U.S. patent application number 12/823449 was filed with the patent office on 2010-12-30 for heterocyclic compounds and their uses.
This patent application is currently assigned to AMGEN INC.. Invention is credited to Minna Bui, Yi Chen, Timothy D. Cushing, Jason A. Duquette, Benjamin Fisher, Felix Gonzalez Lopez De Turiso, Xiaolin Hao, Xiao He, Michael G. Johnson, Brian Lucas.
Application Number | 20100331306 12/823449 |
Document ID | / |
Family ID | 43066540 |
Filed Date | 2010-12-30 |
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United States Patent
Application |
20100331306 |
Kind Code |
A1 |
Bui; Minna ; et al. |
December 30, 2010 |
HETEROCYCLIC COMPOUNDS AND THEIR USES
Abstract
Substituted bicyclic heteroaryls and compositions containing
them, for the treatment of general inflammation, arthritis,
rheumatic diseases, osteoarthritis, inflammatory bowel disorders,
inflammatory eye disorders, inflammatory or unstable bladder
disorders, psoriasis, skin complaints with inflammatory components,
chronic inflammatory conditions, including but not restricted to
autoimmune diseases such as systemic lupus erythematosis (SLE),
myestenia gravis, rheumatoid arthritis, acute disseminated
encephalomyelitis, idiopathic thrombocytopenic purpura, multiples
sclerosis, Sjoegren's syndrome and autoimmune hemolytic anemia,
allergic conditions including all forms of hypersensitivity. The
present invention also enables methods for treating cancers that
are mediated, dependent on or associated with p110.delta. activity,
including but not restricted to leukemias, such as Acute Myeloid
leukaemia (AML) Myelo-dysplastic syndrome (MDS) myelo-proliferative
diseases (MPD) Chronic Myeloid Leukemia (CML) T-cell Acute
Lymphoblastic leukaemia (T-ALL) B-cell Acute Lymphoblastic
leukaemia (B-ALL) Non Hodgkins Lymphoma (NHL) B-cell lymphoma and
solid tumors, such as breast cancer.
Inventors: |
Bui; Minna; (Oakland,
CA) ; Chen; Yi; (San Jose, CA) ; Cushing;
Timothy D.; (Pacifica, CA) ; Duquette; Jason A.;
(Millbrae, CA) ; Fisher; Benjamin; (San Mateo,
CA) ; Gonzalez Lopez De Turiso; Felix; (San Mateo,
CA) ; Hao; Xiaolin; (Foster City, CA) ; He;
Xiao; (Foster City, CA) ; Johnson; Michael G.;
(San Francisco, CA) ; Lucas; Brian; (San
Francisco, CA) |
Correspondence
Address: |
AMGEN INC.
MAIL STOP 28-2-C, ONE AMGEN CENTER DRIVE
THOUSAND OAKS
CA
91320-1799
US
|
Assignee: |
AMGEN INC.
Thousand Oaks
CA
|
Family ID: |
43066540 |
Appl. No.: |
12/823449 |
Filed: |
June 25, 2010 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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61220488 |
Jun 25, 2009 |
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Current U.S.
Class: |
514/210.21 ;
514/210.18; 514/228.2; 514/235.2; 514/252.18; 514/256; 514/262.1;
514/263.22; 514/275; 544/122; 544/262; 544/277; 544/324; 544/328;
544/58.2 |
Current CPC
Class: |
A61P 7/00 20180101; A61P
37/08 20180101; A61P 7/06 20180101; A61P 9/12 20180101; C07D 401/12
20130101; A61P 35/00 20180101; C07D 487/04 20130101; A61P 37/00
20180101; A61P 27/02 20180101; A61P 17/06 20180101; A61P 17/00
20180101; A61P 43/00 20180101; A61P 19/02 20180101; C07D 401/14
20130101; A61P 13/10 20180101; C07D 471/04 20130101; A61P 3/10
20180101; A61P 37/06 20180101; A61P 11/00 20180101; A61P 37/02
20180101; A61P 21/04 20180101; A61P 1/00 20180101; A61P 9/10
20180101; C07D 473/34 20130101; A61P 11/06 20180101; A61P 19/00
20180101; A61P 29/00 20180101; A61P 35/02 20180101; A61P 25/00
20180101 |
Class at
Publication: |
514/210.21 ;
544/277; 514/263.22; 544/262; 514/262.1; 544/328; 514/256; 544/324;
514/275; 544/122; 514/235.2; 544/58.2; 514/228.2; 514/210.18;
514/252.18 |
International
Class: |
A61K 31/52 20060101
A61K031/52; C07D 473/34 20060101 C07D473/34; C07D 487/04 20060101
C07D487/04; A61K 31/519 20060101 A61K031/519; C07D 401/14 20060101
C07D401/14; A61K 31/506 20060101 A61K031/506; C07D 471/04 20060101
C07D471/04; C07D 401/12 20060101 C07D401/12; C07D 413/14 20060101
C07D413/14; A61K 31/5377 20060101 A61K031/5377; C07D 417/14
20060101 C07D417/14; A61K 31/541 20060101 A61K031/541; A61P 35/00
20060101 A61P035/00; A61P 29/00 20060101 A61P029/00; A61P 37/06
20060101 A61P037/06; A61P 17/00 20060101 A61P017/00 |
Claims
1. A compound having the structure: ##STR00206## or any
pharmaceutically-acceptable salt thereof, wherein: X.sup.1 is
C(R.sup.10) or N; X.sup.2 is C or N; X.sup.3 is C or N; X.sup.4 is
C or N; X.sup.5 is C or N; wherein at least two of X.sup.2,
X.sup.3, X.sup.4 and X.sup.5 are C; X.sup.6 is C(R.sup.6) or N;
X.sup.7 is C(R.sup.7) or N; X.sup.8 is C(R.sup.10) or N; Y is
N(R.sup.8), O or S; n is 0, 1, 2 or 3; R.sup.1 is a direct-bonded,
C.sub.1-4alk-linked, OC.sub.1-2alk-linked, C.sub.1-2alkO-linked,
N(R.sup.a)-linked or O-linked saturated, partially-saturated or
unsaturated 5-, 6- or 7-membered monocyclic or 8-, 9-, 10- or
11-membered bicyclic ring containing 0, 1, 2, 3 or 4 atoms selected
from N, O and S, but containing no more than one O or S atom,
substituted by 0, 1, 2 or 3 substituents independently selected
from halo, C.sub.1-6alk, C.sub.1-4haloalk, cyano, nitro,
--C(.dbd.O)R.sup.a, --C(.dbd.O)OR.sup.a,
--C(.dbd.O)NR.sup.aR.sup.a, --C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--OR.sup.a, --OC(.dbd.O)R.sup.a, --OC(.dbd.O)NR.sup.aR.sup.a,
--OC(.dbd.O)N(R.sup.a)S(.dbd.O).sub.2R.sup.a,
--OC.sub.2-6alkNR.sup.aR.sup.a, --OC.sub.2-6alkOR.sup.a,
--SR.sup.a, --S(.dbd.O)R.sup.a, --S(.dbd.O).sub.2R.sup.a,
--S(.dbd.O).sub.2NR.sup.aR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)R.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)OR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--NR.sup.aR.sup.a, --N(R.sup.a)C(.dbd.O)R.sup.a,
--N(R.sup.a)C(.dbd.O)OR.sup.a,
--N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--N(R.sup.a)C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2R.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2NR.sup.aR.sup.a,
--NR.sup.aC.sub.2-6alkNR.sup.aR.sup.a and
--NR.sup.aC.sub.2-6alkOR.sup.a, wherein the available carbon atoms
of the ring are additionally substituted by 0, 1 or 2 oxo or thioxo
groups, and wherein the ring is additionally substituted by 0 or 1
directly bonded, SO.sub.2 linked, C(.dbd.O) linked or CH.sub.2
linked group selected from phenyl, pyridyl, pyrimidyl, morpholino,
piperazinyl, piperadinyl, cyclopentyl, cyclohexyl all of which are
further substituted by 0, 1, 2 or 3 independent R.sup.b groups;
R.sup.2 is selected from H, halo, C.sub.1-6alk, C.sub.1-4haloalk,
cyano, nitro, OR.sup.a, NR.sup.aR.sup.a, --C(.dbd.O)R.sup.a,
--C(.dbd.O)OR.sup.a, --C(.dbd.O)NR.sup.aR.sup.a,
--C(.dbd.NR.sup.a)NR.sup.aR.sup.a, --S(.dbd.O)R.sup.a,
--S(.dbd.O).sub.2R.sup.a, --S(.dbd.O).sub.2NR.sup.aR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)R.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)OR.sup.a and
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a; R.sup.3 is
selected from H, halo, nitro, cyano, C.sub.1-4alk, OC.sub.1-4alk,
OC.sub.1-4haloalk, NHC.sub.1-4alk, N(C.sub.1-4alk)C.sub.1-4alk and
C.sub.1-4haloalk; R.sup.4 is, independently, in each instance,
halo, nitro, cyano, C.sub.1-4alk, OC.sub.1-4alk, OC.sub.1-4haloalk,
NHC.sub.1-4alk, N(C.sub.1-4alk)C.sub.1-4alk, C.sub.1-4haloalk or an
unsaturated 5-, 6- or 7-membered monocyclic ring containing 0, 1,
2, 3 or 4 atoms selected from N, O and S, but containing no more
than one O or S, the ring being substituted by 0, 1, 2 or 3
substituents selected from halo, C.sub.1-4alk, C.sub.1-3haloalk,
--OC.sub.1-4alk, --NH.sub.2, --NHC.sub.1-4alk,
--N(C.sub.1-4alk)C.sub.1-4alk; R.sup.5 is, independently, in each
instance, H, halo, C.sub.1-6alk, C.sub.1-4haloalk, or C.sub.1-6alk
substituted by 1, 2 or 3 substituents selected from halo, cyano,
OH, OC.sub.1-4alk, C.sub.1-4alk, C.sub.1-3haloalk, OC.sub.1-4alk,
NH.sub.2, NHC.sub.1-4alk and N(C.sub.1-4alk)C.sub.1-4alk; or both
R.sup.5 groups together form a C.sub.3-6spiroalk substituted by 0,
1, 2 or 3 substituents selected from halo, cyano, OH,
OC.sub.1-4alk, C.sub.1-4alk, C.sub.1-3haloalk, OC.sub.1-4alk,
NH.sub.2, NHC.sub.1-4alk and N(C.sub.1-4alk)C.sub.1-4alk; R.sup.6
is H, halo, NHR.sup.9 or OH, cyano, OC.sub.1-4alk, C.sub.1-4alk,
C.sub.1-3haloalk, OC.sub.1-4alk, --C(.dbd.O)OR.sup.a,
--C(.dbd.O)N(R.sup.a)R.sup.a or --N(R.sup.a)C(.dbd.O)R.sup.b;
R.sup.7 is selected from H, halo, C.sub.1-4haloalk, cyano, nitro,
--C(.dbd.O)R.sup.a, --C(.dbd.O)OR.sup.a,
--C(.dbd.O)NR.sup.aR.sup.a, --C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--OR.sup.a, --OC(.dbd.O)R.sup.a, --OC(.dbd.O)NR.sup.aR.sup.a,
--OC(.dbd.O)N(R.sup.a)S(.dbd.O).sub.2R.sup.a,
--OC.sub.2-6alkNR.sup.aR.sup.a, --OC.sub.2-6alkOR.sup.a,
--SR.sup.a, --S(.dbd.O)R.sup.a, --S(.dbd.O).sub.2R.sup.a,
--S(.dbd.O).sub.2NR.sup.aR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)R.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)OR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--NR.sup.aR.sup.a, --N(R.sup.a)C(.dbd.O)R.sup.a,
--N(R.sup.a)C(.dbd.O)OR.sup.a,
--N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--N(R.sup.a)C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2R.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2NR.sup.aR.sup.a,
--NR.sup.aC.sub.2-6alkNR.sup.aR.sup.a,
--NR.sup.aC.sub.2-6alkOR.sup.a and C.sub.1-6alk, wherein the
C.sub.1-6alk is substituted by 0, 1, 2 or 3 substituents selected
from halo, C.sub.1-4haloalk, cyano, nitro, --C(.dbd.O)R.sup.a,
--C(.dbd.O)OR.sup.a, --C(.dbd.O)NR.sup.aR.sup.a,
--C(.dbd.NR.sup.a)NR.sup.aR.sup.a, --OR.sup.a, --OC(.dbd.O)R.sup.a,
--OC(.dbd.O)NR.sup.aR.sup.a,
--OC(.dbd.O)N(R.sup.a)S(.dbd.O).sub.2R.sup.a,
--OC.sub.2-6alkNR.sup.aR.sup.a, --OC.sub.2-6alkOR.sup.a,
--SR.sup.a, --S(.dbd.O)R.sup.a, --S(.dbd.O).sub.2R.sup.a,
--S(.dbd.O).sub.2NR.sup.aR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)R.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)OR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--NR.sup.aR.sup.a, --N(R.sup.a)C(.dbd.O)R.sup.a,
--N(R.sup.a)C(.dbd.O)OR.sup.a,
--N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--N(R.sup.a)C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2R.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2NR.sup.aR.sup.a,
--NR.sup.aC.sub.2-6alkNR.sup.aR.sup.a and
--NR.sup.aC.sub.2-6alkOR.sup.a, and the C.sub.1-6alk is
additionally substituted by 0 or 1 saturated, partially-saturated
or unsaturated 5-, 6- or 7-membered monocyclic rings containing 0,
1, 2, 3 or 4 atoms selected from N, O and S, but containing no more
than one O or S, wherein the available carbon atoms of the ring are
substituted by 0, 1 or 2 oxo or thioxo groups, wherein the ring is
substituted by 0, 1, 2 or 3 substituents independently selected
from halo, nitro, cyano, C.sub.1-4alk, OC.sub.1-4alk,
OC.sub.1-4haloalk, NHC.sub.1-4alk, N(C.sub.1-4alk)C.sub.1-4alk and
C.sub.1-4haloalk; or R.sup.7 and R.sup.8 together form a
--C.dbd.N-- bridge wherein the carbon atom is substituted by H,
halo, cyano, or a saturated, partially-saturated or unsaturated 5-,
6- or 7-membered monocyclic ring containing 0, 1, 2, 3 or 4 atoms
selected from N, O and S, but containing no more than one O or S,
wherein the available carbon atoms of the ring are substituted by
0, 1 or 2 oxo or thioxo groups, wherein the ring is substituted by
0, 1, 2, 3 or 4 substituents selected from halo, C.sub.1-6alk,
C.sub.1-4haloalk, cyano, nitro, --C(.dbd.O)R.sup.a,
--C(.dbd.O)OR.sup.a, --C(.dbd.O)NR.sup.aR.sup.a,
--C(.dbd.NR.sup.a)NR.sup.aR.sup.a, --OR.sup.a, --OC(.dbd.O)R.sup.a,
--OC(.dbd.O)NR.sup.aR.sup.a,
--OC(.dbd.O)N(R.sup.a)S(.dbd.O).sub.2R.sup.a,
--OC.sub.2-6alkNR.sup.aR.sup.a, --OC.sub.2-6alkOR.sup.a,
--SR.sup.a, --S(.dbd.O)R.sup.a, --S(.dbd.O).sub.2R.sup.a,
--S(.dbd.O).sub.2NR.sup.aR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)R.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)OR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--NR.sup.aR.sup.a, --N(R.sup.a)C(.dbd.O)R.sup.a,
--N(R.sup.a)C(.dbd.O)OR.sup.a,
--N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--N(R.sup.a)C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2R.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2NR.sup.aR.sup.a,
--NR.sup.aC.sub.2-6alkNR.sup.aR.sup.a and
--NR.sup.aC.sub.2-6alkOR.sup.a; or R.sup.7 and R.sup.9 together
form a --N.dbd.C-- bridge wherein the carbon atom is substituted by
H, halo, C.sub.1-6alk, C.sub.1-4haloalk, cyano, nitro, OR.sup.a,
NR.sup.aR.sup.a, --C(.dbd.O)R.sup.a, --C(.dbd.O)OR.sup.a,
--C(.dbd.O)NR.sup.aR.sup.a, --C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--S(.dbd.O)R.sup.a, --S(.dbd.O).sub.2R.sup.a or
--S(.dbd.O).sub.2NR.sup.aR.sup.a; R.sup.8 is H, C.sub.1-6alk,
C(.dbd.O)N(R.sup.a)R.sup.a, C(.dbd.O)R.sup.b or C.sub.1-4haloalk;
R.sup.9 is H, C.sub.1-6alk or C.sub.1-4haloalk; R.sup.10 is in each
instance H, halo, C.sub.1-3alk, C.sub.1-3haloalk or cyano; R.sup.11
is selected from H, halo, C.sub.1-6alk, C.sub.1-4haloalk, cyano,
nitro, --C(.dbd.O)R.sup.a, --C(.dbd.O)OR.sup.a,
--C(.dbd.O)NR.sup.aR.sup.a, --C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--OR.sup.a, --OC(.dbd.O)R.sup.a, --OC(.dbd.O)NR.sup.aR.sup.a,
--OC(.dbd.O)N(R.sup.a)S(.dbd.O).sub.2R.sup.a,
--OC.sub.2-6alkNR.sup.aR.sup.a, --OC.sub.2-6alkOR.sup.a,
--SR.sup.a, --S(.dbd.O)R.sup.a, --S(.dbd.O).sub.2R.sup.b,
--S(.dbd.O).sub.2NR.sup.aR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)R.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)OR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--NR.sup.aR.sup.a, --N(R.sup.a)C(.dbd.O)R.sup.a,
--N(R.sup.a)C(.dbd.O)OR.sup.a,
--N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--N(R.sup.a)C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2R.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2NR.sup.aR.sup.a,
--NR.sup.aC.sub.2-6alkNR.sup.aR.sup.a,
--NR.sup.aC.sub.2-6alkOR.sup.a,
--NR.sup.aC.sub.2-6alkCO.sub.2R.sup.a,
--NR.sup.aC.sub.2-6alkSO.sub.2R.sup.b, --CH.sub.2C(.dbd.O)R.sup.a,
--CH.sub.2C(.dbd.O)OR.sup.a, --CH.sub.2C(.dbd.O)NR.sup.aR.sup.a,
--CH.sub.2C(.dbd.NR.sup.a)NR.sup.aR.sup.a, --CH.sub.2OR.sup.a,
--CH.sub.2C(.dbd.O)R.sup.a, --CH.sub.2C(.dbd.O)NR.sup.aR.sup.a,
--CH.sub.2C(.dbd.O)N(R.sup.a)S(.dbd.O).sub.2R.sup.a,
--CH.sub.2OC.sub.2-6alkNR.sup.aR.sup.a,
--CH.sub.2OC.sub.2-6alkOR.sup.a, --CH.sub.2SR.sup.a,
--CH.sub.2S(.dbd.O)R.sup.a, --CH.sub.2S(.dbd.O).sub.2R.sup.b,
--CH.sub.2S(.dbd.O).sub.2NR.sup.aR.sup.a,
--CH.sub.2S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)R.sup.a,
--CH.sub.2S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)OR.sup.a,
--CH.sub.2S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--CH.sub.2NR.sup.aR.sup.a, --CH.sub.2N(R.sup.a)C(.dbd.O)R.sup.a,
--CH.sub.2N(R.sup.a)C(.dbd.O)OR.sup.a,
--CH.sub.2N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--CH.sub.2N(R.sup.a)C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--CH.sub.2N(R.sup.a)S(.dbd.O).sub.2R.sup.a,
--CH.sub.2N(R.sup.a)S(.dbd.O).sub.2NR.sup.aR.sup.a,
--CH.sub.2NR.sup.aC.sub.2-6alkNR.sup.aR.sup.a,
--CH.sub.2NR.sup.aC.sub.2-6alkOR.sup.a,
--CH.sub.2NR.sup.aC.sub.2-6alkCO.sub.2R.sup.a,
--CH.sub.2NR.sup.aC.sub.2-6alkSO.sub.2R.sup.b, --CH.sub.2R.sup.c,
--C(.dbd.O)R.sup.c and --C(.dbd.O)N(R.sup.a)R.sup.c; R.sup.a is
independently, at each instance, H or R.sup.b; R.sup.b is
independently, at each instance, phenyl, benzyl or C.sub.1-6alk,
the phenyl, benzyl and C.sub.1-6alk being substituted by 0, 1, 2 or
3 substituents selected from halo, C.sub.1-4alk, C.sub.1-3haloalk,
--OH, --OC.sub.1-4alk, --NH.sub.2, --NHC.sub.1-4alk and
--N(C.sub.1-4alk)C.sub.1-4alk; and R.sup.c is a saturated or
partially-saturated 4-, 5- or 6-membered ring containing 1, 2 or 3
heteroatoms selected from N, O and S, the ring being substituted by
0, 1, 2 or 3 substituents selected from halo, C.sub.1-4alk,
C.sub.1-3haloalk, --OC.sub.1-4alk, --NH.sub.2, --NHC.sub.1-4alk and
--N(C.sub.1-4alk)C.sub.1-4alk.
2. A compound according to claim 1, wherein the compound is:
4-amino-1-((1S)-1-(6-fluoro-3-(5-fluoro-3-pyridinyl)-2-quinolinyl)ethyl)--
1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;
4-amino-1-((1R)-1-(6-fluoro-3-(5-fluoro-3-pyridinyl)-2-quinolinyl)ethyl)--
1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;
4-amino-6-(((1S)-1-(6-fluoro-3-(6-(methylsulfonyl)-2-pyridinyl)-2-quinoli-
nyl)ethyl)amino)-5-pyrimidinecarbonitrile;
N-(1-(6-fluoro-3-(2-pyridinyl)-2-quinolinyl)ethyl)-9H-purin-6-amine;
N-((1S)-1-(6-fluoro-3-(2-pyridinyl)-2-quinolinyl)ethyl)-9H-purin-6-amine;
N-((1R)-1-(6-fluoro-3-(2-pyridinyl)-2-quinolinyl)ethyl)-9H-purin-6-amine;
N-(1-(6-fluoro-3-(2-pyridinyl)-2-quinolinyl)ethyl)-4-pyrimidinamine;
N-(1-(6-fluoro-3-(2-pyridinyl)-2-quinolinyl)ethyl)-4,6-pyrimidinediamine;
N.about.4.about.-((1R)-1-(6-fluoro-3-(2-pyridinyl)-2-quinolinyl)ethyl)-2,-
4-pyrimidinediamine;
4-amino-6-((1-(6-fluoro-3-(2-pyridinyl)-2-quinolinyl)ethyl)amino)-5-pyrim-
idinecarbonitrile;
4-((1-(6-fluoro-3-(2-pyridinyl)-2-quinolinyl)ethyl)amino)-6-hydroxy-5-pyr-
imidinecarbonitrile;
4-amino-1-((1S)-1-(6-fluoro-3-(2-pyridinyl)-2-quinolinyl)ethyl)-1H-pyrazo-
lo[3,4-d]pyrimidine-3-carbonitrile;
4-amino-1-((1R)-1-(6-fluoro-3-(2-pyridinyl)-2-quinolinyl)ethyl)-1H-pyrazo-
lo[3,4-d]pyrimidine-3-carbonitrile;
4-amino-6-((1-(5-chloro-3-(2-pyridinyl)-2-quinolinyl)ethyl)amino)-5-pyrim-
idinecarbonitrile;
4-amino-6-(((1S)-1-(5-chloro-3-(2-pyridinyl)-2-quinolinyl)ethyl)amino)-5--
pyrimidinecarbonitrile;
4-amino-6-(((1R)-1-(5-chloro-3-(2-pyridinyl)-2-quinolinyl)ethyl)amino)-5--
pyrimidinecarbonitrile;
2-((1S)-1-((6-amino-5-cyano-4-pyrimidinyl)amino)ethyl)-3-(2-pyridinyl)-5--
quinolinecarbonitrile;
2-((1R)-1-((6-amino-5-cyano-4-pyrimidinyl)amino)ethyl)-3-(2-pyridinyl)-5--
quinolinecarbonitrile;
4-amino-6-((1-(3-(2-pyridinyl)-1,8-naphthyridin-2-yl)ethyl)amino)-5-pyrim-
idinecarbonitrile;
4-amino-6-((1-(3-(2-pyridinyl)-1,6-naphthyridin-2-yl)ethyl)amino)-5-pyrim-
idinecarbonitrile;
4-amino-6-((1-(6-fluoro-4-(methylsulfonyl)-3-phenyl-2-quinolinyl)ethyl)am-
ino)-5-pyrimidinecarbonitrile;
4-amino-6-((1-(6-fluoro-4-(methylsulfanyl)-3-phenyl-2-quinolinyl)ethyl)am-
ino)-5-pyrimidinecarbonitrile;
4-amino-6-((8-fluoro-3-(2-(methylsulfonyl)phenyl)-2-quinolinyl)methyl)ami-
no)-5-pyrimidinecarbonitrile;
4-amino-6-((8-fluoro-3-(2-pyridinyl)-2-quinolinyl)methyl)amino)-5-pyrimid-
inecarbonitrile;
4-amino-6-((8-fluoro-3-phenyl-2-quinolinyl)methyl)amino)-5-pyrimidinecarb-
onitrile;
4-amino-6-((5-fluoro-3-phenyl-2-quinolinyl)methyl)amino)-5-pyrim-
idinecarbonitrile;
4-amino-6-((5-fluoro-3-(3-fluorophenyl)-2-quinolinyl)methyl)amino)-5-pyri-
midinecarbonitrile;
4-amino-6-((3-(3,5-difluorophenyl)-5-fluoro-2-quinolinyl)methyl)amino)-5--
pyrimidinecarbonitrile;
4-amino-6-((5-fluoro-3-(2-(methylsulfonyl)phenyl)-2-quinolinyl)methyl)ami-
no)-5-pyrimidinecarbonitrile;
4-amino-6-((5-fluoro-3-(2-pyridinyl)-2-quinolinyl)methyl)amino)-5-pyrimid-
inecarbonitrile;
4-amino-6-((-1-(4-(dimethylamino)-6-fluoro-3-(2-pyridinyl)-2-quinolinyl)e-
thyl)amino)-5-pyrimidinecarbonitrile;
4-amino-6-((-1-(6-fluoro-4-(4-morpholinyl)-3-(2-pyridinyl)-2-quinolinyl)e-
thyl)amino)-5-pyrimidinecarbonitrile;
4-amino-6-((-1-(6-fluoro-4-(3-hydroxy-1-azetidinyl)-3-(2-pyridinyl)-2-qui-
nolinyl)ethyl)amino)-5-pyrimidinecarbonitrile;
2-((1S)-1-((6-amino-5-cyano-4-pyrimidinyl)amino)ethyl)-6-fluoro-N,N-dimet-
hyl-3-phenyl-4-quinolinecarboxamide;
4-amino-6-(((1S)-1-(6-fluoro-4-(4-morpholinylcarbonyl)-3-phenyl-2-quinoli-
nyl)ethyl)amino)-5-pyrimidinecarbonitrile;
4-amino-6-(((1S)-1-(6-fluoro-4-(((3S)-3-hydroxy-1-pyrrolidinyl)carbonyl)--
3-phenyl-2-quinolinyl)ethyl)amino)-5-pyrimidinecarbonitrile;
4-amino-6-(((1S)-1-(4-((1,1-dioxido-4-thiomorpholinyl)-carbonyl)-6-fluoro-
-3-phenyl-2-quinolinyl)ethyl)amino)-5-pyrimidinecarbonitrile;
2-((1S)-1-((6-amino-5-cyano-4-pyrimidinyl)amino)ethyl)-6-fluoro-3-phenyl--
4-quinolinecarbonitrile;
2-((1S)-1-((6-amino-5-cyano-4-pyrimidinyl)amino)ethyl)-6-fluoro-3-phenyl--
4-quinolinecarbonitrile;
2-((1R)-1-((6-amino-5-cyano-4-pyrimidinyl)amino)ethyl)-6-fluoro-3-phenyl--
4-quinolinecarbonitrile; methyl
2-(-1-((6-amino-5-cyano-4-pyrimidinyl)amino)ethyl)-6-fluoro-3-phenyl-4-qu-
inolinecarboxylate;
2-((1S)-1-((6-amino-5-cyano-4-pyrimidinyl)amino)ethyl)-6-fluoro-3-phenyl--
4-quinolinecarboxylic acid;
2-((1S)-1-((6-amino-5-carbamoyl-4-pyrimidinyl)amino)ethyl)-6-fluoro-3-phe-
nyl-4-quinolinecarboxylic acid;
2-(-1-(6-amino-5-cyano-4-pyrimidinyl)amino)ethyl)-6-fluoro-N-methyl-3-phe-
nyl-4-quinolinecarboxamide;
4-amino-6-((-1-(6-fluoro-3-phenyl-4-(1-piperazinylcarbonyl)-2-quinolinyl)-
ethyl)amino)-5-pyrimidinecarbonitrile;
4-amino-6-((-1-(6-fluoro-4-((4-methyl-1-piperazinyl)carbonyl)-3-phenyl-2--
quinolinyl)ethyl)amino)-5-pyrimidinecarbonitrile;
2-(-1-(6-amino-5-cyano-4-pyrimidinyl)amino)ethyl)-6-fluoro-N,N-dimethyl-3-
-phenyl-4-quinolinecarboxamide;
4-amino-6-((-1-(6-fluoro-4-(((3R)-3-hydroxy-1-pyrrolidinyl)carbonyl)-3-ph-
enyl-2-quinolinyl)ethyl)amino)-5-pyrimidinecarbonitrile;
4-amino-6-((1-(6-fluoro-3-phenyl-4-(1-pyrrolidinylcarbonyl)-2-quinolinyl)-
ethyl)amino)-5-pyrimidinecarbonitrile;
4-amino-6-((-1-(6-fluoro-4-(4-morpholinylcarbonyl)-3-phenyl-2-quinolinyl)-
ethyl)amino)-5-pyrimidinecarbonitrile;
4-amino-6-((-1-(6-fluoro-4-(((3S)-3-hydroxy-1-pyrrolidinyl)carbonyl)-3-ph-
enyl-2-quinolinyl)ethyl)amino)-5-pyrimidinecarbonitrile;
4-amino-6-((-1-(6-fluoro-4-(((3R)-3-hydroxy-1-pyrrolidinyl)-carbonyl)-3-p-
henyl-2-quinolinyl)ethyl)amino)-5-pyrimidine-carbonitrile;
4-amino-6-((1-(4-((1,1-dioxido-4-thiomorpholinyl)carbonyl)-6-fluoro-3-phe-
nyl-2-quinolinyl)ethyl)amino)-5-pyrimidine-carbonitrile;
4-amino-6-((1-(6-fluoro-4-((3-hydroxy-1-azetidinyl)carbonyl)-3-phenyl-2-q-
uinolinyl)ethyl)amino)-5-pyrimidinecarbonitrile;
4-amino-6-((1-(6-fluoro-4-((3-methoxy-1-azetidinyl)carbonyl)-3-phenyl-2-q-
uinolinyl)ethyl)amino)-5-pyrimidinecarbonitrile;
2-(1-((6-amino-5-cyano-4-pyrimidinyl)amino)ethyl)-6-fluoro-N-(2-(4-morpho-
linyl)ethyl)-3-phenyl-4-quinolinecarboxamide;
4-amino-6-((-1-(6-fluoro-4-(hydroxymethyl)-3-phenyl-2-quinolinyl)ethyl)am-
ino)-5-pyrimidinecarbonitrile;
4-amino-6-(((1S)-1-(6-fluoro-3-phenyl-4-(1-piperazinylcarbonyl)-2-quinoli-
nyl)ethyl)amino)-5-pyrimidinecarbonitrile;
2-((1S)-1-(6-amino-5-cyano-4-pyrimidinyl)amino)ethyl)-6-fluoro-N-methyl-3-
-phenyl-4-quinolinecarboxamide;
4-amino-6-((-1-(6-fluoro-4-((methylsulfonyl)methyl)-3-phenyl-2-quinolinyl-
)ethyl)amino)-5-pyrimidinecarbonitrile;
4-amino-6-(((1S)-1-(6-fluoro-4-((3-hydroxy-1-azetidinyl)-carbonyl)-3-phen-
yl-2-quinolinyl)ethyl)amino)-5-pyrimidine-carbonitrile;
4-amino-6-(((1S)-1-(4-((1,1-dioxido-4-thiomorpholinyl)carbonyl)-6-fluoro--
3-phenyl-2-quinolinyl)ethyl)amino)-5-pyrimidinecarbonitrile;
2-((1S)-1-((6-amino-5-cyano-4-pyrimidinyl)amino)ethyl)-6-fluoro-N,N-dimet-
hyl-3-phenyl-4-quinolinecarboxamide;
2-((1S)-1-((6-amino-5-cyano-4-pyrimidinyl)amino)ethyl)-6-fluoro-N,N-dimet-
hyl-3-phenyl-4-quinolinecarboxamide;
4-amino-6-((-1-(6-fluoro-4-(4-morpholinylmethyl)-3-phenyl-2-quinolinyl)et-
hyl)amino)-5-pyrimidinecarbonitrile;
2-((1S)-1-((6-amino-5-cyano-4-pyrimidinyl)amino)ethyl)-N-ethyl-6-fluoro-3-
-phenyl-4-quinolinecarboxamide;
2-(-1-((6-amino-5-cyano-4-pyrimidinyl)amino)ethyl)-6-fluoro-N-(1-methylet-
hyl)-3-phenyl-4-quinolinecarboxamide;
2-(-1-((6-amino-5-cyano-4-pyrimidinyl)amino)ethyl)-N-(cyclopropylmethyl)--
6-fluoro-3-phenyl-4-quinolinecarboxamide;
4-amino-6-(((1S)-1-(6-fluoro-4-methoxy-3-phenyl-2-quinolinyl)ethyl)amino)-
-5-pyrimidinecarbonitrile;
4-amino-6-(((1R)-1-(6-fluoro-4-methoxy-3-phenyl-2-quinolinyl)ethyl)amino)-
-5-pyrimidinecarbonitrile;
4-amino-6-(((1S)-1-(3-(3,5-difluorophenyl)-6-fluoro-4-methoxy-2-quinoliny-
l)ethyl)amino)-5-pyrimidinecarbonitrile;
4-amino-6-(-1-(6-fluoro-4-((2-methoxyethyl)amino)-3-phenyl-2-quinolinyl)e-
thyl)amino)-5-pyrimidinecarbonitrile;
4-amino-6-(-1-(4-((2-(dimethylamino)ethyl)amino)-6-fluoro-3-phenyl-2-quin-
olinyl)ethyl)amino)-5-pyrimidinecarbonitrile;
4-amino-6-(((1S)-1-(6-fluoro-4-((2-methoxyethyl)amino)-3-phenyl-2-quinoli-
nyl)ethyl)amino)-5-pyrimidinecarbonitrile;
4-amino-6-(((1R)-1-(6-fluoro-4-((2-methoxyethyl)amino)-3-phenyl-2-quinoli-
nyl)ethyl)amino)-5-pyrimidinecarbonitrile;
4-amino-6-(-1-(6-fluoro-4-((2-(methylsulfonyl)ethyl)amino)-3-phenyl-2-qui-
nolinyl)ethyl)amino)-5-pyrimidinecarbonitrile;
4-amino-6-(-1-(6-fluoro-4-((2-hydroxyethyl)amino)-3-phenyl-2-quinolinyl)e-
thyl)amino)-5-pyrimidinecarbonitrile;
4-amino-6-(((1S)-1-(6-fluoro-4-((2-(methylsulfonyl)ethyl)amino)-3-phenyl--
2-quinolinyl)ethyl)amino)-5-pyrimidinecarbonitrile;
4-amino-6-(((1S)-1-(6-fluoro-4-(methylsulfonyl)-3-phenyl-2-quinolinyl)eth-
yl)amino)-5-pyrimidinecarbonitrile;
N-(1-(6-fluoro-4-(methylsulfonyl)-3-phenyl-2-quinolinyl)ethyl)-9H-purin-6-
-amine;
N-(-1-(5-fluoro-4-(methylsulfonyl)-3-phenyl-2-quinolinyl)ethyl)-9H-
-purin-6-amine;
4-amino-6-((-1-(6-fluoro-4-((R)-(2-hydroxyethyl)sulfinyl)-3-phenyl-2-quin-
olinyl)ethyl)amino)-5-pyrimidinecarbonitrile;
4-amino-6-(((1R)-1-(5-fluoro-4-(methylsulfonyl)-3-phenyl-2-quinolinyl)eth-
yl)amino)-5-pyrimidinecarbonitrile;
4-amino-6-(((1S)-1-(5-fluoro-4-(methylsulfonyl)-3-phenyl-2-quinolinyl)eth-
yl)amino)-5-pyrimidinecarbonitrile;
N-((1S)-1-(6-fluoro-4-(methylsulfonyl)-3-phenyl-2-quinolinyl)-ethyl)-9H-p-
urin-6-amine;
N-((1R)-1-(6-fluoro-4-(methylsulfonyl)-3-phenyl-2-quinolinyl)-ethyl)-9H-p-
urin-6-amine;
4-amino-6-((-1-(3-(3,5-difluorophenyl)-6-fluoro-4-(methyl-sulfonyl)-2-qui-
nolinyl)ethyl)amino)-5-pyrimidinecarbonitrile;
4-amino-6-((-1-(6-fluoro-4-((S)-(2-hydroxyethyl)sulfinyl)-3-phenyl-2-quin-
olinyl)ethyl)amino)-5-pyrimidinecarbonitrile;
2-(1-(6-Amino-5-cyanopyrimidin-4-ylamino)ethyl)-6-fluoro-N-methyl-3-(pyri-
din-2-yl)quinoline-4-carboxamide;
(S)-2-(1-(6-Amino-5-cyanopyrimidin-4-ylamino)ethyl)-N-ethyl-6-fluoro-3-(p-
yridin-2-yl)quinoline-4-carboximidamide;
(S)-2-(1-(6-Amino-5-cyanopyrimidin-4-ylamino)ethyl)-6-fluoro-N-(2-hydroxy-
ethyl)-3-(pyridin-2-yl)quinoline-4-carboxamide;
(S)-2-(1-(6-Amino-5-cyanopyrimidin-4-ylamino)ethyl)-N-cyclopropyl-6-fluor-
o-3-(pyridin-2-yl)quinoline-4-carboxamide;
2-1-(((6-Amino-5-cyano-4-pyrimidinyl)amino)ethyl)-6-fluoro-3-(2-pyridinyl-
)-4-quinolinecarboxylic acid;
2-(-1-(((6-Amino-5-cyano-4-pyrimidinyl)amino)ethyl)-6-fluoro-N-methyl-3-(-
2-pyridinyl)-4-quinolinecarboxamide;
2-((1R)-1-((6-Amino-5-cyano-4-pyrimidinyl)amino)ethyl)-6-fluoro-N-methyl--
3-(2-pyridinyl)-4-quinolinecarboxamide;
2-(1-((6-Amino-5-cyano-4-pyrimidinyl)amino)ethyl)-6-fluoro-N,N-dimethyl-3-
-(2-pyridinyl)-4-quinolinecarboxamide;
4-Amino-6-((1-(6-fluoro-4-(1-piperazinylcarbonyl)-3-(2-pyridinyl)-2-quino-
linyl)ethyl)amino)-5-pyrimidinecarbonitrile; or
4-amino-6-(1-(6-fluoro-4-(3-hydroxyazetidine-1-carbonyl)-3-(pyridin-2-yl)-
quinolin-2-yl)ethylamino)pyrimidine-5-carbonitrile; or any
pharmaceutically-acceptable salt thereof.
3. A method of treating rheumatoid arthritis, ankylosing
spondylitis, osteoarthritis, psoriatic arthritis, psoriasis,
inflammatory diseases and autoimmune diseases, inflammatory bowel
disorders, inflammatory eye disorders, inflammatory or unstable
bladder disorders, skin complaints with inflammatory components,
chronic inflammatory conditions, autoimmune diseases, systemic
lupus erythematosis (SLE), myestenia gravis, rheumatoid arthritis,
acute disseminated encephalomyelitis, idiopathic thrombocytopenic
purpura, multiples sclerosis, Sjoegren's syndrome and autoimmune
hemolytic anemia, allergic conditions and hypersensitivity,
comprising the step of administering a compound according to claim
1.
4. A method of treating cancers, which are mediated, dependent on
or associated with p110.delta. activity, comprising the step of
administering a compound according to claim 1.
5. A pharmaceutical composition comprising a compound according to
claim 1 and a pharmaceutically-acceptable diluent or carrier.
Description
[0001] This application claims the benefit of U.S. Provisional
Application No. 61/220,488, filed Jun. 25, 2009, which is hereby
incorporated by reference.
[0002] The present invention relates generally to
phosphatidylinositol 3-kinase (PI3K) enzymes, and more particularly
to selective inhibitors of PI3K activity and to methods of using
such materials.
BACKGROUND OF THE INVENTION
[0003] Cell signaling via 3'-phosphorylated phosphoinositides has
been implicated in a variety of cellular processes, e.g., malignant
transformation, growth factor signaling, inflammation, and immunity
(see Rameh et al., J. Biol Chem, 274:8347-8350 (1999) for a
review). The enzyme responsible for generating these phosphorylated
signaling products, phosphatidylinositol 3-kinase (PI 3-kinase;
PI3K), was originally identified as an activity associated with
viral oncoproteins and growth factor receptor tyrosine kinases that
phosphorylates phosphatidylinositol (PI) and its phosphorylated
derivatives at the 3'-hydroxyl of the inositol ring (Panayotou et
al., Trends Cell Biol 2:358-60 (1992)).
[0004] The levels of phosphatidylinositol-3,4,5-triphosphate
(PIP3), the primary product of PI 3-kinase activation, increase
upon treatment of cells with a variety of stimuli. This includes
signaling through receptors for the majority of growth factors and
many inflammatory stimuli, hormones, neurotransmitters and
antigens, and thus the activation of PI3Ks represents one, if not
the most prevalent, signal transduction events associated with
mammalian cell surface receptor activation (Cantley, Science
296:1655-1657 (2002); Vanhaesebroeck et al. Annu. Rev. Biochem, 70:
535-602 (2001)). PI 3-kinase activation, therefore, is involved in
a wide range of cellular responses including cell growth,
migration, differentiation, and apoptosis (Parker et al., Current
Biology, 5:577-99 (1995); Yao et al., Science, 267:2003-05 (1995)).
Though the downstream targets of phosphorylated lipids generated
following PI 3-kinase activation have not been fully characterized,
it is known that pleckstrin-homology (PH) domain- and FYVE-finger
domain-containing proteins are activated when binding to various
phosphatidylinositol lipids (Sternmark et al., J Cell Sci,
112:4175-83 (1999); Lemmon et al., Trends Cell Biol, 7:237-42
(1997)). Two groups of PH-domain containing PI3K effectors have
been studied in the context of immune cell signaling, members of
the tyrosine kinase TEC family and the serine/threonine kinases of
the AGC family. Members of the Tec family containing PH domains
with apparent selectivity for PtdIns (3,4,5)P.sub.3 include Tec,
Btk, Itk and Etk. Binding of PH to PIP.sub.3 is critical for
tyrsosine kinase activity of the Tec family members (Schaeffer and
Schwartzberg, Curr. Opin. Immunol. 12: 282-288 (2000)) AGC family
members that are regulated by PI3K include the
phosphoinositide-dependent kinase (PDK1), AKT (also termed PKB) and
certain isoforms of protein kinase C (PKC) and S6 kinase. There are
three isoforms of AKT and activation of AKT is strongly associated
with PI3K-dependent proliferation and survival signals. Activation
of AKT depends on phosphorylation by PDK1, which also has a
3-phosphoinositide-selective PH domain to recruit it to the
membrane where it interacts with AKT. Other important PDK1
substrates are PKC and S6 kinase (Deane and Fruman, Annu Rev.
Immunol. 22.sub.--563-598 (2004)). In vitro, some isoforms of
protein kinase C (PKC) are directly activated by PIP3. (Burgering
et al., Nature, 376:599-602 (1995)).
[0005] Presently, the PI 3-kinase enzyme family has been divided
into three classes based on their substrate specificities. Class I
PI3Ks can phosphorylate phosphatidylinositol (PI),
phosphatidylinositol-4-phosphate, and
phosphatidylinositol-4,5-biphosphate (PIP2) to produce
phosphatidylinositol-3-phosphate (PIP),
phosphatidylinositol-3,4-biphosphate, and
phosphatidylinositol-3,4,5-triphosphate, respectively. Class II
PI3Ks phosphorylate PI and phosphatidylinositol-4-phosphate,
whereas Class III PI3Ks can only phosphorylate PI.
[0006] The initial purification and molecular cloning of PI
3-kinase revealed that it was a heterodimer consisting of p85 and
p110 subunits (Otsu et al., Cell, 65:91-104 (1991); Hiles et al.,
Cell, 70:419-29 (1992)). Since then, four distinct Class I PI3Ks
have been identified, designated PI3K .alpha., .beta., .delta., and
.gamma., each consisting of a distinct 110 kDa catalytic subunit
and a regulatory subunit. More specifically, three of the catalytic
subunits, i.e., p110.alpha., p110.beta. and p110.delta., each
interact with the same regulatory subunit, p85; whereas p110.gamma.
interacts with a distinct regulatory subunit, p101. As described
below, the patterns of expression of each of these PI3Ks in human
cells and tissues are also distinct. Though a wealth of information
has been accumulated in recent past on the cellular functions of PI
3-kinases in general, the roles played by the individual isoforms
are not fully understood.
[0007] Cloning of bovine p110.alpha. has been described. This
protein was identified as related to the Saccharomyces cerevisiae
protein: Vps34p, a protein involved in vacuolar protein processing.
The recombinant p110.alpha. product was also shown to associate
with p85.alpha., to yield a PI3K activity in transfected COS-1
cells. See Hiles et al., Cell, 70, 419-29 (1992).
[0008] The cloning of a second human p110 isoform, designated
p110.beta., is described in Hu et al., Mol Cell Biol, 13:7677-88
(1993). This isoform is said to associate with p85 in cells, and to
be ubiquitously expressed, as p110.beta. mRNA has been found in
numerous human and mouse tissues as well as in human umbilical vein
endothelial cells, Jurkat human leukemic T cells, 293 human
embryonic kidney cells, mouse 3T3 fibroblasts, HeLa cells, and NBT2
rat bladder carcinoma cells. Such wide expression suggests that
this isoform is broadly important in signaling pathways.
[0009] Identification of the p110.delta. isoform of PI 3-kinase is
described in Chantry et al., J Biol Chem, 272:19236-41 (1997). It
was observed that the human p110.delta. isoform is expressed in a
tissue-restricted fashion. It is expressed at high levels in
lymphocytes and lymphoid tissues and has been shown to play a key
role in PI 3-kinase-mediated signaling in the immune system
(Al-Alwan etl al. JI 178: 2328-2335 (2007); Okkenhaug et al JI,
177: 5122-5128 (2006); Lee et al. PNAS, 103: 1289-1294 (2006)).
P110.delta. has also been shown to be expressed at lower levels in
breast cells, melanocytes and endothelial cells (Vogt et al.
Virology, 344: 131-138 (2006) and has since been implicated in
conferring selective migratory properties to breast cancer cells
(Sawyer et al. Cancer Res. 63:1667-1675 (2003)). Details concerning
the P110.delta. isoform also can be found in U.S. Pat. Nos.
5,858,753; 5,822,910; and 5,985,589. See also, Vanhaesebroeck et
al., Proc Nat. Acad Sci USA, 94:4330-5 (1997), and international
publication WO 97/46688.
[0010] In each of the PI3K.alpha., .beta., and .delta. subtypes,
the p85 subunit acts to localize PI 3-kinase to the plasma membrane
by the interaction of its SH2 domain with phosphorylated tyrosine
residues (present in an appropriate sequence context) in target
proteins (Rameh et al., Cell, 83:821-30 (1995)). Five isoforms of
p85 have been identified (p85.alpha., p85.beta., p55.gamma.,
p55.alpha. and p50.alpha.) encoded by three genes. Alternative
transcripts of Pik3r1 gene encode the p85 .alpha., p55 .alpha. and
p50.alpha. proteins (Deane and Fruman, Annu. Rev. Immunol. 22:
563-598 (2004)). p85.alpha. is ubiquitously expressed while
p85.beta., is primarily found in the brain and lymphoid tissues
(Volinia et al., Oncogene, 7:789-93 (1992)). Association of the p85
subunit to the PI 3-kinase p110.alpha., .beta., or .delta.
catalytic subunits appears to be required for the catalytic
activity and stability of these enzymes. In addition, the binding
of Ras proteins also upregulates PI 3-kinase activity.
[0011] The cloning of p110.gamma. revealed still further complexity
within the PI3K family of enzymes (Stoyanov et al., Science,
269:690-93 (1995)). The p110.gamma. isoform is closely related to
p110.alpha. and p110.beta. (45-48% identity in the catalytic
domain), but as noted does not make use of p85 as a targeting
subunit. Instead, p110.gamma. binds a p101 regulatory subunit that
also binds to the .beta..gamma. subunits of heterotrimeric G
proteins. The p101 regulatory subunit for PI3 Kgamma was originally
cloned in swine, and the human ortholog identified subsequently
(Krugmann et al., J Biol Chem, 274:17152-8 (1999)). Interaction
between the N-terminal region of p101 with the N-terminal region of
p110.gamma. is known to activate PI3K.gamma. through
G.beta..gamma.. Recently, a p101-homologue has been identified, p84
or p87.sup.PIKAP (PI3K.gamma. adapter protein of 87 kDa) that binds
p110.gamma. (Voigt et al. JBC, 281: 9977-9986 (2006), Suire et al.
Curr. Biol. 15: 566-570 (2005)). p87.sup.PIKAP is homologous to
p101 in areas that bind p110.gamma. and G.beta..gamma. and also
mediates activation of p110.gamma. downstream of G-protein-coupled
receptors. Unlike p101, p87.sup.PIKAP is highly expressed in the
heart and may be crucial to PI3K.gamma. cardiac function.
[0012] A constitutively active PI3K polypeptide is described in
international publication WO 96/25488. This publication discloses
preparation of a chimeric fusion protein in which a 102-residue
fragment of p85 known as the inter-SH2 (iSH2) region is fused
through a linker region to the N-terminus of murine p110. The p85
iSH2 domain apparently is able to activate PI3K activity in a
manner comparable to intact p85 (Klippel et al., Mol Cell Biol,
14:2675-85 (1994)).
[0013] Thus, PI 3-kinases can be defined by their amino acid
identity or by their activity. Additional members of this growing
gene family include more distantly related lipid and protein
kinases including Vps34 TOR1, and TOR2 of Saccharomyces cerevisiae
(and their mammalian homologs such as FRAP and mTOR), the ataxia
telangiectasia gene product (ATR) and the catalytic subunit of
DNA-dependent protein kinase (DNA-PK). See generally, Hunter, Cell,
83:1-4 (1995).
[0014] PI 3-kinase is also involved in a number of aspects of
leukocyte activation. A p85-associated PI 3-kinase activity has
been shown to physically associate with the cytoplasmic domain of
CD28, which is an important costimulatory molecule for the
activation of T-cells in response to antigen (Pages et al., Nature,
369:327-29 (1994); Rudd, Immunity, 4:527-34 (1996)). Activation of
T cells through CD28 lowers the threshold for activation by antigen
and increases the magnitude and duration of the proliferative
response. These effects are linked to increases in the
transcription of a number of genes including interleukin-2 (IL2),
an important T cell growth factor (Fraser et al., Science,
251:313-16 (1991)). Mutation of CD28 such that it can no longer
interact with PI 3-kinase leads to a failure to initiate IL2
production, suggesting a critical role for PI 3-kinase in T cell
activation.
[0015] Specific inhibitors against individual members of a family
of enzymes provide invaluable tools for deciphering functions of
each enzyme. Two compounds, LY294002 and wortmannin, have been
widely used as PI 3-kinase inhibitors. These compounds, however,
are nonspecific PI3K inhibitors, as they do not distinguish among
the four members of Class I PI 3-kinases. For example, the
IC.sub.50 values of wortmannin against each of the various Class I
PI 3-kinases are in the range of 1-10 nM. Similarly, the IC.sub.50
values for LY294002 against each of these PI 3-kinases is about 1
.mu.M (Froman et al., Ann Rev Biochem, 67:481-507 (1998)). Hence,
the utility of these compounds in studying the roles of individual
Class I PI 3-kinases is limited.
[0016] Based on studies using wortmannin, there is evidence that PI
3-kinase function also is required for some aspects of leukocyte
signaling through G-protein coupled receptors (Thelen et al., Proc
Natl Acad Sci USA, 91:4960-64 (1994)). Moreover, it has been shown
that wortmannin and LY294002 block neutrophil migration and
superoxide release. However, inasmuch as these compounds do not
distinguish among the various isoforms of PI3K, it remains unclear
from these studies which particular PI3K isoform or isoforms are
involved in these phenomena and what functions the different Class
I PI3K enzymes perform in both normal and diseased tissues in
general. The co-expression of several PI3K isoforms in most tissues
has confounded efforts to segregate the activities of each enzyme
until recently.
[0017] The separation of the activities of the various PI3K
isozymes has been advanced recently with the development of
genetically manipulated mice that allowed the study of
isoform-specific knock-out and kinase dead knock-in mice and the
development of more selective inhibitors for some of the different
isoforms. P110.alpha. and p110.beta. knockout mice have been
generated and are both embryonic lethal and little information can
be obtained from these mice regarding the expression and function
of p110 alpha and beta (Bi et al. Mamm. Genome, 13:169-172 (2002);
Bi et al. J. Biol. Chem. 274:10963-10968 (1999)). More recently,
p110.alpha. kinase dead knock in mice were generated with a single
point mutation in the DFG motif of the ATP binding pocket
(p110.alpha.D.sup.933A) that impairs kinase activity but preserves
mutant p110.alpha. kinase expression. In contrast to knock out
mice, the knockin approach preserves signaling complex
stoichiometry, scaffold functions and mimics small molecule
approaches more realistically than knock out mice. Similar to the
p110.alpha. KO mice, p110.alpha.D.sup.933A homozygous mice are
embryonic lethal. However, heterozygous mice are viable and fertile
but display severely blunted signaling via insulin-receptor
substrate (IRS) proteins, key mediators of insulin, insulin-like
growth factor-1 and leptin action. Defective responsiveness to
these hormones leads to hyperinsulinaemia, glucose intolerance,
hyperphagia, increase adiposity and reduced overall growth in
heterozygotes (Foukas, et al. Nature, 441: 366-370 (2006)). These
studies revealed a defined, non-redundant role for p110.alpha. as
an intermediate in IGF-1, insulin and leptin signaling that is not
substituted for by other isoforms. We will have to await the
description of the p110.beta. kinase-dead knock in mice to further
understand the function of this isoform (mice have been made but
not yet published; Vanhaesebroeck).
[0018] P110.gamma. knock out and kinase-dead knock in mice have
both been generated and overall show similar and mild phenotypes
with primary defects in migration of cells of the innate immune
system and a defect in thymic development of T cells (Li et al.
Science, 287: 1046-1049 (2000), Sasaki et al. Science, 287:
1040-1046 (2000), Patrucco et al. Cell, 118: 375-387 (2004)).
[0019] Similar to p110.gamma., PI3K delta knock out and kinase-dead
knock-in mice have been made and are viable with mild and like
phenotypes. The p110.delta..sup.D910A mutant knock in mice
demonstrated an important role for delta in B cell development and
function, with marginal zone B cells and CD5+B1 cells nearly
undetectable, and B- and T cell antigen receptor signaling (Clayton
et al. J. Exp. Med. 196:753-763 (2002); Okkenhaug et al. Science,
297: 1031-1034 (2002)). The p110.delta..sup.D910A mice have been
studied extensively and have elucidated the diverse role that delta
plays in the immune system. T cell dependent and T cell independent
immune responses are severely attenuated in p110.delta..sup.D910A
and secretion of TH1 (INF-.gamma.) and TH2 cytokine (IL-4, IL-5)
are impaired (Okkenhaug et al. J. Immunol. 177: 5122-5128 (2006)).
A human patient with a mutation in p110.delta. has also recently
been described. A taiwanese boy with a primary B cell
immunodeficiency and a gamma-hypoglobulinemia of previously unknown
aetiology presented with a single base-pair substitution, m.3256G
to A in codon 1021 in exon 24 of p110.delta.. This mutation
resulted in a mis-sense amino acid substitution (E to K) at codon
1021, which is located in the highly conserved catalytic domain of
p110.delta. protein. The patient has no other identified mutations
and his phenotype is consistent with p110.delta. deficiency in mice
as far as studied. (Jou et al. Int. J. Immunogenet. 33: 361-369
(2006)).
[0020] Isoform-selective small molecule compounds have been
developed with varying success to all Class I PI3 kinase isoforms
(Ito et al. J. Pharm. Exp. Therapeut., 321:1-8 (2007)). Inhibitors
to alpha are desirable because mutations in p110.alpha. have been
identified in several solid tumors; for example, an amplification
mutation of alpha is associated with 50% of ovarian, cervical, lung
and breast cancer and an activation mutation has been described in
more than 50% of bowel and 25% of breast cancers (Hennessy et al.
Nature Reviews, 4: 988-1004 (2005)). Yamanouchi has developed a
compound YM-024 that inhibits alpha and delta equipotently and is
8- and 28-fold selective over beta and gamma respectively (Ito et
al. J. Pharm. Exp. Therapeut., 321:1-8 (2007)).
[0021] P110.beta. is involved in thrombus formation (Jackson et al.
Nature Med. 11: 507-514 (2005)) and small molecule inhibitors
specific for this isoform are thought after for indication
involving clotting disorders (TGX-221: 0.007 uM on beta; 14-fold
selective over delta, and more than 500-fold selective over gamma
and alpha) (Ito et al. J. Pharm. Exp. Therapeut., 321:1-8
(2007)).
[0022] Selective compounds to p110.gamma. are being developed by
several groups as immunosuppressive agents for autoimmune disease
(Rueckle et al. Nature Reviews, 5: 903-918 (2006)). Of note, AS
605240 has been shown to be efficacious in a mouse model of
rheumatoid arthritis (Camps et al. Nature Medicine, 11: 936-943
(2005)) and to delay onset of disease in a model of systemic lupus
erythematosis (Barber et al. Nature Medicine, 11: 933-935
(205)).
[0023] Delta-selective inhibitors have also been described
recently. The most selective compounds include the quinazolinone
purine inhibitors (PIK39 and IC87114). IC87114 inhibits p110.delta.
in the high nanomolar range (triple digit) and has greater than
100-fold selectivity against p110.alpha., is 52 fold selective
against p110.beta. but lacks selectivity against p110.gamma.
(approx. 8-fold). It shows no activity against any protein kinases
tested (Knight et al. Cell, 125: 733-747 (2006)). Using
delta-selective compounds or genetically manipulated mice
(p110.delta..sup.D910A) it was shown that in addition to playing a
key role in B and T cell activation, delta is also partially
involved in neutrophil migration and primed neutrophil respiratory
burst and leads to a partial block of antigen-IgE mediated mast
cell degranulation (Condliffe et al. Blood, 106: 1432-1440 (2005);
Ali et al. Nature, 431: 1007-1011 (2002)). Hence p110.delta. is
emerging as an important mediator of many key inflammatory
responses that are also known to participate in aberrant
inflammatory conditions, including but not limited to autoimmune
disease and allergy. To support this notion, there is a growing
body of p110.delta. target validation data derived from studies
using both genetic tools and pharmacologic agents. Thus, using the
delta-selective compound IC 87114 and the p110.delta..sup.D910A
mice, Ali et al. (Nature, 431: 1007-1011 (2002)) have demonstrated
that delta plays a critical role in a murine model of allergic
disease. In the absence of functional delta, passive cutaneous
anaphylaxis (PCA) is significantly reduced and can be attributed to
a reduction in allergen-IgE induced mast cell activation and
degranulation. In addition, inhibition of delta with IC 87114 has
been shown to significantly ameliorate inflammation and disease in
a murine model of asthma using ovalbumin-induced airway
inflammation (Lee et al. FASEB, 20: 455-465 (2006). These data
utilizing compound were corroborated in p110.delta..sup.D910A
mutant mice using the same model of allergic airway inflammation by
a different group (Nashed et al. Eur. J. Immunol. 37:416-424
(2007)).
[0024] There exists a need for further characterization of
PI3K.delta. function in inflammatory and auto-immune settings.
Furthermore, our understanding of PI3K.delta. requires further
elaboration of the structural interactions of p110.delta., both
with its regulatory subunit and with other proteins in the cell.
There also remains a need for more potent and selective or specific
inhibitors of PI3K delta, in order to avoid potential toxicology
associated with activity on isozymes p110 alpha (insulin signaling)
and beta (platelet activation). In particular, selective or
specific inhibitors of PI3K.delta. are desirable for exploring the
role of this isozyme further and for development of superior
pharmaceuticals to modulate the activity of the isozyme.
SUMMARY
[0025] The present invention comprises a new class of compounds
having the general formula
##STR00001##
which are useful to inhibit the biological activity of human
PI3K.delta.. Another aspect of the invention is to provide
compounds that inhibit PI3K.delta. selectively while having
relatively low inhibitory potency against the other PI3K isoforms.
Another aspect of the invention is to provide methods of
characterizing the function of human PI3K.delta.. Another aspect of
the invention is to provide methods of selectively modulating human
PI3K.delta. activity, and thereby promoting medical treatment of
diseases mediated by PI3K.delta. dysfunction. Other aspects and
advantages of the invention will be readily apparent to the artisan
having ordinary skill in the art.
DETAILED DESCRIPTION
[0026] One aspect of the invention relates to compounds having the
structure:
##STR00002##
or any pharmaceutically-acceptable salt thereof, wherein:
[0027] X.sup.1 is C(R.sup.10) or N;
[0028] X.sup.2 is C or N;
[0029] X.sup.3 is C or N;
[0030] X.sup.4 is C or N;
[0031] X.sup.5 is C or N; wherein at least two of X.sup.2, X.sup.3,
X.sup.4 and X.sup.5 are C;
[0032] X.sup.6 is C(R.sup.6) or N;
[0033] X.sup.7 is C(R.sup.7) or N;
[0034] X.sup.8 is C(R.sup.10) or N; wherein no more than two of
X.sup.1, X.sup.6, X.sup.7 and X.sup.8 are N;
[0035] Y is N(R.sup.8), O or S;
[0036] n is 0, 1, 2 or 3;
[0037] R.sup.1 is a direct-bonded, C.sub.1-4alk-linked,
OC.sub.1-2alk-linked, C.sub.1-2alkO-linked, N(R.sup.a)-linked or
O-linked saturated, partially-saturated or unsaturated 5-, 6- or
7-membered monocyclic or 8-, 9-, 10- or 11-membered bicyclic ring
containing 0, 1, 2, 3 or 4 atoms selected from N, O and S, but
containing no more than one O or S atom, substituted by 0, 1, 2 or
3 substituents independently selected from halo, C.sub.1-6alk,
C.sub.1-4haloalk, cyano, nitro, --C(.dbd.O)R.sup.a,
--C(.dbd.O)OR.sup.a, --C(.dbd.O)NR.sup.aR.sup.a,
--C(.dbd.NR.sup.a)NR.sup.aR.sup.a, --OR.sup.a, --OC(.dbd.O)R.sup.a,
--OC(.dbd.O)NR.sup.aR.sup.a,
--OC(.dbd.O)N(R.sup.a)S(.dbd.O).sub.2R.sup.a,
--OC.sub.2-6alkNR.sup.aR.sup.a, --OC.sub.2-6alkOR.sup.a,
--SR.sup.a, --S(.dbd.O)R.sup.a, --S(.dbd.O).sub.2R.sup.a,
--S(.dbd.O).sub.2NR.sup.aR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)R.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)OR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--NR.sup.aR.sup.a, --N(R.sup.a)C(.dbd.O)R.sup.a,
--N(R.sup.a)C(.dbd.O)OR.sup.a,
--N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--N(R.sup.a)C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2R.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2NR.sup.aR.sup.a,
--NR.sup.aC.sub.2-6alkNR.sup.aR.sup.a and
--NR.sup.aC.sub.2-6alkOR.sup.a, wherein the available carbon atoms
of the ring are additionally substituted by 0, 1 or 2 oxo or thioxo
groups, and wherein the ring is additionally substituted by 0 or 1
directly bonded, SO.sub.2 linked, C(.dbd.O) linked or CH.sub.2
linked group selected from phenyl, pyridyl, pyrimidyl, morpholino,
piperazinyl, piperidinyl, cyclopentyl and cyclohexyl all of which
are further substituted by 0, 1, 2 or 3 independent R.sup.b
groups;
[0038] R.sup.2 is selected from H, halo, C.sub.1-6alk,
C.sub.1-4haloalk, cyano, nitro, OR.sup.a, NR.sup.aR.sup.a,
--C(.dbd.O)R.sup.a, --C(.dbd.O)OR.sup.a,
--C(.dbd.O)NR.sup.aR.sup.a, --C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--S(.dbd.O)R.sup.a, --S(.dbd.O).sub.2R.sup.a,
--S(.dbd.O).sub.2NR.sup.aR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)R.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)OR.sup.a and
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a;
[0039] R.sup.3 is selected from H, halo, nitro, cyano,
C.sub.1-4alk, OC.sub.1-4alk, OC.sub.1-4haloalk, NHC.sub.1-4alk,
N(C.sub.1-4alk)C.sub.1-4alk and C.sub.1-4haloalk;
[0040] R.sup.4 is, independently, in each instance, halo, nitro,
cyano, C.sub.1-4alk, OC.sub.1-4alk, OC.sub.1-4haloalk,
NHC.sub.1-4alk, N(C.sub.1-4alk)C.sub.1-4alk, C.sub.1-4haloalk or an
unsaturated 5-, 6- or 7-membered monocyclic ring containing 0, 1,
2, 3 or 4 atoms selected from N, O and S, but containing no more
than one O or S, the ring being substituted by 0, 1, 2 or 3
substituents selected from halo, C.sub.1-4alk, C.sub.1-3haloalk,
--OC.sub.1-4alk, --NH.sub.2, --NHC.sub.1-4alk and
--N(C.sub.1-4alk)C.sub.1-4alk;
[0041] R.sup.5 is, independently, in each instance, H, halo,
C.sub.1-6alk, C.sub.1-4haloalk, or C.sub.1-6alk substituted by 1, 2
or 3 substituents selected from halo, cyano, OH, OC.sub.1-4alk,
C.sub.1-4alk, C.sub.1-3haloalk, OC.sub.1-4alk, NH.sub.2,
NHC.sub.1-4alk and N(C.sub.1-4alk)C.sub.1-4alk; or both R.sup.5
groups together form a C.sub.3-6-spiroalk substituted by 0, 1, 2 or
3 substituents selected from halo, cyano, OH, OC.sub.1-4alk,
C.sub.1-4alk, C.sub.1-3haloalk, OC.sub.1-4alk, NH.sub.2,
NHC.sub.1-4alk and N(C.sub.1-4alk)C.sub.1-4alk;
[0042] R.sup.6 is selected from halo, cyano, OH, OC.sub.1-4alk,
C.sub.1-4alk, C.sub.1-3haloalk, OC.sub.1-4alk, NHR.sup.9,
N(C.sub.1-4alk)C.sub.1-4alk, --C(.dbd.O)OR.sup.a,
--C(.dbd.O)N(R.sup.a)R.sup.a, --N(R.sup.a)C(.dbd.O)R.sup.b and a 5-
or 6-membered saturated or partially saturated heterocyclic ring
containing 1, 2 or 3 heteroatoms selected from N, O and S, wherein
the ring is substituted by 0, 1, 2 or 3 substituents selected from
halo, cyano, OH, oxo, OC.sub.1-4alk, C.sub.1-4alk,
C.sub.1-3haloalk, OC.sub.1-4alk, NH.sub.2, NHC.sub.1-4alk and
N(C.sub.1-4alk)C.sub.1-4alk;
[0043] R.sup.7 is selected from H, halo, C.sub.1-4haloalk, cyano,
nitro, --C(.dbd.O)R.sup.a, --C(.dbd.O)OR.sup.a,
--C(.dbd.O)NR.sup.aR.sup.a, --C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--OR.sup.a, --OC(.dbd.O)R.sup.a, --OC(.dbd.O)NR.sup.aR.sup.a,
--OC(.dbd.O)N(R.sup.a)S(.dbd.O).sub.2R.sup.a,
--OC.sub.2-6alkNR.sup.aR.sup.a, --OC.sub.2-6alkOR.sup.a,
--SR.sup.a, --S(.dbd.O)R.sup.a, --S(.dbd.O).sub.2R.sup.a,
--S(.dbd.O).sub.2NR.sup.aR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)R.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)OR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--NR.sup.aR.sup.a, --N(R.sup.a)C(.dbd.O)R.sup.a,
--N(R.sup.a)C(.dbd.O)OR.sup.a,
--N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--N(R.sup.a)C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2R.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2NR.sup.aR.sup.a,
--NR.sup.aC.sub.2-6alkNR.sup.aR.sup.a,
--NR.sup.aC.sub.2-6alkOR.sup.a and C.sub.1-6alk, wherein the
C.sub.1-6alk is substituted by 0, 1, 2 or 3 substituents selected
from halo, C.sub.1-4haloalk, cyano, nitro, --C(.dbd.O)R.sup.a,
--C(.dbd.O)OR.sup.a, --C(.dbd.O)NR.sup.aR.sup.a,
--C(.dbd.NR.sup.a)NR.sup.aR.sup.a, --OR.sup.a, --OC(.dbd.O)R.sup.a,
--OC(.dbd.O)NR.sup.aR.sup.a,
--OC(.dbd.O)N(R.sup.a)S(.dbd.O).sub.2R.sup.a,
--OC.sub.2-6alkNR.sup.aR.sup.a, --OC.sub.2-6alkOR.sup.a,
--SR.sup.a, --S(.dbd.O)R.sup.a, --S(.dbd.O).sub.2R.sup.a,
--S(.dbd.O).sub.2NR.sup.aR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)R.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)OR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--NR.sup.aR.sup.a, --N(R.sup.a)C(.dbd.O)R.sup.a,
--N(R.sup.a)C(.dbd.O)OR.sup.a,
--N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--N(R.sup.a)C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2R.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2NR.sup.aR.sup.a,
--NR.sup.aC.sub.2-6alkNR.sup.aR.sup.a and
--NR.sup.aC.sub.2-6alkOR.sup.a, and the C.sub.1-6alk is
additionally substituted by 0 or 1 saturated, partially-saturated
or unsaturated 5-, 6- or 7-membered monocyclic rings containing 0,
1, 2, 3 or 4 atoms selected from N, O and S, but containing no more
than one O or S, wherein the available carbon atoms of the ring are
substituted by 0, 1 or 2 oxo or thioxo groups, wherein the ring is
substituted by 0, 1, 2 or 3 substituents independently selected
from halo, nitro, cyano, C.sub.1-4alk, OC.sub.1-4alk,
OC.sub.1-4haloalk, NHC.sub.1-4alk, N(C.sub.1-4alk)C.sub.1-4alk and
C.sub.1-4haloalk; or R.sup.7 and R.sup.8 together form a
--C.dbd.N-- bridge wherein the carbon atom is substituted by H,
halo, cyano, or a saturated, partially-saturated or unsaturated 5-,
6- or 7-membered monocyclic ring containing 0, 1, 2, 3 or 4 atoms
selected from N, O and S, but containing no more than one O or S,
wherein the available carbon atoms of the ring are substituted by
0, 1 or 2 oxo or thioxo groups, wherein the ring is substituted by
0, 1, 2, 3 or 4 substituents selected from halo, C.sub.1-6alk,
C.sub.1-4haloalk, cyano, nitro, --C(.dbd.O)R.sup.a,
--C(.dbd.O)OR.sup.a, --C(.dbd.O)NR.sup.aR.sup.a,
--C(.dbd.NR.sup.a)NR.sup.aR.sup.a, --OR.sup.a, --OC(.dbd.O)R.sup.a,
--OC(.dbd.O)NR.sup.aR.sup.a,
--OC(.dbd.O)N(R.sup.a)S(.dbd.O).sub.2R.sup.a,
--OC.sub.2-6alkNR.sup.aR.sup.a, --OC.sub.2-6alkOR.sup.a,
--SR.sup.a, --S(.dbd.O)R.sup.a, --S(.dbd.O).sub.2R.sup.a,
--S(.dbd.O).sub.2NR.sup.aR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)R.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)OR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--NR.sup.aR.sup.a, --N(R.sup.a)C(.dbd.O)R.sup.a,
--N(R.sup.a)C(.dbd.O)OR.sup.a,
--N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--N(R.sup.a)C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2R.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2NR.sup.aR.sup.a,
--NR.sup.aC.sub.2-6alkNR.sup.aR.sup.a and
--NR.sup.aC.sub.2-6alkOR.sup.a; or R.sup.7 and R.sup.9 together
form a --N.dbd.C-- bridge wherein the carbon atom is substituted by
H, halo, C.sub.1-6alk, C.sub.1-4haloalk, cyano, nitro, OR.sup.a,
NR.sup.aR.sup.a, --C(.dbd.O)R.sup.a, --C(.dbd.O)OR.sup.a,
--C(.dbd.O)NR.sup.aR.sup.a, --C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--S(.dbd.O)R.sup.a, --S(.dbd.O).sub.2R.sup.a or
--S(.dbd.O).sub.2NR.sup.aR.sup.a;
[0044] R.sup.8 is H, C.sub.1-6alk, C(.dbd.O)N(R.sup.a)R.sup.a,
C(.dbd.O)R.sup.b or C.sub.1-4haloalk;
[0045] R.sup.9 is H, C.sub.1-6alk or C.sub.1-4haloalk;
[0046] R.sup.10 is in each instance H, halo, C.sub.1-3alk,
C.sub.1-3haloalk or cyano;
[0047] R.sup.11 is selected from H, halo, C.sub.1-6alk,
C.sub.1-4haloalk, cyano, nitro, --C(.dbd.O)R.sup.a,
--C(.dbd.O)OR.sup.a, --C(.dbd.O)NR.sup.aR.sup.a,
--C(.dbd.NR.sup.a)NR.sup.aR.sup.a, --OR.sup.a, --OC(.dbd.O)R.sup.a,
--OC(.dbd.O)NR.sup.aR.sup.a,
--OC(.dbd.O)N(R.sup.a)S(.dbd.O).sub.2R.sup.a,
--OC.sub.2-6alkNR.sup.aR.sup.a, --OC.sub.2-6alkOR.sup.a,
--SR.sup.a, --S(.dbd.O)R.sup.a, --S(.dbd.O).sub.2R.sup.b,
--S(.dbd.O).sub.2NR.sup.aR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)R.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)OR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--NR.sup.aR.sup.a, --N(R.sup.a)C(.dbd.O)R.sup.a,
--N(R.sup.a)C(.dbd.O)OR.sup.a,
--N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--N(R.sup.a)C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2R.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2NR.sup.aR.sup.a,
--NR.sup.aC.sub.2-6alkNR.sup.aR.sup.a,
--NR.sup.a(C.sub.2-6alkOR.sup.a,
--NR.sup.aC.sub.2-6alkCO.sub.2R.sup.a,
--NR.sup.aC.sub.2-6alkSO.sub.2R.sup.b, --CH.sub.2C(.dbd.O)R.sup.a,
--CH.sub.2C(.dbd.O)OR.sup.a, --CH.sub.2C(.dbd.O)NR.sup.aR.sup.a,
--CH.sub.2C(.dbd.NR.sup.a)NR.sup.aR.sup.a, --CH.sub.2OR.sup.a,
--CH.sub.2C(.dbd.O)R.sup.a, --CH.sub.2C(.dbd.O)NR.sup.aR.sup.a,
--CH.sub.2C(.dbd.O)N(R.sup.a)S(.dbd.O).sub.2R.sup.a,
--CH.sub.2OC.sub.2-6alkNR.sup.aR.sup.a,
--CH.sub.2OC.sub.2-6alkOR.sup.a, --CH.sub.2SR.sup.a,
--CH.sub.2S(.dbd.O)R.sup.a, --CH.sub.2S(.dbd.O).sub.2R.sup.b,
--CH.sub.2S(.dbd.O).sub.2NR.sup.aR.sup.a,
--CH.sub.2S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)R.sup.a,
--CH.sub.2S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)OR.sup.a,
--CH.sub.2S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--CH.sub.2NR.sup.aR.sup.a, --CH.sub.2N(R.sup.a)C(.dbd.O)R.sup.a,
--CH.sub.2N(R.sup.a)C(.dbd.O)OR.sup.a,
--CH.sub.2N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--CH.sub.2N(R.sup.a)C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--CH.sub.2N(R.sup.a)S(.dbd.O).sub.2R.sup.a,
--CH.sub.2N(R.sup.a)S(.dbd.O).sub.2NR.sup.aR.sup.a,
--CH.sub.2NR.sup.aC.sub.2-6alkNR.sup.aR.sup.a,
--CH.sub.2NR.sup.aC.sub.2-6alkOR.sup.a,
--CH.sub.2NR.sup.aC.sub.2-6alkCO.sub.2R.sup.a,
--CH.sub.2NR.sup.aC.sub.2-6alkSO.sub.2R.sup.b, --CH.sub.2R.sup.c,
--C(.dbd.O)R.sup.c and --C(.dbd.O)N(R.sup.a)R.sup.c;
[0048] R.sup.a is independently, at each instance, H or
R.sup.b;
[0049] R.sup.b is independently, at each instance, phenyl, benzyl
or C.sub.1-6alk, the phenyl, benzyl and C.sub.1-6alk being
substituted by 0, 1, 2 or 3 substituents selected from halo,
C.sub.1-4alk, C.sub.1-3haloalk, --OH, --OC.sub.1-4alk, --NH.sub.2,
--NHC.sub.1-4alk and --N(C.sub.1-4alk)C.sub.1-4alk; and
[0050] R.sup.c is a saturated or partially-saturated 4-, 5- or
6-membered ring containing 1, 2 or 3 heteroatoms selected from N, O
and S, the ring being substituted by 0, 1, 2 or 3 substituents
selected from halo, C.sub.1-4alk, C.sub.1-3haloalk,
--OC.sub.1-4alk, --NH.sub.2, --NHC.sub.1-4alk and
--N(C.sub.1-4alk)C.sub.1-4alk.
[0051] Another aspect of the invention relates to compounds having
the structure
##STR00003##
or any pharmaceutically-acceptable salt thereof, wherein:
[0052] X.sup.1 is C(R.sup.10) or N;
[0053] X.sup.2 is C or N;
[0054] X.sup.3 is C or N;
[0055] X.sup.4 is C or N;
[0056] X.sup.5 is C or N; wherein at least two of X.sup.2, X.sup.3,
X.sup.4 and X.sup.5 are C;
[0057] X.sup.6 is C(R.sup.6) or N;
[0058] X.sup.7 is C(R.sup.7) or N;
[0059] X.sup.8 is C(R.sup.10) or N; wherein no more than two of
X.sup.1, X.sup.6, X.sup.7 and X.sup.8 are N;
[0060] n is 0, 1, 2 or 3;
[0061] R.sup.1 is a direct-bonded, C.sub.1-4alk-linked,
OC.sub.1-2alk-linked, C.sub.1-2alkO-linked, N(R.sup.a)-linked or
O-linked saturated, partially-saturated or unsaturated 5-, 6- or
7-membered monocyclic or 8-, 9-, 10- or 11-membered bicyclic ring
containing 0, 1, 2, 3 or 4 atoms selected from N, O and S, but
containing no more than one O or S atom, substituted by 0, 1, 2 or
3 substituents independently selected from halo, C.sub.1-6alk,
C.sub.1-4haloalk, cyano, nitro, --C(.dbd.O)R.sup.a,
--C(.dbd.O)OR.sup.a, --C(.dbd.O)NR.sup.aR.sup.a,
--C(.dbd.NR.sup.a)NR.sup.aR.sup.a, --OR.sup.a, --OC(.dbd.O)R.sup.a,
--OC(.dbd.O)NR.sup.aR.sup.a,
--OC(.dbd.O)N(R.sup.a)S(.dbd.O).sub.2R.sup.a,
--OC.sub.2-6alkNR.sup.aR.sup.a, --OC.sub.2-6alkOR.sup.a,
--SR.sup.a, --S(.dbd.O)R.sup.a, --S(.dbd.O).sub.2R.sup.a,
--S(.dbd.O).sub.2NR.sup.aR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)R.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)OR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--NR.sup.aR.sup.a, --N(R.sup.a)C(.dbd.O)R.sup.a,
--N(R.sup.a)C(.dbd.O)OR.sup.a,
--N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--N(R.sup.a)C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2R.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2NR.sup.aR.sup.a,
--NR.sup.aC.sub.2-6alkNR.sup.aR.sup.a and
--NR.sup.aC.sub.2-6alkOR.sup.a, wherein the available carbon atoms
of the ring are additionally substituted by 0, 1 or 2 oxo or thioxo
groups, and wherein the ring is additionally substituted by 0 or 1
directly bonded, SO.sub.2 linked, C(.dbd.O) linked or CH.sub.2
linked group selected from phenyl, pyridyl, pyrimidyl, morpholino,
piperazinyl, piperidinyl, cyclopentyl and cyclohexyl all of which
are further substituted by 0, 1, 2 or 3 independent R.sup.b
groups;
[0062] R.sup.2 is selected from H, halo, C.sub.1-6alk,
C.sub.1-4haloalk, cyano, nitro, OR.sup.a, NR.sup.aR.sup.a,
--C(.dbd.O)R.sup.a, --C(.dbd.O)OR.sup.a,
--C(.dbd.O)NR.sup.aR.sup.a, --C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--S(.dbd.O)R.sup.a, --S(.dbd.O).sub.2R.sup.a,
--S(.dbd.O).sub.2NR.sup.aR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)R.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)OR.sup.a and
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a;
[0063] R.sup.3 is selected from H, halo, nitro, cyano,
C.sub.1-4alk, OC.sub.1-4alk, OC.sub.1-4haloalk, NHC.sub.1-4alk,
N(C.sub.1-4alk)C.sub.1-4alk and C.sub.1-4haloalk;
[0064] R.sup.4 is, independently, in each instance, halo, nitro,
cyano, C.sub.1-4alk, OC.sub.1-4alk, OC.sub.1-4haloalk,
NHC.sub.1-4alk, N(C.sub.1-4alk)C.sub.1-4alk, C.sub.1-4haloalk or an
unsaturated 5-, 6- or 7-membered monocyclic ring containing 0, 1,
2, 3 or 4 atoms selected from N, O and S, but containing no more
than one O or S, the ring being substituted by 0, 1, 2 or 3
substituents selected from halo, C.sub.1-4alk, C.sub.1-3haloalk,
--OC.sub.1-4alk, --NH.sub.2, --NHC.sub.1-4alk and
--N(C.sub.1-4alk)C.sub.1-4alk;
[0065] R.sup.5 is, independently, in each instance, H, halo,
C.sub.1-6alk, C.sub.1-4haloalk, or C.sub.1-6alk substituted by 1, 2
or 3 substituents selected from halo, cyano, OH, OC.sub.1-4alk,
C.sub.1-4alk, C.sub.1-3haloalk, OC.sub.1-4alk, NH.sub.2,
NHC.sub.1-4alk and N(C.sub.1-4alk)C.sub.1-4alk; or both R.sup.5
groups together form a C.sub.3-6-spiroalk substituted by 0, 1, 2 or
3 substituents selected from halo, cyano, OH, OC.sub.1-4alk,
C.sub.1-4alk, C.sub.1-3haloalk, OC.sub.1-4alk, NH.sub.2,
NHC.sub.1-4alk and N(C.sub.1-4alk)C.sub.1-4alk;
[0066] R.sup.6 is selected from halo, cyano, OH, OC.sub.1-4alk,
C.sub.1-4alk, C.sub.1-3haloalk, OC.sub.1-4alk, NHR.sup.9,
N(C.sub.1-4alk)C.sub.1-4alk, --C(.dbd.O)OR.sup.a,
--C(.dbd.O)N(R.sup.a)R.sup.a, --N(R.sup.a)C(.dbd.O)R.sup.b and a 5-
or 6-membered saturated or partially saturated heterocyclic ring
containing 1, 2 or 3 heteroatoms selected from N, O and S, wherein
the ring is substituted by 0, 1, 2 or 3 substituents selected from
halo, cyano, OH, oxo, OC.sub.1-4alk, C.sub.1-4alk,
C.sub.1-3haloalk, OC.sub.1-4alk, NH.sub.2, NHC.sub.1-4 alk and
N(C.sub.1-4alk)C.sub.1-4alk;
[0067] R.sup.7 is selected from H, halo, C.sub.1-4haloalk, cyano,
nitro, --C(.dbd.O)R.sup.a, --C(.dbd.O)OR.sup.a,
--C(.dbd.O)NR.sup.aR.sup.a, --C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--OR.sup.a, --OC(.dbd.O)R.sup.a, --OC(.dbd.O)NR.sup.aR.sup.a,
--OC(.dbd.O)N(R.sup.a)S(.dbd.O).sub.2R.sup.a,
--OC.sub.2-6alkNR.sup.aR.sup.a, --OC.sub.2-6alkOR.sup.a,
--SR.sup.a, --S(.dbd.O)R.sup.a, --S(.dbd.O).sub.2R.sup.a,
--S(.dbd.O).sub.2NR.sup.aR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)R.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)OR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--NR.sup.aR.sup.a, --N(R.sup.a)C(.dbd.O)R.sup.a,
--N(R.sup.a)C(.dbd.O)OR.sup.a,
--N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--N(R.sup.a)C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2R.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2NR.sup.aR.sup.a,
--NR.sup.aC.sub.2-6alkNR.sup.aR.sup.a,
--NR.sup.aC.sub.2-6alkOR.sup.a and C.sub.1-6alk, wherein the
C.sub.1-6alk is substituted by 0, 1, 2 or 3 substituents selected
from halo, C.sub.1-4haloalk, cyano, nitro, --C(.dbd.O)R.sup.a,
--C(.dbd.O)OR.sup.a, --C(.dbd.O)NR.sup.aR.sup.a,
--C(.dbd.NR.sup.a)NR.sup.aR.sup.a, --OR.sup.a, --OC(.dbd.O)R.sup.a,
--OC(.dbd.O)NR.sup.aR.sup.a,
--OC(.dbd.O)N(R.sup.a)S(.dbd.O).sub.2R.sup.a,
--OC.sub.2-6alkNR.sup.aR.sup.a, --OC.sub.2-6 alkOR.sup.a,
--SR.sup.a, --S(.dbd.O)R.sup.a, --S(.dbd.O).sub.2R.sup.a,
--S(.dbd.O).sub.2NR.sup.aR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)R.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)OR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--NR.sup.aR.sup.a, --N(R.sup.a)C(.dbd.O)R.sup.a,
--N(R.sup.a)C(.dbd.O)OR.sup.a,
--N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--N(R.sup.a)C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2R.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2NR.sup.aR.sup.a,
--NR.sup.aC.sub.2-6alkNR.sup.aR.sup.a and
--NR.sup.aC.sub.2-6alkOR.sup.a, and the C.sub.1-6alk is
additionally substituted by 0 or 1 saturated, partially-saturated
or unsaturated 5-, 6- or 7-membered monocyclic rings containing 0,
1, 2, 3 or 4 atoms selected from N, O and S, but containing no more
than one O or S, wherein the available carbon atoms of the ring are
substituted by 0, 1 or 2 oxo or thioxo groups, wherein the ring is
substituted by 0, 1, 2 or 3 substituents independently selected
from halo, nitro, cyano, C.sub.1-4 alk, OC.sub.1-4 alk,
OC.sub.1-4haloalk, NHC.sub.1-4 alk, N(C.sub.1-4 alk)C.sub.1-4 alk
and C.sub.1-4haloalk; or R.sup.7 and R.sup.8 together form a
--C.dbd.N-- bridge wherein the carbon atom is substituted by H,
halo, cyano, or a saturated, partially-saturated or unsaturated 5-,
6- or 7-membered monocyclic ring containing 0, 1, 2, 3 or 4 atoms
selected from N, O and S, but containing no more than one O or S,
wherein the available carbon atoms of the ring are substituted by
0, 1 or 2 oxo or thioxo groups, wherein the ring is substituted by
0, 1, 2, 3 or 4 substituents selected from halo, C.sub.1-6alk,
C.sub.1-4haloalk, cyano, nitro, --C(.dbd.O)R.sup.a,
--C(.dbd.O)OR.sup.a, --C(.dbd.O)NR.sup.aR.sup.a,
--C(.dbd.NR.sup.a)NR.sup.aR.sup.a, --OR.sup.a, --OC(.dbd.O)R.sup.a,
--OC(.dbd.O)NR.sup.aR.sup.a,
--OC(.dbd.O)N(R.sup.a)S(.dbd.O).sub.2R.sup.a,
--OC.sub.2-6alkNR.sup.aR.sup.a, --OC.sub.2-6alkOR.sup.a,
--SR.sup.a, --S(.dbd.O)R.sup.a, --S(.dbd.O).sub.2R.sup.a,
--S(.dbd.O).sub.2NR.sup.aR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)R.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)OR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--NR.sup.aR.sup.a, --N(R.sup.a)C(.dbd.O)R.sup.a,
--N(R.sup.a)C(.dbd.O)OR.sup.a,
--N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--N(R.sup.a)C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2R.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2NR.sup.aR.sup.a,
--NR.sup.aC.sub.2-6alkNR.sup.aR.sup.a and
--NR.sup.aC.sub.2-6alkOR.sup.a; or R.sup.7 and R.sup.9 together
form a --N.dbd.C-- bridge wherein the carbon atom is substituted by
H, halo, C.sub.1-6alk, C.sub.1-4haloalk, cyano, nitro, OR.sup.a,
NR.sup.aR.sup.a, --C(.dbd.O)R.sup.a, --C(.dbd.O)OR.sup.a,
--C(.dbd.O)NR.sup.aR.sup.a, --C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--S(.dbd.O)R.sup.a, --S(.dbd.O).sub.2R.sup.a or
--S(.dbd.O).sub.2NR.sup.aR.sup.a;
[0068] R.sup.9 is H, C.sub.1-6alk or C.sub.1-4haloalk;
[0069] R.sup.10 is in each instance H, halo, C.sub.1-3alk,
C.sub.1-3haloalk or cyano;
[0070] R.sup.11 is selected from H, halo, C.sub.1-6alk,
C.sub.1-4haloalk, cyano, nitro, --C(.dbd.O)R.sup.a,
--C(.dbd.O)OR.sup.a, --C(.dbd.O)NR.sup.aR.sup.a,
--C(.dbd.NR.sup.a)NR.sup.aR.sup.a, --OR.sup.a, --OC(.dbd.O)R.sup.a,
--OC(.dbd.O)NR.sup.aR.sup.a,
--OC(.dbd.O)N(R.sup.a)S(.dbd.O).sub.2R.sup.a,
--OC.sub.2-6alkNR.sup.aR.sup.a, --OC.sub.2-6alkOR.sup.a,
--SR.sup.a, --S(.dbd.O)R.sup.a, --S(.dbd.O).sub.2R.sup.b,
--S(.dbd.O).sub.2NR.sup.aR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)R.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)OR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--NR.sup.aR.sup.a, --N(R.sup.a)C(.dbd.O)R.sup.a,
--N(R.sup.a)C(.dbd.O)OR.sup.a,
--N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--N(R.sup.a)C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2R.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2NR.sup.aR.sup.a,
--NR.sup.aC.sub.2-6alkNR.sup.aR.sup.a,
--NR.sup.aC.sub.2-6alkOR.sup.a,
--NR.sup.aC.sub.2-6alkCO.sub.2R.sup.a,
--NR.sup.aC.sub.2-6alkSO.sub.2R.sup.b, --CH.sub.2C(.dbd.O)R.sup.a,
--CH.sub.2C(.dbd.O)OR.sup.a, --CH.sub.2C(.dbd.O)NR.sup.aR.sup.a,
--CH.sub.2C(.dbd.NR.sup.a)NR.sup.aR.sup.a, --CH.sub.2OR.sup.a,
--CH.sub.2C(.dbd.O)R.sup.a, --CH.sub.2C(.dbd.O)NR.sup.aR.sup.a,
--CH.sub.2C(.dbd.O)N(R.sup.a)S(.dbd.O).sub.2R.sup.a,
--CH.sub.2OC.sub.2-6alkNR.sup.aR.sup.a,
--CH.sub.2OC.sub.2-6alkOR.sup.a, --CH.sub.2SR.sup.a,
--CH.sub.2S(.dbd.O)R.sup.a, --CH.sub.2S(.dbd.O).sub.2R.sup.b,
--CH.sub.2S(.dbd.O).sub.2NR.sup.aR.sup.a,
--CH.sub.2S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)R.sup.a,
--CH.sub.2S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)OR.sup.a,
--CH.sub.2S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--CH.sub.2NR.sup.aR.sup.a, --CH.sub.2N(R.sup.a)C(.dbd.O)R.sup.a,
--CH.sub.2N(R.sup.a)C(.dbd.O)OR.sup.a,
--CH.sub.2N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--CH.sub.2N(R.sup.a)C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--CH.sub.2N(R.sup.a)S(.dbd.O).sub.2R.sup.a,
--CH.sub.2N(R.sup.a)S(.dbd.O).sub.2NR.sup.aR.sup.a,
--CH.sub.2NR.sup.aC.sub.2-6alkNR.sup.aR.sup.a,
--CH.sub.2NR.sup.aC.sub.2-6alkOR.sup.a,
--CH.sub.2NR.sup.aC.sub.2-6alkCO.sub.2R.sup.a,
--CH.sub.2NR.sup.aC.sub.2-6alkSO.sub.2R.sup.b, --CH.sub.2R.sup.c,
--C(.dbd.O)R.sup.c and --C(.dbd.O)N(R.sup.a)R.sup.c;
[0071] R.sup.a is independently, at each instance, H or
R.sup.b;
[0072] R.sup.b is independently, at each instance, phenyl, benzyl
or C.sub.1-6alk, the phenyl, benzyl and C.sub.1-6alk being
substituted by 0, 1, 2 or 3 substituents selected from halo,
C.sub.1-4alk, C.sub.1-3haloalk, --OH, --OC.sub.1-4alk, --NH.sub.2,
--NHC.sub.1-4alk and --N(C.sub.1-4alk)C.sub.1-4alk; and
[0073] R.sup.c is a saturated or partially-saturated 4-, 5- or
6-membered ring containing 1, 2 or 3 heteroatoms selected from N, O
and S, the ring being substituted by 0, 1, 2 or 3 substituents
selected from halo, C.sub.1-4alk, C.sub.1-3haloalk,
--OC.sub.1-4alk, --NH.sub.2, --NHC.sub.1-4alk and
--N(C.sub.1-4alk)C.sub.1-4alk.
[0074] Another aspect of the invention relates to compounds having
the structure
##STR00004##
or any pharmaceutically-acceptable salt thereof, wherein:
[0075] X.sup.1 is C(R.sup.10) or N;
[0076] X.sup.2 is C or N;
[0077] X.sup.3 is C or N;
[0078] X.sup.4 is C or N;
[0079] X.sup.5 is C or N; wherein at least two of X.sup.2, X.sup.3,
X.sup.4 and X.sup.5 are C;
[0080] n is 0, 1, 2 or 3;
[0081] R.sup.1 is a direct-bonded, C.sub.1-4alk-linked,
OC.sub.1-2alk-linked, C.sub.1-2alkO-linked, N(R.sup.a)-linked or
O-linked saturated, partially-saturated or unsaturated 5-, 6- or
7-membered monocyclic or 8-, 9-, 10- or 11-membered bicyclic ring
containing 0, 1, 2, 3 or 4 atoms selected from N, O and S, but
containing no more than one 0 or
[0082] S atom, substituted by 0, 1, 2 or 3 substituents
independently selected from halo, C.sub.1-6alk, C.sub.1-4haloalk,
cyano, nitro, --C(.dbd.O)R.sup.a, --C(.dbd.O)OR.sup.a,
--C(.dbd.O)NR.sup.aR.sup.a, --C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--OR.sup.a, --OC(.dbd.O)R.sup.a, --OC(.dbd.O)NR.sup.aR.sup.a,
--OC(.dbd.O)N(R.sup.a)S(.dbd.O).sub.2R.sup.a,
--OC.sub.2-6alkNR.sup.aR.sup.a, --OC.sub.2-6alkOR.sup.a,
--SR.sup.a, --S(.dbd.O)R.sup.a, --S(.dbd.O).sub.2R.sup.a,
--S(.dbd.O).sub.2NR.sup.aR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)R.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)OR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--NR.sup.aR.sup.a, --N(R.sup.a)C(.dbd.O)R.sup.a,
--N(R.sup.a)C(.dbd.O)OR.sup.a,
--N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--N(R.sup.a)C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2R.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2NR.sup.aR.sup.a,
--NR.sup.aC.sub.2-6alkNR.sup.aR.sup.a and
--NR.sup.aC.sub.2-6alkOR.sup.a, wherein the available carbon atoms
of the ring are additionally substituted by 0, 1 or 2 oxo or thioxo
groups, and wherein the ring is additionally substituted by 0 or 1
directly bonded, SO.sub.2 linked, C(.dbd.O) linked or CH.sub.2
linked group selected from phenyl, pyridyl, pyrimidyl, morpholino,
piperazinyl, piperidinyl, cyclopentyl and cyclohexyl all of which
are further substituted by 0, 1, 2 or 3 independent R.sup.b
groups;
[0083] R.sup.2 is selected from H, halo, C.sub.1-6alk,
C.sub.1-4haloalk, cyano, nitro, OR.sup.a, NR.sup.aR.sup.a,
--C(.dbd.O)R.sup.a, --C(.dbd.O)OR.sup.a,
--C(.dbd.O)NR.sup.aR.sup.a, --C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--S(.dbd.O)R.sup.a, --S(.dbd.O).sub.2R.sup.a,
--S(.dbd.O).sub.2NR.sup.aR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)R.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)OR.sup.a and
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a;
[0084] R.sup.3 is selected from H, halo, nitro, cyano,
C.sub.1-4alk, OC.sub.1-4alk, OC.sub.1-4haloalk, NHC.sub.1-4alk,
N(C.sub.1-4alk)C.sub.1-4alk and C.sub.1-4haloalk;
[0085] R.sup.4 is, independently, in each instance, halo, nitro,
cyano, C.sub.1-4alk, OC.sub.1-4alk, OC.sub.1-4haloalk,
NHC.sub.1-4alk, N(C.sub.1-4alk)C.sub.1-4alk, C.sub.1-4haloalk or an
unsaturated 5-, 6- or 7-membered monocyclic ring containing 0, 1,
2, 3 or 4 atoms selected from N, O and S, but containing no more
than one O or S, the ring being substituted by 0, 1, 2 or 3
substituents selected from halo, C.sub.1-4alk, C.sub.1-3haloalk,
--OC.sub.1-4alk, --NH.sub.2, --NHC.sub.1-4alk and
--N(C.sub.1-4alk)C.sub.1-4alk;
[0086] R.sup.5 is, independently, in each instance, H, halo,
C.sub.1-6alk, C.sub.1-4haloalk, or C.sub.1-6alk substituted by 1, 2
or 3 substituents selected from halo, cyano, OH, OC.sub.1-4alk,
C.sub.1-4alk, C.sub.1-3haloalk, OC.sub.1-4alk, NH.sub.2,
NHC.sub.1-4alk and N(C.sub.1-4alk)C.sub.1-4alk; or both R.sup.5
groups together form a C.sub.3-6spiroalk substituted by 0, 1, 2 or
3 substituents selected from halo, cyano, OH, OC.sub.1-4alk,
C.sub.1-4alk, C.sub.1-3haloalk, OC.sub.1-4alk, NH.sub.2,
NHC.sub.1-4alk and N(C.sub.1-4alk)C.sub.1-4alk;
[0087] R.sup.6 is H, halo, NHR.sup.9 or OH, cyano, OC.sub.1-4alk,
C.sub.1-4alk, C.sub.1-3haloalk, OC.sub.1-4alk, --C(.dbd.O)OR.sup.a,
--C(.dbd.O)N(R.sup.a)R.sup.a or --N(R.sup.a)C(.dbd.O)R.sup.b;
[0088] R.sup.7 is selected from H, halo, C.sub.1-4haloalk, cyano,
nitro, --C(.dbd.O)R.sup.a, --C(.dbd.O)OR.sup.a,
--C(.dbd.O)NR.sup.aR.sup.a, --C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--OR.sup.a, --OC(.dbd.O)R.sup.a, --OC(.dbd.O)NR.sup.aR.sup.a,
--OC(.dbd.O)N(R.sup.a)S(.dbd.O).sub.2R.sup.a,
--OC.sub.2-6alkNR.sup.aR.sup.a, --OC.sub.2-6alkOR.sup.a, --SW,
--S(.dbd.O)R.sup.a, --S(.dbd.O).sub.2R.sup.a,
--S(.dbd.O).sub.2NR.sup.aR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)R.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)OR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--NR.sup.aR.sup.a, --N(R.sup.a)C(.dbd.O)R.sup.a,
--N(R.sup.a)C(.dbd.O)OR.sup.a,
--N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--N(R.sup.a)C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2R.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2NR.sup.aR.sup.a,
--NR.sup.aC.sub.2-6alkNR.sup.aR.sup.a,
--NR.sup.aC.sub.2-6alkOR.sup.a and C.sub.1-6alk, wherein the
C.sub.1-6alk is substituted by 0, 1, 2 or 3 substituents selected
from halo, C.sub.1-4haloalk, cyano, nitro, --C(.dbd.O)R.sup.a,
--C(.dbd.O)OR.sup.a, --C(.dbd.O)NR.sup.aR.sup.a,
--C(.dbd.NR.sup.a)NR.sup.aR.sup.a, --OR.sup.a, --OC(.dbd.O)R.sup.a,
--OC(.dbd.O)NR.sup.aR.sup.a,
--OC(.dbd.O)N(R.sup.a)S(.dbd.O).sub.2R.sup.a,
--OC.sub.2-6alkNR.sup.aR.sup.a, --OC.sub.2-6alkOR.sup.a,
--SR.sup.a, --S(.dbd.O)R.sup.a, --S(.dbd.O).sub.2R.sup.a,
--S(.dbd.O).sub.2NR.sup.aR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)R.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)OR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--NR.sup.aR.sup.a, --N(R.sup.a)C(.dbd.O)R.sup.a,
--N(R.sup.a)C(.dbd.O)OR.sup.a,
--N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--N(R.sup.a)C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2R.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2NR.sup.aR.sup.a,
--NR.sup.aC.sub.2-6alkNR.sup.aR.sup.a and
--NR.sup.aC.sub.2-6alkOR.sup.a, and the C.sub.1-6alk is
additionally substituted by 0 or 1 saturated, partially-saturated
or unsaturated 5-, 6- or 7-membered monocyclic rings containing 0,
1, 2, 3 or 4 atoms selected from N, O and S, but containing no more
than one O or S, wherein the available carbon atoms of the ring are
substituted by 0, 1 or 2 oxo or thioxo groups, wherein the ring is
substituted by 0, 1, 2 or 3 substituents independently selected
from halo, nitro, cyano, C.sub.1-4alk, OC.sub.1-4alk,
OC.sub.1-4haloalk, NHC.sub.1-4alk, N(C.sub.1-4alk)C.sub.1-4alk and
C.sub.1-4haloalk; or R.sup.7 and R.sup.8 together form a
--C.dbd.N-- bridge wherein the carbon atom is substituted by H,
halo, cyano, or a saturated, partially-saturated or unsaturated 5-,
6- or 7-membered monocyclic ring containing 0, 1, 2, 3 or 4 atoms
selected from N, O and S, but containing no more than one O or S,
wherein the available carbon atoms of the ring are substituted by
0, 1 or 2 oxo or thioxo groups, wherein the ring is substituted by
0, 1, 2, 3 or 4 substituents selected from halo, C.sub.1-6alk,
C.sub.1-4haloalk, cyano, nitro, --C(.dbd.O)R.sup.a,
--C(.dbd.O)OR.sup.a, --C(.dbd.O)NR.sup.aR.sup.a,
--C(.dbd.NR.sup.a)NR.sup.aR.sup.a, --OR.sup.a, --OC(.dbd.O)R.sup.a,
--OC(.dbd.O)NR.sup.aR.sup.a,
--OC(.dbd.O)N(R.sup.a)S(.dbd.O).sub.2R.sup.a,
--OC.sub.2-6alkNR.sup.aR.sup.a, --OC.sub.2-6alkOR.sup.a,
--SR.sup.a, --S(.dbd.O)R.sup.a, --S(.dbd.O).sub.2R.sup.a,
--S(.dbd.O).sub.2NR.sup.aR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)R.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)OR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--NR.sup.aR.sup.a, --N(R.sup.a)C(.dbd.O)R.sup.a,
--N(R.sup.a)C(.dbd.O)OR.sup.a,
--N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--N(R.sup.a)C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2R.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2NR.sup.aR.sup.a,
--NR.sup.aC.sub.2-6alkNR.sup.aR.sup.a and
--NR.sup.aC.sub.2-6alkOR.sup.a; or R.sup.7 and R.sup.9 together
form a --N.dbd.C-- bridge wherein the carbon atom is substituted by
H, halo, C.sub.1-6alk, C.sub.1-4haloalk, cyano, nitro, OR.sup.a,
NR.sup.aR.sup.a, --C(.dbd.O)R.sup.a, --C(.dbd.O)OR.sup.a,
--C(.dbd.O)NR.sup.aR.sup.a, --C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--S(.dbd.O)R.sup.a, --S(.dbd.O).sub.2R.sup.a or
--S(.dbd.O).sub.2NR.sup.aR.sup.a;
[0089] R.sup.9 is H, C.sub.1-6alk or C.sub.1-4haloalk;
[0090] R.sup.11 is selected from H, halo, C.sub.1-6alk,
C.sub.1-4haloalk, cyano, nitro, --C(.dbd.O)R.sup.a,
--C(.dbd.O)OR.sup.a, --C(.dbd.O)NR.sup.aR.sup.a,
--C(.dbd.NR.sup.a)NR.sup.aR.sup.a, --OR.sup.a, --OC(.dbd.O)R.sup.a,
--OC(.dbd.O)NR.sup.aR.sup.a,
--OC(.dbd.O)N(R.sup.a)S(.dbd.O).sub.2R.sup.a,
--OC.sub.2-6alkNR.sup.aR.sup.a, --OC.sub.2-6alkOR.sup.a,
--SR.sup.a, --S(.dbd.O)R.sup.a, --S(.dbd.O).sub.2R.sup.b,
--S(.dbd.O).sub.2NR.sup.aR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)R.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)OR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--NR.sup.aR.sup.a, --N(R.sup.a)C(.dbd.O)R.sup.a,
--N(R.sup.a)C(.dbd.O)OR.sup.a,
--N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--N(R.sup.a)C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2R.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2NR.sup.aR.sup.a,
--NR.sup.aC.sub.2-6alkNR.sup.aR.sup.a,
--NR.sup.aC.sub.2-6alkOR.sup.a,
--NR.sup.aC.sub.2-6alkCO.sub.2R.sup.a,
--NR.sup.aC.sub.2-6alkSO.sub.2R.sup.b, --CH.sub.2C(.dbd.O)R.sup.a,
--CH.sub.2C(.dbd.O)OR.sup.a, --CH.sub.2C(.dbd.O)NR.sup.aR.sup.a,
--CH.sub.2C(.dbd.NR.sup.a)NR.sup.aR.sup.a, --CH.sub.2OR.sup.a,
--CH.sub.2C(.dbd.O)R.sup.a, --CH.sub.2C(.dbd.O)NR.sup.aR.sup.a,
--CH.sub.2C(.dbd.O)N(R.sup.a)S(.dbd.O).sub.2R.sup.a,
--CH.sub.2OC.sub.2-6alkNR.sup.aR.sup.a,
--CH.sub.2OC.sub.2-6alkOR.sup.a, --CH.sub.2SR.sup.a,
--CH.sub.2S(.dbd.O)R.sup.a, --CH.sub.2S(.dbd.O).sub.2R.sup.b,
--CH.sub.2S(.dbd.O).sub.2NR.sup.aR.sup.a,
--CH.sub.2S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)R.sup.a,
--CH.sub.2S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)OR.sup.a,
--CH.sub.2S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--CH.sub.2NR.sup.aR.sup.a, --CH.sub.2N(R.sup.a)C(.dbd.O)R.sup.a,
--CH.sub.2N(R.sup.a)C(.dbd.O)OR.sup.a,
--CH.sub.2N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--CH.sub.2N(R.sup.a)C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--CH.sub.2N(R.sup.a)S(.dbd.O).sub.2R.sup.a,
--CH.sub.2N(R.sup.a)S(.dbd.O).sub.2NR.sup.aR.sup.a,
--CH.sub.2NR.sup.aC.sub.2-6alkNR.sup.aR.sup.a,
--CH.sub.2NR.sup.aC.sub.2-6alkOR.sup.a,
--CH.sub.2NR.sup.aC.sub.2-6alkCO.sub.2R.sup.a,
--CH.sub.2NR.sup.aC.sub.2-6alkSO.sub.2R.sup.b, --CH.sub.2R.sup.c,
--C(.dbd.O)R.sup.c and --C(.dbd.O)N(R.sup.a)R.sup.c;
[0091] R.sup.a is independently, at each instance, H or
R.sup.b;
[0092] R.sup.b is independently, at each instance, phenyl, benzyl
or C.sub.1-6alk, the phenyl, benzyl and C.sub.1-6alk being
substituted by 0, 1, 2 or 3 substituents selected from halo,
C.sub.1-4alk, C.sub.1-3haloalk, --OH, --OC.sub.1-4alk, --NH.sub.2,
--NHC.sub.1-4alk and --N(C.sub.1-4alk)C.sub.1-4alk; and
[0093] R.sup.c is a saturated or partially-saturated 4-, 5- or
6-membered ring containing 1, 2 or 3 heteroatoms selected from N, O
and S, the ring being substituted by 0, 1, 2 or 3 substituents
selected from halo, C.sub.1-4alk, C.sub.1-3haloalk,
--OC.sub.1-4alk, --NH.sub.2, --NHC.sub.1-4alk and
--N(C.sub.1-4alk)C.sub.1-4alk.
[0094] Another aspect of the invention relates to compounds having
the structure
##STR00005##
or any pharmaceutically-acceptable salt thereof, wherein:
[0095] X.sup.2 is C or N;
[0096] X.sup.3 is C or N;
[0097] X.sup.4 is C or N;
[0098] X.sup.5 is C or N; wherein at least two of X.sup.2, X.sup.3,
X.sup.4 and X.sup.5 are C;
[0099] n is 0, 1, 2 or 3;
[0100] R.sup.1 is a direct-bonded, C.sub.1-4alk-linked,
OC.sub.1-2alk-linked, C.sub.1-2alkO-linked, N(R.sup.a)-linked or
O-linked saturated, partially-saturated or unsaturated 5-, 6- or
7-membered monocyclic or 8-, 9-, 10- or 11-membered bicyclic ring
containing 0, 1, 2, 3 or 4 atoms selected from N, O and S, but
containing no more than one O or S atom, substituted by 0, 1, 2 or
3 substituents independently selected from halo, C.sub.1-6alk,
C.sub.1-4haloalk, cyano, nitro, --C(.dbd.O)R.sup.a,
--C(.dbd.O)OR.sup.a, --C(.dbd.O)NR.sup.aR.sup.a,
--C(.dbd.NR.sup.a)NR.sup.aR.sup.a, --OR.sup.a, --OC(.dbd.O)R.sup.a,
--OC(.dbd.O)NR.sup.aR.sup.a,
--OC(.dbd.O)N(R.sup.a)S(.dbd.O).sub.2R.sup.a,
--OC.sub.2-6alkNR.sup.aR.sup.a, --OC.sub.2-6alkOR.sup.a,
--SR.sup.a, --S(.dbd.O)R.sup.a, --S(.dbd.O).sub.2R.sup.a,
--S(.dbd.O).sub.2NR.sup.aR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)R.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)OR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--NR.sup.aR.sup.a, --N(R.sup.a)C(.dbd.O)R.sup.a,
--N(R.sup.a)C(.dbd.O)OR.sup.a,
--N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--N(R.sup.a)C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2R.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2NR.sup.aR.sup.a,
--NR.sup.aC.sub.2-6alkNR.sup.aR.sup.a and
--NR.sup.aC.sub.2-6alkOR.sup.a, wherein the available carbon atoms
of the ring are additionally substituted by 0, 1 or 2 oxo or thioxo
groups, and wherein the ring is additionally substituted by 0 or 1
directly bonded, SO.sub.2 linked, C(.dbd.O) linked or CH.sub.2
linked group selected from phenyl, pyridyl, pyrimidyl, morpholino,
piperazinyl, piperidinyl, cyclopentyl and cyclohexyl all of which
are further substituted by 0, 1, 2 or 3 independent R.sup.b
groups;
[0101] R.sup.2 is selected from H, halo, C.sub.1-6alk,
C.sub.1-4haloalk, cyano, nitro, OR.sup.a, NR.sup.aR.sup.a,
--C(.dbd.O)R.sup.a, --C(.dbd.O)OR.sup.a,
--C(.dbd.O)NR.sup.aR.sup.a, --C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--S(.dbd.O)R.sup.a, --S(.dbd.O).sub.2R.sup.a,
--S(.dbd.O).sub.2NR.sup.aR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)R.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)OR.sup.a and
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a;
[0102] R.sup.3 is selected from H, halo, nitro, cyano,
C.sub.1-4alk, OC.sub.1-4alk, OC.sub.1-4haloalk, NHC.sub.1-4alk,
N(C.sub.1-4alk)C.sub.1-4alk and C.sub.1-4haloalk;
[0103] R.sup.4 is, independently, in each instance, halo, nitro,
cyano, C.sub.1-4alk, OC.sub.1-4alk, OC.sub.1-4haloalk,
NHC.sub.1-4alk, N(C.sub.1-4alk)C.sub.1-4alk, C.sub.1-4haloalk or an
unsaturated 5-, 6- or 7-membered monocyclic ring containing 0, 1,
2, 3 or 4 atoms selected from N, O and S, but containing no more
than one O or S, the ring being substituted by 0, 1, 2 or 3
substituents selected from halo, C.sub.1-4alk, C.sub.1-3haloalk,
--OC.sub.1-4alk, --NH.sub.2, --NHC.sub.1-4alk and
--N(C.sub.1-4alk)C.sub.1-4alk;
[0104] R.sup.5 is, independently, in each instance, H, halo,
C.sub.1-6alk, C.sub.1-4haloalk, or C.sub.1-6alk substituted by 1, 2
or 3 substituents selected from halo, cyano, OH, OC.sub.1-4alk,
C.sub.1-4alk, C.sub.1-3haloalk, OC.sub.1-4alk, NH.sub.2,
NHC.sub.1-4alk and N(C.sub.1-4alk)C.sub.1-4alk; or both R.sup.5
groups together form a C.sub.3-6spiroalk substituted by 0, 1, 2 or
3 substituents selected from halo, cyano, OH, OC.sub.1-4alk,
C.sub.1-4alk, C.sub.1-3haloalk, OC.sub.1-4alk, NH.sub.2,
NHC.sub.1-4alk and N(C.sub.1-4alk)C.sub.1-4alk;
[0105] R.sup.9 is H, C.sub.1-6alk or C.sub.1-4haloalk;
[0106] R.sup.11 is selected from H, halo, C.sub.1-6alk,
C.sub.1-4haloalk, cyano, nitro, --C(.dbd.O)R.sup.a,
--C(.dbd.O)OR.sup.a, --C(.dbd.O)NR.sup.aR.sup.a,
--C(.dbd.NR.sup.a)NR.sup.aR.sup.a, --OR.sup.a, --OC(.dbd.O)R.sup.a,
--OC(.dbd.O)NR.sup.aR.sup.a,
--OC(.dbd.O)N(R.sup.a)S(.dbd.O).sub.2R.sup.a,
--OC.sub.2-6alkNR.sup.aR.sup.a, --OC.sub.2-6alkOR.sup.a,
--SR.sup.a, --S(.dbd.O)R.sup.a, --S(.dbd.O).sub.2R.sup.b,
--S(.dbd.O).sub.2NR.sup.aR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)R.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)OR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--NR.sup.aR.sup.a, --N(R.sup.a)C(.dbd.O)R.sup.a,
--N(R.sup.a)C(.dbd.O)OR.sup.a,
--N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--N(R.sup.a)C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2R.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2NR.sup.aR.sup.a,
--NR.sup.aC.sub.2-6alkNR.sup.aR.sup.a,
--NR.sup.aC.sub.2-6alkOR.sup.a,
--NR.sup.aC.sub.2-6alkCO.sub.2R.sup.a,
--NR.sup.aC.sub.2-6alkSO.sub.2R.sup.b, --CH.sub.2C(.dbd.O)R.sup.a,
--CH.sub.2C(.dbd.O)OR.sup.a, --CH.sub.2C(.dbd.O)NR.sup.aR.sup.a,
--CH.sub.2C(.dbd.NR.sup.a)NR.sup.aR.sup.a, --CH.sub.2OR.sup.a,
--CH.sub.2C(.dbd.O)R.sup.a, --CH.sub.2C(.dbd.O)NR.sup.aR.sup.a,
--CH.sub.2C(.dbd.O)N(R.sup.a)S(.dbd.O).sub.2R.sup.a,
--CH.sub.2OC.sub.2-6alkNR.sup.aR.sup.a,
--CH.sub.2OC.sub.2-6alkOR.sup.a, --CH.sub.2SR.sup.a,
--CH.sub.2S(.dbd.O)R.sup.a, --CH.sub.2S(.dbd.O).sub.2R.sup.b,
--CH.sub.2S(.dbd.O).sub.2NR.sup.aR.sup.a,
--CH.sub.2S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)R.sup.a,
--CH.sub.2S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)OR.sup.a,
--CH.sub.2S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--CH.sub.2NR.sup.aR.sup.a, --CH.sub.2N(R.sup.a)C(.dbd.O)R.sup.a,
--CH.sub.2N(R.sup.a)C(.dbd.O)OR.sup.a,
--CH.sub.2N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--CH.sub.2N(R.sup.a)C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--CH.sub.2N(R.sup.a)S(.dbd.O).sub.2R.sup.a,
--CH.sub.2N(R.sup.a)S(.dbd.O).sub.2NR.sup.aR.sup.a,
--CH.sub.2NR.sup.aC.sub.2-6alkNR.sup.aR.sup.a,
--CH.sub.2NR.sup.aC.sub.2-6alkOR.sup.a,
--CH.sub.2NR.sup.aC.sub.2-6alkCO.sub.2R.sup.a,
--CH.sub.2NR.sup.aC.sub.2-6alkSO.sub.2R.sup.b, --CH.sub.2R.sup.c,
--C(.dbd.O)R.sup.c and --C(.dbd.O)N(R.sup.a)R.sup.c;
[0107] R.sup.a is independently, at each instance, H or
R.sup.b;
[0108] R.sup.b is independently, at each instance, phenyl, benzyl
or C.sub.1-6alk, the phenyl, benzyl and C.sub.1-6alk being
substituted by 0, 1, 2 or 3 substituents selected from halo,
C.sub.1-4alk, C.sub.1-3haloalk, --OH, --OC.sub.1-4alk, --NH.sub.2,
--NHC.sub.1-4alk and --N(C.sub.1-4alk)C.sub.1-4alk; and
[0109] R.sup.c is a saturated or partially-saturated 4-, 5- or
6-membered ring containing 1, 2 or 3 heteroatoms selected from N, O
and S, the ring being substituted by 0, 1, 2 or 3 substituents
selected from halo, C.sub.1-4alk, C.sub.1-3haloalk,
--OC.sub.1-4alk, --NH.sub.2, --NHC.sub.1-4alk and
--N(C.sub.1-4alk)C.sub.1-4alk.
[0110] Another aspect of the invention relates to compounds having
the structure
##STR00006##
or any pharmaceutically-acceptable salt thereof, wherein:
[0111] X.sup.2 is C or N;
[0112] X.sup.3 is C or N;
[0113] X.sup.4 is C or N;
[0114] X.sup.5 is C or N; wherein at least two of X.sup.2, X.sup.3,
X.sup.4 and X.sup.5 are C;
[0115] n is 0, 1, 2 or 3;
[0116] R.sup.1 is a direct-bonded, C.sub.1-4alk-linked,
OC.sub.1-2alk-linked, C.sub.1-2alkO-linked, N(R.sup.a)-linked or
O-linked saturated, partially-saturated or unsaturated 5-, 6- or
7-membered monocyclic or 8-, 9-, 10- or 11-membered bicyclic ring
containing 0, 1, 2, 3 or 4 atoms selected from N, O and S, but
containing no more than one O or S atom, substituted by 0, 1, 2 or
3 substituents independently selected from halo, C.sub.1-6alk,
C.sub.1-4haloalk, cyano, nitro, --C(.dbd.O)R.sup.a,
--C(.dbd.O)OR.sup.a, --C(.dbd.O)NR.sup.aR.sup.a,
--C(.dbd.NR.sup.a)NR.sup.aR.sup.a, --OR.sup.a, --OC(.dbd.O)R.sup.a,
--OC(.dbd.O)NR.sup.aR.sup.a,
--OC(.dbd.O)N(R.sup.a)S(.dbd.O).sub.2R.sup.a,
--OC.sub.2-6alkNR.sup.aR.sup.a, --OC.sub.2-6alkOR.sup.a,
--SR.sup.a, --S(.dbd.O)R.sup.a, --S(.dbd.O).sub.2R.sup.a,
--S(.dbd.O).sub.2NR.sup.aR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)R.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)OR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--NR.sup.aR.sup.a, --N(R.sup.a)C(.dbd.O)R.sup.a,
--N(R.sup.a)C(.dbd.O)OR.sup.a,
--N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--N(R.sup.a)C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2R.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2NR.sup.aR.sup.a,
--NR.sup.aC.sub.2-6alkNR.sup.aR.sup.a and
--NR.sup.aC.sub.2-6alkOR.sup.a, wherein the available carbon atoms
of the ring are additionally substituted by 0, 1 or 2 oxo or thioxo
groups, and wherein the ring is additionally substituted by 0 or 1
directly bonded, SO.sub.2 linked, C(.dbd.O) linked or CH.sub.2
linked group selected from phenyl, pyridyl, pyrimidyl, morpholino,
piperazinyl, piperidinyl, cyclopentyl and cyclohexyl all of which
are further substituted by 0, 1, 2 or 3 independent R.sup.b
groups;
[0117] R.sup.3 is selected from H, halo, nitro, cyano,
C.sub.1-4alk, OC.sub.1-4alk, OC.sub.1-4haloalk, NHC.sub.1-4alk,
N(C.sub.1-4alk)C.sub.1-4alk or C.sub.1-4haloalk;
[0118] R.sup.4 is, independently, in each instance, halo, nitro,
cyano, C.sub.1-4alk, OC.sub.1-4alk, OC.sub.1-4haloalk,
NHC.sub.1-4alk, N(C.sub.1-4alk)C.sub.1-4alk, C.sub.1-4haloalk or an
unsaturated 5-, 6- or 7-membered monocyclic ring containing 0, 1,
2, 3 or 4 atoms selected from N, O and S, but containing no more
than one O or S, substituted by 0, 1, 2 or 3 substituents selected
from halo, C.sub.1-4alk, C.sub.1-3haloalk, --OC.sub.1-4alk,
--NH.sub.2, --NHC.sub.1-4alk and --N(C.sub.1-4alk)C.sub.1-4alk;
[0119] R.sup.5 is, independently, in each instance, H, halo,
C.sub.1-6alk, C.sub.1-4haloalk, or C.sub.1-6alk substituted by 1, 2
or 3 substituents selected from halo, cyano, OH, OC.sub.1-4alk,
C.sub.1-4alk, C.sub.1-3haloalk, OC.sub.1-4alk, NH.sub.2,
NHC.sub.1-4alk and N(C.sub.1-4alk)C.sub.1-4alk; or both R.sup.5
groups together form a C.sub.3-6spiroalk substituted by 0, 1, 2 or
3 substituents selected from halo, cyano, OH, OC.sub.1-4alk,
C.sub.1-4alk, C.sub.1-3haloalk, OC.sub.1-4alk, NH.sub.2,
NHC.sub.1-4alk and N(C.sub.1-4alk)C.sub.1-4alk;
[0120] R.sup.9 is H, C.sub.1-6alk or C.sub.1-4haloalk;
[0121] R.sup.11 is selected from --C(.dbd.O)R.sup.a,
--C(.dbd.O)OR.sup.a, --C(.dbd.O)NR.sup.aR.sup.a,
--C(.dbd.NR.sup.a)NR.sup.aR.sup.a, --OR.sup.a, --OC(.dbd.O)R.sup.a,
--OC(.dbd.O)NR.sup.aR.sup.a,
--OC(.dbd.O)N(R.sup.a)S(.dbd.O).sub.2R.sup.a,
--OC.sub.2-6alkNR.sup.aR.sup.a, --OC.sub.2-6alkOR.sup.a,
--SR.sup.a, --S(.dbd.O)R.sup.a, --S(.dbd.O).sub.2R.sup.b,
--S(.dbd.O).sub.2NR.sup.aR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)R.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)OR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--NR.sup.aR.sup.a, --N(R.sup.a)C(.dbd.O)R.sup.a,
--N(R.sup.a)C(.dbd.O)OR.sup.a,
--N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--N(R.sup.a)C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2R.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2NR.sup.aR.sup.a,
--NR.sup.aC.sub.2-6alkNR.sup.aR.sup.a,
--NR.sup.aC.sub.2-6alkOR.sup.a,
--NR.sup.aC.sub.2-6alkCO.sub.2R.sup.a,
--NR.sup.aC.sub.2-6alkSO.sub.2R.sup.b, --CH.sub.2C(.dbd.O)R.sup.a,
--CH.sub.2C(.dbd.O)OR.sup.a, --CH.sub.2C(.dbd.O)NR.sup.aR.sup.a,
--CH.sub.2C(.dbd.NR.sup.a)NR.sup.aR.sup.a, --CH.sub.2OR.sup.a,
--CH.sub.2C(.dbd.O)R.sup.a, --CH.sub.2C(.dbd.O)NR.sup.aR.sup.a,
--CH.sub.2C(.dbd.O)N(R.sup.a)S(.dbd.O).sub.2R.sup.a,
--CH.sub.2OC.sub.2-6alkNR.sup.aR.sup.a,
--CH.sub.2OC.sub.2-6alkOR.sup.a, --CH.sub.2SR.sup.a,
--CH.sub.2S(.dbd.O)R.sup.a, --CH.sub.2S(.dbd.O).sub.2R.sup.b,
--CH.sub.2S(.dbd.O).sub.2NR.sup.aR.sup.a,
--CH.sub.2S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)R.sup.a,
--CH.sub.2S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)OR.sup.a,
--CH.sub.2S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--CH.sub.2NR.sup.aR.sup.a, --CH.sub.2N(R.sup.a)C(.dbd.O)R.sup.a,
--CH.sub.2N(R.sup.a)C(.dbd.O)OR.sup.a,
--CH.sub.2N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--CH.sub.2N(R.sup.a)C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--CH.sub.2N(R.sup.a)S(.dbd.O).sub.2R.sup.a,
--CH.sub.2N(R.sup.a)S(.dbd.O).sub.2NR.sup.aR.sup.a,
--CH.sub.2NR.sup.aC.sub.2-6alkNR.sup.aR.sup.a,
--CH.sub.2NR.sup.aC.sub.2-6alkOR.sup.a,
--CH.sub.2NR.sup.aC.sub.2-6alkCO.sub.2R.sup.a,
--CH.sub.2NR.sup.aC.sub.2-6alkSO.sub.2R.sup.b, --CH.sub.2R.sup.c,
--C(.dbd.O)R.sup.c and --C(.dbd.O)N(R.sup.a)R.sup.c;
[0122] R.sup.a is independently, at each instance, H or
R.sup.b;
[0123] R.sup.b is independently, at each instance, phenyl, benzyl
or C.sub.1-6alk, the phenyl, benzyl and C.sub.1-6alk being
substituted by 0, 1, 2 or 3 substituents selected from halo,
C.sub.1-4alk, C.sub.1-3haloalk, --OH, --OC.sub.1-4alk, --NH.sub.2,
--NHC.sub.1-4alk and --N(C.sub.1-4alk)C.sub.1-4alk; and
[0124] R.sup.c is a saturated or partially-saturated 4-, 5- or
6-membered ring containing 1, 2 or 3 heteroatoms selected from N, O
and S, the ring being substituted by 0, 1, 2 or 3 substituents
selected from halo, C.sub.1-4alk, C.sub.1-3haloalk,
--OC.sub.1-4alk, --NH.sub.2, --NHC.sub.1-4alk and
--N(C.sub.1-4alk)C.sub.1-4alk.
[0125] Another aspect of the invention relates to compounds having
the structure
##STR00007##
or any pharmaceutically-acceptable salt thereof, wherein:
[0126] X.sup.1 is C(R.sup.10) or N;
[0127] X.sup.2 is C or N;
[0128] X.sup.3 is C or N;
[0129] X.sup.4 is C or N;
[0130] X.sup.5 is C or N; wherein at least two of X.sup.2, X.sup.3,
X.sup.4 and X.sup.5 are C;
[0131] Y is N(R.sup.8), O or S;
[0132] n is 0, 1, 2 or 3;
[0133] R.sup.1 is a direct-bonded, C.sub.1-4alk-linked,
OC.sub.1-2alk-linked, C.sub.1-2alkO-linked or O-linked saturated,
partially-saturated or unsaturated 5-, 6- or 7-membered monocyclic
or 8-, 9-, 10- or 11-membered bicyclic ring containing 0, 1, 2, 3
or 4 atoms selected from N, O and S, but containing no more than
one O or S atom, substituted by 0, 1, 2 or 3 substituents
independently selected from halo, C.sub.1-6alk, C.sub.1-4haloalk,
cyano, nitro, --C(.dbd.O)R.sup.a, --C(.dbd.O)OR.sup.a,
--C(.dbd.O)NR.sup.aR.sup.a, --C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--OR.sup.a, --OC(.dbd.O)R.sup.a, --OC(.dbd.O)NR.sup.aR.sup.a,
--OC(.dbd.O)N(R.sup.a)S(.dbd.O).sub.2R.sup.a,
--OC.sub.2-6alkNR.sup.aR.sup.a, --OC.sub.2-6alkOR.sup.a,
--SR.sup.a, --S(.dbd.O)R.sup.a, --S(.dbd.O).sub.2R.sup.a,
--S(.dbd.O).sub.2NR.sup.aR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)R.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)OR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--NR.sup.aR.sup.a, --N(R.sup.a)C(.dbd.O)R.sup.a,
--N(R.sup.a)C(.dbd.O)OR.sup.a,
--N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--N(R.sup.a)C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2R.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2NR.sup.aR.sup.a,
--NR.sup.aC.sub.2-6alkNR.sup.aR.sup.a and
--NR.sup.aC.sub.2-6alkOR.sup.a, wherein the available carbon atoms
of the ring are additionally substituted by 0, 1 or 2 oxo or thioxo
groups;
[0134] R.sup.2 is, independently in each instance, selected from H,
halo, C.sub.1-6alk, C.sub.1-4haloalk, cyano, nitro, OR.sup.a,
NR.sup.aR.sup.a, --C(.dbd.O)R.sup.a, --C(.dbd.O)OR.sup.a,
--C(.dbd.O)NR.sup.aR.sup.a, --C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--S(.dbd.O)R.sup.a, --S(.dbd.O).sub.2R.sup.a,
--S(.dbd.O).sub.2NR.sup.aR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)R.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)OR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a;
[0135] R.sup.3 is selected from H, halo, nitro, cyano,
C.sub.1-4alk, OC.sub.1-4alk, OC.sub.1-4haloalk, NHC.sub.1-4alk,
N(C.sub.1-4alk)C.sub.1-4alk or C.sub.1-4haloalk;
[0136] R.sup.4 is, independently, in each instance, halo, nitro,
cyano, C.sub.1-4alk, OC.sub.1-4alk, OC.sub.1-4haloalk,
NHC.sub.1-4alk, N(C.sub.1-4alk)C.sub.1-4alk, C.sub.1-4haloalk or an
unsaturated 5-, 6- or 7-membered monocyclic ring containing 0, 1,
2, 3 or 4 atoms selected from N, O and S, but containing no more
than one O or S, substituted by 0, 1, 2 or 3 substituents selected
from halo, C.sub.1-4alk, C.sub.1-3haloalk, --OC.sub.1-4alk,
--NH.sub.2, --NHC.sub.1-4alk, --N(C.sub.1-4alk)C.sub.1-4alk;
[0137] R.sup.5 is, independently, in each instance, H, halo,
C.sub.1-6alk, C.sub.1-4haloalk, or C.sub.1-6alk substituted by 1, 2
or 3 substituents selected from halo, cyano, OH, OC.sub.1-4alk,
C.sub.1-4alk, C.sub.1-3haloalk, OC.sub.1-4alk, NH.sub.2,
NHC.sub.1-4alk, N(C.sub.1-4alk)C.sub.1-4alk; or both R.sup.5 groups
together form a C.sub.3-6spiroalk substituted by 0, 1, 2 or 3
substituents selected from halo, cyano, OH, OC.sub.1-4alk,
C.sub.1-4alk, C.sub.1-3haloalk, OC.sub.1-4alk, NH.sub.2,
NHC.sub.1-4alk, N(C.sub.1-4alk)C.sub.1-4alk;
[0138] R.sup.6 is H, halo, NHR.sup.9 or OH;
[0139] R.sup.7 is selected from H, halo, C.sub.1-4haloalk, cyano,
nitro, --C(.dbd.O)R.sup.a, --C(.dbd.O)OR.sup.a,
--C(.dbd.O)NR.sup.aR.sup.a, --C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--OR.sup.a, --OC(.dbd.O)R.sup.a, --OC(.dbd.O)NR.sup.aR.sup.a,
--OC(.dbd.O)N(R.sup.a)S(.dbd.O).sub.2R.sup.a,
--OC.sub.2-6alkNR.sup.aR.sup.a, --OC.sub.2-6alkOR.sup.a,
--SR.sup.a, --S(.dbd.O)R.sup.a, --S(.dbd.O).sub.2R.sup.a,
--S(.dbd.O).sub.2NR.sup.aR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)R.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)OR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--NR.sup.aR.sup.a, --N(R.sup.a)C(.dbd.O)R.sup.a,
--N(R.sup.a)C(.dbd.O)OR.sup.a,
--N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--N(R.sup.a)C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2R.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2NR.sup.aR.sup.a,
--NR.sup.aC.sub.2-6alkNR.sup.aR.sup.a,
--NR.sup.aC.sub.2-6alkOR.sup.a and C.sub.1-6alk, wherein the
C.sub.1-6alk is substituted by 0, 1, 2 or 3 substituents selected
from halo, C.sub.1-4haloalk, cyano, nitro, --C(.dbd.O)R.sup.a,
--C(.dbd.O)OR.sup.a, --C(.dbd.O)NR.sup.aR.sup.a,
--C(.dbd.NR.sup.a)NR.sup.aR.sup.a, --OR.sup.a, --OC(.dbd.O)R.sup.a,
--OC(.dbd.O)NR.sup.aR.sup.a,
--OC(.dbd.O)N(R.sup.a)S(.dbd.O).sub.2R.sup.a,
--OC.sub.2-6alkNR.sup.aR.sup.a, --OC.sub.2-6alkOR.sup.a,
--SR.sup.a, --S(.dbd.O)R.sup.a, --S(.dbd.O).sub.2R.sup.a,
--S(.dbd.O).sub.2NR.sup.aR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)R.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)OR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--NR.sup.aR.sup.a, --N(R.sup.a)C(.dbd.O)R.sup.a,
--N(R.sup.a)C(.dbd.O)OR.sup.a,
--N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--N(R.sup.a)C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2R.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2NR.sup.aR.sup.a,
--NR.sup.aC.sub.2-6alkNR.sup.aR.sup.a and
--NR.sup.aC.sub.2-6alkOR.sup.a, and the C.sub.1-6alk is
additionally substituted by 0 or 1 saturated, partially-saturated
or unsaturated 5-, 6- or 7-membered monocyclic rings containing 0,
1, 2, 3 or 4 atoms selected from N, O and S, but containing no more
than one O or S, wherein the available carbon atoms of the ring are
substituted by 0, 1 or 2 oxo or thioxo groups, wherein the ring is
substituted by 0, 1, 2 or 3 substituents independently selected
from halo, nitro, cyano, C.sub.1-4alk, OC.sub.1-4alk,
OC.sub.1-4haloalk, NHC.sub.1-4alk, N(C.sub.1-4alk)C.sub.1-4alk and
C.sub.1-4haloalk; or R.sup.7 and R.sup.8 together form a
--C.dbd.N-- bridge wherein the carbon atom is substituted by H,
halo, cyano, or a saturated, partially-saturated or unsaturated 5-,
6- or 7-membered monocyclic ring containing 0, 1, 2, 3 or 4 atoms
selected from N, O and S, but containing no more than one O or S,
wherein the available carbon atoms of the ring are substituted by
0, 1 or 2 oxo or thioxo groups, wherein the ring is substituted by
0, 1, 2, 3 or 4 substituents selected from halo, C.sub.1-6alk,
C.sub.1-4haloalk, cyano, nitro, --C(.dbd.O)R.sup.a,
--C(.dbd.O)OR.sup.a, --C(.dbd.O)NR.sup.aR.sup.a,
--C(.dbd.NR.sup.a)NR.sup.aR.sup.a, --OR.sup.a, --OC(.dbd.O)R.sup.a,
--OC(.dbd.O)NR.sup.aR.sup.a,
--OC(.dbd.O)N(R.sup.a)S(.dbd.O).sub.2R.sup.a,
--OC.sub.2-6alkNR.sup.aR.sup.a, --OC.sub.2-6alkOR.sup.a,
--SR.sup.a, --S(.dbd.O)R.sup.a, --S(.dbd.O).sub.2R.sup.a,
--S(.dbd.O).sub.2NR.sup.aR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)R.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)OR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--NR.sup.aR.sup.a, --N(R.sup.a)C(.dbd.O)R.sup.a,
--N(R.sup.a)C(.dbd.O)OR.sup.a,
--N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--N(R.sup.a)C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2R.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2NR.sup.aR.sup.a,
--NR.sup.aC.sub.2-6alkNR.sup.aR.sup.a and
--NR.sup.aC.sub.2-6alkOR.sup.a; or R.sup.7 and R.sup.9 together
form a --N.dbd.C-- bridge wherein the carbon atom is substituted by
H, halo, C.sub.1-6alk, C.sub.1-4haloalk, cyano, nitro, OR.sup.a,
NR.sup.aR.sup.a, --C(.dbd.O)R.sup.a, --C(.dbd.O)OR.sup.a,
--C(.dbd.O)NR.sup.aR.sup.a, --C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--S(.dbd.O)R.sup.a, --S(.dbd.O).sub.2R.sup.a,
--S(.dbd.O).sub.2NR.sup.aR.sup.a;
[0140] R.sup.8 is H or C.sub.1-6alk;
[0141] R.sup.9 is H, C.sub.1-6alk or C.sub.1-4haloalk;
[0142] R.sup.10 is H, halo, C.sub.1-3alk, C.sub.1-3haloalk or
cyano;
[0143] R.sup.11 is selected from halo, C.sub.1-6alk,
C.sub.1-4haloalk, cyano, nitro, --C(.dbd.O)R.sup.a,
--C(.dbd.O)OR.sup.a, --C(.dbd.O)NR.sup.aR.sup.a,
--C(.dbd.NR.sup.a)NR.sup.aR.sup.a, --OR.sup.a, --OC(.dbd.O)R.sup.a,
--OC(.dbd.O)NR.sup.aR.sup.a,
--OC(.dbd.O)N(R.sup.a)S(.dbd.O).sub.2R.sup.a,
--OC.sub.2-6alkNR.sup.aR.sup.a, --OC.sub.2-6alkOR.sup.a,
--SR.sup.a, --S(.dbd.O)R.sup.a, --S(.dbd.O).sub.2R.sup.b,
--S(.dbd.O).sub.2NR.sup.aR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)R.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)OR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--NR.sup.aR.sup.a, --N(R.sup.a)C(.dbd.O)R.sup.a,
--N(R.sup.a)C(.dbd.O)OR.sup.a,
--N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--N(R.sup.a)C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2R.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2NR.sup.aR.sup.a,
--NR.sup.aC.sub.2-6alkNR.sup.aR.sup.a and
--NR.sup.aC.sub.2-6alkOR.sup.a;
[0144] R.sup.a is independently, at each instance, H or R.sup.b;
and
[0145] R.sup.b is independently, at each instance, phenyl, benzyl
or C.sub.1-6alk, the phenyl, benzyl and C.sub.1-6alk being
substituted by 0, 1, 2 or 3 substituents selected from halo,
C.sub.1-4alk, C.sub.1-3haloalk, --OC.sub.1-4alk, --NH.sub.2,
--NHC.sub.1-4alk and --N(C.sub.1-4alk)C.sub.1-4-alk.
[0146] In another embodiment, in conjunction with any of the above
or below embodiments, the compound has the structure
##STR00008##
wherein R.sup.7 is selected from H, halo, C.sub.1-4haloalk, cyano,
nitro, --C(.dbd.O)R.sup.a, --C(.dbd.O)OR.sup.a,
--C(.dbd.O)NR.sup.aR.sup.a, --C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--OR.sup.a, --OC(.dbd.O)R.sup.a, --OC(.dbd.O)NR.sup.aR.sup.a,
--OC(.dbd.O)N(R.sup.a)S(.dbd.O).sub.2R.sup.a,
--OC.sub.2-6alkNR.sup.aR.sup.a, --OC.sub.2-6alkOR.sup.a,
--SR.sup.a, --S(.dbd.O)R.sup.a, --S(.dbd.O).sub.2R.sup.a,
--S(.dbd.O).sub.2NR.sup.aR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)R.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)OR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--NR.sup.aR.sup.a, --N(R.sup.a)C(.dbd.O)R.sup.a,
--N(R.sup.a)C(.dbd.O)OR.sup.a,
--N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--N(R.sup.a)C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2R.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2NR.sup.aR.sup.a,
--NR.sup.aC.sub.2-6alkNR.sup.aR.sup.a,
--NR.sup.aC.sub.2-6alkOR.sup.a and C.sub.1-6alk, wherein the
C.sub.1-6alk is substituted by 0, 1, 2 or 3 substituents selected
from halo, C.sub.1-4haloalk, cyano, nitro, --C(.dbd.O)R.sup.a,
--C(.dbd.O)OR.sup.a, --C(.dbd.O)NR.sup.aR.sup.a,
--C(.dbd.NR.sup.a)NR.sup.aR.sup.a, --OR.sup.a, --OC(.dbd.O)R.sup.a,
--OC(.dbd.O)NR.sup.aR.sup.a,
--OC(.dbd.O)N(R.sup.a)S(.dbd.O).sub.2R.sup.a,
--OC.sub.2-6alkNR.sup.aR.sup.a, --OC.sub.2-6alkOR.sup.a,
--SR.sup.a, --S(.dbd.O)R.sup.a, --S(.dbd.O).sub.2R.sup.a,
--S(.dbd.O).sub.2NR.sup.aR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)R.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)OR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--NR.sup.aR.sup.a, --N(R.sup.a)C(.dbd.O)R.sup.a,
--N(R.sup.a)C(.dbd.O)OR.sup.a,
--N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--N(R.sup.a)C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2R.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2NR.sup.aR.sup.a,
--NR.sup.aC.sub.2-6alkNR.sup.aR.sup.a and
--NR.sup.aC.sub.2-6alkOR.sup.a, and the C.sub.1-6alk is
additionally substituted by 0 or 1 saturated, partially-saturated
or unsaturated 5-, 6- or 7-membered monocyclic rings containing 0,
1, 2, 3 or 4 atoms selected from N, O and S, but containing no more
than one O or S, wherein the available carbon atoms of the ring are
substituted by 0, 1 or 2 oxo or thioxo groups, wherein the ring is
substituted by 0, 1, 2 or 3 substituents independently selected
from halo, nitro, cyano, C.sub.1-4alk, OC.sub.1-4alk,
OC.sub.1-4haloalk, NHC.sub.1-4alk, N(C.sub.1-4alk)C.sub.1-4alk and
C.sub.1-4halo alk.
[0147] In another embodiment, in conjunction with any of the above
or below embodiments, the compound has the structure
##STR00009##
[0148] In another embodiment, in conjunction with any of the above
or below embodiments, the compound has the structure
##STR00010##
wherein R.sup.12 is selected from H, halo, C.sub.1-6alk,
C.sub.1-4haloalk, cyano, nitro, OR.sup.a, NR.sup.aR.sup.a,
--C(.dbd.O)R.sup.a, --C(.dbd.O)OR.sup.a,
--C(.dbd.O)NR.sup.aR.sup.a, --C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--S(.dbd.O)R.sup.a, --S(.dbd.O).sub.2R.sup.a,
--S(.dbd.O).sub.2NR.sup.aR.sup.a.
[0149] In another embodiment, in conjunction with any of the above
or below embodiments, the compound has the structure
##STR00011##
wherein R.sup.13 is H, halo, cyano, or a saturated,
partially-saturated or unsaturated 5-, 6- or 7-membered monocyclic
ring containing 0, 1, 2, 3 or 4 atoms selected from N, O and S, but
containing no more than one O or S, wherein the available carbon
atoms of the ring are substituted by 0, 1 or 2 oxo or thioxo
groups, wherein the ring is substituted by 0, 1, 2, 3 or 4
substituents selected from halo, C.sub.1-6alk, C.sub.1-4haloalk,
cyano, nitro, --C(.dbd.O)R.sup.a, --C(.dbd.O)OR.sup.a,
--C(.dbd.O)NR.sup.aR.sup.a, --C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--OR.sup.a, --OC(.dbd.O)R.sup.a, --OC(.dbd.O)NR.sup.aR.sup.a,
--OC(.dbd.O)N(R.sup.a)S(.dbd.O).sub.2R.sup.a,
--OC.sub.2-6alkNR.sup.aR.sup.a, --OC.sub.2-6alkOR.sup.a,
--SR.sup.a, --S(.dbd.O)R.sup.a, --S(.dbd.O).sub.2R.sup.a,
--S(.dbd.O).sub.2NR.sup.aR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)R.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)OR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--NR.sup.aR.sup.a, --N(R.sup.a)C(.dbd.O)R.sup.a,
--N(R.sup.a)C(.dbd.O)OR.sup.a,
--N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--N(R.sup.a)C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2R.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2NR.sup.aR.sup.a,
--NR.sup.aC.sub.2-6alkNR.sup.aR.sup.a and
--NR.sup.aC.sub.2-6alkOR.sup.a; or R.sup.7 and R.sup.9 together
form a --N.dbd.C-- bridge wherein the carbon atom is substituted by
H, halo, C.sub.1-6alk, C.sub.1-4haloalk, cyano, nitro, OR.sup.a,
NR.sup.aR.sup.a, --C(.dbd.O)R.sup.a, --C(.dbd.O)OR.sup.a,
--C(.dbd.O)NR.sup.aR.sup.a, --C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--S(.dbd.O)R.sup.a, --S(.dbd.O).sub.2R.sup.a,
--S(.dbd.O).sub.2NR.sup.aR.sup.a.
[0150] In another embodiment, in conjunction with any of the above
or below embodiments, X.sup.1 is N.
[0151] In another embodiment, in conjunction with any of the above
or below embodiments, X.sup.1 is C(R.sup.10).
[0152] In another embodiment, in conjunction with any of the above
or below embodiments, X.sup.2, X.sup.3, X.sup.4 and X.sup.5 are
each C.
[0153] In another embodiment, in conjunction with any of the above
or below embodiments, X.sup.2 is N.
[0154] In another embodiment, in conjunction with any of the above
or below embodiments, X.sup.3 is N.
[0155] In another embodiment, in conjunction with any of the above
or below embodiments, X.sup.4 is N.
[0156] In another embodiment, in conjunction with any of the above
or below embodiments, X.sup.5 is N.
[0157] In another embodiment, in conjunction with any of the above
or below embodiments, Y is N(R.sup.8).
[0158] In another embodiment, in conjunction with any of the above
or below embodiments, R.sup.1 is a direct-bonded,
C.sub.1-4alk-linked, OC.sub.1-2alk-linked, C.sub.1-2alkO-linked or
O-linked saturated, partially-saturated or unsaturated 5-, 6- or
7-membered monocyclic or 8-, 9-, 10- or 11-membered bicyclic ring
containing 0, 1, 2, 3 or 4 atoms selected from N, O and S, but
containing no more than one O or S atom, substituted by 0, 1, 2 or
3 substituents independently selected from halo, C.sub.1-6alk,
C.sub.1-4haloalk, cyano, nitro, --C(.dbd.O)R.sup.a,
--C(.dbd.O)OR.sup.a, --C(.dbd.O)NR.sup.aR.sup.a,
--C(.dbd.NR.sup.a)NR.sup.aR.sup.a, --OR.sup.a, --OC(.dbd.O)R.sup.a,
--OC(.dbd.O)NR.sup.aR.sup.a,
--OC(.dbd.O)N(R.sup.a)S(.dbd.O).sub.2R.sup.a,
--OC.sub.2-6alkNR.sup.aR.sup.a, --OC.sub.2-6alkOR.sup.a,
--SR.sup.a, --S(.dbd.O)R.sup.a, --S(.dbd.O).sub.2R.sup.a,
--S(.dbd.O).sub.2NR.sup.aR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)R.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)OR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--NR.sup.aR.sup.a, --N(R.sup.a)C(.dbd.O)R.sup.a,
--N(R.sup.a)C(.dbd.O)OR.sup.a,
--N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--N(R.sup.a)C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2R.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2NR.sup.aR.sup.a,
--NR.sup.aC.sub.2-6alkNR.sup.aR.sup.a and
--NR.sup.aC.sub.2-6alkOR.sup.a, wherein the available carbon atoms
of the ring are additionally substituted by 0, 1 or 2 oxo or thioxo
groups;
[0159] In another embodiment, in conjunction with any of the above
or below embodiments, R.sup.1 is a direct-bonded, carbon-linked or
oxygen-linked saturated, partially-saturated or unsaturated 5-, 6-
or 7-membered monocyclic or 8-, 9-, 10- or 11-membered bicyclic
ring containing 0, 1, 2, 3 or 4 atoms selected from N, O and S, but
containing no more than one O or S, wherein the available carbon
atoms of the ring are substituted by 0, 1 or 2 oxo or thioxo
groups, wherein the ring is additionally substituted by 0 or 1
R.sup.2 substituents, and the ring is additionally substituted by
0, 1, 2 or 3 substituents independently selected from halo, nitro,
cyano, C.sub.1-4alk, OC.sub.1-4alk, OC.sub.1-4haloalk,
NHC.sub.1-4alk, N(C.sub.1-4alk)C.sub.1-4alk and
C.sub.1-4haloalk.
[0160] In another embodiment, in conjunction with any of the above
or below embodiments, R.sup.1 is a direct bonded unsaturated
6-membered monocyclic ring containing 0, 1 or 2 N atoms,
substituted by 0, 1, 2 or 3 substituents independently selected
from halo, nitro, cyano, C.sub.1-4alk, OC.sub.1-4alk,
OC.sub.1-4haloalk, NHC.sub.1-4alk, N(C.sub.1-4alk)C.sub.1-4alk and
C.sub.1-4haloalk.
[0161] In another embodiment, in conjunction with any of the above
or below embodiments, R.sup.1 is phenyl or pyridyl, both of which
are substituted by 0, 1, 2 or 3 substituents independently selected
from halo, C.sub.1-6alk, C.sub.1-4haloalk, cyano, nitro,
--C(.dbd.O)R.sup.a, --C(.dbd.O)OR.sup.a,
--C(.dbd.O)NR.sup.aR.sup.a, --C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--OR.sup.a, --OC(.dbd.O)R.sup.a, --OC(.dbd.O)NR.sup.aR.sup.a,
--OC(.dbd.O)N(R.sup.a)S(.dbd.O).sub.2R.sup.a,
--OC.sub.2-6alkNR.sup.aR.sup.a, --OC.sub.2-6alkOR.sup.a,
--SR.sup.a, --S(.dbd.O)R.sup.a, --S(.dbd.O).sub.2R.sup.a and
--S(.dbd.O).sub.2NR.sup.aR.sup.a.
[0162] In another embodiment, in conjunction with any of the above
or below embodiments, R.sup.1 is phenyl or substituted by 0, 1, 2
or 3 substituents independently selected from halo, C.sub.1-6alk,
C.sub.1-4haloalk, cyano, nitro, --C(.dbd.O)R.sup.a,
--C(.dbd.O)OR.sup.a, --C(.dbd.O)NR.sup.aR.sup.a,
--C(.dbd.NR.sup.a)NR.sup.aR.sup.a, --OR.sup.a, --OC(.dbd.O)R.sup.a,
--OC(.dbd.O)NR.sup.aR.sup.a,
--OC(.dbd.O)N(R.sup.a)S(.dbd.O).sub.2R.sup.a,
--OC.sub.2-6alkNR.sup.aR.sup.a, --OC.sub.2-6alkOR.sup.a,
--SR.sup.a, --S(.dbd.O)R.sup.a, --S(.dbd.O).sub.2R.sup.a and
--S(.dbd.O).sub.2NR.sup.aR.sup.a.
[0163] In another embodiment, in conjunction with any of the above
or below embodiments, R.sup.1 is phenyl.
[0164] In another embodiment, in conjunction with any of the above
or below embodiments, R.sup.2 is H.
[0165] In another embodiment, in conjunction with any of the above
or below embodiments, R.sup.6 is NHR.sup.9.
[0166] In another embodiment, in conjunction with any of the above
or below embodiments, R.sup.6 is NH.sub.2.
[0167] In another embodiment, in conjunction with any of the above
or below embodiments, R.sup.11 is selected from --C(.dbd.O)R.sup.a,
--C(.dbd.O)OR.sup.a, --C(.dbd.O)NR.sup.aR.sup.a,
--C(.dbd.NR.sup.a)NR.sup.aR.sup.a, --OR.sup.a, --OC(.dbd.O)R.sup.a,
--OC(.dbd.O)NR.sup.aR.sup.a,
--OC(.dbd.O)N(R.sup.a)S(.dbd.O).sub.2R.sup.a,
--OC.sub.2-6alkNR.sup.aR.sup.a, --OC.sub.2-6alkOR.sup.a,
--SR.sup.a, --S(.dbd.O)R.sup.a, --S(.dbd.O).sub.2R.sup.b,
--S(.dbd.O).sub.2NR.sup.aR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)R.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)OR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--NR.sup.aR.sup.a, --N(R.sup.a)C(.dbd.O)R.sup.a,
--N(R.sup.a)C(.dbd.O)OR.sup.a,
--N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--N(R.sup.a)C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2R.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2NR.sup.aR.sup.a,
--NR.sup.aC.sub.2-6alkNR.sup.aR.sup.a,
--NR.sup.aC.sub.2-6alkOR.sup.a,
--NR.sup.aC.sub.2-6alkCO.sub.2R.sup.a,
--NR.sup.aC.sub.2-6alkSO.sub.2R.sup.b, --CH.sub.2C(.dbd.O)R.sup.a,
--CH.sub.2C(.dbd.O)OR.sup.a, --CH.sub.2C(.dbd.O)NR.sup.aR.sup.a,
--CH.sub.2C(.dbd.NR.sup.a)NR.sup.aR.sup.a, --CH.sub.2OR.sup.a,
--CH.sub.2C(.dbd.O)R.sup.a, --CH.sub.2C(.dbd.O)NR.sup.aR.sup.a,
--CH.sub.2C(.dbd.O)N(R.sup.a)S(.dbd.O).sub.2R.sup.a,
--CH.sub.2OC.sub.2-6alkNR.sup.aR.sup.a,
--CH.sub.2OC.sub.2-6alkOR.sup.a, --CH.sub.2SR.sup.a,
--CH.sub.2S(.dbd.O)R.sup.a, --CH.sub.2S(.dbd.O).sub.2R.sup.b,
--CH.sub.2S(.dbd.O).sub.2NR.sup.aR.sup.a,
--CH.sub.2S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)R.sup.a,
--CH.sub.2S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)OR.sup.a,
--CH.sub.2S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--CH.sub.2NR.sup.aR.sup.a, --CH.sub.2N(R.sup.a)C(.dbd.O)R.sup.a,
--CH.sub.2N(R.sup.a)C(.dbd.O)OR.sup.a,
--CH.sub.2N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--CH.sub.2N(R.sup.a)C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--CH.sub.2N(R.sup.a)S(.dbd.O).sub.2R.sup.a,
--CH.sub.2N(R.sup.a)S(.dbd.O).sub.2NR.sup.aR.sup.a,
--CH.sub.2NR.sup.aC.sub.2-6alkNR.sup.aR.sup.a,
--CH.sub.2NR.sup.aC.sub.2-6alkOR.sup.a,
--CH.sub.2NR.sup.aC.sub.2-6alkCO.sub.2R.sup.a,
--CH.sub.2NR.sup.aC.sub.2-6alkSO.sub.2R.sup.b, --CH.sub.2R.sup.c,
--C(.dbd.O)R.sup.c and --C(.dbd.O)N(R.sup.a)R %
[0168] In another embodiment, in conjunction with any of the above
or below embodiments, R.sup.11 is selected from --C(.dbd.O)R.sup.a,
--C(.dbd.O)OR.sup.a, --C(.dbd.O)NR.sup.aR.sup.a,
--C(.dbd.NR.sup.a)NR.sup.aR.sup.a, --N(R.sup.a)C(.dbd.O)R.sup.a,
--N(R.sup.a)C(.dbd.O)OR.sup.a,
--N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--N(R.sup.a)C(.dbd.NR.sup.a)NR.sup.aR.sup.a and
--N(R.sup.a)S(.dbd.O).sub.2R.sup.a.
[0169] Another aspect of the invention relates to a method of
treating PI3K-mediated conditions or disorders.
[0170] In certain embodiments, the PI3K-mediated condition or
disorder is selected from rheumatoid arthritis, ankylosing
spondylitis, osteoarthritis, psoriatic arthritis, psoriasis,
inflammatory diseases, and autoimmune diseases. In other
embodiments, the PI3K-mediated condition or disorder is selected
from cardiovascular diseases, atherosclerosis, hypertension, deep
venous thrombosis, stroke, myocardial infarction, unstable angina,
thromboembolism, pulmonary embolism, thrombolytic diseases, acute
arterial ischemia, peripheral thrombotic occlusions, and coronary
artery disease. In still other embodiments, the PI3K-mediated
condition or disorder is selected from cancer, colon cancer,
glioblastoma, endometrial carcinoma, hepatocellular cancer, lung
cancer, melanoma, renal cell carcinoma, thyroid carcinoma, cell
lymphoma, lymphoproliferative disorders, small cell lung cancer,
squamous cell lung carcinoma, glioma, breast cancer, prostate
cancer, ovarian cancer, cervical cancer, and leukemia. In yet
another embodiment, the PI3K-mediated condition or disorder is
selected from type II diabetes. In still other embodiments, the
PI3K-mediated condition or disorder is selected from respiratory
diseases, bronchitis, asthma, and chronic obstructive pulmonary
disease. In certain embodiments, the subject is a human.
[0171] Another aspect of the invention relates to the treatment of
rheumatoid arthritis, ankylosing spondylitis, osteoarthritis,
psoriatic arthritis, psoriasis, inflammatory diseases or autoimmune
diseases comprising the step of administering a compound according
to any of the above embodiments.
[0172] Another aspect of the invention relates to the treatment of
rheumatoid arthritis, ankylosing spondylitis, osteoarthritis,
psoriatic arthritis, psoriasis, inflammatory diseases and
autoimmune diseases, inflammatory bowel disorders, inflammatory eye
disorders, inflammatory or unstable bladder disorders, skin
complaints with inflammatory components, chronic inflammatory
conditions, autoimmune diseases, systemic lupus erythematosis
(SLE), myestenia gravis, rheumatoid arthritis, acute disseminated
encephalomyelitis, idiopathic thrombocytopenic purpura, multiples
sclerosis, Sjoegren's syndrome and autoimmune hemolytic anemia,
allergic conditions and hypersensitivity, comprising the step of
administering a compound according to any of the above or below
embodiments.
[0173] Another aspect of the invention relates to the treatment of
cancers that are mediated, dependent on or associated with
p110.delta. activity, comprising the step of administering a
compound according to any of the above or below embodiments.
[0174] Another aspect of the invention relates to the treatment of
cancers are selected from acute myeloid leukaemia, myelo-dysplastic
syndrome, myelo-proliferative diseases, chronic myeloid leukaemia,
T-cell acute lymphoblastic leukaemia, B-cell acute lymphoblastic
leukaemia, non-hodgkins lymphoma, B-cell lymphoma, solid tumors and
breast cancer, comprising the step of administering a compound
according to any of the above or below embodiments.
[0175] Another aspect of the invention relates to a pharmaceutical
composition comprising a compound according to any of the above
embodiments and a pharmaceutically-acceptable diluent or
carrier.
[0176] Another aspect of the invention relates to the use of a
compound according to any of the above embodiments as a
medicament.
[0177] Another aspect of the invention relates to the use of a
compound according to any of the above embodiments in the
manufacture of a medicament for the treatment of rheumatoid
arthritis, ankylosing spondylitis, osteoarthritis, psoriatic
arthritis, psoriasis, inflammatory diseases, and autoimmune
diseases.
[0178] The compounds of this invention may have in general several
asymmetric centers and are typically depicted in the form of
racemic mixtures. This invention is intended to encompass racemic
mixtures, partially racemic mixtures and separate enantiomers and
diasteromers.
[0179] Unless otherwise specified, the following definitions apply
to terms found in the specification and claims:
[0180] "C.sub..alpha.-.beta.alk" means an alk group comprising a
minimum of .alpha. and a maximum of .beta. carbon atoms in a
branched, cyclical or linear relationship or any combination of the
three, wherein .alpha. and .beta. represent integers. The alk
groups described in this section may also contain one or two double
or triple bonds. Examples of C.sub.1-6alk include, but are not
limited to the following:
##STR00012##
[0181] "Benzo group", alone or in combination, means the divalent
radical C.sub.4H.sub.4.dbd., one representation of which is
--CH.dbd.CH--CH.dbd.CH--, that when vicinally attached to another
ring forms a benzene-like ring--for example tetrahydronaphthylene,
indole and the like.
[0182] The terms "oxo" and "thioxo" represent the groups .dbd.O (as
in carbonyl) and .dbd.S (as in thiocarbonyl), respectively.
[0183] "Halo" or "halogen" means a halogen atoms selected from F,
Cl, Br and I.
[0184] "C.sub.V-Whaloalk" means an alk group, as described above,
wherein any number--at least one--of the hydrogen atoms attached to
the alk chain are replaced by F, Cl, Br or I.
[0185] "Heterocycle" means a ring comprising at least one carbon
atom and at least one other atom selected from N, O and S. Examples
of heterocycles that may be found in the claims include, but are
not limited to, the following:
##STR00013## ##STR00014##
[0186] "C.sub..alpha.-.beta.spiroalk" means a geminally-attached
alkyl ring comprising a minimum of a and a maximum of .beta. carbon
atoms that is attached to a chain or another ring--such as:
##STR00015##
[0187] "Available nitrogen atoms" are those nitrogen atoms that are
part of a heterocycle and are joined by two single bonds (e.g.
piperidine), leaving an external bond available for substitution
by, for example, H or CH.sub.3.
[0188] "Pharmaceutically-acceptable salt" means a salt prepared by
conventional means, and are well known by those skilled in the art.
The "pharmacologically acceptable salts" include basic salts of
inorganic and organic acids, including but not limited to
hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric
acid, methanesulfonic acid, ethanesulfonic acid, malic acid, acetic
acid, oxalic acid, tartaric acid, citric acid, lactic acid, fumaric
acid, succinic acid, maleic acid, salicylic acid, benzoic acid,
phenylacetic acid, mandelic acid and the like. When compounds of
the invention include an acidic function such as a carboxy group,
then suitable pharmaceutically acceptable cation pairs for the
carboxy group are well known to those skilled in the art and
include alkaline, alkaline earth, ammonium, quaternary ammonium
cations and the like. For additional examples of "pharmacologically
acceptable salts," see infra and Berge et al., J. Pharm. Sci. 66:1
(1977).
[0189] "Saturated, partially saturated or unsaturated" includes
substituents saturated with hydrogens, substituents completely
unsaturated with hydrogens and substituents partially saturated
with hydrogens.
[0190] "Leaving group" generally refers to groups readily
displaceable by a nucleophile, such as an amine, a thiol or an
alcohol nucleophile. Such leaving groups are well known in the art.
Examples of such leaving groups include, but are not limited to,
N-hydroxysuccinimide, N-hydroxybenzotriazole, halides, triflates,
tosylates and the like. Preferred leaving groups are indicated
herein where appropriate.
[0191] "Protecting group" generally refers to groups well known in
the art which are used to prevent selected reactive groups, such as
carboxy, amino, hydroxy, mercapto and the like, from undergoing
undesired reactions, such as nucleophilic, electrophilic,
oxidation, reduction and the like. Preferred protecting groups are
indicated herein where appropriate. Examples of amino protecting
groups include, but are not limited to, aralk, substituted aralk,
cycloalkenylalk and substituted cycloalkenyl alk, allyl,
substituted allyl, acyl, alkoxycarbonyl, aralkoxycarbonyl, silyl
and the like. Examples of aralk include, but are not limited to,
benzyl, ortho-methylbenzyl, trityl and benzhydryl, which can be
optionally substituted with halogen, alk, alkoxy, hydroxy, nitro,
acylamino, acyl and the like, and salts, such as phosphonium and
ammonium salts. Examples of aryl groups include phenyl, naphthyl,
indanyl, anthracenyl, 9-(9-phenylfluorenyl), phenanthrenyl, durenyl
and the like. Examples of cycloalkenylalk or substituted
cycloalkenylalk radicals, preferably have 6-10 carbon atoms,
include, but are not limited to, cyclohexenyl methyl and the like.
Suitable acyl, alkoxycarbonyl and aralkoxycarbonyl groups include
benzyloxycarbonyl, t-butoxycarbonyl, iso-butoxycarbonyl, benzoyl,
substituted benzoyl, butyryl, acetyl, trifluoroacetyl, trichloro
acetyl, phthaloyl and the like. A mixture of protecting groups can
be used to protect the same amino group, such as a primary amino
group can be protected by both an aralk group and an
aralkoxycarbonyl group. Amino protecting groups can also form a
heterocyclic ring with the nitrogen to which they are attached, for
example, 1,2-bis(methylene)benzene, phthalimidyl, succinimidyl,
maleimidyl and the like and where these heterocyclic groups can
further include adjoining aryl and cycloalk rings. In addition, the
heterocyclic groups can be mono-, di- or tri-substituted, such as
nitrophthalimidyl. Amino groups may also be protected against
undesired reactions, such as oxidation, through the formation of an
addition salt, such as hydrochloride, toluenesulfonic acid,
trifluoroacetic acid and the like. Many of the amino protecting
groups are also suitable for protecting carboxy, hydroxy and
mercapto groups. For example, aralk groups. Alk groups are also
suitable groups for protecting hydroxy and mercapto groups, such as
tert-butyl.
[0192] Silyl protecting groups are silicon atoms optionally
substituted by one or more alk, aryl and aralk groups. Suitable
silyl protecting groups include, but are not limited to,
trimethylsilyl, triethylsilyl, triisopropylsilyl,
tert-butyldimethylsilyl, dimethylphenylsilyl,
1,2-bis(dimethylsilyl)benzene, 1,2-bis(dimethylsilyl)ethane and
diphenylmethylsilyl. Silylation of an amino groups provide mono- or
di-silylamino groups. Silylation of aminoalcohol compounds can lead
to a N,N,O-trisilyl derivative. Removal of the silyl function from
a silyl ether function is readily accomplished by treatment with,
for example, a metal hydroxide or ammonium fluoride reagent, either
as a discrete reaction step or in situ during a reaction with the
alcohol group. Suitable silylating agents are, for example,
trimethylsilyl chloride, tert-butyl-dimethylsilyl chloride,
phenyldimethylsilyl chloride, diphenylmethyl silyl chloride or
their combination products with imidazole or DMF. Methods for
silylation of amines and removal of silyl protecting groups are
well known to those skilled in the art. Methods of preparation of
these amine derivatives from corresponding amino acids, amino acid
amides or amino acid esters are also well known to those skilled in
the art of organic chemistry including amino acid/amino acid ester
or aminoalcohol chemistry.
[0193] Protecting groups are removed under conditions which will
not affect the remaining portion of the molecule. These methods are
well known in the art and include acid hydrolysis, hydrogenolysis
and the like. A preferred method involves removal of a protecting
group, such as removal of a benzyloxycarbonyl group by
hydrogenolysis utilizing palladium on carbon in a suitable solvent
system such as an alcohol, acetic acid, and the like or mixtures
thereof. A t-butoxycarbonyl protecting group can be removed
utilizing an inorganic or organic acid, such as HCl or
trifluoroacetic acid, in a suitable solvent system, such as dioxane
or methylene chloride. The resulting amino salt can readily be
neutralized to yield the free amine. Carboxy protecting group, such
as methyl, ethyl, benzyl, tert-butyl, 4-methoxyphenylmethyl and the
like, can be removed under hydrolysis and hydrogenolysis conditions
well known to those skilled in the art.
[0194] It should be noted that compounds of the invention may
contain groups that may exist in tautomeric forms, such as cyclic
and acyclic amidine and guanidine groups, heteroatom substituted
heteroaryl groups (Y'=O, S, NR), and the like, which are
illustrated in the following examples:
##STR00016##
and though one form is named, described, displayed and/or claimed
herein, all the tautomeric forms are intended to be inherently
included in such name, description, display and/or claim.
[0195] Prodrugs of the compounds of this invention are also
contemplated by this invention. A prodrug is an active or inactive
compound that is modified chemically through in vivo physiological
action, such as hydrolysis, metabolism and the like, into a
compound of this invention following administration of the prodrug
to a patient. The suitability and techniques involved in making and
using prodrugs are well known by those skilled in the art. For a
general discussion of prodrugs involving esters see Svensson and
Tunek Drug Metabolism Reviews 165 (1988) and Bundgaard Design of
Prodrugs, Elsevier (1985). Examples of a masked carboxylate anion
include a variety of esters, such as alk (for example, methyl,
ethyl), cycloalk (for example, cyclohexyl), aralk (for example,
benzyl, p-methoxybenzyl), and alkcarbonyloxyalk (for example,
pivaloyloxymethyl). Amines have been masked as
arylcarbonyloxymethyl substituted derivatives which are cleaved by
esterases in vivo releasing the free drug and formaldehyde
(Bungaard J. Med. Chem. 2503 (1989)). Also, drugs containing an
acidic NH group, such as imidazole, imide, indole and the like,
have been masked with N-acyloxymethyl groups (Bundgaard Design of
Prodrugs, Elsevier (1985)). Hydroxy groups have been masked as
esters and ethers. EP 039,051 (Sloan and Little, Apr. 11, 1981)
discloses Mannich-base hydroxamic acid prodrugs, their preparation
and use.
[0196] The specification and claims contain listing of species
using the language "selected from . . . and . . . " and "is . . .
or . . . " (sometimes referred to as Markush groups). When this
language is used in this application, unless otherwise stated it is
meant to include the group as a whole, or any single members
thereof, or any subgroups thereof. The use of this language is
merely for shorthand purposes and is not meant in any way to limit
the removal of individual elements or subgroups as needed.
[0197] The present invention also includes isotopically-labelled
compounds, which are identical to those recited 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 usually found in nature. Examples of isotopes that can be
incorporated into compounds of the invention include isotopes of
hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and
chlorine, such as .sup.2H, .sup.3H, .sup.13C, .sup.14C, .sup.15N,
.sup.16O, .sup.17O, .sup.31P, .sup.32P, .sup.35S, .sup.18F, and
.sup.36Cl.
[0198] Compounds of the present invention that contain the
aforementioned isotopes and/or other isotopes of other atoms are
within the scope of this invention. Certain isotopically-labelled
compounds of the present invention, for example those into which
radioactive isotopes such as .sup.3H and .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 particularly preferred for their ease of preparation and
detection. 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 labelled compounds of
this invention can generally be prepared by substituting a readily
available isotopically labelled reagent for a non-isotopically
labelled reagent.
Experimental
[0199] The following abbreviations are used: [0200] aq.--aqueous
[0201] BINAP--2,2'-bis(diphenylphosphino)-1,1'-binaphthyl [0202]
concd--concentrated [0203] DCM--dichloromethane [0204]
DMF--N,N-dimethylformamide [0205] Et.sub.2O--diethyl ether [0206]
EtOAc--ethyl acetate [0207] EtOH--ethyl alcohol [0208] h--hour(s)
[0209] min--minutes [0210] MeOH--methyl alcohol [0211]
MsCl-methanesulfonyl chloride [0212] rt--room temperature [0213]
satd--saturated [0214] THF--tetrahydrofuran
General
[0215] Reagents and solvents used below can be obtained from
commercial sources. .sup.1H-NMR spectra were recorded on a Bruker
400 MHz and 500 MHz NMR spectrometer. Significant peaks are
tabulated in the order: multiplicity (s, singlet; d, doublet; t,
triplet; q, quartet; m, multiplet; br s, broad singlet), coupling
constant(s) in hertz (Hz) and number of protons. Mass spectrometry
results are reported as the ratio of mass over charge, followed by
the relative abundance of each ion (in parentheses Electrospray
ionization (ESI) mass spectrometry analysis was conducted on a
Agilent 1100 series LC/MSD electrospray mass spectrometer. All
compounds could be analyzed in the positive ESI mode using
acetonitrile:water with 0.1% formic acid as the delivery solvent.
Reverse phase analytical HPLC was carried out using a Agilent 1200
series on Agilent Eclipse XDB-C18 5 .mu.m column (4.6.times.150 mm)
as the stationary phase and eluting with acetonitrile:water with
0.1% TFA. Reverse phase Semi-Prep HPLC was carried out using a
Agilent 1100 Series on a Phenomenex Gemini.TM. 10 .mu.m C18 column
(250.times.21.20 mm) as the stationary phase and eluting with
acetonitrile:H.sub.2O with 0.1% TFA.
Preparation of
4-amino-6-(3-aryl-quinolin-2-yl)methylamino)-pyrimidine-5-carbonitriles
##STR00017##
[0216] General Method A:
##STR00018## ##STR00019##
[0218] General Procedure: A solution of A1 (1 eq) in anhydrous THF
was cooled to 0.degree. C. and lithium aluminum hydride
(LiAlH.sub.4, 2 eq) was added as a solution in anhydrous Et.sub.2O.
The reaction was allowed to warm to rt and stirred for 3 h, after
which time it was quenched by the subsequent addition of 1.times.
water, 1.times.15% NaOH, and 3.times. water where X=grams of
LiAlH.sub.4 used. Filtration and concentration afforded compound
A2. Compound A2 (1 eq) was dissolved in DCM, MnO.sub.2 (8 eq) was
added and the reaction was allowed to stir overnight. Filtration
and concentration afforded A3. Compound A3 (1 eq) was added to
acetylacetone (1.2 eq) and aq. 1M HCl (1 eq). The reaction was
heated at 60.degree. C. initially, then the temperature was raised
to 90.degree. C. When the reaction was determined to have reached
completion, it was cooled to rt and the pH was adjusted to .about.9
with 1N NaOH. The solid was filtered and washed with water to
afford A4. Compound A4 (1 eq) was combined with hydroxylamine
hydrochloride (1.1 eq) and pyridine (1.1 eq) in EtOH. The reaction
was heated to reflux, and when the reaction was determined to have
reached completion, the solvent was removed in vacuo. The residue
was portioned between EtOAc and water and the layers were
separated. The organic layer was washed with sat. CuSO.sub.4, and
brine, dried over MgSO.sub.4, filtered, and concd. Purification by
column chromatography afforded A5. Compound A5 was dissolved in
acetone and cooled to 0.degree. C. To this was added p-TsCl (1 eq)
and aq. NaOH (1 eq). The reaction was heated to 70.degree. C. After
the reaction had reached completion, it was cooled to rt and the
solvents were removed in vacuo. The resulting solids were dissolved
in EtOAc and water. The layers were separated and the organic layer
was washed with water, NaHCO.sub.3, and brine. The organic layer
was dried over MgSO.sub.4, filtered, and concd in vacuo to afford
A6. Compound A6 (1 eq) was dissolved in aq. 1N HCl (10 eq) and
heated to 95.degree. C. until the reaction was determined to have
reached completion. The reaction was cooled back to 0.degree. C.
and the pH was adjusted to .about.10 using 1N NaOH. The solid was
filtered and washed with water to afford A7. Compound A7 was
dissolved in 48% HBr at rt and then cooled to 0.degree. C. To this
solution was added sodium nitrite (1.5 eq) in water. After 10 min,
the solution was transferred via pipette to a slurry of copper(I)
bromide (1.1 eq) in HBr at 0.degree. C. The mixture was allowed to
warm to rt and monitored by LC/MS for reaction completion. After
the reaction was complete, it was cooled back to 0.degree. C. and
adjusted to pH .about.9 with 1N NaOH. The resultant solid was
filtered and washed with water. After drying, the solid was
slurried in DCM, filtered through a 0.45 .mu.M filter, and concd.
Purification by column chromatography (5% EA in hexanes) afforded
A8. Compound A8 (1 eq) was dissolved in AcOH and N-bromo
succinimide (1 eq) was added in a single portion. The reaction was
heated to 80.degree. C. for 1 h and subsequently cooled to rt and
diluted with 10 mL of water and 50 mL of hexanes. The mixture was
shaken vigorously until all solids had dissolved. The organic layer
was washed with sat. NaHCO.sub.3, dried over MgSO.sub.4 and
filtered. Purification by column chromatography afforded compound
A9. Compound A9 was combined with pthalimide (1 eq) and potassium
carbonate (1 eq) in DMF. The reaction was stirred at rt until it
was determined to have reached completion by LC/MS. The reaction
was diluted with EtOAc and washed with water, sat. NaHCO.sub.3, and
brine. The organic layer was dried over MgSO.sub.4, filtered and
concd to afford a crude product. The product was purified by
slurring in boiling EtOAc and cooling back to 0.degree. C.
Filtration of the solid product and washing with 1:1 hexanes:EtOAc
afforded A10.
General Method B
##STR00020##
[0220] Compound A10 (1 eq), aryl-stannane B1 (1.5 eq) and
tetrakistriphenylphosphine palladium(0) (0.1 eq) were combined and
diluted with anhydrous 1,4-dioxane. The mixture was heated to
100.degree. C. until judged complete by LC/MS. The reaction was
cooled to rt, diluted with DCM, and filtered. Concentration and
purification by column chromatography afforded B2.
General Method C:
##STR00021##
[0222] A mixture of 1,1'-bis(diphenylphosphino)ferrocene-palladium
dichloride (0.1 eq), potassium carbonate (3 eq), boronic acid C1
(1.5 eq), A10 in of DMF was heated to 100.degree. C. under a
nitrogen atmosphere until the reaction was determined to be
complete by LC/MS. After cooling to rt, the reaction was diluted
with EtOAc and washed with NaHCO.sub.3, water, brine. The organic
layer was dried over MgSO.sub.4, filtered and concd. Purification
by column chromatography afforded compound B2.
General Method D:
##STR00022## ##STR00023##
[0224] Compound B2 was slurried in EtOH and treated with hydrazine
hydrate (10 eq). The reaction was heated to 75.degree. C. until
determined to have reached completion by LC/MS. The reaction was
then cooled to rt, diluted with EtOAc, and filtered. The filtrate
was concd in vacuo, then dissolved in EtOAc/water. The layers were
separated and the organic layer was washed with brine, dried over
MgSO.sub.4, filtered, and concd to afford D1. Compound D1 was
combined with 4-amino-6-chloropyrimidine-5-carbonitrile (1.05 eq)
and diisopropylethylamine (1.2 eq) in n-butanol. The mixture was
heated to 115.degree. C. for 1 h, then cooled to rt and filtered.
The solid product was washed with cold EtOH/Et.sub.2O and dried to
afford final compounds D2. Additionally, purification by slurrying
D2 in hot EtOAc may be performed.
General Method E:
##STR00024##
[0226] Compound E1 was dissolved in DCM and treated with wet
montmorillonite clay and oxone (2.5 eq). The mixture was stirred at
rt until the reaction was determined complete by LC/MS and then
filtered and concd to afford compound E2.
Specific Example
Method A
Synthesis of (2-amino-3-fluorophenyl)methanol
##STR00025##
[0228] To a round bottomed flask containing 2-amino-3-fluorobenzoic
acid (15.7 g, 101 mmol) was added 100 mL of anhydrous THF. The
reaction was cooled to 0.degree. C. and lithium aluminum hydride
(7.68 g, 202 mmol) was added as a solution in 200 mL of anhydrous
Et.sub.2O. The reaction was allowed to warm to rt and stirred for 3
h, after which time it was quenched with 7.7 mL water, 7.7 mL of
15% NaOH, and 30 mL of water. The reaction was diluted with 300 mL
of Et.sub.2O and filtered. The filtrated was dried over MgSO.sub.4
and filtered and concd to afford (2-amino-3-fluorophenyl)methanol.
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 6.91 (ddd, J=10.8, 8.2,
1.2 Hz, 1H), 6.86 (br d, J=7.4 Hz, 1H), 6.64 (td, J=7.6, 5.1 Hz,
1H), 4.69 (s, 1H).
2-Amino-3-fluorobenzaldehyde
##STR00026##
[0230] (2-Amino-3-fluorophenyl)methanol (13.5 g, 96 mmol) was
dissolved in 319 mL of DCM. Manganese dioxide (66.5 g, 765 mmol, 8
eq) was added and the resultant slurry was stirred at rt overnight.
The reaction mixture was filtered through Celite.TM. and rinsed
with DCM. The filtrate was concd in vacuo to afford
2-amino-3-fluorobenzaldehyde. .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 9.91 (d, J=2.0 Hz, 1H), 7.32 (dt, J=7.8, 1.2 Hz, 1H), 7.16
(ddd, J=11.4, 8.0, 1.6 Hz, 1H), 6.69 (td, J=7.8, 4.7 Hz, 1H), 6.08
(br s, 2H).
1-(8-Fluoro-2-methylquinolin-3-yl)ethanone
##STR00027##
[0232] Acetylacetone (4.00 mL, 38.8 mmol) and
2-amino-3-fluorobenzaldehyde (4.5 g, 32.3 mmol) were combined at rt
and stirred to dissolve. To this solution was added aq. 1N HCl
(32.3 mL, 32.3 mmol) and the resultant mixture was heated to
60.degree. C. for 20 min, then to 90.degree. C. for 1 h. The
reaction was cooled to rt and quenched with 34 mL of 1N NaOH to
slightly basic (pH.about.8). A voluminous solid precipitated and
was filtered and washed with water. The solid was air-dried
overnight to afford 1-(8-fluoro-2-methylquinolin-3-yl)ethanone.
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.47 (d, J=1.6 Hz, 1H),
7.67 (m, 1H), 7.50 (m, 2H), 2.95 (s, 3H), 2.72 (s, 3H). Mass
Spectrum (ESI) m/e=204.1 (M+1).
(E)-1-(8-Fluoro-2-methylquinolin-3-yl)ethanone oxime
##STR00028##
[0234] To a round-bottomed flask containing
1-(8-fluoro-2-methylquinolin-3-yl)ethanone (1.5 g, 7.38 mmol) and
hydroxylamine hydrochloride (0.338 mL, 8.12 mmol) was added EtOH
(75 mL) and pyridine (0.662 mL, 8.12 mmol). The mixture was heated
to reflux. After 3 h, the reaction was cooled to rt and the solvent
was removed in vacuo. The residue was redissolved in EtOAc and
washed with water, sat. CuSO.sub.4, and brine. The organic layer
was dried over MgSO.sub.4, filtered, and concd. Purification by
column chromatography afforded
(E)-1-(8-fluoro-2-methylquinolin-3-yl)ethanone oxime. .sup.1H NMR
(500 MHz, DMSO-d6) .delta. 8.32 (d, J=1.5 Hz, 1H), 7.80 (m, 1H),
7.55 (m, 2H), 2.70 (s, 3H), 2.22 (s, 3H). (Note: NMR only recorded
up to 9.25 ppm).
N-(8-Fluoro-2-methylquinolin-3-yl)acetamide
##STR00029##
[0236] (E)-1-(8-fluoro-2-methylquinolin-3-yl)ethanone oxime (700
mg, 3.21 mmol) was dissolved in acetone (10 mL) and cooled to
0.degree. C. To this solution was added p-TsCl (612 mg, 3.21 mmol)
followed by NaOH (128 mg, 3.21 mmol) in 3.2 mL of water. The
reaction was warmed to rt and then heated to 70.degree. C. for 2 h.
The solvent was removed in vacuo and the resulting solids were
dissolved in EtOAc and water. The layers were separated and the
organic layer was washed with water, NaHCO.sub.3, and brine.
Additional material was recovered by extraction of the aq. layer
with 3.times.100 mL of EtOAc. The combined organic layers were
dried over MgSO.sub.4, filtered, and concd to afford
N-(8-fluoro-2-methylquinolin-3-yl)acetamide. .sup.1H NMR (500 MHz,
DMSO-d6) .delta. 9.65 (br s, 1H), 8.54 (br s, 1H), 7.71 (dd, J=7.8,
1.5 Hz, 1H), 7.47 (m, 2H), 2.66 (s, 3H), 2.17 (s, 3H). Mass
Spectrum (ESI) m/e=219.1 (M+1).
8-Fluoro-2-methylquinolin-3-amine
##STR00030##
[0238] N-(8-Fluoro-2-methylquinolin-3-yl)acetamide (580 mg, 2.66
mmol) was dissolved in 1M aq. hydrogen chloride solution (26 mL,
26.6 mmol, 10 eq). The reaction was heated to 95.degree. C. for 1.5
h and then cooled to 0.degree. C. The acidic reaction was carefully
quenched with .about.30 mL of 1N NaOH to pH .about.10. The
precipitate was filtered, washed with water, and dried under vacuum
to afford 8-fluoro-2-methylquinolin-3-amine. .sup.1H NMR (500 MHz,
DMSO-d6) .delta. 7.37 dd (J=8.3, 1.2 Hz, 1H), 7.27 (td, J=7.8, 5.1
Hz, 1H), 7.17 (d, J=1.7 Hz, 1H), 7.05 (ddd, J=11.5, 7.6, 1.2 Hz,
1H), 5.60 (br s, 2H), 2.50 (s, 3H). Mass Spectrum (ESI) m/e=177.0
(M+1).
3-Bromo-8-fluoro-2-methylquinoline
##STR00031##
[0240] 8-Fluoro-2-methylquinolin-3-amine (100 mg, 0.568 mmol) was
dissolved in 1.0 mL of 48% HBr at rt and then cooled to 0.degree.
C. To this solution was added sodium nitrite (0.027 mL, 0.851 mmol)
in 0.5 mL water. After 10 min, the solution was transferred via
pipette to a slurry of copper(I) bromide (90 mg, 0.624 mmol) in 0.2
mL HBr at 0.degree. C. The mixture was allowed to warm to rt and
monitored by LC/MS for reaction completion. After the reaction was
complete, it was cooled back to 0.degree. C. and adjusted to pH
.about.9 with 1N NaOH (.about.10 mL). The resultant solid was
filtered and washed with water. After drying, the solid was
slurried in DCM, filtered through a 0.45 .mu.m filter, and concd.
Purification by column chromatography (5% EtOAc in hexanes)
afforded 3-bromo-8-fluoro-2-methylquinoline. .sup.1H NMR (500 MHz,
DMSO-d6) .delta. 8.80 (d, J=1.7 Hz, 1H), 7.77 (m, 1H), 7.60 (m,
2H), 7.88 (s, 3H). Mass Spectrum (ESI) m/e=239.9, 241.9 (M+1).
3-Bromo-2-(bromomethyl)-8-fluoroquinoline
##STR00032##
[0242] To a round-bottomed flask containing
3-bromo-8-fluoro-2-methylquinoline (90 mg, 0.375 mmol) was added
AcOH (750 .mu.L) followed by N-bromo succinimide (66.7 mg, 0.375
mmol). The reaction was heated to 80.degree. C. for 1 h and
subsequently cooled to rt and diluted with 10 mL water and 50 mL of
hexanes. The mixture was shaken vigorously until all solids had
dissolved. The organic layer was washed with 10 mL of sat.
NaHCO.sub.3, dried over MgSO.sub.4 and filtered. Purification by
column chromatography using 3% EA in hexanes afforded the desired
product 3-bromo-2-(bromomethyl)-8-fluoroquinoline contaminated with
8% 3-bromo-8-fluoro-2-methylquinoline starting material. .sup.1H
NMR (500 MHz, CDCl.sub.3) .delta. 8.43 (d, J=1.6 Hz, 1H), 7.54 (m,
2H), 7.44 (m, 1H), 4.92 (s, 2H). Mass Spectrum (ESI) m/e=319.9
(M+1).
2-((3-Bromo-8-fluoroquinolin-2-yl)methyl)isoindoline-1,3-dione
##STR00033##
[0244] In an oven-dried flask was combined potassium carbonate (102
mg, 0.737 mmol), phthalimide (108 mg, 0.737 mmol) and
3-bromo-2-(bromomethyl)-8-fluoroquinoline (235 mg, 0.737 mmol). The
flask was further dried under high vacuum for 30 min, then purged
with N.sub.2 before 3 mL of anhydrous DMF was added. The reaction
was stirred at rt for 2 h, diluted with EtOAc and washed 2.times.10
mL water, 1.times.10 mL NaHCO.sub.3, and 1.times.10 mL brine. The
organic layer was dried over MgSO.sub.4, filtered and concd to
afford the crude product. The product was purified by slurring in 5
mL of boiling EtOAc and cooling back to 0.degree. C. Filtration of
the solid product and washing with 6 mL of 1:1 hexanes:EtOAc
afforded
2-((3-bromo-8-fluoroquinolin-2-yl)methyl)isoindoline-1,3-dione.
.sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 8.37 (d, J=1.5 Hz, 1H),
7.98 (m, 2H), 7.77 (m, 2H), 7.49 (br d, J=8.3 Hz, 1H), 7.42 (td,
J=7.8, 4.6 Hz, 1H), 7.22 (ddd, J=10.0, 7.6, 1.2 Hz, 1H), 5.27 (s,
2H). Mass Spectrum (ESI) m/e=384.9, 387.0 (M+1).
Specific Example of Method B
2-((8-Fluoro-3-(pyridin-2-yl)quinolin-2-yl)methyl)isoindoline-1,3-dione
##STR00034##
[0246]
2-((3-bromo-8-fluoroquinolin-2-yl)methyl)isoindoline-1,3-dione (100
mg, 0.260 mmol), 2-(tributylstannyl)pyridine (104 .mu.L, 0.312
mmol) and tetrakistriphenylphosphine palladium(0) (60.0 mg, 0.052
mmol) were combined and diluted with anhydrous 1,4-dioxane (3 mL).
The mixture was heated to 100.degree. C. for 24 h. The reaction was
cooled to rt, diluted with DCM, and filtered. Concentration and
purification by column chromatography (30-40% EtOAc in hexanes)
afforded
2-((8-fluoro-3-(pyridin-2-yl)quinolin-2-yl)methyl)isoindoline-1,3-dione.
.sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 8.76 (m, 1H), 7.93 (m,
2H), 7.87 (td, J=7.2, 2.0 Hz, 1H), 7.75 (m, 2H), 7.65 (d, J=7.8 Hz,
1H), 7.60 (d, J=7.8 Hz, 1H), 7.41 (td, J=7.8, 4.6 Hz, 1H), 7.36
(dd, J=7.6, 4.9 Hz, 1H), 7.26 (dd, J=10.3, 7.6 Hz, 1H), 5.44 (s,
2H). Mass Spectrum (ESI) m/e=384.1 (M+1).
Specific Example of Method C
2-((8-Fluoro-3-phenylquinolin-2-yl)methyl)isoindoline-1,3-dione
##STR00035##
[0248] A mixture of 1,1'-bis(diphenylphosphino)ferrocene-palladium
dichloride (21.20 mg, 0.026 mmol, 0.1 eq), potassium carbonate (108
mg, 0.779 mmol, 3 eq), phenylboronic acid (47.5 mg, 0.389 mmol, 1.5
eq), 2-((3-bromo-8-fluoroquinolin-2-yl)methyl)isoindoline-1,3-dione
(100 mg, 0.260 mmol, 1 eq) in 3 mL of DMF was heated to 100.degree.
C. under a nitrogen atmosphere. After 3 h, the reaction was
determined to be complete by LC/MS. After cooling to rt, the
reaction was diluted with EtOAc and washed with NaHCO.sub.3, water
and brine. The organic layer was dried over MgSO.sub.4, filtered
and concd. Purification by column chromatography (25% EA in
hexanes) afforded
2-((8-fluoro-3-phenylquinolin-2-yl)methyl)isoindoline-1,3-dione.
.sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 8.00 (d, J=1.5 Hz, 1H),
7.89 (m, 2H), 7.74 (m, 2H), 7.57 (d, J=8.3 Hz, 1H), 7.55-7.43
(series of m, 5H), 7.41 (td, J=8.1, 4.9 Hz, 1H), 7.23 (m, 1H), 5.12
(s, 2H). Mass Spectrum (ESI) m/e=383.0 (M+1).
Specific Example of Method D
(8-Fluoro-3-(pyridin-2-yl)quinolin-2-yl)methanamine
##STR00036##
[0250] To an 83 mg portion of
2-((8-fluoro-3-(pyridin-2-yl)quinolin-2-yl)methyl)isoindoline-1,3-dione
(0.216 mmol) was added 4 mL EtOH at 75.degree. C. To this slurry
was added hydrazine, monohydrate (105 .mu.L, 2.165 mmol). After 2
h, the reaction was diluted with EtOAc, filtered, and concd in
vacuo. The residue was dissolved in EtOAc/water with heating and
sonication. The organic layer was separated and washed with water,
brine, dried over MgSO.sub.4, filtered, and concd in vacuo. The
(8-fluoro-3-(pyridin-2-yl)quinolin-2-yl)methanamine was thus
obtained was used without further purification. .sup.1H NMR (500
MHz, CDCl.sub.3) .delta. 8.78 (d, J=4.4 Hz, 1H), 8.21 (s, 1H), 7.86
(td, J=7.8, 1.2 Hz, 1H), 7.65 (d, J=8.1 Hz, 1H), 7.57 (d, J=8.1 Hz,
1h), 7.49 (td, J=7.8, 4.9 Hz, 1H), 7.37 (dd, J=7.6, 4.9 Hz, 1H),
4.20 (s, 2H), 2.00 Hz, br s, 2H). Mass Spectrum (ESI) m/e=254.1
(M+1).
Example 1
Preparation of
N-((5-chloro-3-(3-fluorophenyl)quinolin-2-yl)methyl)-9H-purin-6-amine
2,5-Dichloroquinolin-3-ylboronic acid
##STR00037##
[0252] To a cold solution of diisopropylamine (2.2 mL, 1.1 eq) in
THF (33 mL) was added drop-wise a solution of n-BuLi (1.1 eq, 2.5M,
6.2 mL) in hexane at -20.degree. C. The resulted LDA solution was
kept in 0.degree. C. for 30 min and cooled to -78.degree. C. before
addition of a solution of 2,5-dichloroquinoline (J. Am. Chem. Soc.
2005, 127, 12657) (2.8 g, 14 mmol) in THF (14 mL) drop-wise. The
temperature was controlled below -72.degree. C. by adjusting the
addition rate (15 min). After another 5 min, trimethyl borate (2.4
mL, 1.5 eq) was added drop-wise. After 30 min, the reaction was
quenched with water, acidified to pH 4 and partitioned between
EtOAc (50 mL) and water (100 mL). The combined organics were washed
with water, brine, dried over Na.sub.2SO.sub.4. Removal of solvent
gave a pale yellow solid which was washed with EtOAc (10
mL.times.2) followed with hexane (10 mL). A pale yellow solid was
obtained. .sup.1H-NMR (500 MHz, CDCl.sub.3) .delta. 9.24 (s, 1H),
7.98 (d, J=5.0 Hz, 1H), 7.74 (t, J=8.0 Hz, 1H), 7.69 (d, J=8.0 Hz,
1H) Mass Spectrum (ESI) m/e=242 (M+1).
2,5-Dichloro-3-(3-fluorophenyl)quinoline
##STR00038##
[0254] A mixture of 2,5-dichloroquinolin-3-ylboronic acid (1.6 g,
7.3 mmol), 1-fluoro-3-iodobenzene (0.89 mL, 1.1 eq),
Na.sub.2CO.sub.3 (2.1 g, 3 eq), Pd(PPh.sub.3).sub.4 (0.38 g, 3%),
MeCN (60 mL) and water (20 mL) was heated to 85.degree. C. under
N.sub.2 overnight. The mixture was cooled to rt and partitioned
between EtOAc and water. The organic residue was purification by
column chromatography on silica gel (DCM/hexane, 1/1) to give a
pale yellow solid. .sup.1H-NMR (400 Hz, CDCl.sub.3) .delta.
8.43-8.47 (m, 2H), 7.88-7.90 (m, 1H), 7.57-7.59 (m, 3H), 7.44 (s,
1H), 7.41 (s, 1H). Mass Spectrum (ESI) m/e=292 (M+1).
5-Chloro-3-(3-fluorophenyl)quinoline-2-carbaldehyde
##STR00039##
[0256] A mixture of 2,5-dichloro-3-(3-fluorophenyl)quinoline (600
mg, 2.1 mmol), tributyl(vinyl)stannane (1.2 mL, 2.0 eq) and
Pd(PPh.sub.3).sub.4 (119 mg, 0.05 eq) in dioxane (10 mL) was heated
to reflux under N.sub.2 for 4 h before cooling to rt The reaction
mixture was concd and purified by column chromatography on silica
gel (EtOAc/hexane, 1/8) to give an off white solid. A mixture of
this solid (230 mg, 0.81 mmol) and catalytic amount of OsO.sub.4 in
acetone (5 mL) and water (2 mL) was treated with
N-methylmorpholineoxide (351 mg, 3.7 eq). The resulting mixture was
stirred at rt for 2 h. The reaction was partitioned between EtOAc
(20 mL) and water (10 mL). The organic layers were washed with
Na.sub.2S.sub.2O.sub.3, water, brine and dried over
Na.sub.2SO.sub.4. A solution of the above residue in THF (10 mL)
and water (5 mL) was treated with NaIO.sub.4 (520 mg, 3 eq)
followed with catalytic amount of OsO.sub.4. After work up, the
reaction mixture was purified by column chromatography to give a
white solid. .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 10.20 (s,
1H), 8.51 (s, 1H), 8.19 (d, J=8.0 Hz, 1H), 7.68-7.75 (m, 2H),
7.37-7.45 (m, 1H), 7.09-7.15 (m, 3H). Mass Spectrum (ESI) m/e=286
(M+1).
N-((5-Chloro-3-(3-fluorophenyl)quinolin-2-yl)methyl)-9H-purin-6-amine
##STR00040##
[0258] To a solution of
5-chloro-3-(3-fluorophenyl)quinoline-2-carbaldehyde (100 mg, 0.35
mmol) in THF (3 mL) at 0.degree. C. was added NaBH.sub.4 (20 mg,
1.5 eq) in one portion. The reaction mixture was then stirred at
0.degree. C. for 2 h before quenching with water. The mixture was
extracted with EtOAc (100 mL.times.2), and combined organics were
washed with water, brine and dried over Na.sub.2SO.sub.4. Removal
of solvents followed with column chromatography (EtOAc/hexane, 1/3)
gave a white solid. A solution of the above material in DCM (3 mL)
was treated with SOCl.sub.2 (0.13 mL, 5 eq) at rt. Removal of
solvents and treatment with aq. NaHCO.sub.3 gave a pale yellow
solid (80 mg). The above solid was treated with the potassium salt
of phthalimide (65 mg, 0.35 mmol) in DMF (1 mL) at rt for 2 h.
Water was added and the resulted solid was filtered and washed with
water to give a white solid. A mixture of this white solid (105 mg,
0.25 mmol) and hydrazine (0.079 mL, 10 eq) in EtOH (2 mL) was
heated to reflux for 2 h. After cooling to rt, the mixture was
filtered, washed with EtOAc and worked up. Removal of solvent gave
a yellow oil, which was treated with 6-chloropurine (47 mg, 1.2
eq), hunig's base (0.088 mL, 2 eq) in BuOH (1.5 mL) at reflux.
After cool to rt, the solid was filtered, washed with EtOH and
dried under vacuum, which gave
N-((5-chloro-3-(3-fluorophenyl)quinolin-2-yl)methyl)-9H-purin-6-amine.
.sup.1H-NMR (400 Hz, DMSO-d.sup.6) .delta. 12.96 (s, 1H), 8.33 (s,
1H), 8.13 (s, 1H), 8.06 (d, J=8.0 Hz, 1H), 7.84-7.77 (m, 2H),
7.59-7.54 (m, 2H), 7.47 (d, J=8.0 Hz, 1H), 7.33 (t, J=8.0 Hz, 1H),
4.92 (s, 2H). Mass Spectrum (ESI) m/e=405 (M+1).
Example 2
Preparation of
N-((S)-1-(5-chloro-3-(3-fluorophenyl)quinolin-2-yl)ethyl)-9H-purin-6-amin-
e, and
Example 3
N-((R)-1-(5-chloro-3-(3-fluorophenyl)-quinolin-2-yl)ethyl)-9H-purin-6
amine
##STR00041##
[0260] To a solution of
5-chloro-3-(3-fluorophenyl)quinoline-2-carbaldehyde (80 mg, 0.28
mmol) in THF (2 mL) at 0.degree. C. was slowly added MeMgBr (1.2
eq, 0.11 mL). The reaction mixture was stirred at 0.degree. C. for
3 hr. After removal of solvent, the residue was triturated with
water and 70 mg crude product was obtained. To a solution of
1-(5-chloro-3-(3-fluorophenyl)quinolin-2-yl)ethanol (70 mg, 0.23
mmol) in THF (2 mL) were added PPh.sub.3 (73 mg, 1.2 eq),
phthalimide (41 mg, 1.2 eq), and DIAD (56 mg, 1.2 eq). The reaction
mixture was stirred at rt for 2 h. LC-MS detected clear product
peak. After removal of solvent, the residue was partitioned between
EtOAc and water, and the combined organic layers were dried over
Na.sub.2SO.sub.4. After removal of solvent, the crude residue was
subjected to combi-flash chromatography and 81 mg desired product
was obtained as
2-((5-chloro-3-(3-fluorophenyl)quinolin-2-yl)methyl)isoindoline-1,3-dione-
. A solution of this material (81 mg, 0.19 mmol) and hydrazine (60
mg, 10 eq) in 2 mL EtOH was heated to 90.degree. C. for 3 h. LC-MS
detected clear product peak. After the usual aq. quench, 50 mg of
the desired product was obtained. A solution of
(5-chloro-3-(3-fluorophenyl)-quinolin-2-yl)methanamine (50 mg, 0.17
mmol), 6-chloro-9H-purine (31 mg, 1.2 eq) and Hunig's base (0.038
mL, 1.3 eq) in EtOH (2 mL) was heated to 90.degree. C. overnight.
LC-MS detected a clear product peak. After the usual aq. quench,
the crude residue was purified by combi-flash chromatography
(MeOH/DCM, 0-15%) and 50 mg solid was obtained as racemates.
Further separation by chiral HPLC (IA column, 10% IPA/90% Hexanes,
45 mins) gave
N-((S)-1-(5-chloro-3-(3-fluorophenyl)quinolin-2-yl)ethyl)-9H-purin-6-amin-
e, as a white solid, and
N-((R)-1-(5-chloro-3-(3-fluorophenyl)-quinolin-2-yl)ethyl)-9H-purin-6
amine. For S enantiomer: .sup.1H-NMR (500 Hz, CD.sub.3OD) .delta.
8.28 (s, 1H), 8.07 (s, H), 8.01 (d, J=8.0 Hz, 2H), 7.63-7.57 (m,
2H), 7.44-7.40 (m, 2H), 7.29-7.26 (m, 2H), 7.11 (t, J=8.0 Hz, 1H),
5.77 (s, 1H), 1.41 (d, J=8.0 Hz, 3H), Mass Spectrum (ESI) m/e=419
(M+1); For R enantiomer: .sup.1H-NMR (500 Hz, CD.sub.3OD) .delta.
8.41 (s, 1H), 8.19 (s, 1H), 8.13 (d, J=8.0 Hz, 2H), 7.77-7.75 (m,
2H), 7.57-7.52 (m, 1H), 7.41-7.39 (m, 2H), 7.24 (t, J=8.0 Hz, 1H),
5.89 (s, 1H), 1.53 (d, J=8.0 Hz, 3H) Mass Spectrum (ESI) m/e=419
(M+1).
Example 4
Preparation of
1-(1-(6-fluoro-3-(5-fluoropyridin-3-yl)quinolin-2-yl)ethyl)-3-iodo-1H-pyr-
azolo[3,4-d]pyrimidin-4-amine
1-(6-Fluoro-3-hydroxyquinolin-2-yl)ethanone
##STR00042##
[0262] To 5-fluoro-2-nitrobenzoic acid (10.0 g, 54 mmol) was added
SOCl.sub.2 (20 mL, 54 mmol). The resultant mixture was heated at
80.degree. C. for 2 h. After cooling to rt, the extra SOCl.sub.2
was evaporated. The resulting acid chloride was dissolved in
Et.sub.2O (20 mL). To magnesium methoxide (47 mL, 10% Wt, 54 mmol),
pentane-2,4-dione (6 mL, 59 mmol) in Et.sub.2O (15 mL) was added
drop-wise at rt. After stirring at 40.degree. C. for 2 h, the
mixture was concd and diluted with Et.sub.2O, cooled at 0.degree.
C., and the acid chloride solution in Et.sub.2O (20 mL) was added
drop-wise into the mixture. The resultant reaction mixture was then
heated to reflux for 30 min. After cooling to rt the mixture was
poured into ice-water (10 mL) containing 2N HCl (2 mL), extracted
with Et.sub.2O, washed with water, brine, dried and concd, which
gave crude intermediate 3-(5-fluoro-2-nitrobenzoyl)
pentane-2,4-dione. Mass Spectrum (ESI) m/e=267.9 (M+1). A mixture
of potassium hydroxide (100 mL, 20%, 54 mmol) and
3-(5-fluoro-2-nitrobenzoyl) pentane-2,4-dione (13.75 g, crude) was
heated to reflux for 1 h. After cooling to rt, it was neutralized
and acidified with conc. HCl to pH 5. extracted with EtOAc, washed
with water, brine, dried, and concd, which gave crude
1-(6-fluoro-3-hydroxyquinolin-2-yl)ethanone. .sup.1H-NMR
(CDCl.sub.3) .delta. 11.22 (s, 1H), 8.00 (dd, J=8.5, 5.0 Hz, 1H),
7.51 (s, 1H), 7.30-7.22 (m, 2H), 2.86 (s, 3H). Mass Spectrum (ESI)
m/e=205.9 (M+1).
2-Acetyl-6-fluoroquinolin-3-yl trifluoromethanesulfonate
##STR00043##
[0264] To a solution of 1-(6-fluoro-3-hydroxyquinolin-2-yl)ethanone
(1.06 g, 5.2 mmol) in DCM (40 mL), pyridine (0.51 mL, 6.2 mmol) and
trifluoromethanesulfonic anhydride (1.0 mL, 6.2 mmol) were added.
The resultant mixture was stirred at rt for 4 h, diluted with DMC,
washed with water, brine, dried and concd. Purification of the
residue by flash chromatography over silica gel, gradient elution,
0-25% EtOAc in hexane, gave 2-acetyl-6-fluoroquinolin-3-yl
trifluoromethanesulfonate. .sup.1H-NMR (DMSO-d.sup.6) .delta. 8.76
(s, 1H), 8.35 (dd, J=8.5, 5.0 Hz, 1H), 8.08 (dd, J=8.5, 5.0 Hz,
1H), 7.98-7.93 (m, 2H), 2.80 (s, 3H). Mass Spectrum (ESI) m/e=337.8
(M+1).
1-(6-Fluoro-3-(5-fluoropyridin-3-yl)quinolin-2-yl)ethanone
##STR00044##
[0266] A mixture of 2-acetyl-6-fluoroquinolin-3-yl
trifluoromethanesulfonate (561 mg, 1.66 mmol),
5-fluoropyridin-3-ylboronic acid (258 mg, 1.83 mmol),
bis(tri-t-butylphosphine)palladium (0) (85 mg, 166 .mu.mol), cesium
fluoride (758 mg, 4.99 mmol) and copper(I) iodide (63 mg, 333
.mu.mol) in DME (10 mL) was heated at 100.degree. C. for 3 h, and
then cooled to rt, and filtered. The filtrates were collected
washed with EtOAc and concd. Purification of the residue by flash
chromatography over silica gel, gradient elution, 0-60% EtOAc in
hexane, gave
1-(6-fluoro-3-(5-fluoropyridin-3-yl)quinolin-2-yl)ethanone. Mass
Spectrum (ESI) m/e=285.0 (M+1).
1-(6-Fluoro-3-(5-fluoropyridin-3-yl)quinolin-2-yl)ethanol
##STR00045##
[0268] A mixture of
1-(6-fluoro-3-(5-fluoropyridin-3-yl)quinolin-2-yl)ethanone (300.0
mg, 1.055 mmol), THF (20 mL) and sodium borohydride (40 mg, 1.055
mmol) were stirred for 2 h. The reaction mixture was then filtered
through a pad of Celite.TM. and rinsed with EtOAc, evaporation of
the solvent, and purification of the residue by flash
chromatography over silica gel, gradient elution, 0-100% EtOAc in
hexane, gave
1-(6-fluoro-3-(5-fluoropyridin-3-yl)quinolin-2-yl)ethanol.
.sup.1H-NMR (CDCl.sub.3) .delta. 8.53 (d, J=5.0 Hz, 1H), 8.44 (br,
1H), 8.08 (dd, J=8.5, 5.0 Hz, 1H), 7.92 (s, 1H), 7.53-7.46 (m, 1H),
7.45-7.40 (m, 2H), 5.06 (q, J=5.0 Hz, 1H), 1.15 (d, J=5.0 Hz, 3H).
Mass Spectrum (ESI) m/e=286.9 (M+1).
2-(1-Chloroethyl)-6-fluoro-3-(5-fluoropyridin-3-yl)quinoline
##STR00046##
[0270] Thionyl chloride (0.4 mL, 5.68 mmol) was added to
1-(6-fluoro-3-(5-fluoropyridin-3-yl)quinolin-2-yl)ethanol (325.0
mg, 1.135 mmol) in DMF (1 mL) and DCM (20 mL). After the addition,
the mixture was stirred at rt for 2 h. The solution was concd and
diluted with Et.sub.2O (20 mL). The Et.sub.2O solution was washed
with water, brine, dried and concd. Purification of the residue by
flash chromatography over silica gel, using 10% EtOAc in Hex, gave
2-(1-chloroethyl)-6-fluoro-3-(5-fluoropyridin-3-yl)quinoline.
.sup.1H-NMR (CDCl.sub.3) .delta. 8.54 (d, J=2.0 Hz, 1H), 8.49 (s,
1H), 8.14 (dd, J=8.5, 5.0 Hz, 1H), 7.93 (s, 1H), 7.62-7.57 (m, 1H),
7.51-7.46 (m, 1H), 7.40-7.36 (m, 1H), 5.11 (q, J=5.0 Hz, 1H), 1.93
(d, J=5.0 Hz, 3H). Mass Spectrum (ESI) m/e=304.9 (M+1).
1-(1-(6-Fluoro-3-(5-fluoropyridin-3-yl)quinolin-2-yl)ethyl)-3-iodo-1H-pyra-
zolo[3,4-d]pyrimidin-4-amine
##STR00047##
[0272] To a solution of 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine
(129 mg, 496 mmol) in DMF (2 mL) was added sodium hydride (60%
dispersion in mineral oil, 20 mg, 496 .mu.mol) at 0.degree. C., the
resulting mixture was stirred at rt for 10 min. To the mixture was
added a solution of
2-(1-chloroethyl)-6-fluoro-3-(5-fluoropyridin-3-yl)quinoline (151.0
mg, 496 .mu.mol) in DMF (1 mL) and the mixture was stirred at rt
for 24 h. The mixture was diluted with Et.sub.2O. The residue was
triturated with Et.sub.2O, after filtration, which gave
1-(1-(6-fluoro-3-(5-fluoropyridin-3-yl)quinolin-2-yl)ethyl)-3-iodo-1H-pyr-
azolo[3,4-d]pyrimidin-4-amine. .sup.1H-NMR (DMSO-d.sup.6) .delta.
8.25-8.22 (m, 2H), 8.17 (s, 1H), 7.99 (br, 1H), 7.97 (s, 1H),
7.84-7.76 (m, 2H), 7.64-7.58 (m, 1H), 6.49 (q, J=5.0 Hz, 1H), 1.86
(d, J=5.0 Hz, 3H). Mass Spectrum (ESI) m/e=530.0 (M+1).
Example 5
Preparation of
1-(1-(6-fluoro-3-(5-fluoropyridin-3-yl)quinolin-2-yl)ethyl)-3-(1H-pyrazol-
-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine and
Example 6
1-(1-(6-fluoro-3-(5-fluoropyridin-3-yl)quinolin-2-yl)ethyl)-1H-pyrazolo[3,-
4-d]pyrimidin-4-amine
##STR00048##
[0274] A solution of
1-(1-(6-fluoro-3-(5-fluoropyridin-3-yl)quinolin-2-yl)ethyl)-3-iodo-1H-pyr-
azolo[3,4-d]pyrimidin-4-amine (50.9 mg, 96 .mu.mol) in DMF (2 mL)
was treated with pyrazole-4-boronic acid pinacol ester (22 mg, 115
.mu.mol), tetrakis(triphenylphosphine)palladium (11 mg, 10 .mu.mol)
and sodium carbonate (2.0M, 0.3 mL, 577 .mu.mol). The resultant
mixture was stirred at 100.degree. C. for 16 h. An additional
portion of pyrazole-4-boronic acid pinacol ester (22 mg, 115
.mu.mol), bis(tri-t-butylphosphine)palladium (11 mg, 10 .mu.mol)
and sodium carbonate (2.0M, 0.3 mL, 577 .mu.mol) was added. The
reaction mixture was stirred at 100.degree. C. for another 24 h.
The resultant mixture was cooled and diluted with Et.sub.2O, and
the Et.sub.2O solution was washed with water, brine, dried and
concd. Purification of the residue by flash chromatography over
silica gel, gradient elution, using 0-10% MeOH in CH.sub.2Cl.sub.2
with 0.1% aq. NH.sub.4OH, gave
1-(1-(6-fluoro-3-(5-fluoropyridin-3-yl)quinolin-2-yl)ethyl)-3-(1H-pyrazol-
-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine. .sup.1H-NMR
(CD.sub.3OD) .delta. 8.14 (dd, J=8.5, 5.0 Hz, 1H), 7.98 (d, J=5.0
Hz, 1H), 7.94 (s, 1H), 7.93 (s, 1H), 7.88 (br, 1H), 7.77 (br, 2H),
7.57-7.49 (m, 2H), 7.35-7.26 (m, 1H), 6.40 (q, J=5.0 Hz, 1H), 1.94
(d, J=5.0 Hz, 3H). Mass Spectrum (ESI) m/e=469.9 (M+1); and
1-(1-(6-fluoro-3-(5-fluoropyridin-3-yl)quinolin-2-yl)ethyl)-1H-pyrazolo[3-
,4-d]pyrimidin-4-amine (6.6 mg, 17%), .sup.1H-NMR (CD.sub.3OD)
.delta. 8.14 (dd, J=8.5, 5.0 Hz, 1H), 8.02 (d, J=5.0 Hz, 1H), 7.94
(s, 1H), 7.89 (s, 2H), 7.81 (s, 1H), 7.57-7.49 (m, 2H), 7.32-7.28
(m, 1H), 6.35 (q, J=5.0 Hz, 1H), 1.88 (d, J=5.0 Hz, 3H). Mass
Spectrum (ESI) m/e=403.9 (M+1).
Example 7
Preparation of
3-ethynyl-1-(1-(6-fluoro-3-(5-fluoropyridin-3-yl)quinolin-2-yl)ethyl)-1H--
pyrazolo[3,4-d]pyrimidin-4-amine
##STR00049##
[0276] A mixture of
1-(1-(6-fluoro-3-(5-fluoropyridin-3-yl)quinolin-2-yl)ethyl)-3-iodo-1H-pyr-
azolo[3,4-d]pyrimidin-4-amine (57.6 mg, 109 .mu.mol), copper(I)
iodide (16 mg, 82 .mu.mol),
dichlorobis(triphenyl-phosphine)palladium (ii) (19 mg, 27 .mu.mol)
and ethynyltrimethylsilane (0.15 mL, 1088 .mu.mol) in triethylamine
(2.0 mL) and DMF (2.0 mL) was stirred under N.sub.2 at rt for 1 h.
Then potassium carbonate (15 mg, 109 .mu.mol) in water (2 mL) was
added and stirred for 30 min at rt. The mixture was diluted with
CH.sub.2Cl.sub.2-MeOH (9:1) and washed with water, brine, dried and
concd. Purification of the residue by flash chromatography over
silica gel, gradient elution, 0-10% MeOH in CH.sub.2Cl.sub.2 with
0.1% aq. NH.sub.4OH, gave
3-ethynyl-1-(1-(6-fluoro-3-(5-fluoropyridin-3-yl)quinolin-2-yl)ethyl)-1H--
pyrazolo-[3,4-d]pyrimidin-4-amine. .sup.1H-NMR (DMSO-d.sup.6)
.delta. 8.26 (d, J=2.0 Hz, 1H), 8.24-8.20 (m, 1H), 8.19 (s, 1H),
8.02 (br, 1H), 7.99 (s, 1H), 7.84-7.76 (m, 2H), 7.79-7.76 (m, 1H),
6.53 (q, J=5.0 Hz, 1H), 4.56 (s, 1H), 1.86 (d, J=5.0 Hz, 3H). Mass
Spectrum (ESI) m/e=427.9 (M+1).
Example 8
Preparation of
1-(1-(6-fluoro-3-(5-fluoropyridin-3-yl)quinolin-2-yl)ethyl)-3-(1-methyl-1-
H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine
##STR00050##
[0278] A solution of
1-(1-(6-fluoro-3-(5-fluoropyridin-3-yl)quinolin-2-yl)ethyl)-3-iodo-1H-pyr-
azolo[3,4-d]pyrimidin-4-amine (92.4 mg, 175 .mu.mol) in DMF (3 mL)
was treated with bis(tri-t-butylphosphine)palladium(0) (18 mg, 35
.mu.mol), 1-methylpyrazole-4-boronic acid pinacol ester (54 mg, 262
.mu.mol) and sodium carbonate (2.0M, 0.5 mL, 1.0 mmol). The
resultant mixture was stirred at 100.degree. C. for 16 h. The
reaction mixture was cooled and diluted with Et.sub.2O. The
Et.sub.2O solution was washed with water, brine, dried and concd.
Purification of the residue by flash chromatography over silica
gel, gradient elution, using 0-10% MeOH in CH.sub.2Cl.sub.2 with
0.1% aq. NH.sub.4OH, gave
1-(1-(6-fluoro-3-(5-fluoropyridin-3-yl)quinolin-2-yl)ethyl)-3-(1-methyl-1-
H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine. .sup.1H-NMR
(CD.sub.3OD) .delta. 8.14 (dd, J=8.5, 5.0 Hz, 1H), 7.97 (d, J=5.0
Hz, 1H), 7.93 (s, 1H), 7.91 (s, 1H), 7.87 (br, 1H), 7.77 (s, 1H),
7.58 (s, 1H), 7.57-7.46 (m, 2H), 7.34-7.27 (m, 1H), 6.39 (q, J=5.0
Hz, 1H), 3.82 (s, 1H), 1.92 (d, J=5.0 Hz, 3H). Mass Spectrum (ESI)
m/e=483.9 (M+1).
Example 9
Preparation of
1-(1-(6-fluoro-3-(5-fluoropyridin-3-yl)quinolin-2-yl)ethyl)-3-(thiazol-4--
yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine
##STR00051##
[0280] A solution of
1-(1-(6-fluoro-3-(5-fluoropyridin-3-yl)quinolin-2-yl)ethyl)-3-iodo-1H-pyr-
azolo[3,4-d]pyrimidin-4-amine (68.0 mg, 128 .mu.mol) in DMF (3 mL)
was treated with bis(tri-t-butylphosphine)palladium(0) (13 mg, 26
.mu.mol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiazole
(41.0 mg, 193 .mu.mol) and sodium carbonate (2.0M, 0.4 mL, 800
.mu.mol). The resultant mixture was stirred at 100.degree. C. for
16 h. The reaction mixture was cooled and diluted with Et.sub.2O.
The Et.sub.2O solution was washed with water, brine, dried and
concd. Purification of the residue by flash chromatography over
silica gel, using MeOH--CH.sub.2Cl.sub.2-EtOAc (1:3:6), gave
1-(1-(6-fluoro-3-(5-fluoropyridin-3-yl)quinolin-2-yl)ethyl)-3-(thiazol-4--
yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine. .sup.1H-NMR (CD.sub.3OD)
.delta. 9.15 (d, J=2.0 Hz, 1H), 8.28 (dd, J=8.5, 5.0 Hz, 1H), 8.10
(d, J=5.0 Hz, 1H), 8.06 (s, 1H), 8.01 (s, 1H), 7.98 (br, 1H), 7.96
(s, 1H), 7.72-7.62 (m, 2H), 7.45-7.38 (m, 1H), 6.53 (q, J=5.0 Hz,
1H), 2.06 (d, J=5.0 Hz, 3H). Mass Spectrum (ESI) m/e=486.9
(M+1).
Example 10
Preparation of
1-(1-(6-fluoro-3-(5-fluoropyridin-3-yl)quinolin-2-yl)ethyl)-3-(thiazol-5--
yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine
##STR00052##
[0282] A mixture of
1-(1-(6-fluoro-3-(5-fluoropyridin-3-yl)quinolin-2-yl)ethyl)-3-iodo-1H-pyr-
azolo[3,4-d]pyrimidin-4-amine (50 mg, 94 .mu.mol),
bis(tri-t-butylphosphine)palladium (o) (4.8 mg, 9.4 .mu.mol) and
5-(tributylstannyl)thiazole (42 mg, 113 .mu.mol) in 1,4-dioxane (10
mL) was heated to 110.degree. C. under N.sub.2 for 16 h. The
resultant mixture was cooled and diluted with CH.sub.2Cl.sub.2-MeOH
(10:1), and the solution was washed with water and brine. The
organic solvent layer was dried and concd. Purification of the
residue by flash chromatography over silica gel, using
MeOH--CH.sub.2Cl.sub.2-EtOAc (0.5:5:5), gave
1-(1-(6-fluoro-3-(5-fluoropyridin-3-yl)quinolin-2-yl)ethyl)-3-(thiazol-5--
yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine. .sup.1H-NMR (CD.sub.3OD)
.delta. 9.06 (s, 1H), 8.285 (dd, J=8.5, 5.0 Hz, 1H), 8.13 (s, 1H),
8.12 (d, J=5.0 Hz, 1H), 8.10 (s, 1H), 8.06 (s, 1H), 8.01 (br, 1H),
7.69-7.62 (m, 2H), 7.50-7.44 (m, 1H), 6.55 (q, J=5.0 Hz, 1H), 2.05
(d, J=5.0 Hz, 3H). Mass Spectrum (ESI) m/e=487.1 (M+1).
Example 11
Preparation of
4-amino-1-((S)-1-(6-fluoro-3-(5-fluoropyridin-3-yl)quinolin-2-yl)ethyl)-1-
H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile and
Example 12
4-amino-1-((R)-1-(6-fluoro-3-(5-fluoropyridin-3-yl)quinolin-2-yl)ethyl)-1H-
-pyrazolo[3,4-d]pyrimidine-3-carbonitrile
4-Amino-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile
##STR00053##
[0284] A mixture of 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine
(1.04 g, 3.98 mmol), zinc cyanide (515 mg, 4.38 mmol),
tris(dibenzylideneacetone)dipalladium (0) (182 mg, 0.199 mmol) and
dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium (II) DCM
adduct (292 mg, 398 .mu.mol) in DMF (10 mL) was heated under
N.sub.2 at 120.degree. C. for 3.5 h, cooled to rt, and concd.
Purification of the residue by flash chromatography over silica
gel, gradient elution, 0-10% MeOH in CH.sub.2Cl.sub.2, gave
4-amino-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile. .sup.1H-NMR
(DMSO-d.sup.6) .delta. 8.29 (s, 1H). Mass Spectrum (ESI) m/e=161.1
(M+1).
4-Amino-1-(1-(6-fluoro-3-(5-fluoropyridin-3-yl)quinolin-2-yl)ethyl)-1H-pyr-
azolo[3,4-d]pyrimidine-3-carbonitrile
##STR00054##
[0286] To a solution of
4-amino-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile (60 mg, 374
.mu.mol) in DMF (2.0 mL) was added sodium hydride (60% dispersion
in mineral oil, (16 mg, 412 .mu.mol) at 0.degree. C. The resulting
mixture was stirred at rt for 10 min. To the mixture was added a
solution of
2-(1-chloroethyl)-6-fluoro-3-(5-fluoropyridin-3-yl)quinoline (114.1
mg, 374 .mu.mol) in DMF (1.0 mL) and the mixture was stirred at rt
for 24 h. The mixture was diluted with Et.sub.2O and triturated
with Et.sub.2O, following a filtration
4-amino-1-(1-(6-fluoro-3-(5-fluoropyridin-3-yl)quinolin-2-yl)ethyl)-1H-py-
razolo[3,4-d]pyrimidine-3-carbonitrile was obtained.
4-Amino-1-((S)-1-(6-fluoro-3-(5-fluoropyridin-3-yl)quinolin-2-yl)ethyl)-1H-
-pyrazolo[3,4-d]pyrimidine-3-carbonitrile and
4-amino-1-((R)-1-(6-fluoro-3-(5-fluoropyridin-3-yl)quinolin-2-yl)ethyl)-1-
H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile
##STR00055##
[0288]
4-Amino-1-(1-(6-fluoro-3-(5-fluoropyridin-3-yl)quinolin-2-yl)ethyl)-
-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile (66.6 mg) in THF-MeOH
10:1 (1.5 mL) was subjected to chiral HPLC resolution (Chiralpak IA
column, 30.times.250 mm, 5 mm), using 15% isopropanol in hexane as
eluent, which gave
4-amino-1-((S)-1-(6-fluoro-3-(5-fluoropyridin-3-yl)quinolin-2-yl)eth-
yl)-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile, the first fraction
collected with 99% ee at 254 nm, and
4-amino-1-((R)-1-(6-fluoro-3-(5-fluoropyridin-3-yl)quinolin-2-yl)ethyl)-1-
H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile, the second fraction
collected with 99% ee at 254 nm, .sup.1H-NMR (DMSO-d.sup.6) .delta.
8.34 (d, J=5.0 Hz, 1H), 8.24 (s, 1H), 8.24-8.18 (m, 1H), 8.14 (br,
1H), 8.10 (s, 1H), 7.86-7.76 (m, 3H), 6.62 (q, J=5.0 Hz, 1H), 1.89
(d, J=5.0 Hz, 3H). Mass Spectrum (ESI) m/e=429.1 (M+1).
Example 13
Preparation of
(S)-4-amino-6-(1-(6-fluoro-3-(6-(methylsulfonyl)pyridin-2-yl)quinolin-2-y-
l)ethylamino)pyrimidine-5-carbonitrile
2-(Methylthio)-6-(tributylstannyl)pyridine
##STR00056##
[0290] A mixture of 6-fluoro-2-(tributylstannyl)pyridine (5.00 mL,
13.0 mmol) and sodium thiomethoxide (1.0 g, 14.3 mmol) in
1-methylpyrrolidin-2-one (10 mL) was heated at 140.degree. C. for
24 h. The mixture was, then diluted with Et.sub.2O and washed with
water, brine, dried and concd. The residue was purified by flash
chromatography over silica gel, gradient elution, 0-50% EtOAc in
hexane, which gave 2-(methylthio)-6-(tributylstannyl)pyridine.
.sup.1H-NMR (CD.sub.3OD) .delta. 7.40 (t, J=5.0 Hz, 1H), 7.15 (d,
J=5.0 Hz, 1H), 7.08 (d, J=5.0 Hz, 1H), 2.56 (s, 3H), 1.69-1.55 (m,
6H), 1.43-1.32 (m, 6H), 1.15 (t, J=10.0 Hz, 6H), 0.91 (t, J=10.0
Hz, 9H). Mass Spectrum (ESI) m/e=416.0 (M+1).
2-(Methylsulfonyl)-6-(tributylstannyl)pyridine
##STR00057##
[0292] A solution of potassium permanganate (9.11 g, 57.6 mmol) in
water (100 mL) was added to a solution of
2-(methylthio)-6-(tributylstannyl)pyridine (1.99 g, 4.80 mmol) and
tetra-n-butylammonium iodide (0.018 g, 0.048 mmol) in a mixture of
acetic acid (10 mL), and benzene (80 mL). The reaction mixture was
stirred at rt for 6 h. A satd solution of Na.sub.2S.sub.2O.sub.5 in
water was added to the mixture until the purple color disappeared.
The mixture was diluted with EtOAc and washed with water, brine,
dried and concd. Purification of the residue by flash
chromatography over silica gel, gradient elution, 0-50% EtOAc in
hexane, gave 2-(methylsulfonyl)-6-(tributylstannyl)pyridine.
.sup.1H-NMR (CDCl.sub.3) .delta. 7.82 (t, J=8.0 Hz, 1H), 7.67 (d,
J=8.0 Hz, 1H), 7.55 (d, J=8.0 Hz, 1H), 3.19 (s, 3H), 1.54-1.46 (m,
6H), 1.31-1.22 (m, 6H), 1.08 (t, J=8.0 Hz, 6H), 0.82 (t, J=8.0 Hz,
9H). Mass Spectrum (ESI) m/e=448.1 (M+1).
1-(6-Fluoro-3-(6-(methylsulfonyl)pyridin-2-yl)quinolin-2-yl)ethanone
##STR00058##
[0294] A mixture of 2-acetyl-6-fluoroquinolin-3-yl
trifluoromethanesulfonate (778 mg, 2.31 mmol),
tetrakis(triphenylphosphine)palladium(0) (222 mg, 0.192 mmol),
bis(tri-t-butylphosphine)palladium (0) (98 mg, 0.192 mmol) and
2-(methylsulfonyl)-6-(tributylstannyl)pyridine (858 mg, 1.92 mmol)
in 1,4-dioxane (10 mL) was heated to 110.degree. C. under N.sub.2
for 5 h. After cooling to rt, and removal of the solvent was
followed by purification of the residue by flash chromatography
over silica gel, gradient elution, 0-100% EtOAc in hexane, it gave
1-(6-fluoro-3-(6-(methylsulfonyl)pyridin-2-yl)quinolin-2-yl)ethanone.
.sup.1H-NMR (DMSO-d.sup.6) .delta. 8.92 (s, 1H), 8.33 (dd, J=8.0,
8.0 Hz, 1H), 8.28 (d, J=8.0 Hz, 1H), 8.24 (dd, J=8.0, 4.0 Hz, 1H),
8.07 (d, J=8.0 Hz, 1H), 7.95 (dd, J=8.0, 4.0 Hz, 1H), 7.86 (dd,
J=8.0, 4.0 Hz, 1H), 3.26 (s, 3H), 2.76 (s, 3H). Mass Spectrum (ESI)
m/e=345.0 (M+1).
(R)-N-(1-(6-Fluoro-3-(6-(methylsulfonyl)pyridin-2-yl)quinolin-2-yl)ethylid-
ene)-2-methylpropane-2-sulfinamide
##STR00059##
[0296] A solution of
1-(6-fluoro-3-(6-(methylsulfonyl)pyridin-2-yl)quinolin-2-yl)ethanone
(220 mg, 0.639 mmol), (r)-(+)-t-butylsulfinamide (0.077 g, 0.639
mmol) and titanium tetraethoxide (0.264 mL, 1.28 mmol) with
molecular sieves 4 A (1.0 g) in THF (30 mL) was stirred and heated
to reflux for 4 days. The reaction was quenched with water and
diluted with DCM (30 mL). The mixture was then filtered through a
pad of Celite.TM. and rinsed with DCM. The combined organics were
washed with water, brine, dried and concd. Purification of the
residue by flash chromatography over silica gel, gradient elution,
CH.sub.2Cl.sub.2-EtOAc (1:1) to CH.sub.2Cl.sub.2-EtOAc-MeOH
(1:1:0.1) gave
(R)-N-(1-(6-fluoro-3-(6-(methylsulfonyl)pyridin-2-yl)quinolin-2-yl)ethyli-
dene)-2-methylpropane-2-sulfinamide. .sup.1H-NMR (CD.sub.3OD)
.delta. 8.78 (s, 0.4H), 8.62 (s, 0.6H), 8.36-8.05 (m, 4H),
7.80-7.65 (m, 2H), 3.31 (s, 1.8H), 3.27 (s, 1.2H), 3.03 (s, 1.8H),
2.88 (s, 1.2H), 0.91 (s, 9H). Mass Spectrum (ESI) m/e=448.0
(M+1).
(R)-N-((S)-1-(6-Fluoro-3-(6-(methylsulfonyl)pyridin-2-yl)quinolin-2-yl)eth-
yl)-2-methylpropane-2-sulfinamide
##STR00060##
[0298] To a solution of
(R)-N-(1-(6-fluoro-3-(6-(methylsulfonyl)pyridin-2-yl)quinolin-2-yl)ethyli-
dene)-2-methylpropane-2-sulfinamide (225 mg, 0.503 mmol) in THF (10
mL) at -78.degree. C. was added L-selectride (1.51 mL, 1.0M, 1.51
mmol) drop-wise. The resultant mixture was stirred at -78.degree.
C. for 4 h. The reaction was quenched with sat. NH.sub.4Cl and
diluted with EtOAc. The organics were washed with water, brine,
dried and concd. Purification of the residue by flash
chromatography over silica gel, gradient elution,
CH.sub.2Cl.sub.2-EtOAc (1:1) to CH.sub.2Cl.sub.2-EtOAc-MeOH
(5:5:0.5), gave
(R)-N-((S)-1-(6-fluoro-3-(6-(methylsulfonyl)pyridin-2-yl)quinolin-2--
yl)ethyl)-2-methylpropane-2-sulfinamide. .sup.1H-NMR (CD.sub.3OD)
.delta. 8.49 (s, 1H), 8.34 (dd, J=8.0, 8.0 Hz, 1H), 8.22-8.19 (m,
2H), 8.10 (d, J=8.0 Hz, 1H), 7.73-7.64 (m, 2H), 5.30 (q, J=8.0 Hz,
1H), 1.72 (d, J=8.0 Hz, 3H), 1.13 (s, 9H). Mass Spectrum (ESI)
m/e=450.1 (M+1).
(S)-1-(6-Fluoro-3-(6-(methylsulfonyl)pyridin-2-yl)quinolin-2-yl)ethanamine
##STR00061##
[0300] To a solution of
(R)-N-((S)-1-(6-fluoro-3-(6-(methylsulfonyl)pyridin-2-yl)quinolin-2-yl)et-
hyl)-2-methylpropane-2-sulfinamide (157 mg, 0.349 mmol) in MeOH (20
mL) was added HCl in dioxane (873 .mu.L, 4.0M, 3.49 mmol). The
mixture was stirred at rt for 1 h. The mixture was concd, and the
residue was diluted with EtOAc. The organics were washed with
water, brine, dried and concd. Purification of the residue by flash
chromatography over silica gel, gradient elution, 0-10%
MeOH--NH.sub.4OH (10:0.05) in CH.sub.2Cl.sub.2, gave
(S)-1-(6-fluoro-3-(6-(methylsulfonyl)pyridin-2-yl)quinolin-2-yl)etha-
namine. .sup.1H-NMR (CD.sub.3OD) .delta. 8.47 (s, 1H), 8.34 (dd,
J=8.0, 8.0 Hz, 1H), 8.22-8.18 (m, 2H), 8.09 (d, J=8.0 Hz, 1H),
7.73-7.64 (m, 2H), 4.71 (q, J=8.0 Hz, 1H), 3.30 (s, 3H), 1.48 (d,
J=8.0 Hz, 3H). Mass Spectrum (ESI) m/e=346.0 (M+1).
(S)-4-Amino-6-(1-(6-fluoro-3-(6-(methylsulfonyl)pyridin-2-yl)quinolin-2-yl-
)ethylamino)pyrimidine-5-carbonitrile
##STR00062##
[0302] A mixture of
(S)-1-(6-fluoro-3-(6-(methylsulfonyl)pyridin-2-yl)quinolin-2-yl)ethanamin-
e (85.1 mg, 0.246 mmol), 4-amino-6-chloropyrimidine-5-carbonitrile
(38.1 mg, 0.246 mmol) and N-ethyl-N-isopropylpropan-2-amine (47.2
.mu.L, 0.271 mmol) in BuOH (20 mL) was heated to 110.degree. C.
overnight. After cooling to rt, the mixture was concd. Purification
of the residue by flash chromatography over silica gel, gradient
elution, 0-10% MeOH in CH.sub.2Cl.sub.2, gave
(S)-4-amino-6-(1-(6-fluoro-3-(6-(methylsulfonyl)pyridin-2-yl)quinolin-2-y-
l)ethylamino)pyrimidine-5-carbonitrile. .sup.1H-NMR (DMSO-d.sup.6)
.delta. 8.59 (s, 1H), 8.36 (dd, J=8.0, 8.0 Hz, 1H), 8.16-8.09 (m,
3H), 7.90-7.86 (m, 2H), 7.78 (dd, J=8.0, 4.0 Hz, 1H), 7.55 (d,
J=8.0 Hz, 1H), 7.28 (br, 2H), 6.04 (m, 1H), 3.44 (s, 3H), 1.42 (d,
J=8.0 Hz, 3H). Mass Spectrum (ESI) m/e=464.0 (M+1).
Example 14
Preparation of
(S)-N-(1-(6-fluoro-3-(pyridin-2-yl)quinolin-2-yl)ethyl)-9H-purin-6-amine
and
Example 15
(R)-N-(1-(6-fluoro-3-(pyridin-2-yl)quinolin-2-yl)ethyl)-9H-purin-6-amine
Tert-butyl 3-oxo-4-(pyridin-2-yl)butan-2-ylcarbamate
##STR00063##
[0304] n-Butyllithium, 2.5M solution in hexane (12 mL, 29 mmol) and
lithium bis(trimethylsilyl)amide (102 mL, 102 mmol) was added
drop-wise to a solution of 2-pyridylacetic acid hydrochloride (5.07
g, 29 mmol) in THF (100 mL) at -78.degree. C. under N.sub.2. The
mixture was stirred at -78.degree. C. for 30 min, then
N-(tert-butoxycarbonyl)-1-alanine methyl ester (6 g, 29 mmol) in
THF (20 mL) was added dropwise. The resultant mixture was stirred
overnight and the cold bath was warmed slowly to rt. The reaction
mixture was washed with water and brine, dried, then concd.
Purification of the residue by flash chromatography over silica
gel, gradient elution, 0-100% EtOAc in hexane, gave tert-butyl
3-oxo-4-(pyridin-2-yl)butan-2-ylcarbamate. .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 8.46 (dd, J=5.0, 1.3 Hz, 1H), 7.72 (dd,
J=5.0, 1.3 Hz, 1H), 7.25-7.23 (m, 2H), 4.11-4.06 (m, 1H), 3.96 (s,
2H), 1.37 (s, 9H), 1.17 (d, J=5.0 Hz, 3H). Mass Spectrum (ESI)
m/e=265.1 (M+1).
(2-Amino-5-fluorophenyl)methanol
##STR00064##
[0306] To 2-amino-5-fluorobenzoic acid (2.0 g, 13 mmol) in THF (20
mL) lithium aluminum hydride (0.73 g, 19 mmol) was added portion
wise at 0.degree. C. The resulting mixture was heated to reflux for
1.5 h. After the reaction mixture was cooled to rt, 1 mL of water,
1 mL of NaOH (1N) and 2 mL of water were added. The resulting
mixture was filtered, rinsed with Et.sub.2O, and concd. The
residue, (2-amino-5-fluorophenyl)methanol was directly used for the
next reaction: .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 6.91
(dd, J=8.0, 4.0 Hz, 1H), 6.77 (ddd, J=8.0, 8.0, 4.0 Hz, 1H), 6.59
(dd, J=8.0, 8.0 Hz, 1H), 5.12 (t, J=4.0 Hz, 1H), 4.75 (s, 2H), 4.35
(t, J=4.0 Hz, 2H). Mass Spectrum (ESI) m/e=142.0 (M+1).
2-Amino-5-fluorobenzaldehyde
##STR00065##
[0308] To (2-amino-5-fluorophenyl)methanol (1.8 g, 13 mmol) in DCM
(50 mL), manganese dioxide (4.4 g, 51 mmol) (fresh activated by
heating with flame and under oil pump vacuum for 5 min), was added
together and stirred at rt overnight. LCMS showed completion of the
reaction. Filtration on a pad of Celite.TM. and rinsing with DCM,
followed by removal of the solvents, purification of the residue by
flash chromatography over silica gel, gradient elution, 0-100%
EtOAc in hexane gave 2-amino-5-fluorobenzaldehyde. .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. 9.78 (s, 1H), 7.39 (dd, J=8.0, 4.0 Hz,
1H), 7.23 (ddd, J=8.0, 8.0, 4.0 Hz, 1H), 7.00 (br, 2H), 6.78 (dd,
J=8.0, 4.0 Hz, 1H). Mass Spectrum (ESI) m/e=140.1 (M+1).
tert-Butyl-1-(6-fluoro-3-(pyridin-2-yl)quinolin-2-yl)ethylcarbamate
##STR00066##
[0310] The mixture of tert-butyl
3-oxo-4-(pyridin-2-yl)butan-2-ylcarbamate (2.7 g, 10 mmol),
2-amino-5-fluorobenzaldehyde (1.43 g, 10 mmol) and potassium
hydroxide (33 ml, 31 mmol) in EtOH (120 mL) was heated to reflux
for 1 h. The resulting mixture was cooled to rt and concd.
Purification of the residue by flash chromatography over silica
gel, gradient elution, 0-100% EtOAc in hexane, gave
tert-butyl-1-(6-fluoro-3-(pyridin-2-yl)quinolin-2-yl)ethylcarbamate.
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 8.75 (d, J=5.0 Hz, 1H),
8.38 (s, 1H), 8.13 (dd, J=9.3, 5.0 Hz, 1H), 8.01 (ddd, J=9.3, 5.0,
2.0 Hz, 1H), 7.85 (dd, J=9.3, 5.0 Hz, 1H), 7.75-7.70 (m, 2H), 7.50
(ddd, J=5.0, 5.0, 2.0 Hz, 1H), 7.00 (d, J=8.0 Hz, 1H), 5.34-5.27
(m, 1H), 1.32 (s, 9H), 1.28 (d, J=9.3 Hz, 3H). Mass Spectrum (ESI)
m/e=368.1 (M+1).
1-(6-Fluoro-3-(pyridin-2-yl) quinolin-2-yl)ethanamine
##STR00067##
[0312] The mixture of tert-butyl 1-(6-fluoro-3-(pyridin-2-yl)
quinolin-2-yl)ethylcarbamate (600 mg, 1.633 mmol), trifluoroacetic
acid (3 mL, 38.9 mmol) in DCM (10 mL) was stirred at rt for 60 min.
An additional amount of trifluoroacetic acid (3 mL, 38.9 mmol) was
added at this time. Stirring was continued for another 10 min. The
reaction mixture was concd and diluted with DCM (15 mL). The DCM
solution was washed with sat. NaHCO.sub.3, water, brine, dried and
concd to provide 1-(6-fluoro-3-(pyridin-2-yl)
quinolin-2-yl)ethanamine. .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. 8.74 (dd, J=4.0 Hz, 1H), 8.34 (s, 1H), 8.10 (dd, J=8.0, 4.0
Hz, 1H), 8.00 (ddd, J=8.0, 8.0, 4.0 Hz, 1H), 7.82 (dd, J=8.0, 4.0
Hz, 1H), 7.72 (d, J=4.0 Hz, 1H), 7.68 (dd, J=8.0, 4.0 Hz, 1H), 7.49
(ddd, J=8.0, 8.0, 4.0 Hz, 1H), 4.41-4.36 (m, 1H), 2.22 (br, 2H),
1.26 (d, J=8.0 Hz, 3H). Mass Spectrum (ESI) m/e=268.1 (M+1).
N-(1-(6-Fluoro-3-(pyridin-2-yl)quinolin-2-yl)ethyl)-9H-purin-6-amine
##STR00068##
[0314] A mixture of
1-(6-fluoro-3-(pyridin-2-yl)quinolin-2-yl)ethanamine (441 mg, 1.650
mmol), 6-chloro-9H-purine (255 mg, 1.650 mmol) and
N-ethyl-N-isopropylpropan-2-amine (345 .mu.L, 1.980 mmol) in BuOH
(20 mL) was heated at 110.degree. C. overnight. After cooling to
rt, the mixture was concd. Purification of the residue by flash
chromatography over silica gel, gradient elution, 0-10% MeOH in
CH.sub.2Cl.sub.2 gave
N-(1-(6-fluoro-3-(pyridin-2-yl)quinolin-2-yl)ethyl)-9H-purin-6-amine.
.sup.1H NMR (500 MHz, MeOH-d.sub.4) .delta. 8.74 (d, J=5.0 Hz, 1H),
8.32 (s, 1H), 8.27 (dd, J=9.3, 5.0 Hz, 1H), 8.16 (s, 1H), 8.14-8.08
(m, 1H), 8.00 (dd, J=9.3, 0.5 Hz, 1H), 7.78 (d, J=5.0 Hz, 1H),
7.71-7.62 (m, 2H), 7.52 (dd, J=9.3, 5.0 Hz, 1H), 6.09-5.96 (m, 1H),
1.56 (d, J=5.0 Hz, 3H). Mass Spectrum (ESI) m/e=386.0 (M+1).
(S)-N-(1-(6-Fluoro-3-(pyridin-2-yl)quinolin-2-yl)ethyl)-9H-purin-6-amine
and
(R)-N-(1-(6-fluoro-3-(pyridin-2-yl)quinolin-2-yl)ethyl)-9H-purin-6-am-
ine
##STR00069##
[0316]
N-(1-(6-Fluoro-3-(pyridin-2-yl)quinolin-2-yl)ethyl)-9H-purin-6-amin-
e was subjected to chiral separation (IC 250.times.30 mm column) to
provide
(S)-N-(1-(6-fluoro-3-(pyridin-2-yl)quinolin-2-yl)ethyl)-9H-purin--
6-amine: .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 8.77 (br, 1H),
8.44 (s, 1H), 8.21-8.15 (m, 1H), 8.11 (br, 2H), 8.01 (br, 1H), 7.87
(dd, J=9.3, 5.0 Hz, 1H), 7.82 (d, J=5.0 Hz, 1H), 7.76-7.68 (m, 2H),
7.50 (br, 1H), 6.00 (br, 1H), 1.47 (br, 3H). Mass Spectrum (ESI)
m/e=386.0 (M+1); and
(R)-N-(1-(6-fluoro-3-(pyridin-2-yl)quinolin-2-yl)ethyl)-9H-purin-6-am-
ine: .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 8.77 (br, 1H),
8.44 (s, 1H), 8.19 (dd, J=9.3, 5.0 Hz, 1H), 8.14 (br, 1H), 8.10 (s,
1H), 8.01 (br, 1H), 7.86 (dd, J=9.3, 5.0 Hz, 1H), 7.80 (d, J=9.3
Hz, 1H), 7.76-7.68 (m, 2H), 7.50 (br, 1H), 6.01 (br, 1H), 1.48 (d,
J=5.0 Hz, 3H). Mass Spectrum (ESI) m/e=386.0 (M+1).
[0317] Using the same or analogous synthetic procedures and
substituting with appropriate reagents, the following compounds
were prepared:
Example 16
Preparation of
N-(1-(6-fluoro-3-(pyridin-2-yl)quinolin-2-yl)ethyl)pyrimidin-4-amine
##STR00070##
[0319]
N-(1-(6-Fluoro-3-(pyridin-2-yl)quinolin-2-yl)ethyl)pyrimidin-4-amin-
e. .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 8.72 (d, J=5.0 Hz,
1H), 8.38 (s, 1H), 8.18 (br, 1H), 8.12 (dd, J=9.3, 5.0 Hz, 1H),
7.98 (dd, J=9.3, 9.3 Hz, 1H), 7.93 (d, J=5.0 Hz, 1H), 7.84 (dd,
J=9.3, 5.0 Hz, 1H), 7.80 (br, 1H), 7.77-7.68 (m, 2H), 7.46 (dd,
J=9.3, 5.0 Hz, 1H), 6.52 (br, 1H), 1.47 (d, J=5.0 Hz, 3H). Mass
Spectrum (ESI) m/e=346.0 (M+1).
Example 17
Preparation of
N4-(1-(6-fluoro-3-(pyridin-2-yl)quinolin-2-yl)ethyl)pyrimidine-4,6-diamin-
e
##STR00071##
[0321]
N4-(1-(6-Fluoro-3-(pyridin-2-yl)quinolin-2-yl)ethyl)pyrimidine-4,6--
diamine. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.73 (d, J=4.0
Hz, 1H), 8.34 (s, 1H), 8.11 (dd, J=9.2, 4.0 Hz, 1H), 7.98 (ddd,
J=9.2, 9.2, 1.8 Hz, 1H), 7.82 (dd, J=9.2, 4.0 Hz, 1H), 7.77 (d,
J=9.2 Hz, 1H), 7.72-7.65 (m, 2H), 7.47 (dd, J=9.2, 4.0 Hz, 1H),
5.94 (br, 2H), 5.52 (br, 1H), 1.38 (d, J=4.0 Hz, 3H). Mass Spectrum
(ESI) m/e=361.1 (M+1).
Example 18
Preparation of
N4-(1-(6-fluoro-3-(pyridin-2-yl)quinolin-2-yl)ethyl)pyrimidine-4,6-diamin-
e
##STR00072##
[0323]
N4-(1-(6-Fluoro-3-(pyridin-2-yl)quinolin-2-yl)ethyl)pyrimidine-4,6--
diamine. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.55 (d, J=4.0
Hz, 1H), 8.14 (s, 1H), 7.89 (dd, J=9.2, 4.0 Hz, 1H), 7.78 (dd,
J=9.2, 9.2 Hz, 1H), 7.63 (dd, J=9.2, 4.0 Hz, 1H), 7.57 (d, J=9.2
Hz, 1H), 7.49 (ddd, J=9.2, 9.2, 4.0 Hz, 1H), 7.33-7.24 (m, 2H),
5.55 (br, 1H), 5.31 (br, 2H), 1.23 (d, J=4.0 Hz, 3H). Mass Spectrum
(ESI) m/e=361.1 (M+1).
Example 19
Preparation of
4-amino-6-(1-(6-fluoro-3-(pyridin-2-yl)quinolin-2-yl)ethylamino)pyrimidin-
e-5-carbonitrile and
4-(1-(6-fluoro-3-(pyridin-2-yl)quinolin-2-yl)ethylamino)-6-hydroxypyrimid-
ine-5-carbonitrile
##STR00073##
[0325]
4-Amino-6-(1-(6-fluoro-3-(pyridin-2-yl)quinolin-2-yl)ethylamino)pyr-
imidine-5-carbonitrile. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
8.73 (d, J=4.0 Hz, 1H), 8.44 (s, 1H), 8.07 (dd, J=9.2, 9.2 Hz, 1H),
7.99 (ddd, J=9.2, 9.2, 4.0 Hz, 1H), 7.95 (s, 1H), 7.85 (dd, J=9.2,
4.0 Hz, 1H), 7.78-7.72 (m, 2H), 7.48 (ddd, J=9.2, 9.2, 1.8 Hz, 1H),
7.26 (br, 1H), 5.92 (br, 1H), 1.30 (d, J=8.0 Hz, 3H). Mass Spectrum
(ESI) m/e=386.0 (M+1).
4-(1-(6-Fluoro-3-(pyridin-2-yl)quinolin-2-yl)ethylamino)-6-hydroxy-
pyrimidine-5-carbonitrile was obtained: .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 8.74 (d, J=4.0 Hz, 1H), 8.48 (s, 1H), 8.29
(d, J=9.2 Hz, 1H), 8.10 (dd, J=9.2, 4.0 Hz, 1H), 8.06 (s, 1H), 8.02
(ddd, J=9.2, 9.2, 1.8 Hz, 1H), 7.88 (dd, J=9.2, 4.0 Hz, 1H),
7.80-7.73 (m, 2H), 7.50 (ddd, J=9.2, 9.2, 2.3 Hz, 1H), 6.02 (br,
1H), 1.35 (d, J=8.0 Hz, 3H). Mass Spectrum (ESI) m/e=387.1
(M+1).
Example 20
1-(6-Fluoro-3-(pyridin-2-yl)quinolin-2-yl)ethanone
##STR00074##
[0327] A mixture of 2-acetyl-6-fluoroquinolin-3-yl
trifluoromethanesulfonate (2.0 g, 5.93 mmol),
tetrakis(triphenylphosphine)palladium(0) (0.343 g, 0.297 mmol) and
tributyl(2-pyridyl)tin (2.62 mL, 7.12 mmol) in 1,4-dioxane (30 mL)
was heated to 110.degree. C. under N.sub.2 for 5 h. After cooling
to rt, removal of the solvent, and purification of the residue by
column chromatography on silica gel (EtOAc/hexane, 0:1 to 1:3) gave
1-(6-fluoro-3-(pyridin-2-yl)quinolin-2-yl)ethanone. .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 8.63 (s, 1H), 8.48 (d, J=4.0 Hz,
1H), 8.06 (dd, J=9.2, 4.0 Hz, 1H), 7.86-7.74 (m, 3H), 7.65 (ddd,
J=9.2, 9.2, 4.0 Hz, 1H), 7.30-7.24 (m, 1H), 2.56 (s, 3H). Mass
Spectrum (ESI) m/e=267.0 (M+1).
1-(6-Fluoro-3-(pyridin-2-yl)quinolin-2-yl)ethanol
##STR00075##
[0329] To 1-(6-fluoro-3-(pyridin-2-yl)quinolin-2-yl)ethanone (328.2
mg, 1.233 mmol) in THF (20 mL) sodium tetrahydroborate (46.6 mg,
1.233 mmol) was added at rt. The resulting mixture was stirred for
2 h. Filtration of the mixture on a pad of Celite.TM. and rinsing
with EtOAc, evaporation of the solvent, and purification of the
residue by flash chromatography over silica gel, gradient elution,
0-100% EtOAc in hexane gave
1-(6-fluoro-3-(pyridin-2-yl)quinolin-2-yl)ethanol. .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. 8.57 (d, J=4.0 Hz, 1H), 8.28 (s, 1H),
7.98 (dd, J=9.2, 4.0 Hz, 1H), 7.86 (ddd, J=9.2, 9.2, 2.0 Hz, 1H),
7.69 (dd, J=9.2, 4.0 Hz, 1H), 7.63 (d, J=9.2 Hz, 1H), 7.56 (ddd,
J=9.2, 9.2, 2.0 Hz, 1H), 7.35 (ddd, J=9.2, 9.2, 4.0 Hz, 1H), 5.31
(d, J=4.0 Hz, 1H), 5.02 (q, J=4.0 Hz, 1H), 1.19 (d, J=4.0 Hz, 3H).
Mass Spectrum (ESI) m/e=269.0 (M+1).
2-(1-Chloroethyl)-6-fluoro-3-(pyridin-2-yl)quinoline
##STR00076##
[0331] Sulfurous dichloride (0.058 mL, 0.792 mmol) was added to
1-(6-fluoro-3-(pyridin-2-yl)quinolin-2-yl) EtOH (213 mg, 0.792
mmol) in DCM (20 mL). After the addition, the mixture was stirred
at rt for 2 min. The mixture was concd and the residue was diluted
with DCM (10 mL), the organic phase was washed with 15 mL of
diluted satd solution of NaHCO.sub.3 (25%, v/v), followed by brine.
The organic layers were dried and concd. Purification of the
residue by flash chromatography over silica gel, using 20% hexane
in EtOAc, gave
2-(1-chloroethyl)-6-fluoro-3-(pyridin-2-yl)quinoline. .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 8.80-8.75 (m, 1H), 8.49 (s, 1H),
8.18 (dd, J=9.2, 4.0 Hz, 1H), 8.04 (ddd, J=9.2, 9.2, 2.0 Hz, 1H),
7.88 (dd, J=9.2, 4.0 Hz, 1H), 7.82-7.73 (m, 2H), 7.53 (ddd, J=9.2,
9.2, 2.0 Hz, 1H), 6.11 (q, J=4.0 Hz, 1H), 1.98 (d, J=4.0 Hz, 3H).
Mass Spectrum (ESI) m/e=287.0 (M+1).
(S)-4-Amino-1-(1-(6-fluoro-3-(pyridin-2-yl)quinolin-2-yl)ethyl)-1H-pyrazol-
o-[3,4-d]pyrimidine-3-carbonitrile and
(R)-4-amino-1-(1-(6-fluoro-3-(pyridin-2-yl)quinolin-2-yl)ethyl)-1H-pyrazo-
lo[3,4-d]pyrimidine-3-carbonitrile
##STR00077##
[0333] To a solution of
4-amino-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile in DMF (2 mL)
was added sodium hydride, 60% dispersion in mineral oil (27.8 mg,
0.694 mmol) with stirring at rt for 10 min. To the mixture was
added a solution of
241-chloroethyl)-6-fluoro-3-(pyridin-2-yl)quinoline (181 mg, 0.631
mmol) in DMF (1 mL) and the stirring continued at rt for 2 days.
Then potassium carbonate (96 mg, 0.694 mmol) was added, and the
stirring was continued at 70.degree. C. for another 7 h. The
mixture was diluted with Et.sub.2O and the resulting solid
triturated with Et.sub.2O and filtered. The solid was rinsed with
EtOAc. The filtrates were concd and purification of the residue by
flash chromatography over silica gel, gradient elution, 50-100%
EtOAc in hexane gave a racemic product. The racemic product was
subjected to chiral separation (Chiralpak.TM. IA column,
30.times.250 mm, 5 mm), using 15% isopropanol in hexane as eluent,
which gave
(S)-4-amino-1-(1-(6-fluoro-3-(pyridin-2-yl)quinolin-2-yl)ethyl)-1H-pyrazo-
lo[3,4-d]pyrimidine-3-carbonitrile. .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 8.51 (ddd, J=5.0, 2.0, 1.0 Hz, 1H), 8.37 (s,
1H), 8.11 (s, 1H), 8.08 (dd, J=9.3, 5.0 Hz, 1H), 7.85 (dd, J=9.3,
5.0 Hz, 1H), 7.80-7.70 (m, 2H), 7.42 (d, J=5.0 Hz, 1H), 7.25-7.21
(m, 1H), 7.03-6.95 (m, 1H), 1.90 (d, J=5.0 Hz, 3H). Mass Spectrum
(ESI) m/e=411.1 (M+1); And
(R)-4-amino-1-(1-(6-fluoro-3-(pyridin-2-yl)quinolin-2-yl)ethyl)-1H-pyrazo-
lo[3,4-d]pyrimidine-3-carbonitrile. .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 8.51 (ddd, J=5.0, 2.0, 1.0 Hz, 1H), 8.37 (s,
1H), 8.11 (s, 1H), 8.08 (dd, J=9.3, 5.0 Hz, 1H), 7.85 (dd, J=9.3,
5.0 Hz, 1H), 7.80-7.70 (m, 2H), 7.42 (d, J=5.0 Hz, 1H), 7.25-7.21
(m, 1H), 7.03-6.95 (m, 1H), 1.90 (d, J=5.0 Hz, 3H). Mass Spectrum
(ESI) m/e=411.1 (M+1).
Example 21
Preparation of
4-amino-6-(((1S)-1-(5-chloro-3-(2-pyridinyl)-2-quinolinyl)ethyl)amino)-5--
pyrimidinecarbonitrile and
Example 22
4-amino-6-(((1R)-1-(5-chloro-3-(2-pyridinyl)-2-quinolinyl)ethyl)amino)-5-p-
yrimidinecarbonitrile
2-Amino-6-chlorobenzaldehyde
##STR00078##
[0335] To a stirred solution of 2-chloro-6-nitrobenzaldehyde (2.0
g, 10.78 mmol) in 1M HCl (20 mL) was added iron powder (6.02 g, 108
mmol) and the reaction was heated at reflux for 2 h. After this
time the reaction was cooled to rt and EtOAc was added. The
separated organic layer was dried over MgSO.sub.4, filtered and
evaporated in vacuum to give 2-amino-6-chlorobenzaldehyde. Mass
Spectrum (ESI) m/e=156.2 (M+1).
tert-Butyl
1-(5-chloro-3-(pyridin-2-yl)quinolin-2-yl)ethylcarbamate
##STR00079##
[0337] Tert-Butyl 3-oxo-4-(pyridin-2-yl)butan-2-ylcarbamate (0.600
g, 2.270 mmol) and 2-amino-6-chlorobenzaldehyde (0.530 g, 3.40
mmol) in EtOH (26.5 mL, 454 mmol) was treated with potassium
hydroxide (0.382 g, 6.81 mmol). The reaction was heated at reflux
for 1 h. After this time LC/MS shows desired product. The reaction
was then cooled to rt and evaporated in vacuum. The product was
purified by column chromatography (hexanes:EtOAc, 1:0 to 2:1) to
give tert-butyl
1-(5-chloro-3-(pyridin-2-yl)quinolin-2-yl)ethylcarbamate.
1-(5-Chloro-3-(pyridin-2-yl)quinolin-2-yl)ethanamine
##STR00080##
[0339] To a stirred solution of tert-butyl
1-(5-chloro-3-(pyridin-2-yl)quinolin-2-yl)ethylcarbamate (150 mg,
0.391 mmol) in DCM (2 mL) was added trifluoroacetic acid (602
.mu.L, 7.82 mmol) and the reaction was stirred at rt for 2 h. After
this time the reaction was evaporated in vacuum and the residue was
dissolved in DCM (30 mL). HCl (1.0M) was then added and the
separated aq. layer was washed with DCM (20 mL). The aq. layer was
then basified to pH 14 and extracted with EtOAc (.times.2). The
combined organic layers were dried over MgSO.sub.4, filtered and
evaporated in vacuum to give
1-(5-chloro-3-(pyridin-2-yl)quinolin-2-yl)ethanamine.
4-Amino-6-(((1S)-1-(5-chloro-3-(2-pyridinyl)-2-quinolinyl)ethyl)amino)-5-p-
yrimidinecarbonitrile and
4-amino-6-(((1R)-1-(5-chloro-3-(2-pyridinyl)-2-quinolinyl)ethyl)amino)-5--
pyrimidinecarbonitrile
##STR00081##
[0341] To a stirred solution of
1-(5-chloro-3-(pyridin-2-yl)quinolin-2-yl)ethanamine (95 mg, 0.335
mmol) in butanol (4.0 mL) was added Hunig's base (116 .mu.L, 0.670
mmol) and 4-amino-6-chloropyrimidine-5-carbonitrile (56.9 mg, 0.368
mmol). The reaction was heated at 120.degree. C. for 2 h. After
this time the reaction was cooled to rt and the precipitate was
collected and washed with hexanes to give a racemic mixture of
4-amino-6-(((1S,1R)-1-(5-chloro-3-(2-pyridinyl)-2-quinolinyl)ethyl)amino)-
-5-pyrimidinecarbonitrile. The racemic mixture was separated by
chiral SFC to give
4-amino-6-(((1S)-1-(5-chloro-3-(2-pyridinyl)-2-quinolinyl)ethyl)a-
mino)-5-pyrimidinecarbonitrile .sup.1H NMR (400 MHz, MeOH) .delta.
ppm 8.76 (1H, ddd, J=4.9, 1.8, 1.0 Hz), 8.60 (1H, d, J=0.8 Hz),
8.11-8.14 (1H, m), 8.05 (1H, td, J=7.7, 1.8 Hz), 7.97 (1H, s),
7.75-7.83 (3H, m), 7.55 (1H, ddd, J=7.7, 4.9, 1.1 Hz), 5.98 (1H, q,
J=6.8 Hz), 1.42 (3H, d, J=6.7 Hz) Mass Spectrum (ESI) m/e=402.0
(M+1); and
4-amino-6-(((1R)-1-(5-chloro-3-(2-pyridinyl)-2-quinolinyl)ethyl)amino)-5--
pyrimidinecarbonitrile (21 mg) .sup.1H NMR (400 MHz, MeOH) .delta.
ppm 8.76 (1H, ddd, J=4.9, 1.8, 1.0 Hz), 8.60 (1H, d, J=0.8 Hz),
8.11-8.14 (1H, m), 8.05 (1H, td, J=7.7, 1.8 Hz), 7.97 (1H, s),
7.75-7.83 (3H, m), 7.55 (1H, ddd, J=7.7, 4.9, 1.1 Hz), 5.98 (1H, q,
J=6.8 Hz), 1.42 (3H, d, J=6.7 Hz). Mass Spectrum (ESI) m/e=402.0
(M+1). (Absolute configuration was assigned based on the
PI3K.delta. potency of each of the separated enantiomers).
Example 23
Preparation of
2-((1S)-1-((6-amino-5-cyano-4-pyrimidinyl)amino)ethyl)-3-(2-pyridinyl)-5--
quinolinecarbonitrile and
Example 24
2-((1R)-1-((6-amino-5-cyano-4-pyrimidinyl)amino)ethyl)-3-(2-pyridinyl)-5-q-
uinolinecarbonitrile
tert-Butyl
1-(5-cyano-3-(pyridin-2-yl)quinolin-2-yl)ethylcarbamate
##STR00082##
[0343] To a stirred solution of tert-butyl
1-(5-chloro-3-(pyridin-2-yl)quinolin-2-yl)ethylcarbamate (120 mg,
0.313 mmol) in NMP/Cy.sub.2NMe (3.0 mL/1.0 mL) was added palladium
bis(trifluoroacetate) (31.2 mg, 0.094 mmol),
2-(dicyclohexylphosphino)-2',4',6',-tri-1-propyl-1,1'-biphenyl (89
mg, 0.188 mmol) and cyanotributyltin (99 mg, 0.313 mmol) and the
reaction was heated at 150.degree. C. for 2 h. After this time the
reaction was partitioned between EtOAc and water and the separated
organic layer was dried, filtered and evaporated in vacuum. Column
chromatography (hexanes:EtOAc, 1:0 to 1:1) gave tert-butyl
1-(5-cyano-3-(pyridin-2-yl)quinolin-2-yl)ethylcarbamate. Mass
Spectrum (ESI) m/e=375.0
2-(1-Aminoethyl)-3-(pyridin-2-yl)quinoline-5-carbonitrile
##STR00083##
[0345] To a stirred solution of tert-butyl
1-(5-cyano-3-(pyridin-2-yl)quinolin-2-yl)ethylcarbamate (150 mg,
0.401 mmol) in DCM (1 mL) was added trifluoroacetic acid (309
.mu.L, 4.01 mmol) and the reaction was stirred at rt for 90 min.
After this time the reaction was evaporated in vacuum and the
residue was dissolved in DCM (30 mL). HCl (1.0M) was then added and
the separated aq. layer was washed with DCM (20 mL). The aq. layer
was then basified to pH 14 and extracted with EtOAc. The separated
organic layer was dried over MgSO.sub.4, filtered and evaporated in
vacuum to give
2-(1-aminoethyl)-3-(pyridin-2-yl)quinoline-5-carbonitrile. Mass
Spectrum (ESI) m/e=275.2
2-((1S)-1-((6-Amino-5-cyano-4-pyrimidinyl)amino)ethyl)-3-(2-pyridinyl)-5-q-
uinolinecarbonitrile and
2-((1R)-1-((6-amino-5-cyano-4-pyrimidinyl)amino)ethyl)-3-(2-pyridinyl)-5--
quinolinecarbonitrile
##STR00084##
[0347] To a stirred solution of
2-(1-aminoethyl)-3-(pyridin-2-yl)quinoline-5-carbonitrile (43 mg,
0.157 mmol) in butanol (1.5 mL) was added Hunig's base (54.5 .mu.L,
0.314 mmol) and 4-amino-6-chloropyrimidine-5-carbonitrile (26.6 mg,
0.172 mmol) and the reaction was heated at 110.degree. C. for 2 h.
After this time the reaction was allowed to cool to rt overnight.
The resulting white solid was filtered and washed with hexanes to
give a racemic mixture of
2-((1S,1R)-1-((6-amino-5-cyano-4-pyrimidinyl)amino)ethyl)-3-(2-pyridinyl)-
-5-quinolinecarbonitrile. The racemic mixture was separated by
chiral SFC to
2-((1S)-1-((6-amino-5-cyano-4-pyrimidinyl)amino)ethyl)-3-(2-pyridinyl)-
-5-quinolinecarbonitrile: .sup.1H NMR (400 MHz, chloroform-d)
.delta. ppm 8.85 (1H, ddd, J=4.9, 1.8, 1.0 Hz), 8.53 (1H, d, J=1.0
Hz), 8.45 (1H, dt, J=8.5, 1.1 Hz), 8.14 (1H, s), 8.02 (1H, dd,
J=7.2, 1.4 Hz), 7.94 (1H, td, J=7.7, 1.8 Hz), 7.84 (1H, dd, J=8.6,
7.2 Hz), 7.65-7.73 (2H, m), 7.46 (1H, ddd, J=7.7, 4.8, 1.2 Hz),
6.17 (1H, dd, J=7.1, 6.7 Hz), 5.31 (2H, s), 1.41 (3H, d, J=6.7 Hz).
Mass Spectrum (ESI) m/e=393.0; and
2-((1R)-1-((6-amino-5-cyano-4-pyrimidinyl)amino)ethyl)-3-(2-pyridinyl)-5--
quinolinecarbonitrile: .sup.1H NMR (400 MHz, chloroform-d) .delta.
ppm 8.85 (1H, ddd, J=4.9, 1.8, 1.0 Hz), 8.53 (1H, d, J=1.0 Hz),
8.45 (1H, dt, J=8.5, 1.1 Hz), 8.14 (1H, s), 8.02 (1H, dd, J=7.2,
1.4 Hz), 7.94 (1H, td, J=7.7, 1.8 Hz), 7.84 (1H, dd, J=8.6, 7.2
Hz), 7.65-7.73 (2H, m), 7.46 (1H, ddd, J=7.7, 4.8, 1.2 Hz), 6.17
(1H, dd, J=7.1, 6.7 Hz), 5.31 (2H, s), 1.41 (3H, d, J=6.7 Hz). Mass
Spectrum (ESI) m/e=393.0. (Absolute configuration was assigned
based on the PI3K.delta. potency of each of the separated
enantiomers).
Example 25
Preparation of
4-amino-6-(((1S,1R)-1-(3-(2-pyridinyl)-1,8-naphthyridin-2-yl)ethyl)amino)-
-5-pyrimidinecarbonitrile
tert-Butyl
1-(3-(pyridin-2-yl)-1,8-naphthyridin-2-yl)ethylcarbamate
##STR00085##
[0349] To a stirred solution of tert-butyl
3-oxo-4-(pyridin-2-yl)butan-2-ylcarbamate (0.6 g, 2.270 mmol) in
EtOH (26.5 mL, 454 mmol) was added potassium hydroxide (0.382 g,
6.81 mmol) and 2-amino-3-formylpyridine (0.277 g, 2.270 mmol). The
reaction was stirred at rt for 5 min and then it was heated at
90.degree. C. for 2 h. After this time the reaction was cooled to
rt, evaporated in vacuum and purified by column chromatography
(hexanes:EtOAc, 1:0 to 0:1) to give tert-butyl
1-(3-(pyridin-2-yl)-1,8-naphthyridin-2-yl)ethylcarbamate.
1-(3-(Pyridin-2-yl)-1,8-naphthyridin-2-yl)ethanamine
##STR00086##
[0351] To a stirred solution of tert-butyl
1-(3-(pyridin-2-yl)-1,8-naphthyridin-2-yl)ethylcarbamate (45 mg,
0.128 mmol) in DCM (1.5 mL) was added trifluoroacetic acid (99
.mu.L, 1.284 mmol). The reaction was stirred at rt for 4 h. After
this time the reaction was partitioned between DCM (40 mL) and
brine (10 mL). The separated organic layer was dried over
MgSO.sub.4, filtered and evaporated in vacuum to give
1-(3-(pyridin-2-yl)-1,8-naphthyridin-2-yl)ethanamine. Mass Spectrum
(ESI) m/e=251.0.
4-Amino-6-(((1S,1R)-1-(3-(2-pyridinyl)-1,8-naphthyridin-2-yl)ethyl)amino)--
5-pyrimidinecarbonitrile
##STR00087##
[0353] To a stirred solution of
1-(3-(pyridin-2-yl)-1,8-naphthyridin-2-yl)ethanamine (30 mg, 0.120
mmol), 4-amino-6-chloropyrimidine-5-carbonitrile (18.52 mg, 0.120
mmol) in n-butanol (1.5 mL) was added Hunig's base (41.7 .mu.L,
0.240 mmol). The reaction was stirred at 120.degree. C. for 4 h.
After this time the reaction was cooled to rt and purified by
reverse phase HPLC (gradient of acetonitrile:water, from 10% to
60%) to give a racemic mixture of
4-amino-6-(((1S,1R)-1-(3-(2-pyridinyl)-1,8-naphthyridin-2-yl)ethyl)amino)-
-5-pyrimidinecarbonitrile. .sup.1H NMR (400 MHz, chloroform-d)
.delta. ppm 9.18 (1H, dd, J=4.3, 2.0 Hz), 8.83 (1H, ddd, J=4.9,
2.0, 1.0 Hz), 8.23-8.28 (2H, m), 8.05 (1H, s), 7.90 (1H, td, J=7.7,
1.8 Hz), 7.66 (1H, dt, J=7.8, 1.2 Hz), 7.55 (1H, dd, J=8.1, 4.2
Hz), 7.42 (1H, ddd, J=7.6, 4.9, 1.2 Hz), 7.15-7.26 (1H, m), 6.06
(1H, t, J=7.1 Hz), 5.25-5.39 (2H, m), 1.56 (3H, d, J=6.7 Hz). Mass
Spectrum (ESI) m/e=369.2.
Example 26
Preparation of
4-amino-6-(((1S,1R)-1-(3-(2-pyridinyl)-1,6-naphthyridin-2-yl)ethyl)amino)-
-5-pyrimidinecarbonitrile
tert-Butyl
1-(3-(pyridin-2-yl)-1,6-naphthyridin-2-yl)ethylcarbamate
##STR00088##
[0355] To a stirred solution of tert-butyl
3-oxo-4-(pyridin-2-yl)butan-2-ylcarbamate (0.20 g, 0.757 mmol) and
4-aminonicotinaldehyde (0.092 g, 0.757 mmol) in EtOH (8.84 mL, 151
mmol) was added potassium hydroxide (0.127 g, 2.270 mmol). The
reaction was heated at reflux for 2 h. After this time the reaction
was evaporated in vacuum and purified by column chromatography
(hexanes:EtOAc, 1:0 to 0:1) to give tert-butyl
1-(3-(pyridin-2-yl)-1,6-naphthyridin-2-yl)ethylcarbamate.
1-(3-(Pyridin-2-yl)-1,6-naphthyridin-2-yl)ethanamine
##STR00089##
[0357] To a stirred solution of tert-butyl
1-(3-(pyridin-2-yl)-1,6-naphthyridin-2-yl)ethylcarbamate (30 mg,
0.086 mmol) in DCM (1.5 mL) was added trifluoroacetic acid (66.0
.mu.L, 0.856 mmol). The reaction was stirred at rt for 4 h. After
this time the reaction was partitioned between DCM (40 mL) and
brine (10 mL). The separated organic layer was dried over
MgSO.sub.4, filtered and evaporated in vacuum to give
1-(3-(pyridin-2-yl)-1,6-naphthyridin-2-yl)ethanamine. Mass Spectrum
(ESI) m/e=251.0.
4-Amino-6-(((1S,1R)-1-(3-(2-pyridinyl)-1,6-naphthyridin-2-yl)ethyl)amino)--
5-pyrimidinecarbonitrile
##STR00090##
[0359] To a stirred solution of
1-(3-(pyridin-2-yl)-1,6-naphthyridin-2-yl)ethanamine (15 mg, 0.060
mmol) in butanol (1.5 mL) was added
4-amino-6-chloropyrimidine-5-carbonitrile (9.26 mg, 0.060 mmol) and
N-ethyl-N-isopropylpropan-2-amine (20.93 .mu.L, 0.120 mmol). The
reaction was heated at 120.degree. C. for 2 h. After this time the
reaction was cooled to rt. The resulting precipitate was filtered
and washed with hexanes to give racemic
4-amino-6-(((1S,1R)-1-(3-(2-pyridinyl)-1,6-naphthyridin-2-yl)ethyl)amino)-
-5-pyrimidinecarbonitrile. .sup.1H NMR (400 MHz, chloroform-d)
.delta. ppm 9.33 (1H, s), 8.83 (2H, d, J=5.9 Hz), 8.33 (1H, s),
8.14 (1H, s), 8.02 (1H, d, J=5.9 Hz), 7.93 (1H, td, J=7.7, 1.8 Hz),
7.64 (2H, d, J=7.8 Hz), 7.44 (1H, ddd, J=7.6, 4.9, 1.0 Hz), 6.15
(1H, m), 5.28 (2H, bs), 1.38-1.43 (3H, m). Mass Spectrum (ESI)
m/e=251.0. Mass Spectrum (ESI) m/e=369.2.
Example 27
Preparation of
4-amino-6-(1-(6-fluoro-4-(methylsulfonyl)-3-phenylquinolin-2-yl)ethylamin-
o)-pyrimidine-5-carbonitrile
2,4-Dichloro-6-fluoro-3-phenylquinoline
##STR00091##
[0361] A stirred solution of diethyl 2-phenylmalonate (31.9 g, 135
mmol) in pyridine (14.56 mL, 180 mmol) was added 4-fluoroaniline
(10.00 g, 90 mmol). The reaction mixture was heated to 130.degree.
C. Stirring continued for 16 h after which the LCMS show very
little starting material. A further diethyl 2-phenylmalonate (31.9
g, 135 mmol) was added and stirring continued for 24 h. The
reaction mixture was concd in vacuum. The residue was taken up in
DCM (100 mL) and washed with NaHCO.sub.3 (.times.2). The separated
organic layer was dried, filtered and evaporated in vacuum. The
residue was purified by column chromatography (hexanes:EtOAc, 3:1)
to give crude ethyl
3-(4-fluorophenylamino)-3-oxo-2-phenylpropanoate as a red oil. A
mixture of ethyl 3-(4-fluorophenylamino)-3-oxo-2-phenylpropanoate
(12 g, crude) in THF-water (40 mL-10 mL) was treated with lithium
hydroxide (1.0 eq) and stirred at rt for 1 h. After this time the
reaction was acidified to pH 2 with concd HCl and then it was
extracted with EtOAc. The separated organic layer was dried over
MgSO.sub.4, filtered and evaporated under reduced pressure to give
3-(4-fluorophenylamino)-3-oxo-2-phenylpropanoic acid, used as such
for the next step. A mixture of
3-(4-fluorophenylamino)-3-oxo-2-phenylpropanoic acid in
polyphosphoric acid (0.6M) was stirred at 130.degree. C. for 2 h.
After this time the reaction was cooled to rt and treated with 2M
aq. sodium hydroxide until a precipitate formed. The precipitate
was filtered and washed with 1M aq. sodium hydroxide and dried
under vacuum to give 6-fluoro-3-phenylquinoline-2,4-diol. A mixture
of 6-fluoro-3-phenylquinoline-2,4-diol (1 eq) and phosphorus
oxychloride (10 eq) was heated at 100.degree. C. for 2 h. After
this time the reaction was cooled to rt and evaporated under
reduced pressure. The resulting brown residue was taken up in DCM
and washed with water. The separated organic layer was dried over
MgSO.sub.4, filtered and evaporated under reduced pressure. The
product was then purified by column chromatography (using a 9:1
mixture of hexanes and EtOAc as eluant) to give
2,4-dichloro-6-fluoro-3-phenylquinoline. Mass Spectrum (ESI)
m/e=292 (M+1).
4-Chloro-2-ethyl-6-fluoro-3-phenylquinoline
##STR00092##
[0363] A mixture of 2,4-dichloro-6-fluoro-3-phenylquinoline (1.46
g, 5 mmol), diethylzinc (1M in hexane, 1.02 eq), K.sub.2CO.sub.3
(2.07 g, 3.0 eq) and PdCl.sub.2(dppf).sub.2 DCM complex (366 mg,
0.1 eq) in THF (25 mL) was purged with N.sub.2 for 5 min before
heating to reflux. After 6 h, the reaction was quenched with
NH.sub.4Cl and extracted with EtOAc. The residue was purified by
combi-flash on silica gel (EtOAc/hexane, 1/3) to give a white solid
as 4-chloro-2-ethyl-6-fluoro-3-phenylquinoline. .sup.1H-NMR (500
Hz, CDCl.sub.3) .delta. 8.03 (dd, J=8.0, 4.0 Hz, 1H), 7.78 (dd,
J=8.0, 4.0 Hz, 1H), 7.41-7.46 (m, 4H), 7.19-7.21 (m, 2H), 2.70 (q,
J=8.0 Hz, 1H), 1.12 (t, J=8.0 Hz, 3H). Mass Spectrum (ESI) m/e=286
(M+1).
2-(1-Bromoethyl)-6-fluoro-4-(methylthio)-3-phenylquinoline
##STR00093##
[0365] A mixture of 4-chloro-2-ethyl-6-fluoro-3-phenylquinoline
(1.0 g, 3.5 mmol) and NaSMe (0.491 g, 2.0 eq) in DMF (8 mL) was
heated to 60.degree. C. under N.sub.2 for 30 min. The reaction
mixture was cooled to rt and partitioned between Et.sub.2O and
water. The organic layer was separated, washed with brine, dried
and concd. The residue was purified on combi-flash on silica gel
(EtOAc/hexane, 1/8) gave a white solid as
2-ethyl-6-fluoro-4-(methylthio)-3-phenylquinoline.
2-Ethyl-6-fluoro-4-(methylthio)-3-phenylquinoline (500 mg, 1.7
mmol) and 1,3-dibromo-5,5-dimethylhydantoin (336.5 mg, 0.7 eq) were
suspended in carbon tetrachloride (20 mL). To the mixture was added
benzoyl peroxide (41 mg, 0.1 eq) and the mixture was heated at
reflux for 3 h. After cooling to rt, to the mixture was added satd
aq. sodium bicarbonate solution (15 mL). The layers were separated
and the aq. layer was extracted with CH.sub.2CH.sub.2 (10
mL.times.2). The combined organic layers were washed with brine (30
mL), dried over Na.sub.2SO.sub.4, filtered, and concd under reduced
pressure to give an orange syrup. This material was used as such
without further purification. Mass Spectrum (ESI) m/e=376, 378
(M+1).
2-(1-(6-Fluoro-4-(methylthio)-3-phenylquinolin-2-yl)ethyl)isoindoline-1,3--
dione
##STR00094##
[0367] A mixture of
2-(1-bromoethyl)-6-fluoro-4-(methylthio)-3-phenylquinoline (120 mg,
0.32 mmol) in DMF (1.5 mL) was treated with phthalimide potassium
salt (89 mg, 1.5 eq) overnight. At this time 50% SM remained. The
reaction mixture was heated to 60.degree. C. for 2 h. when LCMS
showed completion. The reaction was repeated on a 500 mg scale. The
two reaction mixtures were combined and partitioned between
Et.sub.2O and water. The organic layer was separated, washed with
brine, dried, concd and purified by combi-flash (EtOAc/hexane, 0/1
to 1/3) to give a white solid as
2-(1-(6-fluoro-4-(methylthio)-3-phenylquinolin-2-yl)ethyl)isoindoline-1,3-
-dione. .sup.1H-NMR (500 Hz, CDCl.sub.3) .delta. 8.18 (dd, J=10,
5.0 Hz, 1H), 8.13 (dd, J=10, 4.0 Hz, 1H), 7.70-7.74 (m, 4H),
7.50-7.53 (m, 2H), 7.33-7.37 (m, 2H), 7.13-7.14 (m, 2H), 5.65 (q,
J=10 Hz, 1H), 2.09 (s, 3H), 1.81 (d, J=5.0 Hz, 3H). Mass Spectrum
(ESI) m/e=443 (M+1).
1-(6-Fluoro-4-(methylsulfonyl)-3-phenylquinolin-2-yl)ethanamine
##STR00095##
[0369] To solution of
2-(1-(6-fluoro-4-(methylthio)-3-phenylquinolin-2-yl)ethyl)isoindoline-1,3-
-dione (200 mg, 0.45 mmol) in THF (6 mL) and H.sub.2O (2 mL) was
added oxone (556 mg, 0.90 mmol, 2.0 eq) at rt. The resulting
suspension was stirred at rt overnight. The reaction was
incomplete. Oxone (556 mg, 2.0 eq) was added and the reaction
mixture was stirred at rt overnight again. LCMS showed completion.
The reaction mixture was partitioned between EtOAc and water. The
organic layer was separated, washed with brine, dried, and concd.
The residue was dissolved in EtOH (5 mL) and treated with
NH.sub.2NH.sub.2 (0.5 mL) at 60.degree. C. for 30 min. After
cooling to rt, the reaction mixture was partitioned between EtOAc
and water. The organic layer was separated, washed with water,
brine, dried, and concd to give a pale yellow oil as
1-(6-fluoro-4-(methylsulfonyl)-3-phenylquinolin-2-yl)ethanamine.
The material was used as such for the next step. Mass Spectrum
(ESI) m/e=345 (M+1).
4-Amino-6-(1-(6-fluoro-4-(methylsulfonyl)-3-phenylquinolin-2-yl)ethylamino-
)-pyrimidine-5-carbonitrile
##STR00096##
[0371] A mixture of
1-(6-fluoro-4-(methylsulfonyl)-3-phenylquinolin-2-yl)ethanamine
(152 mg, 0.44 mmol), 4-amino-6-chloropyrimidine-5-carbonitrile
(68.2 mg, 1.0 eq) and Hunig's base (0.094 mL, 1.2 eq) in n-BuOH (2
mL) was heated to 130.degree. C. overnight. The mixture was cooled
to rt, concd, then dissolved in DMF (2 mL) and purified by reverse
HPLC. The fractions were combined, concd and filtered to give a
white crystal as
4-amino-6-(1-(6-fluoro-4-(methylsulfonyl)-3-phenylquinolin-2-yl)ethylamin-
o)pyrimidine-5-carbonitrile. .sup.1H-NMR (400 Hz, DMSO-d.sup.6)
.delta. 8.61 (dd, J=8.0, 4.0 Hz, 1H), 8.25 (dd, J=8.0, 4.0 Hz, 1H),
7.87-7.92 (m, 2H), 7.37-7.50 (m, 5H), 7.25 (s, br, 2H), 5.09-5.13
(m, 1H), 3.22 (s, 3H), 1.29 (d, J=8.0 Hz, 3H). Mass Spectrum (ESI)
m/e=463 (M+1).
Example 28
Preparation of
4-amino-6-(1-(6-fluoro-4-(methylsulfonyl)-3-phenylquinolin-2-yl)ethylamin-
o)-pyrimidine-5-carbonitrile
##STR00097##
[0373]
2-(1-(6-Fluoro-4-(methylthio)-3-phenylquinolin-2-yl)ethyl)isoindoli-
ne-1,3-dione (80 mg, 0.18 mmol) was dissolved in EtOH (2 mL) and
treated with NH.sub.2NH.sub.2 (0.2 mL) at 60.degree. C. for 30 min.
After cooling to rt, the reaction mixture was partitioned between
EtOAc and water. The organic layer was separated, washed with
water, brine, dried, and concd to give a pale yellow oil. The
material was used as such for the next step. A mixture of this
material, 4-amino-6-chloropyrimidine-5-carbonitrile (28 mg, 1.0 eq)
and Hunig's base (37.9 .mu.L, 1.2 eq) in n-BuOH (2 mL) was heated
to 130.degree. C. overnight. The mixture was cooled to rt, concd,
dissolved in DCM (2 mL) and purified by combi-flash (DCM/MeOH,
20/1) to give a pale yellow solid. .sup.1H-NMR (400 Hz,
DMSO-d.sup.6) .delta. 8.06-8.12 (m, 2H), 7.86 (s, 1H), 7.72-7.75
(m, 1H), 7.34-7.47 (m, 5H), 7.22 (s, br, 2H), 5.14-5.17 (m, 1H),
2.07 (s, 3H), 1.21 (d, J=8.0 Hz, 3H). Mass Spectrum (ESI) m/e=431
(M+1).
Example 29
Preparation of
4-amino-6-((8-fluoro-3-(2-(methylsulfonyl)phenyl)quinolin-2-yl)methylamin-
o)pyrimidine-5-carbonitrile
2-(2-(Methylsulfinyl)phenyl)acetonitrile
##STR00098##
[0375] A mixture of oxone, monopersulfate compound (14.12 mL, 25.3
mmol), 2-(2-(methylthio)phenyl)acetonitrile (1.65 g, 10.11 mmol)
and 5 g wet montmorillonite clay (ca. 20% water by weight) in DCM
(60 mL) was stirred vigorously at rt for 4 h, after which time no
starting material remained and predominantly sulfoxide was detected
by LC-MS. The reaction was filtered to remove solids, rinsed with
DCM, and the filtrate concd under reduced pressure to afford a
colorless solid, which was used without further purification. Mass
Spectrum (ESI) m/e=180.1 (M+1) (sulfoxide).
8-Fluoro-3-(2-(methylsulfinyl)phenyl)quinolin-2-amine
##STR00099##
[0377] A mixture of sodium ethoxide (6.87 mL, 18.41 mmol),
2-(2-(methylsulfinyl)phenyl)acetonitrile (1.65 g, 9.21 mmol) and
2-amino-3-fluorobenzaldehyde (1.281 g, 9.21 mmol) in EtOH (5 mL)
was heated to 75.degree. C. for 1 h then equilibrated to rt and
left to sit at rt overnight. The reaction was partitioned between
100 mL water and 50 mL EtOAc and left to separate overnight. The
organic layer was stirred over anhydrous magnesium sulfate,
filtered and the filtrate concd under reduced pressure to afford
dark yellow oil. The material was used without further
purification. Mass Spectrum (ESI) m/e=301.1 (M+1).
8-Fluoro-3-(2-(methylsulfonyl)phenyl)quinolin-2-amine
##STR00100##
[0379] A mixture of
8-fluoro-3-(2-(methylsulfinyl)phenyl)quinolin-2-amine (2.26 g, 7.52
mmol), osmium tetroxide (0.118 mL, 0.376 mmol) and
4-methylmorpholine N-oxide (0.881 g, 7.52 mmol) in THF (20 mL) and
water (5.00 mL) was stirred overnight at rt, after which time LC-MS
indicated no starting material remained. The reaction was concd
under reduced pressure and the concentrate partitioned between DCM
and 10% sodium thiosulfate aq. solution. The organic layer was
stirred over magnesium sulfate, filtered and the filtrate concd
under reduced pressure to afford a yellow solid. The crude product
was used without further purification. Mass Spectrum (ESI)
m/e=317.0 (M+1).
8-Fluoro-3-(2-(methylsulfonyl)phenyl)quinolin-2(1H)-one
##STR00101##
[0381] To a solution of
8-fluoro-3-(2-(methylsulfonyl)phenyl)quinolin-2-amine (205 mg,
0.648 mmol) dissolved in hydrochloric acid (2.00 mL, 65.8 mmol) at
rt was added dropwise by pipet a solution of sodium nitrite (447
mg, 6.48 mmol) in water (2 mL) over a period of 2 min. Within
several hours a precipitate developed. The precipitate was
collected by filtration, rinsed with water and dried under vacuum
over P.sub.2O.sub.5 to afford product as a colorless solid. Mass
Spectrum (ESI) m/e=318.1 (M+1).
2-Chloro-8-fluoro-3-(2-(methylsulfonyl)phenyl)quinoline
##STR00102##
[0383] A mixture of
8-fluoro-3-(2-(methylsulfonyl)phenyl)quinolin-2(1H)-one (200 mg,
0.630 mmol) in phosphorus oxychloride (3 mL, 32.2 mmol) was heated
to 120.degree. C. After 24 h the reaction was concd under reduced
pressure and the residue partitioned between 25 mL ea. DCM and satd
aq. sodium bicarbonate solution. The organic separation was stirred
over anhydrous magnesium sulfate, filtered and the filtrate concd
under reduced pressure to afford product as a colorless solid. Mass
Spectrum (ESI) m/e=336.0 (M+1).
8-Fluoro-3-(2-(methylsulfonyl)phenyl)-2-vinylquinoline
##STR00103##
[0385] A mixture of cesium carbonate (256 mg, 0.786 mmol),
1,1'-bis(diphenylphosphino)ferrocene-palladium(ii)dichloride DCM
complex (32.1 mg, 0.039 mmol),
2-chloro-8-fluoro-3-(2-(methylsulfonyl)phenyl)quinoline (132 mg,
0.393 mmol) and potassium vinyltrifluoroborate (263 mg, 1.966 mmol)
in THF (3 mL) and water (0.500 mL) was purged with nitrogen then
heated in a microwave at 120.degree. C. for 1 h, after which time
LC-MS indicated only desired product present. The reaction was
partitioned between 25 mL EtOAc and 25 mL water. The organic layer
was washed with 25 mL brine then stirred over anhydrous magnesium
sulfate, filtered and the filtrate concd under reduced pressure to
afford an intense orange-red film. The product was isolated as a
colorless film by chromatography on silica gel eluting with 5%
EtOAc in DCM. Mass Spectrum (ESI) m/e=328.1 (M+1).
8-Fluoro-3-(2-(methylsulfonyl)phenyl)quinoline-2-carbaldehyde
##STR00104##
[0387] A mixture of
8-fluoro-3-(2-(methylsulfonyl)phenyl)-2-vinylquinoline (88 mg,
0.269 mmol), sodium periodate (172 mg, 0.806 mmol) and osmium
tetroxide (4.22 .mu.L, 0.013 mmol) in THF (3 mL) and water (1 mL)
was stirred at rt for 2.5 h after which time a white precipitate
had developed. The precipitate was removed by filtration and the
filtrate partitioned between 25 mL ea EtOAc and water. The organic
layer was washed with 25 mL brine then stirred over anhydrous
magnesium sulfate, filtered and the filtrate concd under reduced
pressure to afford a tan solid. The product was isolated as a
colorless solid by chromatography on silica gel, eluting with 5%
EtOAc in DCM. Mass Spectrum (ESI) m/e=330.1 (M+1).
(8-Fluoro-3-(2-(methylsulfonyl)phenyl)quinolin-2-yl)methanol
##STR00105##
[0389] To a suspension of
8-fluoro-3-(2-(methylsulfonyl)phenyl)quinoline-2-carbaldehyde (57
mg, 0.173 mmol) in MeOH (4 mL) at rt was added sodium borohydride
(9.82 mg, 0.260 mmol). The reaction was stirred at rt for 30 min,
after which time the LC-MS indicated only the desired product was
present. Water was added to the reaction and the MeOH was removed
under reduced pressure. The residue was partitioned between EtOAc
and water. The organic layer was stirred over anhydrous magnesium
sulfate, filtered and the filtrate concd under reduced pressure to
afford a colorless solid which was used without further
purification. Mass Spectrum (ESI) m/e=332.0 (M+1).
(8-Fluoro-3-(2-(methylsulfonyl)phenyl)quinolin-2-yl)methyl
methanesulfonate
##STR00106##
[0391] To a solution of MsCl (0.017 mL, 0.217 mmol) dissolved in
DCM (3 mL) cooled by an ice bath was added a solution of
(8-fluoro-3-(2-(methylsulfonyl)phenyl)quinolin-2-yl)methanol (60
mg, 0.181 mmol) and triethylamine (0.038 mL, 0.272 mmol) in 2 mL
DCM. After 20 min TLC and LC-MS indicated some starting material
remained and an additional 0.2 equivalents each of MsCl and
triethylamine were added. After 1 h the reaction was diluted with
20 mL DCM and 20 mL water was added. The organic layer was stirred
over anhydrous magnesium sulfate, filtered and the filtrate concd
under reduced pressure to afford a colorless film. The product was
used without further purification. Mass Spectrum (ESI) m/e=410.0
(M+1).
2-(Azidomethyl)-8-fluoro-3-(2-(methylsulfonyl)phenyl)quinoline
##STR00107##
[0393] A mixture of sodium azide (22.23 mg, 0.342 mmol) and
18-crown-6 (2.259 mg, 8.55 .mu.mol) in acetonitrile (2 mL) was
stirred for 20 min at rt before
(8-fluoro-3-(2-(methylsulfonyl)phenyl)quinolin-2-yl)methyl
methanesulfonate (70 mg, 0.171 mmol) in 1 mL acetonitrile was
added. The reaction mixture was stirred overnight at rt. After 16
h, TLC and LC-MS indicated no starting material remained and
desired product predominated. The mixture was filtered and the
filtrate concd under reduced pressure. The concentrate was
partitioned between 25 mL each DCM and water. The organic
separation was stirred over anhydrous magnesium sulfate, filtered
and the filtrate concd under reduced pressure to afford a colorless
film. The product was used without further purification. Mass
Spectrum (ESI) m/e=357.1 (M+1).
(8-Fluoro-3-(2-(methylsulfonyl)phenyl)quinolin-2-yl)methanamine
##STR00108##
[0395] A mixture of triphenylphosphine (56.7 mg, 0.216 mmol) and
2-(azidomethyl)-8-fluoro-3-(2-(methylsulfonyl)phenyl)quinoline (70
mg, 0.196 mmol) in THF (3 mL) was stirred at rt overnight. After 22
h, LC-MS indicated no starting azide remained and 200 uL water was
added to the reaction. The reaction was stirred at rt for 24 h then
concd under reduced pressure. The concentrate was partitioned
between 25 mL each Et.sub.2O and 1N aq. hydrochloric acid solution.
The aq. acidic layer was made alkaline with sodium hydroxide and
extracted with 2.times.25 mL DCM. The combined organic layers were
stirred over anhydrous magnesium sulfate, filtered and the filtrate
concd under reduced pressure to afford a colorless film. The
product was used without further purification. Mass Spectrum (ESI)
m/e=331.1 (M+1).
4-Amino-6-((8-fluoro-3-(2-(methylsulfonyl)phenyl)quinolin-2-yl)methylamino-
)-pyrimidine-5-carbonitrile
##STR00109##
[0397] A mixture of
(8-fluoro-3-(2-(methylsulfonyl)phenyl)quinolin-2-yl)methanamine (28
mg, 0.085 mmol), 4-amino-6-chloropyrimidine-5-carbonitrile (13.75
mg, 0.089 mmol) and diisopropylethylamine (0.016 mL, 0.093 mmol) in
butan-1-ol (2 mL) was heated in a 80.degree. C. oil bath. A
precipitate developed within 60 min. After 2 h LC-MS indicated no
starting amine remained and the reaction mixture was removed from
the hot oil bath and equilibrated to rt for 90 min, after which
time the precipitate was collected by filtration, rinsing with 5 mL
1:1 Et.sub.2O:EtOH at rt. The isolated solid was dried under
vacuum. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 8.42 (d,
J=1.6 Hz, 1H), 8.10-8.21 (m, 1H), 7.91 (s, 1H), 7.75-7.89 (m, 3H),
7.55-7.73 (m, 4H), 7.30 (br. s., 2H), 4.48-4.64 (m, 1H), 4.34-4.48
(m, 1H), 3.03 (s, 3H). Mass Spectrum (ESI) m/e=449.0 (M+1).
Example 30
4-Amino-6-((8-fluoro-3-(pyridin-2-yl)quinolin-2-yl)methylamino)pyrimidine--
5-carbonitrile
##STR00110##
[0399] To a reaction vessel was added
4-amino-6-chloropyrimidine-5-carbonitrile (24.35 mg, 0.158 mmol),
diisopropylethylamine (31.4 .mu.L, 0.180 mmol),
(8-fluoro-3-(pyridin-2-yl)quinolin-2-yl)methanamine (38 mg, 0.150
mmol), and 1.5 mL of n-butanol. The reaction was heated to
115.degree. C. for 1 h, then cooled back to rt and filtered. The
solid product was washed with cold 2:1 Et.sub.2O/EtOH and dried
under high vacuum to afford
4-amino-6-((8-fluoro-3-(pyridin-2-yl)quinolin-2-yl)methylamino)pyrimidine-
-5-carbonitrile. .sup.1H NMR (500 MHz, DMSO-d6) .delta. 8.76 (d,
J=4.2 Hz, 1H), 8.59 (s, 1H), 8.03 (td, J=7.6, 1.5 Hz, 1H), 7.96 (m,
1H), 7.91 (m, 1H), 7.83 (m, 2H), 7.64 (m, 2H), 7.51 (dd, J=6.9, 4.9
Hz, 1H), 7.27 (br s, 2H), 4.99 (d, J=4.9 Hz, 1H). Mass Spectrum
(ESI) m/e=372.1 (M+1).
Specific Example of Method E
2-((5-Fluoro-3-(2-(methylsulfonyl)phenyl)quinolin-2-yl)methyl)isoindoline--
1,3-dione
##STR00111##
[0401] Substrate
2-((5-fluoro-3-(2-(methylthio)phenyl)quinolin-2-yl)methyl)isoindoline-1,3-
-dione (102 mg, 0.238 mmol) was dissolved in 2.4 mL of DCM. To this
solution was added 288 mg of wet montmorillonite clay (0.2 g water
per 1 g clay, 1.2 g wet clay per mmole of substrate) and oxone (366
mg, 0.595 mmol, 2.5 eq). The reaction was stirred overnight,
filtered, and concd to afford
2-((5-fluoro-3-(2-(methylsulfonyl)phenyl)quinolin-2-yl)methyl)isoi-
ndoline-1,3-dione. .sup.1H NMR (500 MHz, DMSO-d6) .delta. 8.43 (d,
J=0.73 Hz, 1H), 8.20 (dd, J=8.1, 1.5 Hz, 1H), 7.89 (m, 5H), 7.81
(td, J=7.6, 1.5 Hz, 1H), 7.71 (m, 1H), 7.62 (m, 2H), 7.45 (ddd,
J=9.8, 7.8, 0.7 Hz, 1H), 4.75 (ABq J.sub.AB=16.9 Hz, .DELTA.v=122
Hz), 3.03 (s, 3H). Mass Spectrum (ESI) m/e=461.0 (M+1).
[0402] The compounds below were made via the same general methods
described above:
Example 31
4-Amino-6-((8-fluoro-3-phenylquinolin-2-yl)methylamino)pyrimidine-5-carbon-
itrile
##STR00112##
[0404]
4-Amino-6-((8-fluoro-3-phenylquinolin-2-yl)methylamino)pyrimidine-5-
-carbonitrile was synthesized from
2-((8-fluoro-3-phenylquinolin-2-yl)methyl)isoindoline-1,3-dione by
Method D. .sup.1H NMR (500 MHz, DMSO-d6) .delta. 8.33 (d, J=1.5 Hz,
1H), 7.95 (s, 1H), 7.86 (m, 1H), 7.70 (t, J=4.6 Hz, 1H), 7.62 (m,
2H), 7.57-7.47 (series of m, 5H), 7.31 (br s, 2H), 4.75 (d, J=4.6
Hz, 1H). Mass Spectrum (ESI) m/e=371.0 (M+1).
2-((3-Bromo-5-fluoroquinolin-2-yl)methyl)isoindoline-1,3-dione
##STR00113##
[0406]
2-((3-Bromo-5-fluoroquinolin-2-yl)methyl)isoindoline-1,3-dione was
synthesized from 2-amino-6-fluorobenzoic acid via Method A. .sup.1H
NMR (500 MHz, DMSO-d6) .delta. 8.81 (s, 1H), 7.99 (m, 2H), 7.94 (m,
2H), 7.69 (dt J=8.3, 6.1 Hz, 1H), 7.51 (d, J=8.6 Hz, 1H), 7.47 (ddd
J=10.0, 7.8, 0.7 Hz, 1H), 5.16 (s, 2H). Mass Spectrum (ESI)
m/e=385.0, 387.0 (M+1).
Example 32
4-amino-6-((5-fluoro-3-phenylquinolin-2-yl)methylamino)pyrimidine-5-carbon-
itrile
##STR00114##
[0408]
4-Amino-6-((5-fluoro-3-phenylquinolin-2-yl)methylamino)pyrimidine-5-
-carbonitrile was synthesized from
2-((3-bromo-5-fluoroquinolin-2-yl)methyl)isoindoline-1,3-dione and
phenylboronic acid via Methods C and D. .sup.1H NMR (500 MHz,
DMSO-d6) .delta. 8.25 (s, 1H), 7.94 (s, 1H), 7.86 (d, J=8.6 Hz,
1H), 7.81 (td, J=7.8, 6.1 Hz, 1H), 7.70 (t, J=4.6 Hz, 1H), 7.57 (m,
4H), 7.49 (m, 2H), 7.31 (br s, 2H), 4.75 (d, J=4.6 Hz, 1H). Mass
Spectrum (ESI) m/e=371.0 (M+1).
Example 33
4-Amino-6-((5-fluoro-3-(3-fluorophenyl)quinolin-2-yl)methylamino)pyrimidin-
e-5-carbonitrile
##STR00115##
[0410]
4-Amino-6-((5-fluoro-3-(3-fluorophenyl)quinolin-2-yl)methylamino)py-
rimidine-5-carbonitrile was synthesized from
2-((3-bromo-5-fluoroquinolin-2-yl)methyl)isoindoline-1,3-dione and
3-fluorophenylboronic acid via Methods C and D. .sup.1H NMR (500
MHz, DMSO-d6) .delta. 8.29 (s, 1H), 7.94 (s, 1H), 7.86 (d, J=8.3
Hz, 1H), 7.81 (td, J=7.8, 6.1 Hz, 1H), 7.70 (t, J=4.6 Hz, 1H), 7.57
(d, J=8.1, 6.1 Hz, 1H), 7.31 (m, 3H), 4.76 (d, J=4.9 Hz, 2H). Mass
Spectrum (ESI) m/e=389.0 (M+1).
Example 34
4-Amino-6-((3-(3,5-difluorophenyl)-5-fluoroquinolin-2-yl)methylamino)pyrim-
idine-5-carbonitrile
##STR00116##
[0412]
4-Amino-6-((3-(3,5-difluorophenyl)-5-fluoroquinolin-2-yl)methylamin-
o)pyrimidine-5-carbonitrile was synthesized from
2-((3-bromo-5-fluoroquinolin-2-yl)methyl)isoindoline-1,3-dione and
3,5-difluorophenylboronic acid via Methods C and D. .sup.1H NMR
(500 MHz, DMSO-d6) .delta. 8.32 (s, 1H), 7.94 (s, 1H), 7.87 (d,
J=8.6 Hz, 1H), 7.82 (td, J=7.6, 5.9 Hz, 1H), 7.69 (t, J=4.6 Hz,
1H), 7.50 (dd, J=9.0, 7.6 Hz, 1H), 7.40-7.25 (series of m, 5), 4.79
(d, J=4.9 Hz, 1H). Mass Spectrum (ESI) m/e=407.0 (M+1).
Example 35
4-Amino-6-((5-fluoro-3-(2-(methylsulfonyl)phenyl)quinolin-2-yl)methylamino-
)pyrimidine-5-carbonitrile
##STR00117##
[0414]
4-Amino-6-((5-fluoro-3-(2-(methylsulfonyl)phenyl)quinolin-2-yl)meth-
ylamino)pyrimidine-5-carbonitrile was synthesized from
2-((3-bromo-5-fluoroquinolin-2-yl)methyl)isoindoline-1,3-dione and
2-(methylthio)phenylboronic acid via Methods C, E, D. .sup.1H NMR
(500 MHz, DMSO-d.sub.6) .delta. 8.42 (d, J=0.7 Hz, 1H), 8.15 (dd,
J=8.1, 1.2 Hz, 1H), 7.91 (s, 1H), 7.90-7.78 (series of m, 4H), 7.66
(t, J=4.6 Hz, 1H), 7.61 (dd, J=7.6, 1.2 Hz, 1H), 7.50 (ddd, J=9.8,
7.8, 1.2 Hz, 1H), 7.30 (s, 2H), 4.53 (ABX, J.sub.AB=17.4 Hz,
J.sub.AX=4.9 Hz, 1H), 4.42 (ABX, J.sub.AB=17.1 Hz, J.sub.BX=4.6 Hz,
1H), 3.03 (s, 3H). Mass Spectrum (ESI) m/e=449.0 (M+1).
Example 36
4-Amino-6-((5-fluoro-3-(pyridin-2-yl)quinolin-2-yl)methylamino)pyrimidine--
5-carbonitrile
##STR00118##
[0416]
4-Amino-6-((5-fluoro-3-(pyridin-2-yl)quinolin-2-yl)methylamino)pyri-
midine-5-carbonitrile carbonitrile was synthesized from
2-((3-bromo-5-fluoroquinolin-2-yl)methyl)isoindoline-1,3-dione and
2-(tributylstannyl)pyridine via Methods B and D. .sup.1H NMR (500
MHz, DMSO-d.sub.6) .delta. 8.76 (ddd, J=4.9, 1.7, 0.7 Hz, 1H), 8.52
(d, J=0.7 Hz, 1H), 8.02 (td, J=7.8, 1.7 Hz, 1H), 7.95 (s, 1H),
7.90-7.79 (series of m, 4H), 7.50 (m, 2H), 4.97 (d, J=5.1 Hz, 2H).
Mass Spectrum (ESI) m/e=372.1 (M+1).
Example 37
2-(1-bromoethyl)-6-fluoro-4-methoxy-3-phenylquinoline
##STR00119##
[0418] A mixture of 4-chloro-2-ethyl-6-fluoro-3-phenylquinoline
(600 mg, 2.1 mmol) and NaOMe (125 mg, 500 mg 25% in MeOH, 1.1 eq)
in MeOH (5 mL) was stirred at rt under N.sub.2 for 30 min. No
product was observed by LCMS. The reaction mixture was heated to
50.degree. C. overnight. Trace amount of product was detected by
LCMS. The reaction mixture was concd and dissolved in DMF (2 mL)
and treated with 0.5 mL 25% NaOMe in MeOH at 80.degree. C. for 5 h.
After cooling to rt, the reaction mixture was neutralized with
acid, diluted with EtOAc washed with water, brine and the organic
layer concd and then purified by combiflash on 80 g column
(EtOAc/hexane, up to 20%) to give a white solid. Mass Spectrum
(ESI) m/e=282 (M+1). 2-Ethyl-6-fluoro-4-methoxy-3-phenylquinoline
(284 mg, 1.0 mmol) and 1,3-dibromo-5,5-dimethylhydantoin (202 mg,
0.7 eq) were suspended in carbon tetrachloride (15 mL). To the
mixture was added benzoyl peroxide (24.5 mg, 0.1 eq) and the
mixture was heated at reflux for 3 h. To the mixture was added satd
aq. sodium bicarbonate solution (3 mL). The layers were separated
and the aq. layer was extracted with DCM (30 mL.times.2). The
combined organic layers were washed with brine (30 mL), dried over
sodium sulfate, filtered, and concd under reduced pressure to give
an orange syrup. Mass Spectrum (ESI) m/e=360, 362 (M+1).
2-(1-(6-Fluoro-4-methoxy-3-phenylquinolin-2-yl)ethyl)isoindoline-1,3-dione
##STR00120##
[0420] A mixture of
2-(1-bromoethyl)-6-fluoro-4-methoxy-3-phenylquinoline (360 mg, 1.0
mmol) in DMF (5 mL) was treated with phthalimide potassium salt
(278 mg, 1.5 eq) overnight. The reaction mixture was heated to
60.degree. C. for 2 h. LCMS showed completion. The reaction mixture
was diluted with water (10 mL) and EtOAc (20 mL). The layers were
separated and the aq. layer was extracted with EtOAc (10
mL.times.2). The combined organic layers were washed with water (10
mL.times.2), brine (10 mL), dried over sodium sulfate, filtered,
and concd under reduced pressure to give a white solid. This
material was purified by combiflash (EtOAc/hexane, 1/4) to give a
white solid. M.S. (ESI) m/e=427 (M+1).
2-(1-(6-Fluoro-4-hydroxy-3-phenylquinolin-2-yl)ethyl)isoindoline-1,3-dione
##STR00121##
[0422] To a solution of
2-(1-(6-fluoro-4-hydroxy-3-phenylquinolin-2-yl)ethyl)isoindoline-1,3-dion-
e (58 mg, 0.14 mmol) in DCM (3 mL) was added BBr.sub.3 (1M, 0.7 mL,
5 eq) at 0.degree. C. The reaction mixture was allowed to warm to
rt overnight. The reaction mixture was partitioned between DCM (5
mL) and NaHCO.sub.3 satd solution (5 mL). The organic layer was
washed with water, brine, dried and concd to give a white solid,
which was used as such for the next step. Mass Spectrum (ESI)
m/e=413 (M+1).
4-Amino-6-(1-(6-fluoro-4-methoxy-3-phenylquinolin-2-yl)ethylamino)pyrimidi-
ne-5-carbonitrile
##STR00122##
[0424]
2-(1-(6-Fluoro-4-methoxy-3-phenylquinolin-2-yl)ethyl)isoindoline-1,-
3-dione (110 mg, 0.26 mmol) was suspended in EtOH (2 mL) and
treated with NH.sub.2NH.sub.2 (0.2 mL) at 60.degree. C. for 30 min.
After cooling to rt, the reaction mixture was partitioned between
EtOAc (10 mL) and water (5 mL). The organic layer was washed with
water, brine, dried and concd to give a yellow foam, which was
treated with 4-amino-6-chloropyrimidine-5-carbonitrile (40 mg, 1.0
eq) and Hunig's base (0.062 mL, 1.2 eq) in n-BuOH (3 mL) at
120.degree. C. overnight. The reaction mixture was cooled to rt and
purified by reverse phase HLPC (MeCN/H.sub.2O, 10%-50% containing
0.1% TFA) to give a white powder as TFA salt. .sup.1H-NMR (500 Hz,
DMSO-d.sup.6) .delta. 8.10 (dd, J=10.0, 5.0 Hz, 1H), 8.00 (s, 1H),
7.84 (dd, J=10.0, 5.0 Hz, 1H), 7.70-7.84 (m, 2H), 7.48-7.56 (m,
4H), 5.28-5.31 (m, 1H), 3.56 (s, 3H), 1.28 (d, J=10.0 Hz, 3H). Mass
Spectrum (ESI) m/e=415 (M+1). [0425] Chiral compounds are purified
using isopropanol/hexane gradient, AD column. [0426] The assignment
of chirality is based on the biochemical data. [0427] Rotamers of
amides are arbitrarily assigned.
Example 38
(S)-4-amino-6-(1-(6-fluoro-4-methoxy-3-phenylquinolin-2-yl)ethylamino)pyri-
midine-5-carbonitrile and
(R)-4-amino-6-(1-(6-fluoro-4-methoxy-3-phenylquinolin-2-yl)ethylamino)pyr-
imidine-5-carbonitrile
##STR00123##
[0429] Racemic
4-amino-6-(1-(6-fluoro-4-methoxy-3-phenylquinolin-2-yl)ethylamino)pyrimid-
ine-5-carbonitrile (60 mg) was purified by AD column
(isopropanol/hexane, up to 15% containing 0.1% Et.sub.2NH). First
fractions were combined and concd under reduced pressure and the
resulted solid was washed with water to give a white solid as
(S)-4-amino-6-(1-(6-fluoro-4-methoxy-3-phenylquinolin-2-yl)ethylamino)pyr-
imidine-5-carbonitrile (stereo center was assigned based on
biological activity compared with earlier compounds), .sup.1H-NMR
(400 Hz, CDCl.sub.3) .delta. 8.06 (dd, J=8.0, 4.0 Hz, 1H), 8.03 (s,
1H), 7.65 (dd, J=8.0, 4.0 Hz, 1H), 7.40-7.47 (m, 4H), 7.30-7.40 (m,
2H), 5.40-5.48 (m, 1H), 5.28 (s, 2H), 3.46 (s, 3H), 1.21 (d, J=8.0
Hz, 3H). Mass Spectrum (ESI) m/e=415 (M+1).
(R)-4-Amino-6-(1-(6-fluoro-4-methoxy-3-phenylquinolin-2-yl)ethylamino)pyr-
imidine-5-carbonitrile (16.8 mg). .sup.1H-NMR (400 Hz, CDCl.sub.3)
.delta. 8.06 (dd, J=8.0, 4.0 Hz, 1H), 8.03 (s, 1H), 7.65 (dd,
J=8.0, 4.0 Hz, 1H), 7.40-7.47 (m, 4H), 7.30-7.40 (m, 2H), 5.40-5.48
(m, 1H), 5.28 (s, 2H), 3.46 (s, 3H), 1.21 (d, J=8.0 Hz, 3H). Mass
Spectrum (ESI) m/e=415 (M+1).
Example 39
4-Amino-6-(1-(6-fluoro-4-hydroxy-3-phenylquinolin-2-yl)ethylamino)pyrimidi-
ne-5-carbonitrile
##STR00124##
[0431]
2-(1-(6-Fluoro-4-hydroxy-3-phenylquinolin-2-yl)ethyl)isoindoline-1,-
3-dione (crude, 60 mg, 0.145 mmol) was suspended in EtOH (2 mL) and
treated with hydrazine (0.2 mL) at 60.degree. C. for 30 min. After
cool to rt, the reaction mixture was partitioned between EtOAc (10
mL) and water (5 mL). The organic layer was washed with water,
brine, dried and concd to give a white solid, Mass Spectrum (ESI)
m/e=283 (M+1). This solid was treated with
4-amino-6-chloropyrimidine-5-carbonitrile (22.5 mg, 1.0 eq) and
Hunig's base (0.031 mL, 1.2 eq) in n-BuOH (1 mL) at 120.degree. C.
overnight. The reaction mixture was cooled to rt. and purified by
reverse phase HLPC (MeCN/H.sub.2O, 10%-50% containing 0.1% TFA) to
give a white powder as TFA salt. .sup.1H-NMR (400 Hz, CD.sub.3OD)
.delta. ppm 1.54 (3H, d) 5.24 (1H, q, J=7.17 Hz) 7.30 (1H, br. s.)
7.42 (1H, m) 7.50 (2H, t, J=7.53 Hz) 7.56 (2H, ddd, J=9.19, 8.02,
2.93 Hz) 7.82 (1H, dd, J=9.19, 4.50 Hz) 7.89 (1H, dd, J=9.19, 2.74
Hz) 8.09 (1H, s). Mass Spectrum (ESI) m/e=401 (M+1).
Example 40
2-(1-Bromoethyl)-4-chloro-6-fluoro-3-phenylquinoline
##STR00125##
[0433] To a solution of 4-chloro-2-ethyl-6-fluoro-3-phenylquinoline
(7 g, 24.50 mmol) and
1,3-dibromo-5,5-dimethylimidazolidine-2,4-dione (4.90 g, 17.15
mmol) in CCl.sub.4 (200 mL) was added benzoic peroxyanhydride
(0.593 g, 2.450 mmol) and the resulting mixture was heated to
refluxed for 2 h. The reaction was monitored using LCMS. The
reaction mixture was warmed to rt. To the mixture was added sat'd
NaHCO.sub.3 (200 mL). The layers were separated and the aq. layer
was extracted with DCM (3.times.) and the combined organic layers
was washed with brine and dried over sodium sulfate, filtered and
concd under reduced pressure to afford
2-(1-bromoethyl)-4-chloro-6-fluoro-3-phenylquinoline.
2-(1-(4-Chloro-6-fluoro-3-phenylquinolin-2-yl)ethyl)isoindoline-1,3-dione
##STR00126##
[0435] A mixture of
2-(1-bromoethyl)-4-chloro-6-fluoro-3-phenylquinoline (9.5 g, 26.1
mmol) and potassium 1,3-dioxoisoindolin-2-ide (7.24 g, 39.1 mmol)
in DMF was heated to 60.degree. C. for 2 h. EtOAc (200 mL) was
added and washed with water (200 mL), brine and dried over sodium
sulfate. The solvent was removed under reduced pressure. The crude
residue was subject to combiflash using EtOAc/hexane (0% to 20%,
Rf=0.4) to give
2-(1-(4-chloro-6-fluoro-3-phenylquinolin-2-yl)ethyl)isoindoline-1-
,3-dione as a yellowish solid.
2-(1-(1,3-Dioxoisoindolin-2-yl)ethyl)-6-fluoro-3-phenylquinoline-4-carboni-
trile
##STR00127##
[0437] A mixture of
2-(1-(4-chloro-6-fluoro-3-phenylquinolin-2-yl)ethyl)isoindoline-1,3-dione
(50 mg, 0.116 mmol), tributylstannanecarbonitrile (36.7 mg, 0.116
mmol), dicyclohexyl(2',4',6'-triisopropylbiphenyl-2-yl)phosphine
(33.2 mg, 0.070 mmol) and palladium(II) trifluoroacetate (11.57 mg,
0.035 mmol) in NMP (2 mL) and Cy.sub.2NMe (0.66 mL) was purged with
N.sub.2 and the resulting mixture was heated to 150.degree. C.
using a microwave for 2 h. The reaction only showed starting
materials. More Pd(TFA).sub.2 (up to 1 Eq) and
dicyclohexyl(2',4',6'-triisopropylbiphenyl-2-yl)phosphine was added
and heated to 150.degree. C. in the microwave for 1 h. At this time
EtOAc was added. The organic extract was washed with water and
dried over sodium sulfate. The solution was filtered and concd in
vacuo. The crude residue was purified via combiflash using
EtOAc/hexane (1:4) to obtain
2-(1-(1,3-dioxoisoindolin-2-yl)ethyl)-6-fluoro-3-phenylquinoline-4-carbon-
itrile as a light yellowish solid.
##STR00128##
[0438] To a solution of
2-(1-(1,3-dioxoisoindolin-2-yl)ethyl)-6-fluoro-3-phenylquinoline-4-carbon-
itrile (73.9 mg, 0.175 mmol) in EtOH (2 mL) was added hydrazine
(0.055 mL, 1.754 mmol) and the resulting mixture was heated to
60.degree. C. for 20 min. The reaction mixture was allowed to warm
to rt and solid was filtered. The filtrate was concd under reduced
pressure and used crude for the next step.
##STR00129##
[0439] To the crude
2-(1-aminoethyl)-6-fluoro-3-phenylquinoline-4-carbonitrile (51.1
mg, 0.175 mmol) in BuOH (1 mL) was added DIEA (0.037 mL, 0.210
mmol) and the resulting mixture was heated at 120.degree. C.
overnight. The reaction mixture was allowed to warm to rt and solid
was filtered and submitted for chiral separation. The filtrate was
subjected to HPLC purification.
2-(1-((6-Amino-5-cyano-4-pyrimidinyl)amino)ethyl)-6-fluoro-3-phenyl-4-quin-
olinecarbonitrile
[0440] .sup.1H-NMR (500 Hz, CD.sub.3OD) .delta. ppm 1.48 (3H, d)
5.67 (1H, q, J=6.77 Hz) 7.56 (1H, m) 7.61 (4H, m) 7.80 (1H, td,
J=8.80, 2.45 Hz) 7.86 (1H, dd, J=8.80, 2.69 Hz) 8.06 (1H, s) 8.32
(1H, dd, J=9.17, 5.26 Hz). Mass Spectrum (ESI) m/e=410 (M+1).
2-((1S)-1-((6-Amino-5-cyano-4-pyrimidinyl)amino)ethyl)-6-fluoro-3-phenyl-4-
-quinolinecarbonitrile
[0441] .sup.1H-NMR (400 Hz, CD.sub.3OD) .delta. ppm 1.41 (3H, d)
5.59 (1H, q, J=6.72 Hz) 7.53 (1H, m) 7.61 (4H, m) 7.80 (2H, m) 7.93
(1H, s) 8.30 (1H, dd, J=9.19, 5.28 Hz). Mass Spectrum (ESI) m/e=410
(M+1).
2-((1R)-1-((6-Amino-5-cyano-4-pyrimidinyl)amino)ethyl)-6-fluoro-3-phenyl-4-
-quinolinecarbonitrile
[0442] .sup.1H-NMR (400 Hz, CD.sub.3OD) .delta. ppm 1.41 (3H, d)
5.59 (1H, q, J=6.78 Hz) 7.53 (1H, m) 7.61 (4H, m) 7.80 (2H, m) 7.93
(1H, s) 8.30 (1H, dd, J=9.29, 5.18 Hz). Mass Spectrum (ESI) m/e=410
(M+1).
Example 41
##STR00130##
[0444] A solution of
2-(1-(4-chloro-6-fluoro-3-phenylquinolin-2-yl)ethyl)isoindoline-1,3-dione
(50 mg, 0.116 mmol), 2-methoxyethanamine (8.72 mg, 0.116 mmol),
dicyclohexyl(2',4',6'-triisopropylbiphenyl-2-yl)phosphine (11.06
mg, 0.023 mmol), sodium tert-butoxide (33.5 mg, 0.348 mmol) and
Pd.sub.2(dba).sub.3 (10.63 mg, 0.012 mmol) in toluene (1 mL) was
stirred at 100.degree. C. for 30 min. The reaction mixture was
allowed to warm to rt and partitioned between EtOAc and water. The
organic layer was washed with brine and dried over sodium sulfate
solvent was removed under reduced pressure. The crude residue was
purified via combiflash using EtOAc/hexane (30%) to obtain
2-(1-(6-fluoro-4-(2-methoxyethylamino)-3-phenylquinolin-2-yl)ethyl)isoind-
oline-1,3-dione as a yellow oil.
4-Amino-6-(1-(6-fluoro-4-((2-methoxyethyl)amino)-3-phenyl-2-quinolinyl)eth-
yl)amino)-5-pyrimidinecarbonitrile
##STR00131##
[0446] To a solution of
2-(1-(6-fluoro-4-(2-methoxyethylamino)-3-phenylquinolin-2-yl)ethyl)isoind-
oline-1,3-dione (73.9 mg, 0.157 mmol) in EtOH (2 mL) was added
hydrazine (0.049 mL, 1.574 mmol) and the resulting mixture was
heated to 60.degree. C. for 20 min. The reaction mixture was
allowed to warm to rt and solid was filtered. The filtrate was
concd under reduced pressure and used crude for the next step. To
the crude solution of
2-(1-aminoethyl)-6-fluoro-N-(2-methoxyethyl)-3-phenylquinolin-4-amine
(25 mg, 0.074 mmol) in BuOH (2 mL) was added DIEA (0.033 mL, 0.189
mmol) and 4-amino-6-chloropyrimidine-5-carbonitrile (24.33 mg,
0.157 mmol) and the resulting mixture was stirred at 110.degree. C.
overnight. The reaction mixture was cooled to rt and purified via
HPLC.
4-Amino-6-(1-(6-fluoro-4-((2-methoxyethyl)amino)-3-phenyl-2-quinolinyl)eth-
yl)amino)-5-pyrimidinecarbonitrile
[0447] .sup.1H-NMR (400 Hz, CD.sub.3OD) .delta. ppm 1.53 (3H, d,
J=7.24 Hz) 3.23 (2H, s) 3.33 (2H, m) 3.41 (2H, m) 4.99 (1H, m) 7.48
(1H, m) 7.64 (3H, m) 7.80 (2H, m) 8.03 (1H, s) 8.08 (1H, dd,
J=9.39, 4.89 Hz) 8.22 (1H, dd, J=10.47, 2.64 Hz). Mass Spectrum
(ESI) m/e=458 (M+1).
4-Amino-6-(((1S)-1-(6-fluoro-4-((2-methoxyethyl)amino)-3-phenyl-2-quinolin-
yl)ethyl)amino)-5-pyrimidinecarbonitrile
[0448] .sup.1H-NMR (400 Hz, CD.sub.3OD) .delta. ppm 1.30 (d, J=6.46
Hz, 3H) 3.18 (s, 3H) 3.19-3.22 (m, 2H) 3.28-3.31 (m, 2H) 5.25 (q,
J=6.65 Hz, 1H) 7.37-7.41 (m, 1H) 7.43-7.47 (m, 1H) 7.48-7.55 (m,
2H) 7.55-7.61 (m, 2H) 7.82 (dd, J=10.76, 2.74 Hz, 1H) 7.94 (s, 1H)
8.01 (dd, J=9.29, 5.58 Hz, 1H). Mass Spectrum (ESI) m/e=458
(M+1).
4-Amino-6-(((1R)-1-(6-fluoro-4-((2-methoxyethyl)amino)-3-phenyl-2-quinolin-
yl)ethyl)amino)-5-pyrimidinecarbonitrile
[0449] .sup.1H-NMR (400 Hz, CD.sub.3OD) .delta. ppm 1.30 (d, J=6.65
Hz, 3H) 3.18 (s, 3H) 3.19 (d, J=1.56 Hz, 0H) 3.21 (d, J=5.28 Hz,
1H) 3.29-3.31 (m, 2H) 5.26 (q, J=6.52 Hz, 1H) 7.37-7.41 (m, 1H)
7.43-7.47 (m, 1H) 7.48-7.54 (m, 2H) 7.55-7.61 (m, 2H) 7.91-7.99 (m,
1H) 8.01 (dd, J=9.19, 5.67 Hz, 1H). Mass Spectrum (ESI) m/e=458
(M+1).
Example 42
4-Amino-6-((1-(6-fluoro-4-((2-(methylsulfonyl)ethyl)amino)-3-phenyl-2-quin-
olinyl)ethyl)amino)-5-pyrimidinecarbonitrile
##STR00132##
[0451] To a solution of
2-(1-(4-chloro-6-fluoro-3-phenylquinolin-2-yl)ethyl)isoindoline-1,3-dione
(300 mg, 0.696 mmol) in EtOH (4 mL) was added hydrazine (0.219 mL,
6.96 mmol) and the resulting mixture was heated to 60.degree. C.
for 20 min. The reaction mixture was allowed to warm to rt and the
solid was filtered. The filtrate was concd under reduced pressure
and used crude for the next step. To a solution of
1-(4-chloro-6-fluoro-3-phenylquinolin-2-yl)ethanamine in DCM (4.00
mL) was added N-ethyl-N-isopropylpropan-2-amine (0.146 mL, 0.836
mmol) followed by the addition of di-tert-butyl dicarbonate (167
mg, 0.766 mmol) and the resulting mixture was stirred at rt for 2
h. The crude solution was washed with water, brine and dried over
MgSO.sub.4 and solvent was removed under reduced pressure to obtain
tert-butyl
1-(4-chloro-6-fluoro-3-phenylquinolin-2-yl)ethylcarbamate. A
solution of tert-butyl
1-(4-chloro-6-fluoro-3-phenylquinolin-2-yl)ethylcarbamate (50 mg,
0.125 mmol), 2-(methylsulfonyl)ethanamine (15.36 mg, 0.125 mmol),
dicyclohexyl(2',6'-dimethoxybiphenyl-2-yl)phosphine (10.24 mg,
0.025 mmol), pd.sub.2(dba).sub.3 (11.42 mg, 0.012 mmol) and sodium
2-methylpropan-2-olate (17.98 mg, 0.187 mmol) in toluene (1 mL) was
heated to 110.degree. C. overnight. The solvent was removed under
reduced pressure and purified via combiflash using EtOAc/hexane
(1:1). To the crude residue tert-butyl
1-(6-fluoro-4-(2-(methylsulfonyl)ethylamino)-3-phenylquinolin-2-yl)ethylc-
arbamate (18 mg, 0.037 mmol) was added HCl (0.1 mL, 0.400 mmol) and
the resulting mixture was stirred at rt. for 1 h. The reaction was
monitored by LCMS. The solvent was removed and used as crude for
the next step. To the crude solution of
2-(1-aminoethyl)-6-fluoro-N-(2-(methylsulfonyl)ethyl)-3-phenylquinolin-4--
amine in BuOH (1 mL) was added N-ethyl-N-isopropylpropan-2-amine
(0.019 mL, 0.111 mmol) and
4-amino-6-chloropyrimidine-5-carbonitrile (6.85 mg, 0.044 mmol) and
the resulting mixture was heated to 110.degree. C. for 3 h. The
solvent was removed and purified via HPLC.
4-Amino-6-((1-(6-fluoro-4-((2-(methylsulfonyl)ethyl)amino)-3-phenyl-2-quin-
olinyl)ethyl)amino)-5-pyrimidinecarbonitrile
[0452] .sup.1H-NMR (400 Hz, CD.sub.3OD) .delta. ppm 1.53 (3H, d,
J=7.04 Hz) 2.91 (3H, s) 3.30 (3H, s) 3.49 (2H, m) 4.97 (1H, m) 7.55
(1H, dd, J=4.40, 2.25 Hz) 7.63 (2H, m) 7.81 (2H, ddd, J=9.29, 7.63,
2.64 Hz) 7.88 (1H, m) 8.02 (1H, s) 8.09 (1H, dd, J=9.39, 4.89 Hz)
8.16 (1H, dd, J=10.17, 2.54 Hz). Mass Spectrum (ESI) m/e=506
(M+1).
4-Amino-6-(((1S)-1-(6-fluoro-4-((2-(methylsulfonyl)ethyl)amino)-3-phenyl-2-
-quinolinyl)ethyl)amino)-5-pyrimidinecarbonitrile
[0453] .sup.1H-NMR (400 Hz, CD.sub.3OD) .delta. ppm 1.55 (d, 3H)
2.92 (s, 3H) 3.28-3.32 (m, 2H) 3.44-3.55 (m, 2H) 5.00 (q, J=7.04
Hz, 1H) 7.57 (dt, J=4.50, 2.25 Hz, 1H) 7.62-7.70 (m, 3H) 7.82 (ddd,
J=9.39, 7.63, 2.74 Hz, 1H) 7.90 (dd, J=6.94, 1.66 Hz, 1H) 8.04 (s,
1H) 8.11 (dd, J=9.39, 4.89 Hz, 1H) 8.17 (dd, J=10.17, 2.54 Hz, 1
H). Mass Spectrum (ESI) m/e=506 (M+1).
Example 43
4-Amino-6-((1-(6-fluoro-4-((2-hydroxyethyl)amino)-3-phenyl-2-quinolinyl)et-
hyl)amino)-5-pyrimidinecarbonitrile
##STR00133##
[0455] A solution of tert-butyl
1-(4-chloro-6-fluoro-3-phenylquinolin-2-yl)ethylcarbamate (100 mg,
0.249 mmol), 2-aminoethanol (15.24 mg, 0.249 mmol),
dicyclohexyl(2',6'-dimethoxybiphenyl-2-yl)phosphine (20.48 mg,
0.050 mmol), sodium 2-methylpropan-2-olate (36.0 mg, 0.374 mmol)
and pd.sub.2(dba).sub.3 (22.84 mg, 0.025 mmol) in toluene (2 mL)
was heated to 110.degree. C. for 1 h. The solvent was removed under
reduced pressure. EtOAc was added and washed with water, brine and
dried over sodium sulfate and the solvent was removed under reduced
pressure. The crude residue was purified using EtOAc/hexane (1:1).
To the crude residue of tert-butyl
1-(6-fluoro-4-(2-hydroxyethylamino)-3-phenylquinolin-2-yl)ethylcarbamate
(17 mg, 0.040 mmol) was added HCl (0.1 mL, 0.400 mmol) and the
resulting mixture was stirred at rt for 1 h. The reaction was
monitored by LCMS. The solvent was removed and used crude for the
next step. To the crude solution of
2-(2-(1-aminoethyl)-6-fluoro-3-phenylquinolin-4-ylamino)ethanol in
BuOH (1 mL) was added N-ethyl-N-isopropylpropan-2-amine (0.021 mL,
0.120 mmol) and 4-amino-6-chloropyrimidine-5-carbonitrile (7.41 mg,
0.048 mmol) and the resulting mixture was heated to 110.degree. C.
for 3 h. The solvent was removed and purified via combiflask using
EtOAc/hexane (1:1) with satd ammonia.
4-Amino-6-((1-(6-fluoro-4-((2-hydroxyethyl)amino)-3-phenyl-2-quinolinyl)et-
hyl)amino)-5-pyrimidinecarbonitrile
[0456] .sup.1H-NMR (400 Hz, CD.sub.3OD) .delta. ppm 1.31 (3H, d,
J=6.65 Hz) 3.08 (2H, m) 3.49 (2H, td, J=5.48, 2.15 Hz) 5.26 (1H, q,
J=6.59 Hz) 7.41 (1H, m) 7.53 (5H, m) 7.88 (1H, dd, J=10.76, 2.74
Hz) 7.95 (1H, m) 8.01 (1H, dd, J=9.29, 5.58 Hz). Mass Spectrum
(ESI) m/e=444 (M+1).
4-Amino-6-((1-(4-((2-(dimethylamino)ethyl)amino)-6-fluoro-3-phenyl-2-quino-
linyl)ethyl)amino)-5-pyrimidinecarbonitrile
[0457] This synthesis is performed as described above.
##STR00134##
[0458] .sup.1H-NMR (400 Hz, CD.sub.3OD) .delta. ppm 5.24 (3H, d)
6.02 (6H, s) 6.27 (2H, m) 7.01 (2H, td, J=6.46, 1.17 Hz) 9.20 (1H,
q, J=6.52 Hz) 11.35 (1H, m) 11.46 (5H, m) 11.78 (1H, dd, J=10.76,
2.54 Hz) 11.88 (1H, s) 11.94 (1H, dd, J=9.29, 5.58 Hz). Mass
Spectrum (ESI) m/e=471 (M+1).
Example 44
N-(1-(6-Fluoro-4-(methylsulfonyl)-3-phenylquinolin-2-yl)ethyl)-9H-purin-6--
amine,
(S)-N-(1-(6-fluoro-4-(methylsulfonyl)-3-phenylquinolin-2-yl)ethyl)--
9H-purin-6-amine,
(R)--N-(1-(6-fluoro-4-(methylsulfonyl)-3-phenylquinolin-2-yl)ethyl)-9H-pu-
rin-6-amine
##STR00135##
[0460] A mixture of
1-(6-fluoro-4-(methylsulfonyl)-3-phenylquinolin-2-yl)ethanamine (90
mg, 0.26 mmol), 6-chloropurine (40.4 mg, 1.0 eq) and Hunig's base
(55 .mu.L, 1.2 eq) in n-BuOH (2 mL) was heated to 130.degree. C.
overnight. The mixture was cooled to rt, and purified by reverse
phase HPLC (MeCN/H.sub.2O, 10%-50% containing 0.1% TFA) to give a
white powder as TFA salt of
N-(1-(6-fluoro-4-(methylsulfonyl)-3-phenylquinolin-2-yl)ethyl)-9H-purin-6-
-amine. .sup.1H-NMR (400 Hz, CD.sub.3OD) .delta. 8.73 (dd, J=8.0,
4.0 Hz, 1H), 8.23 (dd, J=8.0, 4.0 Hz, 1H), 8.14 (s, 1H), 8.08-8.14
(m, 1H), 7.73 (td, J=8.0, 4.0 Hz, 1H), 7.42-7.52 (m, 5H), 5.46 (m,
1H), 3.11 (s, 3H), 1.49 (d, J=8.0 Hz, 3H). Mass Spectrum (ESI)
m/e=463 (M+1).
[0461]
N-(1-(6-fluoro-4-(methylsulfonyl)-3-phenylquinolin-2-yl)ethyl)-9H-p-
urin-6-amine was purified by chiral OD column (isopropanol/hexane,
up to 15%). First fractions were combined and concd under reduced
pressure to give a white solid as
(S)-N-(1-(6-fluoro-4-(methylsulfonyl)-3-phenylquinolin-2-yl)ethyl)-9H-pur-
in-6-amine (20 mg, stereo center was assigned based on biological
activity compared with earlier compounds), .sup.1H-NMR (400 Hz,
CD.sub.3OD) .delta. 8.73 (dd, J=8.0, 4.0 Hz, 1H), 8.23 (dd, J=8.0,
4.0 Hz, 1H), 8.14 (s, 1H), 8.08-8.14 (m, 1H), 7.73 (td, J=8.0, 4.0
Hz, 1H), 7.42-7.52 (m, 5H), 5.46 (m, 1H), 3.11 (s, 3H), 1.49 (d,
J=8.0 Hz, 3H). Mass Spectrum (ESI) m/e=463 (M+1).
(R)-N-(1-(6-fluoro-4-(methylsulfonyl)-3-phenylquinolin-2-yl)ethyl)-9H-pur-
in-6-amine. .sup.1H-NMR (400 Hz, CD.sub.3OD) .delta. 8.73 (dd,
J=8.0, 4.0 Hz, 1H), 8.23 (dd, J=8.0, 4.0 Hz, 1H), 8.14 (s, 1H),
8.08-8.14 (m, 1H), 7.73 (td, J=8.0, 4.0 Hz, 1H), 7.42-7.52 (m, 5H),
5.46 (m, 1H), 3.11 (s, 3H), 1.49 (d, J=8.0 Hz, 3H). Mass Spectrum
(ESI) m/e=463 (M+1).
Example 45
2,4-Dichloro-5-fluoro-3-phenylquinoline
##STR00136##
[0463] A mixture of 3-fluoroaniline (3.33 g, 30 mmol) and
2-phenylmalonic acid (7.89 g, 1.46 eq) was treated with POCl.sub.3
with caution. The resulted suspension was heated to 95.degree. C.
and stirred overnight before increasing the temperature to
145.degree. C. for 1 h. After cooling to rt, the reaction mixture
was poured into ice and stirred for 10 min. The mixture was
extracted with EtOAc (100 mL.times.2), washed, dried, concd and
purified by combiflash (DCM/hexane, 0/1 to 2/3) to give 1st
component undesired region-isomer as a yellow solid and 2nd
fraction 2,4-dichloro-5-fluoro-3-phenylquinoline as a white solid.
.sup.1H-NMR (400 Hz, CDCl.sub.3) .delta. 7.92 (d, J=8.0 Hz, 1H),
7.71-7.76 (m, 1H), 7.51-7.57 (m, 3H), 7.32-7.37 (m, 3H).
N-(1-(5-Fluoro-4-(methylsulfonyl)-3-phenylquinolin-2-yl)ethyl)-9H-purin-6--
amine
##STR00137##
[0465]
1-(5-Fluoro-4-(methylsulfonyl)-3-phenylquinolin-2-yl)ethanamine was
synthesized from 2,4-dichloro-5-fluoro-3-phenylquinoline according
to the procedure for
1-(6-fluoro-4-(methylsulfonyl)-3-phenylquinolin-2-yl)ethanamine. A
mixture of
1-(5-fluoro-4-(methylsulfonyl)-3-phenylquinolin-2-yl)ethanamine (60
mg, 0.17 mmol), 6-chloropurine (27 mg, 1.0 eq) and Hunig's base (55
.mu.L, 1.2 eq) in n-BuOH (2 mL) was heated to 130.degree. C.
overnight. The mixture was cooled to rt, concd, dissolved in DCM (2
mL) and purified by combiflash (DCM/MeOH, 20/1) to give a pale
yellow solid. .sup.1H-NMR (400 Hz, CD.sub.3OD) .delta. 8.40-8.45
(m, 2H), 8.10 (d, J=8.0 Hz, 1H), 7.85-7.95 (m, 1H), 7.65 (d, J=8.0
Hz, 1H), 7.42-7.55 (m, 5H), 5.75-85 (m, 1H), 3.32 (s, 3H), 1.50 (d,
J=8.0 Hz, 3H). Mass Spectrum (ESI) m/e=463 (M+1).
Example 46
(S)-4-Amino-6-(1-(5-fluoro-4-(methylsulfonyl)-3-phenylquinolin-2-yl)ethyla-
mino)pyrimidine-5-carbonitrile
##STR00138##
[0467] A mixture of
1-(5-fluoro-4-(methylsulfonyl)-3-phenylquinolin-2-yl)ethanamine (70
mg, 0.20 mmol), 4-amino-6-chloropyrimidine-5-carbonitrile (31.4 mg,
1.0 eq) and Hunig's base (42.6 .mu.L, 1.2 eq) in n-BuOH (2 mL) was
heated to 130.degree. C. overnight. The mixture was cooled to rt,
filtered and washed with cold EtOH to give a white solid as
4-amino-6-(1-(5-fluoro-4-(methylsulfonyl)-3-phenylquinolin-2-yl)ethylamin-
o)pyrimidine-5-carbonitrile. This material was purified by chiral
OD column (isopropanol/hexane, up to 15%). First fractions were
combined and concd under reduced pressure to give a white solid as
(S)-4-amino-6-(1-(5-fluoro-4-(methylsulfonyl)-3-phenylquinolin-2-yl)ethyl-
amino)pyrimidine-5-carbonitrile (stereo center was assigned based
on biological activity compared with earlier compounds),
.sup.1H-NMR (400 Hz, DMSO-d.sup.6) .delta. 7.92-8.03 (m, 2H),
7.40-7.60 (m, 5H), 7.20-7.30 (m, 1H), 5.30-5.40 (m, 1H), 3.29 (s,
3H), 1.24 (d, J=8.0 Hz, 3H). Mass Spectrum (ESI) m/e=463 (M+1).
Example 47
2-(1-(6-Fluoro-4-(2-hydroxyethylsulfinyl)-3-phenylquinolin-2-yl)ethyl)isoi-
ndoline-1,3-dione
##STR00139##
[0469] A mixture of 4-chloro-2-ethyl-6-fluoro-3-phenylquinoline
(400 mg, 1.4 mmol), Hunig's base (293 .mu.L, 1.2 eq) and
HSCH.sub.2CH.sub.2OH (108 .mu.L, 1.1 eq) in DMF (4 mL) was heated
to 65.degree. C. under N.sub.2 for 2 h. LCMS showed no formation of
product. The reaction mixture was then heated to 100.degree. C.
overnight. LCMS showed 60% product and 40% starting material. To
the reaction mixture was added 50 .mu.L thiol and heated to
100.degree. C. The reaction mixture was diluted with water (10 mL)
and EtOAc (20 mL). The layers were separated and the aq. layer was
extracted with EtOAc (10 mL.times.2). The combined organic layers
were washed with water (10 mL.times.2), brine (10 mL), dried over
sodium sulfate, filtered, and concd under reduced pressure. The
residue was purified by combiflashon silica gel (EtOAc/hexane, 1/8)
to give a white solid as
2-(2-ethyl-6-fluoro-3-phenylquinolin-4-ylthio)ethanol. Mass
Spectrum (ESI) m/e=328 (M+1).
2-(2-ethyl-6-fluoro-3-phenylquinolin-4-ylthio)ethanol (200 mg, 0.61
mmol), imidazole (45.7 mg, 1.1 eq) and TBS-Cl (110 mg, 1.2 eq) in
DMF (3 mL) was stirred at rt overnight, 50% starting material
remained. The reaction mixture was then treated with imidazole
(45.7 mg, 1.1 eq) and TBS-Cl (110 mg, 1.2 eq). After 2 h, the
reaction was complete. The reaction mixture was diluted with water
(10 mL) and EtOAc (20 mL). The layers were separated and the aq.
layer was extracted with EtOAc (10 mL.times.2). The combined
organic layers were washed with water (10 mL.times.2), brine (10
mL), dried over sodium sulfate, filtered, and concd under reduced
pressure. Purification on combiflash gave a colorless oil as
4-(2-(tert-butyldimethylsilyloxy)ethylthio)-2-ethyl-6-fluoro-3-phe-
nylquinoline. Mass Spectrum (ESI) m/e=442 (M+1).
4-(2-(tert-Butyldimethylsilyloxy)ethylthio)-2-ethyl-6-fluoro-3-phenylquin-
oline (262 mg, 0.59 mmol) and 1,3-dibromo-5,5-dimethylhydantoin
(119 mg, 0.7 eq) were suspended in carbon tetrachloride (10 mL). To
the mixture was added benzoyl peroxide (14.4 mg, 0.1 eq) and heated
at reflux for 3 h. After cooling to rt, to the mixture was added
satd aq. sodium bicarbonate solution (3 mL). The layers were
separated and the aq. layer was extracted with DCM (3 mL.times.2).
The combined organic layers were washed with water (3 mL), brine (3
mL), dried over sodium sulfate, filtered, and concd under reduced
pressure to give an orange syrup as
2-(1-bromoethyl)-4-(2-(tert-butyldimethylsilyloxy)ethylthio)-6-fluoro-3-p-
henylquinoline. Mass Spectrum (ESI) m/e=520, 522 (M+1). A mixture
of
2-(1-bromoethyl)-4-(2-(tert-butyldimethylsilyloxy)ethylthio)-6-fluoro-3-p-
henylquinoline (300 mg, 0.58 mmol) in DMF (3 mL) was treated with
phthalimide potassium salt (213 mg, 2.0 eq) at 60.degree. C. for 2
h. LCMS showed completion. The reaction mixture was partitioned
between water and EtOAc, the layers were separated and the aq.
layer was extracted with EtOAc (10 mL.times.2). The combined
organic layers were washed with water (10 mL.times.2), brine (10
mL), dried over sodium sulfate, filtered, and concd under reduced
pressure. The residue was purified by combiflash on silica gel
(DCM/hexane, 0/1 to 1/1) to give a white foam as
2-(1-(4-(2-(tert-butyldimethylsilyloxy)ethylthio)-6-fluoro-3-phenylquinol-
in-2-yl)ethyl)isoindoline-1,3-dione. To a solution of
2-(1-(4-(2-(tert-butyldimethylsilyloxy)ethylthio)-6-fluoro-3-phenylquinol-
in-2-yl)ethyl)isoindoline-1,3-dione (80 mg, 0.14 mmol) in THF (6
mL) and H.sub.2O (2 mL) was added oxone (335 mg, 0.55 mmol, 4.0 eq)
at rt. The resulted suspension was stirred overnight. More oxone
(335 mg, 0.55 mmol, 4.0 eq) was added and the reaction mixture was
stirred at rt overnight again. The reaction mixture was extracted
with EtOAc (10 mL.times.2). The combined organic layers were washed
with brine (10 mL.times.2), dried over sodium sulfate, filtered,
and concd under reduced pressure to give a yellow foam as
2-(1-(6-fluoro-4-(2-hydroxyethylsulfinyl)-3-phenylquinolin-2-yl)ethyl)iso-
indoline-1,3-dione. Mass Spectrum (ESI) m/e=489 (M+1).
4-Amino-6-(1-(6-fluoro-4-((R)-2-hydroxyethylsulfinyl)-3-phenylquinolin-2-y-
l)ethylamino)pyrimidine-5-carbonitrile and
4-amino-6-(1-(6-fluoro-4-((S)-2-hydroxyethylsulfinyl)-3-phenylquinolin-2--
yl)ethylamino)pyrimidine-5-carbonitrile
##STR00140##
[0471]
2-(1-(6-fluoro-4-(2-hydroxyethylsulfinyl)-3-phenylquinolin-2-yl)eth-
yl)isoindoline-1,3-dione was dissolved in EtOH (5 mL) and treated
with hydrazine (0.5 mL) at 60.degree. C. for 30 min. After cooling
to rt, the reaction mixture was extracted with EtOAc (10
mL.times.2). The combined organic layers were washed with water,
brine (10 mL.times.2), dried over sodium sulfate, filtered, and
concd under reduced pressure to give a pale yellow oil as
2-(2-(1-aminoethyl)-6-fluoro-3-phenylquinolin-4-ylsulfinyl)ethanol.
Mass Spectrum (ESI) m/e=359 (M+1). To this oil was added
4-amino-6-chloropyrimidine-5-carbonitrile (15.8 mg, 1.0 eq),
Hunig's base (1.2 eq) n-BuOH (1 mL) and the mixture was heated to
125.degree. C. for 4 h. After cooling to rt, the mixture was
purified by reverse HPLC (MeCN/H.sub.2O, 10-50% containing 1% TFA)
to give a white powders as
4-amino-6-(1-(6-fluoro-4-((R)-2-hydroxyethylsulfinyl)-3-phenylquinolin-2--
yl)ethylamino)pyrimidine-5-carbonitrile. .sup.1H-NMR (500 Hz,
DMSO-d.sup.6) .delta. 8.93 (dd, J=10.0, 5.0 Hz, 1H), 8.23 (dd,
J=10.0, 5.0 Hz, 1H), 7.92 (s, 1H), 7.84 (td, J=10.0, 5.0 Hz, 1H),
7.46-7.53 (m, 5H), 7.37-7.39 (m, 1H), 7.27 (s, br, 1H), 5.10-5.18
(m, 1H), 4.96 (t, J=5.0 Hz, 1H), 3.75-3.84 (m, 2H), 3.17-3.21 (m,
1H), 1.32 (d, J=10.0 Hz, 3H). Mass Spectrum (ESI) m/e=477 (M+1).
4-Amino-6-(1-(6-fluoro-4-((S)-2-hydroxyethylsulfinyl)-3-phenylquinolin-2--
yl)ethylamino)pyrimidine-5-carbonitrile. .sup.1H-NMR (500 Hz,
DMSO-d.sup.6) .delta. 8.97 (dd, J=10.0, 5.0 Hz, 1H), 8.31 (dd,
J=10.0, 5.0 Hz, 1H), 8.05 (s, 1H), 7.75 (td, J=10.0, 5.0 Hz, 1H),
7.59-7.63 (m, 1H), 7.51-7.54 (m, 3H), 7.37-7.39 (m, 1H), 5.46 (q,
J=10.0 Hz, 1H), 4.96 (t, J=5.0 Hz, 1H), 3.97-4.01 (m, 1H),
3.86-3.89 (m, 1H), 3.65-3.70 (m, 1H), 3.17-3.19 (m, 1H), 1.46 (d,
J=10.0 Hz, 3H). Mass Spectrum (ESI) m/e=477 (M+1).
Example 48
2-(1-(3-Bromo-6-fluoro-4-(methylthio)quinolin-2-yl)ethyl)isoindoline-1,3-d-
ione
##STR00141##
[0473] A solution of 4-fluoroaniline (11.11 g, 100 mmol), methyl
propionylacetate (13.01 g, 100 mmol) and p-toluenesulfonic acid
(0.25 g, 0.013 eq) in cyclohexane (35 mL) was heated at 95.degree.
C. in connection with a Dean-Stark water separator overnight.
Filtration followed with removal of solvent gave a red oil. To a
flask fitted with distillation head and dropping funnel was added
Dowtherm.TM. A (35 mL) and heated to 240.degree. C., internal
temperature 220.degree. C. The red oil was added dropwise in 10 min
while keeping the temperature above 210.degree. C. internally.
After addition, the mixture was stirred at 240.degree. C. for 15
min before cooling to rt. The resulted solid was filtered off and
washed with a mixture of hexane and EtOAc (9/1). The solid formed
in the filtrate was filtered again and washed with mixed solvents.
A yellow solid was obtained as 2-ethyl-6-fluoroquinolin-4(1H)-one.
.sup.1H-NMR (500 Hz, CDCl.sub.3) .delta. 9.7 (s, br, 1H), 7.91 (dd,
J=10.0, 5.0 Hz, 1H), 7.39 (dd, J=10.0, 5.0 Hz, 1H), 7.26 (td,
J=10.0, 5.0 Hz, 1H), 6.11 (s, 1H), 2.62 (q, J=10.0 Hz, 2H), 1.27
(t, J=10.0 Hz, 3H). A stirred solution of
2-ethyl-6-fluoroquinolin-4(1H)-one (2.6 g, 13.6 mmol) in AcOH (68
mL) was treated with pyridium tribromide (8.7 g, 2.0 eq) at rt.
After stirring overnight, the reaction mixture was quenched with
Na.sub.2S.sub.2O.sub.3 solution. The resulted solid was washed with
water, cold EtOH and dried in the air to give a white solid as
3-bromo-2-ethyl-6-fluoroquinolin-4(1H)-one. .sup.1H-NMR (500 Hz,
DMSO-d.sup.6) .delta. 12.23 (s, 1H), 7.75 (dd, J=10.0, 5.0 Hz, 1H),
7.68 (dd, J=10.0, 5.0 Hz, 1H), 7.61 (td, J=10.0, 5.0 Hz, 1H), 2.90
(q, J=10.0 Hz, 2H), 1.29 (t, J=10.0 Hz, 3H). A suspension of
3-bromo-2-ethyl-6-fluoroquinolin-4(1H)-one (1.54 g, 5.7 mmol) in
POCl.sub.3 (5 mL) was heated to 100.degree. C. for 2 h. After
cooling to rt, the reaction mixture was poured into ice, the
resulted semi-solid was neutralized with NaHCO.sub.3 satd solution
and extracted with EtOAc (20 mL). The organic layer was separated,
washed with NaHCO.sub.3, water, brine, dried, concd and purified by
combiflash (EtOAc/hexane, 1/9) to give a white solid as
3-bromo-4-chloro-2-ethyl-6-fluoroquinoline.
2-(1-(3-Bromo-6-fluoro-4-(methylthio)quinolin-2-yl)ethyl)isoindoline-1,3--
dione was made by 3 steps in the similar manner as previous
described for preparation of
2-(1-(6-fluoro-4-(methylthio)-3-phenylquinolin-2-yl)ethyl)isoindoline-1,3-
-dione. Mass Spectrum (ESI) m/e=446 (M+1).
2-(1-(3-(3,5-Difluorophenyl)-6-fluoro-4-(methylsulfonyl)quinolin-2-yl)ethy-
l)isoindoline-1,3-dione
##STR00142##
[0475] A mixture of
2-(1-(3-bromo-6-fluoro-4-(methylthio)quinolin-2-yl)ethyl)isoindoline-1,3--
dione (100 mg, 0.23 mmol), 3,5-difluorophenylboronic acid (71 mg,
2.0 eq), K.sub.2CO.sub.3 (93 mg, 3.0 eq) and
tetrakis(triphenylphosphine)palladium(0) (26 mg, 0.05 eq) in DME (5
mL) was purged with N.sub.2 and heated to reflux. After stirring
overnight, the reaction mixture was cooled to rt, partitioned
between water and EtOAc, and the layers were separated. The aq.
layer was extracted with EtOAc (10 mL.times.2). The combined
organic layers were washed with water (10 mL.times.2), brine (10
mL), dried over sodium sulfate, filtered, and concd under reduced
pressure. The residue was purified by combiflash on silica gel
(EtOAc/hexane, 1/4) to give
2-(1-(3-(3,5-difluorophenyl)-6-fluoro-4-(methylthio)quinolin-2-yl)ethyl)i-
soindoline-1,3-dione as a white solid. Mass Spectrum (ESI) m/e=479
(M+1). To a solution of
2-(1-(3-(3,5-difluorophenyl)-6-fluoro-4-(methylthio)quinolin-2-yl)ethyl)i-
soindoline-1,3-dione (42 mg, 0.088 mmol) in THF (3 mL) and H.sub.2O
(1 mL) was added oxone (108 mg, 0.18 mmol, 2.0 eq) at rt. The
resulted suspension was stirred at rt overnight. The reaction was
incomplete. Oxone (108 mg, 2.0 eq) was added and the reaction
mixture was stirred at rt overnight again. This procedure was
repeated for twice and LCMS showed completion. The reaction mixture
was extracted with EtOAc (10 mL.times.2). The combined organic
layers were washed with water, NaHCO.sub.3, brine (10 mL.times.2),
dried over sodium sulfate, filtered, and concd under reduced
pressure to give a white solid. Mass Spectrum (ESI) m/e=511
(M+1).
4-Amino-6-(1-(3-(3,5-difluorophenyl)-6-fluoro-4-(methylsulfonyl)quinolin-2-
-yl)ethylamino)pyrimidine-5-carbonitrile
##STR00143##
[0477]
2-(1-(3-(3,5-Difluorophenyl)-6-fluoro-4-(methylsulfonyl)quinolin-2--
yl)ethyl)isoindoline-1,3-dione was suspended in EtOH (1 mL) and
treated with 0.1 mL hydrazine at 70.degree. C. for 30 min. After
cooling to rt, the reaction mixture was extracted with EtOAc (5
mL.times.2). The combined organic layers were washed with water,
brine (3 mL.times.2), dried over sodium sulfate, filtered, and
concd under reduced pressure to give a white solid.
1-(3-(3,5-difluorophenyl)-6-fluoro-4-(methylsulfonyl)quinolin-2-yl)ethana-
mine (30 mg, 0.079 mmol), 4-amino-6-chloropyrimidine-5-carbonitrile
(12.2 mg, 1.0 eq) and Hunig's base (16.5 .mu.L, 1.2 eq) in n-BuOH
(1 mL) was heated to 130.degree. C. overnight. The mixture was
cooled to rt and purified by reverse HPLC gave a white powder as
TFA salt (25 mg, 63%). .sup.1H-NMR (500 Hz, CD.sub.3OD) .delta.
8.66 (dd, J=10.0, 5.0 Hz, 1H), 8.34 (dd, J=10.0, 5.0 Hz, 1H), 8.08
(s, 1H), 7.81 (td, J=10.0, 5.0 Hz, 1H), 7.12-7.18 (m, 2H),
7.05-7.10 (m, 1H), 5.40 (q, J=10.0 Hz, 1H), 3.27 (s, 3H), 1.52 (d,
J=10.0 Hz, 3H). Mass Spectrum (ESI) m/e=499 (M+1).
Example 49
(S)-2-(1-(3-(3,5-Difluorophenyl)-6-fluoro-4-methoxyquinolin-2-yl)ethyl)iso-
indoline-1,3-dione
##STR00144##
[0479]
2-(1-(3-(3,5-Difluorophenyl)-6-fluoro-4-methoxyquinolin-2-yl)ethyl)-
isoindoline-1,3-dione was synthesized from
3-bromo-4-chloro-2-ethyl-6-fluoroquinoline in a similar manner as
described in the preparation of the corresponding sulfur analog
2-(1-(3-(3,5-difluorophenyl)-6-fluoro-4-(methylthio)quinolin-2-yl)ethyl)i-
soindoline-1,3-dione. Mass Spectrum (ESI) m/e=463 (M+1).
(S)-2-(1-(3-(3,5-difluorophenyl)-6-fluoro-4-methoxyquinolin-2-yl)ethyl)is-
oindoline-1,3-dione was obtained by chiral separation on OD column
(i-PrOH/hexane, up to 15%).
(S)-4-Amino-6-(1-(3-(3,5-difluorophenyl)-6-fluoro-4-methoxyquinolin-2-yl)e-
thylamino)pyrimidine-5-carbonitrile
##STR00145##
[0481] A solution of
(S)-2-(1-(3-(3,5-difluorophenyl)-6-fluoro-4-methoxyquinolin-2-yl)ethyl)is-
oindoline-1,3-dione (45 mg, 0.1 mmol) in EtOH (2 mL) was treated
with hydrazine (0.1 mL) at 70.degree. C. for 30 min. After cooling
to rt, the reaction mixture was partitioned between water (5 mL)
and EtOAc (5 mL). The organic layer was separated, washed with
water, brine, dried and concd to give a white solid, which was
dissolve in n-BuOH (1 mL) and treated with Hunig's base (0.021 mL,
1.2 eq) and 4-amino-6-chloropyrimidine-5-carbonitrile (17 mg, 1.1
eq). The reaction mixture was heated to 120.degree. C. overnight.
After cooling to rt, the reaction mixture was purified by reverse
HPLC (MeCN/H.sub.2O/0.1% TFA, 10-60%) to give a white powder.
.sup.1H-NMR (400 Hz, DMSO-d.sup.6) .delta. 8.11 (dd, J=8.0, 4.0 Hz,
1H), 7.98 (s, 1H), 7.84 (dd, J=8.0, 4.0 Hz, 1H), 7.65-7.79 (m, 2H),
7.46 (s, br, 1H), 7.22-7.34 (m, 3H), 5.29-5.33 (m, 1H), 3.64 (s,
3H), 1.36 (t, J=8.0 Hz, 3H). Mass Spectrum (ESI) m/e=451 (M+1).
Example 50
##STR00146##
[0483] A solution of
2-(1-(3-bromo-6-fluoro-4-methoxyquinolin-2-yl)ethyl)isoindoline-1,3-dione
(10 mg, 0.023 mmol), obtained in a similar why as described for
2-(1-(3-bromo-6-fluoro-4-(methylthio)quinolin-2-yl)ethyl)isoindoline-1,3--
dione, and pyridin-3-ylboronic acid (5.73 mg, 0.047 mmol),
K.sub.2CO.sub.3 (9.66 mg, 0.070 mmol) in DME (2 mL) was purged with
N.sub.2 followed by the addition of Pd(Ph.sub.3P).sub.4 (2.69 mg,
2.330 .mu.mol). The resulting mixture was heated to 100.degree. C.
overnight. The reaction mixture was allowed to cool to rt. The
product isolated as previously described for similar analogs.
2-(1-(6-fluoro-4-methoxy-3-(pyridin-3-yl)quinolin-2-yl)ethyl)isoindoline--
1,3-dione.
4-Amino-6-(((1R)-1-(6-fluoro-4-methoxy-3-(3-pyridinyl)-2-quinolinyl)ethyl)-
amino)-5-pyrimidinecarbonitrile
##STR00147##
[0485] A solution of
(R)-2-(1-(6-fluoro-4-methoxy-3-(pyridin-3-yl)quinolin-2-yl)ethyl)isoindol-
ine-1,3-dione (19.7 mg, 0.046 mmol) and hydrazine (1.447 .mu.L,
0.046 mmol) in EtOH (1 mL) was heated to 60.degree. C. for 30 min.
The solvent was removed and EtOAc was added and washed with water,
brine and dried over sodium sulfate to obtain
(R)-1-(6-fluoro-4-methoxy-3-(pyridin-3-yl)quinolin-2-yl)ethanamine
as clear oil. To solution of
(R)-1-(6-fluoro-4-methoxy-3-(pyridin-3-yl)quinolin-2-yl)ethanamine
(13.9 mg, 0.047 mmol) in BuOH (1.000 mL) was added
4-amino-6-chloropyrimidine-5-carbonitrile (7.12 mg, 0.046 mmol) and
DIEA (8.05 .mu.L, 0.046 mmol). The resulting mixture was heated to
100.degree. C. The solvent was removed and crude residue was
subjected to preparatory. TLC using 3% MeOH (with 7N Ammonia)/DCM
to obtain
(R)-4-amino-6-(1-(6-fluoro-4-methoxy-3-(pyridin-3-yl)quinolin-2-yl)ethyla-
mino)pyrimidine-5-carbonitrile as a light yellowish solid.
Example 51
4-Amino-6-(((1R)-1-(6-fluoro-4-methoxy-3-(3-pyridinyl)-2-quinolinyl)ethyl)-
amino)-5-pyrimidinecarbonitrile
##STR00148##
[0487] A solution of
(S)-2-(1-(3-bromo-6-fluoro-4-methoxyquinolin-2-yl)ethyl)isoindoline-1,3-d-
ione (100 mg, 0.233 mmol), pyridin-3-ylboronic acid (57.3 mg, 0.466
mmol) and potassium carbonate (97 mg, 0.699 mmol) in DME (2 mL) was
purged with N.sub.2 followed by the addition of Pd(PPh.sub.3).sub.4
(26.9 mg, 0.023 mmol) and the resulting mixture was heated to
100.degree. C. overnight. The solvent was removed and EtOAc was
added and washed with water, brine and dried over sodium sulfate.
The crude residue was subjected to combiflash purification using
1:1 EtOAc/hexane to obtain
(S)-2-(1-(6-fluoro-4-methoxy-3-(pyridin-3-yl)quinolin-2-yl)ethyl)isoindol-
ine-1,3-dione as a clear oil. A solution of
(S)-2-(1-(6-fluoro-4-methoxy-3-(pyridin-3-yl)quinolin-2-yl)ethyl)isoindol-
ine-1,3-dione (23.7 mg, 0.055 mmol) and hydrazine (1.740 .mu.L,
0.055 mmol) in EtOH (1 mL) was heated to 60.degree. C. for 30 min.
The solvent was removed and EtOAc was added and washed with water,
brine and dried over sodium sulfate to obtain
(S)-1-(6-fluoro-4-methoxy-3-(pyridin-3-yl)quinolin-2-yl)ethanamine.
To a solution of
(S)-1-(6-fluoro-4-methoxy-3-(pyridin-3-yl)quinolin-2-yl)ethanamine
in BuOH (1.0 mL) was added
4-amino-6-chloropyrimidine-5-carbonitrile (8.57 mg, 0.055 mmol) and
DIEA (9.68 .mu.L, 0.055 mmol). The resulting mixture was heated to
100.degree. C. for 1 h. The crude solution was allowed to cool to
rt. and ppt was observed. The solid was filtered and the filtrate
was concd and subjected to preparatory TLC purification.
.sup.1H-NMR (400 Hz, CD.sub.3OD) .delta. ppm 1.41 (5H, d, J=6.65
Hz) 3.66 (3H, s) 5.42 (1H, q, J=6.59 Hz) 7.66 (2H, m) 7.83 (1H, dd,
J=9.39, 2.93 Hz) 7.96 (1H, s) 8.17 (2H, dd, J=9.19, 5.09 Hz) 8.69
(2H, dd, J=4.89, 1.57 Hz). Mass Spectrum (ESI) m/e=415 (M+1).
Example 52
4-Amino-6-(((1S)-1-(6-fluoro-4-methoxy-3-(3-pyridinyl)-2-quinolinyl)ethyl)-
amino)-5-pyrimidinecarbonitrile
[0488] .sup.1H-NMR (500 Hz, CD.sub.3OD) .delta. ppm 1.41 (3H, d)
3.65 (3H, s) 5.41 (2H, m) 7.66 (2H, m) 7.83 (1H, dd, J=9.41, 2.32
Hz) 7.96 (1H, s) 8.17 (2H, dd, J=9.29, 5.14 Hz) 8.69 (2H, d, J=4.89
Hz). Mass Spectrum (ESI) m/e=415 (M+1).
Example 53
Methyl
2-(1-aminoethyl)-6-fluoro-3-phenylquinoline-4-carboxylate
##STR00149##
[0490] A mixture of 5-fluoroisatin (5.00 g, 30.3 mmol),
1-phenylbutan-2-one (4.94 g, 1.1 eq) and KOH (5.1 g, 3.0 eq) in
EtOH (100 mL) was heated to reflux for 3 h. After cooling to rt,
the reaction mixture was concd, diluted with water, extracted with
ether twice and neutralized to pH 5. The resulted solid was
filtered, washed with water and dried in the air to give a mixture
of isomers. The solid was suspended in DCM (100 mL) and treated
with SOCl.sub.2 (18 g, 5.0 eq) at rt overnight. The solvent was
removed and treated with MeOH (50 mL) at rt for 2 h. Removal of
solvent followed with addition of satd sodium bicarbonate solution
gave a brown oil. The reaction mixture was extracted with EtOAc (20
mL.times.2), the combined organics were washed with water, brine,
dried over sodium sulfate. Removal of solvents followed with
purification on column chromatography on silica gel (hexane/EtOAc,
1/9) gave methyl 2-ethyl-6-fluoro-3-phenylquinoline-4-carboxylate
as an off-white solid. .sup.1H-NMR (400 Hz, CDCl.sub.3) .delta.
8.14 (dd, J=8.0, 4.0 Hz, 1H), 7.40-7.54 (m, 5H), 7.26-7.35 (m, 2H),
3.62 (s, 3H), 2.85 (q, J=8.0 Hz, 2H), 1.23 (t, J=8.0 Hz, 3H). Mass
Spectrum (ESI) m/e=310 (M+1). Methyl
2-ethyl-6-fluoro-3-phenylquinoline-4-carboxylate (1.00 g, 3.2 mmol)
and 1,3-dibromo-5,5-dimethylhydantoin (647 mg, 0.7 eq) were
suspended in carbon tetrachloride (30 mL) and treated with benzoyl
peroxide (78 mg, 0.1 eq) and the mixture was heated at reflux for 3
h. The reaction mixture was cooled to rt and treated with satd aq.
sodium bicarbonate solution (10 mL). The layers were separated and
the aq. layer was extracted with DCM (3 mL.times.2). The combined
organic layers were washed with brine (30 mL), dried over sodium
sulfate, filtered, and concd under reduced pressure to give methyl
2-(1-bromoethyl)-6-fluoro-3-phenylquinoline-4-carboxylate as a
yellow solid (crude, 1.4 g). To a solution of methyl
2-(1-bromoethyl)-6-fluoro-3-phenylquinoline-4-carboxylate (1.17 g,
3.00 mmol) in DMF (6 mL) was added NaN.sub.3 (0.293 g, 1.5 eq) at
rt. After 2 h, LCMS showed completion. The reaction mixture was
diluted with water and extracted with EtOAc (10 mL.times.2). The
organic layers were combined, washed with water, brine, dried,
concd to give methyl
2-(1-azidoethyl)-6-fluoro-3-phenylquinoline-4-carboxylate as a tan
oil. Mass Spectrum (ESI) m/e=351 (M+1). A solution of methyl
2-(1-azidoethyl)-6-fluoro-3-phenylquinoline-4-carboxylate (1.25 g,
3.6 mmol) in MeOH (10 mL) was treated with 10% Pd--C (100 mg) under
H.sub.2 balloon overnight. The reaction mixture was filtered
through a Celite.TM. pad and concd under reduced pressure to give
methyl 2-(1-aminoethyl)-6-fluoro-3-phenylquinoline-4-carboxylate as
a yellow oil. Mass Spectrum (ESI) m/e=325 (M+1).
Methyl
2-(1-(6-amino-5-cyanopyrimidin-4-ylamino)ethyl)-6-fluoro-3-phenylqu-
inoline-4-carboxylate
##STR00150##
[0492] A mixture of methyl
2-(1-aminoethyl)-6-fluoro-3-phenylquinoline-4-carboxylate (200 mg,
0.62 mmol), 4-amino-6-chloropyrimidine-5-carbonitrile (95 mg, 1.0
eq) and Hunig's base (129 .mu.L, 1.2 eq) in DMF (3 mL) was heated
to 130.degree. C. for 2 h. The reaction mixture was cooled to rt,
diluted with water and extracted with EtOAc (20 mL.times.2). The
organic layers were combined, washed with water, brine, dried,
concd and purified by column chromatography on silica gel
(DCM/MeOH/NH.sub.3, 20/1/0.1) to give methyl
2-(1-(6-amino-5-cyanopyrimidin-4-ylamino)ethyl)-6-fluoro-3-phenylquinolin-
e-4-carboxylate as a white solid. .sup.1H-NMR (400 Hz,
DMSO-d.sup.6) .delta. 8.16 (dd, J=8.0, 4.0 Hz, 1H), 7.91 (s, 1H),
7.81 (td, J=8.0, 4.0 Hz, 1H), 7.59 (dd, J=8.0, 4.0 Hz, 1H),
7.45-7.52 (m, 5H), 7.35 (dd, J=8.0, 4.0 Hz, 1H), 7.25 (s, br, 2H),
5.30-5.40 (m, 1H), 3.59 (s, 3H), 1.30 (t, J=8.0 Hz, 3H). Mass
Spectrum (ESI) m/e=443 (M+1).
Example 54
2-(1-(6-Amino-5-cyanopyrimidin-4-ylamino)ethyl)-6-fluoro-3-phenylquinoline-
-4-carboxylic acid and
2-(1-(6-amino-5-carbamoylpyrimidin-4-ylamino)ethyl)-6-fluoro-3-phenylquin-
oline-4-carboxylic acid
##STR00151##
[0494] A suspension of methyl
2-(1-(6-amino-5-cyanopyrimidin-4-ylamino)ethyl)-6-fluoro-3-phenylquinolin-
e-4-carboxylate (150 mg, 0.34 mmol) in a mixture of MeOH (3 mL),
THF (3 mL) and 1 N LiOH (3 mL) was stirred at 60.degree. C. for 3
h. Removal of the solvents followed with neutralizing the aq.
residue gave a white solid, which was dissolved in DMF and purified
by reverse HPLC (MeCN/H.sub.2O/0.1% TFA, 10-50%) to give
2-(1-(6-amino-5-cyanopyrimidin-4-ylamino)ethyl)-6-fluoro-3-phenylquinolin-
e-4-carboxylic acid as a white powder. .sup.1H-NMR (400 Hz,
DMSO-d.sup.6) .delta. 8.16 (dd, J=8.0, 4.0 Hz, 1H), 7.97 (s, 1H),
7.81 (td, J=8.0, 4.0 Hz, 1H), 7.72 (dd, J=8.0, 4.0 Hz, 1H),
7.38-7.52 (m, 8H), 5.30-5.40 (m, 1H), 1.30 (t, J=8.0 Hz, 3H). Mass
Spectrum (ESI) m/e=429 (M+1).
2-(1-(6-Amino-5-carbamoylpyrimidin-4-ylamino)ethyl)-6-fluoro-3-phenylquin-
oline-4-carboxylic acid as a white solid. .sup.1H-NMR (400 Hz,
DMSO-d.sup.6) .delta. 9.0 (s, br, 1H), 8.16 (dd, J=8.0, 4.0 Hz,
1H), 8.08 (s, 1H), 7.80-7.85 (m, 2H), 7.40-7.53 (m, 5H), 7.30 (s,
br, 1H), 5.30-5.40 (m, 1H), 1.27 (t, J=8.0 Hz, 3H). Mass Spectrum
(ESI) m/e=447 (M+1).
Example 55
tert-Butyl
1-(6-fluoro-4-(hydroxymethyl)-3-phenylquinolin-2-yl)ethylcarbam-
ate
##STR00152##
[0496] A mixture of methyl
2-(1-aminoethyl)-6-fluoro-3-phenylquinoline-4-carboxylate (1.3 g,
4.0 mmol) and Boc.sub.2O (1.3 g, 1.5 eq) in THF (20 mL) was treated
with Et.sub.3N (0.84 mL, 1.5 eq). After refluxing for 2 h, the
reaction mixture was concd and purified by silica gel column
(EtOAc/hexane, 1/4) to give methyl
2-(1-(tert-butoxycarbonylamino)-ethyl)-6-fluoro-3-phenylquinoline-4-carbo-
xylate as a white solid. A mixture of methyl
2-(1-(tert-butoxycarbonylamino)-ethyl)-6-fluoro-3-phenylquinoline-4-carbo-
xylate (200 mg, 0.47 mmol) in THF (2 mL), MeOH (2 mL) and 1 N LiOH
solution in water (3 mL) was heated to 60.degree. C. for 4 h before
removal of solvents. The residue was acidified to pH 4 with 3N HCl.
The resulted solid was filtered, washed with water and dried in the
air to give
2-(1-(tert-butoxycarbonylamino)ethyl)-6-fluoro-3-phenylquinoline-4-c-
arboxylic acid as a white solid. Mass Spectrum (ESI) m/e=411 (M+1).
2-(1-(tert-Butoxycarbonylamino)ethyl)-6-fluoro-3-phenylquinoline-4-carbox-
ylic acid was suspended in THF (5 mL) at -10.degree. C. and treated
with Et.sub.3N (0.1 mL, 1.5 eq) followed with ClCO.sub.2Pr.sup.i
(1M in tol, 0.71 mL, 1.5 eq). The reaction mixture was stirred at
this temperature for 1.5 h before addition of ice-water (2 mL)
followed by NaBH.sub.4 (10 eq, 178 mg). The reaction mixture was
stirred overnight and partitioned between EtOAc (10 mL) and water
(5 mL). The organic layer was separated, washed with water, brine,
dried and concd. The residue was purified by column chromatography
on silica gel (EtOAc/hexane, 1/1) to give tert-butyl
1-(6-fluoro-4-(hydroxymethyl)-3-phenylquinolin-2-yl)ethylcarbamate
as a white solid. Mass Spectrum (ESI) m/e=397 (M+1).
4-Amino-6-(1-(6-fluoro-4-(hydroxymethyl)-3-phenylquinolin-2-yl)ethylamino)-
pyrimidine-5-carbonitrile
##STR00153##
[0498] To a solution of tert-butyl
1-(6-fluoro-4-(hydroxymethyl)-3-phenylquinolin-2-yl)ethylcarbamate
(130 mg, 0.33 mmol) in DCM (2 mL) was added TFA (2 mL) at rt. The
mixture was stirred at rt for 30 min before removal of solvents.
The residue was treated with benzene and concd under reduced
pressure and stored under high vacuum for 2 h to give
(2-(1-aminoethyl)-6-fluoro-3-phenylquinolin-4-yl)methanol as TFA
salt. A mixture of
(2-(1-aminoethyl)-6-fluoro-3-phenylquinolin-4-yl)methanol TFA salt
(0.33 mmol, crude), 4-amino-6-chloropyramidine-5-carbonitrile (50.7
mg, 1.0 eq) and Hunig's base (229 .mu.L, 4.0 eq) in n-BuOH (3 mL)
was heated to 120.degree. C. overnight. The mixture was cooled to
rt and purified by reverse phase HPLC (MeCN/H.sub.2O/0.1% TFA,
10-50%) to give
4-amino-6-(1-(6-fluoro-4-(hydroxymethyl)-3-phenylquinolin-2-yl)ethylamino-
)pyrimidine-5-carbonitrile TFA salt as a white powder. .sup.1H-NMR
(400 Hz, CD.sub.3OD) .delta. 8.20 (dd, J=8.0, 4.0 Hz, 1H), 8.13 (s,
1H), 8.06 (dd, J=8.0, 4.0 Hz, 1H), 7.67 (td, J=8.0, 4.0 Hz, 1H),
7.52-7.60 (m, 3H), 7.44-7.46 (m, 2H), 5.49 (q, J=8.0 Hz, 1H), 4.75
(d, J=12 Hz, 1H), 4.70 (d, J=12 Hz, 1H), 1.43 (d, J=8.0 Hz, 3H).
Mass Spectrum (ESI) m/e=415 (M+1).
Example 56
tert-Butyl
1-(6-fluoro-4-(methylsulfonylmethyl)-3-phenylquinolin-2-yl)ethy-
lcarbamate
##STR00154##
[0500] A solution of tert-butyl
1-(6-fluoro-4-(hydroxymethyl)-3-phenylquinolin-2-yl)ethylcarbamate
(220 mg, 0.56 mmol) in DCM (5 mL) at -10.degree. C. was treated
with Et.sub.3N (0.11 mL, 1.4 eq) followed with MsCl (0.053 mL, 1.2
eq). The reaction mixture was slowly warmed to rt. and washed with
NaHCO.sub.3, brine, dried and concd to give
(2-(1-(tert-butoxycarbonylamino)ethyl)-6-fluoro-3-phenylquinolin-4-yl)met-
hyl methane-sulfonate as a white solid. Mass Spectrum (ESI) m/e=475
(M+1). A solution of
(2-(1-(tert-butoxycarbonylamino)ethyl)-6-fluoro-3-phenylquinolin-4-yl)met-
hyl methanesulfonate (100 mg, 0.21 mmol) in DMF (2 mL) was treated
with NaSMe (17.7 mg, 1.2 eq) at rt. After 2 h, the reaction mixture
was partitioned between EtOAc (10 mL) and water (10 mL). The
organic layer was separated, washed, dried and concd to give an oil
which was purified by combiflash (EtOAc/hexane, 1/4) to give
tert-butyl
1-(6-fluoro-4-(methylthiomethyl)-3-phenylquinolin-2-yl)ethylcarbamate
as a white solid. A solution of tert-butyl
1-(6-fluoro-4-(methylthiomethyl)-3-phenylquinolin-2-yl)ethyl-carbamate
(64 mg, 0.15 mmol) in a mixture of acetone (4 mL), THF (2 mL) and
water (2 mL) was treated with NMO (88 mg, 5.0 eq) followed with
OsO.sub.4 (1 crop) at 0.degree. C. The reaction mixture was then
stirred at rt overnight and partitioned between NaHCO.sub.3
solution and EtOAc (10 mL). The organic layer was washed with
NaS.sub.2O.sub.3, water, brine, dried and concd to give tert-butyl
1-(6-fluoro-4-(methylsulfonylmethyl)-3-phenylquinolin-2-yl)ethylcarbamate
as a white solid. Mass Spectrum (ESI) m/e=459 (M+1).
4-Amino-6-(1-(6-fluoro-4-(methylsulfonylmethyl)-3-phenylquinolin-2-yl)ethy-
lamino)pyrimidine-5-carbonitrile
##STR00155##
[0502]
4-Amino-6-(1-(6-fluoro-4-(methylsulfonylmethyl)-3-phenylquinolin-2--
yl)ethylamino)pyrimidine-5-carbonitrile was made in the similar
manner as the preparation of
4-amino-6-(1-(6-fluoro-4-(hydroxymethyl)-3-phenylquinolin-2-yl)ethylamino-
)pyrimidine-5-carbonitrile. .sup.1H-NMR (400 Hz, CD.sub.3OD)
.delta. 8.22 (dd, J=8.0, 4.0 Hz, 1H), 8.09 (s, 1H), 8.07 (dd,
J=8.0, 4.0 Hz, 1H), 7.69 (td, J=8.0, 4.0 Hz, 1H), 7.52-7.60 (m,
3H), 7.44-7.46 (m, 2H), 5.43 (q, J=8.0 Hz, 1H), 4.87 (2H,
overlapped with solvent peak), 2.90 (s, 3H), 1.45 (d, J=8.0 Hz,
3H). Mass Spectrum (ESI) m/e=477 (M+1).
Example 57
2-Ethyl-6-fluoro-3-(pyridin-2-yl)quinoline-4-carboxylic acid and
2-ethyl-6-fluoro-3-(pyridin-2-yl)quinoline-4-carboxamide
##STR00156##
[0504] A mixture of the known 1-(pyridin-2-yl)butan-2-one (19.9 g,
80% purity), 5-fluoroisatin (22.0 g, 1.0 eq), KOH (22.3 g, 3.0 eq),
EtOH (100 mL) and water (100 mL) was heated to 90.degree. C.
overnight. Solvents were concd to 100 mL and extracted with ether
twice. The resulted solid was filtered, washed with water and dried
in the air to provide
2-ethyl-6-fluoro-3-(pyridin-2-yl)quinoline-4-carboxamide (presumed
to have formed via impurity). .sup.1H-NMR (500 Hz, DMSO-d.sup.6)
.delta. 8.71 (dd, J=10.0, 5.0 Hz, 1H), 8.14 (dd, J=10.0, 5.0 Hz,
1H), 8.03 (s, 1H), 7.94 (td, J=10.0, 5.0 Hz, 1H), 7.72-7.76 (m,
2H), 7.56 (d, J=10.0 Hz, 1H), 7.51 (dd, J=10.0, 5.0 Hz, 1H),
7.46-7.48 (m, 1H), 2.47 (q, J=5.0 Hz, 2H), 1.12 (t, J=5.0 Hz, 3H).
Mass Spectrum (ESI) m/e=296 (M+1). The filtrate was acidified with
conc. HCl to pH 3-4. The resulted brown solid was filtered and
dried in the air. The filtrate was concd again to give additional
material. The filtrate was concd and freeze-dried and extracted
with 20% MeOH in DCM (200 mL). Removal of solvents gave a red oily
material used for the next step. .sup.1H-NMR (500 Hz, DMSO-d.sup.6)
.delta. 8.72 (dd, J=10.0, 5.0 Hz, 1H), 8.18 (dd, J=10.0, 5.0 Hz,
1H), 7.96 (td, J=10.0, 5.0 Hz, 1H), 7.78 (td, J=10.0, 5.0 Hz, 1H),
7.56-7.60 (m, 2H), 2.47 (q, J=5.0 Hz, 2H), 1.12 (t, J=5.0 Hz, 3H).
Mass Spectrum (ESI) m/e=297 (M+1).
Methyl
2-(1-(6-amino-5-cyanopyrimidin-4-ylamino)ethyl)-6-fluoro-3-(pyridin-
-2-yl)quinoline-4-carboxylate
##STR00157##
[0506] To a solution of
2-ethyl-6-fluoro-3-(pyridin-2-yl)quinoline-4-carboxylic acid (15 g,
crude, 50.6 mmol) in 75 mL MeOH was added TMSCHN.sub.2 (2M, 46.5
mL, 1.8 eq) at 0.degree. C., the reaction mixture was stirred at rt
for 2 h. Removal of solvents followed with column chromatography on
silica gel (EtOAc/hexane, 2/3) gave methyl
2-ethyl-6-fluoro-3-(pyridin-2-yl)quinoline-4-carboxylate as a pink
solid. .sup.1H-NMR (400 Hz, CDCl.sub.3) .delta. 8.78 (dd, J=8.0,
4.0 Hz, 1H), 8.16 (dd, J=8.0, 4.0 Hz, 1H), 7.85 (td, J=8.0, 4.0 Hz,
1H), 7.53-7.58 (m, 2H), 7.45 (dd, J=8.0, 4.0 Hz, 1H), 7.38 (dd,
J=8.0, 4.0 Hz, 1H), 3.66 (s, 3H), 2.94 (q, J=8.0 Hz, 2H), 1.25 (t,
J=8.0 Hz, 3H). Methyl
2-(1-(6-amino-5-cyanopyrimidin-4-ylamino)ethyl)-6-fluoro-3-(pyridin-2-yl)-
quinoline-4-carboxylate was synthesized starting from methyl
2-ethyl-6-fluoro-3-(pyridin-2-yl)quinoline-4-carboxylate in the
similar manner as previously described for preparation of a
corresponding phenyl analog methyl
2-(1-(6-amino-5-cyanopyrimidin-4-ylamino)ethyl)-6-fluoro-3-phenylquinolin-
e-4-carboxylate. .sup.1H-NMR (500 Hz, CD.sub.3OD) .delta. 8.76 (d,
J=5.0 Hz, 1H), 8.28 (dd, J=10.0, 5.0 Hz, 1H), 8.10 (s, 1H), 8.05
(td, J=10.0, 5.0 Hz, 1H), 7.76 (dd, J=10.0, 5.0 Hz, 1H), 7.69 (dd,
J=10.0, 5.0 Hz, 1H), 7.57-7.60 (m, 1H), 5.65-5.75 (m, 1H), 3.68 (s,
3H), 1.48 (d, J=5.0 Hz, 3H). Mass Spectrum (ESI) m/e=444 (M+1).
Example 58
2-Ethyl-6-fluoro-3-(pyridin-2-yl)quinoline-4-carbonitrile
##STR00158##
[0508] To a suspension of
2-ethyl-6-fluoro-3-(pyridin-2-yl)quinoline-4-carboxamide (200 mg,
0.68 mmol) in dioxane (3 mL) at 0.degree. C. was added pyridine
(2.1 eq, 0.115 mL) followed with trifluoroacetic anhydride (1.2 eq,
0.115 mL) dropwise, and the reaction mixture was warmed to rt.
overnight. The resulted black reaction mixture was partitioned
between DCM and a satd solution of NaHCO.sub.3. The organic layer
was separated, washed with brine, dried over sodium sulfate, concd
and purified by column chromatography on silica gel (EtOAc/hexane,
2/3) to give a white solid. Mass Spectrum (ESI) m/e=278 (M+1).
2-(1-(6-Amino-5-cyanopyrimidin-4-ylamino)ethyl)-6-fluoro-3-(pyridin-2-yl)--
quinoline-4-carbonitrile
##STR00159##
[0510]
2-(1-(6-Amino-5-cyanopyrimidin-4-ylamino)ethyl)-6-fluoro-3-(pyridin-
-2-yl)quinoline-4-carbonitrile was synthesized starting from
2-ethyl-6-fluoro-3-(pyridin-2-yl)quinoline-4-carbonitrile in a
similar manner as previously described for preparation of methyl
2-(1-(6-amino-5-cyanopyrimidin-4-ylamino)ethyl)-6-fluoro-3-(pyridin-2-yl)-
quinoline-4-carboxylate. .sup.1H-NMR (400 Hz, DMSO-d.sup.6) .delta.
8.77 (d, J=4.0 Hz, 1H), 8.31 (dd, J=8.0, 4.0 Hz, 1H), 8.05 (td,
J=8.0, 4.0 Hz, 1H), 7.98 (td, J=8.0, 4.0 Hz, 1H), 7.87 (s, 1H),
7.83-7.88 (m, 2H), 7.53-7.57 (m, 2H), 7.24 (s, br, 2H), 5.49-5.57
(m, 1H), 1.43 (d, J=4.0 Hz, 3H). Mass Spectrum (ESI) m/e=411
(M+1).
Example 59
2-Ethyl-6-fluoro-3-(pyridin-2-yl)quinolin-4(1H)-one
##STR00160##
[0512] A mixture of 2-ethyl-6-fluoro-3-iodoquinolin-4(1H)-one
(18.34 g, 57.8 mmol), 2-(tributylstannyl)pyridine (25.6 g, 1.2 eq),
and tetrakis(triphenylphosphine)palladium(0) (3.34 g, 0.05 eq) in
dioxane (600 mL) was purged with N.sub.2 and heated to reflux
overnight. After cooling to rt, removal of solvent followed with
purification on column chromatography on silica gel (DCM/MeOH, 1/0
to 20/1 containing NH.sub.3) gave
2-ethyl-6-fluoro-3-(pyridin-2-yl)quinolin-4(1H)-one as a white
solid. Mass Spectrum (ESI) m/e=269 (M+1).
2-(1-(4-Chloro-6-fluoro-3-(pyridin-2-yl)quinolin-2-yl)ethyl)isoindoline-1,-
3-dione
##STR00161##
[0514] A suspension of
2-ethyl-6-fluoro-3-(pyridin-2-yl)quinolin-4(1H)-one (1000 mg, 3.7
mmol) in POCl.sub.3 (5 mL) was heated to 100.degree. C. for 2 h.
After cooling to rt, the reaction mixture was poured into a mixture
of ice and water and slowly warmed to rt. Solid NaHCO.sub.3 was
added until the solution reached pH 8. The resulted solid was
extracted with EtOAc, washed with water, brine, dried, concd and
purified by column chromatography on silica gel (EtOAc/hexane, 1/1)
to give 4-chloro-2-ethyl-6-fluoro-3-(pyridin-2-yl)quinoline as a
solid.
2-(1-(4-Chloro-6-fluoro-3-(pyridin-2-yl)quinolin-2-yl)ethyl)isoindoline-1-
,3-dione was obtained in the similar manner as described previously
for the preparation of
2-(1-(3-(3,5-difluorophenyl)-6-fluoro-4-(methylthio)quinolin-2-ypethyl)is-
oindoline-1,3-dione. Mass Spectrum (ESI) m/e=432 (M+1).
tert-Butyl
1-(4-chloro-6-fluoro-3-(pyridin-2-yl)quinolin-2-yl)ethylcarbama-
te
##STR00162##
[0516] A suspension of
2-(1-(4-chloro-6-fluoro-3-(pyridin-2-yl)quinolin-2-yl)ethyl)isoindoline-1-
,3-dione (240 mg, 0.56 mmol) in EtOH (4 mL) was treated with
hydrazine (0.4 mL) at 50.degree. C. for 5 min. After cooling to rt,
the reaction mixture was partitioned between water (5 mL) and EtOAc
(10 mL). The organic layer was separated, washed with water, brine,
dried and concd to give
1-(4-chloro-6-fluoro-3-(pyridin-2-yl)quinolin-2-yl)ethanamine as a
white solid. This was dissolved in THF (5 mL) and treated with
Et.sub.3N (0.10 mL, 1.3 eq) followed by Boc.sub.2O (146 mg, 1.2
eq). The solution was refluxed for 2 h. After cooling to rt,
removal of solvents followed with column chromatography on silica
gel (EtOAc/hexane, 1/1) gave tert-butyl
1-(4-chloro-6-fluoro-3-(pyridin-2-yl)quinolin-2-yl)ethylcarbamate
as a white solid. Mass Spectrum (ESI) m/e=402 (M+1).
tert-Butyl
1-(4-(dimethylamino)-6-fluoro-3-(pyridin-2-yl)quinolin-2-yl)eth-
ylcarbamate
##STR00163##
[0518] A suspension of tert-butyl
1-(4-chloro-6-fluoro-3-(pyridin-2-yl)quinolin-2-yl)ethylcarbamate
(57 mg, 0.14 mmol) in MeOH (1 mL) was treated with Me.sub.2NH in
THF (2.0 M, 2 mL) in a sealed tube at 80.degree. C. for 5 hours and
further at 50.degree. C. overnight. Removal of the solvents gave
tert-butyl
1-(4-(dimethylamino)-6-fluoro-3-(pyridin-2-yl)quinolin-2-yl)ethylcarbamat-
e as a yellow film which was used directly for the next step. Mass
Spectrum (ESI) m/e=411 (M+1).
4-Amino-6-(1-(4-(dimethylamino)-6-fluoro-3-(pyridin-2-yl)quinolin-2-yl)eth-
ylamino)pyrimidine-5-carbonitrile
##STR00164##
[0520] A solution of tert-butyl
1-(4-(dimethylamino)-6-fluoro-3-(pyridin-2-yl)quinolin-2-yl)ethylcarbamat-
e (45 mg, 0.11 mmol) in DCM (2 mL) was treated with TFA (2 mL) at
rt for 2 h. Solvents were removed under reduced pressure and the
residue was stored under vacuum for 1 h to give
2-(1-aminoethyl)-6-fluoro-N,N-dimethyl-3-(pyridin-2-yl)quinolin-4-amine
as TFA salt. This was treated with
4-amino-6-chloropyrimidine-5-carbonitrile (17 mg, 1.0 eq) and
Hunig's base (0.038 mL, 2.0 eq) in n-BuOH (2 mL) at 120.degree. C.
overnight. After cooling to rt, the reaction mixture was diluted
with 1 mL DMF and subjected to reverse phase HPLC (MeCN/water,
15-60%. 0.1% TFA) to give
4-amino-6-(1-(4-(dimethylamino)-6-fluoro-3-(pyridin-2-yl)quinolin-2-yl)et-
hylamino)pyrimidine-5-carbonitrile as a TFA salt. .sup.1H-NMR (400
Hz, CD.sub.3OD) .delta. 8.85 (d, J=8.0 Hz, 1H), 8.06-8.20 (m, 3H),
8.02 (s, 1H), 7.78-7.85 (m, 2H), 7.63-7.67 (m, 1H), 4.95-5.05 (m,
1H), 2.98 (s, 6H), 1.62 (d, J=8.0 Hz, 3H). Mass Spectrum (ESI)
m/e=429 (M+1).
Example 60
4-amino-6-(1-(6-fluoro-4-morpholino-3-(pyridin-2-yl)quinolin-2-yl)ethylami-
no)pyrimidine-5-carbonitrile
##STR00165##
[0522]
4-Amino-6-(1-(6-fluoro-4-morpholino-3-(pyridin-2-yl)quinolin-2-yl)e-
thylamino)pyrimidine-5-carbonitrile was synthesized in a similar
manner as the procedure for the preparation of
4-amino-6-(1-(4-(dimethylamino)-6-fluoro-3-(pyridin-2-yl)quinolin-2-yl)et-
hylamino)pyrimidine-5-carbonitrile. .sup.1H-NMR (400 Hz,
CD.sub.3OD) .delta. 8.88 (d, J=4.0 Hz, 1H), 7.67-8.24 (m, 7H),
5.30-5.40 (m, 1H), 4.95-5.05 (m, 1H), 3.70-3.72 (m, 4H), 2.92-3.20
(m, 4H), 1.56 (d, J=4.0 Hz, 3H). Mass Spectrum (ESI) m/e=471
(M+1).
Example 61
4-Amino-6-(1-(6-fluoro-4-(3-hydroxyazetidin-1-yl)-3-(pyridin-2-yl)quinolin-
-2-yl)ethylamino)pyrimidine-5-carbonitrile
##STR00166##
[0524]
4-amino-6-(1-(6-fluoro-4-(3-hydroxyazetidin-1-yl)-3-(pyridin-2-yl)q-
uinolin-2-yl)ethylamino)pyrimidine-5-carbonitrile was synthesized
in a similar manner as the procedure for preparation of
4-amino-6-(1-(4-(dimethylamino)-6-fluoro-3-(pyridin-2-yl)quinolin-2-yl)et-
hylamino)pyrimidine-5-carbonitrile. .sup.1H-NMR (400 Hz,
CD.sub.3OD) .delta. 8.82 (d, J=4.0 Hz, 1H), 7.98-8.08 (m, 4H),
7.78-7.79 (m, 1H), 7.62-7.65 (m, 1H), 5.30-5.40 (m, 1H), 4.46-4.49
(m, 1H), 3.72-3.79 (m, 1H), 3.23-3.26 (m, 2H), 1.40 (d, J=4.0 Hz,
3H). Mass Spectrum (ESI) m/e=457 (M+1).
Example 62
(S)-2-(1-(6-Amino-5-cyanopyrimidin-4-ylamino)ethyl)-6-fluoro-N-methyl-3-ph-
enylquinoline-4-carboxamide
##STR00167##
[0526] (S)-tert-butyl
1-(methoxy(methyl)amino)-1-oxopropan-2-ylcarbamate (1.16 g, 5 mmol)
in THF (10 mL) was cooled to -15.degree. C. and slowly charged with
isopropylmagnesium chloride (2.0 M, 2.37 mL, 0.95 eq). After a
clear solution was obtained, benzylmagnesium chloride (1.0M, 4.99
mL, 1.0 eq) was added dropwise with stirring at rt for 4 h. The
reaction mixture was quenched with NH.sub.4Cl solution and
extracted with EtOAc (10 mL.times.2). The combined organic layers
were washed with water, brine, dried over sodium sulfate, concd and
purified by combiflash (EtOAc/hexane, up to 1/3) to give a
colorless oil (S)-tert-butyl 3-oxo-4-phenylbutan-2-ylcarbamate.
Mass Spectrum (ESI) m/e=264 (M+1). To a solution of (S)-tert-butyl
3-oxo-4-phenylbutan-2-ylcarbamate (24.6 g, 93 mmol) and
5-fluoroindoline-2,3-dione (15.41 g, 93 mmol) in EtOH (300 mL) was
added KOH (15.71 g, 280 mmol). The resulting mixture was heated to
90.degree. C. overnight, but racemization was observed via chiral
HPLC with C10A30 min method. Water was added and EtOH was removed.
The aq. layer was washed with Et.sub.2O (2.times.), acidified with
1M HCl and the solid filtered. The aq. layer was extracted with
EtOAc, washed with water, brine and dried over sodium sulfate. Both
solids were combined to afford
2-(1-(tert-butoxycarbonylamino)ethyl)-6-fluoro-3-phenylquinoline-4-
-carboxylic acid. 5 g of
2-(1-(tert-butoxycarbonylamino)ethyl)-6-fluoro-3-phenylquinoline-4-carbox-
ylic acid was purified by chiral HPLC (isopropanol/hexane gradient,
AD column) to provide
(S)-2-(1-(tert-butoxycarbonylamino)ethyl)-6-fluoro-3-phenylquinoline-4-ca-
rboxylic acid. Mass Spectrum (ESI) m/e=411 (M+1). To a solution of
2-(1-(tert-butoxycarbonylamino)ethyl)-6-fluoro-3-phenylquinoline-4-carbox-
ylic acid (4 g, 9.75 mmol) in DMF was added HATU (5.56 g, 14.62
mmol), DIEA (3.40 mL, 19.49 mmol) and methanamine (9.75 mL, 19.49
mmol). The resulting mixture was stirred at rt overnight. EtOAc was
added. The organic layer was washed with water, brine and dried
over sodium sulfate. The solution was filtered and concd in vacuo
to give a yellow solid. The crude yellow solid was absorbed onto a
plug of silica gel and purified by chromatography eluting with a
gradient of 0% to 60% EtOAc in hexane, to provide tert-butyl
1-(6-fluoro-4-(methylcarbamoyl)-3-phenylquinolin-2-yl)ethylcarbamate
as light-yellow solid. Mass Spectrum (ESI) m/e=424 (M+1). To
tert-butyl
1-(6-fluoro-4-(methylcarbamoyl)-3-phenylquinolin-2-yl)ethylcarbamate
(20.41 g, 48.2 mmol) was added 4N HCl/1,4-dioxane (20 mL, 80 mmol).
The resulting mixture was stirred at rt for 1 h. Solvent was
removed and the resulting
2-(1-aminoethyl)-6-fluoro-N-methyl-3-phenylquinoline-4-carboxam-
ide was used without further purification. Mass Spectrum (ESI)
m/e=324 (M+1). To a solution of
2-(1-aminoethyl)-6-fluoro-N-methyl-3-phenylquinoline-4-carboxamide
in BuOH (100 mL) was added
4-amino-6-chloropyrimidine-5-carbonitrile (7.45 g, 48.2 mmol) and
DIEA (25.2 mL, 145 mmol). The resulting mixture was heated to
100.degree. C. for 3 h. The reaction was allowed to cool to rt and
the ppt was filtered, washed with hexanes to afford
2-(1-(6-amino-5-cyanopyrimidin-4-ylamino)ethyl)-6-fluoro-N-methyl-3-pheny-
lquinoline-4-carboxamide as an off white powder and purified on a
chiral column (isopropanol/hexane gradient, AD column) to obtain
(S)-2-(1-(6-amino-5-cyanopyrimidin-4-ylamino)ethyl)-6-fluoro-N-methyl-3-p-
henylquinoline-4-carboxamide. .sup.1H-NMR (400 Hz, CD.sub.3OD)
.delta. ppm 1.34 (d, 3H) 2.63 (s, 3H) 5.51 (q, J=6.52 Hz, 1H)
7.32-7.54 (m, 6H) 7.57-7.71 (m, 1H) 7.93 (s, 1H) 8.18 (dd, J=9.39,
5.28 Hz, 1H). Mass Spectrum (ESI) m/e=442 (M+1).
Example 63
2-(1-(6-Amino-5-cyanopyrimidin-4-ylamino)ethyl)-N-(cyclopropylmethyl)-6-fl-
uoro-3-phenylquinoline-4-carboxamide
##STR00168##
[0528] To a solution of
2-(1-(tert-butoxycarbonylamino)ethyl)-6-fluoro-3-phenylquinoline-4-carbox-
ylic acid in DMF (1 mL) was added cyclopropylmethylamine (34.7 mg,
0.487 mmol), DIEA (0.085 mL, 0.487 mmol) and HATU (139 mg, 0.366
mmol). The resulting mixture was stirred at rt overnight. EtOAc was
added and the mixture washed with water, brine and dried over
sodium sulfate. The solvent was removed in vacuo. The crude residue
was subjected to combiflash purification using 0-100% EtOAc/hexanes
to obtain tert-butyl
1-(4-(cyclopropylmethylcarbamoyl)-6-fluoro-3-phenylquinolin-2-yl)ethylcar-
bamate. Mass Spectrum (ESI) m/e=464 (M+1). To a solution of
tert-butyl
1-(4-(cyclopropylmethylcarbamoyl)-6-fluoro-3-phenylquinolin-2-yl)ethylcar-
bamate (98.4 mg, 0.212 mmol) in DCM (1 mL) was added TFA (1 mL,
13.0 mmol) and the resulting mixture was stirred at rt for 1 h. The
solvent was removed and the crude
2-(1-aminoethyl)-N-(cyclopropylmethyl)-6-fluoro-3-phenylquinoline-4-carbo-
xamide was used without further purification. Mass Spectrum (ESI)
m/e=364 (M+1). To a solution of
2-(1-aminoethyl)-N-(cyclopropylmethyl)-6-fluoro-3-phenylquinoline-4-carbo-
xamide in BuOH (1 mL) was added
4-amino-6-chloropyrimidine-5-carbonitrile (37.7 mg, 0.244 mmol) and
DIEA (0.085 mL, 0.487 mmol) the resulting mixture was stirred at
100.degree. C. for 1 h. The crude reaction mixture was purified
using preparatory HPLC to obtain
2-(1-(6-amino-5-cyanopyrimidin-4-ylamino)ethyl)-N-(cyclopropylmethyl)-6-f-
luoro-3-phenylquinoline-4-carboxamide. .sup.1H-NMR (400 Hz,
CD.sub.3OD) .delta. ppm 0.05 (d, 2H) 0.37 (dd, J=8.51, 1.47 Hz, 2H)
0.58-0.74 (m, 1H) 1.45 (d, J=6.85 Hz, 3H) 2.96-3.10 (m, 2H) 5.61
(q, J=6.39 Hz, 1H) 7.42-7.59 (m, 6H) 7.63-7.78 (m, 1H) 8.10 (s, 1H)
8.22 (dd, J=9.19, 5.28 Hz, 1H) 8.57-8.73 (m, 1H). Mass Spectrum
(ESI) m/e=482 (M+1).
Example 64
2-(1-(6-Amino-5-cyanopyrimidin-4-ylamino)ethyl)-6-fluoro-N-isopropyl-3-phe-
nylquinoline-4-carboxamide
##STR00169##
[0530] To a solution of
2-(1-(tert-butoxycarbonylamino)ethyl)-6-fluoro-3-phenylquinoline-4-carbox-
ylic acid in DMF (1 mL) was added isopropylamine (28.8 mg, 0.487
mmol) DIEA (0.085 mL, 0.487 mmol) and HATU (139 mg, 0.336 mmol).
The resulting mixture was stirred at rt overnight. EtOAc was added
to the mixture washed with water, brine and dried over sodium
sulfate. The solvent was removed in vacuo. The crude residue was
subjected to combiflash purification using 0-100% EtOAc/Hexanes to
obtain tert-butyl
1-(6-fluoro-4-(isopropylcarbamoyl)-3-phenylquinolin-2-yl)ethylcarbamate.
Mass Spectrum (ESI) m/e=452 (M+1). To a pure of tert-butyl
1-(6-fluoro-4-(isopropylcarbamoyl)-3-phenylquinolin-2-yl)ethylcarbamate
(95 mg, 0.210 mmol) was added 4N HCl/1,4-dioxane (0.5 mL, 2.000
mmol) and the resulting mixture was stirred at rt for 1 h. The
solvent was removed in vacuo and the crude
2-(1-aminoethyl)-6-fluoro-N-isopropyl-3-phenylquinoline-4-carboxamide
used without further purification. Mass Spectrum (ESI) m/e=352
(M+1). To a solution of
2-(1-aminoethyl)-6-fluoro-N-isopropyl-3-phenylquinoline-4-carboxamide
in BuOH (1 mL) was added 4-amino-6-chloropyrimidine-5-carbonitrile
(37.7 mg, 0.244 mmol) and DIEA (0.085 mL, 0.487 mmol) and the
resulting mixture was stirred at 100.degree. C. overnight. Upon
cooling, a solid precipitated and was filtered. The filtrate was
removed and purified via preparatory TLC using 5% MeOH/DCM to
obtain
2-(1-(6-amino-5-cyanopyrimidin-4-ylamino)ethyl)-6-fluoro-N-isopropyl-3-ph-
enylquinoline-4-carboxamide as white solid. .sup.1H-NMR (400 Hz,
CD.sub.3OD) .delta. ppm 0.80 (br. s., 3H) 0.95 (d, J=6.65 Hz, 3H)
1.34 (d, J=6.65 Hz, 3H) 3.93 (quin, J=6.55 Hz, 1H) 5.52 (q, J=6.52
Hz, 1H) 7.34-7.58 (m, 6H) 7.58-7.73 (m, 1H) 7.93 (s, 1H) 8.10-8.24
(m, 1H). Mass Spectrum (ESI) m/e=470 (M+1).
Example 65
(S)-2-(1-(6-Amino-5-cyanopyrimidin-4-ylamino)ethyl)-N-ethyl-6-fluoro-3-phe-
nylquinoline-4-carboxamide
##STR00170##
[0532] To a solution of
(S)-2-(1-(tert-butoxycarbonylamino)ethyl)-6-fluoro-3-phenylquinoline-4-ca-
rboxylic acid (125 mg, 0.305 mmol) in DMF (1 mL) was added
ethylamine (0.304 mL, 0.609 mmol), DIEA (0.106 mL, 0.609 mmol) and
HATU (174 mg, 0.457 mmol). The resulting mixture was stirred at rt
for 2 h. The solvent was removed in vacuo and diluted with EtOAc.
The organic layer was washed with water, brine and dried over
sodium sulfate. The solvent was removed, and the crude residue was
purified via combiflash using 30% EtOAc/hexane to obtain
(S)-tert-butyl
1-(4-(ethylcarbamoyl)-6-fluoro-3-phenylquinolin-2-yl)ethylcarbamate.
Mass Spectrum (ESI) m/e=438 (M+1). To a pure residue of
(S)-tert-butyl
1-(4-(ethylcarbamoyl)-6-fluoro-3-phenylquinolin-2-yl)ethylcarbamate
(120 mg, 0.274 mmol) was added 4N HCl/1,4-dioxane (1 mL, 0.274
mmol). The resulting mixture was stirred at rt for 1 h. The solvent
was removed in vacuo and the crude
(S)-2-(1-aminoethyl)-N-ethyl-6-fluoro-3-phenylquinoline-4-carboxamide
used without further purification. Mass Spectrum (ESI) m/e=338
(M+1). To a solution of
(S)-2-(1-aminoethyl)-N-ethyl-6-fluoro-3-phenylquinoline-4-carboxamide
in DMF (1 mL) was added 4-amino-6-chloropyrimidine-5-carbonitrile
(106 mg, 0.686 mmol) and DIEA (106 mg, 0.823 mmol). The resulting
mixture was heated to 95.degree. C. overnight. The solvent was
removed and crude residue was subjected to preparatory TLC
purification using 5% MeOH/DCM to obtain
(S)-2-(1-(6-amino-5-cyanopyrimidin-4-ylamino)ethyl)-N-ethyl-6-f-
luoro-3-phenylquinoline-4-carboxamide as white solid. .sup.1H-NMR
(400 Hz, CD.sub.3OD) .delta. ppm 0.78 (2H, t), 1.36 (3H, d, J=6.65
Hz), 3.16 (2H, m), 5.53 (1H, q, J=6.65 Hz), 7.45 (5H, m), 7.64 (1H,
td, J=8.80, 2.93 Hz), 7.95 (1H, s), 8.18 (1H, dd, J=9.39, 5.28 Hz),
8.46 (1H, t, J=6.16 Hz). Mass Spectrum (ESI) m/e=456 (M+1).
[0533] Alternate general procedure F for the preparation of
2-(1-(6-amino-5-cyanopyrimidin-4-ylamino)ethyl)-6-fluoro-3-phenylquinolin-
e-4-carboxamides
##STR00171##
[0534] To a solution of
2-(1-(6-amino-5-cyanopyrimidin-4-ylamino)ethyl)-6-fluoro-3-phenylquinolin-
e-4-carboxylic acid (0.16 mmol) in DMF (1 mL) was added amine (1.5
eq), DIEA (1.1 eq) and PyBop (2.2 eq) and the resulting mixture was
stirred at rt for 1 h. The crude mixture was subjected to HPLC
purification or preparative TLC for purification.
[0535] The following compounds were synthesized according to
general procedure F or the procedure exemplified by examples: 62,
63, 64 or 65.
Example 66
2-(-1-((6-Amino-5-cyano-4-pyrimidinyl)amino)ethyl)-6-fluoro-N-methyl-3-phe-
nyl-4-quinolinecarboxamide
##STR00172##
[0537] .sup.1H-NMR (400 Hz, CD.sub.3OD) .delta. ppm 1.36 (d, 3H)
2.66 (s, 3H) 5.47-5.59 (m, 1H) 7.35-7.57 (m, 6H) 7.61-7.72 (m, 1H)
7.95 (s, 1H) 8.20 (dd, J=9.39, 5.28 Hz, 1H). Mass Spectrum (ESI)
m/e=442 (M+1).
Example 67
2-(1-((6-Amino-5-cyano-4-pyrimidinyl)amino)ethyl)-6-fluoro-N,N-dimethyl-3--
phenyl-4-quinolinecarboxamide
##STR00173##
[0539] .sup.1H-NMR (400 Hz, CD.sub.3OD) .delta. ppm 1.42 (3H, d)
2.67 (3H, s) 2.78 (3H, s) 5.35 (1H, q, J=6.78 Hz) 7.24 (1H, dd,
J=9.19, 2.54 Hz) 7.35 (5H, m) 7.57 (1H, td, J=8.80, 2.54 Hz) 7.76
(1H, s) 8.12 (1H, dd, J=9.10, 5.38 Hz). Mass Spectrum (ESI) m/e=456
(M+1).
Example 68
2-(1-((6-Amino-5-cyano-4-pyrimidinyl)amino)ethyl)-6-fluoro-N,N-dimethyl-3--
phenyl-4-quinolinecarboxamide
##STR00174##
[0541] .sup.1H-NMR (400 Hz, CD.sub.3OD) .delta. ppm 1.16 (3H, d)
2.50 (3H, s) 2.74 (3H, s) 5.51 (1H, q, J=6.65 Hz) 7.26 (1H, dd,
J=9.29, 2.64 Hz) 7.34 (1H, m) 7.43 (3H, m) 7.50 (1H, m) 7.58 (1H,
m) 7.88 (1H, s) 8.11 (1H, dd, J=9.39, 5.28 Hz). Mass Spectrum (ESI)
m/e=456 (M+1).
Example 69
2-((1S)-1-((6-Amino-5-cyano-4-pyrimidinyl)amino)ethyl)-6-fluoro-N,N-dimeth-
yl-3-phenyl-4-quinolinecarboxamide
##STR00175##
[0543] .sup.1H-NMR (400 Hz, CD.sub.3OD) .delta. ppm 1.29 (3H, d)
2.63 (3H, s) 2.86 (3H, s) 5.64 (1H, q, J=6.72 Hz) 7.38 (1H, dd,
J=9.29, 2.64 Hz) 7.46 (1H, m) 7.55 (3H, m) 7.62 (1H, m) 7.70 (1H,
m) 8.02 (1H, m) 8.24 (1H, dd, J=9.19, 5.28 Hz). Mass Spectrum (ESI)
m/e=456 (M+1).
Example 70
2-((1S)-1-((6-Amino-5-cyano-4-pyrimidinyl)amino)ethyl)-6-fluoro-N,N-dimeth-
yl-3-phenyl-4-quinolinecarboxamide
##STR00176##
[0545] .sup.1H-NMR (400 Hz, CD.sub.3OD) .delta. ppm 1.50 (3H, d)
2.65 (3H, s) 2.78 (3H, s) 5.46 (1H, q, J=6.65 Hz) 7.26 (1H, dd,
J=9.19, 2.74 Hz) 7.35 (5H, m) 7.58 (1H, td, J=8.80, 2.74 Hz) 7.91
(1H, s) 8.12 (1H, dd, J=9.29, 5.38 Hz). Mass Spectrum (ESI) m/e=456
(M+1).
Example 71
4-Amino-6-((1-(6-fluoro-3-phenyl-4-(1-pyrrolidinylcarbonyl)-2-quinolinyl)e-
thyl)amino)-5-pyrimidinecarbonitrile
##STR00177##
[0547] .sup.1H-NMR (400 Hz, CD.sub.3OD) .delta. ppm 0.92 (4H, m)
1.26 (2H, m) 1.57 (3H, m) 1.69 (2H, m) 3.02 (1H, m) 3.58 (1H, d)
5.49 (1H, q, J=6.72 Hz) 5.69 (1H, q, J=6.72 Hz) 7.46 (9H, m) 7.67
(2H, m) 7.87 (1H, m) 8.03 (1H, s) 8.23 (1H, dd, J=9.19, 5.28 Hz).
Mass Spectrum (ESI) m/e=482 (M+1).
Example 72
4-Amino-6-O-1-(6-fluoro-3-phenyl-4-(1-piperazinylcarbonyl)-2-quinolinyl)et-
hyl)amino)-5-pyrimidinecarbonitrile
##STR00178##
[0549] .sup.1H-NMR (400 Hz, CD.sub.3OD) .delta. ppm 1.28 (3H, d)
2.50 (1H, s) 2.71 (1H, d, J=16.24 Hz) 2.94 (1H, d, J=7.04 Hz) 3.15
(1H, m) 3.68 (1H, d, J=7.24 Hz) 3.85 (1H, s) 5.79 (1H, d, J=6.65
Hz) 7.51 (2H, m) 7.61 (3H, m) 7.71 (2H, m) 8.15 (1H, s) 8.26 (1H,
dd, J=9.19, 5.28 Hz). Mass Spectrum (ESI) m/e=497 (M+1).
Example 73
4-Amino-6-(((1S)-1-(6-fluoro-3-phenyl-4-(1-piperazinylcarbonyl)-2-quinolin-
yl)ethyl)amino)-5-pyrimidinecarbonitrile
##STR00179##
[0551] .sup.1H-NMR (400 Hz, CD.sub.3OD) .delta. ppm 1.30 (3H, d)
2.52 (1H, m) 2.72 (1H, m) 2.97 (1H, m) 3.17 (1H, m) 3.28 (1H, m)
3.71 (1H, m) 3.89 (1H, ddd, J=14.48, 7.53, 3.42 Hz) 5.82 (1H, q,
J=6.85 Hz) 7.52 (3H, m) 7.62 (2H, m) 7.71 (2H, m) 8.26 (2H, m).
Mass Spectrum (ESI) m/e=497 (M+1).
Example 74
4-Amino-6-((1-(6-fluoro-4-((4-methyl-1-piperazinyl)carbonyl)-3-phenyl-2-qu-
inolinyl)ethyl)amino)-5-pyrimidinecarbonitrile
##STR00180##
[0553] .sup.1H-NMR (400 Hz, CD.sub.3OD) .delta. ppm 1.27 (3H, d,
J=6.7 Hz) 2.76-2.90 (4H, m) 4.87-4.92 (4H, m) 5.71-5.81 (1H, m)
7.51 (2H, d, J=9.2 Hz) 7.60 (2H, br. s) 7.65-7.76 (3H, m) 8.13 (1H,
s) 8.25 (1H, dd, J=9.3, 5.4 Hz). Mass Spectrum (ESI) m/e=511
(M+1).
Example 75
4-Amino-6-((1-(6-fluoro-4-(4-morpholinylcarbonyl)-3-phenyl-2-quinolinyl)et-
hyl)amino)-5-pyrimidinecarbonitrile
##STR00181##
[0555] .sup.1H-NMR (400 Hz, CD.sub.3OD) .delta. ppm 1.66 (4H, d)
3.03-3.29 (4H, m) 3.42-3.54 (2H, m) 3.58-3.75 (2H, m) 5.54 (1H, q,
J=6.52 Hz) 7.41 (1H, dd, J=9.10, 2.64 Hz) 7.44-7.62 (4H, m) 7.68
(1H, ddd, J=9.29, 8.31, 2.74 Hz) 7.81 (1H, s) 7.97 (1H, s) 8.23
(1H, dd, J=9.19, 5.28 Hz). Mass Spectrum (ESI) m/e=498 (M+1).
Example 76
4-Amino-6-((-1-(6-fluoro-4-(4-morpholinylcarbonyl)-3-phenyl-2-quinolinyl)e-
thyl)amino)-5-pyrimidinecarbonitrile
##STR00182##
[0557] .sup.1H-NMR (400 Hz, CD.sub.3OD) .delta. ppm 1.28 (2H, d)
2.92 (1H, d, J=5.67 Hz) 2.95-3.11 (2H, m) 3.14-3.27 (1H, m)
3.35-3.42 (1H, m) 3.46-3.56 (1H, m) 3.56-3.76 (2H, m) 5.76 (1H, q,
J=6.78 Hz) 7.42 (1H, dd, J=9.19, 2.74 Hz) 7.50-7.64 (4H, m) 7.68
(1H, ddd, J=9.19, 8.22, 2.74 Hz) 7.78 (1H, s) 8.14 (1H, s) 8.23
(1H, dd, J=9.19, 5.28 Hz). Mass Spectrum (ESI) m/e=409 (M+1). Mass
Spectrum (ESI) m/e=498 (M+1).
Example 77
4-Amino-6-((1-(6-fluoro-4-(((3R)-3-hydroxy-1-pyrrolidinyl)carbonyl)-3-phen-
yl-2-quinolinyl)ethyl)amino)-5-pyrimidinecarbonitrile
##STR00183##
[0559] .sup.1H-NMR (400 Hz, CD.sub.3OD) .delta. ppm 1.54 (d, J=6.65
Hz, 3H) 2.84-2.97 (m, 1H) 2.98-3.16 (m, 1H) 3.16-3.28 (m, 3H)
3.59-3.82 (m, 1H) 5.51-5.64 (m, 1H) 7.33-7.51 (m, 4H) 7.64-7.78 (m,
2H) 8.00-8.05 (m, 1H) 8.08 (s, 1H) 8.24 (ddd, J=9.10, 5.48, 3.23
Hz, 1H). Mass Spectrum (ESI) m/e=498 (M+1).
Example 78
4-Amino-6-((-1-(6-fluoro-4-(((3S)-3-hydroxy-1-pyrrolidinyl)carbonyl)-3-phe-
nyl-2-quinolinyl)ethyl)amino)-5-pyrimidinecarbonitrile
##STR00184##
[0561] .sup.1H-NMR (400 Hz, CD.sub.3OD) .delta. ppm 1.27 (d, 2H)
1.65 (d, J=6.65 Hz, 3H) 2.96-3.13 (m, 1H) 3.13-3.32 (m, 2H)
3.43-3.56 (m, 1H) 3.56-3.77 (m, 1H) 5.48-5.60 (m, 0H) 5.76 (q,
J=6.85 Hz, 0H) 7.38-7.62 (m, 4H) 7.62-7.72 (m, J=9.19, 8.27, 2.91,
2.91 Hz, 1H) 7.77 (s, 1H) 7.96 (s, 1H) 8.14 (s, 1H) 8.19-8.29 (m,
1H). Mass Spectrum (ESI) m/e=498 (M+1).
Example 79
4-Amino-6-((1-(6-fluoro-4-(((3S)-3-hydroxy-1-pyrrolidinyl)carbonyl)-3-phen-
yl-2-quinolinyl)ethyl)amino)-5-pyrimidinecarbonitrile (Rotomer of
Example 77)
##STR00185##
[0563] .sup.1H-NMR (400 Hz, CD.sub.3OD) .delta. ppm 1.30 (d, 3H)
2.88-3.13 (m, 2H) 3.21 (td, J=7.48, 3.62 Hz, 1H) 3.52 (d, J=5.87
Hz, 1H) 3.58-3.73 (m, 2H) 5.77 (q, J=6.78 Hz, 1H) 7.44 (dd, J=9.19,
2.54 Hz, 1H) 7.49-7.65 (m, 5H) 7.70 (td, J=8.71, 2.74 Hz, 1H) 8.19
(s, 1H) 8.24 (dd, J=9.29, 5.18 Hz, 1H). Mass Spectrum (ESI) m/e=498
(M+1).
Example 80
4-Amino-6-((1-(4-((1,1-dioxido-4-thiomorpholinyl)carbonyl)-6-fluoro-3-phen-
yl-2-quinolinyl)ethyl)amino)-5-pyrimidinecarbonitrile
##STR00186##
[0565] .sup.1H-NMR (400 Hz, CD.sub.3OD) .delta. ppm 1.39 (3H, d,
J=6.65 Hz) 1.66 (0H, d, J=7.24 Hz) 1.87 (1H, m) 2.00 (4H, m) 3.17
(1H, m) 3.50 (1H, m) 4.91 (1H, m) 7.39 (1H, s) 7.51 (1H, dd,
J=7.24, 1.17 Hz) 7.64 (1H, d, J=7.63 Hz) 7.75 (1H, m) 7.84 (1H, s)
7.91 (1H, s) 8.00 (1H, d, J=8.41 Hz) 8.24 (1H, s) 8.32 (1H, m).
Mass Spectrum (ESI) m/e=546 (M+1).
Example 81
4-Amino-6-(((1S)-1-(4-((1,1-dioxido-4-thiomorpholinyl)carbonyl)-6-fluoro-3-
-phenyl-2-quinolinyl)ethyl)amino)-5-pyrimidinecarbonitrile
##STR00187##
[0567] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 1.32 (3H, d,
J=6.65 Hz) 2.34 (1H, t, J=1.86 Hz) 2.68 (1H, d, J=1.76 Hz) 3.44
(1H, s) 3.61 (3H, s) 5.39 (1H, t, J=6.85 Hz) 7.26 (1H, br. s.) 7.36
(1H, m) 7.49 (3H, m) 7.60 (1H, dd, J=9.59, 2.74 Hz) 7.82 (1H, m)
7.93 (1H, s) 8.18 (1H, dd, J=9.19, 5.48 Hz). Mass Spectrum (ESI)
m/e=546 (M+1).
Example 82
4-Amino-6-(((1S)-1-(4-((1,1-dioxido-4-thiomorpholinyl)carbonyl)-6-fluoro-3-
-phenyl-2-quinolinyl)ethyl)amino)-5-pyrimidinecarbonitrile (Rotomer
of Example 81)
##STR00188##
[0569] .sup.1H-NMR (400 Hz, CD.sub.3OD) .delta. ppm 1.55 (3H, d,
J=6.65 Hz) 3.38 (4H, m) 4.89 (4H, m) 5.70 (1H, q, J=6.65 Hz) 6.48
(1H, m) 7.52 (2H, m) 7.71 (7H, m) 7.84 (1H, ddd, J=9.29, 8.31, 2.74
Hz) 8.05 (1H, m) 8.12 (1H, s) 8.37 (1H, dd, J=9.39, 5.28 Hz). Mass
Spectrum (ESI) m/e=546 (M+1).
Example 83
4-Amino-6-((1-(6-fluoro-4-((3-hydroxy-1-azetidinyl)carbonyl)-3-phenyl-2-qu-
inolinyl)ethyl)amino)-5-pyrimidinecarbonitrile
##STR00189##
[0571] .sup.1H-NMR (400 Hz, CD.sub.3OD) .delta. ppm 1.32 (3H, dd,
J=6.65, 1.17 Hz) 1.63 (2H, m) 3.50 (2H, m) 3.92 (2H, m) 4.11 (1H,
m) 4.39 (1H, m) 4.59 (1H, m) 5.61 (1H, dd, J=6.75, 3.03 Hz) 5.75
(1H, q, J=6.65 Hz) 7.54 (9H, m) 7.72 (2H, m) 8.05 (1H, d, J=4.89
Hz) 8.21 (1H, m) 8.25 (1H, m). Mass Spectrum (ESI) m/e=484
(M+1).
Example 84
4-Amino-6-(((1S)-1-(6-fluoro-4-((3-hydroxy-1-azetidinyl)carbonyl)-3-phenyl-
-2-quinolinyl)ethyl)amino)-5-pyrimidinecarbonitrile
##STR00190##
[0573] .sup.1H-NMR (400 Hz, CD.sub.3OD) .delta. ppm 1.26 (3H, d,
J=6.65 Hz) 1.54 (2H, dd, J=7.63, 6.65 Hz) 3.52 (3H, m) 3.72 (1H, m)
3.91 (3H, m) 4.07 (0H, ddd, J=10.03, 6.70, 1.08 Hz) 4.19 (1H, m)
4.39 (1H, m) 4.57 (1H, m) 5.49 (1H, m) 5.67 (1H, qd, J=6.65, 2.54
Hz) 7.53 (11H, m) 7.69 (3H, m) 7.88 (1H, d, J=5.28 Hz) 8.02 (1H, d,
J=1.37 Hz) 8.23 (2H, m). Mass Spectrum (ESI) m/e=484 (M+1).
Example 85
4-Amino-6-((1-(6-fluoro-4-((3-methoxy-1-azetidinyl)carbonyl)-3-phenyl-2-qu-
inolinyl)ethyl)amino)-5-pyrimidinecarbonitrile
##STR00191##
[0575] .sup.1H-NMR (400 Hz, CD.sub.3OD) .delta. ppm 1.32 (3H, d,
J=6.65 Hz) 1.63 (3H, d, J=6.65 Hz) 3.15 (3H, s) 3.50 (1H, m) 3.87
(0H, m) 4.04 (0H, m) 4.35 (0H, m) 5.61 (0H, s) 5.75 (0H, s) 7.53
(5H, m) 7.74 (1H, m) 8.03 (1H, d, J=2.54 Hz) 8.18 (1H, d, J=1.37
Hz) 8.24 (1H, m). Mass Spectrum (ESI) m/e=498 (M+1).
Example 86
2-(1-((6-Amino-5-cyano-4-pyrimidinyl)amino)ethyl)-6-fluoro-N-(2-(4-morphol-
inyl)ethyl)-3-phenyl-4-quinolinecarboxamide
##STR00192##
[0577] .sup.1H-NMR (400 Hz, CD.sub.3OD) .delta. ppm 1.44 (3H, d,
J=6.65 Hz) 2.80 (2H, td, J=6.85, 3.13 Hz) 3.38 (2H, m) 3.56 (2H, m)
4.83 (3H, m) 5.58 (1H, q, J=6.65 Hz) 7.48 (1H, m) 7.57 (5H, m) 7.71
(1H, td, J=8.80, 2.74 Hz) 8.05 (1H, s) 8.24 (1H, dd, J=9.29, 5.38
Hz). Mass Spectrum (ESI) m/e=541 (M+1).
Example 87A
2-(1-(6-Amino-5-cyanopyrimidin-4-ylamino)ethyl)-6-fluoro-N-methyl-3-(pyrid-
in-2-yl)quinoline-4-carboxamide
##STR00193##
[0579] To a solution of methyl
2-(1-(6-amino-5-cyanopyrimidin-4-ylamino)ethyl)-6-fluoro-3-(pyridin-2-yl)-
quinoline-4-carboxylate (2 g, 4.51 mmol) in 20 mL pyridine was
added LiI (1.81 g, 13.53 mmol). The resulting mixture was heated to
100.degree. C. overnight. Solvent was removed and the crude residue
was subject to combiflash using up to 20% MeOH/DCM to obtain
2-(1-(6-amino-5-cyanopyrimidin-4-ylamino)ethyl)-6-fluoro-3-(pyridin-2-yl)-
quinoline-4-carboxylic acid as a brown solid. The pure material was
purified by chiral HPLC (Isopropanol/Hexane gradient, AD column) to
obtain
(S)-2-(1-(6-amino-5-cyanopyrimidin-4-ylamino)ethyl)-6-fluoro-3-(py-
ridin-2-yl)quinoline-4-carboxylic acid. Mass Spectrum (ESI) m/e=430
(M+1). To a solution of
(S)-2-(1-(6-amino-5-cyanopyrimidin-4-ylamino)ethyl)-6-fluoro-3-(pyridin-2-
-yl)quinoline-4-carboxylic acid (100 mg, 0.233 mmol) was added
methanamine (14.47 mg, 0.466 mmol),
N-ethyl-N-isopropylpropan-2-amine (60.2 mg, 0.466 mmol) and PyBop
(267 mg, 0.512 mmol). The resulting mixture was stirred at rt
overnight. The solvent was removed and dissolved in EtOAc. It was
washed with water, brine and dried over sodium sulfate. After
removal of the organic phase in vacuo, the crude residue was
subjected to HPLC purification and preparatory TLC purification
using 2% MeOH/DCM with satd ammonia to afford
(S)-2-(1-(6-amino-5-cyanopyrimidin-4-ylamino)ethyl)-6-fluoro-N-methyl-3-(-
pyridin-2-yl)quinoline-4-carboxamide. .sup.1H-NMR (400 Hz,
CD.sub.3OD) .delta. ppm 1.43 (3H, d) 2.70 (3H, s) 5.60 (1H, q,
J=6.65 Hz) 7.52 (2H, m) 7.64 (1H, dt, J=7.82, 1.17 Hz) 7.71 (1H,
dd, J=2.84, 1.08 Hz) 7.96 (2H, m) 8.24 (1H, dd, J=9.29, 5.38 Hz)
8.73 (1H, m). Mass Spectrum (ESI) m/e=443 (M+1).
Example 87B
(S)-2-(1-(6-Amino-5-cyanopyrimidin-4-ylamino)ethyl)-6-fluoro-N-methyl-3-(p-
yridin-2-yl)quinoline-4-carboxamide
##STR00194##
[0581] tert-Butyl
1-(methoxy(methyl)amino)-1-oxopropan-2-ylcarbamate (50.0 g, 215
mmol) in THF (450 mL) was cooled to -40.degree. C. (dry
ice/acetonitrile) and slowly charged with isopropylmagnesium
chloride (2.0 M, 102.2 mL, 0.95 eq). After a clear solution was
obtained (became clear at -20.degree. C. and milky again at
-40.degree. C.), bromo(pyridin-2-ylmethyl)magnesium solution (see
below for preparation) was added drop wise using cannula before
warming to rt overnight. The reaction mixture was quenched with
NH.sub.4Cl solution and extracted with EtOAc (500 mL.times.2). The
combined organic layers were washed with water, brine, dried over
sodium sulfate, and concentrated under high vacuum to give
(S)-tert-butyl 3-oxo-4-(pyridin-2-yl)butan-2-ylcarbamate as a tan
oil. (Small scale reaction was purified by combiflash
(EtOAc/hexane, up to 1/3) to give a red oil. Mass Spectrum (ESI)
m/e=265 (M+1).
Bromo(pyridin-2-ylmethyl)magnesium
[0582] To a solution of picoline (31.9 mL, 1.5 eq) in THF (300 mL)
was added MeLi (202 mL, 1.6 M, 1.5 eq) drop wise at -40.degree. C.
under nitrogen. The reaction mixture was allowed to warm to
-20.degree. C. and stirred for 10 min. and then cooled to
-40.degree. C. and magnesium bromide (59.4 g, 1.5 eq) was added in
three portions. The reaction mixture was allowed to warm to rt,
stirred for 30 min. to provide bromo(pyridin-2-ylmethyl)magnesium.
KOH (25.05 g, 2.0 eq), 5-fluoroisatin (36.9 g, 1.0 eq) in EtOH (100
mL) and water (350 mL) were stirred at rt for 0.5 h before the
addition of (S)-tert-butyl 3-oxo-4-phenylbutan-2-ylcarbamate (59.00
g, 223 mmol). The reaction mixture was heated to 85.degree. C.
overnight and cooled to rt. The reaction mixture was concd to
remove EtOH and extracted with ether (100 mL.times.2). The filtrate
was cooled at 0.degree. C. and acidified with concd HCl. (50 mL).
The dark homogenous solution became a light yellow suspension after
adjusting to pH 4. The resulted yellow solid was filtered and dried
in the air. A pale yellow solid was obtained. To the filtrate was
added sodium sulfate (300 g), and the mixture was stirred at rt for
2 h followed by the addition of 20 mL conc. HCl. The mixture was
stirred at rt for additional 2 h. The resulted solid was filtered,
washed with cold water and dried in the air to give
2-(1-(tert-butoxycarbonylamino)ethyl)-6-fluoro-3-(pyridin-2-yl)quinoline--
4-carboxylic acid as a pale yellow solid. Overall
2-(1-(tert-butoxycarbonylamino)ethyl)-6-fluoro-3-(pyridin-2-yl)quinoline--
4-carboxylic acid was obtained as pale yellow solid. The racemic
2-(1-(tert-butoxycarbonylamino)ethyl)-6-fluoro-3-(pyridin-2-yl)quinoline--
4-carboxylic acid was submitted for chiral HPLC separation to
obtain
(S)-2-(1-(tert-butoxycarbonylamino)ethyl)-6-fluoro-3-(pyridin-2-yl)quinol-
ine-4-carboxylic acid. Mass Spectrum (ESI) m/e=412 (M+1). To a
solution of
2-(1-(tert-butoxycarbonylamino)ethyl)-6-fluoro-3-(pyridin-2-yl)quinoline--
4-carboxylic acid (1.3 g, 3.16 mmol) in DMF (10 mL) was added
methanamine (3.16 mL, 6.32 mmol), PyBOP (4.11 g, 7.90 mmol) and
DIEA (1.21 mL, 6.95 mmol). The resulting mixture was stirred at rt
overnight. The solvent was removed and diluted with EtOAc. The
organic layer was washed with water (3.times.100 mL), brine and
dried over sodium sulfate. The crude residue was subjected to
combiflash purification using 20-70% EtOAc/hexane to afford
tert-butyl
1-(6-fluoro-4-(methylcarbamoyl)-3-(pyridin-2-yl)quinolin-2-yl)ethylcarbam-
ate as white foam. Mass Spectrum (ESI) m/e=425 (M+1). To a pure
residue of tert-butyl
1-(6-fluoro-4-(methylcarbamoyl)-3-(pyridin-2-yl)quinolin-2-yl)ethylcarbam-
ate (1 g, 2.36 mmol) was added 4N HCl/1,4-dioxane (8 mL, 32.0
mmol). The resulting mixture was stirred at rt for 30 min. The
solvent was removed and crude
2-(1-aminoethyl)-6-fluoro-N-methyl-3-(pyridin-2-yl)quinoline-4--
carboxamide was used without further purification. Mass Spectrum
(ESI) m/e=325 (M+1). To a solution of
2-(1-aminoethyl)-6-fluoro-N-methyl-3-(pyridin-2-yl)quinoline-4-carboxamid-
e in DMF (15 mL) was added
4-amino-6-chloropyrimidine-5-carbonitrile (0.364 g, 2.356 mmol) and
DIEA (1.231 mL, 7.07 mmol). The resulting mixture was heated to
95.degree. C. for 2 h. The solvent was partially removed. EtOAc was
added and the mixture washed with water (3.times.100 mL), brine and
dried over sodium sulfate. The solvent was removed in vacuo and
purified by combiflash using 30% (10:1 MeOH/DCM)/DCM to afford
2-(1-(6-amino-5-cyanopyrimidin-4-ylamino)ethyl)-6-fluoro-N-methyl-3-(pyri-
din-2-yl)quinoline-4-carboxamide. After chiral HPLC separation
(Isopropanol/Hexane gradient, AD column)
(S)-2-(1-(6-amino-5-cyanopyrimidin-4-ylamino)ethyl)-6-fluoro-N-methyl-3-(-
pyridin-2-yl)quinoline-4-carboxamide was obtained.
Example 88
(S)-2-(1-(6-Amino-5-cyanopyrimidin-4-ylamino)ethyl)-N-ethyl-6-fluoro-3-(py-
ridin-2-yl)quinoline-4-carboximidamide
##STR00195##
[0584] To a solution of
(S)-2-(1-(tert-butoxycarbonylamino)ethyl)-6-fluoro-3-(pyridin-2-yl)quinol-
ine-4-carboxylic acid (140 mg, 0.340 mmol) in DMF (1 mL) was added
PyBOP (390 mg, 0.749 mmol), DIEA (0.119 mL, 0.681 mmol) and
ethanamine (0.340 mL, 0.681 mmol). The resulting mixture was
stirred at rt for 2 h. EtOAc was added. The organic solution was
washed with water, brine and dried over sodium sulfate. The solvent
was removed in vacuo. The crude residue was purified via combiflash
using 50% EtOAc/hexane to obtain (S)-tert-butyl
1-(4-(ethylcarbamoyl)-6-fluoro-3-(pyridin-2-yl)quinolin-2-yl)ethylcarbama-
te as light yellow oil. Mass Spectrum (ESI) m/e=439 (M+1). To the
light yellow oil (S)-tert-butyl
1-(4-(ethylcarbamoyl)-6-fluoro-3-(pyridin-2-yl)quinolin-2-yl)ethylcarbama-
te (125 mg, 0.285 mmol) was added 4N HCl/1,4-dioxane (1 mL, 32.9
mmol) and the resulting mixture stirred at rt for 1 h. Solvent was
removed and
(S)-2-(1-aminoethyl)-N-ethyl-6-fluoro-3-(pyridin-2-yl)quinoline-4-carboxa-
mide was used without further purification. Mass Spectrum (ESI)
m/e=339 (M+1). To a
(S)-2-(1-aminoethyl)-N-ethyl-6-fluoro-3-(pyridin-2-yl)quinoline-4-carboxa-
mide in DMF (1 mL) was added DIEA (0.199 mL, 1.140 mmol) and
4-amino-6-chloropyrimidine-5-carbonitrile (44.1 mg, 0.285 mmol).
The resulting mixture was heated to 95.degree. C. overnight. The
solvent was removed in vacuo and the crude residue was purified via
preparatory TLC using 5% MeOH/DCM to obtain
(S)-2-(1-(6-amino-5-cyanopyrimidin-4-ylamino)ethyl)-N-ethyl-6-fluoro-3-(p-
yridin-2-yl)quinoline-4-carboxamide. .sup.1H-NMR (400 Hz,
CD.sub.3OD) .delta. ppm 0.87 (t, 3H) 1.43 (d, J=6.65 Hz, 3H)
3.16-3.27 (m, 2H) 5.59 (q, J=6.65 Hz, 1H) 7.48-7.59 (m, 2H)
7.63-7.77 (m, 2H) 7.92-8.03 (m, 2H) 8.23 (dd, J=9.29, 5.38 Hz, 1H)
8.74 (ddd, J=5.04, 1.81, 0.98 Hz, 1H). Mass Spectrum (ESI) m/e=457
(M+1).
Example 89
(S)-2-(1-(6-Amino-5-cyanopyrimidin-4-ylamino)ethyl)-6-fluoro-N-(2-hydroxye-
thyl)-3-(pyridin-2-yl)quinoline-4-carboxamide
##STR00196##
[0586] To a solution of
(S)-2-(1-(tert-butoxycarbonylamino)ethyl)-6-fluoro-3-(pyridin-2-yl)quinol-
ine-4-carboxylic acid (100 mg, 0.243 mmol) in DMF (1 mL) was added
PyBOP (278 mg, 0.535 mmol), DIEA (0.127 mL, 0.729 mmol) and
2-aminoethanol (29.7 mg, 0.486 mmol). The resulting mixture was
stirred at rt for 2 h. The solvent was removed and EtOAc was added.
The organic solution was washed with water, brine and dried over
sodium sulfate. Solvent was removed in vacuo and purified via
combiflash using 5% MeOH/DCM to obtain (5)-tert-butyl
1-(6-fluoro-4-(2-hydroxyethylcarbamoyl)-3-(pyridin-2-yl)quinolin-2-yl)eth-
ylcarbamate as a dark yellow oil. Mass Spectrum (ESI) m/e=455
(M+1). To the dark yellow oil (S)-tert-butyl
1-(6-fluoro-4-(2-hydroxyethylcarbamoyl)-3-(pyridin-2-yl)quinolin-2-yl)eth-
ylcarbamate (50 mg, 0.110 mmol) was added 4N HCl/1,4-dioxane (1 mL,
32.9 mmol). The resulting mixture was stirred at rt for 1 h.
Solvent was removed and the crude
(S)-2-(1-aminoethyl)-6-fluoro-N-(2-hydroxyethyl)-3-(pyridin-2-yl)quinolin-
e-4-carboxamide was used without further purification. Mass
Spectrum (ESI) m/e=355 (M+1). To a solution of the crude
(S)-2-(1-aminoethyl)-6-fluoro-N-(2-hydroxyethyl)-3-(pyridin-2-yl)quinolin-
e-4-carboxamide in DMF (1 mL) was added DIEA (0.058 mL, 0.330 mmol)
and 4-amino-6-chloropyrimidine-5-carbonitrile (17.00 mg, 0.110
mmol). The resulting mixture was heated to 95.degree. C. The
solvent was removed and purified via preparatory TLC using 5%
MeOH/DCM to obtain
(S)-2-(1-(6-amino-5-cyanopyrimidin-4-ylamino)ethyl)-6-fluoro-N-(2-hydroxy-
ethyl)-3-(pyridin-2-yl)quinoline-4-carboxamide. .sup.1H-NMR (400
Hz, CD.sub.3OD) .delta. ppm 1.37 (d, 3H) 3.20-3.26 (m, 2H)
3.32-3.37 (m, 2H) 5.52 (q, J=6.72 Hz, 1H) 7.46 (ddd, J=7.68, 4.94,
0.88 Hz, 1H) 7.54-7.69 (m, 3H) 7.82-7.97 (m, 2H) 8.18 (dd, J=9.19,
5.28 Hz, 1H) 8.67 (d, J=4.89 Hz, 1H). Mass Spectrum (ESI) m/e=472
(M+1).
Example 90
(S)-2-(1-(6-Amino-5-cyanopyrimidin-4-ylamino)ethyl)-N-cyclopropyl-6-fluoro-
-3-(pyridin-2-yl)quinoline-4-carboxamide
##STR00197##
[0588] To a solution of
(S)-2-(1-(tert-butoxycarbonylamino)ethyl)-6-fluoro-3-(pyridin-2-yl)quinol-
ine-4-carboxylic acid (100 mg, 0.243 mmol) in DMF (1 mL) was added
PyBOP (278 mg, 0.535 mmol), DIEA (0.085 mL, 0.486 mmol) and
cyclopropanamine (0.034 mL, 0.486 mmol). The resulting mixture was
stirred at rt for 2 h, followed by the addition of EtOAc. The
organic solution was washed with water, brine and dried over sodium
sulfate. The solvent was removed and the crude residue purified via
combiflash using 50% EtOAc/Hexane to obtain a yellowish foam
(S)-tert-butyl
1-(4-(cyclopropylcarbamoyl)-6-fluoro-3-(pyridin-2-yl)quinolin-2-yl)ethylc-
arbamate. Mass Spectrum (ESI) m/e=451 (M+1). To the yellow foam
(S)-tert-butyl
1-(4-(cyclopropylcarbamoyl)-6-fluoro-3-(pyridin-2-yl)quinolin-2-yl)ethylc-
arbamate (85 mg, 0.189 mmol) was added 4N HCl/1,4-dioxane (1 mL,
32.9 mmol). The resulting mixture was stirred at rt for 1 h. The
solvent was removed and the crude
(S)-2-(1-aminoethyl)-N-cyclopropyl-6-fluoro-3-(pyridin-2-yl)quinoline-4-c-
arboxamide was used without further purification. Mass Spectrum
(ESI) m/e=351 (M+1). To a solution of
(S)-2-(1-aminoethyl)-N-cyclopropyl-6-fluoro-3-(pyridin-2-yl)quinoline-4-c-
arboxamide in DMF (1 mL) was added DIEA (0.099 mL, 0.566 mmol) and
4-amino-6-chloropyrimidine-5-carbonitrile (29.2 mg, 0.189 mmol).
The resulting mixture was heated to 95.degree. C. After the solvent
was removed, the crude residue was purified using 5% MeOH/DCM with
preparatory TLC to obtain
(S)-2-(1-(6-amino-5-cyanopyrimidin-4-ylamino)ethyl)-N-cyclopropyl-6-fluor-
o-3-(pyridin-2-yl)quinoline-4-carboxamide. .sup.1H-NMR (400 Hz,
CD.sub.3OD) .delta. ppm 0.10 (br. s., 2H) 0.63 (dd, J=7.24, 1.37
Hz, 2H) 1.40 (d, J=6.65 Hz, 3H) 2.65 (dt, J=7.34, 3.57 Hz, 1H) 5.55
(q, J=6.52 Hz, 1H) 7.46-7.66 (m, 3H) 7.66-7.78 (m, 1H) 7.91 (s, 1H)
7.96 (td, J=7.73, 1.76 Hz, 1H) 8.21 (dd, J=9.29, 5.38 Hz, 1H) 8.71
(td, J=2.54, 0.98 Hz, 1H). Mass Spectrum (ESI) m/e=469 (M+1).
[0589] The following examples were synthesized by following
procedures exemplified by examples 87A and/or 87B.
Example 91
2-1-((6-Amino-5-cyano-4-pyrimidinyl)amino)ethyl)-6-fluoro-3-(2-pyridinyl)--
4-quinolinecarboxylic acid
##STR00198##
[0591] .sup.1H-NMR (400 Hz, CD.sub.3OD) .delta. ppm 1.49 (3H, d)
5.65 (1H, m) 7.62 (1H, ddd, J=7.78, 5.14, 0.98 Hz) 7.76 (3H, m)
8.10 (2H, m) 8.27 (1H, m) 8.77 (1H, d, J=5.09 Hz). Mass Spectrum
(ESI) m/e=430 (M+1).
Example 92
2-(-1-((6-Amino-5-cyano-4-pyrimidinyl)amino)ethyl)-6-fluoro-N-methyl-3-(2--
pyridinyl)-4-quinolinecarboxamide
##STR00199##
[0593] .sup.1H-NMR (400 Hz, CD.sub.3OD) .delta. ppm 1.43 (3H, d)
2.70 (3H, s) 5.60 (1H, q, J=6.65 Hz) 7.52 (2H, m) 7.64 (1H, d,
J=7.83 Hz) 7.71 (1H, m) 7.97 (2H, m) 8.24 (1H, dd, J=9.29, 5.38 Hz)
8.73 (1H, m). Mass Spectrum (ESI) m/e=443 (M+1).
Example 93
2-((1R)-1-((6-Amino-5-cyano-4-pyrimidinyl)amino)ethyl)-6-fluoro-N-methyl-3-
-(2-pyridinyl)-4-quinolinecarboxamide
##STR00200##
[0595] .sup.1H-NMR (400 Hz, CD.sub.3OD) .delta. ppm 1.43 (3H, d)
2.70 (3H, s) 5.60 (1H, q, J=6.65 Hz) 7.52 (2H, m) 7.65 (1H, m) 7.72
(1H, m) 7.98 (2H, m) 8.24 (1H, dd, J=9.39, 5.28 Hz) 8.74 (1H, ddd,
J=4.89, 1.76, 0.98 Hz). Mass Spectrum (ESI) m/e=443 (M+1).
Example 94
2-(1-((6-Amino-5-cyano-4-pyrimidinyl)amino)ethyl)-6-fluoro-N,N-dimethyl-3--
(2-pyridinyl)-4-quinolinecarboxamide
##STR00201##
[0597] .sup.1H-NMR (400 Hz, CD.sub.3OD) .delta. ppm 1.32 (3H, d)
1.57 (3H, d, J=6.60 Hz) 2.63 (3 H, s) 2.73 (3H, s) 5.58 (1H, q,
J=6.68 Hz) 5.72 (1H, q, J=6.60 Hz) 7.44 (3H, m) 7.56 (1H, dd,
J=7.09, 5.14 Hz) 7.62 (2H, dd, J=14.06, 7.70 Hz) 7.73 (2H, m) 7.88
(1H, s) 7.93 (1H, td, J=7.83, 1.71 Hz) 8.01 (2H, m) 8.27 (2H, ddd,
J=11.55, 9.23, 5.38 Hz) 8.71 (1H, d, J=4.89 Hz) 8.76 (1H, d, J=4.89
Hz). Mass Spectrum (ESI) m/e=457 (M+1).
Example 95
4-Amino-6-((1-(6-fluoro-4-(1-piperazinylcarbonyl)-3-(2-pyridinyl)-2-quinol-
inyl)ethyl)amino)-5-pyrimidinecarbonitrile
##STR00202##
[0599] .sup.1H-NMR (400 Hz, CD.sub.3OD) .delta. ppm 5.33 (3H, d,
J=6.65 Hz) 5.48 (3H, d, J=6.85 Hz) 6.76 (2H, m) 7.33 (4H, m) 7.77
(2H, m) 9.59 (1H, q, J=6.85 Hz) 9.74 (1H, q, J=6.78 Hz) 11.50 (2H,
m) 11.70 (2H, m) 11.96 (2H, m) 12.24 (1H, ddd, J=12.67, 9.24, 5.28
Hz) 12.73 (1H, m). Mass Spectrum (ESI) m/e=498 (M+1).
Example 96
4-Amino-6-(((1R)-1-(6-fluoro-4-((3-hydroxy-1-azetidinyl)carbonyl)-3-(2-pyr-
idinyl)-2-quinolinyl)ethyl)amino)-5-pyrimidinecarbonitrile
##STR00203##
[0601] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 1.22 (3H, d,
J=6.65 Hz) 1.27 (3H, d, J=6.65 Hz) 1.43 (1H, dd, J=12.13, 6.65 Hz)
3.66 (0H, s) 3.82 (1H, br. s.) 4.04 (1H, s) 4.10 (0H, d, J=5.28 Hz)
4.25 (0H, m) 4.43 (0H, br. s.) 5.50 (0H, d, J=5.67 Hz) 5.78 (0H,
dd, J=6.55, 2.05 Hz) 7.44 (1H, d, J=5.09 Hz) 7.54 (3H, m) 7.88 (1H,
m) 7.97 (1H, m) 8.18 (1H, m) 8.73 (1H, m). Mass Spectrum (ESI)
m/e=485 (M+1).
Example 97
(S)-2-(1-(6-Amino-5-cyanopyrimidin-4-ylamino)ethyl)-N-methyl-3-phenylquino-
line-4-carboxamide
##STR00204##
[0603] Tert-butyl
1-(methoxy(methyl)amino)-1-oxopropan-2-ylcarbamate (10.00 g, 43
mmol) in THF (80 mL) was cooled to -40.degree. C. with MeCN and dry
ice, and slowly charged with isopropylmagnesium chloride (2.0M,
20.45 mL, 0.95 eq). After addition of all reagents, a clear
solution was obtained but quickly became milky. Benzylmagnesium
chloride (2.0 M, 21.53 mL, 1.0 eq) was added dropwise with stirring
at rt for 4 h. The reaction mixture was quenched with NH.sub.4Cl
solution and extracted with EtOAc (200 mL.times.2). The combined
organic layers were washed with water, brine, dried over sodium
sulfate, concd and purified by combiflash (EtOAc/hexane, up to 1/3)
to give tert-butyl 3-oxo-4-(pyridin-2-yl)butan-2-ylcarbamate as a
pale yellow oil, which became a white solid after drying under high
vacuum. Mass Spectrum (ESI) m/e=264 (M+1). tert-Butyl
3-oxo-4-(pyridin-2-yl)butan-2-ylcarbamate (1.00 g, 3.8 mmol), KOH
(0.426 g, 2.0 eq) and isatin (0.559 g, 1.0 eq) in EtOH (5 mL) and
water (5 mL) were heated at 85.degree. C. overnight. After cooling
to rt, the reaction volume was reduced to 4 mL and extracted with
ether twice. The filtrate was acidified with concd HCl to pH 3-4
until no solid was further formed. The solid was filtered, washed
with water and dried in the air to give a yellow solid,
2-(1-(tert-butoxycarbonylamino)ethyl)-3-phenylquinoline-4-carboxylic
acid. Mass Spectrum (ESI) m/e=393 (M+1). To a solution of
2-(1-(tert-butoxycarbonylamino)ethyl)-3-phenylquinoline-4-carboxylic
acid (0.3 g, 0.76 mmol) in DMF (6 mL) was added PyBop (0.875 g,
1.68 mmol), DIEA (0.134 mL, 0.764 mmol) and methanamine (0.573 mL,
1.15 mmol, 2M). The resulting mixture was stirred at room
temperature overnight. The solvent was removed in vacuo and
replaced with EtOAc. The resulting solution was washed with water,
brine and dried over sodium sulfate. The solvent was removed in
vacuo and the crude residue subjected to combiflash purification to
provide tert-butyl
1-(4-(methylcarbamoyl)-3-phenylquinolin-2-yl)ethylcarbamate as a
white solid. Mass Spectrum (ESI) m/e=406 (M+1). To tert-butyl
1-(4-(methylcarbamoyl)-3-phenylquinolin-2-yl)ethylcarbamate (87 mg,
0.215 mmol) was added 4M HCl/1,4-dioxane (1 mL, 4 mmol) and the
resulting solution was stirred at rt for 1 h. The solvent was
removed and the crude
2-(1-aminoethyl)-N-methyl-3-phenylquinoline-4-carboxamide was used
without further purification. Mass Spectrum (ESI) m/e=306 (M+1). To
a solution of the crude
2-(1-aminoethyl)-N-methyl-3-phenylquinoline-4-carboxamide in DMF (5
mL) was added 4-amino-6-chloropyrimidine-5-carbonitrile (33.2 mg,
0.215 mmol) and DIEA (0.112 mL, 0.644 mmol). The resulting mixture
was stirred at 100.degree. C. for 1 h. After the solvent was
removed under reduced pressure, EtOAc was added and the organic
layer was washed with water, brine and dried over sodium sulfate.
The solvent was removed in vacuo and the crude residue was purified
with chiral HPLC (Isopropanol/Hexane gradient, AD column) to
provide
(S)-2-(1-(6-amino-5-cyanopyrimidin-4-ylamino)ethyl)-N-methyl-3-phenylquin-
oline-4-carboxamide. .sup.1H-NMR (400 Hz, CD.sub.3OD) .delta. ppm
1.37 (2H, d, J=6.60 Hz), 2.66 (1H, s), 5.52 (1H, m), 7.47 (5H, m),
7.68 (1H, m), 7.85 (2H, m), 7.97 (1H, m), 8.16 (1H, d, J=8.31 Hz)
Mass Spectrum (ESI) m/e=424 (M+1).
Example 98
(S)-2-(1-(6-Amino-5-cyanopyrimidin-4-ylamino)ethyl)-8-fluoro-N-methyl-3-ph-
enylquinoline-4-carboxamide
##STR00205##
[0605] Tert-butyl 3-oxo-4-(pyridin-2-yl)butan-2-ylcarbamate was
obtained for the route described above. A solution of Tert-butyl
3-oxo-4-(pyridin-2-yl)butan-2-ylcarbamate (1.00 g, 3.8 mmol), KOH
(0.426 g, 2.0 eq) and 7-fluoroisatin (0.627 g, 1.0 eq) in EtOH (5
mL) and water (5 mL) were heated at 85.degree. C. overnight. After
cooling to rt, the reaction volume was reduced to 4 mL and
extracted with Et.sub.2O twice. The filtrate was acidified with
concd HCl to pH 3-4 until no solid was further formed. The solid
was filtered, washed with water and dried in the air to give a
yellow solid
2-(1-(tert-butoxycarbonylamino)ethyl)-8-fluoro-3-phenylquinoline-4-carbox-
ylic acid. Mass Spectrum (ESI) m/e=411 (M+1). To a solution of
2-(1-(tert-butoxycarbonylamino)ethyl)-8-fluoro-3-phenylquinoline-4-carbox-
ylic acid (0.30 g, 0.73 mmol) in DMF (6 mL) was added PyBop (0.837
g, 1.61 mmol), DIEA (0.128 mL, 0.731 mmol) and methanamine (0.548
mL, 1.1 mmol, 2 M). The resulting mixture was stirred at room
temperature overnight. The solvent was removed in vacuo and the
crude residue was subjected to combiflash purification to provide
tert-butyl
1-(8-fluoro-4-(methylcarbamoyl)-3-phenylquinolin-2-yl)ethylcarbamate
as a white solid. Mass Spectrum (ESI) m/e=424 (M+1). To tert-butyl
1-(8-fluoro-4-(methylcarbamoyl)-3-phenylquinolin-2-yl)ethylcarbamate
(280 mg, 0.661 mmol) was added 4M HCl/1,4-dioxane (1 mL, 4 mmol)
and the resulting solution stirred at rt for 1 h. The solvent was
removed and the crude
2-(1-aminoethyl)-8-fluoro-N-methyl-3-phenylquinoline-4-carboxamide
was used without further purification. Mass Spectrum (ESI) m/e=324
(M+1). To a solution of
2-(1-aminoethyl)-8-fluoro-N-methyl-3-phenylquinoline-4-carboxamide
in DMF (2 mL) was added 4-amino-6-chloropyrimidine-5-carbonitrile
(102 mg, 0.661 mmol) and DIEA (0.346 mL, 1.984 mmol). The resulting
mixture was stirred at 100.degree. C. EtOAc was then added and the
organic layer was washed with water, brine and dried over sodium
sulfate. The solvent was removed in vacuo and the crude residue was
purified by chiral HPLC (isopropanol/hexane gradient, AD column) to
provide
(S)-2-(1-(6-amino-5-cyanopyrimidin-4-ylamino)ethyl)-8-fluoro-N-methyl-3-p-
henylquinoline-4-carboxamide. .sup.1H-NMR (500 Hz, CD.sub.3OD)
.delta. ppm 1.39 (3H, d, J=6.60 Hz), 2.65 (3H, s), 5.57 (1H, q,
J=6.20 Hz), 7.43 (1H, m), 7.54 (5H, m), 7.65 (2H, m), 7.95 (1H, m).
(ESI) m/e=442 (M+1).
Biological Assays
Recombinant Expression of PI3Ks
[0606] Full length p110 subunits of PI3k .alpha., .beta. and
.delta., N-terminally labeled with polyHis tag, were coexpressed
with p85 with Baculo virus expression vectors in sf9 insect cells.
P110/p85 heterodimers were purified by sequential Ni-NTA, Q-HP,
Superdex-100 chromatography. Purified .alpha., .beta. and .delta.
isozymes were stored at -20.degree. C. in 20 mM Tris, pH 8, 0.2M
NaCl, 50% glycerol, 5 mM DTT, 2 mM Na cholate. Truncated
PI3K.gamma., residues 114-1102, N-terminally labeled with polyHis
tag, was expressed with Baculo virus in Hi5 insect cells. The
.gamma. isozyme was purified by sequential Ni-NTA, Superdex-200,
Q-HP chromatography. The .gamma. isozyme was stored frozen at
-80.degree. C. in NaH.sub.2PO.sub.4, pH 8, 0.2M NaCl, 1% ethylene
glycol, 2 mM .beta.-mercaptoethanol.
TABLE-US-00001 Alpha Beta Delta gamma 50 mM Tris pH 8 pH 7.5 pH 7.5
pH 8 MgCl2 15 mM 10 mM 10 mM 15 mM Na cholate 2 mM 1 mM 0.5 mM 2 mM
DTT 2 mM 1 mM 1 mM 2 mM ATP 1 uM 0.5 uM 0.5 uM 1 uM PIP2 none 2.5
uM 2.5 uM none time 1 h 2 h 2 h 1 h [Enzyme] 15 nM 40 nM 15 nM 50
nM
In Vitro PI3K Enzyme Assays
[0607] A PI3K Alphascreen.RTM. assay (PerkinElmer, Waltham, Mass.)
was used to measure the activity of a panel of four
phosphoinositide 3-kinases: PI3K.alpha., PI3K.beta., PI3K.gamma.,
and PI3K.delta.. Enzyme reaction buffer was prepared using sterile
water (Baxter, Deerfield, Ill.) and 50 mM Tris HCl pH 7, 14 mM
MgCl.sub.2, 2 mM sodium cholate, and 100 mM NaCl. 2 mM DTT was
added fresh the day of the experiment. The Alphascreen buffer was
made using sterile water and 10 mM Tris HCl pH 7.5, 150 mM NaCl,
0.10% Tween 20, and 30 mM EDTA. 1 mM DTT was added fresh the day of
the experiment. Compound source plates used for this assay were
384-well Greiner clear polypropylene plates containing test
compounds at 5 mM and diluted 1:2 over 22 concentrations. Columns
23 and 24 contained only DMSO as these wells comprised the positive
and negative controls, respectively. Source plates were replicated
by transferring 0.5 uL per well into 384-well Optiplates
(PerkinElmer, Waltham, Mass.).
[0608] Each PI3K isoform was diluted in enzyme reaction buffer to
2.times. working stocks. PI3K.alpha. was diluted to 1.6 nM,
PI3K.beta. was diluted to 0.8 nM, PI3K.gamma. was diluted to 15 nM,
and PI3K.delta. was diluted to 1.6 nM. PI(4,5)P2 (Echelon
Biosciences, Salt Lake City, Utah) was diluted to 10 .mu.M and ATP
was diluted to 20 .mu.M. This 2.times. stock was used in the assays
for PI3K.alpha. and PI3K.beta.. For assay of PI3K.gamma. and
PI3K.delta., PI(4,5)P2 was diluted to 10 .mu.M and ATP was diluted
to 8 .mu.M to prepare a similar 2.times. working stock. Alphascreen
reaction solutions were made using beads from the anti-GST
Alphascreen kit (PerkinElmer, Waltham, Mass.). Two 4.times. working
stocks of the Alphascreen reagents were made in Alphascreen
reaction buffer. In one stock, biotinylated-IP.sub.4 (Echelon
Biosciences, Salt Lake City, Utah) was diluted to 40 nM and
streptavadin-donor beads were diluted to 80 .mu.g/mL. In the second
stock, PIP.sub.3-binding protein (Echelon Biosciences, Salt Lake
City, Utah) was diluted to 40 nM and anti-GST-acceptor beads were
diluted to 80 .mu.g/mL. As a negative control, a reference
inhibitor at a concentration >>Ki (40 uM) was included in
column 24 as a negative (100% inhibition) control.
[0609] Using a 384-well Multidrop (Titertek, Huntsville, Ala.), 10
.mu.L/well of 2.times. enzyme stock was added to columns 1-24 of
the assay plates for each isoform. 10 .mu.L/well of the appropriate
substrate 2.times. stock (containing 20 .mu.M ATP for the
PI3K.alpha. and .beta. assays and containing 8 .mu.M ATP for the
PI3K.gamma. and .delta. assays) was then added to Columns 1-24 of
all plates. Plates were then incubated at room temperature for 20
minutes. In the dark, 10 .mu.L/well of the donor bead solution was
added to columns 1-24 of the plates to quench the enzyme reaction.
The plates were incubated at room temperature for 30 minutes. Still
in the dark, 10 .mu.L/well of the acceptor bead solution was added
to columns 1-24 of the plates. The plates were then incubated in
the dark for 1.5 hours. The plates were read on an Envision
multimode Plate Reader (PerkinElmer, Waltham, Mass.) using a 680 nm
excitation filter and a 520-620 nm emission filter.
Alternative In Vitro Enzyme Assays.
[0610] Assays were performed in 25 .mu.L with the above final
concentrations of components in white polyproplyene plates (Costar
3355). Phospatidyl inositol phosphoacceptor, PtdIns(4,5)P2 P4508,
was from Echelon Biosciences. The ATPase activity of the alpha and
gamma isozymes was not greatly stimulated by PtdIns(4,5)P2 under
these conditions and was therefore omitted from the assay of these
isozymes. Test compounds were dissolved in dimethyl sulfoxide and
diluted with three-fold serial dilutions. The compound in DMSO (1
.mu.L) was added per test well, and the inhibition relative to
reactions containing no compound, with and without enzyme was
determined. After assay incubation at rt, the reaction was stopped
and residual ATP determined by addition of an equal volume of a
commercial ATP bioluminescence kit (Perkin Elmer EasyLite)
according to the manufacturer's instructions, and detected using a
AnalystGT luminometer.
Human B Cells Proliferation Stimulate by Anti-IgM
Isolate Human B Cells:
[0611] Isolate PBMCs from Leukopac or from human fresh blood.
Isolate human B cells by using Miltenyi protocol and B cell
isolation kit II. --human B cells were Purified by using
AutoMacs.column.
Activation of Human B Cells
[0612] Use 96 well Flat bottom plate, plate 50000/well purified B
cells in B cell proliferation medium (DMEM+5% FCS, 10 mM Hepes, 50
.mu.M 2-mercaptoethanol); 150 .mu.L medium contain 250 ng/mL
CD40L-LZ recombinant protein (Amgen) and 2 .mu.g/mL anti-Human IgM
antibody (Jackson ImmunoReseach Lab.#109-006-129), mixed with 50
.mu.L B cell medium containing PI3K inhibitors and incubate 72 h at
37.degree. C. incubator. After 72 h, pulse labeling B cells with
0.5-1 uCi/well .sup.3H thymidine for overnight .about.18 h, and
harvest cell using TOM harvester.
Human B Cells Proliferation Stimulate by IL-4
Isolate Human B Cells:
[0613] Isolate human PBMCs from Leukopac or from human fresh blood.
Isolate human B cells using Miltenyi protocol--B cell isolation
kit. Human B cells were Purified by AutoMacs.column.
Activation of Human B Cells
[0614] Use 96-well flat bottom plate, plate 50000/well purified B
cells in B cell proliferation medium (DMEM+5% FCS, 50 .mu.M
2-mercaptoethanol, 10 mM Hepes). The medium (150 .mu.L) contain 250
ng/mL CD40L-LZ recombinant protein (Amgen) and 10 ng/mL IL-4
(R&D system # 204-IL-025), mixed with 50 150 .mu.L B cell
medium containing compounds and incubate 72 h at 37.degree. C.
incubator. After 72 h, pulse labeling B cells with 0.5-1 uCi/well
3H thymidine for overnight .about.18 h, and harvest cell using TOM
harvester.
Specific T Antigen (Tetanus Toxoid) Induced Human PBMC
Proliferation Assays
[0615] Human PBMC are prepared from frozen stocks or they are
purified from fresh human blood using a Ficoll gradient. Use 96
well round-bottom plate and plate 2.times.10.sup.5 PBMC/well with
culture medium (RPMI1640+10% FCS, 50 uM 2-Mercaptoethanol, 10 mM
Hepes). For IC.sub.50 determinations, PI3K inhibitors was tested
from 10 .mu.M to 0.001 .mu.M, in half log increments and in
triplicate. Tetanus toxoid, T cell specific antigen (University of
Massachusetts Lab) was added at 1 .mu.g/mL and incubated 6 days at
37.degree. C. incubator. Supernatants are collected after 6 days
for IL2 ELISA assay, then cells are pulsed with .sup.3H-thymidine
for .about.18 h to measure proliferation.
GFP Assays for Detecting Inhibition of Class Ia and Class III
PI3K
[0616] AKT1 (PKBa) is regulated by Class Ia PI3K activated by
mitogenic factors (IGF-1, PDGF, insulin, thrombin, NGF, etc.). In
response to mitogenic stimuli, AKT1 translocates from the cytosol
to the plasma membrane Forkhead (FKHRL1) is a substrate for AKT1.
It is cytoplasmic when phosphorylated by AKT (survival/growth).
Inhibition of AKT (stasis/apoptosis)--forkhead translocation to the
nucleus FYVE domains bind to PI(3)P. The majority is generated by
constitutive action of PI3K Class III
AKT Membrane Ruffling Assay (CHO-IR-AKT1-EGFP Cells/GE
Healthcare)
[0617] Wash cells with assay buffer. Treat with compounds in assay
buffer 1 h. Add 10 ng/mL insulin. Fix after 10 min at room temp and
image
Forkhead Translocation Assay (MDA MB468 Forkhead-DiversaGFP
cells)
[0618] Treat cells with compound in growth medium 1 h. Fix and
image.
Class III PI(3)P Assay (U2OS EGFP-2XFYVE Cells/GE Healthcare)
[0619] Wash cells with assay buffer. Treat with compounds in assay
buffer 1 h. Fix and image.
Control for all 3 assays is 10 uM Wortmannin:
[0620] AKT is cytoplasmic
[0621] Forkhead is nuclear
[0622] PI(3)P depleted from endosomes
Biomarker assay: B-cell receptor stimulation of CD69 or B7.2 (CD86)
expression
[0623] Heparinized human whole blood was stimulated with 10
.mu.g/mL anti-IgD (Southern Biotech, #9030-01). 90 .mu.L of the
stimulated blood was then aliquoted per well of a 96-well plate and
treated with 10 .mu.L of various concentrations of blocking
compound (from 10-0.0003 .mu.M) diluted in IMDM+10% FBS (Gibco).
Samples were incubated together for 4 h (for CD69 expression) to 6
h (for B7.2 expression) at 37.degree. C. Treated blood (50 .mu.L)
was transferred to a 96-well, deep well plate (Nunc) for antibody
staining with 10 .mu.L each of CD45-PerCP (BD Biosciences,
#347464), CD19-FITC (BD Biosciences, #340719), and CD69-PE (BD
Biosciences, #341652). The second 50 .mu.L of the treated blood was
transferred to a second 96-well, deep well plate for antibody
staining with 10 .mu.L each of CD19-FITC (BD Biosciences, #340719)
and CD86-PeCy5 (BD Biosciences, #555666). All stains were performed
for 15-30 min in the dark at rt. The blood was then lysed and fixed
using 450 .mu.L of FACS lysing solution (BD Biosciences, #349202)
for 15 min at rt. Samples were then washed 2.times. in PBS+2% FBS
before FACS analysis. Samples were gated on either CD45/CD19 double
positive cells for CD69 staining, or CD19 positive cells for CD86
staining
Gamma Counterscreen: Stimulation of Human Monocytes for Phospho-AKT
Expression
[0624] A human monocyte cell line, THP-1, was maintained in
RPMI+10% FBS (Gibco). One day before stimulation, cells were
counted using trypan blue exclusion on a hemocytometer and
suspended at a concentration of 1.times.10.sup.6 cells per mL of
media. 100 .mu.L of cells plus media (1.times.10.sup.5 cells) was
then aliquoted per well of 4-96-well, deep well dishes (Nunc) to
test eight different compounds. Cells were rested overnight before
treatment with various concentrations (from 10-0.0003 .mu.M) of
blocking compound. The compound diluted in media (12 .mu.L) was
added to the cells for 10 min at 37.degree. C. Human MCP-1 (12
.mu.L, R&D Diagnostics, #279-MC) was diluted in media and added
to each well at a final concentration of 50 ng/mL. Stimulation
lasted for 2 min at rt. Pre-warmed FACS Phosflow Lyse/Fix buffer (1
mL of 37.degree. C.) (BD Biosciences, #558049) was added to each
well. Plates were then incubated at 37.degree. C. for an additional
10-15 min. Plates were spun at 1500 rpm for 10 min, supernatant was
aspirated off, and 1 mL of ice cold 90% MeOH was added to each well
with vigorous shaking Plates were then incubated either overnight
at -70.degree. C. or on ice for 30 min before antibody staining
Plates were spun and washed 2.times. in PBS+2% FBS (Gibco). Wash
was aspirated and cells were suspended in remaining buffer. Rabbit
pAKT (50 .mu.L, Cell Signaling, #4058L) at 1:100, was added to each
sample for 1 h at rt with shaking Cells were washed and spun at
1500 rpm for 10 min. Supernatant was aspirated and cells were
suspended in remaining buffer. Secondary antibody, goat anti-rabbit
Alexa 647 (50 .mu.L, Invitrogen, #A21245) at 1:500, was added for
30 min at rt with shaking Cells were then washed 1.times. in buffer
and suspended in 150 .mu.L of buffer for FACS analysis. Cells need
to be dispersed very well by pipetting before running on flow
cytometer. Cells were run on an LSR II (Becton Dickinson) and gated
on forward and side scatter to determine expression levels of pAKT
in the monocyte population.
Gamma Counterscreen: Stimulation of Monocytes for Phospho-AKT
Expression in Mouse Bone Marrow
[0625] Mouse femurs were dissected from five female BALB/c mice
(Charles River Labs.) and collected into RPMI+10% FBS media
(Gibco). Mouse bone marrow was removed by cutting the ends of the
femur and by flushing with 1 mL of media using a 25 gauge needle.
Bone marrow was then dispersed in media using a 21 gauge needle.
Media volume was increased to 20 mL and cells were counted using
trypan blue exclusion on a hemocytometer. The cell suspension was
then increased to 7.5.times.10.sup.6 cells per 1 mL of media and
100 .mu.L (7.5.times.10.sup.5 cells) was aliquoted per well into
4-96-well, deep well dishes (Nunc) to test eight different
compounds. Cells were rested at 37.degree. C. for 2 h before
treatment with various concentrations (from 10-0.0003 .mu.M) of
blocking compound. Compound diluted in media (12 .mu.L) was added
to bone marrow cells for 10 min at 37.degree. C. Mouse MCP-1 (12
.mu.L, R&D Diagnostics, #479-JE) was diluted in media and added
to each well at a final concentration of 50 ng/mL. Stimulation
lasted for 2 min at rt. 1 mL of 37.degree. C. pre-warmed FACS
Phosflow Lyse/Fix buffer (BD Biosciences, #558049) was added to
each well. Plates were then incubated at 37.degree. C. for an
additional 10-15 min. Plates were spun at 1500 rpm for 10 min.
Supernatant was aspirated off and 1 mL of ice cold 90% MeOH was
added to each well with vigorous shaking Plates were then incubated
either overnight at -70.degree. C. or on ice for 30 min before
antibody staining Plates were spun and washed 2.times. in PBS+2%
FBS (Gibco). Wash was aspirated and cells were suspended in
remaining buffer. Fc block (2 .mu.L, BD Pharmingen, #553140) was
then added per well for 10 min at rt. After block, 50 uL of primary
antibodies diluted in buffer; CD11b-Alexa488 (BD Biosciences,
#557672) at 1:50, CD64-PE (BD Biosciences, #558455) at 1:50, and
rabbit pAKT (Cell Signaling, #4058L) at 1:100, were added to each
sample for 1 h at RT with shaking Wash buffer was added to cells
and spun at 1500 rpm for 10 min. Supernatant was aspirated and
cells were suspended in remaining buffer. Secondary antibody; goat
anti-rabbit Alexa 647 (50 .mu.L, Invitrogen, #A21245) at 1:500, was
added for 30 min at rt with shaking Cells were then washed 1.times.
in buffer and suspended in 100 uL of buffer for FACS analysis.
Cells were run on an LSR II (Becton Dickinson) and gated on
CD11b/CD64 double positive cells to determine expression levels of
pAKT in the monocyte population.
pAKT In Vivo Assay
[0626] Vehicle and compounds are administered p.o. (0.2 mL) by
gavage (Oral Gavage Needles Popper & Sons, New Hyde Park, N.Y.)
to mice (Transgenic Line 3751, female, 10-12 wks Amgen Inc,
Thousand Oaks, Calif.) 15 min prior to the injection i.v (0.2 mLs)
of anti-IgM FITC (50 ug/mouse) (Jackson Immuno Research, West
Grove, Pa.). After 45 min the mice are sacrificed within a CO.sub.2
chamber. Blood is drawn via cardiac puncture (0.3 mL) (1 cc 25 g
Syringes, Sherwood, St. Louis, Mo.) and transferred into a 15 mL
conical vial (Nalge/Nunc International, Denmark). Blood is
immediately fixed with 6.0 mL of BD Phosflow Lyse/Fix Buffer (BD
Bioscience, San Jose, Calif.), inverted 3.times.'s and placed in
37.degree. C. water bath. Half of the spleen is removed and
transferred to an eppendorf tube containing 0.5 mL of PBS
(Invitrogen Corp, Grand Island, N.Y.). The spleen is crushed using
a tissue grinder (Pellet Pestle, Kimble/Kontes, Vineland, N.J.) and
immediately fixed with 6.0 mL of BD Phosflow Lyse/Fix buffer,
inverted 3.times.'s and placed in 37.degree. C. water bath. Once
tissues have been collected the mouse is cervically-dislocated and
carcass to disposed. After 15 min, the 15 mL conical vials are
removed from the 37.degree. C. water bath and placed on ice until
tissues are further processed. Crushed spleens are filtered through
a 70 .mu.m cell strainer (BD Bioscience, Bedford, Mass.) into
another 15 mL conical vial and washed with 9 mL of PBS. Splenocytes
and blood are spun @ 2,000 rpms for 10 min (cold) and buffer is
aspirated. Cells are resuspended in 2.0 mL of cold (-20.degree. C.)
90% methyl alcohol (Mallinckrodt Chemicals, Phillipsburg, N.J.).
MeOH is slowly added while conical vial is rapidly vortexed.
Tissues are then stored at -20.degree. C. until cells can be
stained for FACS analysis.
Multi-Dose TNP Immunization
[0627] Blood was collected by retro-orbital eye bleeds from 7-8
week old BALB/c female mice (Charles River Labs.) at day 0 before
immunization. Blood was allowed to clot for 30 min and spun at
10,000 rpm in serum microtainer tubes (Becton Dickinson) for 10
min. Sera were collected, aliquoted in Matrix tubes (Matrix Tech.
Corp.) and stored at -70.degree. C. until ELISA was performed. Mice
were given compound orally before immunization and at subsequent
time periods based on the life of the molecule. Mice were then
immunized with either 50 .mu.g of TNP-LPS (Biosearch Tech.,
#T-5065), 50 .mu.g of TNP-Ficoll (Biosearch Tech., #F-1300), or 100
.mu.g of TNP-KLH (Biosearch Tech., #T-5060) plus 1% alum (Brenntag,
#3501) in PBS. TNP-KLH plus alum solution was prepared by gently
inverting the mixture 3-5 times every 10 min for 1 h before
immunization. On day 5, post-last treatment, mice were CO.sub.2
sacrificed and cardiac punctured. Blood was allowed to clot for 30
min and spun at 10,000 rpm in serum microtainer tubes for 10 min.
Sera were collected, aliquoted in Matrix tubes, and stored at
-70.degree. C. until further analysis was performed. TNP-specific
IgG1, IgG2a, IgG3 and IgM levels in the sera were then measured via
ELISA. TNP-BSA (Biosearch Tech., #T-5050) was used to capture the
TNP-specific antibodies. TNP-BSA (10 .mu.g/mL) was used to coat
384-well ELISA plates (Corning Costar) overnight. Plates were then
washed and blocked for 1 h using 10% BSA ELISA Block solution
(KPL). After blocking, ELISA plates were washed and sera
samples/standards were serially diluted and allowed to bind to the
plates for 1 h. Plates were washed and Ig-HRP conjugated secondary
antibodies (goat anti-mouse IgG1, Southern Biotech #1070-05, goat
anti-mouse IgG2a, Southern Biotech #1080-05, goat anti-mouse IgM,
Southern Biotech #1020-05, goat anti-mouse IgG3, Southern Biotech
#1100-05) were diluted at 1:5000 and incubated on the plates for 1
h. TMB peroxidase solution (SureBlue Reserve TMB from KPL) was used
to visualize the antibodies. Plates were washed and samples were
allowed to develop in the TMB solution approximately 5-20 min
depending on the Ig analyzed. The reaction was stopped with 2M
sulfuric acid and plates were read at an OD of 450 nm.
[0628] The following compounds showed the associated data in the
above PI3K.delta. Alphascreen.RTM. assay:
TABLE-US-00002 Compound Ki (.mu.M)
4-amino-1-((1S)-1-(6-fluoro-3-(5-fluoro-3-pyridinyl)-2- 0.024997
quinolinyl)ethyl)-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile
4-amino-1-((1R)-1-(6-fluoro-3-(5-fluoro-3-pyridiny1)-2- 5.4689475
quinolinyl)ethyl)-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile
4-amino-6-(((1S)-1-(6-fluoro-3-(6-(methylsulfonyl)-2- 0.1297
pyridinyl)-2-quinolinyl)ethyl)amino)-5-pyrimidinecarbonitrile
N-(1-(6-fluoro-3-(2-pyridiny1)-2-quinolinyl)ethyl)-9H-purin-6-
0.0212875 amine
N-((1S)-1-(6-fluoro-3-(2-pyridinyl)-2-quinolinyl)ethyl)-9H-
0.004147 purin-6-amine
N-((1R)-1-(6-fluoro-3-(2-pyridinyl)-2-quinolinyl)ethyl)-9H- 0.2168
purin-6-amine N-(1-(6-fluoro-3-(2-pyridiny1)-2-quinolinyl)ethyl)-4-
11.632679 pyrimidinamine
N-(1-(6-fluoro-3-(2-pyridiny1)-2-quinolinyl)ethyl)-4,6- 3.7315
pyrimidinediamine N~4~-((1R)-1-(6-fluoro-3-(2-pyridinyl)-2- 5.5205
quinolinyl)ethyl)-2,4- pyrimidinediamine
4-amino-6-((1-(6-fluoro-3-(2-pyridinyl)-2- 0.004217
quinolinyl)ethyl)amino)-5-pyrimidinecarbonitrile
4-((1-(6-fluoro-3-(2-pyridinyl)-2-quinolinyl)ethyl)amino)-6- 0.0548
hydroxy-5-pyrimidinecarbonitrile
4-amino-1-((1S)-1-(6-fluoro-3-(2-pyridinyl)-2- 0.0076745
quinolinyl)ethyl)-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile
4-amino-1-((1R)-1-(6-fluoro-3-(2-pyridinyl)-2- 0.32
quinolinyl)ethyl)-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile
4-amino-6-((1-(5-chloro-3-(2-pyridiny1)-2- 0.0016
quinolinyl)ethyl)amino)-5-pyrimidinecarbonitrile
4-amino-6-(((1S)-1-(5-chloro-3-(2-pyridinyl)-2- 0.0004
quinolinyl)ethyl)amino)-5-pyrimidinecarbonitrile
4-amino-6-(((1R)-1-(5-chloro-3-(2-pyridiny1)-2- 0.0579
quinolinyl)ethyl)amino)-5-pyrimidinecarbonitrile
2-((1S)-1-((6-amino-5-cyano-4-pyrimidinyl)amino)ethyl)-3-(2- 0.0141
pyridiny1)-5-quinolinecarbonitrile
2-((1R)-1-((6-amino-5-cyano-4-pyrimidinyl)amino)ethyl)-3-(2- 2.64
pyridiny1)-5-quinolinecarbonitrile
4-amino-6-((1-(3-(2-pyridiny1)-1,8-naphthyridin-2- 0.225
yl)ethyl)amino)-5-pyrimidinecarbonitrile
4-amino-6-((1-(3-(2-pyridinyl)-1,6-naphthyridin-2- 0.47
yl)ethyl)amino)-5-pyrimidinecarbonitrile
4-amino-6-((1-(6-fluoro-4-(methylsulfony1)-3-phenyl-2- 0.0013
quinolinyl)ethyl)amino)-5-pyrimidinecarbonitrile
4-amino-6-((1-(6-fluoro-4-(methylsulfanyl)-3-phenyl-2- 0.0024
quinolinyl)ethyl)amino)-5-pyrimidinecarbonitrile
4-amino-6-(((8-fluoro-3-(2-(methylsulfonyl)phenyl)-2- 0.0307
quinolinyl)methyl)amino)-5-pyrimidinecarbonitrile
4-amino-6-(((8-fluoro-3-(2-pyridinyl)-2- 0.262
quinolinyl)methyl)amino)-5-pyrimidinecarbonitrile
4-amino-6-(((8-fluoro-3-phenyl-2-quinolinyl)methyl)amino)-5- 0.0123
pyrimidinecarbonitrile
4-amino-6-(((5-fluoro-3-phenyl-2-quinolinyl)methyl)amino)-5- 0.107
pyrimidinecarbonitrile 4-amino-6-(((5-fluoro-3-(3-fluorophenyl)-2-
0.102 quinolinyl)methyl)amino)-5-pyrimidinecarbonitrile
4-amino-6-(((3-(3,5-difluorophenyl)-5-fluoro-2- 0.246
quinolinyl)methyl)amino)-5-pyrimidinecarbonitrile
4-amino-6-(((5-fluoro-3-(2-(methylsulfonyl)phenyl)-2- 0.039
quinolinyl)methyl)amino)-5-pyrimidinecarbonitrile
4-amino-6-(((5-fluoro-3-(2-pyridinyl)-2- 0.137
quinolinyl)methyl)amino)-5-pyrimidinecarbonitrile
4-amino-6-((-1-(4-(dimethylamino)-6-fluoro-3-(2-pyridinyl)-2-
0.0014 quinolinyl)ethyl)amino)-5-pyrimidinecarbonitrile
4-amino-6-((-1-(6-fluoro-4-(4-morpholinyl)-3-(2-pyridinyl)-2-
0.00119 quinolinyl)ethyl)amino)-5-pyrimidinecarbonitrile
4-amino-6-((-1-(6-fluoro-4-(3-hydroxy-1-azetidinyl)-3-(2- 0.00178
pyridiny1)-2-quino linyl)ethyl)amino)-5-pyrimidinecarbonitrile
2-((1S)-1-((6-amino-5-cyano-4-pyrimidinyl)amino)ethyl)-6- 0.0148
fluoro-N,N-dimethyl-3-phenyl-4-quinolinecarboxamide
4-amino-6-(((1S)-1-(6-fluoro-4-(4-morpholinylcarbonyl)-3- 0.000505
phenyl-2-quinolinyl)ethyl)amino)-5-pyrimidinecarbonitrile
4-amino-6-(((1S)-1 -(6-fluoro-4-(((3S)-3-hydroxy-1- 0.000657
pyrrolidinyl)carbony1)-3-pheny1-2-quinolinyl)ethyl)amino)-5-
pyrimidinecarbonitrile
4-amino-6-(((1S)-1-(4-((1,1-dioxido-4-thiomorpholiny1)- 0.00124
carbonyl)-6-fluoro-3-phenyl-2-quinolinyl)ethyl)amino)-5-
pyrimidinecarbonitrile
2-((1S)-1-((6-amino-5-cyano-4-pyrimidinyl)amino)ethyl)-6- 0.00276
fluoro-3-phenyl-4-quinolinecarbonitrile
2-((1S)-1-((6-amino-5-cyano-4-pyrimidinyl)amino)ethyl)-6- 0.00133
fluoro-3-phenyl-4-quinolinecarbonitrile
2-((1R)-146-amino-5-cyano-4-pyrimidinyl)amino)ethyl)-6- 0.0591
fluoro-3-phenyl-4-quinolinecarbonitrile methyl
2-(-1-((6-amino-5-cyano-4-pyrimidinyl)amino)ethyl)-6- 0.00156
fluoro-3-phenyl-4-quinolinecarboxylate
2-((1S)-1-((6-amino-5-cyano-4-pyrimidinyl)amino)ethyl)-6- 0.0742
fluoro-3-phenyl-4-quinolinecarboxylic acid
2-((1S)-1-((6-amino-5-carbamoyl-4-pyrimidinyl)amino)ethyl)- 0.00716
6-fluoro-3-phenyl-4-quinolinecarboxylic acid
2-(-1-((6-amino-5-cyano-4-pyrimidinyl)amino)ethyl)-6-fluoro-
0.000796 N-methyl-3-phenyl-4-quinolinecarboxamide
4-amino-6-((-1-(6-fluoro-3-pheny1-4-(1-piperazinylcarbonyl)-2-
0.000542 quinolinyl)ethyl)amino)-5-pyrimidinecarbonitrile
4-amino-6-((-1-(6-fluoro-4-((4-methyl-l-piperazinyl)carbonyl)-
0.00132 3-pheny1-2-quinolinyl)ethyl)amino)-5-pyrimidinecarbonitrile
2-(-1-((6-amino-5-cyano-4-pyrimidinyl)amino)ethyl)-6-fluoro-
0.00101 N,N-dimethyl-3-phenyl-4-quinolinecarboxamide
4-amino-6-((-1-(6-fluoro-4-(((3R)-3-hydroxy-1- 0.0256
pyrrolidinyl)carbony1)-3-pheny1-2-quinolinyl)ethyl)amino)-5-
pyrimidinecarbonitrile
4-amino-6-((1-(6-fluoro-3-phenyl-4-(1-pyrrolidinylcarbonyl)-2-
0.00706 quinolinyl)ethyl)amino)-5-pyrimidinecarbonitrile
4-amino-6-((-1-(6-fluoro-4-(4-morpholinylcarbonyl)-3-phenyl-
0.00288 2-quinolinyl)ethyl)amino)-5-pyrimidinecarbonitrile
4-amino-6-((-1-(6-fluoro-4-(((3S)-3-hydroxy-1- 0.00102
pyrrolidinyl)carbonyl)-3-phenyl-2-quinolinyl)ethyl)amino)-5-
pyrimidinecarbonitrile
4-amino-6-((-1-(6-fluoro-4-(((3R)-3-hydroxy-1-pyrrolidinyl)-
0.00507 carbony1)-3-phenyl-2-quinolinyl)ethyl)amino)-5-pyrimidine-
carbonitrile
4-amino-6-((1-(4-((1,1-dioxido-4-thiomorpholinyl)carbonyl)-6-
0.000556 fluoro-3-phenyl-2-quinolinyl)ethyl)amino)-5-pyrimidine-
carbonitrile
4-amino-6-((1-(6-fluoro-4-((3-hydroxy-1-azetidinyl)carbonyl)-
0.000755
3-phenyl-2-quinolinyl)ethyl)amino)-5-pyrimidinecarbonitrile
4-amino-6-((1-(6-fluoro-4-((3-methoxy-1-azetidinyl)carbonyl)-
0.00175 3-phenyl-2-quinolinyl)ethyl)amino)-5-pyrimidinecarbonitrile
2-(1-((6-amino-5-cyano-4-pyrimidinyl)amino)ethyl)-6-fluoro- 0.00102
N-(2-(4-morpholinyl)ethyl)-3-phenyl-4-quinolinecarboxamide
4-amino-6-((-1-(6-fluoro-4-(hydroxymethyl)-3-phenyl-2- 0.00168
quinolinyl)ethyl)amino)-5-pyrimidinecarbonitrile
4-amino-6-(((1S)-1-(6-fluoro-3-phenyl-4-(1-piperazinylcarbon-
0.000248 yl)-2-quinolinyl)ethyl)amino)-5-pyrimidinecarbonitrile
2-((1S)-1-((6-amino-5-cyano-4-pyrimidinyl)amino)ethyl)-6- 0.00127
fluoro-N-methyl-3-phenyl-4-quinolinecarboxamide
4-amino-6-((-1-(6-fluoro-4-((methylsulfonyl)methyl)-3-phenyl-
0.00138 2-quinolinyl)ethyl)amino)-5-pyrimidinecarbonitrile
4-amino-6-(((1S)-1-(6-fluoro-4-((3-hydroxy-1-azetidinyl)- 0.0013
carbonyl)-3-phenyl-2-quinolinyl)ethyl)amino)-5-pyrimidine-
carbonitrile 4-amino-6-(((1S)-1-(4-((1,1-dioxido-4- 0.00435
thiomorpholinyl)carbonyl)-6-fluoro-3-phenyl-2-
quinolinyl)ethyl)amino)-5-pyrimidinecarbonitrile
2-((1S)-1-((6-amino-5-cyano-4-pyrimidinyl)amino)ethyl)-6- 0.00083
fluoro-N,N-dimethyl-3-phenyl-4-quinolinecarboxamide
2-((1S)-1-((6-amino-5-cyano-4-pyrimidinyl)amino)ethyl)-6- 0.0218
fluoro-N,N-dimethyl-3-phenyl-4-quinolinecarboxamide
4-amino-6-((-1-(6-fluoro-4-(4-morpholinylmethyl)-3-phenyl-2-
0.00131 quinolinyl)ethyl)amino)-5-pyrimidinecarbonitrile
2-((1S)-1-((6-amino-5-cyano-4-pyrimidinyl)amino)ethyl)-N- 0.0673
ethyl-6-fluoro-3-phenyl-4-quinolinecarboxamide
2-(-1-((6-amino-5-cyano-4-pyrimidinyl)amino)ethyl)-6-fluoro-
0.00317 N-(1-methylethyl)-3-phenyl-4-quinolinecarboxamide
2-(-1-((6-amino-5-cyano-4-pyrimidinyl)amino)ethyl)-N- 0.00515
(cyclopropylmethyl)-6-fluoro-3-phenyl-4- quinolinecarboxamide
4-amino-6-(((1S)-1-(6-fluoro-4-methoxy-3-phenyl-2- 0.00118
quinolinyl)ethyl)amino)-5-pyrimidinecarbonitrile
4-amino-6-(((1R)-1-(6-fluoro-4-methoxy-3-phenyl-2- 0.271
quinolinyl)ethyl)amino)-5-pyrimidinecarbonitrile
4-amino-6-(((1S)-1-(3-(3,5-difluorophenyl)-6-fluoro-4- 0.0684
methoxy-2-quinolinyl)ethyl)amino)-5-pyrimidinecarbonitrile
4-amino-6-(-1-(6-fluoro-4-((2-methoxyethyl)amino)-3-phenyl- 0.00135
2-quinolinyl)ethyl)amino)-5-pyrimidinecarbonitrile
4-amino-6-(-1-(4-((2-(dimethylamino)ethyl)amino)-6-fluoro-3-
0.00133 phenyl-2-quinolinyl)ethyl)amino)-5-pyrimidinecarbonitrile
4-amino-6-(((1S)-1-(6-fluoro-4-((2-methoxyethyl)amino)-3- 0.00061
phenyl-2-quinolinyl)ethyl)amino)-5-pyrimidinecarbonitrile
4-amino-6-(((1R)-1-(6-fluoro-4-((2-methoxyethyl)amino)-3- 0.0622
phenyl-2-quinolinyl)ethyl)amino)-5-pyrimidinecarbonitrile
4-amino-6-(-1-(6-fluoro-4-((2-(methylsulfonyl)ethyl)amino)-3-
0.000463 phenyl-2-quinolinyl)ethyl)amino)-5-pyrimidinecarbonitrile
4-amino-6-(-1-(6-fluoro-4-((2-hydroxyethyl)amino)-3-phenyl-
0.000396 2-quinolinyl)ethyl)amino)-5-pyrimidinecarbonitrile
4-amino-6-(((1S)-1-(6-fluoro-4-((2- 0.000226
(methylsulfonyl)ethyl)amino)-3-phenyl-2-
quinolinyl)ethyl)amino)-5-pyrimidinecarbonitrile
4-amino-6-(((1S)-1-(6-fluoro-4-(methylsulfonyl)-3-phenyl-2-
0.000741 quinolinyl)ethyl)amino)-5-pyrimidinecarbonitrile
N-(1-(6-fluoro-4-(methylsulfonyl)-3-phenyl-2- 0.00234
quinolinyl)ethyl)-9H-purin-6-amine
N-(-1-(5-fluoro-4-(methylsulfony1)-3-phenyl-2- 0.00224
quinolinyl)ethyl)-9H-purin-6-amine
4-amino-6-((-1-(6-fluoro-4-((R)-(2-hydroxyethyl)sulfinyl)-3-
0.00248 phenyl-2-quinolinyl)ethyl)amino)-5-pyrimidinecarbonitrile
4-amino-6-(((1R)-1-(5-fluoro-4-(methylsulfonyl)-3-phenyl-2- 0.466
quinolinyl)ethyl)amino)-5-pyrimidinecarbonitrile
4-amino-6-(((1S)-1-(5-fluoro-4-(methylsulfonyl)-3-phenyl-2- 0.0013
quinolinyl)ethyl)amino)-5-pyrimidinecarbonitrile
N-((1S)-1-(6-fluoro-4-(methylsulfonyl)-3-phenyl-2-quinolinyl)-
0.00112 ethyl)-9H-purin-6-amine
N-((1R)-1-(6-fluoro-4-(methylsulfonyl)-3-phenyl-2-quinolinyl)- 0.41
ethyl)-9H-purin-6-amine
4-amino-6-((-1-(3-(3,5-difluorophenyl)-6-fluoro-4-(methyl- 0.00112
sulfonyl)-2-quinolinyl)ethyl)amino)-5-pyrimidinecarbonitrile
4-amino-6-((-1-(6-fluoro-4-((S)-(2-hydroxyethyl)sulfinyl)-3- 0.0018
phenyl-2-quinolinyl)ethyl)amino)-5-pyrimidinecarbonitrile
2-(1-(6-Amino-5-cyanopyrimidin-4-ylamino)ethyl)-6-fluoro-N- 0.00239
methyl-3-(pyridin-2-yl)quinoline-4-carboxamide
(S)-2-(1-(6-Amino-5-cyanopyrimidin-4-ylamino)ethyl)-N- 0.0036
ethyl-6-fluoro-3-(pyridin-2-yl)quinoline-4-carboximidamide
(S)-2-(1-(6-Amino-5-cyanopyrimidin-4-ylamino)ethyl)-6- 0.00757
fluoro-N-(2-hydroxyethyl)-3-(pyridin-2-yl)quinoline-4- carboxamide
(S)-2-(1-(6-Amino-5-cyanopyrimidin-4-ylamino)ethyl)-N- 0.00164
cyclopropy1-6-fluoro-3-(pyridin-2-yl)quinoline-4-carboxamide
2-1-(((6-Amino-5-cyano-4-pyrimidinyl)amino)ethyl)-6-fluoro- 0.119
3-(2-pyridinyl)-4-quinolinecarboxylic acid
2-(-1-((6-Amino-5-cyano-4-pyrimidinyl)amino)ethyl)-6-fluoro-
0.00176 N-methyl-3-(2-pyridinyl)-4-quinolinecarboxamide
2-((1R)-1-((6-Amino-5-cyano-4-pyrimidinyl)amino)ethyl)-6- 0.123
fluoro-N-methyl-3-(2-pyridinyl)-4-quinolinecarboxamide
2-(1-((6-Amino-5-cyano-4-pyrimidinyl)amino)ethyl)-6-fluoro- 0.00777
N,N-dimethyl-3-(2-pyridinyl)-4-quinolinecarboxamide
4-Amino-6-((1-(6-fluoro-4-(1-piperazinylcarbonyl)-3-(2- 0.00429
pyridiny1)-2-quinolinyl)ethyl)amino)-5-pyrimidinecarbonitrile
4-amino-6-(1-(6-fluoro-4-(3-hydroxyazetidine-1-carbonyl)-3- 0.0119
(pyridin-2-yl)quinolin-2-yl)ethylamino)pyrimidine-5-
carbonitrile
[0629] For the treatment of PI3K.delta.-mediated-diseases, such as
rheumatoid arthritis, ankylosing spondylitis, osteoarthritis,
psoriatic arthritis, psoriasis, inflammatory diseases, and
autoimmune diseases, the compounds of the present invention may be
administered orally, parentally, by inhalation spray, rectally, or
topically in dosage unit formulations containing conventional
pharmaceutically acceptable carriers, adjuvants, and vehicles. The
term parenteral as used herein includes, subcutaneous, intravenous,
intramuscular, intrasternal, infusion techniques or
intraperitoneally.
[0630] Treatment of diseases and disorders herein is intended to
also include the prophylactic administration of a compound of the
invention, a pharmaceutical salt thereof, or a pharmaceutical
composition of either to a subject (i.e., an animal, preferably a
mammal, most preferably a human) believed to be in need of
preventative treatment, such as, for example, rheumatoid arthritis,
ankylosing spondylitis, osteoarthritis, psoriatic arthritis,
psoriasis, inflammatory diseases, and autoimmune diseases and the
like.
[0631] The dosage regimen for treating PI310-mediated diseases,
cancer, and/or hyperglycemia with the compounds of this invention
and/or compositions of this invention is based on a variety of
factors, including the type of disease, the age, weight, sex,
medical condition of the patient, the severity of the condition,
the route of administration, and the particular compound employed.
Thus, the dosage regimen may vary widely, but can be determined
routinely using standard methods. Dosage levels of the order from
about 0.01 mg to 30 mg per kilogram of body weight per day,
preferably from about 0.1 mg to 10 mg/kg, more preferably from
about 0.25 mg to 1 mg/kg are useful for all methods of use
disclosed herein.
[0632] The pharmaceutically active compounds of this invention can
be processed in accordance with conventional methods of pharmacy to
produce medicinal agents for administration to patients, including
humans and other mammals.
[0633] For oral administration, the pharmaceutical composition may
be in the form of, for example, a capsule, a tablet, a suspension,
or liquid. The pharmaceutical composition is preferably made in the
form of a dosage unit containing a given amount of the active
ingredient. For example, these may contain an amount of active
ingredient from about 1 to 2000 mg, preferably from about 1 to 500
mg, more preferably from about 5 to 150 mg. A suitable daily dose
for a human or other mammal may vary widely depending on the
condition of the patient and other factors, but, once again, can be
determined using routine methods.
[0634] The active ingredient may also be administered by injection
as a composition with suitable carriers including saline, dextrose,
or water. The daily parenteral dosage regimen will be from about
0.1 to about 30 mg/kg of total body weight, preferably from about
0.1 to about 10 mg/kg, and more preferably from about 0.25 mg to 1
mg/kg.
[0635] Injectable preparations, such as sterile injectable aq. or
oleaginous suspensions, may be formulated according to the known
are using suitable dispersing or wetting agents and suspending
agents. The sterile injectable preparation may also be a sterile
injectable solution or suspension in a non-toxic parenterally
acceptable diluent or solvent, for example as a solution in
1,3-butanediol. Among the acceptable vehicles and solvents that may
be employed are water, Ringer's solution, and isotonic sodium
chloride solution. In addition, sterile, fixed oils are
conventionally employed as a solvent or suspending medium. For this
purpose any bland fixed oil may be employed, including synthetic
mono- or diglycerides. In addition, fatty acids such as oleic acid
find use in the preparation of injectables.
[0636] Suppositories for rectal administration of the drug can be
prepared by mixing the drug with a suitable non-irritating
excipient such as cocoa butter and polyethylene glycols that are
solid at ordinary temperatures but liquid at the rectal temperature
and will therefore melt in the rectum and release the drug.
[0637] A suitable topical dose of active ingredient of a compound
of the invention is 0.1 mg to 150 mg administered one to four,
preferably one or two times daily. For topical administration, the
active ingredient may comprise from 0.001% to 10% w/w, e.g., from
1% to 2% by weight of the formulation, although it may comprise as
much as 10% w/w, but preferably not more than 5% w/w, and more
preferably from 0.1% to 1% of the formulation.
[0638] Formulations suitable for topical administration include
liquid or semi-liquid preparations suitable for penetration through
the skin (e.g., liniments, lotions, ointments, creams, or pastes)
and drops suitable for administration to the eye, ear, or nose.
[0639] For administration, the compounds of this invention are
ordinarily combined with one or more adjuvants appropriate for the
indicated route of administration. The compounds may be admixed
with lactose, sucrose, starch powder, cellulose esters of alkanoic
acids, stearic acid, talc, magnesium stearate, magnesium oxide,
sodium and calcium salts of phosphoric and sulfuric acids, acacia,
gelatin, sodium alginate, polyvinyl-pyrrolidine, and/or polyvinyl
alcohol, and tableted or encapsulated for conventional
administration. Alternatively, the compounds of this invention may
be dissolved in saline, water, polyethylene glycol, propylene
glycol, ethanol, corn oil, peanut oil, cottonseed oil, sesame oil,
tragacanth gum, and/or various buffers. Other adjuvants and modes
of administration are well known in the pharmaceutical art. The
carrier or diluent may include time delay material, such as
glyceryl monostearate or glyceryl distearate alone or with a wax,
or other materials well known in the art.
[0640] The pharmaceutical compositions may be made up in a solid
form (including granules, powders or suppositories) or in a liquid
form (e.g., solutions, suspensions, or emulsions). The
pharmaceutical compositions may be subjected to conventional
pharmaceutical operations such as sterilization and/or may contain
conventional adjuvants, such as preservatives, stabilizers, wetting
agents, emulsifiers, buffers etc.
[0641] Solid dosage forms for oral administration may include
capsules, tablets, pills, powders, and granules. In such solid
dosage forms, the active compound may be admixed with at least one
inert diluent such as sucrose, lactose, or starch. Such dosage
forms may also comprise, as in normal practice, additional
substances other than inert diluents, e.g., lubricating agents such
as magnesium stearate. In the case of capsules, tablets, and pills,
the dosage forms may also comprise buffering agents. Tablets and
pills can additionally be prepared with enteric coatings.
[0642] Liquid dosage forms for oral administration may include
pharmaceutically acceptable emulsions, solutions, suspensions,
syrups, and elixirs containing inert diluents commonly used in the
art, such as water. Such compositions may also comprise adjuvants,
such as wetting, sweetening, flavoring, and perfuming agents.
[0643] Compounds of the present invention can possess one or more
asymmetric carbon atoms and are thus capable of existing in the
form of optical isomers as well as in the form of racemic or
non-racemic mixtures thereof. The optical isomers can be obtained
by resolution of the racemic mixtures according to conventional
processes, e.g., by formation of diastereoisomeric salts, by
treatment with an optically active acid or base. Examples of
appropriate acids are tartaric, diacetyltartaric,
dibenzoyltartaric, ditoluoyltartaric, and camphorsulfonic acid and
then separation of the mixture of diastereoisomers by
crystallization followed by liberation of the optically active
bases from these salts. A different process for separation of
optical isomers involves the use of a chiral chromatography column
optimally chosen to maximize the separation of the enantiomers.
Still another available method involves synthesis of covalent
diastereoisomeric molecules by reacting compounds of the invention
with an optically pure acid in an activated form or an optically
pure isocyanate. The synthesized diastereoisomers can be separated
by conventional means such as chromatography, distillation,
crystallization or sublimation, and then hydrolyzed to deliver the
enantiomerically pure compound. The optically active compounds of
the invention can likewise be obtained by using active starting
materials. These isomers may be in the form of a free acid, a free
base, an ester or a salt.
[0644] Likewise, the compounds of this invention may exist as
isomers, that is compounds of the same molecular formula but in
which the atoms, relative to one another, are arranged differently.
In particular, the alkylene substituents of the compounds of this
invention, are normally and preferably arranged and inserted into
the molecules as indicated in the definitions for each of these
groups, being read from left to right. However, in certain cases,
one skilled in the art will appreciate that it is possible to
prepare compounds of this invention in which these substituents are
reversed in orientation relative to the other atoms in the
molecule. That is, the substituent to be inserted may be the same
as that noted above except that it is inserted into the molecule in
the reverse orientation. One skilled in the art will appreciate
that these isomeric forms of the compounds of this invention are to
be construed as encompassed within the scope of the present
invention.
[0645] The compounds of the present invention can be used in the
form of salts derived from inorganic or organic acids. The salts
include, but are not limited to, the following: acetate, adipate,
alginate, citrate, aspartate, benzoate, benzenesulfonate,
bisulfate, butyrate, camphorate, camphorsulfonate, digluconate,
cyclopentanepropionate, dodecylsulfate, ethanesulfonate,
glucoheptanoate, glycerophosphate, hemisulfate, heptanoate,
hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide,
2-hydroxyethanesulfonate, lactate, maleate, methansulfonate,
nicotinate, 2-naphthalenesulfonate, oxalate, palmoate, pectinate,
persulfate, 2-phenylpropionate, picrate, pivalate, propionate,
succinate, tartrate, thiocyanate, tosylate, mesylate, and
undecanoate. Also, the basic nitrogen-containing groups can be
quaternized with such agents as lower alkyl halides, such as
methyl, ethyl, propyl, and butyl chloride, bromides and iodides;
dialkyl sulfates like dimethyl, diethyl, dibutyl, and diamyl
sulfates, long chain halides such as decyl, lauryl, myristyl and
stearyl chlorides, bromides and iodides, aralkyl halides like
benzyl and phenethyl bromides, and others. Water or oil-soluble or
dispersible products are thereby obtained.
[0646] Examples of acids that may be employed to from
pharmaceutically acceptable acid addition salts include such
inorganic acids as hydrochloric acid, sulfuric acid and phosphoric
acid and such organic acids as oxalic acid, maleic acid, succinic
acid and citric acid. Other examples include salts with alkali
metals or alkaline earth metals, such as sodium, potassium, calcium
or magnesium or with organic bases.
[0647] Also encompassed in the scope of the present invention are
pharmaceutically acceptable esters of a carboxylic acid or hydroxyl
containing group, including a metabolically labile ester or a
prodrug form of a compound of this invention. A metabolically
labile ester is one which may produce, for example, an increase in
blood levels and prolong the efficacy of the corresponding
non-esterified form of the compound. A prodrug form is one which is
not in an active form of the molecule as administered but which
becomes therapeutically active after some in vivo activity or
biotransformation, such as metabolism, for example, enzymatic or
hydrolytic cleavage. For a general discussion of prodrugs involving
esters see Svensson and Tunek Drug Metabolism Reviews 165 (1988)
and Bundgaard Design of Prodrugs, Elsevier (1985). Examples of a
masked carboxylate anion include a variety of esters, such as alkyl
(for example, methyl, ethyl), cycloalkyl (for example, cyclohexyl),
aralkyl (for example, benzyl, p-methoxybenzyl), and
alkylcarbonyloxyalkyl (for example, pivaloyloxymethyl). Amines have
been masked as arylcarbonyloxymethyl substituted derivatives which
are cleaved by esterases in vivo releasing the free drug and
formaldehyde (Bungaard J. Med. Chem. 2503 (1989)). Also, drugs
containing an acidic NH group, such as imidazole, imide, indole and
the like, have been masked with N-acyloxymethyl groups (Bundgaard
Design of Prodrugs, Elsevier (1985)). Hydroxy groups have been
masked as esters and ethers. EP 039,051 (Sloan and Little, Apr. 11,
1981) discloses Mannich-base hydroxamic acid prodrugs, their
preparation and use. Esters of a compound of this invention, may
include, for example, the methyl, ethyl, propyl, and butyl esters,
as well as other suitable esters formed between an acidic moiety
and a hydroxyl containing moiety. Metabolically labile esters, may
include, for example, methoxymethyl, ethoxymethyl,
iso-propoxymethyl, .alpha.-methoxyethyl, groups such as
.alpha.-((C.sub.1-C.sub.4)alkyloxy)ethyl, for example,
methoxyethyl, ethoxyethyl, propoxyethyl, isopropoxyethyl, etc.;
2-oxo-1,3-dioxolen-4-ylmethyl groups, such as
5-methyl-2-oxo-1,3,dioxolen-4-ylmethyl, etc.; C.sub.1-C.sub.3
alkylthiomethyl groups, for example, methylthiomethyl,
ethylthiomethyl, isopropylthiomethyl, etc.; acyloxymethyl groups,
for example, pivaloyloxymethyl, .alpha.-acetoxymethyl, etc.;
ethoxycarbonyl-1-methyl; or .alpha.-acyloxy-.alpha.-substituted
methyl groups, for example .alpha.-acetoxyethyl.
[0648] Further, the compounds of the invention may exist as
crystalline solids which can be crystallized from common solvents
such as ethanol, N,N-dimethylformamide, water, or the like. Thus,
crystalline forms of the compounds of the invention may exist as
polymorphs, solvates and/or hydrates of the parent compounds or
their pharmaceutically acceptable salts. All of such forms likewise
are to be construed as falling within the scope of the
invention.
[0649] While the compounds of the invention can be administered as
the sole active pharmaceutical agent, they can also be used in
combination with one or more compounds of the invention or other
agents. When administered as a combination, the therapeutic agents
can be formulated as separate compositions that are given at the
same time or different times, or the therapeutic agents can be
given as a single composition.
[0650] The foregoing is merely illustrative of the invention and is
not intended to limit the invention to the disclosed compounds.
Variations and changes which are obvious to one skilled in the art
are intended to be within the scope and nature of the invention
which are defined in the appended claims.
[0651] From the foregoing description, one skilled in the art can
easily ascertain the essential characteristics of this invention,
and without departing from the spirit and scope thereof, can make
various changes and modifications of the invention to adapt it to
various usages and conditions.
* * * * *