U.S. patent application number 16/532378 was filed with the patent office on 2019-11-28 for amino-pyrrolopyrimidinone compounds and methods of use thereof.
The applicant listed for this patent is ArQule, Inc.. Invention is credited to Craig BATES, Sudharshan Eathiraj, Hiroaki Inagaki, Jean-Marc Lapierre, Takayuki Momose, Kiyoshi Nakayama, Takashi Odagiri, Masahiro Ota, Yusuke Ota, Yoshihiro Shibata, Manish Tandon, Tomoyuki Tsunemi.
Application Number | 20190358233 16/532378 |
Document ID | / |
Family ID | 61241149 |
Filed Date | 2019-11-28 |
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United States Patent
Application |
20190358233 |
Kind Code |
A1 |
BATES; Craig ; et
al. |
November 28, 2019 |
AMINO-PYRROLOPYRIMIDINONE COMPOUNDS AND METHODS OF USE THEREOF
Abstract
The application relates to a compound of Formula (I):
##STR00001## or a pharmaceutically acceptable salt, hydrate,
solvate, prodrug, stereoisomer, or tautomer thereof, which
modulates the activity of BTK, a pharmaceutical composition
comprising a compound of Formula (I), and a method of treating or
preventing a disease in which BTK plays a role.
Inventors: |
BATES; Craig; (Pelham,
NH) ; Eathiraj; Sudharshan; (Shrewsbury, MA) ;
Inagaki; Hiroaki; (Tokyo, JP) ; Lapierre;
Jean-Marc; (Pelham, NH) ; Momose; Takayuki;
(Tokyo, JP) ; Nakayama; Kiyoshi; (Tokyo, JP)
; Odagiri; Takashi; (Tokyo, JP) ; Ota;
Masahiro; (Tokyo, JP) ; Ota; Yusuke; (Tokyo,
JP) ; Shibata; Yoshihiro; (Tokyo, JP) ;
Tandon; Manish; (Framingham, MA) ; Tsunemi;
Tomoyuki; (Tokyo, JP) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
ArQule, Inc. |
Burlington |
MA |
US |
|
|
Family ID: |
61241149 |
Appl. No.: |
16/532378 |
Filed: |
August 5, 2019 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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15683913 |
Aug 23, 2017 |
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16532378 |
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62378868 |
Aug 24, 2016 |
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62378871 |
Aug 24, 2016 |
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62378872 |
Aug 24, 2016 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61P 35/00 20180101;
A61P 25/00 20180101; A61K 31/519 20130101; A61P 43/00 20180101;
A61P 11/06 20180101; A61P 35/02 20180101; A61K 31/341 20130101;
C07D 487/04 20130101; A61P 9/00 20180101; A61P 29/00 20180101; A61P
37/08 20180101; A61K 31/03 20130101; A61P 19/02 20180101; A61P 7/04
20180101; A61P 37/00 20180101; A61P 1/04 20180101; A61K 31/4188
20130101; A61P 17/00 20180101; C12N 9/12 20130101; A61P 37/06
20180101 |
International
Class: |
A61K 31/519 20060101
A61K031/519; C12N 9/12 20060101 C12N009/12; C07D 487/04 20060101
C07D487/04; A61K 31/4188 20060101 A61K031/4188 |
Claims
1. A compound of Formula (I): ##STR00747## or a pharmaceutically
acceptable salt, solvate, prodrug, stereoisomer, or tautomer
thereof, wherein: A is (C.sub.6-C.sub.10) aryl or 5- or 6-membered
heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S,
wherein the aryl and heteroaryl are optionally substituted with one
or more R.sub.4; R.sub.1 is (C.sub.3-C.sub.7) cycloalkyl or 4- to
9-membered heterocyclyl comprising 1 to 3 heteroatoms selected from
N, O, and S, wherein the cycloalkyl and heterocyclyl are optionally
substituted with one or more R.sub.5; R.sub.2 is H or
(C.sub.1-C.sub.4) alkyl; or when q is 0, R.sub.1 and R.sub.2
together with the nitrogen atom to which they are attached form a
5- or 6-membered heterocyclyl ring comprising 0 to 1 additional
heteroatoms selected from N, O, and S and optionally substituted
with one or more NR.sub.6R.sub.7; R.sub.3 is H or N(R.sub.5).sub.2;
each R.sub.4 is independently (i) (C.sub.1-C.sub.4) alkyl, (ii)
(C.sub.1-C.sub.4) alkoxy optionally substituted with one or more
(C.sub.1-C.sub.4) alkoxy, (iii) (C.sub.1-C.sub.4) haloalkyl, (iv)
(C.sub.1-C.sub.4) haloalkoxy, (v) halogen, (vi)
NR.sub.9S(O).sub.pR.sub.10, (vii) O(CH.sub.2).sub.nR.sub.11, (viii)
NH(CH.sub.2).sub.nR.sub.111, (ix)
(CH.sub.2).sub.nC(.dbd.O)NHR.sub.25, (x)
(CH.sub.2).sub.nNHC(.dbd.O)R.sub.25, (xi)
(CH.sub.2).sub.nNHC(.dbd.O)NHR.sub.25, (xii) C(.dbd.O)R.sub.25, or
(xiii) heterocyclyl comprising one or two 4- to 6-membered rings
and 1 to 3 heteroatoms selected from N, O, and S and optionally
substituted with one or more substituents selected from
(C.sub.1-C.sub.4) alkyl, (C.sub.1-C.sub.4) haloalkyl,
C(.dbd.O)(C.sub.1-C.sub.4) alkyl, and halogen; each R.sub.5 is
independently (i) (C.sub.1-C.sub.6) alkyl optionally substituted
with one or more (C.sub.1-C.sub.4) alkoxy or phenyl, (ii)
(C.sub.2-C.sub.4) alkenyl optionally substituted with one or more
C(.dbd.O)(C.sub.1-C.sub.4) alkyl, (iii)
(C(R.sub.12).sub.2).sub.rOH, (iv)
(C(R.sub.12).sub.2).sub.rNR.sub.13R.sub.14, (v) C(.dbd.O)OH, (vi)
C(.dbd.O)O(C.sub.1-C.sub.4) alkyl, (vii)
C(.dbd.O)NR.sub.13R.sub.15, (viii) C(.dbd.O)R.sub.16, (ix)
S(O).sub.pR.sub.16, or (x) 5- or 6-membered heteroaryl comprising 1
to 3 heteroatoms selected from N, O, and S and optionally
substituted with one or more (C.sub.1-C.sub.4) alkyl, (xi) or two
R.sub.5 together with the carbon atom to which they are attached
form (.dbd.O), or (xii) two R.sub.5 together with the atoms to
which they are attached form a bridged 3- to 6-membered
heterocyclyl ring comprising 1 to 3 heteroatoms selected from N, O,
and S; R.sub.6 is H or (C.sub.1-C.sub.4) alkyl; R.sub.7 is H,
(C.sub.1-C.sub.4) alkyl, or C(.dbd.O)R.sub.24; each R.sub.8 is
independently (i) H, (ii) (C.sub.1-C.sub.4) alkyl, or (iii) 5- or
6-membered heterocyclyl comprising 1 to 3 heteroatoms selected from
N, O, and S and optionally substituted with one or more
(C.sub.1-C.sub.4) alkyl, or (iv) two R.sub.8 together with the
nitrogen atom to which they are attached form a 5- or 6-membered
heterocyclyl ring comprising 0 to 1 additional heteroatoms selected
from N, O, and S and optionally substituted with one or more
(C.sub.1-C.sub.4) alkyl; R.sub.9 is H or (C.sub.1-C.sub.4) alkyl;
R.sub.10 is (C.sub.1-C.sub.4) alkyl or (C.sub.6-C.sub.10) aryl;
R.sub.11 is (C.sub.3-C.sub.7) cycloalkyl, (C.sub.4-C.sub.7)
cycloalkenyl, (C.sub.6-C.sub.10) aryl, or 5- or 6-membered
heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S,
wherein the aryl and heteroaryl are optionally substituted with one
or more R.sub.17; each R.sub.12 is independently H or
(C.sub.1-C.sub.6) alkyl; R.sub.13 is H or (C.sub.1-C.sub.4) alkyl;
R.sub.14 is (i) H, (ii) (C.sub.1-C.sub.4) alkyl, (iii)
(C(R.sub.18).sub.2).sub.rC(.dbd.O)NR.sub.19R.sub.20, (iv)
(CH.sub.2).sub.n(C.sub.6-C.sub.10) aryl optionally substituted with
one or more (C.sub.1-C.sub.4) alkyl or halogen, (v)
C(.dbd.O)R.sub.21, (vi) C(.dbd.O)O(C.sub.1-C.sub.4) alkyl, (vii)
S(O).sub.2(C.sub.1-C.sub.8) alkyl, (viii)
S(O).sub.2NH(C.sub.1-C.sub.8) alkyl, (ix)
S(O).sub.2N((C.sub.1-C.sub.8) alkyl).sub.2, or (x)
C(.dbd.O)(C.sub.1-C.sub.8) alkyl optionally substituted with one or
more R.sub.22; or R.sub.13 and R.sub.14 together with the nitrogen
atom to which they are attached form a 4- to 6-membered
heterocyclyl ring comprising 1 to 3 heteroatoms selected from N, O,
and S and optionally substituted with one or more substituents
selected from (C.sub.1-C.sub.4) alkyl, (C.sub.1-C.sub.4) alkoxy,
OH, NH.sub.2, and (.dbd.O); R.sub.15 is (i) H, (ii) 5- or
6-membered heterocyclyl comprising 1 to 3 heteroatoms selected from
N, O, and S, or (iii) (C.sub.1-C.sub.4) alkyl optionally
substituted with one or more substituents selected from OH, 5- or
6-membered heterocyclyl comprising 1 to 3 heteroatoms selected from
N, O, and S, and 5- or 6-membered heteroaryl comprising 1 to 3
heteroatoms selected from N, O, and S; or R.sub.13 and R.sub.15
together with the nitrogen atom to which they are attached form a
4- to 6-membered heterocyclyl ring comprising 1 to 3 heteroatoms
selected from N, O, and S and optionally substituted with one or
more substituents selected from (C.sub.1-C.sub.4) alkyl,
(C.sub.1-C.sub.4) alkoxy, and OH, or form a 5- to 8-membered
bicyclic heterocyclyl ring comprising 1 to 3 heteroatoms selected
from N, O, and S and optionally substituted with one or more
substituents selected from (C.sub.1-C.sub.4) alkyl,
(C.sub.1-C.sub.4) alkoxy, and OH; R.sub.16 is (C.sub.1-C.sub.4)
alkyl, (C.sub.2-C.sub.4) alkenyl, (C.sub.2-C.sub.4) alkynyl, or 3-
to 6-membered heterocyclyl comprising 1 to 3 heteroatoms selected
from N, O, and S, wherein the alkyl, alkenyl, and alkynyl are
optionally substituted with one or more substituents selected from
(C.sub.1-C.sub.4) alkoxy, O-phenyl, halogen, CN, NH.sub.2,
(C.sub.1-C.sub.4) alkylamino, di-(C.sub.1-C.sub.4) alkylamino, and
OS(O).sub.2(C.sub.1-C.sub.4) alkyl, and wherein the heterocyclyl is
optionally substituted with one or more R.sub.23; each R.sub.17 is
independently (C.sub.1-C.sub.4) alkyl, (C.sub.1-C.sub.4) alkoxy,
(C.sub.1-C.sub.4) haloalkyl, (C.sub.1-C.sub.4) haloalkoxy, halogen,
C(.dbd.O)NH.sub.2, C(.dbd.O)NH(C.sub.1-C.sub.4) alkyl, or
C(.dbd.O)N((C.sub.1-C.sub.4) alkyl).sub.2; each R.sub.18 is
independently H or (C.sub.1-C.sub.4) alkyl; R.sub.19 is H or
(C.sub.1-C.sub.4) alkyl; R.sub.20 is H or
(CH.sub.2).sub.n(C.sub.6-C.sub.10) aryl optionally substituted with
one or more (C.sub.1-C.sub.4) alkyl; R.sub.21 is (C.sub.3-C.sub.7)
cycloalkyl, 5- or 6-membered heterocyclyl comprising 1 to 3
heteroatoms selected from N, O, and S, (C.sub.6-C.sub.10) aryl, or
5- or 6-membered heteroaryl comprising 1 to 3 heteroatoms selected
from N, O, and S, wherein the aryl, heteroaryl, cycloalkyl, and
heterocyclyl are optionally substituted with one or more
substituents selected from (C.sub.1-C.sub.4) alkyl,
(C.sub.1-C.sub.4) alkoxy, (C.sub.1-C.sub.4) haloalkyl,
(C.sub.1-C.sub.4) haloalkoxy, OH, and halogen; each R.sub.22 is
independently (i) (C.sub.1-C.sub.4) alkoxy, (ii) OH, (iii)
NH.sub.2, (iv) (C.sub.1-C.sub.4) alkylamino, (v)
di-(C.sub.1-C.sub.4) alkylamino, or (vi) 5- or 6-membered
heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and
S and optionally substituted with one or more substituents selected
from (a) (C.sub.1-C.sub.4) alkyl, (b)
(CH.sub.2).sub.x(C.sub.6-C.sub.10) aryl, and (c)
C(.dbd.O)(C.sub.6-C.sub.10)aryl optionally substituted with one or
more (C.sub.1-C.sub.4) alkyl; each R.sub.23 is independently
(C.sub.1-C.sub.4) alkyl or C(.dbd.O)(C.sub.1-C.sub.4) alkyl, or two
R.sub.23 together with the atoms to which they are attached form a
5- or 6-membered heterocyclyl ring comprising 1 to 3 heteroatoms
selected from N, O, and S; R.sub.24 is (C.sub.1-C.sub.4) alkyl
optionally substituted with one or more substituents selected from
(C.sub.1-C.sub.4) alkoxy and 5- or 6-membered heterocyclyl
comprising 1 to 3 heteroatoms selected from N, O, and S; R.sub.25
is (C.sub.1-C.sub.4) alkyl optionally substituted with one or more
(C.sub.1-C.sub.4) alkoxy,
(C(R.sub.26).sub.2).sub.x(C.sub.6-C.sub.10) aryl,
(C(R.sub.26).sub.2).sub.x-heteroaryl, wherein the heteroaryl
comprises one or two 5- or 6-membered rings and 1 to 3 heteroatoms
selected from N, O, and S, or
(C(R.sub.26).sub.2).sub.x-heterocyclyl, wherein the heterocyclyl
comprises one or two 4- to 6-membered rings and 1 to 3 heteroatoms
selected from N, O, and S, wherein the alkyl, alkoxy, aryl,
heteroaryl, and heterocyclyl are optionally substituted with one or
more substituents selected from (C.sub.1-C.sub.4) alkyl,
(C.sub.1-C.sub.4) alkoxy, (C.sub.1-C.sub.4) haloalkyl,
(C.sub.1-C.sub.4) haloalkoxy, cyano, halogen, OH, NH.sub.2,
(C.sub.6-C.sub.10) aryl, and 5- or 6-membered heteroaryl comprising
1 to 3 heteroatoms selected from N, O, and S; each R.sub.26 is
independently H or (C.sub.1-C.sub.4) alkyl, or two R.sub.26
together with the atom to which they are attached form a
(C.sub.3-C.sub.6) cycloalkyl ring or 3- or 6-membered heterocyclyl
ring comprising 1 to 3 heteroatoms selected from N, O, and S; each
n and each p is independently 0, 1, or 2; each r is independently
0, 1, 2, or 3; each q and each x is independently 0, 1, 2, or 3;
and provided that when R.sub.4 is NR.sub.9S(O).sub.pR.sub.10, A is
optionally substituted with one additional R.sub.4; and provided
that the compound is not
(2-chloro-4-phenoxyphenyl)(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyr-
an-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone.
2. The compound of claim 1, wherein A is phenyl, thiophenyl, or
pyridinyl optionally substituted with one or more R.sub.4.
3. The compound of claim 1, wherein A is phenyl, thiophenyl, or
pyridinyl substituted with one to two R.sub.4.
4. The compound of claim 1, wherein A is phenyl substituted with
one to two R.sub.4.
5. The compound of claim 1, wherein R.sub.2 is H.
6. The compound of claim 1, wherein R.sub.3 is H, NH.sub.2,
NHCH.sub.3, or 4-methylpiperazine.
7. The compound of claim 1, wherein R.sub.3 is H.
8. The compound of claim 1, wherein each R.sub.4 is independently
(C.sub.1-C.sub.4) alkyl, (C.sub.1-C.sub.4) alkoxy optionally
substituted with one or more (C.sub.1-C.sub.4) alkoxy, halogen,
NR.sub.9S(O).sub.pR.sub.10, O(CH.sub.2).sub.nR.sub.11,
NH(CH.sub.2).sub.nR.sub.11, (CH.sub.2).sub.nC(.dbd.O)NHR.sub.25,
(CH.sub.2).sub.nNHC(.dbd.O)R.sub.25,
(CH.sub.2).sub.nNHC(.dbd.O)NHR.sub.25, C(.dbd.O)R.sub.25, or
heterocyclyl comprising one or two 4- to 6-membered rings and 1 to
3 heteroatoms selected from N, O, and S and optionally substituted
with one or more substituents selected from (C.sub.1-C.sub.4)
alkyl, (C.sub.1-C.sub.4) haloalkyl, C(.dbd.O)(C.sub.1-C.sub.4)
alkyl, and halogen.
9. The compound of claim 1, wherein each R.sub.4 is independently
(C.sub.1-C.sub.4) alkyl, (C.sub.1-C.sub.4) alkoxy optionally
substituted with one or more (C.sub.1-C.sub.4) alkoxy, halogen,
(CH.sub.2).sub.nC(.dbd.O)NHR.sub.25,
(CH.sub.2).sub.nNHC(.dbd.O)R.sub.25,
(CH.sub.2).sub.nNHC(.dbd.O)NHR.sub.25, or C(.dbd.O)R.sub.25.
10. The compound of claim 1, wherein at least one R.sub.4 is
C(.dbd.O)NHR.sub.25, NHC(.dbd.O)R.sub.25,
(CH.sub.2)C(.dbd.O)NHR.sub.25, or
(CH.sub.2)NHC(.dbd.O)R.sub.25.
11. The compound of claim 1, wherein at least one R.sub.4 is
(CH.sub.2)NHC(.dbd.O)R.sub.25.
12. The compound of claim 1, wherein at least one R.sub.4 is
heterocyclyl comprising one or two 4- to 6-membered rings and 1 to
3 heteroatoms selected from N, O, and S and optionally substituted
with one or more substituents selected from (C.sub.1-C.sub.4)
alkyl, (C.sub.1-C.sub.4) haloalkyl, C(.dbd.O)(C.sub.1-C.sub.4)
alkyl, and halogen.
13. The compound of claim 1, wherein R.sub.11 is (C.sub.6-C.sub.10)
aryl or 5- or 6-membered heteroaryl comprising 1 to 3 heteroatoms
selected from N, O, and S, wherein the aryl and heteroaryl are
optionally substituted with one to three R.sub.17.
14. The compound of claim 1, wherein R.sub.11 is phenyl or
pyridinyl, and is optionally substituted with one to three
R.sub.17.
15. The compound of claim 1, wherein R.sub.1 is (C.sub.4-C.sub.7)
cycloalkyl substituted with one to three R.sub.5.
16. The compound of claim 1, wherein R.sub.1 is cyclohexyl
substituted with one to three R.sub.5.
17. The compound of claim 1, wherein R.sub.1 is 4- to 7-membered
heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and
S optionally substituted with one to three R.sub.5.
18. The compound of claim 1, wherein R.sub.1 is piperidinyl,
tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, or 1,4-dioxanyl
optionally substituted with one to three R.sub.5.
19. The compound of claim 1, wherein R.sub.1 is tetrahydropyranyl
optionally substituted with one to three R.sub.5.
20. The compound of claim 1, wherein R.sub.5 is C(.dbd.O)R.sub.16
or S(O).sub.pR.sub.16 and R.sub.16 is (C.sub.2-C.sub.4) alkenyl or
(C.sub.2-C.sub.4) alkynyl, wherein the alkenyl and alkynyl are
optionally substituted with one or more CN.
21. The compound of claim 1, wherein two R.sub.5 together with the
atoms to which they are attached form a bridged 3- to 6-membered
heterocyclyl ring comprising 1 to 3 heteroatoms selected from N, O,
and S.
22. The compound of claim 1, wherein q is 0 or 1.
23. The compound of claim 1, wherein the compound is of Formula
(Ia'), (Ib'), or (Ic'): ##STR00748## or a pharmaceutically
acceptable salt, solvate, prodrug, stereoisomer, or tautomer
thereof, wherein w is 1 or 2.
24. The compound of claim 1, wherein the compound is of Formula
(Id'), (Ie'), or (If'): ##STR00749## or a pharmaceutically
acceptable salt, solvate, prodrug, stereoisomer, or tautomer
thereof, wherein R.sub.5' is H or R.sub.5.
25. The compound of claim 1, wherein the compound is of any of
Formulae (Ig1)-(Ig12), (Ih1)-(Ih12), and (Ii1)-(Ii12): ##STR00750##
##STR00751## ##STR00752## ##STR00753## ##STR00754## ##STR00755## or
a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer,
or tautomer thereof.
26. A pharmaceutical composition comprising a compound of claim 1,
or a pharmaceutically acceptable salt, solvate, prodrug,
stereoisomer, or tautomer thereof, and a pharmaceutically
acceptable diluent, excipient or carrier.
27. A method of treating a BTK-mediated disorder, comprising
administering to a subject in need thereof a compound of claim 1,
or a pharmaceutically acceptable salt, solvate, prodrug,
stereoisomer, or tautomer thereof.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. Ser. No.
15/683,913, filed on Aug. 23, 2017, which claims priority to, and
the benefit of, U.S. Ser. No. 62/378,868, 62/378,871, and
62/378,872, each filed on Aug. 24, 2016, the contents of each of
which are incorporated herein by reference in their entirety.
FIELD OF THE APPLICATION
[0002] The present application is directed to inhibitors of
Bruton's Tyrosine Kinase (BTK), including mutant BTK, useful in the
treatment of diseases or disorders associated with BTK kinase,
including immune disorders, cancer, cardiovascular diseases, viral
infections, inflammation, metabolism/endocrine function disorders,
and neurological disorders. Specifically, the application is
concerned with compounds and compositions thereof, which inhibit
BTK, methods of treating diseases or disorders associated with BTK
and methods of synthesis of these compounds.
BACKGROUND
[0003] BTK is a member of the Tec family of tyrosine kinases and
plays an important role in the regulation of early B-cell
development and mature B-cell activation and survival (Hunter,
Cell, 1987 50, 823-829). Functioning downstream of multiple
receptors, such as growth factors, B-cell antigen, chemokine, and
innate immune receptors, BTK initiates a number of cellular
processes including cell proliferation, survival, differentiation,
motility, angiogenesis, cytokine production, and antigen
presentation.
[0004] BTK-deficient mouse models have shown the role BTK plays in
allergic disorders and/or autoimmune disease and/or inflammatory
disease. For instance, BTK deficiency in standard murine
preclinical models of systemic lupus erythematosus (SLE) has been
shown to result in a marked amelioration of disease progression.
Furthermore, BTK-deficient mice can be resistant to developing
collagen-induced arthritis and less susceptible to
Staphylococcus-induced arthritis. Due to BTK's role in B-cell
activation, BTK inhibitors can also be useful as inhibitors of
B-cell mediated pathogenic activity (such as autoantibody
production). Expression of BTK in osteoclasts, mast cells and
monocytes has been shown to be important for the function of these
cells. For example, impaired IgE-mediated mast cell activation and
reduced TNF-alpha production by activated monocytes has been
associated with BTK deficiency in mice and humans. Thus, BTK
inhibition can be useful for the treatment of allergic disorders
and/or autoimmune and/or inflammatory diseases such as: SLE,
rheumatoid arthritis, multiple vasculitides, idiopathic
thrombocytopenic purpura (ITP), myasthenia gravis, allergic
rhinitis, and asthma (DiPaolo et al., Nature Chem. Biol. 2011,
7(1):41-50; Liu et al., Jour. Pharmacol. and Exp. Ther. 2011,
338(1):154-163).
[0005] Moreover, BTK's role in apoptosis demonstrates the utility
of inhibition of BTK activity for the treatment of cancers, B-cell
lymphoma, leukemia, and other hematological malignancies. In
addition, given the role of BTK in osteoclast function, inhibition
of BTK activity can be useful for the treatment of bone disorders
such as osteoporosis.
[0006] Inhibition of BTK with small molecule inhibitors therefore
has the potential to be a treatment for immune disorders, cancer,
cardiovascular diseases, viral infections, inflammation,
metabolism/endocrine function disorders, and neurological
disorders. Thus, there remains a considerable need for potent small
molecule inhibitors of BTK.
SUMMARY
[0007] A first aspect of the application relates to a compound of
Formula (I):
##STR00002##
or a pharmaceutically acceptable salt, solvate, prodrug,
stereoisomer, or tautomer thereof, wherein R.sub.1, R.sub.2,
R.sub.3, A, and q are as described in detail below.
[0008] Another aspect of the application relates to a
pharmaceutical composition comprising a compound of Formula (I), or
a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer,
or tautomer thereof, and a pharmaceutically acceptable diluent,
excipient or carrier.
[0009] Another aspect of the application relates to a method of
treating a BTK-mediated disorder. The method comprises
administering to a subject in need of a treatment for a disease or
disorder associated with modulation of BTK kinase a therapeutically
effective amount of a compound of Formula (I), or a
pharmaceutically acceptable salt, solvate, prodrug, stereoisomer,
or tautomer thereof.
[0010] Another aspect of the application relates to a method of
treating a BTK-mediated disorder. The method comprises
administering to a subject in need of a treatment for a disease or
disorder associated with modulation of BTK kinase a therapeutically
effective amount of a pharmaceutical composition comprising a
compound of Formula (I), or a pharmaceutically acceptable salt,
solvate, prodrug, stereoisomer, or tautomer thereof, and a
pharmaceutically acceptable diluent, excipient or carrier.
[0011] Another aspect of the application relates to a method of
treating a cell proliferative disorder. The method comprises
administering to a subject in need thereof a therapeutically
effective amount of a compound of Formula (I), or a
pharmaceutically acceptable salt, solvate, prodrug, stereoisomer,
or tautomer thereof.
[0012] Another aspect of the application relates to a method of
treating a cell proliferative disorder. The method comprises
administering to a subject in need thereof a therapeutically
effective amount of a pharmaceutical composition comprising a
compound of Formula (I), or a pharmaceutically acceptable salt,
solvate, prodrug, stereoisomer, or tautomer thereof, and a
pharmaceutically acceptable diluent, excipient or carrier.
[0013] Another aspect of the application relates to a method of
treating cancer. The method comprises administering to a subject in
need thereof a therapeutically effective amount of a compound of
Formula (I), or a pharmaceutically acceptable salt, solvate,
prodrug, stereoisomer, or tautomer thereof.
[0014] Another aspect of the application relates to a method of
treating cancer. The method comprises administering to a subject in
need thereof a therapeutically effective amount of a pharmaceutical
composition comprising a compound of Formula (I), or a
pharmaceutically acceptable salt, solvate, prodrug, stereoisomer,
or tautomer thereof, and a pharmaceutically acceptable diluent,
excipient or carrier.
[0015] Another aspect of the application relates to a method of
modulating (e.g., inhibiting) BTK. The method comprises
administering to a subject in need thereof a therapeutically
effective amount of a compound of Formula (I), or a
pharmaceutically acceptable salt, solvate, prodrug, stereoisomer,
or tautomer thereof.
[0016] Another aspect of the application relates to a method of
modulating (e.g., inhibiting) BTK. The method comprises
administering to a subject in need thereof a therapeutically
effective amount of a pharmaceutical composition comprising a
compound of Formula (I), or a pharmaceutically acceptable salt,
solvate, prodrug, stereoisomer, or tautomer thereof, and a
pharmaceutically acceptable diluent, excipient or carrier.
[0017] Another aspect of the application relates to a compound of
Formula (I), or a pharmaceutically acceptable salt, solvate,
prodrug, stereoisomer, or tautomer thereof, for use in a method of
treating a BTK-mediated disorder, a cell proliferative disorder, or
cancer, or of modulating (e.g., inhibiting) BTK. The compound of
Formula (I), or a pharmaceutically acceptable salt, solvate,
prodrug, stereoisomer, or tautomer thereof, is administered in a
therapeutically effective amount to a subject in need thereof.
[0018] Another aspect of the application relates to a
pharmaceutical composition comprising a compound of Formula (I), or
a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer,
or tautomer thereof, and a pharmaceutically acceptable diluent,
excipient or carrier for use in a method of treating a BTK-mediated
disorder, a cell proliferative disorder, or cancer, or of
modulating (e.g., inhibiting) BTK. The composition is administered
in a therapeutically effective amount to a subject in need
thereof.
[0019] Another aspect of the application relates to the use of a
compound of Formula (I), or a pharmaceutically acceptable salt,
solvate, prodrug, stereoisomer, or tautomer thereof, in the
manufacture of a medicament for treating a BTK-mediated disorder, a
cell proliferative disorder, or cancer, or for modulating (e.g.,
inhibiting) BTK. The compound of Formula (I), or a pharmaceutically
acceptable salt, solvate, prodrug, stereoisomer, or tautomer
thereof, is administered in a therapeutically effective amount to a
subject in need thereof.
[0020] Another aspect of the application relates to the use of a
pharmaceutical composition comprising a compound of Formula (I), or
a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer,
or tautomer thereof, and a pharmaceutically acceptable diluent,
excipient or carrier in the manufacture of a medicament for
treating a BTK-mediated disorder, a cell proliferative disorder, or
cancer, or for modulating (e.g., inhibiting) BTK. The composition
is administered in a therapeutically effective amount to a subject
in need thereof
[0021] The present application further provides methods of treating
a disease or disorder associated with modulation of BTK kinase
including, but not limited to, immune disorders, cancer,
cardiovascular diseases, viral infections, inflammation,
metabolism/endocrine function disorders, and neurological disorders
comprising, administering to a subject suffering from at least one
of the diseases or disorders a compound of Formula (I), or a
pharmaceutically acceptable salt, solvate, prodrug, stereoisomer,
or tautomer thereof.
[0022] The present application provides inhibitors of BTK that are
therapeutic agents in the treatment of diseases such as immune
disorders, cancer, cardiovascular diseases, viral infections,
inflammation, metabolism/endocrine function disorders, neurological
disorders and other disease associated with the modulation of BTK
kinase.
[0023] The present application further provides compounds and
compositions with an improved efficacy and safety profile relative
to known BTK inhibitors. The present application also provides
agents with novel mechanisms of action toward BTK kinase in the
treatment of various types of diseases including immune disorders,
cancer, cardiovascular diseases, viral infections, inflammation,
metabolism/endocrine function disorders, and neurological
disorders. Ultimately the present application provides the medical
community with a novel pharmacological strategy for the treatment
of diseases and disorders associated with BTK kinase.
DETAILED DESCRIPTION
Compounds of the Application
[0024] The present application relates to compounds and
compositions thereof that are capable of modulating the activity
Bruton's Tyrosine Kinase (BTK). The application features methods of
treating, preventing or ameliorating a disease or disorder in which
BTK plays a role by administering to a subject in need thereof a
therapeutically effective amount of a compound of Formula (I), or a
pharmaceutically acceptable salt, solvate, prodrug, stereoisomer,
or tautomer thereof. The methods of the present application can be
used in the treatment of a variety of BTK-mediated diseases and
disorders by inhibiting the activity of BTK kinase. Inhibition of
BTK provides treatment, prevention, or amelioration of diseases
including, but not limited to, immune disorders, cancer,
cardiovascular diseases, viral infections, inflammation,
metabolism/endocrine function disorders and neurological
disorders.
[0025] In a first aspect of the application, a compound of Formula
(I) is described:
##STR00003##
or a pharmaceutically acceptable salt, solvate, prodrug,
stereoisomer, or tautomer thereof, wherein:
[0026] A is (C.sub.6-C.sub.10) aryl or 5- or 6-membered heteroaryl
comprising 1 to 3 heteroatoms selected from N, O, and S, wherein
the aryl and heteroaryl are optionally substituted with one or more
R.sub.4;
[0027] R.sub.1 is (C.sub.3-C.sub.7) cycloalkyl or 4- to 9-membered
heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and
S, wherein the cycloalkyl and heterocyclyl are optionally
substituted with one or more R.sub.5;
[0028] R.sub.2 is H or (C.sub.1-C.sub.4) alkyl; or
[0029] when q is 0, R.sub.1 and R.sub.2 together with the nitrogen
atom to which they are attached form a 5- or 6-membered
heterocyclyl ring comprising 0 to 1 additional heteroatoms selected
from N, O, and S and optionally substituted with one or more
NR.sub.6R.sub.7;
[0030] R.sub.3 is H or N(R.sub.5).sub.2;
[0031] each R.sub.4 is independently (i) (C.sub.1-C.sub.4) alkyl,
(ii) (C.sub.1-C.sub.4) alkoxy optionally substituted with one or
more (C.sub.1-C.sub.4) alkoxy, (iii) (C.sub.1-C.sub.4) haloalkyl,
(iv) (C.sub.1-C.sub.4) haloalkoxy, (v) halogen, (vi)
NR.sub.9S(O).sub.pR.sub.10, (vii) O(CH.sub.2).sub.nR.sub.11, (viii)
NH(CH.sub.2).sub.nR.sub.11, (ix)
(CH.sub.2).sub.nC(.dbd.O)NHR.sub.25, (x)
(CH.sub.2).sub.nNHC(.dbd.O)R.sub.25, (xi)
(CH.sub.2).sub.nNHC(.dbd.O)NHR.sub.25, (xii) C(.dbd.O)R.sub.25, or
(xiii) heterocyclyl comprising one or two 4- to 6-membered rings
and 1 to 3 heteroatoms selected from N, O, and S and optionally
substituted with one or more substituents selected from
(C.sub.1-C.sub.4) alkyl, (C.sub.1-C.sub.4) haloalkyl,
C(.dbd.O)(C.sub.1-C.sub.4) alkyl, and halogen;
[0032] each R.sub.5 is independently (i) (C.sub.1-C.sub.6) alkyl
optionally substituted with one or more (C.sub.1-C.sub.4) alkoxy or
phenyl, (ii) (C.sub.2-C.sub.4) alkenyl optionally substituted with
one or more C(.dbd.O)(C.sub.1-C.sub.4) alkyl, (iii)
(C(R.sub.12).sub.2).sub.rOH, (iv)
(C(R.sub.12).sub.2).sub.rNR.sub.13R.sub.14, (v) C(.dbd.O)OH, (vi)
C(.dbd.O)O(C.sub.1-C.sub.4) alkyl, (vii)
C(.dbd.O)NR.sub.13R.sub.15, (viii) C(.dbd.O)R.sub.16, (ix)
S(O).sub.pR.sub.16, or (x) 5- or 6-membered heteroaryl comprising 1
to 3 heteroatoms selected from N, O, and S and optionally
substituted with one or more (C.sub.1-C.sub.4) alkyl, (xi) or two
R.sub.5 together with the carbon atom to which they are attached
form (.dbd.O), or (xii) two R.sub.5 together with the atoms to
which they are attached form a bridged 3- to 6-membered
heterocyclyl ring comprising 1 to 3 heteroatoms selected from N, O,
and S;
[0033] R.sub.6 is H or (C.sub.1-C.sub.4) alkyl;
[0034] R.sub.7 is H, (C.sub.1-C.sub.4) alkyl, or
C(.dbd.O)R.sub.24;
[0035] each R.sub.8 is independently (i) H, (ii) (C.sub.1-C.sub.4)
alkyl, or (iii) 5- or 6-membered heterocyclyl comprising 1 to 3
heteroatoms selected from N, O, and S and optionally substituted
with one or more (C.sub.1-C.sub.4) alkyl, or (iv) two R.sub.8
together with the nitrogen atom to which they are attached form a
5- or 6-membered heterocyclyl ring comprising 0 to 1 additional
heteroatoms selected from N, O, and S and optionally substituted
with one or more (C.sub.1-C.sub.4) alkyl;
[0036] R.sub.9 is H or (C.sub.1-C.sub.4) alkyl;
[0037] R.sub.10 is (C.sub.1-C.sub.4) alkyl or (C.sub.6-C.sub.10)
aryl;
[0038] R.sub.11 is (C.sub.3-C.sub.7) cycloalkyl, (C.sub.4-C.sub.7)
cycloalkenyl, (C.sub.6-C.sub.10) aryl, or 5- or 6-membered
heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S,
wherein the aryl and heteroaryl are optionally substituted with one
or more R.sub.17;
[0039] each R.sub.12 is independently H or (C.sub.1-C.sub.6)
alkyl;
[0040] R.sub.13 is H or (C.sub.1-C.sub.4) alkyl;
[0041] R.sub.14 is (i) H, (ii) (C.sub.1-C.sub.4) alkyl, (iii)
(C(R.sub.18).sub.2).sub.rC(.dbd.O)NR.sub.19R.sub.20, (iv)
(CH.sub.2).sub.n(C.sub.6-C.sub.10) aryl optionally substituted with
one or more (C.sub.1-C.sub.4) alkyl or halogen, (v)
C(.dbd.O)R.sub.21, (vi) C(.dbd.O)O(C.sub.1-C.sub.4) alkyl, (vii)
S(O).sub.2(C.sub.1-C.sub.8) alkyl, (viii)
S(O).sub.2NH(C.sub.1-C.sub.8) alkyl, (ix)
S(O).sub.2N((C.sub.1-C.sub.8) alkyl).sub.2, or (x)
C(.dbd.O)(C.sub.1-C.sub.8) alkyl optionally substituted with one or
more R.sub.22; or
[0042] R.sub.13 and R.sub.14 together with the nitrogen atom to
which they are attached form a 4- to 6-membered heterocyclyl ring
comprising 1 to 3 heteroatoms selected from N, O, and S and
optionally substituted with one or more substituents selected from
(C.sub.1-C.sub.4) alkyl, (C.sub.1-C.sub.4) alkoxy, OH, NH.sub.2,
and (.dbd.O);
[0043] R.sub.15 is (i) H, (ii) 5- or 6-membered heterocyclyl
comprising 1 to 3 heteroatoms selected from N, O, and S, or (iii)
(C.sub.1-C.sub.4) alkyl optionally substituted with one or more
substituents selected from OH, 5- or 6-membered heterocyclyl
comprising 1 to 3 heteroatoms selected from N, O, and S, and 5- or
6-membered heteroaryl comprising 1 to 3 heteroatoms selected from
N, O, and S; or
[0044] R.sub.13 and R.sub.15 together with the nitrogen atom to
which they are attached form a 4- to 6-membered heterocyclyl ring
comprising 1 to 3 heteroatoms selected from N, O, and S and
optionally substituted with one or more substituents selected from
(C.sub.1-C.sub.4) alkyl, (C.sub.1-C.sub.4) alkoxy, and OH, or form
a 5- to 8-membered bicyclic heterocyclyl ring comprising 1 to 3
heteroatoms selected from N, O, and S and optionally substituted
with one or more substituents selected from (C.sub.1-C.sub.4)
alkyl, (C.sub.1-C.sub.4) alkoxy, and OH;
[0045] R.sub.16 is (C.sub.1-C.sub.4) alkyl, (C.sub.2-C.sub.4)
alkenyl, (C.sub.2-C.sub.4) alkynyl, or 3- to 6-membered
heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and
S, wherein the alkyl, alkenyl, and alkynyl are optionally
substituted with one or more substituents selected from
(C.sub.1-C.sub.4) alkoxy, O-phenyl, halogen, CN, NH.sub.2,
(C.sub.1-C.sub.4) alkylamino, di-(C.sub.1-C.sub.4) alkylamino, and
OS(O).sub.2(C.sub.1-C.sub.4) alkyl, and wherein the heterocyclyl is
optionally substituted with one or more R.sub.23;
[0046] each R.sub.17 is independently (C.sub.1-C.sub.4) alkyl,
(C.sub.1-C.sub.4) alkoxy, (C.sub.1-C.sub.4) haloalkyl,
(C.sub.1-C.sub.4) haloalkoxy, halogen, C(.dbd.O)NH.sub.2,
C(.dbd.O)NH(C.sub.1-C.sub.4) alkyl, or C(.dbd.O)N((C.sub.1-C.sub.4)
alkyl).sub.2;
[0047] each R.sub.18 is independently H or (C.sub.1-C.sub.4)
alkyl;
[0048] R.sub.19 is H or (C.sub.1-C.sub.4) alkyl;
[0049] R.sub.20 is H or (CH.sub.2).sub.n(C.sub.6-C.sub.10) aryl
optionally substituted with one or more (C.sub.1-C.sub.4)
alkyl;
[0050] R.sub.21 is (C.sub.3-C.sub.7) cycloalkyl, 5- or 6-membered
heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and
S, (C.sub.6-C.sub.10) aryl, or 5- or 6-membered heteroaryl
comprising 1 to 3 heteroatoms selected from N, O, and S, wherein
the aryl, heteroaryl, cycloalkyl, and heterocyclyl are optionally
substituted with one or more substituents selected from
(C.sub.1-C.sub.4) alkyl, (C.sub.1-C.sub.4) alkoxy,
(C.sub.1-C.sub.4) haloalkyl, (C.sub.1-C.sub.4) haloalkoxy, OH, and
halogen;
[0051] each R.sub.22 is independently (i) (C.sub.1-C.sub.4) alkoxy,
(ii) OH, (iii) NH.sub.2, (iv) (C.sub.1-C.sub.4) alkylamino, (v)
di-(C.sub.1-C.sub.4) alkylamino, or (vi) 5- or 6-membered
heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and
S and optionally substituted with one or more substituents selected
from (a) (C.sub.1-C.sub.4) alkyl, (b)
(CH.sub.2).sub.x(C.sub.6-C.sub.10) aryl, and (c)
C(.dbd.O)(C.sub.6-C.sub.10)aryl optionally substituted with one or
more (C.sub.1-C.sub.4) alkyl;
[0052] each R.sub.23 is independently (C.sub.1-C.sub.4) alkyl or
C(.dbd.O)(C.sub.1-C.sub.4) alkyl, or two R.sub.23 together with the
atoms to which they are attached form a 5- or 6-membered
heterocyclyl ring comprising 1 to 3 heteroatoms selected from N, O,
and S;
[0053] R.sub.24 is (C.sub.1-C.sub.4) alkyl optionally substituted
with one or more substituents selected from (C.sub.1-C.sub.4)
alkoxy and 5- or 6-membered heterocyclyl comprising 1 to 3
heteroatoms selected from N, O, and S;
[0054] R.sub.25 is (C.sub.1-C.sub.4) alkyl optionally substituted
with one or more (C.sub.1-C.sub.4) alkoxy,
(C(R.sub.26).sub.2).sub.x(C.sub.6-C.sub.10) aryl,
(C(R.sub.26).sub.2).sub.x-heteroaryl, wherein the heteroaryl
comprises one or two 5- or 6-membered rings and 1 to 3 heteroatoms
selected from N, O, and S, or
(C(R.sub.26).sub.2).sub.x-heterocyclyl, wherein the heterocyclyl
comprises one or two 4- to 6-membered rings and 1 to 3 heteroatoms
selected from N, O, and S, wherein the alkyl, alkoxy, aryl,
heteroaryl, and heterocyclyl are optionally substituted with one or
more substituents selected from (C.sub.1-C.sub.4) alkyl,
(C.sub.1-C.sub.4) alkoxy, (C.sub.1-C.sub.4) haloalkyl,
(C.sub.1-C.sub.4) haloalkoxy, cyano, halogen, OH, NH.sub.2,
(C.sub.6-C.sub.10) aryl, and 5- or 6-membered heteroaryl comprising
1 to 3 heteroatoms selected from N, O, and S;
[0055] each R.sub.26 is independently H or (C.sub.1-C.sub.4) alkyl,
or two R.sub.26 together with the atom to which they are attached
form a (C.sub.3-C.sub.6) cycloalkyl ring or 3- or 6-membered
heterocyclyl ring comprising 1 to 3 heteroatoms selected from N, O,
and S;
[0056] each n and each p is independently 0, 1, or 2;
[0057] each r is independently 0, 1, 2, or 3;
[0058] each q and each x is independently 0, 1, 2, or 3; and
[0059] provided that when R.sub.4 is NR.sub.9S(O).sub.pR.sub.10, A
is optionally substituted with one additional R.sub.4; and
[0060] provided that the compound is not
(2-chloro-4-phenoxyphenyl)(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyr-
an-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone.
[0061] In some embodiments, the compounds of Formula (I) have the
structure of Formula (Ia) or (Ia'):
##STR00004##
or a pharmaceutically acceptable salt, solvate, prodrug,
stereoisomer, or tautomer thereof.
[0062] In some embodiments, the compounds of Formula (I) have the
structure of Formula (Ib) or (Ib'):
##STR00005##
or a pharmaceutically acceptable salt, solvate, prodrug,
stereoisomer, or tautomer thereof.
[0063] In some embodiments, the compounds of Formula (I) have the
structure of Formula (Ic) or (Ic'):
##STR00006##
or a pharmaceutically acceptable salt, solvate, prodrug,
stereoisomer, or tautomer thereof.
[0064] In some embodiments, the compounds of Formula (I) have the
structure of Formula (Id) or (Id'):
##STR00007##
or a pharmaceutically acceptable salt, solvate, prodrug,
stereoisomer, or tautomer thereof.
[0065] In some embodiments, the compounds of Formula (I) have the
structure of Formula (Ie) or (Ie'):
##STR00008##
and pharmaceutically acceptable salts, solvates, prodrugs,
stereoisomers, and tautomers thereof.
[0066] In some embodiments, the compounds of Formula (I) have the
structure of Formula (If) or (If):
##STR00009##
and pharmaceutically acceptable salts, solvates, prodrugs,
stereoisomers, and tautomers thereof.
[0067] In some embodiments, the compounds of Formula (I) have the
structure any of Formulae (Ig1) and (Ig12):
##STR00010##
and pharmaceutically acceptable salts, solvates, prodrugs,
stereoisomers, and tautomers thereof.
[0068] In some embodiments, the compounds of Formula (I) have the
structure any of Formulae (Ih1) and (Ih12):
##STR00011##
and pharmaceutically acceptable salts, solvates, prodrugs,
stereoisomers, and tautomers thereof.
[0069] In some embodiments, the compounds of Formula (I) have the
structure any of Formulae (Ii1) and (Ii12):
##STR00012##
and pharmaceutically acceptable salts, solvates, prodrugs,
stereoisomers, and tautomers thereof.
[0070] In some embodiments of the formulae above, A is
(C.sub.6-C.sub.10) aryl optionally substituted with one or more
R.sub.4. In one embodiment, A is 5- or 6-membered heteroaryl
comprising 1 to 3 heteroatoms selected from N, O, and S (e.g.,
pyridinyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl,
thiazolyl, oxazolyl, isooxazolyl, thiadiazolyl, oxadiazolyl,
thiophenyl, and furanyl), optionally substituted with one or more
R.sub.4. In another embodiment, A is 5-membered heteroaryl
comprising 1 to 3 heteroatoms selected from N, O, and S (e.g.,
pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isooxazolyl,
thiadiazolyl, oxadiazolyl, thiophenyl, and furanyl), optionally
substituted with one or more R.sub.4. In another embodiment, A is
6-membered heteroaryl comprising 1 to 3 heteroatoms selected from
N, O, and S (e.g., pyridinyl, pyrazinyl, and pyrimidinyl),
optionally substituted with one or more R.sub.4. In another
embodiment, A is (C.sub.6-C.sub.10) aryl or 5-membered heteroaryl
comprising 1 to 3 heteroatoms selected from N, O, and S, wherein
each is optionally substituted with one or more R.sub.4. In another
embodiment, A is (C.sub.6-C.sub.10) aryl or 6-membered heteroaryl
comprising 1 to 3 heteroatoms selected from N, O, and S, wherein
each is optionally substituted with one or more R.sub.4.
[0071] In another embodiment, A is phenyl, thiophenyl, or pyridinyl
wherein each is optionally substituted with one or more R.sub.4. In
another embodiment, A is phenyl, thiophenyl, or pyridinyl wherein
each is substituted with one or more R.sub.4. In another
embodiment, A is phenyl, thiophenyl, or pyridinyl. In another
embodiment, A is phenyl optionally substituted with one to two
R.sub.4. In another embodiment, A is phenyl substituted with one to
two R.sub.4. In another embodiment, A is phenyl. In another
embodiment, A is thiophenyl optionally substituted with one to two
R.sub.4. In another embodiment, A is thiophenyl substituted with
one to two R.sub.4. In another embodiment, A is thiophenyl. In
another embodiment, A is pyridinyl optionally substituted with one
to two R.sub.4. In another embodiment, A is pyridinyl substituted
with one to two R.sub.4. In another embodiment, A is pyridinyl. In
a further embodiment, A is phenyl, thiophenyl, or pyridinyl wherein
each is optionally substituted with one to two R.sub.4. In another
further embodiment, A is phenyl, thiophenyl, or pyridinyl wherein
each is substituted with one to two R.sub.4.
[0072] In some embodiments of the formulae above, each R.sub.4 is
independently (C.sub.1-C.sub.4) alkyl, (C.sub.1-C.sub.4) alkoxy
optionally substituted with one or more (C.sub.1-C.sub.4) alkoxy,
(C.sub.1-C.sub.4) haloalkyl, (C.sub.1-C.sub.4) haloalkoxy, halogen,
NR.sub.9S(O).sub.pR.sub.10, O(CH.sub.2).sub.nR.sub.11,
C(.dbd.O)NHR.sub.25, NHC(.dbd.O)R.sub.25, or heterocyclyl
comprising one or two 4- to 6-membered rings and 1 to 3 heteroatoms
selected from N, O, and S and optionally substituted with one or
more substituents selected from (C.sub.1-C.sub.4) alkyl,
(C.sub.1-C.sub.4) haloalkyl, C(.dbd.O)(C.sub.1-C.sub.4) alkyl, and
halogen.
[0073] In some embodiments of the formulae above, each R.sub.4 is
independently (C.sub.1-C.sub.4) alkyl, (C.sub.1-C.sub.4) alkoxy,
(C.sub.1-C.sub.4) haloalkyl, (C.sub.1-C.sub.4) haloalkoxy, halogen,
or O(CH.sub.2).sub.nR.sub.11, wherein the alkoxy is optionally
substituted with one or more (C.sub.1-C.sub.4) alkoxy.
[0074] In some embodiments of the formulae above, at least one
R.sub.4 is (C.sub.1-C.sub.4) alkyl (e.g., methyl, ethyl, n-propyl,
i-propyl, n-butyl, i-butyl, or t-butyl). In another embodiment, at
least one R.sub.4 is methyl, ethyl, n-propyl, or i-propyl. In
another embodiment, at least one R.sub.4 is methyl or ethyl. In
another embodiment, at least one R.sub.4 is methyl.
[0075] In some embodiments of the formulae above, at least one
R.sub.4 is (C.sub.1-C.sub.4) alkoxy (e.g., methoxy, ethoxy,
n-propoxy, i-propoxy, n-butoxy, i-butoxy, or t-butoxy) optionally
substituted with one or more (C.sub.1-C.sub.4) alkoxy (e.g.,
methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, or
t-butoxy). In another embodiment, at least one R.sub.4 is methoxy
or ethoxy, wherein each is optionally substituted with one or more
(C.sub.1-C.sub.4) alkoxy (e.g., methoxy, ethoxy, n-propoxy,
i-propoxy, n-butoxy, i-butoxy, or t-butoxy). In another embodiment,
at least one R.sub.4 is methoxy or ethoxy, wherein each is
optionally substituted with one or more methoxy or ethoxy. In
another embodiment, at least one R.sub.4 is methoxy or ethoxy,
wherein each is optionally substituted with one to two methoxy. In
a further embodiment, at least one R.sub.4 is methoxy or ethoxy,
wherein each is optionally substituted with one methoxy.
[0076] In some embodiments of the formulae above, at least one
R.sub.4 is (C.sub.1-C.sub.4) haloalkyl (e.g., CF.sub.3, CHF.sub.2,
CH.sub.2F, CH.sub.2CF.sub.3, CF.sub.2CF.sub.3, CCl.sub.3,
CHCl.sub.2, CH.sub.2Cl, etc.). In a further embodiment, at least
one R.sub.4 is CF.sub.3.
[0077] In some embodiments of the formulae above, at least one
R.sub.4 is (C.sub.1-C.sub.4) haloalkoxy (e.g., OCF.sub.3,
OCHF.sub.2, OCH.sub.2F, OCH.sub.2CF.sub.3, OCF.sub.2CF.sub.3,
OCCl.sub.3, OCHCl.sub.2, OCH.sub.2Cl, etc.).
[0078] In some embodiments of the formulae above, at least one
R.sub.4 is halogen (e.g., F, Cl, Br, or I). In another embodiment,
at least one R.sub.4 is F or Cl. In another embodiment, at least
one R.sub.4 is F. In another embodiment, at least one R.sub.4 is
Cl.
[0079] In some embodiments of the formulae above, at least one
R.sub.4 is OR.sub.11, O(CH.sub.2)R.sub.11, or
O(CH.sub.2).sub.2R.sub.11. In another embodiment, at least one
R.sub.4 is OR.sub.11 or O(CH.sub.2)R.sub.11.
[0080] In some embodiments of the formulae above, at least one
R.sub.4 is NHR.sub.11, NH(CH.sub.2)R.sub.11, or
NH(CH.sub.2).sub.2R.sub.11. In another embodiment, at least one
R.sub.4 is NHR.sub.11 or NH(CH.sub.2)R.sub.11.
[0081] In some embodiments of the formulae above, at least one
R.sub.4 is C(.dbd.O)NHR.sub.25, (CH.sub.2)C(.dbd.O)NHR.sub.25, or
(CH.sub.2).sub.2C(.dbd.O)NHR.sub.25. In another embodiment, at
least one R.sub.4 is C(.dbd.O)NHR.sub.25 or
(CH.sub.2)C(.dbd.O)NHR.sub.25.
[0082] In some embodiments of the formulae above, at least one
R.sub.4 is NHC(.dbd.O)R.sub.25, (CH.sub.2)NHC(.dbd.O)R.sub.25, or
(CH.sub.2).sub.2NHC(.dbd.O)R.sub.25. In another embodiment, at
least one R.sub.4 is NHC(.dbd.O)R.sub.25 or
(CH.sub.2)NHC(.dbd.O)R.sub.25.
[0083] In some embodiments of the formulae above, at least one
R.sub.4 is NHC(.dbd.O)NHR.sub.25, (CH.sub.2)NHC(.dbd.O)NHR.sub.25,
or (CH.sub.2).sub.2NHC(.dbd.O)NHR.sub.25. In another embodiment, at
least one R.sub.4 is NHC(.dbd.O)NHR.sub.25 or
(CH.sub.2)NHC(.dbd.O)NHR.sub.25.
[0084] In some embodiments of the formulae above, at least one
R.sub.4 is (CH.sub.2)C(.dbd.O)NHR.sub.25,
(CH.sub.2)NHC(.dbd.O)NHR.sub.25, or
(CH.sub.2)NHC(.dbd.O)NHR.sub.25.
[0085] In some embodiments of the formulae above, at least one
R.sub.4 is CH.sub.2)C(.dbd.O)NHR.sub.25 or
(CH.sub.2)NHC(.dbd.O)NHR.sub.25.
[0086] In some embodiments of the formulae above, at least one
R.sub.4 is CH.sub.2)NHC(.dbd.O)NHR.sub.25.
[0087] In some embodiments of the formulae above, at least one
R.sub.4 is (i) (C.sub.1-C.sub.4) alkyl (e.g., methyl, ethyl,
n-propyl, i-propyl, n-butyl, i-butyl, or t-butyl), (ii)
(C.sub.1-C.sub.4) alkoxy (e.g., methoxy, ethoxy, n-propoxy,
i-propoxy, n-butoxy, i-butoxy, or t-butoxy) optionally substituted
with one or more (C.sub.1-C.sub.4) alkoxy (e.g., methoxy, ethoxy,
n-propoxy, i-propoxy, n-butoxy, i-butoxy, or t-butoxy), (iii)
(C.sub.1-C.sub.4) haloalkyl (e.g., CF.sub.3, CHF.sub.2, CH.sub.2F,
CH.sub.2CF.sub.3, CF.sub.2CF.sub.3, CCl.sub.3, CHCl.sub.2,
CH.sub.2Cl, etc.), (iv) (C.sub.1-C.sub.4) haloalkoxy (e.g.,
OCF.sub.3, OCHF.sub.2, OCH.sub.2F, OCH.sub.2CF.sub.3,
OCF.sub.2CF.sub.3, OCCl.sub.3, OCHCl.sub.2, OCH.sub.2Cl, etc.), (v)
halogen (e.g., F, Cl, Br, or I), (vi) NR.sub.9S(O).sub.pR.sub.10,
(vii) O(CH.sub.2).sub.nR.sub.11, (viii) NH(CH.sub.2).sub.nR.sub.11,
(ix) (CH.sub.2).sub.nC(.dbd.O)NHR.sub.25, (x)
(CH.sub.2).sub.nNHC(.dbd.O)R.sub.25, (xi)
(CH.sub.2).sub.nNHC(.dbd.O)NHR.sub.25, (xii) C(.dbd.O)R.sub.25, or
(xiii) heterocyclyl comprising one or two 4- to 6-membered rings
and 1 to 3 heteroatoms selected from N, O, and S (e.g.,
pyrrolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl,
piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl,
tetrahydropyranyl, thiazolidinyl, isothiazolidinyl,
tetrahydrofuryl, dioxanyl, and a spiroheterocyclyl such as
oxaazaspiro[3.3]heptanyl) and optionally substituted with one to
three substituents selected from (C.sub.1-C.sub.4) alkyl (e.g.,
methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, or t-butyl),
(C.sub.1-C.sub.4) haloalkyl (e.g., CF.sub.3, CHF.sub.2, CH.sub.2F,
CH.sub.2CF.sub.3, CF.sub.2CF.sub.3, CCl.sub.3, CHCl.sub.2,
CH.sub.2Cl, etc.), C(.dbd.O)(C.sub.1-C.sub.4) alkyl (wherein
(C.sub.1-C.sub.4) alkyl is methyl, ethyl, n-propyl, i-propyl,
n-butyl, i-butyl, or t-butyl), and halogen (e.g., F, Cl, Br, or I).
In another embodiment, at least one R.sub.4 is (i)
O(CH.sub.2).sub.nR.sub.11, (ii) NH(CH.sub.2).sub.nR.sub.11, (iii)
(CH.sub.2).sub.nC(.dbd.O)NHR.sub.25, (iv)
(CH.sub.2).sub.nNHC(.dbd.O)R.sub.25, (v)
(CH.sub.2).sub.nNHC(.dbd.O)NHR.sub.25, (vi) C(.dbd.O)R.sub.25, or
(vii) heterocyclyl comprising one or two 4- to 6-membered rings and
1 to 3 heteroatoms selected from N, O, and S and optionally
substituted with one to three substituents selected from
(C.sub.1-C.sub.4) alkyl, (C.sub.1-C.sub.4) haloalkyl,
C(.dbd.O)(C.sub.1-C.sub.4) alkyl, and halogen. In another
embodiment, at least one R.sub.4 is heterocyclyl comprising one or
two 4- to 6-membered rings and 1 to 3 heteroatoms selected from N,
O, and S and optionally substituted with one to three substituents
selected from (C.sub.1-C.sub.4) alkyl, (C.sub.1-C.sub.4) haloalkyl,
C(.dbd.O)(C.sub.1-C.sub.4) alkyl, and halogen.
[0088] In some embodiments of the formulae above, at least one
R.sub.4 is (C.sub.1-C.sub.4) alkyl (e.g., methyl, ethyl, n-propyl,
i-propyl, n-butyl, i-butyl, or t-butyl), (C.sub.1-C.sub.4) alkoxy
(e.g., methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy,
or t-butoxy) optionally substituted with one to two
(C.sub.1-C.sub.4) alkoxy (e.g., methoxy, ethoxy, n-propoxy,
i-propoxy, n-butoxy, i-butoxy, or t-butoxy), (C.sub.1-C.sub.4)
haloalkyl (e.g., CF.sub.3, CHF.sub.2, CH.sub.2F, CH.sub.2CF.sub.3,
CF.sub.2CF.sub.3, CCl.sub.3, CHCl.sub.2, CH.sub.2Cl, etc.),
(C.sub.1-C.sub.4) haloalkoxy (e.g., OCF.sub.3, OCHF.sub.2,
OCH.sub.2F, OCH.sub.2CF.sub.3, OCF.sub.2CF.sub.3, OCCl.sub.3,
OCHCl.sub.2, OCH.sub.2Cl, etc.), halogen (e.g., F, Cl, Br, or I),
NR.sub.9S(O).sub.pR.sub.10, O(CH.sub.2).sub.nR.sub.11,
NH(CH.sub.2).sub.nR.sub.11, (CH.sub.2).sub.nC(.dbd.O)NHR.sub.25,
(CH.sub.2).sub.nNHC(.dbd.O)R.sub.25,
(CH.sub.2).sub.nNHC(.dbd.O)NHR.sub.25, C(.dbd.O)R.sub.25, or
heterocyclyl comprising one or two 4- to 6-membered rings and 1 to
3 heteroatoms selected from N, O, and S (e.g., pyrrolidinyl,
pyrazolidinyl, imidazolidinyl, piperidinyl, piperazinyl,
oxazolidinyl, isoxazolidinyl, morpholinyl, tetrahydropyranyl,
thiazolidinyl, isothiazolidinyl, tetrahydrofuryl, dioxanyl, and
spiroheterocyclyl such as oxaazaspiro[3.3]heptanyl) and optionally
substituted with one or more substituents selected from
(C.sub.1-C.sub.4) alkyl (e.g., methyl, ethyl, n-propyl, i-propyl,
n-butyl, i-butyl, or t-butyl). In another embodiment, at least one
R.sub.4 is (C.sub.1-C.sub.4) alkyl, (C.sub.1-C.sub.4) alkoxy
optionally substituted with one to two (C.sub.1-C.sub.4) alkoxy,
(C.sub.1-C.sub.4) haloalkyl, (C.sub.1-C.sub.4) haloalkoxy, halogen,
or O(CH.sub.2).sub.nR.sub.11, NH(CH.sub.2).sub.nR.sub.11,
(CH.sub.2).sub.nC(.dbd.O)NHR.sub.25,
(CH.sub.2).sub.nNHC(.dbd.O)R.sub.25,
(CH.sub.2).sub.nNHC(.dbd.O)NHR.sub.25, C(.dbd.O)R.sub.25, or 5- or
6-membered heterocyclyl comprising 1 to 3 heteroatoms selected from
N, O, and S and optionally substituted with one or more
(C.sub.1-C.sub.4) alkyl.
[0089] In some embodiments of the formulae above, at least one
R.sub.4 is (C.sub.1-C.sub.4) alkyl (e.g., methyl, ethyl, n-propyl,
i-propyl, n-butyl, i-butyl, or t-butyl), (C.sub.1-C.sub.4) alkoxy
(e.g., methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy,
or t-butoxy), (C.sub.1-C.sub.4) haloalkyl (e.g., CF.sub.3,
CHF.sub.2, CH.sub.2F, CH.sub.2CF.sub.3, CF.sub.2CF.sub.3,
CCl.sub.3, CHCl.sub.2, CH.sub.2Cl, etc.), (C.sub.1-C.sub.4)
haloalkoxy (e.g., OCF.sub.3, OCHF.sub.2, OCH.sub.2F,
OCH.sub.2CF.sub.3, OCF.sub.2CF.sub.3, OCCl.sub.3, OCHCl.sub.2,
OCH.sub.2Cl, etc.), halogen (e.g., F, Cl, Br, or I),
O(CH.sub.2).sub.nR.sub.11, NH(CH.sub.2).sub.nR.sub.11,
(CH.sub.2).sub.nC(.dbd.O)NHR.sub.25,
(CH.sub.2).sub.nNHC(.dbd.O)R.sub.25,
(CH.sub.2).sub.nNHC(.dbd.O)NHR.sub.25, or C(.dbd.O)R.sub.25,
wherein the alkoxy is optionally substituted with one or more
(C.sub.1-C.sub.4) alkoxy (e.g., methoxy, ethoxy, n-propoxy,
i-propoxy, n-butoxy, i-butoxy, or t-butoxy). In another embodiment,
at least one R.sub.4 is (C.sub.1-C.sub.2) alkyl (i.e., methyl or
ethyl), (C.sub.1-C.sub.2) alkoxy (i.e., methoxy or ethoxy),
(C.sub.1-C.sub.2) haloalkyl (e.g., CF.sub.3, CHF.sub.2, CH.sub.2F,
CH.sub.2CF.sub.3, CF.sub.2CF.sub.3, CCl.sub.3, CHCl.sub.2,
CH.sub.2Cl, etc.), (C.sub.1-C.sub.2) haloalkoxy (e.g., OCF.sub.3,
OCHF.sub.2, OCH.sub.2F, OCH.sub.2CF.sub.3, OCF.sub.2CF.sub.3,
OCCl.sub.3, OCHCl.sub.2, OCH.sub.2Cl, etc.), halogen (e.g., F, Cl,
Br, or I), NR.sub.9S(O).sub.pR.sub.10, O(CH.sub.2).sub.nR.sub.11,
NH(CH.sub.2).sub.nR.sub.11, (CH.sub.2).sub.nC(.dbd.O)NHR.sub.25,
(CH.sub.2).sub.nNHC(.dbd.O)R.sub.25,
(CH.sub.2).sub.nNHC(.dbd.O)NHR.sub.25, or C(.dbd.O)R.sub.25,
wherein the alkoxy is optionally substituted with one or more
(C.sub.1-C.sub.4) alkoxy (e.g., methoxy, ethoxy, n-propoxy,
i-propoxy, n-butoxy, i-butoxy, or t-butoxy). In another embodiment,
at least one R.sub.4 is (C.sub.1-C.sub.2) alkyl, (C.sub.1-C.sub.2)
alkoxy, (C.sub.1-C.sub.2) haloalkyl, (C.sub.1-C.sub.2) haloalkoxy,
halogen, O(CH.sub.2).sub.nR.sub.11, NH(CH.sub.2).sub.nR.sub.11,
(CH.sub.2).sub.nC(.dbd.O)NHR.sub.25,
(CH.sub.2).sub.nNHC(.dbd.O)R.sub.25,
(CH.sub.2).sub.nNHC(.dbd.O)NHR.sub.25, or C(.dbd.O)R.sub.25,
wherein the alkoxy is optionally substituted with one or more
(C.sub.1-C.sub.4) alkoxy. In another embodiment, at least one
R.sub.4 is methyl, F, Cl, methoxy, OCH.sub.2CH.sub.2OCH.sub.3,
NR.sub.9S(O).sub.pR.sub.10, O(CH.sub.2).sub.nR.sub.11,
NH(CH.sub.2).sub.nR.sub.11, (CH.sub.2).sub.nC(.dbd.O)NHR.sub.25,
(CH.sub.2).sub.nNIHC(.dbd.O)R.sub.25,
(CH.sub.2).sub.nNIHC(.dbd.O)NHR.sub.25, or C(.dbd.O)R.sub.25. In
another embodiment, at least one R.sub.4 is methyl, F, Cl, methoxy,
OCH.sub.2CH.sub.2OCH.sub.3, O(CH.sub.2).sub.nR.sub.11,
NH(CH.sub.2).sub.nR.sub.11, (CH.sub.2).sub.nC(.dbd.O)NHR.sub.25,
(CH.sub.2).sub.nNIHC(.dbd.O)R.sub.25,
(CH.sub.2).sub.nNIHC(.dbd.O)NHR.sub.25, C(.dbd.O)R.sub.25. In a
further embodiment, at least one R.sub.4 is methyl, fluoro, chloro,
methoxy, OCH.sub.2CH.sub.2OCH.sub.3, OR.sub.11, or
O(CH.sub.2)R.sub.11, NHR.sub.11, NH(CH.sub.2)R.sub.11,
C(.dbd.O)NHR.sub.25, (CH.sub.2)C(.dbd.O)NHR.sub.25,
NHC(.dbd.O)R.sub.25, (CH.sub.2)NHC(.dbd.O)R.sub.25,
NHC(.dbd.O)NHR.sub.25, (CH.sub.2)NHC(.dbd.O)NHR.sub.25, or
C(.dbd.O)R.sub.25.
[0090] In some embodiments of the formulae above, R.sub.9 is
(C.sub.1-C.sub.4) alkyl (e.g., methyl, ethyl, n-propyl, i-propyl,
n-butyl, i-butyl, or t-butyl). In another embodiment, R.sub.9 is H
or (C.sub.1-C.sub.3) alkyl (e.g., methyl, ethyl, n-propyl, or
i-propyl). In another embodiment, R.sub.9 is H, methyl, or ethyl.
In another embodiment, R.sub.9 is H or methyl. In a further
embodiment, R.sub.9 is H.
[0091] In some embodiments of the formulae above, R.sub.10 is
(C.sub.1-C.sub.3) alkyl (e.g., methyl, ethyl, n-propyl, or
i-propyl) or (C.sub.6-C.sub.10) aryl. In another embodiment,
R.sub.10 is (C.sub.1-C.sub.3) alkyl (e.g., methyl, ethyl, n-propyl,
or i-propyl) or phenyl. In another embodiment, R.sub.10 is methyl,
ethyl, or phenyl. In a further embodiment, R.sub.10 is methyl or
phenyl
[0092] In some embodiments of the formulae above, R.sub.11 is
(C.sub.3-C.sub.7) cycloalkyl (e.g., cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, or cycloheptyl) or (C.sub.4-C.sub.7)
cycloalkenyl (e.g., cyclobutenyl, cyclopentenyl, cyclohexenyl, or
cycloheptenyl). In another embodiment, R.sub.11 is
(C.sub.6-C.sub.10) aryl or 5- or 6-membered heteroaryl comprising 1
to 3 heteroatoms selected from N, O, and S (e.g., pyridinyl,
pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl,
oxazolyl, isooxazolyl, thiadiazolyl, oxadiazolyl, thiophenyl, and
furanyl), wherein the aryl and heteroaryl are optionally
substituted with one or more R.sub.17. In another embodiment,
R.sub.11 is (C.sub.6-C.sub.10) aryl or 5- or 6-membered heteroaryl
comprising 1 to 3 heteroatoms selected from N, O, and S, wherein
the aryl and heteroaryl are optionally substituted with one to
three R.sub.17. In another embodiment, R.sub.11 is
(C.sub.4-C.sub.7) cycloalkenyl, (C.sub.6-C.sub.10) aryl, or 5- or
6-membered heteroaryl comprising 1 to 3 heteroatoms selected from
N, O, and S, wherein the aryl and heteroaryl are optionally
substituted with one to three R.sub.17. In another embodiment,
R.sub.11 is (C.sub.4-C.sub.7) cycloalkenyl, phenyl, or 5- or
6-membered heteroaryl comprising 1 to 3 heteroatoms selected from
N, O, and S, wherein the phenyl and heteroaryl are optionally
substituted with one to three R.sub.17.
[0093] In another embodiment, R.sub.11 is (C.sub.4-C.sub.7)
cycloalkenyl (e.g., cyclobutenyl, cyclopentenyl, cyclohexenyl, or
cycloheptenyl), phenyl, or 5-membered heteroaryl comprising 1 to 3
heteroatoms selected from N, O, and S (e.g., pyrrolyl, pyrazolyl,
imidazolyl, thiazolyl, oxazolyl, isooxazolyl, thiadiazolyl,
oxadiazolyl, thiophenyl, and furanyl), wherein the phenyl and
heteroaryl are optionally substituted with one to three R.sub.17.
In another embodiment, R.sub.11 is (C.sub.4-C.sub.7) cycloalkenyl,
phenyl, or 6-membered heteroaryl comprising 1 to 3 heteroatoms
selected from N, O, and S (e.g., pyridinyl, pyrazinyl, and
pyrimidinyl), wherein the phenyl and heteroaryl are optionally
substituted with one to three R.sub.17. In another embodiment,
R.sub.11 is phenyl or 5-membered heteroaryl comprising 1 to 3
heteroatoms selected from N, O, and S, wherein the phenyl and
heteroaryl are optionally substituted with one to three R.sub.17.
In another embodiment, R.sub.11 is phenyl or 6-membered heteroaryl
comprising 1 to 3 heteroatoms selected from N, O, and S, wherein
the phenyl and heteroaryl are optionally substituted with one to
three R.sub.17. In another embodiment, R.sub.11 is phenyl
optionally substituted with one to three R.sub.17. In another
embodiment, R.sub.11 is (C.sub.4-C.sub.7) cycloalkenyl, phenyl, or
pyridinyl, wherein the phenyl and pyridinyl are optionally
substituted with one to three R.sub.17. In a further embodiment,
R.sub.11 is cycloalkenyl, phenyl, or pyridinyl, wherein the phenyl
and pyridinyl are optionally substituted with one to three
R.sub.17. In another embodiment, R.sub.11 is phenyl or pyridinyl,
wherein the phenyl and pyridinyl are optionally substituted with
one to three R.sub.17.
[0094] In some embodiments of the formulae above, each R.sub.17 is
independently C(.dbd.O)NH.sub.2, C(.dbd.O)NH(C.sub.1-C.sub.4) alkyl
(wherein (C.sub.1-C.sub.4) alkyl is methyl, ethyl, n-propyl,
i-propyl, n-butyl, i-butyl, or t-butyl), or
C(.dbd.O)N((C.sub.1-C.sub.4) alkyl).sub.2 (wherein
(C.sub.1-C.sub.4) alkyl is methyl, ethyl, n-propyl, i-propyl,
n-butyl, i-butyl, or t-butyl).
[0095] In some embodiments of the formulae above, at least one
R.sub.17 is (C.sub.1-C.sub.3) alkyl (e.g., methyl, ethyl, n-propyl,
or i-propyl), (C.sub.1-C.sub.3) alkoxy (e.g., methoxy, ethoxy,
n-propoxy, or i-propoxy), (C.sub.1-C.sub.3) haloalkyl (e.g.,
CF.sub.3, CHF.sub.2, CH.sub.2F, CH.sub.2CF.sub.3, CF.sub.2CF.sub.3,
CCl.sub.3, CHCl.sub.2, CH.sub.2Cl, etc.), (C.sub.1-C.sub.3)
haloalkoxy (e.g., OCF.sub.3, OCHF.sub.2, OCH.sub.2F,
OCH.sub.2CF.sub.3, OCF.sub.2CF.sub.3, OCCl.sub.3, OCHCl.sub.2,
OCH.sub.2Cl, etc.), or halogen (e.g., F, Cl, Br, or I). In another
embodiment, at least one R.sub.17 is (C.sub.1-C.sub.3) alkyl or
(C.sub.1-C.sub.3) alkoxy. In another embodiment, at least one
R.sub.17 is (C.sub.1-C.sub.3) haloalkyl, (C.sub.1-C.sub.3)
haloalkoxy, or halogen. In another embodiment, at least one
R.sub.17 is (C.sub.1-C.sub.3) alkyl, (C.sub.1-C.sub.3) haloalkyl,
or halogen. In another embodiment, at least one R.sub.17 is methyl,
ethyl, F, Cl, methoxy, ethoxy, CF.sub.3, or OCF.sub.3. In another
embodiment, at least one R.sub.17 is methyl, ethyl, F, Cl, or
CF.sub.3. In a further embodiment, at least one R.sub.17 is methyl,
F, Cl, or CF.sub.3.
[0096] In some embodiments of the formulae above, R.sub.25 is
(C.sub.1-C.sub.4) alkyl (e.g., methyl, ethyl, n-propyl, i-propyl,
n-butyl, i-butyl, or t-butyl) optionally substituted with one or
more (C.sub.1-C.sub.4) alkoxy (e.g., methoxy, ethoxy, n-propoxy,
i-propoxy, n-butoxy, i-butoxy, or t-butoxy), wherein the alkyl and
alkoxy are optionally substituted with one or more substituents
selected from (C.sub.1-C.sub.4) alkoxy (e.g., methoxy, ethoxy,
n-propoxy, i-propoxy, n-butoxy, i-butoxy, or t-butoxy),
(C.sub.1-C.sub.4) haloalkyl (e.g., CF.sub.3, CHF.sub.2, CH.sub.2F,
CH.sub.2CF.sub.3, CF.sub.2CF.sub.3, CCl.sub.3, CHCl.sub.2,
CH.sub.2Cl, etc.), (C.sub.1-C.sub.4) alkoxy (e.g., methoxy, ethoxy,
n-propoxy, i-propoxy, n-butoxy, i-butoxy, or t-butoxy),
(C.sub.1-C.sub.4) haloalkyl (e.g., CF.sub.3, CHF.sub.2, CH.sub.2F,
CH.sub.2CF.sub.3, CF.sub.2CF.sub.3, CCl.sub.3, CHCl.sub.2,
CH.sub.2Cl, etc.), (C.sub.1-C.sub.4) haloalkoxy (e.g., OCF.sub.3,
OCHF.sub.2, OCH.sub.2F, OCH.sub.2CF.sub.3, OCF.sub.2CF.sub.3,
OCCl.sub.3, OCHCl.sub.2, OCH.sub.2Cl, etc.), cyano, halogen (e.g.,
F, Cl, Br, or I), OH, NH.sub.2, (C.sub.6-C.sub.10) aryl, and 5- or
6-membered heteroaryl comprising 1 to 3 heteroatoms selected from
N, O, and S (e.g., pyridinyl, pyrazinyl, pyrimidinyl, pyrrolyl,
pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isooxazolyl,
thiadiazolyl, oxadiazolyl, thiophenyl, and furanyl). In some
embodiments of the formulae above, R.sub.25 is methyl or ethyl
optionally substituted with methoxy or ethoxy, each of which is
optionally substituted.
[0097] In some embodiments of the formulae above, R.sub.25 is
(C(R.sub.26).sub.2).sub.x(C.sub.6-C.sub.10) aryl,
(C(R.sub.26).sub.2).sub.x-heteroaryl, wherein the heteroaryl
comprises one or two 5- or 6-membered rings and 1 to 3 heteroatoms
selected from N, O, and S (e.g., pyridinyl, pyrazinyl, pyrimidinyl,
pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isooxazolyl,
thiadiazolyl, oxadiazolyl, thiophenyl, furanyl, and isoquinolinyl),
or (C(R.sub.26).sub.2).sub.x-heterocyclyl, wherein the heterocyclyl
comprises one or two 4- to 6-membered rings and 1 to 3 heteroatoms
selected from N, O, and S (e.g., pyrrolidinyl, pyrazolidinyl,
imidazolidinyl, piperidinyl, piperazinyl, oxazolidinyl,
isoxazolidinyl, morpholinyl, tetrahydropyranyl, thiazolidinyl,
isothiazolidinyl, tetrahydrofuryl, dioxanyl,
tetrahydroisoquinolinyl, and a spiroheterocyclyl such as
oxaazaspiro[3.3]heptanyl), wherein the aryl, heteroaryl, and
heterocyclyl are optionally substituted with one to three
substituents selected from (C.sub.1-C.sub.4) alkyl (e.g., methyl,
ethyl, n-propyl, i-propyl, n-butyl, i-butyl, or t-butyl),
(C.sub.1-C.sub.4) alkoxy (e.g., methoxy, ethoxy, n-propoxy,
i-propoxy, n-butoxy, i-butoxy, or t-butoxy), (C.sub.1-C.sub.4)
haloalkyl (e.g., CF.sub.3, CHF.sub.2, CH.sub.2F, CH.sub.2CF.sub.3,
CF.sub.2CF.sub.3, CCl.sub.3, CHCl.sub.2, CH.sub.2Cl, etc.),
(C.sub.1-C.sub.4) haloalkoxy (e.g., OCF.sub.3, OCHF.sub.2,
OCH.sub.2F, OCH.sub.2CF.sub.3, OCF.sub.2CF.sub.3, OCCl.sub.3,
OCHCl.sub.2, OCH.sub.2Cl, etc.), cyano, halogen (e.g., F, Cl, Br,
or I), OH, NH.sub.2, (C.sub.6-C.sub.10) aryl, and 5- or 6-membered
heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S
(e.g., pyridinyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl,
imidazolyl, thiazolyl, oxazolyl, isooxazolyl, thiadiazolyl,
oxadiazolyl, thiophenyl, and furanyl).
[0098] In another embodiment, R.sub.25 is (C.sub.6-C.sub.10) aryl,
(C(R.sub.26).sub.2)(C.sub.6-C.sub.10) aryl, or
(C(R.sub.26).sub.2).sub.2(C.sub.6-C.sub.10) aryl, wherein the aryl
is optionally substituted with one to three substituents selected
from (C.sub.1-C.sub.4) alkyl, (C.sub.1-C.sub.4) alkoxy,
(C.sub.1-C.sub.4) haloalkyl, (C.sub.1-C.sub.4) haloalkoxy, cyano,
halogen, OH, and NH.sub.2. In another embodiment, R.sub.25 is
(C.sub.6-C.sub.10)-heteroaryl, (C(R.sub.26).sub.2)-heteroaryl, or
(C(R.sub.26).sub.2).sub.2-heteroaryl, wherein the heteroaryl is
optionally substituted with one to three substituents selected from
(C.sub.1-C.sub.4) alkyl, (C.sub.1-C.sub.4) alkoxy,
(C.sub.1-C.sub.4) haloalkyl, (C.sub.1-C.sub.4) haloalkoxy, cyano,
halogen, OH, and NH.sub.2. In another embodiment, R.sub.25 is
(C.sub.6-C.sub.10)-heteroaryl, (C(R.sub.26).sub.2)-heteroaryl, or
(C(R.sub.26).sub.2).sub.2-heteroaryl, wherein the heteroaryl is
5-membered heteroaryl comprising 1 to 3 heteroatoms selected from
N, O, and S (e.g., pyrrolyl, pyrazolyl, imidazolyl, thiazolyl,
oxazolyl, isooxazolyl, thiadiazolyl, oxadiazolyl, thiophenyl, and
furanyl) and optionally substituted with one to three substituents
selected from (C.sub.1-C.sub.4) alkyl, (C.sub.1-C.sub.4) alkoxy,
(C.sub.1-C.sub.4) haloalkyl, (C.sub.1-C.sub.4) haloalkoxy, cyano,
halogen, OH, and NH.sub.2. In another embodiment, R.sub.25 is
(C.sub.6-C.sub.10)-heteroaryl, (C(R.sub.26).sub.2)-heteroaryl, or
(C(R.sub.26).sub.2).sub.2-heteroaryl, wherein the heteroaryl is
6-membered heteroaryl comprising 1 to 3 heteroatoms selected from
N, O, and S (e.g., pyridinyl, pyrazinyl, and pyrimidinyl) and
optionally substituted with one to three substituents selected from
(C.sub.1-C.sub.4) alkyl, (C.sub.1-C.sub.4) alkoxy,
(C.sub.1-C.sub.4) haloalkyl, (C.sub.1-C.sub.4) haloalkoxy, cyano,
halogen, OH, and NH.sub.2. In another embodiment, R.sub.25 is
(C.sub.6-C.sub.10)-heterocyclyl, (C(R.sub.26).sub.2)-heterocyclyl,
or (C(R.sub.26).sub.2).sub.2-heterocyclyl optionally substituted
with one to three substituents selected from (C.sub.1-C.sub.4)
alkyl, (C.sub.1-C.sub.4) alkoxy, (C.sub.1-C.sub.4) haloalkyl,
(C.sub.1-C.sub.4) haloalkoxy, cyano, halogen, OH, and NH.sub.2. In
another embodiment, R.sub.25 is phenyl or pyridinyl comprising 1 to
3 heteroatoms selected from N, O, and S, and optionally substituted
with one to three substituents selected from (C.sub.1-C.sub.4)
alkyl, (C.sub.1-C.sub.4) alkoxy, (C.sub.1-C.sub.4) haloalkyl,
(C.sub.1-C.sub.4) haloalkoxy, cyano, halogen, OH, and NH.sub.2. In
another embodiment, R.sub.25 is phenyl or pyridinyl comprising 1 to
3 heteroatoms selected from N, O, and S, and optionally substituted
with one to three halogen.
[0099] In some embodiments of the formulae above, each R.sub.26 is
H.
[0100] In some embodiments of the formulae above, at least one
R.sub.26 is (C.sub.1-C.sub.4) alkyl (e.g., methyl, ethyl, n-propyl,
i-propyl, n-butyl, i-butyl, or t-butyl).
[0101] In some embodiments of the formulae above, two R.sub.26
together with the atom to which they are attached form a
(C.sub.3-C.sub.6) cycloalkyl ring (e.g., cyclopropyl, cyclobutyl,
cyclopentyl, or cyclohexyl) or 3- or 6-membered heterocyclyl ring
comprising 1 to 3 heteroatoms selected from N, O, and S (e.g.,
[1,3]dioxolanyl, pyrrolidinyl, pyrazolinyl, pyrazolidinyl,
imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl,
oxazolidinyl, isoxazolidinyl, morpholinyl, tetrahydropyranyl,
thiazolidinyl, isothiazolidinyl, tetrahydrofuryl, dioxanyl,
oxiranyl, aziridinyl, oxetanyl, azetidinyl, and thietanyl). In
another embodiment, two R.sub.26 together with the atom to which
they are attached form a cyclopropyl or cyclobutyl ring, or 3- or
4-membered heterocyclyl ring comprising 1 or 2 heteroatoms selected
from N, O, and S (e.g., oxiranyl, aziridinyl, oxetanyl, azetidinyl,
and thietanyl).
[0102] In some embodiments of the formulae above, R.sub.1 is
(C.sub.3-C.sub.7) cycloalkyl optionally substituted with one or
more R.sub.5. In another embodiment, R.sub.1 is cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl optionally
substituted with one to three R.sub.5. In another embodiment,
R.sub.1 is cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl
optionally substituted with one to three R.sub.5. In another
embodiment, R.sub.1 is cyclobutyl, cyclopentyl, cyclohexyl, or
cycloheptyl substituted with one to three R.sub.5. In another
embodiment, R.sub.1 is cyclopropyl optionally substituted with one
to three R.sub.5. In another embodiment, R.sub.1 is cyclopropyl
substituted with one to three R.sub.5. In another embodiment,
R.sub.1 is cyclobutyl optionally substituted with one to three
R.sub.5. In another embodiment, R.sub.1 is cyclobutyl substituted
with one to three R.sub.5. In another embodiment, R.sub.1 is
cyclopentyl optionally substituted with one to three R.sub.5. In
another embodiment, R.sub.1 is cyclopentyl substituted with one to
three R.sub.5. In another embodiment, R.sub.1 is cyclohexyl
optionally substituted with one to three R.sub.5. In another
embodiment, R.sub.1 is cyclohexyl substituted with one to three
R.sub.5. In another embodiment, R.sub.1 is cycloheptyl optionally
substituted with one to three R.sub.5. In another embodiment,
R.sub.1 is cycloheptyl substituted with one to three R.sub.5.
[0103] In another embodiment, R.sub.1 is 4- to 6-membered
heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and
S (e.g., [1,3]dioxolanyl, pyrrolidinyl, pyrazolinyl, pyrazolidinyl,
imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl,
oxazolidinyl, isoxazolidinyl, morpholinyl, tetrahydropyranyl,
thiazolidinyl, isothiazolidinyl, tetrahydrofuryl, dioxanyl,
oxetanyl, azetidinyl, and thietanyl), optionally substituted with
one or more R.sub.5. In another embodiment, R.sub.1 is 4-membered
heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and
S (e.g., oxetanyl, azetidinyl, and thietanyl), optionally
substituted with one or more R.sub.5. In another embodiment,
R.sub.1 is 5-membered heterocyclyl comprising 1 to 3 heteroatoms
selected from N, O, and S (e.g., [1,3]dioxolanyl, pyrrolidinyl,
pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl,
oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, and
tetrahydrofuryl), optionally substituted with one or more R.sub.5.
In another embodiment, R.sub.1 is 6-membered heterocyclyl
comprising 1 to 3 heteroatoms selected from N, O, and S (e.g.,
piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, and
dioxanyl), optionally substituted with one or more R.sub.5. In
another embodiment, R.sub.1 is piperidinyl, tetrahydrofuranyl,
tetrahydropyranyl, pyrrolidinyl, or 1,4-dioxanyl optionally
substituted with one or more R.sub.5. In another embodiment,
R.sub.1 is piperidinyl, tetrahydrofuranyl, tetrahydropyranyl,
pyrrolidinyl, or 1,4-dioxanyl optionally substituted with one to
three R.sub.5. In another embodiment, R.sub.1 is piperidinyl,
tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, or 1,4-dioxanyl
substituted with one to three R.sub.5. In another embodiment,
R.sub.1 is piperidinyl optionally substituted with one to three
R.sub.5. In another embodiment, R.sub.1 is tetrahydrofuranyl
optionally substituted with one to three R.sub.5. In another
embodiment, R.sub.1 is tetrahydropyranyl optionally substituted
with one to three R.sub.5. In another embodiment, R.sub.1 is
pyrrolidinyl optionally substituted with one to three R.sub.5. In
another embodiment, R.sub.1 is 1,4-dioxanyl optionally substituted
with one to three R.sub.5. In a further embodiment, R.sub.1 is
cyclohexyl, cyclopentyl, cyclobutyl, tetrahydropyran,
tetrahydrofuran, piperidinyl, 1,4-dioxane, pyrrolyl, or
cyclohexanone wherein each substituted with one to two R.sub.5.
[0104] In some embodiments of the formulae above, at least one
R.sub.5 is (i) (C.sub.1-C.sub.6) alkyl (e.g., methyl, ethyl,
n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, pentyl, or hexyl)
optionally substituted with one to three (C.sub.1-C.sub.4) alkoxy
(e.g., methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy,
or t-butoxy) or phenyl, (ii) (C.sub.2-C.sub.4) alkenyl (e.g.,
ethenyl, propenyl, or butenyl) optionally substituted with one or
more C(.dbd.O)(C.sub.1-C.sub.4) alkyl (wherein (C.sub.1-C.sub.4)
alkyl is methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, or
t-butyl), (iii) (C(R.sub.12).sub.2).sub.rOH, (iv)
(C(R.sub.12).sub.2).sub.rNR.sub.13R.sub.14, (v) C(.dbd.O)OH, (vi)
C(.dbd.O)O(C.sub.1-C.sub.4) alkyl (wherein (C.sub.1-C.sub.4) alkyl
is methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, or
t-butyl), (vii) C(.dbd.O)NR.sub.13R.sub.15, (viii)
C(.dbd.O)R.sub.16, (ix) S(O).sub.pR.sub.16, or (x) 5- or 6-membered
heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S
(e.g., pyridinyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl,
imidazolyl, thiazolyl, oxazolyl, isooxazolyl, thiadiazolyl,
oxadiazolyl, thiophenyl, and furanyl) and optionally substituted
with one to three (C.sub.1-C.sub.4) alkyl (e.g., methyl, ethyl,
n-propyl, i-propyl, n-butyl, i-butyl, or t-butyl), (xi) or two
R.sub.5 together with the carbon atom to which they are attached
form (.dbd.O), or (xii) two R.sub.5 together with the atoms to
which they are attached form a bridged 3- to 6-membered
heterocyclyl ring comprising 1 to 3 heteroatoms selected from N, O,
and S (e.g., pyrrolidinyl, pyrazolidinyl, imidazolidinyl,
piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl,
morpholinyl, tetrahydropyranyl, thiazolidinyl, isothiazolidinyl,
tetrahydrofuryl, dioxanyl, oxetanyl, azetidinyl, thietanyl,
oxiranyl, aziridinyl, and thiiranyl). In another embodiment, at
least one R.sub.5 is (i) (C.sub.1-C.sub.6) alkyl optionally
substituted with one to three (C.sub.1-C.sub.4) alkoxy or phenyl,
(ii) (C.sub.2-C.sub.4) alkenyl optionally substituted with one or
more C(.dbd.O)(C.sub.1-C.sub.4) alkyl, (iii)
(C(R.sub.12).sub.2).sub.rOH, (iv)
(C(R.sub.12).sub.2).sub.rNR.sub.13R.sub.14, (v) C(.dbd.O)OH, (vi)
C(.dbd.O)O(C.sub.1-C.sub.4) alkyl, (vii)
C(.dbd.O)NR.sub.13R.sub.15, (viii) C(.dbd.O)R.sub.16, (ix)
S(O).sub.pR.sub.16, or (x) 5- or 6-membered heteroaryl comprising 1
to 3 heteroatoms selected from N, O, and S and optionally
substituted with one to three (C.sub.1-C.sub.4) alkyl, (xi) or two
R.sub.5 together with the carbon atom to which they are attached
form (.dbd.O). In another embodiment, at least one R.sub.5 is (i)
(C.sub.2-C.sub.4) alkenyl optionally substituted with one or more
C(.dbd.O)(C.sub.1-C.sub.4) alkyl, (ii) (C(R.sub.12).sub.2).sub.rOH,
(iii) (C(R.sub.12).sub.2).sub.rNR.sub.13R.sub.14, (iv)
C(.dbd.O)O(C.sub.1-C.sub.4) alkyl, (v) C(.dbd.O)NR.sub.13R.sub.15,
(vi) C(.dbd.O)R.sub.16, or (vii) S(O).sub.pR.sub.16. In another
embodiment, at least one R.sub.5 is (i) (C.sub.2-C.sub.4) alkenyl
optionally substituted with one or more C(.dbd.O)(C.sub.1-C.sub.4)
alkyl or (ii) S(O).sub.pR.sub.16.
[0105] In some embodiments of the formulae above, at least one
R.sub.5 is (i) (C.sub.1-C.sub.4) alkyl (e.g., methyl, ethyl,
n-propyl, i-propyl, n-butyl, i-butyl, or t-butyl) optionally
substituted with one to two (C.sub.1-C.sub.4) alkoxy (e.g.,
methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, or
t-butoxy) or phenyl, (ii) (C(R.sub.12).sub.2).sub.rOH, (iii)
(C(R.sub.12).sub.2).sub.rNR.sub.13R.sub.14, (iv) C(.dbd.O)OH, (v)
C(.dbd.O)O(C.sub.1-C.sub.4) alkyl (wherein (C.sub.1-C.sub.4) alkyl
is methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, or
t-butyl), (vi) C(.dbd.O)NR.sub.13R.sub.15, (vii) C(.dbd.O)R.sub.16,
(viii) S(O).sub.pR.sub.16, or (ix) 5- or 6-membered heteroaryl
comprising 1 to 3 heteroatoms selected from N, O, and S (e.g.,
pyridinyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl,
thiazolyl, oxazolyl, isooxazolyl, thiadiazolyl, oxadiazolyl,
thiophenyl, and furanyl) and optionally substituted with one or
more (C.sub.1-C.sub.4) alkyl (e.g., methyl, ethyl, n-propyl,
i-propyl, n-butyl, i-butyl, or t-butyl), or (x) two R.sub.5
together with the carbon atom to which they are attached form
(.dbd.O), or (xi) two R.sub.5 together with the atoms to which they
are attached form a bridged 3- to 6-membered heterocyclyl ring
comprising 1 to 3 heteroatoms selected from N, O, and S (e.g.,
pyrrolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl,
piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl,
tetrahydropyranyl, thiazolidinyl, isothiazolidinyl,
tetrahydrofuryl, dioxanyl, oxetanyl, azetidinyl, thietanyl,
oxiranyl, aziridinyl, and thiiranyl). In another embodiment,
R.sub.5 is independently (i) (C.sub.1-C.sub.4) alkyl optionally
substituted with one to two (C.sub.1-C.sub.4) alkoxy or phenyl,
(ii) (C(R.sub.12).sub.2).sub.rOH, (iii)
(C(R.sub.12).sub.2).sub.rNR.sub.13R.sub.14, (iv)
C(.dbd.O)O(C.sub.1-C.sub.4) alkyl, (v) C(.dbd.O)NR.sub.13R.sub.15,
(vi) C(.dbd.O)R.sub.16, or (vii) S(O).sub.pR.sub.16. In another
embodiment, (i) two R.sub.5 together with the carbon atom to which
they are attached form (.dbd.O), or (ii) two R.sub.5 together with
the atoms to which they are attached form a bridged 3- to
6-membered heterocyclyl ring comprising 1 to 3 heteroatoms selected
from N, O, and S.
[0106] In some embodiments of the formulae above, at least one
R.sub.5 is (i) (C.sub.1-C.sub.3) alkyl (e.g., methyl, ethyl,
n-propyl, or i-propyl) optionally substituted with one to three
(C.sub.1-C.sub.4) alkoxy (e.g., methoxy, ethoxy, n-propoxy,
i-propoxy, n-butoxy, i-butoxy, or t-butoxy) or phenyl, (ii)
(C(R.sub.12).sub.2).sub.rOH, (iii)
(C(R.sub.12).sub.2).sub.rNR.sub.13R.sub.14, (iv) C(.dbd.O)OH, (v)
C(.dbd.O)O(C.sub.1-C.sub.4) alkyl (wherein (C.sub.1-C.sub.4) alkyl
is methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, or
t-butyl), (vi) C(.dbd.O)NR.sub.13R.sub.15, (vii) C(.dbd.O)R.sub.16,
or (viii) 5- or 6-membered heteroaryl comprising 1 to 3 heteroatoms
selected from N, O, and S (e.g., pyridinyl, pyrazinyl, pyrimidinyl,
pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isooxazolyl,
thiadiazolyl, oxadiazolyl, thiophenyl, and furanyl), and optionally
substituted with one or more (C.sub.1-C.sub.4) alkyl (e.g., methyl,
ethyl, n-propyl, i-propyl, n-butyl, i-butyl, or t-butyl). In
another embodiment, at least one R.sub.5 is (i) (C.sub.1-C.sub.3)
alkyl optionally substituted with one to three (C.sub.1-C.sub.4)
alkoxy or phenyl, (ii) (C(R.sub.12).sub.2).sub.rOH, (iii)
(C(R.sub.12).sub.2).sub.rNR.sub.13R.sub.14, (iv) C(.dbd.O)OH, (v)
C(.dbd.O)O(C.sub.1-C.sub.4) alkyl, (vi) C(.dbd.O)NR.sub.13R.sub.15,
(vii) C(.dbd.O)R.sub.16, (viii) 5- or 6-membered heteroaryl
comprising 1 to 3 heteroatoms selected from N, O, and S and
optionally substituted with one or more (C.sub.1-C.sub.4) alkyl, or
(ix) two R.sub.5 together with the carbon atom to which they are
attached form (.dbd.O). In another embodiment, at least one R.sub.5
is (i) (C.sub.1-C.sub.2) alkyl (i.e., methyl or ethyl) optionally
substituted with one to three (C.sub.1-C.sub.4) alkoxy (e.g.,
methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, or
t-butoxy) or phenyl, (ii) (C(R.sub.12).sub.2).sub.rOH, or (iii)
(C(R.sub.12).sub.2).sub.rNR.sub.13R.sub.14. In another embodiment,
at least one R.sub.5 is (i) C(.dbd.O)OH, (ii)
C(.dbd.O)O(C.sub.1-C.sub.4) alkyl, (iii)
C(.dbd.O)NR.sub.13R.sub.15, or (iv) C(.dbd.O)R.sub.16. In another
embodiment, at least one R.sub.5 is (i)
(C(R.sub.12).sub.2).sub.rOH, (ii)
(C(R.sub.12).sub.2).sub.rNR.sub.13R.sub.14, (iii)
C(.dbd.O)NR.sub.13R.sub.15, or (iv) C(.dbd.O)R.sub.16. In another
embodiment, at least one R.sub.5 is (i) (C.sub.1-C.sub.2) alkyl
optionally substituted with one to three (C.sub.1-C.sub.4) alkoxy
or phenyl, (ii) (C(R.sub.12).sub.2).sub.rOH, (iii)
(C(R.sub.12).sub.2).sub.rNR.sub.13R.sub.14, (iv)
C(.dbd.O)O(C.sub.1-C.sub.4) alkyl, or (v)
C(.dbd.O)NR.sub.13R.sub.15. In another embodiment, at least one
R.sub.5 is (i) (C.sub.1-C.sub.2) alkyl optionally substituted with
one to three (C.sub.1-C.sub.4) alkoxy or phenyl, (ii)
(C(R.sub.12).sub.2).sub.rOH, (iii)
(C(R.sub.12).sub.2).sub.rNR.sub.13R.sub.14, (iv)
C(.dbd.O)NR.sub.13R.sub.15, (v) C(.dbd.O)R.sub.16.
[0107] In another embodiment, at least one R.sub.5 is (i)
C(.dbd.O)OH, (ii) C(.dbd.O)O(C.sub.1-C.sub.4) alkyl (wherein
(C.sub.1-C.sub.4) alkyl is methyl, ethyl, n-propyl, i-propyl,
n-butyl, i-butyl, or t-butyl), (iii) C(.dbd.O)NR.sub.13R.sub.15, or
(iv) C(.dbd.O)R.sub.16. In another embodiment, at least one R.sub.5
is (i) (C(R.sub.12).sub.2).sub.rOH, (ii)
(C(R.sub.12).sub.2).sub.rNR.sub.13R.sub.14, (iii)
C(.dbd.O)NR.sub.13R.sub.15, or (iv) C(.dbd.O)R.sub.16. In another
embodiment, at least one R.sub.5 is (i)
(C(R.sub.12).sub.2).sub.rOH, (ii)
(C(R.sub.12).sub.2).sub.rNR.sub.13R.sub.14, (iii)
C(.dbd.O)NR.sub.13R.sub.15, (iv) C(.dbd.O)R.sub.16, or (v) two
R.sub.5 together with the carbon atom to which they are attached
form (.dbd.O). In another embodiment, at least one R.sub.5 is (i)
(C.sub.1-C.sub.2) alkyl (i.e., methyl or ethyl) optionally
substituted with one to three (C.sub.1-C.sub.4) alkoxy (e.g.,
methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, or
t-butoxy) or phenyl, (ii) (C(R.sub.12).sub.2).sub.rOH, (iii)
(C(R.sub.12).sub.2).sub.rNR.sub.13R.sub.14, (iv)
C(.dbd.O)O(C.sub.1-C.sub.4) alkyl, or (v)
C(.dbd.O)NR.sub.13R.sub.15. In another embodiment, at least one
R.sub.5 is (i) (C.sub.1-C.sub.2) alkyl (i.e., methyl or ethyl)
optionally substituted with one to three (C.sub.1-C.sub.4) alkoxy
(e.g., methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy,
or t-butoxy) or phenyl, (ii) (C(R.sub.12).sub.2).sub.rOH, (iii)
(C(R.sub.12).sub.2).sub.rNR.sub.13R.sub.14, (iv)
C(.dbd.O)NR.sub.13R.sub.15, or (v) C(.dbd.O)R.sub.16.
[0108] In some embodiments of the formulae above, two R.sub.5
together with the carbon atom to which they are attached form
(.dbd.O). In another embodiment, at least one R.sub.5 is (i)
(C.sub.1-C.sub.2) alkyl (i.e., methyl or ethyl) optionally
substituted with one to three (C.sub.1-C.sub.4) alkoxy (e.g.,
methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, or
t-butoxy) or phenyl, (ii) (C(R.sub.12).sub.2).sub.rOH, (iii)
(C(R.sub.12).sub.2).sub.rNR.sub.13R.sub.14, (iv)
C(.dbd.O)NR.sub.13R.sub.15, (v) C(.dbd.O)R.sub.16, or (vi) two
R.sub.5 together with the carbon atom to which they are attached
form (.dbd.O).
[0109] In some embodiments of the formulae above, at least one
R.sub.12 is (C.sub.1-C.sub.4) alkyl (e.g., methyl, ethyl, n-propyl,
i-propyl, n-butyl, i-butyl, or t-butyl). In another embodiment, at
least one R.sub.12 is H or (C.sub.1-C.sub.3) alkyl (e.g., methyl,
ethyl, n-propyl, or i-propyl). In another embodiment, at least one
R.sub.12 is H, methyl, or ethyl. In another embodiment, at least
one R.sub.12 is H. In a further embodiment, at least one R.sub.12
is H or methyl. In another embodiment, each R.sub.12 is H.
[0110] In some embodiments of the formulae above, R.sub.13 is
(C.sub.1-C.sub.4) alkyl (e.g., methyl, ethyl, n-propyl, i-propyl,
n-butyl, i-butyl, or t-butyl). In another embodiment, R.sub.13 is H
or (C.sub.1-C.sub.3) alkyl (e.g., methyl, ethyl, n-propyl, or
i-propyl). In another embodiment, R.sub.13 is H, methyl, or ethyl.
In another embodiment, R.sub.13 is H or methyl. In another
embodiment, R.sub.13 is H.
[0111] In some embodiments of the formulae above, R.sub.14 is (i)
H, (ii) (C.sub.1-C.sub.4) alkyl (e.g., methyl, ethyl, n-propyl,
i-propyl, n-butyl, i-butyl, or t-butyl), (iii)
(C(R.sub.18).sub.2).sub.rC(.dbd.O)NR.sub.19R.sub.20, (iv)
(CH.sub.2).sub.n(C.sub.6-C.sub.10) aryl optionally substituted with
one to three (C.sub.1-C.sub.4) alkyl (e.g., methyl, ethyl,
n-propyl, i-propyl, n-butyl, i-butyl, or t-butyl) or halogen (e.g.,
F, Cl, Br, or I), (v) C(.dbd.O)R.sub.21, (vi)
C(.dbd.O)O(C.sub.1-C.sub.4) alkyl (wherein (C.sub.1-C.sub.4) alkyl
is methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, or
t-butyl), (vii) S(O).sub.2(C.sub.1-C.sub.8) alkyl (wherein
(C.sub.1-C.sub.8) alkyl is methyl, ethyl, n-propyl, i-propyl,
n-butyl, i-butyl, t-butyl, hexyl, heptyl, octyl), (viii)
S(O).sub.2NH(C.sub.1-C.sub.8) alkyl (wherein (C.sub.1-C.sub.8)
alkyl is methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl,
t-butyl, hexyl, heptyl, octyl), (ix) S(O).sub.2N((C.sub.1-C.sub.8)
alkyl).sub.2, or (x) C(.dbd.O)(C.sub.1-C.sub.8) alkyl (wherein
(C.sub.1-C.sub.8) alkyl is methyl, ethyl, n-propyl, i-propyl,
n-butyl, i-butyl, t-butyl, hexyl, heptyl, octyl) optionally
substituted with one or more R.sub.22. In another embodiment,
R.sub.14 is (i) S(O).sub.2(C.sub.1-C.sub.8) alkyl, (ii)
S(O).sub.2NH(C.sub.1-C.sub.8) alkyl, (iii)
S(O).sub.2N((C.sub.1-C.sub.8) alkyl).sub.2, or (iv)
C(.dbd.O)(C.sub.1-C.sub.8) alkyl optionally substituted with one or
more R.sub.22.
[0112] In some embodiments of the formulae above, R.sub.14 is (i)
H, (ii) (C.sub.1-C.sub.2) alkyl (i.e., methyl or ethyl), (iii)
(C(R.sub.18).sub.2).sub.rC(.dbd.O)NR.sub.19R.sub.20, (iv)
(CH.sub.2).sub.n(C.sub.6-C.sub.10) aryl optionally substituted with
one to three (C.sub.1-C.sub.4) alkyl (e.g., methyl, ethyl,
n-propyl, i-propyl, n-butyl, i-butyl, or t-butyl) or halogen (e.g.,
F, Cl, Br, or I), (v) C(.dbd.O)R.sub.21, (vi)
C(.dbd.O)O(C.sub.1-C.sub.4) alkyl (wherein (C.sub.1-C.sub.4) alkyl
is methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, or
t-butyl), or (viii) C(.dbd.O)(C.sub.1-C.sub.8) alkyl (wherein
(C.sub.1-C.sub.8) alkyl is methyl, ethyl, n-propyl, i-propyl,
n-butyl, i-butyl, t-butyl, hexyl, heptyl, octyl) optionally
substituted with one or more R.sub.22. In another embodiment,
R.sub.14 is (i) H, (ii) (C.sub.1-C.sub.2) alkyl, (iii)
(C(R.sub.18).sub.2).sub.rC(.dbd.O)NR.sub.19R.sub.20, (iv)
(CH.sub.2).sub.n(C.sub.6-C.sub.10) aryl optionally substituted with
one to three (C.sub.1-C.sub.4) alkyl or halogen. In another
embodiment, R.sub.14 is (i) H, (ii) (C.sub.1-C.sub.2) alkyl, (iii)
C(.dbd.O)R.sub.21, (iv) C(.dbd.O)O(C.sub.1-C.sub.4) alkyl, or (v)
C(.dbd.O)(C.sub.1-C.sub.8) alkyl optionally substituted with one or
more R.sub.22. In another embodiment, R.sub.14 is (i)
(C(R.sub.18).sub.2).sub.rC(.dbd.O)NR.sub.19R.sub.20, (ii)
(CH.sub.2).sub.n(C.sub.6-C.sub.10) aryl optionally substituted with
one to three (C.sub.1-C.sub.4) alkyl or halogen, (iii)
C(.dbd.O)R.sub.21, (iv) C(.dbd.O)O(C.sub.1-C.sub.4) alkyl, or (v)
C(.dbd.O)(C.sub.1-C.sub.8) alkyl optionally substituted with one or
more R.sub.22. In another embodiment, R.sub.14 is (i) H, (ii)
(C.sub.1-C.sub.2) alkyl, (iii) (CH.sub.2).sub.n(C.sub.6-C.sub.10)
aryl optionally substituted with one to three (C.sub.1-C.sub.4)
alkyl or halogen, (iv) C(.dbd.O)R.sub.21, (v)
C(.dbd.O)O(C.sub.1-C.sub.4) alkyl, or (v)
C(.dbd.O)(C.sub.1-C.sub.8) alkyl optionally substituted with one or
more R.sub.22. In another embodiment, R.sub.14 is (i)
C(.dbd.O)R.sub.21, (ii) C(.dbd.O)O(C.sub.1-C.sub.4) alkyl, or (iii)
C(.dbd.O)(C.sub.1-C.sub.8) alkyl optionally substituted with one or
more R.sub.22.
[0113] In some embodiments of the formulae above, at least one
R.sub.22 is (i) (C.sub.1-C.sub.2) alkoxy (i.e., methoxy or ethoxy),
(ii) OH, (iii) NH.sub.2, (iv) (C.sub.1-C.sub.2) alkylamino (i.e.,
methylamino or ethylamino), (v) di-(C.sub.1-C.sub.2) alkylamino
(i.e., dimethylamino, methylethylamino or diethylamino), or (vi) 5-
or 6-membered heterocyclyl comprising 1 to 3 heteroatoms selected
from N, O, and S (e.g., pyrrolidinyl, pyrazolidinyl,
imidazolidinyl, piperidinyl, piperazinyl, oxazolidinyl,
isoxazolidinyl, morpholinyl, tetrahydropyranyl, thiazolidinyl,
isothiazolidinyl, tetrahydrofuryl, and dioxanyl) and optionally
substituted with one or more substituents selected from (a)
(C.sub.1-C.sub.4) alkyl (e.g., methyl, ethyl, n-propyl, i-propyl,
n-butyl, i-butyl, or t-butyl), (b)
(CH.sub.2).sub.x(C.sub.6-C.sub.10) aryl, and (c)
C(.dbd.O)(C.sub.6-C.sub.10)aryl optionally substituted with one or
more (C.sub.1-C.sub.4) alkyl (e.g., methyl, ethyl, n-propyl,
i-propyl, n-butyl, i-butyl, or t-butyl). In another embodiment, at
least one R.sub.22 is (i) (C.sub.1-C.sub.4) alkoxy (e.g., methoxy,
ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, or t-butoxy),
(ii) OH, (iii) NH.sub.2, (iv) (C.sub.1-C.sub.4) alkylamino (e.g.,
methylamino, ethylamino, propylamino, or butylamino), or (v)
di-(C.sub.1-C.sub.4) alkylamino (e.g., dimethylamino, diethylamino,
dipropylamino, or dibutylamino). In another embodiment, at least
one R.sub.22 is 5- or 6-membered heterocyclyl comprising 1 to 3
heteroatoms selected from N, O, and S and optionally substituted
with one or more substituents selected from (a) (C.sub.1-C.sub.4)
alkyl, (b) (CH.sub.2).sub.x(C.sub.6-C.sub.10) aryl, and (c)
C(.dbd.O)(C.sub.6-C.sub.10)aryl optionally substituted with one or
more (C.sub.1-C.sub.4) alkyl.
[0114] In another embodiment, at least one R.sub.22 is (i)
(C.sub.1-C.sub.2) alkoxy (i.e., methoxy or ethoxy), (ii) OH, (iii)
di-(C.sub.1-C.sub.2) alkylamino (i.e., dimethylamino,
methylethylamino or diethylamino), or (iv) 5- or 6-membered
heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and
S (e.g., pyrrolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl,
piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl,
tetrahydropyranyl, thiazolidinyl, isothiazolidinyl,
tetrahydrofuryl, and dioxanyl) and optionally substituted with one
to two substituents selected from (a) (C.sub.1-C.sub.4) alkyl
(e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, or
t-butyl), (b) (CH.sub.2).sub.x(C.sub.6-C.sub.10) aryl, and (c)
C(.dbd.O)(C.sub.6-C.sub.10)aryl optionally substituted with one or
more (C.sub.1-C.sub.4) alkyl (e.g., methyl, ethyl, n-propyl,
i-propyl, n-butyl, i-butyl, or t-butyl). In another embodiment, at
least one R.sub.22 is (i) (C.sub.1-C.sub.2) alkoxy, (ii) OH, (iii)
di-(C.sub.1-C.sub.2) alkylamino, or (iv) 6-membered heterocyclyl
comprising 1 to 3 heteroatoms selected from N, O, and S (e.g.,
piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, and
dioxanyl) and optionally substituted with one to two substituents
selected from (a) (C.sub.1-C.sub.4) alkyl, (b)
(CH.sub.2).sub.x(C.sub.6-C.sub.10) aryl, and (c)
C(.dbd.O)(C.sub.6-C.sub.10) aryl optionally substituted with one or
more (C.sub.1-C.sub.4) alkyl.
[0115] In some embodiments of the formulae above, at least one
R.sub.18 is (C.sub.1-C.sub.4) alkyl (e.g., methyl, ethyl, n-propyl,
i-propyl, n-butyl, i-butyl, or t-butyl). In another embodiment, at
least one R.sub.18 is H or (C.sub.1-C.sub.3) alkyl (e.g., methyl,
ethyl, n-propyl, or i-propyl). In another embodiment, at least one
R.sub.18 is H, methyl, or ethyl. In another embodiment, at least
one R.sub.18 is H or methyl. In another embodiment, each R.sub.18
is H.
[0116] In some embodiments of the formulae above, R.sub.19 is
(C.sub.1-C.sub.4) alkyl (e.g., methyl, ethyl, n-propyl, i-propyl,
n-butyl, i-butyl, or t-butyl). In another embodiment, R.sub.19 is H
or (C.sub.1-C.sub.3) alkyl (e.g., methyl, ethyl, n-propyl, or
i-propyl). In another embodiment, R.sub.19 is H, methyl, or ethyl.
In another embodiment, R.sub.19 is H or methyl. In another
embodiment, R.sub.19 is H.
[0117] In some embodiments of the formulae above, R.sub.20 is H or
(CH.sub.2).sub.n(C.sub.6-C.sub.10) aryl optionally substituted with
one to three (C.sub.1-C.sub.4) alkyl (e.g., methyl, ethyl,
n-propyl, i-propyl, n-butyl, i-butyl, or t-butyl). In another
embodiment, R.sub.20 is H. In another embodiment, R.sub.20 is
(CH.sub.2).sub.nphenyl optionally substituted with one to three
(C.sub.1-C.sub.4) alkyl (e.g., methyl, ethyl, n-propyl, i-propyl,
n-butyl, i-butyl, or t-butyl). In another embodiment, R.sub.20 is H
or (CH.sub.2).sub.nphenyl optionally substituted with one to three
(C.sub.1-C.sub.4) alkyl.
[0118] In some embodiments of the formulae above, R.sub.21 is
(C.sub.3-C.sub.7) cycloalkyl (e.g., cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, or cycloheptyl), 5- or 6-membered
heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and
S (e.g., pyrrolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl,
piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl,
tetrahydropyranyl, thiazolidinyl, isothiazolidinyl,
tetrahydrofuryl, and dioxanyl), (C.sub.6-C.sub.10) aryl, or 5- or
6-membered heteroaryl comprising 1 to 3 heteroatoms selected from
N, O, and S (e.g., pyridinyl, pyrazinyl, pyrimidinyl, pyrrolyl,
pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isooxazolyl,
thiadiazolyl, oxadiazolyl, thiophenyl, and furanyl), wherein the
aryl, heteroaryl, cycloalkyl, and heterocyclyl are optionally
substituted with one to three substituents selected from
(C.sub.1-C.sub.4) alkyl (e.g., methyl, ethyl, n-propyl, i-propyl,
n-butyl, i-butyl, or t-butyl), (C.sub.1-C.sub.4) alkoxy (e.g.,
methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, or
t-butoxy), (C.sub.1-C.sub.4) haloalkyl (e.g., CF.sub.3, CHF.sub.2,
CH.sub.2F, CH.sub.2CF.sub.3, CF.sub.2CF.sub.3, CCl.sub.3,
CHCl.sub.2, CH.sub.2Cl, etc.), (C.sub.1-C.sub.4) haloalkoxy (e.g.,
OCF.sub.3, OCHF.sub.2, OCH.sub.2F, OCH.sub.2CF.sub.3,
OCF.sub.2CF.sub.3, OCCl.sub.3, OCHCl.sub.2, OCH.sub.2Cl, etc.), OH,
and halogen (e.g., F, Cl, Br, or I). In another embodiment,
R.sub.21 is (C.sub.3-C.sub.7) cycloalkyl or 5- or 6-membered
heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and
S, wherein the cycloalkyl and heterocyclyl are optionally
substituted with one to three substituents selected from
(C.sub.1-C.sub.4) alkyl, (C.sub.1-C.sub.4) alkoxy,
(C.sub.1-C.sub.4) haloalkyl, (C.sub.1-C.sub.4) haloalkoxy, OH, and
halogen. In another embodiment, R.sub.21 is (C.sub.6-C.sub.10) aryl
or 5- or 6-membered heteroaryl comprising 1 to 3 heteroatoms
selected from N, O, and S, wherein the aryl and heteroaryl are
optionally substituted with one to three substituents selected from
(C.sub.1-C.sub.4) alkyl, (C.sub.1-C.sub.4) alkoxy,
(C.sub.1-C.sub.4) haloalkyl, (C.sub.1-C.sub.4) haloalkoxy, OH, and
halogen.
[0119] In some embodiments of the formulae above, R.sub.16 is (i)
(C.sub.1-C.sub.4) alkyl (e.g., methyl, ethyl, n-propyl, i-propyl,
n-butyl, i-butyl, or t-butyl), (ii) (C.sub.2-C.sub.4) alkenyl
(e.g., ethenyl, propenyl, butenyl), (iii) (C.sub.2-C.sub.4) alkynyl
(e.g., ethynyl, propynyl, butynyl), or (iv) 3- to 6-membered
heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and
S (e.g., pyrrolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl,
piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl,
tetrahydropyranyl, thiazolidinyl, isothiazolidinyl,
tetrahydrofuryl, dioxanyl, oxetanyl, azetidinyl, thietanyl,
oxiranyl, aziridinyl, and thiiranyl), wherein the alkyl, alkenyl,
and alkynyl are optionally substituted with one to three
substituents selected from (C.sub.1-C.sub.4) alkoxy (e.g., methoxy,
ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, or t-butoxy),
O-phenyl, halogen (e.g., F, Cl, Br, or I), CN, NH.sub.2,
(C.sub.1-C.sub.4) alkylamino (e.g., methylamino, ethylamino,
propylamino, or butylamino), di-(C.sub.1-C.sub.4) alkylamino (e.g.,
dimethylamino, diethylamino, dipropylamino, or dibutylamino), and
OS(O).sub.2(C.sub.1-C.sub.4) alkyl (wherein (C.sub.1-C.sub.4) alkyl
is methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, or
t-butyl), and wherein the heterocyclyl is optionally substituted
with one or more R.sub.23. In another embodiment, R.sub.16 is (ii)
(C.sub.2-C.sub.4) alkenyl, (iii) (C.sub.2-C.sub.4) alkynyl, or (iv)
3- to 6-membered heterocyclyl comprising 1 to 3 heteroatoms
selected from N, O, and S, wherein the alkenyl and alkynyl are
optionally substituted with one to three substituents selected from
(C.sub.1-C.sub.4) alkoxy, O-phenyl, halogen, CN, NH.sub.2,
(C.sub.1-C.sub.4) alkylamino, di-(C.sub.1-C.sub.4) alkylamino, and
OS(O).sub.2(C.sub.1-C.sub.4) alkyl, and wherein the heterocyclyl is
optionally substituted with one or more R.sub.23. In another
embodiment, R.sub.16 is (ii) (C.sub.2-C.sub.4) alkenyl, (iii)
(C.sub.2-C.sub.4) alkynyl, or (iv) 3- to 6-membered heterocyclyl
comprising 1 to 3 heteroatoms selected from N, O, and S, wherein
the alkenyl, and alkynyl are optionally substituted with one to
three substituents selected from O-phenyl, halogen, CN, and
OS(O).sub.2(C.sub.1-C.sub.4) alkyl, and wherein the heterocyclyl is
optionally substituted with one or more R.sub.23.
[0120] In some embodiments of the formulae above, R.sub.16 is
(C.sub.1-C.sub.4) alkyl (e.g., methyl, ethyl, n-propyl, i-propyl,
n-butyl, i-butyl, or t-butyl) or 5- or 6-membered heterocyclyl
(e.g., pyrrolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl,
piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl,
tetrahydropyranyl, thiazolidinyl, isothiazolidinyl,
tetrahydrofuryl, and dioxanyl) comprising 1 to 3 heteroatoms
selected from N, O, and S, wherein the alkyl is optionally
substituted with one to three substituents selected from
(C.sub.1-C.sub.4) alkoxy (e.g., methoxy, ethoxy, n-propoxy,
i-propoxy, n-butoxy, i-butoxy, or t-butoxy), NH.sub.2,
(C.sub.1-C.sub.4) alkylamino (e.g., methylamino, ethylamino,
propylamino, or butylamino), and di-(C.sub.1-C.sub.4) alkylamino
(e.g., dimethylamino, diethylamino, dipropylamino, or
dibutylamino), and wherein the heterocyclyl is optionally
substituted with one to three R.sub.23. In another embodiment,
R.sub.16 is (C.sub.1-C.sub.4) alkyl optionally substituted with one
to three substituents selected from (C.sub.1-C.sub.4) alkoxy,
NH.sub.2, (C.sub.1-C.sub.4) alkylamino, and di-(C.sub.1-C.sub.4)
alkylamino. In another embodiment, R.sub.16 is 5- or 6-membered
heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and
S and optionally substituted with one to three R.sub.23. In another
embodiment, R.sub.16 is 5-membered heterocyclyl comprising 1 to 3
heteroatoms selected from N, O, and S (e.g., pyrrolidinyl,
pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl,
thiazolidinyl, isothiazolidinyl, and tetrahydrofuryl) and
optionally substituted with one to three R.sub.23. In another
embodiment, R.sub.16 is 6-membered heterocyclyl comprising 1 to 3
heteroatoms selected from N, O, and S (e.g., piperidinyl,
piperazinyl, morpholinyl, tetrahydropyranyl, and dioxanyl) and
optionally substituted with one to three R.sub.23.
[0121] In another embodiment, R.sub.16 is (C.sub.1-C.sub.4) alkyl
(e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, or
t-butyl) optionally substituted with one to three substituents
selected from (C.sub.1-C.sub.4) alkoxy (e.g., methoxy, ethoxy,
n-propoxy, i-propoxy, n-butoxy, i-butoxy, or t-butoxy) and
di-(C.sub.1-C.sub.4) alkylamino (e.g., dimethylamino, diethylamino,
dipropylamino, or dibutylamino). In another embodiment, R.sub.16 is
(C.sub.1-C.sub.4) alkyl optionally substituted with one to three
substituents selected from (C.sub.1-C.sub.4) alkoxy and
di-(C.sub.1-C.sub.4) alkylamino, or 5- or 6-membered heterocyclyl
comprising 1 to 3 heteroatoms selected from N, O, and S (e.g.,
pyrrolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl,
piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl,
tetrahydropyranyl, thiazolidinyl, isothiazolidinyl,
tetrahydrofuryl, and dioxanyl) and optionally substituted with one
to three R.sub.23. In another embodiment, R.sub.16 is
(C.sub.1-C.sub.4) alkyl optionally substituted with one to three
substituents selected from (C.sub.1-C.sub.4) alkoxy and
di-(C.sub.1-C.sub.4) alkylamino, or 6-membered heterocyclyl
comprising 1 to 3 heteroatoms selected from N, O, and S (e.g.,
piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, and
dioxanyl) and optionally substituted with one to three R.sub.23. In
another embodiment, R.sub.16 is (C.sub.1-C.sub.4) alkyl optionally
substituted with one to three substituents selected from
(C.sub.1-C.sub.4) alkoxy, and di-(C.sub.1-C.sub.4) alkylamino or
5-membered heterocyclyl comprising 1 to 3 heteroatoms selected from
N, O, and S (e.g., pyrrolidinyl, pyrazolidinyl, imidazolidinyl,
oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, and
tetrahydrofuryl) and optionally substituted with one to three
R.sub.23.
[0122] In another embodiment, R.sub.16 is (i) (C.sub.1-C.sub.4)
alkyl (e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl,
or t-butyl), (ii) (C.sub.2-C.sub.4) alkenyl (e.g., ethenyl,
propenyl, butenyl), (iii) (C.sub.2-C.sub.4) alkynyl (e.g., ethynyl,
propynyl, butynyl), or (iv) 5- or 6-membered heterocyclyl
comprising 1 to 3 heteroatoms selected from N, O, and S (e.g.,
pyrrolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl,
piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl,
tetrahydropyranyl, thiazolidinyl, isothiazolidinyl,
tetrahydrofuryl, and dioxanyl), wherein the alkyl, alkenyl, and
alkynyl are optionally substituted with one to three substituents
selected from (C.sub.1-C.sub.4) alkoxy (e.g., methoxy, ethoxy,
n-propoxy, i-propoxy, n-butoxy, i-butoxy, or t-butoxy), CN,
NH.sub.2, (C.sub.1-C.sub.4) alkylamino (e.g., methylamino,
ethylamino, propylamino, or butylamino), and di-(C.sub.1-C.sub.4)
alkylamino (e.g., dimethylamino, diethylamino, dipropylamino, or
dibutylamino), and wherein the heterocyclyl is optionally
substituted with one or more R.sub.23. In another embodiment,
R.sub.16 is (i) (C.sub.1-C.sub.4) alkyl, (ii) (C.sub.2-C.sub.4)
alkenyl, or (iii) (C.sub.2-C.sub.4) alkynyl, wherein the alkyl,
alkenyl, and alkynyl are optionally substituted with one to three
substituents selected from (C.sub.1-C.sub.4) alkoxy, CN, NH.sub.2,
(C.sub.1-C.sub.4) alkylamino, and di-(C.sub.1-C.sub.4) alkylamino.
In another embodiment, R.sub.16 is (i) (C.sub.2-C.sub.4) alkenyl or
(ii) (C.sub.2-C.sub.4) alkynyl, wherein the alkenyl and alkynyl are
optionally substituted with one to three substituents selected from
(C.sub.1-C.sub.4) alkoxy, CN, NH.sub.2, (C.sub.1-C.sub.4)
alkylamino, and di-(C.sub.1-C.sub.4) alkylamino.
[0123] In some embodiments of the formulae above, at least one
R.sub.23 is (C.sub.1-C.sub.4) alkyl (e.g., methyl, ethyl, n-propyl,
i-propyl, n-butyl, i-butyl, or t-butyl) or
C(.dbd.O)(C.sub.1-C.sub.4) alkyl (wherein (C.sub.1-C.sub.4) alkyl
is methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, or
t-butyl). In another embodiment, at least one R.sub.23 is
(C.sub.1-C.sub.3) alkyl (e.g., methyl, ethyl, n-propyl, or
i-propyl). In another embodiment, at least one R.sub.23 is methyl
or ethyl. In another embodiment, each R.sub.23 is independently
C(.dbd.O)(C.sub.1-C.sub.4) alkyl or two R.sub.23 together with the
atoms to which they are attached form a 5- or 6-membered
heterocyclyl ring comprising 1 to 3 heteroatoms selected from N, O,
and S (e.g., pyrrolidinyl, pyrazolidinyl, imidazolidinyl,
oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, and
tetrahydrofuryl). In another embodiment, each R.sub.23 is
independently C(.dbd.O)(C.sub.1-C.sub.4) alkyl.
[0124] In some embodiments of the formulae above, two R.sub.23
together with the atoms to which they are attached form a
5-membered heterocyclyl ring comprising 1 to 3 heteroatoms selected
from N, O, and S (e.g., pyrrolidinyl, pyrazolidinyl,
imidazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl,
isothiazolidinyl, and tetrahydrofuryl). In another embodiment, two
R.sub.23 together with the atoms to which they are attached form a
6-membered heterocyclyl ring comprising 1 to 3 heteroatoms selected
from N, O, and S (e.g., piperidinyl, piperazinyl, morpholinyl,
tetrahydropyranyl, and dioxanyl).
[0125] In some embodiments of the formulae above, R.sub.13 and
R.sub.14 together with the nitrogen atom to which they are attached
form a 4- to 6-membered heterocyclyl ring comprising 1 to 3
heteroatoms selected from N, O, and S (e.g., pyrrolidinyl,
pyrazolidinyl, imidazolidinyl, piperidinyl, piperazinyl,
oxazolidinyl, isoxazolidinyl, morpholinyl, tetrahydropyranyl,
thiazolidinyl, isothiazolidinyl, tetrahydrofuryl, dioxanyl,
oxetanyl, azetidinyl, and thietanyl) optionally substituted with
one to three substituents selected from (C.sub.1-C.sub.4) alkyl
(e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, or
t-butyl), (C.sub.1-C.sub.4) alkoxy (e.g., methoxy, ethoxy,
n-propoxy, i-propoxy, n-butoxy, i-butoxy, or t-butoxy), OH,
NH.sub.2, and (.dbd.O). In another embodiment, R.sub.13 and
R.sub.14 together with the nitrogen atom to which they are attached
form a 4- or 5-membered heterocyclyl ring comprising 1 to 3
heteroatoms selected from N, O, and S (e.g., pyrrolidinyl,
pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl,
thiazolidinyl, isothiazolidinyl, tetrahydrofuryl, oxetanyl,
azetidinyl, and thietanyl) optionally substituted with one to three
substituents selected from (C.sub.1-C.sub.4) alkyl (e.g., methyl,
ethyl, n-propyl, i-propyl, n-butyl, i-butyl, or t-butyl),
(C.sub.1-C.sub.4) alkoxy (e.g., methoxy, ethoxy, n-propoxy,
i-propoxy, n-butoxy, i-butoxy, or t-butoxy), OH, NH.sub.2, and
(.dbd.O). In another embodiment, R.sub.13 and R.sub.14 together
with the nitrogen atom to which they are attached form a 5- or
6-membered heterocyclyl ring comprising 1 to 3 heteroatoms selected
from N, O, and S (e.g., pyrrolidinyl, pyrazolidinyl,
imidazolidinyl, piperidinyl, piperazinyl, oxazolidinyl,
isoxazolidinyl, morpholinyl, tetrahydropyranyl, thiazolidinyl,
isothiazolidinyl, tetrahydrofuryl, and dioxanyl) optionally
substituted with one to three substituents selected from
(C.sub.1-C.sub.4) alkyl (e.g., methyl, ethyl, n-propyl, i-propyl,
n-butyl, i-butyl, or t-butyl), (C.sub.1-C.sub.4) alkoxy (e.g.,
methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, or
t-butoxy), OH, NH.sub.2, and (.dbd.O). In another embodiment,
R.sub.13 and R.sub.14 together with the nitrogen atom to which they
are attached form a 4-membered heterocyclyl ring comprising 1 to 3
heteroatoms selected from N, O, and S (e.g., oxetanyl, azetidinyl,
and thietanyl) optionally substituted with one to three
substituents selected from (C.sub.1-C.sub.4) alkyl (e.g., methyl,
ethyl, n-propyl, i-propyl, n-butyl, i-butyl, or t-butyl),
(C.sub.1-C.sub.4) alkoxy (e.g., methoxy, ethoxy, n-propoxy,
i-propoxy, n-butoxy, i-butoxy, or t-butoxy), OH, NH.sub.2, and
(.dbd.O). In another embodiment, R.sub.13 and R.sub.14 together
with the nitrogen atom to which they are attached form a 5-membered
heterocyclyl ring comprising 1 to 3 heteroatoms selected from N, O,
and S (e.g., pyrrolidinyl, pyrazolidinyl, imidazolidinyl,
oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, and
tetrahydrofuryl) optionally substituted with one to three
substituents selected from (C.sub.1-C.sub.4) alkyl (e.g., methyl,
ethyl, n-propyl, i-propyl, n-butyl, i-butyl, or t-butyl),
(C.sub.1-C.sub.4) alkoxy (e.g., methoxy, ethoxy, n-propoxy,
i-propoxy, n-butoxy, i-butoxy, or t-butoxy), OH, NH.sub.2, and
(.dbd.O). In another embodiment, R.sub.13 and R.sub.14 together
with the nitrogen atom to which they are attached form a 6-membered
heterocyclyl ring comprising 1 to 3 heteroatoms selected from N, O,
and S (e.g., piperidinyl, piperazinyl, morpholinyl,
tetrahydropyranyl, and dioxanyl) optionally substituted with one to
three substituents selected from (C.sub.1-C.sub.4) alkyl (e.g.,
methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, or t-butyl),
(C.sub.1-C.sub.4) alkoxy (e.g., methoxy, ethoxy, n-propoxy,
i-propoxy, n-butoxy, i-butoxy, or t-butoxy), OH, NH.sub.2, and
(.dbd.O).
[0126] In some embodiments of the formulae above, R.sub.15 is (i) H
or (ii) (C.sub.1-C.sub.4) alkyl (e.g., methyl, ethyl, n-propyl,
i-propyl, n-butyl, i-butyl, or t-butyl) optionally substituted with
one or more substituents selected from OH, 5- or 6-membered
heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and
S (e.g., pyrrolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl,
piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl,
tetrahydropyranyl, thiazolidinyl, isothiazolidinyl,
tetrahydrofuryl, and dioxanyl), and 5- or 6-membered heteroaryl
comprising 1 to 3 heteroatoms selected from N, O, and S (e.g.,
pyridinyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl,
thiazolyl, oxazolyl, isooxazolyl, thiadiazolyl, oxadiazolyl,
thiophenyl, and furanyl). In another embodiment, R.sub.15 is (i) 5-
or 6-membered heterocyclyl comprising 1 to 3 heteroatoms selected
from N, O, and S (e.g., pyrrolidinyl, pyrazolidinyl,
imidazolidinyl, piperidinyl, piperazinyl, oxazolidinyl,
isoxazolidinyl, morpholinyl, tetrahydropyranyl, thiazolidinyl,
isothiazolidinyl, tetrahydrofuryl, and dioxanyl) or (ii)
(C.sub.1-C.sub.4) alkyl (e.g., methyl, ethyl, n-propyl, i-propyl,
n-butyl, i-butyl, or t-butyl) optionally substituted with one or
more substituents selected from OH, 5- or 6-membered heterocyclyl
comprising 1 to 3 heteroatoms selected from N, O, and S (e.g.,
pyrrolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl,
piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl,
tetrahydropyranyl, thiazolidinyl, isothiazolidinyl,
tetrahydrofuryl, and dioxanyl), and 5- or 6-membered heteroaryl
comprising 1 to 3 heteroatoms selected from N, O, and S (e.g.,
pyridinyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl,
thiazolyl, oxazolyl, isooxazolyl, thiadiazolyl, oxadiazolyl,
thiophenyl, and furanyl). In another embodiment, R.sub.15 is (i) H,
(ii) 6-membered heterocyclyl comprising 1 to 3 heteroatoms selected
from N, O, and S (e.g., piperidinyl, piperazinyl, morpholinyl,
tetrahydropyranyl, and dioxanyl), or (iii) (C.sub.1-C.sub.4) alkyl
(e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, or
t-butyl) optionally substituted with one or more substituents
selected from OH, 5- or 6-membered heterocyclyl comprising 1 to 3
heteroatoms selected from N, O, and S (e.g., pyrrolidinyl,
pyrazolidinyl, imidazolidinyl, piperidinyl, piperazinyl,
oxazolidinyl, isoxazolidinyl, morpholinyl, tetrahydropyranyl,
thiazolidinyl, isothiazolidinyl, tetrahydrofuryl, and dioxanyl),
and 5- or 6-membered heteroaryl comprising 1 to 3 heteroatoms
selected from N, O, and S (e.g., pyridinyl, pyrazinyl, pyrimidinyl,
pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isooxazolyl,
thiadiazolyl, oxadiazolyl, thiophenyl, and furanyl). In another
embodiment, R.sub.15 is (i) H, (ii) 5-membered heterocyclyl
comprising 1 to 3 heteroatoms selected from N, O, and S (e.g.,
pyrrolidinyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl,
isoxazolidinyl, thiazolidinyl, isothiazolidinyl, and
tetrahydrofuryl), or (iii) (C.sub.1-C.sub.4) alkyl (e.g., methyl,
ethyl, n-propyl, i-propyl, n-butyl, i-butyl, or t-butyl) optionally
substituted with one or more substituents selected from OH, 5- or
6-membered heterocyclyl comprising 1 to 3 heteroatoms selected from
N, O, and S (e.g., pyrrolidinyl, pyrazolidinyl, imidazolidinyl,
piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl,
morpholinyl, tetrahydropyranyl, thiazolidinyl, isothiazolidinyl,
tetrahydrofuryl, and dioxanyl), and 5- or 6-membered heteroaryl
comprising 1 to 3 heteroatoms selected from N, O, and S (e.g.,
pyridinyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl,
thiazolyl, oxazolyl, isooxazolyl, thiadiazolyl, oxadiazolyl,
thiophenyl, and furanyl). In another embodiment, R.sub.15 is H. In
another embodiment, R.sub.15 is 5- or 6-membered heterocyclyl
comprising 1 to 3 heteroatoms selected from N, O, and S. In another
embodiment, R.sub.15 is 5-membered heterocyclyl comprising 1 to 3
heteroatoms selected from N, O, and S. In another embodiment,
R.sub.15 is 6-membered heterocyclyl comprising 1 to 3 heteroatoms
selected from N, O, and S. In another embodiment, R.sub.15 is
(C.sub.1-C.sub.4) alkyl optionally substituted with one or more
substituents selected from OH, 5- or 6-membered heterocyclyl
comprising 1 to 3 heteroatoms selected from N, O, and S, and 5- or
6-membered heteroaryl comprising 1 to 3 heteroatoms selected from
N, O, and S. In another embodiment, R.sub.15 is (C.sub.1-C.sub.4)
alkyl optionally substituted with one or more substituents selected
from OH, 6-membered heterocyclyl comprising 1 to 3 heteroatoms
selected from N, O, and S, and 6-membered heteroaryl comprising 1
to 3 heteroatoms selected from N, O, and S. In another embodiment,
R.sub.15 is (C.sub.1-C.sub.4) alkyl optionally substituted with one
or more substituents selected from OH, 5-membered heterocyclyl
comprising 1 to 3 heteroatoms selected from N, O, and S, and
5-membered heteroaryl comprising 1 to 3 heteroatoms selected from
N, O, and S.
[0127] In some embodiments of the formulae above, R.sub.13 and
R.sub.15 together with the nitrogen atom to which they are attached
form a 4- to 6-membered heterocyclyl ring comprising 1 to 3
heteroatoms selected from N, O, and S (e.g., [1,3]dioxolanyl,
pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl,
imidazolidinyl, piperidinyl, piperazinyl, oxazolidinyl,
isoxazolidinyl, morpholinyl, tetrahydropyranyl, thiazolidinyl,
isothiazolidinyl, tetrahydrofuryl, dioxanyl, oxetanyl, azetidinyl,
and thietanyl) and optionally substituted with one to three
substituents selected from (C.sub.1-C.sub.4) alkyl (e.g., methyl,
ethyl, n-propyl, i-propyl, n-butyl, i-butyl, or t-butyl),
(C.sub.1-C.sub.4) alkoxy (e.g., methoxy, ethoxy, n-propoxy,
i-propoxy, n-butoxy, i-butoxy, or t-butoxy), and OH, or form a 5-
to 8-membered bicyclic heterocyclyl ring comprising 1 to 3
heteroatoms selected from N, O, and S and optionally substituted
with one to three substituents selected from (C.sub.1-C.sub.4)
alkyl (e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl,
or t-butyl), (C.sub.1-C.sub.4) alkoxy (e.g., methoxy, ethoxy,
n-propoxy, i-propoxy, n-butoxy, i-butoxy, or t-butoxy), and OH. In
another embodiment, R.sub.13 and R.sub.15 together with the
nitrogen atom to which they are attached form a 4- to 6-membered
heterocyclyl ring comprising 1 to 3 heteroatoms selected from N, O,
and S and optionally substituted with one to three substituents
selected from (C.sub.1-C.sub.4) alkyl, (C.sub.1-C.sub.4) alkoxy,
and OH. In another embodiment, R.sub.13 and R.sub.15 together with
the nitrogen atom to which they are attached form a 5- to
8-membered bicyclic heterocyclyl ring comprising 1 to 3 heteroatoms
selected from N, O, and S and optionally substituted with one to
three substituents selected from (C.sub.1-C.sub.4) alkyl,
(C.sub.1-C.sub.4) alkoxy, and OH. In another embodiment, R.sub.13
and R.sub.15 together with the nitrogen atom to which they are
attached form a 4- to 6-membered heterocyclyl ring comprising 1 to
3 heteroatoms selected from N, O, and S and optionally substituted
with one to three substituents selected from (C.sub.1-C.sub.4)
alkyl, (C.sub.1-C.sub.4) alkoxy, and OH, or form a 7- to 8-membered
bicyclic heterocyclyl ring comprising 1 to 3 heteroatoms selected
from N, O, and S and optionally substituted with one to three
substituents selected from (C.sub.1-C.sub.4) alkyl,
(C.sub.1-C.sub.4) alkoxy, and OH.
[0128] In some embodiments of the formulae above, R.sub.2 is
(C.sub.1-C.sub.4) alkyl (e.g., methyl, ethyl, n-propyl, i-propyl,
n-butyl, i-butyl, or t-butyl). In another embodiment, R.sub.2 is H
or (C.sub.1-C.sub.3) alkyl (e.g., methyl, ethyl, n-propyl, or
i-propyl). In another embodiment, R.sub.2 is H, methyl, or ethyl.
In another embodiment, R.sub.2 is H or methyl. In a further
embodiment, R.sub.2 is H.
[0129] In some embodiments of the formulae above, when q is 0,
R.sub.1 and R.sub.2 together with the nitrogen atom to which they
are attached form a 5- or 6-membered heterocyclyl ring comprising 0
to 1 additional heteroatoms selected from N, O, and S (e.g.,
pyrrolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl,
piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl,
tetrahydropyranyl, thiazolidinyl, isothiazolidinyl,
tetrahydrofuryl, and dioxanyl) and optionally substituted with one
to two NR.sub.6R.sub.7. In another embodiment, when q is 0, R.sub.1
and R.sub.2 together with the nitrogen atom to which they are
attached form a 5- or 6-membered heterocyclyl ring comprising 0 to
1 additional heteroatoms selected from N, O, and S and substituted
with one to two NR.sub.6R.sub.7. In another embodiment, when q is
0, R.sub.1 and R.sub.2 together with the nitrogen atom to which
they are attached form a 5-membered heterocyclyl ring comprising 0
to 1 additional heteroatoms selected from N, O, and S (e.g.,
pyrrolidinyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl,
isoxazolidinyl, thiazolidinyl, isothiazolidinyl, and
tetrahydrofuryl) and optionally substituted with one or more
NR.sub.6R.sub.7. In another embodiment, when q is 0, R.sub.1 and
R.sub.2 together with the nitrogen atom to which they are attached
form a 5-membered heterocyclyl ring comprising 0 to 1 additional
heteroatoms selected from N, O, and S and optionally substituted
with one to two NR.sub.6R.sub.7. In another embodiment, when q is
0, R.sub.1 and R.sub.2 together with the nitrogen atom to which
they are attached form a 5-membered heterocyclyl ring comprising 0
to 1 additional heteroatoms selected from N, O, and S and
substituted with one to two NR.sub.6R.sub.7. In another embodiment,
when q is 0, R.sub.1 and R.sub.2 together with the nitrogen atom to
which they are attached form a 6-membered heterocyclyl ring
comprising 0 to 1 additional heteroatoms selected from N, O, and S
(e.g., piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl,
and dioxanyl) and optionally substituted with one or more
NR.sub.6R.sub.7. In another embodiment, when q is 0, R.sub.1 and
R.sub.2 together with the nitrogen atom to which they are attached
form a 6-membered heterocyclyl ring comprising 0 to 1 additional
heteroatoms selected from N, O, and S and optionally substituted
with one to two NR.sub.6R.sub.7. In another embodiment, when q is
0, R.sub.1 and R.sub.2 together with the nitrogen atom to which
they are attached form a 6-membered heterocyclyl ring comprising 0
to 1 additional heteroatoms selected from N, O, and S and
substituted with one to two NR.sub.6R.sub.7.
[0130] In some embodiments of the formulae above, R.sub.6 is
(C.sub.1-C.sub.4) alkyl (e.g., methyl, ethyl, n-propyl, i-propyl,
n-butyl, i-butyl, or t-butyl). In another embodiment, R.sub.6 is H
or (C.sub.1-C.sub.3) alkyl (e.g., methyl, ethyl, n-propyl, or
i-propyl). In another embodiment, R.sub.6 is H, methyl, or ethyl.
In another embodiment, R.sub.6 is H or methyl. In another
embodiment, R.sub.6 is H.
[0131] In some embodiments of the formulae above, R.sub.7 is H or
(C.sub.1-C.sub.4) alkyl (e.g., methyl, ethyl, n-propyl, i-propyl,
n-butyl, i-butyl, or t-butyl). In another embodiment, R.sub.7 is
(C.sub.1-C.sub.4) alkyl (e.g., methyl, ethyl, n-propyl, i-propyl,
n-butyl, i-butyl, or t-butyl) or C(.dbd.O)R.sub.24. In another
embodiment, R.sub.7 is H, (C.sub.1-C.sub.3) alkyl (e.g., methyl,
ethyl, n-propyl, or i-propyl), or C(.dbd.O)R.sub.24. In another
embodiment, R.sub.7 is H, methyl, ethyl, or C(.dbd.O)R.sub.24. In
another embodiment, R.sub.7 is methyl, ethyl, or C(.dbd.O)R.sub.24.
In another embodiment, R.sub.7 is H or C(.dbd.O)R.sub.24.
[0132] In some embodiments of the formulae above, R.sub.24 is
(C.sub.1-C.sub.4) alkyl (e.g., methyl, ethyl, n-propyl, i-propyl,
n-butyl, i-butyl, or t-butyl) optionally substituted with one to
three (C.sub.1-C.sub.4) alkoxy (e.g., methoxy, ethoxy, n-propoxy,
i-propoxy, n-butoxy, i-butoxy, or t-butoxy). In another embodiment,
R.sub.24 is (C.sub.1-C.sub.4) alkyl (e.g., methyl, ethyl, n-propyl,
i-propyl, n-butyl, i-butyl, or t-butyl) optionally substituted with
one to three 5- or 6-membered heterocyclyl comprising 1 to 3
heteroatoms selected from N, O, and S (e.g., pyrrolidinyl,
pyrazolidinyl, imidazolidinyl, piperidinyl, piperazinyl,
oxazolidinyl, isoxazolidinyl, morpholinyl, tetrahydropyranyl,
thiazolidinyl, isothiazolidinyl, tetrahydrofuryl, and dioxanyl). In
another embodiment, R.sub.24 is (C.sub.1-C.sub.4) alkyl substituted
with one to three substituents selected from (C.sub.1-C.sub.4)
alkoxy and 5- or 6-membered heterocyclyl comprising 1 to 3
heteroatoms selected from N, O, and S. In another embodiment,
R.sub.24 is (C.sub.1-C.sub.2) alkyl (i.e., methyl or ethyl)
optionally substituted with one to three substituents selected from
(C.sub.1-C.sub.4) alkoxy (e.g., methoxy, ethoxy, n-propoxy,
i-propoxy, n-butoxy, i-butoxy, or t-butoxy) and 5- or 6-membered
heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and
S (e.g., pyrrolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl,
piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl,
tetrahydropyranyl, thiazolidinyl, isothiazolidinyl,
tetrahydrofuryl, and dioxanyl). In another embodiment, R.sub.24 is
(C.sub.1-C.sub.2) alkyl optionally substituted with one to three
substituents selected from (C.sub.1-C.sub.2) alkoxy (i.e., methoxy
or ethoxy) and 6-membered heterocyclyl comprising 1 to 3
heteroatoms selected from N, O, and S (e.g., piperidinyl,
piperazinyl, morpholinyl, tetrahydropyranyl, tetrahydrofuryl, and
dioxanyl).
[0133] In some embodiments of the formulae above, R.sub.3 is
N(R.sub.8).sub.2. In another embodiment, R.sub.3 is NH.sub.2,
NHCH.sub.3, N(CH.sub.3).sub.2, or 4-methylpiperzinyl. In another
embodiment, R.sub.3 is H, NH.sub.2, NHCH.sub.3, N(CH.sub.3).sub.2,
or 4-methylpiperzinyl. In another embodiment, R.sub.3 is H,
NH.sub.2, NHCH.sub.3, or 4-methylpiperzinyl. In a further
embodiment, R.sub.3 is H.
[0134] In some embodiments of the formulae above, at least one
R.sub.8 is (i) H, (ii) (C.sub.1-C.sub.4) alkyl (e.g., methyl,
ethyl, n-propyl, i-propyl, n-butyl, i-butyl, or t-butyl), or (iii)
5- or 6-membered heterocyclyl comprising 1 to 3 heteroatoms
selected from N, O, and S (e.g., pyrrolidinyl, pyrazolidinyl,
imidazolidinyl, piperidinyl, piperazinyl, oxazolidinyl,
isoxazolidinyl, morpholinyl, tetrahydropyranyl, thiazolidinyl,
isothiazolidinyl, tetrahydrofuryl, and dioxanyl) and optionally
substituted with one or more (C.sub.1-C.sub.4) alkyl (e.g., methyl,
ethyl, n-propyl, i-propyl, n-butyl, i-butyl, or t-butyl). In
another embodiment, at least one R.sub.8 is (i) H, (ii)
(C.sub.1-C.sub.2) alkyl (i.e., methyl or ethyl), or (iii) 5- or
6-membered heterocyclyl comprising 1 to 3 heteroatoms selected from
N, O, and S and optionally substituted with one to three
(C.sub.1-C.sub.4) alkyl (e.g., methyl, ethyl, n-propyl, i-propyl,
n-butyl, i-butyl, or t-butyl). In another embodiment, at least one
R.sub.8 is (i) H, (ii) (C.sub.1-C.sub.2) alkyl, or (iii) 5-membered
heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and
S (e.g., pyrrolidinyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl,
isoxazolidinyl, thiazolidinyl, isothiazolidinyl, and
tetrahydrofuryl) and optionally substituted with one to three
(C.sub.1-C.sub.4) alkyl (e.g., methyl, ethyl, n-propyl, i-propyl,
n-butyl, i-butyl, or t-butyl). In another embodiment, at least one
R.sub.8 is (i) H, (ii) (C.sub.1-C.sub.2) alkyl, or (iii) 6-membered
heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and
S (e.g., piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl,
and dioxanyl) and optionally substituted with one to three
(C.sub.1-C.sub.4) alkyl (e.g., methyl, ethyl, n-propyl, i-propyl,
n-butyl, i-butyl, or t-butyl). In another embodiment, at least one
R.sub.8 is (i) H or (ii) (C.sub.1-C.sub.2) alkyl.
[0135] In some embodiments of the formulae above, two R.sub.8
together with the nitrogen atom to which they are attached form a
5- or 6-membered heterocyclyl ring comprising 0 to 1 additional
heteroatoms selected from N, O, and S (e.g., pyrrolidinyl,
pyrazolidinyl, imidazolidinyl, piperidinyl, piperazinyl,
oxazolidinyl, isoxazolidinyl, morpholinyl, tetrahydropyranyl,
thiazolidinyl, isothiazolidinyl, tetrahydrofuryl, and dioxanyl) and
optionally substituted with one to three (C.sub.1-C.sub.4) alkyl
(e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, or
t-butyl). In another embodiment, two R.sub.8 together with the
nitrogen atom to which they are attached form a 5-membered
heterocyclyl ring comprising 0 to 1 additional heteroatoms selected
from N, O, and S (e.g., pyrrolidinyl, pyrazolidinyl,
imidazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl,
isothiazolidinyl, and tetrahydrofuryl) and optionally substituted
with one or more (C.sub.1-C.sub.4) alkyl (e.g., methyl, ethyl,
n-propyl, i-propyl, n-butyl, i-butyl, or t-butyl). In another
embodiment, two R.sub.8 together with the nitrogen atom to which
they are attached form a 6-membered heterocyclyl ring comprising 0
to 1 additional heteroatoms selected from N, O, and S (e.g.,
piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, and
dioxanyl) and optionally substituted with one or more
(C.sub.1-C.sub.4) alkyl (e.g., methyl, ethyl, n-propyl, i-propyl,
n-butyl, i-butyl, or t-butyl). In another embodiment, two R.sub.8
together with the nitrogen atom to which they are attached form a
5-membered heterocyclyl ring comprising 0 to 1 additional
heteroatoms selected from N, O, and S and optionally substituted
with one to three (C.sub.1-C.sub.4) alkyl. In another embodiment,
two R.sub.8 together with the nitrogen atom to which they are
attached form a 6-membered heterocyclyl ring comprising 0 to 1
additional heteroatoms selected from N, O, and S and optionally
substituted with one to three (C.sub.1-C.sub.4) alkyl. In another
embodiment, two R.sub.8 together with the nitrogen atom to which
they are attached form a 5-membered heterocyclyl ring comprising 0
to 1 additional heteroatoms selected from N, O, and S and
substituted with one to three (C.sub.1-C.sub.4) alkyl. In another
embodiment, two R.sub.8 together with the nitrogen atom to which
they are attached form a 6-membered heterocyclyl ring comprising 0
to 1 additional heteroatoms selected from N, O, and S and
substituted with one to three (C.sub.1-C.sub.4) alkyl.
[0136] In another embodiment, at least one R.sub.8 is (i) H, (ii)
(C.sub.1-C.sub.2) alkyl (i.e., methyl or ethyl), (iii) 6-membered
heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and
S (e.g., piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl,
and dioxanyl) and optionally substituted with one to three
(C.sub.1-C.sub.4) alkyl (e.g., methyl, ethyl, n-propyl, i-propyl,
n-butyl, i-butyl, or t-butyl), or (iv) two R.sub.8 together with
the nitrogen atom to which they are attached form a 5- or
6-membered heterocyclyl ring comprising 0 to 1 additional
heteroatoms selected from N, O, and S (e.g., pyrrolidinyl,
pyrazolidinyl, imidazolidinyl, piperidinyl, piperazinyl,
oxazolidinyl, isoxazolidinyl, morpholinyl, tetrahydropyranyl,
thiazolidinyl, isothiazolidinyl, tetrahydrofuryl, and dioxanyl) and
optionally substituted with one to three (C.sub.1-C.sub.4) alkyl
(e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, or
t-butyl). In a further embodiment, at least one R.sub.8 is (i) H,
(ii) (C.sub.1-C.sub.2) alkyl (i.e., methyl or ethyl), or (iii) two
R.sub.8 together with the nitrogen atom to which they are attached
form a 6-membered heterocyclyl ring (e.g., piperidinyl,
piperazinyl, morpholinyl, tetrahydropyranyl, and dioxanyl)
comprising 0 to 1 additional heteroatoms selected from N, O, and S
and substituted with one to three (C.sub.1-C.sub.4) alkyl (e.g.,
methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, or
t-butyl).
[0137] In some embodiments of the formulae above, n is 0 or 1. In
another embodiment, n is 1 or 2. In another embodiment, n is 0. In
another embodiment, n is 1. In another embodiment, n is 2.
[0138] In some embodiments of the formulae above, p is 0 or 1. In
another embodiment, p is 1 or 2. In another embodiment, p is 0. In
another embodiment, p is 1. In another embodiment, p is 2.
[0139] In some embodiments of the formulae above, r is 0, 1 or 2.
In another embodiment, r is 1, 2, or 3. In another embodiment, r is
0 or 1. In another embodiment, r is 1 or 2. In another embodiment,
r is 2 or 3. In another embodiment, r is 0. In another embodiment,
r is 1. In another embodiment, r is 2. In another embodiment, r is
3.
[0140] In some embodiments of the formulae above, q is 0, 1 or 2.
In another embodiment, q is 1, 2, or 3. In another embodiment, q is
0 or 1. In another embodiment, q is 1 or 2. In another embodiment,
q is 2 or 3. In another embodiment, q is 0. In another embodiment,
q is 1. In another embodiment, q is 2. In another embodiment, q is
3.
[0141] In some embodiments of the formulae above, x is 0, 1 or 2.
In another embodiment, x is 1, 2, or 3. In another embodiment, x is
0 or 1. In another embodiment, x is 1 or 2. In another embodiment,
x is 2 or 3. In another embodiment, x is 0. In another embodiment,
x is 1. In another embodiment, x is 2. In another embodiment, x is
3.
[0142] In some embodiments of the formulae above, when R.sub.4 is
NR.sub.9S(O).sub.pR.sub.10, O(CH.sub.2).sub.nR.sub.11,
NH(CH.sub.2).sub.nR.sub.11, (CH.sub.2).sub.nC(.dbd.O)NHR.sub.25,
(CH.sub.2).sub.nNHC(.dbd.O)R.sub.25,
(CH.sub.2).sub.nNHC(.dbd.O)NHR.sub.25, C(.dbd.O)R.sub.25, or
heterocyclyl comprising one or two 4- to 6-membered rings and 1 to
3 heteroatoms selected from N, O, and S and optionally substituted
with one or more substituents selected from (C.sub.1-C.sub.4)
alkyl, (C.sub.1-C.sub.4) haloalkyl, C(.dbd.O)(C.sub.1-C.sub.4)
alkyl, and halogen, A is optionally substituted with one additional
R.sub.4. In some embodiments of the formulae above, when R.sub.4 is
NR.sub.9S(O).sub.pR.sub.10, O(CH.sub.2).sub.nR.sub.11,
NH(CH.sub.2).sub.nR.sub.11, (CH.sub.2).sub.nC(.dbd.O)NHR.sub.25,
(CH.sub.2).sub.nNHC(.dbd.O)R.sub.25,
(CH.sub.2).sub.nNHC(.dbd.O)NHR.sub.25, or C(.dbd.O)R.sub.25, A is
optionally substituted with one additional R.sub.4. In some
embodiments of the formulae above, when R.sub.4 is
(CH.sub.2).sub.nC(.dbd.O)NHR.sub.25,
(CH.sub.2).sub.nNHC(.dbd.O)R.sub.25,
(CH.sub.2).sub.nNHC(.dbd.O)NHR.sub.25, or C(.dbd.O)R.sub.25, A is
optionally substituted with one additional R.sub.4. In some
embodiments of the formulae above, when R.sub.4 is
(CH.sub.2).sub.nC(.dbd.O)NHR.sub.25 or
(CH.sub.2).sub.nNHC(.dbd.O)R.sub.25, A is optionally substituted
with one additional R.sub.4. In some embodiments of the formulae
above, when R.sub.4 is O(CH.sub.2).sub.nR.sub.11 or
NH(CH.sub.2).sub.nR.sub.11, A is optionally substituted with one
additional R.sub.4.
[0143] In some embodiments of the formulae above, when R.sub.4 is
(CH.sub.2).sub.nC(.dbd.O)NHR.sub.25,
(CH.sub.2).sub.nNHC(.dbd.O)R.sub.25, or NR.sub.9S(O).sub.pR.sub.10,
A is optionally substituted with one additional R.sub.4.
[0144] In some embodiments of the formulae above, A is substituted
with one to two R.sub.4 and R.sub.4 is (C.sub.1-C.sub.4) alkyl
(e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, or
t-butyl), (C.sub.1-C.sub.4) alkoxy (e.g., methoxy, ethoxy,
n-propoxy, i-propoxy, n-butoxy, i-butoxy, or t-butoxy),
(C.sub.1-C.sub.4) haloalkyl (e.g., CF.sub.3, CHF.sub.2, CH.sub.2F,
CH.sub.2CF.sub.3, CF.sub.2CF.sub.3, CCl.sub.3, CHCl.sub.2,
CH.sub.2Cl, etc.), (C.sub.1-C.sub.4) haloalkoxy (e.g., OCF.sub.3,
OCHF.sub.2, OCH.sub.2F, OCH.sub.2CF.sub.3, OCF.sub.2CF.sub.3,
OCCl.sub.3, OCHCl.sub.2, OCH.sub.2Cl, etc.), halogen (e.g., F, Cl,
Br, or I), NR.sub.9S(O).sub.pR.sub.10, O(CH.sub.2).sub.nR.sub.11,
NH(CH.sub.2).sub.nR.sub.11, (CH.sub.2).sub.nC(.dbd.O)NHR.sub.25,
(CH.sub.2).sub.nNHC(.dbd.O)R.sub.25,
(CH.sub.2).sub.nNHC(.dbd.O)NHR.sub.25, or C(.dbd.O)R.sub.25. In
another embodiment, A is substituted with one or more R.sub.4 and
R.sub.4 is (C.sub.1-C.sub.4) alkyl (e.g., methyl, ethyl, n-propyl,
i-propyl, n-butyl, i-butyl, or t-butyl), (C.sub.1-C.sub.4) alkoxy
(e.g., methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy,
or t-butoxy), (C.sub.1-C.sub.4) haloalkyl (e.g., CF.sub.3,
CHF.sub.2, CH.sub.2F, CH.sub.2CF.sub.3, CF.sub.2CF.sub.3,
CCl.sub.3, CHCl.sub.2, CH.sub.2Cl, etc.), (C.sub.1-C.sub.4)
haloalkoxy (e.g., OCF.sub.3, OCHF.sub.2, OCH.sub.2F,
OCH.sub.2CF.sub.3, OCF.sub.2CF.sub.3, OCCl.sub.3, OCHCl.sub.2,
OCH.sub.2Cl, etc.), halogen (e.g., F, Cl, Br, or I),
O(CH.sub.2).sub.nR.sub.11, NH(CH.sub.2).sub.nR.sub.11,
(CH.sub.2).sub.nC(.dbd.O)NHR.sub.25,
(CH.sub.2).sub.nNHC(.dbd.O)R.sub.25,
(CH.sub.2).sub.nNHC(.dbd.O)NHR.sub.25, or C(.dbd.O)R.sub.25.
[0145] In some embodiments of the formulae above, the compounds of
Formula (I) is not
(2-chloro-4-phenoxyphenyl)(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyr-
an-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone.
[0146] In some embodiments of the formulae above, A is phenyl,
thiophenyl, or pyridinyl optionally substituted with one or more
R.sub.4.
[0147] In some embodiments of the formulae above, A is phenyl,
thiophenyl, or pyridinyl substituted with one to two R.sub.4.
[0148] In some embodiments of the formulae above, A is phenyl
substituted with one to two R.sub.4.
[0149] In some embodiments of the formulae above, R.sub.3 is H,
NH.sub.2, NHCH.sub.3, or 4-methylpiperazine.
[0150] In some embodiments of the formulae above, at least one
R.sub.4 is (C.sub.1-C.sub.4) alkyl (e.g., methyl, ethyl, n-propyl,
i-propyl, n-butyl, i-butyl, or t-butyl), (C.sub.1-C.sub.4) alkoxy
(e.g., methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy,
or t-butoxy), halogen (e.g., F, Cl, Br, or I),
NR.sub.9S(O).sub.pR.sub.10, O(CH.sub.2).sub.nR.sub.11,
NH(CH.sub.2).sub.nR.sub.11, C(.dbd.O)NHR.sub.25,
NHC(.dbd.O)R.sub.25, NHC(.dbd.O)NHR.sub.25,
(CH.sub.2)C(.dbd.O)NHR.sub.25, (CH.sub.2)NHC(.dbd.O)R.sub.25,
(CH.sub.2)NHC(.dbd.O)NHR.sub.25, or C(.dbd.O)R.sub.25.
[0151] In some embodiments of the formulae above, at least one
R.sub.4 is (C.sub.1-C.sub.4) alkyl (e.g., methyl, ethyl, n-propyl,
i-propyl, n-butyl, i-butyl, or t-butyl), (C.sub.1-C.sub.4) alkoxy
(e.g., methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy,
or t-butoxy), halogen (e.g., F, Cl, Br, or I), or
O(CH.sub.2).sub.nR.sub.11, C(.dbd.O)NHR.sub.25,
NHC(.dbd.O)R.sub.25, NHC(.dbd.O)NHR.sub.25,
(CH.sub.2)C(.dbd.O)NHR.sub.25, (CH.sub.2)NHC(.dbd.O)R.sub.25,
(CH.sub.2)NHC(.dbd.O)NHR.sub.25, or C(.dbd.O)R.sub.25.
[0152] In some embodiments of the formulae above, R.sub.11 is
(C.sub.6-C.sub.10) aryl or 5- or 6-membered heteroaryl comprising 1
to 3 heteroatoms selected from N, O, and S, wherein the aryl and
heteroaryl are optionally substituted with one to three
R.sub.17.
[0153] In some embodiments of the formulae above, R.sub.11 is
phenyl or pyridinyl, and is optionally substituted with one to
three R.sub.17.
[0154] In some embodiments of the formulae above, R.sub.1 is
(C.sub.4-C.sub.6) cycloalkyl (e.g., cyclobutyl, cyclopentyl,
cyclohexyl) substituted with one to three R.sub.5.
[0155] In some embodiments of the formulae above, R.sub.1 is
cyclohexyl substituted with one to three R.sub.5.
[0156] In some embodiments of the formulae above, R.sub.1 is 4- to
6-membered heterocyclyl comprising 1 to 3 heteroatoms selected from
N, O, and S optionally substituted with one to three R.sub.5.
[0157] In some embodiments of the formulae above, R.sub.1 is
piperidinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, or
1,4-dioxanyl optionally substituted with one to three R.sub.5.
[0158] In some embodiments of the formulae above, R.sub.1 is
tetrahydropyranyl optionally substituted with one to three
R.sub.5.
[0159] In some embodiments of the formulae above, each R.sub.4 is
independently (C.sub.1-C.sub.4) alkyl, (C.sub.1-C.sub.4) alkoxy
optionally substituted with one or more (C.sub.1-C.sub.4) alkoxy,
halogen, NR.sub.9S(O).sub.pR.sub.10, O(CH.sub.2).sub.nR.sub.11,
NH(CH.sub.2).sub.nR.sub.111, C(.dbd.O)NHR.sub.25,
NHC(.dbd.O)R.sub.25, NHC(.dbd.O)NHR.sub.25,
(CH.sub.2)C(.dbd.O)NHR.sub.25, (CH.sub.2)NHC(.dbd.O)R.sub.25,
(CH.sub.2)NHC(.dbd.O)NHR.sub.25, C(.dbd.O)R.sub.25, or 5- or
6-membered heterocyclyl comprising 1 to 3 heteroatoms selected from
N, O, and S and optionally substituted with one or more
(C.sub.1-C.sub.4) alkyl.
[0160] In some embodiments of the formulae above, each R.sub.4 is
independently (C.sub.1-C.sub.4) alkyl, (C.sub.1-C.sub.4) alkoxy,
halogen, O(CH.sub.2).sub.nR.sub.11, NH(CH.sub.2).sub.nR.sub.11,
C(.dbd.O)NHR.sub.25, NHC(.dbd.O)R.sub.25, NHC(.dbd.O)NHR.sub.25,
(CH.sub.2)C(.dbd.O)NHR.sub.25, (CH.sub.2)NHC(.dbd.O)R.sub.25,
(CH.sub.2)NHC(.dbd.O)NHR.sub.25, C(.dbd.O)R.sub.25, or 5- or
6-membered heterocyclyl comprising 1 to 3 heteroatoms selected from
N, O, and S and optionally substituted with one or more
(C.sub.1-C.sub.4) alkyl.
[0161] In some embodiments of the formulae above, R.sub.1 is
(C.sub.4-C.sub.7) cycloalkyl substituted with one to three
R.sub.5.
[0162] In some embodiments of the formulae above, R.sub.1 is 4- to
7-membered heterocyclyl comprising 1 to 3 heteroatoms selected from
N, O, and S optionally substituted with one to three R.sub.5.
[0163] In some embodiments of the formulae above, R.sub.5 is
C(.dbd.O)R.sub.16 or S(O).sub.pR.sub.16 and R.sub.16 is
(C.sub.2-C.sub.4) alkenyl or (C.sub.2-C.sub.4) alkynyl, wherein the
alkenyl and alkynyl are optionally substituted with one or more
CN.
[0164] In some embodiments of the formulae above, two R.sub.5
together with the atoms to which they are attached form a bridged
3- to 6-membered heterocyclyl ring comprising 1 to 3 heteroatoms
selected from N, O, and S.
[0165] In some embodiments of the formulae above, R.sub.2 is H. In
another embodiment, R.sub.2 is H and R.sub.3 is H. In another
embodiment, R.sub.2 is H, R.sub.3 is H, and A is (C.sub.6-C.sub.10)
aryl optionally substituted with one to two R.sub.4. In another
embodiment, R.sub.2 is H, R.sub.3 is H, and A is (C.sub.6-C.sub.10)
aryl optionally substituted with one to two R.sub.4, and R.sub.1 is
(C.sub.3-C.sub.7) cycloalkyl (e.g., cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, or cycloheptyl) or 4- to 6-membered
heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and
S, wherein the cycloalkyl and heterocyclyl are optionally
substituted with one to three R.sub.5.
[0166] In some embodiments of the formulae above, R.sub.2 is H. In
another embodiment, R.sub.2 is H and R.sub.3 is H. In another
embodiment, R.sub.2 is H, R.sub.3 is H, and A is (C.sub.6-C.sub.10)
aryl substituted with one to two R.sub.4. In another embodiment,
R.sub.2 is H, R.sub.3 is H, and A is (C.sub.6-C.sub.10) aryl
substituted with one to two R.sub.4, and R.sub.1 is
(C.sub.3-C.sub.7) cycloalkyl (e.g., cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, or cycloheptyl) or 4- to 6-membered
heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and
S, wherein the cycloalkyl and heterocyclyl are optionally
substituted with one to three R.sub.5.
[0167] In some embodiments of the formulae above, R.sub.2 is H. In
another embodiment, R.sub.2 is H and R.sub.3 is H. In another
embodiment, R.sub.2 is H, R.sub.3 is H, and A is phenyl optionally
substituted with one to two R.sub.4. In another embodiment, R.sub.2
is H, R.sub.3 is H, and A is phenyl optionally substituted with one
to two R.sub.4, and R.sub.1 is (C.sub.3-C.sub.7) cycloalkyl (e.g.,
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl)
or 4- to 6-membered heterocyclyl comprising 1 to 3 heteroatoms
selected from N, O, and S, wherein the cycloalkyl and heterocyclyl
are optionally substituted with one to three R.sub.5.
[0168] In some embodiments of the formulae above, R.sub.2 is H. In
another embodiment, R.sub.2 is H and R.sub.3 is H. In another
embodiment, R.sub.2 is H, R.sub.3 is H, and A is phenyl substituted
with one to two R.sub.4. In another embodiment, R.sub.2 is H,
R.sub.3 is H, and A is phenyl substituted with one to two R.sub.4,
and R.sub.1 is (C.sub.3-C.sub.7) cycloalkyl (e.g., cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl) or 4- to
6-membered heterocyclyl comprising 1 to 3 heteroatoms selected from
N, O, and S, wherein the cycloalkyl and heterocyclyl are optionally
substituted with one to three R.sub.5.
[0169] In some embodiments of the formulae above, R.sub.2 is H. In
another embodiment, R.sub.2 is H and R.sub.3 is H. In another
embodiment, R.sub.2 is H, R.sub.3 is H, and A is 5- or 6-membered
heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S
and optionally substituted with one to two R.sub.4. In another
embodiment, R.sub.2 is H, R.sub.3 is H, and A is 5- or 6-membered
heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S
and optionally substituted with one to two R.sub.4, and R.sub.1 is
(C.sub.3-C.sub.7) cycloalkyl (e.g., cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, or cycloheptyl) or 4- to 6-membered
heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and
S, wherein the cycloalkyl and heterocyclyl are optionally
substituted with one to three R.sub.5.
[0170] In some embodiments of the formulae above, R.sub.2 is H. In
another embodiment, R.sub.2 is H and R.sub.3 is H. In another
embodiment, R.sub.2 is H, R.sub.3 is H, and A is 5- or 6-membered
heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S
and substituted with one to two R.sub.4. In another embodiment,
R.sub.2 is H, R.sub.3 is H, and A is 5- or 6-membered heteroaryl
comprising 1 to 3 heteroatoms selected from N, O, and S and
substituted with one to two R.sub.4, and R.sub.1 is
(C.sub.3-C.sub.7) cycloalkyl (e.g., cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, or cycloheptyl) or 4- to 6-membered
heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and
S, wherein the cycloalkyl and heterocyclyl are optionally
substituted with one to three R.sub.5.
[0171] In some embodiments of the formulae above, R.sub.2 is H. In
another embodiment, R.sub.2 is H and R.sub.3 is H. In another
embodiment, R.sub.2 is H, R.sub.3 is H, and A is 5-membered
heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S
and optionally substituted with one to two R.sub.4. In another
embodiment, R.sub.2 is H, R.sub.3 is H, and A is 5-membered
heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S
and optionally substituted with one to two R.sub.4, and R.sub.1 is
(C.sub.3-C.sub.7) cycloalkyl (e.g., cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, or cycloheptyl) or 4- to 6-membered
heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and
S, wherein the cycloalkyl and heterocyclyl are optionally
substituted with one to three R.sub.5.
[0172] In some embodiments of the formulae above, R.sub.2 is H. In
another embodiment, R.sub.2 is H and R.sub.3 is H. In another
embodiment, R.sub.2 is H, R.sub.3 is H, and A is 5-membered
heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S
and substituted with one to two R.sub.4. In another embodiment,
R.sub.2 is H, R.sub.3 is H, and A is 5-membered heteroaryl
comprising 1 to 3 heteroatoms selected from N, O, and S and
substituted with one to two R.sub.4, and R.sub.1 is
(C.sub.3-C.sub.7) cycloalkyl (e.g., cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, or cycloheptyl) or 4- to 6-membered
heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and
S, wherein the cycloalkyl and heterocyclyl are optionally
substituted with one to three R.sub.5.
[0173] In some embodiments of the formulae above, R.sub.2 is H. In
another embodiment, R.sub.2 is H and R.sub.3 is H. In another
embodiment, R.sub.2 is H, R.sub.3 is H, and A is 6-membered
heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S
and optionally substituted with one to two R.sub.4. In another
embodiment, R.sub.2 is H, R.sub.3 is H, and A is 6-membered
heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S
and optionally substituted with one to two R.sub.4, and R.sub.1 is
(C.sub.3-C.sub.7) cycloalkyl (e.g., cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, or cycloheptyl) or 4- to 6-membered
heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and
S, wherein the cycloalkyl and heterocyclyl are optionally
substituted with one to three R.sub.5.
[0174] In some embodiments of the formulae above, R.sub.2 is H. In
another embodiment, R.sub.2 is H and R.sub.3 is H. In another
embodiment, R.sub.2 is H, R.sub.3 is H, and A is 6-membered
heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S
and substituted with one to two R.sub.4. In another embodiment,
R.sub.2 is H, R.sub.3 is H, and A is 5- or 6-membered heteroaryl
comprising 1 to 3 heteroatoms selected from N, O, and S and
substituted with one to two R.sub.4, and R.sub.1 is
(C.sub.3-C.sub.7) cycloalkyl (e.g., cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, or cycloheptyl) or 4- to 6-membered
heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and
S, wherein the cycloalkyl and heterocyclyl are optionally
substituted with one to three R.sub.5.
[0175] In some embodiments of the formulae above, R.sub.2 is H. In
another embodiment, R.sub.2 is H and R.sub.3 is H. In another
embodiment, R.sub.2 is H, R.sub.3 is H, and A is pyridinyl
optionally substituted with one to two R.sub.4. In another
embodiment, R.sub.2 is H, R.sub.3 is H, and A is pyridinyl
optionally substituted with one to two R.sub.4, and R.sub.1 is
(C.sub.3-C.sub.7) cycloalkyl (e.g., cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, or cycloheptyl) or 4- to 6-membered
heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and
S, wherein the cycloalkyl and heterocyclyl are optionally
substituted with one to three R.sub.5.
[0176] In some embodiments of the formulae above, R.sub.2 is H. In
another embodiment, R.sub.2 is H and R.sub.3 is H. In another
embodiment, R.sub.2 is H, R.sub.3 is H, and A is pyridinyl
substituted with one to two R.sub.4. In another embodiment, R.sub.2
is H, R.sub.3 is H, and A is pyridinyl substituted with one to two
R.sub.4, and R.sub.1 is (C.sub.3-C.sub.7) cycloalkyl (e.g.,
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl)
or 4- to 6-membered heterocyclyl comprising 1 to 3 heteroatoms
selected from N, O, and S, wherein the cycloalkyl and heterocyclyl
are optionally substituted with one to three R.sub.5.
[0177] In some embodiments of the formulae above, R.sub.2 is H. In
another embodiment, R.sub.2 is H and R.sub.3 is H. In another
embodiment, R.sub.2 is H, R.sub.3 is H, and A is thiophenyl
optionally substituted with one to two R.sub.4. In another
embodiment, R.sub.2 is H, R.sub.3 is H, and A is thiophenyl
optionally substituted with one to two R.sub.4, and R.sub.1 is
(C.sub.3-C.sub.7) cycloalkyl (e.g., cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, or cycloheptyl) or 4- to 6-membered
heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and
S, wherein the cycloalkyl and heterocyclyl are optionally
substituted with one to three R.sub.5.
[0178] In some embodiments of the formulae above, R.sub.2 is H. In
another embodiment, R.sub.2 is H and R.sub.3 is H. In another
embodiment, R.sub.2 is H, R.sub.3 is H, and A is thiophenyl
substituted with one to two R.sub.4. In another embodiment, R.sub.2
is H, R.sub.3 is H, and A is thiophenyl substituted with one to two
R.sub.4, and R.sub.1 is (C.sub.3-C.sub.7) cycloalkyl (e.g.,
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl)
or 4- to 6-membered heterocyclyl comprising 1 to 3 heteroatoms
selected from N, O, and S, wherein the cycloalkyl and heterocyclyl
are optionally substituted with one to three R.sub.5.
[0179] In some embodiments of the formulae above, R.sub.1 is a
heterocycloalkyl selected from:
##STR00013## ##STR00014##
wherein W is O, S, NH, or N(C.sub.1-C.sub.6)alkyl.
[0180] Non-limiting illustrative compounds of the application
include:
TABLE-US-00001 Cmpd No. Structure Chemical name I-1 ##STR00015##
(2-chlorophenyl)(4-((trans-4- hydroxycyclohexyl)amino)-7H-
pyrrolo[2,3-d]pyrimidin-5-yl)methanone I-2 ##STR00016## tert-butyl
(cis-4-((5-(2-chlorobenzoyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-
yl)amino)cyclohexyl)carbamate I-3 ##STR00017## tert-butyl
((1S,3R)-3-((5-(2- chlorobenzoyl)-7H-pyrrolo[2,3- d]pyrimidin-4-
yl)amino)cyclopentyl)carbamate I-4 ##STR00018##
(4-((3-aminocyclohexyl)amino)-7H- pyrrolo[2,3-d]pyrimidin-5-yl)(2-
chlorophenyl)methanone I-5 ##STR00019##
(4-((trans-4-aminocyclohexyl)amino)-
7H-pyrrolo[2,3-d]pyrimidin-5-yl)(2- chlorophenyl)methanone I-6
##STR00020## (4-((cis-4-aminocyclohexyl)amino)-7H-
pyrrolo[2,3-d]pyrimidin-5-yl)(2- chlorophenyl)methanone I-7
##STR00021## (4-(((1R,3S)-3- aminocyclopentyl)amino)-7H-
pyrrolo[2,3-d]pyrimidin-5-yl)(2- chlorophenyl)methanone I-8
##STR00022## N-(trans-4-((5-(2-chlorobenzoyl)-7H-
pyrrolo[2,3-d]pyrimidin-4- yl)amino)cyclohexyl)-2-(1-
methylpiperidin-4-yl)acetamide I-9 ##STR00023##
N-(cis-4-((5-(2-chlorobenzoyl)-7H- pyrrolo[2,3-d]pyrimidin-4-
yl)amino)cyclohexyl)-2-(1- methylpiperidin-4-yl)acetamide I-10
##STR00024## N-((1S,3R)-3-((5-(2-chlorobenzoyl)-7H-
pyrrolo[2,3-d]pyrimidin-4- yl)amino)cyclopentyl)-2-(1-
methylpiperidin-4-yl)acetamide I-11 ##STR00025##
N-(3-((5-(2-chlorobenzoyl)-7H- pyrrolo[2,3-d]pyrimidin-4-
yl)amino)cyclohexyl)-2-(1- methylpiperidin-4-yl)acetamide I-12
##STR00026## tert-butyl (cis-4-((5-(2-methylbenzoyl)-
7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)cyclohexyl)carbamate I-13
##STR00027## (4-(((3R,6S)-6- (hydroxymethyl)tetrahydro-2H-pyran-3-
yl)amino)-7H-pyrrolo[2,3-d]pyrimidin- 5-yl)(o-tolyl)methanone I-14
##STR00028## (4-((cis-4-aminocyclohexyl)amino)-7H-
pyrrolo[2,3-d]pyrimidin-5-yl)(o- tolyl)methanone I-15 ##STR00029##
N-(cis-4-((5-(2-methylbenzoyl)-7H- pyrrolo[2,3-d]pyrimidin-4-
yl)amino)cyclohexyl)-2-(4- methylpiperazin-1-yl)acetamide I-16
##STR00030## (4-((1-methylpiperidin-4-yl)amino)-7H-
pyrrolo[2,3-d]pyrimidin-5-yl)(o- tolyl)methanone I-17 ##STR00031##
tert-butyl 4-((5-(2-methylbenzoyl)-7H- pyrrolo[2,3-d]pyrimidin-4-
yl)amino)piperidine-1-carboxylate I-18 ##STR00032## (4-((cis-4-
(dimethylamino)cyclohexyl)amino)-7H-
pyrrolo[2,3-d]pyrimidin-5-yl)(o- tolyl)methanone I-19 ##STR00033##
methyl trans-4-((5-(2-methylbenzoyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-
yl)amino)cyclohexane-1-carboxylate I-20 ##STR00034##
(4-(((3R,6S)-6-(2-hydroxypropan-2-
yl)tetrahydro-2H-pyran-3-yl)amino)-
7H-pyrrolo[2,3-d]pyrimidin-5-yl)(o- tolyl)methanone I-21
##STR00035## (4-((trans-4-hydroxycyclohexyl)amino)-
7H-pyrrolo[2,3-d]pyrimidin-5-yl)(o- tolyl)methanone I-22
##STR00036## (4-((cis-4-hydroxycyclohexyl)amino)-
7H-pyrrolo[2,3-d]pyrimidin-5-yl)(o- tolyl)methanone I-23
##STR00037## ((2S,5R)-5-((5-(2-methylbenzoyl)-7H-
pyrrolo[2,3-d]pyrimidin-4- yl)amino)tetrahydro-2H-pyran-2-yl)(4-
methylpiperazin-1-yl)methanone I-24 ##STR00038##
(4-(((3R,6S)-6-((R)-1- hydroxyethyl)tetrahydro-2H-pyran-3-
yl)amino)-7H-pyrrolo[2,3-d]pyrimidin- 5-yl)(o-tolyl)methanone I-25
##STR00039## 4-(tert-butyl)-N-(cis-4-((5-(2-
methylbenzoyl)-7H-pyrrolo[2,3- d]pyrimidin-4-
yl)amino)cyclohexyl)benzamide I-26 ##STR00040##
(4-((cis-4-aminocyclohexyl)amino)-7H- pyrrolo[2,3-d]pyrimidin-5-
yl)(phenyl)methanone I-27 ##STR00041## (S)-(4-(((1,4-dioxan-2-
yl)methyl)amino)-7H-pyrrolo[2,3-
d]pyrimidin-5-yl)(o-tolyl)methanone I-28 ##STR00042##
2-(4-(4-(tert-butyl)benzoyl)piperazin-1-
yl)-N-(cis-4-((5-(2-methylbenzoyl)-7H- pyrrolo[2,3-d]pyrimidin-4-
yl)amino)cyclohexyl)acetamide I-29 ##STR00043##
2-(4-benzoylpiperazin-1-yl)-N-(cis-4-
((5-(2-methylbenzoyl)-7H-pyrrolo[2,3- d]pyrimidin-4-
yl)amino)cyclohexyl)acetamide I-30 ##STR00044##
N-(cis-4-((5-(2-methylbenzoyl)-7H- pyrrolo[2,3-d]pyrimidin-4-
yl)amino)cyclohexyl)benzamide I-31 ##STR00045##
(2-chlorophenyl)(4-((cis-4- hydroxycyclohexyl)amino)-7H-
pyrrolo[2,3-d]pyrimidin-5-yl)methanone I-32 ##STR00046##
(2-chlorophenyl)(4-((trans-4- hydroxycyclohexyl)amino)-7H-
pyrrolo[2,3-d]pyrimidin-5-yl)methanone I-33 ##STR00047##
N-(cis-4-((5-(2-methylbenzoyl)-7H- pyrrolo[2,3-d]pyrimidin-4-
yl)amino)cyclohexyl)acetamide I-34 ##STR00048##
(2S,5R)-5-((5-(2-methylbenzoyl)-7H-
pyrrolo[2,3-d]pyrimidin-4-yl)amino)-N- ((tetrahydro-2H-pyran-4-
yl)methyl)tetrahydro-2H-pyran-2- carboxamide I-35 ##STR00049##
tert-butyl ((3R,6S)-6-(((5-(2- methylbenzoyl)-7H-pyrrolo[2,3-
d]pyrimidin-4- yl)amino)methyl)tetrahydro-2H-pyran- 3-yl)carbamate
I-36 ##STR00050## 4-((5-(2-chlorobenzoyl)-7H-pyrrolo[2,3-
d]pyrimidin-4-yl)amino)cyclohexan-1- one I-37 ##STR00051##
(trans-4-((5-(2-methylbenzoyl)-7H- pyrrolo[2,3-d]pyrimidin-4-
yl)amino)cyclohexyl)(4- methylpiperazin-1-yl)methanone I-38
##STR00052## (2-chlorophenyl)(4-(((3R,6S)-6-((R)-1-
hydroxyethyl)tetrahydro-2H-pyran-3-
yl)amino)-7H-pyrrolo[2,3-d]pyrimidin- 5-yl)methanone I-39
##STR00053## (4-((cis-4- (benzylamino)cyclohexyl)amino)-7H-
pyrrolo[2,3-d]pyrimidin-5-yl)(o- tolyl)methanone I-40 ##STR00054##
2-(4-benzylpiperazin-1-yl)-N-(cis-4-((5-
(2-methylbenzoyl)-7H-pyrrolo[2,3- d]pyrimidin-4-
yl)amino)cyclohexyl)acetamide I-41 ##STR00055## (4-((cis-4-
(hydroxymethyl)cyclohexyl)amino)-7H-
pyrrolo[2,3-d]pyrimidin-5-yl)(o- tolyl)methanone I-42 ##STR00056##
(2S,5R)-N-(((S)-1,4-dioxan-2-
yl)methyl)-5-((5-(2-methylbenzoyl)-7H- pyrrolo[2,3-d]pyrimidin-4-
yl)amino)tetrahydro-2H-pyran-2- carboxamide I-43 ##STR00057##
(2-chlorophenyl)(4-((cis-4- (methylamino)cyclohexyl)amino)-7H-
pyrrolo[2,3-d]pyrimidin-5-yl)methanone I-44 ##STR00058##
(2-chlorophenyl)(4-((cis-4- (dimethylamino)cyclohexyl)amino)-7H-
pyrrolo[2,3-d]pyrimidin-5-yl)methanone I-45 ##STR00059##
N-(trans-4-((5-(2-chlorobenzoyl)-7H- pyrrolo[2,3-d]pyrimidin-4-
yl)amino)cyclohexyl)acetamide I-46 ##STR00060##
(4-((((2S,5R)-5-aminotetrahydro-2H- pyran-2-yl)methyl)amino)-7H-
pyrrolo[2,3-d]pyrimidin-5-yl)(o- tolyl)methanone I-47 ##STR00061##
N-(((2S,5R)-5-((5-(2-methylbenzoyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-
yl)amino)tetrahydro-2H-pyran-2- yl)methyl-2-(4-methylpiperazin-1-
yl)acetamide I-48 ##STR00062## (2S,5R)-5-((5-(2-chlorobenzoyl)-7H-
pyrrolo[2,3-d]pyrimidin-4-yl)amino)-N- ((tetrahydro-2H-pyran-4-
yl)methyl)tetrahydro-2H-pyran-2- carboxamide I-49 ##STR00063##
(2-chlorophenyl)(4-(((3R,6S)-6-(2-
hydroxypropan-2-yl)tetrahydro-2H- pyran-3-yl)amino)-7H-pyrrolo[2,3-
d]pyrimidin-5-yl)methanone I-50 ##STR00064##
N-(cis-4-((5-(2-chlorobenzoyl)-7H- pyrrolo[2,3-d]pyrimidin-4-
yl)amino)cyclohexyl)-N- methylacetamide I-51 ##STR00065##
1-(cis-4-((5-(2-chlorobenzoyl)-7H- pyrrolo[2,3-d]pyrimidin-4-
yl)amino)cyclohexyl)pyrrolidin-2-one I-52 ##STR00066##
1-(4-((5-(2-methylbenzoyl)-7H- pyrrolo[2,3-d]pyrimidin-4-
yl)amino)piperidin-1-yl)ethan-1-one I-53 ##STR00067##
2-methoxy-1-(4-((5-(2-methylbenzoyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-
yl)amino)piperidin-1-yl)ethan-1-one I-54 ##STR00068##
3-methoxy-1-(4-((5-(2-methylbenzoyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-
yl)amino)piperidin-1-yl)propan-1-one I-55 ##STR00069##
2-(dimethylamino)-1-(4-((5-(2- methylbenzoyl)-7H-pyrrolo[2,3-
d]pyrimidin-4-yl)amino)piperidin-1- yl)ethan-1-one I-56
##STR00070## (4-((1-(2-methoxyethyl)piperidin-4-
yl)amino)-7H-pyrrolo[2,3-d]pyrimidin- 5-yl)(o-tolyl)methanone I-57
##STR00071## (4-(((4- aminocyclohexyl)methyl)amino)-7H-
pyrrolo[2,3-d]pyrimidin-5-yl)(o- tolyl)methanone I-58 ##STR00072##
(4-((4- (aminomethyl)cyclohexyl)amino)-7H-
pyrrolo[2,3-d]pyrimidin-5-yl)(o- tolyl)methanone I-59 ##STR00073##
(4-((4-((4-(tert- butyl)benzyl)amino)cyclohexyl)amino)-
7H-pyrrolo[2,3-d]pyrimidin-5-yl)(o- tolyl)methanone I-60
##STR00074## (4-((4-((3,5- dichlorobenzyl)amino)cyclohexyl)amino)-
7H-pyrrolo[2,3-d]pyrimidin-5-yl)(o- tolyl)methanone I-61
##STR00075## N-(cis-4-((5-(2-chlorobenzoyl)-7H-
pyrrolo[2,3-d]pyrimidin-4- yl)amino)cyclohexyl)-N-methyl-2-
(tetrahydro-2H-pyran-4-yl)acetamide I-62 ##STR00076##
cis-4-((5-(2-chlorobenzoyl)-7H- pyrrolo[2,3-d]pyrimidin-4-
yl)amino)cyclohexane-1-carboxylic acid I-63 ##STR00077##
cis-4-((5-(2-chlorobenzoyl)-7H- pyrrolo[2,3-d]pyrimidin-4-
yl)amino)cyclohexane-1-carboxamide I-64 ##STR00078##
cis-4-((5-(2-chlorobenzoyl)-7H-
pyrrolo[2,3-d]pyrimidin-4-yl)amino)- N,N-dimethylcyclohexane-1-
carboxamide I-65 ##STR00079## cis-4-((5-(2-chlorobenzoyl)-7H-
pyrrolo[2,3-d]pyrimidin-4-yl)amino)-N-
(tetrahydro-2H-pyran-4-yl)cyclohexane- 1-carboxamide I-66
##STR00080## cis-4-((5-(2-chlorobenzoyl)-7H-
pyrrolo[2,3-d]pyrimidin-4-yl)amino)-N- ((tetrahydro-2H-pyran-4-
yl)methyl)cyclohexane-1-carboxamide I-67 ##STR00081##
cis-4-((5-(2-chlorobenzoyl)-7H-
pyrrolo[2,3-d]pyrimidin-4-yl)amino)-N-
(2-(pyridin-3-yl)ethyl)cyclohexane-1- carboxamide I-68 ##STR00082##
cis-4-((5-(2-chlorobenzoyl)-7H-
pyrrolo[2,3-d]pyrimidin-4-yl)amino)-N-
methylcyclohexane-1-carboxamide I-69 ##STR00083##
(2-chlorophenyl)(4-((cis-4-(pyrrolidin-
1-yl)cyclohexyl)amino)-7H-pyrrolo[2,3- d]pyrimidin-5-yl)methanone
I-70 ##STR00084## (4-((cis-4-(azetidin-1-
yl)cyclohexyl)amino)-7H-pyrrolo[2,3- d]pyrimidin-5-yl)(2-
chlorophenyl)methanone I-71 ##STR00085## (4-((trans-4-(azetidin-1-
yl)cyclohexyl)amino)-7H-pyrrolo[2,3- d]pyrimidin-5-yl)(2-
chlorophenyl)methanone
I-72 ##STR00086## N-(4-(tert-butyl)benzyl)-2-methyl-2-
((cis-4-((5-(2-methylbenzoyl)-7H- pyrrolo[2,3-d]pyrimidin-4-
yl)amino)methyl)cyclohexyl) amino)propanamide I-73 ##STR00087##
N-benzyl-2-methyl-2-((cis-4-(((5-(2- methylbenzoyl)-7H-pyrrolo[2,3-
d]pyrimidin-4- yl)amino)methyl)cyclohexyl) amino)propanamide I-74
##STR00088## N-(cis-4-(((5-(2-methylbenzoyl)-7H-
pyrrolo[2,3-d]pyrimidin-4- yl)amino)methyl)cyclohexyl)benzamide
I-75 ##STR00089## N-((cis-4-((5-(2-methylbenzoyl)-7H-
pyrrolo[2,3-d]pyrimidin-4- yl)amino)cyclohexyl)methyl)benzamide
I-76 ##STR00090## (4-((1S,2S)-2-
(hydroxymethyl)cyclohexyl)amino)-7H-
pyrrolo[2,3-d]pyrimidin-5-yl)(o- tolyl)methanone I-77 ##STR00091##
(4-((1- (hydroxymethyl)cyclopentyl)amino)-
7H-pyrrolo[2,3-d]pyrimidin-5-yl)(o- tolyl)methanone I-78
##STR00092## (cis-4-((5-(2-chlorobenzoyl)-7H-
pyrrolo[2,3-d]pyrimidin-4- yl)amino)cyclohexyl)(morpholino)
methanone I-79 ##STR00093## (cis-4-((5-(2-chlorobenzoyl)-7H-
pyrrolo[2,3-d]pyrimidin-4- yl)amino)cyclohexyl)((2S,6R)-2,6-
dimethylmorpholino)methanone I-80 ##STR00094##
(4-((cis-4-((1R,5S)-8-oxa-3- azabicyclo[3.2.1]octane-3-
carbonyl)cyclohexyl)amino)-7H- pyrrolo[2,3-d]pyrimidin-5-yl)(2-
chlorophenyl)methanone I-81 ##STR00095##
(cis-4-((5-(2-chlorobenzoyl)-7H- pyrrolo[2,3-d]pyrimidin-4-
yl)amino)cyclohexyl)(3- hydroxyazetidin-1-yl)methanone I-82
##STR00096## (cis-4-((5-(2-chlorobenzoyl)-7H-
pyrrolo[2,3-d]pyrimidin-4- yl)amino)cyclohexyl)(4-
methylpiperazin-1-yl)methanone I-83 ##STR00097##
(cis-4-((5-(2-chlorobenzoyl)-7H- pyrrolo[2,3-d]pyrimidin-4-
yl)amino)cyclohexyl)((3S,5R)-3,5- dimethylpiperazin-1-yl)methanone
I-84 ##STR00098## N-(trans-4-((5-(2-chlorobenzoyl)-7H-
pyrrolo[2,3-d]pyrimidin-4- yl)amino)cyclohexyl)acetamide I-85
##STR00099## (S)-N-(cis-4-((5-(2-chlorobenzoyl)-7H-
pyrrolo[2,3-d]pyrimidin-4- yl)amino)cyclohexyl)-2-
hydroxypropanamide I-86 ##STR00100##
(R)-N-(cis-4-((5-(2-chlorobenzoyl)-7H- pyrrolo[2,3-d]pyrimidin-4-
yl)amino)cyclohexyl)-2- hydroxypropanamide I-87 ##STR00101##
N-(cis-4-((5-(2-chlorobenzoyl)-7H- pyrrolo[2,3-d]pyrimidin-4-
yl)amino)cyclohexyl)-2- methoxyacetamide I-88 ##STR00102##
(2-chlorophenyl)(4-((cis-4-(3- hydroxyazetidin-1-
yl)cyclohexyl)amino)-7H-pyrrolo[2,3- d]pyrimidin-5-yl)methanone
I-89 ##STR00103## (2-chlorophenyl)(4-((trans-4-(3-
hydroxyazetidin-1- yl)cyclohexyl)amino)-7H-pyrrolo[2,3-
d]pyrimidin-5-yl)methanone I-90 ##STR00104## methyl
(2S,5R)-5-((5-(2- methylbenzoyl)-7H-pyrrolo[2,3-
d]pyrimidin-4-yl)amino)tetrahydro-2H- pyran-2-carboxylate I-91
##STR00105## (2S,5R)-5-((5-(2-chlorobenzoyl)-7H-
pyrrolo[2,3-d]pyrimidin-4- yl)amino)tetrahydro-2H-pyran-2-
carboxamide I-92 ##STR00106## N-(cis-4-((5-(2-chlorobenzoyl)-7H-
pyrrolo[2,3-d]pyrimidin-4- yl)amino)cyclohexyl)propionamide I-93
##STR00107## N-(cis-4-((5-(2-chlorobenzoyl)-7H-
pyrrolo[2,3-d]pyrimidin-4- yl)amino)cyclohexyl)isobutyramide I-94
##STR00108## N-(cis-4-((5-(2-chlorobenzoyl)-7H-
pyrrolo[2,3-d]pyrimidin-4- yl)amino)cyclohexyl)
cyclopropanecarboxamide I-95 ##STR00109## 4-methyl-N-(cis-4-((5-(2-
methylbenzoyl)-7H-pyrrolo[2,3- d]pyrimidin-4-
yl)amino)cyclohexyl)benzamide I-96 ##STR00110##
3-methyl-N-(cis-4-((5-(2- methylbenzoyl)-7H-pyrrolo[2,3-
d]pyrimidin-4- yl)amino)cyclohexyl)benzamide I-97 ##STR00111##
2-methyl-N-(cis-4-((5-(2- methylbenzoyl)-7H-pyrrolo[2,3-
d]pyrimidin-4- yl)amino)cyclohexyl)benzamide I-98 ##STR00112##
(S)-N-(cis-4-((5-(2-chlorobenzoyl)-7H- pyrrolo[2,3-d]pyrimidin-4-
yl)amino)cyclohexyl)-2- methoxypropanamide I-99 ##STR00113##
(R)-N-(cis-4-((5-(2-chlorobenzoyl)-7H- pyrrolo[2,3-d]pyrimidin-4-
yl)amino)cyclohexyl)-2- methoxypropanamide I-100 ##STR00114##
(S)-N-(cis-4-((5-(2-chlorobenzoyl)-7H- pyrrolo[2,3-d]pyrimidin-4-
yl)amino)cyclohexyl)tetrahydrofuran-2- carboxamide I-101
##STR00115## (R)-N-(cis-4-((5-(2-chlorobenzoyl)-7H-
pyrrolo[2,3-d]pyrimidin-4- yl)amino)cyclohexyl)tetrahydrofuran-2-
carboxamide I-102 ##STR00116## N-(cis-4-((5-(2-chlorobenzoyl)-7H-
pyrrolo[2,3-d]pyrimidin-4- yl)amino)cyclohexyl)-1-
hydroxycyclopropane-1-carboxamide I-103 ##STR00117##
(2-chlorophenyl)(4-((cis-4-hydroxy-4- methylcyclohexyl)amino)-7H-
pyrrolo[2,3-d]pyrimidin-5-yl)methanone I-104 ##STR00118##
(2-chlorophenyl)(4-((trans-4-hydroxy-4- methylcyclohexyl)amino)-7H-
pyrrolo[2,3-d]pyrimidin-5-yl)methanone I-105 ##STR00119##
trans-4-((5-(2-methylbenzoyl)-7H- pyrrolo[2,3-d]pyrimidin-4-
yl)amino)cyclohexane-1-carboxamide I-106 ##STR00120##
(S)-N-(cis-4-((5-(2-chlorobenzoyl)-7H- pyrrolo[2,3-d]pyrimidin-4-
yl)amino)cyclohexyl)-2-hydroxy-N- methylpropanamide I-107
##STR00121## (2-chlorophenyl)(4-((trans-4-hydroxy-4-
(methoxymethyl)cyclohexyl)amino)- 7H-pyrrolo[2,3-d]pyrimidin-5-
yl)methanone I-108 ##STR00122##
(2-chlorophenyl)(4-((cis-4-hydroxy-4-
(methoxymethyl)cyclohexyl)amino)- 7H-pyrrolo[2,3-d]pyrimidin-5-
yl)methanone I-109 ##STR00123## (2-chlorophenyl)(4-((cis-4-(3-
methoxyazetidin-1- yl)cyclohexyl)amino)-7H-pyrrolo[2,3-
d]pyrimidin-5-yl)methanone I-110 ##STR00124##
(2-chlorophenyl)(4-((trans-4-(3- methoxyazetidin-1-
yl)cyclohexyl)amino)-7H-pyrrolo[2,3- d]pyrimidin-5-yl)methanone
I-111 ##STR00125## (2-chlorophenyl)(4-((cis-4-(3-hydroxy-
3-methylazetidin-1- yl)cyclohexyl)amino)-7H-pyrrolo[2,3-
d]pyrimidin-5-yl)methanone I-112 ##STR00126##
(2-chlorophenyl)(4-((trans-4-(3- hydroxy-3-methylazetidin-1-
yl)cyclohexyl)amino)-7H-pyrrolo[2,3- d]pyrimidin-5-yl)methanone
I-113 ##STR00127## (4-((cis-4-(3-amino-3-methylazetidin-1-
yl)cyclohexyl)amino)-7H-pyrrolo[2,3- d]pyrimidin-5-yl)(2-
chlorophenyl)methanone I-114 ##STR00128##
(4-((trans-4-(3-amino-3-methylazetidin-
1-yl)cyclohexyl)amino)-7H-pyrrolo[2,3- d]pyrimidin-5-yl)(2-
chlorophenyl)methanone I-115 ##STR00129##
N-(cis-4-((5-(2-chlorobenzoyl)-7H- pyrrolo[2,3-d]pyrimidin-4-
yl)amino)cyclohexyl)-2-hydroxy-2- methylpropanamide I-116
##STR00130## N-((S)-1-((2S,5R)-5-((5-(2-
chlorobenzoyl)-7H-pyrrolo[2,3-
d]pyrimidin-4-yl)amino)tetrahydro-2H- pyran-2-yl)ethyl)acetamide
I-117 ##STR00131## N-((S)-1-((2S,5R)-5-((5-(2-
methylbenzoyl)-7H-pyrrolo[2,3-
d]pyrimidin-4-yl)amino)tetrahydro-2H- pyran-2-yl)ethyl)acetamide
I-118 ##STR00132## N-(((2S,5R)-5-((5-(2-chlorobenzoyl)-
7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)tetrahydro-2H-pyran-2-
yl)methyl)acetamide I-119 ##STR00133##
N-(((2S,5R)-5-((5-(2-methylbenzoyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-
yl)amino)tetrahydro-2H-pyran-2- yl)methyl)acetamide I-120
##STR00134## N-(3-(4-((cis-4- aminocyclohexyl)amino)-7H-
pyrrolo[2,3-d]pyrimidine-5- carbonyl)phenyl)methanesulfonamide
I-121 ##STR00135## N-(3-(4-((cis-4- aminocyclohexyl)amino)-7H-
pyrrolo[2,3-d]pyrimidine-5- carbonyl)phenyl)benzenesulfonamide
I-122 ##STR00136## N-((S)-1-((2S,5R)-5-((5-(2-chloro-4-
phenoxybenzoyl)-7H-pyrrolo[2,3-
d]pyrimidin-4-yl)amino)tetrahydro-2H- pyran-2-yl)ethyl)acetamide
I-124 ##STR00137## (2-chloro-4-phenoxyphenyl)(4-
(((3S,6R)-6-(hydroxymethyl)tetrahydro-
2H-pyran-3-yl)amino)-7H-pyrrolo[2,3- d]pyrimidin-5-yl)methanone
I-125 ##STR00138## (2-chloro-4-phenoxyphenyl)(4-
(((3R,6R)-6-(hydroxymethyl)tetrahydro-
2H-pyran-3-yl)amino)-7H-pyrrolo[2,3- d]pyrimidin-5-yl)methanone
I-126 ##STR00139## (2-chloro-4-phenoxyphenyl)(4-
(((3S,6S)-6-(hydroxymethyl)tetrahydro-
2H-pyran-3-yl)amino)-7H-pyrrolo[2,3- d]pyrimidin-5-yl)methanone
I-127 ##STR00140## N-(((2S,5R)-5-((5-(2-chloro-4-
phenoxybenzoyl)-7H-pyrrolo[2,3-
d]pyrimidin-4-yl)amino)tetrahydro-2H- pyran-2-yl)methyl)acetamide
I-128 ##STR00141## 2-(4-methylpiperazin-1-yl)-N-(cis-4-((5-
(3-methylthiophene-2-carbonyl)-7H- pyrrolo[2,3-d]pyrimidin-4-
yl)amino)cyclohexyl)acetamide I-129 ##STR00142##
(4-((4-methylcyclohexyl)amino)-7H- pyrrolo[2,3-d]pyrimidin-5-yl)(3-
methylthiophen-2-yl)methanone I-130 ##STR00143##
(4-((cis-4-aminocyclohexyl)amino)-7H-
pyrrolo[2,3-d]pyrimidin-5-yl)(4- phenoxyphenyl)methanone I-131
##STR00144## (4-((cis-4-aminocyclohexyl)amino)-7H-
pyrrolo[2,3-d]pyrimidin-5-yl)(3- phenoxyphenyl)methanone I-132
##STR00145## 2-(4-methylpiperazin-1-yl)-N-(cis-4-((5-
(2-methylthiophene-3-carbonyl)-7H- pyrrolo[2,3-d]pyrimidin-4-
yl)amino)cyclohexyl)acetamide I-133 ##STR00146## tert-butyl
(cis-4-((5-(3- methoxybenzoyl)-7H-pyrrolo[2,3- d]pyrimidin-4-
yl)amino)cyclohexyl)carbamate I-134 ##STR00147## tert-butyl
(cis-4-((5-(5-methoxy-2- methylbenzoyl)-7H-pyrrolo[2,3-
d]pyrimidin-4- yl)amino)cyclohexyl)carbamate I-135 ##STR00148##
(4-((cis-4-aminocyclohexyl)amino)-7H-
pyrrolo[2,3-d]pyrimidin-5-yl)(3- methoxyphenyl)methanone I-136
##STR00149## (4-((cis-4-aminocyclohexyl)amino)-7H-
pyrrolo[2,3-d]pyrimidin-5-yl)(5- methoxy-2-methylphenyl)methanone
I-137 ##STR00150## (4-((cis-4-aminocyclohexyl)amino)-7H-
pyrrolo[2,3-d]pyrimidin-5-yl)(2-chloro- 5-methoxyphenyl)methanone
I-138 ##STR00151## (4-((cis-4-aminocyclohexyl)amino)-7H-
pyrrolo[2,3-d]pyrimidin-5-yl)(4-fluoro- 3-methoxyphenyl)methanone
I-139 ##STR00152## N-(cis-4-((5-(4-phenoxybenzoyl)-7H-
pyrrolo[2,3-d]pyrimidin-4- yl)amino)cyclohexyl)acetamide I-140
##STR00153## N-(cis-4-((5-(3-phenoxybenzoyl)-7H-
pyrrolo[2,3-d]pyrimidin-4- yl)amino)cyclohexyl)acetamide I-141
##STR00154## (4-((cis-4-aminocyclohexyl)amino)-7H-
pyrrolo[2,3-d]pyrimidin-5-yl)(2-chloro- 4-phenoxyphenyl)methanone
I-142 ##STR00155## (4-(((3R,6S)-6-((R)-1-
hydroxyethyl)tetrahydro-2H-pyran-3-
yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-
5-yl)(4-phenoxyphenyl)methanone I-143 ##STR00156##
(4-((cis-4-aminocyclohexyl)amino)-7H-
pyrrolo[2,3-d]pyrimidin-5-yl)(4-(2- methoxyethoxy)phenyl)methanone
I-144 ##STR00157## rac-(4-((cis-6-
(hydroxymethyl)tetrahydro-2H-pyran-3-
yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-
5-yl)(4-phenoxyphenyl)methanone
I-145 ##STR00158## rac-(4-((trans-6-
(hydroxymethyl)tetrahydro-2H-pyran-3-
yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-
5-yl)(4-phenoxyphenyl)methanone I-146 ##STR00159## (4-(((3R,6S)-6-
(hydroxymethyl)tetrahydro-2H-pyran-3-
yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-
5-yl)(4-phenoxyphenyl)methanone I-147 ##STR00160##
(4-(((3R,6S)-6-(2-hydroxypropan-2-
yl)tetrahydro-2H-pyran-3-yl)amino)-
7H-pyrrolo[2,3-d]pyrimidin-5-yl)(4- phenoxyphenyl)methanone I-148
##STR00161## (4-((cis-4-aminocyclohexyl)amino)-7H-
pyrrolo[2,3-d]pyrimidin-5-yl)(4-(3- fluorophenoxy)phenyl)methanone
I-149 ##STR00162## (4-(((3R,6S)-6-((R)-1-
hydroxyethyl)tetrahydro-2H-pyran-3-
yl)amino)-7H-pyrrolo[2,3-d]pyrimidin- 5-yl)(4-(pyridin-3-
yloxy)phenyl)methanone I-150 ##STR00163##
(2-chloro-4-phenoxyphenyl)(4- (((3R,6S)-6-((R)-1-
hydroxyethyl)tetrahydro-2H-pyran-3-
yl)amino)-7H-pyrrolo[2,3-d]pyrimidin- 5-yl)methanone I-151
##STR00164## N-(cis-4-((5-(2-chloro-4-
phenoxybenzoyl)-7H-pyrrolo[2,3- d]pyrimidin-4-
yl)amino)cyclohexyl)acetamide I-152 ##STR00165##
N-(cis-4-((5-(4-(4- fluorophenoxy)benzoyl)-7H-
pyrrolo[2,3-d]pyrimidin-4- yl)amino)cyclohexyl)acetamide I-153
##STR00166## N-(cis-4-((5-(4-(3-
(trifluoromethyl)phenoxy)benzoyl)-7H- pyrrolo[2,3-d]pyrimidin-4-
yl)amino)cyclohexyl)acetamide I-154 ##STR00167##
(4-((cis-4-aminocyclohexyl)amino)-7H-
pyrrolo[2,3-d]pyrimidin-5-yl)(4- (benzyloxy)phenyl)methanone I-155
##STR00168## rac-(4-phenoxyphenyl)(4-((tetrahydro-
2H-pyran-3-yl)amino)-7H-pyrrolo[2,3- d]pyrimidin-5-yl)methanone
I-156 ##STR00169## (4-phenoxyphenyl)(4-((tetrahydro-2H-
pyran-4-yl)amino)-7H-pyrrolo[2,3- d]pyrimidin-5-yl)methanone I-157
##STR00170## (2S,5R)-5-((5-(4-phenoxybenzoyl)-7H-
pyrrolo[2,3-d]pyrimidin-4- yl)amino)tetrahydro-2H-pyran-2-
carboxamide I-158 ##STR00171## (4-((trans-4-(1,3,4-oxadiazol-2-
yl)cyclohexyl)amino)-7H-pyrrolo[2,3- d]pyrimidin-5-yl)(4-
phenoxyphenyl)methanone I-159 ##STR00172##
(4-((trans-4-(5-methyl-1,3,4-oxadiazol-
2-yl)cyclohexyl)amino)-7H-pyrrolo[2,3- d]pyrimidin-5-yl)(4-
phenoxyphenyl)methanone I-160 ##STR00173## (4-(((3R,6S)-6-((S)-1-
hydroxyethyl)tetrahydro-2H-pyran-3-
yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-
5-yl)(4-phenoxyphenyl)methanone I-161 ##STR00174##
N-(cis-4-((5-(4-(4- chlorophenoxy)benzoyl)-7H-
pyrrolo[2,3-d]pyrimidin-4- yl)amino)cyclohexyl)acetamide I-162
##STR00175## N-(cis-4-((5-(4-(p-tolyloxy)benzoyl)-
7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)cyclohexyl)acetamide I-163
##STR00176## N-(cis-4-((5-(4-(cyclohex-2-en-1-
yloxy)benzoyl)-7H-pyrrolo[2,3- d]pyrimidin-4-
yl)amino)cyclohexyl)acetamide I-164 ##STR00177##
N-(cis-4-((5-(2-chloro-6- phenoxynicotinoyl)-7H-pyrrolo[2,3-
d]pyrimidin-4- yl)amino)cyclohexyl)acetamide I-165 ##STR00178##
(4-((trans-4- (hydroxymethyl)cyclohexyl)amino)-7H-
pyrrolo[2,3-d]pyrimidin-5-yl)(4- phenoxyphenyl)methanone I-166
##STR00179## (4-(((3R,6S)-6-((S)-1-
aminoethyl)tetrahydro-2H-pyran-3-
yl)amino)-7H-pyrrolo[2,3-d]pyrimidin- 5-yl)(2-chloro-4-
phenoxyphenyl)methanone I-167 ##STR00180##
(2-chloro-4-phenoxyphenyl)(4- (((3R,6S)-6-((S)-1-
(dimethylamino)ethyl)tetrahydro-2H-
pyran-3-yl)amino)-7H-pyrrolo[2,3- d]pyrimidin-5-yl)methanone I-168
##STR00181## (4-((trans-4-hydroxycyclohexyl)amino)-
7H-pyrrolo[2,3-d]pyrimidin-5-yl)(4- phenoxyphenyl)methanone I-169
##STR00182## (2-chloro-4-phenoxyphenyl)(4-((trans-
4-hydroxycyclohexyl)amino)-7H-
pyrrolo[2,3-d]pyrimidin-5-yl)methanone I-170 ##STR00183##
2-(dimethylamino)-N-(cis-4-((5-(4- phenoxybenzoyl)-7H-pyrrolo[2,3-
d]pyrimidin-4- yl)amino)cyclohexyl)acetamide I-171 ##STR00184##
(4-(((3R,6S)-6-((R)-1- hydroxyethyl)tetrahydro-2H-pyran-3-
yl)amino)-7H-pyrrolo[2,3-d]pyrimidin- 5-yl)(4-(pyridin-2-
yloxy)phenyl)methanone I-172 ##STR00185## (4-((6-chloropyridin-2-
yl)oxy)phenyl)(4-(((3R,6S)-6-((R)-1-
hydroxyethyl)tetrahydro-2H-pyran-3-
yl)amino)-7H-pyrrolo[2,3-d]pyrimidin- 5-yl)methanone I-173
##STR00186## (R)-(2-chloro-4-phenoxyphenyl)(4-
((tetrahydrofuran-3-yl)amino)-7H-
pyrrolo[2,3-d]pyrimidin-5-yl)methanone I-174 ##STR00187##
(S)-(2-chloro-4-phenoxyphenyl)(4- ((tetrahydrofuran-3-yl)amino)-7H-
pyrrolo[2,3-d]pyrimidin-5-yl)methanone I-175 ##STR00188##
(2S,5R)-N-((2R,3R)-1,3- dihydroxybutan-2-yl)-5-((5-(4-
phenoxybenzoyl)-7H-pyrrolo[2,3-
d]pyrimidin-4-yl)amino)tetrahydro-2H- pyran-2-carboxamide I-176
##STR00189## (2S,5R)-N-((R)-2,3-dihydroxypropyl)-5-
((5-(4-phenoxybenzoyl)-7H- pyrrolo[2,3-d]pyrimidin-4-
yl)amino)tetrahydro-2H-pyran-2- carboxamide I-177 ##STR00190##
(2-chloro-4-phenoxyphenyl)(4-((trans- 4-((dimethylamino)methyl)-4-
hydroxycyclohexyl)amino)-7H- pyrrolo[2,3-d]pyrimidin-5-yl)methanone
I-178 ##STR00191## (2-chloro-4-phenoxyphenyl)(4-((cis-4-
((dimethylamino)methyl)-4- hydroxycyclohexyl)amino)-7H-
pyrrolo[2,3-d]pyrimidin-5-yl)methanone I-179 ##STR00192##
rac-(2-chloro-4-phenoxyphenyl)(4- (((1S,3S,4R)-3,4-
dihydroxycyclohexyl)amino)-7H-
pyrrolo[2,3-d]pyrimidin-5-yl)methanone I-180 ##STR00193##
rac-(2-chloro-4-phenoxyphenyl)(4- (((1S,3R,4S)-3,4-
dihydroxycyclohexyl)amino)-7H-
pyrrolo[2,3-d]pyrimidin-5-yl)methanone I-181 ##STR00194##
N-(cis-4-((5-(2-chloro-4- phenoxybenzoyl)-7H-pyrrolo[2,3-
d]pyrimidin-4-yl)amino)cyclohexyl)-2- (dimethylamino)acetamide
I-182 ##STR00195## (2-chloro-4-(3-
fluorophenoxy)phenyl)(4-(((3R,6S)-6-
((R)-1-hydroxyethyl)tetrahydro-2H-
pyran-3-yl)amino)-7H-pyrrolo[2,3- d]pyrimidin-5-yl)methanone I-183
##STR00196## (2-chloro-4-(3- chlorophenoxy)phenyl)(4-(((3R,6S)-6-
((R)-1-hydroxyethyl)tetrahydro-2H-
pyran-3-yl)amino)-7H-pyrrolo[2,3- d]pyrimidin-5-yl)methanone I-184
##STR00197## tert-butyl ((1S,3S)-3-((5-(4-
phenoxybenzoyl)-7H-pyrrolo[2,3- d]pyrimidin-4-
yl)amino)cyclopentyl)carbamate I-185 ##STR00198## tert-butyl
(trans-3-((5-(4- phenoxybenzoyl)-7H-pyrrolo[2,3- d]pyrimidin-4-
yl)amino)cyclobutyl)carbamate I-186 ##STR00199## tert-butyl
(cis-3-((5-(4- phenoxybenzoyl)-7H-pyrrolo[2,3- d]pyrimidin-4-
yl)amino)cyclobutyl)carbamate I-187 ##STR00200## (4-((trans-3-
(hydroxymethyl)cyclobutyl)amino)-7H-
pyrrolo[2,3-d]pyrimidin-5-yl)(4- phenoxyphenyl)methanone I-188
##STR00201## (2-chloro-4-phenoxyphenyl)(4-
(((3R,6S)-6-(2-hydroxypropan-2- yl)tetrahydro-2H-pyran-3-yl)amino)-
7H-pyrrolo[2,3-d]pyrimidin-5- yl)methanone I-189 ##STR00202##
(4-(((1R,3R)-3- aminocyclopentyl)amino)-7H-
pyrrolo[2,3-d]pyrimidin-5-yl)(4- phenoxyphenyl)methanone I-190
##STR00203## (4-((cis-3-aminocyclobutyl)amino)-7H-
pyrrolo[2,3-d]pyrimidin-5-yl)(4- phenoxyphenyl)methanone I-191
##STR00204## (4-((trans-3 -aminocyclobutyl)amino)-
7H-pyrrolo[2,3-d]pyrimidin-5-yl)(4- phenoxyphenyl)methanone I-192
##STR00205## N-((1R,3R)-3-((5-(4-phenoxybenzoyl)-
7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)cyclopentyl)acetamide I-193
##STR00206## (S)-N-(cis-4-((5-(2-chloro-4-
phenoxybenzoyl)-7H-pyrrolo[2,3-
d]pyrimidin-4-yl)amino)cyclohexyl)-2- hydroxypropanamide I-194
##STR00207## N-(cis-4-((5-(2-chloro-4-
phenoxybenzoyl)-7H-pyrrolo[2,3-
d]pyrimidin-4-yl)amino)cyclohexyl)-2- hydroxy-2-methylpropanamide
I-195 ##STR00208## N-((R)-1-((2S,5R)-5-((5-(2-chloro-4-
phenoxybenzoyl)-7H-pyrrolo[2,3- pyrimidin-4-yl)amino)tetrahydro-2H-
pyran-2-yl)ethyl)acetamide I-196 ##STR00209##
N-(cis-3-((5-(4-phenoxybenzoyl)-7H- pyrrolo[2,3-d]pyrimidin-4-
yl)amino)cyclobutyl)acetamide I-197 ##STR00210##
(4-(((3R,6S)-6-((R)-1- hydroxyethyl)tetrahydro-2H-pyran-3-
yl)amino)-7H-pyrrolo[2,3-d]pyrimidin- 5-yl)(2-methyl-4-
phenoxyphenyl)methanone I-198 ##STR00211##
N-((S)-1-((2S,5R)-5-((5-(4- phenoxybenzoyl)-7H-pyrrolo[2,3-
d]pyrimidin-4-yl)amino)tetrahydro-2H- pyran-2-yl)ethyl)acetamide
I-199 ##STR00212## N-(trans-3-((5-(4-phenoxybenzoyl)-7H-
pyrrolo[2,3-d]pyrimidin-4- yl)amino)cyclobutyl)acetamide I-200
##STR00213## (2-chloro-4-phenoxyphenyl)(4-((cis-4-
hydroxy-4-methylcyclohexyl)amino)- 7H-pyrrolo[2,3-d]pyrimidin-5-
yl)methanone I-201 ##STR00214##
(2-chloro-4-phenoxyphenyl)(4-((trans-
4-hydroxy-4-methylcyclohexyl)amino)- 7H-pyrrolo[2,3-d]pyrimidin-5-
yl)methanone I-202 ##STR00215## (S)-2-hydroxy-N-(cis-4-((5-(4-
phenoxybenzoyl)-7H-pyrrolo[2,3- d]pyrimidin-4-
yl)amino)cyclohexyl)propanamide I-203 ##STR00216##
2-hydroxy-2-methyl-N-(cis-4-((5-(4- phenoxybenzoyl)-7H-pyrrolo[2,3-
d]pyrimidin-4- yl)amino)cyclohexyl)propanamide I-204 ##STR00217##
N-((S)-1-((2S,5R)-5-((5-(2-methyl-4-
phenoxybenzoyl)-7H-pyrrolo[2,3-
d]pyrimidin-4-yl)amino)tetrahydro-2H- pyran-2-yl)ethyl)acetamide
I-205 ##STR00218## N-(((2S,5R)-5-((5-(4-phenoxybenzoyl)-
7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)tetrahydro-2H-pyran-2-
yl)methyl)acetamide I-206 ##STR00219##
(R)-2-hydroxy-N-(cis-4-((5-(4- phenoxybenzoyl)-7H-pyrrolo[2,3-
d]pyrimidin-4- yl)amino)cyclohexyl)propanamide I-207 ##STR00220##
(2-chloro-4-phenoxyphenyl)(4-((trans-
3-(hydroxymethyl)cyclobutyl)amino)- 7H-pyrrolo[2,3-d]pyrimidin-5-
yl)methanone I-208 ##STR00221##
(S)-N-((S)-1-((2S,5R)-5-((5-(2-chloro-4-
phenoxybenzoyl)-7H-pyrrolo[2,3-
d]pyrimidin-4-yl)amino)tetrahydro-2H- pyran-2-yl)ethyl)-2-
hydroxypropanamide I-209 ##STR00222##
(S)-2-hydroxy-N-((S)-1-((2S,5R)-5-((5-
(4-phenoxybenzoyl)-7H-pyrrolo[2,3-
d]pyrimidin-4-yl)amino)tetrahydro-2H- pyran-2-yl)ethyl)propanamide
I-210 ##STR00223## (S)-N-(((2S,5R)-5-((5-(2-chloro-4-
phenoxybenzoyl)-7H-pyrrolo[2,3-
d]pyrimidin-4-yl)amino)tetrahydro-2H- pyran-2-yl)methyl)-2-
hydroxypropanamide I-211 ##STR00224##
(S)-2-hydroxy-N-(((2S,5R)-5-((5-(4- phenoxybenzoyl)-7H-pyrrolo[2,3-
d]pyrimidin-4-yl)amino)tetrahydro-2H- pyran-2-yl)methyl)propanamide
I-212 ##STR00225## rac-N-(cis-4-((5-(2-chloro-4-
phenoxybenzoyl)-7H-pyrrolo[2,3-
d]pyrimidin-4-yl)amino)cyclohexyl)-6- hydroxyheptanamide I-213
##STR00226## (R)-N-((S)-1-((2S,5R)-5-((5-(2-chloro-4-
phenoxybenzoyl)-7H-pyrrolo[2,3-
d]pyrimidin-4-yl)amino)tetrahydro-2H- pyran-2-yl)ethyl)-2-
hydroxypropanamide I-214 ##STR00227## rac-N-(cis-4-((5-(2-chloro-4-
phenoxybenzoyl)-7H-pyrrolo[2,3-
d]pyrimidin-4-yl)amino)cyclohexyl)-7- hydroxyoctanamide I-215
##STR00228## (R)-2-hydroxy-N-((S)-1-((2S,5R)-5-((5-
(4-phenoxybenzoyl)-7H-pyrrolo[2,3-
d]pyrimidin-4-yl)amino)tetrahydro-2H- pyran-2-yl)ethyl)propanamide
I-216 ##STR00229## (R)-N-(((2S,5R)-5-((5-(2-chloro-4-
phenoxybenzoyl)-7H-pyrrolo[2,3-
d]pyrimidin-4-yl)amino)tetrahydro-2H- pyran-2-yl)methyl)-2-
hydroxypropanamide I-217 ##STR00230##
(R)-2-hydroxy-N-(((2S,5R)-5-((5-(4- phenoxybenzoyl)-7H-pyrrolo[2,3-
d]pyrimidin-4-yl)amino)tetrahydro-2H- pyran-2-yl)methyl)propanamide
I-218 ##STR00231## (4-((cis-4-aminocyclohexyl)amino)-2-
((1-methylpiperidin-4-yl)amino)-7H-
pyrrolo[2,3-d]pyrimidin-5-yl)(o- tolyl)methanone I-219 ##STR00232##
(2-amino-4-(cis-4- aminocyclohexyl)amino)-7H-
pyrrolo[2,3-d]pyrimidin-5-yl)(o- tolyl)methanone I-220 ##STR00233##
(4-((cis-4-aminocyclohexyl)amino)-2- (methylamino)-7H-pyrrolo[2,3-
d]pyrimidin-5-yl)(o-tolyl)methanone I-221 ##STR00234##
(4-((cis-4-aminocyclohexyl)amino)-2- (4-methylpiperazin-1-yl)-7H-
pyrrolo[2,3-d]pyrimidin-5-yl)(o- tolyl)methanone I-222 ##STR00235##
N-(cis-4-((5-(2-chlorobenzoyl)-7H- pyrrolo[2,3-d]pyrimidin-4-
yl)amino)cyclohexyl)-2-(4- methylpiperazin-1-yl)acetamide I-223
##STR00236## rac-(4-(3-aminopyrrolidin-1-yl)-7H-
pyrrolo[2,3-d]pyrimidin-5- yl)(phenyl)methanone I-224 ##STR00237##
rac-N-(1-(5-benzoyl-7H-pyrrolo[2,3-
d]pyrimidin-4-yl)pyrrolidin-3-yl)-2-
(tetrahydro-2H-pyran-4-yl)acetamide I-225 ##STR00238##
rac-N-(1-(5-benzoyl-7H-pyrrolo[2,3-
d]pyrimidin-4-yl)pyrrolidin-3-yl)-3- methoxypropanamide I-226
##STR00239## rac-tert-butyl 3-((5-benzoyl-7H-
pyrrolo[2,3-d]pyrimidin-4- yl)amino)pyrrolidine-1-carboxylate I-227
##STR00240## rac-phenyl(4-(pyrrolidin-3-ylamino)-
7H-pyrrolo[2,3-d]pyrimidin-5- yl)methanone I-228 ##STR00241##
rac-1-(3-((5-benzoyl-7H-pyrrolo[2,3-
d]pyrimidin-4-yl)amino)pyrrolidin-1-
yl)-2-(tetrahydro-2H-pyran-4-yl)ethan- 1-one I-229 ##STR00242##
rac-1-(3-((5-benzoyl-7H-pyrrolo[2,3-
d]pyrimidin-4-yl)amino)pyrrolidin-1- yl)-3-methoxypropan-1-one
I-230 ##STR00243## 1-(3-((5-benzoyl-7H-pyrrolo[2,3- d]pyrimidin-4-
yl)amino)propyl)pyrrolidin-2-one
[0181] In another embodiment, non-limiting examples of compounds of
the invention include:
TABLE-US-00002 Cmpd No. Structure Chemical name I-231 ##STR00244##
4-(4-(((3R,6S)-6- (hydroxymethyl)tetrahydro-2H-pyran-3-
yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-
5-carbonyl)-N-phenylbenzamide I-232 ##STR00245##
4-(4-((6-(hydroxymethyl)tetrahydro-2H-
pyran-3-yl)amino)-7H-pyrrolo[2,3- d]pyrimidine-5-carbonyl)-N-
phenylbenzamide I-233 ##STR00246## 4-(4-(((3S,6R)-6-
(hydroxymethyl)tetrahydro-2H-pyran-3-
yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-
5-carbonyl)-N-phenylbenzamide I-234 ##STR00247## 4-(4-(((3S,6S)-6-
(hydroxymethyl)tetrahydro-2H-pyran-3-
yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-
5-carbonyl)-N-phenylbenzamide I-235 ##STR00248## 4-(4-(((3R,6R)-6-
(hydroxymethyl)tetrahydro-2H-pyran-3-
yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-
5-carbonyl)-N-phenylbenzamide I-236 ##STR00249##
3-chloro-4-(4-(((3R,6S)-6- (hydroxymethyl)tetrahydro-2H-pyran-3-
yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-
5-carbonyl)-N-phenylbenzamide I-237 ##STR00250## 3-chloro-4-(4-((6-
(hydroxymethyl)tetrahydro-2H-pyran-3-
yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-
5-carbonyl)-N-phenylbenzamide I-238 ##STR00251##
3-chloro-4-(4-(((3S,6R)-6- (hydroxymethyl)tetrahydro-2H-pyran-3-
yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-
5-carbonyl)-N-phenylbenzamide I-239 ##STR00252##
3-chloro-4-(4-(((3S,6S)-6- (hydroxymethyl)tetrahydro-2H-pyran-3-
yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-
5-carbonyl)-N-phenylbenzamide I-240 ##STR00253##
3-chloro-4-(4-(((3R,6R)-6- (hydroxymethyl)tetrahydro-2H-pyran-3-
yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-
5-carbonyl)-N-phenylbenzamide I-241 ##STR00254## 4-(4-(((3R,6S)-6-
(hydroxymethyl)tetrahydro-2H-pyran-3-
yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-
5-carbonyl)-N-(pyridin-4-yl)benzamide I-242 ##STR00255##
4-(4-((6-(hydroxymethyl)tetrahydro-2H-
pyran-3-yl)amino)-7H-pyrrolo[2,3-
d]pyrimidine-5-carbonyl)-N-(pyridin-4- yl)benzamide I-243
##STR00256## 4-(4-(((3S,6R)-6-
(hydroxymethyl)tetrahydro-2H-pyran-3-
yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-
5-carbonyl)-N-(pyridin-4-yl)benzamide I-244 ##STR00257##
4-(4-(((3S,6S)-6- (hydroxymethyl)tetrahydro-2H-pyran-3-
yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-
5-carbonyl)-N-(pyridin-4-yl)benzamide I-245 ##STR00258##
4-(4-(((3R,6R)-6- (hydroxymethyl)tetrahydro-2H-pyran-3-
yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-
5-carbonyl)-N-(pyridin-4-yl)benzamide I-246 ##STR00259##
3-chloro-4-(4-(((3R,6S)-6- (hydroxymethyl)tetrahydro-2H-pyran-3-
yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-
5-carbonyl)-N-(pyridin-4-yl)benzamide I-247 ##STR00260##
3-chloro-4-(4-((6- (hydroxymethyl)tetrahydro-2H-pyran-3-
yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-
5-carbonyl)-N-(pyridin-4-yl)benzamide I-248 ##STR00261##
3-chloro-4-(4-(((3S,6R)-6- (hydroxymethyl)tetrahydro-2H-pyran-3-
yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-
5-carbonyl)-N-(pyridin-4-yl)benzamide I-249 ##STR00262##
3-chloro-4-(4-(((3S,6S)-6- (hydroxymethyl)tetrahydro-2H-pyran-3-
yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-
5-carbonyl)-N-(pyridin-4-yl)benzamide I-250 ##STR00263##
3-chloro-4-(4-(((3R,6R)-6- (hydroxymethyl)tetrahydro-2H-pyran-3-
yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-
5-carbonyl)-N-(pyridin-4-yl)benzamide I-251 ##STR00264##
4-(4-(((3R,6S)-6- (hydroxymethyl)tetrahydro-2H-pyran-3-
yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-
5-carbonyl)-N-(pyridin-3-yl)benzamide I-252 ##STR00265##
4-(4-((6-(hydroxymethyl)tetrahydro-2H-
pyran-3-yl)amino)-7H-pyrrolo[2,3-
d]pyrimidine-5-carbonyl)-N-(pyridin-3- yl)benzamide I-253
##STR00266## 4-(4-(((3S,6R)-6-
(hydroxymethyl)tetrahydro-2H-pyran-3-
yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-
5-carbonyl)-N-(pyridin-3-yl)benzamide I-254 ##STR00267##
4-(4-(((3S,6S)-6- (hydroxymethyl)tetrahydro-2H-pyran-3-
yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-
5-carbonyl)-N-(pyridin-3-yl)benzamide I-255 ##STR00268##
4-(4-(((3R,6R)-6- (hydroxymethyl)tetrahydro-2H-pyran-3-
yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-
5-carbonyl)-N-(pyridin-3-yl)benzamide I-256 ##STR00269##
3-chloro-4-(4-(((3R,6S)-6- (hydroxymethyl)tetrahydro-2H-pyran-3-
yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-
5-carbonyl)-N-(pyridin-3-yl)benzamide I-257 ##STR00270##
3-chloro-4-(4-((6- (hydroxymethyl)tetrahydro-2H-pyran-3-
yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-
5-carbonyl)-N-(pyridin-3-yl)benzamide I-258 ##STR00271##
3-chloro-4-(4-(((3S,6R)-6- (hydroxymethyl)tetrahydro-2H-pyran-3-
yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-
5-carbonyl)-N-(pyridin-3-yl)benzamide I-259 ##STR00272##
3-chloro-4-(4-(((3S,6S)-6- (hydroxymethyl)tetrahydro-2H-pyran-3-
yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-
5-carbonyl)-N-(pyridin-3-yl)benzamide I-260 ##STR00273##
3-chloro-4-(4-(((3R,6R)-6- (hydroxymethyl)tetrahydro-2H-pyran-3-
yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-
5-carbonyl)-N-(pyridin-3-yl)benzamide I-261 ##STR00274##
4-(4-(((3R,6S)-6- (hydroxymethyl)tetrahydro-2H-pyran-3-
yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-
5-carbonyl)-N-(pyridin-2-yl)benzamide I-262 ##STR00275##
4-(4-((6-(hydroxymethyl)tetrahydro-2H-
pyran-3-yl)amino)-7H-pyrrolo[2,3-
d]pyrimidine-5-carbonyl)-N-(pyridin-2- yl)benzamide I-263
##STR00276## 4-(4-(((3S,6R)-6-
(hydroxymethyl)tetrahydro-2H-pyran-3-
yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-
5-carbonyl)-N-(pyridin-2-yl)benzamide I-264 ##STR00277##
4-(4-(((3S,6S)-6- (hydroxymethyl)tetrahydro-2H-pyran-3-
yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-
5-carbonyl)-N-(pyridin-2-yl)benzamide I-265 ##STR00278##
4-(4-(((3R,6R)-6- (hydroxymethyl)tetrahydro-2H-pyran-3-
yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-
5-carbonyl)-N-(pyridin-2-yl)benzamide I-266 ##STR00279##
3-chloro-4-(4-(((3R,6S)-6- (hydroxymethyl)tetrahydro-2H-pyran-3-
yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-
5-carbonyl)-N-(pyridin-2-yl)benzamide I-267 ##STR00280##
3-chloro-4-(4-((6- (hydroxymethyl)tetrahydro-2H-pyran-3-
yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-
5-carbonyl)-N-(pyridin-2-yl)benzamide I-268 ##STR00281##
3-chloro-4-(4-(((3S,6R)-6- (hydroxymethyl)tetrahydro-2H-pyran-3-
yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-
5-carbonyl)-N-(pyridin-2-yl)benzamide I-269 ##STR00282##
3-chloro-4-(4-(((3S,6S)-6- (hydroxymethyl)tetrahydro-2H-pyran-3-
yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-
5-carbonyl)-N-(pyridin-2-yl)benzamide I-270 ##STR00283##
3-chloro-4-(4-((3R,6R)-6- (hydroxymethyl)tetrahydro-2H-pyran-3-
yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-
5-carbonyl)-N-(pyridin-2-yl)benzamide I-271 ##STR00284##
N-(4-(4-(((3R,6S)-6- (hydroxymethyl)tetrahydro-2H-pyran-3-
yl)amino)-7H-pyrrolo[2,3-d]pyrimidine- 5-carbonyl)phenyl)benzamide
I-272 ##STR00285## N-(4-(4-((6-(hydroxymethyl)tetrahydro-
2H-pyran-3-yl)amino)-7H-pyrrolo[2,3- d]pyrimidine-5-
carbonyl)phenyl)benzamide I-273 ##STR00286## N-(4-(4-(((3S,6R)-6-
(hydroxymethyl)tetrahydro-2H-pyran-3-
yl)amino)-7H-pyrrolo[2,3-d]pyrimidine- 5-carbonyl)phenyl)benzamide
I-274 ##STR00287## N-(4-(4-(((3S,6S)-6-
(hydroxymethyl)tetrahydro-2H-pyran-3-
yl)amino)-7H-pyrrolo[2,3-d]pyrimidine- 5-carbonyl)phenyl)benzamide
I-275 ##STR00288## N-(4-(4-(((3R,6R)-6-
(hydroxymethyl)tetrahydro-2H-pyran-3-
yl)amino)-7H-pyrrolo[2,3-d]pyrimidine- 5-carbonyl)phenyl)benzamide
I-276 ##STR00289## N-(3-chloro-4-(4-(((3R,6S)-6-
(hydroxymethyl)tetrahydro-2H-pyran-3-
yl)amino)-7H-pyrrolo[2,3-d]pyrimidine- 5-carbonyl)phenyl)benzamide
I-277 ##STR00290## N-(3-chloro-4-(4-((6-
(hydroxymethyl)tetrahydro-2H-pyran-3-
yl)amino)-7H-pyrrolo[2,3-d]pyrimidine- 5-carbonyl)phenyl)benzamide
I-278 ##STR00291## N-(3-chloro-4-(4-(((3S,6R)-6-
(hydroxymethyl)tetrahydro-2H-pyran-3-
yl)amino)-7H-pyrrolo[2,3-d]pyrimidine- 5-carbonyl)phenyl)benzamide
I-279 ##STR00292## N-(3-chloro-4-(4-(((3S,6S)-6-
(hydroxymethyl)tetrahydro-2H-pyran-3-
yl)amino)-7H-pyrrolo[2,3-d]pyrimidine- 5-carbonyl)phenyl)benzamide
I-280 ##STR00293## N-(3-chloro-4-(4-(((3R,6R)-6-
(hydroxymethyl)tetrahydro-2H-pyran-3-
yl)amino)-7H-pyrrolo[2,3-d]pyrimidine- 5-carbonyl)phenyl)benzamide
I-281 ##STR00294## N-(4-(4-(((3R,6S)-6-
(hydroxymethyl)tetrahydro-2H-pyran-3-
yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-
5-carbonyl)phenyl)isonicotinamide I-282 ##STR00295##
N-(4-(4-((6-(hydroxymethyl)tetrahydro-
2H-pyran-3-yl)amino)-7H-pyrrolo[2,3- d]pyrimidine-5-
carbonyl)phenyl)isonicotinamide I-283 ##STR00296##
N-(4-(4-(((3S,6R)-6- (hydroxymethyl)tetrahydro-2H-pyran-3-
yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-
5-carbonyl)phenyl)isonicotinamide I-284 ##STR00297##
N-(4-(4-(((3S,6S)-6- (hydroxymethyl)tetrahydro-2H-pyran-3-
yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-
5-carbonyl)phenyl)isonicotinamide I-285 ##STR00298##
N-(4-(4-(((3R,6R)-6- (hydroxymethyl)tetrahydro-2H-pyran-3-
yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-
5-carbonyl)phenyl)isonicotinamide
I-286 ##STR00299## N-(3-chloro-4-(4-(((3R,6S)-6-
(hydroxymethyl)tetrahydro-2H-pyran-3-
yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-
5-carbonyl)phenyl)isonicotinamide I-287 ##STR00300##
N-(3-chloro-4-(4-((6- (hydroxymethyl)tetrahydro-2H-pyran-3-
yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-
5-carbonyl)phenyl)isonicotinamide I-288 ##STR00301##
N-(3-chloro-4-(4-(((3S,6R)-6- (hydroxymethyl)tetrahydro-2H-pyran-3-
yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-
5-carbonyl)phenyl)isonicotinamide I-289 ##STR00302##
N-(3-chloro-4-(4-(((3S,6S)-6- (hydroxymethyl)tetrahydro-2H-pyran-3-
yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-
5-carbonyl)phenyl)isonicotinamide I-290 ##STR00303##
N-(3-chloro-4-(4-(((3R,6R)-6- (hydroxymethyl)tetrahydro-2H-pyran-3-
yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-
5-carbonyl)phenyl)isonicotinamide I-291 ##STR00304##
N-(4-(4-(((3R,6S)-6- (hydroxymethyl)tetrahydro-2H-pyran-3-
yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-
5-carbonyl)phenyl)nicotinamide I-292 ##STR00305##
N-(4-(4-((6-(hydroxymethyl)tetrahydro-
2H-pyran-3-yl)amino)-7H-pyrrolo[2,3- d]pyrimidine-5-
carbonyl)phenyl)nicotinamide I-293 ##STR00306##
N-(4-(4-(((3S,6R)-6- (hydroxymethyl)tetrahydro-2H-pyran-3-
yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-
5-carbonyl)phenyl)nicotinamide I-294 ##STR00307##
N-(4-(4-(((3S,6S)-6- (hydroxymethyl)tetrahydro-2H-pyran-3-
yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-
5-carbonyl)phenyl)nicotinamide I-295 ##STR00308##
N-(4-(4-(((3R,6R)-6- (hydroxymethyl)tetrahydro-2H-pyran-3-
yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-
5-carbonyl)phenyl)nicotinamide I-296 ##STR00309##
N-(3-chloro-4-(4-(((3R,6S)-6- (hydroxymethyl)tetrahydro-2H-pyran-3-
yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-
5-carbonyl)phenyl)nicotinamide I-297 ##STR00310##
N-(3-chloro-4-(4-((6- (hydroxymethyl)tetrahydro-2H-pyran-3-
yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-
5-carbonyl)phenyl)nicotinamide I-298 ##STR00311##
N-(3-chloro-4-(4-(((3S,6R)-6- (hydroxymethyl)tetrahydro-2H-pyran-3-
yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-
5-carbonyl)phenyl)nicotinamide I-299 ##STR00312##
N-(3-chloro-4-(4-(((3S,6S)-6- (hydroxymethyl)tetrahydro-2H-pyran-3-
yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-
5-carbonyl)phenyl)nicotinamide I-300 ##STR00313##
N-(3-chloro-4-(4-(((3R,6R)-6- (hydroxymethyl)tetrahydro-2H-pyran-3-
yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-
5-carbonyl)phenyl)nicotinamide I-301 ##STR00314##
N-(4-(4-(((3R,6S)-6- (hydroxymethyl)tetrahydro-2H-pyran-3-
yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-
5-carbonyl)phenyl)picolinamide I-302 ##STR00315##
N-(4-(4-((6-(hydroxymethyl)tetrahydro-
2H-pyran-3-yl)amino)-7H-pyrrolo[2,3- d]pyrimidine-5-
carbonyl)phenyl)picolinamide I-303 ##STR00316##
N-(4-(4-(((3S,6R)-6- (hydroxymethyl)tetrahydro-2H-pyran-3-
yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-
5-carbonyl)phenyl)picolinamide I-304 ##STR00317##
N-(4-(4-(((3S,6S)-6- (hydroxymethyl)tetrahydro-2H-pyran-3-
yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-
5-carbonyl)phenyl)picolinamide I-305 ##STR00318##
N-(4-(4-(((3R,6R)-6- (hydroxymethyl)tetrahydro-2H-pyran-3-
yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-
5-carbonyl)phenyl)picolinamide I-306 ##STR00319##
N-(3-chloro-4-(4-(((3R,6S)-6- (hydroxymethyl)tetrahydro-2H-pyran-3-
yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-
5-carbonyl)phenyl)picolinamide I-307 ##STR00320##
N-(3-chloro-4-(4-((6- (hydroxymethyl)tetrahydro-2H-pyran-3-
yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-
5-carbonyl)phenyl)picolinamide I-308 ##STR00321##
N-(3-chloro-4-(4-(((3S,6R)-6- (hydroxymethyl)tetrahydro-2H-pyran-3-
yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-
5-carbonyl)phenyl)picolinamide I-309 ##STR00322##
N-(3-chloro-4-(4-(((3S,6S)-6- (hydroxymethyl)tetrahydro-2H-pyran-3-
yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-
5-carbonyl)phenyl)picolinamide I-310 ##STR00323##
N-(3-chloro-4-(4-(((3R,6R)-6- (hydroxymethyl)tetrahydro-2H-pyran-3-
yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-
5-carbonyl)phenyl)picolinamide I-311 ##STR00324##
(2-chloro-4-morpholinophenyl)(4-
(((3S,6S)-6-(hydroxymethyl)tetrahydro-
2H-pyran-3-yl)amino)-7H-pyrrolo[2,3- d]pyrimidin-5-yl)methanone
I-311i ##STR00325## (2-chloro-4-morpholinophenyl)(4-
(((3R,6S)-6-(hydroxymethyl)tetrahydro-
2H-pyran-3-yl)amino)-7H-pyrrolo[2,3- d]pyrimidin-5-yl)methanone
I-312 ##STR00326## (4-(((3S,6S)-6-
(hydroxymethyl)tetrahydro-2H-pyran-3-
yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-
5-yl)(4-morpholinophenyl)methanone I-313 ##STR00327##
(2-chloro-4-(4-methylpiperazin-1- yl)phenyl)(4-(((3S,6S)-6-
(hydroxymethyl)tetrahydro-2H-pyran-3-
yl)amino)-7H-pyrrolo[2,3-d]pyrimidin- 5-yl)methanone I-314
##STR00328## (4-(((3S,6S)-6- (hydroxymethyl)tetrahydro-2H-pyran-3-
yl)amino)-7H-pyrrolo[2,3-d]pyrimidin- 5-yl)(4-(4-methylpiperazin-1-
yl)phenyl)methanone I-315 ##STR00329##
(4-(4-butylpiperazin-1-yl)-2- chlorophenyl)(4-(((3S,6S)-6-
(hydroxymethyl)tetrahydro-2H-pyran-3-
yl)amino)-7H-pyrrolo[2,3-d]pyrimidin- 5-yl)methanone I-316
##STR00330## (4-(4-butylpiperazin-1-yl)phenyl)(4-
(((3S,6S)-6-(hydroxymethyl)tetrahydro-
2H-pyran-3-yl)amino)-7H-pyrrolo[2,3- d]pyrimidin-5-yl)methanone
I-317 ##STR00331## (2-chloro-4-(2-
methoxyethoxy)phenyl)(4-(((3S,6S)-6-
(hydroxymethyl)tetrahydro-2H-pyran-3-
yl)amino)-7H-pyrrolo[2,3-d]pyrimidin- 5-yl)methanone I-317i
##STR00332## 2-chloro-4-(2- methoxyethoxy)phenyl)(4-(((3R,6S)-6-
(hydroxymethyl)tetrahydro-2H-pyran-3-
yl)amino)-7H-pyrrolo[2,3-d]pyrimidin- 5-yl)methanone I-318
##STR00333## (4-(((3S,6S)-6- (hydroxymethyl)tetrahydro-2H-pyran-3-
yl)amino)-7H-pyrrolo[2,3-d]pyrimidin- 5-yl)(4-(2-
methoxyethoxy)phenyl)methanone I-318i ##STR00334## (4-(((3R,6S)-6-
(hydroxymethyl)tetrahydro-2H-pyran-3-
yl)amino)-7H-pyrrolo[2,3-d]pyrimidin- 5-yl)(4-(2-
methoxyethoxy)phenyl)methanone I-319 ##STR00335##
6-(3-chloro-4-(4-(((3R,6S)-6- (hydroxymethyl)tetrahydro-2H-pyran-3-
yl)amino)-7H-pyrrolo[2,3-d]pyrimidine- 5-carbonyl)phenoxy)-N-
methylpicolinamide I-320 ##STR00336## 6-(4-(4-(((3R,6S)-6-
(hydroxymethyl)tetrahydro-2H-pyran-3-
yl)amino)-7H-pyrrolo[2,3-d]pyrimidine- 5-carbonyl)phenoxy)-N-
methylpicolinamide I-321 ##STR00337##
1-(3-((5-(2-chloro-4-phenoxybenzoyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-
yl)amino)piperidin-1-yl)prop-2-en-1- one I-321r ##STR00338##
(racemic)-1-(3-((5-(2-chloro-4- phenoxybenzoyl)-7H-pyrrolo[2,3-
d]pyrimidin-4-yl)amino)piperidin-1- yl)prop-2-en-1-one I-322
##STR00339## (2-chloro-4-phenoxyphenyl)(4-((1-
(vinylsulfonyl)piperidin-3-yl)amino)- 7H-pyrrolo[2,3-d]pyrimidin-5-
yl)methanone I-322r ##STR00340## (racemic)-(2-chloro-4-
phenoxyphenyl)(4-((1- (vinylsulfonyl)piperidin-3-yl)amino)-
7H-pyrrolo[2,3-d]pyrimidin-5- yl)methanone I-323 ##STR00341##
(E)-2-(3-((5-(2-chloro-4- phenoxybenzoyl)-7H-pyrrolo[2,3-
d]pyrimidin-4-yl)amino)piperidine-1- carbonyl)but-2-enenitrile
I-324 ##STR00342## 1-(3-((5-(2-chloro-4-phenoxybenzoyl)-
7H-pyrrolo[2,3-d]pyrimidin-4-
yl)amino)piperidin-1-yl)but-2-yn-1-one I-324r ##STR00343##
(racemic)-1-(3-((5-(2-chloro-4- phenoxybenzoyl)-7H-pyrrolo[2,3-
d]pyrimidin-4-yl)amino)piperidin-1- yl)but-2-yn-1-one I-325
##STR00344## 1-(2-(((5-(2-chloro-4-phenoxybenzoyl)-
7H-pyrrolo[2,3-d]pyrimidin-4-
yl)amino)methyl)pyrrolidin-1-yl)prop-2- en-1-one I-325r
##STR00345## (racemic)-1-(2-(((5-(2-chloro-4-
phenoxybenzoyl)-7H-pyrrolo[2,3- d]pyrimidin-4-
yl)amino)methyl)pyrrolidin-1-yl)prop-2- en-1-one I-326 ##STR00346##
(2-chloro-4-phenoxyphenyl)(4-(((1- (vinylsulfonyl)pyrrolidin-2-
yl)methyl)amino)-7H-pyrrolo[2,3- d]pyrimidin-5-yl)methanone I-326r
##STR00347## (racemic)-(2-chloro-4- phenoxyphenyl)(4-(((1-
(vinylsulfonyl)pyrrolidin-2- yl)methyl)amino)-7H-pyrrolo[2,3-
d]pyrimidin-5-yl)methanone I-327 ##STR00348##
(E)-2-(2-(((5-(2-chloro-4- phenoxybenzoyl)-7H-pyrrolo[2,3-
d]pyrimidin-4- yl)amino)methyl)pyrrolidine-1-
carbonyl)but-2-enenitrile I-328 ##STR00349##
1-(2-(((5-(2-chloro-4-phenoxybenzoyl)-
7H-pyrrolo[2,3-d]pyrimidin-4-
yl)amino)methyl)pyrrolidin-1-yl)but-2- yn-1-one I-328r ##STR00350##
(racemic)-1-(2-(((5-(2-chloro-4- phenoxybenzoyl)-7H-pyrrolo[2,3-
d]pyrimidin-4- yl)amino)methyl)pyrrolidin-1-yl)but-2- yn-1-one
I-329 ##STR00351## (2-chloro-4-phenoxyphenyl)(4-((5-
(hydroxymethyl)-7- oxabicyclo[2.2.1]heptan-2-yl)amino)-
7H-pyrrolo[2,3-d]pyrimidin-5- yl)methanone I-330 ##STR00352##
(2-chloro-4-phenoxyphenyl)(4-((5- (hydroxymethyl)-7-
oxabicyclo[2.2.1]heptan-2-yl)amino)- 7H-pyrrolo[2,3-d]pyrimidin-5-
yl)methanone I-331 ##STR00353## (2-chloro-4-phenoxyphenyl)(4-((1-
(hydroxymethyl)-2- oxabicyclo[2.2.2]octan-4-yl)amino)-7H-
pyrrolo[2,3-d]pyrimidin-5-yl)methanone I-332 ##STR00354##
(2-chloro-4-phenoxyphenyl)(4-((6- (hydroxymethyl)quinuclidin-3-
yl)amino)-7H-pyrrolo[2,3-d]pyrimidin- 5-yl)methanone I-333
##STR00355## (2-chloro-4-phenoxyphenyl)(4-((7-
(hydroxymethyl)oxepan-3-yl)amino)- 7H-pyrrolo[2,3-d]pyrimidin-5-
yl)methanone I-334 ##STR00356## (2-chloro-4-phenoxyphenyl)(4-((6-
(hydroxymethyl)tetrahydro-2H- thiopyran-3-yl)amino)-7H-pyrrolo[2,3-
d]pyrimidin-5-yl)methanone I-335 ##STR00357##
(2-chloro-4-phenoxyphenyl)(4-((5- (hydroxymethyl)tetrahydrofuran-3-
yl)amino)-7H-pyrrolo[2,3-d]pyrimidin- 5-yl)methanone I-336
##STR00358## (2-chloro-4-phenoxyphenyl)(4-((2-
(hydroxymethyl)oxetan-3-yl)amino)- 7H-pyrrolo[2,3-d]pyrimidin-5-
yl)methanone I-337 ##STR00359## (2-chloro-4-phenoxyphenyl)(4-((1-
ethyl-6-(hydroxymethyl)piperidin-3-
yl)amino)-7H-pyrrolo[2,3-d]pyrimidin- 5-yl)methanone I-338
##STR00360## (2-chloro-4-phenoxyphenyl)(4-((1-
ethyl-6-(1-hydroxyethyl)piperidin-3-
yl)amino)-7H-pyrrolo[2,3-d]pyrimidin- 5-yl)methanone I-339
##STR00361## (2-chloro-4-phenoxyphenyl)(4-((1-
ethyl-5-(hydroxymethyl)pyrrolidin-3-
yl)amino)-7H-pyrrolo[2,3-d]pyrimidin- 5-yl)methanone I-340
##STR00362## (2-chloro-4-phenoxyphenyl)(4-((6-
(hydroxymethyl)-1-methylpiperidin-3-
yl)amino)-7H-pyrrolo[2,3-d]pyrimidin- 5-yl)methanone I-341
##STR00363## (2-chloro-4-phenoxyphenyl)(4-((6-(1-
hydroxyethyl)-1-methylpiperidin-3-
yl)amino)-7H-pyrrolo[2,3-d]pyrimidin- 5-yl)methanone I-342
##STR00364## (2-chloro-4-phenoxyphenyl)(4-((5-
(hydroxymethyl)-1-methylpyrrolidin-3-
yl)amino)-7H-pyrrolo[2,3-d]pyrimidin- 5-yl)methanone I-342e
##STR00365## (2-chloro-4-phenoxyphenyl)(4-
(((3R,5S)-5-(hydroxymethyl)-1- methylpyrrolidin-3-yl)amino)-7H-
pyrrolo[2,3-d]pyrimidin-5-yl)methanone I-343 ##STR00366##
(2-chloro-4-phenoxyphenyl)(4-((6-
(hydroxymethyl)piperidin-3-yl)amino)- 7H-pyrrolo[2,3-d]pyrimidin-5-
yl)methanone I-343r ##STR00367## (racemic)-(2-chloro-4-
phenoxyphenyl)(4-((6- (hydroxymethyl)piperidin-3-yl)amino)-
7H-pyrrolo[2,3-d]pyrimidin-5- yl)methanone I-344 ##STR00368##
(2-chloro-4-phenoxyphenyl)(4-((6-(1-
hydroxyethyl)piperidin-3-yl)amino)-7H-
pyrrolo[2,3-d]pyrimidin-5-yl)methanone I-345 ##STR00369##
(2-chloro-4-phenoxyphenyl)(4-((5-
(hydroxymethyl)pyrrolidin-3-yl)amino)-
7H-pyrrolo[2,3-d]pyrimidin-5- yl)methanone I-345e ##STR00370##
(2-chloro-4-phenoxyphenyl)(4-
(((3R,5S)-5-(hydroxymethyl)pyrrolidin- 3-yl)amino)-7H-pyrrolo[2,3-
d]pyrimidin-5-yl)methanone I-346 ##STR00371##
(2-chloro-4-phenoxyphenyl)(4-((6-(1-
hydroxyethyl)tetrahydro-2H-thiopyran- 3-yl)amino)-7H-pyrrolo[2,3-
d]pyrimidin-5-yl)methanone I-347 ##STR00372##
(2-chloro-4-phenoxyphenyl)(4-((6- (hydroxymethyl)tetrahydro-2H-
thiopyran-3-yl)amino)-7H-pyrrolo[2,3- d]pyrimidin-5-yl)methanone
I-348 ##STR00373## (2-chloro-4-phenoxyphenyl)(4-((6-(1-
hydroxyethyl)tetrahydro-2H-pyran-3-
yl)amino)-7H-pyrrolo[2,3-d]pyrimidin- 5-yl)methanone I-349
##STR00374## (2-chloro-4-phenoxyphenyl)(4-((6-
(hydroxymethyl)tetrahydro-2H-pyran-3-
yl)amino)-7H-pyrrolo[2,3-d]pyrimidin- 5-yl)methanone I-350
##STR00375## (2-chloro-4-phenoxyphenyl)(4-((5-
(hydroxymethyl)tetrahydrofuran-3-
yl)amino)-7H-pyrrolo[2,3-d]pyrimidin- 5-yl)methanone I-351
##STR00376## (2-chloro-4-phenoxyphenyl)(4-((5-
(hydroxymethyl)tetrahydrothiophen-3-
yl)amino)-7H-pyrrolo[2,3-d]pyrimidin- 5-yl)methanone I-352
##STR00377## (2-chloro-4-phenoxyphenyl)(4-((5-
(hydroxymethyl)tetrahydrofuran-2-
yl)amino)-7H-pyrrolo[2,3-d]pyrimidin- 5-yl)methanone I-353
##STR00378## (2-chloro-4-phenoxyphenyl)(4-((5-
(hydroxymethyl)tetrahydrothiophen-2-
yl)amino)-7H-pyrrolo[2,3-d]pyrimidin- 5-yl)methanone I-354
##STR00379## (2-chloro-4-phenoxyphenyl)(4-((5-
(hydroxymethyl)pyrrolidin-2-yl)amino)-
7H-pyrrolo[2,3-d]pyrimidin-5- yl)methanone I-355 ##STR00380##
(2-chloro-4-phenoxyphenyl)(4-((5-
(hydroxymethyl)-1-methylpyrrolidin-2-
yl)amino)-7H-pyrrolo[2,3-d]pyrimidin- 5-yl)methanone I-356
##STR00381## (2-chloro-4-phenoxyphenyl)(7-ethyl-4-
((5-(hydroxymethyl)pyrrolidin-2-
yl)amino)-7H-pyrrolo[2,3-d]pyrimidin- 5-yl)methanone I-357
##STR00382## (2-chloro-4-phenoxyphenyl)(4-(((6-
(hydroxymethyl)tetrahydro-2H-pyran-2-
yl)methyl)amino)-7H-pyrrolo[2,3- d]pyrimidin-5-yl)methanone I-358
##STR00383## (2-chloro-4-phenoxyphenyl)(4-(((6-
(hydroxymethyl)tetrahydro-2H- thiopyran-2-yl)methyl)amino)-7H-
pyrrolo[2,3-d]pyrimidin-5-yl)methanone I-359 ##STR00384##
(2-chloro-4-phenoxyphenyl)(4-(((6- (hydroxymethyl)piperidin-2-
yl)methyl)amino)-7H-pyrrolo[2,3- d]pyrimidin-5-yl)methanone I-359e
##STR00385## racemic-cis-(2-chloro-4-
phenoxyphenyl)(4-(((6-(hydroxymethyl)
piperidin-2-yl)methyl)amino)-7H-
pyrrolo[2,3-d]pyrimidin-5-yl)methanone I-360 ##STR00386##
(2-chloro-4-phenoxyphenyl)(4-(((6-
(hydroxymethyl)-1-methylpiperidin-2-
yl)methyl)amino)-7H-pyrrolo[2,3- d]pyrimidin-5-yl)methanone I-360e
##STR00387## racemic-cis-(2-chloro-4- phenoxyphenyl)(4-(((6-
(hydroxymethyl)-1-methylpiperidin-2-
yl)methyl)amino)-7H-pyrrolo[2,3- d]pyrimidin-5-yl)methanone I-361
##STR00388## (2-chloro-4-phenoxyphenyl)(4-(((1-
ethyl-6-(hydroxymethyl)piperidin-2-
yl)methyl)amino)-7H-pyrrolo[2,3- d]pyrimidin-5-yl)methanone I-362
##STR00389## (2-chloro-4-phenoxyphenyl)(4-(((5-
(hydroxymethyl)tetrahydrofuran-2- yl)methyl)amino)-7H-pyrrolo[2,3-
d]pyrimidin-5-yl)methanone I-362e ##STR00390##
(2-chloro-4-phenoxyphenyl)(4- ((((2R,5S)-5-
(hydroxymethyl)tetrahydrofuran-2- yl)methyl)amino)-7H-pyrrolo[2,3-
d]pyrimidin-5-yl)methanone I-363 ##STR00391##
(2-chloro-4-phenoxyphenyl)(4-(((5-
(hydroxymethyl)tetrahydrofuran-3- yl)methyl)amino)-7H-pyrrolo[2,3-
d]pyrimidin-5-yl)methanone I-364 ##STR00392##
(2-chloro-4-phenoxyphenyl)(4-(((5-
(hydroxymethyl)tetrahydrothiophen-2-
yl)methyl)amino)-7H-pyrrolo[2,3- d]pyrimidin-5-yl)methanone I-365
##STR00393## (2-chloro-4-phenoxyphenyl)(4-(((5-
(hydroxymethyl)tetrahydrothiophen-3-
yl)methyl)amino)-7H-pyrrolo[2,3- d]pyrimidin-5-yl)methanone I-366
##STR00394## (2-chloro-4-phenoxyphenyl)(4-(((5-
(hydroxymethyl)pyrrolidin-2- yl)methyl)amino)-7H-pyrrolo[2,3-
d]pyrimidin-5-yl)methanone I-367 ##STR00395##
(2-chloro-4-phenoxyphenyl)(4-(((5-
(hydroxymethyl)-1-methylpyrrolidin-2-
yl)methyl)amino)-7H-pyrrolo[2,3- d]pyrimidin-5-yl)methanone I-368
##STR00396## (2-chloro-4-phenoxyphenyl)(4-(((1-
ethyl-5-(hydroxymethyl)pyrrolidin-2-
yl)methyl)amino)-7H-pyrrolo[2,3- d]pyrimidin-5-yl)methanone I-369
##STR00397## (2-chloro-4-phenoxyphenyl)(4-(((5-
(hydroxymethyl)pyrrolidin-3- yl)methyl)amino)-7H-pyrrolo[2,3-
d]pyrimidin-5-yl)methanone I-369e ##STR00398##
(2-chloro-4-phenoxyphenyl)(4-
((((3R,5S)-5-(hydroxymethyl)pyrrolidin-
3-yl)methyl)amino)-7H-pyrrolo[2,3- d]pyrimidin-5-yl)methanone I-370
##STR00399## (2-chloro-4-phenoxyphenyl)(4-(((5-
(hydroxymethyl)-1-methylpyrrolidin-3-
yl)methyl)amino)-7H-pyrrolo[2,3- d]pyrimidin-5-yl)methanone I-370e
##STR00400## (2-chloro-4-phenoxyphenyl)(4-
((((3S,5S)-5-(hydroxymethyl)-1-
methylpyrrolidin-3-yl)methyl)amino)- 7H-pyrrolo[2,3-d]pyrimidin-5-
yl)methanone I-371 ##STR00401## (2-chloro-4-phenoxyphenyl)(4-(((1-
ethyl-5-(hydroxymethyl)pyrrolidin-3-
yl)methyl)amino)-7H-pyrrolo[2,3- d]pyrimidin-5-yl)methanone I-372
##STR00402## 1-(3-((5-(4-phenoxybenzoyl)-7H-
pyrrolo[2,3-d]pyrimidin-4- yl)amino)piperidin-1-yl)prop-2-en-1- one
I-373 ##STR00403## (4-phenoxyphenyl)(4-((1-
(vinylsulfonyl)piperidin-3-yl)amino)- 7H-pyrrolo[2,3-d]pyrimidin-5-
yl)methanone I-374 ##STR00404## (E)-2-(3-((5-(4-phenoxybenzoyl)-7H-
pyrrolo[2,3-d]pyrimidin-4- yl)amino)piperidine-1-carbonyl)but-2-
enenitrile I-375 ##STR00405## 1-(3-((5-(4-phenoxybenzoyl)-7H-
pyrrolo[2,3-d]pyrimidin-4- yl)amino)piperidin-1-yl)but-2-yn-1-one
I-376 ##STR00406## 1-(2-(((5-(4-phenoxybenzoyl)-7H-
pyrrolo[2,3-d]pyrimidin-4- yl)amino)methyl)pyrrolidin-1-yl)prop-2-
en-1-one I-377 ##STR00407## (4-phenoxyphenyl)(4-(((1-
(vinylsulfonyl)pyrrolidin-2- yl)methyl)amino)-7H-pyrrolo[2,3-
d]pyrimidin-5-yl)methanone I-378 ##STR00408##
(E)-2-(2-(((5-(4-phenoxybenzoyl)-7H- pyrrolo[2,3-d]pyrimidin-4-
yl)amino)methyl)pyrrolidine-1- carbonyl)but-2-enenitrile I-379
##STR00409## 1-(2-(((5-(4-phenoxybenzoyl)-7H-
pyrrolo[2,3-d]pyrimidin-4- yl)amino)methyl)pyrrolidin-1-yl)but-2-
yn-1-one I-380 ##STR00410## 1-(3-((5-(4-phenoxybenzoyl)-7H-
pyrrolo[2,3-d]pyrimidin-4- yl)amino)piperidin-1-yl)prop-2-en-1- one
I-381 ##STR00411## (2-fluoro-4-phenoxyphenyl)(4-((1-
(vinylsulfonyl)piperidin-3-yl)amino)- 7H-pyrrolo[2,3-d]pyrimidin-5-
yl)methanone I-382 ##STR00412## (E)-2-(3-((5-(2-fluoro-4-
phenoxybenzoyl)-7H-pyrrolo[2,3-
d]pyrimidin-4-yl)amino)piperidine-1- carbonyl)but-2-enenitrile
I-383 ##STR00413## 1-(3-((5-(2-fluoro-4-phenoxybenzoyl)-
7H-pyrrolo[2,3-d]pyrimidin-4-
yl)amino)piperidin-1-yl)but-2-yn-1-one I-384 ##STR00414##
1-(2-(((5-(2-fluoro-4-phenoxybenzoyl)-
7H-pyrrolo[2,3-d]pyrimidin-4-
yl)amino)methyl)pyrrolidin-1-yl)prop-2- en-1-one I-385 ##STR00415##
(2-fluoro-4-phenoxyphenyl)(4-(((1- (vinylsulfonyl)pyrrolidin-2-
yl)methyl)amino)-7H-pyrrolo[2,3- d]pyrimidin-5-yl)methanone I-386
##STR00416## (E)-2-(2-(((5-(2-fluoro-4-
phenoxybenzoyl)-7H-pyrrolo[2,3- d]pyrimidin-4-
yl)amino)methyl)pyrrolidine-1- carbonyl)but-2-enenitrile I-387
##STR00417## 1-(2-(((5-(2-fluoro-4-phenoxybenzoyl)-
7H-pyrrolo[2,3-d]pyrimidin-4-
yl)amino)methyl)pyrrolidin-1-yl)but-2- yn-1-one I-388 ##STR00418##
1-(3-((5-(4-phenoxybenzoyl)-7H- pyrrolo[2,3-d]pyrimidin-4-
yl)amino)azepan-1-yl)prop-2-en-1-one I-389 ##STR00419##
(4-phenoxyphenyl)(4-((1- (vinylsulfonyl)azepan-3-yl)amino)-7H-
pyrrolo[2,3-d]pyrimidin-5-yl)methanone I-390 ##STR00420##
1-(3-((5-(2-chloro-4-phenoxybenzoyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-
yl)amino)azepan-1-yl)prop-2-en-1-one I-391 ##STR00421##
(2-chloro-4-phenoxyphenyl)(4-((1-
(vinylsulfonyl)azepan-3-yl)amino)-7H-
pyrrolo[2,3-d]pyrimidin-5-yl)methanone I-392 ##STR00422##
1-(3-((5-(2-fluoro-4-phenoxybenzoyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-
yl)amino)azepan-1-yl)prop-2-en-1-one I-393 ##STR00423##
(2-fluoro-4-phenoxyphenyl)(4-((1-
(vinylsulfonyl)azepan-3-yl)amino)-7H-
pyrrolo[2,3-d]pyrimidin-5-yl)methanone I-394 ##STR00424##
1-(3-((5-(2-fluoro-4-phenoxybenzoyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-
yl)amino)azepan-1-yl)but-2-yn-1-one I-395 ##STR00425##
1-(3-((5-(2-chloro-4-phenoxybenzoyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-
yl)amino)azepan-1-yl)but-2-yn-1-one I-396 ##STR00426##
1-(3-((5-(4-phenoxybenzoyl)-7H- pyrrolo[2,3-d]pyrimidin-4-
yl)amino)azepan-1-yl)but-2-yn-1-one
I-397 ##STR00427## (E)-2-(3-((5-(2-fluoro-4-
phenoxybenzoyl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)amino)azepane-1-
carbonyl)but-2-enenitrile I-398 ##STR00428##
(E)-2-(3-((5-(2-chloro-4- phenoxybenzoyl)-7H-pyrrolo[2,3-
d]pyrimidin-4-yl)amino)azepane-1- carbonyl)but-2-enenitrile I-399
##STR00429## (E)-2-(3-((5-(4-phenoxybenzoyl)-7H-
pyrrolo[2,3-d]pyrimidin-4- yl)amino)azepane-1-carbonyl)but-2-
enenitrile I-400 ##STR00430## 1-(3-((5-(4-phenoxybenzoyl)-7H-
pyrrolo[2,3-d]pyrimidin-4- yl)amino)pyrrolidin-1-yl)prop-2-en-1-
one I-401 ##STR00431## 1-(3-((5-(2-fluoro-4-phenoxybenzoyl)-
7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)pyrrolidin-1-yl)prop-2-en-1-
one I-402 ##STR00432## 1-(3-((5-(2-chloro-4-phenoxybenzoyl)-
7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)pyrrolidin-1-yl)prop-2-en-1-
one I-403 ##STR00433## (2-chloro-4-phenoxyphenyl)(4-((1-
(vinylsulfonyl)pyrrolidin-3-yl)amino)-
7H-pyrrolo[2,3-d]pyrimidin-5- yl)methanone I-404 ##STR00434##
(2-fluoro-4-phenoxyphenyl)(4-((1-
(vinylsulfonyl)pyrrolidin-3-yl)amino)-
7H-pyrrolo[2,3-d]pyrimidin-5- yl)methanone I-405 ##STR00435##
(4-phenoxyphenyl)(4-((1- (vinylsulfonyl)pyrrolidin-3-yl)amino)-
7H-pyrrolo[2,3-d]pyrimidin-5- yl)methanone I-406 ##STR00436##
1-(3-((5-(2-chloro-4-phenoxybenzoyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-
yl)amino)pyrrolidin-1-yl)but-2-yn-1-one I-407 ##STR00437##
1-(3-((5-(2-fluoro-4-phenoxybenzoyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-
yl)amino)pyrrolidin-1-yl)but-2-yn-1-one I-408 ##STR00438##
1-(3-((5-(4-phenoxybenzoyl)-7H- pyrrolo[2,3-d]pyrimidin-4-
yl)amino)pyrrolidin-1-yl)but-2-yn-1-one I-409 ##STR00439##
(E)-2-(3-((5-(2-fluoro-4- phenoxybenzoyl)-7H-pyrrolo[2,3-
d]pyrimidin-4-yl)amino)pyrrolidine-1- carbonyl)but-2-enenitrile
I-410 ##STR00440## (E)-2-(3-((5-(2-chloro-4-
phenoxybenzoyl)-7H-pyrrolo[2,3-
d]pyrimidin-4-yl)amino)pyrrolidine-1- carbonyl)but-2-enenitrile
I-411 ##STR00441## (E)-2-(3-((5-(4-phenoxybenzoyl)-7H-
pyrrolo[2,3-d]pyrimidin-4- yl)amino)pyrrolidine-1-carbonyl)but-2-
enenitrile I-412 ##STR00442## oxiran-2-yl(3-((5-(4-phenoxybenzoyl)-
7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)pyrrolidin-1-yl)methanone
I-413 ##STR00443## (3-((5-(2-fluoro-4-phenoxybenzoyl)-7H-
pyrrolo[2,3-d]pyrimidin-4- yl)amino)pyrrolidin-1-yl)(oxiran-2-
yl)methanone I-414 ##STR00444## (3-((5-(2-chloro-4-phenoxybenzoyl)-
7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)pyrrolidin-1-yl)(oxiran-2-
yl)methanone I-415 ##STR00445## (3-methyloxiran-2-yl)(3-((5-(4-
phenoxybenzoyl)-7H-pyrrolo[2,3-
d]pyrimidin-4-yl)amino)pyrrolidin-1- yl)methanone I-416
##STR00446## (3-((5-(2-fluoro-4-phenoxybenzoyl)-7H-
pyrrolo[2,3-d]pyrimidin-4- yl)amino)pyrrolidin-1-yl)(3-
methyloxiran-2-yl)methanone I-417 ##STR00447##
(3-((5-(2-chloro-4-phenoxybenzoyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-
yl)amino)pyrrolidin-1-yl)(3- methyloxiran-2-yl)methanone I-418
##STR00448## methyl 3-(3-((5-(4-phenoxybenzoyl)-
7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)pyrrolidine-1-
carbonyl)oxirane-2-carboxylate I-419 ##STR00449## methyl
3-(3-((5-(2-fluoro-4- phenoxybenzoyl)-7H-pyrrolo[2,3-
d]pyrimidin-4-yl)amino)pyrrolidine-1-
carbonyl)oxirane-2-carboxylate I-420 ##STR00450## methyl
3-(3-((5-(2-chloro-4- phenoxybenzoyl)-7H-pyrrolo[2,3-
d]pyrimidin-4-yl)amino)pyrrolidine-1-
carbonyl)oxirane-2-carboxylate I-421 ##STR00451##
(3-((5-(2-fluoro-4-phenoxybenzoyl)-7H- pyrrolo[2,3-d]pyrimidin-4-
yl)amino)piperidin-1-yl)(oxiran-2- yl)methanone I-422 ##STR00452##
(3-((5-(2-chloro-4-phenoxybenzoyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-
yl)amino)piperidin-1-yl)(oxiran-2- yl)methanone I-423 ##STR00453##
oxiran-2-yl(3-((5-(4-phenoxybenzoyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-
yl)amino)piperidin-1-yl)methanone I-424 ##STR00454##
(3-methyloxiran-2-yl)(3-((5-(4- phenoxybenzoyl)-7H-pyrrolo[2,3-
d]pyrimidin-4-yl)amino)piperidin-1- yl)methanone I-425 ##STR00455##
(3-((5-(2-fluoro-4-phenoxybenzoyl)-7H- pyrrolo[2,3-d]pyrimidin-4-
yl)amino)piperidin-1-yl)(3- methyloxiran-2-yl)methanone I-426
##STR00456## (3-((5-(2-chloro-4-phenoxybenzoyl)-
7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)piperidin-1-yl)(3-
methyloxiran-2-yl)methanone I-427 ##STR00457## methyl
3-(3-((5-(2-chloro-4- phenoxybenzoyl)-7H-pyrrolo[2,3-
d]pyrimidin-4-yl)amino)piperidine-1- carbonyl)oxirane-2-carboxylate
I-428 ##STR00458## methyl 3-(3-((5-(2-fluoro-4-
phenoxybenzoyl)-7H-pyrrolo[2,3-
d]pyrimidin-4-yl)amino)piperidine-1- carbonyl)oxirane-2-carboxylate
I-429 ##STR00459## methyl 3-(3-((5-(4-phenoxybenzoyl)-
7H-pyrrolo[2,3-d]pyrimidin-4-
yl)amino)piperidine-1-carbonyl)oxirane- 2-carboxylate I-430
##STR00460## oxiran-2-yl(3-((5-(4-phenoxybenzoyl)-
7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)azepan-1-yl)methanone I-431
##STR00461## (3-((5-(2-chloro-4-phenoxybenzoyl)-
7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)azepan-1-yl)(oxiran-2-
yl)methanone I-432 ##STR00462##
(3-((5-(2-fluoro-4-phenoxybenzoyl)-7H- pyrrolo[2,3-d]pyrimidin-4-
yl)amino)azepan-1-yl)(oxiran-2- yl)methanone I-433 ##STR00463##
(3-methyloxiran-2-yl)(3-((5-(4- phenoxybenzoyl)-7H-pyrrolo[2,3-
d]pyrimidin-4-yl)amino)azepan-1- yl)methanone I-434 ##STR00464##
(3-((5-(2-chloro-4-phenoxybenzoyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-
yl)amino)azepan-1-yl)(3-methyloxiran- 2-yl)methanone I-435
##STR00465## (3-((5-(2-fluoro-4-phenoxybenzoyl)-7H-
pyrrolo[2,3-d]pyrimidin-4- yl)amino)azepan-1-yl)(3-methyloxiran-
2-yl)methanone I-436 ##STR00466## methyl
3-(3-((5-(4-phenoxybenzoyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-
yl)amino)azepane-1-carbonyl)oxirane-2- carboxylate I-437
##STR00467## methyl 3-(3-((5-(2-chloro-4-
phenoxybenzoyl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)amino)azepane-1-
carbonyl)oxirane-2-carboxylate I-438 ##STR00468## methyl
3-(3-((5-(2-fluoro-4- phenoxybenzoyl)-7H-pyrrolo[2,3-
d]pyrimidin-4-yl)amino)azepane-1- carbonyl)oxirane-2-carboxylate
I-439 ##STR00469## (E)-5-(3-((5-(2-chloro-4-
phenoxybenzoyl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)amino)piperidin-1-
yl)pent-3-en-2-one I-440 ##STR00470## (E)-5-(3-((5-(2-fluoro-4-
phenoxybenzoyl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)amino)piperidin-1-
yl)pent-3-en-2-one I-441 ##STR00471##
(E)-5-(3-((5-(4-phenoxybenzoyl)-7H- pyrrolo[2,3-d]pyrimidin-4-
yl)amino)piperidin-1-yl)pent-3-en-2-one I-442 ##STR00472##
(E)-5-(3-((5-(2-chloro-4- phenoxybenzoyl)-7H-pyrrolo[2,3-
d]pyrimidin-4-yl)amino)azepan-1- yl)pent-3-en-2-one I-443
##STR00473## (E)-5-(3-((5-(2-fluoro-4-
phenoxybenzoyl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)amino)azepan-1-
yl)pent-3-en-2-one I-444 ##STR00474##
(E)-5-(3-((5-(4-phenoxybenzoyl)-7H- pyrrolo[2,3-d]pyrimidin-4-
yl)amino)azepan-1-yl)pent-3-en-2-one I-445 ##STR00475##
(E)-5-(3-((5-(2-chloro-4- phenoxybenzoyl)-7H-pyrrolo[2,3-
d]pyrimidin-4-yl)amino)pyrrolidin-1- yl)pent-3-en-2-one I-446
##STR00476## (E)-5-(3-((5-(2-fluoro-4-
phenoxybenzoyl)-7H-pyrrolo[2,3-
d]pyrimidin-4-yl)amino)pyrrolidin-1- yl)pent-3-en-2-one I-447
##STR00477## (E)-5-(3-((5-(4-phenoxybenzoyl)-7H-
pyrrolo[2,3-d]pyrimidin-4- yl)amino)pyrrolidin-1-yl)pent-3-en-2-
one I-448 ##STR00478## 2-chloro-1-(3-((5-(4-phenoxybenzoyl)-
7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)pyrrolidin-1-yl)ethan-1-one
I-449 ##STR00479## 2-chloro-1-(3-((5-(2-chloro-4-
phenoxybenzoyl)-7H-pyrrolo[2,3-
d]pyrimidin-4-yl)amino)pyrrolidin-1- yl)ethan-1-one I-450
##STR00480## 2-chloro-1-(3-((5-(2-fluoro-4-
phenoxybenzoyl)-7H-pyrrolo[2,3-
d]pyrimidin-4-yl)amino)pyrrolidin-1- yl)ethan-1-one I-451
##STR00481## 2-bromo-1-(3-((5-(4-phenoxybenzoyl)-
7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)pyrrolidin-1-yl)ethan-1-one
I-452 ##STR00482## 2-bromo-1-(3-((5-(2-chloro-4-
phenoxybenzoyl)-7H-pyrrolo[2,3-
d]pyrimidin-4-yl)amino)pyrrolidin-1- yl)ethan-1-one I-453
##STR00483## 2-bromo-1-(3-((5-(2-fluoro-4-
phenoxybenzoyl)-7H-pyrrolo[2,3-
d]pyrimidin-4-yl)amino)pyrrolidin-1- yl)ethan-1-one I-454
##STR00484## 2-iodo-1-(3-((5-(4-phenoxybenzoyl)-
7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)pyrrolidin-1-yl)ethan-1-one
I-455 ##STR00485## 1-(3-((5-(2-chloro-4-phenoxybenzoyl)-
7H-pyrrolo[2,3-d]pyrimidin-4-
yl)amino)pyrrolidin-1-yl)-2-iodoethan- 1-one I-456 ##STR00486##
1-(3-((5-(2-fluoro-4-phenoxybenzoyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-
yl)amino)pyrrolidin-1-yl)-2-iodoethan- 1-one I-457 ##STR00487##
2-phenoxy-1-(3-((5-(4- phenoxybenzoyl)-7H-pyrrolo[2,3-
d]pyrimidin-4-yl)amino)pyrrolidin-1- yl)ethan-1-one I-458
##STR00488## 1-(3-((5-(2-chloro-4-phenoxybenzoyl)-
7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)pyrrolidin-1-yl)-2-
phenoxyethan-1-one I-459 ##STR00489##
1-(3-((5-(2-fluoro-4-phenoxybenzoyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-
yl)amino)pyrrolidin-1-yl)-2- phenoxyethan-1-one I-460 ##STR00490##
2-oxo-2-(3-((5-(4-phenoxybenzoyl)-7H- pyrrolo[2,3-d]pyrimidin-4-
yl)amino)pyrrolidin-1-yl)ethyl methanesulfonate I-461 ##STR00491##
2-(3-((5-(2-fluoro-4-phenoxybenzoyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-
yl)amino)pyrrolidin-1-yl)-2-oxoethyl methanesulfonate I-462
##STR00492## 2-(3-((5-(2-chloro-4-phenoxybenzoyl)-
7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)pyrrolidin-1-yl)-2-oxoethyl
methanesulfonate I-463 ##STR00493## 2-chloro-1-(3-((5-(2-fluoro-4-
phenoxybenzoyl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)amino)azepan-1-
yl)ethan-1-one
I-464 ##STR00494## 2-chloro-1-(3-((5-(2-chloro-4-
phenoxybenzoyl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)amino)azepan-1-
yl)ethan-1-one I-465 ##STR00495##
2-chloro-1-(3-((5-(4-phenoxybenzoyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-
yl)amino)azepan-1-yl)ethan-1-one I-466 ##STR00496##
2-bromo-1-(3-((5-(2-fluoro-4- phenoxybenzoyl)-7H-pyrrolo[2,3-
d]pyrimidin-4-yl)amino)azepan-1- yl)ethan-1-one I-467 ##STR00497##
2-bromo-1-(3-((5-(2-chloro-4- phenoxybenzoyl)-7H-pyrrolo[2,3-
d]pyrimidin-4-yl)amino)azepan-1- yl)ethan-1-one I-468 ##STR00498##
2-bromo-1-(3-((5-(4-phenoxybenzoyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-
yl)amino)azepan-1-yl)ethan-1-one I-469 ##STR00499##
1-(3-((5-(2-fluoro-4-phenoxybenzoyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-
yl)amino)azepan-1-yl)-2-iodoethan-1- one I-470 ##STR00500##
1-(3-((5-(2-chloro-4-phenoxybenzoyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-
yl)amino)azepan-1-yl)-2-iodoethan-1- one I-471 ##STR00501##
2-iodo-1-(3-((5-(4-phenoxybenzoyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-
yl)amino)azepan-1-yl)ethan-1-one I-472 ##STR00502##
2-phenoxy-1-(3-((5-(4- phenoxybenzoyl)-7H-pyrrolo[2,3-
d]pyrimidin-4-yl)amino)azepan-1- yl)ethan-1-one I-473 ##STR00503##
1-(3-((5-(2-fluoro-4-phenoxybenzoyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-
yl)amino)azepan-1-yl)-2-phenoxyethan- 1-one I-474 ##STR00504##
1-(3-((5-(2-chloro-4-phenoxybenzoyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-
yl)amino)azepan-1-yl)-2-phenoxyethan- 1-one I-475 ##STR00505##
2-oxo-2-(3-((5-(4-phenoxybenzoyl)-7H- pyrrolo[2,3-d]pyrimidin-4-
yl)amino)azepan-1-yl)ethyl methanesulfonate I-476 ##STR00506##
2-(3-((5-(2-fluoro-4-phenoxybenzoyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-
yl)amino)azepan-1-yl)-2-oxoethyl methanesulfonate I-477
##STR00507## 2-(3-((5-(2-chloro-4-phenoxybenzoyl)-
7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)azepan-1-yl)-2-oxoethyl
methanesulfonate I-478 ##STR00508##
(2-(((5-(2-chloro-4-phenoxybenzoyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-
yl)amino)methyl)pyrrolidin-1- yl)(oxiran-2-yl)methanone I-479
##STR00509## (2-(((5-(2-fluoro-4-phenoxybenzoyl)-
7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)methyl)pyrrolidin-1-
yl)(oxiran-2-yl)methanone I-480 ##STR00510##
oxiran-2-yl(2-(((5-(4-phenoxybenzoyl)-
7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)methyl)pyrrolidin-1-
yl)methanone I-481 ##STR00511##
(2-(((5-(2-chloro-4-phenoxybenzoyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-
yl)amino)methyl)pyrrolidin-1-yl)(3- methyloxiran-2-yl)methanone
I-482 ##STR00512## (2-(((5-(2-fluoro-4-phenoxybenzoyl)-
7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)methyl)pyrrolidin-1-yl)(3-
methyloxiran-2-yl)methanone I-483 ##STR00513##
(3-methyloxiran-2-yl)(2-(((5-(4- phenoxybenzoyl)-7H-pyrrolo[2,3-
d]pyrimidin-4- yl)amino)methyl)pyrrolidin-1- yl)methanone I-484
##STR00514## methyl 3-(2-(((5-(2-chloro-4-
phenoxybenzoyl)-7H-pyrrolo[2,3- d]pyrimidin-4-
yl)amino)methyl)pyrrolidine-1- carbonyl)oxirane-2-carboxylate I-485
##STR00515## methyl 3-(2-(((5-(2-fluoro-4-
phenoxybenzoyl)-7H-pyrrolo[2,3- d]pyrimidin-4-
yl)amino)methyl)pyrrolidine-1- carbonyl)oxirane-2-carboxylate I-486
##STR00516## methyl 3-(2-(((5-(4-phenoxybenzoyl)-
7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)methyl)pyrrolidine-1-
carbonyl)oxirane-2-carboxylate I-487 ##STR00517##
oxiran-2-yl(2-(((5-(4-phenoxybenzoyl)-
7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)methyl)piperidin-1-
yl)methanone I-488 ##STR00518##
(2-(((5-(2-fluoro-4-phenoxybenzoyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-
yl)amino)methyl)piperidin-1-yl)(oxiran- 2-yl)methanone I-489
##STR00519## (2-(((5-(2-chloro-4-phenoxybenzoyl)-
7H-pyrrolo[2,3-d]pyrimidin-4-
yl)amino)methyl)piperidin-1-yl)(oxiran- 2-yl)methanone I-490
##STR00520## (3-methyloxiran-2-yl)(2-(((5-(4-
phenoxybenzoyl)-7H-pyrrolo[2,3- d]pyrimidin-4-
yl)amino)methyl)piperidin-1- yl)methanone I-491 ##STR00521##
(2-(((5-(2-fluoro-4-phenoxybenzoyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-
yl)amino)methyl)piperidin-1-yl)(3- methyloxiran-2-yl)methanone
I-492 ##STR00522## (2-(((5-(2-chloro-4-phenoxybenzoyl)-
7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)methyl)piperidin-1-yl)(3-
methyloxiran-2-yl)methanone I-493 ##STR00523## methyl
3-(2-(((5-(2-chloro-4- phenoxybenzoyl)-7H-pyrrolo[2,3-
d]pyrimidin-4- yl)amino)methyl)piperidine-1-
carbonyl)oxirane-2-carboxylate I-494 ##STR00524## methyl
3-(2-(((5-(2-fluoro-4- phenoxybenzoyl)-7H-pyrrolo[2,3-
d]pyrimidin-4- yl)amino)methyl)piperidine-1-
carbonyl)oxirane-2-carboxylate I-495 ##STR00525## methyl
3-(2-(((5-(4-phenoxybenzoyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-
yl)amino)methyl)piperidine-1- carbonyl)oxirane-2-carboxylate I-496
##STR00526## oxiran-2-yl(2-(((5-(4-phenoxybenzoyl)-
7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)methyl)azepan-1-
yl)methanone I-497 ##STR00527##
(2-(((5-(2-fluoro-4-phenoxybenzoyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-
yl)amino)methyl)azepan-1-yl)(oxiran-2- yl)methanone I-498
##STR00528## (2-(((5-(2-chloro-4-phenoxybenzoyl)-
7H-pyrrolo[2,3-d]pyrimidin-4-
yl)amino)methyl)azepan-1-yl)(oxiran-2- yl)methanone I-499
##STR00529## (3-methyloxiran-2-yl)(2-(((5-(4-
phenoxybenzoyl)-7H-pyrrolo[2,3-
d]pyrimidin-4-yl)amino)methyl)azepan- 1-yl)methanone I-500
##STR00530## (2-(((5-(2-fluoro-4-phenoxybenzoyl)-
7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)methyl)azepan-1-yl)(3-
methyloxiran-2-yl)methanone I-501 ##STR00531##
(2-(((5-(2-chloro-4-phenoxybenzoyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-
yl)amino)methyl)azepan-1-yl)(3- methyloxiran-2-yl)methanone I-502
##STR00532## methyl 3-(2-(((5-(2-chloro-4-
phenoxybenzoyl)-7H-pyrrolo[2,3- d]pyrimidin-4-
yl)amino)methyl)azepane-1- carbonyl)oxirane-2-carboxylate I-503
##STR00533## methyl 3-(2-(((5-(2-fluoro-4-
phenoxybenzoyl)-7H-pyrrolo[2,3- d]pyrimidin-4-
yl)amino)methyl)azepane-1- carbonyl)oxirane-2-carboxylate I-504
##STR00534## methyl 3-(2-(((5-(4-phenoxybenzoyl)-
7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)methyl)azepane-1-
carbonyl)oxirane-2-carboxylate I-505 ##STR00535##
(E)-5-(2-(((5-(2-chloro-4- phenoxybenzoyl)-7H-pyrrolo[2,3-
d]pyrimidin-4- yl)amino)methyl)pyrrolidin-1-yl)pent-3- en-2-one
I-506 ##STR00536## (E)-5-(2-(((5-(2-fluoro-4-
phenoxybenzoyl)-7H-pyrrolo[2,3- d]pyrimidin-4-
yl)amino)methyl)pyrrolidin-1-yl)pent-3- en-2-one I-507 ##STR00537##
(E)-5-(2-(((5-(4-phenoxybenzoyl)-7H- pyrrolo[2,3-d]pyrimidin-4-
yl)amino)methyl)pyrrolidin-1-yl)pent-3- en-2-one I-508 ##STR00538##
(E)-5-(2-(((5-(4-phenoxybenzoyl)-7H- pyrrolo[2,3-d]pyrimidin-4-
yl)amino)methyl)piperidin-1-yl)pent-3- en-2-one I-509 ##STR00539##
(E)-5-(2-(((5-(2-fluoro-4- phenoxybenzoyl)-7H-pyrrolo[2,3-
d]pyrimidin-4- yl)amino)methyl)piperidin-1-yl)pent-3- en-2-one
I-510 ##STR00540## (E)-5-(2-(((5-(2-chloro-4-
phenoxybenzoyl)-7H-pyrrolo[2,3- d]pyrimidin-4-
yl)amino)methyl)piperidin-1-yl)pent-3- en-2-one I-511 ##STR00541##
(E)-5-(2-(((5-(2-fluoro-4- phenoxybenzoyl)-7H-pyrrolo[2,3-
d]pyrimidin-4-yl)amino)methyl)azepan- 1-yl)pent-3-en-2-one I-512
##STR00542## (E)-5-(2-(((5-(2-chloro-4-
phenoxybenzoyl)-7H-pyrrolo[2,3-
d]pyrimidin-4-yl)amino)methyl)azepan- 1-yl)pent-3-en-2-one I-513
##STR00543## (E)-5-(2-(((5-(4-phenoxybenzoyl)-7H-
pyrrolo[2,3-d]pyrimidin-4- yl)amino)methyl)azepan-1-yl)pent-3-en-
2-one I-514 ##STR00544## 2-chloro-1-(2-(((5-(2-fluoro-4-
phenoxybenzoyl)-7H-pyrrolo[2,3- d]pyrimidin-4-
yl)amino)methyl)pyrrolidin-1-yl)ethan- 1-one I-515 ##STR00545##
2-chloro-1-(2-(((5-(2-chloro-4- phenoxybenzoyl)-7H-pyrrolo[2,3-
d]pyrimidin-4- yl)amino)methyl)pyrrolidin-1-yl)ethan- 1-one I-516
##STR00546## 2-chloro-1-(2-(((5-(4-phenoxybenzoyl)-
7H-pyrrolo[2,3-d]pyrimidin-4-
yl)amino)methyl)pyrrolidin-1-yl)ethan- 1-one I-517 ##STR00547##
2-bromo-1-(2-(((5-(2-fluoro-4- phenoxybenzoyl)-7H-pyrrolo[2,3-
d]pyrimidin-4- yl)amino)methyl)pyrrolidin-1-yl)ethan- 1-one I-518
##STR00548## 2-bromo-1-(2-(((5-(2-chloro-4-
phenoxybenzoyl)-7H-pyrrolo[2,3- d]pyrimidin-4-
yl)amino)methyl)pyrrolidin-1-yl)ethan- 1-one I-519 ##STR00549##
2-bromo-1-(2-(((5-(4-phenoxybenzoyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-
yl)amino)methyl)pyrrolidin-1-yl)ethan- 1-one I-520 ##STR00550##
1-(2-(((5-(2-fluoro-4-phenoxybenzoyl)-
7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)methyl)pyrrolidin-1-yl)-2-
iodoethan-1-one I-521 ##STR00551##
1-(2-(((5-(2-chloro-4-phenoxybenzoyl)-
7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)methyl)pyrrolidin-1-yl)-2-
iodoethan-1-one I-522 ##STR00552##
2-iodo-1-(2-(((5-(4-phenoxybenzoyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-
yl)amino)methyl)pyrrolidin-1-yl)ethan- 1-one I-523 ##STR00553##
2-phenoxy-1-(2-(((5-(4- phenoxybenzoyl)-7H-pyrrolo[2,3-
d]pyrimidin-4- yl)amino)methyl)pyrrolidin-1-yl)ethan- 1-one I-524
##STR00554## 1-(2-(((5-(2-fluoro-4-phenoxybenzoyl)-
7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)methyl)pyrrolidin-1-yl)-2-
phenoxyethan-1-one I-525 ##STR00555##
1-(2-(((5-(2-chloro-4-phenoxybenzoyl)-
7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)methyl)pyrrolidin-1-yl)-2-
phenoxyethan-1-one I-526 ##STR00556##
2-oxo-2-(2-(((5-(4-phenoxybenzoyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-
yl)amino)methyl)pyrrolidin-1-yl)ethyl methanesulfonate I-527
##STR00557## 2-(2-(((5-(2-fluoro-4-phenoxybenzoyl)-
7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)methyl)pyrrolidin-1-yl)-2-
oxoethyl methanesulfonate I-528 ##STR00558##
2-(2-(((5-(2-chloro-4-phenoxybenzoyl)-
7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)methyl)pyrrolidin-1-yl)-2-
oxoethyl methanesulfonate
I-529 ##STR00559## 2-chloro-1-(2-(((5-(2-fluoro-4-
phenoxybenzoyl)-7H-pyrrolo[2,3- d]pyrimidin-4-
yl)amino)methyl)piperidin-1-yl)ethan-1- one I-530 ##STR00560##
2-chloro-1-(2-(((5-(2-chloro-4- phenoxybenzoyl)-7H-pyrrolo[2,3-
d]pyrimidin-4- yl)amino)methyl)piperidin-1-yl)ethan-1- one I-531
##STR00561## 2-chloro-1-(2-(((5-(4-phenoxybenzoyl)-
7H-pyrrolo[2,3-d]pyrimidin-4-
yl)amino)methyl)piperidin-1-yl)ethan-1- one I-532 ##STR00562##
2-bromo-1-(2-(((5-(2-fluoro-4- phenoxybenzoyl)-7H-pyrrolo[2,3-
d]pyrimidin-4- yl)amino)methyl)piperidin-1-yl)ethan-1- one I-533
##STR00563## 2-bromo-1-(2-(((5-(2-chloro-4-
phenoxybenzoyl)-7H-pyrrolo[2,3- d]pyrimidin-4-
yl)amino)methyl)piperidin-1-yl)ethan-1- one I-534 ##STR00564##
2-bromo-1-(2-(((5-(4-phenoxybenzoyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-
yl)amino)methyl)piperidin-1-yl)ethan-1- one I-535 ##STR00565##
1-(2-(((5-(2-fluoro-4-phenoxybenzoyl)-
7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)methyl)piperidin-1-yl)-2-
iodoethan-1-one I-536 ##STR00566##
1-(2-(((5-(2-chloro-4-phenoxybenzoyl)-
7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)methyl)piperidin-1-yl)-2-
iodoethan-1-one I-537 ##STR00567##
2-iodo-1-(2-(((5-(4-phenoxybenzoyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-
yl)amino)methyl)piperidin-1-yl)ethan-1- one I-538 ##STR00568##
2-phenoxy-1-(2-(((5-(4- phenoxybenzoyl)-7H-pyrrolo[2,3-
d]pyrimidin-4- yl)amino)methyl)piperidin-1-yl)ethan-1- one I-539
##STR00569## 1-(2-(((5-(2-chloro-4-phenoxybenzoyl)-
7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)methyl)piperidin-1-yl)-2-
phenoxyethan-1-one I-540 ##STR00570##
1-(2-(((5-(2-fluoro-4-phenoxybenzoyl)-
7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)methyl)piperidin-1-yl)-2-
phenoxyethan-1-one I-541 ##STR00571##
2-oxo-2-(2-(((5-(4-phenoxybenzoyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-
yl)amino)methyl)piperidin-1-yl)ethyl methanesulfonate I-542
##STR00572## 2-(2-(((5-(2-chloro-4-phenoxybenzoyl)-
7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)methyl)piperidin-1-yl)-2-
oxoethyl methanesulfonate I-543 ##STR00573##
2-(2-(((5-(2-fluoro-4-phenoxybenzoyl)-
7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)methyl)piperidin-1-yl)-2-
oxoethyl methanesulfonate I-544 ##STR00574##
2-chloro-1-(2-(((5-(4-phenoxybenzoyl)-
7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)methyl)azepan-1-yl)ethan-1-
one I-545 ##STR00575## 2-chloro-1-(2-(((5-(2-chloro-4-
phenoxybenzoyl)-7H-pyrrolo[2,3-
d]pyrimidin-4-yl)amino)methyl)azepan- 1-yl)ethan-1-one I-546
##STR00576## 2-chloro-1-(2-(((5-(2-fluoro-4-
phenoxybenzoyl)-7H-pyrrolo[2,3-
d]pyrimidin-4-yl)amino)methyl)azepan- 1-yl)ethan-1-one I-547
##STR00577## 2-bromo-1-(2-(((5-(4-phenoxybenzoyl)-
7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)methyl)azepan-1-yl)ethan-1-
one I-548 ##STR00578## 2-bromo-1-(2-(((5-(2-chloro-4-
phenoxybenzoyl)-7H-pyrrolo[2,3-
d]pyrimidin-4-yl)amino)methyl)azepan- 1-yl)ethan-1-one I-549
##STR00579## 2-bromo-1-(2-(((5-(2-fluoro-4-
phenoxybenzoyl)-7H-pyrrolo[2,3-
d]pyrimidin-4-yl)amino)methyl)azepan- 1-yl)ethan-1-one I-550
##STR00580## 2-iodo-1-(2-(((5-(4-phenoxybenzoyl)-
7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)methyl)azepan-1-yl)ethan-1-
one I-551 ##STR00581## 1-(2-(((5-(2-chloro-4-phenoxybenzoyl)-
7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)methyl)azepan-1-yl)-2-
iodoethan-1-one I-552 ##STR00582##
1-(2-(((5-(2-fluoro-4-phenoxybenzoyl)-
7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)methyl)azepan-1-yl)-2-
iodoethan-1-one I-553 ##STR00583##
1-(2-(((5-(2-fluoro-4-phenoxybenzoyl)-
7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)methyl)azepan-1-yl)-2-
phenoxyethan-1-one I-554 ##STR00584##
1-(2-(((5-(2-chloro-4-phenoxybenzoyl)-
7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)methyl)azepan-1-yl)-2-
phenoxyethan-1-one I-555 ##STR00585## 2-phenoxy-1-(2-(((5-(4-
phenoxybenzoyl)-7H-pyrrolo[2,3-
d]pyrimidin-4-yl)amino)methyl)azepan- 1-yl)ethan-1-one I-556
##STR00586## 2-(2-(((5-(2-fluoro-4-phenoxybenzoyl)-
7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)methyl)azepan-1-yl)-2-
oxoethyl methanesulfonate I-557 ##STR00587##
2-(2-(((5-(2-chloro-4-phenoxybenzoyl)-
7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)methyl)azepan-1-yl)-2-
oxoethyl methanesulfonate I-558 ##STR00588##
2-oxo-2-(2-(((5-(4-phenoxybenzoyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-
yl)amino)methyl)azepan-1-yl)ethyl methanesulfonate I-559
##STR00589## (E)-2-(2-(((5-(2-fluoro-4-
phenoxybenzoyl)-7H-pyrrolo[2,3- d]pyrimidin-4-
yl)amino)methyl)piperidine-1- carbonyl)but-2-enenitrile I-560
##STR00590## (E)-2-(2-(((5-(2-chloro-4-
phenoxybenzoyl)-7H-pyrrolo[2,3- d]pyrimidin-4-
yl)amino)methyl)piperidine-1- carbonyl)but-2-enenitrile I-561
##STR00591## (E)-2-(2-(((5-(4-phenoxybenzoyl)-7H-
pyrrolo[2,3-d]pyrimidin-4- yl)amino)methyl)piperidine-1-
carbonyl)but-2-enenitrile I-562 ##STR00592##
2-(2-(((5-(2-fluoro-4-phenoxybenzoyl)-
7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)methyl)piperidine-1-
carbonyl)acrylonitrile I-563 ##STR00593##
2-(2-(((5-(2-chloro-4-phenoxybenzoyl)-
7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)methyl)piperidine-1-
carbonyl)acrylonitrile I-564 ##STR00594##
2-(2-(((5-(4-phenoxybenzoyl)-7H- pyrrolo[2,3-d]pyrimidin-4-
yl)amino)methyl)piperidine-1- carbonyl)acrylonitrile I-565
##STR00595## 2-(2-(((5-(2-chloro-4-phenoxybenzoyl)-
7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)methyl)pyrrolidine-1-
carbonyl)acrylonitrile I-566 ##STR00596##
2-(2-(((5-(2-fluoro-4-phenoxybenzoyl)-
7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)methyl)pyrrolidine-1-
carbonyl)acrylonitrile I-567 ##STR00597##
2-(2-(((5-(4-phenoxybenzoyl)-7H- pyrrolo[2,3-d]pyrimidin-4-
yl)amino)methyl)pyrrolidine-1- carbonyl)acrylonitrile I-568
##STR00598## 2-(2-(((5-(2-fluoro-4-phenoxybenzoyl)-
7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)methyl)azepane-1-
carbonyl)acrylonitrile I-569 ##STR00599##
2-(2-(((5-(2-chloro-4-phenoxybenzoyl)-
7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)methyl)azepane-1-
carbonyl)acrylonitrile I-570 ##STR00600##
2-(2-(((5-(4-phenoxybenzoyl)-7H- pyrrolo[2,3-d]pyrimidin-4-
yl)amino)methyl)azepane-1- carbonyl)acrylonitrile I-571
##STR00601## (E)-2-(2-(((5-(2-fluoro-4-
phenoxybenzoyl)-7H-pyrrolo[2,3- d]pyrimidin-4-
yl)amino)methyl)azepane-1- carbonyl)but-2-enenitrile I-572
##STR00602## (E)-2-(2-(((5-(2-chloro-4-
phenoxybenzoyl)-7H-pyrrolo[2,3- d]pyrimidin-4-
yl)amino)methyl)azepane-1- carbonyl)but-2-enenitrile I-573
##STR00603## (E)-2-(2-(((5-(4-phenoxybenzoyl)-7H-
pyrrolo[2,3-d]pyrimidin-4- yl)amino)methyl)azepane-1-
carbonyl)but-2-enenitrile I-574 ##STR00604##
1-(2-(((5-(2-fluoro-4-phenoxybenzoyl)-
7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)methyl)azepan-1-yl)but-2-yn-
1-one I-575 ##STR00605## 1-(2-(((5-(2-chloro-4-phenoxybenzoyl)-
7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)methyl)azepan-1-yl)but-2-yn-
1-one I-576 ##STR00606## 1-(2-(((5-(4-phenoxybenzoyl)-7H-
pyrrolo[2,3-d]pyrimidin-4- yl)amino)methyl)azepan-1-yl)but-2-yn-
1-one I-577 ##STR00607## 1-(2-(((5-(2-chloro-4-phenoxybenzoyl)-
7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)methyl)piperidin-1-yl)but-2-
yn-1-one I-578 ##STR00608## 1-(2-(((5-(2-fluoro-4-phenoxybenzoyl)-
7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)methyl)piperidin-1-yl)but-2-
yn-1-one I-579 ##STR00609## 1-(2-(((5-(4-phenoxybenzoyl)-7H-
pyrrolo[2,3-d]pyrimidin-4- yl)amino)methyl)piperidin-1-yl)but-2-
yn-1-one I-580 ##STR00610## 1-(2-(((5-(2-chloro-4-phenoxybenzoyl)-
7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)methyl)azepan-1-yl)prop-2-
en-1-one I-581 ##STR00611## 1-(2-(((5-(2-fluoro-4-phenoxybenzoyl)-
7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)methyl)azepan-1-yl)prop-2-
en-1-one I-582 ##STR00612## 1-(2-(((5-(4-phenoxybenzoyl)-7H-
pyrrolo[2,3-d]pyrimidin-4- yl)amino)methyl)azepan-1-yl)prop-2-
en-1-one I-583 ##STR00613## 1-(2-(((5-(2-chloro-4-phenoxybenzoyl)-
7H-pyrrolo[2,3-d]pyrimidin-4-
yl)amino)methyl)piperidin-1-yl)prop-2- en-1-one I-584 ##STR00614##
1-(2-(((5-(2-fluoro-4-phenoxybenzoyl)-
7H-pyrrolo[2,3-d]pyrimidin-4-
yl)amino)methyl)piperidin-1-yl)prop-2- en-1-one I-585 ##STR00615##
1-(2-(((5-(4-phenoxybenzoyl)-7H- pyrrolo[2,3-d]pyrimidin-4-
yl)amino)methyl)piperidin-1-yl)prop-2- en-1-one I-586 ##STR00616##
(2-chloro-4-phenoxyphenyl)(4-(((1- (vinylsulfonyl)piperidin-2-
yl)methyl)amino)-7H-pyrrolo[2,3- d]pyrimidin-5-yl)methanone I-587
##STR00617## (2-fluoro-4-phenoxyphenyl)(4-(((1-
(vinylsulfonyl)piperidin-2- yl)methyl)amino)-7H-pyrrolo[2,3-
d]pyrimidin-5-yl)methanone I-588 ##STR00618##
(4-phenoxyphenyl)(4-(((1- (vinylsulfonyl)piperidin-2-
yl)methyl)amino)-7H-pyrrolo[2,3- d]pyrimidin-5-yl)methanone I-589
##STR00619## (2-chloro-4-phenoxyphenyl)(4-(((1-
(vinylsulfonyl)azepan-2- yl)methyl)amino)-7H-pyrrolo[2,3-
d]pyrimidin-5-yl)methanone I-590 ##STR00620##
(2-fluoro-4-phenoxyphenyl)(4-(((1- (vinylsulfonyl)azepan-2-
yl)methyl)amino)-7H-pyrrolo[2,3- d]pyrimidin-5-yl)methanone I-591
##STR00621## (4-phenoxyphenyl)(4-(((1- (vinylsulfonyl)azepan-2-
yl)methyl)amino)-7H-pyrrolo[2,3- d]pyrimidin-5-yl)methanone I-592
##STR00622## 2-(3-((5-(2-fluoro-4-phenoxybenzoyl)-
7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)pyrrolidine-1-
carbonyl)acrylonitrile I-593 ##STR00623##
2-(3-((5-(2-chloro-4-phenoxybenzoyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-
yl)amino)pyrrolidine-1-
carbonyl)acrylonitrile I-594 ##STR00624##
2-(3-((5-(4-phenoxybenzoyl)-7H- pyrrolo[2,3-d]pyrimidin-4-
yl)amino)pyrrolidine-1- carbonyl)acrylonitrile I-595 ##STR00625##
2-(3-((5-(2-fluoro-4-phenoxybenzoyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-
yl)amino)azepane-1- carbonyl)acrylonitrile I-596 ##STR00626##
2-(3-((5-(2-chloro-4-phenoxybenzoyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-
yl)amino)azepane-1- carbonyl)acrylonitrile I-597 ##STR00627##
2-(3-((5-(4-phenoxybenzoyl)-7H- pyrrolo[2,3-d]pyrimidin-4-
yl)amino)azepane-1- carbonyl)acrylonitrile I-598 ##STR00628##
2-(3-((5-(2-fluoro-4-phenoxybenzoyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-
yl)amino)piperidine-1- carbonyl)acrylonitrile I-599 ##STR00629##
2-(3-((5-(2-chloro-4-phenoxybenzoyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-
yl)amino)piperidine-1- carbonyl)acrylonitrile I-600 ##STR00630##
2-(3-((5-(4-phenoxybenzoyl)-7H- pyrrolo[2,3-d]pyrimidin-4-
yl)amino)piperidine-1- carbonyl)acrylonitrile I-601 ##STR00631##
N-(4-chloro-3-(4-(((3R,6S)-6- (hydroxymethyl)tetrahydro-2H-pyran-3-
yl)amino)-7H-pyrrolo[2,3-d]pyrimidine- 5-carbonyl)phenyl)benzamide
I-602 ##STR00632## N-(4-chloro-3-(4-(((3R,6S)-6-
(hydroxymethyl)tetrahydro-2H-pyran-3-
yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-
5-carbonyl)phenyl)-2-phenylacetamide I-603 ##STR00633##
N-(4-chloro-3-(4-(((3R,6S)-6- (hydroxymethyl)tetrahydro-2H-pyran-3-
yl)amino)-7H-pyrrolo[2,3- d]pyrimidine-5-
carbonyl)phenyl)tetrahydro-2H-pyran-4- carboxamide I-604
##STR00634## N-(4-chloro-3-(4-(((3R,6S)-6-
(hydroxymethyl)tetrahydro-2H-pyran-3-
yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-
5-carbonyl)phenyl)thiazole-5- carboxamide I-605 ##STR00635##
N-(4-chloro-3-(4-(((3R,6S)-6- (hydroxymethyl)tetrahydro-2H-pyran-3-
yl)amino)-7H-pyrrolo[2,3-d]pyrimidine- 5-carbonyl)phenyl)-1-
phenylcyclopropane-1-carboxamide I-606 ##STR00636##
N-(4-chloro-3-(4-(((3R,6S)-6- (hydroxymethyl)tetrahydro-2H-pyran-3-
yl)amino)-7H-pyrrolo[2,3-d]pyrimidine- 5-carbonyl)phenyl)-5,6,7,8-
tetrahydroisoquinoline-3-carboxamide I-607 ##STR00637##
N-(4-chloro-3-(4-(((3R,6S)-6- (hydroxymethyl)tetrahydro-2H-pyran-3-
yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-
5-carbonyl)phenyl)isoquinoline-1- carboxamide I-608 ##STR00638##
1-(4-chloro-3-(4-(((3R,6S)-6- (hydroxymethyl)tetrahydro-2H-pyran-3-
yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-
5-carbonyl)phenyl)-3-phenylurea I-609 ##STR00639##
1-(4-chloro-3-(4-(((3R,6S)-6- (hydroxymethyl)tetrahydro-2H-pyran-3-
yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-
5-carbonyl)phenyl)-3-(pyridin-3-yl)urea I-610 ##STR00640##
3-chloro-4-(4-(((3R,6S)-6- (hydroxymethyl)tetrahydro-2H-pyran-3-
yl)amino)-7H-pyrrolo[2,3-d]pyrimidine- 5-carbonyl)-N-(2-
methoxyethyl)benzamide I-611 ##STR00641##
(3-chloro-4-(4-(((3R,6S)-6- (hydroxymethyl)tetrahydro-2H-pyran-3-
yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-
5-carbonyl)phenyl)(morpholino) methanone I-612 ##STR00642##
(4-chloro-3-(4-(((3R,6S)-6- (hydroxymethyl)tetrahydro-2H-pyran-3-
yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-
5-carbonyl)phenyl)(morpholino) methanone I-613 ##STR00643##
3-chloro-4-(4-(((3R,6S)-6- (hydroxymethyl)tetrahydro-2H-pyran-3-
yl)amino)-7H-pyrrolo[2,3-d]pyrimidine- 5-carbonyl)-N-(2-
morpholinoethyl)benzamide I-614 ##STR00644##
3-chloro-N-(3-cyanophenyl)-4-(4-
(((3R,6S)-6-(hydroxymethyl)tetrahydro-
2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-
d]pyrimidine-5-carbonyl)benzamide I-615 ##STR00645##
(2-chloro-4-(1,2,3,4- tetrahydroisoquinoline-2-
carbonyl)phenyl)(4-(((3R,6S)-6-
(hydroxymethyl)tetrahydro-2H-pyran-3-
yl)amino)-7H-pyrrolo[2,3-d]pyrimidin- 5-yl)methanone I-616
##STR00646## (3-chloro-4-(4-(((3R,6S)-6-
(hydroxymethyl)tetrahydro-2H-pyran-3-
yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-
5-carbonyl)phenyl)(4-(pyridin-2- yl)piperazin-1-yl)methanone I-617
##STR00647## (3-chloro-4-(4-(((3R,6S)-6-
(hydroxymethyl)tetrahydro-2H-pyran-3-
yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-
5-carbonyl)phenyl)(piperidin-1- yl)methanone I-618 ##STR00648##
N-benzyl-3-chloro-4-(4-(((3R,6S)-6-
(hydroxymethyl)tetrahydro-2H-pyran-3-
yl)amino)-7H-pyrrolo[2,3-d]pyrimidine- 5-carbonyl)benzamide I-619
##STR00649## 3-chloro-4-(4-(((3R,6S)-6-
(hydroxymethyl)tetrahydro-2H-pyran-3-
yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-
5-carbonyl)-N-(1-methyl-1H-pyrazol-4- yl)benzamide I-620
##STR00650## (3-chloro-4-(4-(((3R,6S)-6-
(hydroxymethyl)tetrahydro-2H-pyran-3-
yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-
5-carbonyl)phenyl)(4-methylpiperazin- 1-yl)methanone I-621
##STR00651## 3-chloro-4-(4-(((3R,6S)-6-
(hydroxymethyl)tetrahydro-2H-pyran-3-
yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-
5-carbonyl)-N-(2-oxaspiro[3.3]heptan- 6-yl)benzamide I-622
##STR00652## (4-chloro-3-(4-(((3R,6S)-6-
(hydroxymethyl)tetrahydro-2H-pyran-3-
yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-
5-carbonyl)phenyl)(4-methylpiperazin- 1-yl)methanone I-623
##STR00653## (4-chloro-3-(4-(((3R,6S)-6-
(hydroxymethyl)tetrahydro-2H-pyran-3-
yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-
5-carbonyl)phenyl)(piperidin-1- yl)methanone I-624 ##STR00654##
4-chloro-3-(4-(((3R,6S)-6- (hydroxymethyl)tetrahydro-2H-pyran-3-
yl)amino)-7H-pyrrolo[2,3-d]pyrimidine- 5-carbonyl)-N-(2-
methoxyethyl)benzamide I-625 ##STR00655##
(4-chloro-3-(4-(((3R,6S)-6- (hydroxymethyl)tetrahydro-2H-pyran-3-
yl)amino)-7H-pyrrolo[2,3-d]pyrimidine- 5-carbonyl)phenyl)(3,4-
dihydroisoquinolin-2(1H)-yl)methanone I-626 ##STR00656##
4-chloro-3-(4-(((3R,6S)-6- (hydroxymethyl)tetrahydro-2H-pyran-3-
yl)amino)-7H-pyrrolo[2,3-d]pyrimidine- 5-carbonyl)-N-(2-
morpholinoethyl)benzamide I-627 ##STR00657##
(4-chloro-3-(4-(((3R,6S)-6- (hydroxymethyl)tetrahydro-2H-pyran-3-
yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-
5-carbonyl)phenyl)(4-(pyridin-2- yl)piperazin-1-yl)methanone I-628
##STR00658## N-benzyl-4-chloro-3-(4-(((3R,6S)-6-
(hydroxymethyl)tetrahydro-2H-pyran-3-
yl)amino)-7H-pyrrolo[2,3-d]pyrimidine- 5-carbonyl)benzamide I-629
##STR00659## 4-chloro-3-(4-(((3R,6S)-6-
(hydroxymethyl)tetrahydro-2H-pyran-3-
yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-
5-carbonyl)-N-(1-methyl-1H-pyrazol-4- yl)benzamide I-630
##STR00660## 4-chloro-N-(3-cyanophenyl)-3-(4-
(((3R,6S)-6-(hydroxymethyl)tetrahydro-
2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-
d]pyrimidine-5-carbonyl)benzamide I-631 ##STR00661##
4-chloro-3-(4-(((3R,6S)-6- (hydroxymethyl)tetrahydro-2H-pyran-3-
yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-
5-carbonyl)-N-phenylbenzamide I-632 ##STR00662## (4-(((3R,6S)-6-
(hydroxymethyl)tetrahydro-2H-pyran-3-
yl)amino)-7H-pyrrolo[2,3-d]pyrimidin- 5-yl)(4-(morpholine-4-
carbonyl)phenyl)methanone I-633 ##STR00663## 4-(4-(((3R,6S)-6-
(hydroxymethyl)tetrahydro-2H-pyran-3-
yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-
5-carbonyl)-N-(1-methyl-1H-pyrazol-4- yl)benzamide I-634
##STR00664## 3-(4-(((3R,6S)-6-
(hydroxymethyl)tetrahydro-2H-pyran-3-
yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-
5-carbonyl)-N-phenylbenzamide I-635 ##STR00665## (4-(((3R,6S)-6-
(hydroxymethyl)tetrahydro-2H-pyran-3-
yl)amino)-7H-pyrrolo[2,3-d]pyrimidin- 5-yl)(3-(morpholine-4-
carbonyl)phenyl)methanone I-636 ##STR00666## 4-(4-(((3R,6S)-6-
(hydroxymethyl)tetrahydro-2H-pyran-3-
yl)amino)-7H-pyrrolo[2,3-d]pyrimidine- 5-carbonyl)-N-(2-
methoxyethyl)benzamide I-637 ##STR00667## 3-(4-(((3R,6S)-6-
(hydroxymethyl)tetrahydro-2H-pyran-3-
yl)amino)-7H-pyrrolo[2,3-d]pyrimidine- 5-carbonyl)-N-(2-
methoxyethyl)benzamide I-638 ##STR00668## 3-(4-(((3R,6S)-6-
(hydroxymethyl)tetrahydro-2H-pyran-3-
yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-
5-carbonyl)-N-(1-methyl-1H-pyrazol-4- yl)benzamide I-639
##STR00669## N-(3-chloro-4-(4-(((3R,6S)-6-
(hydroxymethyl)tetrahydro-2H-pyran-3-
yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-
5-carbonyl)phenyl)-2-phenylacetamide I-640 ##STR00670##
N-(3-chloro-4-(4-(((3R,6S)-6- (hydroxymethyl)tetrahydro-2H-pyran-3-
yl)amino)-7H-pyrrolo[2,3-d]pyrimidine- 5-carbonyl)phenyl)-1-
phenylcyclopropane-1-carboxamide I-641 ##STR00671##
2-(benzyloxy)-N-(3-chloro-4-(4-
(((3R,6S)-6-(hydroxymethyl)tetrahydro-
2H-pyran-3-yl)amino)-7H-pyrrolo[2,3- d]pyrimidine-5-
carbonyl)phenyl)acetamide I-642 ##STR00672## N-(3-(4-(((3R,6S)-6-
(hydroxymethyl)tetrahydro-2H-pyran-3-
yl)amino)-7H-pyrrolo[2,3-d]pyrimidine- 5-carbonyl)phenyl)benzamide
I-643 ##STR00673## N-(3-(4-(((3R,6S)-6-
(hydroxymethyl)tetrahydro-2H-pyran-3-
yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-
5-carbonyl)phenyl)picolinamide I-644 ##STR00674##
N-(3-(4-(((3R,6S)-6- (hydroxymethyl)tetrahydro-2H-pyran-3-
yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-
5-carbonyl)phenyl)tetrahydro-2H-pyran- 4-carboxamide I-645
##STR00675## N-(3-(4-(((3R,6S)-6-
(hydroxymethyl)tetrahydro-2H-pyran-3-
yl)amino)-7H-pyrrolo[2,3-d]pyrimidine- 5-carbonyl)phenyl)-2-
methoxyacetamide I-646 ##STR00676##
(2-chloro-4-(piperidin-1-yl)phenyl)(4-
(((3R,6S)-6-(hydroxymethyl)tetrahydro-
2H-pyran-3-yl)amino)-7H-pyrrolo[2,3- d]pyrimidin-5-yl)methanone
I-647 ##STR00677## (2-chloro-4-(2-oxa-6-
azaspiro[3.3]heptan-6-yl)phenyl)(4-
(((3R,6S)-6-(hydroxymethyl)tetrahydro-
2H-pyran-3-yl)amino)-7H-pyrrolo[2,3- d]pyrimidin-5-yl)methanone
I-648 ##STR00678## (2-chloro-5-(2-
methoxyethoxy)phenyl)(4-(((3R,6S)-6-
(hydroxymethyl)tetrahydro-2H-pyran-3-
yl)amino)-7H-pyrrolo[2,3-d]pyrimidin- 5-yl)methanone I-649
##STR00679## (4-(((3R,6S)-6-
(hydroxymethyl)tetrahydro-2H-pyran-3-
yl)amino)-7H-pyrrolo[2,3-d]pyrimidin- 5-yl)(3-(2-
methoxyethoxy)phenyl)methanone I-650 ##STR00680##
(2-chloro-4-(phenylamino)phenyl)(4-
(((3R,6S)-6-(hydroxymethyl)tetrahydro-
2H-pyran-3-yl)amino)-7H-pyrrolo[2,3- d]pyrimidin-5-yl)methanone
I-651 ##STR00681## 5-(3-chloro-4-(4-(((3R,6S)-6-
(hydroxymethyl)tetrahydro-2H-pyran-3-
yl)amino)-7H-pyrrolo[2,3-d]pyrimidine- 5-carbonyl)phenoxy)-N-
methylpicolinamide I-652 ##STR00682## N-(4-(4-(((3R,6S)-6-
(hydroxymethyl)tetrahydro-2H-pyran-3-
yl)amino)-7H-pyrrolo[2,3-d]pyrimidine- 5-carbonyl)benzyl)-2-
methoxybenzamide I-653 ##STR00683## (racemic)-(2-chloro-4-
phenoxyphenyl)(4-((6-(hydroxymethyl)-
1-(methylsulfonyl)piperidin-3-
yl)amino)-7H-pyrrolo[2,3-d]pyrimidin- 5-yl)methanone I-654
##STR00684## (racemic)-1-(5-((5-(2-chloro-4-
phenoxybenzoyl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)amino)-2-
(hydroxymethyl)-piperidin-1-yl)ethan-1- one I-655 ##STR00685##
1-((2S,4R)-4-((5-(2-chloro-4- phenoxybenzoyl)-7H-pyrrolo[2,3-
d]pyrimidin-4-yl)amino)-2- (hydroxymethyl)pyrrolidin-1-yl)ethan-
1-one I-656 ##STR00686## (2-chloro-4-phenoxyphenyl)(4-
(((3R,5S)-5-(hydroxymethyl)-1-
(methylsulfonyl)pyrrolidin-3-yl)amino)-
7H-pyrrolo[2,3-d]pyrimidin-5- yl)methanone I-657 ##STR00687##
(4-((((3S,5S)-1-benzyl-5- (hydroxymethyl)pyrrolidin-3-
yl)methyl)amino)-7H-pyrrolo[2,3- d]pyrimidin-5-yl)(2-chloro-4-
phenoxyphenyl)methanone
[0182] In one embodiment, a compound of the present application
(e.g., a compound of any of the formulae or any individual
compounds disclosed herein) is a pharmaceutically acceptable salt.
In another embodiment, a compound of the present application (e.g.,
a compound of any of the formulae or any individual compounds
disclosed herein) is a solvate. In another embodiment, a compound
of the present application (e.g., a compound of any of the formulae
or any individual compounds disclosed herein) is a hydrate.
[0183] The details of the application are set forth in the
accompanying description below. Although methods and materials
similar or equivalent to those described herein can be used in the
practice or testing of the present application, illustrative
methods and materials are now described. Other features, objects,
and advantages of the application will be apparent from the
description and from the claims. In the specification and the
appended claims, the singular forms also include the plural unless
the context clearly dictates otherwise. Unless defined otherwise,
all technical and scientific terms used herein have the same
meaning as commonly understood by one of ordinary skill in the art
to which this application belongs. All patents and publications
cited in this specification are incorporated herein by reference in
their entireties.
Definitions
[0184] The articles "a" and "an" are used in this application to
refer to one or more than one (i.e., at least one) of the
grammatical object of the article. By way of example, "an element"
means one element or more than one element.
[0185] The term "and/or" is used in this application to mean either
"and" or "or" unless indicated otherwise.
[0186] The application also includes pharmaceutical compositions
comprising an effective amount of a compound of Formula (I) and a
pharmaceutically acceptable carrier.
[0187] The term "alkyl," as used herein, refers to saturated,
straight or branched-chain hydrocarbon radicals containing, in
certain embodiments, between one and six carbon atoms. Examples of
C.sub.1-C.sub.8 alkyl radicals include, but are not limited to,
methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, neopentyl,
n-hexyl, n-heptyl, and n-octyl radicals. Examples of
C.sub.1-C.sub.6 alkyl radicals include, but are not limited to,
methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, neopentyl,
and n-hexyl radicals.
[0188] The term "alkenyl," as used herein, denotes a monovalent
group derived from a hydrocarbon moiety containing, in certain
embodiments, from two to six carbon atoms having at least one
carbon-carbon double bond. The double bond may or may not be the
point of attachment to another group. Alkenyl groups include, but
are not limited to, for example, ethenyl, propenyl, butenyl,
1-methyl-2-buten-1-yl and the like.
[0189] The term "alkoxy" refers to an --O-alkyl radical.
[0190] The terms "hal," "halo," and "halogen," as used herein,
refer to an atom selected from fluorine, chlorine, bromine and
iodine.
[0191] The term "aryl," as used herein, refers to a mono- or
poly-cyclic carbocyclic ring system having one or more aromatic
rings, fused or non-fused, including, but not limited to, phenyl,
naphthyl, tetrahydronaphthyl, indanyl, indenyl and the like.
[0192] The term "aralkyl," as used herein, refers to an alkyl
residue attached to an aryl ring. Examples include, but are not
limited to, benzyl, phenethyl and the like.
[0193] The term "cycloalkyl," as used herein, denotes a monovalent
group derived from a monocyclic or polycyclic saturated or
partially unsaturated carbocyclic ring compound. Examples of
C.sub.3-C.sub.8 cycloalkyl include, but not limited to,
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentyl and
cyclooctyl; and examples of C.sub.3-C.sub.12-cycloalkyl include,
but not limited to, cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl, bicyclo [2.2.1] heptyl, and bicyclo [2.2.2] octyl. Also
contemplated is a monovalent group derived from a monocyclic or
polycyclic carbocyclic ring compound having at least one
carbon-carbon double bond by the removal of a single hydrogen atom.
Examples of such groups include, but are not limited to,
cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl,
cycloheptenyl, cyclooctenyl, and the like.
[0194] The term "heteroaryl," as used herein, refers to a mono- or
poly-cyclic (e.g., bi-, or tri-cyclic or more) fused or non-fused,
radical or ring system having at least one aromatic ring, having
from five to ten ring atoms of which one ring atoms is selected
from S, O, and N; zero, one, or two ring atoms are additional
heteroatoms independently selected from S, O, and N; and the
remaining ring atoms are carbon. Heteroaryl includes, but is not
limited to, pyridinyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl,
imidazolyl, thiazolyl, oxazolyl, isooxazolyl, thiadiazolyl,
oxadiazolyl, thiophenyl, furanyl, quinolinyl, isoquinolinyl,
benzimidazolyl, benzooxazolyl, quinoxalinyl, and the like.
[0195] The term "heteroaralkyl" as used herein, refers to an alkyl
residue attached to a heteroaryl ring. Examples include, but are
not limited to, pyridinylmethyl, pyrimidinylethyl and the like.
[0196] The term "heterocyclyl," or "heterocycloalkyl," as used
herein, refers to a saturated or unsaturated non-aromatic 3-, 4-,
5-, 6-, 7-, or 8-membered monocyclic, 7-, 8-, 9-, 10-, 11-, or
12-membered bicyclic (fused, bridged, or spiro rings), or 11-, 12,
13, or 14-membered tricyclic ring system (fused, bridged, or spiro
rings), where (i) each ring contains between one and three
heteroatoms independently selected from oxygen, sulfur and
nitrogen, (ii) each 5-membered ring has 0 to 1 double bonds and
each 6-membered ring has 0 to 2 double bonds, (iii) the nitrogen
and sulfur heteroatoms may optionally be oxidized, and (iv) the
nitrogen heteroatom may optionally be quaternized. Representative
heterocycloalkyl groups include, but are not limited to,
[1,3]dioxolanyl, pyrrolidinyl, pyrazolidinyl, pyrazolinyl,
imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl,
oxazolidinyl, isoxazolidinyl, morpholinyl, tetrahydropyranyl,
thiazolidinyl, isothiazolidinyl, tetrahydrofuryl, dioxanyl,
oxetanyl, azetidinyl, thietanyl, oxiranyl, aziridinyl, thiiranyl,
2-oxa-5-azabicyclo[2.2.1]heptanyl, 2,5-diazabicyclo[2.2.1]heptanyl,
2-oxa-6-azaspiro[3.3]heptanyl, 2,6-diazaspiro[3.3]heptanyl,
1,4-dioxa-8-azaspiro[4.5]decanyl, 2-azaspiro[3.3]heptan-5-amine,
1-azaspiro[3.3]heptan-5-amine, 1-oxa-6-azaspiro[3.3]heptan-3-amine,
2-azaspiro[3.3]heptan-6-amine, 1-azaspiro[3.3]heptan-6-amine,
6-azaspiro[3.4]octan-2-amine, 5-azaspiro[3.4]octan-2-amine,
6-azaspiro[3.4]octan-1-amine, 5-azaspiro[3.4]octan-1-amine,
5-oxa-2-azaspiro[3.4]octan-7-amine,
7-amino-5-thia-2-azaspiro[3.4]octane 5,5-dioxide,
5-oxa-2-azaspiro[3.4]octan-8-amine,
8-amino-5-thia-2-azaspiro[3.4]octane 5,5-dioxide, and the like.
[0197] The term "alkylamino" refers to a group having the
structure, e.g., NH(C.sub.1-C.sub.6 alkyl), where C.sub.1-C.sub.6
alkyl is as previously defined.
[0198] The term "dialkylamino" refers to a group having the
structure, e.g., N(C.sub.1-C.sub.6 alkyl).sub.2, where
C.sub.1-C.sub.6 alkyl is as previously defined.
[0199] The term "acyl" includes residues derived from acids,
including but not limited to carboxylic acids, carbamic acids,
carbonic acids, sulfonic acids, and phosphorous acids. Examples
include aliphatic carbonyls, aromatic carbonyls, aliphatic
sulfonyls, aromatic sulfinyls, aliphatic sulfinyls, aromatic
phosphates and aliphatic phosphates. Examples of aliphatic
carbonyls include, but are not limited to, acetyl, propionyl,
2-fluoroacetyl, butyryl, 2-hydroxy acetyl, and the like.
[0200] In accordance with the application, any of the aryls,
substituted aryls, heteroaryls and substituted heteroaryls
described herein, can be any aromatic group. Aromatic groups can be
substituted or unsubstituted.
[0201] As described herein, compounds of the application may
optionally be substituted with one or more substituents, such as
are illustrated generally above, or as exemplified by particular
classes, subclasses, and species of the application. It will be
appreciated that the phrase "optionally substituted" is used
interchangeably with the phrase "substituted or unsubstituted." In
general, the term "substituted", whether preceded by the term
"optionally" or not, refers to the replacement of hydrogen radicals
in a given structure with the radical of a specified substituent.
Unless otherwise indicated, an optionally substituted group may
have a substituent at each substitutable position of the group, and
when more than one position in any given structure may be
substituted with more than one substituent selected from a
specified group, the substituent may be either the same or
different at every position. The terms "optionally substituted",
"optionally substituted alkyl," "optionally substituted alkenyl,"
"optionally substituted cycloalkyl," "optionally substituted
cycloalkenyl," "optionally substituted aryl", "optionally
substituted heteroaryl," "optionally substituted aralkyl",
"optionally substituted heteroaralkyl," "optionally substituted
heterocyclyl," and any other optionally substituted group as used
herein, refer to groups that are substituted or unsubstituted by
independent replacement of one, two, or three or more of the
hydrogen atoms thereon with substituents including, but not limited
to: --F, --Cl, --Br, --I, --OH, protected hydroxy, --NO.sub.2,
--CN, --NH.sub.2, protected amino, --NH--C.sub.1-C.sub.12-alkyl,
--NH--C.sub.2-C.sub.12-alkenyl, --NH--C.sub.2-C.sub.12-alkenyl,
--NH--C.sub.3-C.sub.12-cycloalkyl, --NH-aryl, --NH-heteroaryl,
--NH-heterocycloalkyl, -dialkylamino, -diarylamino,
-diheteroarylamino, --O--C.sub.1-C.sub.12-alkyl,
--O--C.sub.2-C.sub.12-alkenyl, --O--C.sub.2-C.sub.12-alkenyl,
--O--C.sub.3-C.sub.12-cycloalkyl, --O-aryl, --O-heteroaryl,
--O-heterocycloalkyl, --C(O)--C.sub.1-C.sub.12-alkyl,
--C(O)--C.sub.2-C.sub.12-alkenyl, --C(O)--C.sub.2-C.sub.12-alkenyl,
--C(O)--C.sub.3-C.sub.12-cycloalkyl, --C(O)-aryl,
--C(O)-heteroaryl, --C(O)-heterocycloalkyl, --CONH.sub.2,
--CONH--C.sub.1-C.sub.12-alkyl, --CONH--C.sub.2-C.sub.12-alkenyl,
--CONH--C.sub.2-C.sub.12-alkenyl,
--CONH--C.sub.3-C.sub.12-cycloalkyl, --CONH-aryl,
--CONH-heteroaryl, --CONH-heterocycloalkyl,
--OCO.sub.2--C.sub.1-C.sub.12-alkyl,
--OCO.sub.2--C.sub.2-C.sub.12-alkenyl,
--OCO.sub.2--C.sub.2-C.sub.12-alkenyl,
--OCO.sub.2--C.sub.3-C.sub.12-cycloalkyl, --OCO.sub.2-aryl,
--OCO.sub.2-heteroaryl, --OCO.sub.2-heterocycloalkyl,
--OCONH.sub.2, --OCONH--C.sub.1-C.sub.12-alkyl,
--OCONH--C.sub.2-C.sub.12-alkenyl,
--OCONH--C.sub.2-C.sub.12-alkenyl,
--OCONH--C.sub.3-C.sub.12-cycloalkyl, --OCONH-aryl,
--OCONH-heteroaryl, --OCONH-heterocycloalkyl,
--NHC(O)--C.sub.1-C.sub.12-alkyl,
--NHC(O)--C.sub.2-C.sub.12-alkenyl,
--NHC(O)--C.sub.2-C.sub.12-alkenyl,
--NHC(O)--C.sub.3-C.sub.12-cycloalkyl, --NHC(O)-aryl,
--NHC(O)-heteroaryl, --NHC(O)-heterocycloalkyl,
--NHCO.sub.2--C.sub.1-C.sub.12-alkyl,
--NHCO.sub.2--C.sub.2-C.sub.12-alkenyl,
--NHCO.sub.2--C.sub.2-C.sub.12-alkenyl,
--NHCO.sub.2--C.sub.3-C.sub.12-cycloalkyl, --NHCO.sub.2-aryl,
--NHCO.sub.2-heteroaryl, --NHCO.sub.2-heterocycloalkyl,
--NHC(O)NH.sub.2, --NHC(O)NH--C.sub.1-C.sub.12-alkyl,
--NHC(O)NH--C.sub.2-C.sub.12-alkenyl,
--NHC(O)NH--C.sub.2-C.sub.12-alkenyl,
--NHC(O)NH--C.sub.3-C.sub.12-cycloalkyl, --NHC(O)NH-aryl,
--NHC(O)NH-heteroaryl, NHC(O)NH-heterocycloalkyl, --NHC(S)NH.sub.2,
--NHC(S)NH--C.sub.1-C.sub.12-alkyl,
--NHC(S)NH--C.sub.2-C.sub.12-alkenyl,
--NHC(S)NH--C.sub.2-C.sub.12-alkenyl,
--NHC(S)NH--C.sub.3-C.sub.12-cycloalkyl, --NHC(S)NH-aryl,
--NHC(S)NH-heteroaryl, --NHC(S)NH-heterocycloalkyl,
--NHC(NH)NH.sub.2, --NHC(NH)NH--C.sub.1-C.sub.12-alkyl,
--NHC(NH)NH--C.sub.2-C.sub.12-alkenyl,
--NHC(NH)NH--C.sub.2-C.sub.12-alkenyl,
--NHC(NH)NH--C.sub.3-C.sub.12-cycloalkyl, --NHC(NH)NH-aryl,
--NHC(NH)NH-heteroaryl, --NHC(NH)NHheterocycloalkyl,
--NHC(NH)--C.sub.1-C.sub.12-alkyl,
--NHC(NH)--C.sub.2-C.sub.12-alkenyl,
--NHC(NH)--C.sub.2-C.sub.12-alkenyl,
--NHC(NH)--C.sub.3-C.sub.12-cycloalkyl, --NHC(NH)-aryl,
--NHC(NH)-heteroaryl, --NHC(NH)-heterocycloalkyl,
--C(NH)NH--C.sub.1-C.sub.12-alkyl,
--C(NH)NH--C.sub.2-C.sub.12-alkenyl,
--C(NH)NH--C.sub.2-C.sub.12-alkenyl,
C(NH)NH--C.sub.3-C.sub.12-cycloalkyl, --C(NH)NH-aryl,
--C(NH)NH-heteroaryl, --C(NH)NHheterocycloalkyl,
--S(O)--C.sub.1-C.sub.12-alkyl, --S(O)--C.sub.2-C.sub.12-alkenyl,
--S(O)--C.sub.2-C.sub.12-alkenyl,
--S(O)--C.sub.3-C.sub.12-cycloalkyl, --S(O)-aryl,
--S(O)-heteroaryl, --S(O)-heterocycloalkyl --SO.sub.2NH.sub.2,
--SO.sub.2NH--C.sub.1-C.sub.12-alkyl,
--SO.sub.2NH--C.sub.2-C.sub.12-alkenyl,
--SO.sub.2NH--C.sub.2-C.sub.12-alkenyl,
--SO.sub.2NH--C.sub.3-C.sub.12-cycloalkyl, --SO.sub.2NH-aryl,
--SO.sub.2NH-heteroaryl, --SO.sub.2NH-heterocycloalkyl,
--NHSO.sub.2--C.sub.1-C.sub.12-alkyl,
--NHSO.sub.2--C.sub.2-C.sub.12-alkenyl,
--NHSO.sub.2--C.sub.2-C.sub.12-alkenyl,
--NHS.sub.2--C.sub.3-C.sub.12-cycloalkyl, --NHSO.sub.2-aryl,
--NHSO.sub.2-heteroaryl, --NHSO.sub.2-heterocycloalkyl,
--CH.sub.2NH.sub.2, --CH.sub.2SO.sub.2CH.sub.3, -aryl, -arylalkyl,
-heteroaryl, -heteroarylalkyl, -heterocycloalkyl,
--C.sub.3-C.sub.12-cycloalkyl, polyalkoxyalkyl, polyalkoxy,
-methoxymethoxy, -methoxyethoxy, --SH, --S--C.sub.1-C.sub.12-alkyl,
--S--C.sub.2-C.sub.12-alkenyl, --S--C.sub.2-C.sub.12-alkenyl,
--S--C.sub.3-C.sub.12-cycloalkyl, --S-aryl, --S-heteroaryl,
--S-heterocycloalkyl, or methylthiomethyl.
[0202] The term "carrier", as used in this application, encompasses
carriers, excipients, and diluents and means a material,
composition or vehicle, such as a liquid or solid filler, diluent,
excipient, solvent or encapsulating material, involved in carrying
or transporting a pharmaceutical agent from one organ, or portion
of the body, to another organ, or portion of the body of a
subject.
[0203] The compounds of the present application may form salts
which are also within the scope of this application. Reference to a
compound of the Formula herein is understood to include reference
to salts thereof, unless otherwise indicated.
[0204] Representative "pharmaceutically acceptable salts" include,
e.g., water-soluble and water-insoluble salts, such as the acetate,
amsonate (4,4-diaminostilbene-2,2-disulfonate), benzenesulfonate,
benzonate, bicarbonate, bisulfate, bitartrate, borate, bromide,
butyrate, calcium, calcium edetate, camsylate, carbonate, chloride,
citrate, clavulariate, dihydrochloride, edetate, edisylate,
estolate, esylate, fumerate, fiunarate, gluceptate, gluconate,
glutamate, glycollylarsanilate, hexafluorophosphate,
hexylresorcinate, hydrabamine, hydrobromide, hydrochloride,
hydroxynaphthoate, iodide, isothionate, lactate, lactobionate,
laurate, magnesium, malate, maleate, mandelate, mesylate,
methylbromide, methylnitrate, methylsulfate, mucate, napsylate,
nitrate, N-methylglucamine ammonium salt, 3-hydroxy-2-naphthoate,
oleate, oxalate, palmitate, pamoate
(1,1-methene-bis-2-hydroxy-3-naphthoate, einbonate), pantothenate,
phosphate/diphosphate, picrate, polygalacturonate, propionate,
p-toluenesulfonate, salicylate, stearate, subacetate, succinate,
sulfate, sulfosalicylate, suramate, tannate, tartrate, teoclate,
tosylate, triethiodide, and valerate salts.
[0205] The compounds of the present application, for example,
including the pharmaceutically acceptable salts, tautomers,
prodrugs, and polymorphs of the compounds, can exist in a solvated
form with other solvent molecules or in an unsolvated form.
[0206] "Solvate" means solvent addition forms that contain either
stoichiometric or non stoichiometric amounts of solvent. Some
compounds or salts have a tendency to trap a fixed molar ratio of
solvent molecules in the crystalline solid state, thus forming a
solvate. If the solvent is water the solvate formed is a hydrate;
and if the solvent is alcohol, the solvate formed is an alcoholate.
Hydrates are formed by the combination of one or more molecules of
water with one molecule of the substance in which the water retains
its molecular state as H.sub.2O.
[0207] All stereoisomers (for example, geometric isomers, optical
isomers and the like) of the present compounds (including those of
the salts, solvates, esters and prodrugs of the compounds as well
as the salts, solvates and esters of the prodrugs), such as those
which may exist due to asymmetric carbons on various substituents,
including enantiomeric forms (which may exist even in the absence
of asymmetric carbons), rotameric forms, atropisomers, and
diastereomeric forms, are contemplated within the scope of this
application, as are positional isomers (such as, for example,
4-pyridyl and 3-pyridyl). For example, if a compound of Formula (I)
incorporates a double bond or a fused ring, both the cis- and
trans-forms, as well as mixtures, are embraced within the scope of
the application. Individual stereoisomers of the compound of the
application may, for example, be substantially free of other
isomers, or may be admixed, for example, as racemates or with all
other, or other selected, stereoisomers. The chiral centers of the
present application can have the S or R configuration as defined by
the IUPAC 1974 Recommendations. The use of the terms "salt",
"solvate", "ester," "prodrug" and the like, is intended to equally
apply to the salt, solvate, ester and prodrug of enantiomers,
stereoisomers, rotamers, tautomers, positional isomers, racemates
or prodrugs of the inventive compounds.
[0208] The term "isomer" refers to compounds that have the same
composition and molecular weight but differ in physical and/or
chemical properties. The structural difference may be in
constitution (geometric isomers) or in the ability to rotate the
plane of polarized light (stereoisomers). With regard to
stereoisomers, the compounds of Formula (I) may have one or more
asymmetric carbon atom and may occur as racemates, racemic mixtures
or as individual enantiomers or diastereomers.
[0209] In the present specification, the structural formula of the
compound represents a certain isomer for convenience in some cases,
but the present application includes all isomers, such as
geometrical isomers, optical isomers based on an asymmetrical
carbon, stereoisomers, tautomers, and the like.
[0210] "Isomerism" means compounds that have identical molecular
formulae but differ in the sequence of bonding of their atoms or in
the arrangement of their atoms in space. Isomers that differ in the
arrangement of their atoms in space are termed "stereoisomers".
Stereoisomers that are not mirror images of one another are termed
"diastereoisomers", and stereoisomers that are non-superimposable
mirror images of each other are termed "enantiomers" or sometimes
optical isomers. A mixture containing equal amounts of individual
enantiomeric forms of opposite chirality is termed a "racemic
mixture".
[0211] The compounds of the application may contain asymmetric or
chiral centers, and, therefore, exist in different stereoisomeric
forms. It is intended that all stereoisomeric forms of the
compounds of the application as well as mixtures thereof, including
racemic mixtures, form part of the present application. In
addition, the present application embraces all geometric and
positional isomers. For example, if a compound of the application
incorporates a double bond or a fused ring, both the cis- and
trans-forms, as well as mixtures, are embraced within the scope of
the application. Each compound herein disclosed includes all the
enantiomers that conform to the general structure of the compound.
The compound may be in a racemic or enantiomerically pure form, or
any other form in terms of stereochemistry. The assay results may
reflect the data collected for the racemic form, the
enantiomerically pure form, or any other form in terms of
stereochemistry.
[0212] A carbon atom bonded to four non-identical substituents is
termed a "chiral center".
[0213] "Chiral isomer" means a compound with at least one chiral
center. Compounds with more than one chiral center may exist either
as an individual diastereomer or as a mixture of diastereomers,
termed "diastereomeric mixture". When one chiral center is present,
a stereoisomer may be characterized by the absolute configuration
(R or S) of that chiral center. Absolute configuration refers to
the arrangement in space of the substituents attached to the chiral
center. The substituents attached to the chiral center under
consideration are ranked in accordance with the Sequence Rule of
Cahn, Ingold and Prelog. (Cahn et al., Angew. Chem. Inter. Edit.
1966, 5, 385; errata 511; Cahn et al., Angew. Chem. 1966, 78, 413;
Cahn and Ingold, J. Chem. Soc. 1951 (London), 612; Cahn et al.,
Experientia 1956, 12, 81; Cahn, J. Chem. Educ. 1964, 41, 116).
[0214] "Geometric isomer" means the diastereomers that owe their
existence to hindered rotation about double bonds. These
configurations are differentiated in their names by the prefixes
cis and trans, or Z and E, which indicate that the groups are on
the same or opposite side of the double bond in the molecule
according to the Cahn-Ingold-Prelog rules.
[0215] In another embodiment of the application, the compound of
Formula (I) is an enantiomer. In some embodiments the compound is
the (S)-enantiomer. In other embodiments the compound is the
(R)-enantiomer. In yet other embodiments, the compounds of Formula
(I) may be (+) or (-) enantiomers. The compound may contain more
than one stereocenter.
[0216] In another embodiment of the application, the compounds of
Formula (I) are diastereomers. In some embodiments, the compounds
are the syn diastereomer. In other embodiments, the compounds are
the anti diastereomer.
[0217] Diastereomeric mixtures can be separated into their
individual diastereomers on the basis of their physical chemical
differences by methods well known to those skilled in the art, such
as, for example, by chromatography and/or fractional
crystallization. Enantiomers can be separated by converting the
enantiomeric mixture into a diastereomeric mixture by reaction with
an appropriate optically active compound (e.g., chiral auxiliary
such as a chiral alcohol or Mosher's acid chloride), separating the
diastereomers and converting (e.g., hydrolyzing) the individual
diastereomers to the corresponding pure enantiomers. Enantiomers
can also be separated by use of a chiral HPLC column.
[0218] It is also possible that the compounds of the application
may exist in different tautomeric forms, and all such forms are
embraced within the scope of the application. Also, for example,
all keto-enol and imine-enamine forms of the compounds are included
in the application.
[0219] "Tautomer" is one of two or more structural isomers that
exist in equilibrium and is readily converted from one isomeric
form to another. This conversion results in the formal migration of
a hydrogen atom accompanied by a switch of adjacent conjugated
double bonds. Tautomers exist as a mixture of a tautomeric set in
solution. In solid form, usually one tautomer predominates. In
solutions where tautomerization is possible, a chemical equilibrium
of the tautomers will be reached. The exact ratio of the tautomers
depends on several factors, including temperature, solvent and pH.
The concept of tautomers that are interconvertable by
tautomerizations is called tautomerism.
[0220] Of the various types of tautomerism that are possible, two
are commonly observed. In keto-enol tautomerism a simultaneous
shift of electrons and a hydrogen atom occurs. Ring-chain
tautomerism arises as a result of the aldehyde group (--CHO) in a
sugar chain molecule reacting with one of the hydroxy groups (--OH)
in the same molecule to give it a cyclic (ring-shaped) form as
exhibited by glucose.
[0221] Common tautomeric pairs are: ketone-enol, amide-nitrile,
lactam-lactim, amide-imidic acid tautomerism in heterocyclic rings
(e.g., in nucleobases such as guanine, thymine and cytosine),
amine-enamine and enamine-imine. For example,
(Pyrrolopyrimidinyl)methanone-(Pyrrolopyrimidinyl)methanol
tautomeric pairs are included in the present application:
##STR00688##
[0222] The present application relates to a compound of Formula (I)
or pharmaceutically acceptable salts thereof, tautomers, prodrugs,
solvates, metabolites, polymorphs, analogs or derivatives thereof,
capable of inhibiting BTK, which are useful for the treatment of
diseases and disorders associated with modulation of a BTK kinase.
The application further relates to compounds of Formula (I), or
pharmaceutically acceptable salts thereof, tautomers, prodrugs,
solvates, metabolites, polymorphs, analogs or derivatives thereof,
which are useful for inhibiting BTK. In some embodiments, the BTK
is wild-type BTK. In other embodiments, the BTK is a mutant
BTK.
[0223] Another aspect of the application relates to a compound of
Formula (I), wherein the compound inhibits kinase activity of a
mutant BTK, such as a drug-resistant mutant BTK harboring a
drug-resistance mutation (e.g., C481S mutation). In some
embodiments, the patient or subject does not respond to a BTK
inhibitor or relapses after the treatment with a BTK inhibitor, due
to a mutation of BTK kinase (e.g., a C481S mutation) that prevents
target inhibition. In one embodiment, the BTK mutation is a C481S
mutation.
[0224] In some embodiments, the application provides a compound of
Formula (I), wherein the compound is more potent than one or more
known BTK inhibitors, including, but not limited to Ibrutinib,
GDC-0834, RN486, CGI-560, CGI-1746, HM-71224, CC-292, ONO-4059,
CNX-774, and LFM-A13, at inhibiting the activity of BTK. For
example, the compound can be at least about 2-fold, 3-fold, 5-fold,
10-fold, 25-fold, 50-fold or about 100-fold more potent (e.g., as
measured by IC.sub.50) than Ibrutinib, GDC-0834, RN486, CGI-560,
CGI-1746, HM-71224, CC-292, ONO-4059, CNX-774, and/or LFM-A13 at
inhibiting the activity of the BTK.
[0225] In some embodiments, the application provides a compound of
Formula (I), wherein the compound is more potent than one or more
known BTK inhibitors, including, but not limited to Ibrutinib,
GDC-0834, RN486, CGI-560, CGI-1746, HM-71224, CC-292, ONO-4059,
CNX-774, and LFM-A13, at inhibiting the activity of BTK containing
one or more mutations as described herein, e.g., C481S. For
example, the compound can be at least about 2-fold, 3-fold, 5-fold,
10-fold, 25-fold, 50-fold or about 100-fold more potent (e.g., as
measured by IC.sub.50) than Ibrutinib, GDC-0834, RN486, CGI-560,
CGI-1746, HM-71224, CC-292, ONO-4059, CNX-774, and/or LFM-A13 at
inhibiting the activity of the BTK containing one or more mutations
as described herein. A drug-resistant BTK mutant can have without
limitation a drug resistance mutation comprising C481S
mutation.
[0226] Potency of the inhibitor can be determined by IC.sub.50
value. A compound with a lower IC.sub.50 value, as determined under
substantially similar conditions, is a more potent inhibitor
relative to a compound with a higher IC.sub.50 value.
[0227] The compounds of the present application can be converted to
N-oxides by treatment with an oxidizing agent (e.g.,
3-chloroperoxybenzoic acid (m-CPBA) and/or hydrogen peroxides) to
afford other compounds of the present application. Thus, all shown
and claimed nitrogen-containing compounds are considered, when
allowed by valency and structure, to include both the compound as
shown and its N-oxide derivative (which can be designated as
N.fwdarw.O or N.sup.+--O.sup.-). Furthermore, in other instances,
the nitrogens in the compounds of the present application can be
converted to N-hydroxy or N-alkoxy compounds. For example,
N-hydroxy compounds can be prepared by oxidation of the parent
amine by an oxidizing agent such as m-CPBA. All shown and claimed
nitrogen-containing compounds are also considered, when allowed by
valency and structure, to cover both the compounds as shown and its
N-hydroxy (i.e., N--OH) and N-alkoxy (i.e., N--OR, wherein R is
substituted or unsubstituted C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6
alkenyl, C.sub.1-C.sub.6 alkynyl, 3-14-membered carbocycle or
3-14-membered heterocycle) derivatives.
[0228] The term "prodrug," as used in this application, means a
compound which is convertible in vivo by metabolic means (e.g., by
hydrolysis) to a disclosed compound.
[0229] Since prodrugs are known to enhance numerous desirable
qualities of pharmaceuticals (e.g., solubility, bioavailability,
manufacturing, etc.) the compounds of Formula (I), or
pharmaceutically acceptable salts, tautomers, solvates,
metabolites, polymorphs, analogs or derivatives thereof can be
delivered in prodrug form. Thus, the present application is
intended to cover prodrugs of a compound of Formula (I), or a
pharmaceutically acceptable salt, tautomer, solvate, metabolite,
polymorph, analog or derivative thereof, methods of delivering the
same and compositions containing the same. "Prodrugs" are intended
to include any covalently bonded carriers that release an active
parent drug of the present application in vivo when such prodrug is
administered to a mammalian subject. Prodrugs are prepared by
modifying functional groups present in the compound in such a way
that the modifications are cleaved, either in routine manipulation
or in vivo, to the parent compound. Prodrugs include compounds of
the application wherein a hydroxyl or amino, group is bonded to any
group that, when the prodrug of the present application is
administered to a mammalian subject, it cleaves to form a free
hydroxyl or free amino group, respectively. Examples of prodrugs
include, but are not limited to, acetate, formate, and benzoate
derivatives of alcohol and amine functional groups in the compounds
of each of the formulae described herein or a pharmaceutically
acceptable salt, solvate, prodrug, stereoisomer, or tautomer
thereof.
[0230] The term "crystal polymorphs", "polymorphs" or "crystal
forms" means crystal structures in which a compound (or a salt or
solvate thereof) can crystallize in different crystal packing
arrangements, all of which have the same elemental composition.
Different crystal forms usually have different X-ray diffraction
patterns, infrared spectral, melting points, density hardness,
crystal shape, optical and electrical properties, stability and
solubility. Recrystallization solvent, rate of crystallization,
storage temperature, and other factors may cause one crystal form
to dominate. Crystal polymorphs of the compounds can be prepared by
crystallization under different conditions.
[0231] As used herein, the term "analog" refers to a compound that
is structurally similar to another compound but differs slightly in
composition (as in the replacement of one atom by an atom of a
different element or in the presence of a particular functional
group, or the replacement of one functional group by another
functional group). Thus, an analog is a compound that is similar or
comparable in function and appearance, but not in structure or
origin to the reference compound.
[0232] The application also comprehends isotopically-labeled
compounds, which are identical to those recited in the each of the
formulae described herein, but for the fact that one or more atoms
are replaced by an atom having an atomic mass or mass number
different from the atomic mass or mass number most commonly found
in nature. Examples of isotopes that can be incorporated into
compounds of the application include isotopes of hydrogen, carbon,
nitrogen, fluorine, such as .sup.3H, .sup.11C, .sup.14C, .sup.2H
and .sup.18F.
[0233] Compounds of Formula (I), or pharmaceutically acceptable
salts, tautomers, prodrugs, solvates, metabolites, polymorphs,
analogs or derivatives thereof, that contain the aforementioned
isotopes and/or other isotopes of other atoms are within the scope
of the present application. Isotopically-labeled compounds of the
present application, for example those into which radioactive
isotopes such as .sup.3H, .sup.14C are incorporated, are useful in
drug and/or substrate tissue distribution assays. Tritiated, i.e.,
.sup.3H, and carbon-14, i.e., .sup.14C, isotopes are useful for
their ease of preparation and detectability. .sup.11C and .sup.18F
isotopes are useful in PET (positron emission tomography). PET is
useful in brain imaging. Further, substitution with heavier
isotopes such as deuterium, i.e., .sup.2H, can afford certain
therapeutic advantages resulting from greater metabolic stability,
for example increased in vivo half-life or reduced dosage
requirements and, hence, may be preferred in some circumstances,
isotopically labeled compounds of Formula (I), or pharmaceutically
acceptable salts, tautomers, prodrugs, solvates, metabolites,
polymorphs, analogs or derivatives thereof, can generally be
prepared by carrying out the procedures disclosed in the Schemes
and/or in the Examples described herein, by substituting a readily
available isotopically labeled reagent for a non-isotopically
labeled reagent. In one embodiment, the compound of Formula (I) or
pharmaceutically acceptable salts, tautomers, prodrugs, solvates,
metabolites, polymorphs, analogs or derivatives thereof, is not
isotopically labelled.
[0234] The present application relates to a compound which is a
modulator of BTK (wild-type BTK or mutant BTK). In one embodiment,
the compound of the present application is an inhibitor of BTK
(wild-type BTK or mutant BTK).
[0235] The term "administer", "administering", or "administration"
as used in this application refers to either directly administering
a disclosed compound or pharmaceutically acceptable salt of the
disclosed compound or a composition to a subject, or administering
a prodrug, derivative or analog of the compound or pharmaceutically
acceptable salt of the compound or a composition to the subject,
which can form an equivalent amount of active compound within the
subject's body.
[0236] A "patient" or "subject" is a mammal, e.g., a human, mouse,
rat, guinea pig, dog, cat, horse, cow, pig, or non-human primate,
such as a monkey, chimpanzee, baboon or rhesus.
[0237] An "effective amount" or "therapeutically effective amount"
when used in connection with a compound or pharmaceutical
composition is an amount effective for treating or preventing a
disease in a subject as described herein.
[0238] The term "treating" with regard to a subject, refers to
improving at least one symptom of the subject's disorder. Treating
includes curing, improving, or at least partially ameliorating the
disorder.
[0239] The compounds of the present application, or a
pharmaceutically acceptable salt, solvate, prodrug, stereoisomer,
or tautomer thereof, can also be used to prevent a disease,
condition or disorder. As used herein, "preventing" or "prevent"
describes reducing or eliminating the onset of the symptoms or
complications of the disease, condition or disorder.
[0240] The term "disorder" is used in this application to mean, and
is used interchangeably with, the terms disease, condition, or
illness, unless otherwise indicated.
[0241] As used herein, the term "BTK-mediated" diseases or
disorders means any disease or other deleterious condition in which
BTK, or a mutant thereof, is known to play a role. Accordingly,
another embodiment of the present application relates to treating
or lessening the severity of one or more diseases in which BTK, or
a mutant thereof, is known to play a role. Specifically, the
present application relates to a method of treating or lessening
the severity of a disease or condition selected from a
proliferative disorder or an autoimmune disorder, wherein said
method comprises administering to a subject in need thereof a
compounds of Formula (I), or pharmaceutically acceptable salts,
tautomers, prodrugs, solvates, metabolites, polymorphs, analogs or
derivatives thereof, or a composition according to the present
application.
[0242] As used herein, the term "cell proliferative disorder"
refers to conditions in which unregulated or abnormal growth, or
both, of cells can lead to the development of an unwanted condition
or disease, which may or may not be cancerous. Exemplary cell
proliferative disorders of the application encompass a variety of
conditions wherein cell division is deregulated. Exemplary cell
proliferative disorder include, but are not limited to, neoplasms,
benign tumors, malignant tumors, pre-cancerous conditions, in situ
tumors, encapsulated tumors, metastatic tumors, liquid tumors,
solid tumors, immunological tumors, hematological tumors, cancers,
carcinomas, leukemias, lymphomas, sarcomas, and rapidly dividing
cells. The term "rapidly dividing cell" as used herein is defined
as any cell that divides at a rate that exceeds or is greater than
what is expected or observed among neighboring or juxtaposed cells
within the same tissue. A cell proliferative disorder includes a
precancer or a precancerous condition. A cell proliferative
disorder includes cancer. Preferably, the methods provided herein
are used to treat or alleviate a symptom of cancer. The term
"cancer" includes solid tumors, as well as, hematologic tumors
and/or malignancies. A "precancer cell" or "precancerous cell" is a
cell manifesting a cell proliferative disorder that is a precancer
or a precancerous condition. A "cancer cell" or "cancerous cell" is
a cell manifesting a cell proliferative disorder that is a cancer.
Any reproducible means of measurement may be used to identify
cancer cells or precancerous cells. Cancer cells or precancerous
cells can be identified by histological typing or grading of a
tissue sample (e.g., a biopsy sample). Cancer cells or precancerous
cells can be identified through the use of appropriate molecular
markers.
[0243] Exemplary non-cancerous conditions or disorders include, but
are not limited to, rheumatoid arthritis; inflammation; autoimmune
disease; lymphoproliferative conditions; acromegaly; rheumatoid
spondylitis; osteoarthritis; gout, other arthritic conditions;
sepsis; septic shock; endotoxic shock; gram-negative sepsis; toxic
shock syndrome; asthma; adult respiratory distress syndrome;
chronic obstructive pulmonary disease; chronic pulmonary
inflammation; inflammatory bowel disease; Crohn's disease;
psoriasis; eczema; ulcerative colitis; pancreatic fibrosis; hepatic
fibrosis; acute and chronic renal disease; irritable bowel
syndrome; pyresis; restenosis; cerebral malaria; stroke and
ischemic injury; neural trauma; Alzheimer's disease; Huntington's
disease; Parkinson's disease; acute and chronic pain; allergic
rhinitis; allergic conjunctivitis; chronic heart failure; acute
coronary syndrome; cachexia; malaria; leprosy; leishmaniasis; Lyme
disease; Reiter's syndrome; acute synovitis; muscle degeneration,
bursitis; tendonitis; tenosynovitis; herniated, ruptures, or
prolapsed intervertebral disk syndrome; osteopetrosis; thrombosis;
restenosis; silicosis; pulmonary sarcosis; bone resorption
diseases, such as osteoporosis; graft-versus-host reaction;
Multiple Sclerosis; lupus; fibromyalgia; AIDS and other viral
diseases such as Herpes Zoster, Herpes Simplex I or II, influenza
virus and cytomegalovirus; and diabetes mellitus.
[0244] Exemplary cancers include, but are not limited to,
adrenocortical carcinoma, AIDS-related cancers, AIDS-related
lymphoma, anal cancer, anorectal cancer, cancer of the anal canal,
appendix cancer, childhood cerebellar astrocytoma, childhood
cerebral astrocytoma, basal cell carcinoma, skin cancer
(non-melanoma), biliary cancer, extrahepatic bile duct cancer,
intrahepatic bile duct cancer, bladder cancer, urinary bladder
cancer, bone and joint cancer, osteosarcoma and malignant fibrous
histiocytoma, brain cancer, brain tumor, brain stem glioma,
cerebellar astrocytoma, cerebral astrocytoma/malignant glioma,
ependymoma, medulloblastoma, supratentorial primitive
neuroectodermal tumors, visual pathway and hypothalamic glioma,
breast cancer, bronchial adenomas/carcinoids, carcinoid tumor,
gastrointestinal, nervous system cancer, nervous system lymphoma,
central nervous system cancer, central nervous system lymphoma,
cervical cancer, childhood cancers, chronic lymphocytic leukemia,
chronic myelogenous leukemia, chronic myeloproliferative disorders,
colon cancer, colorectal cancer, cutaneous T-cell lymphoma,
lymphoid neoplasm, mycosis fungoides, Seziary Syndrome, endometrial
cancer, esophageal cancer, extracranial germ cell tumor,
extragonadal germ cell tumor, extrahepatic bile duct cancer, eye
cancer, intraocular melanoma, retinoblastoma, gallbladder cancer,
gastric (stomach) cancer, gastrointestinal carcinoid tumor,
gastrointestinal stromal tumor (GIST), germ cell tumor, ovarian
germ cell tumor, gestational trophoblastic tumor glioma, head and
neck cancer, hepatocellular (liver) cancer, Hodgkin lymphoma,
hypopharyngeal cancer, intraocular melanoma, ocular cancer, islet
cell tumors (endocrine pancreas), Kaposi Sarcoma, kidney cancer,
renal cancer, kidney cancer, laryngeal cancer, acute lymphoblastic
leukemia, acute myeloid leukemia, chronic lymphocytic leukemia,
chronic myelogenous leukemia, hairy cell leukemia, lip and oral
cavity cancer, liver cancer, lung cancer, non-small cell lung
cancer, small cell lung cancer, AIDS-related lymphoma, non-Hodgkin
lymphoma, primary central nervous system lymphoma, Waldenstram
macroglobulinemia, medulloblastoma, melanoma, intraocular (eye)
melanoma, merkel cell carcinoma, mesothelioma malignant,
mesothelioma, metastatic squamous neck cancer, mouth cancer, cancer
of the tongue, multiple endocrine neoplasia syndrome, mycosis
fungoides, myelodysplastic syndromes,
myelodysplastic/myeloproliferative diseases, chronic myelogenous
leukemia, acute myeloid leukemia, multiple myeloma, chronic
myeloproliferative disorders, nasopharyngeal cancer, neuroblastoma,
oral cancer, oral cavity cancer, oropharyngeal cancer, ovarian
cancer, ovarian epithelial cancer, ovarian low malignant potential
tumor, pancreatic cancer, islet cell pancreatic cancer, paranasal
sinus and nasal cavity cancer, parathyroid cancer, penile cancer,
pharyngeal cancer, pheochromocytoma, pineoblastoma and
supratentorial primitive neuroectodermal tumors, pituitary tumor,
plasma cell neoplasm/multiple myeloma, pleuropulmonary blastoma,
prostate cancer, rectal cancer, renal pelvis and ureter,
transitional cell cancer, retinoblastoma, rhabdomyosarcoma,
salivary gland cancer, ewing family of sarcoma tumors, Kaposi
Sarcoma, soft tissue sarcoma, uterine cancer, uterine sarcoma, skin
cancer (non-melanoma), skin cancer (melanoma), merkel cell skin
carcinoma, small intestine cancer, soft tissue sarcoma, squamous
cell carcinoma, stomach (gastric) cancer, supratentorial primitive
neuroectodermal tumors, testicular cancer, throat cancer, thymoma,
thymoma and thymic carcinoma, thyroid cancer, transitional cell
cancer of the renal pelvis and ureter and other urinary organs,
gestational trophoblastic tumor, urethral cancer, endometrial
uterine cancer, uterine sarcoma, uterine corpus cancer, vaginal
cancer, vulvar cancer, and Wilm's Tumor.
Methods for Preparing the Compounds
[0245] The compounds of the present application may be made by a
variety of methods, including standard chemistry. Suitable
synthetic routes are depicted in the Schemes given below.
[0246] The compounds of Formula (I) may be prepared by methods
known in the art of organic synthesis as set forth in part by the
following synthetic schemes. In the scheme described below, it is
well understood that protecting groups for sensitive or reactive
groups are employed where necessary in accordance with general
principles or chemistry. Protecting groups are manipulated
according to standard methods of organic synthesis (T. W. Greene
and P. G. M. Wuts, "Protective Groups in Organic Synthesis", Third
edition, Wiley, New York 1999). These groups are removed at a
convenient stage of the compound synthesis using methods that are
readily apparent to those skilled in the art. The selection
processes, as well as the reaction conditions and order of their
execution, shall be consistent with the preparation of the
compounds of the present application.
[0247] Those skilled in the art will recognize if a stereocenter
exists in the compounds of Formula (I). Accordingly, the present
application includes both possible stereoisomers (unless specified
in the synthesis) and includes not only racemic compound but the
individual enantiomers and/or diastereomers as well. When a
compound is desired as a single enantiomer or diastereomer, it may
be obtained by stereospecific synthesis or by resolution of the
final product or any convenient intermediate. Resolution of the
final product, an intermediate, or a starting material may be
affected by any suitable method known in the art. See, for example,
"Stereochemistry of Organic Compounds" by E. L. Eliel, S. H. Wilen,
and L. N. Mander (Wiley-lnterscience, 1994).
[0248] The compounds described herein may be made from commercially
available starting materials or synthesized using known organic,
inorganic, and/or enzymatic processes.
[0249] The compounds of the present application can be prepared in
a number of ways well known to those skilled in the art of organic
synthesis. By way of example, the compounds of the present
application can be synthesized using the methods described below,
together with synthetic methods known in the art of synthetic
organic chemistry, or variations thereon as appreciated by those
skilled in the art. Preferred methods include but are not limited
to those methods described below. The compounds of the present
application (i.e., a compound of Formula (I)) can be synthesized by
following the steps outlined in General Schemes 1-3 which comprises
a sequence of assembling intermediates 7-a to 7-i. Starting
materials are either commercially available or made by known
procedures in the reported literature or as illustrated.
##STR00689##
[0250] The general way of preparing compounds of Formula (I) by
using intermediates 7-a, 7-b, 7-c, and 7-d is outlined in General
Scheme 1 and further illustrated in Example 2. Acylation of 7-a
with aroyl chloride or heteroaroyl chloride 7-b using a lewis acid
catalyst (e.g., aluminum chloride (AlCl.sub.3)) and a solvent
(e.g., nitrobenzene, toluene, etc.) provides intermediate 7-c.
Amination of 7-c with amine 7-d optionally using a base (e.g.,
triethylamine (TEA), pyridine, and/or potassium carbonate
(K.sub.2CO.sub.3)), optionally in a solvent (e.g.,
N,N-dimethylformamide (DMF), isopropyl alcohol, etc.) and
optionally at elevated temperature provides a compound of Formula
(I).
##STR00690##
[0251] X is Cl or O-alkyl
[0252] Another general way of preparing compounds of Formula (I) by
using intermediates 7-e, 7-b', 7-c, and 7-d is outlined in General
Scheme 2 and further illustrated in Example 99. Acylation of 7-e
with aroyl chloride or heteroaroyl chloride or alkyl ester 7-b'
using a strong base (e.g., n-butyl lithium) and a solvent (e.g.,
hexanes, tetrahydrofuran, diethylether, etc.) provides intermediate
7-c. Amination of 7-c with amine 7-d optionally using a base (e.g.,
triethylamine (TEA), pyridine, and/or potassium carbonate
(K.sub.2CO.sub.3)), optionally in a solvent (e.g.,
N,N-dimethylformamide (DMF), isopropyl alcohol, etc.) and
optionally at elevated temperature provides a compound of Formula
(I).
##STR00691##
[0253] Another general way of preparing compounds of Formula (I) by
using intermediates 7-b, 7-d, 7-f, 7-g, 7-h, and 7-i is outlined in
General Scheme 3 and further illustrated in Example 141. Acylation
of 7-f with aroyl chloride or heteroaroyl chloride 7-b using a
lewis acid catalyst (e.g., aluminum chloride (AlCl.sub.3)) and a
solvent (e.g., nitrobenzene, toluene, etc.) provides intermediate
7-g. Amination of 7-g with amine 7-d optionally using a base (e.g.,
triethylamine (TEA), pyridine, and/or potassium carbonate
(K.sub.2CO.sub.3)), optionally in a solvent (e.g.,
N,N-dimethylformamide (DMF), isopropyl alcohol, etc.) and
optionally at elevated temperature provides intermediate 7-h.
Amination of 7-h with amine 7-i optionally using a base (e.g.,
triethylamine (TEA), pyridine, and/or potassium carbonate
(K.sub.2CO.sub.3)), optionally in a solvent (e.g.,
N,N-dimethylformamide (DMF), isopropyl alcohol, etc.) and
optionally at elevated temperature provides a compound of Formula
(I).
##STR00692##
General Procedure D
##STR00693##
[0255] To a solution of pyrrolo[2,3-d]pyrimidine (8-A) (1 eq.) in
DMF (1 mL/0.28 mmol) at room temperature was added potassium
carbonate (2 eq.) and SEM-Cl (1.2 eq.). The reaction mixture was
stirred at room temperature for 3 hours. The reaction mixture was
then poured into 1:1 water/EtOAc and partitioned. The aqueous layer
was extracted with EtOAc. The combined organic layers were washed
with brine, dried over MgSO.sub.4, filtered and concentrated to
dryness. The residue was purified by flash chromatography on silica
gel eluting with 30-100% EtOAc/hexanes to afford the product.
General Procedure E
##STR00694##
[0257] A suspension of the arylnitro compound (9-A) (1 eq.),
ammonium chloride (10 eq. and iron (5 eq) in EtOH (1 mL/0.12 mmol)
and water (1 mL/0.25 mmol) was heated to 80.degree. C. for 2 hours.
Upon cooling to room temperature, methanol was added, the reaction
mixture was vigorously stirred for 30 min, filtered through Celite
and washed with methanol and EtOAc. The filtrate was concentrated
to dryness. The residue was triturated in water and the solids were
collected by filtration, dried under high vacuum to afford the
corresponding arylamine.
General Procedure F
##STR00695##
[0259] To a solution of the arylamine (10-A) (1 eq.) in DMF (2
mL/0.16 mmol) were added carboxylic acid (1.5 eq.), HATU (1.2 eq.)
and DIPEA (2.5 eq.) and the reaction mixture was allowed to stir at
room temperature for 18 hours or heated to 40-50.degree. C. for
3-90 hours. Upon cooling to room temperature, the reaction mixture
diluted with aqueous saturated NaHCO.sub.3 and ethyl acetate. The
layers were partitioned and the aqueous layer was extracted with
ethyl acetate. The combined organic layer were washed with brine,
dried over magnesium sulfate, filtered and concentrated to dryness
under reduced pressure. The crude product was adsorbed onto silica
gel for purification by ISCO CombiFlash (eluted with 0-10% MeOH/DCM
or EtOAc/hexanes) or purified by reverse phase C18 column
chromatography (10-95% acetonitrile in water, 0.1% formic acid) to
yield the amide product (11-A).
General Procedure G
##STR00696##
[0261] To a solution of the arylamine (1 eq.) in THF (2 mL/0.343
mmol) were added isocyanate (1.2 eq.) and DIPEA (2.5 eq.). The
reaction mixture was allowed to stir at room temperature for 18
hours. The volatiles were removed under reduced pressure and the
residue was adsorbed in silica gel purification by ISCO CombiFlash
eluting with EtOAc/hexanes to yield the urea product.
General Procedure H
##STR00697##
[0263] To a solution of SEM-protected substrate (8-A) (1 eq.) in
DCM (1 mL/0.044 mmol) was added a solution of HCl (4 N in dioxane,
60-81 eq.). The mixture was heated to 40.degree. C. for 18 hours
and concentrated to dryness under reduced pressure. The residue was
diluted with 10 mL of DCM/MeOH/NH.sub.4OH (90:9:1) and adsorbed
onto silica gel for purification by flash chromatography on silica
gel eluting with MeOH/DCM (9:1) and DCM/MeOH/NH.sub.4OH (90:9:1) to
yield the deprotected product.
##STR00698##
Step 1
[0264] To a solution of aryl halide (14-A) in DMA (1 mL/0.12 mmol)
was added zinc dust (0.1 eq.) and zinc cyanide (0.5 eq.). The
mixture was bubbled with nitrogen gas for 10 min, and
Pd(PPh.sub.3).sub.4 (0.05 eq.) was added. The mixture was bubbled
again with nitrogen for 10 min and heated to 85.degree. C.
overnight. Upon cooling to room temperature, the reaction mixture
was diluted with EtOAc and water. The layers were partitioned; the
aqueous layer was extracted with EtOAc. The combined organic layers
were washed with brine, dried over MgSO.sub.4, and concentrated
under reduced pressure. The residue was purified by flash
chromatography on silica gel using MeOH/DCM to afford the desired
material.
Step 2
[0265] The benzonitrile substrate (15-A) (1 eq.) was suspended in
EtOH (1 mL/0.05 mmol) and 2N NaOH (10 eq.) was added. The
suspension became a clear yellow solution. The reaction mixture was
heated at 85.degree. C. overnight. Upon cooling to room
temperature, the pH was adjusted to 6 with 1N HCl and the mixture
was concentrated to dryness under reduced pressure. The residue was
dissolved in DMF to make a stock solution of 0.04 M. The mixture
was filtered through fritted funnel to remove NaCl residue. The
stock solution of the benzoic acid product (0.04 M) was used as
such for subsequent amide coupling without further
purification.
Step 3
[0266] To the benzoic acid substrate (16-A) (1 eq.) in DMF (0.04 M)
was added amine (1.1 eq.), EDCi (1.2 eq.) and HOAt (1.3 eq.) and
the reaction mixture was allowed to stir at room temperature for
3-72 hours. Water (2-5 mL/mmol) was added and the mixture was
concentrated to dryness under reduced pressure. The crude product
was adsorbed onto silica gel for purification by ISCO CombiFlash
eluting with 0-10% MeOH/DCM. Purification by reverse phase C18
column chromatography (5-95% acetonitrile in water, 0.1% Formic
acid) was also used as an alternative method. The product fractions
were combined and concentrated to dryness under reduced pressure to
yield the amide product.
Step 3 (Alternative Method)
[0267] To the benzoic acid substrate (16-A) (1 eq.) in DMF (0.04 M)
was added amine (1.5-3 eq.), HATU (1.5-2 eq.) and DIPEA (2.5-5 eq.)
and the reaction mixture was allowed to stir at room temperature
for 18 hours or heated to 60.degree. C. for 18 hours. Water (2-5
mL/mmol) was added and the mixture was concentrated to dryness
under reduced pressure or the reaction mixture was diluted with
aqueous saturated NaHCO.sub.3 and ethyl acetate. The layers were
partitioned and the aqueous layer was extracted with ethyl acetate.
The combined organic layer were washed with brine, dried over
magnesium sulfate, filtered and concentrated to dryness under
reduced pressure. The crude product was adsorbed onto silica gel
for purification by ISCO CombiFlash eluting with 0-10% MeOH/DCM or
purified by high pressure HPLC system (column: Max-RP C-18,
21.times.50 mm, 10 .mu.M), 10-80% acetonitrile in water, +0.1%
formic acid) to yield the amide product.
##STR00699##
General Procedure I
[0268] General Procedure for the Saponification of a Benzoic
Ester
##STR00700##
[0269] The benzoic ester substrate (17-A) (1 eq.) were suspended in
THF (1 mL/0.2 mmol) and methanol (1 mL/0.2 mmol). A solution of 1N
lithium hydroxide was then added (2 eq.) and left to stir at room
temperature overnight. The reaction crude was neutralized with a 1N
aqueous solution of HCl and was concentrated to dryness. The crude
product was used as is without further purification.
##STR00701## ##STR00702##
##STR00703##
##STR00704##
##STR00705##
##STR00706##
##STR00707##
##STR00708##
##STR00709##
##STR00710##
##STR00711##
##STR00712## ##STR00713##
##STR00714##
##STR00715##
General Procedure J
[0270] A general method for amide formation using an acyl chloride
with silyl-protected aniline substrate followed by desilylation
##STR00716##
[0271] A solution of
(4-amino-2-chlorophenyl)(4-(((3R,6S)-6-(((tert-butyldimethylsilyl)
oxy)methyl)-tetrahydro-2H-pyran-3-yl)amino)-7-((2-(trimethylsilyl)ethoxy)-
methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (23-A) (1 eq) in
DCM (1 mL/0.05 mmol) is treated with corresponding acyl chloride
(1.5 eq) and triethylamine (3 eq) at room temperature for 3 h. The
mixture is then concentrated and 4M HCl in dioxane (2 mL/0.05 mmol)
is added. The mixture is stirred at 40.degree. C. overnight then
concentrated and the residue purified by preparative reverse phase
HPLC (gradient from 30% to 95% of acetonitrile+0.1% formic
acid).
Step 5: Synthesis of
N-(3-chloro-4-(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amin-
o)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)phenyl)benzamide
(I-276)
[0272]
N-(3-Chloro-4-(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-y-
l)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)phenyl)benzamide
was synthesized according to General Scheme 7, using benzoyl
chloride. .sup.1H NMR (DMSO-d.sub.6, 400 MHz): .delta. 12.90 (bs,
1H), 10.62 (s, 1), 8.85 (bs, 1H), 8.29 (s, 1H), 8.13 (d, J=1.8 Hz,
1H), 7.99-7.97 (m, 2H), 7.87 (dd, J=8.4 Hz, J=1.8 Hz, 1H),
7.65-7.55 (m, 5H), 4.18-4.10 (m, 2H), 3.45-3.33 (m, 3H), 3.18-3.13
(m, 1H), 2.22-2.19 (m, 1H), 1.81-1.75 (m, 1H), 1.66-1.56 (m, 1H),
1.44-1.34 (m, 1H). LCMS [M+H].sup.+: 506.2.
General Procedure K
A General Procedure for Arylamine Formation
##STR00717##
[0274] The arylfluoride substrate (26-A) (1 eq.) was diluted in NMP
(1 mL/1.32 mmol). Cyclic amine (1.1 eq.) and potassium carbonate (2
eq.) were added and the mixture was stirred at 120.degree. C.
overnight. The reaction mixture was allowed to cool to room
temperature and was diluted with water. The crude mixture was
extracted with ethyl acetate (.times.3) and the combined organics
were washed with water (.times.2). Organics were dried over
magnesium sulfate, filtered and concentrated to dryness. The
product was purified by silica gel chromatography (0-50% ethyl
acetate in hexanes).
General Procedure L
A General Procedure for Phenol Alkylation
##STR00718##
[0276] A mixture of phenol (26-B) (1 eq.), 1-chloro-2-methoxyethane
(1.5 eq.), potassium carbonate (2 eq.) and sodium iodide (0.2 eq.)
in DMF (1 mL/0.45 mmol) is heated overnight at 80.degree. C. The
reaction mixture is then cooled to room temperature and poured in
water, stirred for 15 min and filtered then dried under high
vacuum. The product was used as is without further
purification.
General Procedure M
A General Procedure for Ketone Formation Through Aryllithium Attack
on an Ester
##STR00719##
[0278] 5-bromo-4-chloro-7H-pyrrolo[2,3-d]pyrimidine (3-A) (1 eq.)
was diluted in dry THF (1 mL/0.21 mmol) and was cooled to
-78.degree. C. n-BuLi (2.1 eq.) was added dropwise and the
temperature was monitored with an internal thermocouple to ensure
the reaction temperature never rose above -60.degree. C. The
reaction mixture was stirred for 1 hour before the substituted
methyl benzoate (27-A/B) (1.05 eq.) in dry THF (1 mL/0.9 mmol) was
added dropwise with the internal temperature never exceeding
-60.degree. C. The mixture was stirred at -78.degree. C. for 1 hour
then quenched with saturated aqueous Ammonium chloride solution and
extracted with ethyl acetate (.times.3). The combined organic
layers were washed with sodium bicarbonate and dried over magnesium
sulfate, filtered and concentrated. The resulting residue was
purified by silica gel column chromatography (10-100% ethyl acetate
in hexanes).
General Procedure N
[0279] One general procedure for formation of a diaryl ether is
described.
##STR00720##
[0280] Fluoropyridine substrate (29-B) (1 eq.),
methyl-hydroxy-benzoate (29-A) (1 eq.) and potassium carbonate (1
eq.) were dissolved in DMSO (1 mL/0.3 mmol). The mixture was
stirred at 120.degree. C. under argon atmosphere overnight. After
cooled, the reaction mixture was diluted in water and extracted
several times with ethyl acetate. Combined organics were washed
with water and dried over magnesium sulfate and concentrated under
reduced pressure. The product was purified by column chromatography
(0-100% ethyl acetate in hexanes).
General Procedure 0
[0281] One general procedure for Boc-deprotection is described.
##STR00721##
[0282] Boc-protected amine (37-A/B) (1.0 equiv) was dissolved in
DCM (1.0 mL/mmol) and a 4.0M HCl/Dioxane solution (4.0 equiv) was
added. Mixture was stirred at room temperature for 2.0 h, then
concentrated under vacuum. A 1:10 solution of aqueous ammonia in
EtOH was added until complete dissolution of the residue. The
residue was absorbed onto silica and purified by normal phase
column chromatography to give the purified amine product.
Step 2: Synthesis of
(racemic)-(2-chloro-4-phenoxyphenyl)(4-(piperidin-3-ylamino)-7H-pyrrolo[2-
,3-d]pyrimidin-5-yl)methanone (38-A)
Step 2': Synthesis of
(racemic)-(2-chloro-4-phenoxyphenyl)(4-((pyrrolidin-2-ylmethyl)amino)-7H--
pyrrolo[2,3-d]pyrimidin-5-yl)methanone (38-B)
General Procedure P
One General Procedure for Vinysulfonamide Formation.
##STR00722##
[0284] A solution of 2-chloroethanesulfonyl chloride (1.0 equiv)
and Et.sub.3N (1.0 equiv) in DCM (18 mL/mmol) cooled to 0.degree.
C. was added dropwise to a suspension of secondary amine (38-A/B)
(1.0 equiv) and Et.sub.3N (1.0 equiv) in DCM (18 mL/mmol), also
cooled to 0.degree. C. After 15 minutes, the reaction mixture was
washed with saturated aqueous NaHCO.sub.3 (twice), dried over
MgSO.sub.4 and concentrated under vacuum. The residue was purified
by normal phase chromatography (75%-100% EtOAc/hexanes).
[0285] A mixture of enantiomers, diastereomers, cis/trans isomers
resulting from the processes described above can be separated into
their single components by chiral salt technique, chromatography
using normal phase, reverse phase or chiral column, depending on
the nature of the separation.
Analytical Methods, Materials, and Instrumentation
[0286] Unless otherwise noted, reagents and solvents were used as
received from commercial suppliers. Proton nuclear magnetic
resonance (NMR) spectra were obtained on either Bruker or Varian
spectrometers at 400 MHz. Spectra are given in ppm (.delta.) and
coupling constants, J, are reported in Hertz. Tetramethylsilane
(TMS) was used as an internal standard. Mass spectra were collected
using a Waters ZQ Single Quad Mass Spectrometer (ion trap ESI).
Purity and low resolution mass spectral data were measured using
Waters Acquity i-class ultra-performance liquid chromatography
(UPLC) system with Acquity Photo Diode Array Detector, Acquity
Evaporative Light Scattering Detector (ELSD) and Waters ZQ Mass
Spectrometer. Data was acquired using Waters MassLynx 4.1 software
and purity characterized by UV wavelength 220 nm, ELSD and ESI.
Column: Acquity UPLC BEH C18 1.7 .mu.m 2.1.times.50 mm; Flow rate
0.6 mL/min; Solvent A (95/5/0.1 10 mM ammonium
formate/acetonitrile/formic acid), Solvent B (95/5/0.09
acetonitrile/water/formic acid); gradient: 5-100% B from 0 to 2
min, hold 100% B to 2.2 min, then 5% B at 2.21 min.
[0287] Abbreviations used in the following examples and elsewhere
herein are:
[0288] DIPEA N,N-diisopropylethylamine
[0289] DMF N,N-dimethylformamide
[0290] DMSO dimethylsulfoxide
[0291] IPA iso-propyl alcohol
[0292] IPE di-isopropyl ether
[0293] LC/MS liquid chromatography-mass spectrometry
[0294] MeOH methanol
[0295] MS mass spectrometry
[0296] n-BuOH n-butyl alcohol
[0297] NMP N-methyl pyrrolidinone
[0298] NMR nuclear magnetic resonance
[0299] ppm parts per million
[0300] TEA triethylamine
Biological Assays
[0301] Radiometric Assay
[0302] Enzyme assay using full length recombinant active form of
wild-type BTK and BTK-C481S is measured as described previously
(Anastassiadis T, et al., Nat. Biotechnol. 29(11):1039-45 (2011)).
Compounds are tested in multi-point dose IC.sub.50 mode with
several folds serial dilution. BTK kinase activity is assayed in a
buffer solution. Compounds are mixed with kinase (wild-type BTK or
mutant BTK), and substrate is added into the kinase reaction
mixture and incubated. The reaction is initiated by adding ATP
containing .sup.33P-ATP into the mixture and incubated. Kinase
activity is detected by P81 filter-binding .sup.33P radioisotope
based radiometric method. The raw data is fit to a 4-parameter
logistic model to derive the IC.sub.50 value for kinase activity
inhibition.
[0303] Mobility Shift Assay
[0304] Compounds are tested either in the inactive or active BTK
assays on Caliper LabChip microfluidic mobility shift assay
platform.
[0305] Full length unphosphorylated form of BTK expressed in Sf9
cells is employed to test inhibitory activity in the inactive BTK
assay. The enzyme and increasing concentrations of inhibitor are
incubated, and the kinase reaction is initiated by the addition an
activation mixture containing ATP. The plates are incubated, and
after the reaction is stopped, measured.
[0306] The active BTK assay consists of phosphorylated form of full
length BTK. The assay is performed in a buffer solution utilized in
the inactive BTK assay. The enzyme inhibitor complexes is
incubated, before the kinase activation reaction is initiated.
After incubation, the reaction is stopped and the mobility shift is
measured as described above for the inactive BTK assay. The data of
inactive and active BTK assays is fit to a 4 parameter logistic
model to calculate the IC.sub.50 value.
Methods of Using the Compounds
[0307] Another aspect of the application relates to a method of
treating, preventing, inhibiting, or eliminating a disease or
disorder associated with modulation of BTK (e.g., inhibition of
BTK). The method comprises administering to a subject in need of a
treatment for diseases or disorders associated with modulation of
BTK an effective amount a compound of Formula (I) or a
pharmaceutically acceptable salt, solvate, prodrug, stereoisomer,
or tautomer thereof or a pharmaceutical composition of a compound
of Formula (I). In one embodiment, the BTK-mediated disorder is
selected from immune disorders, cancer, cardiovascular diseases,
viral infections, inflammation, metabolism/endocrine function
disorders and neurological disorders. In some embodiments, the
method further comprises administering an additional therapeutic
agent selected from an anti-inflammatory agent, an immunomodulatory
agent, chemotherapeutic agent, a neurotropic factor, an agent for
treating cardiovascular disease, an agent for treating liver
disease, an anti-viral agent, an agent for treating blood
disorders, an agent for treating diabetes, and an agent for
treating immunodeficiency disorders. In some embodiments, the BTK
is wild-type BTK. In other embodiments, the BTK is mutant BTK
(e.g., BTK C481S mutant).
[0308] Another aspect of the application relates to a method of
treating, preventing, inhibiting, or eliminating a cell
proliferative disorder, the method comprising administering to a
subject in need thereof a therapeutically effective amount of a
compound of Formula (I), or a pharmaceutically acceptable salt,
solvate, prodrug, stereoisomer, or tautomer thereof, or a
pharmaceutical composition of a compound of Formula (I). In one
embodiment, the cell proliferative disorder is a cancer. In some
embodiments, the method further comprises administering an
additional therapeutic agent selected from an anti-inflammatory
agent, an immunomodulatory agent, chemotherapeutic agent, a
neurotropic factor, an agent for treating cardiovascular disease,
an agent for treating liver disease, an anti-viral agent, an agent
for treating blood disorders, an agent for treating diabetes, and
an agent for treating immunodeficiency disorders.
[0309] Another aspect of the application relates to a method of
modulating BTK, the method comprising administering to a subject in
need thereof a therapeutically effective amount of a compound of
Formula (I), or a pharmaceutically acceptable salt, solvate,
prodrug, stereoisomer, or tautomer thereof, or a pharmaceutical
composition of a compound of Formula (I). In one embodiment,
modulating BTK is inhibiting BTK. In some embodiments, the BTK is
wild-type BTK. In other embodiments, the BTK is mutant BTK (e.g.,
BTK C481S mutant).
[0310] Another aspect of the application relates to a compound of
Formula (I), or a pharmaceutically acceptable salt, solvate,
prodrug, stereoisomer, or tautomer thereof, for use in a method of
treating a BTK-mediated disorder. In one embodiment, the disease or
disorder is selected from immune disorders, cancer, cardiovascular
diseases, viral infections, inflammation, metabolism/endocrine
function disorders and neurological disorders. In some embodiments,
the method further comprises administering an additional
therapeutic agent selected from an anti-inflammatory agent, an
immunomodulatory agent, chemotherapeutic agent, a neurotropic
factor, an agent for treating cardiovascular disease, an agent for
treating liver disease, an anti-viral agent, an agent for treating
blood disorders, an agent for treating diabetes, and an agent for
treating immunodeficiency disorders. In some embodiments, the BTK
is wild-type BTK. In other embodiments, the BTK is mutant BTK
(e.g., BTK C481S mutant).
[0311] In another aspect, the present application relates to a
pharmaceutical composition of a compound of Formula (I), or a
pharmaceutically acceptable salt, solvate, prodrug, stereoisomer,
or tautomer thereof, for use in a method of treating a BTK-mediated
disorder. In one embodiment, the disease or disorder is selected
from immune disorders, cancer, cardiovascular diseases, viral
infections, inflammation, metabolism/endocrine function disorders
and neurological disorders. In some embodiments, the method further
comprises administering an additional therapeutic agent selected
from an anti-inflammatory agent, an immunomodulatory agent,
chemotherapeutic agent, a neurotropic factor, an agent for treating
cardiovascular disease, an agent for treating liver disease, an
anti-viral agent, an agent for treating blood disorders, an agent
for treating diabetes, and an agent for treating immunodeficiency
disorders. In some embodiments, the BTK is wild-type BTK. In other
embodiments, the BTK is mutant BTK (e.g., BTK C481S mutant).
[0312] Another aspect of the application relates to a compound of
Formula (I), or a pharmaceutically acceptable salt, solvate,
prodrug, stereoisomer, or tautomer thereof, for use in a method of
treating, preventing, inhibiting, or eliminating a cell
proliferative disorder. In one embodiment, the cell proliferative
disorder is a cancer.
[0313] In another aspect, the present application relates to a
pharmaceutical composition of a compound of Formula (I), or a
pharmaceutically acceptable salt, solvate, prodrug, stereoisomer,
or tautomer thereof, for use in a method of treating, preventing,
inhibiting, or eliminating a cell proliferative disorder. In one
embodiment, the cell proliferative disorder is a cancer.
[0314] Another aspect of the application relates to a compound of
Formula (I), or a pharmaceutically acceptable salt, solvate,
prodrug, stereoisomer, or tautomer thereof, for use in modulating
BTK. In one embodiment, modulating BTK is inhibiting BTK. In some
embodiments, the BTK is wild-type BTK. In other embodiments, the
BTK is mutant BTK (e.g., BTK C481S mutant).
[0315] In another aspect, the present application relates to a
pharmaceutical composition of a compound of Formula (I), or a
pharmaceutically acceptable salt, solvate, prodrug, stereoisomer,
or tautomer thereof, for use in modulating BTK. In one embodiment,
modulating BTK is inhibiting BTK. In some embodiments, the BTK is
wild-type BTK. In other embodiments, the BTK is mutant BTK (e.g.,
BTK C481S mutant).
[0316] Another aspect of the application relates to the use of a
compound of Formula (I), or a pharmaceutically acceptable salt,
solvate, prodrug, stereoisomer, or tautomer thereof, in the
manufacture of a medicament for treating a BTK-mediated disease or
disorder. In one embodiment, the disease or disorder is selected
from immune disorders, cancer, cardiovascular diseases, viral
infections, inflammation, metabolism/endocrine function disorders
and neurological disorders. In some embodiments, the treatment
further comprises administering an additional therapeutic agent
selected from an anti-inflammatory agent, an immunomodulatory
agent, chemotherapeutic agent, a neurotropic factor, an agent for
treating cardiovascular disease, an agent for treating liver
disease, an anti-viral agent, an agent for treating blood
disorders, an agent for treating diabetes, and an agent for
treating immunodeficiency disorders. In some embodiments, the BTK
is wild-type BTK. In other embodiments, the BTK is mutant BTK
(e.g., BTK C481S mutant).
[0317] In another aspect, the present application relates to the
use of a pharmaceutical composition of a compound of Formula (I),
or a pharmaceutically acceptable salt, solvate, prodrug,
stereoisomer, or tautomer thereof, in the manufacture of a
medicament for treating a BTK-mediated disease or disorder. In one
embodiment, the disease or disorder is selected from immune
disorders, cancer, cardiovascular diseases, viral infections
inflammation, metabolism/endocrine function disorders and
neurological disorders. In some embodiments, the treatment further
comprises administering an additional therapeutic agent selected
from an anti-inflammatory agent, an immunomodulatory agent,
chemotherapeutic agent, a neurotropic factor, an agent for treating
cardiovascular disease, an agent for treating liver disease, an
anti-viral agent, an agent for treating blood disorders, an agent
for treating diabetes, and an agent for treating immunodeficiency
disorders. In some embodiments, the BTK is wild-type BTK. In other
embodiments, the BTK is mutant BTK (e.g., BTK C481S mutant).
[0318] Another aspect of the application relates to the use of a
compound of Formula (I), or a pharmaceutically acceptable salt,
solvate, prodrug, stereoisomer, or tautomer thereof, in the
manufacture of a medicament for treating, preventing, inhibiting,
or eliminating a cell proliferative disorder. In one embodiment,
the cell proliferative disorder is a cancer.
[0319] In another aspect, the present application relates to the
use of a pharmaceutical composition of a compound of Formula (I),
or a pharmaceutically acceptable salt, solvate, prodrug,
stereoisomer, or tautomer thereof, in the manufacture of a
medicament for treating, preventing, inhibiting, or eliminating a
cell proliferative disorder. In one embodiment, the cell
proliferative disorder is a cancer.
[0320] Another aspect of the application relates to the use of a
compound of Formula (I), or a pharmaceutically acceptable salt,
solvate, prodrug, stereoisomer, or tautomer thereof, in the
manufacture of a medicament for modulating BTK. In one embodiment,
modulating BTK is inhibiting BTK. In some embodiments, the BTK is
wild-type BTK. In other embodiments, the BTK is mutant BTK (e.g.,
BTK C481S mutant).
[0321] In another aspect, the present application relates to the
use of a pharmaceutical composition of a compound of Formula (I),
or a pharmaceutically acceptable salt, solvate, prodrug,
stereoisomer, or tautomer thereof, in the manufacture of a
medicament for modulating BTK. In one embodiment, modulating BTK is
inhibiting BTK. In some embodiments, the BTK is wild-type BTK. In
other embodiments, the BTK is mutant BTK (e.g., BTK C481S
mutant).
[0322] In some embodiments of the methods and uses described
herein, the cancer is selected from breast, ovary, cervix,
prostate, testis, genitourinary tract, esophagus, larynx,
glioblastoma, neuroblastoma, stomach, skin, keratoacanthoma, lung,
epidermoid carcinoma, large cell carcinoma, non-small cell lung
carcinoma (NSCLC), small cell carcinoma, lung adenocarcinoma, bone,
colon, adenoma, pancreas, adenocarcinoma, thyroid, follicular
carcinoma, undifferentiated carcinoma, papillary carcinoma,
seminoma, melanoma, sarcoma, bladder carcinoma, liver carcinoma and
biliary passages, kidney carcinoma, pancreatic, myeloid disorders,
lymphoma, hairy cells, buccal cavity, naso-pharyngeal, pharynx,
lip, tongue, mouth, small intestine, colon-rectum, large intestine,
rectum, brain and central nervous system, Hodgkin's leukemia,
bronchus, thyroid, liver and intrahepatic bile duct,
hepatocellular, gastric, glioma/glioblastoma, endometrial,
melanoma, kidney and renal pelvis, urinary bladder, uterine corpus,
uterine cervix, multiple myeloma, acute myelogenous leukemia,
chronic myelogenous leukemia, lymphocytic leukemia, chronic
lymphoid leukemia (CLL), myeloid leukemia, oral cavity and pharynx,
non-Hodgkin lymphoma, melanoma, and villous colon adenoma.
[0323] In any of the embodiments of the application, the cancer can
be any cancer in any organ, for example, a cancer is selected from
the group consisting of glioma, thyroid carcinoma, breast
carcinoma, small-cell lung carcinoma, non-small-cell carcinoma,
gastric carcinoma, colon carcinoma, gastrointestinal stromal
carcinoma, pancreatic carcinoma, bile duct carcinoma, CNS
carcinoma, ovarian carcinoma, endometrial carcinoma, prostate
carcinoma, renal carcinoma, anaplastic large-cell lymphoma,
leukemia, multiple myeloma, mesothelioma, and melanoma, and
combinations thereof.
[0324] In some embodiments of the methods and uses described
herein, the disease or disorder is an immune disorder. In one
embodiment, the immune disorder is rheumatoid arthritis.
[0325] In some embodiments of the methods and uses described
herein, the disease or disorder is systemic and local inflammation,
arthritis, inflammation related to immune suppression, organ
transplant rejection, allergies, ulcerative colitis, Crohn's
disease, dermatitis, asthma, systemic lupus erythematosus,
Sjogren's Syndrome, multiple sclerosis, scleroderma/systemic
sclerosis, idiopathic thrombocytopenic purpura (ITP),
anti-neutrophil cytoplasmic antibodies (ANCA) vasculitis, chronic
obstructive pulmonary disease (COPD), psoriasis.
[0326] In one embodiment, methods of treating a disease or disorder
associated with modulation of BTK including, immune disorders,
cancer, cardiovascular diseases, viral infections, inflammation,
metabolism/endocrine function disorders and neurological disorders,
comprise administering to a subject suffering from at least one of
said diseases or disorder a compound of Formula (I).
[0327] The disclosed compound of the application can be
administered in effective amounts to treat or prevent a disorder
and/or prevent the development thereof in subjects.
[0328] The compound of the application can be administered in
therapeutically effective amounts in a combinational therapy with
one or more therapeutic agents (pharmaceutical combinations) or
modalities, e.g., non-drug therapies. For example, synergistic
effects can occur with other anti-proliferative, anti-cancer,
immunomodulatory or anti-inflammatory substances. In some
embodiments, a compound of Formula (I) is administered in
combination with an additional therapeutic agent selected from an
anti-inflammatory agent, an immunomodulatory agent,
chemotherapeutic agent, a neurotropic factor, an agent for treating
cardiovascular disease, an agent for treating liver disease, an
anti-viral agent, an agent for treating blood disorders, an agent
for treating diabetes, and an agent for treating immunodeficiency
disorders. Where the compound of the application is administered in
conjunction with other therapies, dosages of the co-administered
compounds will of course vary depending on the type of co-drug
employed, on the specific drug employed, on the condition being
treated and so forth.
[0329] Combination therapy includes the administration of the
subject compound in further combination with other biologically
active ingredients (such as, but not limited to, an
anti-inflammatory agent, an immunomodulatory agent,
chemotherapeutic agent, a neurotropic factor, an agent for treating
cardiovascular disease, an agent for treating liver disease, an
anti-viral agent, an agent for treating blood disorders, an agent
for treating diabetes, and an agent for treating immunodeficiency
disorders) and non-drug therapies (such as, but not limited to,
surgery or radiation treatment). For instance, the compound of the
application can be used in combination with other pharmaceutically
active compounds, preferably compounds that are able to enhance the
effect of the compound of the application. The compound of the
application can be administered simultaneously (as a single
preparation or separate preparation) or sequentially to the other
drug therapy or treatment modality. In general, a combination
therapy envisions administration of two or more drugs during a
single cycle or course of therapy.
Pharmaceutical Compositions
[0330] The present application also provides pharmaceutical
compositions comprising a compound of Formula (I), or a
pharmaceutically acceptable salt, solvate, prodrug, stereoisomer,
or tautomer thereof, in combination with at least one
pharmaceutically acceptable excipient or carrier.
[0331] A "pharmaceutical composition" is a formulation containing
the compound of the present application in a form suitable for
administration to a subject. In one embodiment, the pharmaceutical
composition is in bulk or in unit dosage form. The unit dosage form
is any of a variety of forms, including, for example, a capsule, an
IV bag, a tablet, a single pump on an aerosol inhaler or a vial.
The quantity of active ingredient (e.g., a formulation of the
disclosed compound or a pharmaceutically acceptable salt, solvate,
prodrug, stereoisomer, or tautomer thereof) in a unit dose of
composition is an effective amount and is varied according to the
particular treatment involved. One skilled in the art will
appreciate that it is sometimes necessary to make routine
variations to the dosage depending on the age and condition of the
patient. The dosage will also depend on the route of
administration. A variety of routes are contemplated, including
oral, pulmonary, rectal, parenteral, transdermal, subcutaneous,
intravenous, intramuscular, intraperitoneal, inhalational, buccal,
sublingual, intrapleural, intrathecal, intranasal, and the like.
Dosage forms for the topical or transdermal administration of a
compound of this application include powders, sprays, ointments,
pastes, creams, lotions, gels, solutions, patches and inhalants. In
one embodiment, the active compound is mixed under sterile
conditions with a pharmaceutically acceptable carrier, and with any
preservatives, buffers or propellants that are required.
[0332] As used herein, the phrase "pharmaceutically acceptable"
refers to those compounds, materials, compositions, carriers,
and/or dosage forms which are, within the scope of sound medical
judgment, suitable for use in contact with the tissues of human
beings and animals without excessive toxicity, irritation, allergic
response, or other problem or complication, commensurate with a
reasonable benefit/risk ratio.
[0333] "Pharmaceutically acceptable excipient" means an excipient
that is useful in preparing a pharmaceutical composition that is
generally safe, non-toxic and neither biologically nor otherwise
undesirable, and includes excipient that is acceptable for
veterinary use as well as human pharmaceutical use. A
"pharmaceutically acceptable excipient" as used in the
specification and claims includes both one and more than one such
excipient.
[0334] A pharmaceutical compositions of the application are
formulated to be compatible with its intended route of
administration. Examples of routes of administration include
parenteral, e.g., intravenous, intradermal, subcutaneous, oral
(e.g., inhalation), transdermal (topical), and transmucosal
administration. Solutions or suspensions used for parenteral,
intradermal, or subcutaneous application can include the following
components: a sterile diluent such as water for injection, saline
solution, fixed oils, polyethylene glycols, glycerine, propylene
glycol or other synthetic solvents; antibacterial agents such as
benzyl alcohol or methyl parabens; antioxidants such as ascorbic
acid or sodium bisulfite; chelating agents such as
ethylenediaminetetraacetic acid; buffers such as acetates, citrates
or phosphates, and agents for the adjustment of tonicity such as
sodium chloride or dextrose. The pH can be adjusted with acids or
bases, such as hydrochloric acid or sodium hydroxide. The
parenteral preparation can be enclosed in ampoules, disposable
syringes or multiple dose vials made of glass or plastic.
[0335] A compound or pharmaceutical composition of the application
can be administered to a subject in many of the well-known methods
currently used for chemotherapeutic treatment. For example, for
treatment of cancers, a compound of the application may be injected
directly into tumors, injected into the blood stream or body
cavities or taken orally or applied through the skin with patches.
The dose chosen should be sufficient to constitute effective
treatment but not as high as to cause unacceptable side effects.
The state of the disease condition (e.g., cancer, precancer, and
the like) and the health of the patient should preferably be
closely monitored during and for a reasonable period after
treatment.
[0336] The term "therapeutically effective amount", as used herein,
refers to an amount of a pharmaceutical agent to treat, ameliorate,
or prevent an identified disease or condition, or to exhibit a
detectable therapeutic or inhibitory effect. The effect can be
detected by any assay method known in the art. The precise
effective amount for a subject will depend upon the subject's body
weight, size, and health; the nature and extent of the condition;
and the therapeutic or combination of therapeutics selected for
administration. Therapeutically effective amounts for a given
situation can be determined by routine experimentation that is
within the skill and judgment of the clinician. In one embodiment,
the disease or disorder is selected from immune disorders, cancer,
cardiovascular diseases, viral infections, inflammation,
metabolism/endocrine function disorders and neurological disorders.
In another embodiment, the disease or condition to be treated is
cancer. In another embodiment, the disease or condition to be
treated is a cell proliferative disorder.
[0337] For any compound, the therapeutically effective amount can
be estimated initially either in cell culture assays, e.g., of
neoplastic cells, or in animal models, usually rats, mice, rabbits,
dogs, or pigs. The animal model may also be used to determine the
appropriate concentration range and route of administration. Such
information can then be used to determine useful doses and routes
for administration in humans. Therapeutic/prophylactic efficacy and
toxicity may be determined by standard pharmaceutical procedures in
cell cultures or experimental animals, e.g., ED.sub.50 (the dose
therapeutically effective in 50% of the population) and LD.sub.50
(the dose lethal to 50% of the population). The dose ratio between
toxic and therapeutic effects is the therapeutic index, and it can
be expressed as the ratio, LD.sub.50/ED.sub.50. Pharmaceutical
compositions that exhibit large therapeutic indices are preferred.
The dosage may vary within this range depending upon the dosage
form employed, sensitivity of the patient, and the route of
administration.
[0338] Dosage and administration are adjusted to provide sufficient
levels of the active agent(s) or to maintain the desired effect.
Factors which may be taken into account include the severity of the
disease state, general health of the subject, age, weight, and
gender of the subject, diet, time and frequency of administration,
drug combination(s), reaction sensitivities, and tolerance/response
to therapy. Long-acting pharmaceutical compositions may be
administered every 3 to 4 days, every week, or once every two weeks
depending on half-life and clearance rate of the particular
formulation.
[0339] The pharmaceutical compositions containing active compound
(i.e., a compound of Formula (I)) of the present application may be
manufactured in a manner that is generally known, e.g., by means of
conventional mixing, dissolving, granulating, dragee-making,
levigating, emulsifying, encapsulating, entrapping, or lyophilizing
processes. Pharmaceutical compositions may be formulated in a
conventional manner using one or more pharmaceutically acceptable
carriers comprising excipients and/or auxiliaries that facilitate
processing of the active compound into preparations that can be
used pharmaceutically. Of course, the appropriate formulation is
dependent upon the route of administration chosen.
[0340] Pharmaceutical compositions suitable for injectable use
include sterile aqueous solutions (where water soluble) or
dispersions and sterile powders for the extemporaneous preparation
of sterile injectable solutions or dispersion. For intravenous
administration, suitable carriers include physiological saline,
bacteriostatic water, Cremophor EL.TM. (BASF, Parsippany, N.J.) or
phosphate buffered saline (PBS). In all cases, the composition must
be sterile and should be fluid to the extent that easy
syringeability exists. It must be stable under the conditions of
manufacture and storage and must be preserved against the
contaminating action of microorganisms such as bacteria and fungi.
The carrier can be a solvent or dispersion medium containing, for
example, water, ethanol, polyol (for example, glycerol, propylene
glycol, and liquid polyethylene glycol, and the like), and suitable
mixtures thereof. The proper fluidity can be maintained, for
example, by the use of a coating such as lecithin, by the
maintenance of the required particle size in the case of dispersion
and by the use of surfactants. Prevention of the action of
microorganisms can be achieved by various antibacterial and
antifungal agents, for example, parabens, chlorobutanol, phenol,
ascorbic acid, thimerosal, and the like. In many cases, it will be
preferable to include isotonic agents, for example, sugars,
polyalcohols such as mannitol, sorbitol, sodium chloride in the
composition. Prolonged absorption of the injectable compositions
can be brought about by including in the composition an agent which
delays absorption, for example, aluminum monostearate and
gelatin.
[0341] Sterile injectable solutions can be prepared by
incorporating the active compound in the required amount in an
appropriate solvent with one or a combination of ingredients
enumerated above, as required, followed by filtered sterilization.
Generally, dispersions are prepared by incorporating the active
compound into a sterile vehicle that contains a basic dispersion
medium and the required other ingredients from those enumerated
above. In the case of sterile powders for the preparation of
sterile injectable solutions, methods of preparation are vacuum
drying and freeze-drying that yields a powder of the active
ingredient plus any additional desired ingredient from a previously
sterile-filtered solution thereof.
[0342] Oral compositions generally include an inert diluent or an
edible pharmaceutically acceptable carrier. They can be enclosed in
gelatin capsules or compressed into tablets. For the purpose of
oral therapeutic administration, the active compound can be
incorporated with excipients and used in the form of tablets,
troches, or capsules. Oral compositions can also be prepared using
a fluid carrier for use as a mouthwash, wherein the compound in the
fluid carrier is applied orally and swished and expectorated or
swallowed. Pharmaceutically compatible binding agents, and/or
adjuvant materials can be included as part of the composition. The
tablets, pills, capsules, troches and the like can contain any of
the following ingredients, or compounds of a similar nature: a
binder such as microcrystalline cellulose, gum tragacanth or
gelatin; an excipient such as starch or lactose, a disintegrating
agent such as alginic acid, Primogel, or corn starch; a lubricant
such as magnesium stearate or Sterotes; a glidant such as colloidal
silicon dioxide; a sweetening agent such as sucrose or saccharin;
or a flavoring agent such as peppermint, methyl salicylate, or
orange flavoring.
[0343] For administration by inhalation, the compound is delivered
in the form of an aerosol spray from pressured container or
dispenser, which contains a suitable propellant, e.g., a gas such
as carbon dioxide, or a nebulizer.
[0344] Systemic administration can also be by transmucosal or
transdermal means. For transmucosal or transdermal administration,
penetrants appropriate to the barrier to be permeated are used in
the formulation. Such penetrants are generally known in the art,
and include, for example, for transmucosal administration,
detergents, bile salts, and fusidic acid derivatives. Transmucosal
administration can be accomplished through the use of nasal sprays
or suppositories. For transdermal administration, the active
compound is formulated into ointments, salves, gels, or creams as
generally known in the art.
[0345] The active compound can be prepared with pharmaceutically
acceptable carriers that will protect the compound against rapid
elimination from the body, such as a controlled release
formulation, including implants and microencapsulated delivery
systems. Biodegradable, biocompatible polymers can be used, such as
ethylene vinyl acetate, polyanhydrides, polyglycolic acid,
collagen, polyorthoesters, and polylactic acid. Methods for
preparation of such formulations will be apparent to those skilled
in the art. The materials can also be obtained commercially from
Alza Corporation and Nova Pharmaceuticals, Inc. Liposomal
suspensions (including liposomes targeted to infected cells with
monoclonal antibodies to viral antigens) can also be used as
pharmaceutically acceptable carriers. These can be prepared
according to methods known to those skilled in the art, for
example, as described in U.S. Pat. No. 4,522,811.
[0346] It is especially advantageous to formulate oral or
parenteral compositions in dosage unit form for ease of
administration and uniformity of dosage. Dosage unit form as used
herein refers to physically discrete units suited as unitary
dosages for the subject to be treated; each unit containing a
predetermined quantity of active compound calculated to produce the
desired therapeutic effect in association with the required
pharmaceutical carrier. The specification for the dosage unit forms
of the application are dictated by and directly dependent on the
unique characteristics of the active compound and the particular
therapeutic effect to be achieved.
[0347] In therapeutic applications, the dosages of the
pharmaceutical compositions used in accordance with the application
vary depending on the agent, the age, weight, and clinical
condition of the recipient patient, and the experience and judgment
of the clinician or practitioner administering the therapy, among
other factors affecting the selected dosage. Generally, the dose
should be sufficient to result in slowing, and preferably
regressing, the growth of the tumors and also preferably causing
complete regression of the cancer. Dosages can range from about
0.01 mg/kg per day to about 5000 mg/kg per day. An effective amount
of a pharmaceutical agent is that which provides an objectively
identifiable improvement as noted by the clinician or other
qualified observer. For example, regression of a tumor in a subject
may be measured with reference to the diameter of a tumor. Decrease
in the diameter of a tumor indicates regression. Regression is also
indicated by failure of tumors to reoccur after treatment has
stopped. As used herein, the term "dosage effective manner" refers
to amount of an active compound to produce the desired biological
effect in a subject or cell.
[0348] The pharmaceutical compositions can be included in a
container, pack, or dispenser together with instructions for
administration.
[0349] As used herein, "pharmaceutically acceptable salts" refer to
derivatives of the compound of the present application wherein the
parent compound is modified by making acid or base salts thereof.
Examples of pharmaceutically acceptable salts include, but are not
limited to, mineral or organic acid salts of basic residues such as
amines, alkali or organic salts of acidic residues such as
carboxylic acids, and the like. The pharmaceutically acceptable
salts include the conventional non-toxic salts or the quaternary
ammonium salts of the parent compound formed, for example, from
non-toxic inorganic or organic acids. For example, such
conventional non-toxic salts include, but are not limited to, those
derived from inorganic and organic acids selected from
2-acetoxybenzoic, 2-hydroxyethane sulfonic, acetic, ascorbic,
benzene sulfonic, benzoic, bicarbonic, carbonic, citric, edetic,
ethane disulfonic, 1,2-ethane sulfonic, fumaric, glucoheptonic,
gluconic, glutamic, glycolic, glycollyarsanilic, hexylresorcinic,
hydrabamic, hydrobromic, hydrochloric, hydroiodic, hydroxymaleic,
hydroxynaphthoic, isethionic, lactic, lactobionic, lauryl sulfonic,
maleic, malic, mandelic, methane sulfonic, napsylic, nitric,
oxalic, pamoic, pantothenic, phenylacetic, phosphoric,
polygalacturonic, propionic, salicyclic, stearic, subacetic,
succinic, sulfamic, sulfanilic, sulfuric, tannic, tartaric, toluene
sulfonic, and the commonly occurring amine acids, e.g., glycine,
alanine, phenylalanine, arginine, etc.
[0350] Other examples of pharmaceutically acceptable salts include
hexanoic acid, cyclopentane propionic acid, pyruvic acid, malonic
acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid,
4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid,
4-toluenesulfonic acid, camphorsulfonic acid,
4-methylbicyclo-[2.2.2]-oct-2-ene-1-carboxylic acid,
3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic
acid, muconic acid, and the like. The present application also
encompasses salts formed when an acidic proton present in the
parent compound either is replaced by a metal ion, e.g., an alkali
metal ion, an alkaline earth ion, or an aluminum ion; or
coordinates with an organic base such as ethanolamine,
diethanolamine, triethanolamine, tromethamine, N-methylglucamine,
and the like.
[0351] It should be understood that all references to
pharmaceutically acceptable salts include solvent addition forms
(solvates) or crystal forms (polymorphs) as defined herein, of the
same salt.
[0352] The compound of the present application can also be prepared
as esters, for example, pharmaceutically acceptable esters. For
example, a carboxylic acid function group in a compound can be
converted to its corresponding ester, e.g., a methyl, ethyl or
other ester. Also, an alcohol group in a compound can be converted
to its corresponding ester, e.g., an acetate, propionate or other
ester.
[0353] The compound of the present application can also be prepared
as prodrugs, for example, pharmaceutically acceptable prodrugs. The
terms "pro-drug" and "prodrug" are used interchangeably herein and
refer to any compound which releases an active parent drug in vivo.
Since prodrugs are known to enhance numerous desirable qualities of
pharmaceuticals (e.g., solubility, bioavailability, manufacturing,
etc.), the compound of the present application can be delivered in
prodrug form. Thus, the present application is intended to cover
prodrugs of the presently claimed compound, methods of delivering
the same and compositions containing the same. "Prodrugs" are
intended to include any covalently bonded carriers that release an
active parent drug of the present application in vivo when such
prodrug is administered to a subject. Prodrugs in the present
application are prepared by modifying functional groups present in
the compound in such a way that the modifications are cleaved,
either in routine manipulation or in vivo, to the parent compound.
Prodrugs include the compound of the present application wherein a
hydroxy, amino, sulfhydryl, carboxy or carbonyl group is bonded to
any group that may be cleaved in vivo to form a free hydroxyl, free
amino, free sulfhydryl, free carboxy or free carbonyl group,
respectively.
[0354] Examples of prodrugs include, but are not limited to, esters
(e.g., acetate, dialkylaminoacetates, formates, phosphates,
sulfates and benzoate derivatives) and carbamates (e.g.,
N,N-dimethylaminocarbonyl) of hydroxy functional groups, esters
(e.g., ethyl esters, morpholinoethanol esters) of carboxyl
functional groups, N-acyl derivatives (e.g., N-acetyl)N-Mannich
bases, Schiff bases and enaminones of amino functional groups,
oximes, acetals, ketals and enol esters of ketone and aldehyde
functional groups in the compound of the application, and the like,
See Bundegaard, H., Design of Prodrugs, p 1-92, Elsevier, New
York-Oxford (1985).
[0355] The compound, or pharmaceutically acceptable salts,
tautomers, prodrugs, solvates, metabolites, polymorphs, analogs or
derivatives thereof, are administered orally, nasally,
transdermally, pulmonary, inhalationally, buccally, sublingually,
intraperintoneally, subcutaneously, intramuscularly, intravenously,
rectally, intrapleurally, intrathecally and parenterally. In one
embodiment, the compound or a pharmaceutically acceptable salt,
solvate, prodrug, stereoisomer, or tautomer thereof is administered
orally. One skilled in the art will recognize the advantages of
certain routes of administration.
[0356] The dosage regimen utilizing the compound is selected in
accordance with a variety of factors including type, species, age,
weight, sex and medical condition of the patient; the severity of
the condition to be treated; the route of administration; the renal
and hepatic function of the patient; and the particular compound or
pharmaceutically acceptable salt, tautomer, prodrug, solvate,
metabolite, polymorph, analog or derivative thereof employed. An
ordinarily skilled physician or veterinarian can readily determine
and prescribe the effective amount of the drug required to prevent,
counter or arrest the progress of the condition.
[0357] Techniques for formulation and administration of the
disclosed compound of the application can be found in Remington:
the Science and Practice of Pharmacy, 19.sup.th edition, Mack
Publishing Co., Easton, Pa. (1995). In an embodiment, the compound
described herein, and the pharmaceutically acceptable salts,
tautomers, prodrugs, solvates, metabolites, polymorphs, analogs or
derivatives thereof, are used in pharmaceutical preparations in
combination with a pharmaceutically acceptable carrier or diluent.
Suitable pharmaceutically acceptable carriers include inert solid
fillers or diluents and sterile aqueous or organic solutions. The
compound or pharmaceutically acceptable salts, prodrugs, solvates,
metabolites, polymorphs, analogs or derivatives thereof will be
present in such pharmaceutical compositions in amounts sufficient
to provide the desired dosage amount in the range described
herein.
[0358] All percentages and ratios used herein, unless otherwise
indicated, are by weight. Other features and advantages of the
present application are apparent from the different examples. The
provided examples illustrate different components and methodology
useful in practicing the present application. The examples do not
limit the claimed application. Based on the present application the
skilled artisan can identify and employ other components and
methodology useful for practicing the present application.
EXAMPLES
[0359] The application is further illustrated by the following
examples and synthesis schemes, which are not to be construed as
limiting this application in scope or spirit to the specific
procedures herein described. It is to be understood that the
examples are provided to illustrate certain embodiments and that no
limitation to the scope of the application is intended thereby. It
is to be further understood that resort may be had to various other
embodiments, modifications, and equivalents thereof which may
suggest themselves to those skilled in the art without departing
from the spirit of the present application and/or scope of the
appended claims.
Example 1:
(2-chlorophenyl)-(4-((trans-4-hydroxycyclohexyl)amino)-7H-pyrro-
lo[2,3-d]pyrimidin-5-yl)methanone (I-1)
##STR00723##
[0360] Step 1: Synthesis of
(2-chlorophenyl)-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone
(2-C)
[0361] A mixture of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (2-A, 4.61
g, 30 mmol), 2-chlorobenzoyl chloride (2-B, 5.21 mL, 39 mmol),
AlCl.sub.3 (12.0 g, 90 mmol) and nitrobenzene (30 mL) was heated at
80.degree. C. for 9.5 hrs. The resultant mixture was poured into
ice-water (300 mL) and extracted with EtOAc (.times.3). The
combined extracts were washed with water (.times.2), saturated
aqueous NaHCO.sub.3, and brine, then dried over anhydrous
Na.sub.2SO.sub.4, filtered through silica gel pad and concentrated
in vacuo. Hexane was added to the residue. The resulting
precipitated solid was collected by filtration, washed with hexane
(.times.2) and IPE (.times.2), and then dried at 50.degree. C. to
provide
(2-chlorophenyl)-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone
(2-C, 6.07 g, 22.4 mmol, 75%) as pale brown powder. .sup.1H-NMR
(DMSO-d.sub.6) .delta.: 13.44 (1H, br s), 8.76 (1H, s), 8.03 (1H,
s), 7.62-7.55 (3H, m), 7.50-7.45 (1H, m). LC/MS: 292 [M+H].
Step 2: Synthesis of
(2-chlorophenyl)-(4-((trans-4-hydroxycyclohexyl)amino)-7H-pyrrolo[2,3-d]p-
yrimidin-5-yl)methanone (I-1)
[0362] A mixture of
(2-chlorophenyl)-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)
methanone (2-C, 406 mg, 1.39 mmol), trans-4-aminocyclohexanol (240
mg, 2.08 mmol), DIPEA (363 .mu.L, 2.08 mmol) and IPA (12 mL) was
stirred at 160.degree. C. for 1 h under microwave irradiation
followed by concentration under reduced pressure. Water was added
to the resultant mixture and extracted with EtOAc, and then the
extract was washed with brine, dried over anhydrous
Na.sub.2SO.sub.4, filtered, and concentrated in vacuo. The residue
was purified by column chromatography over SiO.sub.2 with
CHCl.sub.3-MeOH, then the obtained crude product was suspended in
diethyl ether and precipitate was collected by filtration to give
(2-chlorophenyl)-(4-((trans-4-hydroxycyclohexyl)amino)-7H-pyrrolo[2,3-d]p-
yrimidin-5-yl)methanone (I-1, 510 mg, 1.38 mmol, 99%) as pale
yellow solid. .sup.1H-NMR (DMSO-d.sub.6) .delta.: 12.71 (1H, s),
8.71 (1H, d, J=7.9 Hz), 8.24 (1H, s), 7.59-7.55 (3H, m), 7.49-7.44
(2H, m), 4.63-4.60 (1H, m), 4.03-4.01 (1H, m), 3.54-3.52 (1H, m),
2.09-2.06 (2H, m), 1.91-1.88 (2H, m), 1.38-1.24 (4H, m). LC/MS: 371
[M+H].
Example 2: General Procedure A
##STR00724##
[0363] Step 1. Intermediate 2-E
[0364] A mixture of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (2-A), an
aroyl chloride or heteroaroyl chloride (2-D, 1.1-1.5 eq.),
AlCl.sub.3 (2-5 eq.) and nitrobenzene (0.3-1 M) was heated at
80-100.degree. C. for 1 to 10 hrs. Work-up and/or purification
provided the corresponding aryl- or
heteroaryl-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone
(2-E).
Step 2. Compounds of Formula I-X
[0365] A mixture of 2-E, a primary amine (2-F, 1-4 eq.), and
optionally a base (e.g., TEA, DIPEA, pyridine, and/or
K.sub.2CO.sub.3 (1-5 eq.)) in a solvent (e.g., DMF, NMP, IPA,
n-BuOH or neat) was heated (70-160.degree. C.) for 5-50 hrs or
heated (100-220.degree. C.) under microwave radiation for 0.5-5
hrs. Work-up and/or purification provided a compound of Formula (I)
(aryl- or
heteroaryl-[4-(substituted-amino)]-7H-pyrrolo[2,3-d]pyrimidin-5-yl]methan-
one (I-X)).
[0366] The compounds of Formula (I) in Table 1 below were made
according to General Procedure A.
TABLE-US-00003 TABLE 1 Cmpd No. .sup.1H NMR and/or LC/MS data I-2
.sup.1H-NMR (DMSO-d.sub.6) .delta.: 12.69 (1H, s), 8.89 (1H, d, J =
7.3 Hz), 8.23 (1H, s), 7.61-7.54 (3H, m), 7.50-7.45 (2H, m),
7.00-6.96 (1H, m), 4.25-4.18 (1H, m), 3.46-3.40 (1H, m), 1.84-1.58
(8H, m), 1.38 (9H, s). LC/MS: 470 [M + H]. I-3 .sup.1H-NMR
(DMSO-d.sub.6) .delta.: 12.71 (1H, s), 8.83 (1H, d, J = 6.7 Hz),
8.24 (1H, s), 7.62-7.53 (3H, m), 7.49-7.45 (2H, m), 7.05 (1H, d, J
= 7.3 Hz), 4.43-4.34 (1H, m), 3.87-3.78 (1H, m), 2.49-2.40 (1H, m),
2.13-2.03 (1H, m), 1.93-1.84 (1H, m), 1.54-1.67 (2H, m), 1.39-1.48
(1H, m), 1.37 (9H, s). LC/MS: 456 [M + H]. I-4 .sup.1H-NMR
(DMSO-d.sub.6) .delta.: 8.97 (0.4H, d, J = 7.9 Hz), 8.73 (0.6H, d,
J = 7.9 Hz), 8.19 (0.4H, s), 8.18 (0.6H, s), 7.57-7.53 (3H, m),
7.48-7.43 (1H, m), 7.40 (0.4H, s), 7.39 (0.6H, s), 4.58-4.52 (0.4H,
m), 4.09-3.98 (0.6H, m), 3.11-3.04 (0.4H, m), 2.73-2.81 (0.6H, m),
2.26-1.00 (8H, m). LC/MS: 370 [M + H]. (6:4 diastereomeric mixture
of I-4). I-13 .sup.1H-NMR (CDCl.sub.3) .delta.: 12.36 (1H, br s),
9.01 (1H, d, J = 7.3 Hz), 8.32 (1H, s), 7.43-7.37 (2H, m), 7.30
(2H, t, J = 8.5 Hz), 4.41-4.32 (2H, m), 3.71-3.65 (1H, m),
3.61-3.49 (2H, m), 3.31 (1H, t, J = 11.3 Hz), 2.40-2.31 (4H, m),
1.80-1.55 (4H, m). LC/MS: 367 [M + H]. I-16 .sup.1H-NMR
(DMSO-d.sub.6) .delta.: 12.43 (1H, br s), 8.95 (1H, d, J = 7.3 Hz),
8.23 (1H, s), 7.45-7.28 (5H, m), 4.09-4.04 (1H, m), 2.73-2.68 (2H,
m), 2.28 (3H, s), 2.19 (3H, s), 2.17-2.11 (2H, m), 2.04-1.98 (2H,
m), 1.61-1.53 (2H, m). LC/MS: 350 [M + H]. I-17 .sup.1H-NMR
(DMSO-d.sub.6) .delta.: 12.63 (1H, br s), 8.99 (1H, d, J = 7.3 Hz),
8.24 (1H, s), 7.45-7.28 (5H, m), 4.31-4.23 (1H, m), 3.87-3.81 (2H,
m), 3.16-3.05 (2H, m), 2.28 (3H, s), 2.04-1.99 (2H, m), 1.47-1.40
(11H, m). LC/MS: 436 [M + H]. I-19 .sup.1H-NMR (CDCl.sub.3)
.delta.: 12.80 (1H, br s), 9.13 (1H, d, J = 7.3 Hz), 8.31 (1H, s),
7.44-7.37 (2H, m), 7.33-7.25 (2H, m), 4.63-4.62 (4H, m), 4.21-4.10
(1H, m), 3.69 (3H, s), 2.42-2.26 (5H, m), 2.14-2.07 (2H, m),
1.54-1.42 (2H, m). LC/MS: 393 [M + H]. I-20 .sup.1H-NMR
(CDCl.sub.3) .delta.: 12.60 (1H, br s), 9.02 (1H, d, J = 7.9 Hz),
8.33 (1H, s), 7.45-7.37 (2H, m), 7.33-7.26 (3H, m), 4.45-4.26 (2H,
m), 3.29 (1H, t, J = 10.7 Hz), 3.22-3.16 (1H, m), 2.40-2.32 (4H,
m), 1.84-1.18 (10H, m). LC/MS: 395 [M + H]. I-21 .sup.1H-NMR
(DMSO-d.sub.6) .delta.: 12.59 (1H, br s), 8.85 (1H, d, J = 7.3 Hz),
8.22 (1H, s), 7.45-7.40 (2H, m), 7.35-7.27 (3H, m), 4.61 (1H, d, J
= 4.3 Hz), 4.02-4.00 (1H, m), 3.55-3.52 (1H, m), 2.27 (3H, s),
2.08-2.06 (2H, m), 1.91-1.88 (2H, m), 1.37-1.35 (4H, m). LC/MS: 351
[M + H]. I-22 .sup.1H-NMR (DMSO-d.sub.6) .delta.: 12.58 (1H, s),
9.04 (1H, d, J = 7.3 Hz), 8.21 (1H, s), 7.44 (2H, t, J = 7.3 Hz),
7.35-7.30 (3H, m), 4.55 (1H, d, J = 3.7 Hz), 4.20-4.17 (1H, m),
3.68-3.66 (1H, m), 2.29 (3H, s), 1.81-1.63 (8H, m). LC/MS: 351 [M +
H]. I-24 .sup.1H-NMR (CDCl.sub.3) .delta.: 8.98 (1H, d, J = 7.3
Hz), 8.33 (1H, s), 7.43-7.36 (2H, m), 7.33-7.22 (3H, m), 4.42-4.28
(2H, m), 3.95-3.87 (1H, m), 3.36-3.27 (2H, m), 2.40-2.33 (4H, m),
1.79-1.24 (4H, m), 1.18 (3H, d, J = 6.0 Hz). LC/MS: 381 [M + H].
I-26 .sup.1H-NMR (DMSO-d.sub.6) .delta.: 9.05 (1H, d, J = 7.3 Hz),
8.19 (1H, s), 7.78 (2H, d, J = 6.7 Hz), 7.69 (1H, s), 7.63 (1H, t,
J = 7.3 Hz), 7.54 (2H, t, J = 7.6 Hz), 4.25-4.20 (1H, m), 2.84-2.77
(1H, m), 1.89-1.80 (2H, m), 1.70-1.60 (4H, m), 1.43-1.53 (2H, m).
LC/MS: 336 [M + H]. I-27 .sup.1H-NMR (CDCl.sub.3) .delta.: 12.62
(1H, br s), 9.31 (1H, t, J = 5.5 Hz), 8.34 (1H, s), 7.43-7.38 (2H,
m), 7.33-7.25 (3H, m), 4.01-3.49 (9H, m), 2.39 (3H, s). LC/MS: 353
[M + H]. I-31 .sup.1H-NMR (DMSO-d.sub.6) .delta.: 12.69 (1H, s),
8.88 (1H, d, J = 7.3 Hz), 8.22 (1H, s), 7.59-7.56 (3H, m),
7.49-7.45 (2H, m), 4.56 (1H, d, J = 3.1 Hz), 4.20-4.18 (1H, m),
3.69-3.66 (1H, m), 1.81-1.63 (8H, m). LC/MS: 371 [M + H]. I-32
.sup.1H-NMR (DMSO-d.sub.6) .delta.: 12.71 (1H, s), 8.71 (1H, d, J =
7.9 Hz), 8.24 (1H, s), 7.59-7.55 (3H, m), 7.49-7.44 (2H, m),
4.63-4.60 (1H, m), 4.03-4.01 (1H, m), 3.54-3.52 (1H, m), 2.09-2.06
(2H, m), 1.91-1.88 (2H, m), 1.38-1.24 (4H, m). LC/MS: 371 [M + H].
I-35 .sup.1H-NMR (CDCl.sub.3) .delta.: 11.92 (1H, br s), 9.31-9.25
(1H, m), 8.33 (1H, s), 7.42-7.22 (5H, m), 4.28-4.13 (2H, m),
3.86-3.78 (1H, m), 3.73-3.57 (3H, m), 3.09 (1H, t, J = 10.7 Hz),
2.38 (3H, s), 2.18-2.10 (1H, m), 1.91-1.84 (1H, m), 1.62-1.27 (11H,
m). LC/MS: 466 [M + H]. I-38 .sup.1H-NMR (CDCl.sub.3) .delta.:
13.48 (1H, br s), 8.88 (1H, d, J = 7.9 Hz), 8.31 (1H, s), 7.53-7.36
(4H, m), 7.32 (1H, s), 4.41-4.28 (2H, m), 3.95-3.87 (1H, m),
3.37-3.27 (2H, m), 2.39-2.30 (1H, m), 1.80-1.66 (3H, m), 1.18 (3H,
d, J = 6.1 Hz). LC/MS: 401 [M + H]. I-41 .sup.1H-NMR (DMSO-d.sub.6)
.delta.: 12.57 (1H, s), 9.22 (1H, d, J = 7.3 Hz), 8.21 (1H, s),
7.44 (2H, t, J = 6.1 Hz), 7.28-7.36 (3H, m), 4.44-4.45 (2H, m),
3.27-3.28 (2H, m), 2.28 (3H, s), 1.50-1.89 (7H, m), 1.36-1.39 (2H,
m). LC/MS: 365 [M + H]. I-49 .sup.1H-NMR (CDCl.sub.3) .delta.:
13.11 (1H, s), 8.86 (1H, d, J = 7.3 Hz), 8.34 (1H, s), 7.54-7.37
(4H, m), 7.31 (1H, s), 4.43-4.26 (2H, m), 3.29 (1H, t, J = 10.4
Hz), 3.22-3.16 (1H, m), 2.39-2.31 (1H, m), 1.85-1.55 (4H, m), 1.22
(3H, s), 1.19 (3H, s). LC/MS: 415 [M + H]. I-62 .sup.1H-NMR
(DMSO-d.sub.6) .delta.: 12.69 (1H, br s), 12.15 (1H, br s), 8.92
(1H, d, J = 7.3 Hz), 8.23 (1H, s), 7.61-7.53 (3H, m), 7.50-7.41
(2H, m), 4.33-4.26 (1H, m), 2.40-2.46 (1H, m), 1.68-1.91 (8H, m).
LC/MS: 399 [M + H]. I-76 .sup.1H-NMR (CDCl.sub.3) .delta.: 13.17
(1H, br s), 9.19 (1H, d, J = 8.0 Hz), 8.26 (1H, s), 7.44-7.38 (2H,
m), 7.33-7.26 (3H, m), 4.09-3.98 (1H, m), 3.76 (1H, dd, J = 12.2,
2.2 Hz), 3.34 (1H, d, J = 12.2 Hz), 2.39 (3H, s), 2.18-2.11 (1H,
m), 1.91-1.58 (6H, m), 1.48-1.28 (3H, m). LC/MS: 365 [M + H]. I-77
.sup.1H-NMR (CDCl.sub.3) .delta.: 13.23 (1H, s), 9.65 (1H, s), 8.24
(1H, s), 7.44-7.25 (5H, m), 3.82 (2H, s), 2.38 (3H, s), 2.15-2.00
(4H, m), 1.94-1.70 (4H, m). LC/MS: 351 [M + H]. I-90 .sup.1H-NMR
(CDCl.sub.3) .delta.: 13.32 (1H, br s), 9.08 (1H, d, J = 7.3 Hz),
8.31 (1H, s), 7.44-7.37 (2H, m), 7.33-7.25 (3H, m), 4.51-4.40 (2H,
m), 4.09 (1H, dd, J = 10.4, 2.4 Hz), 3.80 (3H, s), 3.44-3.35 (1H,
m), 2.42-2.34 (4H, m), 2.25-2.18 (1H, m), 1.95-1.72 (2H, m). LC/MS:
395 [M + H]. I-91 .sup.1H-NMR (CDCl.sub.3) .delta.: 12.12 (1H, br
s), 8.88 (1H, d, J = 7.3 Hz), 8.35 (1H, s), 7.53-7.37 (4H, m), 7.30
(1H, s), 6.58 (1H, d, J = 4.3 Hz), 5.55 (1H, d, J = 4.3 Hz),
4.46-4.30 (2H, m), 3.90 (1H, dd, J = 11.0, 2.4 Hz), 3.35 (1H, t, J
= 10.4 Hz), 2.43-2.30 (2H, m), 1.84-1.69 (2H, m). LC/MS: 400 [M +
H]. I-103 .sup.1H-NMR (DMSO-d.sub.6) .delta.: 12.67 (1H, s), 8.71
(1H, d, J = 7.3 Hz), 8.22 (1H, s), 7.61-7.53 (3H, m), 7.49-7.44
(2H, m), 4.18 (1H, s), 4.00-3.98 (1H, m), 1.83-1.81 (2H, m),
1.73-1.60 (4H, m), 1.46-1.40 (2H, m), 1.11 (3H, s). LC/MS: 385 [M +
H]. I-104 .sup.1H-NMR (DMSO-d.sub.6) .delta.: 12.69 (1H, s), 8.92
(1H, d, J = 7.9 Hz), 8.23 (1H, s), 7.61-7.53 (3H, m), 7.49-7.45
(2H, m), 4.27-4.24 (2H, m), 2.00-1.98 (2H, m), 1.68-1.64 (2H, m),
1.57-1.46 (4H, m), 1.15 (3H, s). LC/MS: 385 [M + H]. I-105
.sup.1H-NMR (CDCl.sub.3) .delta.: 13.06 (1H, br s), 9.12 (1H, d, J
= 7.3 Hz), 8.30 (1H, s), 7.43-7.37 (2H, m), 7.33-7.25 (3H, m), 5.84
(1H, br s), 5.55 (1H, br s), 4.22-4.10 (1H, m), 2.40-2.30 (5H, m),
2.28-2.03 (3H, m), 1.80-1.66 (2H, m), 1.54-1.42 (2H, m). LC/MS: 378
[M + H]. I-107 .sup.1H-NMR (DMSO-d.sub.6) .delta.: 12.68 (1H, s),
8.72 (1H, d, J = 7.3 Hz), 8.22 (1H, s), 7.61-7.54 (3H, m),
7.47-7.45 (2H, m), 4.31 (1H, s), 3.98-3.95 (1H, m), 3.28 (3H, s),
3.15 (2H, s), 1.87-1.84 (2H, m), 1.64-1.55 (6H, m). LC/MS: 415 [M +
H]. I-108 .sup.1H-NMR (DMSO-d.sub.6) .delta.: 12.67 (1H, s), 8.95
(1H, d, J = 7.3 Hz), 8.23 (1H, s), 7.59-7.56 (3H, m), 7.47-7.44
(2H, m), 4.30 (2H, s), 3.29 (3H, s), 3.23 (2H, s), 2.00-1.95 (2H,
m), 1.78-1.71 (2H, m), 1.60-1.57 (2H, m), 1.46-1.43 (2H, m). LC/MS:
415 [M + H].
Example 3:
(4-((trans-4-aminocyclohexyl)amino)-7H-pyrrolo[2,3-d]pyrimidin--
5-yl)(2-chlorophenyl) methanone (I-5)
[0367] Boc deprotection of tert-butyl
N-(trans-4-((5-(2-chlorobenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amino]cy-
clohexyl]carbamate provided Compound I-5. tert-Butyl
N-(trans-4-((5-(2-chlorobenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amino]cy-
clohexyl]carbamate was synthesized according to General Procedure A
using tert-butyl N-(trans-4-amino-1-cyclohexyl)carbamate.
.sup.1H-NMR (DMSO-d.sub.6) .delta.: 8.70 (1H, d, J=7.3 Hz), 8.19
(1H, s), 7.59-7.51 (3H, m), 7.47-7.43 (1H, m), 7.38 (1H, s),
4.01-3.91 (1H, m), 2.76-2.66 (1H, m), 2.12-2.06 (2H, m), 1.89-1.82
(2H, m), 1.21-1.39 (4H, m). LC/MS: 370 [M+H].
Example 4:
(4-((cis-4-aminocyclohexyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5--
yl)(2-chlorophenyl) methanone (I-6)
[0368] Boc deprotection of Compound I-2 provided Compound I-6.
.sup.1H-NMR (DMSO-d.sub.6) .delta.: 8.95 (1H, d, J=7.9 Hz), 8.18
(1H, s), 7.60-7.51 (3H, m), 7.49-7.44 (1H, m), 7.40 (1H, s),
4.28-4.21 (1H, m), 2.89-2.82 (1H, m), 1.89-1.79 (2H, m), 1.72-1.63
(4H, m), 1.45-1.56 (2H, m). LC/MS: 370 [M+H].
Example 5:
(4-(((1R,3S)-3-aminocyclopentyl)amino)-7H-pyrrolo[2,3-d]pyrimid-
in-5-yl)(2-chlorophenyl) methanone (I-7)
[0369] Boc deprotection of Compound I-3 provided Compound I-7.
.sup.1H-NMR (DMSO-d.sub.6) .delta.: 8.89 (1H, d, J=6.7 Hz), 8.19
(1H, s), 7.59-7.51 (3H, m), 7.48-7.43 (1H, m), 7.39 (1H, s),
4.46-4.38 (1H, m), 3.37-3.29 (7H, m), 2.43-2.36 (1H, m), 2.12-2.03
(1H, m), 1.89-1.80 (1H, m), 1.74-1.64 (1H, m), 1.55-1.46 (1H, m),
1.27-1.35 (1H, m). LC/MS: 356 [M+H].
Example 6:
N-(trans-4-((5-(2-chlorobenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-y-
l)amino)cyclohexyl)-2-(1-methylpiperidin-4-yl)acetamide (I-8)
[0370] Acylation of Compound I-5 provided Compound I-8. .sup.1H-NMR
(DMSO-d.sub.6) .delta.: 12.66 (1H, br s), 8.70 (1H, d, J=7.3 Hz),
8.24 (1H, s), 7.75 (1H, d, J=7.9 Hz), 7.61-7.53 (3H, m), 7.49-7.44
(2H, m), 4.02-3.93 (1H, m), 3.65-3.56 (1H, br m), 2.74-2.66 (2H,
m), 2.16-2.10 (5H, m), 1.96 (2H, d, J=6.7 Hz), 1.88-1.76 (3H, m),
1.62-1.52 (3H, m), 1.43-1.27 (4H, m), 1.09-1.21 (2H, m). LC/MS: 509
[M+H].
Example 7:
N-(cis-4-((5-(2-chlorobenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-
amino)cyclohexyl)-2-(1-methylpiperidin-4-yl)acetamide (I-9)
[0371] Acylation of Compound I-6 provided Compound I-9. .sup.1H-NMR
(DMSO-d.sub.6) .delta.: 8.92 (1H, d, J=7.3 Hz), 8.23 (1H, s), 7.86
(1H, d, J=7.9 Hz), 7.62-7.53 (3H, m), 7.49-7.45 (2H, m), 4.25-4.19
(1H, m), 3.78-3.71 (1H, m), 2.65-2.70 (2H, m), 2.09 (3H, s), 1.99
(2H, d, J=6.7 Hz), 1.80-1.52 (13H, m), 1.19-1.08 (2H, m). LC/MS:
509 [M+H].
Example 8:
N-((1S,3R)-3-((5-(2-chlorobenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-
-yl)amino)cyclopentyl)-2-(1-methylpiperidin-4-yl)acetamide
(I-10)
[0372] Acylation of Compound I-7 provided Compound I-10.
.sup.1H-NMR (DMSO-d.sub.6) .delta.: 8.85 (1H, d, J=7.3 Hz), 8.24
(1H, s), 7.95 (1H, d, J=7.3 Hz), 7.61-7.54 (3H, m), 7.49-7.45 (2H,
m), 4.46-4.37 (1H, m), 4.11-4.04 (1H, m), 2.69-2.58 (2H, m),
2.49-2.41 (1H, m), 2.16-2.06 (4H, m), 1.96-1.87 (3H, m), 1.76-1.41
(8H, m), 1.05-1.17 (2H, m). LC/MS: 495 [M+H].
Example 9:
N-(3-((5-(2-chlorobenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amin-
o)cyclohexyl)-2-(1-methylpiperidin-4-yl)acetamide (6:4
diastereomeric mixture) (I-11)
[0373] Acylation of Compound I-4 provided Compound I-11.
.sup.1H-NMR (DMSO-d.sub.6) .delta.: 12.68 (1H, br s), 8.92 (0.4H,
d, J=7.9 Hz), 8.71 (0.6H, d, J=7.9 Hz), 8.24 (0.6H, s), 8.22 (0.4H,
s), 7.81-7.76 (1H, m), 7.62-7.53 (3H, m), 7.49-7.45 (2H, m),
4.53-4.46 (0.4H, m), 4.14-4.02 (0.6H, m), 4.01-3.91 (0.4H, m),
3.75-3.64 (0.6H, m), 2.69-2.65 (2H, m), 2.05-2.23 (4H, m),
1.99-1.09 (16H, m). LC/MS: 509 [M+H].
Example 10: tert-butyl
(cis-4-((5-(2-methylbenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cycloh-
exyl) carbamate (I-12)
[0374] Compound I-12 was synthesized according to General Procedure
A described herein above using
(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-(o-tolyl)methanone.
[0375] NMR data for
(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-(o-tolyl)methanone
intermediate: .sup.1H-NMR (DMSO-d.sub.6) .delta.: 13.30 (1H, br s),
8.74 (1H, s), 7.94 (1H, d, J=3.1 Hz), 7.48-7.44 (2H, m), 7.38-7.35
(1H, m), 7.31-7.26 (1H, m), 2.36 (3H, s).
[0376] NMR data for Compound I-12: .sup.1H-NMR (DMSO-d.sub.6)
.delta.: 12.58 (1H, br s), 9.05 (1H, d, J=7.3 Hz), 8.21 (1H, s),
7.46-7.40 (2H, m), 7.37-7.27 (3H, m), 6.99-6.94 (1H, m), 4.25-4.19
(1H, m), 3.45-3.39 (1H, m), 2.29 (3H, s), 1.87-1.78 (2H, m),
1.58-1.76 (6H, m). LC/MS: 450 [M+H].
Example 11:
(4-((cis-4-aminocyclohexyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(o-toly-
l)methanone (I-14)
[0377] Boc deprotection of Compound I-12 provided Compound I-14.
.sup.1H-NMR (DMSO-d.sub.6) .delta.: 9.12 (1H, d, J=7.3 Hz), 8.19
(1H, s), 7.44-7.39 (2H, m), 7.35-7.27 (3H, m), 4.28-4.21 (1H, m),
2.85-2.78 (1H, m), 2.28 (3H, s), 1.89-1.79 (2H, m), 1.71-1.60 (4H,
m), 1.54-1.43 (2H, m). LC/MS: 350 [M+H].
Example 12:
N-(cis-4-((5-(2-methylbenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)
cyclohexyl)-2-(4-methylpiperazin-1-yl)acetamide (I-15)
[0378] Acylation of Compound I-14 provided Compound I-15.
.sup.1H-NMR (DMSO-d.sub.6) .delta.: 12.61 (1H, s), 9.17 (1H, d,
J=7.3 Hz), 8.22 (1H, s), 7.55 (1H, d, J=7.9 Hz), 7.46-7.41 (2H, m),
7.38-7.27 (3H, m), 4.33-4.25 (1H, m), 3.82-3.74 (1H, m), 2.89 (2H,
s), 2.16-2.45 (12H, m), 2.02 (3H, s), 1.82-1.63 (8H, m). LC/MS: 490
[M+H].
Example 13:
(4-((cis-4-(dimethylamino)cyclohexyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5--
yl)(o-tolyl) methanone (I-18)
[0379] Reductive alkylation of Compound I-14 with formaline
provided Compound I-18. .sup.1H-NMR (DMSO-d.sub.6) .delta.: 12.58
(1H, br s), 9.19 (1H, d, J=7.9 Hz), 8.21 (1H, s), 7.45-7.42 (2H,
m), 7.37-7.28 (3H, m), 4.37-4.32 (1H, m), 2.27 (3H, s), 2.22-2.8
(1H, m) 2.20 (6H, s), 1.82-1.89 (2H, m), 1.60-1.77 (6H, m). LC/MS:
378 [M+H].
Example 14:
((2S,5R)-5-((5-(2-methylbenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)te-
trahydro-2H-pyran-2-yl)(4-methylpiperazin-1-yl)methanone (I-23)
[0380] Synthesis of
(2S,5R)-5-((5-(2-methylbenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)tet-
rahydro-2H-pyran-2-carboxylic acid using General Procedure A
(LC/MS: 381 [M+H]) followed by a subsequent condensation reaction
provided Compound I-23. .sup.1H-NMR (CDCl.sub.3) .delta.: 9.09 (1H,
d, J=7.3 Hz), 8.33 (1H, s), 7.43-7.37 (2H, m), 7.33-7.25 (3H, m),
4.47-4.30 (2H, m), 4.22-4.17 (1H, m), 3.80-3.67 (2H, m), 3.64-3.53
(2H, m), 3.45-3.38 (1H, m), 2.49-2.37 (8H, m), 2.32 (3H, s),
2.10-1.99 (2H, m), 1.83-1.71 (1H, m). LC/MS: 463 [M+H].
Example 15:
4-(tert-butyl)-N-(cis-4-((5-(2-methylbenzoyl)-7H-pyrrolo[2,3-d]pyrimidin--
4-yl)amino) cyclohexyl)benzamide (I-25)
[0381] Acylation of Compound I-14 provided Compound I-25.
.sup.1H-NMR (DMSO-d.sub.6) .delta.: 12.60 (1H, br s), 9.14 (1H, d,
J=7.3 Hz), 8.27 (1H, d, J=7.3 Hz), 8.24 (1H, s), 7.76-7.78 (2H, m),
7.44 (4H, t, J=5.8 Hz), 7.30-7.35 (3H, m), 4.29-4.31 (1H, m),
3.91-3.93 (1H, m), 2.30 (3H, s), 1.96-1.99 (2H, m), 1.78-1.79 (6H,
m), 1.28 (9H, s). LC/MS: 510 [M+H].
Example 16:
2-(4-(4-(tert-butyl)benzoyl)piperazin-1-yl)-N-(cis-4-((5-(2-methylbenzoyl-
)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexyl)acetamide
(I-28)
Step 1. tert-butyl
4-(2-((4-((5-(2-methylbenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cycl-
ohexyl)amino)-2-oxo-ethyl)piperazine-1-carboxylate (28a)
[0382] Acylation of Compound I-14 provided Compound 28a.
.sup.1H-NMR (CDCl.sub.3) .delta.: 9.45 (1H, d, J=7.3 Hz), 8.33 (1H,
s), 7.20-7.45 (6H, m), 4.46-4.48 (1H, m), 3.99-4.02 (1H, m), 3.39
(4H, s), 3.00 (2H, s), 2.45 (4H, s), 2.39 (3H, s), 1.65-1.99 (8H,
m), 1.44 (9H, s). LC/MS: 576 [M+H].
Step 2.
N-(4-((5-(2-methylbenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)c-
yclohexyl)-2-piperazin-1-yl-acetamide (28b)
[0383] Boc deprotection of 28a provided Compound 28b. .sup.1H-NMR
(CDCl.sub.3) .delta.: 9.39 (1H, d, J=7.9 Hz), 8.33 (1H, s),
7.41-7.42 (2H, m), 7.25-7.30 (5H, m), 4.43-4.46 (1H, m), 3.99-4.02
(1H, m), 2.96-2.98 (2H, m), 2.83-2.84 (4H, m), 2.47-2.49 (4H, m),
2.40 (3H, s), 1.71.91 (8H, m), 1.57-1.59 (5H, m). LC/MS: 476
[M+H].
Step 3.
2-(4-(4-(tert-butyl)benzoyl)piperazin-1-yl)-N-(cis-4-((5-(2-methyl-
benzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexyl)acetamide
(I-28)
[0384] Acylation of 28b provided Compound I-28. .sup.1H-NMR
(DMSO-d.sub.6) .delta.: 12.61 (1H, s), 9.13 (1H, d, J=7.3 Hz), 8.23
(1H, s), 7.68 (1H, d, J=7.9 Hz), 7.28-7.40 (8H, m), 4.27 (1H, s),
3.78 (1H, s), 3.57 (1H, s), 3.29-3.35 (4H, m), 2.97 (2H, s),
2.41-2.51 (4H, m), 2.28 (3H, s), 1.63-1.78 (8H, m), 1.28 (9H, s).
LC/MS: 636 [M+H].
Example 17:
2-(4-benzoylpiperazin-1-yl)-N-(cis-4-((5-(2-methylbenzoyl)-7H-pyrrolo[2,3-
-d]pyrimidin-4-yl)amino)cyclohexyl)acetamide (I-29)
[0385] Acylation of
N-(4-((5-(2-methylbenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohex-
yl)-2-piperazin-1-yl-acetamide provided Compound I-29. .sup.1H-NMR
(DMSO-d.sub.6) .delta.: 12.61 (1H, s), 9.13 (1H, d, J=7.3 Hz), 8.22
(1H, s), 7.69 (1H, d, J=7.3 Hz), 7.28-7.45 (9H, m), 4.27-4.29 (1H,
m), 3.76-3.79 (1H, m), 3.58-3.60 (1H, m), 3.30-3.32 (4H, m), 2.98
(2H, s), 2.48-2.49 (4H, m), 2.28 (3H, s), 1.66-1.77 (8H, m). LC/MS:
580 [M+H].
Example 18:
N-(cis-4-((5-(2-methylbenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cycl-
ohexyl)benzamide (I-30)
[0386] Acylation of Compound I-14 provided Compound I-30.
.sup.1H-NMR (DMSO-d.sub.6) .delta.: 12.60 (1H, s), 9.15 (1H, d,
J=6.7 Hz), 8.37 (1H, d, J=7.3 Hz), 8.24 (1H, s), 7.84 (2H, d, J=7.3
Hz), 7.35-7.44 (8H, m), 4.29-4.31 (1H, m), 3.92-3.94 (1H, m), 2.30
(3H, s), 1.97-1.99 (2H, m), 1.79-1.80 (6H, m). LC/MS: 454
[M+H].
Example 19:
N-(cis-4-((5-(2-methylbenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cycl-
ohexyl)acetamide (I-33)
[0387] Acylation of Compound I-14 provided Compound I-33.
.sup.1H-NMR (DMSO-d.sub.6) .delta.: 12.60 (1H, s), 9.09 (1H, d,
J=7.3 Hz), 8.22 (1H, s), 7.89 (1H, d, J=7.3 Hz), 7.46-7.42 (2H, m),
7.36-7.28 (3H, m), 4.27-4.21 (1H, m), 3.68-3.75 (1H, m), 2.29 (3H,
s), 1.83-1.59 (11H, m). LC/MS: 392 [M+H].
Example 20:
(2S,5R)-5-((5-(2-methylbenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-N--
((tetrahydro-2H-pyran-4-yl)methyl)tetrahydro-2H-pyran-2-carboxamide
(I-34)
[0388] Condensation of
(2S,5R)-5-((5-(2-methylbenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)tet-
rahydro-2H-pyran-2-carboxylic acid with the applicable amine
provided Compound 1-34. .sup.1H-NMR (CDCl.sub.3) .delta.: 9.04 (1H,
d, J=7.3 Hz), 8.35 (1H, s), 7.44-7.23 (5H, m), 6.72 (1H, t, J=6.4
Hz), 4.46-4.29 (2H, m), 3.99 (2H, dd, J=11.3, 4.0 Hz), 3.90-3.85
(1H, m), 3.43-3.29 (3H, m), 3.25-3.12 (2H, m), 2.41-2.32 (5H, m),
1.85-1.24 (7H, m). LC/MS: 478 [M+H].
Example 21:
(4-((5-(2-chlorobenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexan-
-1-one (I-36)
[0389] Oxidation of Compound I-32 using Dess-Martin Periodinane
provided Compound I-36. .sup.1H-NMR (DMSO-d.sub.6) .delta.: 12.76
(1H, s), 8.92 (1H, d, J=7.3 Hz), 8.29 (1H, s), 7.61-7.53 (3H, m),
7.50-7.45 (2H, m), 4.56-4.54 (1H, m), 2.61-2.53 (1H, m), 2.38-2.28
(5H, m), 1.92-1.89 (2H, m). LC/MS: 369 [M+H].
Example 22:
(trans-4-((5-(2-methylbenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cycl-
ohexyl)(4-methylpiperazin-1-yl)methanone (I-37)
[0390] Condensation of
trans-4-((5-(2-methylbenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amino]cyclo-
hexanecarboxylic acid with the applicable amine provided Compound
I-37.
trans-4-((5-(2-methylbenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amino]cyclo-
hexanecarboxylic acid was synthesized according to General
Procedure A. .sup.1H-NMR (CDCl.sub.3) .delta.: 9.13 (1H, d, J=7.9
Hz), 8.31 (1H, s), 7.43-7.37 (2H, m), 7.33-7.25 (3H, m), 4.25-4.14
(1H, m), 3.69-3.62 (2H, m), 3.57-3.51 (2H, m), 2.60-2.29 (13H, m),
1.92-1.41 (6H, m). LC/MS: 461 [M+H].
Example 23:
(4-((cis-4-(benzylamino)cyclohexyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl-
)(o-tolyl)methanone (I-39)
[0391] Reductive alkylation of Compound I-14 with benzaldehyde
provided Compound I-39. .sup.1H-NMR (CDCl.sub.3) .delta.: 9.45 (1H,
d, J=7.3 Hz), 8.30 (1H, s), 7.20-7.42 (10H, m), 4.40-4.43 (1H, m),
3.84 (2H, s), 2.71-2.73 (1H, m), 2.37 (3H, d, J=7.9 Hz), 2.00-2.03
(2H, m), 1.69-1.89 (6H, m). LC/MS: 440 [M+H].
Example 24:
2-(4-benzylpiperazin-1-yl)-N-(cis-4-((5-(2-methylbenzoyl)-7H-pyrrolo[2,3--
d]pyrimidin-4-yl)amino)cyclohexyl)acetamide (I-40)
[0392] Reductive alkylation of
N-(4-((5-(2-methylbenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohex-
yl)-2-piperazin-1-yl-acetamide with benzaldehyde provided Compound
I-40. .sup.1H-NMR (DMSO-d.sub.6) .delta.: 12.61 (1H, s), 9.17 (1H,
d, J=7.9 Hz), 8.23 (1H, s), 7.56 (1H, d, J=7.9 Hz), 7.16-7.47 (10H,
m), 4.29-4.31 (1H, m), 3.77-3.80 (1H, m), 3.30 (2H, s), 2.90 (2H,
s), 2.23-2.51 (11H, m), 1.63-1.82 (8H, m). LC/MS: 566 [M+H].
Example 25:
(2S,5R)--N--(((S)-1,4-dioxan-2-yl)methyl)-5-((5-(2-methylbenzoyl)-7H-pyrr-
olo[2,3-d]pyrimidin-4-yl)amino)tetrahydro-2H-pyran-2-carboxamide
(I-42)
[0393] Condensation of
(2S,5R)-5-((5-(2-methylbenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)tet-
rahydro-2H-pyran-2-carboxylic acid with the applicable amine
provided Compound 1-42. .sup.1H-NMR (CDCl.sub.3) .delta.: 12.99
(1H, s), 9.09 (1H, d, J=7.3 Hz), 8.34 (1H, s), 7.45-7.26 (5H, m),
6.94 (1H, t, J=5.8 Hz), 4.47-4.29 (2H, m), 3.92-3.58 (7H, m),
3.50-3.42 (1H, m), 3.37-3.29 (2H, m), 3.25-3.17 (1H, m), 2.41-2.31
(5H, m), 1.85-1.60 (2H, m). LC/MS: 480 [M+H].
Example 26:
(2-chlorophenyl)(4-((cis-4-(methylamino)cyclohexyl)amino)-7H-pyrrolo[2,3--
d]pyrimidin-5-yl)methanone (I-43)
[0394] tert-Butyl N-(cis-4-amino-1-cyclohexyl)carbamate was
derivatized to the corresponding 2-nitrobezenesulfonamide product.
N-methylation of the sulfonamide followed by Boc deprotection
provided
N-(cis-4-amino-1-cyclohexyl)-N-methyl-2-nitrobenzenesulfonamide.
[0395] Compound I-43 was then synthesized according to General
Procedure A from reaction of
N-(cis-4-amino-1-cyclohexyl)-N-methyl-2-nitrobenzenesulfonamide
with
(2-chlorophenyl)-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone.
.sup.1H-NMR (DMSO-d.sub.6) .delta.: 8.91 (1H, d, J=7.3 Hz), 8.20
(1H, s), 7.60-7.53 (3H, m), 7.49-7.42 (2H, m), 4.28-4.22 (1H, m),
2.48-2.48 (1H, m), 2.29 (3H, s), 1.84-1.76 (2H, m), 1.72-1.62 (4H,
m), 1.51-1.61 (2H, m). LC/MS: 384 [M+H].
Example 27:
(2-chlorophenyl)(4-((cis-4-(dimethylamino)cyclohexyl)amino)-7H-pyrrolo[2,-
3-d]pyrimidin-5-yl)methanone (I-44)
[0396] Reductive alkylation of Compound I-6 with formaline provided
Compound I-44. .sup.1H-NMR (DMSO-d.sub.6) .delta.: 12.57 (1H, br
s), 9.00 (1H, d, J=7.9 Hz), 8.22 (1H, s), 7.61-7.53 (3H, m),
7.50-7.44 (2H, m), 4.37-4.31 (1H, m), 2.21-2.17 (7H, m), 1.81-1.89
(2H, m), 1.75-1.62 (6H, m). LC/MS: 398 [M+H].
Example 28:
N-(trans-4-((5-(2-chlorobenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cy-
clohexyl)acetamide (I-45)
[0397] Acylation of Compound I-6 provided Compound I-45.
.sup.1H-NMR (DMSO-d.sub.6) .delta.: 12.70 (1H, br s), 8.93 (1H, d,
J=7.3 Hz), 8.23 (1H, s), 7.90 (1H, d, J=7.9 Hz), 7.62-7.54 (3H, m),
7.50-7.45 (2H, m), 4.28-4.20 (1H, m), 3.69-3.77 (1H, m), 1.85-1.58
(11H, m). LC/MS: 412 [M+H].
Example 29:
(4-((((2S,5R)-5-aminotetrahydro-2H-pyran-2-yl)methyl)amino)-7H-pyrrolo[2,-
3-d]pyrimidin-5-yl)(o-tolyl)methanone (I-46)
[0398] Boc deprotection of Compound I-35 provided Compound I-46.
.sup.1H-NMR (CDCl.sub.3) .delta.: 9.32 (1H, t, J=5.5 Hz), 8.33 (1H,
s), 7.43-7.25 (5H, m), 4.06-4.00 (1H, m), 3.86-3.79 (1H, m),
3.72-3.58 (2H, m), 3.08 (1H, t, J=10.6 Hz), 2.92-2.83 (1H, m), 2.38
(3H, s), 2.12-2.04 (1H, m), 1.89-1.22 (5H, m). LC/MS: 366
[M+H].
Example 30:
N-(((2S,5R)-5-((5-(2-methylbenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino-
)tetrahydro-2H-pyran-2-yl)methyl)-2-(4-methylpiperazin-1-yl)acetamide
(I-47)
[0399] tert-butyl
N-((3R,6S)-6-(((2-(4-methylpiperazin-1-yl)acetyl)amino)methyl)tetrahydro--
2H-pyran-3-yl]carbamate was synthesized using a typical
condensation reaction. LC/MS: 371 [M+H]. Boc deprotection of
tert-butyl
N-((3R,6S)-6-(((2-(4-methylpiperazin-1-yl)acetyl)amino)methyl)tetrahydro--
2H-pyran-3-yl]carbamate followed by halogen displacement using
(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-(o-tolyl)methanone
provided Compound I-47. .sup.1H-NMR (CDCl.sub.3) .delta.: 12.38
(1H, br s), 9.00 (1H, d, J=6.7 Hz), 8.33 (1H, s), 7.57-7.50 (1H,
m), 7.45-7.36 (2H, m), 7.33-7.24 (2H, m), 4.40-4.27 (2H, m),
3.68-3.60 (1H, m), 3.51-3.42 (1H, m), 3.32-3.24 (1H, m), 3.20-3.11
(1H, m), 3.06 (1H, d, J=16.1 Hz), 3.01 (1H, d, J=16.1 Hz),
2.65-2.26 (15H, m), 1.85-1.50 (4H, m). LC/MS: 506 [M+H].
Example 31:
(2S,5R)-5-((5-(2-chlorobenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-N--
((tetrahydro-2H-pyran-4-yl)methyl)tetrahydro-2H-pyran-2-carboxamide
(I-48)
[0400] Condensation of
(2S,5R)-5-((5-(2-chlorobenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4
yl)amino)tetrahydro-2H-pyran-2-carboxylic acid with the applicable
amine provided Compound 1-48. .sup.1H-NMR (CDCl.sub.3) .delta.:
13.61 (1H, br s), 8.94 (1H, d, J=7.9 Hz), 8.34 (1H, s), 7.54-7.38
(4H, m), 7.34 (1H, s), 6.73 (1H, t, J=6.1 Hz), 4.45-4.30 (2H, m),
4.02-3.95 (2H, m), 3.88 (1H, dd, J=11.6, 1.8 Hz), 3.43-3.29 (3H,
m), 3.26-3.13 (2H, m), 2.42-2.32 (2H, m), 2.06-1.57 (5H, m),
1.40-1.27 (2H, m). LCMS: 498 [M+H].
Example 32:
N-(cis-4-((5-(2-chlorobenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cycl-
ohexyl)-N-methylacetamide (I-50)
[0401] Acylation of Compound I-43 provided Compound I-50.
.sup.1H-NMR (DMSO-d.sub.6) .delta.: 12.75 (1H, br s), 9.22 (1H, d,
J=7.9 Hz), 8.25 (1H, s), 7.62-7.55 (3H, m), 7.51-7.47 (2H, m),
4.50-4.38 (1.6H, m), 3.69-3.78 (0.4H, m), 2.87 (1.8H, s), 2.73
(1.2H, s), 2.06-1.42 (11H, m). LC/MS: 426 [M+H].
Example 33:
1-(cis-4-((5-(2-chlorobenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cycl-
ohexyl)pyrrolidin-2-one (I-51)
Step 1. 1-(cis-4-aminocyclohexyl)pyrrolidin-2-one (51a)
[0402] Acylation of tert-butyl N-(4-aminocyclohexyl)carbamate with
4-chlorobutanoyl chloride followed cyclization using sodium hydride
Boc deprotection provided 51a. .sup.1H-NMR (CD.sub.3OD) .delta.:
3.94-3.85 (1H, m), 3.52-3.46 (3H, m), 2.38 (2H, t, J=8.2 Hz),
2.08-1.64 (11H, m). LC/MS: 183 [M+H].
Step 2.
1-(cis-4-((5-(2-chlorobenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)ami-
no)cyclohexyl)pyrrolidin-2-one (I-51)
[0403] Compound I-51 was synthesized using General Procedure A from
51a and
(2-chlorophenyl)-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone.
.sup.1H-NMR (DMSO-d.sub.6) .delta.: 12.74 (1H, br s), 9.19 (1H, d,
J=7.9 Hz), 8.25 (1H, s), 7.63-7.54 (3H, m), 7.51-7.46 (2H, m),
4.49-4.43 (1H, m), 3.95-3.86 (1H, m), 3.38-3.31 (2H, m), 2.20 (2H,
t, J=7.9 Hz), 1.99-1.80 (6H, m), 1.77-1.67 (2H, m), 1.55-1.47 (2H,
m). LC/MS: 438 [M+H].
Example 34:
1-(4-((5-(2-methylbenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidi-
n-1-yl)ethan-1-one (I-52)
[0404] Boc deprotection of Compound I-17 followed by acylation
provided Compound I-52. .sup.1H-NMR (CDCl.sub.3) .delta.:
12.62-11.97 (1H, m), 9.36-9.32 (1H, m), 8.33 (1H, s), 7.49-7.39
(2H, m), 7.33-7.26 (3H, m), 4.49-4.42 (1H, m), 4.38-4.28 (1H, m),
3.88-3.82 (1H, m), 3.46-3.34 (1H, m), 3.24-3.18 (1H, m), 2.38 (3H,
s), 2.21-2.08 (5H, m), 1.79-1.67 (2H, m). LC/MS: 378 [M+H].
Example 35:
2-methoxy-1-(4-((5-(2-methylbenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amin-
o)piperidin-1-yl)ethan-1-one (I-53)
[0405] Boc deprotection of Compound I-17 followed by acylation
provided Compound I-53. .sup.1H-NMR (CDCl.sub.3) .delta.:
12.46-11.92 (1H, m), 9.32 (1H, d, J=7.3 Hz), 8.33 (1H, s),
7.43-7.38 (2H, m), 7.32-7.26 (3H, m), 4.50-4.42 (1H, m), 4.35-4.29
(1H, m), 4.15 (2H, d, J=2.4 Hz), 3.93-3.87 (1H, m), 3.45 (3H, s),
3.41-3.33 (1H, m), 3.28-3.21 (1H, m), 2.38 (3H, s), 2.22-2.15 (2H,
m), 1.79-1.69 (2H, m). LC/MS: 408 [M+H].
Example 36:
3-methoxy-1-(4-((5-(2-methylbenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amin-
o)piperidin-1-yl)propan-1-one (I-54)
[0406] Boc deprotection of Compound I-17 followed by acylation
provided Compound I-54. .sup.1H-NMR (CDCl.sub.3) .delta.: 9.34 (1H,
d, J=7.3 Hz), 8.32 (1H, s), 7.43-7.37 (2H, m), 7.32-7.25 (3H, m),
4.46-4.42 (1H, m), 4.37-4.31 (1H, m), 3.93-3.87 (1H, m), 3.74-3.68
(2H, m), 3.42-3.33 (4H, m), 3.26-3.19 (1H, m), 2.65 (2H, t, J=6.7
Hz), 2.38 (3H, s), 2.19-2.13 (2H, m), 1.81-1.66 (2H, m). LC/MS: 422
[M+H].
Example 37:
2-(dimethylamino)-1-(4-((5-(2-methylbenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-
-yl)amino)piperidin-1-yl)ethan-1-one (I-55)
[0407] Boc deprotection of Compound I-17 followed by acylation
provided Compound I-55. 1H-NMR (CDCl.sub.3) .delta.: 12.96 (1H, br
s), 9.32 (1H, d, J=7.9 Hz), 8.33 (1H, s), 7.42-7.38 (2H, m),
7.32-7.27 (3H, m), 4.47-4.41 (1H, m), 4.35-4.29 (1H, m), 4.11-4.05
(1H, m), 3.43-3.36 (1H, m), 3.22-3.10 (3H, m), 2.38 (3H, s), 2.30
(6H, s), 2.20-2.13 (2H, m), 1.78-1.62 (2H, m). LC/MS: 421
[M+H].
Example 38:
(4-((1-(2-methoxyethyl)piperidin-4-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-
-yl)(o-tolyl)methanone (I-56)
[0408] Boc deprotection of Compound I-17 followed by acylation
provided Compound I-56. .sup.1H-NMR (D.sub.2O) .delta.: 8.11 (1H,
s), 7.51 (1H, s), 7.39-718 (4H, m), 4.00-3.92 (1H, m), 3.52 (2H, t,
J=5.9 Hz), 3.32 (3H, s), 2.74-2.66 (2H, m), 2.53 (2H, t, J=5.9 Hz),
2.42-2.34 (2H, m), 2.23 (3H, s), 2.00-1.93 (2H, m), 1.69-1.60 (2H,
m). LC/MS: 394 [M+H].
Example 39:
(4-(((4-aminocyclohexyl)methyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(o--
tolyl)methanone (I-57)
Step 1. tert-butyl
N-(4-(((5-(2-methylbenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)-
-cyclohexyl)carbamate (57a)
[0409] tert-butyl
N-(4-(((5-(2-methylbenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)-
-cyclohexyl)carbamate (57a) was synthesized according to General
Procedure A from
(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(o-tolyl)methanone.
.sup.1H-NMR (DMSO-d.sub.6) .delta.: 12.59 (1H, s), 8.95 (1H, t,
J=5.5 Hz), 8.22 (1H, s), 7.41-7.45 (2H, m), 7.28-7.35 (3H, m), 6.75
(1H, d, J=6.7 Hz), 3.46-3.48 (3H, m), 2.27 (3H, s), 1.73-1.76 (1H,
m), 1.50-1.58 (8H, m), 1.38 (9H, s). LC/MS: 464 [M+H].
Step 2.
(4-(((4-aminocyclohexyl)methyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-
-yl)(o-tolyl)methanone (I-57)
[0410] Boc deprotection of 57a provided Compound I-57. .sup.1H-NMR
(DMSO-d.sub.6) .delta.: 8.35 (1H, s), 7.95 (3H, s), 7.58 (1H, s),
7.44-7.49 (2H, m), 7.31-7.38 (2H, m), 3.58 (3H, t, J=6.4 Hz), 3.23
(1H, m), 2.29 (3H, s), 1.90 (1H, m), 1.60-1.73 (8H, m). LC/MS: 364
[M+H].
Example 40:
(4-((4-(aminomethyl)cyclohexyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(o--
tolyl)methanone (I-58)
Step 1.
2-((4-((5-(2-methyl-benzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino-
)cyclohexyl) methyl)isoindoline-1,3-dione (58a)
[0411]
2-((4-((5-(2-methyl-benzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-
cyclohexyl) methyl)isoindoline-1,3-dione (58a) was synthesized
according to General Procedure A from
cis-2-((4-aminocyclohexyl)methyl)benzo[c]azolidine-1,3-dione and
(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-(2-methylphenyl)methanone.
.sup.1H-NMR (DMSO-d.sub.6) .delta.: 1.41-1.51 (2H, m), 1.62-1.65
(4H, m), 1.84-1.85 (3H, m), 2.27 (3H, s), 3.54 (2H, d, J=6.7 Hz),
4.38-4.41 (1H, m), 7.29-7.47 (5H, m), 7.77-7.80 (4H, m), 8.20 (1H,
s), 9.24 (1H, d, J=7.9 Hz), 12.57 (1H, s). LC/MS: 494 [M+H].
Step 2.
(4-((4-(aminomethyl)cyclohexyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-
-yl)(o-tolyl)methanone (I-58)
[0412] Deprotection of the phthalimide group on 58a provided
Compound I-58. .sup.1H-NMR (DMSO-d.sub.6) .delta.: 9.24 (1H, d,
J=7.3 Hz), 8.19 (1H, s), 7.41-7.43 (2H, m), 7.28-7.34 (3H, m),
4.41-4.44 (1H, m), 2.47 (2H, d, J=4.9 Hz), 2.27 (3H, s), 1.78-1.82
(2H, m), 1.64-1.65 (4H, m), 1.36-1.38 (3H, m). LC/MS: 364
[M+H].
Example 41:
(4-((4-((4-(tert-butyl)benzyl)amino)cyclohexyl)amino)-7H-pyrrolo[2,3-d]py-
rimidin-5-yl)(o-tolyl)methanone (I-59)
[0413] Reductive alkylation of Compound I-14 provided Compound
I-59. .sup.1H-NMR (DMSO-d.sub.6) .delta.: 9.08 (1H, d, J=7.9 Hz),
8.21 (1H, s), 7.43-7.44 (2H, m), 7.25-7.36 (7H, m), 4.23-4.25 (1H,
m), 3.69 (2H, s), 2.60-2.62 (1H, m), 2.29 (3H, s), 1.82-1.83 (2H,
m), 1.64-1.66 (6H, m), 1.26 (9H, s). LC/MS: 496 [M+H].
Example 42:
(4-((4-((3,5-dichlorobenzyl)amino)cyclohexyl)amino)-7H-pyrrolo[2,3-d]pyri-
midin-5-yl)(o-tolyl)methanone (I-60)
[0414] Reductive alkylation of Compound I-14 provided Compound
I-60. .sup.1H-NMR (DMSO-d.sub.6) .delta.: 12.57 (1H, brs), 9.09
(1H, d, J=7.3 Hz), 8.21 (1H, s), 7.44 (5H, dd, J=7.9, 4.9 Hz),
7.28-7.35 (3H, m), 4.23-4.26 (1H, m), 3.75 (2H, s), 2.54-2.56 (1H,
m), 2.29 (3H, s), 1.81-1.84 (2H, m), 1.62-1.66 (6H, m). LC/MS: 508
[M+H].
Example 43:
N-(cis-4-((5-(2-chlorobenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)
cyclohexyl)-N-methyl-2-(tetrahydro-2H-pyran-4-yl)acetamide
(I-61)
[0415] Acylation of Compound I-43 provided compound I-61.
.sup.1H-NMR (DMSO-d.sub.6) .delta.: 12.73 (1H, br s), 9.21 (1H, d,
J=7.9 Hz), 8.24 (1H, s), 7.62-7.55 (3H, m), 7.51-7.46 (2H, m),
4.51-4.42 (1.8H, m), 3.84-3.76 (2.2H, m), 3.30-3.23 (2H, m), 2.88
(1.8H, s), 2.75 (1.2H, s), 2.33-2.30 (0.8H, m), 2.23-2.20 (1.2H,
m), 1.99-1.16 (13H, m). LC/MS: 510 [M+H].
Example 44:
cis-4-((5-(2-chlorobenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)
cyclohexane-1-carboxamide (I-63)
[0416] Amidation of Compound I-62 with the applicable amine
provided Compound I-63. .sup.1H-NMR (DMSO-d.sub.6) .delta.: 12.68
(1H, br s), 8.95 (1H, d, J=7.3 Hz), 8.23 (1H, s), 7.61-7.52 (3H,
m), 7.49-7.43 (2H, m), 7.19 (1H, s), 6.72 (1H, s), 4.32 (1H, s),
2.20-2.27 (1H, m), 1.63-1.89 (8H, m). LC/MS: 398 [M+H].
Example 45:
cis-4-((5-(2-chlorobenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-N,N-di-
methylcyclohexane-1-carboxamide (I-64)
[0417] Amidation of Compound I-62 with the applicable amine
provided Compound I-64. .sup.1H-NMR (DMSO-d.sub.6) .delta.: 12.68
(1H, br s), 9.03 (1H, d, J=7.3 Hz), 8.23 (1H, s), 7.62-7.53 (3H,
m), 7.50-7.44 (2H, m), 4.42-4.36 (1H, m), 3.02 (3H, s), 2.79 (3H,
s), 2.74-2.66 (1H, m), 1.97-1.91 (2H, m), 1.81-1.71 (4H, m),
1.56-1.63 (2H, m). LC/MS: 426 [M+H].
Example 46:
cis-4-((5-(2-chlorobenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-N-(tet-
rahydro-2H-pyran-4-yl)cyclohexane-1-carboxamide (I-65)
[0418] Amidation of Compound I-62 with the applicable amine
provided Compound I-65. .sup.1H-NMR (DMSO-d.sub.6) .delta.: 12.68
(1H, br s), 8.97 (1H, d, J=7.3 Hz), 8.22 (1H, s), 7.67 (1H, d,
J=7.9 Hz), 7.62-7.53 (3H, m), 7.49-7.45 (2H, m), 4.36-4.31 (1H, m),
3.82-3.66 (3H, m), 3.33-3.27 (2H, m), 2.26-2.19 (1H, m), 1.90-1.60
(10H, m), 1.31-1.41 (2H, m). LC/MS: 482 [M+H].
Example 47:
cis-4-((5-(2-chlorobenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-N-((te-
trahydro-2H-pyran-4-yl)methyl)cyclohexane-1-carboxamide (I-66)
[0419] Amidation of Compound I-62 with the applicable amine
provided Compound I-66. .sup.1H-NMR (DMSO-d.sub.6) .delta.: 12.68
(1H, br s), 8.98 (1H, d, J=7.3 Hz), 8.22 (1H, s), 7.72 (1H, t,
J=5.8 Hz), 7.61-7.54 (3H, m), 7.49-7.45 (2H, m), 4.37-4.32 (1H, m),
3.81-3.75 (2H, m), 3.23-3.16 (2H, m), 2.92 (2H, t, J=6.4 Hz),
2.28-2.23 (1H, m), 1.91-1.49 (10H, m), 1.13-1.07 (2H, m). LC/MS:
496 [M+H].
Example 48:
cis-4-((5-(2-chlorobenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-N-(2-(-
pyridin-3-yl)ethyl)cyclohexane-1-carboxamide (I-67)
[0420] Amidation of Compound I-62 with the applicable amine
provided Compound I-67. .sup.1H-NMR (DMSO-d.sub.6) .delta.: 12.68
(1H, br s), 8.96 (1H, d, J=7.3 Hz), 8.40-8.36 (2H, m), 8.22 (1H,
s), 7.82 (1H, t, J=5.5 Hz), 7.62-7.53 (4H, m), 7.50-7.45 (2H, m),
7.28 (1H, dd, J=7.6, 4.6 Hz), 4.35-4.29 (1H, m), 3.32-3.26 (2H, m),
2.74-2.69 (2H, m), 2.16-2.24 (1H, m), 1.87-1.58 (8H, m). LC/MS: 503
[M+H].
Example 49:
cis-4-((5-(2-chlorobenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-N-meth-
ylcyclohexane-1-carboxamide (I-68)
[0421] Amidation of Compound I-62 with the applicable amine
provided Compound I-68. .sup.1H-NMR (DMSO-d.sub.6) .delta.: 12.68
(1H, br s), 8.96 (1H, d, J=7.3 Hz), 8.22 (1H, s), 7.68-7.64 (1H,
m), 7.62-7.54 (3H, m), 7.50-7.45 (2H, m), 4.36-4.30 (1H, m), 2.55
(3H, d, J=4.9 Hz), 2.19-2.26 (1H, m), 1.89-1.62 (8H, m). LC/MS: 412
[M+H].
Example 50:
(2-chlorophenyl)(4-((cis-4-(pyrrolidin-1-yl)cyclohexyl)amino)-7H-pyrrolo[-
2,3-d]pyrimidin-5-yl)methanone (I-69)
[0422] Reductive amination of Compound I-36 provided Compound I-69.
.sup.1H-NMR (DMSO-d.sub.6) .delta.: 8.89 (1H, d, J=7.9 Hz), 8.22
(1H, s), 7.61-7.53 (3H, m), 7.49-7.45 (2H, m), 4.28-4.26 (1H, m),
3.46-3.33 (4H, m), 2.13-2.10 (1H, m), 1.81-1.69 (12H, m). LC/MS:
424 [M+H].
Example 51:
(4-((cis-4-(azetidin-1-yl)cyclohexyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5--
yl)(2-chlorophenyl)methanone (I-70)
[0423] Reductive amination of Compound I-36 and subsequent isomer
separation provided Compound I-70. .sup.1H-NMR (DMSO-d.sub.6)
.delta.: 12.65 (1H, br s), 8.85 (1H, d, J=7.3 Hz), 8.21 (1H, s),
7.62-7.54 (3H, m), 7.49-7.44 (2H, m), 4.21-4.20 (1H, m), 3.07-3.06
(4H, m), 2.14-2.12 (1H, m), 1.94-1.87 (2H, m), 1.72-1.68 (4H, m),
1.53-1.36 (4H, m). LC/MS: 410 [M+H].
Example 52:
(4-((trans-4-(azetidin-1-yl)cyclohexyl)amino)-7H-pyrrolo[2,3-d]pyrimidin--
5-yl)(2-chlorophenyl)methanone (I-71)
[0424] Reductive amination of Compound I-36 and subsequent isomer
separation provided Compound I-71. .sup.1H-NMR (DMSO-d.sub.6)
.delta.: 8.72 (1H, d, J=7.3 Hz), 8.23 (1H, s), 7.59-7.54 (3H, m),
7.48-7.45 (2H, m), 4.00-3.99 (1H, m), 3.08 (4H, t, J=7.0 Hz),
2.08-2.05 (3H, m), 1.93-1.87 (2H, m), 1.78-1.75 (2H, m), 1.33-1.27
(2H, m), 1.11-1.05 (2H, m). LC/MS: 410 [M+H].
Example 53:
N-(4-(tert-butyl)benzyl)-2-methyl-2-((cis-4-(((5-(2-methylbenzoyl)-7H-pyr-
rolo[2,3-d]pyrimidin-4-yl)amino)methyl)cyclohexyl)
amino)propanamide (I-72)
Step 1. 2-bromo-N-[(4-tert-butylphenyl)methyl]-2-methyl-propanamide
(72a)
[0425] Acylation of 4-tert-butylbenzylamine with
2-bromo-2-methylpropanoic acid chloride provided
2-bromo-N-[(4-tert-butylphenyl)methyl]-2-methyl-propanamide (72a).
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.38 (2H, d, J=7.9 Hz), 7.23 (2H,
d, J=7.9 Hz), 6.99 (1H, br s), 4.44 (2H, d, J=6.1 Hz), 2.00 (6H,
s), 1.32 (9H, s). LC/MS: 312 [M+H].
Step 2.
N-(4-(tert-butyl)benzyl)-2-methyl-2-((cis-4-(((5-(2-methylbenzoyl)-
-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)cyclohexyl)
amino)propanamide (I-72)
[0426] Alkylation of Compound I-57 with
2-bromo-N-[(4-tert-butylphenyl)methyl]-2-methyl-propanamide (72a)
provided Compound I-72. .sup.1H-NMR (CDCl.sub.3) .delta.: 9.17 (1H,
t, J=4.9 Hz), 8.32 (1H, s), 7.83 (1H, t, J=5.5 Hz), 7.23-7.36 (9H,
m), 4.36 (2H, d, J=5.5 Hz), 3.55 (2H, t, J=6.1 Hz), 2.80 (1H, s),
3.35 (1H, m), 2.36 (3H, s), 1.24-1.88 (23H, m). LC/MS: 595
[M+H].
Example 54:
N-benzyl-2-methyl-2-((cis-4-(((5-(2-methylbenzoyl)-7H-pyrrolo[2,3-d]pyrim-
idin-4-yl)amino)methyl)cyclohexyl) amino)propanamide (I-73)
[0427] Alkylation of Compound I-57 provided Compound I-73.
.sup.1H-NMR (CDCl.sub.3) .delta.: 9.17 (1H, t, J=5.2 Hz), 8.32 (1H,
s), 7.87 (1H, t, J=6.1 Hz), 7.19-7.42 (10H, m), 4.38 (2H, d, J=6.1
Hz), 3.54 (2H, t, J=6.1 Hz), 2.80 (1H, s), 2.37 (3H, s), 1.40-1.89
(9H, m), 1.34 (6H, s). LC/MS: 539 [M+H].
Example 55:
N-(cis-4-(((5-(2-methylbenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)met-
hyl) cyclohexyl)benzamide (I-74)
[0428] Acylation of Compound I-57 provided Compound I-74.
.sup.1H-NMR (DMSO-d.sub.6) .delta.: 12.60 (1H, s), 8.98 (1H, t,
J=5.5 Hz), 8.23 (1H, s), 8.13 (1H, d, J=7.3 Hz), 7.84-7.83 (2H, m),
7.52-7.28 (8H, m), 3.97 (1H, m), 3.58 (2H, t, J=6.4 Hz), 2.27 (3H,
s), 1.91-1.57 (9H, m). LC/MS: 468 [M+H].
Example 56:
N-((cis-4-((5-(2-methylbenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)
cyclohexyl)methyl)benzamide (I-75)
[0429] Acylation of Compound I-58 provided Compound I-75.
.sup.1H-NMR (DMSO-d.sub.6) .delta.: 12.58 (1H, s), 9.24 (1H, d,
J=7.3 Hz), 8.50 (1H, t, J=5.8 Hz), 8.22 (1H, s), 7.83-7.82 (2H, m),
7.51-7.29 (8H, m), 4.43-4.40 (1H, m), 3.20 (2H, t, J=6.4 Hz), 2.29
(3H, s), 1.86-1.67 (7H, m), 1.47-1.44 (2H, m). LC/MS: 468
[M+H].
Example 57:
(cis-4-((5-(2-chlorobenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cycloh-
exyl)(morpholino)methanone (I-78)
[0430] Amidation of Compound I-62 provided Compound I-78.
.sup.1H-NMR (DMSO-d.sub.6) .delta.: 12.68 (1H, br s), 9.04 (1H, d,
J=7.3 Hz), 8.23 (1H, s), 7.62-7.54 (3H, m), 7.49-7.45 (2H, m),
4.42-4.37 (1H, m), 3.59-3.40 (8H, m), 2.74-2.66 (1H, m), 1.95-1.90
(2H, m), 1.84-1.69 (4H, m), 1.57-1.63 (2H, m). LC/MS: 468
[M+H].
Example 58:
(cis-4-((5-(2-chlorobenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cycloh-
exyl)((2S,6R)-2,6-dimethylmorpholino)methanone (I-79)
[0431] Amidation of Compound I-62 provided Compound I-79.
.sup.1H-NMR (DMSO-d.sub.6) .delta.: 12.68 (1H, s), 9.03 (1H, d,
J=7.3 Hz), 8.23 (1H, s), 7.61-7.54 (3H, m), 7.49-7.45 (2H, m),
4.43-4.38 (1H, m), 4.25 (1H, d, J=12.8 Hz), 3.86 (1H, d, J=13.4
Hz), 3.51-3.35 (2H, m), 2.79-2.67 (2H, m), 2.17 (1H, t, J=11.9 Hz),
1.97-1.51 (8H, m), 1.04-1.13 (6H, m). LC/MS: 496 [M+H].
Example 59:
(4-((cis-4-((1R,5S)-8-oxa-3-azabicyclo[3.2.1]octane-3-carbonyl)cyclohexyl-
)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(2-chlorophenyl)methanone
(I-80)
[0432] Amidation of Compound I-62 provided Compound I-80.
.sup.1H-NMR (DMSO-d.sub.6) .delta.: 12.67 (1H, br s), 9.03 (1H, d,
J=7.3 Hz), 8.23 (1H, s), 7.62-7.54 (3H, m), 7.50-7.45 (2H, m),
4.41-4.37 (1H, m), 4.32-4.28 (2H, m), 3.95 (1H, d, J=12.8 Hz), 3.64
(1H, d, J=12.2 Hz), 3.31-3.22 (2H, m), 2.76-2.62 (2H, m), 1.99-1.50
(12H, m). LC/MS: 494 [M+H].
Example 60:
(cis-4-((5-(2-chlorobenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)
cyclohexyl)(3-hydroxyazetidin-1-yl)methanone (I-81)
[0433] Amidation of Compound I-62 provided Compound I-81.
.sup.1H-NMR (DMSO-d.sub.6) .delta.: 12.68 (1H, br s), 8.98 (1H, d,
J=7.3 Hz), 8.22 (1H, s), 7.61-7.54 (3H, m), 7.49-7.45 (2H, m), 5.69
(1H, d, J=6.1 Hz), 4.46-4.39 (1H, m), 4.34 (2H, t, J=7.6 Hz), 3.99
(1H, dd, J=9.5, 7.0 Hz), 3.88 (1H, dd, J=8.5, 4.3 Hz), 3.54 (1H,
dd, J=9.8, 4.3 Hz), 2.38-2.31 (1H, m), 1.55-1.93 (8H, m). LC/MS:
454 [M+H].
Example 61:
(cis-4-((5-(2-chlorobenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)
cyclohexyl)(4-methylpiperazin-1-yl)methanone (I-82)
[0434] Amidation of Compound I-62 provided Compound I-82.
.sup.1H-NMR (DMSO-d.sub.6) .delta.: 12.68 (1H, br s), 9.03 (1H, d,
J=7.3 Hz), 8.23 (1H, s), 7.62-7.54 (3H, m), 7.50-7.45 (2H, m),
4.42-4.37 (1H, m), 3.52-3.39 (4H, m), 2.74-2.66 (1H, m), 2.35-2.16
(7H, m), 1.94-1.89 (2H, m), 1.80-1.70 (4H, m), 1.62-1.55 (2H, m).
LC/MS: 481 [M+H].
Example 62:
(cis-4-((5-(2-chlorobenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)
cyclohexyl)((3S,5R)-3,5-dimethylpiperazin-1-yl)methanone (I-83)
[0435] Amidation of Compound I-62 provided Compound I-83.
.sup.1H-NMR (CDCl.sub.3) .delta.: 9.30 (1H, d, J=6.7 Hz), 8.33 (1H,
s), 7.49-7.34 (4H, m), 7.25 (1H, s), 4.56-4.42 (2H, m), 3.72 (1H,
d, J=11.5 Hz), 2.84-2.57 (4H, m), 2.23-2.01 (5H, m), 1.84-1.68 (4H,
m), 1.04-1.13 (6H, m). LC/MS: 495 [M+H].
Example 63:
N-(trans-4-((5-(2-chlorobenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)
cyclohexyl)acetamide (I-84)
[0436] Acylation of Compound I-5 provided Compound I-84.
.sup.1H-NMR (DMSO-d.sub.6) .delta.: 12.69 (1H, br s), 8.70 (1H, d,
J=7.3 Hz), 8.24 (1H, s), 7.78 (1H, d, J=7.9 Hz), 7.61-7.53 (3H, m),
7.49-7.45 (2H, m), 4.03-3.95 (1H, m), 3.63-3.54 (1H, m), 2.15-2.10
(2H, m), 1.90-1.85 (2H, m), 1.27-1.44 (4H, m). LC/MS: 412
[M+H].
Example 64:
(S)--N-(cis-4-((5-(2-chlorobenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino-
) cyclohexyl)-2-hydroxypropanamide (I-85)
[0437] Acylation of Compound I-6 provided Compound I-85.
.sup.1H-NMR (DMSO-d.sub.6) .delta.: 12.71 (1H, br s), 8.96 (1H, d,
J=6.7 Hz), 8.24 (1H, s), 7.62-7.53 (3H, m), 7.49-7.43 (3H, m),
5.40-5.34 (1H, m), 4.31-4.25 (1H, m), 3.99-3.93 (1H, m), 3.76-3.70
(1H, m), 1.59-1.84 (8H, m), 1.19 (3H, d, J=6.7 Hz). LC/MS: 442
[M+H].
Example 65:
(R)--N-(cis-4-((5-(2-chlorobenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino-
) cyclohexyl)-2-hydroxypropanamide (I-86)
[0438] Acylation of Compound I-6 provided Compound I-86.
.sup.1H-NMR (DMSO-d.sub.6) .delta.: 12.71 (1H, s), 8.95 (1H, d,
J=7.3 Hz), 8.24 (1H, s), 7.62-7.54 (3H, m), 7.49-7.43 (3H, m), 5.37
(1H, d, J=5.5 Hz), 4.31-4.25 (1H, m), 3.99-3.93 (1H, m), 3.78-3.69
(1H, m), 1.59-1.85 (8H, m), 1.19 (3H, d, J=6.7 Hz). LC/MS: 442
[M+H].
Example 66:
N-(cis-4-((5-(2-chlorobenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)
cyclohexyl)-2-methoxyacetamide (I-87)
[0439] Acylation of Compound I-6 provided Compound I-87.
.sup.1H-NMR (DMSO-d.sub.6) .delta.: 12.71 (1H, s), 8.95 (1H, d,
J=7.3 Hz), 8.24 (1H, s), 7.66 (1H, d, J=7.9 Hz), 7.62-7.54 (3H, m),
7.50-7.46 (2H, m), 4.31-4.25 (1H, m), 3.76-3.80 (3H, m), 3.28 (3H,
s), 1.87-1.64 (8H, m). LC/MS: 442 [M+H].
Example 67:
(2-chlorophenyl)(4-((cis-4-(3-hydroxyazetidin-1-yl)cyclohexyl)amino)-7H-p-
yrrolo[2,3-d]pyrimidin-5-yl)methanone (I-88)
[0440] Reductive amination of Compound I-36 and subsequent isomer
separation provided Compound I-88.
[0441] .sup.1H-NMR (DMSO-d.sub.6) .delta.: 12.67 (1H, s), 8.84 (1H,
d, J=7.9 Hz), 8.22 (1H, s), 7.60-7.55 (3H, m), 7.48-7.44 (2H, m),
5.22 (1H, d, J=6.1 Hz), 4.21-4.12 (2H, m), 3.49 (2H, t, J=6.7 Hz),
2.65-2.63 (2H, m), 2.13-2.10 (1H, m), 1.72-1.66 (4H, m), 1.55-1.46
(4H, m). LC/MS: 426 [M+H].
Example 68:
(2-chlorophenyl)(4-((trans-4-(3-hydroxyazetidin-1-yl)cyclohexyl)amino)-7H-
-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (I-89)
[0442] Reductive amination of Compound I-36 and subsequent isomer
separation provided Compound I-89. .sup.1H-NMR (DMSO-d.sub.6)
.delta.: 8.71 (1H, d, J=7.3 Hz), 8.23 (1H, s), 7.61-7.53 (3H, m),
7.48-7.45 (2H, m), 5.23 (1H, d, J=6.7 Hz), 4.12 (1H, dd, J=12.5,
6.4 Hz), 4.00-3.99 (1H, m), 3.48 (2H, t, J=6.7 Hz), 2.68 (2H, t,
J=6.7 Hz), 2.07-2.03 (3H, m), 1.78 (2H, d, J=9.8 Hz), 1.31 (2H, dd,
J=22.9, 9.5 Hz), 1.13-1.03 (2H, m). LC/MS: 426 [M+H].
Example 69:
N-(cis-4-((5-(2-chlorobenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)
cyclohexyl)propionamide (I-92)
[0443] Acylation of Compound I-6 provided Compound I-92.
.sup.1H-NMR (DMSO-d.sub.6) .delta.: 12.70 (1H, s), 8.93 (1H, d,
J=7.3 Hz), 8.24 (1H, s), 7.81 (1H, d, J=7.3 Hz), 7.62-7.54 (3H, m),
7.50-7.45 (2H, m), 4.27-4.22 (1H, m), 3.69-3.76 (1H, m), 2.08 (2H,
q, J=7.5 Hz), 1.83-1.59 (8H, m), 0.97 (3H, t, J=7.6 Hz). LC/MS: 426
[M+H].
Example 70:
N-(cis-4-((5-(2-chlorobenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)
cyclohexyl)isobutyramide (I-93)
[0444] Acylation of Compound I-6 provided Compound I-93.
.sup.1H-NMR (DMSO-d.sub.6) .delta.: 12.71 (1H, s), 8.93 (1H, d,
J=6.7 Hz), 8.24 (1H, s), 7.76 (1H, d, J=7.3 Hz), 7.62-7.53 (3H, m),
7.50-7.46 (2H, m), 4.27-4.20 (1H, m), 3.75-3.68 (1H, m), 2.38-2.46
(1H, m), 1.56-1.87 (8H, m), 0.95 (6H, d, J=6.7 Hz). LC/MS: 440
[M+H].
Example 71:
N-(cis-4-((5-(2-chlorobenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)
cyclohexyl)cyclopropanecarboxamide (I-94)
[0445] Acylation of Compound I-6 provided Compound I-94.
.sup.1H-NMR (DMSO-d.sub.6) .delta.: 12.70 (1H, s), 8.95 (1H, d,
J=7.9 Hz), 8.24 (1H, s), 8.11 (1H, d, J=7.3 Hz), 7.62-7.54 (3H, m),
7.50-7.46 (2H, m), 4.29-4.21 (1H, m), 3.78-3.71 (1H, m), 1.84-1.61
(9H, m), 0.56-0.67 (4H, m). LC/MS: 438 [M+H].
Example 72:
4-methyl-N-(cis-4-((5-(2-methylbenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)a-
mino)cyclohexyl)benzamide (I-95)
[0446] Acylation of Compound I-14 provided Compound I-95.
.sup.1H-NMR (DMSO-d.sub.6) .delta.: 12.60 (1H, s), 9.15 (1H, d,
J=6.7 Hz), 8.27 (1H, d, J=6.7 Hz), 8.24 (1H, s), 7.76 (2H, d, J=8.5
Hz), 7.44-7.42 (2H, m), 7.37-7.28 (3H, m), 7.23 (2H, d, J=7.9 Hz),
4.32-4.29 (1H, m), 3.93-3.90 (1H, m), 2.33 (3H, s), 2.30 (3H, s),
1.98 (2H, d, J=9.2 Hz), 1.78 (6H, d, J=4.9 Hz). LC/MS: 468
[M+H].
Example 73:
3-methyl-N-(cis-4-((5-(2-methylbenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)a-
mino)cyclohexyl)benzamide (I-96)
[0447] Acylation of Compound I-14 provided Compound I-96.
.sup.1H-NMR (DMSO-d.sub.6) .delta.: 12.60 (1H, s), 9.15 (1H, d,
J=6.7 Hz), 8.30 (1H, d, J=7.3 Hz), 8.24 (1H, s), 7.65-7.62 (2H, m),
7.45-7.42 (2H, m), 7.35-7.30 (5H, m), 4.32-4.29 (1H, m), 3.93-3.90
(1H, m), 2.33 (3H, s), 2.30 (3H, s), 1.99-1.97 (2H, m), 1.79-1.78
(6H, m). LC/MS: 468 [M+H].
Example 74:
2-methyl-N-(cis-4-((5-(2-methylbenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)a-
mino)cyclohexyl)benzamide (I-97)
[0448] Acylation of Compound I-14 provided Compound I-97.
.sup.1H-NMR (DMSO-d.sub.6) .delta.: 12.58 (1H, s), 9.08 (1H, d,
J=7.3 Hz), 8.37 (1H, d, J=7.3 Hz), 8.23 (1H, s), 7.42-7.40 (2H, m),
7.35-7.16 (7H, m), 4.28-4.25 (1H, m), 3.95-3.92 (1H, m), 2.31 (3H,
s), 2.27 (3H, s), 1.91-1.89 (2H, m), 1.81-1.79 (6H, m). LC/MS: 468
[M+H].
Example 75:
(S)--N-(cis-4-((5-(2-chlorobenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino-
) cyclohexyl)-2-methoxypropanamide (I-98)
[0449] Acylation of Compound I-6 provided Compound I-98.
.sup.1H-NMR (DMSO-d.sub.6) .delta.: 12.71 (1H, s), 8.94 (1H, d,
J=7.3 Hz), 8.24 (1H, s), 7.75 (1H, d, J=7.3 Hz), 7.62-7.53 (3H, m),
7.50-7.45 (2H, m), 4.30-4.23 (1H, m), 3.68-3.80 (2H, m), 3.20 (3H,
s), 1.61-1.87 (8H, m), 1.18 (3H, d, J=6.7 Hz). LC/MS: 456
[M+H].
Example 76:
(R)--N-(cis-4-((5-(2-chlorobenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino-
) cyclohexyl)-2-methoxypropanamide (I-99)
[0450] Acylation of Compound I-6 provided Compound I-99.
.sup.1H-NMR (DMSO-d.sub.6) .delta.: 12.71 (1H, s), 8.95 (1H, d,
J=7.3 Hz), 8.24 (1H, s), 7.75 (1H, d, J=7.3 Hz), 7.62-7.54 (3H, m),
7.50-7.46 (2H, m), 4.30-4.23 (1H, m), 3.78-3.68 (2H, m), 3.20 (3H,
s), 1.60-1.89 (8H, m), 1.18 (3H, d, J=6.7 Hz). LC/MS: 456
[M+H].
Example 77:
(S)--N-(cis-4-((5-(2-chlorobenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino-
) cyclohexyl)tetrahydrofuran-2-carboxamide (I-100)
[0451] Acylation of Compound I-6 provided Compound I-100.
.sup.1H-NMR (DMSO-d.sub.6) .delta.: 12.71 (1H, s), 8.95 (1H, d,
J=6.7 Hz), 8.23 (1H, d, J=5.5 Hz), 7.62-7.54 (4H, m), 7.50-7.46
(2H, m), 4.19-4.30 (2H, m), 3.89-3.83 (1H, m), 3.75-3.69 (2H, m),
2.11-2.01 (1H, m), 1.87-1.63 (11H, m). LC/MS: 468 [M+H].
Example 78:
(R)--N-(cis-4-((5-(2-chlorobenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino-
) cyclohexyl)tetrahydrofuran-2-carboxamide (I-101)
[0452] Acylation of Compound I-6 provided Compound I-101.
.sup.1H-NMR (DMSO-d.sub.6) .delta.: 12.71 (1H, s), 8.95 (1H, d,
J=7.3 Hz), 8.24 (1H, s), 7.63-7.54 (4H, m), 7.50-7.46 (2H, m),
4.30-4.19 (2H, m), 3.89-3.83 (1H, m), 3.75-3.69 (2H, m), 2.02-2.11
(1H, m), 1.87-1.63 (11H, m). LC/MS: 468 [M+H].
Example 79:
N-(cis-4-((5-(2-chlorobenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)
cyclohexyl)-1-hydroxycyclopropane-1-carboxamide (I-102)
[0453] Acylation of Compound I-6 provided Compound I-102.
.sup.1H-NMR (DMSO-d.sub.6) .delta.: 12.71 (1H, s), 8.98 (1H, d,
J=7.3 Hz), 8.24 (1H, s), 7.62-7.54 (3H, m), 7.50-7.42 (3H, m), 6.29
(1H, s), 4.35-4.27 (1H, m), 3.80-3.71 (1H, m), 1.66-1.85 (8H, m),
1.01 (2H, q, J=3.9 Hz), 0.81 (2H, q, J=3.9 Hz). LC/MS: 454
[M+H].
Example 80:
(S)--N-(cis-4-((5-(2-chlorobenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino-
) cyclohexyl)-2-hydroxy-N-methylpropanamide (I-106)
[0454] Acylation of Compound I-43 provided Compound I-106.
.sup.1H-NMR (DMSO-d.sub.6) .delta.: 12.34 (1H, br s), 9.05 (1H, d,
J=7.3 Hz), 8.22 (1H, s), 7.57-7.44 (4H, m), 7.34 (1H, s), 4.54-4.33
(3H, m), 2.86 (3H, s), 2.05-1.91 (5H, m), 1.80-1.70 (2H, m),
1.49-1.59 (2H, m), 1.20 (3H, d, J=6.1 Hz). LC/MS: 442 [M+H].
Example 81:
(2-chlorophenyl)(4-((cis-4-(3-methoxyazetidin-1-yl)cyclohexyl)amino)-7H-p-
yrrolo[2,3-d]pyrimidin-5-yl)methanone (I-109)
[0455] Reductive amination of Compound I-36 and subsequent isomer
separation provided Compound I-109. .sup.1H-NMR (DMSO-d.sub.6)
.delta.: 12.69 (1H, s), 8.85 (1H, d, J=7.9 Hz), 8.22 (1H, s),
7.59-7.57 (3H, m), 7.49-7.45 (2H, m), 4.21 (1H, s), 3.95-3.90 (1H,
m), 3.48 (2H, t, J=6.7 Hz), 3.14 (3H, s), 2.71 (2H, t, J=6.7 Hz),
2.14 (1H, s), 1.72-1.67 (4H, m), 1.56-1.46 (4H, m). LC/MS: 440
[M+H].
Example 82:
(2-chlorophenyl)(4-((trans-4-(3-methoxyazetidin-1-yl)cyclohexyl)amino)-7H-
-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (I-110)
[0456] Reductive amination of Compound I-36 and subsequent isomer
separation provided Compound I-110. .sup.1H-NMR (DMSO-d.sub.6)
.delta.: 12.69 (1H, br s), 8.72 (1H, d, J=7.3 Hz), 8.23 (1H, s),
7.59-7.55 (3H, m), 7.48-7.43 (2H, m), 4.04-3.99 (1H, m), 3.94-3.88
(1H, m), 3.49-3.43 (2H, m), 3.14 (3H, s), 2.76 (2H, t, J=6.7 Hz),
2.10-2.02 (3H, m), 1.79 (2H, d, J=10.4 Hz), 1.33-1.26 (2H, m),
1.12-1.05 (2H, m). LC/MS: 440 [M+H].
Example 83:
(2-chlorophenyl)(4-((cis-4-(3-hydroxy-3-methylazetidin-1-yl)cyclohexyl)
amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (I-111)
[0457] Reductive amination of Compound I-36 and subsequent isomer
separation provided Compound I-111. .sup.1H-NMR (DMSO-d.sub.6)
.delta.: 12.69 (1H, s), 8.87 (1H, d, J=7.3 Hz), 8.22 (1H, s),
7.59-7.56 (3H, m), 7.49-7.45 (2H, m), 5.08 (1H, s), 4.24 (1H, s),
3.17-3.14 (2H, m), 2.81-2.78 (2H, m), 2.13 (1H, s), 1.79-1.76 (2H,
m), 1.68-1.63 (2H, m), 1.55-1.53 (2H, m), 1.45-1.43 (2H, m), 1.33
(3H, s). LC/MS: 440 [M+H].
Example 84:
(2-chlorophenyl)(4-((trans-4-(3-hydroxy-3-methylazetidin-1-yl)cyclohexyl)
amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (I-112)
[0458] Reductive amination of Compound I-36 and subsequent isomer
separation provided Compound I-112. .sup.1H-NMR (DMSO-d.sub.6)
.delta.: 12.68 (1H, br s), 8.70 (1H, d, J=7.3 Hz), 8.23 (1H, s),
7.59-7.54 (3H, m), 7.49-7.44 (2H, m), 5.09 (1H, s), 3.99 (1H, d,
J=6.7 Hz), 3.16 (2H, d, J=7.3 Hz), 2.82 (2H, d, J=6.7 Hz),
2.09-2.05 (3H, m), 1.78 (2H, d, J=10.4 Hz), 1.34-1.23 (5H, m),
1.14-1.03 (2H, m). LC/MS: 440 [M+H].
Example 85:
(4-((cis-4-(3-amino-3-methylazetidin-1-yl)cyclohexyl)amino)-7H-pyrrolo[2,-
3-d]pyrimidin-5-yl)(2-chlorophenyl)methanone (I-113)
[0459] Reductive amination of Compound I-36 with tert-butyl
N-(3-methylazetidin-3-yl)carbamate and subsequent isomer
separation, followed by Boc deprotection provided Compound I-113.
.sup.1H-NMR (DMSO-d.sub.6) .delta.: 8.87 (1H, d, J=7.9 Hz), 8.21
(1H, s), 7.61-7.53 (3H, m), 7.49-7.44 (2H, m), 4.23 (1H, s), 3.10
(2H, d, J=7.3 Hz), 3.30-2.80 (2H, br m), 2.67 (2H, d, J=6.7 Hz),
2.11-2.09 (1H, m), 1.82-1.79 (2H, m), 1.67-1.41 (6H, m), 1.27 (3H,
s). LC/MS: 439 [M+H].
Example 86:
(4-((trans-4-(3-amino-3-methylazetidin-1-yl)cyclohexyl)amino)-7H-pyrrolo[-
2,3-d]pyrimidin-5-yl)(2-chlorophenyl)methanone (I-114)
[0460] Reductive amination of Compound I-36 with tert-butyl
N-(3-methylazetidin-3-yl)carbamate and subsequent isomer
separation, followed by Boc deprotection provided Compound I-114.
.sup.1H-NMR (DMSO-d.sub.6) .delta.: 8.70 (1H, d, J=7.3 Hz), 8.22
(1H, s), 7.59-7.54 (3H, m), 7.48-7.43 (2H, m), 3.98-3.96 (1H, m),
3.11 (2H, d, J=7.3 Hz), 3.21-2.80 (2H, br m), 2.70 (2H, d, J=6.7
Hz), 2.11-1.99 (3H, m), 1.79-1.68 (2H, m), 1.33-1.23 (5H, m),
1.12-1.03 (2H, m). LC/MS: 439 [M+H].
Example 87:
N-(cis-4-((5-(2-chlorobenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)
cyclohexyl)-2-hydroxy-2-methylpropanamide (I-115)
[0461] Acylation of Compound I-6 provided Compound I-115.
.sup.1H-NMR (DMSO-d.sub.6) .delta.: 12.72 (1H, s), 8.96 (1H, d,
J=7.3 Hz), 8.24 (1H, s), 7.62-7.53 (3H, m), 7.50-7.46 (2H, m), 7.29
(1H, d, J=7.3 Hz), 5.45 (1H, s), 4.31-4.25 (1H, m), 3.73-3.65 (1H,
m), 1.59-1.84 (8H, m), 1.23 (6H, s). LC/MS: 456 [M+H].
Example 88:
N--((S)-1-((2S,5R)-5-((5-(2-chlorobenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-y-
l)amino)tetrahydro-2H-pyran-2-yl)ethyl)acetamide (I-116)
[0462]
N--((S)-1-((2S,5R)-5-((5-(2-chlorobenzoyl)-7H-pyrrolo[2,3-d]pyrimid-
in-4-yl)amino) tetrahydro-2H-pyran-2-yl)ethyl)acetamide (I-116) was
synthesized according to General Procedure A, Step 2 via halogen
displacement using
N-((1S)-1-((2S,5R)-5-aminotetrahydro-2H-pyran-2-yl)ethyl)acetamide.
.sup.1H-NMR (DMSO-d.sub.6) .delta.: 12.53 (1H, s), 8.60 (1H, d,
J=7.3 Hz), 8.25 (1H, s), 7.71 (1H, d, J=8.5 Hz), 7.61-7.54 (3H, m),
7.50-7.45 (2H, m), 4.25-4.10 (2H, m), 3.94-3.83 (1H, m), 3.31-3.28
(1H, m), 3.14-3.08 (1H, m), 2.20-2.16 (1H, m), 1.83 (3H, s),
1.70-1.42 (3H, m), 1.05 (3H, d, J=6.7 Hz). LC/MS: 442 [M+H].
Example 89:
N--((S)-1-((2S,5R)-5-((5-(2-methylbenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-y-
l)amino)tetrahydro-2H-pyran-2-yl)ethyl)acetamide (I-117)
[0463]
N--((S)-1-((2S,5R)-5-((5-(2-methylbenzoyl)-7H-pyrrolo[2,3-d]pyrimid-
in-4-yl)amino) tetrahydro-2H-pyran-2-yl)ethyl)acetamide (I-117) was
synthesized according to General Procedure A, Step 2 via halogen
displacement using
N-((1S)-1-((2S,5R)-5-aminotetrahydro-2H-pyran-2-yl)ethyl)acetamide.
.sup.1H-NMR (DMSO-d.sub.6) .delta.: 8.75 (1H, d, J=6.7 Hz), 8.24
(1H, s), 7.70 (1H, d, J=9.2 Hz), 7.45-7.28 (5H, m), 4.23-4.13 (2H,
m), 3.90-3.88 (1H, m), 3.31-3.29 (1H, m), 3.12-3.10 (1H, m), 2.27
(3H, s), 2.20-2.17 (1H, m), 1.84-1.82 (3H, m), 1.67-1.42 (3H, m),
1.05 (3H, d, J=6.7 Hz). LC/MS: 422 [M+H].
Example 90:
N-(((2S,5R)-5-((5-(2-chlorobenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino-
)tetrahydro-2H-pyran-2-yl)methyl)acetamide (I-118)
[0464]
N-(((2S,5R)-5-((5-(2-chlorobenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl-
)amino)tetrahydro-2H-pyran-2-yl)methyl)acetamide (I-118) was
synthesized according to General Procedure A, Step 2 via halogen
displacement using
N-(((2S,5R)-5-aminotetrahydro-2H-pyran-2-yl)methyl)acetamide.
.sup.1H-NMR (DMSO-d.sub.6) .delta.: 12.75 (1H, s), 8.60 (1H, d,
J=7.3 Hz), 8.26 (1H, s), 7.95 (1H, t, J=5.8 Hz), 7.61-7.45 (5H, m),
4.16-4.13 (2H, m), 3.39-3.37 (1H, m), 3.21-3.05 (3H, m), 2.19-2.16
(1H, m), 1.83 (3H, s), 1.78-1.74 (1H, m), 1.60-1.57 (1H, m),
1.44-1.35 (1H, m). LC/MS: 428 [M+H].
Example 91:
N-(((2S,5R)-5-((5-(2-methylbenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino-
)tetrahydro-2H-pyran-2-yl)methyl)acetamide (I-119)
[0465]
N-(((2S,5R)-5-((5-(2-methylbenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl-
)amino)tetrahydro-2H-pyran-2-yl)methyl)acetamide (I-119) was
synthesized according to General Procedure A, Step 2 via halogen
displacement using
N-(((2S,5R)-5-aminotetrahydro-2H-pyran-2-yl)methyl)acetamide.
.sup.1H-NMR (DMSO-d.sub.6) .delta.: 8.75 (1H, d, J=6.7 Hz), 8.24
(1H, s), 7.95 (1H, t, J=5.8 Hz), 7.45-7.28 (5H, m), 4.18-4.17 (2H,
m), 3.21-3.05 (4H, m), 2.27 (3H, s), 2.19-2.16 (1H, m), 1.83 (3H,
s), 1.77-1.74 (1H, m), 1.62-1.54 (1H, m), 1.42-1.36 (1H, m). LC/MS:
408 [M+H].
Example 92:
N-(3-(4-((cis-4-aminocyclohexyl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carb-
onyl)phenyl)methanesulfonamide (I-120)
Step 1:
(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-(3-nitrophenyl)methanon-
e (120a)
[0466]
(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-(3-nitrophenyl)methanone
(120a) was synthesized according to General Procedure A, Step 1.
.sup.1H-NMR (DMSO-D.sub.6) .delta.: 13.45 (1H, s), 8.77 (1H, s),
8.56 (1H, s), 8.52 (1H, d, J=7.6 Hz), 8.33 (1H, s), 8.29 (1H, d,
J=7.6 Hz), 7.86 (1H, t, J=7.6 Hz).
Step 2: tert-butyl
N-(cis-4-((5-(3-nitrobenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-cycl-
ohexyl)-carbamate (120b)
[0467] tert-butyl
N-(cis-4-((5-(3-nitrobenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-cycl-
ohexyl)-carbamate (120b) was synthesized according to General
Procedure A, Step 2 via halogen displacement using tert-butyl
(cis-4-aminocyclohexyl)carbamate. LC/MS: 481 [M+H].
Step 3: tert-butyl
N-(cis-4-((5-(3-aminobenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-cycl-
ohexyl)carbamate (120c)
[0468] Reduction of the nitro group using Palladium on Carbon
(Pd/C) and ammonium formate provided tert-butyl
N-(cis-4-((5-(3-aminobenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-cycl-
ohexyl)carbamate (120c). LC/MS: 451 [M+H].
Step 4.
N-(3-(4-((cis-4-aminocyclohexyl)amino)-7H-pyrrolo[2,3-d]pyrimidine-
-5-carbonyl)phenyl)methanesulfonamide (I-120)
[0469] Sulfonylation of 120c followed by a Boc deprotection of Boc
provided Compound I-120. .sup.1H-NMR (DMSO-d.sub.6) .delta.: 10.13
(1H, s), 8.40 (1H, s), 8.16-7.98 (4H, m), 7.70-7.42 (3H, m), 4.29
(1H, br s), 3.25 (1H, br s), 3.10 (3H, s), 2.33-2.23 (8H, m).
LC/MS: 429 [M+H].
Example 93:
N-(3-(4-((cis-4-aminocyclohexyl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carb-
onyl)phenyl)benzenesulfonamide (I-121)
[0470] Phenylsulfonylation of tert-butyl
N-(cis-4-((5-(3-aminobenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-cycl-
ohexyl)carbamate followed by Boc deprotection provided Compound
I-121. .sup.1H-NMR (DMSO-d.sub.6) .delta.: 10.74 (1H, s), 8.40 (1H,
s), 8.15-8.02 (3H, br m), 7.86-7.40 (10H, m), 4.27 (1H, br s), 3.24
(1H, br s), 2.05-1.68 (8H, m). LC/MS: 491 [M+H].
Example 93: Intermediate methyl 2-chloro-4-phenoxybenzoate
(4-1)
##STR00725##
[0472] To a stirred solution of methyl 2-chloro-4-fluorobenzoate
(4-a, 7.35 g, 39.0 mmol) and phenol (4-b, 4.40 g, 46.8 mmol) in DMF
(100 mL) was added Cs.sub.2CO.sub.3 (19.0 g, 58.5 mmol) at room
temperature. The reaction mixture was stirred at 90.degree. C. for
3 h and then extracted with Et.sub.2O. The extract was washed with
water and brine, dried over Na.sub.2SO.sub.4, and concentrated
under reduced pressure. The residue was purified by column
chromatography over SiO.sub.2 with n-hexane-EtOAc to give methyl
2-chloro-4-phenoxybenzoate (4-1, 9.58 g, 94%) as a colorless oil.
.sup.1H-NMR (400 MHz, CDCl.sub.3) .delta.: 7.87 (1H, d, J=8.5 Hz),
7.43-7.39 (2H, m), 7.22 (1H, t, J=7.3 Hz), 7.07-7.05 (2H, m), 7.01
(1H, d, J=2.4 Hz), 6.88 (1H, dd, J=8.5, 2.4 Hz), 3.91 (3H, s).
LC/MS: 263 [M+H].
Example 94: Intermediate
N-((1S)-1-((2S,5R)-5-aminotetrahydro-2H-pyran-2-yl)ethyl)-acetamide
hydrochloride (5-1)
##STR00726##
[0473] Step 1. tert-butyl
N-((3R,6S)-6-((1S)-1-(1,3-dioxoisoindolin-2-yl)-ethyl)tetrahydro-2H-pyran-
-3-yl)carbamate (5-b)
[0474] To a stirred solution of tert-butyl
N-((3R,6S)-6-((1R)-1-hydroxyethyl) tetrahydro-pyran-3-yl)carbamate
(5-a, 9.96 g, 40.6 mmol), phthalimide (7.19 g, 48.7 mmol), and
PPh.sub.3 (12.77 g, 48.7 mmol) in THF (100 mL) was added dropwise
diethyl azodicarboxylate (2.2 M in toluene, 22.1 mL, 48.7 mmol) at
0.degree. C. The resulting mixture was stirred for 3 h at room
temperature and under reduced pressure. Addition of Et.sub.2O to
the mixture gave a precipitate which was removed by filtration. The
filtrate was concentrated under reduced pressure and the resulting
residue was purified by column chromatography over SiO.sub.2
eluting with n-hexane-EtOAc to provide tert-butyl
N-((3R,6S)-6-((1S)-1-(1,3-dioxoisoindolin-2-yl)ethyl)tetrahydro-2H-pyran--
3-yl)-carbamate (5-b, 13.82 g, 91%). .sup.1H-NMR (400 MHz,
CDCl.sub.3) .delta.: 7.87-7.77 (2H, m), 7.72-7.68 (2H, m),
4.30-4.19 (2H, m), 3.92-3.87 (2H, m), 3.59-3.57 (1H, m), 2.88 (1H,
t, J=10.4 Hz), 2.17-2.15 (1H, m), 1.94-1.91 (1H, m), 1.46-1.29
(14H, m). LC/MS: 375 [M+H].
Step 2. tert-butyl
N-((3R,6S)-6-((1S)-1-aminoethyl)tetrahydro-2H-pyran-3-yl)carbamate
(5-c)
[0475] The mixture of tert-butyl
N-((3R,6S)-6-((1S)-1-(1,3-dioxoisoindolin-2-yl)ethyl)-tetrahydro-2H-pyran-
-3-yl)carbamate (5-b, 13.82 g, 36.9 mmol) and hydrazine monohydrate
(5.4 mL, 110.7 mmol) in EtOH (200 mL) was stirred under reflux for
3 h and then cooled to room temperature. After the resulting solid
was removed by filtration, the filtrate was concentrated under
reduced pressure. To the resulting residue was added EtOAc and the
resulting solid was again removed. This was repeated until no
precipitate came out of the solution. Concentration under reduced
pressure provided tert-butyl
N-((3R,6S)-6-((1S)-1-amino-ethyl)tetrahydro-2H-pyran-3-yl)carbamate
(5-c, 7.54 g, 83%) which was used in the next step without further
purification. LC/MS: 245 [M+H].
Step 3. tert-butyl
N-((3R,6S)-6-((1S)-1-acetamidoethyl)-tetrahydro-pyran-3-yl)carbamate
(5-d)
[0476] To a stirred solution of tert-butyl
N-((3R,6S)-6-((1S)-1-aminoethyl)-tetrahydro-2H-pyran-3-yl)-carbamate
(5-c, 7.54 g, 30.9 mmol) and Et.sub.3N (8.6 mL, 61.7 mL) in DMF (30
mL) was added acetic anhydride (Ac.sub.2O, 4.3 mL, 46.3 mL) at room
temperature. After stirring for 1 h at room temperature, the
reaction mixture was quenched with saturated aqueous NaHCO.sub.3
and then concentration in vacuo. The resulting residue was
extracted with CH.sub.2Cl.sub.2, washed with H.sub.2O, dried over
Na.sub.2SO.sub.4, filtered, and concentrated under reduced
pressure. The resulting residue was purified by column
chromatography over SiO.sub.2 and eluting with n-hexane-EtOAc to
provide tert-butyl
N-((3R,6S)-6-((1S)-1-acetamidoethyl)-tetrahydro-pyran-3-yl)carbamate
(5-d) which was used in the next step without further purification.
.sup.1H-NMR (CDCl.sub.3) .delta.: 5.77-5.74 (1H, m), 4.28 (1H, d,
J=7.9 Hz), 4.10-4.07 (1H, m), 4.03-3.96 (1H, m), 3.61-3.52 (1H, m),
3.19 (1H, d, J=11.0 Hz), 2.98-2.96 (1H, m), 2.08-2.06 (1H, m), 1.99
(3H, s), 1.64-1.24 (12H, m), 1.18 (3H, d, J=6.7 Hz). LC/MS: 287
[M+H].
Step 4.
N-((1S)-1-((2S,5R)-5-aminotetrahydro-2H-pyran-2-yl)ethyl)-acetamid-
e hydrochloride (5-1)
[0477] To a stirred solution of tert-butyl
N-((3R,6S)-6-((1S)-1-acetamidoethyl)-tetra-hydro-2H-pyran-3-yl)carbamate
(5-d, 30.9 mmol) in DCM (40 mL) was added 4 N HCl in dioxane (40
mL) at room temperature and the reaction mixture was stirred at
room temperature for 1 h. The resulting mixture was concentrated in
vacuo. The resulting solid was washed with EtOAc under sonication
and then collected by filtration to give
N-((1S)-1-((2S,5R)-5-aminotetrahydro-2H-pyran-2-yl)ethyl)acetamide
hydrochloride (5-1, 6.87 g, over 2 steps) as a colorless solid.
LC/MS: 187 [M+H].
Example 95:
N--((S)-1-((2S,5R)-5-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyr-
imidin-4-yl)amino)tetrahydro-2H-pyran-2-yl)ethyl)acetamide
(I-122)
##STR00727##
[0478] Step 1.
(2-chloro-4-phenoxy-phenyl)-(4-chloro-7H-pyrrolo-[2,3-d]pyrimidin-5-yl)me-
thanone (122a)
[0479] To a stirred solution of
3-bromo-4-chloro-7H-pyrrolo[2,3-d]pyrimidine (3-A, 6.90 g, 29.7
mmol) in THF (200 mL) was added dropwise n-BuLi (2.69 M in hexane,
23.2 mL, 62.3 mmol) at -78.degree. C. under an atmosphere of
nitrogen (N.sub.2). The reaction mixture was stirred at -78.degree.
C. for 50 min and methyl 2-chloro-4-phenoxybenzoate (4-1, 8.19 g,
31.2 mmol) was then added at the same temperature. After stirring
at -78.degree. C. for 50 min, the reaction mixture was quenched
with 1 N HCl (65 mL), warmed to room temperature, and extracted
with EtOAc. The extract was washed with brine, dried over
Na.sub.2SO.sub.4, filtered, and concentrated under reduced
pressure. The resulting residue was purified by column
chromatography over SiO.sub.2 eluting with n-hexane-EtOAc to give
(2-chloro-4-phenoxy-phenyl)-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)met-
hanone (122a, 4.73 g, 41%) as a colorless solid. .sup.1H-NMR (400
MHz, CDCl.sub.3/CD.sub.3OD=9/1) .delta.: 8.69 (1H, d, J=1.8 Hz),
7.71 (1H, d, J=1.8 Hz), 7.50 (1H, dd, J=8.5, 1.8 Hz), 7.46-7.41
(2H, m), 7.27-7.21 (1H, m), 7.13-7.09 (2H, m), 7.07-7.05 (1H, m),
6.96-6.93 (1H, m), 3.40 (1H, br s). LC/MS: 386 [M+H,
.sup.35Cl+.sup.35Cl], 384 [M+H, .sup.35Cl+.sup.37Cl].
Step 2.
N--((S)-1-((2S,5R)-5-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,-
3-d]pyrimidin-4-yl)amino)tetrahydro-2H-pyran-2-yl)ethyl)acetamide
(I-122)
[0480] The mixture of
(2-chloro-4-phenoxy-phenyl)-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-me-
thanone (122a, 1.0 g, 2.60 mmol),
N-((1S)-1-((2S,5R)-5-aminotetrahydro-2H-pyran-2-yl)ethyl)acetamide
hydrochloride (5-1, 638 mg, 2.86 mmol), and DIPEA (1.359 mL, 7.80
mmol) in IPA (10 mL) was stirred at 160.degree. C. for 1 h under
microwave irradiation and the resulting mixture was concentrated
under reduced pressure. The resulting residue was purified by
column chromatography over NH.sub.2--SiO.sub.2 eluting with
CH.sub.2Cl.sub.2-MeOH to give
N--((S)-1-((2S,5R)-5-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyr-
imidin-4-yl)amino)tetrahydro-2H-pyran-2-yl)ethyl)acetamide (I-122,
638 mg, 2.86 mmol) as a colorless solid. .sup.1H-NMR (DMSO-d.sub.6)
.delta.: 12.76 (1H, s), 8.58 (1H, d, J=7.3 Hz), 8.25 (1H, s), 7.70
(1H, d, J=8.5 Hz), 7.64 (1H, s), 7.57 (1H, d, J=7.9 Hz), 7.49-7.47
(2H, m), 7.27-7.25 (1H, m), 7.19-7.18 (3H, m), 7.03-7.01 (1H, m),
4.21-4.14 (2H, m), 3.90-3.88 (1H, m), 3.31-3.30 (1H, m), 3.12-3.09
(1H, m), 2.19-2.16 (1H, m), 1.83 (3H, s), 1.68-1.42 (3H, m), 1.05
(3H, d, J=6.7 Hz). LC/MS: 536 [M+H, .sup.37Cl], 534 [M+H,
.sup.35Cl].
Example 96:
(2-chloro-4-phenoxyphenyl)(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyr-
an-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone
(I-123)
##STR00728##
[0482] The mixture of
(2-chloro-4-phenoxy-phenyl)-(4-chloro-7H-pyrrolo[2,3-d]-pyrimidin-5-yl)me-
thanone (122a, 200 mg, 0.52 mmol),
((2S,5R)-5-aminotetrahydro-2H-pyran-2-yl)-methanol (123a, 72 mg,
0.54 mmol), and DIPEA (272 .mu.L, 1.56 mmol) in IPA (4 mL) was
stirred at 160.degree. C. for 1 h under microwave irradiation and
then concentrated under reduced pressure. The resulting residue was
purified by column chromatography over NH.sub.2--SiO.sub.2 eluting
with CH.sub.2Cl.sub.2-MeOH to give
(2-chloro-4-phenoxyphenyl)(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyr-
an-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (I-123,
175 mg, 70%) as a colorless solid. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta.: 12.75 (1H, brs), 8.60 (1H, d, J=6.7 Hz),
8.25 (1H, d, J=1.8 Hz), 7.64 (1H, d, J=1.8 Hz), 7.49-7.48 (2H, m),
7.27-7.25 (1H, m), 7.20-7.18 (3H, m), 7.04-7.01 (1H, m), 4.68-4.67
(1H, m), 4.17-4.15 (2H, m), 3.43-3.32 (3H, m), 3.14-3.11 (1H, m),
2.21-2.18 (1H, m), 1.80-1.77 (1H, m), 1.58-1.55 (1H, m), 1.41-1.38
(1H, m). LC/MS: 481 [M+H, .sup.37Cl], 479 [M+H, .sup.35Cl].
Example 97:
Intermediate-N-(((2S,5R)-5-aminotetrahydro-2H-pyran-2-yl)methyl)acetamide
hydrochloride (6-1)
##STR00729##
[0483] Step 1. tert-butyl
N-((3R,6S)-6-((1,3-dioxoisoindolin-2-yl)methyl)-tetrahydro-2H-pyran-3-yl)-
carbamate (6-b)
[0484] tert-butyl
N-((3R,6S)-6-((1,3-dioxoisoindolin-2-yl)methyl)tetrahydro-2H-pyran-3-yl)c-
arbamate (6-b, 2.5 g, 81%) was synthesized according to the
procedure described above for
Step 1 in Example 94 from tert-butyl
N-((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)carbamate
(6-a, 2.0 g, 8.6 mmol). LC/MS: 305 [M-tBu+2H]
Step 2. tert-butyl
N-((3R,6S)-6-(aminomethyl)tetrahydro-2H-pyran-3-yl)carbamate
(6-c)
[0485] tert-butyl
N-((3R,6S)-6-(aminomethyl)tetrahydro-2H-pyran-3-yl)carbamate (6-c,
1.6 g, quantitative) was synthesized according to the procedure
described above for Step 2 in Example 94 from tert-butyl
N-((3R,6S)-6-((1,3-dioxo-isoindolin-2-yl)methyl)tetrahydro-2H-pyran-3-yl)-
carbamate (6-b, 2.5 g, 7.0 mmol). LC/MS: 231 [M+H].
Step 3. tert-butyl
N-((3R,6S)-6-(acetamidomethyl)tetrahydro-2H-pyran-3-yl)carbamate
(6-d)
[0486] tert-butyl
N-((3R,6S)-6-(acetamidomethyl)tetrahydro-2H-pyran-3-yl)carbamate
(845 mg, 44%) was synthesized according to the procedure described
above for Step 3 in Example 94 from tert-butyl
N-((3R,6S)-6-(aminomethyl)-tetrahydro-2H-pyran-3-yl)carbamate (1.6
g, 7.0 mmol). .sup.1H-NMR (CDCl.sub.3) .delta.: 5.90 (1H, br s),
4.26 (1H, br s), 4.08-4.06 (1H, m), 3.61-3.58 (2H, m), 3.33-3.31
(1H, m), 3.01-2.98 (2H, m), 2.08-2.05 (1H, m), 1.99 (3H, s),
1.44-1.19 (13H, m). LC/MS: 273 [M+H].
Step 4.
N-(((2S,5R)-5-aminotetrahydro-2H-pyran-2-yl)methyl)acetamide
hydrochloride (6-1)
[0487] N-(((2S,5R)-5-aminotetrahydro-2H-pyran-2-yl)methyl)acetamide
hydrochloride (607 mg, 98%) was synthesized according to the
procedure described above for Step 4 in Example 94 from tert-butyl
N-((3R,6S)-6-(acetamidomethyl)tetrahydro-2H-pyran-3-yl)carbamate
(845 mg, 3.1 mmol). .sup.1H-NMR (DMSO-d.sub.6) .delta.: 8.30 (3H,
br s), 8.00 (1H, t, J=5.5 Hz), 4.03-4.00 (1H, m), 3.28-3.24 (2H,
m), 3.13-2.99 (3H, m), 2.08-2.05 (1H, m), 1.82-1.78 (3H, m),
1.70-1.66 (1H, m), 1.57-1.51 (1H, m), 1.26-1.17 (1H, m). LC/MS: 173
[M+H].
Example 98:
N-(((2S,5R)-5-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin--
4-yl)amino)tetrahydro-2H-pyran-2-yl)methyl)acetamide (I-127)
##STR00730##
[0489]
N-(((2S,5R)-5-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyri-
midin-4-yl)amino)tetrahydro-2H-pyran-2-yl)methyl)acetamide (I-127,
88 mg, 61%) was synthesized according to the procedure described
herein above for Example 96 from
N-(((2S,5R)-5-aminotetrahydro-2H-pyran-2-yl)methyl)acetamide
hydrochloride (6-1, 100 mg, 0.26 mmol). .sup.1H-NMR (DMSO-d.sub.6)
.delta.: 12.63 (1H, br s), 8.59 (1H, d, J=6.7 Hz), 8.26 (1H, s),
7.95 (1H, t, J=5.8 Hz), 7.64 (1H, s), 7.58 (1H, d, J=8.5 Hz),
7.51-7.45 (2H, m), 7.27-7.25 (1H, m), 7.19-7.18 (3H, m), 7.02 (1H,
dd, J=8.5, 2.4 Hz), 4.20-4.10 (2H, m), 3.22-3.04 (4H, m), 2.21-2.12
(1H, m), 1.85-1.73 (4H, m), 1.64-1.50 (1H, m), 1.45-1.33 (1H, m).
LC/MS: 522 [M+H, .sup.37Cl], 520 [M+H, .sup.35Cl].
Example 99: General Procedure B
##STR00731##
[0490] Step 1. Intermediate 3-C
[0491] To a stirred solution of
3-bromo-4-chloro-7H-pyrrolo[2,3-d]pyrimidine (3-A) in THF was added
n-BuLi solution (in hexane, 2-3 eq.) dropwise at -78.degree. C. and
under inert atmosphere. The reaction mixture was stirred at
-78.degree. C. for 0.5-2 hrs and an ester or acid chloride (3-B,
1-2 eq.) was then added at -78.degree. C. After stirring at
-78.degree. C. for 0.5-2 hrs, the reaction mixture was quenched
with 1 N HCl aqueous. Work-up and/or purification provided the
corresponding aryl- or
heteroaryl-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone
(3-C).
Step 2. Compounds of Formula I-Y
[0492] A mixture of 3-C, a primary amine (3-D, 1-4 eq.), and
optionally a base (e.g., TEA, DIPEA, pyridine, and/or
K.sub.2CO.sub.3 (1-5 eq.)) in a solvent (e.g., DMF, NMP, IPA,
n-BuOH or neat) was heated (70-160.degree. C.) for 5-50 hrs or
heated (100-220.degree. C.) under microwave radiation for 0.5-5
hrs. Work-up and/or purification provided a compound of Formula (I)
(aryl- or
heteroaryl-[4-(substituted-amino)]-7H-pyrrolo[2,3-d]pyrimidin-5-yl]methan-
one (I-Y)).
[0493] The compounds of Formula (I) in Table 2 below were made
according to General Procedure B using the applicable aryl or
heteroaryl ester or acid chloride and amine.
TABLE-US-00004 TABLE 2 Cmpd No. .sup.1H NMR and/or LC/MS data I-124
.sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta.: 12.71 (1H, brs), 8.57
(1H, d, J = 6.9 Hz), 8.23 (1H, s,), 7.61 (1H, s), 7.55 (1H, d, J =
8.4 Hz), 7.46 (2H, t, J = 8.0 Hz), 7.30-7.00 (4H, m), 6.99 (1H, dd,
J = 8.7, 2.1 Hz), 4.70-4.60 (1H, m), 4.20-3.90 (2H, m), 3.45-3.30
(1H, m), 3.10 (1H, t, J = 11.6 Hz), 2.16 (1H, d, J = 10.5 Hz), 1.76
(1H, d, J = 12.6 Hz), 1.65-1.45 (1H, m), 1.45-1.25 (1H, m),
1.20-1.05 (1H, m), 1.05-0.90 (1H, m). LC/MS: 481 [M + H,
.sup.37Cl], 479 [M + H, .sup.35Cl]. I-125 .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta.: 12.63 (1H, br s), 9.19 (1H, d, J = 8.1 Hz),
8.20 (1H, s), 7.60-7.55 (2H, m), 7.46 (2H, t, J = 8.0 Hz),
7.26-7.10 (4H, m), 7.01 (1H, dd, J = 8.7, 2.4 Hz), 4.65-4.60 (1H,
m), 4.35-4.25 (1H, m), 4.05-3.85 (1H, m), 3.62 (1H, d, J = 10.5
Hz), 3.60-3.25 (3H, m), 1.95-1.80 (2H, m), 1.65-1.50 (2H, m).
LC/MS: 481 [M + H, .sup.37Cl], 479 [M + H, .sup.35Cl]. I-126
.sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta.: 12.69 (1H, br s), 9.19
(1H, d, J = 7.8 Hz), 8.21 (1H, s), 7.62-7.54 (2H, m), 7.46 (2H, t,
J = 8.0 Hz), 7.26-7.01 (4H, m), 7.01 (1H, dd, J = 8.4, 2.4 Hz),
4.64-4.60 (1H, m), 4.31 (1H, d, J = 7.5 Hz), 3.91 (1H, d, J = 11.7
Hz), 3.62 (1H, d, J = 10.2 Hz), 3.47-3.25 (3H, m), 2.01-1.75 (2H,
m), 1.65-1.45 (2H, m). LC/MS: 481 [M + H, .sup.37Cl], 479 [M + H,
.sup.35Cl]. I-129 .sup.1H-NMR (DMSO-d.sub.6) .delta.: 12.61 (1H,
s), 8.89 (0.65H, d, J = 7.9 Hz), 8.43 (0.35H, d, J = 7.3 Hz), 8.20
(0.65H, s), 8.21 (0.35H, s), 7.98 (0.35H, s), 8.01 (0.65H, s),
7.82-7.84 (1H, m), 7.14-7.15 (1H, m), 4.38-4.39 (0.65H, m),
3.96-4.00 (0.35H, m), 2.43 (1.05H, s), 2.45 (1.95H, s), 2.06-2.09
(0.65H, m), 1.03-1.81 (8.35H, m), 0.84-0.95 (3H, m). LC/MS: 355 [M
+ H]. (diastereo mixture: 65/35) I-130 .sup.1H-NMR (DMSO-d.sub.6)
.delta.: 8.36 (1H, s), 8.06-8.01 (4H, m), 7.89 (2H, d, J = 7.9 Hz),
7.49 (2H, t, J = 7.6 Hz), 7.27 (1H, t, J = 7.0 Hz), 7.17 (2H, d, J
= 7.9 Hz), 7.12 (2H, d, J = 7.9 Hz), 4.27-4.23 (1H, m), 3.24-3.18
(1H, m), 2.00-1.71 (8H, m). LC/MS: 428 [M + H]. I-131 .sup.1H-NMR
(DMSO-d.sub.6) .delta.: 8.37 (1H, s), 8.10-8.02 (4H, m), 7.60-7.58
(2H, m), 7.47-7.43 (2H, m), 7.35-7.32 (2H, m), 7.21 (1H, t, J = 7.3
Hz), 7.13 (2H, d, J = 7.9 Hz), 4.27-4.25 (1H, m), 3.23-3.20 (1H,
m), 1.98-1.69 (8H, m). LC/MS: 428 [M + H]. I-133 .sup.1H-NMR
(DMSO-d.sub.6) .delta.: 12.62 (1H, s), 8.95 (1H, d, J = 7.3 Hz),
8.21 (1H, s), 7.76 (1H, s), 7.46 (1H, t, J = 7.9 Hz), 7.36 (1H, d,
J = 7.9 Hz), 7.29 (1H, s), 7.21 (1H, d, J = 7.3 Hz), 6.96-6.93 (1H,
m), 4.23-4.19 (1H, m), 3.83 (3H, s), 3.45-3.37 (1H, m), 1.88-1.80
(2H, m), 1.73-1.59 (6H, m), 1.38 (9H, s). LC/MS: 466 [M + H]. I-134
.sup.1H-NMR (DMSO-d.sub.6) .delta.: 12.57 (1H, s), 9.03 (1H, d, J =
7.3 Hz), 8.21 (1H, s), 7.41 (1H, s), 7.24 (1H, d, J = 8.5 Hz),
7.01-6.95 (3H, m), 4.24-4.20 (1H, m), 3.76 (3H, s), 3.44-3.40 (1H,
m), 2.19 (3H, s), 1.86-1.79 (2H, m), 1.74-1.59 (6H, m), 1.38 (9H,
s). LC/MS: 480 [M + H]. I-142 .sup.1H-NMR (DMSO-d.sub.6) .delta.:
12.67 (1H, s), 8.65 (1H, d, J = 7.3 Hz), 8.23 (1H, s), 7.85-7.80
(3H, m), 7.50-7.46 (2H, m), 7.25 (1H, t, J = 7.3 Hz), 7.17-7.14
(2H, m), 7.10-7.07 (2H, m), 4.59 (1H, d, J = 5.5 Hz), 4.17-4.12
(2H, m), 3.53-3.45 (1H, m), 3.11-3.04 (2H, m), 2.20-2.16 (1H, m),
1.94-1.89 (1H, m), 1.57-1.35 (2H, m), 1.08 (3H, d, J = 6.1 Hz).
LC/MS: 459 [M + H]. I-146 .sup.1H-NMR (DMSO-d.sub.6) .delta.: 12.67
(1H, br s), 8.66 (1H, d, J = 7.3 Hz), 8.24 (1H, s), 7.86-7.80 (3H,
m), 7.51-7.45 (2H, m), 7.28-7.23 (1H, m), 7.18-7.14 (2H, m),
7.11-7.06 (2H, m), 4.66 (1H, t, J = 5.8 Hz), 4.18-4.09 (2H, m),
3.45-3.35 (2H, m), 3.10 (1H, t, J = 11.3 Hz), 2.20-2.13 (1H, m),
1.81-1.74 (1H, m), 1.62-1.50 (1H, m), 1.44-1.31 (1H, m). LC/MS: 445
[M + H]. I-147 .sup.1H-NMR (CDCl.sub.3) .delta.: 8.80 (1H, d, J =
7.3 Hz), 8.37 (1H, s), 7.80 (2H, d, J = 8.5 Hz), 7.58 (1H, s), 7.42
(2H, t, J = 8.2 Hz), 7.25-7.19 (1H, m), 7.13-7.06 (4H, m),
4.42-4.28 (2H, m), 3.27 (1H, t, J = 10.4 Hz), 3.21-3.15 (1H, m),
2.55 (1H, br s), 2.38-2.31 (1H, m), 1.84-1.51 (4H, m), 1.21 (6H, d,
J = 10.4 Hz). LC/MS: 473 [M + H]. I-149 .sup.1H-NMR (DMSO-d.sub.6)
.delta.: 12.70 (1H, s), 8.65 (1H, d, J = 7.3 Hz), 8.50 (1H, d, J =
3.1 Hz), 8.48-8.46 (1H, m), 8.24 (1H, s), 7.87-7.82 (3H, m),
7.64-7.61 (1H, m), 7.51 (1H, dd, J = 8.2, 4.6 Hz), 7.16 (2H, d, J =
8.5 Hz), 4.60 (1H, d, J = 4.9 Hz), 4.17-4.11 (2H, m), 3.52-3.46
(1H, m), 3.11-3.04 (2H, m), 2.20-2.15 (1H, m), 1.94-1.90 (1H, m),
1.58-1.48 (1H, m), 1.45-1.35 (1H, m), 1.08 (3H, d, J = 6.7 Hz).
LC/MS: 460 [M + H]. I-150 .sup.1H-NMR (DMSO-d.sub.6) .delta.: 12.76
(1H, s), 8.58 (1H, d, J = 7.3 Hz), 8.25 (1H, s), 7.64 (1H, s), 7.58
(1H, d, J = 8.5 Hz), 7.51-7.46 (2H, m), 7.28-7.24 (1H, m),
7.20-7.17 (3H, m), 7.02 (1H, dd, J = 8.2, 2.1 Hz), 4.60 (1H, d, J =
5.5 Hz), 4.19-4.10 (2H, m), 3.51-3.46 (1H, m), 3.13-3.06 (2H, m),
2.22-2.17 (1H, m), 1.95-1.90 (1H, m), 1.59-1.50 (1H, m), 1.46-1.36
(1H, m), 1.08 (3H, d, J = 6.7 Hz). LC/MS: 493 [M + H]. I-151
.sup.1H-NMR (DMSO-d.sub.6) .delta.: 12.72 (1H, s), 8.92 (1H, d, J =
7.3 Hz), 8.23 (1H, s), 7.90 (1H, d, J = 7.3 Hz), 7.62 (1H, s), 7.59
(1H, d, J = 8.5 Hz), 7.51-7.46 (2H, m), 7.28-7.24 (1H, m),
7.20-7.17 (3H, m), 7.03 (1H, dd, J = 8.2, 2.1 Hz), 4.26-4.22 (1H,
m), 3.75-3.70 (1H, m), 1.81 (3H, s), 1.84-1.57 (8H, m). LC/MS: 504
[M + H]. I-152 .sup.1H-NMR (DMSO-d.sub.6) .delta.: 12.64 (1H, s),
8.97 (1H, d, J = 6.7 Hz), 8.22 (1H, s), 7.88-7.83 (3H, m), 7.78
(1H, s), 7.34-7.29 (2H, m), 7.24-7.20 (2H, m), 7.10-7.06 (2H, m),
4.23-4.20 (1H, m), 3.73-3.69 (1H, m), 1.85-1.57 (8H, m), 1.80 (3H,
s). LC/MS: 488 [M + H]. I-153 .sup.1H-NMR (DMSO-d.sub.6) .delta.:
12.66 (1H, s), 8.98 (1H, d, J = 7.3 Hz), 8.23 (1H, s), 7.90-7.86
(3H, m), 7.81 (1H, s), 7.70 (1H, t, J = 7.9 Hz), 7.60 (1H, d, J =
7.9 Hz), 7.50 (1H, s), 7.47-7.44 (1H, m), 7.21-7.17 (2H, m),
4.24-4.20 (1H, m), 3.74-3.69 (1H, m), 1.80 (3H, s), 1.87-1.55 (8H,
m). LC/MS: 538 [M + H]. I-155 .sup.1H-NMR (DMSO-d.sub.6) .delta.:
12.67 (1H, s), 8.93 (1H, d, J = 7.3 Hz), 8.23 (1H, s), 7.86-7.84
(2H, m), 7.82-7.80 (1H, m), 7.49-7.46 (2H, m), 7.27-7.23 (1H, m),
7.17-7.14 (2H, m), 7.10-7.08 (2H, m), 4.24-4.21 (1H, m), 3.89-3.87
(1H, m), 3.69-3.64 (1H, m), 3.59-3.54 (1H, m), 3.42-3.38 (1H, m),
2.05-1.99 (1H, m), 1.83-1.81 (1H, m), 1.74-1.56 (2H, m). LC/MS: 415
[M + H]. I-156 .sup.1H-NMR (DMSO-d.sub.6) .delta.: 12.67 (1H, s),
8.88 (1H, d, J = 7.3 Hz), 8.24 (1H, s), 7.87-7.84 (2H, m), 7.81
(1H, s), 7.51-7.45 (2H, m), 7.27-7.24 (1H, m), 7.17-7.14 (2H, m),
7.10-7.08 (2H, m), 4.30-4.27 (1H, m), 3.91-3.89 (2H, m), 3.54-3.48
(2H, m), 2.02-2.00 (2H, m), 1.56-1.51 (2H, m). LC/MS: 415 [M + H].
I-157 .sup.1H-NMR (CDCl.sub.3) .delta.: 13.03 (1H, br s), 8.94 (1H,
d, J = 7.3 Hz), 8.38 (1H, s), 7.80 (2H, d, J = 8.5 Hz), 7.64 (1H,
s), 7.46-7.39 (2H, m), 7.22 (1H, t, J = 7.3 Hz), 7.10 (4H, t, J =
9.2 Hz), 6.61 (1H, d, J = 3.1 Hz), 5.91 (1H, d, J = 3.1 Hz),
4.45-4.34 (2H, m), 3.93-3.87 (1H, m), 3.33 (1H, t, J = 10.4 Hz),
2.42-2.30 (2H, m), 1.85-1.64 (2H, m). LC/MS: 458 [M + H]. I-158
.sup.1H-NMR (DMSO-d.sub.6) .delta.: 12.66 (1H, s), 9.16 (1H, s),
8.83 (1H, d, J = 7.3 Hz), 8.24 (1H, s), 7.87-7.84 (2H, m), 7.81
(1H, s), 7.50-7.46 (2H, m), 7.27-7.24 (1H, m), 7.17-7.16 (2H, m),
7.10-7.08 (2H, m), 4.12-4.07 (1H, m), 3.13-3.07 (1H, m), 2.23-2.16
(4H, m), 1.74-1.68 (2H, m), 1.54-1.47 (2H, m). LC/MS: 481 [M + H].
I-159 .sup.1H-NMR (DMSO-d.sub.6) .delta.: 12.13 (1H, s), 8.83 (1H,
d, J = 7.3 Hz), 8.24 (1H, s), 7.86-7.84 (2H, m), 7.82-7.79 (1H, m),
7.50-7.46 (2H, m), 7.27-7.25 (1H, m), 7.17-7.15 (2H, m), 7.10-7.08
(2H, m), 4.13-4.05 (1H, m), 3.34 (3H, s), 3.01 (1H, s), 2.20-2.14
(4H, m), 1.75-1.66 (2H, m), 1.54-1.45 (2H, m). LC/MS: 495 [M + H].
I-160 .sup.1H-NMR (CDCl.sub.3) .delta.: 13.32 (1H, br s), 8.89 (1H,
d, J = 7.3 Hz), 8.36 (1H, s), 7.83-7.78 (2H, m), 7.64 (1H, s),
7.45-7.39 (2H, m), 7.22 (1H, t, J = 7.3 Hz), 7.13-7.06 (4H, m),
4.41-4.29 (2H, m), 3.70-3.63 (1H, m), 3.30-3.21 (1H, m), 3.18-3.11
(1H, m), 2.37-2.29 (1H, m), 1.84-1.65 (3H, m), 1.61-1.49 (1H, m),
1.19 (3H, d, J = 6.7 Hz). LCMS: 459 [M + H]. I-161 .sup.1H-NMR
(DMSO-d.sub.6) .delta.: 12.65 (1H, s), 8.97 (1H, d, J = 7.3 Hz),
8.22 (1H, s), 7.88-7.85 (3H, m), 7.79 (1H, s), 7.53-7.50 (2H, m),
7.19-7.18 (2H, m), 7.14-7.13 (2H, m), 4.23-4.20 (1H, m), 3.72-3.70
(1H, m), 1.88-1.55 (11H, m). LC/MS: 504 [M + H]. (Synthesized from
[4-(4-chlorophenoxy)phenyl]-(4-chloro-7H-pyrrolo[2,3-
d]pyrimidin-5-yl)methanone, LC/MS: 384 [M + H].) I-162 .sup.1H-NMR
(DMSO-d.sub.6) .delta.: 12.63 (1H, s), 8.97 (1H, d, J = 7.3 Hz),
8.22 (1H, s), 7.88-7.82 (3H, m), 7.78 (1H, s), 7.28 (2H, d, J = 8.5
Hz), 7.05 (4H, d, J = 8.5 Hz), 4.22-4.19 (1H, m), 3.72-3.70 (1H,
m), 2.33 (3H, s), 1.87-1.53 (11H, m). LC/MS: 484 [M + H].
(Synthesized from (4-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-(4-(4-
methylphenoxy)phenyl)methanone LC/MS: 364 [M + H]) I-163
.sup.1H-NMR (DMSO-d.sub.6) .delta.: 12.58 (1H, s), 8.98 (1H, d, J =
6.7 Hz), 8.21 (1H, s), 7.87 (1H, d, J = 7.3 Hz), 7.79-7.77 (3H, m),
7.09 (2H, d, J = 9.2 Hz), 6.01-5.97 (1H, m), 5.87-5.85 (1H, m),
5.05-5.02 (1H, m), 4.22-4.20 (1H, m), 3.72-3.71 (1H, m), 2.13-1.91
(3H, m), 1.80-1.57 (14H, m). LC/MS: 474 [M + H]. (Synthesized from
methyl 4- hydroxybenzoate and 3-bromocyclohexene LC/MS: 233 [M + H]
and (4-chloro-7H-
pyrrolo[2,3-d]pyrimidin-5-yl)-(4-cyclohex-2-en-1-yloxyphenyl)methanone
LC/MS: 354 [M + H].) I-164 .sup.1H-NMR (DMSO-d.sub.6) .delta.:
12.78 (1H, s), 8.82 (1H, d, J = 7.3 Hz), 8.24 (1H, s), 8.10 (1H, d,
J = 7.9 Hz), 7.90 (1H, d, J = 7.3 Hz), 7.82 (1H, s), 7.50-7.48 (2H,
m), 7.31-7.26 (3H, m), 7.11 (1H, d, J = 7.9 Hz), 4.24-4.21 (1H, m),
3.74-3.71 (1H, m), 1.81-1.58 (11H, m). LC/MS: 505 [M + H].
(Synthesized from (2-chloro-6-phenoxy-3-
pyridyl)-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone LC/MS:
385 [M + H].) I-165 .sup.1H-NMR (CDCl.sub.3) .delta.: 8.98 (1H, d,
J = 7.9 Hz), 8.34 (1H, s), 7.81 (2H, d, J = 8.8 Hz), 7.59 (1H, s),
7.42 (2H, t, J = 7.9 Hz), 7.24-7.19 (1H, m), 7.13-7.06 (4H, m),
4.19-4.07 (1H, m), 3.52 (2H, d, J = 6.1 Hz), 2.30-2.23 (2H, m),
1.96-1.38 (6H, m), 1.27-1.15 (2H, m). LC/MS: 443 [M + H]. I-168
.sup.1H-NMR (DMSO-d.sub.6) .delta.: 12.62 (1H, s), 8.75 (1H, d, J =
7.3 Hz), 8.22 (1H, s), 7.85-7.81 (2H, m), 7.78 (1H, s), 7.50-7.46
(2H, m), 7.25 (1H, t, J = 7.3 Hz), 7.16 (2H, d, J = 7.9 Hz),
7.10-7.06 (2H, m), 4.60 (1H, d, J = 4.3 Hz), 4.02-3.97 (1H, m),
3.54-3.50 (1H, m), 2.09-2.03 (2H, m), 1.89-1.85 (2H, m), 1.38-1.29
(4H, m). LC/MS: 429 [M + H]. I-169 .sup.1H-NMR (DMSO-d.sub.6)
.delta.: 12.70 (1H, s), 8.69 (1H, d, J = 7.9 Hz), 8.23 (1H, s),
7.60-7.58 (1H, m), 7.57 (1H, d, J = 7.3 Hz), 7.50-7.46 (2H, m),
7.26 (1H, t, J = 7.6 Hz), 7.20-7.17 (3H, m), 7.02 (1H, dd, J = 8.2,
2.1 Hz), 4.60 (1H, d, J = 4.3 Hz), 4.03-3.98 (1H, m), 3.55-3.49
(1H, m), 2.10-2.05 (2H, m), 1.90-1.85 (2H, m), 1.40-1.28 (4H, m).
LC/MS: 463 [M + H]. I-171 .sup.1H-NMR (DMSO-d.sub.6) .delta.: 12.70
(1H, s), 8.67 (1H, d, J = 6.7 Hz), 8.24-8.22 (1H, m), 8.24 (1H, s),
7.95-7.91 (1H, m), 7.88-7.83 (3H, m), 7.27 (2H, d, J = 7.9 Hz),
7.24-7.20 (1H, m), 7.15 (1H, d, J = 7.9 Hz), 4.60 (1H, d, J = 5.5
Hz),
4.18-4.12 (2H, m), 3.52-3.47 (1H, m), 3.12-3.05 (2H, m), 2.21-2.16
(1H, m), 1.95-1.90 (1H, m), 1.59-1.49 (1H, m), 1.46-1.36 (1H, m),
1.08 (3H, d, J = 5.5 Hz). LC/MS: 460 [M + H]. I-172 .sup.1H-NMR
(DMSO-d.sub.6) .delta.: 12.71 (1H, s), 8.66 (1H, d, J = 7.3 Hz),
8.24 (1H, s), 7.98 (1H, t, J = 7.9 Hz), 7.91-7.84 (3H, m),
7.35-7.31 (3H, m), 7.15 (1H, d, J = 7.9 Hz), 4.60 (1H, d, J = 5.5
Hz), 4.18-4.12 (2H, m), 3.52-3.47 (1H, m), 3.12-3.05 (2H, m),
2.21-2.16 (1H, m), 1.95-1.90 (1H, m), 1.59-1.49 (1H, m), 1.46-1.36
(1H, m), 1.08 (3H, d, J = 6.1 Hz). LC/MS: 494 [M + H]. I-173
.sup.1H-NMR (DMSO-d.sub.6) .delta.: 12.77 (1H, s), 8.92 (1H, d, J =
6.7 Hz), 8.27 (1H, s), 7.65 (1H, s), 7.58 (1H, d, J = 8.5 Hz),
7.50-7.46 (2H, m), 7.28-7.24 (1H, m), 7.20-7.17 (3H, m), 7.03 (1H,
dd, J = 8.2, 2.1 Hz), 4.73-4.66 (1H, m), 3.96-3.90 (2H, m),
3.83-3.76 (1H, m), 3.68 (1H, dd, J = 8.9, 3.4 Hz), 2.39-2.30 (1H,
m), 1.94-1.85 (1H, m). LC/MS: 435 [M + H]. I-174 .sup.1H-NMR
(DMSO-d.sub.6) .delta.: 12.77 (1H, s), 8.92 (1H, d, J = 6.7 Hz),
8.27 (1H, s), 7.65 (1H, s), 7.58 (1H, d, J = 8.5 Hz), 7.51-7.45
(2H, m), 7.26 (1H, t, J = 7.6 Hz), 7.20-7.17 (3H, m), 7.02 (1H, dd,
J = 8.5, 2.4 Hz), 4.73-4.66 (1H, m), 3.96-3.90 (2H, m), 3.82-3.76
(1H, m), 3.66-3.70 (1H, m), 2.39-2.30 (1H, m), 1.93-1.86 (1H, m).
LC/MS: 435 [M + H]. I-179 .sup.1H-NMR (DMSO-d.sub.6) .delta.: 12.71
(1H, s), 8.71 (1H, d, J = 7.3 Hz), 8.23 (1H, s), 7.60-7.58 (2H, m),
7.49-7.47 (2H, m), 7.27-7.25 (1H, m), 7.20-7.18 (3H, m), 7.02 (1H,
dd, J = 8.5, 2.4 Hz), 4.55 (1H, d, J = 5.5 Hz), 4.35 (1H, d, J =
3.1 Hz), 4.13-4.00 (1H, m), 3.76-3.74 (1H, m), 3.54-3.52 (1H, m),
3.17 (3H, d, J = 5.5 Hz), 1.95-1.92 (1H, m), 1.78-1.74 (2H, m).
LC/MS: 479 [M + H]. Racemic mixture. I-180 .sup.1H-NMR
(DMSO-d.sub.6) .delta.: 12.71 (1H, s), 8.71 (1H, d, J = 7.9 Hz),
8.23 (1H, s), 7.59-7.56 (2H, m), 7.50-7.46 (2H, m), 7.26-7.25 (1H,
m), 7.19-7.18 (3H, m), 7.02 (1H, dd, J = 8.5, 2.4 Hz), 4.43-4.40
(3H, m), 3.84-3.83 (1H, m), 3.60-3.59 (1H, m), 2.04-2.01 (2H, m),
1.73-1.57 (3H, m), 1.35-1.33 (1H, m). LC/MS: 479 [M + H]. Racemic
mixture. I-184 .sup.1H-NMR (CDCl.sub.3) .delta.: 9.14 (1H, d, J =
7.3 Hz), 8.36 (1H, s), 7.82-7.78 (2H, m), 7.60 (1H, s), 7.45-7.39
(2H, m), 7.24-7.18 (1H, m), 7.13-7.06 (4H, m), 4.74-4.60 (2H, m),
4.21 (1H, br s), 2.39-2.24 (2H, m), 2.18-1.99 (2H, m), 1.79-1.67
(1H, m), 1.62-1.47 (1H, m), 1.45 (9H, s). LC/MS: 514 [M + H]. I-185
.sup.1H-NMR (CDCl.sub.3) .delta.: 9.34 (1H, d, J = 5.5 Hz), 8.36
(1H, s), 7.81 (2H, d, J = 8.5 Hz), 7.62 (1H, s), 7.42 (2H, t, J =
7.9 Hz), 7.21 (1H, t, J = 7.3 Hz), 7.13-7.06 (4H, m), 4.92 (1H, br
s), 4.81-4.71 (1H, m), 4.33 (1H, br s), 2.62-2.38 (4H, m), 1.45
(9H, s). LC/MS: 500 [M + H]. I-186 .sup.1H-NMR (CDCl.sub.3)
.delta.: 9.19 (1H, d, J = 7.3 Hz), 8.36 (1H, s), 7.81 (2H, d, J =
8.5 Hz), 7.62 (1H, s), 7.45-7.40 (2H, m), 7.22 (1H, t, J = 7.3 Hz),
7.14-7.06 (4H, m), 4.76 (1H, d, J = 6.7 Hz), 4.53-4.40 (1H, m),
4.06-3.93 (1H, m), 3.05-2.93 (2H, m), 2.03-1.91 (2H, m), 1.45 (9H,
s). LC/MS: 500 [M + H]. I-187 .sup.1H-NMR (CDCl.sub.3) .delta.:
12.64 (1H, s), 9.01 (1H, d, J = 7.3 Hz), 8.21 (1H, s), 7.85 (2H,
dt, J = 9.2, 2.3 Hz), 7.80 (1H, s), 7.51-7.45 (2H, m), 7.28-7.23
(1H, m), 7.19-7.15 (2H, m), 7.12-7.07 (2H, m), 4.69-4.62 (2H, m),
3.51 (2H, dd, J = 6.7, 5.5 Hz), 2.41-2.21 (3H, m), 2.07-1.98 (2H,
m). LC/MS: 415 [M + H]. I-188 .sup.1H-NMR (DMSO-d.sub.6) .delta.:
12.78 (1H, s), 8.58 (1H, d, J = 7.3 Hz), 8.25 (1H, s), 7.64 (1H,
s), 7.58 (1H, d, J = 8.5 Hz), 7.49-7.47 (2H, m), 7.27-7.25 (1H, m),
7.19-7.18 (3H, m), 7.03-7.01 (1H, m), 4.29 (1H, s), 4.22-4.19 (1H,
m), 4.13-4.11 (1H, m), 3.13-3.07 (2H, m), 2.22-2.19 (1H, m),
1.88-1.84 (1H, m), 1.55-1.46 (2H, m), 1.11 (3H, s), 1.06 (3H, s).
LC/MS: 507 [M + H]. I-198 .sup.1H-NMR (DMSO-d.sub.6) .delta.: 11.88
(1H, br s), 8.66 (1H, d, J = 7.3 Hz), 8.24 (1H, s), 7.86-7.81 (3H,
m), 7.71 (1H, d, J = 8.5 Hz), 7.48 (2H, m), 7.28-7.24 (1H, m),
7.19-7.16 (2H, m), 7.09-7.08 (2H, m), 4.21-4.09 (2H, m), 3.93-3.83
(1H, m), 3.29-3.29 (1H, m), 3.10-3.08 (1H, m), 2.18-2.15 (1H, m),
1.83 (3H, s), 1.67-1.44 (3H, m), 1.05 (3H, d, J = 6.7 Hz). LC/MS:
500 [M + H]. I-200 .sup.1H-NMR (DMSO-d.sub.6) .delta.: 12.69 (1H,
s), 8.70 (1H, d, J = 7.3 Hz), 8.22 (1H, s), 7.59-7.56 (2H, m),
7.49-7.47 (2H, m), 7.27-7.25 (1H, m), 7.20-7.18 (3H, m), 7.03-7.01
(1H, m), 4.18 (1H, s), 4.00-3.99 (1H, m), 1.82-1.81 (2H, m),
1.72-1.60 (4H, m), 1.46-1.40 (2H, m), 1.14 (3H, s). LC/MS: 477 [M +
H]. I-201 .sup.1H-NMR (DMSO-d.sub.6) .delta.: 12.71 (1H, s), 8.92
(1H, d, J = 7.9 Hz), 8.22 (1H, s), 7.60-7.57 (2H, m), 7.49-7.47
(2H, m), 7.26-7.24 (1H, m), 7.19-7.17 (3H, m), 7.03-7.01 (1H, m),
4.25 (1H, s), 4.24-4.22 (1H, m), 2.00-1.97 (2H, m), 1.66-1.64 (2H,
m), 1.51-1.49 (4H, m), 1.14 (3H, s). LC/MS: 477 [M + H]. I-204
.sup.1H-NMR (DMSO-d.sub.6) .delta.: 8.72 (1H, d, J = 7.3 Hz), 8.24
(1H, s), 7.71 (1H, d, J = 8.5 Hz), 7.52 (1H, s), 7.47-7.42 (3H, m),
7.22-7.20 (1H, m), 7.13-7.11 (2H, m), 6.98 (1H, d, J = 2.4 Hz),
6.85 (1H, dd, J = 7.9, 2.4 Hz), 4.22-4.10 (2H, m), 3.90-3.88 (1H,
m), 3.32-3.29 (1H, m), 3.12-3.09 (1H, m), 2.28 (3H, s), 2.19-2.16
(1H, m), 1.83 (3H, s), 1.67-1.42 (3H, m), 1.05 (3H, d, J = 6.7 Hz).
LC/MS: 514 [M + H]. I-205 .sup.1H-NMR (DMSO-d.sub.6) .delta.: 12.69
(1H, s), 8.66 (1H, d, J = 7.3 Hz), 8.24 (1H, s), 7.96 (1H, t, J =
5.5 Hz), 7.85-7.83 (3H, m), 7.51-7.45 (2H, m), 7.28-7.24 (1H, m),
7.17-7.16 (2H, m), 7.10-7.07 (2H, m), 4.15-4.13 (2H, m), 3.21-3.04
(4H, m), 2.15 (1H, m), 1.82 (3H, s), 1.77-1.73 (1H, m), 1.57-1.53
(1H, m), 1.41-1.35 (1H, m). LC/MS: 486 [M + H]. I-207 .sup.1H-NMR
(DMSO-d.sub.6) .delta.: 12.73 (1H, br s), 8.96 (1H, d, J = 7.3 Hz),
8.22 (1H, s), 7.63-7.57 (2H, m), 7.52-7.46 (2H, m), 7.29-7.16 (4H,
m), 7.03 (1H, dd, J = 8.5, 1.8 Hz), 4.69-4.61 (2H, m), 3.51 (2H, t,
J = 6.1 Hz), 2.41-1.98 (5H, m). LC/MS: 449 [M + H]. I-209
.sup.1H-NMR (DMSO-d.sub.6) .delta.: 12.89 (1H, s), 8.94 (1H, s),
8.30 (1H, s), 7.89-7.85 (3H, m), 7.50-7.47 (2H, m), 7.28-7.26 (2H,
m), 7.18-7.16 (2H, m), 7.10-7.09 (2H, m), 4.18-4.14 (2H, m),
4.01-3.99 (1H, m), 3.88-3.85 (1H, m), 3.40-3.37 (1H, m), 3.16-3.14
(1H, m), 2.18-2.16 (1H, m), 1.66-1.47 (3H, m), 1.22-1.21 (3H, m),
1.10-1.09 (3H, m). LC/MS: 530 [M + H]. I-211 .sup.1H-NMR
(DMSO-d.sub.6) .delta.: 12.78 (1H, br s), 8.80 (1H, br s), 8.26
(1H, s), 7.85-7.83 (3H, m), 7.60-7.59 (1H, m), 7.49-7.47 (2H, m),
7.26-7.25 (1H, m), 7.17-7.15 (2H, m), 7.09-7.08 (2H, m), 4.15-4.13
(2H, m), 3.98 (1H, q, J = 6.7 Hz), 3.45-3.42 (1H, m), 3.20-3.13
(2H, m), 2.17-2.15 (1H, m), 1.77-1.73 (1H, m), 1.57-1.54 (1H, m),
1.42-1.39 (1H, m), 1.21 (3H, d, J = 6.7 Hz). LC/MS: 516 [M + H].
I-212 .sup.1H-NMR (CDCl.sub.3) .delta.: 9.20 (1H, d, J = 8.5 Hz),
8.29-8.25 (1H, m), 7.47-7.40 (3H, m), 7.33-7.21 (3H, m), 7.13-7.07
(3H, m), 7.00-6.95 (1H, m), 4.53 (1H, br s), 3.94 (1H, br s),
3.81-3.73 (1H, m), 2.36-2.29 (1H, m), 2.21-2.13 (2H, m), 1.95-1.40
(15H, m), 1.13 (3H, d, J = 6.1 Hz). LC/MS: 590 [M + H]. I-214
.sup.1H-NMR (CDCl.sub.3) .delta.: 9.30 (1H, d, J = 7.9 Hz),
8.32-8.24 (1H, m), 7.47-6.95 (10H, m), 5.68 (1H, d, J = 7.9 Hz),
4.47 (1H, s), 3.98 (1H, br s), 3.82-3.76 (1H, m), 2.40-2.32 (2H,
m), 2.19-13 (1H, m), 1.93-1.41 (15H, m), 1.15 (3H, d, J = 6.1 Hz).
LC/MS: 604 [M + H]. (Synthesized by method described herein for
Compound I-181) I-215 .sup.1H-NMR (DMSO-d.sub.6) .delta.: 12.78
(1H, s), 8.79 (1H, s), 8.27 (1H, s), 7.86-7.83 (3H, m), 7.49-7.47
(2H, m), 7.26-7.24 (2H, m), 7.17-7.15 (2H, m), 7.10-7.08 (2H, m),
4.18-4.14 (2H, m), 3.98-3.97 (1H, m), 3.88-3.85 (1H, m), 3.40-3.37
(1H, m), 3.15-3.12 (1H, m), 2.15 (1H, s), 1.63-1.49 (3H, m), 1.24
(3H, d, J = 6.7 Hz), 1.10 (3H, d, J = 6.7 Hz). LC/MS: 530 [M + H].
I-217 .sup.1H-NMR (DMSO-d.sub.6) .delta.: 12.82 (1H, br s), 8.85
(1H, br s), 8.28 (1H, s), 7.86-7.84 (3H, m), 7.60-7.58 (1H, m),
7.49-7.47 (2H, m), 7.27-7.25 (1H, m), 7.16-7.09 (4H, m), 4.16-4.14
(2H, m), 3.99-3.97 (1H, m), 3.44-3.41 (1H, m), 3.29-3.23 (1H, m),
3.15-3.12 (2H, m), 2.17-2.14 (1H, m), 1.78-1.74 (1H, m), 1.60-1.57
(1H, m), 1.42-1.39 (1H, m), 1.22 (3H, d, J = 6.7 Hz). LC/MS: 516 [M
+ H].
Example 100:
2-(4-methylpiperazin-1-yl)-N-(cis-4-((5-(3-methylthiophene-2-carbonyl)-7H-
-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexyl)acetamide
(I-128)
[0494]
2-(4-Methylpiperazin-1-yl)-N-(cis-4-((5-(3-methylthiophene-2-carbon-
yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexyl)acetamide
(I-128) was made according to General Procedure B from
(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-(3-methyl-2-thienyl)methanone
(128a) and
N-(cis-4-aminocyclohexyl)-2-(4-methylpiperazin-1-yl)-acetamide
(128b). .sup.1H-NMR (DMSO-d.sub.6) .delta.: 12.64 (1H, br s), 8.76
(1H, d, J=7.3 Hz), 8.22 (1H, s), 8.01 (1H, s), 7.83 (1H, d, J=4.9
Hz), 7.57 (1H, d, J=7.9 Hz), 7.15 (1H, d, J=4.9 Hz), 4.22-4.24 (1H,
m), 3.76-3.79 (1H, m), 2.90 (2H, s), 2.35-2.41 (11H, m), 1.64-1.76
(8H, m), 2.07 (3H, s). LC/MS: 496 [M+H].
[0495]
(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-(3-methyl-2-thienyl)meth-
anone (128a) was synthesized from 3-methylthiophen-2-carbonyl
chloride. .sup.1H-NMR (DMSO-d.sub.6) .delta.: 13.24 (1H, s), 8.73
(1H, s), 8.31 (1H, s), 7.88 (1H, d, J=4.9 Hz), 7.17 (1H, d, J=4.9
Hz), 2.45 (3H, s). LC/MS: 278 [M+H].
[0496] Condensation of 4-methylpiperazin-1-yl)acetic acid and
tert-butyl N-(cis-4-aminocyclohexyl)carbamate followed by Boc
deprotection provided tert-butyl
N-(cis-4-((2-(4-methylpiperazin-1-yl)acetyl)amino)cyclohexyl)carbamate.
.sup.1H-NMR (CDCl.sub.3) .delta.: 7.25 (1H, br s), 4.56 (1H, br s),
3.93-3.94 (1H, m), 3.63 (1H, s), 2.99 (2H, s), 2.47-2.57 (8H, m),
2.32 (3H, s), 1.42-1.82 (17H, m). LC/MS: 355 [M+H]. Subsequent Boc
deprotection provided
N-(cis-4-aminocyclohexyl)-2-(4-methylpiperazin-1-yl)-acetamide
(128b). LC/MS: 255 [M+H].
Example 101:
2-(4-methylpiperazin-1-yl)-N-(cis-4-((5-(2-methylthiophene-3-carbonyl)-7H-
-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexyl)acetamide
(I-132)
[0497]
2-(4-methylpiperazin-1-yl)-N-(cis-4-((5-(2-methylthiophene-3-carbon-
yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexyl)acetamide
(I-132) was synthesized from
N-methoxy-N,2-dimethyl-thiophene-3-carboxamide (132a) and
(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-(2-methyl-3-thienyl)methan-
one (132b). .sup.1H-NMR (DMSO-d.sub.6) .delta.: 12.60 (1H, s), 9.04
(1H, d, J=7.3 Hz), 8.21 (1H, s), 7.69 (1H, s), 7.58 (1H, d, J=7.9
Hz), 7.42 (1H, d, J=5.5 Hz), 7.32 (1H, d, J=5.5 Hz), 4.24-4.26 (1H,
m), 3.76-3.79 (1H, m), 2.91 (2H, s), 2.57 (3H, s), 2.33-2.42 (8H,
m), 2.11 (3H, s), 1.63-1.81 (8H, m). LC/MS: 496 [M+H].
[0498] N-methoxy-N,2-dimethyl-thiophene-3-carboxamide (132a) was
synthesized from 2-methylthiophen-3-carboxylic acid by condensation
reaction. .sup.1H-NMR (CDCl.sub.3) .delta.: 7.12 (1H, d, J=4.9 Hz),
7.02 (1H, dd, J=4.9, 1.2 Hz), 3.56 (3H, s), 3.32 (3H, s), 2.57 (3H,
d, J=1.2 Hz). LC/MS: 186 [M+H].
(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-(2-methyl-3-thienyl)methanone
(132b) was synthesized from the Weinreb amide. LC/MS: 278
[M+H].
Example 102:
(4-((cis-4-aminocyclohexyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(3-meth-
oxyphenyl)methanone (I-135)
[0499] Boc deprotection of Compound I-133 provided
(4-((cis-4-aminocyclohexyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(3-meth-
oxyphenyl)methanone (I-135). .sup.1H-NMR (DMSO-d.sub.6) .delta.:
13.31 (1H, br s), 8.37 (1H, s), 8.10-8.01 (4H, m), 7.50 (1H, t,
J=7.9 Hz), 7.39 (1H, d, J=7.9 Hz), 7.32 (1H, s), 7.27-7.24 (1H, m),
4.29-4.25 (1H, m), 3.84 (3H, s), 3.24-3.20 (1H, m), 1.99-1.70 (8H,
m). LC/MS: 366 [M+H].
Example 103:
(4-((cis-4-aminocyclohexyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(5-meth-
oxy-2-methylphenyl)methanone (I-136)
[0500] Boc deprotection of Compound I-134 provided
(4-((cis-4-aminocyclohexyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(5-meth-
oxy-2-methylphenyl)methanone (I-136). .sup.1H-NMR (DMSO-d.sub.6)
.delta.: 8.36 (1H, s), 8.08-8.06 (3H, m), 7.67 (1H, br s), 7.28
(1H, d, J=8.5 Hz), 7.04 (1H, dd, J=8.2, 2.7 Hz), 7.00-7.00 (1H, m),
4.29-4.27 (1H, m), 3.76 (3H, s), 3.24-3.21 (1H, m), 2.21 (3H, s),
1.99-1.73 (8H, m). LC/MS: 380 [M+H].
Example 104:
(4-((cis-4-aminocyclohexyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(2-chlo-
ro-5-methoxyphenyl)methanone (I-137)
[0501]
(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-(2-chloro-5-methoxypheny-
l)methanone was synthesized from methyl 2-chloro-5-methoxybenzoate,
then tert-butyl N-(cis-4-aminocyclohexyl)carbamate was introduced
and the Boc group was deprotected to provide 1-137 according to
General Procedure B followed by Boc deprotection. .sup.1H-NMR
(DMSO-d.sub.6) .delta.: 8.33 (1H, s), 8.07-7.97 (3H, m), 7.71 (1H,
s), 7.51 (1H, d, J=8.5 Hz), 7.16-7.15 (1H, m), 7.13 (1H, d, J=3.1
Hz), 4.29-4.26 (1H, m), 3.80 (3H, s), 3.24-3.21 (1H, m), 1.95-1.72
(8H, m). LC/MS: 400 [M+H].
Example 105:
(4-((cis-4-aminocyclohexyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(4-fluo-
ro-3-methoxyphenyl)methanone (I-138)
[0502]
(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-(4-fluoro-3-methoxypheny-
l)methanone was synthesized from methyl 4-fluoro-3-methoxybenzoate,
then tert-butyl N-(cis-4-aminocyclohexyl)carbamate was introduced
and the Boc group was deprotected to provide 1-138 according to
General Procedure B followed by Boc deprotection. .sup.1H-NMR
(DMSO-d.sub.6) .delta.: 8.33 (1H, s), 8.04-7.97 (4H, m), 7.55 (1H,
dd, J=8.5, 1.8 Hz), 7.44-7.38 (2H, m), 4.27-4.24 (1H, m), 3.93 (3H,
s), 3.22-3.19 (1H, m), 1.99-1.68 (8H, m). LC/MS: 384 [M+H].
Example 106:
N-(cis-4-((5-(4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyc-
lohexyl)acetamide (I-139)
[0503] Acylation of Compound I-130 provided
N-(cis-4-((5-(4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyc-
lohexyl)acetamide (I-139). .sup.1H-NMR (DMSO-d.sub.6) .delta.:
12.62 (1H, br s), 8.98 (1H, d, J=6.7 Hz), 8.22 (1H, s), 7.89-7.83
(3H, m), 7.80 (1H, s), 7.51-7.46 (2H, m), 7.28-7.23 (1H, m),
7.18-7.14 (2H, m), 7.12-7.07 (2H, m), 4.21 (1H, s), 3.67-3.74 (1H,
m), 1.85-1.57 (11H, m). LC/MS: 470 [M+H].
Example 107:
N-(cis-4-((5-(3-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyc-
lohexyl)acetamide (I-140)
[0504] Acylation of Compound I-131 provided
N-(cis-4-((5-(3-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyc-
lohexyl)acetamide (I-140). .sup.1H-NMR (DMSO-d.sub.6) .delta.:
12.68 (1H, br s), 8.93-8.89 (1H, m), 8.22 (1H, s), 7.87 (1H, d,
J=7.3 Hz), 7.78 (1H, s), 7.57-7.55 (2H, m), 7.47-7.42 (2H, m),
7.32-7.28 (2H, m), 7.22-7.18 (1H, m), 7.15-7.11 (2H, m), 4.22-4.17
(1H, m), 3.75-3.68 (1H, m), 1.81-1.55 (11H, m). LC/MS: 470
[M+H].
Example 108:
(4-((cis-4-aminocyclohexyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(2-chlo-
ro-4-phenoxyphenyl)methanone (I-141)
[0505] SNAr reaction with
(2-chloro-4-phenoxy-phenyl)-(4-chloro-7H-pyrrolo-[2,3-d]pyrimidin-5-yl)me-
thanone and tert-butyl N-(cis-4-aminocyclohexyl)carbamate followed
by subsequent Boc deprotection provided
(4-((cis-4-aminocyclohexyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(2-chlo-
ro-4-phenoxyphenyl)methanone (I-141). .sup.1H-NMR (DMSO-d.sub.6)
.delta.: 8.32 (1H, s), 8.04-7.95 (4H, m), 7.76 (1H, s), 7.60 (1H,
d, J=8.5 Hz), 7.49 (2H, dd, J=8.5, 7.3 Hz), 7.27 (1H, t, J=7.3 Hz),
7.22 (1H, d, J=2.4 Hz), 7.20-7.17 (2H, m), 7.04 (1H, dd, J=8.2, 2.1
Hz), 4.28-4.25 (1H, m), 3.24-3.19 (1H, m), 1.97-1.70 (8H, m).
LC/MS: 462 [M+H].
Example 109:
(4-((cis-4-aminocyclohexyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(4-(2-m-
ethoxyethoxy)phenyl)methanone (I-143)
[0506]
(4-((cis-4-aminocyclohexyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(-
4-(2-methoxyethoxy)phenyl)methanone (I-143) was synthesized from
(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-(3-(2-methoxyethoxy)phenyl)met-
hanone and tert-butyl N-(cis-4-aminocyclohexyl) carbamate according
to General Procedure B followed by Boc deprotection. .sup.1H-NMR
(DMSO-d.sub.6) .delta.: 8.34 (1H, s), 7.98-7.94 (4H, m), 7.84 (2H,
d, J=8.5 Hz), 7.12 (2H, d, J=8.5 Hz), 4.25-4.20 (3H, m), 3.72-3.69
(2H, m), 3.33 (3H, s), 3.23-3.18 (1H, m), 1.98-1.69 (8H, m). LC/MS:
410 [M+H].
Example 110: Compound 144:
rac-(4-((cis-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[-
2,3-d]pyrimidin-5-yl)(4-phenoxyphenyl)methanone (I-144)
Step 1.
6-((tert-butyl(diphenyl)-silyl)oxymethyl)tetrahydro-2H-pyran-3-one
(144a)
[0507] Hydroboration of
tert-butyl-(3,4-dihydro-2H-pyran-2-ylmethoxy)-diphenylsilane
followed by oxidation of the secondary alcohol using Dess-Martin
periodinane provided
6-((tert-butyl(diphenyl)-silyl)oxymethyl)tetrahydro-2H-pyran-3-one
(144a). .sup.1H-NMR (CDCl.sub.3) .delta.: 7.70-7.65 (4H, m),
7.46-7.36 (6H, m), 4.14 (1H, d, J=16.5 Hz), 3.94 (1H, d, J=16.5
Hz), 3.84-3.77 (2H, m), 3.71-3.65 (1H, m), 2.65-2.57 (1H, m),
2.50-2.41 (1H, m), 2.15-2.08 (1H, m), 1.99-1.88 (1H, m), 1.07 (9H,
s).
Step 2. rac-tert-butyl
N-[cis-6-(hydroxymethyl)tetrahydro-pyran-3-yl]carbamate (144b) and
rac-tert-butyl
N-(trans-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)carbamate
(144c)
[0508] Reductive amination of Intermediate 144a using ammonium
acetate/sodium triacetoxyborohydride followed by Boc protection of
the generated amino group, and removal of TBDPS group provided
intermediates 144b and 144c.
[0509] rac-tert-butyl
N-[cis-6-(hydroxymethyl)tetrahydro-pyran-3-yl]carbamate (144b):
.sup.1H-NMR (CDCl.sub.3) .delta.: 5.20-5.14 (0.8H, m), 3.89 (1H, d,
J=12.2 Hz), 3.76-3.70 (1H, m), 3.65-3.43 (5H, m), 2.06-1.92 (2H,
m), 1.78-1.68 (1H, m), 1.59-1.41 (10H, m).
[0510] rac-tert-butyl
N-(trans-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)carbamate
(144c): .sup.1H-NMR (CDCl.sub.3) .delta.: 4.35-4.25 (1H, m),
4.15-4.09 (1H, m), 3.65-3.44 (4H, m), 3.40-3.33 (1H, m), 3.02 (1H,
t, J=10.7 Hz), 2.15-2.06 (2H, m), 1.66-1.58 (1H, m), 1.52-1.40 (9H,
m), 1.35-1.24 (1H, m).
Step 3.
rac-(4-((cis-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-p-
yrrolo[2,3-d]pyrimidin-5-yl)(4-phenoxyphenyl)methanone (I-144)
[0511]
rac-(4-((cis-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-py-
rrolo[2,3-d]pyrimidin-5-yl)(4-phenoxyphenyl)methanone (I-144) was
synthesized according to General Procedure B from rac-tert-butyl
N-(cis-6-(hydroxymethyl)tetrahydro-pyran-3-yl)carbamate 144c (after
Boc deprotection) and
(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-(4-phenoxy-phenyl)methanone.
.sup.1H-NMR (DMSO-d.sub.6) .delta.: 12.62 (1H, br s), 9.23 (1H, d,
J=7.9 Hz), 8.22 (1H, s), 7.86-7.83 (2H, m), 7.79 (1H, s), 7.50-7.45
(2H, m), 7.27-7.22 (1H, m), 7.18-7.15 (2H, m), 7.12-7.08 (2H, m),
4.65 (1H, t, J=5.8 Hz), 4.33-4.28 (1H, m), 3.95-3.89 (1H, m),
3.66-3.61 (1H, m), 3.49-3.37 (2H, m), 1.97-1.82 (2H, m), 1.62-1.56
(2H, m). LC/MS: 445 [M+H].
Example 111:
rac-(4-((trans-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrol-
o[2,3-d]pyrimidin-5-yl)(4-phenoxyphenyl)methanone (I-145)
[0512]
rac-(4-((trans-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H--
pyrrolo[2,3-d]pyrimidin-5-yl)(4-phenoxyphenyl)methanone (I-145) was
synthesized according to General Procedure B from rac-tert-butyl
N-(trans-6-(hydroxymethyl)tetrahydro-pyran-3-yl)carbamate 144c
(after Boc deprotection and
(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-(4-phenoxy-phenyl)methanone.
.sup.1H-NMR (DMSO-d.sub.6) .delta.: 12.67 (1H, br s), 8.66 (1H, d,
J=7.3 Hz), 8.24 (1H, s), 7.86-7.80 (3H, m), 7.51-7.45 (2H, m),
7.28-7.23 (1H, m), 7.18-7.14 (2H, m), 7.11-7.06 (2H, m), 4.66 (1H,
t, J=5.8 Hz), 4.18-4.09 (2H, m), 3.45-3.35 (2H, m), 3.10 (1H, t,
J=11.3 Hz), 2.20-2.13 (1H, m), 1.81-1.74 (1H, m), 1.62-1.50 (1H,
m), 1.44-1.31 (1H, m). LC/MS: 445 [M+H].
Example 112:
(4-((cis-4-aminocyclohexyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(4-(3-f-
luorophenoxy)phenyl)methanone (I-148)
[0513]
(4-((cis-4-aminocyclohexyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(-
4-(3-fluorophenoxy)phenyl)methanone (I-148) was synthesized
according to General Procedure B from ethyl
4-(3-fluorophenoxy)benzoate and tert-butyl
N-(4-aminocyclo-hexyl)carbamate followed by Boc deprotection.
.sup.1H-NMR (DMSO-d.sub.6) .delta.: 8.38 (1H, s), 8.09 (4H, s),
7.92 (2H, d, J=8.5 Hz), 7.52 (1H, q, J=7.7 Hz), 7.20 (2H, d, J=8.5
Hz), 7.13-7.05 (2H, m), 7.01-6.98 (1H, m), 4.29-4.24 (1H, m),
3.25-3.19 (1H, m), 2.00-1.71 (8H, m). LC/MS: 446 [M+H].
Example 113:
(4-((cis-4-aminocyclohexyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(4-(ben-
zyloxy)phenyl)methanone (I-154)
[0514]
(4-((cis-4-aminocyclohexyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(-
4-(benzyloxy)phenyl)methanone (I-154) was synthesized from
(4-benzyloxyphenyl)-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone
(154a) and tert-butyl N-(4-aminocyclo-hexyl)carbamate according to
General Procedure B followed by Boc deprotection. .sup.1H-NMR
(DMSO-d.sub.6) .delta.: 8.35 (1H, s), 8.02-7.99 (4H, m), 7.86 (2H,
d, J=9.2 Hz), 7.50-7.49 (2H, m), 7.44-7.41 (2H, m), 7.38-7.35 (1H,
m), 7.19 (2H, d, J=6.7 Hz), 5.24 (2H, s), 4.25-4.23 (1H, m),
3.18-3.15 (1H, m), 1.99-1.71 (8H, m). LC/MS: 442 [M+H].
[0515]
(4-benzyloxyphenyl)-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)metha-
none (154a): .sup.1H-NMR (DMSO-d.sub.6) .delta.: 13.21 (1H, s),
8.72 (1H, s), 8.14 (1H, s), 7.86 (2H, d, J=9.2 Hz), 7.51-7.33 (5H,
m), 7.16 (2H, d, J=9.2 Hz), 5.23 (2H, s). LC/MS: 364 [M+H].
Example 114:
(4-(((3R,6S)-6-((S)-1-aminoethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrro-
lo[2,3-d]pyrimidin-5-yl)(2-chloro-4-phenoxyphenyl)methanone
(I-166)
[0516] Removal of the phthaloyl group from
2-((S)-1-((2S,5R)-5-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyri-
midin-4-yl)amino)tetrahydro-2H-pyran-2-yl)ethyl)isoindoline-1,3-dione
(166a) provided
(((3R,6S)-6-((S)-1-aminoethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[-
2,3-d]pyrimidin-5-yl)(2-chloro-4-phenoxyphenyl)methanone (I-166).
.sup.1H-NMR (DMSO-d.sub.6) .delta.: 8.60 (1H, d, J=7.3 Hz), 8.22
(1H, s), 7.58 (1H, s), 7.55 (1H, d, J=8.5 Hz), 7.49-7.46 (2H, m),
7.26-7.24 (1H, m), 7.19-7.17 (3H, m), 7.02-7.00 (1H, m), 4.22-4.18
(1H, m), 4.12-4.09 (1H, m), 3.13-3.03 (2H, m), 2.79-2.77 (1H, m),
2.19-2.16 (1H, m), 1.80-1.76 (1H, m), 1.56-1.42 (2H, m), 0.98 (3H,
q, J=6.7 Hz). LC/MS: 492 [M+H].
[0517]
2-((S)-1-((2S,5R)-5-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3--
d]pyrimidin-4-yl)amino)tetrahydro-2H-pyran-2-yl)ethyl)isoindoline-1,3-dion-
e (166a) was synthesized according to General Procedure A from
(2-chloro-4-phenoxy-phenyl)-(4-chloro-7H-pyrrolo[2,3-d]-pyrimidin-5-yl)me-
thanone and
2-((S)-1-((2S,5R)-5-aminotetrahydro-2H-pyran-2-yl)ethyl)isoindoline-1,3-d-
ione (166b). .sup.1H-NMR (DMSO-d.sub.6) .delta.: 8.57 (1H, d, J=7.3
Hz), 8.21 (1H, s), 7.88-7.83 (4H, m), 7.62 (1H, s), 7.56 (1H, d,
J=8.5 Hz), 7.49-7.47 (2H, m), 7.26-7.24 (1H, m), 7.19-7.18 (3H, m),
7.02-7.00 (1H, m), 4.21-4.04 (3H, m), 3.93-3.90 (1H, m), 3.00-2.98
(1H, m), 2.22-2.19 (1H, m), 2.02-2.00 (1H, m), 1.71-1.57 (1H, m),
1.53-1.39 (4H, m). LC/MS: 622 [M+H].
[0518] Boc deprotection of
N-((3R,6S)-6-((1S)-1-(1,3-dioxoisoindolin-2-yl)ethyl)-tetrahydro-2H-pyran-
-3-yl)carbamate provided
2-((S)-1-((2S,5R)-5-aminotetrahydro-2H-pyran-2-yl)ethyl)isoindoline-1,3-d-
ione 166b. LC/MS: 275 [M+H].
Example 115:
(2-chloro-4-phenoxyphenyl)(4-(((3R,6S)-6-((S)-1-(dimethylamino)ethyl)
[0519]
tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)met-
hanone (I-167)
[0520] Reductive methylation of Compound I-166 with
formaline/sodium triacetoxyborohydride provided
(2-chloro-4-phenoxyphenyl)(4-(((3R,6S)-6-((S)-1-(dimethylamino)ethyl)tetr-
ahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone
(I-167). .sup.1H-NMR (DMSO-d.sub.6) .delta.: 12.62 (1H, br s), 8.59
(1H, d, J=7.3 Hz), 8.25 (1H, s), 7.62 (1H, s), 7.57 (1H, d, J=8.5
Hz), 7.49-7.47 (2H, m), 7.27-7.25 (1H, m), 7.19-7.18 (3H, m),
7.03-7.01 (1H, m), 4.18-4.10 (2H, m), 3.39-3.37 (2H, m), 3.10-3.08
(1H, m), 2.21-2.17 (7H, m), 1.66-1.52 (3H, m), 0.93-0.92 (3H, m).
LC/MS: 520 [M+H].
Example 116:
2-(dimethylamino)-N-(cis-4-((5-(4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]
pyrimidin-4-yl)amino)cyclohexyl)acetamide (I-170)
[0521] Acylation of Compound I-130 provided
2-(dimethylamino)-N-(cis-4-((5-(4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimi-
din-4-yl)amino)cyclohexyl)acetamide (I-170). .sup.1H-NMR
(DMSO-d.sub.6) .delta.: 12.65 (1H, s), 8.99 (1H, d, J=7.3 Hz), 8.22
(1H, s), 7.85 (2H, d, J=8.5 Hz), 7.80 (1H, s), 7.61 (1H, d, J=7.3
Hz), 7.48 (2H, t, J=7.9 Hz), 7.25 (1H, t, J=7.3 Hz), 7.16 (2H, d,
J=7.9 Hz), 7.10 (2H, d, J=8.5 Hz), 4.26-4.22 (1H, m), 3.78-3.74
(1H, m), 2.85 (2H, s), 2.19 (6H, s), 1.84-1.59 (8H, m). LC/MS: 513
[M+H].
Example 117:
(2S,5R)--N-((2R,3R)-1,3-dihydroxybutan-2-yl)-5-((5-(4-phenoxybenzoyl)-7H--
pyrrolo[2,3-d]pyrimidin-4-yl)amino)tetrahydro-2H-pyran-2-carboxamide
(I-175)
[0522] Condensation of
(2S,5R)-5-((5-(4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)te-
trahydro-2H-pyran-2-carboxylic acid (LC/MS: 459 [M+H]) and
(2R,3R)-2-aminobutane-1,3-diol provided
(2S,5R)--N-((2R,3R)-1,3-dihydroxybutan-2-yl)-5-((5-(4-phenoxybenzoyl)-7H--
pyrrolo[2,3-d]pyrimidin-4-yl)amino)
tetrahydro-2H-pyran-2-carboxamide (I-175). .sup.1H-NMR
(DMSO-d.sub.6) .delta.: 12.71 (1H, s), 8.71 (1H, d, J=7.3 Hz), 8.25
(1H, s), 7.87-7.82 (3H, m), 7.51-7.45 (2H, m), 7.25 (1H, t, J=7.3
Hz), 7.18-7.14 (2H, m), 7.09 (2H, d, J=8.5 Hz), 6.95 (1H, d, J=8.5
Hz), 4.82 (1H, d, J=4.9 Hz), 4.72 (1H, t, J=5.5 Hz), 4.28-4.17 (2H,
m), 3.98-3.86 (2H, m), 3.65-3.58 (1H, m), 3.44-3.22 (3H, m),
2.23-2.10 (2H, m), 1.74-1.46 (2H, m), 1.02 (3H, d, J=6.7 Hz).
LC/MS: 546 [M+H].
Example 118:
(2S,5R)--N--((R)-2,3-dihydroxypropyl)-5-((5-(4-phenoxybenzoyl)-7H-pyrrolo-
[2,3-d]pyrimidin-4-yl)amino)tetrahydro-2H-pyran-2-carboxamide
(I-176)
[0523] Condensation of (R)-3-aminopropane-1,2-diol and
(2S,5R)-5-((5-(4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)te-
trahydro-2H-pyran-2-carboxylic acid and the applicable amine
provided
(2S,5R)--N--((R)-2,3-dihydroxypropyl)-5-((5-(4-phenoxybenzoyl)-7H-pyrrolo-
[2,3-d]pyrimidin-4-yl)amino)tetrahydro-2H-pyran-2-carboxamide
(I-176). .sup.1H-NMR (CDCl.sub.3) .delta.: 12.70 (1H, s), 8.71 (1H,
d, J=7.3 Hz), 8.25 (1H, s), 7.87-7.82 (3H, m), 7.54-7.45 (3H, m),
7.28-7.23 (1H, m), 7.19-7.14 (2H, m), 7.11-7.07 (2H, m), 4.87 (1H,
d, J=5.5 Hz), 4.60 (1H, t, J=5.8 Hz), 4.27-4.14 (2H, m), 3.88 (1H,
dd, J=11.0, 2.4 Hz), 3.55-3.47 (1H, m), 3.36-3.21 (4H, m),
3.07-3.00 (1H, m), 2.23-2.06 (2H, m), 1.73-1.47 (2H, m). LC/MS: 532
[M+H].
Example 119:
(2-chloro-4-phenoxyphenyl)(4-((trans-4-((dimethylamino)methyl)-4-hydroxyc-
yclohexyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone
(I-177)
[0524]
(2-chloro-4-phenoxyphenyl)(4-((trans-4-((dimethylamino)methyl)-4-hy-
droxycyclohexyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone
(I-177) was synthesized from
4-amino-1-((dimethylamino)methyl)cyclohexan-1-ol (177a) and
(2-chloro-4-phenoxy-phenyl)-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-me-
thanone according to General Procedure B.
[0525] Synthesis of 177a: Cbz deprotection of benzyl
N-(4-((dimethylamino)methyl)-4-hydroxy-cyclohexyl)carbamate (177b)
provided 4-amino-1-((dimethylamino)methyl)cyclohexan-1-ol
(177a).
[0526] Synthesis of 177b: Benzyl
N-(4-((dimethylamino)methyl)-4-hydroxy-cyclohexyl)carbamate (177b,
cis stereoisomer) was synthesized from benzyl
N-(1-oxaspiro[2.5]octan-6-yl)carbamate (cis/trans mixture) and
dimethylamine followed by stereoisomer separation (isomer A, B;
configurations are unknown). Cbz group of isomer A (given trans
configuration for differentiation purposes only) was removed.
.sup.1H-NMR (DMSO-d.sub.6) .delta.: 12.69 (1H, s), 8.71 (1H, d,
J=7.3 Hz), 8.22 (1H, s), 7.59-7.58 (2H, m), 7.50-7.47 (2H, m),
7.27-7.24 (1H, m), 7.20-7.18 (3H, m), 7.02 (1H, dd, J=8.5, 2.4 Hz),
4.04-3.97 (2H, m), 2.30-2.25 (9H, m), 1.85-1.83 (2H, m), 1.68-1.65
(4H, m), 1.45-1.42 (2H, m). LC/MS: 520 [M+H].
Example 120:
(2-chloro-4-phenoxyphenyl)(4-((cis-4-((dimethylamino)methyl)-4-hydroxycyc-
lohexyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone
(I-178)
[0527] Cbz group of isomer B from Example 119 above (given cis
configuration for differentiation purposes only) was removed.
(2-chloro-4-phenoxyphenyl)(4-((cis-4-((dimethylamino)methyl)-4-hydroxycyc-
lohexyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (I-178)
was synthesized from the resultant cis amine and
(2-chloro-4-phenoxy-phenyl)-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-me-
thanone according to General Procedure B. .sup.1H-NMR
(DMSO-d.sub.6) .delta.: 12.70 (1H, s), 8.89 (1H, d, J=7.3 Hz), 8.23
(1H, s), 7.60-7.59 (2H, m), 7.50-7.46 (2H, m), 7.27-7.23 (1H, m),
7.20-7.17 (3H, m), 7.02 (1H, dd, J=8.5, 2.4 Hz), 4.22-4.05 (2H, m),
2.30-2.23 (9H, m), 2.00-1.95 (2H, m), 1.75-1.73 (2H, m), 1.48-1.46
(4H, m). LC/MS: 520 [M+H].
Example 121:
N-(cis-4-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-
amino)cyclohexyl)-2-(dimethylamino)acetamide (I-181)
[0528] Acylation of Compound I-141 provided
N-(cis-4-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-
amino)cyclohexyl)-2-(dimethylamino)acetamide (I-181). .sup.1H-NMR
(DMSO-d.sub.6) .delta.: 12.73 (1H, s), 8.95 (1H, d, J=7.3 Hz), 8.24
(1H, s), 7.63-7.59 (3H, m), 7.48 (2H, t, J=7.6 Hz), 7.26 (1H, t,
J=7.3 Hz), 7.21-7.18 (3H, m), 7.03 (1H, dd, J=8.5, 2.4 Hz),
4.29-4.25 (1H, m), 3.79-3.74 (1H, m), 2.86 (2H, s), 2.19 (6H, s),
1.81-1.60 (8H, m). LC/MS: 547 [M+H].
Example 122:
(2-chloro-4-(3-fluorophenoxy)phenyl)(4-(((3R,6S)-6-((R)-1-hydroxyethyl)
tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone
(I-182)
[0529]
(2-chloro-4-(3-fluorophenoxy)phenyl)(4-(((3R,6S)-6-((R)-1-hydroxyet-
hyl)
tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)metha-
none (I-182) was synthesized from according to General Procedure B
using chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone and the
applicable amine. .sup.1H-NMR (DMSO-d.sub.6) .delta.: 12.78 (1H,
s), 8.58 (1H, d, J=7.3 Hz), 8.25 (1H, s), 7.68 (1H, s), 7.60 (1H,
d, J=8.5 Hz), 7.50 (1H, q, J=7.9 Hz), 7.31 (1H, d, J=2.4 Hz),
7.13-7.05 (3H, m), 7.02 (1H, dd, J=7.9, 1.8 Hz), 4.60 (1H, d, J=5.5
Hz), 4.19-4.10 (2H, m), 3.53-3.46 (1H, m), 3.13-3.06 (2H, m),
2.22-2.17 (1H, m), 1.95-1.90 (1H, m), 1.59-1.49 (1H, m), 1.46-1.36
(1H, m), 1.08 (3H, d, J=6.1 Hz). LC/MS: 511 [M+H].
[0530]
(2-chloro-4-(3-fluorophenoxy)phenyl)-(4-chloro-7H-pyrrolo[2,3-d]pyr-
imidin-5-yl)methanone was synthesized from methyl
2-chloro-4-(3-fluorophenoxy)benzoate. Methyl
2-chloro-4-(3-fluorophenoxy)benzoate was synthesized from methyl
2-chloro-4-fluorobenzoate and 3-fluorophenol.
Example 123:
(2-chloro-4-(3-chlorophenoxy)phenyl)(4-(((3R,6S)-6-((R)-1-hydroxyethyl)
tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone
(I-183)
[0531]
(2-chloro-4-(3-chlorophenoxy)phenyl)(4-(((3R,6S)-6-((R)-1-hydroxyet-
hyl)
tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)metha-
none (I-183) was synthesized according to General Procedure B from
(2-chloro-4-(3-chlorophenoxy)phenyl)-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-
-5-yl)methanone and the applicable amine. .sup.1H-NMR
(DMSO-d.sub.6) .delta.: 12.78 (1H, s), 8.58 (1H, d, J=7.3 Hz), 8.25
(1H, s), 7.68 (1H, d, J=2.4 Hz), 7.60 (1H, d, J=8.5 Hz), 7.48 (1H,
t, J=8.2 Hz), 7.32-7.29 (3H, m), 7.17-7.14 (1H, m), 7.10 (1H, dd,
J=8.2, 2.1 Hz), 4.60 (1H, d, J=5.5 Hz), 4.19-4.10 (2H, m),
3.53-3.46 (1H, m), 3.13-3.06 (2H, m), 2.22-2.18 (1H, m), 1.95-1.90
(1H, m), 1.60-1.49 (1H, m), 1.46-1.36 (1H, m), 1.08 (3H, d, J=6.1
Hz). LC/MS: 527 [M+H].
[0532]
(2-chloro-4-(3-chlorophenoxy)phenyl)-(4-chloro-7H-pyrrolo[2,3-d]pyr-
imidin-5-yl)methanone was synthesized from methyl
2-chloro-4-(3-chlorophenoxy)benzoate. Methyl
2-chloro-4-(3-chlorophenoxy)benzoate was synthesized from methyl
2-chloro-4-fluorobenzoate and 3-chlorophenol.
Example 124:
(4-(((1R,3R)-3-aminocyclopentyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(4-
-phenoxyphenyl)methanone (I-189)
[0533] Deprotection of Compound I-184 provided
(4-(((1R,3R)-3-aminocyclopentyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(4-
-phenoxyphenyl)methanone (I-189). .sup.1H-NMR (DMSO-d.sub.6)
.delta.: 13.35 (1H, br s), 9.75 (1H, br s), 8.39 (1H, s), 8.16 (3H,
br s), 8.04 (1H, br s), 7.90-7.84 (2H, m), 7.52-7.46 (2H, m), 7.27
(1H, t, J=7.3 Hz), 7.17 (2H, d, J=7.9 Hz), 7.13-7.08 (2H, m),
4.73-4.63 (1H, m), 3.80-3.69 (1H, m), 2.40-2.32 (1H, m), 2.27-2.15
(2H, m), 2.11-2.03 (1H, m), 1.79-1.66 (2H, m). LC/MS: 414
[M+H].
Example 125:
(4-((cis-3-aminocyclobutyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(4-phen-
oxyphenyl)methanone (I-190)
[0534] Deprotection of Compound I-186 provided
(4-((cis-3-aminocyclobutyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(4-phen-
oxyphenyl)methanone (I-190). .sup.1H-NMR (DMSO-d.sub.6) .delta.:
13.13 (1H, br s), 9.52 (1H, br s), 8.33 (1H, s), 8.17 (3H, br s),
7.99 (1H, s), 7.90-7.85 (2H, m), 7.52-7.46 (2H, m), 7.30-7.25 (1H,
m), 7.19-7.15 (2H, m), 7.13-7.09 (2H, m), 4.55-4.43 (1H, m),
3.60-3.47 (1H, m), 2.86-2.77 (2H, m), 2.27-2.16 (2H, m). LC/MS: 400
[M+H].
Example 126:
(4-((trans-3-aminocyclobutyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(4-ph-
enoxyphenyl)methanone (I-191)
[0535] Deprotection of Compound I-185 provided
(4-((trans-3-aminocyclobutyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(4-ph-
enoxyphenyl)methanone (I-191). .sup.1H-NMR (DMSO-d.sub.6) .delta.:
13.09 (1H, br s), 8.34 (1H, s), 8.31-8.22 (3H, br m), 7.98 (1H, br
s), 7.88 (2H, d, J=9.2 Hz), 7.52-7.47 (2H, m), 7.29-7.24 (1H, m),
7.19-7.15 (2H, m), 7.13-7.09 (2H, m), 4.86-4.75 (1H, m), 4.06-3.61
(1H, m), 2.71-2.60 (2H, m), 2.48-2.39 (2H, m). LC/MS: 400
[M+H].
Example 127: Compound 192:
N-((1R,3R)-3-((5-(4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino-
)cyclopentyl)acetamide (I-192)
[0536] Acylation of Compound I-189 gave
N-((1R,3R)-3-((5-(4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino-
)cyclopentyl)acetamide (I-192). .sup.1H-NMR (CDCl.sub.3) .delta.:
9.17 (1H, d, J=7.3 Hz), 8.34 (1H, s), 7.82-7.77 (2H, m), 7.60 (1H,
s), 7.46-7.38 (2H, m), 7.21 (1H, t, J=7.3 Hz), 7.14-7.04 (4H, m),
5.73 (1H, d, J=7.3 Hz), 4.76-4.63 (1H, m), 4.54-4.43 (1H, m),
2.42-2.28 (2H, m), 2.20-2.00 (2H, m), 1.98 (3H, s), 1.83-1.70 (1H,
m), 1.62-1.49 (1H, m). LC/MS: 456 [M+H].
Example 128:
(S)--N-(cis-4-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin--
4-yl)amino)cyclohexyl)-2-hydroxypropanamide (I-193)
[0537] Acylation of Compound I-141 provided
(S)--N-(cis-4-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin--
4-yl)amino)cyclohexyl)-2-hydroxypropanamide (I-193). .sup.1H-NMR
(DMSO-d.sub.6) .delta.: 12.74 (1H, s), 8.95 (1H, d, J=7.3 Hz), 8.24
(1H, s), 7.63 (1H, s), 7.60 (1H, d, J=8.5 Hz), 7.51-7.43 (3H, m),
7.27-7.24 (1H, m), 7.21-7.17 (3H, m), 7.03 (1H, dd, J=8.5, 2.4 Hz),
5.39 (1H, d, J=5.5 Hz), 4.31-4.24 (1H, m), 4.00-3.93 (1H, m),
3.77-3.69 (1H, m), 1.59-1.83 (8H, m), 1.19 (3H, d, J=6.7 Hz).
LC/MS: 534 [M+H].
Example 129:
N-(cis-4-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-
amino)cyclohexyl)-2-hydroxy-2-methylpropanamide (I-194)
[0538] Acylation of compound I-141 gave
N-(cis-4-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-
amino)cyclohexyl)-2-hydroxy-2-methylpropanamide (I-194).
.sup.1H-NMR (DMSO-d.sub.6) .delta.: 12.74 (1H, s), 8.96 (1H, d,
J=7.3 Hz), 8.24 (1H, s), 7.64 (1H, s), 7.61 (1H, d, J=8.5 Hz),
7.50-7.46 (2H, m), 7.29-7.24 (2H, m), 7.21-7.17 (3H, m), 7.03 (1H,
dd, J=8.5, 2.4 Hz), 5.46 (1H, s), 4.32-4.25 (1H, m), 3.74-3.65 (1H,
m), 1.60-1.83 (8H, m), 1.24 (6H, s). LC/MS: 548 [M+H].
Example 130:
N--((R)-1-((2S,5R)-5-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyr-
imidin-4-yl)amino)tetrahydro-2H-pyran-2-yl)ethyl)acetamide
(I-195)
[0539]
N--((R)-1-((2S,5R)-5-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-
-d]pyrimidin-4-yl)amino)tetrahydro-2H-pyran-2-yl)ethyl)acetamide
(I-195) was synthesized according to General Procedure B from
N-((1R)-1-((2S,5R)-5-aminotetrahydro-2H-pyran-2-yl)ethyl)acetamide
hydrochloride salt (195a) and
(2-chloro-4-phenoxy-phenyl)-(4-chloro-7H-pyrrolo[2,3-d]-pyrimidin-5-yl)me-
thanone. .sup.1H-NMR (DMSO-d.sub.6) .delta.: 12.77 (1H, s), 8.59
(1H, d, J=6.7 Hz), 8.25 (1H, s), 7.80 (1H, d, J=8.5 Hz), 7.64 (1H,
s), 7.57 (1H, d, J=8.5 Hz), 7.51-7.45 (2H, m), 7.28-7.23 (1H, m),
7.20-7.17 (3H, m), 7.02 (1H, dd, J=8.2, 2.1 Hz), 4.22-4.10 (2H, m),
3.82-3.76 (1H, m), 3.25-3.18 (1H, m), 3.15-3.08 (1H, m), 2.22-2.15
(1H, m), 1.82-1.75 (4H, m), 1.60-1.41 (2H, m), 1.05 (3H, d, J=6.7
Hz). LC/MS: 534 [M+H].
[0540] Synthesis of
N-((1R)-1-((2S,5R)-5-aminotetrahydro-2H-pyran-2-yl)ethyl)acetamide
hydrochloride salt (195a):
[0541] tert-butyl
N-((3R,6S)-6-((1R)-1-azidoethyl)tetrahydro-2H-pyran-3-yl)carbamate
was synthesized from tert-butyl
N-((3R,6S)-6-((1S)-1-hydroxyethyl)tetrahydro-2H-pyran-3-yl)carbamate
under Mitsunobu conditions using DPPA. LC/MS: 215 [M-t-Bu+2H].
Reduction of the Azide group via hydrogenation (LC/MS: 245 [M+H])
followed by acetylation provided tert-butyl
N-((3R,6S)-6-((1R)-1-acetamidoethyl)tetrahydro-2H-pyran-3-yl)carbamate.
.sup.1H-NMR (CDCl.sub.3) .delta.: 5.85 (1H, br s), 4.24 (1H, br s),
4.10-4.07 (1H, m), 4.04-3.96 (1H, m), 3.59-3.56 (1H, m), 3.27-3.25
(1H, m), 2.97-2.95 (1H, m), 2.12-2.06 (1H, m), 1.98 (3H, s),
1.50-1.47 (10H, m), 1.32-1.19 (2H, m), 1.09 (3H, d, J=6.7 Hz).
LC/MS: 287 [M+H].
[0542] Boc deprotection of tert-butyl
N-((3R,6S)-6-((1R)-1-acetamidoethyl)tetrahydro-2H-pyran-3-yl)carbamate
provided
N-((1R)-1-((2S,5R)-5-aminotetrahydro-2H-pyran-2-yl)ethyl)acetami-
de hydrochloride salt (195a). .sup.1H-NMR (DMSO-d.sub.6) .delta.:
8.21 (3H, br s), 7.81 (1H, d, J=8.5 Hz), 4.05-4.02 (1H, m),
3.74-3.70 (1H, m), 3.32-3.20 (1H, m), 3.09-3.01 (2H, m), 2.08-2.05
(1H, m), 1.79 (3H, s), 1.69-1.65 (1H, m), 1.55-1.50 (1H, m),
1.33-1.28 (1H, m), 1.01 (3H, d, J=6.7 Hz). LC/MS: 187 [M+H].
Example 131:
N-(cis-3-((5-(4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)
cyclobutyl)acetamide (I-196)
[0543] Acylation of Compound I-190 gave
N-(cis-3-((5-(4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyc-
lobutyl)acetamide (I-196). .sup.1H-NMR (DMSO-d.sub.6) .delta.:
12.70 (1H, br s), 8.98 (1H, d, J=6.1 Hz), 8.23 (1H, s), 8.21 (1H,
d, J=7.9 Hz), 7.88-7.81 (3H, m), 7.51-7.46 (2H, m), 7.29-7.24 (1H,
m), 7.19-7.15 (2H, m), 7.09 (2H, d, J=8.5 Hz), 4.42-4.30 (1H, m),
4.10-3.98 (1H, m), 2.77-2.67 (2H, m), 1.94-1.84 (2H, m), 1.78 (3H,
s). LC/MS: 442 [M+H].
Example 132:
(4-(((3R,6S)-6-((R)-1-hydroxyethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyr-
rolo[2,3-d]pyrimidin-5-yl)(2-methyl-4-phenoxyphenyl)methanone
(I-197)
[0544]
(4-(((3R,6S)-6-((R)-1-hydroxyethyl)tetrahydro-2H-pyran-3-yl)amino)--
7H-pyrrolo[2,3-d]pyrimidin-5-yl)(2-methyl-4-phenoxyphenyl)methanone
(I-197) was synthesized according to General Procedure B from
(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-(2-methyl-4-phenoxy-phenyl)-me-
thanone and the applicable amine. .sup.1H-NMR (DMSO-d.sub.6)
.delta.: 8.72 (1H, d, J=7.3 Hz), 8.24 (1H, s), 7.51 (1H, s),
7.47-7.43 (3H, m), 7.21 (1H, t, J=7.6 Hz), 7.12 (2H, d, J=7.9 Hz),
6.98 (1H, d, J=2.4 Hz), 6.85 (1H, dd, J=7.9, 2.4 Hz), 4.61 (1H, d,
J=5.5 Hz), 4.19-4.09 (2H, m), 3.53-3.46 (1H, m), 3.13-3.05 (2H, m),
2.28 (3H, s), 2.21-2.17 (1H, m), 1.95-1.90 (1H, m), 1.59-1.49 (1H,
m), 1.46-1.36 (1H, m), 1.08 (3H, d, J=6.1 Hz). LC/MS: 473
[M+H].
Example 133:
N-(trans-3-((5-(4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)c-
yclobutyl)acetamide (I-199)
[0545] Acylation of Compound I-191 provided
N-(trans-3-((5-(4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)c-
yclobutyl)acetamide (I-199). .sup.1H-NMR (DMSO-d.sub.6) .delta.:
13.13 (1H, br s), 8.37-8.32 (2H, m), 8.00 (1H, br s), 7.92-7.87
(2H, m), 7.52-7.46 (2H, m), 7.29-7.24 (1H, m), 7.19-7.15 (2H, m),
7.11 (2H, d, J=8.5 Hz), 4.57 (1H, br s), 4.40-4.30 (1H, m),
2.48-2.39 (2H, m), 2.38-2.28 (2H, m), 1.82 (3H, s). LC/MS: 442
[M+H].
Example 134:
(S)-2-hydroxy-N-(cis-4-((5-(4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin--
4-yl)amino)cyclohexyl)propanamide (I-202)
[0546] Acylation of Compound I-130 provided
(S)-2-hydroxy-N-(cis-4-((5-(4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin--
4-yl)amino)cyclohexyl)propanamide (I-202). .sup.1H-NMR
(DMSO-d.sub.6) .delta.: 12.65 (1H, s), 9.00 (1H, d, J=7.3 Hz), 8.22
(1H, s), 7.87-7.84 (2H, m), 7.80 (1H, s), 7.50-7.46 (3H, m), 7.25
(1H, t, J=7.3 Hz), 7.18-7.15 (2H, m), 7.09 (2H, d, J=8.5 Hz), 5.38
(1H, d, J=5.5 Hz), 4.27-4.22 (1H, m), 4.00-3.93 (1H, m), 3.75-3.69
(1H, m), 1.83-1.63 (8H, m), 1.19 (3H, d, J=6.7 Hz). LC/MS: 500
[M+H].
Example 135:
2-hydroxy-2-methyl-N-(cis-4-((5-(4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrim-
idin-4-yl)amino)cyclohexyl)propanamide (I-203)
[0547] Acylation of Compound I-130 provided
2-hydroxy-2-methyl-N-(cis-4-((5-(4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrim-
idin-4-yl)amino)cyclohexyl)propanamide (I-203). .sup.1H-NMR
(DMSO-d.sub.6) .delta.: 12.65 (1H, s), 9.00 (1H, d, J=7.3 Hz), 8.23
(1H, s), 7.87-7.84 (2H, m), 7.80 (1H, s), 7.50-7.46 (2H, m), 7.32
(1H, d, J=7.9 Hz), 7.25 (1H, t, J=7.3 Hz), 7.18-7.15 (2H, m),
7.11-7.08 (2H, m), 5.44 (1H, s), 4.27-4.23 (1H, m), 3.71-3.67 (1H,
m), 1.81-1.63 (8H, m), 1.24 (6H, s). LC/MS: 514 [M+H].
Example 136:
(R)-2-hydroxy-N-(cis-4-((5-(4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin--
4-yl)amino)cyclohexyl)propanamide (I-206)
[0548] Acylation of Compound I-130 provided
(R)-2-hydroxy-N-(cis-4-((5-(4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin--
4-yl)amino)cyclohexyl)propanamide (I-206). .sup.1H-NMR
(DMSO-d.sub.6) .delta.: 12.65 (1H, s), 9.00 (1H, d, J=7.9 Hz), 8.22
(1H, s), 7.86 (2H, d, J=8.5 Hz), 7.80 (1H, s), 7.50-7.46 (3H, m),
7.25 (1H, t, J=7.6 Hz), 7.17-7.15 (2H, m), 7.11-7.08 (2H, m), 5.38
(1H, d, J=5.5 Hz), 4.26-4.23 (1H, m), 3.99-3.93 (1H, m), 3.75-3.70
(1H, m), 1.83-1.63 (8H, m), 1.19 (3H, d, J=6.7 Hz). LC/MS: 500
[M+H].
Example 137:
(S)--N--((S)-1-((2S,5R)-5-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3--
d]pyrimidin-4-yl)amino)tetrahydro-2H-pyran-2-yl)ethyl)-2-hydroxypropanamid-
e (I-208)
[0549]
(S)--N--((S)-1-((2S,5R)-5-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrol-
o[2,3-d]pyrimidin-4-yl)amino)tetrahydro-2H-pyran-2-yl)ethyl)-2-hydroxyprop-
anamide (I-208) was synthesized according to General Procedure B
from
(S)--N--((S)-1-((2S,5R)-5-aminotetrahydro-2H-pyran-2-yl)ethyl)-2-hydroxyp-
ropanamide (208a). .sup.1H-NMR (DMSO-d.sub.6) .delta.: 12.94 (1H,
br s), 8.80 (1H, br s), 8.30 (1H, s), 7.71 (1H, s), 7.58 (1H, d,
J=8.5 Hz), 7.50-7.47 (2H, m), 7.27-7.26 (2H, m), 7.20-7.19 (3H, m),
7.04-7.02 (1H, m), 4.19-4.14 (2H, m), 4.01-3.99 (1H, m), 3.88-3.86
(1H, m), 3.41-3.38 (1H, m), 3.18-3.15 (1H, m), 2.19-2.17 (1H, m),
1.65-1.52 (3H, m), 1.22 (3H, d, J=6.7 Hz), 1.10 (3H, d, J=6.7 Hz).
LC/MS: 564 [M+H].
[0550] Synthesis of
(S)--N--((S)-1-((2S,5R)-5-aminotetrahydro-2H-pyran-2-yl)ethyl)-2-hydroxyp-
ropanamide (208a): Boc deprotection of tert-butyl
N-((3R,6S)-6-((1S)-1-(((2S)-2-hydroxy-propanoyl)amino)ethyl)tetrahydro-2H-
-pyran-3-yl)carbamate (208b) provided amine 208a. LC/MS: 217
[M+H].
[0551] Synthesis of tert-butyl
N-((3R,6S)-6-((1S)-1-(((2S)-2-hydroxy-propanoyl)amino)
ethyl)tetrahydro-2H-pyran-3-yl)carbamate (208b): Acylation of
tert-butyl
N-((3R,6S)-6-((1S)-1-aminoethyl)tetrahydro-2H-pyran-3-yl)carbamate
with (2S)-2-hydroxypropanoic acid provided tert-butyl
N-((3R,6S)-6-((1S)-1-(((2S)-2-hydroxy-propanoyl)amino)ethyl)tetrahydro-2H-
-pyran-3-yl)carbamate (208b). .sup.1H-NMR (CDCl.sub.3) .delta.:
6.55 (1H, d, J=8.5 Hz), 4.26-4.18 (2H, m), 4.09-4.07 (1H, m),
4.04-3.96 (1H, m), 3.52-3.49 (1H, m), 3.24-3.20 (1H, m), 3.00-2.92
(2H, m), 2.08-2.06 (1H, m), 1.47-1.43 (13H, m), 1.32-1.26 (2H, m),
1.20 (3H, d, J=7.3 Hz). LC/MS: 317 [M+H].
Example 138:
(S)--N-(((2S,5R)-5-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrim-
idin-4-yl)amino)tetrahydro-2H-pyran-2-yl)methyl)-2-hydroxypropanamide
(I-210)
[0552] Acylation of tert-Butyl
N-((3R,6S)-6-(aminomethyl)tetrahydro-2H-pyran-3-yl)carbamate with
(2S)-2-hydroxypropanoic acid provided tert-butyl
N-((3R,6S)-6-((((2S)-2-hydroxypropanoyl)-amino)methyl)tetrahydro-2H-pyran-
-3-yl)carbamate (210a). LC/MS: 303 [M+H].
[0553] Boc deprotection of 210a provided
(S)--N-(((2S,5R)-5-aminotetrahydro-2H-pyran-2-yl)methyl)-2-hydroxypropana-
mide (210b). LC/MS: 203 [M+H].
[0554]
(S)--N-(((2S,5R)-5-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d-
]pyrimidin-4-yl)amino)tetrahydro-2H-pyran-2-yl)methyl)-2-hydroxypropanamid-
e (I-210) was synthesized according to General Procedure B from
(S)--N-(((2S,5R)-5-aminotetrahydro-2H-pyran-2-yl)methyl)-2-hydroxypropana-
mide (210b) and
(2-chloro-4-phenoxy-phenyl)-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-me-
thanone. .sup.1H-NMR (DMSO-d.sub.6) .delta.: 12.92 (1H, br s), 8.78
(1H, br s), 8.31-8.28 (1H, m), 7.70 (1H, s), 7.59-7.57 (2H, m),
7.50-7.48 (2H, m), 7.27-7.26 (1H, m), 7.20-7.18 (3H, m), 7.02 (1H,
dd, J=8.2, 2.1 Hz), 4.18-4.16 (2H, m), 4.04-3.96 (1H, m), 3.45 (1H,
s), 3.17-3.15 (3H, m), 2.19-2.16 (1H, m), 1.78-1.75 (1H, m),
1.61-1.58 (1H, m), 1.43-1.40 (1H, m), 1.22-1.21 (3H, m). LC/MS: 550
[M+H].
Example 139:
(R)--N--((S)-1-((2S,5R)-5-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3--
d]pyrimidin-4-yl)amino)tetrahydro-2H-pyran-2-yl)ethyl)-2-hydroxypropanamid-
e (I-213)
[0555] Acylation of tert-butyl
N-((3R,6S)-6-((1S)-1-aminoethyl)tetrahydro-2H-pyran-3-yl)carbamate
with (2R)-2-hydroxypropanoic acid provided tert-butyl
N-((3R,6S)-6-((1S)-1-(((2R)-2-hydroxy-propanoyl)amino)ethyl)tetrahydro-2H-
-pyran-3-yl)carbamate (213a). LC/MS: 317 [M+H].
[0556] Boc deprotection of tert-butyl
N-((3R,6S)-6-((1S)-1-(((2R)-2-hydroxy-propanoyl)amino)ethyl)tetrahydro-2H-
-pyran-3-yl)carbamate (213a) provided
(R)--N--((S)-1-((2S,5R)-5-aminotetrahydro-2H-pyran-2-yl)ethyl)-2-hydroxyp-
ropanamide (213b) LC/MS: 217 [M+H].
[0557]
(R)--N--((S)-1-((2S,5R)-5-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrol-
o[2,3-d]pyrimidin-4-yl)amino)tetrahydro-2H-pyran-2-yl)ethyl)-2-hydroxyprop-
anamide (I-213) was synthesized according to General Procedure B
from
(R)--N--((S)-1-((2S,5R)-5-aminotetrahydro-2H-pyran-2-yl)ethyl)-2-hydroxyp-
ropanamide (213b) and
(2-chloro-4-phenoxy-phenyl)-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)met-
hanone. .sup.1H-NMR (DMSO-d.sub.6) .delta.: 12.92 (1H, br s), 8.79
(1H, br s), 8.30 (1H, s), 7.70 (1H, s), 7.58 (1H, d, J=7.9 Hz),
7.49-7.47 (2H, m), 7.25-7.21 (5H, m), 7.03-7.01 (1H, m), 4.19-4.14
(2H, m), 3.98-3.97 (1H, m), 3.88-3.85 (1H, m), 3.41-3.38 (1H, m),
3.18-3.15 (1H, m), 2.21-2.18 (1H, m), 1.69-1.45 (3H, m), 1.24 (3H,
d, J=6.7 Hz), 1.10 (3H, d, J=6.7 Hz). LC/MS: 564 [M+H].
Example 140:
(R)--N-(((2S,5R)-5-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrim-
idin-4-yl)amino)tetrahydro-2H-pyran-2-yl)methyl)-2-hydroxypropanamide
(I-216)
[0558] Acylation of tert-Butyl
N-((3R,6S)-6-(aminomethyl)tetrahydro-2H-pyran-3-yl)carbamate with
(2R)-2-hydroxypropanoic acid provided tert-butyl
N-((3R,6S)-6-((((2R)-2-hydroxypropanoyl)-amino)methyl)tetrahydro-2H-pyran-
-3-yl)carbamate (216a). LC/MS: 303 [M+H].
[0559] Boc deprotection of tert-butyl
N-((3R,6S)-6-((((2R)-2-hydroxypropanoyl)-amino)methyl)tetrahydro-2H-pyran-
-3-yl)carbamate (216a) provided
(R)--N-(((2S,5R)-5-aminotetrahydro-2H-pyran-2-yl)methyl)-2-hydroxypropana-
mide (216b) LC/MS: 203 [M+H].
[0560]
(R)--N-(((2S,5R)-5-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d-
]pyrimidin-4-yl)amino)tetrahydro-2H-pyran-2-yl)methyl)-2-hydroxypropanamid-
e (I-216) was synthesized according to General Procedure B from
(R)--N-(((2S,5R)-5-aminotetrahydro-2H-pyran-2-yl)methyl)-2-hydroxypropana-
mide (216b) and
(2-chloro-4-phenoxy-phenyl)-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)met-
hanone. .sup.1H-NMR (DMSO-d.sub.6) .delta.: 12.89 (1H, br s), 8.75
(1H, br s), 8.29 (1H, s), 7.69 (1H, s), 7.60-7.58 (2H, m),
7.49-7.47 (2H, m), 7.27-7.25 (1H, m), 7.19-7.18 (3H, m), 7.03-7.02
(1H, m), 4.18-4.15 (2H, m), 3.98 (1H, q, J=6.5 Hz), 3.46-3.44 (1H,
m), 3.27-3.25 (1H, m), 3.15-3.13 (2H, m), 2.20-2.17 (1H, m),
1.78-1.75 (1H, m), 1.61-1.58 (1H, m), 1.42-1.40 (1H, m), 1.22 (3H,
d, J=6.7 Hz). LC/MS: 550 [M+H].
Example 141: General Procedure C
##STR00732##
[0561] Step 1. Intermediate 6-C
[0562] A mixture of 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine (6-A,
2.00 g, 10.6 mmol), an aroyl chloride or heteroaroyl chloride (2-B,
1-3 eq.), and AlCl.sub.3 (2-5 eq.) in nitrobenzene was heated at
70-90.degree. C. for 1-6 hrs. Work-up and/or purification provided
the corresponding aryl- or
heteroaryl-(2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone
(6-C).
Step 2. Intermediate I-Y
[0563] A mixture of 6-C (1.00 g, 3.27 mmol), a primary amine (3-D,
1-4 eq.), and optionally a base (e.g., TEA, DIPEA, pyridine, and/or
K.sub.2CO.sub.3 (1-5 eq.)) in a solvent (e.g., DMF, NMP, IPA,
n-BuOH or neat) was heated (70-160.degree. C.) for 5-50 hrs or
heated (100-220.degree. C.) under microwave radiation for 0.5-5
hrs. Work-up and/or purification provided the corresponding aryl-
or
heteroaryl-(4-substituted-amino-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-
-methanone (I-Y).
Step 3. Compounds of Formula I-Z
[0564] A mixture of I-Y (70 mg, 0.145 mmol), a primary amine (6-D,
1-4 eq.), and optionally a base (e.g., TEA, DIPEA, pyridine, and/or
K.sub.2CO.sub.3 (1-5 eq.)) in a solvent (e.g., DMF, NMP, IPA,
n-BuOH or neat) was heated (70-160.degree. C.) for 5-50 hrs or
heated (100-220.degree. C.) under microwave radiation for 0.5-5
hrs. Work-up and/or purification provided a compound of Formula (I)
(aryl- or
heteroaryl-(2-substituted-amino-4-substituted-amino-7H-pyrrolo[2,3-d]pyri-
midin-5-yl)methanone (I-Z)).
[0565] The compounds of Formula (I) in Table 3 below were made
according to General Procedure C.
TABLE-US-00005 TABLE 3 Cmpd No. .sup.1H NMR and/or LC/MS data I-226
.sup.1H-NMR (CDCl.sub.3) .delta.: 12.73-12.90 (1H, m), 9.27-9.30
(1H, m), 8.38 (1H, d, J = 8.5 Hz), 7.79 (2H, d, J = 7.6 Hz),
7.60-7.63 (2H, m), 7.53 (2H, t, J = 7.6 Hz), 4.78-4.85 (1H, m),
3.85 (1H, dd, J = 11.3, 6.4 Hz), 3.61-3.71 (1H, m), 3.35-3.57 (2H,
m), 2.31-2.40 (1H, m), 2.05-2.15 (1H, m), 1.46 (9H, s). MS (ESI)
m/z: 408 [M + H].sup.+. I-230 .sup.1H-NMR (DMSO-d.sub.6) .delta.:
12.67 (1H, s), 8.82 (1H, t, J = 5.5 Hz), 8.24 (1H, s), 7.78 (2H, d,
J = 7.3 Hz), 7.74 (1H, s), 7.65 (1H, t, J = 7.3 Hz), 7.55 (2H, t, J
= 7.6 Hz), 3.52 (2H, q, J = 6.5 Hz), 3.29-3.39 (4H, m), 2.20 (2H,
t, J = 7.9 Hz), 1.78-1.95 (4H, m). MS (ESI) m/z: 364 [M +
H].sup.+.
Example 142:
(4-((cis-4-aminocyclohexyl)amino)-2-((1-methylpiperidin-4-yl)amino)-7H-py-
rrolo[2,3-d]pyrimidin-5-yl)(o-tolyl)methanone (I-218)
##STR00733##
[0566] Step 1.
(2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-(o-tolyl)methanone
(218 b)
[0567] The mixture of 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine
(6-A, 2.00 g, 10.6 mmol), 2-methylbenzoyl chloride (218a, 2.00 mL,
15.3 mmol), AlCl.sub.3 (5.00 g, 37.5 mmol) and nitrobenzene (30 mL)
was heated at 70.degree. C. for 3 hrs. The resultant mixture was
poured into ice and extracted with EtOAc. The extract was washed
with water and brine, then dried over anhydrous Na.sub.2SO.sub.4,
filtered and concentrated in vacuo. EtOAc and hexane was added to
the residue and precipitate was collected by filtration to give
(2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-(o-tolyl)-methanone
(218b, 2.20 g, 7.18 mmol, 68%). LC/MS: 306 [M+H].
Step 2. tert-butyl
N-(cis-4-((2-chloro-5-(2-methylbenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)a-
mino)cyclohexyl)carbamate (218c)
[0568] The mixture of
(2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-(o-tolyl)-methanone
(218b, 1.00 g, 3.27 mmol), tert-butyl
N-(cis-4-aminocyclohexyl)carbamate (909 mg, 4.25 mmol), DIPEA (850
.mu.L, 4.97 mmol) and IPA (15 mL) was stirred at 160.degree. C. for
1 h under microwave irradiation. The resultant mixture was diluted
with chloroform and purified by column chromatography over
SiO.sub.2 eluting with CHCl.sub.3-MeOH to give tert-butyl
N-(cis-4-((2-chloro-5-(2-methylbenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)a-
mino)cyclohexyl)carbamate (218c, 1.40 g, 2.89 mmol, 89%) as
colorless solid. LC/MS: 484 [M+H].
Step 3. tert-butyl
N-(cis-4-((5-(2-methylbenzoyl)-2-((1-methyl-4-piperidyl)amino)-7H-pyrrolo-
[2,3-d]pyrimidin-4-yl)amino)cyclohexyl)carbamate (218d)
[0569] The mixture of tert-butyl
N-(cis-4-((2-chloro-5-(2-methylbenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)a-
mino)cyclohexyl)carbamate (218c, 70 mg, 0.145 mmol) and
1-methylpiperidin-4-amine (1 mL) was stirred at 160.degree. C. for
1 h under microwave irradiation. The resultant mixture was poured
into water, extracted with CHCl.sub.3, dried over anhydrous
Na.sub.2SO.sub.4, filtered, and concentrated in vacuo. The
resulting residue was purified by column chromatography over
SiO.sub.2 eluting with CHCl.sub.3-MeOH to give tert-butyl
N-(cis-4-((5-(2-methylbenzoyl)-2-((1-methyl-4-piperidyl)amino)-7H-pyrrolo-
[2,3-d]pyrimidin-4-yl)amino)cyclohexyl)carbamate (218d, 68 mg,
0.121 mmol, 84%) as yellow oil. LC/MS: 562 [M+H].
Step 4.
(4-((cis-4-aminocyclohexyl)amino)-2-((1-methyl-4-piperidyl)amino)--
7H-pyrrolo[2,3-d]pyrimidin-5-yl)-(o-tolyl)methanone (I-218)
[0570] The mixture of tert-butyl
N-(cis-4-((5-(2-methylbenzoyl)-2-((1-methyl-4-piperidyl)amino)-7H-pyrrolo-
[2,3-d]pyrimidin-4-yl)amino)cyclohexyl)carbamate (218d, 65 mg,
0.116 mmol) and dichloromethane (5 mL) was treated with TFA (2 mL)
at ambient temperature and stirred for 1 hr. The mixture was
concentrated in vacuo and the residue was purified by column
chromatography over SiO.sub.2 with CHCl.sub.3-MeOH. Then the
product was lyophilized to give
(4-((cis-4-aminocyclohexyl)amino)-2-((1-methyl-4-piperidyl)amino)-7H-pyrr-
olo[2,3-d]pyrimidin-5-yl)-(o-tolyl)methanone (15 mg, 0.0325 mmol,
28%) as pale yellow solid. .sup.1H-NMR (400 MHz, CD.sub.3OD)
.delta.: 7.42-7.26 (5H, m), 4.39-4.35 (1H, m), 3.85-3.79 (1H, m),
2.87-2.81 (3H, m), 2.33 (3H, s), 2.29 (3H, s), 2.25-2.15 (2H, m),
2.08-1.97 (4H, m), 1.84-1.57 (8H, m). LC/MS: 462 [M+H].
Example 143:
(2-amino-4-(cis-4-aminocyclohexyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-
(o-tolyl)methanone (I-219)
[0571]
(2-amino-4-(cis-4-aminocyclohexyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-
-5-yl)(o-tolyl)methanone (I-219) was synthesized according to
General Procedure C from 4-methoxybenzyl amine (LC/MS: 585 [M+H])
followed by simultaneous Boc and benzyl deprotection. .sup.1H-NMR
(CD.sub.3OD) .delta.: 7.42-7.26 (5H, m), 4.39-4.35 (1H, m),
2.80-2.74 (1H, m), 2.33 (3H, s), 2.01-1.94 (2H, m), 1.84-1.58 (6H,
m). LC/MS: 365 [M+H].
Example 144:
(4-((cis-4-aminocyclohexyl)amino)-2-(methylamino)-7H-pyrrolo[2,3-d]pyrimi-
din-5-yl)(o-tolyl)methanone (I-220)
[0572]
(4-((cis-4-aminocyclohexyl)amino)-2-(methylamino)-7H-pyrrolo[2,3-d]-
pyrimidin-5-yl)(o-tolyl)methanone (I-220) was synthesized according
to General Procedure C from N-methylamine (LC/MS: 479 [M+H])
followed by Boc deprotection. .sup.1H-NMR (CDCl.sub.3) .delta.:
9.10 (1H, d, J=7.8 Hz), 7.33-7.28 (2H, m), 7.23-7.17 (2H, m), 6.85
(1H, s), 4.73-4.69 (1H, m), 4.37-4.30 (1H, m), 2.92 (3H, d, J=5.1
Hz), 2.80-274 (1H, m), 2.32 (3H, s), 1.97-1.92 (2H, m), 1.77-1.54
(6H, m). LC/MS: 379 [M+H].
Example 145:
(4-((cis-4-aminocyclohexyl)amino)-2-(4-methylpiperazin-1-yl)-7H-pyrrolo[2-
,3-d]pyrimidin-5-yl)(o-tolyl)methanone (I-221)
[0573]
(4-((cis-4-aminocyclohexyl)amino)-2-(4-methylpiperazin-1-yl)-7H-pyr-
rolo[2,3-d]pyrimidin-5-yl)(o-tolyl)methanone (I-221) was
synthesized according to General Procedure C from
N-methylpiperazine followed by Boc deprotection. .sup.1H-NMR
(CD.sub.3OD) .delta.: 9.06 (1H, d, J=6.7 Hz), 7.00-7.42 (5H, m),
4.38-4.42 (1H, m), 3.79-3.82 (4H, m), 2.82-2.89 (1H, m), 2.48-2.51
(4H, m), 2.34 (3H, s), 2.33 (3H, s), 2.02-2.06 (2H, m), 1.62-1.87
(6H, m). MS (ESI) m/z: 448 [M+H].sup.+.
Example 146:
N-(cis-4-((5-(2-chlorobenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)
cyclohexyl)-2-(4-methylpiperazin-1-yl)acetamide (I-222)
[0574] Acylation of Compound I-6 gave
N-(cis-4-((5-(2-chlorobenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cycl-
ohexyl)-2-(4-methylpiperazin-1-yl)acetamide (I-222). .sup.1H-NMR
(DMSO-d.sub.6) .delta.: 9.01 (1H, d, J=7.9 Hz), 8.23 (1H, s),
7.53-7.62 (4H, m), 7.45-7.49 (2H, m), 4.30 (1H, br s), 3.73-3.83
(1H, m), 3.57 (1H, s), 2.89 (2H, s), 2.16-2.49 (8H, m), 2.02 (3H,
s), 1.60-1.84 (8H, m). MS (ESI) m/z: 510 [M+H].sup.+.
Example 147:
rac-(4-(3-aminopyrrolidin-1-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)
(phenyl)methanone (I-223)
[0575]
rac-(4-(3-aminopyrrolidin-1-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)
(phenyl)methanone (I-223) was synthesized according to General
Procedure C from tert-butyl pyrrolidin-3-ylcarbamate followed by
Boc deprotection. .sup.1H-NMR (DMSO-d.sub.6) .delta.: 8.16 (1H, s),
7.93 (2H, dd, J=7.6, 1.2 Hz), 7.68 (1H, t, J=7.6 Hz), 7.56 (2H, t,
J=7.6 Hz), 7.44 (1H, s), 3.66-3.71 (1H, m), 3.62 (1H, dd, J=11.3,
5.8 Hz), 3.50-3.56 (1H, m), 3.29-3.33 (1H, m), 3.19 (1H, dd,
J=11.0, 4.9 Hz), 1.79-1.87 (1H, m), 1.48-1.56 (1H, m). MS (ESI)
m/z: 308 [M+H].sup.+.
Example 148:
rac-N-(1-(5-benzoyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3-yl)-2-(t-
etrahydro-2H-pyran-4-yl)acetamide (I-224)
[0576] Acylation of Compound I-223 provided
rac-N-(1-(5-benzoyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3-yl)-2-(t-
etrahydro-2H-pyran-4-yl)acetamide (I-224). .sup.1H-NMR
(DMSO-d.sub.6) .delta.: 12.34 (1H, s), 8.19 (1H, s), 7.97 (1H, d,
J=6.1 Hz), 7.90 (2H, d, J=7.6 Hz), 7.68 (1H, t, J=7.6 Hz), 7.57
(2H, t, J=7.6 Hz), 7.45 (1H, d, J=1.8 Hz), 4.03-4.07 (1H, m),
3.55-3.77 (5H, m), 3.44 (1H, dd, J=11.6, 4.3 Hz), 3.08-3.18 (2H,
m), 1.93-1.98 (1H, m), 1.89 (2H, d, J=10.0 Hz), 1.69-1.78 (2H, m),
1.36-1.39 (1H, m), 1.21-1.25 (1H, m), 0.93-1.11 (2H, m). MS (ESI)
m/z: 434 [M+H].sup.+.
Example 149:
rac-N-(1-(5-benzoyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3-yl)-3-me-
thoxypropanamide (I-225)
[0577] Acylation of Compound I-223 provided
rac-N-(1-(5-benzoyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3-yl)-3-me-
thoxypropanamide (I-225). .sup.1H-NMR (DMSO-d.sub.6) .delta.: 12.73
(1H, br s), 9.05 (1H, dd, J=14.3, 6.4 Hz), 8.28 (1H, d, J=1.8 Hz),
7.77-7.79 (3H, m), 7.65 (1H, t, J=7.6 Hz), 7.55 (2H, t, J=7.6 Hz),
4.61-4.76 (1H, m), 3.90 (0.5H, dd, J=10.4, 6.1 Hz), 3.65-3.73
(1.5H, m), 3.45-3.57 (4H, m), 3.35-3.39 (1H, m), 3.20 (1.5H, s),
3.18 (1.5H, s), 2.46-2.54 (2H, m), 2.21-2.38 (1H, m), 1.90-2.09
(1H, m). MS (ESI) m/z: 394 [M+H].sup.+.
Example 150:
rac-phenyl(4-(pyrrolidin-3-ylamino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)metha-
none (I-227)
[0578]
rac-phenyl(4-(pyrrolidin-3-ylamino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl-
)methanone (I-227) was synthesized according to General Procedure C
followed by Boc deprotection. .sup.1H-NMR (DMSO-d.sub.6) .delta.:
13.01 (1H, br s), 9.14-9.25 (3H, m), 8.36 (1H, s), 7.89 (1H, s),
7.80 (2H, dd, J=7.6, 1.2 Hz), 7.68 (1H, t, J=7.6 Hz), 7.57 (2H, t,
J=7.6 Hz), 4.73-4.81 (1H, m), 3.58-3.63 (1H, m), 3.37-3.45 (1H, m),
3.28-3.36 (1H, m), 3.18-3.25 (1H, m), 2.39-2.47 (1H, m), 2.00-2.09
(1H, m).
Example 151: Compound 228:
rac-1-(3-((5-benzoyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)pyrrolidin-1-y-
l)-2-(tetrahydro-2H-pyran-4-yl)ethan-1-one (I-228)
[0579] Acylation of Compound I-227 provided
rac-1-(3-((5-benzoyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)pyrrolidin-1-y-
l)-2-(tetrahydro-2H-pyran-4-yl)ethan-1-one (I-228). .sup.1H-NMR
(DMSO-d.sub.6) .delta.: 12.73 (1H, br s), 9.05 (1H, dd, J=11.0, 6.7
Hz), 8.28 (1H, d, J=4.3 Hz), 7.76-7.78 (3H, m), 7.65 (1H, t, J=7.6
Hz), 7.55 (2H, t, J=7.6 Hz), 4.62-4.75 (1H, m), 3.62-3.86 (4H, m),
3.40-3.57 (2H, m), 3.33-3.30 (1H, m), 3.15-3.27 (2H, m), 1.85-2.34
(5H, m), 1.51-1.60 (2H, m), 1.10-1.24 (2H, m). MS (ESI) m/z: 434
[M+H].sup.+.
Example 152:
rac-1-(3-((5-benzoyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)pyrrolidin-1-y-
l)-3-methoxypropan-1-one (I-229)
[0580] Acylation of Compound I-227 provided
rac-1-(3-((5-benzoyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)pyrrolidin-1-y-
l)-3-methoxypropan-1-one (I-229). .sup.1H-NMR (DMSO-d.sub.6)
.delta.: 12.73 (1H, br s), 9.05 (1H, dd, J=14.3, 6.4 Hz), 8.28 (1H,
d, J=1.8 Hz), 7.77-7.79 (3H, m), 7.65 (1H, t, J=7.6 Hz), 7.55 (2H,
t, J=7.6 Hz), 4.61-4.76 (1H, m), 3.90 (0.5H, dd, J=10.4, 6.1 Hz),
3.65-3.73 (1.5H, m), 3.45-3.57 (4H, m), 3.35-3.39 (1H, m), 3.20
(1.5H, s), 3.18 (1.5H, s), 2.46-2.54 (2H, m), 2.21-2.38 (1H, m),
1.90-2.09 (1H, m). MS (ESI) m/z: 394 [M+H].sup.+.
General Procedure D
##STR00734##
[0582] To a solution of pyrrolo[2,3-d]pyrimidine (8-A)(1 eq.) in
DMF (1 mL/0.28 mmol) at room temperature was added potassium
carbonate (2 eq.) and SEM-Cl (1.2 eq.). The reaction mixture was
stirred at room temperature for 3 hours. The reaction mixture was
then poured into 1:1 water/EtOAc and partitioned. The aqueous layer
was extracted with EtOAc. The combined organic layers were washed
with brine, dried over MgSO.sub.4, filtered and concentrated to
dryness. The residue was purified by flash chromatography on silica
gel eluting with 30-100% EtOAc/hexanes to afford the product.
General Procedure E
##STR00735##
[0584] A suspension of the arylnitro compound (9-A) (1 eq.),
ammonium chloride (10 eq. and iron (5 eq) in EtOH (1 mL/0.12 mmol)
and water (1 mL/0.25 mmol) was heated to 80.degree. C. for 2 hours.
Upon cooling to room temperature, methanol was added, the reaction
mixture was vigorously stirred for 30 min, filtered through Celite
and washed with methanol and EtOAc. The filtrate was concentrated
to dryness. The residue was triturated in water and the solids were
collected by filtration, dried under high vacuum to afford the
corresponding arylamine.
General Procedure F
##STR00736##
[0586] To a solution of the arylamine (10-A) (1 eq.) in DMF (2
mL/0.16 mmol) were added carboxylic acid (1.5 eq.), HATU (1.2 eq.)
and DIPEA (2.5 eq.) and the reaction mixture was allowed to stir at
room temperature for 18 hours or heated to 40-50.degree. C. for
3-90 hours. Upon cooling to room temperature, the reaction mixture
diluted with aqueous saturated NaHCO.sub.3 and ethyl acetate. The
layers were partitioned and the aqueous layer was extracted with
ethyl acetate. The combined organic layer were washed with brine,
dried over magnesium sulfate, filtered and concentrated to dryness
under reduced pressure. The crude product was adsorbed onto silica
gel for purification by ISCO CombiFlash (eluted with 0-10% MeOH/DCM
or EtOAc/hexanes) or purified by reverse phase C18 column
chromatography (10-95% acetonitrile in water, 0.1% formic acid) to
yield the amide product (11-A).
General Procedure G
##STR00737##
[0588] To a solution of the arylamine (1 eq.) in THF (2 mL/0.343
mmol) were added isocyanate (1.2 eq.) and DIPEA (2.5 eq.). The
reaction mixture was allowed to stir at room temperature for 18
hours. The volatiles were removed under reduced pressure and the
residue was adsorbed in silica gel purification by ISCO CombiFlash
eluting with EtOAc/hexanes to yield the urea product.
General Procedure H
##STR00738##
[0590] To a solution of SEM-protected substrate (8-A) (1 eq.) in
DCM (1 mL/0.044 mmol) was added a solution of HCl (4 N in dioxane,
60-81 eq.). The mixture was heated to 40.degree. C. for 18 hours
and concentrated to dryness under reduced pressure. The residue was
diluted with 10 mL of DCM/MeOH/NH.sub.4OH (90:9:1) and adsorbed
onto silica gel for purification by flash chromatography on silica
gel eluting with MeOH/DCM (9:1) and DCM/MeOH/NH.sub.4OH (90:9:1) to
yield the deprotected product.
Example 153: Synthesis of
N-(4-chloro-3-(4-(((3R,6S)-6-(hydroxymethyl)
tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)ph-
enyl)benzamide (I-601)
[0591]
N-(4-Chloro-3-(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-y-
l)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)phenyl)benzamide
was synthesized according to General Scheme 4, General Procedures
A, D, E, F, H. .sup.1H NMR (DMSO-d.sub.6, 400 mHz): .delta. 12.79
(s; 1H); 10.50 (s; 1H); 8.59 (d; J 7.06 Hz; 1H); 8.26 (s; 1H); 8.01
(d; J 2.53 Hz; 1H); 7.93-7.97 (m; 3H); 7.53-7.63 (m; 5H); 4.66 (t;
J 5.58 Hz; 1H); 4.14-4.19 (m; 2H); 3.34-3.44 (m; 3H); 3.14 (t; J
11.24 Hz; 1H); 2.18-2.22 (m; 1H); 1.77-1.81 (m; 1H); 1.57-1.61 (m;
1H); 1.37-1.43 (m; 1H). LCMS [M+H].sup.+: 506.2
Example 154: Synthesis of
N-(4-chloro-3-(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amin-
o)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)phenyl)-2-phenylacetamide
(I-602)
[0592]
N-(4-Chloro-3-(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-y-
l)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)phenyl)-2-phenylacetamide
was synthesized according to General Scheme 4, General Procedures
A, D, E, F, H. .sup.1H NMR (DMSO-d.sub.6, 400 mHz): .delta. 12.75
(s; 1H); 10.46 (s; 1H); 8.56 (d; J=7.05 Hz; 1H); 8.25 (s; 1H); 7.81
(d; J=2.54 Hz; 1H); 7.70 (dd; J=8.80; 2.56 Hz; 1H); 7.58 (s; 1H);
7.52 (d; J=8.78 Hz; 1H); 7.32 (d; J=4.37 Hz; 4H); 7.23-7.26 (m;
1H); 4.66 (t; J=5.15 Hz; 1H); 4.12-4.18 (m; 2H); 3.65 (s; 2H);
3.34-3.41 (m; 3H); 3.12 (t; J=11.05 Hz; 1H); 2.17-2.21 (m; 1H);
1.76-1.80 (m; 1H); 1.56-1.60 (m; 1H); 1.36-1.42 (m; 1H). LCMS
[M+H].sup.+: 520.2.
Example 155: Synthesis of
N-(4-chloro-3-(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amin-
o)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)phenyl)tetrahydro-2H-pyran-4-car-
boxamide (I-603)
[0593]
N-(4-Chloro-3-(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-y-
l)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)phenyl)tetrahydro-2H-pyran-
-4-carboxamide was synthesized according to General Scheme 4,
General Procedures A, D, E, F, H. .sup.1H NMR (DMSO-d.sub.6, 400
mHz): .delta. 10.22 (s; 1H); 8.56-8.58 (m; 1H); 8.24 (s; 1H); 7.83
(d; J=2.52 Hz; 1H); 7.71 (dd; J=8.79; 2.55 Hz; 1H); 7.56 (s; 1H);
7.50 (d; J=8.77 Hz; 1H); 4.60-4.71 (m; 1H); 4.10-4.18 (m; 2H);
3.88-3.92 (m; 2H); 3.36-3.41 (m; 5H); 3.09-3.16 (m; 1H); 2.52-2.63
(m; 1H); 2.16-2.21 (m; 1H); 1.54-1.77 (m; 6H); 1.33-1.43 (m; 1H).
NH of indole not observed. 0.2 equiv. of formic acid (8.36 ppm)
observed. LCMS [M+H].sup.+: 514.2.
Example 156: Synthesis of
N-(4-chloro-3-(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amin-
o)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)phenyl)thiazole-5-carboxamide
(I-604)
[0594]
N-(4-Chloro-3-(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-y-
l)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)phenyl)thiazole-5-carboxam-
ide was synthesized according to General Scheme 4, General
Procedures A, D, E, F, H. .sup.1H NMR (DMSO-d.sub.6, 400 mHz):
.delta. 12.83 (s; 1H); 10.71 (s; 1H); 9.33 (s; 1H); 8.70 (s; 1H);
8.61 (d; J=6.93 Hz; 1H); 8.27 (s; 1H); 7.92 (d; J=2.53 Hz; 1H);
7.89 (dd; J=8.75; 2.59 Hz; 1H); 7.64 (s; 1H); 7.61 (d; J=8.73 Hz;
1H); 4.13-4.19 (m; 2H); 3.39-3.46 (m; 5H); 3.14 (t; J=11.03 Hz;
1H); 2.18-2.22 (m; 1H); 1.76-1.80 (m; 1H); 1.57-1.63 (m; 1H);
1.37-1.43 (m; 1H). OH of alcohol not observed. LCMS [M+H].sup.+:
513.1.
Example 157: Synthesis of
N-(4-chloro-3-(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amin-
o)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)phenyl)-1-phenylcyclopropane-1-c-
arboxamide (I-605)
[0595]
N-(4-Chloro-3-(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-y-
l)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)phenyl)-1-phenylcyclopropa-
ne-1-carboxamide was synthesized according to General Scheme 4,
General Procedures A, D, E, F, H. .sup.1H NMR (DMSO-d.sub.6, 400
mHz): .delta. 12.75 (s; 1H); 9.32 (s; 1H); 8.55 (d; J=7.12 Hz; 1H);
8.24 (s; 1H); 7.74-7.76 (m; 2H); 7.55 (s; 1H); 7.47-7.49 (m; 1H);
7.33-7.40 (m; 4H); 7.26-7.30 (m; 1H); 4.65 (t; J=5.58 Hz; 1H);
4.12-4.16 (m; 2H); 3.36-3.44 (m; 3H); 3.11 (t; J=11.35 Hz; 1H);
2.16-2.20 (m; 1H); 1.76-1.80 (m; 1H); 1.54-1.58 (m; 1H); 1.37-1.47
(m; 3H); 1.10-1.13 (m; 2H). LCMS [M+H].sup.+: 546.2.
Example 158: Synthesis of
N-(4-chloro-3-(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amin-
o)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)phenyl)-5,6,7,8-tetrahydroisoqui-
noline-3-carboxamide (I-606)
[0596]
N-(4-Chloro-3-(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-y-
l)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)phenyl)-5,6,7,8-tetrahydro-
isoquinoline-3-carboxamide was synthesized according to General
Scheme 4, General Procedures A, D, E, F, H. .sup.1H NMR
(DMSO-d.sub.6, 400 mHz): .delta. 12.79 (s; 1H); 10.88 (s; 1H); 8.61
(d; J=7.06 Hz; 1H); 8.41 (s; 1H); 8.26 (s; 1H); 8.11-8.15 (m; 2H);
7.85 (s; 1H); 7.63 (s; 1H); 7.57 (d; J=8.58 Hz; 1H); 4.66 (t;
J=5.51 Hz; 1H); 4.14-4.19 (m; 2H); 3.35-3.42 (m; 3H); 3.14 (t;
J=11.12 Hz; 1H); 2.81-2.83 (m; 4H); 2.18-2.22 (m; 1H); 1.76-1.80
(m; 5H); 1.57-1.63 (m; 1H); 1.37-1.41 (m; 1H). LCMS [M+H].sup.+:
561.3.
Example 159: Synthesis of
N-(4-chloro-3-(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amin-
o)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)phenyl)isoquinoline-1-carboxamid-
e (I-607)
[0597]
N-(4-Chloro-3-(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-y-
l)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)phenyl)isoquinoline-1-carb-
oxamide was synthesized according to General Scheme 4, General
Procedures A, D, E, F, H. .sup.1H NMR (DMSO-d.sub.6, 400 mHz):
.delta. 12.86 (s; 1H); 11.19 (s; 1H); 8.92 (d; J=8.63 Hz; 1H); 8.71
(d; J=5.58 Hz; 1H); 8.67 (d; J=7.07 Hz; 1H); 8.33 (s; 1H); 8.21 (d;
J=2.55 Hz; 1H); 8.18 (s; 1H); 8.16 (d; J=2.20 Hz; 1H); 8.12 (dd;
J=8.80; 2.56 Hz; 1H); 7.93 (t; J=7.59 Hz; 1H); 7.83 (t; J=7.81 Hz;
1H); 7.74 (s; 1H); 7.69 (d; J=8.78 Hz; 1H); 4.73 (t; J=5.52 Hz;
1H); 4.20-4.26 (m; 2H); 3.41-3.51 (m; 3H); 3.21 (t; J=11.10 Hz;
1H); 2.25-2.29 (m; 1H); 1.83-1.87 (m; 1H); 1.65-1.69 (m; 1H);
1.44-1.50 (m; 1H). LCMS [M+H].sup.+: 557.2.
Example 160: Synthesis of
1-(4-chloro-3-(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amin-
o)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)phenyl)-3-phenylurea
(I-608)
[0598]
1-(4-Chloro-3-(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-y-
l)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)phenyl)-3-phenylurea
was synthesized according to General Scheme 4, General Procedures
A, D, E, F, G. .sup.1H NMR (DMSO-d.sub.6, 400 mHz): .delta. 12.74
(br s; 1H); 9.38 (s; 1H); 9.19 (s; 1H); 8.60 (d; J=7.05 Hz; 1H);
8.25 (s; 1H); 7.70 (d; J=2.59 Hz; 1H); 7.57-7.60 (m; 2H); 7.44-7.48
(m; 3H); 7.24-7.28 (m; 2H); 6.96 (t; J=7.37 Hz; 1H); 4.66 (t;
J=5.36 Hz; 1H); 4.12-4.19 (m; 2H); 3.35-3.42 (m; 3H); 3.11-3.17 (m;
1H); 2.17-2.22 (m; 1H); 1.76-1.80 (m; 1H); 1.53-1.64 (m; 1H);
1.32-1.43 (m; 1H). Contained 0.2 equiv. of formic acid. LCMS
[M+H].sup.+: 521.1.
Example 161: Synthesis of
1-(4-chloro-3-(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amin-
o)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)phenyl)-3-(pyridin-3-yl)urea
(I-609)
[0599]
1-(4-Chloro-3-(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-y-
l)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)phenyl)-3-(pyridin-3-yl)ur-
ea was synthesized according to General Scheme 4, General
Procedures A, D, E, F, G. .sup.1H NMR (DMSO-d.sub.6, 400 mHz):
.delta. 12.76 (br s; 1H); 9.56 (s; 1H); 9.44 (s; 1H); 8.59-8.62 (m;
2H); 8.25 (s; 1H); 8.18 (dd; J=4.67; 1.43 Hz; 1H); 7.92 (ddd;
J=8.36; 2.58; 1.46 Hz; 1H); 7.70 (d; J=2.59 Hz; 1H); 7.59-7.62 (m;
2H); 7.49 (d; J=8.77 Hz; 1H); 7.30 (dd; J=8.34; 4.67 Hz; 1H); 4.66
(s; 1H); 4.12-4.19 (m; 2H); 3.37-3.45 (m; 3H); 3.10-3.16 (m; 1H);
2.18-2.22 (m; 1H); 1.77-1.81 (m; 1H); 1.54-1.64 (m; 1H); 1.33-1.43
(m; 1H). LCMS [M+H].sup.+: 522.2.
Example 162: Synthesis of
3-chloro-4-(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)--
7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-N-phenylbenzamide
(I-236)
[0600]
3-Chloro-4-(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)a-
mino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-N-phenylbenzamide was
synthesized according to General Scheme 5, using aniline as the
amine. .sup.1H NMR (DMSO-d.sub.6, 400 mHz): .delta. 12.80 (br s;
1H); 10.45 (s; 1H); 8.56 (d; J=7.03 Hz; 1H); 8.27 (s; 1H); 8.17 (d;
J=1.53 Hz; 1H); 8.04 (dd; J=7.92; 1.59 Hz; 1H); 7.79 (d; J=8.03 Hz;
2H); 7.74 (d; J=7.89 Hz; 1H); 7.59 (s; 1H); 7.39 (t; J=7.77 Hz;
2H); 7.12-7.16 (m; 1H); 4.66 (t; J=5.42 Hz; 1H); 4.08-4.17 (m; 2H);
3.40-3.49 (m; 3H); 3.11-3.18 (m; 1H); 2.17-2.22 (m; 1H); 1.78-1.88
(m; 1H); 1.52-1.65 (m; 1H); 1.32-1.45 (m; 1H). LCMS [M+H].sup.+:
506.2.
Example 163: Synthesis of
3-chloro-4-(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)--
7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-N-(2-methoxyethyl)
benzamide (I-610)
[0601]
3-Chloro-4-(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)a-
mino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-N-(2-methoxyethyl)benzamide
was synthesized according to General Scheme 5 using
2-methoxyethylamine. .sup.1H NMR (DMSO-d.sub.6, 400 mHz): .delta.
12.78 (s; 1H); 8.78-8.80 (m; 1H); 8.55 (d; J=7.09 Hz; 1H); 8.26 (s;
1H); 8.05 (d; J=1.51 Hz; 1H); 7.93 (dd; J=7.92; 1.56 Hz; 1H); 7.66
(d; J=7.91 Hz; 1H); 7.58 (s; 1H); 4.66 (t; J=5.57 Hz; 1H);
4.15-4.17 (m; 2H); 3.35-3.50 (m; 7H); 3.28 (s; 3H); 3.13 (t;
J=11.33 Hz; 1H); 2.18 (s; 1H); 1.78 (d; J=12.89 Hz; 1H); 1.58 (d;
J=12.92 Hz; 1H); 1.38 (d; J=13.18 Hz; 1H). LCMS [M+H].sup.+:
488.2.
Example 164: Synthesis of
(3-chloro-4-(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-
-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)phenyl)(morpholino)
methanone (I-611)
[0602]
(3-Chloro-4-(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)-
amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)phenyl)(morpholino)methanone
was synthesized according to General Scheme 5, using morpholine as
the amine. .sup.1H NMR (DMSO-d.sub.6, 400 mHz): .delta. 12.80 (s;
1H); 8.56 (d; J=7.11 Hz; 1H); 8.26 (s; 1H); 7.66 (s; 1H); 7.63 (s;
1H); 7.62 (d; J=6.31 Hz; 1H); 7.46 (dd; J=7.74; 1.45 Hz; 1H); 4.66
(t; J=5.58 Hz; 1H); 4.16 (d; J=9.36 Hz; 2H); 3.58-3.69 (m; 6H);
3.34-3.44 (m; 5H); 3.13 (t; J=11.37 Hz; 1H); 2.17-2.20 (m; 1H);
1.77-1.81 (m; 1H); 1.55-1.59 (m; 1H); 1.36-1.39 (m; 1H). LCMS
[M+H].sup.+: 500.2.
Example 165: Synthesis of
(4-chloro-3-(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-
-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)phenyl)(morpholino)
methanone (I-612)
[0603]
(4-Chloro-3-(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)-
amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)phenyl)(morpholino)methanone
was synthesized according to General Scheme 5, using morpholine as
the amine. .sup.1H NMR (DMSO-d.sub.6, 400 mHz): .delta. 12.77 (br
s; 1H); 8.55 (d; J=7.06 Hz; 1H); 8.25 (s; 1H); 7.57-7.69 (m; 4H);
4.66 (s; 1H); 4.16 (m; 2H); 3.32-3.57 (m; 11H); 3.12 (t; J=11.26
Hz; 1H); 2.19 (d; J=11.57 Hz; 1H); 1.76-1.79 (m; 1H); 1.52-1.61 (m;
1H); 1.38 (q; J=11.99 Hz; 1H). LCMS [M+H].sup.+: 500.2, 502.2.
Example 166: Synthesis of
3-chloro-4-(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)--
7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-N-(2-morpholinoethyl)
benzamide (I-613)
[0604]
3-Chloro-4-(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)a-
mino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-N-(2-morpholinoethyl)benzami-
de was synthesized according to General Scheme 5, using
2-morpholinoethan-1-amine. .sup.1H NMR (DMSO-d.sub.6, 400 mHz):
.delta. 12.78 (s; 1H); 8.67-8.70 (m, 1H); 8.55 (d; J 7.05 Hz; 1H);
8.26 (s; 1H); 8.02 (d; J 1.52 Hz; 1H); 7.90 (dd; J=7.94; 1.56 Hz;
1H); 7.66 (d; J=7.91 Hz; 1H); 7.55 (s; 1H); 4.66 (t; J 5.58 Hz;
1H); 4.14-4.18 (m; 2H); 3.58 (t; J 4.51 Hz; 4H); 3.34-3.45 (m; 6H);
3.13 (t; J=11.30 Hz; 1H); 2.39-2.46 (m; 5H); 2.16-2.21 (m; 1H);
1.77-1.80 (m; 1H); 1.55-1.59 (m; 1H); 1.36-1.41 (m; 1H). LCMS
[M+H].sup.+: 543.3.
Example 167: Synthesis of
3-chloro-N-(3-cyanophenyl)-4-(4-(((3R,6S)-6-(hydroxymethyl)
tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)be-
nzamide (I-614)
[0605]
3-Chloro-N-(3-cyanophenyl)-4-(4-(((3R,6S)-6-(hydroxymethyl)tetrahyd-
ro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)benzamide
was synthesized according to General Scheme 5, using
3-aminobenzonitrile. .sup.1H NMR (DMSO-d.sub.6, 400 mHz): .delta.
12.74-12.89 (bs; 1H); 10.76 (s; 1H); 8.55 (d; J 7.05 Hz; 1H);
8.26-8.28 (m; 2H); 8.18 (d; J 1.57 Hz; 1H); 8.03-8.08 (m; 2H); 7.76
(d; J 7.91 Hz; 1H); 7.62 (d; J 4.90 Hz; 2H); 7.59 (s; 1H);
4.64-4.67 (m; 1H); 4.15-4.19 (m; 2H); 3.35-3.44 (m; 3H); 3.10-3.16
(m; 1H); 2.15-2.22 (m; 1H); 1.76-1.81 (m; 1H); 1.52-1.64 (m; 1H);
1.33-1.44 (m; 1H). LCMS [M+H].sup.+: 531.2.
Example 168: Synthesis of
3-chloro-4-(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)--
7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-N-(pyridin-3-yl)benzamide
(I-256)
[0606]
3-Chloro-4-(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)a-
mino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-N-(pyridin-3-yl)benzamide
was synthesized according to General Scheme 5, using
pyridine-3-amine. .sup.1H NMR (DMSO-d.sub.6, 400 mHz): .delta.
12.79 (br s; 1H); 10.66 (s; 1H); 8.95 (s; 1H); 8.55 (d; J=7.01 Hz;
1H); 8.36 (dd; J=4.66; 1.81 Hz; 1H); 8.27 (s; 1H); 8.19-8.22 (m;
2H); 8.03-8.06 (m; 1H); 7.75-7.78 (m; 1H); 7.60 (s; 1H); 7.43 (dd;
J=8.30; 4.69 Hz; 1H); 4.66 (t; J=5.50 Hz; 1H); 4.11-4.29 (m; 2H);
3.33-3.42 (m; 3H); 3.10-3.17 (m; 1H); 2.16-2.23 (m; 1H); 1.76-1.81
(m; 1H); 1.54-1.64 (m; 1H); 1.33-1.44 (m; 1H). LCMS [M+H].sup.+:
507.2.
Example 169: Synthesis of
(2-chloro-4-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)(4-(((3R,6S-
)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimi-
din-5-yl)methanone (I-615)
[0607]
(2-Chloro-4-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)(4-((-
(3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]-
pyrimidin-5-yl)methanone was synthesized according to General
Scheme 5, using 1,2,3,4-tetrahydroisoquinoline. .sup.1H NMR
(DMSO-d.sub.6, 400 mHz): .delta. 8.57-8.59 (m; 1H); 8.24-8.26 (m;
1H); 7.63-7.70 (m; 3H); 7.49-7.53 (m; 1H); 7.10-7.29 (m; 4H);
4.78-4.79 (m; 1H); 4.62-4.67 (m; 2H); 4.13-4.19 (m; 2H); 3.82-3.89
(m; 1H); 3.61-3.64 (m; 1H); 3.40-3.44 (m; 3H); 3.10-3.16 (m; 1H);
2.85-2.91 (m; 2H); 2.16-2.21 (m; 1H); 1.77-1.80 (m; 1H); 1.53-1.60
(m; 1H); 1.36-1.44 (m; 1H). NH of indole not observed. LCMS
[M+H].sup.+: 546.02.
Example 170: Synthesis of
(3-chloro-4-(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-
-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)phenyl)(4-(pyridin-2-yl)piperazin--
1-yl)methanone (I-616)
[0608]
(3-Chloro-4-(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)-
amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)phenyl)(4-(pyridin-2-yl)pipe-
razin-1-yl)methanone was synthesized according to General Scheme 5,
using 1-(pyridin-2-yl)piperazine. .sup.1H NMR (DMSO-d.sub.6, 400
mHz): .delta. 12.82 (s; 1H); 8.57 (d; J=7.09 Hz; 1H); 8.27 (s; 1H);
8.13-8.14 (m; 1H); 7.68 (s; 1H); 7.66 (d; J=1.43 Hz; 1H); 7.64 (d;
J=7.72 Hz; 1H); 7.55-7.59 (m; 1H); 7.50 (dd; J=7.75; 1.44 Hz; 1H);
6.87 (d; J=8.63 Hz; 1H); 6.68 (dd; J=7.05; 4.93 Hz; 1H); 4.66 (t;
J=5.58 Hz; 1H); 4.12-4.19 (m; 2H); 3.44-3.78 (m; 8H); 3.34-3.42 (m;
3H); 3.13 (t; J=11.28 Hz; 1H); 2.18-2.22 (m; 1H); 1.76-1.80 (m;
1H); 1.56-1.60 (m; 1H); 1.37-1.43 (m; 1H). LCMS [M+H].sup.+:
576.3.
Example 171: Synthesis of
(3-chloro-4-(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-
-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)phenyl)(piperidin-1-yl)methanone
(I-617)
[0609]
(3-Chloro-4-(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)-
amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)phenyl)(piperidin-1-yl)metha-
none was synthesized according to General Scheme 5, using
piperidine. .sup.1H NMR (DMSO-d.sub.6, 400 mHz): .delta. 12.79 (s;
1H); 8.57 (d; J=7.10 Hz; 1H); 8.26 (s; 1H); 7.67 (s; 1H); 7.61 (d;
J=7.73 Hz; 1H); 7.57 (d; J=1.40 Hz; 1H); 7.42 (dd; J=7.73; 1.46 Hz;
1H); 4.66 (t; J=5.59 Hz; 1H); 4.12-4.17 (m; 2H); 3.53-3.63 (m; 2H);
3.34-3.44 (m; 5H); 3.13 (t; J=11.27 Hz; 1H); 2.17-2.21 (m; 1H);
1.77-1.81 (m; 1H); 1.49-1.62 (m; 7H); 1.36-1.42 (m; 1H). LCMS
[M+H].sup.+: 498.2.
Example 172: Synthesis of
N-benzyl-3-chloro-4-(4-(((3R,6S)-6-(hydroxymethyl)
tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)be-
nzamide (I-618)
[0610]
N-Benzyl-3-chloro-4-(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyr-
an-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)benzamide was
synthesized according to General Scheme 5, using benzylamine.
.sup.1H NMR (DMSO-d.sub.6, 400 mHz): .delta. 12.80 (s; 1H); 9.30
(t; J=5.94 Hz; 1H); 8.55 (d; J=7.09 Hz; 1H); 8.26 (s; 1H); 8.09 (d;
J=1.52 Hz; 1H); 7.97 (dd; J=7.93; 1.56 Hz; 1H); 7.68 (d; J=7.91 Hz;
1H); 7.59 (s; 1H); 7.34-7.35 (m; 4H); 7.25-7.28 (m; 1H); 4.66 (t;
J=5.58 Hz; 1H); 4.52 (d; J=5.87 Hz; 2H); 4.16 (d; J=9.29 Hz; 2H);
3.36-3.44 (m; 3H); 3.13 (t; J=11.36 Hz; 1H); 2.17-2.21 (m; 1H);
1.76-1.80 (m; 1H); 1.56-1.60 (m; 1H); 1.35-1.41 (m; 1H). LCMS
[M+H].sup.+: 520.2.
Example 173: Synthesis of
3-chloro-4-(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)--
7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-N-(1-methyl-1H-pyrazol-4-yl)benzam-
ide (I-619)
[0611]
3-Chloro-4-(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)a-
mino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-N-(1-methyl-1H-pyrazol-4-yl)-
benzamide was synthesized according to General Scheme 5, using
1-methyl-1H-pyrazol-4-amine. .sup.1H NMR (DMSO-d.sub.6, 400 mHz):
.delta. 10.67 (s; 1H); 8.56 (d; J=7.08 Hz; 1H); 8.26 (s; 1H); 8.14
(d; J=1.56 Hz; 1H); 8.07 (s; 1H); 8.02 (dd; J=7.93; 1.59 Hz; 1H);
7.73 (d; J=7.93 Hz; 1H); 7.60 (s; 2H); 4.66 (t; J=5.47 Hz; 1H);
4.15-4.19 (m; 2H); 3.84 (s; 3H); 3.35-3.43 (m; 3H); 3.10-3.17 (m;
1H); 2.17-2.22 (m; 1H); 1.76-1.81 (m; 1H); 1.55-1.61 (m; 1H);
1.36-1.43 (m; 1H), NH of indole not observed. LCMS [M+H].sup.+:
510.2.
Example 174: Synthesis of
3-chloro-4-(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)--
7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-N-(pyridin-4-yl)benzamide
(I-246)
[0612]
3-Chloro-4-(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)a-
mino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-N-(pyridin-4-yl)benzamide
was synthesized according to General Scheme 5, using
pyridine-4-amine. .sup.1H NMR (DMSO-d.sub.6, 400 mHz): .delta.
10.83 (s; 1H); 8.55 (d; J=7.11 Hz; 1H); 8.52 (dd; J=5.29; 1.46 Hz;
2H); 8.26 (s; 1H); 8.18 (d; J=1.57 Hz; 1H); 8.04 (dd; J=7.91; 1.60
Hz; 1H); 7.81 (dd; J=5.19; 1.53 Hz; 2H); 7.76 (d; J=7.91 Hz; 1H);
7.57 (s; 1H); 4.15-4.19 (m; 2H); 3.36-3.44 (m; 3H); 3.10-3.16 (m;
1H); 2.18-2.22 (m; 1H); 1.77-1.81 (m; 1H); 1.56-1.60 (m; 1H);
1.37-1.43 (m; 1H). NH of indole and OH not observed. Contained
formic acid at 8.38 ppm (0.4 eq.). LCMS [M+H].sup.+: 507.2.
Example 175: Synthesis of
(3-chloro-4-(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-
-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)phenyl)(4-methylpiperazin-1-yl)met-
hanone (I-620)
[0613]
(3-Chloro-4-(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)-
amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)phenyl)(4-methylpiperazin-1--
yl)methanone was synthesized according to General Scheme 5, using
1-methylpiperazine. .sup.1H NMR (DMSO-d.sub.6, 400 mHz): .delta.
12.79 (s; 1H); 8.56 (d; J=7.10 Hz; 1H); 8.26 (s; 1H); 7.67 (s; 1H);
7.58-7.61 (m; 2H); 7.43 (dd; J=7.73; 1.47 Hz; 1H); 4.65 (t; J=5.58
Hz; 1H); 4.12-4.17 (m; 2H); 3.56-3.66 (m; 2H); 3.33-3.45 (m; 5H);
3.13 (t; J=11.35 Hz; 1H); 2.28-2.39 (m; 4H); 2.21 (s; 3H);
2.17-2.19 (m; 1H); 1.77-1.80 (m; 1H); 1.56-1.60 (m; 1H); 1.36-1.42
(m; 1H). LCMS [M+H].sup.+: 514.3.
Example 176: Synthesis of
3-chloro-4-(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)--
7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-N-(2-oxaspiro[3.3]heptan-6-yl)benz-
amide (I-621)
[0614]
3-Chloro-4-(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)a-
mino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-N-(2-oxaspiro[3.3]heptan-6-y-
l)benzamide was synthesized according to General Scheme 5, using
2-oxa-6-azaspiro[3.3]heptane. .sup.1H NMR (DMSO-d.sub.6, 400 mHz):
.delta. 12.78 (s; 1H); 8.81 (d; J=7.16 Hz; 1H); 8.55 (d; J=7.05 Hz;
1H); 8.26 (s; 1H); 8.02 (d; J=1.52 Hz; 1H); 7.90 (dd; J=7.94; 1.56
Hz; 1H); 7.66 (d; J=7.91 Hz; 1H); 7.55 (s; 1H); 4.63-4.66 (m; 3H);
4.52 (s; 2H); 4.21-4.27 (m; 1H); 4.14-4.18 (m; 2H); 3.33-3.43 (m; 3
H); 3.12 (t; J=11.30 Hz; 1H); 2.57-2.62 (m; 2H); 2.26 (t; J=10.09
Hz; 2H); 2.16-2.21 (m; 1H); 1.77-1.80 (m; 1H); 1.55-1.59 (m; 1H);
1.36-1.41 (m; 1H). LCMS [M+H].sup.+: 526.3.
Example 177: Synthesis of
(4-chloro-3-(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-
-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)phenyl)(4-methylpiperazin-1-yl)met-
hanone (I-622)
[0615]
(4-Chloro-3-(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)-
amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)phenyl)(4-methylpiperazin-1--
yl)methanone was prepared according to General Scheme 5, using
1-methylpiperazine. .sup.1H NMR (DMSO-d.sub.6, 400 mHz): .delta.
8.53 (d; J=7.11 Hz; 1H); 8.28 (s; 1.3H); 8.24 (s; 1H); 7.65 (d;
J=8.84 Hz; 1H); 7.60 (s; 1H); 7.53 (m; 2H); 4.14 (m; 2H); 3.57 (br
s; 2H); 3.32-3.42 (m; 5H); 3.10 (t; J=11.34 Hz; 1H); 2.29 (br s;
6H); 2.16 (s; 3H); 1.77 (d; J=13.06 Hz; 1H); 1.51-1.58 (m; 1H);
1.32-1.40 (m; 1H). LCMS [M+H].sup.+: 513.3, 515.3.
Example 178: Synthesis of
(4-chloro-3-(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-
-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)phenyl)(piperidin-1-yl)methanone
(I-623)
[0616]
(4-Chloro-3-(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)-
amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)phenyl)(piperidin-1-yl)metha-
none was prepared according to General Scheme 5, using piperidine.
.sup.1H NMR (DMSO-d.sub.6, 400 mHz): .delta. 8.55 (d; J=7.12 Hz;
1H); 8.35 (s; 0.3H); 8.25 (s; 1H); 7.66 (d; J=8.77 Hz; 1H); 7.59
(s; 1H); 7.52-7.54 (m; 2H); 4.66 (br s; 1H); 4.16 (m; 2H); 3.8 (m,
2H); 3.6 (m, 6H); 3.12 (t; J=11.31 Hz; 1H); 2.19 (d; J=11.68 Hz;
1H); 1.78 (d; J=13.20 Hz; 1H); 1.59 (br s; 8H). LCMS [M+H].sup.+:
498.3, 500.3.
Example 179: Synthesis of
4-chloro-3-(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)--
7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-N-(2-methoxyethyl)
benzamide (I-624)
[0617]
4-Chloro-3-(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)a-
mino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-N-(2-methoxyethyl)benzamide
was prepared according to General Scheme 5, using
2-methoxyethan-1-amine. .sup.1H NMR (DMSO-d.sub.6, 400 mHz):
.delta. 8.67 (s; 1H); 8.56 (d; J=7.05 Hz; 1H); 8.35 (s; 0.1H); 8.26
(s; 1H); 8.00-8.02 (m; 2H); 7.70 (d; J=9.04 Hz; 1H); 7.61 (s; 1H);
4.66 (s; 1H); 4.16 (m; 2H); 3.40-3.44 (m; 5H); 3.35 (m; 2H); 3.25
(s; 3H); 3.12 (t; J=11.56 Hz; 1H); 2.19 (s; 1H); 1.79 (d; J=13.13
Hz; 1H); 1.53-1.62 (m; 1H); 1.34-1.43 (m; 1H). LCMS [M+H].sup.+:
488.2, 490.2.
Example 180: Synthesis of
(4-chloro-3-(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-
-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)phenyl)(3,4-dihydroisoquinolin-2(1-
H)-yl)methanone (I-625)
[0618]
(4-Chloro-3-(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)-
amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)phenyl)(3,4-dihydroisoquinol-
in-2(1H)-yl)methanone was prepared according to General Scheme 5,
using 1,2,3,4-tetrahydroisoquinoline. .sup.1H NMR (DMSO-d.sub.6,
400 mHz): .delta. 8.48 (d; J=7.03 Hz; 1H); 8.26 (s; 1.3H); 7.66 (d;
J=8.51 Hz; 1H); 7.58 (m; 3H); 7.19 (s; 4H); 4.72 (s; 2H); 4.20 (s;
2H); 3.74 (s; 2H); 3.43 (t; J=6.82 Hz; 1H); 3.35 (m; 2H); 3.14 (m;
2H); 2.85 (m; 2H); 2.20 (d; J=11.69 Hz; 1H); 1.79 (d; J=13.23 Hz;
1H); 1.52-1.61 (m; 1H); 1.42 (t; J=12.35 Hz; 1H). LCMS [M+H].sup.+:
546.3, 548.25.
Example 181: Synthesis of
4-chloro-3-(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)--
7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-N-(2-morpholinoethyl)
benzamide (I-626)
[0619]
4-Chloro-3-(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)a-
mino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-N-(2-morpholinoethyl)benzami-
de was prepared according to General Scheme 5, using
2-morpholinoethan-1-amine. .sup.1H NMR (DMSO-d.sub.6, 400 mHz):
.delta. 8.56 (d; J=6.97 Hz; 2H); 8.34 (s; 1H); 8.26 (s; 1.3H);
7.98-8.00 (m; 2H); 7.70 (d; J=8.96 Hz; 1H); 7.60 (s; 1H); 4.16 (d;
J=9.22 Hz; 2H); 3.55 (t; J=4.54 Hz; 4H); 3.33-3.43 (m; 6H); 3.12
(t; J=11.57 Hz; 1H); 2.44 (t; J=6.91 Hz; 2H); 2.39 (m; 4H); 2.19
(d; J=11.85 Hz; 1H); 1.79 (d; J=13.00 Hz; 1H); 1.53-1.59 (m; 1H);
1.34-1.40 (m; 1H). LCMS [M+H].sup.+: 543.3, 545.3.
Example 182: Synthesis of
(4-chloro-3-(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-
-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)phenyl)(4-(pyridin-2-yl)piperazin--
1-yl)methanone (I-627)
[0620]
(4-Chloro-3-(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)-
amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)phenyl)(4-(pyridin-2-yl)pipe-
razin-1-yl)methanone was prepared according to General Scheme 5,
using 1-(pyridin-2-yl)piperazine. .sup.1H NMR (DMSO-d.sub.6, 400
mHz): .delta. 8.55 (d; J=7.05 Hz; 1H); 8.34 (s; 0.4H); 8.25 (s;
1H); 8.12 (d; J=4.91 Hz; 1H); 7.52-7.69 (m; 5H); 6.84 (d; J=8.62
Hz; 1H); 6.66 (dd; J=7.09; 4.93 Hz; 1H); 4.15 (d; J=9.32 Hz; 2H);
3.34-3.57 (br m; 12H); 3.12 (t; J=11.30 Hz; 1H); 2.19 (d; J=11.63
Hz; 1H); 1.78 (d; J=13.12 Hz; 1H); 1.52-1.61 (m; 1H); 1.33-1.42 (m;
1H). LCMS [M+H].sup.+: 576.3, 578.3.
Example 183: Synthesis of
N-benzyl-4-chloro-3-(4-(((3R,6S)-6-(hydroxymethyl)
tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)be-
nzamide (I-628)
[0621]
N-Benzyl-4-chloro-3-(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyr-
an-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)benzamide was
prepared according to General Scheme 5, using benzylamine. .sup.1H
NMR (DMSO-d.sub.6, 400 mHz): .delta. 9.17 (t; J=5.91 Hz; 1H); 8.56
(d; J=7.05 Hz; 1H); 8.32 (s; 0.2H); 8.25 (s; 1H); 8.03-8.05 (m;
2H); 7.72 (d; J=8.45 Hz; 1H); 7.63 (s; 1H); 7.31 (d; J=4.43 Hz;
4H); 7.24 (d; J=5.57 Hz; 1H); 4.66 (br s; 1H); 4.47 (d; J=5.85 Hz;
2H); 4.15 (d; J=9.12 Hz; 2H); 3.33-3.41 (m; 3H); 3.12 (t; J=11.58
Hz; 1H); 2.19 (d; J=11.63 Hz; 1H); 1.78 (d; J=13.16 Hz; 1H); 1.56
(dd; J=14.28; 11.21 Hz; 1H); 1.34-1.40 (m; 1H). LCMS [M+H].sup.+:
520.2, 523.3.
Example 184: Synthesis of
4-chloro-3-(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)--
7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-N-(1-methyl-1H-pyrazol-4-yl)benzam-
ide (I-629)
[0622]
4-Chloro-3-(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)a-
mino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-N-(1-methyl-1H-pyrazol-4-yl)-
benzamide was prepared according to General Scheme 5, using
1-methyl-1H-pyrazol-4-amine. .sup.1H NMR (DMSO-d.sub.6, 400 mHz):
.delta. 12.85 (br s; 1H); 10.52 (s; 1H); 8.58 (d; J=7.03 Hz; 1H);
8.37 (s; 0.1H); 8.26 (s; 1H); 8.08-8.11 (m; 2H); 8.02 (s; 1H); 7.76
(d; J=8.20 Hz; 1H); 7.65 (s; 1H); 7.54 (s; 1H); 4.66 (s; 1H); 4.17
(d; J=9.13 Hz; 2H); 3.82 (s; 3H); 3.32-3.41 (m; 3H); 3.13 (t;
J=11.60 Hz; 1H); 2.20 (d; J=11.64 Hz; 1H); 1.79 (d; J=13.12 Hz;
1H); 1.53-1.62 (m; 1H); 1.39-1.41 (br m; 1H). LCMS [M+H].sup.+:
510.2, 512.2.
Example 185: Synthesis of
4-chloro-N-(3-cyanophenyl)-3-(4-(((3R,6S)-6-(hydroxymethyl)
tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)be-
nzamide (I-630)
[0623]
4-Chloro-N-(3-cyanophenyl)-3-(4-(((3R,6S)-6-(hydroxymethyl)tetrahyd-
ro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)benzamide
was prepared according to General Scheme 5, using
3-aminobenzonitrile. .sup.1H NMR (DMSO-d.sub.6, 400 mHz): .delta.
10.61 (s; 1H); 8.58 (d; J=7.05 Hz; 1H); 8.39 (s; 0.2H); 8.24 (m;
2H); 8.10-8.17 (m; 2H); 8.01-8.04 (m; 1H); 7.80 (m; 1H); 7.65 (s;
1H); 7.58 (m; 2H); 4.66 (s; 1H); 4.17 (d; J=9.29 Hz; 2H); 3.36-3.42
(m; 3H); 3.13 (t; J=11.56 Hz; 1H); 2.20 (d; J=11.65 Hz; 1H); 1.79
(d; J=13.07 Hz; 1H); 1.53-1.62 (m; 1H); 1.34-1.43 (m; 1H). LCMS
[M+H].sup.+: 531.2, 533.2.
Example 186: Synthesis of
4-chloro-3-(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)--
7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-N-phenylbenzamide
(I-631)
[0624]
4-Chloro-3-(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)a-
mino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-N-phenylbenzamide was
prepared according to General Scheme 5, using aniline. .sup.1H NMR
(DMSO-d.sub.6, 400 mHz): .delta. 10.31 (s; 1H); 8.59 (d; J=7.06 Hz;
1H); 8.41 (s; 0.2H); 8.26 (s; 1H); 8.09-8.16 (m; 2H); 7.76 (m; 3H);
7.64 (s; 1H); 7.35 (m; 2H); 7.11 (t; J=7.39 Hz; 1H); 4.66 (s; 1H);
4.17 (m; 2H); 3.33-3.41 (m; 3H); 3.13 (t; J=11.53 Hz; 1H); 2.20 (d;
J=11.72 Hz; 1H); 1.79 (d; J=11.57 Hz; 1H); 1.53-1.62 (m; 1H); 1.39
(q; J=12.08 Hz; 1H). LCMS [M+H].sup.+: 506.2, 508.2.
General Procedure I
[0625] General procedure for the saponification of a benzoic
ester
##STR00739##
[0626] The benzoic ester substrate (17-A) (1 eq.) were suspended in
THF (1 mL/0.2 mmol) and methanol (1 mL/0.2 mmol). A solution of 1N
lithium hydroxide was then added (2 eq.) and left to stir at room
temperature overnight. The reaction crude was neutralized with a 1N
aqueous solution of HCl and was concentrated to dryness. The crude
product was used as is without further purification.
Example 187: Synthesis of
(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[-
2,3-d]pyrimidin-5-yl)(4-(morpholine-4-carbonyl)phenyl) methanone
(I-632)
[0627]
(4-(((3R,6S)-6-(Hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-py-
rrolo[2,3-d]pyrimidin-5-yl)(4-(morpholine-4-carbonyl)phenyl)methanone
was synthesized according to General Scheme 6. .sup.1H NMR
(DMSO-d.sub.6, 400 mHz): .delta. 12.74 (s; 1H); 8.66 (d; J=7.13 Hz;
1H); 8.25 (s; 1H); 7.81-7.83 (m; 3H); 7.55 (d; J=7.88 Hz; 2H); 4.65
(t; J=5.51 Hz; 1H); 4.12-4.17 (m; 2H); 3.55-3.68 (m; 7H); 3.35-3.45
(m; 5H); 3.11 (t; J=11.26 Hz; 1H); 2.15-2.20 (m; 1H); 1.77-1.80 (m;
1H); 1.53-1.59 (m; 1H); 1.36-1.42 (m; 1H). LCMS [M+H].sup.+:
466.1.
Example 188: Synthesis of
4-(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrol-
o[2,3-d]pyrimidine-5-carbonyl)-N-(1-methyl-1H-pyrazol-4-yl)benzamide
(I-633)
[0628]
4-(4-(((3R,6S)-6-(Hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H--
pyrrolo[2,3-d]pyrimidine-5-carbonyl)-N-(1-methyl-1H-pyrazol-4-yl)benzamide
was synthesized according to General Scheme 6. .sup.1H NMR
(DMSO-d.sub.6, 400 mHz): .delta. 12.76 (br s; 1H); 10.62 (s; 1H);
8.69 (d; J=7.17 Hz; 1H); 8.25 (s; 1H); 8.17 (s; 1H); 8.09 (d;
J=8.10 Hz; 2H); 8.07 (s; 1H); 7.90 (d; J=8.09 Hz; 2H); 7.79 (s;
1H); 7.60 (s; 1H); 4.65 (s; 1H); 4.11-4.21 (m; 2H); 3.84 (s; 3H);
3.38-3.45 (m; 1H); 3.30-3.35 (m; 6H); 3.12 (t; J=11.19 Hz; 1H);
2.13-2.23 (m; 1H); 1.74-1.82 (m; 1H); 1.51-1.63 (m; 1H); 1.31-1.44
(m; 1H). LCMS [M+H].sup.+: 476.2.
Example 189: Synthesis of
3-(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrol-
o[2,3-d]pyrimidine-5-carbonyl)-N-phenylbenzamide (I-634)
[0629]
3-(4-(((3R,6S)-6-(Hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H--
pyrrolo[2,3-d]pyrimidine-5-carbonyl)-N-phenylbenzamide was
synthesized according to General Scheme 6. .sup.1H NMR
(DMSO-d.sub.6, 400 mHz): .delta. 12.76 (s; 1H); 10.37 (s; 1H); 8.70
(d; J=7.11 Hz; 1H); 8.35 (s; 1H); 8.26 (s; 1H); 8.20 (d; J=7.86 Hz;
1H); 7.99 (d; J=7.69 Hz; 1H); 7.89 (s; 1H); 7.78 (d; J=8.06 Hz;
2H); 7.71 (t; J=7.73 Hz; 1H); 7.36 (t; J=7.79 Hz; 2H); 7.12 (t;
J=7.39 Hz; 1H); 4.13-4.19 (m; 2H); 3.29-3.45 (m; 5H); 3.12 (t;
J=11.03 Hz; 1H); 2.16-2.21 (m; 1H); 1.76-1.81 (m; 1H); 1.52-1.59
(m; 1H); 1.34-1.43 (m; 1H). LCMS [M+H].sup.+: 472.2.
Example 190: Synthesis of
(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[-
2,3-d]pyrimidin-5-yl)(3-(morpholine-4-carbonyl)phenyl) methanone
(I-635)
[0630]
(4-(((3R,6S)-6-(Hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-py-
rrolo[2,3-d]pyrimidin-5-yl)(3-(morpholine-4-carbonyl)phenyl)methanone
was synthesized according to General Scheme 6. .sup.1H NMR
(DMSO-d.sub.6, 400 mHz): .delta. 12.72 (s; 1H); 8.65 (d; J=7.24 Hz;
1H); 8.26 (s; 1H); 7.86 (dt; J=7.46; 1.57 Hz; 1H); 7.78 (s; 1H);
7.76 (t; J=1.65 Hz; 1H); 7.68 (dt; J=7.65; 1.51 Hz; 1H); 7.63 (t;
J=7.54 Hz; 1H); 4.67 (t; J=5.53 Hz; 1H); 4.13-4.21 (m; 2H);
3.50-3.71 (m; 7H); 3.35-3.49 (m; 5H); 3.12 (t; J=11.32 Hz; 1H);
2.16-2.23 (m; 1H); 1.77-1.83 (m; 1H); 1.51-1.63 (m; 1H); 1.35-1.45
(m; 1H). LCMS [M+H].sup.+: 466.2.
Example 191: Synthesis of
4-(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrol-
o[2,3-d]pyrimidine-5-carbonyl)-N-(2-methoxyethyl)benzamide
(I-636)
[0631]
4-(4-(((3R,6S)-6-(Hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H--
pyrrolo[2,3-d]pyrimidine-5-carbonyl)-N-(2-methoxyethyl)benzamide
was synthesized according to General Scheme 6. .sup.1H NMR
(DMSO-d.sub.6, 400 mHz): .delta. 8.67-8.72 (m; 2H); 8.24 (s; 1H);
7.98-8.00 (m; 2H); 7.82-7.84 (m; 2H); 7.76 (s; 1H); 4.65 (t; J=5.48
Hz; 1H); 4.11-4.17 (m; 2H); 3.58-3.61 (m; 1H); 3.38-3.50 (m; 6H);
3.28 (s; 3H); 3.11 (t; J=11.28 Hz; 1H); 2.15-2.21 (m; 1H);
1.75-1.81 (m; 2H); 1.54-1.61 (m; 1H); 1.33-1.43 (m; 1H). LCMS
[M+H].sup.+: 454.2.
Example 192: Synthesis of
3-(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrol-
o[2,3-d]pyrimidine-5-carbonyl)-N-(2-methoxyethyl)benzamide
(I-637)
[0632]
3-(4-(((3R,6S)-6-(Hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H--
pyrrolo[2,3-d]pyrimidine-5-carbonyl)-N-(2-methoxyethyl)benzamide
was synthesized according to General Scheme 6. .sup.1H NMR
(DMSO-d.sub.6, 400 mHz): .delta. 12.73 (br s; 1H); 8.66-8.71 (m;
2H); 8.25 (s; 1H); 8.22-8.23 (m; 1H); 8.08-8.11 (m; 1H); 7.91-7.93
(m; 1H); 7.80 (s; 1H); 7.63 (t; J=7.73 Hz; 1H); 4.65 (t; J=5.55 Hz;
1H); 4.11-4.18 (m; 2H); 3.37-3.49 (m; 8H); 3.27 (s; 3H); 3.11 (t;
J=11.22 Hz; 1H); 2.14-2.22 (m; 1H); 1.74-1.82 (m; 1H); 1.51-1.61
(m; 1H); 1.32-1.44 (m; 1H). LCMS [M+H].sup.+: 454.2.
Example 193: Synthesis of
3-(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrol-
o[2,3-d]pyrimidine-5-carbonyl)-N-(1-methyl-1H-pyrazol-4-yl)benzamide
(I-638)
[0633]
3-(4-(((3R,6S)-6-(Hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H--
pyrrolo[2,3-d]pyrimidine-5-carbonyl)-N-(1-methyl-1H-pyrazol-4-yl)benzamide
was synthesized according to General Scheme 6. .sup.1H NMR
(DMSO-d.sub.6, 400 mHz): .delta. 12.76 (s; 1H); 10.56 (s; 1H); 8.68
(d; J=7.22 Hz; 1H); 8.34 (t; J=1.66 Hz; 1H); 8.24-8.25 (m; 1H);
8.20 (dt; J=7.82; 1.40 Hz; 1H); 8.05 (s; 1H); 7.96 (dt; J=7.69;
1.35 Hz; 1H); 7.86 (s; 1H); 7.69 (t; J=7.74 Hz; 1H); 7.58 (d;
J=0.72 Hz; 1H); 4.66 (t; J=5.45 Hz; 1H); 4.13-4.21 (m; 3H); 3.83
(s; 3H); 3.38-3.45 (m; 2H); 3.34-3.37 (m; 3H); 3.11 (t; J=11.07 Hz;
2H); 2.16-2.19 (m; 2H); 1.77-1.80 (m; 2H); 1.52-1.62 (m; 2H);
1.34-1.44 (m; 2H). LCMS [M+H].sup.+: 476.2.
Example 194: Synthesis of
4-(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrol-
o[2,3-d]pyrimidine-5-carbonyl)-N-phenylbenzamide (I-231)
[0634]
4-(4-(((3R,6S)-6-(Hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H--
pyrrolo[2,3-d]pyrimidine-5-carbonyl)-N-phenylbenzamide was
synthesized according to General Scheme 6. .sup.1H NMR
(DMSO-d.sub.6, 400 mHz): .delta. 12.80 (s; 1H); 10.46 (s; 1H); 8.74
(d; J=7.15 Hz; 1H); 8.30 (s; 1H); 8.15 (d; J=8.03 Hz; 2H); 7.95 (d;
J=8.03 Hz; 2H); 7.86 (s; 1H); 7.83 (d; J=5.06 Hz; 2H); 7.42 (t;
J=7.77 Hz; 2H); 7.17 (t; J=7.37 Hz; 1H); 4.70 (t; J=5.53 Hz; 1H);
4.16-4.23 (m; 2H); 3.42-3.47 (m; 1H); 3.37-3.41 (m; 2H); 3.16 (t;
J=11.18 Hz; 1H); 2.19-2.25 (m; 1H); 1.81-1.85 (m; 1H); 1.60-1.66
(m; 1H); 1.38-1.47 (m; 1H). LCMS [M+H].sup.+: 472.2.
Example 195: Synthesis of
N-(3-chloro-4-(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amin-
o)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)phenyl)benzamide
(I-276)
Step 1: Synthesis of
(2-chloro-4-nitrophenyl)(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methano-
ne
[0635]
(2-Chloro-4-nitrophenyl)(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)m-
ethanone was synthesized according General Procedure A, step 1,
using 4-chloro-7H-pyrrolo[2,3-d]pyrimidine and
2-chloro-4-nitrobenzoyl chloride. LCMS [M+H]: 337.9.
Step 2: Synthesis of
(2-chloro-4-nitrophenyl)(4-chloro-7-((2-(trimethylsilyl)ethoxy)
methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone
[0636] Protection of the nitrogen was achieved according to General
Procedure A, step 1 LCMS [M+H].sup.+: 467.0.
Step 2: Synthesis of
(2-chloro-4-nitrophenyl)(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-
-3-yl)amino)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimid-
in-5-yl)methanone
[0637] The chloride displacement was done according to General
Procedure A, step 2, with
((2S,5R)-5-aminotetrahydro-2H-pyran-2-yl)methanol. LCMS
[M+H].sup.+: 562.2
Step 3: Synthesis of
(4-(((3R,6S)-6-(((tert-butyldimethylsilyl)oxy)methyl)tetrahydro-2H-pyran--
3-yl)amino)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidi-
n-5-yl)(2-chloro-4-nitrophenyl)methanone
[0638] To a solution of
(2-chloro-4-nitrophenyl)(4-(((3R,6S)-6-(hydroxymethyl)
tetrahydro-2H-pyran-3-yl)amino)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-p-
yrrol[2,3-d]pyrimidin-5-yl)methanone (1260 mg, 2.242 mmol) in DMF
(12 mL) were added TBDMS-C.sub.1 (405 mg, 2.69 mmol) and imidazole
(305 mg, 4.483 mmol). The reaction mixture was stirred at room
temperature for 18 hours. The reaction mixture was diluted with
EtOAc (50 mL) and aqueous saturated NH.sub.4Cl (60 mL). The layers
were partitioned and the aqueous layer was extracted with EtOAc (40
mL). The combined organic layers were washed with aqueous saturated
NaHCO.sub.3(60 mL), water (60 mL) and brine. The n it was dried
over MgSO.sub.4, filtered and concentrated to dryness to afford
1600 mg of the desired material which was used in the subsequent
step without further purification.
Step 4: Synthesis of
(4-Amino-2-chlorophenyl)(4-(((3R,6S)-6-(((tert-butyldimethylsilyl)
oxy)
methyl)tetrahydro-2H-pyran-3-yl)amino)-7-((2-(trimethylsilyl)ethoxy)methy-
l)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone
[0639] Sylilation was achieved under standard conditions. LCMS
[M+H]: 646.4.
General Procedure J
[0640] A General Method for Amide Formation Using an Acyl Chloride
with Silyl-Protected Aniline Substrate Followed by Desilylation
##STR00740##
[0641] A solution of
(4-amino-2-chlorophenyl)(4-(((3R,6S)-6-(((tert-butyldimethylsilyl)
oxy)methyl)-tetrahydro-2H-pyran-3-yl)amino)-7-((2-(trimethylsilyl)ethoxy)-
methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (23-A) (1 eq) in
DCM (1 mL/0.05 mmol) is treated with corresponding acyl chloride
(1.5 eq) and triethylamine (3 eq) at room temperature for 3h. The
mixture is then concentrated and 4M HCl in dioxane (2 mL/0.05 mmol)
is added. The mixture is stirred at 40.degree. C. overnight then
concentrated and the residue purified by preparative reverse phase
HPLC (gradient from 30% to 95% of acetonitrile+0.1% formic
acid).
Step 5: Synthesis of
N-(3-chloro-4-(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amin-
o)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)phenyl)benzamide
(I-276)
[0642]
N-(3-Chloro-4-(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-y-
l)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)phenyl)benzamide
was synthesized according to General Scheme 7, using benzoyl
chloride. .sup.1H NMR (DMSO-d.sub.6, 400 MHz): .delta. 12.90 (bs,
1H), 10.62 (s, 1), 8.85 (bs, 1H), 8.29 (s, 1H), 8.13 (d, J=1.8 Hz,
1H), 7.99-7.97 (m, 2H), 7.87 (dd, J=8.4 Hz, J=1.8 Hz, 1H),
7.65-7.55 (m, 5H), 4.18-4.10 (m, 2H), 3.45-3.33 (m, 3H), 3.18-3.13
(m, 1H), 2.22-2.19 (m, 1H), 1.81-1.75 (m, 1H), 1.66-1.56 (m, 1H),
1.44-1.34 (m, 1H). LCMS [M+H].sup.+: 506.2.
Example 196: Synthesis of
N-(3-chloro-4-(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amin-
o)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)phenyl)-2-phenylacetamide
(I-639)
[0643]
N-(3-Chloro-4-(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-y-
l)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)phenyl)-2-phenylacetamide
was synthesized according to General Scheme 7, using 2-phenylacetyl
chloride. .sup.1H NMR (DMSO-d.sub.6, 400 mHz): .delta. 12.70 (bs,
1H), 10.63 (s, 1H), 8.60 (d, J=7.2 Hz, 1H), 8.23 (s, 1H), 7.95 (d,
J=1.8 Hz, 1H), 7.59 (dd, J=8.4 Hz, J=1.8 Hz, 1H), 7.54 (s, 1H),
7.51 (d, J=8.4 Hz, 1H), 7.35-7.32 (m, 3H), 7.28-7.25 (m, 1H), 4.66
(bs, 1H), 4.19-4.10 (m, 2H), 3.70 (s, 2H), 3.43-3.40 (m, 1H),
3.45-3.31 (m, 3H), 3.14-3.08 (m, 1H), 2.19-2.16 (m, 1H), 1.79-1.76
(m, 1H), 1.62-1.52 (m, 1H), 1.43-1.32 (m, 1H). LCMS [M+H].sup.+:
520.1.
Example 197: Synthesis of
N-(3-chloro-4-(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amin-
o)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)phenyl)-1-phenylcyclopropane-1-c-
arboxamide (I-640)
[0644]
N-(3-Chloro-4-(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-y-
l)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)phenyl)-1-phenylcyclopropa-
ne-1-carboxamide was synthesized according to General Scheme 7,
using 1-phenylcyclopropane-1-carbonyl chloride.
[0645] .sup.1H NMR (DMSO-d.sub.6, 400 mHz): .delta. 9.58 (s, 1H),
8.60 (d, J=7.0 Hz, 1H), 8.22 (s, 1H), 7.91 (d, J=2.0 Hz, 1H), 7.65
(dd, J=8.4 Hz, J=1.8 Hz, 1H), 7.51 (s, 1H), 7.46 (d, J=8.4 Hz, 1H),
7.42-7.35 (m, 4H), 7.32-7.28 (m, 1H), 4.65 (bs, 1H), 4.18-4.10 (m,
2H), 3.44-3.33 (m, 7H) 3.14-3.08 (m, 1H), 2.19-2.16 (m, 1H),
1.79-1.76 (m, 1H), 1.62-1.52 (m, 1H), 1.48 (dd, J=6.8 Hz, J=4.5 Hz,
2H), 1.42-1.32 (m, 1H), 1.16 (dd, J=6.8 Hz, J=4.5 Hz, 2H). LCMS
[M+H].sup.+: 546.3.
Example 198: Synthesis of
2-(benzyloxy)-N-(3-chloro-4-(4-(((3R,6S)-6-(hydroxymethyl)
tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)ph-
enyl) acetamide (I-641)
[0646]
2-(Benzyloxy)-N-(3-chloro-4-(4-(((3R,6S)-6-(hydroxymethyl)tetrahydr-
o-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)phenyl)aceta-
mide was synthesized according to General Scheme 7, using
2-(benzyloxy)acetyl chloride. .sup.1H NMR (DMSO-d.sub.6, 400 mHz):
.delta. 12.73 (bs, 1H), 10.24 (s, 1H), 8.62 (d, J=7.0 Hz, 1H), 8.24
(s, 1H), 8.00 (d, J=1.8 Hz, 1H), 7.70 (dd, J=8.4 Hz, J=1.8 Hz, 1H),
7.55 (s, 1H), 7.53 (d, J=8.4 Hz, 1H), 7.43-7.37 (m, 3H), 7.34-7.31
(m, 1H), 4.64 (s, 2H), 4.15 (bs, 4H), 4.06-3.88 (m, 1H), 3.57-3.51
(m, 3H), 3.46-3.33 (m, 11H+H.sub.2O), 3.15-3.09 (m, 1H), 2.20-2.17
(m, 1H), 1.91-1.80 (m, 1H), 1.63-1.50 (m, 1H), 1.44-1.31 (m, 1H).
LCMS [M+H].sup.+: 550.2.
Example 199: Synthesis of
N-(3-(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyr-
rolo[2,3-d]pyrimidine-5-carbonyl)phenyl)benzamide (I-642)
[0647]
N-(3-(4-(((3R,6S)-6-(Hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)--
7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)phenyl)benzamide was
prepared according to General Scheme 8 and using benzoic acid.
.sup.1H NMR (DMSO-d.sub.6, 400 mHz): d 12.71 (s; 1H); 10.45 (s;
1H); 8.72 (d; J 6.93 Hz; 1H); 8.23 (s; 2H); 8.03 (d; J 6.49 Hz;
1H); 7.97 (d; J 7.51 Hz; 2H); 7.83 (s; 1H); 7.51-7.60 (m; 5H); 4.64
(t; J 5.34 Hz; 1H); 4.14 (d; J 9.29 Hz; 2H); 3.35-3.43 (m; 3H);
3.11 (t; J 11.33 Hz; 1H); 2.15-2.18 (m; 1H); 1.75-1.78 (m; 1H);
1.52-1.61 (m; 1H); 1.32-1.41 (m; 1H). LCMS [M+H].sup.+: 472.2.
Example 200: Synthesis of
N-(3-(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyr-
rolo[2,3-d]pyrimidine-5-carbonyl)phenyl)picolinamide (I-643)
[0648]
N-(3-(4-(((3R,6S)-6-(Hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)--
7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)phenyl)picolinamide was
prepared according to General Scheme 8 and using 2-picolinic acid.
.sup.1H NMR (DMSO-d.sub.6, 400 mHz): .delta. 12.75 (s; 1H); 10.94
(s; 1H); 8.77 (m; 2H); 8.38 (s; 1H); 8.25 (s; 1H); 8.15-8.19 (m;
3H); 8.07-8.11 (m; 1H); 7.89 (s; 1H); 7.68-7.71 (m; 1H); 7.54 (m;
2H); 4.15 (d; J 9.34 Hz; 2H); 3.13 (t; J 11.53 Hz; 1H); 2.18 (s;
1H); 1.78 (d; J 13.08 Hz; 1H); 1.59 (d; J=12.82 Hz; 1H); 1.39 (d; J
12.79 Hz; 1H). LCMS [M+H].sup.+: 472.1.
Example 201: Synthesis of
N-(3-(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyr-
rol[2,3-d]pyrimidine-5-carbonyl)phenyl)tetrahydro-2H-pyran-4-carboxamide
(I-644)
[0649]
N-(3-(4-(((3R,6S)-6-(Hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)--
7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)phenyl)tetrahydro-2H-pyran-4-carbox-
amide was prepared according to General Scheme 8 and using
tetrahydro-2H-pyran-4-carboxylic acid. .sup.1H NMR (DMSO-d.sub.6,
400 mHz): .delta. 12.70 (s; 1H); 10.12 (s; 1H); 8.70 (d; J=7.05 Hz;
1H); 8.24 (s; 1H); 8.08 (s; 1H); 7.78-7.81 (m; 2H); 7.45-7.49 (m;
2H); 4.65 (t; J=5.56 Hz; 1H); 4.14 (d; J=9.28 Hz; 2H); 3.91 (d;
J=11.26 Hz; 2H); 3.11 (t; J=11.56 Hz; 1H); 2.60 (s; 1H); 2.17 (s;
1H); 1.65-1.71 (m; 4H); 1.40 (s; 1H). LCMS [M+H].sup.+: 480.3.
Example 202: Synthesis of
N-(3-(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyr-
rolo[2,3-d]pyrimidine-5-carbonyl)phenyl)-2-methoxyacetamide
(I-645)
[0650]
N-(3-(4-(((3R,6S)-6-(Hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)--
7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)phenyl)-2-methoxyacetamide
was prepared according to General Scheme 8 and using
2-methoxyacetic acid. .sup.1H NMR (DMSO-d.sub.6, 400 mHz): .delta.
12.71 (s; 1H); 10.01 (s; 1H); 8.71 (d; J=7.08 Hz; 1H); 8.24 (s;
1H); 8.13 (s; 1H); 7.89-7.92 (m; 1H); 7.80 (s; 1H); 7.48 (m; 2H);
4.65 (t; J=5.58 Hz; 1H); 4.14 (m; 2H); 4.03 (s; 2H); 3.11 (t;
J=11.53 Hz; 1H); 2.17 (m; 1H); 1.78 (m; 1H); 1.57 (m; 1H);
1.33-1.43 (m; 1H). LCMS [M+H].sup.+: 440.2.
General Procedure K
A General Procedure for Arylamine Formation
##STR00741##
[0652] The arylfluoride substrate (26-A) (1 eq.) was diluted in NMP
(1 mL/1.32 mmol). Cyclic amine (1.1 eq.) and potassium carbonate (2
eq.) were added and the mixture was stirred at 120.degree. C.
overnight. The reaction mixture was allowed to cool to room
temperature and was diluted with water. The crude mixture was
extracted with ethyl acetate (.times.3) and the combined organics
were washed with water (.times.2). Organics were dried over
magnesium sulfate, filtered and concentrated to dryness. The
product was purified by silica gel chromatography (0-50% ethyl
acetate in hexanes).
General Procedure L
A General Procedure for Phenol Alkylation
##STR00742##
[0654] A mixture of phenol (26-B) (1 eq.), 1-chloro-2-methoxyethane
(1.5 eq.), potassium carbonate (2 eq.) and sodium iodide (0.2 eq.)
in DMF (1 mL/0.45 mmol) is heated overnight at 80.degree. C. The
reaction mixture is then cooled to room temperature and poured in
water, stirred for 15 min and filtered then dried under high
vacuum. The product was used as is without further
purification.
General Procedure M
A General Procedure for Ketone Formation Through Aryllithium Attack
on an Ester
##STR00743##
[0656] 5-Bromo-4-chloro-7H-pyrrolo[2,3-d]pyrimidine (3-A) (1 eq.)
was diluted in dry THF (1 mL/0.21 mmol) and was cooled to
-78.degree. C. n-BuLi (2.1 eq.) was added dropwise and the
temperature was monitored with an internal thermocouple to ensure
the reaction temperature never rose above -60.degree. C. The
reaction mixture was stirred for 1 hour before the substituted
methyl benzoate (27-A/B) (1.05 eq.) in dry THF (1 mL/0.9 mmol) was
added dropwise with the internal temperature never exceeding
-60.degree. C. The mixture was stirred at -78.degree. C. for 1 hour
then quenched with saturated aqueous Ammonium chloride solution and
extracted with ethyl acetate (.times.3). The combined organic
layers were washed with sodium bicarbonate and dried over magnesium
sulfate, filtered and concentrated. The resulting residue was
purified by silica gel column chromatography (10-100% ethyl acetate
in hexanes).
Example 203: Synthesis of
(2-chloro-4-morpholinophenyl)(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H--
pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone
(I-311i)
[0657]
(2-Chloro-4-morpholinophenyl)(4-(((3R,6S)-6-(hydroxymethyl)tetrahyd-
ro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone
was synthesized according to General Scheme 9, using
((2S,5R)-5-aminotetrahydro-2H-pyran-2-yl)methanol. .sup.1H NMR
(DMSO-d.sub.6, 400 mHz): .delta. 12.61 (s; 1H); 8.65 (d; J=6.98 Hz;
1H); 8.23 (s; 1H); 7.50 (s; 1H); 7.43 (d; J=8.54 Hz; 1H); 7.07 (s;
1H); 6.96 (d; J=8.68 Hz; 1H); 4.65 (t; J=5.29 Hz; 1H); 4.10-4.15
(m; 2H); 3.73-3.75 (m; 4H); 3.38-3.43 (m; 3H); 3.26-3.27 (m; 4H);
3.11 (t; J=11.29 Hz; 1H); 2.15-2.20 (m; 1H); 1.76-1.79 (m; 1H);
1.49-1.60 (m; 1H); 1.33-1.43 (m; 1H). LCMS [M+H].sup.+: 472.
Example 204: Synthesis of
(2-chloro-4-(piperidin-1-yl)phenyl)(4-(((3R,6S)-6-(hydroxymethyl)tetrahyd-
ro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone
(I-646)
[0658]
(2-Chloro-4-(piperidin-1-yl)phenyl)(4-(((3R,6S)-6-(hydroxymethyl)te-
trahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone
was synthesized according to General Scheme 9, using
((2S,5R)-5-aminotetrahydro-2H-pyran-2-yl)methanol. .sup.1H NMR
(DMSO-d.sub.6, 400 mHz): .delta. 12.60 (s; 1H); 8.66 (d; J=7.11 Hz;
1H); 8.22 (s; 1H); 7.51 (s; 1H); 7.38 (d; J=8.66 Hz; 1H); 7.01 (d;
J=2.36 Hz; 1H); 6.91 (dd; J=8.75; 2.40 Hz; 1H); 4.66 (t; J=5.54 Hz;
1H); 4.12-4.18 (m; 2H); 3.36-3.42 (m; 3H); 3.30-3.32 (m; 4H); 3.11
(t; J=11.42 Hz; 1H); 2.16-2.20 (m; 1H); 1.74-1.79 (m; 1H);
1.51-1.58 (m; 8H); 1.33-1.43 (m; 1H). LCMS [M+H].sup.+: 470.
Example 205: Synthesis of
(2-chloro-4-(2-oxa-6-azaspiro[3.3]heptan-6-yl)phenyl)(4-(((3R,6S)-6-(hydr-
oxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-
methanone (I-647)
[0659]
(2-Chloro-4-(2-oxa-6-azaspiro[3.3]heptan-6-yl)phenyl)(4-(((3R,6S)-6-
-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-
-5-yl)methanone was synthesized according to General Scheme 9,
using 2-oxa-6-azaspiro[3.3]heptane, and
((2S,5R)-5-aminotetrahydro-2H-pyran-2-yl)methanol. .sup.1H NMR
(DMSO-d.sub.6, 400 mHz): .delta. 12.59 (s; 1H); 8.65 (d; J=7.08 Hz;
1H); 8.22 (s; 1H); 7.44 (s; 1H); 7.39 (d; J=8.37 Hz; 1H); 6.54 (d;
J=2.18 Hz; 1H); 6.41 (dd; J=8.42; 2.21 Hz; 1H); 4.73 (s; 4H); 4.65
(t; J=5.57 Hz; 1H); 4.11-4.17 (m; 2H); 4.10 (s; 4H); 3.35-3.44 (m;
3H); 3.10 (t; J=11.53 Hz; 1H); 2.15-2.19 (m; 1H); 1.76-1.80 (m;
1H); 1.51-1.61 (m; 1H); 1.32-1.42 (m; 1H). LCMS [M+H].sup.+:
484.
Example 206: Synthesis of
(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[-
2,3-d]pyrimidin-5-yl)(4-(2-methoxyethoxy)phenyl)methanone
(I-318i)
[0660]
(4-(((3R,6S)-6-(Hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-py-
rrolo[2,3-d]pyrimidin-5-yl)(4-(2-methoxyethoxy)phenyl)methanone was
prepared according to General Scheme 9, using methyl
4-hydroxybenzoate and
((2S,5R)-5-aminotetrahydro-2H-pyran-2-yl)methanol. .sup.1H NMR
(DMSO-d.sub.6, 400 mHz): .delta. 12.63 (bs, 1H), 8.66 (d, J=7.2 Hz,
1H), 8.23 (s, 1H), 7.79 (d, J=8.8 Hz, 2H), 7.76 (s, 1H), 7.08 (d,
J=8.8 Hz, 2H), 4.65 (bs, 1H), 4.22-4.19 (m, 2H), 4.16-4.11 (m, 2H),
3.71-3.69 (m, 2H), 3.42-3.39 (m, 1H), 3.36-3.30 (m, 4H+H.sub.2O),
3.13-3.07 (m, 1H), 2.18-2.15 (m, 1H), 1.79-1.76 (m, 1H), 1.61-1.51
(m, 1H), 1.42-1.32 (m, 1H). LCMS [M+H.sup.+]: 427.30.
Example 207: Synthesis of
(2-chloro-4-(2-methoxyethoxy)phenyl)(4-(((3R,6S)-6-(hydroxymethyl)tetrahy-
dro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone
(I-317i)
[0661]
(2-Chloro-4-(2-methoxyethoxy)phenyl)(4-(((3R,6S)-6-(hydroxymethyl)t-
etrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone
was prepared according to General Scheme 9, using methyl
2-chloro-4-hydroxybenzoate and
((2S,5R)-5-aminotetrahydro-2H-pyran-2-yl)methanol. .sup.1H NMR
(DMSO-d.sub.6, 400 mHz): .delta. 12.70 (bs, 1H), 8.61 (d, J=7.0 Hz,
1H), 8.21 (s, 1H), 7.48 (s, 1H), 7.47 (d, J=8.6 Hz, 1H), 7.16 (d,
J=2.3 Hz, 1H), 7.00 (dd, J=8.4, 2.3 Hz, 1H), 4.45 (bs, 1H),
4.20-4.17 (m, 2H), 4.17-4.11 (m, 2H), 3.68-3.65 (m, 2H), 3.48-3.33
(m, 3H), 3.30 (m, 3H), 3.13-3.07 (m, 1H), 2.18-2.15 (m, 1H),
1.79-1.76 (m, 1H), 1.60-1.50 (m, 1H), 1.40-1.34 (m, 1H). Presence
of formic acid at 8.42 mm (0.2 equivalents). LCMS [M+H.sup.+]:
461.20.
Example 208: Synthesis of
(2-chloro-5-(2-methoxyethoxy)phenyl)(4-(((3R,6S)-6-(hydroxymethyl)tetrahy-
dro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone
(I-648)
[0662]
(2-Chloro-5-(2-methoxyethoxy)phenyl)(4-(((3R,6S)-6-(hydroxymethyl)t-
etrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone
was prepared according to General Scheme 9, using methyl methyl
2-chloro-5-hydroxybenzoate and
((2S,5R)-5-aminotetrahydro-2H-pyran-2-yl)methanol. .sup.1H NMR
(DMSO-d.sub.6, 400 mHz): .delta. 12.73 (bs, 1H), 8.57 (d, J=7.4 Hz,
1H), 8.23 (s, 1H), 7.51 (s, 1H), 7.44 (d, J=8.6 Hz, 1H), 7.12-7.07
(m, 2H), 4.64 (bs, 1H), 4.15-4.10 (m, 4H), 3.63-3.61 (m, 2H),
3.45-3.31 (m, 3H), 3.27 (m, 3H), 3.12-3.07 (m, 1H), 2.18-2.15 (m,
1H), 1.78-1.74 (m, 1H), 1.60-1.51 (m, 1H), 1.41-1.32 (m, 1H).
Presence of formic acid at 8.37 ppm (0.08 equivalents). LCMS
[M+H.sup.+]: 461.20.
Example 209: Synthesis of
(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyrrolo[-
2,3-d]pyrimidin-5-yl)(3-(2-methoxyethoxy)phenyl)methanone
(I-649)
[0663]
(4-(((3R,6S)-6-(Hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-py-
rrolo[2,3-d]pyrimidin-5-yl)(3-(2-methoxyethoxy)phenyl)methanone was
prepared according to General Scheme 9, using methyl
3-hydroxybenzoate and
((2S,5R)-5-aminotetrahydro-2H-pyran-2-yl)methanol. .sup.1H NMR
(DMSO-d.sub.6, 400 mHz): .delta. 12.67 (bs, 1H), 8.68 (d, J=7.2 Hz,
1H), 8.24 (s, 1H), 7.77 (s, 1H), 7.44 (t, J=7.6 Hz, 1H), 7.33 (d,
J=7.6 Hz, 1H), 7.28 (m, 1H), 7.20 (dd, J=8.2 Hz, J=2.0 Hz, 1H),
4.65 (bs, 1H), 4.19-4.11 (m, 4H), 3.69-3.67 (m, 2H), 3.44-3.40 (m,
1H), 3.35-3.27 (m, 6H), 3.13-3.08 (m, 1H), 2.19-2.16 (m, 1H),
1.79-1.76 (m, 1H), 1.61-1.51 (m, 1H), 1.44-1.33 (m, 1H). Presence
of formic acid at 8.37 ppm (0.1 equivalents). LCMS [M+H.sup.+]:
427.20.
Example 210: Synthesis of
(2-chloro-4-(phenylamino)phenyl)(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro--
2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone
(I-650)
Step 1: Synthesis of
(4-(((3R,6S)-6-(((tert-butyldimethylsilyl)oxy)methyl)tetrahydro-2H-pyran--
3-yl)amino)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidi-
n-5-yl)(2-chloro-4-(phenylamino)phenyl)methanone and
(2-chloro-4-(phenylamino)phenyl)(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro--
2H-pyran-3-yl)amino)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d-
]pyrimidin-5-yl)methanone
[0664]
(4-Amino-2-chlorophenyl)(4-(((3R,6S)-6-(((tert-butyldimethylsilyl)o-
xy)methyl)tetrahydro-2H-pyran-3-yl)amino)-7-((2-(trimethylsilyl)-ethoxy)me-
thyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (200 mg, 0.309
mmol) was dissolved in dioxane (2 mL). Bromobenzene (36 .mu.L, 0.34
mmol) and sodium tert-butoxide (42 mg, 0.43 mmol) were added. The
crude was degassed with argon and Pd.sub.2(dba).sub.3 (6 mg, 0.006
mmol) and BINAP (14 mg, 0.022 mmol) were added. The reaction was
then capped and heated to 100.degree. C. for 3 hours. After cooling
to room temperature the crude was diluted in water and ethyl
acetate. The biphasic mixture was extracted with ethyl acetate
(.times.2). The combined organics were dried over MgSO.sub.4,
filtered and concentrated. The residue was purified by silica gel
column chromatography eluting a gradient of 0% to 100% ethyl
acetate in hexanes. Combined both products to get 150 mg of yellow
oil.
Step 2: Synthesis of
(2-Chloro-4-(phenylamino)phenyl)(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro--
2H-pyran-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone
(I-650)
[0665] Deprotection of the silyl groups was achieved using General
Procedure H. .sup.1H NMR (DMSO-d.sub.6, 400 mHz): .delta. 12.64 (s;
1H); 8.75 (s; 1H); 8.66 (d; J=7.13 Hz; 1H); 8.23 (s; 1H); 7.59 (s;
1H); 7.43 (d; J=8.43 Hz; 1H); 7.32-7.37 (m; 2H); 7.20 (dd; J=7.97;
1.21 Hz; 2H); 7.09 (d; J=2.16 Hz; 1H); 6.99-7.04 (m; 2H); 4.65 (t;
J=5.58 Hz; 1H); 4.08-4.17 (m; 2H); 3.39-3.45 (m; 1H); 3.34-3.38 (m;
2H); 3.11 (t; J=11.42 Hz; 1H); 2.16-2.20 (m; 1H); 1.76-1.80 (m;
1H); 1.52-1.62 (m; 1H); 1.33-1.43 (m; 1H). LCMS [M+H].sup.+:
478.
General Procedure N
[0666] One general procedure for formation of a diaryl ether is
described.
##STR00744##
[0667] Fluoropyridine substrate (29-B) (1 eq.),
methyl-hydroxy-benzoate (29-A) (1 eq.) and potassium carbonate (1
eq.) were dissolved in DMSO (1 mL/0.3 mmol). The mixture was
stirred at 120.degree. C. under argon atmosphere overnight. After
cooled, the reaction mixture was diluted in water and extracted
several times with ethyl acetate. Combined organics were washed
with water and dried over magnesium sulfate and concentrated under
reduced pressure. The product was purified by column chromatography
(0-100% ethyl acetate in hexanes).
Example 211: Synthesis of
6-(4-(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyr-
rolo[2,3-d]pyrimidine-5-carbonyl)phenoxy)-N-methylpicolinamide
(I-320)
[0668]
6-(4-(4-(((3R,6S)-6-(Hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)--
7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)phenoxy)-N-methylpicolinamide
was synthesized according to General Scheme 11, using
6-fluoro-N-methylpicolinamide and methyl-4-hydroxy-benzoate.
.sup.1H NMR (DMSO-d.sub.6, 400 mHz): .delta. 8.61 (d; J=7.13 Hz;
1H); 8.15-8.17 (m; 2H); 8.02 (dd; J=8.22; 7.41 Hz; 1H); 7.78-7.82
(m; 4H); 7.22 (t; J=8.83 Hz; 3H); 4.53-4.66 (m; 1 H); 4.06-4.12 (m;
2H); 3.32-3.42 (m; 3H); 3.04 (t; J=11.35 Hz; 1H); 2.72 (d; J=4.81
Hz; 3H); 2.08-2.13 (m; 1H); LCMS [M+H]: 503.1.
Example 212: Synthesis of
6-(3-chloro-4-(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amin-
o)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)phenoxy)-N-methyl
picolinamide (I-319)
[0669]
6-(3-Chloro-4-(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-y-
l)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)phenoxy)-N-methylpicolinam-
ide was synthesized according to General Scheme 11, using
6-fluoro-N-methylpicolinamide and methyl
2-chloro-4-hydroxybenzoate. .sup.1H NMR (DMSO-d.sub.6, 400 mHz):
.delta. 12.72 (br s; 1H); 8.54 (d; J=7.11 Hz; 1H); 8.23 (q; J=4.87
Hz; 1H); 8.19 (s; 1H); 8.03 (dd; J=8.21; 7.43 Hz; 1H); 7.79 (dd;
J=7.41; 0.80 Hz; 1H); 7.64 (s; 1H); 7.56 (d; J=8.41 Hz; 1H); 7.41
(d; J=2.28 Hz; 1H); 7.25 (dd; J=8.19; 0.81 Hz; 1H); 7.18 (dd;
J=8.40; 2.30 Hz; 1H); 4.57-4.60 (m; 1H); 4.05-4.12 (m; 2H);
3.27-3.35 (m; 3H); 3.06 (t; J=11.29 Hz; 1H); 2.73 (d; J=4.83 Hz;
3H); 2.11-2.14 (m; 1H); 1.71-1.74 (m; 1H); 1.45-1.58 (m; 1H);
1.27-1.37 (m; 1H). LCMS [M+H]: 537.2.
Example 213: Synthesis of
5-(3-chloro-4-(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amin-
o)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)phenoxy)-N-methyl
picolinamide (I-651)
[0670]
5-(3-Chloro-4-(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-y-
l)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)phenoxy)-N-methylpicolinam-
ide was synthesized according to General Scheme 11, using
5-fluoro-N-methylpicolinamide and methyl
2-chloro-4-hydroxybenzoate. .sup.1H NMR (DMSO-d.sub.6, 400 mHz):
.delta. 12.73 (br s; 1H); 8.62-8.66 (m; 1H); 8.52 (d; J=7.11 Hz;
1H); 8.47 (d; J=2.78 Hz; 1H); 8.19 (s; 1H); 8.01 (d; J=8.64 Hz;
1H); 7.66 (dd; J=8.63; 2.81 Hz; 1H); 7.61 (s; 1H); 7.57 (d; J=8.42
Hz; 1H); 7.38 (d; J=2.34 Hz; 1H); 7.15 (dd; J=8.42; 2.36 Hz; 1H);
4.57-4.60 (m; 1H); 4.03-4.12 (m; 2H); 3.28-3.37 (m; 3H); 3.06 (t;
J=11.30 Hz; 1H); 2.76 (d; J=4.81 Hz; 3H); 2.10-2.16 (m; 1H);
1.70-1.73 (m; 1H); 1.46-1.56 (m; 1H); 1.26-1.38 (m; 1H). LCMS
[M+H]: 537.1.
Example 214: Synthesis of
N-(4-(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyr-
rolo[2,3-d]pyrimidine-5-carbonyl)benzyl)-2-methoxybenzamide
(I-652)
Step 1: Synthesis of methyl 4-((2-methoxybenzamido)methyl)benzoate
(652a)
[0671] The compound was prepared according to General Procedure F,
using methyl 4-(aminomethyl)benzoate hydrochloride and
2-methoxybenzoic acid. LCMS [M+H]: 300.1.
Step 2: Synthesis of
N-(4-(4-chloro-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)benzyl)-2-methoxybe-
nzamide (652b)
[0672]
N-(4-(4-Chloro-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)benzyl)-2-met-
hoxybenzamide was prepared according to General Procedure M, using
methyl 4-((2-methoxybenzamido)methyl) benzoate and 3-A. After 1 h
at -78.degree. C., the reaction mixture was allowed to warm up to
0.degree. C. over 1 h. LCMS [M+H]: 421.1.
Step 3: Synthesis of
N-(4-(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)-7H-pyr-
rolo[2,3-d]pyrimidine-5-carbonyl)benzyl)-2-methoxybenzamide
(I-652)
[0673]
N-(4-(4-(((3R,6S)-6-(Hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)--
7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)benzyl)-2-methoxybenzamide
was prepared according to General Scheme 12, General Procedure A,
step 2, with ((2S,5R)-5-aminotetrahydro-2H-pyran-2-yl)methanol.
After removal of solvents, the residue was diluted with EtOAc (30
mL) and water (20 mL). The layers were partitioned and the organic
layer was washed with water (20 mL) and brine, dried over
MgSO.sub.4, filtered and concentrated to dryness. The residue was
purified by reverse phase C18 using Isco CombiFlash (30 g column,
loaded with DMSO) eluting with 5-80% CH.sub.3CN/water (+0.1% formic
acid) over 20 minutes. .sup.1H NMR (DMSO-d.sub.6, 400 mHz): .delta.
12.66 (s; 1H); 8.80-8.83 (m; 1H); 8.71-8.73 (m; 1H); 8.23 (s; 1H);
7.75-7.78 (m; 4H); 7.47-7.51 (m; 3H); 7.17 (d; J=8.35 Hz; 1H);
7.03-7.07 (m; 1H); 4.65 (t; J=5.56 Hz; 1H); 4.60 (d; J=6.13 Hz;
2H); 4.09-4.18 (m; 2H); 3.92 (s; 3H); 3.26-3.36 (m; 3H); 3.08-3.14
(m; 1H); 2.13-2.20 (m; 1H); 1.74-1.81 (m; 1H); 1.50-1.60 (m; 1H);
1.32-1.43 (m; 1H). LCMS [M+H]: 516.3.
Step 1: Synthesis of tert-butyl
(racemic)-3-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4--
yl)amino)piperidine-1-carboxylate (37-A)
[0674] The intermediate 37-A was prepared according General
Procedure A, using 3-amino-N-Boc-piperidine and
(2-chloro-4-phenoxyphenyl)(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)metha-
none (36-A). LCMS [M+H].sup.+: 548.1.
Step 1': Synthesis of tert-butyl
(racemic)-2-(((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-
-yl)amino)methyl)pyrrolidine-1-carboxylate (37-B)
[0675] The intermediate 37-B was prepared according General
Procedure A, using tert-butyl
2-(aminomethyl)pyrrolidine-1-carboxylate and
(2-chloro-4-phenoxyphenyl)(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)metha-
none. LCMS [M+H].sup.+: 548.1.
General Procedure O
[0676] One general procedure for Boc-deprotection is described.
##STR00745##
[0677] Boc-protected amine (37-A/B) (1.0 equiv) was dissolved in
DCM (1.0 mL/mmol) and a 4.0M HCl/Dioxane solution (4.0 equiv) was
added. Mixture was stirred at room temperature for 2.0 h, then
concentrated under vacuum. A 1:10 solution of aqueous ammonia in
EtOH was added until complete dissolution of the residue. The
residue was absorbed onto silica and purified by normal phase
column chromatography to give the purified amine product.
Step 2: Synthesis of
(racemic)-(2-chloro-4-phenoxyphenyl)(4-(piperidin-3-ylamino)-7H-pyrrolo[2-
,3-d]pyrimidin-5-yl)methanone (38-A)
[0678] Intermediate 37-A was BOC-deprotected according to General
Scheme 13 General Procedure O. LCMS [M+H].sup.+: 448.10.
Step 2': Synthesis of
(racemic)-(2-chloro-4-phenoxyphenyl)(4-((pyrrolidin-2-ylmethyl)amino)-7H--
pyrrolo[2,3-d]pyrimidin-5-yl)methanone (38-B)
[0679] Intermediate 37-B was BOC-deprotected according to General
Scheme 13 General Procedure O. LCMS [M+H].sup.+: 448.10.
Example 215: Synthesis of
(racemic)-1-(3-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-
-4-yl)amino)piperidin-1-yl)but-2-yn-1-one (I-324r)
[0680]
(racemic)-1-(3-((5-(2-Chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyr-
imidin-4-yl)amino)piperidin-1-yl)but-2-yn-1-one was prepared
according to General Scheme 13 and General Scheme 5, step 3, using
(racemic)-(2-chloro-4-phenoxyphenyl)(4-(piperidin-3-ylamino)-7H-pyrrolo[2-
,3-d]pyrimidin-5-yl)methanone and 2-butynoic acid. .sup.1H NMR
(CDCl.sub.3, 400 mHz, 3:2 amide rotamer/conformer ratio, asterisks
denote minor rotamer/conformer peaks): .delta. 9.11 (d, J 7.0 Hz,
1H), 9.07* (d, J 7.6 Hz, 1H), 8.37 (s, 1H), 8.30* (s, 1H),
7.41-7.45 (m, 3H), 7.37 (d, J 7.6 Hz, 1H), 7.23 (t, J 7.5 Hz, 1H),
7.11 (s, 1H), 7.07-7.08 (m, 2H), 6.95-6.99 (m, 1H), 4.24-4.39 (m,
2H), 3.97-4.02* (m, 1H), 3.81-3.87 (m, 1H), 3.73 (dd, J 13.0, 7.4
Hz, 1H), 3.41-3.56 (m, 1H), 3.34* (dd, J 12.6, 8.0 Hz, 1H),
2.14-2.25 (m, 1H), 1.60-2.10 (m, 3H), 2.01* (s, 3H), 1.80 (s, 3H).
LCMS [M+H].sup.+: 514.10.
Example 216: Synthesis of
(racemic)-1-(2-(((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidi-
n-4-yl)amino)methyl)pyrrolidin-1-yl)but-2-yn-1-one (I-328r)
[0681]
(racemic)-1-(2-(((5-(2-Chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]py-
rimidin-4-yl)amino)methyl)pyrrolidin-1-yl)but-2-yn-1-one was
prepared according to General Scheme 13 and General Scheme 5, step
3, using
(racemic)-(2-chloro-4-phenoxyphenyl)(4-((pyrrolidin-2-ylmethyl)amino)-7H--
pyrrolo[2,3-d]pyrimidin-5-yl)methanone and 2-butynoic acid. .sup.1H
NMR (CDCl.sub.3, 400 mHz, 2:1 amide rotamer ratio, asterisks denote
minor rotamer peaks): .delta. 9.17 (t, J=6.2 Hz, 1H), 9.01* (t,
J=5.9 Hz, 1H), 8.34 (s, 1H), 7.34-7.47 (m, 4H), 7.20-7.26 (m, 1H),
7.12 (s, 1H), 7.08-7.09 (m, 2H), 6.97 (dd, J=8.4, 2.3 Hz, 1H),
4.40-4.54 (m, 1H), 3.98-4.10 (m, 1H), 3.69-3.88 (m, 2H), 3.49-3.66
(m, 1H) 1.92-2.17 (4H, m), 1.98* (3H, s), 1.89 (3H, s). LCMS
[M+H].sup.+: 514.10.
Example 217: Synthesis of
(racemic)-1-(3-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-
-4-yl)amino)piperidin-1-yl)prop-2-en-1-one (I-321r)
[0682]
(racemic)-1-(3-((5-(2-Chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyr-
imidin-4-yl)amino)piperidin-1-yl)prop-2-en-1-one was prepared
according to General Scheme 13 and General Scheme 5, step 3, using
(racemic)-(2-chloro-4-phenoxyphenyl)(4-(piperidin-3-ylamino)-7H-pyrrolo[2-
,3-d]pyrimidin-5-yl)methanone and acrylic acid. .sup.1H NMR 400 MHz
(DMSO-d6. 3:2 amide rotamer ratio, asterisks denote minor rotamer
peaks): .delta. 12.8 (br s, 1H); 8.85 (d, J=7.3 Hz, 1H); 8.27 (br
s, 1H); 7.62 (s, 1H); 7.55 (d, J=8.4 Hz, 1H); 7.48 (t, J=7.6 Hz,
2H); 7.25 (t, J=7.3 Hz, 1H); 7.17-7.19 (m, 3H); 7.02 (d, J=8.4 Hz,
1H); *6.77-6.84 (m, 1H); 6.56-6.64 (m, 1H); 5.93-6.05 (m, 1H);
*5.60-5.65 (m, 1H); 5.46-5.51 (m, 1H); 4.17-4.25 (m, 1H);
*4.00-4.06 (m, 1H); 3.89-3.95 (m, 1H); 3.45-3.71 (m, 2H); 3.20-3.30
(m, 1H); 2.01-2.10 (m, 1H); 1.72-1.85 (m, 2H); 1.53-1.63 (m, 1H).
LCMS [M+H].sup.+: 502.10.
Example 218: Synthesis of
(racemic)-1-(2-(((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidi-
n-4-yl)amino)methyl)pyrrolidin-1-yl)prop-2-en-1-one (I-325r)
[0683]
(racemic)-1-(2-(((5-(2-Chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]py-
rimidin-4-yl)amino)methyl)pyrrolidin-1-yl)prop-2-en-1-one was
prepared according to General Scheme 13 and General Scheme 5, step
3, using
(racemic)-(2-chloro-4-phenoxyphenyl)(4-((pyrrolidin-2-ylmethyl)amino)-7H--
pyrrolo[2,3-d]pyrimidin-5-yl)methanone and acrylic acid. .sup.1H
NMR 400 MHz (DMSO-d.sub.6, 5:4 amide rotamer ratio, asterisks
denote minor rotamer peaks): .delta. 12.76 (br s, 1H); 8.88 (t,
J=6.1 Hz, 1H); 8.75-8.80* (m, 1H); 8.31 (s, 1H); 8.24* (s, 1H);
7.64 (dd, J=6.5, 2.9 Hz, 1H); 7.57 (dd, J=8.5, 3.7 Hz, 1H); 7.48
(t, J=7.8 Hz, 2H); 7.26 (t, J=7.4 Hz, 1H); 7.20 (s, 1H); 7.19 (d,
J=5.0 Hz, 2H); 7.08 (dd, J=16.6, 10.3 Hz, 1H); 7.03 (dd, J=8.3, 2.3
Hz, 1H); 6.60* (dd, J=16.8, 10.3 Hz, 1H); 6.14 (ddd, J=16.7, 3.8,
2.5 Hz, 1H); 5.65 (td, J=9.9, 2.5 Hz, 1H); 4.31-4.36 (m, 1H);
4.24-4.29* (m, 1H); 3.95-4.01 (m, 1H); 3.68-3.82 (m, 1H); 3.55-3.67
(m, 1H); 3.39-3.49 (m, 2H); 3.39-3.49* (m, 1H); 1.86-2.03 (m, 3H);
1.81-1.89 (m, 1H). LCMS [M+H].sup.+: 502.10.
General Procedure P
One General Procedure for Vinysulfonamide Formation.
##STR00746##
[0685] A solution of 2-chloroethanesulfonyl chloride (1.0 equiv)
and Et.sub.3N (1.0 equiv) in DCM (18 mL/mmol) cooled to 0.degree.
C. was added dropwise to a suspension of secondary amine (38-A/B)
(1.0 equiv) and Et.sub.3N (1.0 equiv) in DCM (18 mL/mmol), also
cooled to 0.degree. C. After 15 minutes, the reaction mixture was
washed with saturated aqueous NaHCO.sub.3 (twice), dried over
MgSO.sub.4 and concentrated under vacuum. The residue was purified
by normal phase chromatography (75%-100% EtOAc/hexanes).
Example 219: Synthesis of
(racemic)-(2-chloro-4-phenoxyphenyl)(4-((1-(vinylsulfonyl)piperidin-3-yl)-
amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (I-322r)
[0686]
(racemic)-(2-Chloro-4-phenoxyphenyl)(4-((1-(vinylsulfonyl)piperidin-
-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone was prepared
according to General Scheme 13 and General Procedure P, using
(racemic)-(2-chloro-4-phenoxyphenyl)(4-(piperidin-3-ylamino)-7H-pyrrolo[2-
,3-d]pyrimidin-5-yl)methanone. .sup.1H NMR 400 MHz (DMSO-d.sub.6):
.delta. 12.75 (br s, 1H); 8.84 (d, J=7.4 Hz, 1H); 8.26 (s, 1H);
7.63 (s, 1H); 7.57 (d, J=8.5 Hz, 1H); 7.46 (s, 2H); 7.24 (t, J=7.4
Hz, 1H); 7.18 (s, 1H); 7.17 (d, J=6.1 Hz, 2H); 7.01 (dd, J=8.5, 2.4
Hz, 1H); 6.79 (dd, J=16.5, 10.0 Hz, 1H); 6.10 (d, J=4.5 Hz, 1H);
6.07 (d, J=11.0 Hz, 1H); 4.24-4.33 (m, 1H); 3.55 (d, J=11.2 Hz,
2H); 3.18-3.23 (m, 1H); 2.88-2.99 (m, 2H); 1.83-1.97 (m, 2H);
1.56-1.72 (m, 2H). LCMS [M+H].sup.+: 538.10.
Example 220: Synthesis of
(racemic)-(2-chloro-4-phenoxyphenyl)(4-(((1-(vinylsulfonyl)pyrrolidin-2-y-
l)methyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone
(I-326r)
[0687]
(racemic)-(2-Chloro-4-phenoxyphenyl)(4-(((1-(vinylsulfonyl)pyrrolid-
in-2-yl)methyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone was
prepared according to General Scheme 13 and General Procedure P,
using
(racemic)-(2-chloro-4-phenoxyphenyl)(4-((pyrrolidin-2-ylmethyl)amino)-7H--
pyrrolo[2,3-d]pyrimidin-5-yl)methanone. .sup.1H NMR 400 MHz
(DMSO-d.sub.6): .delta. 12.75 (s, 1H); 8.85 (dd, J=6.7, 4.7 Hz,
1H); 8.25 (s, 1H); 7.63 (d, J=2.7 Hz, 1H); 7.58 (d, J=8.5 Hz, 1H);
7.48 (dd, J=8.4, 7.3 Hz, 2H); 7.25 (t, J=7.4 Hz, 1H); 7.20 (s, 1H);
7.18 (d, J=6.1 Hz, 2H); 7.03 (dd, J=8.4, 2.3 Hz, 1H); 6.93 (dd,
J=16.5, 10.0 Hz, 1H); 6.52 (s, 1H); 6.15 (d, J=10.2 Hz, 1H); 6.12
(d, J=3.7 Hz, 1H); 3.95-4.01 (m, 1H); 3.86-3.90 (m, 1H); 3.54-3.60
(m, 1H); 3.19-3.27 (m, 2H); 1.88-1.96 (m, 2H); 1.81-1.85 (m, 1H);
1.73-1.77 (m, 1H). LCMS [M+H].sup.+: 538.10.
Example 221: Synthesis of
(racemic)-(2-chloro-4-phenoxyphenyl)(4-((6-(hydroxymethyl)-1-(methylsulfo-
nyl)piperidin-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone
(I-653)
Step 1: Synthesis of
rac-methyl-2-((tert-butoxycarbonyl)amino)-6-(dimethyl(oxo)-16-sulfaneylid-
ene)-5-oxohexanoate (653b)
[0688] To a solution of trimethylsulfonium iodide (4.5 g, 21 mmol)
in dry DMSO (20 mL) is added tBuOK (2.1 g, 18 mmol) and the mixture
is stirred for 1 h at RT. rac-1-(tert-butyl) 2-methyl
5-oxopyrrolidine-1,2-dicarboxylate (653a) (5 g, 21 mmol) is then
added and the mixture is stirred at room temperature for 3h. The
mixture is then quenched by addition of water and extracted with
EtOAc. Combined organic phases are dried over MgSO.sub.4, filtered
and concentrated. Purification by chromatography (DCM/MeOH 9/1)
yielded the title compound.
[0689] .sup.1H NMR (CDCl.sub.3): .delta. 5.44 (d, J=7.4 Hz, 1H),
4.38 (s, 1H), 4.29-4.24 (m, 1H), 3.73 (s, 3H), 3.39-3.38 (m, 6H),
2.33-2.19 (m, 2H), 2.14-2.04 (m, 1H), 1.98-1.89 (m, 1H), 1.42 (s,
9H).
Step 2: Synthesis of rac-1-(tert-butyl) 2-methyl
5-oxopiperidine-1,2-dicarboxylate (653c)
[0690] A solution of methyl
rac-2-((tert-butoxycarbonyl)amino)-6-(dimethyl(oxo)-16-sulfaneylidene)-5--
oxohexanoate (2.7 g, 8.0 mmol) and [Ir(COD)C.sub.1]2 (54 mg, 0.1
mmol) in DCE (80 mL) is degassed by bubbling argon for 20 min. The
mixture is then heated at reflux for 2h. The mixture is then
concentrated and then purified by normal phase chromatography
(gradient from 100% hexane to 100% EtOAc). .sup.1H NMR (CDCl.sub.3,
400 mHz): .delta. 4.82 (t, J=6.7 Hz, 0.5H), 4.58 (t, J=7.0 Hz,
0.5H), 4.43-4.27 (m, 1H), 3.95-3.85 (m, 1H), 3.77 (s, 1H),
2.51-2.28 (m, 3H), 2.21-2.04 (m, 1H), 1.46-1.43 (m, 9H).
Step 3: Synthesis of rac-1-(tert-butyl) 2-methyl
5-hydroxypiperidine-1,2-dicarboxylate (653 d)
[0691] To a solution of rac-1-(tert-butyl) 2-methyl
5-oxopiperidine-1,2-dicarboxylate (5.9 g, 22.9 mmol) in THF (200
mL) at -45.degree. C. is added a solution of L-Selectride (1.0M,
27.5 mL, 37.5 mmol). The mixture is stirred for 1 h at -45.degree.
C. then quenched with saturated aqueous NH.sub.4Cl. The aqueous
phase is extracted with EtOAc. Combined organic phases are dried
over MgSO.sub.4, filtered and concentrated. The crude is purified
by chromatography (gradient from 100% hexane to 100% EtOAc). LCMS
[M+Na].sup.+: 282.1.
Step 4: Synthesis of rac-1-(tert-butyl) 2-methyl 5-((methyl
sulfonyl)oxy)piperidine-1,2-dicarboxylate (653e)
[0692] A solution of rac-1-(tert-butyl) 2-methyl
5-hydroxypiperidine-1,2-dicarboxylate (2.4 g, 9.3 mmol),
methanesulfonyl chloride (788 .mu.L, 10.2 mmol) and triethylamine
(1.9 mL, 13.9 mmol) in DCM (50 mL) is stirred for 3h at room
temperature. The mixture is then washed twice with a sat. aq. sol.
of NaHCO.sub.3, twice with HCl 1M and once with water, dried over
MgSO.sub.4, filtered and concentrated. The crude is used as is in
the next step.
Step 5: Synthesis of rac-1-(tert-butyl) 2-methyl
5-azidopiperidine-1,2-dicarboxylate (653f)
[0693] A solution of rac-1-(tert-butyl) 2-methyl 5-((methyl
sulfonyl)oxy)piperidine-1,2-dicarboxylate (2.70 g, 8.0 mmol) and
sodium azide (3.12 g, 48.0 mmol) in DMF (20 mL) is stirred
overnight at 80.degree. C. After cooling to room temperature the
mixture is diluted in water and extracted with EtOAc. Combined
organic phases are washed with 1M HCl, brine, dried over
MgSO.sub.4, filtered and concentrated. LCMS [M+Na].sup.+:
307.1.
Step 6: Synthesis of rac-tert-butyl
5-azido-2-(hydroxymethyl)piperidine-1-carboxylate (653g)
[0694] To a solution of rac-1-(tert-butyl) 2-methyl
5-azidopiperidine-1,2-dicarboxylate (2.1 g, 7.4 mmol) in THF (70
mL) is added ethanol (1.3 mL, 22.2 mmol) and lithium borohydride
(2M, 11.1 mL, 22.2 mmol) and the mixture is stirred overnight at
room temperature. The mixture is then quenched with sat. aq.
NaHCO.sub.3 and extracted with EtOAc. Combined organic phases are
dried over MgSO.sub.4, filtered and concentrated. The crude is
purified by chromatography (gradient from DCM to DCM/MeOH 9/1).
LCMS [M+Na].sup.+: 279.0.
Step 7: Synthesis of rac-tert-butyl-5-azido-2-(((tert-butyldiphenyl
silyl)oxy)methyl) piperidine-1-carboxylate (653h)
[0695] A mixture of
rac-tert-butyl-5-azido-2-(hydroxymethyl)piperidine-1-carboxylate
(700 mg, 2.73 mmol), TBDPSCl (781 .mu.L, 3.00 mmol) and imidazole
(242 mg, 3.55 mmol) in DMF (10 mL) is stirred overnight at room
temperature. The mixture is then diluted in water and extracted
with EtOAc. Combined organic phases are washed with brine, dried
over MgSO.sub.4, filtered and concentrated. The crude is purified
by chromatography (gradient from hexane to hexane/EtOAc 1/1). LCMS
[M+H-Boc].sup.+: 395.2.
Step 8: Synthesis of
rac-5-azido-2-(((tert-butyldiphenylsilyl)oxy)methyl)piperidin-1-ium
2,2,2-trifluoroacetate (653i)
[0696] To a solution of
rac-tert-butyl-5-azido-2-(((tert-butyldiphenylsilyl)oxy)methyl)piperidine-
-1-carboxylate (1.07 g, 2.17 mmol) in DCM (18 mL) is added TFA (2
mL) and the mixture is stirred for 1 h at RT. The mixture is then
concentrated to dryness, co-evaporated with DCM and the crude is
brought on to the next step without further purification. LCMS
[M+H]: 395.2
Step 9: Synthesis of
rac-5-azido-2-(((tert-butyldiphenylsilyl)oxy)methyl)-1-(methylsulfonyl)
piperidine (653j)
[0697] To a solution of rac-5-azido-2-(((tert-butyldiphenyl
silyl)oxy)methyl)piperidine (150 mg, 0.38 mmol) and triethylamine
(264.9 .mu.L, 1.90 mmol) in DCM (3.75 mL) at 0.degree. C. is added
methanesulfonyl chloride (32.4 .mu.L, 0.42 mmol). The mixture is
stirred for 2h at 0.degree. C. then concentrated and the crude is
purified by chromatography (gradient from 100% hexanes to 50%
EtOAc/hexanes). LCMS [M+Na]: 495.1.
Step 10: Synthesis of
rac-6-(((tert-butyldiphenylsilyl)oxy)methyl)-1-(methylsulfonyl)
piperidin-3-amine (653k)
[0698] To a solution of azide (653j) in methanol (0.1 M) is added
Pd(OH).sub.2/C (10% w/w) and the mixture is stirred under hydrogen
atmosphere at room temperature and atmospheric pressure. The
mixture is then filtered through Celite and concentrated. The crude
is used as is without further purification. LCMS [M+H]: 447.2.
Step 11: Synthesis of
rac-(4-((6-(((tert-butyldiphenylsilyl)oxy)methyl)-1-(methylsulfonyl)piper-
idin-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(2-chloro-4-phenoxyphenyl-
)methanone (6531)
[0699]
rac-(4-((6-(((Tert-butyldiphenylsilyl)oxy)methyl)-1-(methylsulfonyl-
)piperidin-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(2-chloro-4-phenoxy-
phenyl)methanone was prepared according to General Procedure A,
using
rac-6-(((tert-butyldiphenylsilyl)oxy)methyl)-1-(methylsulfonyl)
piperidin-3-amine with 36-A. LCMS [M+H]: 794.3.
Step 12: Synthesis of
rac-(2-chloro-4-phenoxyphenyl)(4-((6-(hydroxymethyl)-1-(methylsulfonyl)pi-
peridin-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone
(I-653)
[0700]
rac-(4-((6-(((Tert-butyldiphenylsilyl)oxy)methyl)-1-(methylsulfonyl-
)piperidin-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(2-chloro-4-phenoxy-
phenyl)methanone in methanolic HCl solution (1.25M) was stirred at
room temperature for 2 hours then concentrated to dryness and
purified by RP chromatography (gradient from 30% to 90% MeCN+0.1%
formic acid in water. Two distinct isomers were observed but kept
together. .sup.1H NMR (DMSO-d.sub.6, 400 MHz): mixture of cis and
trans isomers: .delta. 9.14 (d, J=7.2 Hz, 0.5H), 8.69 (d, J=7.2 Hz,
0.5H), 8.27 (s, 1H), 7.64 (s, 1H), 7.59-7.53 (m, 1H), 7.50-7.46 (m,
1H), 7.28-7.23 (m, 1H), 7.19-7.17 (m, 1H), 7.04-7.01 (m, 1H), 4.95
(bs, 1H), 4.34-4.32 (m, 0.5H), 4.12-3.99 (m, 1.5H), 3.90-3.84 (m,
1.5H), 3.69-3.58 (m, 2H), 3.28-3.25 (m, 1H), 3.04 (s, 1.5H),
3.59-2.84 (m, 2H), 2.07-1.61 (m, 4H). LCMS [M+H]: 556.1.
Example 222: Synthesis of
rac-(2-chloro-4-phenoxyphenyl)(4-((6-(hydroxymethyl)piperidin-3-yl)amino)-
-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (I-343r)
Step 1: Synthesis of
rac-tert-butyl-5-amino-2-(hydroxymethyl)piperidine-1-carboxylate
(343ra)
[0701] Analogous to the preparation of 653k, a solution of azide
(653g) in methanol (0.1 M) is added Pd(OH).sub.2/C (10% w/w) and
the mixture is stirred under hydrogen atmosphere at room
temperature and atmospheric pressure. The mixture is then filtered
through Celite and concentrated. The crude is used as is without
further purification. LCMS [M+H]: 231.2.
Step 2: Synthesis of
rac-tert-butyl-5-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimid-
in-4-yl)amino)-2-(hydroxymethyl)-piperidine-1-carboxylate
(343rb)
[0702]
rac-Tert-butyl-5-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]p-
yrimidin-4-yl)amino)-2-(hydroxymethyl)-piperidine-1-carboxylate was
prepared according General Procedure A, using
rac-tert-butyl-5-amino-2-(hydroxymethyl)piperidine-1-carboxylate
with 36-A. LCMS [M+H]: 578.3.
Step 3: Synthesis of
rac-(2-chloro-4-phenoxyphenyl)(4-((6-(hydroxymethyl)piperidin-3-yl)amino)-
-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (I-343r)
[0703] A solution of tert-butyl
rac-5-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)ami-
no)-2-(hydroxymethyl)piperidine-1-carboxylate (113 mg, 0.19 mmol)
in DCM (3 mL) is treated with trifluoroacetic acid (3 mL) for 1 h.
The mixture is then concentrated to dryness and purified by
preparative HPLC (gradient from 20% to 95% of acetonitrile+0.1%
formic acid). .sup.1H NMR (DMSO-d.sub.6, 400 mHz): .delta. 8.94 (d,
J=6.3 Hz, 0.5H), 8.65 (d, J=7.0 Hz, 0.5H), 8.21 (d, J=5.9 Hz, 1H),
7.61 (d, J=7.4 Hz, 1H), 7.51-7.42 (m, 3H), 7.21-7.19 (m, 1H),
7.15-7.11 (m, 3H), 6.98-6.95 (m, 1H), 5.26 (bs, 0.5H), 5.06 (bs,
0.5H), 4.25-4.30 (m, 1H), 3.54-3.33 (m, 3H), 3.03-2.96 (m, 1.5H),
2.80-2.60 (m, 0.5H), 2.11-2.10 (m, 0.5H), 1.86-1.81 (m, 1.5H),
1.67-1.62 (m, 1.5H), 1.45-1.42 (m, 0.5H). LCMS [M+H]: 478.2.
Example 223: Synthesis of
rac-1-(5-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-
amino)-2-(hydroxymethyl)-piperidin-1-yl)ethan-1-one (I-654)
[0704] A mixture of
rac-(2-chloro-4-phenoxyphenyl)(4-((6-(hydroxymethyl)piperidin-3-yl)amino)-
-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (I-343r) (30 mg, 0.063
mmol), sodium acetate (5.7 mg, 0.069 mmol), EDCI (12.6 mg, 0.066
mmol), HOAt (9.0 mg, 0.066 mmol) and DIPEA (32.8 .mu.L, 0.19 mmol)
in DCM (0.5 mL) is stirred at RT for 24h. The mixture is then
concentrated to dryness and purified by RP (gradient from 35% to
90% MeCN+0.1% formic acid). .sup.1H NMR (DMSO-d.sub.6, 400 mHz):
(mixture of cis/trans, presence of rotamers) .delta. 9.09-9.04 (m,
1H), 8.74-8.69 (m, 1H), 8.44 (s, 1H), 8.26-8.23 (m, 1H), 7.61-7.54
(m, 3H), 7.50-7.46 (m, 3H), 7.27-7.24 (m, 1H), 7.20-7.18 (m, 3H),
7.03-7.01 (m, 1H), 4.98-4.66 (m, 2H), 4.63-4.31 (m, 2H), 4.20-3.89
(m, 3H), 3.75-3.70 (m, 1H), 3.64-3.13 (m, 18H+H.sub.2O), 2.94-2.84
(m, 1H), 2.45-2.39 (m, 1H), 2.12-1.52 (m, 10H). LCMS [M+H]:
520.2.
Example 224: Synthesis of
(2-chloro-4-phenoxyphenyl)(4-(((3R,5S)-5-(hydroxymethyl)
pyrrolidin-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone
(I-345e)
Step 1: Synthesis of tert-butyl
(2S,4R)-4-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl-
)amino)-2-(hydroxymethyl)pyrrolidine-1-carboxylate (345ea)
[0705] Tert-butyl
(2S,4R)-4-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl-
)amino)-2-(hydroxymethyl)pyrrolidine-1-carboxylate was prepared
according to Procedure A using tert-butyl
(2S,4R)-4-amino-2-(hydroxymethyl)pyrrolidine-1-carboxylate and
36-A. LCMS [M+H].sup.+: 564.3, 566.3.
Step 2: Synthesis of
(2-chloro-4-phenoxyphenyl)(4-(((3R,5S)-5-(hydroxymethyl)pyrrolidin-3-yl)a-
mino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (I-345e)
[0706]
(2-Chloro-4-phenoxyphenyl)(4-(((3R,5S)-5-(hydroxymethyl)pyrrolidin--
3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone was prepared
according to General Scheme 15. To a solution of tert-butyl
(2S,4R)-4-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl-
)amino)-2-(hydroxymethyl)-pyrrolidine-1-carboxylate (42 mg, 0.0746
mmol) in DCM (2 mL) was added TFA (1 mL) and the solution stirred 2
h at room temperature. The reaction mixture was concentrated under
reduced pressure and the residue co-distilled with MeCN. The
residue was dissolved in water and lyophilized affording
(2-chloro-4-phenoxyphenyl)(4-(((3R,5S)-5-(hydroxymethyl)pyrrolidin-3-yl)a-
mino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone as the
trifluoroacetate salt (50.5 mg, 0.073 mmol, 98%). .sup.1H NMR
(DMSO-d.sub.6, 400 mHz): .delta. 12.89 (s; 1H); 9.38 (s; 1H); 8.92
(d; J=5.85 Hz; 1H); 8.70 (s; 1H); 8.32 (s; 0.7H); 7.72 (s; 1H);
7.55 (d; J=8.47 Hz; 1H); 7.49 (m; 2H); 7.26 (t; J=7.40 Hz; 1H);
7.18-7.22 (m; 3H); 7.03 (dd; J=8.46; 2.37 Hz; 1H); 4.75-4.79 (m;
1H); 3.90 (t; J=7.26 Hz; 1H); 3.74 (dd; J=11.75; 3.80 Hz; 1H); 3.66
(dd; J=11.53; 5.78 Hz; 1H); 3.60 (dd; J=11.88; 7.00 Hz; 1H);
3.24-3.31 (m; 1H); 2.22 (d; J=7.77 Hz; 1H); 2.16 (s; 1H). LCMS
[M+H].sup.+: 464.20, 466.2.
Example 225: Synthesis of
(2-chloro-4-phenoxyphenyl)(4-(((3R,5S)-5-(hydroxymethyl)-1-methylpyrrolid-
in-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone
(I-342e)
[0707]
(2-Chloro-4-phenoxyphenyl)(4-(((3R,5S)-5-(hydroxymethyl)pyrrolidin--
3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone
trifluoroacetate (68.8 mg, 0.1045 mmol) was suspended in
concentrated ammonium hydroxide solution, water was added and the
mixture lyophilized. The solid residue was dissolved in
2,2,2-trifluoroethanol (2.6 mL). Paraformaldehyde (25.1 mg, 0.8311
mmol) and sodium borohydride (5.5 mg, 0.1463 mmol) were added and
the mixture stirred at room temperature overnight. MeOH (1 mL) was
added and the mixture stirred 30 min at RT. The solution was
concentrated under reduced pressure. The residue was dissolved in
water (1 mL) and DMSO (0.5 mL), filtered through a Teflon filter
and purified by preparative HPLC, 10% MeCN (5 min), 5% to 80% MeCN
(30 min) in water, the tubes containing the product were
lyophilized affording
(2-chloro-4-phenoxyphenyl)(4-(((3R,5S)-5-(hydroxymethyl)-1-methylpyrrolid-
in-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (18 mg,
0.0344 mmol, 33%). .sup.1H NMR (DMSO-d.sub.6, 400 mHz): .delta.
8.84 (d; J=6.81 Hz; 1H); 8.25 (s; 2H); 7.62 (s; 1H); 7.58 (d;
J=8.45 Hz; 1H); 7.46-7.50 (m; 2H); 7.26 (t; J=7.34 Hz; 1H);
7.18-7.20 (m; 3H); 7.02 (dd; J=8.46; 2.36 Hz; 1H); 4.50-4.54 (m;
1H); 3.45-3.49 (m; 2H); 3.33 (m; 2H); 2.34 (s; 3H); 2.21 (t; J=8.54
Hz; 1H); 2.13 (dt; J=13.03; 8.02 Hz; 1H); 1.76-1.83 (m; 1H). LCMS
[M+H].sup.+: 478.25, 480.20.
Example 226: Synthesis of
1-((2S,4R)-4-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-
-yl)amino)-2-(hydroxymethyl)pyrrolidin-1-yl)ethan-1-one (I-655)
[0708]
1-((2S,4R)-4-((5-(2-Chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]pyrim-
idin-4-yl)amino)-2-(hydroxymethyl)pyrrolidin-1-yl)ethan-1-one was
prepared according to General Scheme 15. A solution of
(2-chloro-4-phenoxyphenyl)(4-(((3R,5S)-5-(hydroxymethyl)pyrrolidin-3-yl)a-
mino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (30 mg, 0.0434
mmol) was dissolved in 0.3 mL 1N HCl and 5 mL water and
lyophilized. The product was dissolved in DMF (0.4 mL). DIPEA
(16.61 ml, 0.0954 mmol) was added and the solution was stirred 30
min at room temperature. AcONa (3.7 mg, 0.0455 mmol), HOAt (5.9 mg,
0.0434 mmol) and EDCI (8.3 mg, 0.0434 mmol) were added at room
temperature and the reaction mixture stirred overnight. The crude
was diluted with DMF, water was added and the solution concentrated
under reduced pressure. The residue was dissolved in water (1 mL)
and DMSO (0.5 mL), filtered through a Teflon filter and purified by
preparative HPLC, 10% MeCN (5 min), 5% to 80% MeCN (30 min) in
water.
1-((2S,4R)-4-((5-(2-chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-d]p-
yrimidin-4-yl)amino)-2-(hydroxymethyl) pyrrolidin-1-yl)ethan-1-one
(23.5 mg, 0.0452 mmol, 46%) was isolated as a white solid after
lyophilization. .sup.1H NMR (DMSO-d.sub.6, 400 mHz): .delta. 8.88
(t; J=6.02 Hz; 1H); 8.44 (s; 0.3H); 8.27 (d; J=3.14 Hz; 1H); 7.62
(d; J=3.06 Hz; 1H); 7.57 (dd; J=8.46; 1.82 Hz; 1H); 7.46-7.50 (m;
2H); 7.25 (t; J=7.40 Hz; 1H); 7.18-7.20 (m; 3H); 7.02 (dd; J=8.45;
2.37 Hz; 1H); 4.78-4.87 (m; 1.7H); 4.10 (d; J=6.86 Hz; 1H); 3.94
(dd; J=10.29; 6.78 Hz; 0.7H); 3.64 (t; J=6.50 Hz; 0.3H); 2.33-2.37
(m; 3.3H); 2.03 (s; 1H); 1.97-2.00 (m; 1H); 1.95 (s; 2H). LCMS
[M+H].sup.+: 506.2, 508.2.
Example 227: Synthesis of
(2-chloro-4-phenoxyphenyl)(4-(((3R,5S)-5-(hydroxymethyl)-1-(methylsulfony-
l)pyrrolidin-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone
(I-656)
Step 1: Synthesis of tert-butyl
(2S,4R)-4-azido-2-(((tert-butyldiphenylsilyl)oxy)methyl)
pyrrolidine-1-carboxylate (656a)
[0709] To a solution of tert-butyl
(2S,4R)-4-azido-2-(hydroxymethyl)pyrrolidine-1-carboxylate (see J.
Org. Chem. 2003, 68, 4439-4445 for preparation procedures) (400 mg,
1.65 mmol) in DMF (8.2 mL), TBDPSCl (472 mL, 1.82 mmol) and
imidazole (123.6 mg, 1.82 mmol) were added and the reaction mixture
was stirred overnight at room temperature. The crude mixture was
diluted with EtOAc, washed with water and brine, dried over
anhydrous sodium sulfate and concentrated tio drieness. The crude
mixture was purified by flash chromatography, ISCO, 12 g column,
(EtOAc/hexanes mixture) 0% EtOAc (3 min), 0% to 5% EtOAc (12 min,
5% EtOAc (3 min) affording tert-butyl
(2S,4R)-4-azido-2-(((tert-butyldiphenylsilyl)oxy)methyl)pyrrolidine-1-car-
boxylate (570 mg, 1.1858 mmol, 72%) as a transparent oil. .sup.1H
NMR (CDCl.sub.3, 400 mHz): .delta. 7.72 (dd; J=7.39; 1.88 Hz; 1H);
7.62-7.64 (m; 2H); 7.36-7.43 (m; 5H); 3.96-4.17 (m; 2H); 3.49-3.75
(m; 2H); 2.24 (t; J=46.59 Hz; 1H); 1.59 (s; 1H); 1.48 (s; 2H); 1.07
(s; 4H); 1.05 (s; 5H). LCMS
Step 2: Synthesis of
(2S,4R)-4-azido-2-(((tert-butyldiphenylsilyl)oxy)methyl)pyrrolidine
(656b)
[0710] To a solution of tert-butyl
(2S,4R)-4-azido-2-(((tert-butyldiphenylsilyl)oxy)methyl)pyrrolidine-1-car-
boxylate (42 mg, 0.0746 mmol) in DCM (2 mL) was added TFA (1 mL)
and the solution stirred 2 h at room temperature. The reaction
mixture was concentrated under reduced pressure and the residue
codestilled with MeCN. The residue was suspended in EtOAc, washed
with saturated sodium bicarbonate, dried over anhydrous sodium
sulfate and concentrated under reduced pressure affording
(2S,4R)-4-azido-2-(((tert-butyldiphenylsilyl)oxy)methyl)pyrrolidine
as the TFA salt (50.5 mg, 0.073 mmol, 98%). LCMS 381.3
[M+H].sup.+.
Step 3: Synthesis of
(2S,4R)-4-azido-2-(((tert-butyldiphenylsilyl)oxy)methyl)-1-(methylsulfony-
l)pyrrolidine (656c)
[0711]
(2S,4R)-4-Azido-2-(((tert-butyldiphenylsilyl)oxy)methyl)pyrrolidine
(70 mg, 0.18 mmol) was dissolved in 0.5 mL of dry dichloromethane,
cooled to 0.degree. C., DIPEA (128 mL, 0.74 mmol) was added
followed by methanesulfonyl chloride (15.7 mL, 22.42 mmol). The
reaction mixture was stirred at room temperature under N.sub.2 for
about 8 hours and diluted with dichloromethane. The reaction
mixture was washed with 1N HCl, saturated aqueous Na.sub.2CO.sub.3
and water. The organic phase was dried over anhydrous sodium
sulfate and concentrated under reduced pressure affording
(2S,4R)-4-azido-2-(((tert-butyldiphenylsilyl)oxy)methyl)-1-(met-
hylsulfonyl) pyrrolidine (42.3 mg, 0.0922 mmol, 50%) as a white
solid. .sup.1H NMR (CDCl.sub.3, 400 mHz): .delta. 7.66 (m; 4H);
7.37-7.46 (m; 6H); 4.21 (t; J=4.01 Hz; 1H); 3.81-3.87 (m; 3H);
3.46-3.55 (m; 2H); 2.84 (s; 3H); 2.30-2.36 (m; 1H); 2.21 (m; 1H);
1.08 (s; 9H). LCMS 481.2 [M+Na].sup.+.
Step 4: Synthesis of
(3R,5S)-5-(((Tert-butyldiphenylsilyl)oxy)methyl)-1-(methylsulfonyl)
pyrrolidin-3-amine (656d)
[0712] A mixture of
(2S,4R)-4-azido-2-(((tert-butyldiphenylsilyl)oxy)methyl)-1-(methylsulfony-
l) pyrrolidine (42.3 mg, 0.09 mmol) and 10% palladium on carbon (5
mg) in methanol (10 mL) was stirred under 1 atm of hydrogen at room
temperature for 16 h. The catalyst was filtered off through a
Teflon filter and the filtrate afforded
(3R,5S)-5-(((tert-butyldiphenylsilyl)oxy)methyl)-1-(methylsulfonyl)pyrrol-
idin-3-amine (39 mg, 0.0901 mmol, 98%) as an oil after evaporation.
LCMS 433.2 [M+H].sup.+.
Step 5: Synthesis of
(4-(((3R,5S)-5-(((tert-butyldiphenylsilyl)oxy)methyl)-1-(methylsulfonyl)p-
yrrolidin-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(2-chloro-4-phenoxyp-
henyl)methanone (656e)
[0713]
(4-(((3R,5S)-5-(((Tert-butyldiphenylsilyl)oxy)methyl)-1-(methylsulf-
onyl)
pyrrolidine-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(2-chloro-4--
phenoxyphenyl) methanone was prepared according General Procedure A
with (3R,5S)-5-(((tert-butyl
diphenylsilyl)oxy)methyl)-1-(methylsulfonyl)pyrrolidin-3-amine
(656d) and 36-A. LCMS 780.3, 782.3 [M+H].sup.+.
Step 6: Synthesis of
(2-chloro-4-phenoxyphenyl)(4-(((3R,5S)-5-(hydroxymethyl)-1-(methylsulfony-
l)pyrrolidin-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone
(I-656)
[0714]
(2-Chloro-4-phenoxyphenyl)(4-(((3R,5S)-5-(hydroxymethyl)-1-(methyls-
ulfonyl)pyrrolidin-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone
was prepared according to General Scheme 16. A solution of
(4-(((3R,5S)-5-(((tert-butyldiphenylsilyl)oxy)methyl)-1-methylpyrrolidin--
3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(2-chloro-4-phenoxyphenyl)meth-
anone (83.4 mg, 0.116 mmol) in 1.25N HCl in MeOH was stirred
overnight at room temperature. The reaction mixture was
concentrated under reduced pressure and the residue purified by
preparative HPLC (5% to 80% MeCN in water, 0.1% TFA, 30 min)
affording
(4-(((3R,5S)-5-(((tert-butyldiphenylsilyl)oxy)methyl)-1-(methylsulfonyl)p-
yrrolidin-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(2-chloro-4-phenoxyp-
henyl)methanone (11.9 mg, 0.022 mmol, 32%) as a white solid after
lyophilization. .sup.1H NMR (DMSO-d.sub.6, 400 mHz): .delta. 8.87
(d; J=6.13 Hz; 1H); 8.37 (s; 0.2H); 8.30 (s; 1H); 7.67 (s; 1H);
7.56 (d; J=8.46 Hz; 1H); 7.48 (m; 2H); 7.25 (t; J=7.40 Hz; 1H);
7.19 (m; 3H); 7.03 (dd; J=8.45; 2.37 Hz; 1H); 4.96 (br s; 1H); 4.70
(d; J=6.59 Hz; 1H); 3.86 (s; 1H); 3.72 (dd; J 10.15; 5.62 Hz; 1H);
3.61 (d; J=8.71 Hz; 1H); 3.46 (t; J=8.81 Hz; 1H); 3.30-3.32 (m;
1H); 2.89 (s; 3H); 2.36-2.42 (m; 1H); 2.11-2.18 (m; 1H). LCMS
[M+H].sup.+:542.2, 544.2.
Example 228: Synthesis of
(2-chloro-4-phenoxyphenyl)(4-((((3R,5S)-5-(hydroxymethyl)pyrrolidin-3-yl)-
methyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone
(I-369e)
Step 1: Synthesis of 1-(tert-butyl) 2-methyl (2S,4S)-4-((methyl
sulfonyl)oxy)pyrrolidine-1,2-dicarboxylate (369ea)
[0715] To a solution of 1-(tert-butyl) 2-methyl
(2S,4S)-4-hydroxypyrrolidine-1,2-dicarboxylate (10 g, 40.766 mmol)
in DCM (100 mL) at 0.degree. C. was added MsCl (3.8 mL, 49.096
mmol) followed by slow addition of DIPEA (8.5 mL, 48.801 mmol).
After the addition, the reaction mixture was allowed to warm up to
rt and stirred for 5 hours. The reaction mixture was poured into a
cooled aqueous saturated NH.sub.4Cl (250 mL). The layers were
partitioned and the aqueous layer was extracted with DCM (80 mL).
The combined organic layers were washed with aqueous saturated
NaHCO.sub.3(250 mL), water (250 mL) and brine. It was dried over
MgSO.sub.4, filtered and concentrated to dryness to afford 13 g of
the desired product as a yellow oil which was used as such in the
subsequent step without further purification.
Step 2: Synthesis of tert-butyl
(2S,4S)-2-(hydroxymethyl)-4-((methylsulfonyl)oxy)
pyrrolidine-1-carboxylate (369eb)
[0716] To a solution of 1-(tert-butyl) 2-methyl
(2S,4S)-4-((methylsulfonyl)oxy)pyrrolidine-1,2-dicarboxylate (500
mg, 1.546 mmol) in THE (125 mL) at 0.degree. C. was added
LiBH.sub.4 (2 M, 39 mL, 78.0 mmol) followed by slow addition of
methanol (3.13 mL, 77.27 mmol). The reaction mixture was allowed to
warm up slowly to rt and stirred at rt for 18 h. Acetone (10 mL)
was added slowly, stirred for 1 h, then the mixture was poured into
a cooled aqueous saturated NH.sub.4Cl (300 mL). The mixture was
extracted with EtOAc (2.times.80 mL). The combined organic layers
were washed with water (100 mL) and brine, dried over MgSO.sub.4,
filtered and concentrated to dryness to afford 11.37 g of the
desired product as a colorless solid which was used as such in the
subsequent step without further purification. LCMS [M+Na].sup.+:
318.1.
Step 3: Synthesis of tert-butyl
(2S,4S)-2-(((tert-butyldiphenylsilyl)oxy)methyl)-4-((methylsulfonyl)oxy)--
pyrrolidine-1-carboxylate (369ec)
[0717] To a solution of tert-butyl
(2S,4S)-2-(hydroxymethyl)-4-((methylsulfonyl)oxy)pyrrolidine-1-carboxylat-
e (11.37 g, 35.16 mmol) in DCM (100 mL) at rt were added imidazole
(4.8 g, 70.505 mmol) and TBDPS-Cl (11.0 mL, 42.30 mmol). The
reaction mixture was stirred at rt for 18 hours. The mixture was
diluted with water (100 mL) and DCM (50 mL). The layers were
partitioned and DCM layer was washed with brine, dried over
MgSO.sub.4, filtered and concentrated to dryness to afford 18.5 g
of the desired product as a colorless gum which was used as such in
the subsequent step without further purification. LCMS
[M+Na].sup.+: 556.3.
Step 4: Synthesis of tert-butyl
(2S,4S)-2-(((tert-butyldiphenylsilyl)oxy)methyl)-4-((methylsulfonyl)oxy)--
pyrrolidine-1-carboxylate (369ed)
[0718] To a solution of tert-butyl
(2S,4S)-2-(((tert-butyldiphenylsilyl)oxy)methyl)-4-((methylsulfonyl)oxy)p-
yrrolidine-1-carboxylate (18 g, 33.723 mmol) in DMF (100 mL) at rt
was added sodium cyanide (2 g, 40.808 mmol). The reaction mixture
was heated to 80.degree. C. for 18 hours. Upon cooling to rt, the
reaction mixture was diluted with EtOAc (30 mL) and water (30 mL).
The layers were partitioned and the aqueous layer was extracted
with EtOAc (15 mL). The combined organic layers were washed with
brine, dried over MgSO.sub.4, filtered and concentrated to dryness.
The residue was purified by flash chromatography on silica gel
eluting with 10 and 15% EtOAc/hexanes to afford 6 g of the desired
material as a colorless gum. LCMS [M+Na].sup.+: 487.3.
Step 5: Synthesis of tert-butyl
(2S,4S)-4-(aminomethyl)-2-(((tert-butyldiphenylsilyl)
oxy)methyl)pyrrolidine-1-carboxylate (369ee)
[0719] To a solution of tert-butyl
(2S,4S)-2-(((tert-butyldiphenylsilyl)oxy)methyl)-4-((methylsulfonyl)oxy)p-
yrrolidine-1-carboxylate (220 mg, 0.473 mmol) in ethanol (3 mL) at
0.degree. C. was added nickel chloride (II) (62 mg, 0.478 mmol)
followed by portion wise addition of NaBH.sub.4 (68 mg, 1.798
mmol). The reaction mixture was allowed to stir at rt for 6 hours.
TLC showed complete reaction. The mixture was cooled to 0.degree.
C. and 10% NH.sub.4OH (20 mL) was added slowly, extracted with
EtOAc (2.times.25 mL). The combined organic layers were washed with
water (2.times.20 mL) and brine (20 mL), dried over MgSO.sub.4,
filtered and concentrated to dryness to afford 200 mg of the
desired product as a light yellow oil. The crude material was used
as such in the subsequent step without further purification. LCMS
[M+Na].sup.+: 491.3.
Step 6: Synthesis of tert-butyl
(2S,4S)-2-(((tert-butyldiphenylsilyl)oxy)methyl)-4-(((5-(2-chloro-4-pheno-
xybenzoyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)methyl)pyrrolidine-1-carb-
oxylate (369ef)
[0720] Prepared according to General Procedure A using tert-butyl
(2S,4S)-4-(aminomethyl)-2-(((tert-butyldiphenylsilyl)oxy)methyl)pyrrolidi-
ne-1-carboxylate and 36-A. LCMS [M+H].sup.+: 816.3.
Step 7: Synthesis of
(2-chloro-4-phenoxyphenyl)(4-((((3R,5S)-5-(hydroxymethyl)pyrrolidin-3-yl)-
methyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone
(I-369e)
[0721]
(2-Chloro-4-phenoxyphenyl)(4-((((3R,5S)-5-(hydroxymethyl)pyrrolidin-
-3-yl)methyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone was
prepared according to General Error! Reference source not found.
using General Procedure. Product was isolated as a formate salt
after reverse phase purification (Biotage C18, 5-80%
CH.sub.3CN/H.sub.2O+0.1% formic acid). .sup.1H NMR (DMSO-d.sub.6,
400 mHz): .delta. 8.84 (t; J=5.66 Hz; 1H); 8.35 (s; 1H); 8.24 (s;
1H); 7.63 (s; 1H); 7.58 (d; J=8.46 Hz; 1H); 7.48 (t; J=7.82 Hz;
2H); 7.25 (t; J=7.40 Hz; 1H); 7.18-7.20 (m; 3H); 7.02 (dd; J=8.45;
2.37 Hz; 1H); 3.55-3.60 (m; 2H); 3.40-3.48 (m; 4H); 3.22 (dd;
J=11.02; 7.02 Hz; 1H); 2.82 (dd; J=10.96; 7.04 Hz; 1H); 2.54-2.60
(m; 1H); 1.73-1.78 (m; 2H). NH of indole not observed. LCMS
[M+H].sup.+: 478.1.
Example 229: Synthesis of
(2-chloro-4-phenoxyphenyl)(4-((((3S,5S)-5-(hydroxymethyl)-1-methylpyrroli-
din-3-yl)methyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone
(I-370e)
[0722] To a solution of
(2-chloro-4-phenoxyphenyl)(4-((((3R,5S)-5-(hydroxymethyl)pyrrolidin-3-yl)-
methyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (500 mg,
1.372 mmol) in 2,2,2-trifluoroethanol (5 mL) at rt were added
paraformaldehyde (330 mg, 10.989 mmol) and sodium borohydride (73
mg, 1.930 mmol). The reaction mixture was stirred at rt for 18
hours. LCMS showed complete reaction. The reaction mixture was
diluted with (1:1) aqueous sat. NaHCO.sub.3/water (30 mL) and EtOAc
(30 mL). The layers were partitioned and the aqueous layer was
extracted with EtOAc (20 mL). The combined organic layers were
washed with brine, dried over MgSO.sub.4, filtered and concentrated
to dryness. The residue was purified by reverse phase C18 ISCO
CombiFlash (13 g column) eluting with 5-80% CH.sub.3CN/water (0.1%
formic acid) over 25 minutes. The product fractions were combined
and concentrated to dryness. The residue was freeze dried to afford
22 mg of the title compound as a colorless powder. .sup.1H NMR
(DMSO-d.sub.6, 400 mHz): .delta. 8.79 (t; J=5.41 Hz; 1H); 8.24 (s;
2H); 7.62 (s; 1H); 7.58 (d; J=8.46 Hz; 1H); 7.48 (dd; J=8.45; 7.27
Hz; 2H); 7.25 (t; J=7.39 Hz; 1H); 7.18-7.20 (m; 3H); 7.02 (dd;
J=8.44; 2.37 Hz; 1H); 3.55 (t; J=6.31 Hz; 2H); 3.43 (dd; J 10.90;
4.63 Hz; 1H); 3.30 (dd; J=10.90; 5.90 Hz; 1H); 3.17 (t; J=7.86 Hz;
1H); 2.41-2.46 (m; 2H); 2.33 (s; 3H); 2.13 (t; J=9.33 Hz; 1H);
1.77-1.82 (m; 1H); 1.67-1.72 (m; 1H). LCMS [M+H].sup.+: 492.3.
Example 230: Synthesis of
(4-((((3S,5S)-1-benzyl-5-(hydroxymethyl)pyrrolidin-3-yl)methyl)amino)-7H--
pyrrolo[2,3-d]pyrimidin-5-yl)(2-chloro-4-phenoxyphenyl)methanone
(I-657)
Step 1: Synthesis of
(3R,5S)-5-(((tert-butyldiphenylsilyl)oxy)methyl)pyrrolidine-3-carbonitril-
e (657a)
[0723] Tert-butyl
(2S,4R)-2-(((tert-butyldiphenylsilyl)oxy)methyl)-4-cyanopyrrolidine-1-car-
boxylate (3 g, 4.639 mmol) in DCM (30 mL) at 0.degree. C. was added
TFA (10 mL, 130.591 mmol). The reaction mixture was allowed to stir
at rt for 3 hours. Toluene (15 mL) was added and the volatiles were
removed under reduced pressure. The residue was dissolved in EtOAc
(40 mL) and aqueous sat. NaHCO.sub.3(50 mL) was added (pH.about.8).
The layers were partitioned and the aqueous layer was extracted
with EtOAc (30 mL). The combined organic layers were washed with
brine, dried over MgSO.sub.4, filtered and concentrated to dryness
under reduced pressure to 1.7 g of the desired product as a red
oil. This crude material was used as such in the subsequent step
without further purification. LCMS [M+H].sup.+: 365.3.
Step 2: Synthesis of
(3R,5S)-1-benzyl-5-(((tert-butyldiphenylsilyl)oxy)methyl)pyrrolidine-3-ca-
rbonitrile (657b)
[0724] To a solution of
(3R,5S)-5-(((tert-butyldiphenylsilyl)oxy)methyl)pyrrolidine-3-carbonitril-
e (500 mg, 1.372 mmol) in acetonitrile (5 mL) at rt were added
potassium carbonate (569 mg, 4.117 mmol) and benzyl bromide (0.163
mL, 1.370 mmol). The reaction mixture was stirred at rt for 18
hours. LCMS showed complete reaction. The reaction mixture was
diluted with water (30 mL) and EtOAc (30 mL). The layers were
partitioned and the aqueous layer was extracted with EtOAc (20 mL).
The combined organic layers were washed with brine, dried over
MgSO.sub.4, filtered and concentrated to dryness. The residue was
purified by ISCO CombiFlash (24 g column) eluting with 0-50%
EtOAc/hexanes to afford 480 mg of the desired product as a
colorless oil. LCMS [M+H].sup.+: 455.1.
Step 3: Synthesis of
(((3S,5S)-1-benzyl-5-(((tert-butyldiphenylsilyl)oxy)methyl)pyrrolidin-3-y-
l)methanamine (657c)
[0725] To a solution of
(3R,5S)-1-benzyl-5-(((tert-butyldiphenylsilyl)oxy)methyl)pyrrolidine-3-ca-
rbonitrile (480 mg, 1.056 mmol) in ethanol (4 mL) at 0.degree. C.
was added nickel chloride (II) (137 mg, 1.057 mmol) followed by
portion wise addition of NaBH.sub.4 (152 mg, 4.018 mmol). The
reaction mixture was allowed to stir at rt for 6 hours. Additional
nickel chloride (II) (137 mg, 1.057 mmol) followed by portionwise
addition of NaBH.sub.4 (152 mg, 4.018 mmol) and the mixture was
allowed to stir at rt for 18 hours. The mixture was cooled to
0.degree. C. and 10% NH.sub.4OH (20 mL) was added slowly, extracted
with EtOAc (2.times.30 mL). The combined organic layers were washed
with water (2.times.30 mL) and brine (30 mL), dried over
MgSO.sub.4, filtered and concentrated to dryness to afford 430 mg
of the desired product as a light yellow oil. The crude material
was used as such in the subsequent step without further
purification. LCMS [M+H].sup.+: 459.3.
Step 4: Synthesis of
(4-((((3S,5S)-1-benzyl-5-(((tert-butyldiphenylsilyl)oxy)methyl)
pyrrolidin-3-yl)methyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(2-chloro-4-
-phenoxyphenyl)methanone (657d)
[0726] According to General Procedure A, using
(4-((((3S,5S)-1-benzyl-5-(((tert-butyl diphenylsilyl)oxy)methyl)
pyrrolidin-3-yl)methyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(2-chloro-4-
-phenoxyphenyl)methanone and
((3S,5S)-1-benzyl-5-(((tert-butyldiphenylsilyl)oxy)methyl)pyrrolidin-3-yl-
)methanamine. LCMS [M+H].sup.+: 806.4.
Step 5: Synthesis of
(4-((((3S,5S)-1-benzyl-5-(hydroxymethyl)pyrrolidin-3-yl)methyl)amino)-7H--
pyrrolo[2,3-d]pyrimidin-5-yl)(2-chloro-4-phenoxyphenyl)methanone
(I-657)
[0727]
(4-((((3S,5S)-1-benzyl-5-(hydroxymethyl)pyrrolidin-3-yl)methyl)amin-
o)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(2-chloro-4-phenoxyphenyl)methanone
was prepared according to General Procedure H. The product was
isolated as formate salt after purification (Biotage C18, 5-85%
acetonitrile in water+0.1% formic acid). .sup.1H NMR (DMSO-d.sub.6,
400 mHz): .delta. 12.71 (br s; 1H); 8.74-8.77 (m; 1H); 8.22 (s;
1H); 7.60 (s; 1H); 7.56 (d; J=8.46 Hz; 1H); 7.46-7.50 (m; 2H);
7.26-7.32 (m; 5H); 7.16-7.23 (m; 4H); 7.02 (dd; J=8.45; 2.37 Hz;
1H); 4.03-4.06 (m; 1H); 3.51-3.54 (m; 2H); 3.28-3.46 (m; 3H); 2.99
(dd; J=8.87; 6.52 Hz; 1H); 2.74-2.79 (m; 1H); 2.33-2.46 (m; 1H);
2.08-2.13 (m; 1H); 1.82-1.89 (m; 1H); 1.68-1.75 (m; 1H). Contained
0.48 eq. of formic acid at 8.14 ppm. LCMS [M+H].sup.+: 568.3.
Example 231: Synthesis of
(2-chloro-4-phenoxyphenyl)(4-((((2R,5S)-5-(hydroxymethyl)tetrahydrofuran--
2-yl)methyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone
(I-362e)
[0728]
(2-Chloro-4-phenoxyphenyl)(4-((((2R,5S)-5-(hydroxymethyl)tetrahydro-
furan-2-yl)methyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone
was prepared according to General Procedure A, using 36-A and
((2S,5R)-5-(aminomethyl)tetrahydrofuran-2-yl)methanol. .sup.1H NMR
(DMSO-d.sub.6, 400 mHz): .delta. 8.82 (t; J=5.57 Hz; 1H); 8.43 (s;
0.16H); 8.22 (s; 1H); 7.6 (s, 1H), 7.57 (m; 2H); 7.48 (d; J=8.45
Hz; 1H); 7.25 (t; J=7.40 Hz; 1H); 7.18-7.20 (m; 3H); 7.03 (dd;
J=8.44; 2.37 Hz; 1H); 4.61 (s; 1H); 4.10 (t; J=5.74 Hz; 1H); 3.87
(t; J=5.91 Hz; 1H); 3.61-3.72 (m; 2H); 3.37-3.47 (m; 2H); 1.86-1.95
(m; 2H); 1.63-1.69 (m; 2H). LCMS [M+H].sup.+: 479.2, 481.2.
Example 232: Synthesis of
racemic-cis-(2-chloro-4-phenoxyphenyl)(4-(((6-(hydroxymethyl)piperidin-2--
yl)methyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone
(I-359e)
Step 1: Synthesis of methyl 6-((hydroxyimino)methyl)picolinate
(359ea)
[0729] To methyl 5-formylpicolinate (1.0 g, 6.055 mmol) dissolved
in ethanol-water (14.4 mL, 2:1) was added hydroxylamine
hydrochloride (0.463 g, 6.66 mmol) and sodium acetate (0.546 mg,
0.6661 mmol). The reaction mixture was stirred overnight at
55.degree. C. The reaction was concentrated under reduced pressure
and redissolved in EtOAc (100 mL). The organic phase was washed
with water, dried over sodium sulfate, filtered and concentrated
under reduced pressure. The solid residue was dissolved triturated
with EtOAc, filtered and dried under reduced pressure affording
methyl 6-(hydroxyimino)methyl)picolinate (990 mg, 5.495 mmol, 91%)
as a beige solid. LCMS [M+H].sup.+: 181.1.
Step 2: Synthesis of racemic-cis-methyl
6-(aminomethyl)piperidine-2-carboxylate dihydrochloride (359eb)
[0730] To a suspension of methyl 6-(hydroxyimino)methyl)picolinate
(200 mg, 1.161 mmol) and PtO.sub.2 (26.37 mg, 0.116 mmol) in EtOH
(5.8 mL), conc. HCl (0.2 mL) was added and the mixture was stirred
over night under hydrogen (1 atm), the crude was filtered through
Celite and concentrated under reduced pressure. The residue was
dissolved in water and lyophilized affording a cis-isomer mixture
of methyl 6-(aminomethyl)piperidine-2-carboxylate dihydrochloride
(343 mg, 1.366 mmol, 100%) as a white solid. .sup.1H NMR (D.sub.2O,
400 mHz): .delta. 4.03 (dd; J=12.04; 3.58 Hz; 1H); 3.71 (s; 23H);
3.49 (dtd; J=12.46; 6.29; 2.93 Hz; 1H); 3.29 (dd; J=13.80; 5.98 Hz;
1H); 3.16 (dd; J=13.81; 6.76 Hz; 1H); 2.24 (d; J=10.21 Hz; 1H);
1.91-1.99 (m; 2H); 1.52-1.64 (m; 2H); 1.43 (t; J=13.38 Hz; 1H).
LCMS [M+H].sup.+: 173.2.
Step 3: Synthesis of racemic-cis-1-benzyl 2-methyl
6-((((benzyloxy)carbonyl) amino)
methyl)piperidine-1,2-dicarboxylate (359ec)
[0731] A cis-isomer mixture of methyl
6-(aminomethyl)piperidine-2-carboxylate dihydrochloride (300 mg,
1.195 mmol), CbzCl (374 mL, 2.63 mmol), saturated sodium
bicarbonate in water (6.5 mL) and dioxane (6.5 mL) was stirred
overnight at room temperature. The mixture was diluted with EtOAc,
the phases separated. The aqueous phase extracted with EtOAc. The
combined organic phases were combined and dried over anhydrous
sodium sulfate. The solution was concentrated under reduced
pressure and the residue purified bu flash chromatography (ISCO, 12
g column, EtOAc in hexanes) affording a cis-isomer mixture of
1-benzyl 2-methyl 6-((((benzyloxy)
carbonyl)amino)methyl)piperidine-1,2-dicarboxylate (OS03-034A1)
(543.1 mg, 1.23 mmol, 62%) as a transparent syrup. LCMS
[M+H].sup.+: 441.3.
Step 4: Synthesis of racemic-cis-benzyl
2-((((benzyloxy)carbonyl)amino)methyl)-6-(hydroxymethyl)piperidine-1-carb-
oxylate (359ed)
[0732] A solution of 2M lithium borohydride in THF (0.62 mL, 1.23
mmol) was added to a solution of a mixture of cis-isomers of
1-benzyl 2-methyl 6-((((benzyloxy)carbonyl)amino)methyl)
piperidine-1,2-dicarboxylate (543.1 mg, 1.23 mmol) in diethylether
(3.5 mL) at 0.degree. C. The reaction mixture was stirred at
0.degree. C. 2 h. A saturated aqueous sodium bicarbonate solution
was added dropwise, the mixture was stirred 1 h at room
temperature. The layers were separated. The aqueous layer extracted
with diethyl ether, the organic phased were combined, dried over
anhydrous sodium sulfate and concentrated under reduced pressure
affording a cis-isomer mixture of benzyl
2-((((benzyloxy)carbonyl)amino)methyl)-6-(hydroxymethyl)piperidine-1-carb-
oxylate (270 mg, 0.654 mmol, 100%) as transparent syrup. LCMS
[M+H].sup.+: 413.2.
Step 5: Synthesis of
racemic-cis-6-(aminomethyl)piperidin-2-yl)methanol (359ee)
[0733] To a suspension of a cis-isomer mixture of benzyl
2-((((benzyloxy)carbonyl)amino)methyl)-6-(hydroxymethyl)piperidine-1-carb-
oxylate (270 mg, 0.654 mmol) and 20% palladium hydroxide on carbon
(130 mg) in MeOH (15 mL), 1N HCl (2 mL) was added and the mixture
was stirred overnight under hydrogen (1 atm), the crude was
filtered through Celite and concentrated under reduced pressure.
The residue was dissolved in water and lyophilized affording a
cis-isomer mixture of 6-(aminomethyl)piperidin-2-yl)methanol
dihydrochloride (140 mg, 0.65 mmol, 100%) as a white solid. LCMS
[M+H].sup.+: 145.1.
Step 6: Synthesis of
racemic-cis-(2-chloro-4-phenoxyphenyl)(4-(((6-(hydroxymethyl)
piperidin-2-yl)methyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone
(I-359e)
[0734]
Racemic-cis-(2-chloro-4-phenoxyphenyl)(4-(((6-(hydroxymethyl)
piperidin-2-yl)methyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone
was prepared according to General Procedure A, using a cis-isomer
mixture of 6-(aminomethyl)piperidin-2-yl)methanol dihydrochloride
and 36-A. .sup.1H NMR (DMSO-d.sub.6, 400 mHz): .delta. 8.86 (t;
J=5.71 Hz; 1H); 8.32 (s; 0.1H); 8.25 (s; 2H); 7.63 (s; 1H); 7.57
(d; J=8.46 Hz; 1H); 7.46-7.50 (m; 2H); 7.26 (t; J=7.40 Hz; 1H);
7.18-7.20 (m; 3H); 7.03 (dd; J=8.45; 2.37 Hz; 1H); 3.60-3.66 (m;
1H); 3.51-3.57 (m; 1H); 3.40 (dd; J=10.64; 4.31 Hz; 1H); 3.26 (dd;
J=10.64; 7.23 Hz; 1H); 2.93 (br s; 1H); 2.68 (br s; 1H); 1.77 (m;
2H); 1.55 (d; J=12.64 Hz; 1H); 1.36 (q; J=12.90 Hz; 1H); 1.18 (q;
J=12.16 Hz; 1H); 1.03 (q; J=12.11 Hz; 1H). LCMS [M+H].sup.+: 492.2,
494.2.
Example 233: Synthesis of
racemic-cis-(2-chloro-4-phenoxyphenyl)(4-(((6-(hydroxymethyl)-1-methylpip-
eridin-2-yl)methyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone
(I-360e)
[0735] A cis-isomer mixture of
(2-chloro-4-phenoxyphenyl)(4-(((6-(hydroxymethyl)piperidin-2-yl)methyl)am-
ino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (I-359e) (20.9 mg,
0.0421 mmol) was dissolved in 2,2,2-trifluoroethanol (1.05 mL),
paraformaldehyde (10.1 mg, 0.3367 mmol) and sodium borohydride (2.2
mg, 0.0589 mmol) were added and the mixture stirred at RT
overnight. MeOH (1 mL) was added and the mixture stirred 30 min at
room temperature. The solution was concentrated under reduced
pressure. The residue was purified by preparative HPLC 10% to 85%0
MeCN in water). The fractions containing the product were combined
and lyophilized affording a mixture of
(2-chloro-4-phenoxyphenyl)(4-((((2R,6S)-6-(hydroxymethyl)-1-methylpiperid-
in-2-yl)methyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone and
(2-chloro-4-phenoxyphenyl)(4-((((2S,6R)-6-(hydroxymethyl)-1-methylpiperid-
in-2-yl)methyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone
(10.1 mg, 0.0183 mmol, 43%) as a white powder. .sup.1H NMR
(DMSO-d.sub.6, 400 mHz): .delta. 8.90 (t; J=4.88 Hz; 1H); 8.24 (s;
1H); 8.22 (s; 1H); 7.56-7.59 (m; 2H); 7.48 (m; 2H); 7.25 (t; J=7.39
Hz; 1H); 7.18-7.20 (m; 3H); 7.02 (dd; J=8.45; 2.37 Hz; 1H);
3.60-3.67 (m; 2H); 3.40-3.49 (m; 2H); 2.43 (s; 1H); 2.30 (s; 3H);
2.23 (s; 1H); 1.72 (s; 1H); 1.60-1.64 (m; 2H); 1.47 (d; J=13.15 Hz;
1H); 1.32 (s; 2H). LCMS [M+H].sup.+: 506.26,
Example 234: BTK Kinase Activity Assay
[0736] Radiometric Assay
[0737] Enzyme assay using full length recombinant active form of
wild-type BTK and BTK-C481 S was measured as described previously
(Anastassiadis T, et al., Nat. Biotechnol. 29(11):1039-45 (2011)).
Compounds were tested in 10-point dose IC.sub.50 mode with 3-fold
serial dilution starting at 1 or 10 .mu.M concentration. BTK kinase
activity was assayed in a buffer solution containing 20 mM Hepes
(pH 7.5), 10 mM MgCl2, 1 mM EGTA, 0.02% Brij35, 0.02 mg/ml BSA, 0.1
mM Na3VO4, 2 mM DTT, 1% DMSO. Compounds in 100% DMSO were mixed
with kinase (8 nM wild-type BTK or 5 nM BTK-C481S mutant) with
substrate into the kinase reaction mixture by Acoustic technology
(Echo550; nanoliter range) and incubated for 20 min at room temp.
The reaction was initiated by adding 10 .mu.M ATP containing
.sup.33P-ATP into the mixture and incubated for 2 hours at room
temperature. Kinase activity was detected by P81 filter-binding
.sup.33P radioisotope based radiometric method. All compounds were
tested in duplicate. The raw data was fit to a 4-parameter logistic
model to derive the IC.sub.50 value for kinase activity
inhibition.
[0738] Mobility Shift Assay (MSA)
[0739] Compounds were tested either in the inactive or active BTK
assays on Caliper LabChip microfluidic mobility shift assay
platform.
[0740] Full length unphosphorylated form of BTK expressed in Sf9
cells was employed to test inhibitory activity in the inactive BTK
assay. The assay was measured in buffer solution containing 100 mM
HEPES pH7.5, 0.01% Triton X-100, 0.1% BSA, 5 mM MgCl2.1 mM DTT. The
enzyme and increasing concentrations of inhibitor was incubated at
room temperature for 30 minutes and the kinase reaction was
initiated by the addition an activation mixture diluted in assay
buffer containing Srctide peptide substrate, DOPS/DOPC,
PtdIns(3,4,5)P3, and ATP for final concentrations of 1 .mu.M
Srctide, 5.5 .mu.M DOPS, 5.5 .mu.M DOPC, 0.5 .mu.M PtdIns(3,4,5)P3,
and 16 .mu.M ATP. The plates were incubated for 60 minutes at room
temperature, and then the reaction stopped with 100 mM HEPES buffer
containing 0.01% Triton and 40 mM EDTA and read on Caliper Life
Sciences Labchip EZ Reader II instrument.
[0741] The active BTK assay consisted of phosphorylated form of
full length BTK. The assay was performed in a buffer solution
utilized in the inactive BTK assay. The enzyme inhibitor complexes
was incubated for 30 minutes at the room temperature and the kinase
activation reaction was initiated by the addition of 1 M Srctide
peptide substrate and 16 M ATP. After incubation at room
temperature for 60 minutes, the reaction was stopped and the
mobility shift was measured as described above for the inactive BTK
assay. The data of inactive and active BTK assays was fit to a 4
parameter logistic model to calculate the IC.sub.50 value.
[0742] Alpha Screen Assay
[0743] Purified full-length inactive BTK (wild type and C.sub.481
mutant, N-terminal 6.times.HIS tagged BTK, Mwt=78.2 kDa) were
activated using soluble inositol hexakisphosphate (IP6) and ATP as
described (Q. Wang, E. M. Vogan, L. M. Nocka, C. E. Rosen, J. A.
Zorn, S. C. Harrison J. Kuriyan, eLife 2015; 4:e06074), with minor
modification. To 190 .mu.l of 1 mM IP6 in activation buffer (25 mM
Tris, pH 7.5, 150 mM NaCl, 5% glycerol) was added 10 .mu.l of
inactive BTK at 5-6 mg/ml and incubated for 10 min at room
temperature followed by addition of 200 .mu.l of 2 mM ATP in assay
buffer (50 mM Tris, pH 8, 10 mM MgCl2, 1 mM EDTA, 0.1 mM NaF, 0.02
mg/ml BSA, 10% glycerol, 2 mM sodium orthovanadate, 0.25 mM DTT)
for a further 10 min. The activated BTK was frozen in 50 .mu.l
aliquots (125-150 .mu.g/ml).
[0744] BTK activity was assayed using a PLC.gamma.2-derived
biotinylated peptide substrate (biotin-EELNNQLFLYDTHQNLR-OH) and
AlphaScreen.TM. (Amplified Luminescent Proximity Homogeneous Assay)
technology. The extent of peptide phosphorylation was determined by
using acceptor beads conjugated to phosphotyrosine antibody that
recognized the phosphorylated peptide and donor beads conjugated to
streptavidin that binds to the biotin on the peptide. Excitation of
the donor beads converted ambient oxygen to excited singlet oxygen
which when in close proximity to acceptor beads, reacted with
acceptor beads resulting in signal amplification.
[0745] Test inhibitors and controls were prepared in 10% DMSO at
10-fold the desired final concentration and added to each well of a
reaction plate (Corning 96-well half-area solid white nonbinding
surface plate) in a volume of 2.5 .mu.l. Full-length activated BTK
(wildtype or mutant C481S) diluted to 0.179 nM in assay buffer (50
mM Tris, pH 8, 10 mM MgCl2, 1 mM EDTA, 0.1 mM NaF, 0.02 mg/ml BSA,
10% glycerol, 0.2 mM Na3VO4, 0.1 mM beta-glycerophosphate, 0.25 mM
DTT) was added to each well in a volume of 17.5 .mu.l and incubated
with the inhibitors for 30 min. The kinase reaction was initiated
by the addition of 5 .mu.l of biotin-PLC.gamma.2 peptide and ATP
mixture diluted in assay buffer for a final concentration in the 25
.mu.l reaction of 150 nM and 180 .mu.M respectively and 0.125 nM
enzyme. The plate was incubated for 120 min at room temperature and
the reaction stopped by the addition of 10 .mu.l stop/detection
mixture containing 35 mM EDTA, 50 ug/ml AlphaScreen.TM.
Streptavidin Donor beads (final concentration is 500 ng/well) and
AlphaScreen.TM. Phospho-tyrosine (P-Tyr-100) Acceptor beads (final
concentration is 500 ng/well) under green light conditions. The
plate was incubated overnight at room temperature in the dark and
the plates read on the BMG PolarStar Omega (excitation wavelength:
640 nm, emission wavelength: 570 nm, Gain=4000). Data were archived
and analyzed with a 4-parameter fit to generate IC.sub.50 values
using the CDD Vault from Collaborative Drug Discovery.
TABLE-US-00006 TABLE 4 Biological activity of Compounds of Formula
(I) in BTK Kinase Assay Type A (MSA using active BTK), Assay Type B
(MSA using active BTK), and Assay Type C (radiometric assay with
active enzyme). Cmpd BTK IC.sub.50 Assay No. (nM) type I-1 11 A I-2
17 A I-3 19 A I-4 107 A I-5 90 A I-6 7.4 A I-7 93 A I-8 74 A I-9
6.1 A I-10 30 A I-11 151 A I-12 37 A I-13 25 A I-14 14 A I-15 8.3 A
I-16 134 A I-17 80 A I-18 9.7 A I-19 9.2 A I-20 9.5 A I-21 9.7 A
I-22 5.9 A I-23 5.9 A I-24 6.2 A I-25 154 A I-26 33 A I-27 46 A
I-28 8.3 A I-29 9.3 A I-30 4.9 A I-31 9.0 A I-32 11 A I-33 4.2 A
I-34 4.4 A I-35 150 A I-36 29 A I-37 15 A I-38 5.2 A I-39 3.0 A
I-40 10 A I-41 2.6 A I-42 5.4 A I-43 2.1 A I-44 5.4 A I-45 2.6 A
I-46 66 A I-47 10 A I-48 6.0 A I-49 8.6 A I-50 2.7 A I-51 1.9 A
I-52 70 A I-53 76 A I-54 83 A I-55 81 A I-56 158 A I-57 63 A I-58
3.6 A I-59 6.7 A I-60 7.0 A I-61 3.4 A I-62 5.0 A I-63 3.3 A I-64
4.1 A I-65 11 A I-66 11 A I-67 5.4 A I-68 5.6 A I-69 2.2 A I-70 4.6
A I-71 19 A I-72 447 A I-73 66 A I-74 20 A I-75 12 A I-76 52 A I-77
56 A I-78 3.0 A I-79 3.7 A I-80 4.1 A I-81 5.5 A I-82 12 A I-83 19
A I-84 14 A I-85 2.3 A I-86 2.9 A I-87 4.9 A I-88 2.5 A I-89 23 A
I-90 5.7 A I-91 3.5 A I-92 3.1 A I-93 3.4 A I-94 2.9 A I-95 8.1 A
I-96 8.9 A I-97 7.0 A I-98 5.3 A I-99 4.8 A I-100 5.3 A I-101 5.1 A
I-102 1.9 A I-103 3.5 A I-104 3.5 A I-105 7.0 A I-106 4.6 B I-107
12 B I-108 7.0 B I-109 3.2 B I-110 16 B I-111 3.0 B I-112 18 B
I-113 3.6 B I-114 23 B I-115 5.8 B I-116 5.9 B I-117 5.9 B I-118
4.4 B I-119 5.1 B I-120 121 B I-121 7.3 B I-122 0.77 A I-123 0.85 C
I-124 9.7 C I-125 0.56 C I-126 2.4 C I-127 1.63 B I-128 15 A I-129
34 A I-130 3.2 B I-131 3.8 B I-132 12 A I-133 188 A I-134 292 A
I-135 63 A I-136 154 A I-137 95 A I-138 41 A I-139 2.3 A I-140 8.0
A I-141 2.2 A I-142 6.8 A I-143 2359 A I-144 9.2 A I-145 7.2 A
I-146 3.9 A I-147 7.5 A I-148 12 A I-149 89 A I-150 0.93 A I-151
1.3 A I-152 133 A I-153 27 A I-154 32 A I-155 9.3 A I-156 30 A
I-157 4.0 A I-158 9.6 A I-159 15 A I-160 6.0 A I-161 102 A I-162 45
A I-163 29 A I-164 19 A I-165 8.4 A I-166 1.1 A I-167 1.4 A I-168
7.2 A I-169 1.7 A I-170 7.0 A I-171 39 A I-172 20 A I-173 4.3 A
I-174 7.2 A I-175 3.1 B I-176 2.5 B I-177 1.7 B I-178 2.2 B I-179
1.8 B I-180 1.8 B I-181 0.98 B I-182 1.5 B I-183 2.2 B I-184 61 B
I-185 57 B I-186 12 B I-187 4.2 B I-188 1.7 B I-189 17 B I-190 17 B
I-191 37 B I-192 4.4 B I-193 1.2 B I-194 1.5 B I-195 2.2 B I-196
3.2 B I-197 1.6 B I-198 2.6 B I-199 6.8 B I-200 1.4 B I-201 1.5 B
I-202 1.0 B I-203 1.4 B I-204 1.1 B I-205 1.6 B I-206 1.8 B I-207
4.1 B I-208 3.1 B I-209 4.0 B I-210 1.9 B I-211 2.9 B I-212 2.9 B
I-213 2.5 B I-214 7.4 B I-215 3.9 B I-216 1.9 B I-217 3.2 B I-218
470 A I-219 >4000 A I-220 14 A I-221 >4000 A I-222 5.4 A
I-223 >4000 A I-224 >4000 A I-225 >4000 A I-226 364 A
I-227 >4000 A I-228 4300 A I-229 2195 A I-230 4000 A
TABLE-US-00007 TABLE 5a Biological activity of Compounds of Formula
(I) in BTK wild-type and BTK mutant C481S Kinase Assay (radiometric
assay). Compound BTK BTK-C481S No. IC.sub.50 (nM) IC.sub.50 (nM)
I-123 0.85 0.39 I-124 9.7 7.0 I-125 0.56 0.37 I-126 2.4 0.79
TABLE-US-00008 TABLE 5b Biological activity of Compounds of Formula
(I) in BTK wild-type and BTK mutant C481S Kinase Assay
(AlphaScreen). Compound BTK BTK-C481S IC.sub.50 No. IC.sub.50 (nM)
(nM) I-601 20.9 116 I-602 140 317 I-603 466 1770 I-604 304 731
I-605 467 1860 I-606 0.98 55.9 I-607 13.8 216 I-608 8.19 187 I-609
114 519 I-236 181 98.4 I-610 491 1150 I-611 1140 1510 I-612 1630
82% @ 10 uM I-613 87% @ 10 uM 64% @ 10 uM I-614 142 228 I-256 156
317 I-615 86.4 34.1 I-616 116 506 I-617 16.2 48.7 I-618 87.4 399
I-619 376 942 I-246 103 514 I-620 598 70% @ 10 uM I-621 571 85% @
10 uM I-622 847 62% @ 10 uM I-623 124 185 I-624 1210 53% @ 10 uM
I-625 110 170 I-626 164 757 I-627 777 664 I-628 59.7 161 I-629 89.5
804 I-630 18.4 189 I-631 52.1 177 I-632 84% @ 10 uM 66% @ 10 uM
I-633 77% @ 10 uM 50% @ 10 uM I-634 619.5 690 I-635 73% @ 10 uM 49%
@ 10 uM I-636 62% @ 10 uM 41% @ 10 uM I-637 76% @ 10 uM 55% @ 10 uM
I-638 63% @ 10 uM 54% @ 10 uM I-231 318 248 I-276 17.6 58 I-639
14.2 25.6 I-640 69.5 203 I-641 8.28 32.6 I-642 251 203 I-643 269
150 I-644 58% @ 10 uM 44% @ 10 uM I-645 743 81% @ 10 uM I-311i 867
81% @ 10 uM I-646 380 781 I-647 1440 108 I-318i 423 714 I-317i 40.7
156 I-648 731 810 I-649 959 82% @ 10 uM I-650 202 326 I-320 336
63.1 I-319 444 127 I-651 332 230 I-652 177 497 I-324r 17.2 105
I-328r 0.98 18.4 I-321r 4.5 179 I-325r 0.98 136 I-322r 10.4 98.6
I-326r 4.33 419 I-653 10 38.8 I-343r 11 34 I-654 6.55 20.7 I-345e
10.1 68.2 I-342e 14.2 33.4 I-655 44.5 52 I-656 123 254 I-369e 19.8
137 I-370e 59.5 49.8 I-657 236 832 I-362e 35.6 44.5 I-359e 29.4 124
I-360e 1.07 59.4
EQUIVALENTS
[0746] Those skilled in the art will recognize, or be able to
ascertain, using no more than routine experimentation, numerous
equivalents to the specific embodiments described specifically
herein. Such equivalents are intended to be encompassed in the
scope of the following claims.
* * * * *