m, 4H), 3.27-3.34 (m, 1H), 3.55-3.61 (m, 2H),
3.76-3.83 (m, 5H), 4.22 (s, 2H), 5.82 (t, 1H, J=6.0 Hz), 6.27 (s,
1H), 6.80-6.92 (m, 2H), 7.10-7.20 (m, 3H), 7.43-7.51 (m, 3H),
8.41-8.45 (m, 2H), 10.25 (brs, 1H); MS (ES): 542.9 (M.sup.++1).
[0711]
N-[2-(6-{1-[2-(3-Methoxyphenyl)ethyl]piperidin4-yloxymethyl}-2-phen-
yl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)ethyl]acetamide (17.12): 7%
yield. .sup.1H-NMR (200 MHz, CDCl.sub.3) .delta. 1.50-1.80 (m, 2H),
1.81 (s, 3H), 1.90-2.10 (m, 4H), 2.65-2.75 (m, 2H), 2.76-2.96 (m,
4H), 3.27-3.50 (m, 1H), 3.55-3.63 (m, 2H), 3.79 (s, 3H), 3.80-3.93
(m, 2H), 4.51 (s, 2H), 5.78 (brs, 1H), 6.27 (s, 1H), 6.74-6.79 (m,
3H), 6.98 (brs, 1H), 7.17-7.20 (m, 1H), 7.45-7.48 (m, 3H),
8.40-8.45 (m, 2H), 10.00 (brs, 1H); MS (ES): 542.9 (M.sup.++1).
[0712]
N-[2-(6-{1-[2-(4-Methoxyphenyl)ethyl]piperidin-4-yloxymethyl}-2-phe-
nyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)ethyl]acetamide (17.13):
6% yield. .sup.1H-NMR (200 MHz, CDCl.sub.3) .delta. 1.54-1.72 (m,
2H), 1.82 (s, 3H), 1.83-1.96 (m, 2H), 2.71-2.86 (m, 8H), 3.22-3.40
(m, 1H), 3.50-3.65 (m, 2H), 3.76 (s, 3H), 3.80-3.91 (m, 2H), 4.35
(s, 2H), 6.11 (t, 1H, J=5.0 Hz), 6.31 (s, 1H), 6.83 (d, 2H, J=8.4
Hz), 7.14 (t, 1H, J=5.0 Hz), 7.26 (d, 2H, J=8.4 Hz), 7.43-7.46 (m,
3H), 8.40-8.43 (m, 2H), 10.90 (brs, 1H); MS (ES): 543.0
(M.sup.++1).
[0713]
N-[2-(6-{1-[2-(4-Fluorophenyl)ethyl]piperidin-4-yloxymethyl}-2-phen-
yl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)ethyl]acetamide (17.14):
14% yield. .sup.1H-NMR (200 MHz, CDCl.sub.3) .delta. 1.58-1.78 (m,
2H), 1.80 (s, 3H), 1.82-2.10 (m, 2H), 2.44-2.60 (m, 2H), 2.60-2.80
(m, 2H), 2.80-2.92 (m, 4H), 3.38-3.48 (m, 1H), 3.50-3.65 (m, 2H),
3.82-3.94 (m, 2H), 4.53 (s, 2H), 5.77 (t, 1H, J=5.4 Hz), 6.27 (s,
1H), 6.90-7.06 (m, 31H), 7.08-7.20 (m, 2H), 7.40-7.60 (m, 3H),
8.38-8.43 (m, 2H), 9.90 (brs, 1H); MS (ES): 530.8 (M.sup.++1).
[0714]
N-[2-(6-{1-[2-(2-Chloro-4-fluorophenyl)ethyl]piperidin-4-yloxymethy-
l}-2-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)ethyl]acetamide
(17.15): 10% yield. .sup.1H-NMR (200 MHz, CDCl.sub.3) .delta.
1.48-1.70 (m, 2H), 1.77 (s, 3H), 1.82-1.90 (m, 2H), 2.24-2.40 (m,
2H), 2.46-2.64 (m, 2H), 2.74-2.94 (m, 4H), 3.18-3.24 (m, 1H),
3.48-3.60 (m, 2H), 3.83-4.00 (m, 2H), 4.57 (s, 2H), 5.64 (t, 1H,
J=-6.0 Hz), 6.25 (s, 1H), 6.84-7.20 (m, 4H), 8.38-8.45 (m, 2H),
9.40 (brs, 11H).
[0715]
N-[2-(6-{1-[2-(2-Chloro-6-fluorophenyl)ethyl]piperidin-4-yloxymethy-
l}-2-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)ethyl]acetamide
(17.16): 13% yield. .sup.1H-NMR (200 MHz, CDCl.sub.3) .delta.
1.48-1.64 (m, 2H), 1.77 (s, 3H), 1.78-1.94 (m, 2H), 1.95-2.08 (m,
2H), 2.50-2.55 (m, 2H), 2.70-3.01 (m, 6H), 3.33-3.39 (m, 1H),
3.54-3.62 (m, 2H), 3.86-3.94 (m, 2H), 4.55 (s, 2H), 5.59 (t, 1H,
J=5.8 Hz), 6.25 (s, 1H), 6.90-7.00 (m, 1H), 7.04-7.20 (m, 3H),
7.42-7.52 (m, 3H), 8.39-8.44 (m, 2H), 9.55 (brs, 1H).
[0716]
N-[2-(6-{1-[2-(2-Trifluoromethylphenyl)ethyl]piperidin4-yloxymethyl-
}-2-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)ethyl]acetamide
(17.17): 7% yield. .sup.1H-NMR (200 MHz, CDCl.sub.3) .delta.
1.58-1.76 (m, 2H), 1.78 (s, 3H), 1.84-1.90 (m, 2H), 2.26-2.50 (m,
2H), 2.61-2.67 (m, 2H), 2.78-2.90 (m, 2H), 2.92-3.10 (m, 2H),
3.35-3.45 (m, 1H), 3.57-3.63 (m, 2H), 3.86-3.91 (m, 2H), 4.60 (s,
2H), 5.64 (t, IlH, J-5.2 Hz), 6.26 (s, 1H), 7.03 (t, 1H, J=5.2 Hz),
7.24-7.40 (m, 2H), 7.42-7.60 (m, 5H), 8.39-8.44 (m, 2H), 9.50 (brs,
1H).
[0717]
N-[2-(6-{1-[2-(2-Bromophenyl)ethyl]piperidin-4-yloxymethyl}-2-pheny-
l-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)ethyl]acetamide (17.18): MS
(ES): 590.9 (M.sup.++1).
[0718]
2-(6-{1-[2-(4-Chlorophenyl)-ethyl]piperidin-4-yloxymethyl}-2-phenyl-
-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-acetamide (17.19): Obtained
by the same route using glycinamide. MS (ES): 518.8
(M.sup.++1).
EXAMPLE 8
Open-Chain Analogs of Piperidine Derivatives 17
[0719] A series of open-chain analogs 19.1-19.5 of the piperidine
derivatives 17 was prepared from 7 in two steps (scheme 8). 84
[0720] The following amines 19.1-19.5 were prepared according to
the general procedures for silver-mediated bromide displacement and
C-4 chloride displacement:
[0721]
N-(2-(6-{2-[Methyl-(3-phenylallyl)amino]ethoxymethyl}-2-phenyl-7H-p-
yrrolo[2,3-d]pyrimidin-4-ylamino}ethyl]acetamide (19.1): 2% yield.
.sup.1H-NMR (200 MHz, CDCl.sub.3): .delta. 1.78 (s, 3H), 2.45 (s,
3H), 2.79 (t, 2H, J=4.8 Hz), 3.38-3.48 (m, 2H), 3.53-3.58 (m, 2H),
3.70 (t, 2H, J=4.8 Hz), 3.82-3.94 (m, 2H), 4.65 (s, 2H), 5.60 (brs,
1H), 6.23.(s, 1H), 6.36-6.47 (m, 1H), 6.62 (d, 1H, J=15.8 Hz),
7.20-7.32 (m, 6H), 7.38-7.50 (m, 3H), 8.39-8.44 (m, 2H), 9.60 (brs,
1H); MS (ES): 499.1 (M.sup.++1).
[0722]
N-(2-{2-Phenyl-6-[2-(3-phenylpropylamino)ethoxymethyl]-7H-pyrrolo[2-
,3-d]pyrimidin-4-ylamino}ethyl)acetamide TFA salt (19.2): 77%
yield. .sup.1H-NMR (200 MHz, CDCl.sub.3) .delta. 1.78-2.10 (m, 5H),
2.55-2.60 (m, 2H), 2.80-3.00 (m, 2H), 3.55-3.70 (m, 2H), 3.78-3.95
(m, 2H), 4.16-4.19 (m, 2H), 4.28-4.30 (m, 2H), 4.95 (s, 2H), 6.55
(s, 1H), 7.10-7.25 (m, 5H), 7.45-7.60 (m, 3H), 7.85 (brs, 3H),
8.21-8.25 (m, 2H), 10.13 (brs, 1H).
[0723]
N-(2-{6-13-(4-Methoxyphenyl)propoxymethyl]-2phenyl-7H-pyrrolo[2,3-d-
]pyrimidin-4-ylamino}ethyl)acetamide (19.3): 40% yield. .sup.1H-NMR
(200 MHz, CDCl.sub.3) .delta. 1.70-1.90 (m, 5H), 2.53 (t, 2H, J=8.0
Hz), 3.30 (t, 2H, J=6.2 Hz), 3.78 (s, 3H), 3.88-3.90 (m, 2H), 4.42
(s, 2H), 5.64 (t, 1H, J=5.2 Hz), 6.22 (s, 1H), 6.80 (d, 2H, J=8.4
Hz), 6.95-7.20 (m, 3H), 7.40-7.51 (m, 3H), 8.40-8.45 (m, 2H), 10.00
(brs, 1H). MS (ES): 474.0 (M.sup.++1).
[0724]
N-{2-[6-(3-Hydroxy-3-phenylpropoxymethyl)-2phenyl-7H-pyrrolo[2,3-d]-
pyrimidin-4-ylamino}ethyl)acetamide (19.4): 31% yield. .sup.1H-NMR
(200 MHz, CDCl.sub.3) .delta. 2.61 (s, 3H), 3.05-3.18 (m, 2H),
3.30-3.39 (m, 2H), 3.60-3.70 (m, 2H), 3.87-3.95 (m, 2H), 5.29 (brs,
1H), 5.95 (brs, 1H), 6.05 (brs, 2H), 7.17 (s, 1H), 7.40-7.60 (m,
8H), 7.83-7.88 (m, 1H), 8.41-8.46 (m, 2H), 9.30 (brs, 11H). MS
(ES): 460.0 (M.sup.++1).
[0725]
N-[2-(6-Cyclopentyloxymethyl-2-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4--
ylamino)-ethyl]-acetamide (19.5): .sup.1H NMR (200 MHz,
CDCl.sub.3): .delta. 1.40-1.70 (m, 8H), 1.76 (s, 3H), 3.58 (m, 2H),
3.87 (m, 3H), 4.44 (s, 2H), 5.65 (brt, 1H), 6.24 (s, 1H), 7.20
(brs, 1H), 7.44 5 (m, 3H), 8.41 (m, 2H); MS (ES): 393.9
[MH.sup.+].
2TABLE 2 A.sub.2B antagonists 15, 17, and 19. Comp. # Structure MW
15.1 85 548.67 15.2 86 562.70 15.3 87 573.68 17.1 88 498.63 17.2 89
512.66 17.3 90 526.69 17.4 91 577.53 17.5 92 470.58 17.6 93 524.67
17.7 94 547.11 17.8 95 547.11 17.9 96 533.08 17.10 97 547.11 17.11
98 542.69 17.12 99 542.69 17.13 100 542.69 17.14 101 530.65 17.15
102 565.10 17.16 103 565.10 17.17 104 580.66 17.18 105 591.56 17.19
106 519.05 19.1 107 498.63 19.2 108 486.62 19.3 109 473.58 19.4 110
459.55 19.5 111 393.49
EXAMPLE 9
C-6 Oxime Ethers
[0726] Oxime ethers 22 were prepared from the bromide 7 via Komblum
oxidation to the aldehyde 20, followed by oxime ether formation and
C-4 chloride displacement (scheme 9). 112
[0727]
4-Chloro-6-formyl-2-phenylpyrrolo[2,3-d]pyrimidine-7-carboxylic
acid tert-butyl ester (20): A suspension of the bromide 7 (2.00 g,
4.73 mmol), Na.sub.2HPO.sub.4 (806 mg, 5.68 mmol) and
NaH.sub.2PO.sub.4 (227 mg, 1.89 mmol) in DMSO (50 mL) is heated
under nitrogen to 48.degree. C. After 1 h, all solids are
dissolved, and the reaction is continued for 2 h. The solution is
then poured in H.sub.2O (600 mL), and the mixture is extracted with
EtOAc (2.times.150 mL). The combined EtOAc layers are washed with
H.sub.2O (3.times.400 mL) and brine and dried over MgSO.sub.4.
Filtration and concentration yields a yellow solid, which is
triturated with EtOH giving 1.06 g (2.97 mmol, 63%) of the title
compound as a yellow solid. MS (ES): m/z 304.7/306.7 (33/10)
[MH.sup.+-Boc-H.sub.2O+2 MeOH], 272.7/274.7 (100/32)
[MH.sup.+-Boc-H.sub.2O+MeOH]. .sup.1H NMR (200 MHz, CDCl.sub.3):
.delta.=1.79 (s, 9H), 7.44 (s, 1H), 7.48-7.55 (m, 3H), 8.51-8.60
(m, 2H), 10.39 (s, 1H). t.sub.R (method A)=10.4 min.
[0728]
6-(Benzyloxyiminomethyl)-4-chloro-2-phenylpyrrolo[2,3-d]pyrimidine--
7-carboxylic acid tert-butyl ester (21.1): A solution of the
aldehyde 20 (50 mg, 0.14 mmol), O-benzylhydroxylamine hydrochloride
(26 mg, 0.16 mmol), and pyridine (12 mg, 0.15 mmol) in
CH.sub.2Cl.sub.2 (2 mL) is stirred at ambient temp. for 5 h, then
sat. NH.sub.4Cl solution is added, and the mixture is extracted
with EtOAc (3.times.5 mL). The combined extracts are washed with
brine and dried over MgSO.sub.4. Crystallization of the crude solid
from hexanes gives 31 mg (0.067 mmol, 48%) of the title compound as
colorless solid, single oxime isomer. MS (ES): m/z 463.0/465.0
(90/48) [MH.sup.+, 363.1/365.2 (100/32) [MH.sup.+-Boc].
[0729]
6-(tert-Butoxyiminomethyl)-4-chloro-2-phenylpyrrolo[2,3-d]pyrimidin-
e-7-carboxylic acid tert-butyl ester (21.2): Following the
procedure for the corresponding benzyl-oxyiminomethyl compound, the
title compound was obtained in 58% yield as pale yellow solid.
.sup.1H NMR (200 MHz, CDCl.sub.3): (E) isomer (85%): .delta.=1.39
(s, 9H), 1.77 (s, 9H), 7.06 (s, 1H), 7.45-7.52 (m, 3H), 8.48-8.56
(m, 2H), 8.61 (s, 1H); (Z) isomer (15%): .delta.=1.45 (s, 9H), 1.78
(s, 9H), 7.05 (s, 1H), 7.45-7.52 (m, 3H), 8.48-8.56 (m, 2H), 8.62
(s, 1H).
[0730]
N-{2-[6-(Benzyloxyiminomethyl)-2-phenyl-7H-pyrrolo[2,3-d]pyrimidin--
4-ylamino]-ethyl}-acetamide (22.1): Following the general procedure
for C-4 chloride displacements, the title compound was obtained
after purification by prep. TLC as yellow foam in 69% yield, single
oxime isomer, mp. 83-87.degree. C. (decomp.). MS (ES): m/z 429.1
(100) [MH.sup.+]. .sup.1H NMR (200 MHz, CDCl.sub.3): .delta.=1.82
(s, 3H), 3.53-3.65 (m, 2H), 3.84-3.96 (m, 2H), 5.18 (s, 2H), 5.94
(brs, 1H), 6.51 (s, 1H), 6.84 (brs, 1H), 7.31-7.52 (m, 8H), 8.05
(s, 1H), 8.37-8.45 (m, 2H), 9.16 (brs, 1H). t.sub.R (method A)=8.7
min.
[0731]
N-{2-[6-(tert-Butoxyiminomethyl)-2-phenyl-7H-pyrrolo[2,3-d]pyrimidi-
n-4-ylamino]-ethyl}-acetamide (22.2): Following the general
procedure for C-4 chloride displacements, the title compound was
obtained after purification by prep. TLC as colorless oil in 56%
yield. MS (ES): m/z 395.2 (100) [MH.sup.+]. t.sub.R (method A)=8.5
min.
3TABLE 3 16/25 A.sub.2B antagonists 22. Comp. # Structure MW 22.1
113 428.50 22.2 114 394.48
EXAMPLE 10
C-6 Amides
[0732] The key intermediate for pyrrolo[2,3-d]pyrimidines 26 with
an amide moiety at C-6 is the N-benzenesulfonyl-protected
pyrrolopyrimidine 24. The amide moiety can be introduced directly
by metalation and quench with carbamoyl chlorides or isocyanates,
followed by displacement of the chloride at C-4 with amines and
concomitant removal of the benzenesulfonyl group (scheme 10).
115
[0733] Alternatively, the anion of 24 is reacted with carbon
dioxide to give the lithium salt 27, which is used as such because
the free acid decarboxylates readily. Chloride displacement at C-4
with amines followed by removal of the sulfonyl group and amide
coupling using PyBOP, TBTU, or EDC yields the A.sub.2B antagonists
26. The amide formation could be accomplished very conveniently by
reacting the hydroxysuccinimide ester 32 (prepared from the acid 30
using EDC and HOBt for the coupling) with the amines. The order of
the last two steps (i.e., pyrrole deprotection and amide formation)
can be reversed (scheme 11a). Selected amides were converted to
their methanesulfonic acid salts. 116 117 118
[0734] Several amides 26 were derivatized further (scheme 12).
Boc-protected 26.66 was deprotected to 26.65 and reacted with
sulfonyl chlorides to give 26.67-26.68. The acetylene 26.83
underwent Sonogashira coupling with aryl iodides to yield
26.89-26.91. The acid 26.85 was coupled with a series of primary
and secondary amines using TBTU in DMF to yield amides
26.97-26.107. The ketal 26.87 was deprotected and reacted with a
series of primary and secondary amines using polymer-supported
cyanoborohydride as reducing agent in 45-95% yield. 119120
4TABLE 4 A.sub.2B antagonists 26.1-26.250. Comp. # Structure MW
26.1 121 408.46 26.2 122 506.57 26.3 123 523.64 26.4 124 464.57
26.5 125 525.66 26.6 126 533.03 26.7 127 498.59 26.8 128 512.62
26.9 129 504.98 26.10 130 566.59 26.11 131 511.63 26.12 132 534.67
26.13 133 515.02 26.14 134 497.60 26.15 135 497.60 26.16 136 562.08
26.17 137 432.53 26.18 138 516.58 26.19 139 507.60 26.20 140 506.57
26.21 141 521.63 26.22 142 435.53 26.23 143 439.57 26.24 144 553.71
26.25 145 558.69 26.26 146 558.69 26.27 147 512.62 26.28 148 514.61
26.29 149 530.61 26.30 150 553.71 26.31 151 435.53 26.32 152 525.66
26.33 153 539.69 26.34 154 756.87 26.35 155 484.57 26.36 156 496.62
26.37 157 552.56 26.38 158 501.57 26.39 159 552.56 26.40 160 553.46
26.41 161 623.16 26.42 162 547.06 26.43 163 533.03 26.44 164 727.70
26.45 165 519.01 26.46 166 595.11 26.47 167 609.13 26.48 168 530.61
26.49 169 565.68 26.50 170 489.97 26.51 171 826.37 26.52 172 797.33
26.53 173 522.66 26.54 174 496.62 26.55 175 511.63 26.56 176 539.69
26.57 177 524.67 26.58 178 475.60 26.59 179 531.71 26.60 180 491.64
26.61 181 577.49 26.62 182 482.59 26.63 183 489.63 26.64 184 475.60
26.65 185 421.51 26.66 186 521.62 26.67 187 499.60 26.68 188 475.69
26.69 189 528.62 26.70 190 528.62 26.71 191 518.02 26.72 192 451.53
26.73 193 510.60 26.74 194 512.62 26.75 195 512.62 26.76 196 524.62
26.77 197 517.68 26.78 198 446.51 26.79 199 504.60 26.80 200 551.65
26.81 201 531.06 26.82 202 547.06 26.83 203 445.53 26.84 204 540.67
26.85 205 526.60 26.86 206 462.60 26.87 207 464.53 26.88 208 510.64
26.89 209 546.64 26.90 210 546.64 26.91 211 546.64 26.92 212 540.63
26.93 213 526.64 26.94 214 550.67 26.95 215 554.65 26.96 216 512.62
26.97 217 525.62 26.98 218 539.64 26.99 219 553.67 26.100 220
615.74 26.101 221 553.67 26.102 222 581.72 26.103 223 565.68 26.104
224 579.71 26.105 225 593.74 26.106 226 595.71 26.107 227 581.72
26.108 228 496.62 26.109 229 540.67 26.110 230 524.67 26.111 231
527.65 26.112 232 594.72 26.113 233 486.55 26.114 234 547.06 26.115
235 580.62 26.116 236 478.60 26.117 237 539.64 26.118 238 568.68
26.119 239 492.59 26.120 240 540.63 26.121 241 542.64 26.122 242
518.62 26.123 243 510.60 26.124 244 542.64 26.125 245 597.60 26.126
246 510.60 26.127 247 512.62 26.128 248 510.64 26.129 249 526.64
26.130 250 526.64 26.131 251 526.64 26.132 252 497.60 26.133 253
560.10 26.134 254 560.10 26.135 255 560.10 26.136 256 538.61 26.137
257 507.00 26.138 258 512.60 26.139 259 555.69 26.140 260 555.69
26.141 261 555.69 26.142 262 518.62 26.143 263 574.09 26.144 264
574.09 26.145 265 574.09 26.146 266 583.10 26.147 267 554.66 26.148
268 541.61 26.149 269 552.64 26.150 270 541.61 26.151 271 478.56
26.152 272 478.56 26.153 273 511.63 26.154 274 559.68 26.155 275
420.47 26.156 276 539.69 26.157 277 525.66 26.158 278 560.10 26.159
279 515.62 26.160 280 526.65 26.161 281 526.65 26.162 282 511.63
26.163 283 525.66 26.164 284 525.66 26.165 285 512.62 26.166 286
526.65 26.167 287 551.70 26.168 288 381.44 26.169 289 525.66 26.170
290 537.67 26.171 291 428.50 26.172 292 412.45 26.173 293 454.54
26.174 294 450.55 26.175 295 534.62 26.176 296 497.60 26.177 297
449.52 26.178 298 588.72 26.179 299 435.53 26.180 300 493.57 26.181
301 434.55 26.182 302 593.66 26.183 303 543.65 26.184 304 569.67
26.185 305 539.69 26.186 306 604.56 26.187 307 594.55 26.188 308
594.55 26.189 309 497.61 26.190 310 511.63 26.191 311 525.66 26.192
312 539.69 26.193 313 498.59 26.194 314 533.03 26.195 315 528.62
26.196 316 498.59 26.197 317 463.54 26.198 318 454.54 26.199 319
545.05 26.200 320 540.63 26.201 321 454.54 26.202 322 508.59 26.203
323 508.59 26.204 324 436.52 26.205 325 472.55 26.206 326 554.66
26.207 327 527.63 26.208 328 458.52 26.209 329 449.52 26.210 330
511.63 26.211 331 527.63 26.212 332 513.60 26.213 333 518.02 26.214
334 501.57 26.215 335 483.58 26.216 336 519.56 26.217 337 511.63
26.218 338 543.63 26.219 339 548.05 26.220 340 547.06 26.221 341
509.62 26.222 342 499.58 26.223 343 552.47 26.224 344 530.03 26.225
345 512.62 26.226 346 537.63 26.227 347 537.63 26.228 348 529.67
26.229 349 528.58 26.230 350 518.02 26.231 351 551.58 26.232 352
541.61 26.233 353 497.60 26.234 354 513.60 26.235 355 581.51 26.236
356 537.63 26.237 357 542.05 26.238 358 545.67 26.239 359 526.60
26.240 360 537.63 26.241 361 542.05 26.242 362 537.63 26.243 363
542.05 26.244 364 537.63 26.245 365 531.02 26.246 366 549.08 26.247
367 513.99 26.248 368 532.05 26.249 369 528.02 26.250 370
546.08
[0735]
7-Benzenesulfonyl-4-chloro-2-phenyl-7H-pyrrolo[2,3-d]pyrimidine
(24): To a suspension of sodium hydride (780 mg of a 60% oil
suspension, 19.5 mmol) in dry DMF (20 mL), cooled by an ice/water
bath, under nitrogen, is added a solution of the pyrrolopyrimidine
23 (2.00 g, 7.52 mmol) in DMF (10 mL) over 5 min. After 15 min,
benzenesulfonyl chloride (1.2 mL, 9.40 mmol) is added, then the
cooling bath is removed. After 4 h, the reaction mixture is poured
into a mixture of ice and sat. NaHCO.sub.3 sol., the precipitated
solid is filtered off and triturated with acetone (3.times.) and
methanol (2.times.), yielding 2.37 g of a beige solid. This solid
contains approx. 10 mol-% DMF (based on that 83% yield) and can be
used in the next step; a pure sample can be obtained by
chromatography on silica gel using acetone as eluent. .sup.1H-NMR
(CDCl.sub.3): .delta. 6.70 (d, J=4.2 Hz, 1H), 7.47-7.68 (m, 6H),
7.76 (d, J=4.2 Hz, 1H), 8.24-8.32 (m, 2H), 8.48-8.56 (m, 2H); IR
(solid): v=3146 cm.sup.-1, 1585, 1539, 1506, 1450, 1417, 1386,
1370, 1186, 1176, 1154, 1111, 1015, 919, 726, 683, 616, 607; MS
(ES): 372/370 (MH.sup.+); mp=226-227.degree. C.
C.sub.18H.sub.12ClN.sub.3O.sub.2S (369.83): calcd. C, 58.46; H,
3.27; N, 11.36, Cl 9.59; found C 58.17, H 3.24, N 11.36, Cl
9.48.
[0736]
7-Benzenesulfonyl-4-chloro-2-phenyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl-
)-morpholin-4-yl-methanone (25.1): To a solution of the N-sulfonyl
compound 24 (100 mg, 0.270 mmol) in dry THF (10 mL), cooled by dry
ice/acetone, is added LDA-THF (270 .mu.L, 1.5M solution in
cyclohexane, 0.405 mmol). After 60 min, morpholinecarbamoyl
chloride (47 .mu.L, 0.405 mmol) is added. After 1.5 h, the reaction
is quenched by adding sat. NH.sub.4Cl solution, the mixture is
extracted with EtOAc (3.times.15 mL), combined EtOAc layers are
washed with water and brine and dried over MgSO.sub.4.
Chromatography on silica gel yields 59 mg (0.12 mmol, 45%) of the
title compound as white solid, mp. 259-260.degree. C. MS (ES): m/z
483.0/485.0 (100) [MH.sup.+]. t.sub.R (method A)=10.8 min.
[0737]
7-Benzenesulfonyl-4-chloro-2-phenyl-7H-pyrrolo[2,3-d]pyrimidine-6-c-
arboxylic acid (4-phenoxyphenyl)-amide (25.2): Following the above
procedure, 25.2 was obtained in 37% yield as white solid, mp.
250-253.degree. C. MS (ES): m/z 581.0/583.0 (100) [MH.sup.+].
t.sub.R (method A)=12.8 min.
[0738] Lithium
7-benzenesulfonyl-4-chloro-2-phenyl-7H-pyrrolo[2,3-d]pyrimi-
dine-6-carboxylate (27): To a solution of the N-sulfonyl compound
24 (1.504 g, 4.07 mmol) in dry THF (150 mL), cooled by dry
ice/acetone, is added LDA-THF (3.8 mL, 1.5M solution in
cyclohexane, 5.7 mmol). After 45 min, carbon dioxide is bubbled
into the solution for 5 min, then the cooling bath is removed. When
the solution has reached ambient temp., the solvents are
evaporated, yielding 1.73 g of the salt 27 [containing
(iPr).sub.2NCO.sub.2Li] as pale yellow solid. The salt is used
without purification in the next step. .sup.1H-NMR (D.sub.6-DMSO):
.delta.=6.44 (s, 1H), 7.50-7.75 (m, 6H), 8.33-8.40 (m, 2H), 8.53
(dd, J=8.0, 1.6 Hz, 2H).
[0739]
4-(2-Acetylaminoethylamino)-7-benzenesulfonyl-2-phenyl-7H-pyrrolo[2-
,3-d]pyrimidine6-carboxylic acid (28a): A solution of the lithium
salt 3 (2.02 g, 4.8 mmol) and N-acetylethylenediamine (4.91 g, 48.1
mmol) in dry DMSO (20 mL) is heated under nitrogen to 80.degree. C.
for 4.5 h. DMSO and the excess amine are evaporated, 2N NaOH (30
mL) is added, and the mixture is extracted with EtOAc (4.times.30
mL). The aqueous layer is acidified to pHz.apprxeq.3-4 with aq. HCl
(first with 12N HCl until some solid has precipitated, then with 2N
HCl until pH 3-4 is reached and no more solid precipitates). The
beige solid is filtered off and dried, giving 1.59 g of 28a, which
is used without further purification in the next step. LC/MS
analysis of this material: 83% of 28a, 10% of 30a (desulfonylated
material), 6% of desacetyl-28a. .sup.1H-NMR (D.sub.6-DMSO):
.delta.=1.78 (s, 3H), 3.3 (m, 2H; hidden under water peak), 3.62
(m, 2H), 7.35 (s, 1H), 7.5-7.6 (m, 3H), 7.6-7.8 (m, 3H), 8.0-8.1
(brm, 2H, NH), 8.34 (d, J=8.6 Hz, 2H), 8.40-8.50 (m, 2H). MS (ES):
480 (MH.sup.+)
[0740]
7-Benzenesulfonyl-4-(carbamoylmethylamino)-2-phenyl-7H-pyrrolo[2,3--
d]pyrimidine6-carboxylic acid (28b): Prepared according to the
procedure for 28a. MS (ES): m/z 451.7 (100) [MH.sup.+]. t.sub.R
(method A)=7.1 min.
[0741]
4-(2-Acetylaminoethylamino)-2-phenyl-7H-pyrrolo[2;3-d]pyrimidine-6--
carboxylic acid (30a): A solution of sodium hydroxide in methanol
(65 mL, 5M, 325 mmol) is added to a solution of the
pyrrolopyrimidine 28a (6.3 g, 13.1 mmol) in methanol (35 mL). After
1.5 h, MeOH is evaporated. The residue is dissolved in 2N NaOH (200
mL) and extracted with Et.sub.2O (2.times.30 mL). The aqueous layer
is acidified to pH 3-4 with aq. HCl (first with 12N HCl until some
solid has precipitated, then with 2N HCl until pH 34 is reached and
no more solid precipitates). The beige solid is filtered off and
dried, giving 4.345 g (12.8 mmol, 98% yield) of 30a. LC/MS analysis
of this material: 95% of 30a, 3% of desacetyl-30a. This material is
used without further purification. .sup.1H-NMR (D.sub.6-DMSO):
3=1.81 (s, 3H), 3.3 (m, 2H; hidden under water peak), 3.62 (m, 2H),
7.29 (s, 1H), 7.44-7.50 (m, 3H), 8.0-8.1 (brm, 2H, NH), 8.40-8.45
(m, 2H). .sup.1H NMR (CDCl.sub.3/CD.sub.3OD, 200 MHz): o=1.82 (s,
3H), 3.53 (me, 2H), 3.87 (t, J=5.7 Hz, 2H), 7.24 (s, 1H), 7.44-7.50
(m, 3H), 8.33-8.40 (m, 2H). .sup.13C NMR (d.sub.6-DMSO, 50.3 MHz,
DEPT135): .delta.=22.66 (+), 38.45 (-), 39.53 (-), 102.22
(C.sub.quart), 106.11 (C.sub.quart), 124.94 (+), 127.65 (+, 2C),
128.09 (+, 2C), 129.53 (C.sub.quart), 138.98 (+), 152.02
(C.sub.quart), 157.15 (C.sub.quart), 159.21 (C.sub.quart), 162.14
(C.sub.quart), 169.47 (C.sub.quart). MS (ES): m/z 339.9 (100)
[MH.sup.+]. t.sub.R (method A)=5.0 min.
[0742]
4-(Carbamoylmethylamino)-2-phenyl-7H-pyrrolo[2,3-d]pyrimidine6-carb-
oxylic acid (30b): Prepared according to the procedure for 30a. MS
(ES): m/z 311.9 (100) [MH.sup.+]. t.sub.R (method A)=4.6 min.
[0743]
4-(2-Acetylaminoethylamino)-2-phenyl-7H-pyrrolo[2,3-d]pyrimidine-6--
carboxylic acid 2,5-dioxopyrrolidin-1-yl ester ("succinimide")
(32): Acid 30a (3.0 g, 8.84 mmol), EDC (5.1 g, 26.0 mmol),
hydroxybenzotriazole hydrate (1.35 g, 8.84 mmol) and
hydroxysuccinimide (3.1 g, 26 mmol) were dissolved in DMF (70 mL).
4-Dimethylamino-pyridine (216 mg, 0.2 mmol) was added and the
reaction was stirred at room temperature. After 19 h, the reaction
mixture was partitioned between EtOAc and water. The layers were
separated and the aqueous layer was re-extracted with EtOAc
(3.times.). The combined EtOAc extracted are washed with water
(2.times.) and brine, dried over MgSO.sub.4, filtered and
concentrated to yield a yellow foam. The solid was triturated
twice, once with Et.sub.2O and once with DCM, to yield 2.92 g of a
pale yellow solid (76%). An analytical sample was obtained by
chromatography on silica gel eluting with CHCl.sub.3 o 15% iPrOH in
CHCl.sub.3, mp. 230-234.degree. C. (decomp.).
C.sub.21H.sub.20N.sub.6O.sub.5 (436.4): calcd. C, 57.79; H, 4.62;
N, 19.26; found C, 58.06; H, 4.81; N, 18.99. .sup.1H NMR
(d.sub.6-DMSO, 200 MHz): .delta.=1.78 (s, 3H), 2.87 (s, 4H), 3.35
(m, 2H), 3.60 (m, 2H), 7.45 (m, 3H), 7.69 (s, 1H), 8.03 (brs, 1H),
8.25 (brs, 1H), 8.42 (m, 2H). MS (ES): 436.7 (MH.sup.+). t.sub.R
(method A)=6.6 min.
[0744] General Procedure for the synthesis of amides 26 from
succininiide 32: A solution of succinimide 32 (52 mg, 0.12 mmol),
amine 29 or its hydrochloride salt (0.14 mmol) and triethylamine
(22 .mu.L, 0.16 mmol if free amine is used, twice the amount if the
hydrochloride salt is used) in dry DMF (2 mL) is stirred at ambient
temperature for 24-48 h. The solvent is then evaporated, the
residue is partitioned between EtOAc (15 mL) and water (10 mL), and
the aqueous layer is extracted with more EtOAc (3.times.15 mL). The
combined organic layers are washed with 2N NaOH, water (2.times.)
and brine, dried over MgSO.sub.4, filtered and concentrated. The
crude material is purified by chromatography followed by
trituration or crystallization.
[0745] General Procedure for the synthesis of amides 26 from acid
30a: TBTU (48 mg, 0.15 mmol) is added to a solution of acid 30a (41
mg, 0.12 mmol) in DMF (1.5 mL), cooled by ice/water. After 30 min,
amine 29 or its hydrochloride salt (0.14 mmol) and triethylamine
(22 .mu.L, 0.16 mmol if free amine is used, twice the amount if the
hydrochloride salt is used) are added, the cooling bath is removed,
and the reaction mixture is stirred at ambient temperature until
TLC indicates complete consumption of the acid. DMF is then
evaporated, the residue is partitioned between EtOAc (15 mL) and
water (10 mL), and the aqueous layer is extracted with more EtOAc
(3.times.15 mL). The combined organic layers are washed with 2N
NaOH, water (2.times.) and brine, dried over MgSO.sub.4, filtered
and concentrated. The crude material is purified by chromatography
followed by trituration or crystallization.
[0746]
N-{2-[6-(Morpholine-4-carbonyl)-2-phenyl-7H-pyrrolo[2,3-d]pyrimidin-
-4-ylamino]-ethyl}-acetamide (26.1): Following the general
procedure for C-4 chloride displacement, 26.1 was prepared from
25.1 as an off-white solid, mp 250.degree. C. MS (ES): m/z 409.2
(100) [MH.sup.+]. .sup.1H NMR (CDCl.sub.3, 200 MHz): .delta.=1.82
(s, 3H), 3.59 (q, J=5.4 Hz, 2H), 3.72-3.80 (m, 4H), 3.83-3.92 (m,
6H), 6.08 (brs, 1H), 6.68 (s, 1H), 6.80 (brs, 1H), 7.43-7.49 (m,
3H), 8.38-8.45 (m, 2H), 9.81 (brs, 1H). t.sub.R (method A)=5.2
min.
[0747]
4-(2-Acetylaminoethylamino)-2-phenyl-7H-pyrrolo[2,3-d]pyrimidine-6--
carboxylic acid (4-phenoxyphenyl)-amide (26.2): Following the
general procedure for C-4 chloride displacement, 26.2 was prepared
from 26.1 as a white solid, mp 250-257.degree. C. (decomp.). MS
(ES): m/z 506.9 (100) [MH.sup.+]. .sup.1H NMR (DMSO-D.sub.6, 200
MHz): .delta.=1.79 (s, 3H), 3.40 (m.sub.c, 2H), 3.65 (q, J=6.2 Hz,
2H), 6.89-7.13 (m, 5H), 7.29-7.48 (m, 6H), 7.76 (d, J=9.2 Hz, 2H),
7.88 (brs, 1H), 8.04 (brs, 1H), 8.37-8.44 (m, 2H), 10.16 (s, 1H),
12.13 (s, 1H). t.sub.R (method A)=8.5 min.
[0748]
N-(2-{2-Phenyl-6-14-(3-phenylallyl)-piperazine-1-carbonyl]-7H-pyrro-
lo[2,3-d]pyrimidin-4-ylamino}-ethyl)-acetamide (26.3): off-white
solid. MS (ES): m/z 524.2 (10) [MH.sup.+], 408.2 (100) [MH.sup.+-
PhC.sub.3H.sub.3]. .sup.1H NMR (CDCl.sub.3, 200 MHz): .delta.=1.81
(s, 3H), 2.61 (mi, 4H), 3.22 (d, J=6.6 Hz, 2H), 3.60 (q, J=5.2 Hz,
2H), 3.88-3.98 (m, 6H), 5.87 (brs, 11H), 6.28 (dt, J=15.7, 6.6 Hz,
11H), 6.54 (d, J=15.7 Hz, 11H), 6.66 (s, 11H), 6.80 (brs, 1H),
7.20-7.50 (m, 8H), 8.40-8.45 (m, 2H), 9.45 (brs, 11H). t.sub.R
(method A)=6.0 min.
[0749]
N-{2-[6-(4-Hydroxy4-isopropylpiperidine-1-carbonyl)-2-phenyl-7H-pyr-
rolo[2,3-d]pyrimidin-4-ylamino]-ethyl}-acetamide (26.4): white
solid, mp 140-145.degree. C. (decomp.). MS (ES): m/z 465.2 (100)
[MH.sup.+]. IR (film): v=3332 cm .sup.-1, 2964, 2877, 1654, 1590,
1574, 1532, 1438, 1387, 1327, 1278, 1255, 1170, 1071, 1026, 936,
776, 750, 706. .sup.1H NMR (CD.sub.3OD, 200 MHz): .delta.=0.96 (d,
J=7.0 Hz, 6H), 1.55-1.70 (m, 5H), 1.85 (s, 3H), 3.40-3.56 (m, 4H),
3.83 (t, J=6.0 Hz, 2H), 4.37 (brd, J=12.0 Hz, 2H), 6.92 (s, 1H),
7.40-7.46 (m, 3H), 8.37-8.45 (m, 2H). t.sub.R (method A)=5.8
min.
[0750]
N-(2-{2-Phenyl-6-[4-(3-phenylpropyl)-piperazine-1-carbonyl]-7H-pyrr-
olo[2,3-d]pyrimidin-4-ylamino}-ethyl)-acetamide (26.5): Mp
198-200.degree. C. MS (ES): m/z 526.1 (51) [MH.sup.+]. IR (film):
v=3295 cm.sup.-1, 3062, 3024, 2929, 2857, 1654, 1589, 1573, 1530,
1454, 1432, 1387, 1328, 1297, 1170, 1132, 1027, 1001, 776, 749,
703. .sup.1HNMR(CDCl.sub.3, 400 MHz): .delta.=1.79 (s, 3H), 1.83
(quint, J=7.4 Hz, 2H), 2.39 (t, J=7.6 Hz, 2H), 2.47 (me, 4H), 2.65
(t, J=7.6 Hz, 2H), 3.52-3.56 (m, 2H), 3.80-3.90 (m, 6H), 6.19 (brs,
1H), 6.67 (s, 1H), 7.01 (brs, 1H), 7.16-7.42 (m, 8H), 8.37-8.40 (m,
2H), 10.12 (brs, 1H). .sup.13C NMR (CDCl.sub.3/CD.sub.3OD, 50.3
MHz, additional DEPT135): .delta.=22.97 (+), 28.31 (-), 33.50 (-),
40.85 (-), 41.19 (-), 41.35 (-), 53.01 (-), 57.66 (-), 101.95 (2C,
+, C.sub.quart), 125.85 (+), 126.35 (C.sub.quart), 127.96 (+),
128.33 (+), 129.91 (+), 138.64 (C.sub.quart), 141.84 (C.sub.quart),
150.95 (C.sub.quart), 157.59 (C.sub.quart), 160.07 (C.sub.quart),
161.49 (C.sub.quart), 171.42 (C.sub.quart). t.sub.R (method A)=4.4
min. C.sub.30H.sub.35N.sub.7O.sub.2 (525.66): calcd. C, 68.55; H,
6.71; N, 18.65; found C, 68.93; H, 6.78; N, 18.26.
[0751]
N-(2-{6-[4-(4-Chlorophenyl)-4-hydroxypiperidine-1-carbonyl]-2-pheny-
l-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino}-ethyl)-acetamide (26.6):
pale yellow solid. MS (ES): m/z 533/535 (100/37) [MH.sup.+]. IR
(film): v=3354 cm.sup.-, 3062, 2928, 2869, 1653, 1589, 1573, 1529,
1493, 1437, 1388, 1327, 1275, 1208, 1170, 1095, 1026, 1012, 934,
776, 749, 706. .sup.1H NMR (CD.sub.3OD, 200 MHz): .delta.=1.82
(brd, J=13.0 Hz, 2H), 1.85 (s, 3H), 2.11 (dt, J=13.0, 3.8 Hz, 2H),
3.42-3.62 (m, 4H), 3.83 (t, J=6.1 Hz, 2H), 4.48 (brd, J=13.6 Hz,
2H), 6.97 (s, 1H), 7.30-7.54 (m, 7H), 8.38-8.45 (m, 2H). t.sub.R
(method A)=7.0 min.
[0752]
N-{2-[6-(4-Hydroxy4-phenylpiperidine-1-carbonyl)-2-phenyl-7H-pyrrol-
o[2,3-d]pyrimidin-4-ylamino]-ethyl}-acetamide (26.7): off-white
solid, mp 158-162.degree. C. (decomp.). MS (ES): m/z 499.0 (100)
[MH.sup.+]. IR (film): v=3308 cm.sup.-1, 3062, 2948, 2925, 2853,
1653, 1591, 1575, 1534, 1447, 1385, 1328, 1277, 1172, 1108, 1037,
1016, 950, 802, 776, 759, 702. .sup.1H NMR (CD.sub.3OD, 200 MHz):
.delta.=1.82 (brd, J=13.0 Hz, 2H), 1.84 (s, 3H), 2.11 (dt, J=13.0,
3.8 Hz, 2H), 3.41-3.65 (m, 4H), 3.82 (t, J=5.8 Hz, 2H), 4.46 (brd,
J=11.8 Hz, 2H), 6.96 (s, 1H), 7.18-7.54 (m, 8H), 8.38-8.45 (m, 2H).
t.sub.R (method A)=6.7 min.
[0753]
N-{2-[6-(4-Benzyl-4-hydroxypiperidine-1-carbonyl)-2-phenyl-7H-pyrro-
lo[2,3-d]pyrimidin-4-ylamino]-ethyl}-acetamide (26.8): off-white
solid, mp 140-145.degree. C. (decomp.). MS (ES): m/z 512.9 (100)
[MH.sup.+]. IR (film): v=3281 cm.sup.-, 3065, 2922, 2852, 1654,
1589, 1574, 1532, 1432, 1385, 1327, 1272, 1170, 1084, 1026, 992,
951, 803, 776, 703. .sup.1H NMR (CD.sub.3OD, 200 MHz):
.delta.=1.50-1.75 (m, 4H), 1.85 (s, 3H), 2.80 (s, 2H), 3.30-3.56
(m, 4H), 3.82 (t, J=6.2 Hz, 2H), 4.30 (brd, J=13.2 Hz, 2H), 6.89
(s, 1H), 7.18-7.35 (m, 5H), 7.35-7.55 (m, 3H), 8.38-8.45 (m, 2H).
t.sub.R (method A)=6.9 min.
[0754]
2-{6-[4-(4-Chlorophenyl)-4-hydroxypiperidine-1-carbonyl]-2-phenyl-7-
H-pyrrolo[2,3-d]pyrimidin-4-ylamino}-acetamide (26.9): off-white
solid, mp 200-205.degree. C. (decomp.). MS (ES): m/z 504.8/506.9
(100/37) [MH.sup.+]. IR (film): v=3309 cm.sup.-1, 2954, 2926, 2853,
1684, 1613, 1569, 1532, 1455, 1445, 1430, 1383, 1326, 1265, 1203,
1094, 1010, 950, 911, 824, 760, 737, 705. .sup.1H NMR (CD.sub.3OD,
200 MHz): .delta.=1.80-1.90 (m, 2H), 2.08-2.21 (m, 2H), 3.50-3.65
(m, 2H), 4.29 (s, 2H), 4.42-4.55 (m, 2H), 7.01 (s, 1H), 7.32-7.43
(m, 3H), 7.53 (d, J=8.4 Hz, 2H), 8.38-8.45 (m, 2H). t.sub.R (method
A)=7.1 min.
[0755]
N-(2-{6-4-Hydroxy4-(3-trifluoromethylphenyl)-piperidine-1-carbonyl]-
-2-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino}-ethyl)-acetamide
(26.10): off-white solid, mp 145-150.degree. C. MS (ES): m/z 566.9
(100) [MH.sup.+]. IR (film): v=3284 cm.sup.-1, 2933, 1654, 1591,
1574, 1533, 1435, 1387, 1329, 1278, 1165, 1124, 1075, 1026, 931,
803, 776, 751, 703. .sup.1H NMR (CD.sub.3OD, 200 MHz): .delta.=1.82
(brd, J=13.0 Hz, 2H), 1.84 (s, 3H), 2.15 (dt, J=13.0, 3.8 Hz, 2H),
3.42-3.70 (m, 4H), 3.82 (t, J=6.2 Hz, 2H), 4.47 (brd, J=12.8 Hz,
2H), 6.97 (s, 1H), 7.40-7.50 (m, 3H), 7.50-7.60 (m, 2H), 7.70-7.80
(m, 1H), 7.88 (s, 1H), 8.37-8.45 (m, 2H). t.sub.R (method-A)=7.8
min.
[0756]
N-{2-[6-(4-Phenethylpiperazine-1-carbonyl)-2-phenyl-7H-pyrrolo[2,3--
d]pyrimidin-4-ylamino]-ethyl}-acetamide (26.11): white solid, mp
226-228.degree. C. MS (ES): m/z 511.8 (15) [MH.sup.+], 407.8 (48)
[MH.sup.+-PhCH.dbd.CH.sub.2]. IR (film): v=3295 cm.sup.-1, 3066,
3027, 2934, 2809, 1654, 1598, 1574, 1533, 1453, 1432, 1387, 1327,
1297, 1170, 1132, 1029, 1000, 776, 749, 703. .sup.1H NMR
(CD.sub.3OD/CDCl.sub.3, 200 MHz): .delta.=1.84 (s, 3H), 2.52-2.78
(m, 6H), 2.78-2.90 (m, 2H), 3.52-3.60 (m, 2H), 3.80-4.00 (m, 6H),
6.19 (brs, 1H), 6.92 (s, 1H), 7.16-7.38 (m, 5H), 7.38-7.50 (m, 3H),
8.35-8.40 (m, 2H). t.sub.R (method A)=4.5 min.
[0757]
N-(2-{6-[4-(3-Morpholin-4-ylpropyl)-piperazine-1-carbonyl]-2-phenyl-
-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino}-ethyl)-acetamide (26.12):
white solid, mp 225-230.degree. C. (decomp.). MS (ES): m/z 535.3
(10) [MH.sup.+], 322.0 (52)
[MH.sup.+-1-(3-morpholin-4-ylpropyl)piperazine]. t.sub.R (method
B)=5.3 min.
[0758]
N-(2-{6-[4-(4-Chlorophenyl)-3,6-dihydro-2H-pyridine-17carbonyl]-2-p-
henyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino}-ethyl)-acetamide
(26.13): beige solid, mp 172-175.degree. C. MS (ES): m/z
515.2/517.3 (50/20) [MH.sup.+]. t.sub.R (method A)=8.9 min.
[0759]
N-{2-[6-(4-Benzylpiperazine-1-carbonyl)-2-phenyl-7H-pyrrolo[2,3-d]p-
yrimidin-4-ylamino]-ethyl}-acetamide (26.14): off-white solid, mp
235-240.degree. C. (decomp.). MS (ES): m/z 497.9 (10) [MH.sup.+],
407.9 (100) [MH.sup.+-PhCH.sub.2+]. t.sub.R (method A)=4.3 min.
2-{2-Phenyl-6-[4-(3-phenylpropyl)-piperazine-1-carbonyl]-7H-pyrrolo[2,3-d-
]pyrimidin-4-ylamino}-acetamide (26.151: white solid, mp
213-217.degree. C. MS (ES): m/z 498.0 (100) [MH.sup.+]. t.sub.R
(method A)=4.3 min.
[0760]
N-[2-(6-{4-[2-(4-Chlorophenoxy)-ethyl]-piperazine-1-carbonyl}-2-phe-
nyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-ethyl]-acetamide (26.16):
off-white solid, mp 227-228-C. MS (ES): m/z 561.9/563.9 (50/22)
[MH.sup.+], 321.9 (85)
[MH.sup.+2-(4-chlorophenoxy)ethylpiperazine]. t.sub.R (method
A)=5.0 min.
[0761]
4-(2-Acetylaminoethylamino)-2-phenyl-7H-pyrrolo[2,3-d]pyrimidine-6--
carboxylic acid bicyclo[2.2.1hept-2-ylamide (26.17): off-white
solid, mp 280-285.degree. C. (decomp.). MS (ES): m/z 432.9 (100)
[MH.sup.+]. t.sub.R (method A)=7.3 min.
[0762]
N-(2-{6-[4-(4-Fluorophenyl).sub.4-hydroxypiperidine-1-carbonyl]-2-p-
henyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino}-ethyl)-acetamide
(26.18): pale yellow solid, mp 150-153-C. MS (ES): m/z 516.9 (100)
[MH.sup.+]. t.sub.R (method A)=6.9 min.
[0763]
N-{2-[6-(4-Cyano-4-phenylpiperidine-1-carbonyl)-2-phenyl-7H-pyrrolo-
[2,3-d]pyrimidin-4-ylamino]-ethyl}-acetamide (26.19): off-white
solid, mp 150-155.degree. C. (decomp.). MS (ES): m/z 508.0 (100)
[MH.sup.+]. t.sub.R (method A)=7.7 min.
[0764]
4-(2-Acetylaminoethylamino)-2-phenyl-7H-pyrrolo[2,3-d]pyrimidine-6--
carboxylic acid (3-phenoxyphenyl)-amide (26.20): pale yellow solid,
mp 140-142.degree. C. MS (ES): m/z 506.9 (100) [MH.sup.+]. t.sub.R
(method A)=8.8 min.
[0765]
N-(2-{2-Phenyl-6-[4-(3-phenylprop-2-ynyl)-piperazine-1-carbonyl]-7H-
-pyrrolo[2,3-d]pyrimidin-4-ylamino}-ethyl)-acetamide (26.21):
off-white solid, mp 213-215.degree. C. MS (ES): m/z 521.8 (100)
[MH.sup.+], 321.8 (100) [MH.sup.+-(3-phenylprop-2-ynyl)piperazine].
IR (film): v=3302 cm.sup.-1, 3061, 3022, 2924, 2850, 1654, 1589,
1573, 1531, 1455, 1429, 1386, 1367, 1327, 1298, 1270, 1171, 1135,
1027, 999, 970, 803, 776, 755, 704, 691. .sup.1H NMR (CDCl.sub.3,
200 MHz): .delta.=1.80 (s, 3H), 2.73 (me, 4H), 3.50-3.61 (m, 4H),
3.80-4.00 (m, 6H), 5.93 (brs, 1H), 6.68 (s, 1H), 6.82 (brs, 1H),
7.25-7.35 (m, 3H), 7.35-7.55 (m, 5H), 8.37-8.47 (m, 2H), 9.63 (brs,
1H). .sup.13C NMR (CDCl.sub.3, 50.3 MHz, DEPT135): .delta.=23.03
(+), 29.66 (-), 40.60 (-), 41.70 (-), 47.67 (-), 51.93 (-), 83.63
(C.sub.quart), 85.81 (C.sub.quart), 101.97 (+), 102.20
(C.sub.quart), 122.70 (C.sub.quart), 126.40 (C.sub.quart), 128.04
(+), 128.28 (+, 4C), 129.81 (+), 131.69 (+, 4C), 138.70
(C.sub.quart), 151.13 (C.sub.quart), 157.67 (C.sub.quart), 159.89
(C.sub.quart), 161.60 (C.sub.quart), 171.17 (C.sub.quart). t.sub.R
(method A)=7.5 min.
[0766]
N-{2-[6-(cis-3,5-Dimethylpiperazine-1-carbonyl)-2-phenyl-7H-pyrrolo-
[2,3-d]pyrimidin-4-ylamino]-ethyl}-acetamide (26.22): off-white
solid, mp 138-140.degree. C. MS (ES): m/z 435.8 (100) [MH.sup.+].
t.sub.R (method A)=3.1 min.
[0767]
(4-Benzylpiperidin-1-yl)-(4-dimethylamino-2-phenyl-7H-pyrrolo[2,3-d-
]pyrimidin-6-yl)-methanone (26.23): pale yellow solid. MS (ES): m/z
439.8 (100) [MH.sup.+]. t.sub.R (method A)=11.3 min.
[0768]
N-(2-{6-[cis-3,5-Dimethyl-4-(3-phenylpropyl)-piperazine-1-carbonyl]-
-2-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino}-ethyl)-acetamide
(26.24): pale yellow solid, mp 86-89.degree. C. MS (ES): m/z 554.0
(18) [MH.sup.+], 321.9 (48)
[MH.sup.+-cis-3,5-dimethyl-4-(3-phenylpropyl)-pipe- razine].
t.sub.R (method A)=5.8 min.
[0769]
N-{2-[6-(4,4-Diphenylpiperidine-1-carbonyl)-2-phenyl-7H-pyrrolo[2,3-
-d]pyrimidin-4-ylamino]-ethyl}-acetamide (26.25): off-white solid,
mp 254-256.degree. C. MS (ES): m/z 558.9 (100) [MH.sup.+]. t.sub.R
(method A)=8.7 min.
[0770]
N-{2-[6-(3,3-Diphenylpiperidine-1-carbonyl)-2-phenyl-7H-pyrrolo[2,3-
-d]pyrimidin-4-ylamino]-ethyl}-acetamide (26.26): white solid, mp
156-159.degree. C. (decomp.). MS (ES): m/z 558.9 (100) [MH.sup.+].
t.sub.R (method A)=8.8 min.
[0771]
N-{2-[6-(4-Methoxy-4-phenylpiperidine-1-carbonyl)-2-phenyl-7H-pyrro-
lo[2,3-d]pyrimidin-4-ylamino]-ethyl}-acetamide (26.27): white
solid, mp 135-138.degree. C. MS (ES): m/z 512.9 (100) [MH.sup.+].
t.sub.R (method A)=7.7 min.
[0772]
N-(2-{6-[4-(4-Fluorobenzyl)-piperidine-1-carbonyl]-2-phenyl-7H-pyrr-
olo[2,3-d]pyrimidin-4-ylamino}-ethyl)-acetamide (26.28): off-white
solid, mp 283-284.degree. C. (decomp.). MS (ES): mii/z 515.0 (100)
[MH.sup.+]. IR (film): v=3286 cm.sup.-1, 3059, 2940, 2868, 1649,
1589, 1573, 1531, 1509, 1447, 1432, 1386, 1327, 1299, 1271, 1220,
1168, 1105, 1068, 954, 837, 803, 776, 732, 705. .sup.1H NMR
(CDCl.sub.3/CD.sub.3OD, 200 MHz): .delta.=1.20-1.40 (m, 2H),
1.75-1.90 (m, 3H), 1.18 (s, 3H), 2.58 (d, J=7.0 Hz, 2H), 2.99 (brs,
2H), 3.48-3.55 (m, 2H), 3.82-3.90 (m, 2H), 4.57 (brd, J=12.0 Hz,
2H), 6.78 (s, 1H), 6.94-7.16 (m, 4H), 7.44-7.52 (m, 3H), 7.80 (brs,
1H), 8.30-8.39 (m, 2H). t.sub.R (method A) =8.1 min.
[0773]
N-[2-(6-{4-l(4-Fluorophenyl)-hydroxymethyl]-piperidine-1-carbonyl}--
2-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-ethyl]-acetamide
(26.29): off-white solid, mp 135-145.degree. C. (decomp.). MS (ES):
m/z 530.8 (100) [MH.sup.+]. t.sub.R (method A)=6.9 min.
[0774]
N-(2-{6-trans-2,5-Dimethyl-4-(3-phenylpropyl)-piperazine-1-carbonyl-
]-2-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino}-ethyl)-acetamide
(26.30): off-white solid, mp 98-100.degree. C. MS (ES): m/z 553.9
(48) [MH.sup.+], 321.8 (79)
[MH.sup.+-trans-2,5-dimethyl4-(3-phenylpropyl)-piperazine]. t.sub.R
(method A)=5.7 min.
[0775]
N-{2-[6-(trans-2,5-Dimethylpiperazine-1-carbonyl)-2-phenyl-7H-pyrro-
lo[2,3-d]pyrimidin-4-ylamino]-ethyl}-acetamide (26.31): yellowish
solid, mp 120-125.degree. C. MS (ES): m/z 436.0 (18) [MH.sup.+],
321.9 (100) [MH.sup.+-trans-2,5-dimethylpiperazine]. t.sub.R
(method B)=8.8 min.
[0776]
N-{2-316-(4-Benzyl-cis-3,5-dimethylpiperazin-1-carbonyl)-2-phenyl-7-
H-pyrrolo[2,3-d]pyrimidin-4-ylamino]-ethyl}-acetamide (26.32):
white solid, mp 196-198.degree. C. MS (ES): m/z 526.0 (29)
[MH.sup.+], 435.9 (100) [MH.sup.+-PhCH.sub.2+]. t.sub.R (method
A)=5.1 min.
[0777]
N-{2-[6-(cis-3,5-Dimethyl-4-phenethylpiperazine-1-carbonyl)-2-pheny-
l-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino]-ethyl}-acetamide (26.33):
off-white solid, mp 110-115.degree. C. (decomp.). MS (ES): m/z
540.0 (82) [MH.sup.+], 435.8 (73) [MH.sup.+-PhCHCH.sub.2], 321.8
(100) [MH.sup.+-cis-3,5-dimethyl-4-phenethylpiperazine]. t.sub.R
(method A)=5.4 min.
[0778]
N-[2-(6-{4-[4-(2-Acetylaminoethylamino)-2-phenyl-7H-pyrrolo[2,3-d]p-
yrimidine-6-carbonyl]-trans-2,5-dimethylpiperazine-1-carbonyl}-2-phenyl-7H-
-pyrrolo[2,3-d]pyrimidin-4-ylamino)-ethyl]-acetamide (26.34): white
solid. MS (ES.): m/z 757.1 (10) [MH.sup.+], 436.0 (9)
[N-{2-[6-(cis-3,5-dimethyl-
-4-phenethylpiperazine-1-carbonyl)-2-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-y-
lamino]-ethyl}-acetamide.H.sup.+], 379.1 (100)
[MH.sup.+-N-{2-[6-(cis-3,5--
dimethyl-4-phenethylpiperazine-1-carbonyl)-2-phenyl-7H-pyrrolo[2,3-d]pyrim-
idin-4-ylamino]-ethyl}-acetamide]. t.sub.R (method A)=6.6 min.
[0779]
N-{2-[2-Phenyl-6-(4-pyridin-2-yl-piperazine-1-carbonyl)-7H-pyrrolo[-
2,3-d]pyrimidin-4-ylamino]-ethyl}-acetamide (26.35): off-white
solid, mp 223-226.degree. C. (decomp.). MS (ES): m/z 484.9 (22)
[MH.sup.+], 321.9 (100) [MH.sup.+- pyridin-2-yl-piperazine].
t.sub.R (method A)=4.8 min.
[0780]
N-{2-[6-(3-Methyl-3-phenylpiperidine-1-carbonyl)-2-phenyl-7H-pyrrol-
o[2,3-d]pyrimidin-4-ylamino]-ethyl}-acetamide (26.36): Mp
140-145.degree. C. MS (ES): m/z 497.0 (100) [MH.sup.+]. IR (film):
v=3294 cm.sup.-1, 3063, 2936, 2861, 1654, 1590, 1573, 1531, 1432,
1386, 1327, 1296, 1271, 1168, 908, 776, 762, 730, 701. .sup.1H NMR
(CDCl.sub.3, 200 MHz): .delta.=1.2-1.3 (m, 1H), 1.31 (s,.3H),
1.6-1.8 (m, 2H), 1.79 (s, 3H), 2.15-2.25 (m, 1H), 3.5-3.7 (m, 3H),
3.8-4.1 (m, 5H), 5.85 (brs, 1H), 6.63 (s, 1H), 6.87 (brs, 1H),
7.2-7.5 (m, 10H), 8.40-8.50 (m, 2H), 9.40 (s, 1H). t.sub.R (method
A)=8.1 min.
[0781]
N-(2-{2-Phenyl-6-[4-(3-trifluoromethylpyridin-2-yl)-piperazine-1-ca-
rbonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino}-ethyl)-acetamide
(26.37): off-white solid, mp 225-228-C. MS (ES): m/z 553.0 (100)
[MH.sup.+]. .sup.1H NMR (DMSO-d.sub.6, 400 MHz): .delta.=1.79 (s,
3H), 3.26 (m,, 4H), 3.30-3.38 (m, 2H), 3.60-3.67 (m, 2H), 3.85
(brs, 4H), 7.00 (s, 1H), 7.24 (dd, J=4.8, 7.6 Hz, 1H), 7.40-7.48
(m, 3H), 7.83 (brs, 1H), 8.05 (t, J=5.2 Hz, 1H), 8.11 (dd, J=1.6,
7.6 Hz, 1H), 8.38-8.42 (m, 2H), 8.55 (d, J=4.8 Hz, 1H). t.sub.R
(method A)=7.6 min.
[0782]
N-(2-{6-[4-(4-Fluorophenyl)-piperazine-1-carbonyl]-2-phenyl-7H-pyrr-
olo[2,3-d]pyrimidin-4-ylamino}-ethyl)-acetamide (26.38): Mp
234.degree. C. MS (ES): m/z 502.0 (100) [MH.sup.+], 321.9 (84)
[MH.sup.+-1-(4-fluorophen- yl)piperazine]. IR (film): v=3301
cm.sup.-1, 3049, 2923, 2861, 1654, 1590, 1574, 1532, 1508, 1430,
1387, 1328, 1277, 1232, 1164, 1027, 916, 828, 816, 776, 731, 706.
.sup.1H NMR (CDCl.sub.3/CD.sub.3OD, 200 MHz): .delta.=1.79 (s, 3H),
3.21 (m.sub.c, 4H), 3.54 (m, 2H), 3.86 (t, J=6.2 Hz, 2H), 4.04
(m.sub.c, 4H), 6.86 (s, 1H), 6.9-7.1 (m, 4H), 7.45-7.55 (m, 3H),
7.75 (brs, 1H), 8.30-8.40 (m, 2H). t.sub.R (method A)=7.5 min.
[0783]
N-(2-{2-Phenyl-6-[4-(5-trifluoromethylpyridin-2-yl)-piperazine-1-ca-
rbonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino}-ethyl)-acetamide
(26.39): off-white solid, mp 270-273.degree. C. MS (ES): m/z 553.0
(100) [MH.sup.+]. t.sub.R (method A)=8.0 min.
[0784]
N-(2-{6-[4-(3,5-Dichloropyridin-4-yl)-piperazine-1-carbonyl]-2-phen-
yl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino}-ethyl)-acetamide (26.40):
MS (ES): m/z 552.9/554.9/556.9 (100/71/14) [MH.sup.+], 321.9 (83)
[MH.sup.+-pyridinylpiperazine]. IR (film): v=3282 cm.sup.-1, 3080,
2962, 2926, 2854, 1652, 1598, 1574, 1532, 1434, 1383, 1328, 1282,
1241, 1149, 1026, 933, 806, 777, 750, 706. .sup.1H NMR
(CDCl.sub.3/CD.sub.3OD, 200 MHz): .delta.=1.80 (s, 3H), 3.45
(m.sub.c, 4H), 3.54 (m, 2H), 3.88 (t, J=6.2 Hz, 2H), 4.04 (m.sub.c,
4H), 6.82 (s, 1H), 7.30-7.55 (m, 3H), 8.30-8.40 (m, 4H). t.sub.R
(method A)=7.2 min.
[0785]
N-(2-{6-[4-(2'-Chlorobiphenyl-2-yl)-4-methoxypiperidine-1-carbonyl]-
-2-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino}-ethyl)-acetamide
(26.41): MS (ES): m/z 623.0/625.0 (100/38) [MH.sup.+]. IR (film):
v=3306 cm.sup.-1, 3022, 2945, 2924, 1652, 1591, 1574, 1537, 1434,
1384, 1328, 1286, 1243, 1071, 1016, 776, 753, 704. .sup.1H NMR
(CDCl.sub.3, 200 MHz): .delta.=1.80 (s, 3H), 1.8-2.3 (m, 4H), 3.08
(s, 3H), 3.3-3.6 (m, 4H), 3.80-3.90 (m, 2H), 4.31 (m.sub.c, 2H),
5.81 (m.sub.c, 1H), 6.53 (s, 1H), 6.88 (brs, 1H), 7.01-7.10 (m,
1H), 7.25-7.50 (m, 9H), 7.64 (d, J=7.6 Hz, 1H), 8.35-8.45 (m, 2H),
9.47 (brs, 1H). t.sub.R (method A)=8.9 min.
[0786]
N-(2-{6-[4-(2-Chlorophenyl)-4-methoxypiperidine-1-carbonyl]-2-pheny-
l-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino}-ethyl)-acetamide (26.42):
white solid, mp. 201-202.degree. C. MS (ES): m/z 547.0/549.0
(100/38) [MH.sup.+]. IR (film): v=3312 cm.sup.-1, 3034, 2934, 1653,
1599, 1574, 1534, 1433, 1390, 1328, 1286, 1252, 1071, 1016, 776,
754, 705. .sup.1H NMR (CDCl.sub.3/CD.sub.3OD, 200 MHz):
.delta.=1.78 (s, 3H), 1.99 (m.sub.c, 2H), 2.52 (brd, J=12.8 Hz,
2H), 3.05 (s, 3H), 3.4-3.6 (m, 4H), 3.80-3.90 (m, 2H), 4.51 (brd,
J=11.2 Hz, 2H), 6.75 (s, 1H), 7.25-7.40 (m, 3H), 7.40-7.50 (m, 4H),
8.35-8.45 (m, 2H). t.sub.R (method A)=7.2 min.
C.sub.29H.sub.31ClN.sub.6O.sub.3 (547.06): calcd. C, 63.67; H,
5.71; N, 15.36, Cl 6.48; found C 63.54, H 5.74, N 15.40, Cl
6.65.
[0787]
N-(2-{6-[4-(2-Chlorophenyl)-4-methoxypiperidine-1-carbonyl]-2-pheny-
l-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino}-ethyl)-acetamide
methanesulfonic acid salt (26.42-MsOH): 26.42 (1.570 g, 2.87 mmol)
is dissolved in dry MeOH (25 mL), the solution is filtered, and the
flask and the filter are rinsed with additional MeOH (5 mL).
Methanesulfonic acid (290 mg, 3.01 mmol) is added, 10 mL of MeOH
are evaporated, and Et.sub.2O is added until a persistent
precipitate just forms (85 mL). After standing for 1 h at ambient
temp., crystallization is completed by cooling to -20.degree. C.
overnight. The solid is filtered off and dried, giving 1.613 g
(2.508 mmol, 87%) of the salt as white solid, mp. 190-191.degree.
C.
[0788]
N-(2-{6-[4-(2-Chlorophenyl)-4-hydroxypiperidine-1-carbonyl]-2-pheny-
l-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino}-ethyl)-acetamide (26.43):
MS (ES): m/z 533.0/535.0 (100/36) [MH.sup.+]. IR (film): v=3312
cm.sup.-1, 3054, 2961, 2924, 2857, 1658, 1598, 1574, 1533, 1431,
1388, 1328, 1274, 1170, 1016, 776, 756, 705. .sup.1H NMR
(CDCl.sub.3, 200 MHz): .delta.=1.78 (s, 3H), 2.09 (brd, J=12.8 Hz,
2H), 2.38 (brdt,J=3.6, 12.6 Hz, 2H), 3.4-3.6 (m, 4H), 3.80-3.90 (m,
2H), 4.54 (brd, J=13.2 Hz, 2H), 6.31 (brs, 1H), 6.75 (s, 1H),
7.15-7.60 (m, 8H), 8.35-8.45 (m, 2H). t.sub.R (method A)=6.5
min.
[0789]
2-{6-[4-(2-Chlorophenyl).sub.4-methoxypiperidine-1-carbonyl]-2-phen-
yl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino]-1-[4-(2-chlorophenyl)-4-methoxypi-
peridin-1-yl]-ethanone (26.44): off-white solid. MS (ES): m/z
727.1/729.1/731.1 (100/69/14) [MH.sup.+]. t.sub.R (method A)=11.3
min.
[0790]
2-{6-[4-(2-Chlorophenyl)-4-methoxypiperidine-1-carbonyl]-2-phenyl-7-
H-pyrrolo[2,3-d]pyrimidin-4-ylamino}-acetamide (26.45): MS (ES):
m/z 519.0/521.0 (100/37) [MH.sup.+]. IR (film): v=3310 cm.sup.-1,
3024, 2960, 2936, 2873, 1673, 1590, 1573, 1532, 1446, 1431, 1389,
1324, 1298, 1285, 1199, 1071, 1016, 776, 754, 705. .sup.1H NMR
(CDCl.sub.3/CD.sub.3OD, 200 MHz): .delta.=2.05 (m, 2H), 2.57 (brd,
J=13.6 Hz, 2H), 3.09 (s, 3H), 3.45-3.65 (m, 2H), 4.36 (s, 2H),
4.45-4.60 (m, 2H), 6.81 (s, 1H), 7.25-7.50 (m, 7H), 8.32-8.40 (m,
2H). t.sub.R (method A)=7.5 min.
[0791]
2-{6-[4-(2'-Chlorobiphenyl-2-yl)-4-methoxypiperidine-1-carbonyl]-2--
phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino}-acetamide (26.46): m/z
595.0/597.0 (100/38) [MH.sup.+]. IR (film): v=3362 cm.sup.-1, 3023,
2924, 2850, 1669, 1594, 1573, 1532, 1463, 1438, 1388, 1324, 1284,
1071, 1017, 803, 755, 705. .sup.1H NMR (CDCl.sub.3/CD.sub.3OD, 200
MHz): .delta.=1.75-2.25 (m, 4H), 3.09 (s, 3H), 3.3-3.6 (m, 2H),
4.20-4.35 (m, 2H), 4.39 (s, 2H), 6.58 (s, 1H), 7.01-7.10 (m, 1H),
7.25-7.50 (m, 9H), 7.64 (d, J=7.4 Hz, 1H), 8.35-8.45 (m, 2H).
t.sub.R (method A)=8.9 min.
[0792]
N-(2-{6-[4-(2'-Chlorobiphenyl-2-yl)-4-hydroxypiperidine-1-carbonyl]-
-2-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino}-ethyl)-acetamide
(26.47): MS (ES): m/z 609.0/611.0 (100/38) [MH.sup.+]. IR (film):
v=3352 cm.sup.-1, 3022, 2924, 1652, 1599, 1575, 1538, 1463, 1451,
1382, 1328, 1272, 1112, 1015, 754, 705. .sup.1HNMR(CDCl.sub.3, 200
MHz): .delta.=1.79 (s, 3H), 1.8-2.2 (m, 4H), 3.3-3.5 (m, 2H), 3.60
(m.sub.c, 2H), 3.80-3.90 (m, 2H), 4.43 (m.sub.c, 2H), 5.96 (brs,
1H), 6.62 (s, 1H), 6.91 (brs, 1H), 6.90-7.07 (m, 1H), 7.25-7.57 (m,
10H), 8.35-8.45 (m, 2H), 9.62 (brs, 11H). t.sub.R (method A)=7.8
min.
[0793]
N-(2-{6-[4-(4-Fluorophenyl).sub.4-methoxypiperidine-1-carbonyl]-2-p-
henyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino}-ethyl)-acetamide
(26.48): white solid, mp 134-137.degree. C. MS (ES): m/z 531.0
(100) [MH.sup.+]. IR (film): v=3305 cm.sup.-1, 3056, 2932, 2824,
1651, 1599, 1574, 1533, 1447, 1432, 1387, 1327, 1280, 1223, 1163,
1071, 1025, 900, 834, 776, 751, 706. .sup.1H NMR
(CDCl.sub.3/CD.sub.3OD, 200 MHz): .delta.=1.78 (s, 3H), 1.92 (dt,
J=4.8, 12.8 Hz, 2H), 2.14 (brd, J=13.2 Hz, 2H), 3.01 (s, 3H),
3.4-3.6 (m, 4H), 3.86 (t, J=5.4 Hz, 2H), 4.49 (brd, J=13.2 Hz, 2H),
6.75 (s, 1H), 7.06 (app t, J=8.8 Hz, 2H), 7.25-7.40 (m, 2H),
7.40-7.50 (m, 3H), 8.35-8.45 (m, 2H). t.sub.R (method A)=7.4
min.
[0794]
N-{2-[6-(2-Benzyl-1-oxo-2,8-diazaspiro[4.5]decane-8-carbonyl)-2-phe-
ny1-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino]-ethyl}-acetamide (26.49):
white solid, mp 140.degree. C. (decomp.). MS (ES): m/z 565.9 (100)
[MH.sup.+]. t.sub.R (method A)=6.9 min.
[0795]
2-{6-[4-(4-Chlorophenyl)-piperazine-1-carbonyl]-2-phenyl-7H-pyrrolo-
[2,3-d]pyrimidin-4-ylamino}-acetamide (26.50): MS (ES): mz/z
489.9/491.9 (100/34) [MH.sup.+]. t.sub.R (method A)=7.6 min.
[0796]
4-(2-Acetylaminoethylamino)-2-phenyl-7H-pyrrolo[2,3-d]pyrimidine-6--
carboxylic acid
(2-{6-[4-(2-chlorophenyl)-4-methoxypiperidine-1-carbonyl]--
2-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino}-ethyl)-amide
(26.51): white solid, mp. 180-185.degree. C. (decomp.). MS (ES):
m/z 826.0/828.0 (52/21) [MH.sup.+]. t.sub.R (method A)=8.2 min.
[0797]
4-(2-Acetylaminoethylamino)-2-phenyl-7H-pyrrolo[2,3-d]pyrimidine-6--
carboxylic acid
(2-{6-[4-(4-chlorophenyl)-piperazine-1-carbonyl]-2-pheny!--
7H-pyrrolo[2,3-d]pyrimidin-4-ylamino}-ethyl)-amide (26.52):
off-white solid. MS (ES): m/z 797.0/799.0 (6/3) [MH.sup.+]. t.sub.R
(method A)=8.3 min.
[0798]
N-(2-{2-Phenyl-6-[4-(3-phenylallyl)-piperidine-1-carbonyl]-7H-pyrro-
lo[2,3-d]pyrimidin-4-ylamino}-ethyl)-acetamide (26.53): .sup.1H NMR
(CDCl.sub.3, 200 MHz) .delta. 1.79 (m, 7H), 2,21 (t, 1H, J=6.6 Hz),
2.33 (m, 1H), 3.00 (brs, 2H), 3.15 (m, 1H), 3.59 (brs, 2H), 3.90
(brs, 2H), 4.58 (brs 2H), 5.99 (brs, 1H), 6.23 (m, 1H), 6.37 (m,
1H), 6.66 (d, 1H), 6.99 (brs, 1H), 7.24-7.46 (m, 8H), 8.40 (m, 2H),
9.70 (brs, 1H). MS (ES) 522.8 [MH.sup.+]. t.sub.R (method A)=9.2
min.
[0799]
N-{2-[6-(4-Benzylpiperidine-1-carbonyl)-2-phenyl-7H-pyrrolo[2,3-d]p-
yrimidin-4-ylamino]-ethyl}-acetamide (26.54): white solid, mp.
260-261.degree. C. .sup.1H NMR (CDCl.sub.3, 200 MHz): .delta.=1.78
(m, 7H), 2.54 (d, 2H, J=6.6 Hz), 2.91 (brs, 2H), 3.56 (brs, 2H),
3.84 (brs, 2H), 4.53 (d, 2H, J=13.6 Hz), 6.40 (brs, 11H), 6.71 (s,
11H), 7.12-7.45 (m, 9H), 8.40 (q, 2H, J=2.2 Hz), 9.98 (brs, 1H). MS
(ES) 496.8 [MH.sup.+]. t.sub.R (method A)=8.6 min.
C.sub.29H.sub.32N.sub.6O.sub.2.0.- 33H.sub.2O (502.57): calcd. C,
69.30; H, 6.55; N, 16.72; found C, 69.46; H, 6.48; N, 16.70.
[0800]
4-(2-Acetylaminoethylamino)-2-phenyl-7H-pyrrolo[2,3-d]pyrimidine-6--
carboxylic acid (1-benzylpiperidin-4-yl)-amide (26.55): .sup.1H NMR
(CDCl.sub.3, 200 MHz) .delta. 1.61-2.05 (m, 7H), 2.18 (m, 2H), 2.89
(d, 2H, J=12 Hz), 3.56 (s, 2H), 3.60 (d, 2H, J=4.8 Hz), 3.87 (brs,
2H), 3.99 (brs, 1H), 6.22 (brs, 1H), 6.33 (brs, 1H), 6.68 (b, 1H),
6.86 (brs, 1H), 7.26-7.45 (m, 9H), 8.40 (q, 2H, J=3.2 Hz), 9.64
(brs, 11H). MS (ES) 512.1 [MH.sup.+]. t.sub.R (method A)=4.9
min.
[0801]
N-(2-{2-Phenyl-6-[4-(4-phenylbutyl)-piperazine-1-carbonyl]-7H-pyrro-
lo[2,3-d]pyrimidin-4-ylamino}-ethyl)-acetamide (26.56): .sup.1H NMR
(CDCl.sub.3, 200 MHz) .delta. 1.52-1.68 (m, 4H), 1.78 (s, 3H), 2.37
(t, 2H, J=7 Hz), 2.44 (brs, 4H), 2.63 (t, 2H, J=7.6 Hz), 3.54 (brs,
2H), 3.81 (brs, 6H), 6.28 (brs, 1H), 6.66 (s, 1H), 7.12-7.44 (m,
9H), 8.40 (q, 2H, J=4.2 Hz), 10.40 (brs, 11H). MS (ES) 540.1
[MH.sup.+]. t.sub.R (method A)=4.9 min.
[0802]
N-(2-{2-Phenyl-6-[4-(3-phenylpropyl)-piperidine-1-carbonyl]-7H-pyrr-
olo[2,3-d]pyrimidin-4-ylamino}-ethyl)-acetamide (26.57): .sup.1H
NMR (CDCl.sub.3, 200 MHz) .delta. 1.17-1.38 (m, 5H), 1.58-1.69 (m,
4H), 1.79 (s, 3H), 2.61 (t, 2H, J=7.6 Hz), 3.00 (brs, 2H), 3.55 (q,
2H, J=5.4 Hz), 3.86 (brs, 2H), 4.53 (d, 2H, J=13.2 Hz), 6.05 (brs,
1H), 6.65 (s, 1H), 7.03 (brs, 1H), 7.16-7.32 (m, 5H), 7.33-7.48 (m,
3H), 8.40 (q, 2H, J=3.2 Hz), 9.81 (brs, 1H). MS (ES) 524.9
[MH.sup.+1. t.sub.R (method A)=9.6 min.
[0803]
N-{2-[2-Phenyl-6-(4-pyrrolidin-1-yl-piperidine-1-carbonyl)-7H-pyrro-
lo[2,3-d]pyrimidin-4-ylamino]-ethyl}-acetamide (26.58): .sup.1H NMR
(CDCl.sub.3, 200 MHz) .delta. 1.62-2.00 (m, 7H), 1.84 (s, 3H), 2.74
(brs, 4H), 3.03 (t, 2H, J=14 Hz), 3.62 (m, 2H), 3.91 (brs, 2H),
4.49 (d, 2H, J=13.6 Hz), 6.57 (brs, 1H), 6.87 (s, 1H), 7.20 (m,
1H), 7.33-7.45 (m, 3H), 8.42 (q, 2H, J=3.2 Hz), 9.90 (brs, 1H). MS
(ES) 475.9 [MH.sup.+]. t.sub.R (method A)=3.7 min.
[0804]
N-(2-{6-[4-(3-Cyclohexylpropyl)-piperazine-1-carbonyl]-2-phenyl-7H--
pyrrolo[2,3-d]pyrimidin-4-ylamino}-ethyl)-acetamide (26.59):
.sup.1H NMR (CDCl.sub.3, 200 MHz) .delta. 0.90 (t, 2H, J=10.1 Hz),
1.19 (d, 6H, J=7.4 Hz), 1.50 (brs, 2H), 1.67 (d, 5H, J=10.6 Hz),
1.77 (s, 3H), 2.33 (t, 2H, J=7.7 Hz), 2.47 (brs, 4H), 3.48 (m, 2H),
3.82 (brs, 6H), 6.28 (brs, 1H), 6.67 (s, 1H), 7.16 (brs, 1H), 7.42
(m, 3H), 8.37 (m, 2H), 10.44 (brs, 1H). MS (ES) 532.0 [MH.sup.+].
t.sub.R (method A)=5.1 min.
[0805]
N-(2-{6-[4-(4-Methylpentyl)-piperazine-1-carbonyl]-2-phenyl-7H-pyrr-
olo[2,3-d]pyrimidin-4-ylamino}-ethyl)-acetamide (26.60): .sup.1H
NMR (CDCl, 200 MHz) .delta. 0.87 (d, 6H, J=6.6 Hz), 1.20 (m, 2H),
1.49 (m, 3H), 1.74 (s, 3H), 2.33 (t, 2H, J=7.5 Hz), 2.44 (brs, 4H),
3.47 (brs, 2H), 3.78 (brs, 6H), 6.60 (brs, 1H), 6.68 (s, 1H), 7.41
(brs, 4H), 8.35 (brs, 2H), 11.11 (brs, 1H). MS (ES) 492.3
[MH.sup.+]. t.sub.R (method A)=4.5 min.
[0806]
N-(2-{6-[4-(4-Bromomphenyl)-4-hydroxypiperidine-1-carbonyl]-2-pheny-
l-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino}-ethyl)-acetamide (26.61):
.sup.1H NMR (CD.sub.3OD, 200 MHz) .delta. 1.80 (brs, 2H), 1.85 (s,
3H), 2.11 (m, 2H), 3.52 (m, 4H), 3.83 (t, 2H, J=6 Hz), 4.51 (d, 2H,
J=12.4 Hz), 6.97 (s, 1H), 7.43-7.48 (m, 7H), 8.42 (m, 2H). MS (ES)
576.5/578.4 [MH.sup.+]. t.sub.R (method A)=7.5 min.
[0807]
N-{2-[2-Phenyl-6-(4-phenylpiperidine-1-carbonyl)-7H-pyrrolo[2,3-d]p-
yrimidin-4-ylamino]-ethyl}-acetamide (26.62): .sup.1H NMR
(CDCl.sub.3, 200 MHz) .delta. 1.63-1.89 (m, 4H), 1.71 (s, 3H), 2.73
(t,1H, J=10.7 Hz), 2.94 (brs, 2H), 3.46 (brs, 2H), 3.71 (brs, 2H),
4.63 (d, 2H, J=12.6 Hz), 6.34 (brs, 1H), 6.74 (s, 1H), 7.15-7.41
(m, 9H), 8.37 (brs, 2H), 11.12 (brs, 1H). MS (ES) 483.0 [MH.sup.+].
t.sub.R (method A)=7.7 min.
[0808]
N-{2-[6-([1,4']Bipiperidinyl-1'-carbonyl)-2-phenyl-7H-pyrrolo[2,3-d-
]pyrimidin-4-ylamino]-ethyl}-acetamide (26.63): .sup.1H NMR
(CDCl.sub.3, 200 MHz) .delta. 1.44 (brs, 2H), 1.70 (brs, 6H), 1.83
(s, 3H), 1.96 (d, 2H), 2.63 (brs, 4H), 2.91 (brs, 3H), 3.62 (brs,
2H), 3.91 (brs, 2H), 4.60 (d, 2H, J=11.4 Hz), 6.74 (brs, 1H), 6.94
(s, 1H), 7.42 (m, 4H), 8.40 (m, 2H), 10.30 (brs, 1H). MS (ES) 489.8
[MH.sup.+]. t.sub.R (method A)=3.9 min.
[0809]
N-{2-[6-(4-Cyclopentylpiperazine-1-carbonyl)-2-phenyl-7H-pyrrolo[2,-
3-d]pyrimidin-4-ylamino]-ethyl}-acetamide (26.64): .sup.1H NMR
(CDCl.sub.3, 200 MHz) .delta. 1.51-1.71 (m, 8H), 1.80 (s, 3H), 2.56
(brs, 4H), 3.33 (t, 1H), 3.59 (m, 6H), 6.12 (brs, 1H), 6.67 (s,
1H), 7.01 (brs, 1H), 7.44 (m, 3H), 8.41 (m, 2H), 9.98 (brs, 1H). MS
(ES) 475.9 [MH.sup.+]. t.sub.R (method A)=4.0 min.
[0810]
N-{2-[6-(4-Aminopiperidine-1-carbonyl)-2-phenyl-7H-pyrrolo[2,3-d]py-
rimidin-4-ylamino]-ethyl}-acetamide (26.65): Prepared from 26.66 by
stirring in TFA followed by basic workup; 25% yield. .sup.1H NMR
(CD.sub.3OD, 200 MHz) .delta. 1.42 (m, 2H), 1.86 (s, 3H), 1.97
(brs, 2H), 3.15 (m, 3H), 3.53 (t, 2H, J=6 Hz), 3.83 (t, 2H, J=6
Hz), 4.50 (d, 2H, J=13.6 Hz), 6.92 (s, 1H), 7.42 (m, 3H), 8.40 (m,
2H), 9.98 (brs, 1H). MS (ES) 421.8 [MH.sup.+]. t.sub.R (method
A)=3.2 min.
[0811]
{1-[4-(2-Acetylaminoethylamino)-2-phenyl-7H-pyrrolo[2,3-d]pyrimidin-
e-6-carbonyl]piperidin-4-yl}-carbamic acid tert-butyl ester
(26.66): .sup.1H NMR (CDCl.sub.3, 200 MHz) .delta. 1.46 (s, 9H),
1.61 (brs, 4H), 1.82 (s, 3H), 2.11 (m, 1H), 3.19 (t, 2H, J=11.2
Hz), 3.60 (q, 2H, J=5 Hz), 3.74 (brs, 1H), 3.91 (m, 2H), 4.50 (d,
2H, J=13.2 Hz), 5.97 (brs, 1H), 6.65 (s, 1H), 6.79 (brs, 1H), 7.45
(m, 3H), 8.43 (m, 2H), 9.44 (brs, 1H). MS (ES) 522.0 [MH.sup.+].
t.sub.R (method A)=7.2 min.
[0812]
N-{2-[6-(4-Methanesulfonylaminopiperidine-1-carbonyl)-2-phenyl-7H-p-
yrrolo[2,3-d]pyrimidin-4-ylamino]-ethyl}-acetamide (26.67):
Prepared from 26.65 and methanesulfonyl chloride in 11% yield.
.sup.1H NMR (CDCl.sub.3, 200 MHz) .delta. 1.49 (m, 2H), 1.76 (s,
3H), 1.97 (m, 2H), 2.90 (s, 3H), 3.25 (brs, 2H), 3.43 (t, 2H,J=6.1
Hz), 3.50 (m, 1H), 3.74 (t, 2H, J=6.1 Hz), 4.31 (d, 2H, J=13.6 Hz),
6.83 (s, 1H), 7.33-7.38 (m, 3H), 8.43 (m, 2H). MS (ES) 500.0
[MH.sup.+]. t.sub.R (method A)=5.4 min.
[0813]
N-(2-{2-Phenyl-6-[4-(toluene-4-sulfonylamino)-piperidine-1-carbonyl-
]-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino}-ethyl)-acetamide (26.68):
Prepared from 26.65 and tosyl chloride in 35% yield. .sup.1H NMR
(CD.sub.3OD, 200 MHz) .delta. 1.80 (m, 2H), 1.89 (s, 3H), 2.35 (s,
1H), 2.43(brs, 2H), 2.49 (s, 3H), 3.54 (t, 2H, J=6.2 Hz), 3.89 (t,
2H, J=6.2 Hz), 4.23 (d, 2H, J=14.4 Hz), 7.07-7.97 (m, 8H), 8.21 (m,
2H). MS (ES) 576.1 [MH.sup.+]. t.sub.R (method A)=7.2 min.
[0814]
N-(2-{6-[4-Hydroxy4-(3-methoxyphenyl)-piperidine-1-carbonyl]-7H-pyr-
rolo[2,3-d]pyrimidin-4-ylamino}-ethyl)-acetamide (26.69): .sup.1H
NMR (CD.sub.3OD, 200 MHz) .delta. 1.80 (brs, 1H), 1.85 (s, 3H),
1.97 (s, 1H), 2.14 (m, 2H), 2.49 (brs, 4H), 3.80 (s, 3H), 3.83 (d,
2H, J=5.8 Hz), 4.44 (d, 2H, J=12.8 Hz), 6.78-6.84 (m, 1H), 6.97 (s,
1H), 7.05-7.13 (m, 2H), 7.26 (t, 1H, J=7.9 Hz), 7.42-7.47 (m, 3H),
8.41 (m, 2H). MS (ES) 529 [MH.sup.+]. t.sub.R (method A)=7.2
min.
[0815]
N-(2-{6-[4-Hydroxy-4-(2-methoxyphenyl)-piperidine-1-carbonyl]-2-phe-
nyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino}-ethyl)-acetamide (26.70):
.sup.1H NMR (CD.sub.3OD, 200 MHz) .delta. 1.74 (d, 1H, J=0.8 Hz),
1.81 (brs, 1H), 1.85 (s, 3H), 2.56 (m, 2H), 0.52 (brs, 4H), 3.80
(d, 2H, J=6.6 Hz), 3.85 (s, 3H), 4.43 (d, 2H, J=13.2 Hz), 6.92-7.01
(m, 3H), 7.25 (m, 1H), 7.42-7.47 (m, 3H), 7.53 (m, 1H), 8.41 (m,
2H). MS (ES) 529.0 [MH.sup.+]. t.sub.R (method A)=6.7 min.
[0816]
N-(2-{6-[4-(4-Chlorophenyl)-piperazine-1-carbonyl]-2-phenyl-7H-pyrr-
olo[2,3-d]pyrimidin-4-ylamino}-ethyl)-acetamide (26.71): .sup.1H
NMR (CD.sub.3OD, 200 MHz) .delta. 1.86 (s, 3H), 3.23 (m, 4H), 3.53
(t, 2H, J=6.2 Hz), 3.84 (t, 2H, J=6.3 Hz), 3.99 (t, 4H, J=4.8 Hz),
6.95-6.99 (m, 3H), 7.20 (d, 2H, J=9.2 Hz), 7.42-7.44 (m, 3H), 8.41
(m, 2H). MS (ES) 517.9/519.9 [MH.sup.+]. t.sub.R (method A)=8.8
min. C.sub.27H.sub.28ClN.sub.7O.sub.2 (518.02): calcd. C 62.60, H
5.45, N 18.93, Cl 6.84; found C, 62.66; H, 5.46; N, 18.39, Cl
6.49.
[0817]
N-(2-{6-[4-(2-Hydroxyethyl)-piperazine-1-carbonyl]-2-phenyl-7H-pyrr-
olo[2,3-d]pyrimidin-4-ylamino}-ethyl)-acetamide (26.72): .sup.1H
NMR (CD.sub.3OD, 200 MHz) .delta. 1.86 (s, 3H), 2.62 (m, 4H), 3.52
(t, 2H, J=6 Hz), 3.71 (t, 2H, J=5.6 Hz), 3.85 (m, 4H), 6.92 (s,
1H), 7.41-7.44 (m, 3H), 8.39 (m, 2H). MS (ES) 451.9 [MH.sup.+].
t.sub.R (method A)=3.6 min.
[0818]
N-{2-[6-(4-Benzoylpiperidine-1-carbonyl)-2-phenyl-7H-pyrrolo[2,3-d]-
pyrimidin-4-ylamino]-ethyl}-acetamide (26.73): .sup.1H NMR
(CDCl.sub.3, 200 MHz) .delta. 1.76 (s, 3H), 1.89 (brs, 3H), 3.19
(brs, 2H); 3.49 (brs, 4H), 3.77 (brs, 2H), 4.45 (d, 2H, J=13.2 Hz),
6.55 (brs, 3H), 6.74 (s, 1H), 7.43-7.62 (m, 6H), 7.90 (d, 2H, J=7.4
Hz), 8.38 (brs, 2H), 10.67 (brs, 1H). MS (ES) 510.9 [MH.sup.+].
t.sub.R (method A)=7.5 min.
[0819]
N-(2-{6-[4-(2-Methoxyphenyl)-piperidine-1-carbonyl]-2-phenyl-7H-pyr-
rolo[2,3-d]pyrimidin-4-ylamino}-ethyl)-acetamide (26.74): .sup.1H
NMR (CDCl.sub.3, 200 MHz) .delta. 1.68 (brs, 2H), 1.78 (s, 3H),
1.90 (d, 2H, J=11.6 Hz), 3.20 (m, 3H), 3.55 (brs, 2H), 3.83 (brs,
5H), 4.77 (brs, 2H), 6.22 (brs, 1H), 6.74 (brs, 1H), 6.89 (q, 2H,
J=6.9 Hz), 7.16 (t, 3H, J=8.8 Hz), 7.43 (brs, 3H), 8.40 (brs, 2H),
10.20 (brs, 1H). MS (ES) 512.9 [MH.sup.+]. t.sub.R (method A)=8.3
min.
[0820]
N-(2-{6-[4-(Hydroxyphenylmethyl)-piperidine-1-carbonyl]-2-phenyl-7H-
-pyrrolo[2,3-d]pyrimidin-4-ylamino}-ethyl)-acetamide (26.75):
.sup.1H NMR (CDCl.sub.3, 200 MHz) .delta. 1.29 (brs, 3H), 1.75 (s,
3H), 1.83-2.08 (m, 2H), 2.87 (brs, 2H), 3.53 (brs, 2H), 3.81 (brs,
2H), 4.33 (d, 1H, J-7 Hz), 4.52 (t, 2H, J=15 Hz), 6.43 (brs, 1H),
6.67 (s, 1H), 7.16 (brs, 1H), 7.26-7.31 (m, 5H), 7.42 (t, 3H, J=2.9
Hz), 8.32 (m, 2H). MS (ES) 512.9 [MH.sup.+]. t.sub.R (method A)=6.8
min.
[0821]
N-{2-[6-(4-Acetyl-4-phenylpiperidine-1-carbonyl)-2-phenyl-7H-pyrrol-
o[2,3-d]pyrimidin-4-ylamino]-ethyl}-acetamide (26.76): .sup.1H NMR
(CDC.sub.3, 200 MHz) .delta. 1.82 (s, 3H), 1.96 (s, 3H), 2.01 (brs,
2H), 2.45 (brs, 2H), 3.58 (brs, 4H), 3.87 (brs, 2H), 4.20 (brs,
2H), 6.24 (brs, 1H), 6.70 (s, 1H), 6.90 (brs, 1H), 7.21-7.43 (m,
7H), 8.37 (brs, 2H), 9.74 (brs, 1H). MS (ES) 524.9 [MH.sup.+].
t.sub.R (method A)=7.6 min.
[0822]
N-(2-{6-[4-(2-Cyclohexylethyl)-piperazine-1-carbonyl]-2-phenyl-7H-p-
yrrolo[2,3-d]pyrimidin-4-ylamino}-ethyl)-acetamide (26.77): .sup.1H
NMR (CDC.sub.3, 200 MHz) .delta. 0.94 (t, 2H, J=10.8 Hz), 1.20-1.44
(m, 7H), 1.67-1.73 (m, 4H), 1.77 (s, 3H), 2.46 (m, 6H), 3.53 (brs,
2H), 3.81 (brs, 6H), 6.31 (brs, 1H), 6.67 (s, 1H), 7.18 (brs, 1H),
7.40-7.44 (t, 3H, J=3.1 Hz), 8.38 (m, 2H), 10.56 (brs, 1H). MS (ES)
517.9 [MH.sup.+]. t.sub.R (method A)=4.8 min.
[0823]
N-{2-[6-(4-Ethynyl-4-hydroxypiperidine-1-carbonyl)-2-phenyl-7H-pyrr-
olo[2,3-d]pyrimidin-4-ylamino]-ethyl}-acetamide (26.78): .sup.1H
NMR (CDC.sub.3, 200 MHz) .delta. 1.83 (s, 3H), 1.89 (m, 2H), 2.04
(m, 2H), 2.61 (s, 1H), 3.64 (m, 2H), 3.74 (m, 2H), 3.91 (s, 2H),
4.20 (m, 2H), 6.68 (brs, 1H), 6.74 (s, 1H), 7.45-7.48 (m, 3H), 8.42
(m, 2H). MS (ES) 446.8 [MH.sup.+]. t.sub.R (method A)=5.5 min.
[0824]
N-{2-[2-Phenyl-6-(4-phenylethynyl-3,6-dihydro-2H-pyridine-1-carbony-
l)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino]-ethyl}-acetamide (26.79):
.sup.1H NMR (CDCl.sub.3, 200 MHz) .delta. 1.83 (s, 3H), 2.50 (brs,
2H), 3.56 (q, 2H, J=6 Hz), 3.84 (t, 2H, J=5.2 Hz), 4.00 (t, 2H,
J=5.7 Hz), 4.44 (brs, 2H), 6.25 (brs, 1H), 7.07 (s, 1H), 7.37-7.45
(m, 10H), 8.54 (m, 2H). MS (ES) 504.9 [MH.sup.+]. t.sub.R (method
A)=8.7 min.
[0825]
N-(2-{2-Phenyl-6-[4-(2-phenylcyclopropanecarbonyl)-piperazine-1-car-
bonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino}-ethyl)-acetamide
(26.80): .sup.1H NMR (CDCl.sub.3, 200 MHz) .delta. 1.32.(m, 1H),
1.68 (p, 1H, J=4.6 Hz), 1.95 (p, 1H, J=3.8 Hz), 2.51 (m, 1H), 3.56
(brs, 2H), 3.70 (brs, 4H), 3.83 (brs, 6H), 6.47 (brs, 1H), 6.74
(brs, 1H), 7.00 (brs, 1H), 7.12 (d, 2H, J=6.6 Hz), 7.21-7.33 (m,
3H), 7.41 (brs, 3H), 8.38 (brs, 2H), 10.39 (brs, 1H). MS (ES) 552.2
[MH.sup.+]. t.sub.R (method A)=7.3 min.
[0826]
N-(2-{6-[4-(4-Chlorobenzyl)-piperidine-1-carbonyl]-2-phenyl-7H-pyrr-
olo[2,3-d]pyrimidin-4-ylamino}-ethyl)-acetamide (26.81): .sup.1H
NMR (CDCl.sub.3, 200 MHz) .delta. 1.70 (m, 3H), 1.80 (s, 3H), 2.07
(d, 2H, J=5.2 Hz), 2.52 (d, 2H, J=6.2 Hz), 2.94 (brs, 2H), 3.57
(brs, 2H), 3.88 (brs, 2H), 4.54 (d, 2H, J=13.8 Hz), 6.07 (brs, 1H),
6.66 (s, 1H), 6.99-7.46 (m, 8H), 8.41 (q, 2H, J=3.2 Hz), 9.69 (brs,
1 Hz. MS (ES) 530.9/532.9 [MH.sup.+]. t.sub.R (method A)=9.1
min
[0827]
N-(2-(6-{4-[(4-Chlorophenyl)-hydroxymethyl]-piperidine-1-carbonyl}--
2-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-ethyl]-acetamide
(26.82): .sup.1H NMR (CDCl.sub.3, 200 MHz) .delta. 1.43 (brs, 3H),
1.79 (s, 3H), 1.86 (m, 2H), 2.01 (brs, 2H), 2.93 (brs, 2H), 3.59
(brs, 2H), 3.88 (brs, 2H), 4.39 (d, 1H, J=6.8 Hz), 4.61 (t, 2H,
J=2.9 Hz), 6.03 (brs, 1H), 6.65 (s, 1H), 6.89 (brs, 1H), 7.21-7.34
(m, 5H), 7.43 (t, 3H, J=6.2 Hz), 8.41 (m, 2H). MS (ES) 547.1/549.0
[MH.sup.+]. t.sub.R (method A)=7.4 min.
[0828]
N-{2-[2-Phenyl-6-(4-prop-2-ynylpiperazine-1-carbonyl)-7H-pyrrolo[2,-
3-d]pyrimidin-4-ylamino]-ethyl}-acetamide (26.83): Prepared from
30a in 43% yield. .sup.1H NMR (CD.sub.3COCD.sub.3, 200 MHz) .delta.
1.82 (s, 3H), 2.62 (t, 4H, J=5 Hz), 2.74 (t, 2H, J=2.2 Hz), 3.40
(d, 2H, J=2.2 Hz), 3.56 (q, 2H, J=3.1 Hz), 3.84 (m, 6H), 6.95 (s,
1H), 7.43(m, 4H), 8.54 (m, 2H). MS (ES) 445.9 [MH.sup.+]. t.sub.R
(method A)=4.5 min.
[0829]
N-(2-{6-[4-(2-Benzyloxyethyl)-piperidine-1-carbonyl]-2-phenyl-7H-py-
rrolo[2,3-d]pyrimidin-4-ylamino}-ethyl)-acetamide (26.84): .sup.1H
NMR (CDCl.sub.3, 200 MHz) .delta. 1.20 (m, 3H), 1.57 (m, 2H), 1.73
(brs, 2H), 1.78 (s, 3H), 2.94 (brs, 2H), 3.50 (m, 4H), 3.83 (brs,
2H), 4.49 (s, 2H), 4.55 (brs, 2H), 6.22 (brs, 11H), 6.66 (s, 1H),
7.13 (brs, 1H), 7.33-7.44 (m, 8H), 8.40 (m, 2H), 10.12 (brs, 1H).
MS (ES) 540.9 [MH.sup.+]. t.sub.R (method A) 8.5 min.
[0830]
1-[4-(2-Acetylaminoethylamino)-2-phenyl-7H-pyrrolo[2,3-d]pyrimidine-
-6-carbonyl]-4-phenylpiperidine-4-carboxylic acid (26.85): .sup.1H
NMR (CD.sub.3COCD.sub.3, 200 MHz) .delta. 1.82 (s, 3H), 2.68 (d,
2H, J=13.4 Hz), 3.41 (m, 2H), 3.55 (m, 2H), 3.84 (t, 2H, J=5.5 Hz),
4.50 (d, 2H, J=13.6 Hz), 7.00 (s, 1H), 7.42 (m, 9H), 8.52 (m, 2H),
10.82 (brs, 1H). MS (ES) 526.8 [MH.sup.+]. t.sub.R (method B)=6.7
min.
[0831]
N-{2-[6-(4-tert-Butylpiperidine-1-carbonyl)-2-phenyl-7H-pyrrolo[2,3-
-d]pyrimidin-4-ylamino]-ethyl}-acetamide (26.86): .sup.1H NMR
(CDCl.sub.3, 200 MHz) .delta. 1.33 (m, 3H), 1.61 (brs, 9H), 1.81
(s, 3H), 1.85 (brs, 2H), 2.96 (brs, 2H), 3.62 (m, 2H), 3.92 (m,
2H), 4.74 (d, 2H, J=12.4 Hz), 5.82 (brs, 1H), 6.65 (s, 1H), 6.85
(brs, 1H), 7.46 (m, 3H), 8.44 (m, 2H), 9.42 (brs, 1H). MS (ES)
462.9 [MH.sup.+]. t.sub.R (method A)=8.6 min.
[0832]
N-{2-[6-(1,4-Dioxa-8-azaspiro[4.5]decane-8-carbonyl)-2-phenyl-7H-py-
rrolo[2,3-d]pyrimidin-4-ylamino]-ethyl}-acetamide (26.87): .sup.1H
NMR (CDCl.sub.3, 200 MHz) .delta. 1.74 (brs, 7H), 3.49 (m, 2H),
3.84 (m, 6H), 3.96 (s, 4H), 6.55 (brs, 1H), 6.69 (s, 1H), 7.30
(brs, 1H), 7.40 (m, 3H), 8.31 (m, 2H), 9.42 (brs, 1H). MS (ES)
464.8 [MH.sup.+]. t.sub.R (method A)=5.9 min.
[0833]
N-{2-[6-(4-Phenethylpiperidine-1-carbonyl)-2-phenyl-7H-pyrrolo[2,3--
d]pyrimidin-4-ylamino]-ethyl}-acetamide (26.88): .sup.1H NMR
(CDCl.sub.3, 200 MHz) .delta. 1.63 (brs, 5H), 1.81 (s, 3H), 1.85
(m, 2H), 2.67 (t, 2H, J=7.8 Hz), 3.03 (brs, 2H), 3.61.(brs, 2H),
3.91 (brs, 2H), 4.65 (brs, 2H), 5.90 (brs, 1H), 6.66 (s, 1H), 6.86
(brs, 1H), 7.17-7.26 (m, 5H), 7.45 (brs, 3H), 8.42 (brs, 2H), 9.58
(brs, 1H). MS (ES) 510.8 [MH.sup.+]. t.sub.R (method A)=9.0
min.
[0834] General Procedure for Soniogashira Reaction with 26.83:
[0835] Combine acetylene 26.83 (20 mg, 0.0449 mmol),
2-iodobenzonitrile (12.4 mg, 1.2 eq.) and diethylamine (1 ml) and
stir under N.sub.2 at rt for 3 h. Add Pd(PPh.sub.3).sub.2Cl.sub.2
(1.6 mg, 5% eq.) and CuI (0.5 mg, 5% eq.). After 3 h, remove
solvent and pour into 10 ml of H.sub.2O. Extracted with 5.times.8
ml of EtOAc, washed with 2.times.10 ml of H.sub.2O and 10 ml of
brine, dried over MgSO.sub.4. The crude material is purified by
prep. TLC.
[0836] The following 3 compounds 26.89-26.91 were synthesized by
this method:
[0837]
N-[2-(6-{4-[3-(2-Cyanophenyl)-prop-2-ynyl]-piperazine-1-carbonyl}-2-
-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-ethyl]-acetamide
(26.89): .sup.1H NMR (CDCl.sub.3, 200 MHz) .delta. 1.78 (s, 3H),
2.87 (brs, 4H), 3.62 (brs, 2H), 3.76 (s, 2H), 3.93 (brs, 6H), 6.05
(brs, 1H), 6.86 (s, 1H), 7.08 (brs, 1H), 7.46 (brs, 4H), 7.56 (m,
2H), 7.66 (d, 2H, J=8 Hz), 8.44 (brs, 2H), 9.45 (brs, 1H). MS (ES)
546.9 [MH.sup.+]. t.sub.R (method A)=6.4 min.
[0838]
N-[2-(6-{4-[3-(3-Cyanophenyl)-prop-2-ynyl]-piperazine-1-carbonyl}-2-
-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-ethyl]-acetamide
(26.90): .sup.1H NMR (CDCl.sub.3, 200 MHz) .delta. 1.84 (s, 3H),
2.74 (brs, 4H), 3.61 (brs, 4H), 3.96 (brs, 6H), 6.70 (s, 1H), 7.46
(brs, 4H), 7.58-7.78 (m, 4H), 8.42 (m, 2H), 9.40 (brs, 1H). MS (ES)
546.8 [MH.sup.+]. t.sub.R (method A)=6.3 min.
[0839]
N-[2-(6-{4-[3-(4-Cyanophenyl)-prop-2-ynyl]-piperazine-1-carbonyl}-2-
-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-ethyl]-acetamide
(26.91): .sup.1H NMR (CDCl.sub.3, 200 MHz) .delta. 1.83 (s, 3H),
2.73 (brs, 4H), 3.62 (brs, 4H), 3.98 (brs, 6H), 5.93 (brs, 1H),
6.69 (brs, 2H), 7.46 (m, 4H), 7.58 (t, 3H, J=9.2 Hz), 8.44 (brs,
2H), 9.40 (brs, 11H). MS (ES) 546.9 [MH.sup.+]. t.sub.R (method
A)=6.4 min.
[0840]
1-[4-(2-Acetylaminoethylamino)-2-phenyl-7H-pyrrolo[2,3-d]pyrimidine-
-6-carbonyl]-4-phenylpiperidine-4-carboxylic acid methyl ester
(26.92): .sup.1H NMR (CDCl.sub.3, 200 MHz) .delta. 1.80 (s, 3H),
1.96 (m, 2H), 2.63 (t, 2H, J=6.9 Hz), 3.35 (brs, 2H), 3.57 (brs,
2H), 3.70 (s, 3H), 3.86 (brs, 2H), 4.46 (brs, 2H), 6.21 (brs, 1H),
6.73 (s, 1H), 7.00 (brs, 1H), 7.34-7.41 (m, 8H), 8.39 (brs, 2H),
9.90 (brs, 1H). MS (ES) 540.8 [MH.sup.+]. t.sub.R (method A)=7.8
min.
[0841]
N-(2-{6-[4-(-Hydroxyethyl)-4-phenylpiperidine-1-carbonyl]-2-phenyl--
7H-pyrrolo[2,3-d]pyrimidin-4-ylamino}-ethyl)-acetamide (26.93):
.sup.1H NMR (CDCl.sub.3, 200 MHz) .delta. 0.98 (d, 3H, J=6.2 Hz),
1.78 (s, 3H), 1.86 (brs, 2H), 2.20 (d, 1H, J=10.2 Hz), 2.44 (d, 1H,
J=12.6 Hz), 3.02 (brs, 2H), 3.60 (m, 3H), 3.83 (brs, 2H), 4.40 (d,
2H, J=11 Hz), 6.37 (brs, 1H), 6.66 (s, 1H), 7.12 (brs, 1H),
7.27-7.39 (m, 8H), 8.34 (t, 2H, J=3.7 Hz), 10.50 (brs, 11H). MS
(ES) 526.9 [MH.sup.+]. t.sub.R (method A)=6.9 min.
[0842]
N-[2-(6-{4-[3-(4-Cyanophenyl)-propyl]-piperazine-1-carbonyl}-2-phen-
yl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-ethyl]-acetamide (26.94):
.sup.1H NMR (CDCl.sub.3, 200 MHz) .delta. 1.82 (brs, 5H), 2.39 (t,
2H, J=7 Hz), 2.50 (brs, 4H), 2.72 (t, 2H, J=7.5 Hz), 3.60 (brs,
2H), 3.87 (brs, 6H), 6.13 (brs, 1H), 6.68 (s, 1H), 6.88 (brs, 1H),
7.31 (brs, 2H), 7.44 (brs, 3H), 7.60 (d, 2H, J=8 Hz), 8.40 (m, 2H),
9.78 (brs, 1H). MS (ES) 550.9 [MH.sup.+]. t.sub.R (method A)=5.4
min.
[0843]
1-[4-(2-Acetylaminoethylamino)-2-phenyl-7H-pyrrolo[2,3-d]pyrimidine-
-6-carbonyl]-4-phenylpiperidine-4-carboxylic acid ethyl ester
(26.95): .sup.1H NMR (CDCl.sub.3, 200 MHz) .delta. 1.21 (t, 3H,
J=7.6 Hz), 1.81 (s, 3H), 2.01 (m, 2H), 2.64 (m, 2H), 3.40 (brs,
2H), 3.60 (brs, 2H), 3.91 (brs, 2H), 4.20 (q, 2H, J=7.2), 4.47
(brs, 2H), 6.03 (brs, 1H), 6.71 (s, 1H), 6.91 (brs, 1H), 7.34-7.44
(m, 8H), 8.44 (brs, 2H), 9.70 (brs, 1H). MS (ES) 555.0 [MH.sup.+].
t.sub.R (method A)=7.8 min.
[0844]
N-{2-[6-(4-Benzyloxypiperidine-1-carbonyl)-2-phenyl-7H-pyrrolo[2,3--
d]pyrimidin-4-ylamino]-ethyl}-acetamide (26.96): .sup.1H NMR
(CDCl.sub.3, 200 MHz) .delta. 1.22 (m, 1H), 1.71 (s, 3H), 1.82
(brs, 2H), 3.43 (brs, 2H), 3.66 (m, 6H), 3.96 (brs, 2H), 4.53 (s,
2H), 6.66 (brs, 1H), 6.71 (s, 1H), 7.33-7.44 (m,8H), 8.36 (m, 2H),
11.14 (brs, 1H). MS (ES) 512.9 [MH.sup.+]. t.sub.R (method A)=7.5
min.
[0845] Amide Formation with 26.85:
[0846] Acid 26.85 (16 mg, 0.0304 mmol) and triethylamine (8.51lw, 2
eq.) were dissolved in DMF (2 ml) and cooled in ice bath. 5 min.
later, TBTU (11.7 mg, 1.2 eq.) was added. 30 min later, pyrrolidine
(3.1 .mu.l, 1.2 eq.) was added and then stirred at rt for 2 days.
The reaction mixture was poured into 10 ml of 5% HOAc aqueous
solution, extracted with 5.times.8 ml of EtOAc, washed with 8 ml of
5% HOAc aqueous solution, 2.times.8 ml of H.sub.2O and 8 ml of
brine, dried over MgSO.sub.4. Filter out and remove solvent and
purify by TLC to obtain 12.6 mg of 26.104 as off-white solid.
[0847] The amides 26.97-26.107 were prepared by this method.
[0848]
1-[4-(2-Acetylaminoethylamino)-2-phenyl-7H-pyrrolo[2,3-d]pyrimidine-
-6-carbonyl]-4-phenylpiperidine-4-carboxylic acid amide (26.97):
.sup.1H NMR (CDCl.sub.3, 200 MHz) .delta. 1.80 (s, 3H), 2.17 (brs,
2H), 2.48 (brs, 2H), 3.61 (brs, 2H), 3.90 (brs, 2H), 4.11 (brs,
2H), 5.30 (brs, 1H), 5.52 (brs, 1H), 5.99 (brs, 1H), 6.70 (s, 1H),
6.86 (brs, 1H), 7.32-7.46 (m, 8H), 8.41 (m, 2H), 9.64 (brs, 1H). MS
(ES) 525.9 [MH.sup.+]. t.sub.R (method B)=12.6 min.
[0849]
1-[4-(2-Acetylaminoethylamino)-2-phenyl-7H-pyrrolo[2,3-d]pyrimidine-
-6-carbonyl]-4-phenylpiperidine-4-carboxylic acid methylamide
(26.98): .sup.1H NMR (CDCl.sub.3, 200 MHz) .delta. 1.71 (s, 3H),
2.13 (brs, 2H), 2.41 (brs, 2H), 3.66 (d, 3H, J=4.8 Hz), 3.48 (brs,
2H), 3.81 (m, 4H), 3.93 (brs, 2H), 5.87 (d, 1H, J=4.4 Hz), 6.76 (s,
1H), 7.29-7.39 (m, 8H), 7.64 (brs, 1H), 8.29 (brs, 2H). MS (ES)
539.9 [MH.sup.+]. t.sub.R (method B)=13.0 min.
[0850]
1-[4-(2-Acetylaminoethylamino)-2-phenyl-7H-pyrrolo[2,3-d]pyrimidine-
-6-carbonyl]-4-phenylpiperidine-4-carboxylic acid dimethylamide
(26.99): .sup.1H NMR (CDCl.sub.3, 200 MHz) .delta. 1.75 (s, 3H),
2.41 (d, 2H, J=13.2 Hz), 2.50-3.00 (brs, 6H), 3.35 (brs, 4H), 3.86
(brs, 4H), 4.41 (brs, 2H), 6.38 (t, 1H, J=5.2 Hz), 6.74 (s, 1H),
7.20-7.43 (m, 8H), 8.41 (m, 2H), 10.09 (brs, 1H). MS (ES) 553.9
[MH.sup.+]. t.sub.R (Method B)=14.5 min.
[0851]
1-[4-(2-Acetylaminoethylamino)-2-phenyl-7H-pyrrolo[2,3-d]pyrimidine-
-6-carbonyl]-4-phenylpiperidine-4-carboxylic acid benzylamide
(26.100): .sup.1H NMR (CDCl.sub.3, 200 MHz) .delta. 1.80 (s, 3H),
2.17 (brs, 2H), 2.49 (brs, 2H), 3.59 (brs, 2H), 3.89 (brs, 4H),
4.09 (brs, 2H), 4.36 (brs, 2H), 5.57 (brs, 1H), 6.71 (s, 1H), 7.04
(m, 3H), 7.23-7.43 (m, 1H), 8.40 (brs, 2H), 9.59 (brs, 1H). MS (ES)
615.9 [MH.sup.+]. t.sub.R (method A).=7.7 min.
[0852]
1-[4-(2-Acetylaminoethylamino)-2-phenyl-7H-pyrrolo[2,3-d]pyrimidine-
-6-carbonyl]-4-phenylpiperidine-4-carboxylic acid ethylamide
(26.101): .sup.1H NMR (CDCl.sub.3, 200 MHz) .delta. 1.00 (t, 3H,
J=7.2 Hz), 1.78 (s, 3H), 2.20 (brs, 2H), 2.44 (brs, 2H), 3.21 (d,
2H, J=6.4 Hz), 3.56 (brs, 2H), 3.85 (brs, 4H), 4.03 (brs, 2H), 5.30
(brs, 1H), 6.21 (brs, 1H), 6.71 (s, 1H), 7.04 (brs, 1H), 7.37-7.40
(m, 8H), 8.38 (brs, 2H), 9.97 (brs, 1H). MS (ES) 553.9 [MH.sup.+].
t.sub.R (method A)=6.6 min.
[0853]
1-[4-(2-Acetylaminoethylamino)-2-phenyl-7H-pyrrolo[2,3-d]pyrimidine-
-6-carbonyl]-4-phenylpiperidine-4-carboxylic acid diethylamide
(26.102): .sup.1H NMR (CDCl.sub.3, 200 MHz) .delta. 0.68 (brs, 3H),
1.23 (brs, 3H), 1.76 (s, 3H), 2.39 (d, 2H), 2.91 (brs, 2H), 3.33
(brs, 2H), 3.58 (brs, 4H), 3.88 (brs, 4H), 4.40 (brs, 2H), 6.24
(brs, 1H), 6.74 (s, 1H), 7.15 (brs, 1H), 7.22-7.44 (m, 8H), 8.42
(m, 2H), 9.97 (brs, 1H). MS (ES) 581.9 [MH.sup.+]. t.sub.R (method
B)=16.5 min.
[0854]
N-(2-{6-[4-(Azetidine-1-carbonyl)-4-phenylpiperidine-1-carbonyl]-2--
phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino}-ethyl)-acetamide
(26.103): .sup.1H NMR (CDCl.sub.3, 200 MHz) .delta. 1.76 (s, 3H),
1.80 (brs, 2H), 2.02 (t, 4H, J=7.4 Hz), 2.43 (d, 2H, J=12 Hz), 3.57
(brs, 4H), 3.87 (brs, 2H), 3.99 (brs, 2H), 4.38 (brs, 2H), 6.38
(brs, 1H), 6.74 (s, 1H), 7.22-7.40 (m, 9H), 8.41 (m, 2H), 10.01
(brs, 1H). MS (ES) 556.0 [MH.sup.+]. t.sub.R (method B)=14.6
min.
[0855]
N-(2-{2-Phenyl-6-[4-phenyl-4-(pyrrolidine-1-carbonyl)-piperidine-1--
carbonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino}-ethyl)-acetamide
(26.104): .sup.1H NMR (CDCl.sub.3, 200 MHz) .delta. 1.56 (brs, 4H),
1.76 (brs, 4H), 1.78 (s, 3H), 2.47 (d, 2H), 2.82 (brs, 2H), 3.57
(brs, 4H), 3.89 (brs, 2H), 4.40 (brs, 2H), 6.22 (brs, 1H), 6.74 (s,
1H), 7.10 (brs, 1H), 7.22-7.43 (m, 8H), 8.42 (m, 2H), 9.80 (brs,
1H). MS (ES) 580.0 [MH.sup.+]. t.sub.R (method B)=15.6 min.
[0856]
N-(2-{2-Phenyl-6-[4-phenyl-4-(piperidine-1-carbonyl)-piperidine-1-c-
arbonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino}-ethyl)-acetamide
(26.105): .sup.1H NMR (CDCl.sub.3, 200 MHz) .delta. 1.48 (brs, 4H),
1.68 (brs, 4H), 1.79 (s, 3H), 2.41 (d, 2H), 3.32 (brs, 4H), 3.61
(brs, 4H), 4.46 (brs, 2H), 6.06 (brs, 1H), 6.72 (s, 1H), 7.04 (brs,
1H), 7.24-7.46 (m, 8H), 8.43 (m, 2H), 9.66 (brs, 1H). MS (ES) 593.9
[MH.sup.+]. t.sub.R (method A)=7.9 min.
[0857]
N-(2-{6-[4-(Morpholine-4-carbonyl)-4-phenylpiperidine-1-carbonyl]-2-
-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino}-ethyl)-acetamide
(26.106): .sup.1H NMR (CDCl.sub.3, 200 MHz) .delta. 1.80 (s, 3H),
2.38 (d, 2H), 3.35 (brs, 8H), 3.61 (brs, 4H), 3.90 (brs, 4H), 4.47
(brs, 2H), 6.05 (brs, 1H), 6.72 (s, 1H), 6.96 (brs, 1H), 7.24-7.44
(m, 8H), 8.43 (m, 2H), 9.66 (brs, 1H). MS (ES) 595.9 [MH.sup.+].
t.sub.R (method B)=14.2 min.
[0858]
1-[4-(2-Acetylaminoethylamino)-2-phenyl-7H-pyrrolo[2,3-d]pyrimidine-
-6-carbonyl]-4-phenylpiperidine-4-carboxylic acid tert-butylamide
(26.107): .sup.1H NMR (CDCl.sub.3, 200 MHz) .delta. 1.24 (s, 9H),
1.81 (s, 3H), 2.40 (d, 2H), 3.61 (brs, 4H), 3.91 (brs, 4H), 4.11
(brs, 2H), 6.01 (brs, 1H), 6.72 (s, 1H), 6.91 (brs, 1H), 7.30-7.45
(m, 8H), 8.41 (m, 2H), 9.56 (brs, 1H). MS (ES) 581.9 [MH.sup.+].
t.sub.R (method A)=7.8 min.
[0859]
N-{2-[6-(4-Methyl-4-phenylpiperidine-1-carbonyl)-2-phenyl-7H-pyrrol-
o[2,3-d]pyrimidin-4-ylamino]-ethyl}-acetamide (26.108): .sup.1H NMR
(CDCl.sub.3, 200 MHz) .delta. 1.30 (s, 3H), 1.77 (m, 5H), 2.18
(brs, 2H), 3.54 (brs, 2H), 3.69 (brs, 2H), 3.81 (brs, 4H), 6.20
(brs, 1H), 6.67 (s, 1H), 7.09 (brs, 1H), 7.23-7.42 (m, 8H), 8.40
(m, 2H), 10.23 (brs, 1H). MS (ES) 496.9 [MH.sup.+]. t.sub.R (method
A)=7.9 min.
[0860]
N-(2-{6-[4-(1-Hydroxy-1-methylethyl)-4-phenylpiperidine-1-carbonyl]-
-2-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino}-ethyl)-acetamide
(26.109): .sup.1H NMR (CDCl.sub.3, 200 MHz) .delta. 1.09 (s, 6H),
1.79 (s, 3H), 1.97 (t, 2H, J=12.8 Hz), 2.41 (d, 2H, J=13 Hz), 2.87
(brs, 2H), 3.57 (brs, 2H), 3.69 (s, 1H), 3.85 (brs, 2H), 4.50 (d,
2H, J=9.8 Hz), 6.11 (brs, 1H), 6.64 (s, 1H), 7.02 (brs, 1H),
7.29-7.40 (m, 8H), 8.37 (brs, 2H), 10.01 (brs, 1H). MS (ES) 540.9
[MH.sup.+]. t.sub.R (method A)=7.0 min.
[0861]
N-{2-[6-(4-Isopropyl-4-phenylpiperidine-1-carbonyl)-2-phenyl-7H-pyr-
rolo[2,3-d]pyrimidin-4-ylamino]-ethyl}-acetamide (26.110): .sup.1H
NMR (CDCl.sub.3, 200 MHz) .delta. 1.15 (brs, 2H), 1.24 (s, 6H),
1.48 (d, 2H, J=11.6 Hz), 1.69 (m, 1H), 1.75 (s, 3H), 2.76 (brs,
2H), 3.51 (brs, 2H), 3.79 (brs, 2H), 4.52 (d, 2H, J=11 Hz), 6.32
(brs, 1H), 6.64 (s, 1H), 7.13-7.42 (m, 9H), 8.38 (brs, 2H), 10.41
(brs, 1H). MS (ES) 524.9 [MH.sup.+]. t.sub.R (method A) =8.8
min.
[0862]
N-(2-{2-Phenyl-6-[4-(3-thiophen-2-yl-prop-2-ynyl)-piperazine-1-carb-
onyl]-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino}-ethyl)-acetamide
(26.111): .sup.1H NMR (CDCl.sub.3, 200 MHz) .delta. 1.81 (s, 3H),
2.71 (brs, 4H), 3.61 (brs, 4H), 3.94 (brm, 6H), 5.94 (brs, 1H),
6.69 (s, 1H), 6.83 (brs, 1H), 6.96 (dd, 1H, J=5 Hz, J=3.8 Hz),
7.22(m, 2H), 7.45 (brd, 3H), 8.40 (brd, 2H), 9.62 (brs, 1H).
[0863]
1-[4-(2-Acetylaminoethylamino)-2-phenyl-7H-pyrrolo[2,3-d]pyrimidine-
-6-carbonyl]-4-phenylpiperidine4-carboxylic acid cyclobutylmethyl
ester (26.112): .sup.1H NMR (CDCl.sub.3, 200 MHz) .delta. 0.89-1.34
(m, 7H), 1.70 (t, 2H, J=10 Hz), 1.78 (s, 3H), 2.02 (brt, 2H), 2.53
(d, 2H, J=13.6 Hz), 3.42 (brt, 2H), 3.59 (brs, 2H), 3.89 (brs, 2H),
4.39 (d, 2H, J=12.4 Hz), 6.04(brs, 1H), 6.15 (brs, 1H), 6.73 (s,
1H), 7.09 (brs, 1H), 7.26-7.45 (m, 7H), 8.42 (m, 2H).
[0864]
2-{6-[4-(4-Fluorobenzyl)-piperidine-1-carbonyl]-2-phenyl-7H-pyrrolo-
[2,3-d]pyrimidin-4-ylamino}-acetamide (26.113): -.sup.1H NMR
(CDCl.sub.3, 200 MHz) .delta. 1.30 (brs, 2H), 1.75 (s, 3H), 1.81
(bis, 3H), 2.55 (m, 2H), 2.96 (brs, 2H), 4.42 (d, 2H, J=5 Hz), 4.58
(d, 2H, J=14.2 Hz), 5.52 (brs, 1H), 5.89 (brs, 1H), 6.28 (brs, 1H),
6.65 (s, 1H), 6.95-7.15 (m, 4H), 7.46 (m, 3H), 8.41 (m, 2H).
[0865]
N-(2-{6-[4-(4-Chlorophenyl)-4-methoxypiperidine-1-carbonyl]-2-pheny-
l-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino}-ethyl)-acetamide (26.114):
.sup.1H NMR (CDCl.sub.3, 200 MHz) .delta. 1.77 (s, 3H), 1.87-2.12
(m, 4H), 2.95 (s, 3H), 3.51 (brs, 4H), 3.78 (brs, 2H), 4.40 (d, 2H,
J=10.6 Hz), 6.47 (brs, 1H), 6.74 (s, 1H), 7.23-7.41 (m, 8H), 8.35
(m, 2H), 10.83 (brs, 1H). MS (ES) 547.0/549.0 [MH.sup.+]. t.sub.R
(method A)=8.6 min.
[0866]
N-(2-{6-[4-Methoxy-4-(3-trifluoromethylphenyl)-piperidine-1-carbony-
l]-2-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino}-ethyl)-acetamide
(26.115): .sup.1H NMR (CDCl.sub.3, 200 MHz) .delta. 1.80 (s, 3H),
1.90-2.18 (m, 4H), 3.03 (s, 3H), 3.59 (brs, 4H), 3.86 (brs, 2H),
4.51 (d, 2H, J=13.4 Hz), 6.10 (brs, 1H), 6.72 (s, 1H), 6.92 (brs,
1H), 7.42-7.64 (m, 8H), 8.38 (m, 2H), 10.05 (brs, 1H). MS (ES) 581
[MH.sup.+]. t.sub.R (method A)=8.8 min.
[0867]
N-{2-[6-(4-Isopropyl-4-methoxypiperidine-1-carbonyl)-2-phenyl-7H-py-
rrolo[2,3-d]pyrimidin-4-ylamino]-ethyl}-acetamide (26.116): .sup.1H
NMR (CDCl.sub.3, 200 MHz) .delta. 0.91 (d, 6H, J=6.8 Hz), 1.69 (m,
4H), 1.80 (s, 3H), 1.99 (m, 1H), 3.19 (s, 3H), 3.61 (brs, 4H), 3.89
(brs, 2H), 4.41 (d, 2H, J=12.4 Hz), 6.03 (brs, 1H), 6.68 (s, 1H),
6.96 (brs, 1H), 7.45 (m, 3H), 8.39 (m, 2H), 9.89 (brs, 1H). MS (ES)
478.9 [MH.sup.+]. t.sub.R (method A)=7.0 min.
[0868]
N-{2-[6-(4-Acetylamino-4-phenylpiperidine-1-carbonyl)-2-phenyl-7H-p-
yrrolo[2,3-d]pyrimidin-4-ylamino]-ethyl}-acetamide (26.117):
.sup.1H NMR (CDCl.sub.3, 200 MHz) .delta. 1.65 (s, 3H), 1.88 (s,
3H), 2.50 (brs, 6H), 3.36 (m, 2H), 3.67 (m, 2H), 4.26 (d, 2H,
J=13.2 Hz), 6.76 (s, 1H), 6.94 (brs, 1H), 7.05-7.25 (m, 8H), 7.48
(brs, 1H), 8.28 (m, 2H), 10.34 (brs, 1H). MS (ES) 540 [MH.sup.+].
t.sub.R (method B)=13.5 min.
[0869]
1-[4-(2-Acetylaminoethylamino)-2-phenyl-7H-pyrrolo[2,3-d]pyrimidine-
-6-carbonyl]-4-phenylpiperidine-4-carboxylic acid isopropyl ester
(26.118): .sup.1H NMR (CDCl.sub.3, 200 MHz) .delta. 1.19 (d, 6H,
J=6.2 Hz), 1.77 (s, 3H), 1.93 (t, 2H, J=11 Hz), 2.60 (d, 2H, J=12.8
Hz), 3.32 (brs, 2H), 3.54 (brs, 2H), 3.82 (brs, 2H), 4.42 (d, 2H,
J=13.2 Hz), 5.05 (m, 1H, J=6.2 Hz), 6.31 (brs, 1H), 6.72 (s, 1H),
7.12 (brs, 1H), 7.31-7.42 (m, 8H), 8.35 (m, 2H), 10.46 (brs, 1H).
MS (ES) 568.9 [MH.sup.+]. t.sub.R (method A)=8.4 min.
[0870]
1-[4-(2-Acetylaminoethylamino)-2-phenyl-7H-pyrrolo[2,3-d]pyrimidine-
-6-carbonyl]-4-ethylaminopiperidine-4-carboxylic acid amide
(26.119): .sup.1H NMR (CD.sub.3OD, 200 MHz) 6.1.13 (t, 3H, J=7 Hz),
1.74 (m, 2H), 1.85 (s, 3H), 2.09 (m, 2H), 2.55 (q, 2H, J=7.1 Hz),
3.52 (t, 2H, J=6 Hz), 3.83 (t, 4H, J=6 Hz), 3.94 (m, 2H), 6.92 (s,
1H), 7.41-7.47 (m, 3H), 8.39-8.44 (m, 2H). MS (ES) 493.0
[MH.sup.+]. t.sub.R (method A)=6.6 min.
[0871]
1-[4-(2-Acetylaminoethylamino)-2-phenyl-7H-pyrrolo[2,3-d]pyrimidine-
-6-carbonyl]-4-phenylaminopiperidine-4-carboxylic acid amide
(26.120): .sup.1H NMR (CD.sub.3OD, 200 MHz) .delta. 1.84 (s, 3H),
2.13 (m, 4H), 3.51 (m, 4H), 3.82 (t, 2H, J=6 Hz), 4.24 (d, 2H,
J=6.9 Hz), 6.67-6.74 (m, 31H), 6.92 (s, 1H), 7.13 (t, 2H, J=7.9
Hz), 7.42 (m, 3H), 8.41 (m, 2H). MS (ES) 541.0 [MH.sup.+]. t.sub.R
(method A)=6.3 min.
[0872]
N-(2-{6-[4-Methoxy-4-(3-methoxyphenyl)-piperidine-1-carbonyl]-2-phe-
nyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino}-ethyl)-acetamide
(26.121): .sup.1H NMR (CDCl.sub.3, 200 MHz) .delta. 1.75 (s, 3H),
1.87 (d, 2H, J=11.6 Hz), 2.05 (d, 2H, J=12.8 Hz), 3.00 (s, 3H),
3.48 (brs, 2H), 3.81 (brs, 4H), 4.41 (d, 2H, J=13 Hz), 6.39 (brs,
1H), 6.74 (s, 1H), 6.81 (d, 2H, J=8.2 Hz), 6.93(brs, 2H), 7.24-7.38
(m, 5H), 8.35 (m, 2H),. 10.64 (brs, 1H). MS (ES) 543.0 [MH.sup.+].
t.sub.R (method A)=7.3 min.
[0873]
1-[4-(2-Acetylaminoethylamino)-2-phenyl-7H-pyrrolo[2,3-d]pyrimidine-
-6-carbonyl]-4-pyrrolidin-1-ylpiperidine-4-carboxylic acid amide
(26.122): .sup.1H NMR (CD.sub.3OD, 200 MHz) .delta. 1.78 (brs, 4H),
1.85 (s, 3H), 1.96 (m, 2H), 2.07 (m, 2H), 2.75 (brs, 4H), 3.53 (t,
2H, J=6 Hz), 3.68 (brs, 2H), 3.84 (t, 2H, J=6 Hz), 4.08 (m, 2H),
6.92 (s, 1H), 7.42-7.45 (m, 3H), 8.38-8.42 (m, 2H). MS (ES) 519.0
[MH.sup.+]. t.sub.R (method A)=3.4 min.
[0874]
N-(2-{6-[4-(2-Methoxyphenyl)-3,6-dihydro-2H-pyridine-1-carbonyl]-2--
phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino}-ethyl)-acetamide
(26.123): .sup.1H NMR (CDCl.sub.3, 200 MHz) .delta. 1.81 (s, 3H),
2.69 (brs, 2H), 3.05 (d, 2H, J=4.8 Hz), 3.63 (m, 2H), 3.82 (d, 3H,
J=3.2 Hz), 3.92 (m, 2H), 4.52 (brs, 2H), 5.84 (brs, 1H), 6.75 (s,
1H), 6.94 (m, 3H), 7.15-7.26 (m, 2H), 7.45 (m, 3H), 8.43 (m, 2H),
9.48 (brs, 1H). MS (ES) 511.0 [MH.sup.+]. t.sub.R (method A)=7.7
min.
[0875]
N-(2-{6-[4-Methoxy-4-(2-methoxyphenyl)-piperidine-1-carbonyl]-2-phe-
nyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino}-ethyl)-acetamide
(26.124): .sup.1H NMR (CDCl.sub.3, 200 MHz) .delta. 1.80 (s, 3H),
2.31 (m, 4H), 3.14 (s, 3H), 3.62 (brs, 4H), 3.63 (m, 2H), 3.84 (s,
3H), 3.93 (m, 4H), 4.47 (d, 2H), 5.90 (brs, 1H), 6.70 (s, 1H), 6.96
(m, 3H), 7.30 (m, 2H), 7.45 (m, 3H), 8.41 (m, 2H), 9.47 (brs, 1H).
MS (ES) 543.0 [MH.sup.+]. t.sub.R (method A)=7.1 min.
[0876]
N-{2-[6-(4-Amino-4-phenylpiperidine-1-carbonyl)-2-phenyl-7H-pyrrolo-
[2,3-d]pyrimidin-4-ylamino]-ethyl}-acetamide (26.125): .sup.1H NMR
(CD.sub.3OD, 200 MHz) .delta. 1.85 (s, 3H), 1.94 (brs, 2H), 2.32
(brs, 2H), 3.52 (t, 2H, J=6.2 Hz), 3.83 (t, 2H, J=5.8 Hz), 3.84 (s,
3H), 3.99 (m, 4H), 4.47 (d, 2H), 6.94 (s, 1H), 7.24-7.59 (m, 8H),
8.42 (m, 2H). MS (ES) 498.0 [MH.sup.+]. t.sub.R (method B)=8.4
min.
[0877]
N-{2-[6-(4-Formyl-4-phenylpiperidine-1-carbonyl)-2-phenyl-7H-pyrrol-
o[2,3-d]pyrimidin-4-ylamino]-ethyl}-acetamide (26.126): .sup.1H NMR
(CDCl.sub.3+CD.sub.3OD, 200 MHz) .delta. 1.75 (s, 3H), 2.12 (brs,
2H), 2.46 (brs, 2H), 3.46 (brs, 4H), 3.83 (brs, 2H), 4.31 (brs,
2H), 6.73 (s, 1H), 7.25-7.41 (m, 8H), 8.32 (m, 2H), 9.45 (s, 1H).
MS (ES) 511.0 [MH.sup.+]. t.sub.R (method A)=2.9 min.
[0878]
N-{2-[6-(4-Hydroxymethyl-4-phenylpiperidine-1-carbonyl)-2-phenyl-7H-
-pyrrolo[2,3-d]pyrimidin-4-ylamino]-ethyl}-acetamide (26.127):
.sup.1H NMR (CDCl.sub.3+CD.sub.3OD, 200 MHz) .delta. 1.79 (s, 3H),
2.02 (brs, 2H), 2.31 (d, 2H, J=12.2 Hz), 3.40 (m, 2H), 3.50 (brs,
2H), 3.57 (s, 2H), 3.87 (m, 2H), 4.27 (d, 2H, J=12.8 Hz), 6.77 (s,
1H), 7.31-7.48 (m, 8H), 8.34 (m, 2H). MS (ES) 511.0 [MH.sup.+].
t.sub.R (method A)=2.9 min.
[0879]
N-{2-[6-(4-Ethyl-4-phenylpiperidine-1-carbonyl)-2-phenyl-7H-pyrrolo-
[2,3-d]pyrimidin-4-ylamino]-ethyl}-acetamide (26.128): .sup.1H NMR
(CDCl.sub.3, 200 MHz) .delta. 1.16 (m, 2H), 1.24 (d, 3H, J=7 Hz),
1.44 (m, 2H), 1.62 (m, 2H), 1.75 (s, 3H), 2.88 (brs, 2H), 3.56
(brs, 2H), 3.85 (brs, 2H), 4.45 (d, 1H, J=13.4 Hz), 4.60 (d, 1H,
J=10.4 Hz), 5.99 (brs, 1H), 6.61 (s, 1H), 6.99 (brs, 1H), 7.11-7.43
(m, 8H), 8.38 (m, 2H) 9.87 (brs, 1H). MS (ES) 511.0 [MH.sup.+].
t.sub.R (method A)=8.3 min.
[0880]
N-{2-[6-(4-Benzyl4-methoxypiperidine-1-carbonyl)-2-phenyl-7H-pyrrol-
o[2,3-d]pyrimidin-4-ylamino]-ethyl}-acetamide (26.129): .sup.1H NMR
(CDCl.sub.3, 200 MHz) .delta. 1.48 (t, 2H, J=1.1 Hz), 1.76 (m, 5H),
2.76 (s, 2H), 3.35 (m, 5H), 3.52 (brs, 2H), 3.80 (brs, 2H), 4.24
(d, 2H, J=12.2 Hz), 6.25 (brs, 1H), 6.63 (s, 1H), 7.10-7.43 (m,
9H), 8.35 (m, 2H), 10.41 (brs, 1H). MS (ES) 527.0 [MH.sup.+].
t.sub.R (method A)=7.3 min.
[0881]
N-{2-[6-(4-Methoxy-4-o-tolylpiperidine-1-carbonyl)-2-phenyl-7H-pyrr-
olo[2,3-d]pyrimidin-4-ylamino]-ethyl}-acetamide (26.130): .sup.1H
NMR (CDCl.sub.3, 200 MHz) .delta. 1.77 (s, 3H), 1.88 (t, 2H, J=11.8
Hz), 2.28 (d, 2H, J=14.4 Hz), 2.55 (s, 3H), 2.98 (s, 3H), 3.49
(brs, 4H), 3.79 (brs, 2H), 4.44 (d, 2H, J=12.8 Hz), 6.31 (brs, 1H),
6.73 (s, 1H), 7.18 (brs, 5H), 7.40 (m, 3H), 8.35 (m, 2H), 10.60
(brs, 1H). MS (ES) 527.0 [MH.sup.+]. t.sub.R (method A)=7.9
min.
[0882]
N-{2-[6-(4-Methoxymethyl-4-phenylpiperidine-1-carbonyl)-2-phenyl-7H-
-pyrrolo[2,3-d]pyrimidin-4-ylamino]-ethyl}-acetamide (26.131):
.sup.1H NMR (CDCl.sub.3, 200 MHz) .delta. 1.75 (s, 3H), 1.94 (t,
2H, J=10.6 Hz), 2.17 (t, 2H, J=13.0 Hz), 3.21 (brs, 4H), 3.30 (s,
3H), 3.48 (d, 2H, J=4.0 Hz), 3.75 (brs, 2H), 4.15 (d, 2H, J=13.2
Hz), 6.43 (brs, 1H), 6.66 (s, 1H), 7.26-7.42 (m, 9H), 8.32 (m, 2H),
10.76 (brs, 1H). MS (ES) 527.0 [MH.sup.+]. t.sub.R (method A)=7.5
min.
[0883]
4-(2-Acetylaminoethylamino)-2-phenyl-7H-pyrrolo[2,3-d]pyrimidine-6--
carboxylic acid (1-benzylpyrrolidin-3-yl)-amide (26.132): MS (ES):
497.7 (M.sup.++1), t.sub.R (method A) =4.4 min.
[0884]
N-[2-(6-{4-[3-(2-Chlorophenyl)-propyl]-piperazine-1-carbonyl}-2-phe-
ny1-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-ethyl]-acetamide
(26.133): MS (ES): 560.1 (M.sup.++1), t.sub.R (method A)=4.9
min.
[0885]
N-[2-(6-{4-[3-(3-Chlorophenyl)-propyl]-piperazine-1-carbonyl}-2-phe-
nyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-ethyl]-acetamide
(26.134): MS (ES): 560.1 (M.sup.++1).
[0886]
N-[2-(6-{4-[3-(4-Chlorophenyl)-propyl]-piperazine-1-carbonyl}-2-phe-
nyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-ethyl]-acetamide
(26.135): .sup.1H NMR (d.sub.6-DMSO, 200 MHz): .delta.=1.72 (tt,
J=6.8, 6.8 Hz, 2H), 1.82 (s, 3H), 2.34 (t, J=6.8 Hz, 2H), 2.42
(brs, 4H), 2.59 (t, J=7.0 Hz, 2H), 3.32-3.45 (m, 2H), 3.60-3.80 (m,
6H), 6.95 (d, J=1.8 Hz, 1H), 7.24-7.35 (AA'BB', 4H), 7.40-7.50 (m,
3H), 7.83 (t, J=5.5 Hz, 1H), 8.07 (t, J=5.7 Hz, 1H), 8.40-8.47 (m,
2H), 12.00 (d, J=1.4 Hz, 1H). .sup.13C NMR (d.sub.6-DMSO, 50.3 MHz,
DEPT135): .delta.=22.67 (+), 27.79 (t), 32.07 (-), 38.60 (-), 39.67
(-), 44.63 (-), 52.80 (-), 56.82 (-), 101.54 (C.sub.quart), 102.33
(+), 126.58 (C.sub.quart), 127.55 (+), 128.10 (+), 129.33 (+),
130.15 (+), 130.24 (C.sub.quart), 139.12 (C.sub.quart), 140.99
(C.sub.quart), 151.08 (C.sub.quart), 156.86 (C.sub.quart), 158.30
(C.sub.quart), 161.36 (C.sub.quart), 169.44 (C.sub.quart). MS (ES):
559.2 (M.sup.++1), t.sub.R (method A)=4.9 min.
[0887]
N-[2-(6-{4-[3-(4-Chlorophenyl)-propyl]-piperazine-1-carbonyl}-2-phe-
nyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-ethyl]-acetamide
methanesulfonate salt (26.135.MsOH): Compound 26.135 (5.37 g, 9.59
mmol) is dissolved in a mixture of methanol (50 mL) and THF (100
mL), and methanesulfonic acid (921 mg, 9.59 mmol) is added
dropwise. The solution is allowed to stand for 15 minutes and then
concentrated in vacuo. The pale yellow foam is dissolved in ethanol
and concentrated to give 6.3 g (100%) of a pale yellow amorphous
solid, mp. 150-156.degree. C. .sup.1H NMR (400 MHz, DMSO-D.sub.6):
.delta.=1.79 (s, 3H), 1.96 (m, 2H), 2.30 (s, 3H), 2.64 (t, 2H,
J=7.2 Hz), 3.12 (m, 4H), 3.35 (m, 6H), 3.50-3.70 (m, 4H), 4.46 (d,
2H, J=6.8 Hz), 7.02 (s, 1H), 7.26 (d, 2H, J=8.4 Hz), 7.36 (d, 2H,
J=8.4 Hz), 7.40-7.48 (m, 3H), 7.87 (brs, 1H), 8.04 (brs, 1H), 8.39
(dd, 2H, J=2.0, 7.2 Hz), 9.68 (brs, 1H), 12.09 (brs, 1H). MS (ES):
560.0/562.0 (100/33) [MH.sup.+]. t.sub.R (method B)=10.5 min.
[0888]
N-(2-{6-[4-(2-Oxo-2,3-dihydrobenzoimidazol-1-yl)-piperidine-1-carbo-
nyl]-2-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino}-ethyl)-acetamide
(26.136): .sup.1H NMR (d.sub.6-DMSO, 400 MHz) .delta. 1.79 (s, 3H),
1.82 (m, 2H), 2.36 (m, 2H), 3.13 (m, 2H), 3.40 (m, 2H), 3.62 (m,
2H), 4.52 (m, 3H), 6.94 (s, 1H), 6.97 (m, 3H), 7.26 (d, 1H, J=5.2
Hz), 7.43 (m, 3H), 7.85 (brs, 1H), 8.05 (brs, 1H), 8.40 (d, 2H,
J=6.8 Hz), 10.9 (brs, 1H), 12.0 (brs, 1H); MS (ES): 538.9
(M.sup.++1), t.sub.R (method B)=12.9 min.
[0889]
4-(2-Acetylaminoethylamino)-2-phenyl-7H-pyrrolo[2,3-d]pyrimidine-6--
carboxylic acid [1-(4-chlorobenzyl)-2-hydroxyethyl]-amide (26.137):
.sup.1H NMR (d6-DMSO, 400 MHz) .delta. 1.79 (s, 3H), 1.82 (m, 2H),
2.75 (m, 2H), 3.35 (m, 2H), 3.40 (m, 2H), 3.45 (m, 2H), 3.62 (m,
2H), 4.11 (brs, 1H), 4.91 (t, 1H, J=5.4 Hz), 7.09 (s, 1H), 7.17 (d,
2H, J=8.8 Hz), 7.43 (m, 3H), 8.01 (d, 2H, J=8.4 Hz), 8.38 (d, 2H,
J=8.4 Hz), 11.92 (brs, 1H); MS (ES): 506.9 (M.sup.++1), t.sub.R
(method B)=14.5 min.
[0890]
4-(2-Acetylaminoethylamino)-2-phenyl-7H-pyrrolo[2,3-d]pyrimidine-6--
carboxylic acid 4-[1,2,3]thiadiazol-4-yl-benzylamide (26.138): MS
(ES): 512.9 (M.sup.++1), t.sub.R (method B)=14.2 min.
[0891]
N-[2-(6-{4-[3-(2-Methoxyphenyl)-propyl]-piperazine-1-carbonyl}-2-ph-
enyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-ethyl]-acetamide
(26.139): MS (ES): 555.9 (M.sup.++1), t.sub.R (method B)=11.7
min.
[0892]
N-[2-(6-{4-[3-(3-Methoxyphenyl)-propyl]-piperazine-1-carbonyl}-2-ph-
enyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-ethyl]-acetamide
(26.140): MS (ES): 556.0 (M.sup.++1), t.sub.R (method B)=11.4
min.
[0893]
N-[2-(6-{4-[3-(4-Methoxyphenyl)-propyl]-piperazine-1-carbonyl}-2-ph-
enyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-ethyl]-acetamide
(26.141): - MS (ES): 555.9 (M.sup.++1), t.sub.R (method B)=11.3
min.
[0894]
N-(2-{6-[4-(2-Oxo-2-pyrrolidin-1-ylethyl)-piperazine-1-carbonyl]-2--
phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino}-ethyl)-acetamide
(26.142): MS (ES): 518.9 (M.sup.++1), t.sub.R (method B)=8.7
min.
[0895]
N-[2-(6-{4-[3-(4-Chlorophenyl)-propionyl]-piperazine-1-carbonyl}-2--
phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-ethyl]-acetamide
(26.143): MS (ES): 573.9 (M.sup.++1), t.sub.R (method B)=15.5
min.
[0896]
N-[2-(6-{4-[3-(3-Chlorophenyl)-propionyl]-piperazine-1-carbonyl}-2--
phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-ethyl]-acetamide
(26.144): MS (ES): 573.9 (M.sup.++1), t.sub.R (method B)=15.5
min.
[0897]
N-[2-(6-{4-[3-(2-Chlorophenyl)-propionyl]-piperazine-1-carbonyl}-2--
phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-ethyl]-acetamide
(26.145): MS (ES): 573.8 (M.sup.++1), t.sub.R (method B)=15.2
min.
[0898]
N-[2-(6-{4-[5-(4-Chlorophenyl)-2H-pyrazol-3-yl]-piperidine-1-carbon-
yl}-2-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-ethyl]-acetamide
(26.146): MS (ES): 582.9 (M.sup.++1), t.sub.R (method B)=16.4
min.
[0899]
2-{4-[4-(2-Acetylaminoethylamino)-2-phenyl-7H-pyrrolo[2,3-d]pyrimid-
ine-6-carbonyl]-piperazin-1-yl}-N-methyl-N-phenylacetamide
(26.147): MS (ES): 555.0 (M.sup.++1), t.sub.R (method B)=10.4
min.
[0900]
4-[4-(2-Acetylaminoethylamino)-2-phenyl-7H-pyrrolo[2,3-d]pyrimidine-
-6-carbonyl]-piperazine-1-carboxylic acid benzyl ester (26.148): MS
(ES): 541.9 (M.sup.++1), t.sub.R (method B)=15.3 min.
[0901] N-{2-[6-(4-Oxo-1-phenyl-1,3,8-triazaspiro
[4.5]decane-8-carbonyl)-2-
-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino]-ethyl}-acetamide
(26.149): MS (ES): 552.9 (M.sup.++1), t.sub.R (method B)=13.9
min.
[0902] N-{2-[6-(4-Benzo
[1,3]dioxol-5-ylmethylpiperazine-1-carbonyl)-2-phe-
nyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino]-ethyl}-acetamide
(26.150): MS (ES): 541.9 (M.sup.++1), t.sub.R (method A)=3.8
min.
[0903]
1-[4-(2-Acetylaminoethylamino)-2-phenyl-7H-pyrrolo[2,3-d]pyrimidine-
-6-carbonyl]-piperidine-4-carboxylic acid ethyl ester (26.151): MS
(ES): 479.0 (M.sup.++1), t.sub.R (method A)=6.7 min.
[0904]
1-[4-(2-Acetylaminoethylamino)-2-phenyl-7H-pyrrolo[2,3-d]pyrimidine-
6-carbonyl]-piperidine-3-carboxylic acid ethyl ester (26.152): MS
(ES): 479.0 (M.sup.++1), t.sub.R (method A)=6.9 min.
[0905]
4-(2-Acetylaminoethylamino)-2-phenyl-7H-pyrrolo[2,3-d]pyrimidine6-c-
arboxylic acid (1-benzylpyrrolidin-3-yl)-methylamide (26.153): MS
(ES): 512.0 (M.sup.++1), t.sub.R (method A)=4.3 min.
[0906]
N-{2-[6-(4-Biphenyl-4-yl-piperazinel-carbonyl)-2-phenyl-7H-pyrrolo[-
2,3-d]pyrimidin-4-ylamino]-ethyl}-acetamide (26.154): .sup.1H NMR
(d.sub.6-DMSO, 200 MHz) .delta. 1.73 (s, 3H), 3.60 (m, 2H), 3.84
(m, 2H), 7.01 (m, 4H), 7.20-7.40 (m, 9H), 7.82 (brs, 1H), 8.02
(brs, 1H), 8.40 (m, 2H), 12.03 (brs, 1H); MS (ES): 559.9
(M.sup.++1), t.sub.R (method A)=9.0 min.
[0907]
N-{2-[6-(4-Oxopiperidine-1-carbonyl)-2-phenyl-7H-pyrrolo[2,3-d]pyri-
midin-4-ylamino]-ethyl}-acetamide (26.155): Compound 26.87 (400 mg,
0.86 mmol) was dissolved in 5 mL of 12M HCl (aq). After 45 minutes,
the reaction was basified by its slow addition to cold NaHCO.sub.3
(sat). The solution was then partitioned between EtOAc and water.
The layers were separated and the aqueous layer was re-extracted
with EtOAc (2.times.). The combined EtOAc extracts were dried over
MgSO.sub.4, filtered and concentrated to yield 325 mg of a white
solid (90%). .sup.1H NMR (CDCl.sub.3, 200 MHz) .delta. 1.83 (s,
3H), 2.59 (m, 4H), 3.60 (m, 2H), 3.88 (m, 2H), 4.20 (m, 4H), 6.17
(brs, 1H), 6.69 (brs, 1H), 6.76 (s, 1H), 7.43 (m, 3H), 8.42 (m,
2H), 9.84 (brs, 1H); MS (ES): 420.9 (M.sup.++1).
[0908] General procedure for the reductive amination of 26.155
using polymer-supported cyanoborolydride:
[0909] The amine (0.14 mmol) is dissolved in 1 mL of a DCM/AcOH
(100:1) mixture. Ketone 26.155 (40 mg, 0.095 mmol ) and
polystyrylmethyltrimethyl- ammonium cyanoborohydride (60 mg,
loading=3-5 mmol/g) are added and the reaction is placed on an
orbital shaker. After 17 h, the reaction mixture is filtered and
the resin is washed with DCM. Alternatively, after filtration the
reaction can be worked up with EtOAc and 5% Na.sub.2CO.sub.3 (aq.).
The resulting homogeneous solution is concentrated, yielding the
products in 45-95% yield.
[0910] The following 11 amines 26.156-26.166 were prepared by this
method:
[0911]
N-(2-{6-[4-(Methylphenethylamino)-piperidine-1-carbonyl]-2-phenyl-7-
H-pyrrolo[2,3-d]pyrimidin-4-ylamino}-ethyl)-acetamide (26.156):
.sup.1H NMR (d.sub.6-DMSO, 200 MHz) .delta. 1.30-1.50 (m, 2H), 1.77
(m, 2H), 1.87 (s, 3H), 2.26 (s, 3H), 2.67 (m, 5H), 2.80-3.10 (m,
2H), 3.33 (m, 2H), 3.61 (m, 2H), 4.34 (d, 2H, J=13.2 Hz), 6.89 (S,
1H), 7.1-7.3 (6H, m), 7.42 (m, 3H), 7.78 (brs, 1H), 8.02 (brs, 1H),
8.40 (m, 2H). MS (ES): 539.9 (M.sup.++1), t.sub.R (method B)=11.1
min.
[0912]
N-{2-[6-(4-Phenethylaminopiperidine-1-carbonyl)-2-phenyl-7H-pyrrolo-
[2,3-d]pyrimidin-4-ylamino]-ethyl}-acetamide (26.157): .sup.1H NMR
(CDCl.sub.3, 200 MHz) .delta. 1.40-1.60 (m, 2H), 1.80 (s, 3H), 2.00
(m, 2H), 2.80-2.90 (m, 3H), 2.94 (d, 2H, J=6.0 Hz), 3.10-3.30 (m,
2H), 3.60 (m, 2H), 3.90 (m, 2H), 4.44 (d, 2H, J=13.8 Hz), 5.98
(brs, 1H), 6.66 (s, 1H), 6.82 (brs, 1H), 7.17-7.30 (m, 5H), 7.45
(m, 3H), 8.40 (d, 1H, J=5.6 Hz) 8.42 (d, 1H, J=7.8 Hz). MS (ES):
526.0 (M.sup.++1), t.sub.R (method B)=10.8 min.
[0913]
N-[2-(6-{4-[2-(4-Chlorophenyl)-ethylamino]-piperidine-1-carbonyl}-2-
-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-ethyl]-acetamide
(26.158): .sup.1H NMR (CDCl.sub.3, 200 MHz): .delta.=1.38-1.55 (m,
2H), 1.79 (s, 3H), 1.90-2.10 (m, 2H), 2.70-2.85 (m, 3H), 2.90 (d,
2H, J=6.6 Hz), 3.10-3.30 (m, 2H), 3.61 (m, 2H), 3.90 (m, 2H), 4.45
(d, 2H, J=13.2 Hz), 5.97 (brs, 1H), 6.65 (s, 1H), 6.81 (brs, 1H),
7.14 (d, 2H,J=8.0 Hz), 7.27 (d, 2H, J=7.4 Hz), 7.45 (m, 3H), 8.40
(m, 3H); MS (ES): 560.0 (M.sup.++1), t.sub.R (method B)=12.0
min.
[0914]
N-[2-(6-{4-[2-(3H-Imidazol-4-yl)-ethylamino]-piperidine-1-carbonyl}-
-2-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-ethyl]-acetamide
(26.159): .sup.1H NMR (d.sub.6-DMSO, 200 MHz): .delta.=1.20-1.30
(m, 2H), 1.78 (s, 3H), 1.80-1.90 (m, 2H), 2.60 (m, 3H), 2.78 (m,
4H), 3.34 (m, 2H), 3.62 (m, 2H), 4.20 (m, 2H), 6.73 (s, 1H), 6.76
(s, 1H), 6.90 (s, 1H), 7.36-7.52 (m, 5H), 7.79 (brs, 1H), 8.03 (m,
1H), 8.39 (m, 2H); MS (ES): 516.0 (M.sup.++1), t.sub.R (method
B)=7.2 min.
[0915]
N-(2-{2-Phenyl-6-[4-(2-pyridin-4-ylethylamino)-piperidine-1-carbony-
l]-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino}-ethyl)-acetamide (26.160):
.sup.1H NMR (d6-DMSO, 200 MHz): .delta.=1.15-1.30 (m;22H), 1.78 (s,
3H), 1.82-1.95 (m, 2H), 2.60-2.92 (m, 5H), 3.12 (m, 2H), 3.33 (m,
2H), 3.61 (m, 2H), 4.20 (m, 2H), 6.89 (s, 1H), 6.90-7.20 (brs, 1H),
7.24 (d, 1H, J=5.6 Hz), 7.42 (m, 3H), 7.76 (m, 1H), 8.01 (m, 1H),
8.40 (m, 3H); MS (ES): 527.0 (M.sup.++1), t.sub.R (method B)=7.6
min.
[0916]
N-(2-{2-Phenyl-6-[4-(2-pyridin-2-ylethylamino)-piperidine-1-carbony-
l]-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino}-ethyl)-acetamide (26.161):
.sup.1H NMR (d.sub.6-DMSO, 200 MHz): .delta.=1.15-1.30 (m, 2H),
1.80 (s, 3H), 1.82-1.95 (m, 2H), 2.70-3.00 (m, 5H), 3.15 (m, 2H),
3.33 (m, 2H), 3.63 (m, 2H), 4.20 (m, 2H), 6.87 (s, 1H), 6.90-7.20
(brs, 1H), 7.10-7.30 (m, 2H), 7.42 (m, 3H), 7.60-7.80 (m, 2H), 8.00
(brs, 1H), 8.40 (m, 2H); MS (ES): 526.9 (MH.sup.+), t.sub.R (method
B)=9.1 min.
[0917]
N-{2-[6-(4-Benzylaminopiperidine-1-carbonyl)-2-phenyl-7H-pyrrolo[2,-
3-d]pyrimidin-4-ylamino]-ethyl}-acetamide (26.162): .sup.1H NMR
(CDCl.sub.3, 200 MHz): .delta.=1.40-1.60 (m, 2H), 1.79 (s, 3H),
2.00 (m, 2H), 1.90 (brs, 1H), 3.21 (m, 2H), 3.59 (m, 2H), 3.89 (m,
2H), 4.30 (d, 2H, J=13.6 Hz), 5.95 (brs, 1H), 6.66 (s, 1H), 6.85
(brs, 1H), 7.30 (m, 5H), 7.43 (m, 3H), 8.42 (m, 2H); MS (ES): 512.0
(M.sup.++1), t.sub.R (method B)=10.0 min.
[0918]
N-(2-{6-[4-(Benzylmethylamino)-piperidine-1-carbonyl]-2-phenyl-7H-p-
yrrolo[2,3-d]pyrimidin-4-ylamino}-ethyl)-acetamide (26.163):
.sup.1H NMR (CDCl.sub.3, 200 MHz): .delta.=1.60-1.80 (m, 2H), 1.80
(s, 3H), 1.98 (m, 2H), 2.23 (s, 3H), 2.80 (brs, 1H), 3.10 (m, 2H),
3.60 (m, 4H), 3.90 (m, 2H), 4.66 (d, 2H, J=13.6 Hz), 5.90 (brs,
1H), 6.68 (s, 1H), 7.24 7.35 (m, 5H), 7.44 (m, 3H), 8.42 (m, 2H);
MS (ES): 526.0 (M.sup.++1), t.sub.R (method B)=10.2 min.
[0919]
N-(2-{2-Phenyl-6-[4-(1-phenylethylamino)-piperidine-1-carbonyl]-7H--
pyrrolo[2,3-d]pyrimidin-4-ylamino}-ethyl)-acetamide (26.164):
.sup.1H NMR (CDCl.sub.3, 200 MHz): .delta.=1.35 (d, 3H, J=5.8 Hz),
1.60-1.80 (m, 2H), 1.79 (s, 3H), 2.00-2.15 (m, 2H), 2.65 (m, 1H),
2.80 (brs, 1H), 3.10 (m, 2H), 3.60 (m, 2H), 3.80-4.20 (m, 3H), 5.92
(brs, 1H), 6.61 (s, 1H), 6.84 (brs, 1H), 7.32 (s, 5H), 7.44 (m, 3H)
8.40 (m, 2H); MS (ES): 526.0 (M.sup.++1), t.sub.R (method B)=10.5
min.
[0920]
N-[2-(2-Phenyl-6-{4-[(pyridin-4-ylmethyl)-amino]-piperidine-1-carbo-
nyl}-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-ethyl]-acetamide
(26.165): .sup.1H NMR (d.sub.6-DMSO, 200 MHz) .delta.=1.20-1.40 (m,
2H), 1.78 (s, 3H), 1.80-2.00 (m, 2H), 3.10 (m, 2H), 3.36 (m, 2H),
3.63 (m, 3H), 3.78 (s, 2H), 4.12 (m, 2H), 6.90 (s, 1H), 7.42 (m,
6H), 7.80 (brs, 1H), 8.05 (brs, 1H), 8.40 (m, 2H), 8.47 (m, 2H); MS
(ES): 512.9 (M.sup.++1), t.sub.R (method B)=8.4 min.
[0921]
N-(2-{2-Phenyl-6-[4-(2-pyridin-3-ylethylamino)-piperidine-1-carbony-
l]-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino}-ethyl)-acetamide (26.166):
.sup.1H NMR (d.sub.6-DMSO, 200 MHz): .delta.=1.20-1.40 (m, 2H),
1.78 (s, 3H), 1.80-2.00 (m, 2H), 2.60-2.90 (m, 6H), 3.00-3.25 (m,
3H), 3.62 (m, 2H), 4.39 (m, 2H), 6.85 (s, 1H), 7.25 (m, 1H), 7.40
(m, 3H), 7.63 (m, 1H), 7.79 (brs, 1H), 8.02 (m, 1H), 8.39 (m, 3H);
MS (ES): 526.9 (M.sup.++1), t.sub.R (method B)=7.7 min.
[0922]
N-[2-(6-Methyl-{2-oxo-2-[4-(3-phenylallyl)-piperazin-1-yl]-ethyl}-2-
-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-ethyl]-acetamide
(26.167): Prepared from 5 by alkylation similar to the preparation
of 47 and C-4 chloride displacement according to the general
procedure. MS(ES) 552 (MH.sup.+); t.sub.R (method B)=3.9 min
[0923]
3-[4-(2-Acetylaminoethylamino)-2-phenyl-7H-pyrrolo[2,3-d]pyrimidin--
6-yl]-propionic acid methyl ester (26.168): Wittig reaction of 20
followed by double bond reduction using the conditions for
43.fwdarw.44 and C-4 chloride displacement according to the general
procedure gave the title compound. .sup.1H NMR (CDCl.sub.3, 200
MHz) .delta. 9.95 (s, 1H), 8.39 (m, 2H), 7.43 (m, 3H), 6.05 (m,
1H), 5.52 (m, 1H), 3.89 (m, 2H), 3.65 (s, 3H), 3.58 (m, 2H), 2.90
(t, 2H), 2.62 (t, 2H), 1.76 (s, 3H); t.sub.R (method B)=5.0
min.
[0924]
N-(2-{6-[3-(4-Benzylpiperazin-1-yl)-3-oxopropyl]-2-phenyl-7H-pyrrol-
o[2,3-d]pyrimidin-4-ylamino}-ethyl)-acetamide (26.169): Prepared by
hydrolysis of the methyl ester of 26.128 and amide formation
according to the general procedure for 30a.fwdarw.26. .sup.1H NMR
(CDCl.sub.3, 200 MHz) .delta. 9.99 (s, 1H), 8.41 (m, 2H), 7.42 (m,
3H), 7.30 (m, 5H), 6.05 (s, 1H), 5.45 (m, 1H), 3.88 (m, 2H), 3.63
(m, 2H), 3.56 (m, 2H), 3.45 (s, 2H), 3.38 (m, 2H), 3.05 (t, 2H),
2.61 (t, 2H), 2.39 (m, 2H), 2.34 (m, 2H), 1.75 (s, 3H); t.sub.R
(method A)=3.9 min.
[0925]
N-(2-{7-Methyl-2-phenyl-6-[4-(3-phenylallyl)-piperazine-1-carbonyl]-
-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino}-ethyl)-acetamide (26.170):
Amide formation of 27 with 4-(3-phenylallyl)piperazine (29.3)
according to the general procedure 30a.fwdarw.26 gave amide 45,
MS(ES) 598/600 (MH.sup.+). Sulfonyl group removal as described for
28.fwdarw.30, except that the pH was adjusted to 7, yielded 46,
MS(ES) 458/460 (MH.sup.+). Alkylation with methyl iodide and NaH in
DMF according to the procedure for Boc-29.200.fwdarw.Boc-26.206,
followed by C-4 chloride displacement according to the general
procedure yielded 26.170. .sup.1H NMR (CDCl.sub.3, 200 MHz) .delta.
8.51 (m, 2H), 7.5-7.25 (brm, 10H), 7.07 (m, 1H), 5.43 (d, 1H,
J-16.0 Hz), 6.48 (s, 1H), 6.25 (dt, 1H, J=16.0, 6.6 Hz), 5.76 (m,
1H), 3.92 (m, 5H), 3.79 (m, 4H), 3.57 (m, 2H), 3.21 (d, 2H, J=6.6
Hz), 2.56 (m, 4H), 1.76 (s, 3H); MS(ES) 537 (MH.sup.+); t.sub.R
(method A)=5.4 min.
[0926]
4-(2-Acetylaminoethylamino)-2-phenyl-7H-pyrrolo[2,3-d]pyrimidine-6--
carboxylic acid benzylamide (26.171): MS (ES) 428 (MH.sup.+);
t.sub.R (method A)=7.0 min.
[0927]
4-(2-Acetylaminoethylamino)-2-phenyl-7H-pyrrolo[2,3-d]pyrimidine-6--
carboxylic acid (2-hydroxy-1-hydroxymethylethyl)-amide (26.172): MS
(ES) 413 (MH.sup.+); t.sub.R (method A)=9.3 min.
[0928]
N-{2-[6-(3,4-Dihydro-1H-isoquinoline-2-carbonyl)-2-phenyl-7H-pyrrol-
o[2,3-d]pyrimidin-4-ylamino]-ethyl}-acetamide (26.173): MS (ES) 454
(MH.sup.+); t.sub.R (method A)=7.4 min.
[0929]
4-(2-Acetylaminoethylamino)-2-phenyl-7H-pyrrolo[2,3-d]pyrimidine-6--
carboxylic acid (1-hydroxycyclohexylmethyl)-amide (26.174): MS (ES)
451 (MH.sup.+); t.sub.R (method A)=6.3 min.
[0930]
4-(2-Acetylaminoethylamino)-2-phenyl-7H-pyrrolo[2,3-d]pyrimidine-6--
carboxylic acid [2-(4-phenoxyphenyl)-ethyl]-amide (26.175): MS (ES)
535 (MH.sup.+).
[0931]
N-{2-[2-Phenyl-6-((S)-2-phenylaminomethylpyrrolidine-1-carbonyl)-7H-
-pyrrolo[2,3-d]pyrimidin-4-ylamino]-ethyl}-acetamide (26.176): MS
(ES) 498 (MH.sup.+); t.sub.R (method A)=7.7 min.
[0932]
4-(2-Acetylaminoethylamino)-2-phenyl-7H-pyrrolo[2,3-d]pyrimidine-6--
carboxylic acid ((S)-2-oxoazepan-3-yl)-amide (26.177): MS (ES) 450
(MH.sup.+); t.sub.R (method A)=5.6 min.
[0933]
N-(2-{6-[4-(Hydroxydiphenylmethyl)-piperidine-1-carbonyl]-2-phenyl--
7H-pyrrolo[2,3-d]pyrimidin-4-ylamino}-ethyl)-acetamide (26.178): MS
(ES) 589 (MH.sup.+); t.sub.R (method A)=8.4 min.
[0934]
N-{2-[6-(4-Methyl-[1,4]diazepane-1-carbonyl)-2-phenyl-7H-pyrrolo[2,-
3-d]pyrimidin-4-ylamino]-ethyl}-acetamide (26.179): MS (ES) 436
(MH.sup.+); t.sub.R (method A)=6.9 min.
[0935]
N-{2-[2-Phenyl-6-(1,3,4,9-tetrahydro-.beta.-carboline-2-carbonyl)-7-
H-pyrrolo[2,3-d]pyrimidin-4-ylamino]-ethyl}-acetamide (26.180): MS
(ES) 494 (MH.sup.+); t.sub.R (method A)=7.7 min.
[0936]
N-{2-[6-(Azocane-1-carbonyl)-2-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4--
ylamino]ethyl}-acetamide (26.181): MS (ES) 435 (MH.sup.+); t.sub.R
(method A)=7.3 min.
[0937]
N-[2-(2-Phenyl-6-{4-[3-(4-trifluoromethylphenyl)-propyl]-piperazine-
-1-carbonyl}-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-ethyl]-acetamide
(26.182): MS (ES) 594 (MH.sup.+); t.sub.R (method A)=5.1 min.
[0938]
N-[2-(6-{4-[3-(4-Fluorophenyl)-propyl]-piperazine-1-carbonyl}-2-phe-
nyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-ethyl]-acetamide
(26.183): MS (ES) 544 (MH.sup.+); t.sub.R (method A)=4.6 min.
[0939]
N-(2-{6-[4-(3-Benzo[1,3dioxol-5-yl-propyl)-piperazine-1-carbonyl]-2-
-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino}-ethyl)-acetamide
(26.184): MS (ES) 570 (MH.sup.+); t.sub.R (method A)=4.4 min.
[0940]
N-(2-{2-Phenyl-6-[4-(3-p-tolylpropyl)-piperazine-1-carbonyl]-7H-pyr-
rolo[2,3-d]pyrimidin-4-ylamino}-ethyl)-acetamide (26.185): MS (ES)
540 (MH.sup.+); t.sub.R (method A)=4.8 min.
[0941]
N-[2-(6-{4-[3-(4-Bromophenyl)-propyl]-piperazine-1-carbonyl}-2-phen-
yl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-ethyl]-acetamide (26.186):
MS (ES) 606 (MH.sup.+); t.sub.R (method A)=5.0 min.
[0942]
N-[2-(6-{4-[3-(3,4-Dichlorophenyl)-propyl]-piperazine-1-carbonyl}-2-
-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-ethyl]-acetamide
(26.187): MS (ES) 596 (M.sup.++H); t.sub.R (method B)=4.4 min.
[0943]
N-[2-(6-{4-[3-(2,4-Dichlorophenyl)-propyl]-piperazine-1-carbonyl}-2-
-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-ethyl]-acetamide
(26.188): MS (ES) 596 (M.sup.++H); t.sub.R (method B)=4.4 min.
[0944]
N-2-[2-Phenyl-6-(4-phenyl-[1,4]diazepane-1-carbonyl)-7H-pyrrolo[2,3-
-d]pyrimidin-4-ylamino]-ethyl}-acetamide (26.189): MS (ES) 498
(MH.sup.+); t.sub.R (method B)=15.5 min.
[0945]
N-{2-[6-(4-Benzyl-1,4diazepane-1-carbonyl)-2-phenyl-7H-pyrrolo[2,3--
d]pyrimidin-4-ylamino]-ethyl}-acetamide (26.190): MS (ES) 512
(MH.sup.+); t.sub.R (method B)=10.3 min.
[0946]
N-{2-[6-(4-Phenethyl-1,4diazepane-1-carbonyl)-2-phenyl-7H-pyrrolo[2-
,3-d]pyrimidin-4-ylamino]-ethyl}-acetamide (26.191): MS (ES) 527
(M.sup.++H); t.sub.R (method B)=11.2 min.
[0947]
N-(2-{2-Phenyl-6-[4-(3-phenylpropyl)-[1,4]diazepane-1-carbonyl]-7H--
pyrrolo[2,3-d]pyrimidin-4-ylamino}-ethyl)-acetamide (26.192): MS
(ES) 540 (MH.sup.+); t.sub.R (method B) 11.8 min.
[0948]
(R,S)-(N-{2-[6-(3-Phenoxypiperidine-1-carbonyl)-2-phenyl-7H-pyrrolo-
[2,3-d]pyrimidin-4-ylamino]-ethyl}-acetamide (26.193): MS (ES) 499
(MH.sup.+); t.sub.R (method B)=15.6 min.
[0949]
N-(2-{6-[4-(4-Chlorophenoxy)-piperidine-1-carbonyl]-2-phenyl-7H-pyr-
rolo[2,3-d]pyrimidin-4-ylamino}-ethyl)-acetamide (26.194): MS (ES)
533 (MIH+); t.sub.R (method B)=17.1 min.
[0950]
N-(2-{6-[4-(4-Methoxyphenoxy)-piperidine-1-carbonyl]-2-phenyl-7H-py-
rrolo[2,3-d]pyrimidin-4-ylamino}-ethyl)-acetamide (26.195): MS (ES)
529 (MH.sup.+); t.sub.R (method B)=15.8 min.
[0951]
N-{2-[6-(4-Phenoxypiperidine-1-carbonyl)-2-phenyl-7H-pyrrolo[2,3-d]-
pyrimidin-4-ylamino]-ethyl}-acetamide (26.196): MS (ES) 499
(MH.sup.+); t.sub.R (method B)=16.3 min.
[0952]
4-(2-Acetylaminoethylamino)-2-phenyl-7H-pyrrolo[2,3-d]pyrimidine-6--
carboxylic acid [3-(2-oxopyrrolidin-1-yl)-propyl]-amide (26.197):
MS (ES) 464.08 [MH.sup.+], t.sub.R (method A)=5.44 min.
[0953]
4-(2-Acetylaminoethylamino)-2-phenyl-7H-pyrrolo[2,3-d]pyrimidine-6--
carboxylic acid (2-phenylcyclopropyl)-amide (26.198): MS (ES)
455.14 [MH.sup.+], t.sub.R (method A)=7.74 min.
[0954]
N-(2-{6-[4-(4-Chlorobenzoyl)-piperidine-1-carbonyl]-2-phenyl-7H-pyr-
rolo[2,3-d]pyrimidin-4-ylamino}-ethyl)-acetamide (26.199): MS (ES)
545.0 [MH.sup.+], t.sub.R (method A)=8.15 min.
[0955]
N-(2-{6-[4-(4-Acetylaminophenyl)-piperazine-1-carbonyl]-2-phenyl-7H-
-pyrrolo[2,3-d]pyrimidin-4-ylamino}-ethyl)-acetamide (26.200): MS
(ES) 541.11 [MH.sup.+], t.sub.R (method A)=5.83 min.
[0956]
4-(2-Acetylaminoethylamino)-2-phenyl-7H-pyrrolo[2,3-d]pyrimidine-6--
carboxylic acid indan-2-ylamide (26.201): MS (ES) 455.03
[MH.sup.+], t.sub.R (method A)=7.52 min.
[0957]
N-(2-{6-[4-(4-Cyanophenyl)-piperazine-1-carbonyl]-2-phenyl-7H-pyrro-
lo[2,3-d]pyrimidin-4-ylamino}-ethyl)-acetamide (26.202): .sup.1H
NMR (CDCl.sub.3, 200 MHz): .delta. 1.81 (s, 3H), 2.72 (brs, 3H),
3.42-3.60 (m, 6H), 3.87 (t, 2H, J=4.8 Hz), 3.97-4.10 (m, 4H), 6.86
(s, 2H), 6.89 (s, 1H), 7.4-7.6 (m, 6H), 8.30-8.42 (m, 2H). MS (ES)
509.0 [MH.sup.+], t.sub.R (method A)=7,22 min.
[0958]
N-(2-{6-[4-(2-Cyanophenyl)-piperazine-1-carbonyl]-2-phenyl-7H-pyrro-
lo[2,3-d]pyrimidin-4-ylamino}-ethyl)-acetamide (26.203): .sup.1H
NMR (CD.sub.3OD, 200 MHz): .delta. 1.86 (s, 3H), 3.20-3.35 (m, 4H),
3.47-3.60 (m, 2H), 3.84 (brt, 2H, J=6.3 Hz), 4.05 (brt, 4H, J=4.4
Hz), 6.67 (s, 1H), 7.08-7.22 (m, 2H), 7.38-7.50 (m, 3H), 7.53-7.70
(m, 2H), 7.90 (s, 1H), 8.37-8.48 (m, 2H). MS (ES) 508.95
[MH.sup.+], t.sub.R (method A)=7.43 min.
[0959]
N-{2-[6-(4-Hydroxymethylpiperidine-1-carbonyl)-2-phenyl-7H-pyrrolo[-
2,3-d]pyrimidin-4-ylamino]-ethyl}-acetamide (26.204): .sup.1H NMR
(CD.sub.3OD, 200 MHz): .delta.=1.22-1.40 (m, 2H), 1.70-1.94 (m,
6H), 2.9-3.2 (m, 2H), 3.4-3.6 (m, 4H), 3.83 (brt, 2H, J=6.2 Hz),
4.56 (brd, 2H, J=12.2 Hz), 6.90(s, 1H), 7.38-7.5 (m, 3H), 7.90 (s,
1H), 8.35-8.47 (m, 2H). MS (ES) 437.11 [MH.sup.+], t.sub.R (method
A)=5.19 min.
[0960]
4-(2-Acetylaminoethylamino)-2-phenyl-7H-pyrrolo[2,3-d]pyrimidine-6--
carboxylic acid [2-(4-methoxyphenyl)-ethyl]-amide (26.205): MS (ES)
472.93 [MH.sup.+], t.sub.R (method A)=7.23 min.
[0961]
N-[2-(6-{4-[4-(Acetylmethylamino)-phenyl]-piperazine-1-carbonyl}-2--
phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-ethyl]-acetamide
(26.206): MS (ES) 554.9 [MH.sup.+], t.sub.R (method A)=6.20
min.
[0962]
N-(2-{6-[4-(4-Methoxyphenyl)-3-methylpiperazine-1-carbonyl]-2-pheny-
l-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino}-ethyl)-acetamide (26.207):
.sup.1H NMR (CDCl.sub.3, 200 MHz): .delta.=0.90 (d, 6H, J=6.2 Hz),
1.77 (s, 3H), 2.91-3.10 (m, 2H), 3.2-3.7 (m, 6H), 3.7-4.5 (m, 7H),
6.53 (m, 1H), 6.73-7.00 (m, 6H), 7.25 (m, 1H), 7.35-7.50 (m, 2H),
8.31-8.47 (m, 1H). MS (ES) 528.0 [MH.sup.+], t.sub.R (method A)=6.9
min.
[0963]
4-(2-Acetylaminoethylamino)-2-phenyl-7H-pyrrolo[2,3-d]pyrimidine-6--
carboxylic acid (2-phenoxyethyl)-amide (26.208): MS (ES) 458.94
[MH.sup.+], t.sub.R (method A)=7.3 min.
[0964]
N-{2-[6-(3-Acetylaminopyrrolidine-1-carbonyl)-2-phenyl-7H-pyrrolo[2-
,3-d]pyrimidin-4-ylamino]-ethyl}-acetamide (26.209): MS (ES) 449.95
[MH.sup.+], t.sub.R (method A)=5.1 min.
[0965]
N-(2-{6-[4-(2,6-Dimethylphenyl)-piperazine-1-carbonyl]-2-phenyl-7H--
pyrrolo[2,3-d]pyrimidin-4-ylamino}-ethyl)-acetamide (26.210): MS
(ES) 511.89 [MH.sup.+], t.sub.R (method A)=9.0 min.
[0966]
N-(2-{6-[4-(2-Ethoxyphenyl)-piperazine-1-carbonyl]-2-phenyl-7H-pyrr-
olo[2,3-d]pyrimidin-4-ylamino}-ethyl)-acetamide (26.211): .sup.1H
NMR (CDCl.sub.3, 200 MHz): .delta.=1.75 (s, 3H), 3.09 (brt, 4H,
J=4.4 Hz), 3.43-3.57 (m, 2H), 3.70-3.85 (m, 2H), 3.90-4.05 (m, 4H),
6.35-6.45 (m, 1H), 6.74 (s, 1H), 6.8-7.07 (m, 4H), 7.19-7.3 (m,
1H), 7.34-7.49 (m, 3H), 8.31-8.48 (m, 2H), 10.7 (brs, 1H). MS (ES)
527.84 [MH.sup.+], t.sub.R (method A)=7.91 min.
[0967]
N-(2-{6-[4-(2-Methoxyphenyl)-piperazine-1-carbonyl]-2-phenyl-7H-pyr-
rolo[2,3-d]pyrimidin-4-ylamino}-ethyl)-acetamide (26.212): MS (ES)
513.87 [MH.sup.+], t.sub.R (method A)=7.33 min.
[0968]
N-(2-{6-[4-(2-Chlorophenyl)-piperazine-1-carbonyl]-2-phenyl-7H-pyrr-
olo[2,3-d]pyrimidin-4-ylamino}-ethyl)-acetamide (26.213): MS (ES)
517.82 [MH.sup.+], t.sub.R (method A)=8.28 min.
[0969]
N-(2-{6-[4-(2-Fluorophenyl)-piperazine-1-carbonyl]-2-phenyl-7H-pyrr-
olo[2,3-d]pyrimidin-4-ylamino}-ethyl)-acetamide (26.214): MS (ES)
501.88 [MH.sup.+], t.sub.R (method A)=7.76 min.
[0970]
N-{2-[2-Phenyl-6-(4-phenylpiperazine-1-carbonyl)-7H-pyrrolo[2,3-d]p-
yrimidin-4-ylamino]-ethyl}-acetamide (26.215): .sup.1H NMR
(CD.sub.3OD, 200 MHz): .delta.=1.86 (s, 3H), 3.17-3.28 (m, 4H),
3.47-3.61 (m, 2H), 3.84 (brt, 2H, J=5.8 Hz), 3.98 (brt, 4H, J=4.8
Hz), 6.87 (t, 1H, J=7.4 Hz), 6.96(s, 1H), 6.99 (dd, 2H, J=8.9, 1.0
Hz), 7.25 (dd, 2H, J=7.6, 1.6 Hz), 7.35-7.52 (m, 3H), 8.36-8.49 (m,
2H); MS (ES) 483.84 [MH.sup.+], t.sub.R (method A)=7.50 min.
[0971]
N-(2-{6-[4-(2,4-Difluorophenyl)-piperazine-1-carbonyl]-2-phenyl-7H--
pyrrolo[2,3-d]pyrimidin-4-ylamino}-ethyl)-acetamide (26.216):
.sup.1H NMR (CD.sub.3OD, 200 MHz): .delta.=1.86 (s, 3H), 3.10 (brt,
4H, J=5.2 Hz), 3.53 (t, 2H, J=6.2 Hz) 3.83 (t, 2H, J=6.2 Hz), 3.99
(brt, 4H, J=4.8 Hz), 6.80-7.16 (m, 4H), 7.36-7.51 (m, 3H),
8.33-8.49 (m, 2H); MS (ES) 519.81 [MH.sup.+], t.sub.R (method
A)=7.92 min.
[0972]
N-(2-{6-[4-(2-Ethylphenyl)-piperazine-1-carbonyl]-2-phenyl-7H-pyrro-
lo[2,3-d]pyrimidin-4-ylamino}-ethyl)-acetamide (26.217): .sup.1H
NMR (CD.sub.3OD, 200 MHz): .delta.=1.28 (t, 3H, J=7.4 Hz), 1.85 (s,
1H), 2.76 (q, 2H, J=7.2 Hz), 2.87-3.10 (m, 4H), 3.45-3.59 (m, 2H),
3.83 (brt, 2H, J=5.8 Hz), 3.91-4.5 (m, 4H), 6.95 (s, 1H), 6.99-7.19
(m, 3H), 7.20-7.27 (m, 1H), 7.37-7.49 (m, 3H), 8.37-8.48 (m, 2H).
MS (ES) 511.86 [MH.sup.+], t.sub.R (method A)=8.92 min.
[0973]
N-(2-{6-[4-(2,4-Dimethoxyphenyl)-piperazine-1-carbonyl]-2-phenyl-7H-
-pyrrolo[2,3-d]pyrimidin-4-ylamino}-ethyl)-acetamide (26.218):
.sup.1H NMR (CD.sub.3OD, 200 MHz): .delta.=1.85 (s, 3H), 2.93-3.08
(m, 4H), 3.46-3.59 (m, 2H), 3.75 (s, 3H), 3.78-3.88 (m, 5H),
3.90-4.40 (m, 4H), 6.45 (dd, 1H, J=8.6, 2.6 Hz), 6.56 (d, 1H, J=2.6
Hz), 6.90 (d, 1H, J=8.8 Hz), 6.94 (s, 1H), 7.33-7.52 (m, 3H),
8.35-8.48 (m, 2H); MS (ES) 543.86 [MH.sup.+], t.sub.R (method
A)=7.00 min.
[0974]
N-(2-{6-[4-(5-Chloro-2-methoxyphenyl)-piperazine-1-carbonyl]-2-phen-
yl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino}-ethyl)-acetamide (26.219):
.sup.1H NMR (d.sub.6-DMSO, 200 MHz): .delta.=1.81 (s, 3H), 3.0-3.12
(m, 4H), 3.34-3.45 (m, 2H), 3.59-3.71 (m, 2H), 3.82 (s, 1H),
3.83-3.92 (m, 4H), 6.89 (d, 1H, J=1.8 Hz), 6.98-7.40 (m, 3H),
7.39-7.51 (m, 3H), 7.76-7.87 (m, 1H), 8.01-8.11 (m, 1H), 8.35-8.47
(m, 2H); MS (ES) 547.83 [MH.sup.+], t.sub.R (method A)=8.11
min.
[0975]
N-(2-{6-[4-(4-Chlorophenoxymethyl)-piperidine-1-carbonyl]-2-phenyl--
7H-pyrrolo[2,3-d]pyrimidin-4-ylamino}-ethyl)-acetamide (26.220):
.sup.1H NMR (d6-DMSO, 200 MHz): .delta.=1.22-1.50 (m, 2H), 1.80 (s,
3H), 1.81-1.97 (m, 2H), 2.91-3.17 (m, 2H), 3.30-3.44 (m, 2H),
3.56-3.73 (m, 2H), 3.85-3.96 (m, 2H), 4.33-4.54 (m, 2H), 6.98 (d,
2H, J=9.2 Hz), 7.33 (d, 2H, J=9.0 Hz), 7.38-7.54 (m, 3H), 7.80-7.91
(m, 1H), 8.02-8.13 (m, 1H), 8.36-8.48 (m, 2H); MS (ES) 546.82
[MH.sup.+], t.sub.R (method A)=8.96 min.
[0976]
N-{2-[6-(5-Benzyl-2,5-diazabicyclo[2.2.1]heptane-2-carbonyl)-2-phen-
y1-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino]-ethyl}-acetamide (26.221):
MS (ES) 509.87 [MH.sup.+], t.sub.R (method A)=4.05 min.
[0977]
N-(2-{6-[4-(2-Hydroxyphenyl)-piperazine-1-carbonyl]-2-phenyl-7H-pyr-
rolo[2,3-d]pyrimidin-4-ylamino}-ethyl)-acetamide (26.222):]H NMR
(d.sub.6-DMSO, 200 MHz): .delta.=1.81 (s, 3H), 2.95-3.08 (m, 4H),
3.33-3.45 (m, 2H), 3.58-3.71 (m, 2H), 3.80-3.96 (m, 4H), 6.69-6.96
(m, 4H), 6.99 (s, 1H), 7.39-7.53 (m, 3H), 7.76-7.88 (m, 1H),
8.00-8.11 (m, 1H), 8.35-8.48 (m, 2H); MS (ES) 321.81 [MH.sup.+],
t.sub.R (method A)=6.86 min.
[0978]
N-(2-{6-[4-(2,3-Dichlorophenyl)-piperazine-1-carbonyl]-2-phenyl-7H--
pyrrolo[2,3-d]pyrimidin-4-ylamino}-ethyl)-acetamide (26.223):
.sup.1H NMR (d.sub.6-DMSO, 200 MHz): .delta.=1.81 (s, 3H),
3.00-3.15 (m, 4H), 3.43-3.75 (m, 2H), 3.80-4.00 (m, 4H), 7.01 (s,
1H), 7.18 (t, 1H, J=4.6 Hz), 7.30-7.39 (m, 2H), 7.40-7.53 (m, 3H),
7.76-7.90 (m, 1H), 8.00-8.12 (m, 1H), 8.34-8.48 (m, 1H); MS (ES)
551.73 [MH.sup.+], t.sub.R (method A)=8.83 min.
[0979] N-(2-{6-[5-(4-Chlorophenyl)-2,5-diazabicyclo [2.2.11
heptane-2-carbonyl]-2-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino}-ethyl)-
-acetamide (26.224): MS (ES) 529.77 [MH.sup.+], t.sub.R (method
A)=8.15 min.
[0980]
N-{2-[6-(4-Phenoxymethylpiperidine-1-carbonyl)-2-phenyl-7H-pyrrolo[-
2,3-d]pyrimidin-4-ylamino]-ethyl}-acetamide (26.225): .sup.1H
NMR(d.sub.6-DMSO, 200 MHz): .delta.=1.20-1.50 (m, 2H), 1.80 (s,
3H), 1.82-2.00 (m, 2H), 2.10-2.30 (m, 1H), 2.95-3.18 (m, 2H),
3.32-3.45 (m, 2H), 3.57-3.71 (m, 2H), 3.90 (d, 2H, J=5.8 Hz), 4.45
(brd, 2H, J=11.8 Hz), 6.86-7.20 (m, 4H), 7.29 (dd, 2H, J=7.0, 1.4
Hz), 7.38-7.53 (m, 3H), 7.76-7.89 (m, 1H), 8.00-8.11 (m, 1H),
8.35-8.48 (m, 2H); MS (ES) 512.90 [MH.sup.+], t.sub.R (method
A)=8.12 min.
[0981]
N-(2-{6-[4-(4-Cyanophenoxymethyl)-piperidine-1-carbonyl]-2-phenyl-7-
H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-ethyl)-acetamide (26.226):
.sup.1H NMR(d.sub.6-DMSO, 200 MHz): .delta.=1.22-1.49 (m, 2H), 1.80
(s, 3H), 1.82-1.98 (m, 2H), 2.02-2.24 (m, 1H), 2.92-3.17 (m, 2H),
3.32-3.44 (m, 2H), 3.56-3.74 (m, 2H), 4.01 (d, 2H, J=6.0 Hz),
4.35-4.52 (m, 2H), 6.94 (s, 1H), 7.13 (d, 2H, J=9.2 Hz), 7.38-7.52
(m, 3H), 7.77 (d, 2H, J=8.8 Hz), 7.80-7.88 (m, 1H), 7.99-8.10 (m,
1H), 8.33-8.47 (m, 2H); MS (ES) 537.88 [MH.sup.+], t.sub.R (method
A)=7.61 min.
[0982]
N-(2-{6-[4-(3-Cyanophenoxymethyl)-piperidine-1-carbonyl]-2-phenyl-7-
H-pyrrolo[2,3-d]pyrimidin-4-ylamino}-ethyl)-acetamide (26.227):
.sup.1H NMR (d.sub.6-DMSO, 200 MHz): .delta.=1.22-1.48 (m, 2H),
1.80 (s, 3H), 1.83-1.98 (m, 2H), 2.03-2.25 (m, 1H), 2.94-3.19 (m,
2H), 3.32-3.45 (m, 2H), 3.56-3.73 (m, 2H), 3.98 (d, 2H, J=6.2 Hz),
4.34-4.54 (m, 2H), 6.94 (s, 1H), 7.26-7.36 (m, 1H), 7.36-7.55 (m,
6H), 7.78-7.89 (m, 1H), 8.00-8.12 (m, 1H), 8.35-8.47 (m, 2H); MS
(ES) 537.87 [MH.sup.+], t.sub.R (method A)=7.80 min.
[0983]
N-(2-{6-[4-(2-Methylsulfanylphenyl)-piperazine-1-carbonyl]-2-phenyl-
-7H-pyrrolo[-2,3-d]pyrimidin-4-ylamino}-ethyl)-acetamide (26.228):
.sup.1H NMR (d.sub.6-DMSO, 200 MHz): .delta.=1.78 (s, 3H), 2.38 (s,
3H), 2.89-3.03 (m, 4H), 3.30-3.42 (m, 2H), 3;55-3.70 (m, 2H),
3.77-3.92 (m, 4H), 6.98 (s, 1H), 7.06-7.22 (m, 4H), 7.74-7.87 (m,
1H), 7.97-8.13 (m, 1H), 8.32-8.48 (m, 2H); MS (ES) 529.91
[MH.sup.+], t.sub.R (method A)=8.09 min.
[0984]
N-(2-{6-[4-(2-Nitrophenyl)-piperazine-1-carbonyl]-2-phenyl-7H-pyrro-
lo[2,3-d]pyrimidin-4-ylamino}-ethyl)-acetamide (26.229): .sup.1H
NMR(d.sub.6-DMSO, 200 MHz): .delta.=1.81 (s, 3H), 3.06-3.19 (m,
4H), 3.33-3.45 (m, 2H), 3.58-3.74 (m, 2H), 3.78-3.94 (m, 4H), 7.01
(s, 1H), 7.20 (dd, 1H, J=7.6, 0.8 Hz), 7.34-7.53 (m, 4H), 7.63 (dd,
1H, J=7.7, 1.4 Hz), 7.86 (dd, 1H, J=8.0, 1.4 Hz), 8.00-8.11 (m,
1H), 8.34-8.48 (m, 2H); MS (ES) 528.89 [MH.sup.+], t.sub.R (method
A)=7.49 min.
[0985]
N-(2-{6-[4-(3-Chlorophenyl)-piperazine-1-carbonyl]-2-phenyl-7H-pyrr-
olo[2,3-d]pyrimidin-4-ylamino}-ethyl)-acetamide (26.230): .sup.1H
NMR (d6-DMSO, 200 MHz): .delta.=1.81 (s, 1H), 3.32-3.45 (m, 6H),
3.58-3.77 (m, 2H), 3.80-3.93 (m, 4H), 6.78-7.04 (m, 4H), 7.26 (t,
1H, J=8 Hz), 7.40-7.53 (m, 3H), 7.80-7.93 (m, 1H), 8.01-8.13 (m,
1H), 8.37-8.49 (m, 2H); MS (ES) 517.85 [MH.sup.+], t.sub.R (method
A)=8.13 min.
[0986]
N-(2-{2-Phenyl-6-[4-(3-trifluoromethylphenyl)-piperazine-1-carbonyl-
]-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino}-ethyl)-acetamide (26.231):
.sup.1H NMR(d.sub.6-DMSO, 200 MHz): .delta.=1.81 (s, 3H), 3.33-3.46
(m, 7H), 3.59-3.74 (m, 2H), 3.81-3.94 (m, 4H), 7.01 (s, 1H), 7.12
(brd, 1H, J=7.4 Hz), 7.20-7.32 (m, 2H), 7.40-7.53 (m, 4H),
7.80-7.91 (m, 1H), 8.00-8.11 (m, 1H), 8.36-8.47 (m, 2H); MS (ES)
551.88 [MH.sup.+], t.sub.R (method A)=8.41 min.
[0987]
2-{4-[4-(2-Acetylaminoethylamino)-2-phenyl-7H-pyrrolo[2,3-d]pyrimid-
ine-6-carbonyl]-piperazin-1-yl}-benzoic acid methyl ester (26.232):
.sup.1H NMR (d.sub.6-DMSO, 200 MHz): .delta.=1.81 (s, 3H),
2.99-3.12 (m, 4H), 3.32-3.71 (m, 4H), 3.80-3.91 (m, 7H), 6.94-7.20
(m, 4H), 7.35-7.57 (m, 3H), 7.65 (dd, 1H, J=6.8, 1.4 Hz), 7.76-7.89
(m, 1H), 7.99-8.11 (m, 1H), 8.34-8.47 (m, 2H); MS (ES) 541.89
[MH.sup.+], t.sub.R (method A)=7.36 min.
[0988]
N-{2-[2-Phenyl-6-(4-o-tolylpiperazine-1-carbonyl)-7H-pyrrolo[2,3-d]-
pyrimidin-4-ylamino]-ethyl}-acetamide (26.233): .sup.1H NMR
(d.sub.6-DMSO, 200 MHz): .delta.=1.81 (s, 3H), 2.31 (s, 3H),
2.85-3.00 (m, 4H), 3.33-3.45 (m, 2H), 3.58-3.72 (m, 2H), 3.82-3.93
(m, 4H), 6.92-7.09 (m, 3H), 7.18 (brt, 2H, J=7.4 Hz), 7.39-7.53 (m,
3H), 7.76-7.89 (m, 1H), 8.00-8.12 (m, 1H), 8.36-8.48 (m, 2H); MS
(ES) 497.89 [MH.sup.+], t.sub.R (method A)=8.15 min.
[0989]
N-(2-{6-[4-(3-Methoxyphenyl)-piperazine-1-carbonyl]-2-phenyl-7H-pyr-
rolo[2,3-d]pyrimidin-4-ylamino}-ethyl)-acetamide (26.234): .sup.1H
NMR (d.sub.6-DMSO, 200 MHz): .delta.=1.81 (s, 3H), 3.16-3.45 (m,
6H), 3.57-3.70 (m, 2H), 3.73 (s, 3H), 3.80-3.91 (m, 4H), 6.36-6.63
(m, 3H), 7.00 (s,1H), 7.15 (t, 1H, J=7.6 Hz), 7.38-7.53 (m, 3H),
7.77-7.91 (m, 1H), 7.99-8.12 (m, 1H), 8.34-8.48 (m, 2H); MS (ES)
513.95 [MH.sup.+], t.sub.R (method A)=7.37 min.
[0990]
N-(2-{6-[4-(3,4-Dichlorophenoxymethyl)-piperidine-1-carbonyl]-2-phe-
nyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino}-ethyl)-acetamide
(26.235): .sup.1H NMR (d.sub.6-DMSO, 200 MHz): .delta.=1.20-1.45
(m, 2H), 1.80 (s, 3H), 1.81-1.97 (m, 2H), 2.20-2.23 (m, 1H),
2.92-3.17 (m, 2H), 3.32-3.47 (m, 2H), 3.58-3.72 (m, 2H), 3.95 (d,
2H, J=6.8 Hz), 4.35-4.53 (m, 2H), 6.94 (s, 1H), 6.99 (dd, 1H,
J=8.8, 3.0 Hz), 7.27 (d, 1H, J=2.8 Hz), 7.39-7.57 (m, 4H),
7.76-7.89 (m, 1H), 7.99-8.12 (m, 1H), 8.35-8.49 (m, 2H); MS (ES)
580.80 [MH.sup.+], t.sub.R (method A)=9.40 min.
[0991]
N-(2-{6-[4-(2-Cyanophenoxymethyl)-piperidine-1-carbonyl]-2-phenyl-7-
H-pyrrolo[2,3-d]pyrimidin-4-ylamino}-ethyl)-acetamide (26.236):
.sup.1H NMR (d.sub.6-DMSO, 200 MHz): .delta.=1.27-1.48 (m, 2H),
1.78 (s, 3H), 1.82-1.99 (m, 2H), 2.06-2.26 (m, 1H), 2.93-3.16 (m,
2H), 3.31-3.42 (m, 2H), 3.53-3.73 (m, 2H), 4.06 (brd, 2H, J=6.2
Hz), 4.31-4.53 (m, 2H), 6.93 (s, 1H), 7.07 (t, 1H, J=7.7 Hz), 7.26
(d, 1H, J=8.4 Hz), 7.37-7.50 (m, 3H), 7.58-7.76 (m, 2H), 7.77-7.85
(m, 1H), 7.97-8.08 (m, 1H), 8.34-8.45 (m, 2H); MS (ES) 538.12
[MH.sup.+], t.sub.R (method A )=6.22 min.
[0992]
N-(2-{6-[4-(2-Chlorophenyl)-4-cyanopiperidine-1-carbonyl]-2-phenyl--
7H-pyrrolo[2,3-d]pyrimidin-4-ylamino}-ethyl)-acetamide (26.237):
.sup.1H NMR (d.sub.6-DMSO, 200 MHz): .delta.=1.80 (s, 3H),
2.02-2.24 (m, 2H), 2.54=2.70 (m, 2H), 3.3-3.5 (m, 4H), 3.56 3.74
(m, 2H), 4.50-4.70 (m, 2H), 7.02 (s, 1H), 7.40-7.53 (m, 5H),
7.54-7.65 (m, 2H), 7.74-7.84 (m, 1H), 7.99-8.10 (m, 1H), 8.35-8.48
(m, 2H); MS (ES) 541.99 [MH.sup.+], t.sub.R (method A)=6.5 min.
[0993]
N-(2-{6-[4-(2-Chlorophenyl).sub.4-cyanopiperidine-1-carbonyl]-2-phe-
nyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino}-ethyl)-acetamide
methanesulfonic acid salt (26.237-MsOH): .sup.1H NMR (CD.sub.3OD,
200 MHz): .delta.=1.90 (s, 3H), 2.08-2.32 (m, 2H), 2.66 (brs, 2H),
2.72 (brs, 3H), 3.57 (brt, 2H, J=6.4 Hz), 3.93 (brt, 2H, J=6.2 Hz),
4.73 (brd, 2H, J=12.8 Hz), 7.18 (brs, 1H), 7.35-7.49 (m, 2H),
7.50-7.74 (m, 5H), 8.07-8.31 (m, 2H); MS (ES) 541.8 [MH.sup.+],
t.sub.R (method A)=7.7 min.
[0994]
N-(2-{6-[4-(2-Methanesulfinylphenyl)-piperazine-1-carbonyl]-2-pheny-
l-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino}-ethyl)-acetamide (26.238):
.sup.1H NMR (CD.sub.3OD, 200 MHz): .delta.=1.86 (s, 3H), 2.89 (brs,
5H), 3.13-3.38 (m, 3H), 3.46-3.60 (m, 2H), 3.75-3.90 (m, 2H),
3.91-4.08 (m, 3H), 6.95 (s, 1H), 7.20-7.63 (m, 6H), 7.70-7.96 (m,
1H), 8.30-8.59 (m, 2H); MS (ES) 545.85 [MH.sup.+], t.sub.R (method
A)=6.12 min.
[0995]
2-{4-[4-(2-Acetylaminoethylamino)-2-phenyl-7H-pyrrolo[2,3-d]pyrimid-
ine-6-carbonyl]-piperazin-1-yl}-benzamide-(26.239): .sup.1H NMR
(d.sub.6-DMSO, 200 MHz): .delta. 1.78 (s, 3H), 2.92-3.09 (m, 4H),
3.31-3.42 (m, 2H), 3.54-3.70 (m, 2H), 3.80-3.96 (m, 4H), 6.98 (s,
1H), 7.06-7.22 (m, 2H), 7.35-7.55 (m, 5H), 7.67 (dd, 1H, J=7.6, 1.8
Hz), 7.74-7.86 (m, 1H), 7.97-8.80 (m, 1H), 8.32-8.44 (m, 2H); MS
(ES) 526.89 [MH.sup.+], t.sub.R (method B)=12.60 min.
[0996]
N-(2-{6-[4-Cyano-4-(2-methoxyphenyl)-piperidine-1-carbonyl]-2-pheny-
l-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino}-ethyl)-acetamide (26.240):
.sup.1H NMR (CD.sub.3OD, 200 MHz) .delta.=1.85 (s, 3H), 1.98-2.22
(m, 2H), 2.35-2.55 (m, 2H), 3.40-3.64 (m, 4H), 3.83 (t, 2H, J=5.8
Hz), 3.92 (s, 3H), 4.70 (brd, 2H, J=14.2 Hz), 6.96 (s, 1H),
6.98-7.14 (m, 2H), 7.26-7.53 (m, 5H), 8.31-8.51 (m, 2H); MS (ES)
537.93 [MH.sup.+], t.sub.R (method A)=7.55 min.
[0997]
N-(2-{6-[4-(3-Chlorophenyl)-4-cyanopiperidine-1-carbonyl]-2-phenyl--
7H-pyrrolo[2,3-d]pyrimidin-4-ylamino}-ethyl)-acetamide (26.241):
.sup.1H NMR (CD.sub.3OD, 200 MHz): .delta.=1.86 (s, 3H), 2.03-2.35
(m, 4H), 3.36-3.63 (m, 4H), 3.83 (brt, 2H, J=6.2 Hz), 4.74 (brd,
2H, J=13.8 Hz), 6.98 (s, 1H), 7.32-7.56 (m, 6H), 7.57-7.66 (m, 1H),
8.34-8.52 (m, 2H); MS (ES) 541.91 [MH.sup.+], t.sub.R (method
A)=8.14 min.
[0998]
N-(2-{6-[4-Cyano-4-(3-methoxyphenyl)-piperidine-1-carbonyl]-2-pheny-
l-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino}-ethyl)-acetamide (26.242):
.sup.1H NMR (CD.sub.3OD, 200 MHz): .delta.=1.85 (s, 3H), 2.03-2.28
(m, 4H), 3.36-3.61 (m, 4H), 3.52-3.61 (m, 5H), 4.71 (brd, 2H,
J=14.4 Hz), 6.85-7.01 (m, 2H), 7.05-7.16 (m, 2H), 7.28-7.50 (m,
4H), 8.33-8.50 (m, 2H); MS (ES) 537.93 [MH.sup.+], t.sub.R (method
A)=7.66 min.
[0999]
N-(2-{6-[4-(4-Chlorophenyl)-4-cyanopiperidine-1-carbonyl]-2-phenyl--
7H-pyrrolo[2,3-d]pyrimidin-4-ylamino}-ethyl)-acetamide (26.243):
.sup.1H NMR (CD.sub.3OD, 200 MHz): .delta.=1.86 (s, 3H), 2.00-2.31
(m, 4H), 3.36-3.62 (m, 4H), 3.83 (brt, 2H, J=6.0 Hz), 4.73 (brd,
2H, J=14 Hz), 6.97 (s, 1H), 7.33-7.49 (m, 5H), 7.50-7.61 (m, 2H),
8.34-8.50 (m, 2H); MS (ES) 541.92 [MH.sup.+], t.sub.R (method
A)=8.18 min.
[1000]
N-(2-{6-[4-Cyano-4-(4-methoxyphenyl)-piperidine-1-carbonyl]-2-pheny-
l-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino}-ethyl)-acetamide (26.244):
.sup.1H NMR (CD.sub.3OD, 200 MHz): .delta.=1.87 (s, 3H), 1.97-2.32
(m, 4H), 3.42-3.60 (m, 4H), 3.80 (s, 3H), 3.81-3.89 (m, 2H), 4.72
(brd, 2H, J=14 Hz), 6.88-7.04 (m, 3H), 7.34-7.53 (m, 5H), 8.34-8.49
(m, 2H); MS (ES) 537.94 [MH.sup.+], t.sub.R (method A)=7.57
min.
[1001]
(S)-7-Benzenesulfonyl-4-(2,3-dihydroxypropylamino)-2-phenyl-7H-pyrr-
olo[2,3-d]pyrimidine-6-carboxylic acid (28.c): 27 (126 mg) and
dihydroxypropylamine (273 mg) were stirred in anhydrous DMSO (2 mL)
at 80.degree. C. under nitrogen for 4 h. The reaction mixture was
cooled to rt and diluted with water (10 mL). The resulting mixture
was acidified with 0.5N HCl until a white solid formed (pH
3.5-4.0). The solid was collected by filtration, washed with cold
water, and dried in vacuo. A white solid (131 mg) was obtained in
93% yield. .sup.1H-NMR (200 MHz, DMSO-d.sub.6): .delta.=3.30-3.33
(m, 2H), 3.57-3.60 (m, 2H), 3.65-6.71 (m, 1H), 3.82-3.97 (m, 2H),
7.32 (s, 1H), 7.46-7.50 (m, 3H), 7.55-7.68 (m, 3H), 8.38-8.49 (m,
4H). MS (ES): 468.9 (M.sup.++1).
[1002]
(S)-1-[7-Benzenesulfonyl-4-(2,3-dihydroxypropylamino)-2-phenyl-7H-p-
yrrolol2,3-d]pyrimidine-6-carbonyl]-4-(2-chlorophenyl)piperidine-4-carboni-
trile (31.c):
(S)-7-Benzenesulfonyl-4-(2,3-dihydroxypropylamino)-2-phenyl--
7H-pyrrolo[2,3-d]-pyrimidine-6-carboxylic acid (28.c) (47 mg),
29.237 (25 mg, 1.1 eq), and PyBop (100 mg, 2.0 eq) were stirred at
rt under nitrogen for 6 h. DMF was removed in vacuo. The residue
was partitioned between DCM and saturated NaHCO.sub.3 aqueous
solution. The aqueous layer was extracted with DCM twice. The
combined DCM layers was washed with saturated NaHCO.sub.3 aqueous
solution, brine, and dried over MgSO.sub.4. After removal of
solvent, an off-white solid (163 mg) was obtained. Pure product (63
mg) was obtained by TLC purification (silica gel, EtOAc/Hexane=3/1)
in 94% yield. .sup.1H-NMR (200 MHz, DMSO-d.sub.6+MeOH-d.sub.4):
.delta.=2.40-2.75 (m, 2H), 2.78-2.90 (m, 4H), 3.30-3.50 (m, 1H),
3.50-3.60 (m, 2H), 3.60-3.97 (m, 4H), 6.70 (s, 1H), 7.20-7.68 (m,
9H), 8.34-8.37 (m, 4H).
[1003]
(S)-4-(2-Chlorophenyl)-1-[4-(2,3-dihydroxypropylamino)-2-phenyl-7H--
pyrrolo[2,3-d]pyrimidine-6-carbonyl]piperidine-4-carbonitrile
(26.245):
(S)-1-[7-Benzene-sulfonyl-4-(2,3-dihydroxypropylamino)-2-phenyl-7H-pyrrol-
o[2,3-d]-pyrimidine-6-carbonyl]-4-(2-chlorophenyl)piperidine-4-carbonitril-
e 31.c (55 mg) was stirred in MeOH and treated with 1M NaOH aqueous
solution at rt under nitrogen for 2 h. The resulting mixture was
neutralized with 3M HCl aqueous solution (pH.apprxeq.7). The
solvent was then removed in vacuo. The residue was dissolved in
DCM+MeOH and charged onto a TLC plate. A white foam (29 mg) was
obtained in 67% yield. .sup.1H-NMR (200 MHz,
CDCl.sub.3+MeOH-d.sub.4): .delta.=1.95-2.20 (m, 2H), 2.50-2.70 (m,
2H), 3.40-3.70 (m, 4H), 3.78-3.95 (m, 3H), 4.65-4.78 (m, 2H), 6.75
(s, 1H), 7.25-7.47 (m, 7H), 8.18-8.23 (m, 4H). MS (ES): 531.0
[MH.sup.+].
[1004] The following compounds 26.246-26.250 were prepared in the
same manner:
[1005]
(S)-[4-(2,3-dihydroxypropylamino)-2-phenyl-7H-pyrrolo[2,3-d]pyrimid-
ine-6-yl]-{4-[3-(4-chlorophenyl)propyl]piperazin-1-yl}methanone
(26.246): 2% yield. .sup.1H-NMR (200 MHz, CDCl.sub.3):
.delta.=1.50-1.70 (m, 2H), 2.38-2.48 (m, 2H), 2.50-2.60 (m, 4H),
2.60-2.70 (m, 2H), 3.60-3.70 (m, 2H), 3.80-4.02 (m, 8H), 4.18-4.25
(m, 2H), 6.63 (s, 1H), 7.05-7.15 (m, 3H), 7.40-7.60 (m, 5H),
8.18-840 (m, 2H), 9.52 (brs, 1H); MS (ES): 548.9 (M.sup.++1).
[1006]
2-{6-[4-(2-Chlorophenyl)-4-cyanopiperidine-1-carbonyl]-2-phenyl-7H--
pyrrolo[2,3-d]pyrimidin-4-ylamino}acetamide (26.247): 2% yield.
.sup.1H-NMR (200 MHz, CDCl.sub.3+MeOH-d.sub.4): .delta.=2.10-2.30
(m, 2H), 2.60-2.75 (m, 2H), 3.10-3.25 (m, 2H), 3.65-3.75 (m, 2H),
4.30 (s, 2H), 7.02 (s, 1H), 7.38-7.45 (m, 5H), 7.48-7.60 (m, 2H),
8.38-8.40 (m, 2H). MS (ES): 513.9 (M.sup.++1).
[1007]
3-(6-{4-[3-(4-Chlorophenyl)propyl]piperazine-1-carbonyl}-2-phenyl-7-
H-pyrrolo[2,3-d]pyrimidin-4-ylamino)acetamide (26.248): 5% yield.
.sup.1H-NMR (200 MHz, MeOH-d.sub.4): .delta.=1.80-1.95 (m, 2H),
2.40-2.50 (m, 2H), 2.52-2.62 (m, 4H), 2.62-2.72 (m, 2H), 3.82-3.95
(m, 4H), 4.30 (m, 2H), 6.93 (s, 1H), 7.18 (d, 2H, J=8.4 Hz), 7.23
(d, 2H, J=8.4 Hz), 7.55-7.65 (m, 3H), 8.36-842 (m, 2H). MS (ES):
532.0 (M.sup.++1).
[1008]
3-{6-[4-(2-Chlorophenyl)-4-cyanopiperidine-1-carbonyl]-2-phenyl-7H--
pyrrolo[2,3-d]pyrimidin-4-ylamino}propionamide (26.249): 1% yield.
.sup.1H-NMR (200 MHz, CDCl.sub.3): .delta.=2.00-2.20 (m, 2H),
2.55-2.80 (m, 4H), 3.65-3.75 (m, 2H), 4.00-4.15 (m, 2H), 4.70-4.85
(m, 2H), 6.00 (brs, 1H), 6.20 (brs, 1H), 6.75 (s, 1H), 7.20-7.60
(m, 8H), 8.38-8.48 (m, 2H), 9.77 (brs, 1H). MS (ES): 527.9
(M.sup.++1).
[1009]
3-(6-{4-[3-(4-Chlorophenyl)propyl]piperazine-1-carbonyl}-2-phenyl-7-
H-pyrrolo[2,3-d]pyrimidin-4-ylamino)propionamide (26.250): 2%
yield. .sup.1H-NMR (200 MHz, CDCl.sub.3): .delta.=1.35-1.55 (m,2H),
1.78-1.95 (m,2H), 2.34-2.43 (m, 2H), 2.45-2.58 (m,4H), 2.60-2.70
(m, 2H), 2.70-3.76 (m, 2H), 3.80-3.95 (m, 4H), 4.00-4.18 (m, 2H),
5.41 (brs, 1H), 5.67 (brs, 1H), 5.91 (brs, 1H), 6.62 (s, 1H), 7.10
(d, 2H, J=8.0 Hz), 7.27 (d, 2H, J=8.0 Hz), 7.40-7.55 (m, 3H),
8.38-8.50 (m, 2H), 9.40 (brs, 1H). MS (ES): 546.0 (M.sup.++1).
[1010] Activity of Compounds
[1011] The biological activity of the compounds of the present
invention is illustrated by performing a radioligand binding assay.
Selected compounds disclosed herein show a selectivity for the
A.sub.2b adenosine receptor over the A.sub.1, A.sub.2a, and A.sub.3
receptors of 2-57 fold and nanomolar potency in binding assays. The
preparation of the binding assay is described below.
[1012] Specifically, the following selectivities for the A.sub.2B
receptor relative to the A.sub.1, A.sub.2A, and A.sub.3 receptor
were observed:
[1013] 17.7: 26.times., 17.7.MsOH: 24.times., 26.5: 20.times.,
26.42: 57.times., 26.135: 19.times., 26.135.MsOH: 17.times.,
26.237: 57.times., 26.237.MsOH: 33.times., 26.71: A.sub.1/A.sub.2B
dual antagonist with 82.times..
[1014] Specifically, the following K.sub.i for the A.sub.2B
receptor was observed:
[1015] 17.7: 5 nM.
[1016] Materials and Methods
[1017] Materials. [.sup.3H]--DPCPX
[cyclopentyl-1,3-dipropylxanthine] (120 Ci/mmol) was purchased from
New England Nuclear (Boston, Mass.). The adenosine deaminase and
complete protease inhibitor cocktail tablets were purchased from
Boehringer Mannheim Corp. (Indianapolis, Ind.). Cell culture
reagents were from Life Technologies (Grass Island, N.Y.) except
for serum that was from Hyclone (Logan, Utah).
[1018] Cell line. HEK293 stably expressing the human A.sub.2B
receptor were used for radioligand binding assays. Cells were grown
in DMEM Glutamax containing 10% FBS, 0.2 mg/ml G418 at 37.degree.
C. in 5% CO.sub.2/95% atmosphere.
[1019] Membrane Preparation. Cells were washed with cold PBS buffer
twice, scraped off the plates, and centrifuged at 1000.times.g for
5 minutes. Cells were homogenized with ice-cold buffer of 5 mM
Tris, pH 7.4, 5 mM EDTA, 5 mM EGTA, protease inhibitor cocktail
tablets and incubated for 10 min on ice. The homogenate was
centrifuged at 32,000.times.g for 30 min. The membranes were
resuspended in buffer of 50 mM Tris, pH 7.4, 0.6 mM EDTA, 5 mM
MgCl.sub.2, stored at -80.degree. C. until use. Protein
concentration was determined by the methods of Bradford.
[1020] Radioligand binding assay. Membranes were homogenized in
buffer containing 10 mM HEPES-KOH, pH 7.4 containing 1.0 mM EDTA; 2
U/ml adenosine deaminase; and 0.1 mM Benzamidine and incubated for
30 min at room temperature. Dissociation constants of radioligand
(K.sub.d values) and maximum binding sites (B.sub.max) were
determined in saturation binding experiments. Saturation binding
assays were carried out in a reaction mixture containing 50 .mu.l
of membrane suspension, 25 .mu.l of 4% DMSO, 25 .mu.l of increasing
amounts of radioligand, [.sup.3H]--DPCPX (final concentration 1-200
nM). Competition binding assays were performed in a reaction
mixture containing 50 .mu.l of membrane suspension (.about.5
.mu.g/well), 25 .mu.l of [.sup.3H]--DPCPX (final concentration is
.about.22 nM), and 25 .mu.l compounds. Nonspecific binding was
measured in the presence of 100 pM NECA. Compounds were dissolved
in
[1021] DMSO and then diluted with 4% DMSO; the final maximum DMSO
concentrations were 1%. Incubations were carried out in triplicate
for 1 hr at 23.5.degree. C. Reactions were terminated by rapid
filtration over GF/C filters using a cell harvester. The filters
were washed ten times with 0.4 ml of ice-cold buffer containing 10
mM HEPES-KOH, pH 7.4. The filters were dried, covered with
scintillation fluid and counted with a TopCount.
[1022] Equivalents
[1023] Those skilled in the art will recognize, or be able to
ascertain, using no more than routine experimentation, many
equivalents to specific embodiments of the invention described
specifically herein. Such equivalents are intended to be
encompassed in the scope of the following claims.
* * * * *