U.S. patent application number 13/036236 was filed with the patent office on 2011-06-23 for heterocyclic compounds and their uses.
Invention is credited to Yi Chen, Timothy D. Cushing, Xiaolin Hao, Xiao He, Andreas Reichelt, Robert M. Rzasa, Jennifer Seganish, Youngsook Shin, Dawei Zhang.
Application Number | 20110152277 13/036236 |
Document ID | / |
Family ID | 39712323 |
Filed Date | 2011-06-23 |
United States Patent
Application |
20110152277 |
Kind Code |
A1 |
Chen; Yi ; et al. |
June 23, 2011 |
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: |
Chen; Yi; (San Mateo,
CA) ; Cushing; Timothy D.; (Pacifica, CA) ;
Hao; Xiaolin; (Foster City, CA) ; He; Xiao;
(Foster City, CA) ; Reichelt; Andreas; (Moorpark,
CA) ; Rzasa; Robert M.; (Ventura, CA) ;
Seganish; Jennifer; (Garwood, NJ) ; Shin;
Youngsook; (Emeryville, CA) ; Zhang; Dawei;
(Thousand Oaks, CA) |
Family ID: |
39712323 |
Appl. No.: |
13/036236 |
Filed: |
February 28, 2011 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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12079281 |
Mar 24, 2008 |
7919498 |
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13036236 |
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60919565 |
Mar 23, 2007 |
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Current U.S.
Class: |
514/249 ;
514/262.1; 514/263.22; 514/264.11; 514/265.1; 544/262; 544/277;
544/279; 544/280 |
Current CPC
Class: |
A61P 29/00 20180101;
A61P 37/04 20180101; A61P 9/00 20180101; A61P 13/10 20180101; C07D
487/04 20130101; A61P 19/02 20180101; A61P 7/06 20180101; A61P
37/02 20180101; A61P 37/00 20180101; A61P 37/08 20180101; A61P
37/06 20180101; C07D 519/00 20130101; A61P 1/00 20180101; A61P
17/00 20180101; A61P 17/06 20180101; A61P 35/00 20180101; A61P
21/04 20180101; A61P 25/00 20180101; A61P 7/04 20180101; C07D
471/04 20130101; A61P 27/02 20180101 |
Class at
Publication: |
514/249 ;
544/277; 514/263.22; 544/279; 514/264.11; 544/262; 514/262.1;
514/265.1; 544/280 |
International
Class: |
A61K 31/519 20060101
A61K031/519; C07D 473/34 20060101 C07D473/34; A61K 31/52 20060101
A61K031/52; A61P 19/02 20060101 A61P019/02; A61P 17/06 20060101
A61P017/06; A61P 29/00 20060101 A61P029/00; A61P 35/00 20060101
A61P035/00; C07D 471/04 20060101 C07D471/04; C07D 487/04 20060101
C07D487/04 |
Claims
1. A compound having the structure: ##STR00068## or any
pharmaceutically-acceptable salt thereof, wherein: X.sup.1 is
C(R.sup.9) or N; X.sup.2 is N; Z is --CR.sup.11.dbd.CR.sup.11--; n
is 0, 1, 2 or 3; R.sup.1 is a direct-bonded or oxygen-linked
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 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.1-4alkyl, OC.sub.1-4alkyl, OC.sub.1-4haloalkyl,
NHC.sub.1-4alkyl, N(C.sub.1-4-alkyl)C.sub.1-4alkyl and
C.sub.1-4haloalkyl; R.sup.2 is selected from halo,
C.sub.1-4haloalkyl, 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.2-6alkylNR.sup.aR.sup.a, --OC.sub.2-6alkylOR.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.2-6alkylNR.sup.aR.sup.a and
--NR.sup.aC.sub.2-6alkylOR.sup.a; or R.sup.2 is selected from
C.sub.1-6alkyl, phenyl, benzyl, heteroaryl, heterocycle,
--(C.sub.1-3alkyl)heteroaryl, --(C.sub.1-3alkyl)heterocycle,
--O(C.sub.1-3alkyl)heteroaryl, --O(C.sub.1-3alkyl)hetero cycle,
--NR.sup.a(C.sub.1-3alkyl)hetero aryl,
--NR.sup.a(C.sub.1-3alkyl)hetero cycle, --(C.sub.1-3alkyl)phenyl,
--O(C.sub.1-3alkyl)phenyl and --NR.sup.a(C.sub.1-3alkyl)phenyl all
of which are substituted by 0, 1, 2 or 3 substituents selected from
C.sub.1-4haloalkyl, OC.sub.1-4alkyl, Br, Cl, F, I and
C.sub.1-4alkyl; R.sup.3 is selected from H, halo,
C.sub.1-4haloalkyl, 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.2-6alkylNR.sup.aR.sup.a, --OC.sub.2-6alkylOR.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.2-6alkylNR.sup.aR.sup.a,
--NR.sup.aC.sub.2-6alkylOR.sup.a, C.sub.1-6alkyl, phenyl, benzyl,
heteroaryl and heterocycle, wherein the C.sub.1-6alkyl, phenyl,
benzyl, heteroaryl and heterocycle are additionally substituted by
0, 1, 2 or 3 substituents selected from C.sub.1-6haloalkyl,
OC.sub.1-6alkyl, Br, Cl, F, I and C.sub.1-6alkyl; R.sup.4 is,
independently, in each instance, halo, nitro, cyano,
C.sub.1-4alkyl, OC.sub.1-4alkyl, OC.sub.1-4halo alkyl,
NHC.sub.1-4alkyl, N(C.sub.1-4alkyl)C.sub.1-4alkyl or
C.sub.1-4haloalkyl; R.sup.5 is, independently, in each instance, H,
halo, C.sub.1-6alkyl, C.sub.1-4haloalkyl, or C.sub.1-6alkyl
substituted by 1, 2 or 3 substituents selected from halo, cyano,
OH, OC.sub.1-4alkyl, C.sub.1-4alkyl, C.sub.1-3haloalkyl,
OC.sub.1-4alkyl, NH.sub.2, NHC.sub.1-4alkyl,
N(C.sub.1-4alkyl)C.sub.1-4alkyl; or both R.sup.5 groups together
form a C.sub.3-6spiroalkyl substituted by 0, 1, 2 or 3 substituents
selected from halo, cyano, OH, OC.sub.1-4alkyl, C.sub.1-4alkyl,
C.sub.1-3halo alkyl, OC.sub.1-4alkyl, NH.sub.2, NHC.sub.1-4alkyl,
N(C.sub.1-4alkyl)C.sub.1-4alkyl; R.sup.6 is selected from H,
C.sub.1-6haloalkyl, Br, Cl, F, I, OR.sup.a, NR.sup.aR.sup.a,
C.sub.1-6alkyl, phenyl, benzyl, heteroaryl and heterocycle, wherein
the C.sub.1-6alkyl, phenyl, benzyl, heteroaryl and heterocycle are
additionally substituted by 0, 1, 2 or 3 substituents selected from
C.sub.1-6haloalkyl, OC.sub.1-6alkyl, Br, Cl, F, I and
C.sub.1-6alkyl; R.sup.7 is selected from H, C.sub.1-6haloalkyl, Br,
Cl, F, I, OR.sup.a, NR.sup.aR.sup.a, C.sub.1-6alkyl, phenyl,
benzyl, heteroaryl and heterocycle, wherein the C.sub.1-6alkyl,
phenyl, benzyl, heteroaryl and heterocycle are additionally
substituted by 0, 1, 2 or 3 substituents selected from
C.sub.1-6haloalkyl, OC.sub.1-6alkyl, Br, Cl, F, I and
C.sub.1-6alkyl; R.sup.8 is selected from H, C.sub.1-6haloalkyl, Br,
Cl, F, I, OR.sup.a, NR.sup.aR.sup.a, C.sub.1-6alkyl, phenyl,
benzyl, heteroaryl and heterocycle, wherein the C.sub.1-6alkyl,
phenyl, benzyl, heteroaryl and heterocycle are additionally
substituted by 0, 1, 2 or 3 substituents selected from
C.sub.1-6haloalkyl, OC.sub.1-6alkyl, Br, Cl, F, I and
C.sub.1-6alkyl; R.sup.9 is selected from H, halo,
C.sub.1-4haloalkyl, 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.2-6alkylNR.sup.aR.sup.a, --OC.sub.2-6alkylOR.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.2-6alkylNR.sup.aR.sup.a,
--NR.sup.aC.sub.2-6alkylOR.sup.a, C.sub.1-6alkyl, phenyl, benzyl,
heteroaryl and heterocycle, wherein the C.sub.1-6alkyl, phenyl,
benzyl, heteroaryl and heterocycle are additionally substituted by
0, 1, 2 or 3 substituents selected from halo, C.sub.1-4haloalkyl,
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.2-6alkylNR.sup.aR.sup.a, --OC.sub.2-6alkylOR.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.2-6alkylNR.sup.aR.sup.a,
--NR.sup.aC.sub.2-6alkylOR.sup.a; or R.sup.9 is 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.1-4haloalkyl, 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.2-6alkylNR.sup.aR.sup.a, --OC.sub.2-6alkylOR.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.2-6alkylNR.sup.aR.sup.a and
--NR.sup.aC.sub.2-6alkylOR.sup.a; R.sup.10 is H, C.sub.1-3alkyl,
C.sub.1-3haloalkyl, cyano, nitro, CO.sub.2R.sup.a,
C(.dbd.O)NR.sup.aR.sup.a, --C(.dbd.NR.sup.a)NR.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,
S(.dbd.O)R.sup.b, S(.dbd.O).sub.2R.sup.b or
S(.dbd.O).sub.2NR.sup.aR.sup.a; R.sup.11 is selected from H, halo,
C.sub.1-4haloalkyl, 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.2-6alkylNR.sup.aR.sup.a, --OC.sub.2-6alkylOR.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.2-6alkylNR.sup.aR.sup.a and
--NR.sup.aC.sub.2-6alkylOR.sup.a; or R.sup.11 is C.sub.1-9alkyl or
C.sub.1-4alkyl(phenyl) wherein either is substituted by 0, 1, 2, 3
or 4 substituents selected from halo, C.sub.1-4haloalkyl, 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.2-6alkylNR.sup.aR.sup.a, --OC.sub.2-6alkylOR.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.2-6alkylNR.sup.aR.sup.a and
--NR.sup.aC.sub.2-6alkylOR.sup.a; and additionally substituted by
0, 1, 2, 3, 4 or 5 substituents independently selected from Br, Cl,
F and I; or R.sup.11 is 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.1-4haloalkyl, 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.2-6alkylNR.sup.aR.sup.a, --OC.sub.2-6alkylOR.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.2-6alkylNR.sup.aR.sup.a and
--NR.sup.aC.sub.2-6alkylOR.sup.a; R.sup.a is independently, at each
instance, H or R.sup.b; and R.sup.b is independently, at each
instance, phenyl, benzyl or C.sub.1-6alkyl, the phenyl, benzyl and
C.sub.1-6alkyl being substituted by 0, 1, 2 or 3 substituents
selected from halo, C.sub.1-4alkyl, C.sub.1-3haloalkyl,
--OC.sub.1-4alkyl, --NH.sub.2, --NHC.sub.1-4alkyl,
--N(C.sub.1-4alkyl)C.sub.1-4alkyl.
2. A compound according to claim 1, having the structure:
##STR00069##
3. A compound according to claim 1, having the structure:
##STR00070##
4. A compound according to claim 1, having the structure:
##STR00071##
5. A compound according to claim 1, wherein R.sup.3 is F, Cl or Br;
and n is O.
6. A compound according to claim 1, wherein R.sup.1 is phenyl
substituted by 0 or 1 R.sup.2 substituents, and the phenyl is
additionally substituted by 0, 1, 2 or 3 substituents independently
selected from halo, nitro, cyano, C.sub.1-4alkyl, OC.sub.1-4alkyl,
OC.sub.1-4halo alkyl, NHC.sub.1-4alkyl,
N(C.sub.1-4alkyl)C.sub.1-4alkyl and C.sub.1-4halo alkyl.
7. A compound according to claim 1, wherein R.sup.1 is a
direct-bonded or oxygen-linked saturated, partially-saturated or
unsaturated 5-, 6- or 7-membered monocyclic ring containing 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 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.1-4alkyl, OC.sub.1-4alkyl,
OC.sub.1-4haloalkyl, NHC.sub.1-4alkyl,
N(C.sub.1-4alkyl)C.sub.1-4alkyl and C.sub.1-4haloalkyl.
8. 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.
9. 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.
10. A pharmaceutical composition comprising a compound according to
claim 1 and a pharmaceutically-acceptable diluent or carrier.
Description
[0001] This application is a division and claims the benefit of
application Ser. No. 12/079,281, filed Mar. 24, 2008 which claims
the benefit of U.S. Provisional Application No. 60/919,565, filed
Mar. 23, 2007, which are 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
to 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
phosphatidyl-inositol-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 phosphatidyl-inositol-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 (Fruman 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).
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)).
[0018] 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 unkown
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
his phenotype is consistent with p110.delta. deficiency in mice as
far as studied. (Jou et al. Int. J. Immunogenet. 33: 361-369
(2006)).
[0019] 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 equi-potently and is
8- and 28-fold selective over beta and gamma respectively (Ito et
al. J. Pharm. Exp. Therapeut., 321:1-8 (2007)).
[0020] 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)).
[0021] 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)).
[0022] 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)).
[0023] 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
[0024] 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
[0025] One aspect of the invention relates to compounds having the
structure:
##STR00002##
or any pharmaceutically-acceptable salt thereof, wherein:
[0026] X.sup.1 is C(R.sup.9) or N;
[0027] X.sup.2 is C(R.sup.10) or N;
[0028] Z is --CR.sup.11.dbd.CR.sup.11--, --CR.sup.11.dbd.N--,
--N.dbd.CR.sup.11--, --CR--C(.dbd.O)-- and
--C(.dbd.O)--CR.sup.11.dbd.CR.sup.11--;
[0029] n is 0, 1, 2 or 3;
[0030] R.sup.1 is a direct-bonded or oxygen-linked 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 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.1-4alkyl, OC.sub.1-4alkyl, OC.sub.1-4haloalkyl,
NHC.sub.1-4alkyl, N(C.sub.1-4alkyl)C.sub.1-4alkyl and
C.sub.1-4haloalkyl;
[0031] R.sup.2 is selected from halo, C.sub.1-4haloalkyl, 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.2-6alkylNR.sup.aR.sup.a, --OC.sub.2-6alkylOR.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.2-6alkylNR.sup.aR.sup.a and
--NR.sup.aC.sub.2-6alkylOR.sup.a; or R.sup.2 is selected from
C.sub.1-6alkyl, phenyl, benzyl, heteroaryl, heterocycle,
--(C.sub.1-3alkyl)heteroaryl, --(C.sub.1-3alkyl)heterocycle,
--O(C.sub.1-3alkyl)heteroaryl, --O(C.sub.1-3alkyl)hetero cycle,
--NR.sup.a(C.sub.1-3alkyl)hetero aryl,
--NR.sup.a(C.sub.1-3alkyl)hetero cycle, --(C.sub.1-3 alkyl)phenyl,
--O(C.sub.1-3alkyl)phenyl and --NR.sup.a(C.sub.1-3alkyl)phenyl all
of which are substituted by 0, 1, 2 or 3 substituents selected from
C.sub.1-4haloalkyl, OC.sub.1-4alkyl, Br, Cl, F, I and
C.sub.1-4alkyl;
[0032] R.sup.3 is selected from H, halo, C.sub.1-4haloalkyl, 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.2-6alkylNR.sup.aR.sup.a, --OC.sub.2-6alkylOR.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.2-6alkylNR.sup.aR.sup.a,
--NR.sup.aC.sub.2-6alkylOR.sup.a, C.sub.1-6alkyl, phenyl, benzyl,
heteroaryl and heterocycle, wherein the C.sub.1-6alkyl, phenyl,
benzyl, heteroaryl and heterocycle are additionally substituted by
0, 1, 2 or 3 substituents selected from C.sub.1-6haloalkyl,
OC.sub.1-6alkyl, Br, Cl, F, I and C.sub.1-6alkyl;
[0033] R.sup.4 is, independently, in each instance, halo, nitro,
cyano, C.sub.1-4alkyl, OC.sub.1-4alkyl, OC.sub.1-4haloalkyl,
NHC.sub.1-4alkyl, N(C.sub.1-4alkyl)C.sub.1-4alkyl or
C.sub.1-4haloalkyl;
[0034] R.sup.5 is, independently, in each instance, H, halo,
C.sub.1-6alkyl, C.sub.1-4haloalkyl, or C.sub.1-6alkyl substituted
by 1, 2 or 3 substituents selected from halo, cyano, OH,
OC.sub.1-4alkyl, C.sub.1-4alkyl, C.sub.1-3haloalkyl,
OC.sub.1-4alkyl, NH.sub.2, NHC.sub.1-4alkyl,
N(C.sub.1-4alkyl)C.sub.1-4alkyl; or both R.sup.5 groups together
form a C.sub.3-6spiroalkyl substituted by 0, 1, 2 or 3 substituents
selected from halo, cyano, OH, OC.sub.1-4alkyl, C.sub.1-4alkyl,
C.sub.1-3halo alkyl, OC.sub.1-4alkyl, NH.sub.2, NHC.sub.1-4alkyl,
N(C.sub.1-4alkyl)C.sub.1-4alkyl;
[0035] R.sup.6 is selected from H, C.sub.1-6haloalkyl, Br, Cl, F,
I, OR.sup.a, NR.sup.aR.sup.a, C.sub.1-6alkyl, phenyl, benzyl,
heteroaryl and heterocycle, wherein the C.sub.1-6alkyl, phenyl,
benzyl, heteroaryl and heterocycle are additionally substituted by
0, 1, 2 or 3 substituents selected from C.sub.1-6haloalkyl,
OC.sub.1-6alkyl, Br, Cl, F, I and C.sub.1-6alkyl;
[0036] R.sup.7 is selected from H, C.sub.1-6haloalkyl, Br, Cl, F,
I, OR.sup.a, NR.sup.aR.sup.a, C.sub.1-6alkyl, phenyl, benzyl,
heteroaryl and heterocycle, wherein the C.sub.1-6alkyl, phenyl,
benzyl, heteroaryl and heterocycle are additionally substituted by
0, 1, 2 or 3 substituents selected from C.sub.1-6haloalkyl,
OC.sub.1-6alkyl, Br, Cl, F, I and C.sub.1-6alkyl;
[0037] R.sup.8 is selected from H, C.sub.1-6haloalkyl, Br, Cl, F,
I, OR.sup.a, NR.sup.aR.sup.a, C.sub.1-6alkyl, phenyl, benzyl,
heteroaryl and heterocycle, wherein the C.sub.1-6alkyl, phenyl,
benzyl, heteroaryl and heterocycle are additionally substituted by
0, 1, 2 or 3 substituents selected from C.sub.1-6haloalkyl,
OC.sub.1-6alkyl, Br, Cl, F, I and C.sub.1-6alkyl;
[0038] R.sup.9 is selected from H, halo, C.sub.1-4haloalkyl, 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.2-6alkylNR.sup.aR.sup.a, --OC.sub.2-6alkylOR.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.2-6alkylNR.sup.aR.sup.a,
--NR.sup.aC.sub.2-6alkylOR.sup.a, C.sub.1-6alkyl, phenyl, benzyl,
heteroaryl and heterocycle, wherein the C.sub.1-6alkyl, phenyl,
benzyl, heteroaryl and heterocycle are additionally substituted by
0, 1, 2 or 3 substituents selected from halo, C.sub.1-4haloalkyl,
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.2-6alkylNR.sup.aR.sup.a, --OC.sub.2-6alkylOR.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.2-6alkylNR.sup.aR.sup.a,
--NR.sup.aC.sub.2-6alkylOR.sup.a; or R.sup.9 is 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.1-4haloalkyl, 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.2-6alkylNR.sup.aR.sup.a, --OC.sub.2-6alkylOR.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.2-6alkylNR.sup.aR.sup.a and
--NR.sup.aC.sub.2-6alkylOR.sup.a;
[0039] R.sup.10 is H, C.sub.1-3alkyl, C.sub.1-3haloalkyl, cyano,
nitro, CO.sub.2R.sup.a, C(.dbd.O)NR.sup.aR.sup.a,
--C(.dbd.NR.sup.a)NR.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,
S(.dbd.O)R.sup.b, S(.dbd.O).sub.2R.sup.b or
S(.dbd.O).sub.2NR.sup.aR.sup.a;
[0040] R.sup.11 is selected from H, halo, C.sub.1-4haloalkyl,
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.2-6alkylNR.sup.aR.sup.a, --OC.sub.2-6alkylOR.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.2-6alkylNR.sup.aR.sup.a and
--NR.sup.aC.sub.2-6alkylOR.sup.a; or R.sup.11 is C.sub.1-9alkyl or
C.sub.1-4alkyl(phenyl) wherein either is substituted by 0, 1, 2, 3
or 4 substituents selected from halo, C.sub.1-4haloalkyl, 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.2-6alkylNR.sup.aR.sup.a, --OC.sub.2-6alkylOR.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.2-6alkylNR.sup.aR.sup.a and
--NR.sup.aC.sub.2-6alkylOR.sup.a; and additionally substituted by
0, 1, 2, 3, 4 or 5 substituents independently selected from Br, Cl,
F and I; or R.sup.11 is 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.1-4haloalkyl, 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.2-6alkylNR.sup.aR.sup.a, --OC.sub.2-6alkylOR.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.2-6alkylNR.sup.aR.sup.a and
--NR.sup.aC.sub.2-6alkylOR.sup.a;
[0041] R.sup.a is independently, at each instance, H or R.sup.b;
and
[0042] R.sup.b is independently, at each instance, phenyl, benzyl
or C.sub.1-6alkyl, the phenyl, benzyl and C.sub.1-6alkyl being
substituted by 0, 1, 2 or 3 substituents selected from halo,
C.sub.1-4alkyl, C.sub.1-3haloalkyl, --OC.sub.1-4alkyl, --NH.sub.2,
--NHC.sub.1-4 alkyl, --N(C.sub.1-4alkyl)C.sub.1-4alkyl.
[0043] Another aspect of the invention relates to compounds having
the structure:
##STR00003##
or any pharmaceutically-acceptable salt thereof, wherein:
[0044] X.sup.1 is C(R.sup.9) or N;
[0045] X.sup.2 is C(R.sup.10) or N;
[0046] Z is --CR.sup.11.dbd.CR.sup.11--, --CR.sup.11.dbd.N--,
--N.dbd.CR.sup.11--, --CR.sup.11.dbd.CR.sup.11--C(.dbd.O)-- and
--C(.dbd.O)--CR.sup.11.dbd.CR.sup.11--;
[0047] n is 0, 1, 2 or 3;
[0048] R.sup.1 is a direct-bonded or oxygen-linked 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 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.1-4alkyl, OC.sub.1-4alkyl, OC.sub.1-4haloalkyl,
NHC.sub.1-4alkyl, N(C.sub.1-4alkyl)C.sub.1-4alkyl and
C.sub.1-4haloalkyl;
[0049] R.sup.2 is selected from halo, C.sub.1-4haloalkyl, 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.2-6alkylNR.sup.aR.sup.a, --OC.sub.2-6alkylOR.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.2-6alkylNR.sup.aR.sup.a and
--NR.sup.aC.sub.2-6alkylOR.sup.a; or R.sup.2 is selected from
C.sub.1-6alkyl, phenyl, benzyl, heteroaryl, heterocycle,
--(C.sub.1-3alkyl)hetero aryl, --(C.sub.1-3alkyl)hetero cycle,
--O(C.sub.1-3alkyl)heteroaryl, --O(C.sub.1-3alkyl)hetero cycle,
--NR.sup.a(C.sub.1-3alkyl)hetero aryl,
--NR.sup.a(C.sub.1-3alkyl)hetero cycle, --(C.sub.1-3alkyl)phenyl,
--O(C.sub.1-3alkyl)phenyl and --NR.sup.a(C.sub.1-3alkyl)phenyl all
of which are substituted by 0, 1, 2 or 3 substituents selected from
C.sub.1-4haloalkyl, OC.sub.1-4alkyl, Br, Cl, F, I and
C.sub.1-4alkyl;
[0050] R.sup.3 is selected from H, halo, C.sub.1-4haloalkyl, 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.2-6alkylNR.sup.aR.sup.a, --OC.sub.2-6alkylOR.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.2-6alkylNR.sup.aR.sup.a,
--NR.sup.aC.sub.2-6alkylOR.sup.a, C.sub.1-6alkyl, phenyl, benzyl,
heteroaryl and heterocycle, wherein the C.sub.1-6alkyl, phenyl,
benzyl, heteroaryl and heterocycle are additionally substituted by
0, 1, 2 or 3 substituents selected from C.sub.1-6haloalkyl,
OC.sub.1-6alkyl, Br, Cl, F, I and C.sub.1-6alkyl;
[0051] R.sup.4 is, independently, in each instance, halo, nitro,
cyano, C.sub.1-4alkyl, OC.sub.1-4alkyl, OC.sub.1-4haloalkyl,
NHC.sub.1-4alkyl, N(C.sub.1-4alkyl)C.sub.1-4alkyl or
C.sub.1-4haloalkyl;
[0052] R.sup.5 is, independently, in each instance, H, halo,
C.sub.1-6alkyl, C.sub.1-4haloalkyl, or C.sub.1-6alkyl substituted
by 1, 2 or 3 substituents selected from halo, cyano, OH,
OC.sub.1-4alkyl, C.sub.1-4alkyl, C.sub.1-3haloalkyl,
OC.sub.1-4alkyl, NH.sub.2, NHC.sub.1-4alkyl,
N(C.sub.1-4alkyl)C.sub.1-4alkyl; or both R.sup.5 groups together
form a C.sub.3-6-spiroalkyl substituted by 0, 1, 2 or 3
substituents selected from halo, cyano, OH, OC.sub.1-4alkyl,
C.sub.1-4alkyl, C.sub.1-3haloalkyl, OC.sub.1-4alkyl, NH.sub.2,
NHC.sub.1-4alkyl, N(C.sub.1-4alkyl)C.sub.1-4alkyl;
[0053] R.sup.6 is selected from H, C.sub.1-6haloalkyl, Br, Cl, F,
I, OR.sup.a, NR.sup.aR.sup.a, C.sub.1-6alkyl, phenyl, benzyl,
heteroaryl and heterocycle, wherein the C.sub.1-6alkyl, phenyl,
benzyl, heteroaryl and heterocycle are additionally substituted by
0, 1, 2 or 3 substituents selected from C.sub.1-6haloalkyl,
OC.sub.1-6alkyl, Br, Cl, F, I and C.sub.1-6alkyl;
[0054] R.sup.7 is selected from H, C.sub.1-6haloalkyl, Br, Cl, F,
I, OR.sup.a, NR.sup.aR.sup.a, C.sub.1-6alkyl, phenyl, benzyl,
heteroaryl and heterocycle, wherein the C.sub.1-6alkyl, phenyl,
benzyl, heteroaryl and heterocycle are additionally substituted by
0, 1, 2 or 3 substituents selected from C.sub.1-6haloalkyl,
OC.sub.1-6alkyl, Br, Cl, F, I and C.sub.1-6alkyl;
[0055] R.sup.8 is selected from H, C.sub.1-6haloalkyl, Br, Cl, F,
I, OR.sup.a, NR.sup.aR.sup.a, C.sub.1-6alkyl, phenyl, benzyl,
heteroaryl and heterocycle, wherein the C.sub.1-6alkyl, phenyl,
benzyl, heteroaryl and heterocycle are additionally substituted by
0, 1, 2 or 3 substituents selected from C.sub.1-6haloalkyl,
OC.sub.1-6alkyl, Br, Cl, F, I and C.sub.1-6alkyl;
[0056] R.sup.9 is selected from H, halo, C.sub.1-4haloalkyl, 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.2-6alkylNR.sup.aR.sup.a, --OC.sub.2-6alkylOR.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.2-6alkylNR.sup.aR.sup.a,
--NR.sup.aC.sub.2-6alkylOR.sup.a, C.sub.1-6alkyl, phenyl, benzyl,
heteroaryl and heterocycle, wherein the C.sub.1-6alkyl, phenyl,
benzyl, heteroaryl and heterocycle are additionally substituted by
0, 1, 2 or 3 substituents selected from halo, C.sub.1-4haloalkyl,
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.2-6alkylNR.sup.aR.sup.a, --OC.sub.2-6alkylOR.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.2-6alkylNR.sup.aR.sup.a,
--NR.sup.aC.sub.2-6alkylOR.sup.a; or R.sup.9 is 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.1-4haloalkyl, 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.2-6alkylNR.sup.aR.sup.a, --OC.sub.2-6alkylOR.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.2-6alkylNR.sup.aR.sup.a and
--NR.sup.aC.sub.2-6alkylOR.sup.a;
[0057] R.sup.10 is H, C.sub.1-3alkyl, C.sub.1-3haloalkyl, cyano,
nitro, CO.sub.2R.sup.a, C(.dbd.O)NR.sup.aR.sup.a,
--C(.dbd.NR.sup.a)NR.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,
S(.dbd.O)R.sup.b, S(.dbd.O).sub.2R.sup.b or
S(.dbd.O).sub.2NR.sup.aR.sup.a;
[0058] R.sup.11 is selected from H, halo, C.sub.1-4haloalkyl,
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.2-6alkylNR.sup.aR.sup.a, --OC.sub.2-6alkylOR.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.2-6alkylNR.sup.aR.sup.a and
--NR.sup.aC.sub.2-6alkylOR.sup.a; or R.sup.11 is C.sub.1-9alkyl or
C.sub.1-4alkyl(phenyl) wherein either is substituted by 0, 1, 2, 3
or 4 substituents selected from halo, C.sub.1-4haloalkyl, 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.2-6alkylNR.sup.aR.sup.a, --OC.sub.2-6alkylOR.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.2-6alkylNR.sup.aR.sup.a and
--NR.sup.aC.sub.2-6alkylOR.sup.a; and additionally substituted by
0, 1, 2, 3, 4 or 5 substituents independently selected from Br, Cl,
F and I; or R.sup.11 is 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.1-4haloalkyl, 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.2-6alkylNR.sup.aR.sup.a, --OC.sub.2-6alkylOR.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.2-6alkylNR.sup.aR.sup.a and
--NR.sup.aC.sub.2-6alkylOR.sup.a;
[0059] R.sup.a is independently, at each instance, H or R.sup.b;
and
[0060] R.sup.b is independently, at each instance, phenyl, benzyl
or C.sub.1-6alkyl, the phenyl, benzyl and C.sub.1-6alkyl being
substituted by 0, 1, 2 or 3 substituents selected from halo,
C.sub.1-4alkyl, C.sub.1-3haloalkyl, --OC.sub.1-4alkyl, --NH.sub.2,
--NHC.sub.1-4alkyl, --N(C.sub.1-4alkyl)C.sub.1-4alkyl.
[0061] Another aspect of the invention relates to compounds having
the structure:
##STR00004##
or any pharmaceutically-acceptable salt thereof, wherein:
[0062] X.sup.1 is C(R.sup.9) or N;
[0063] X.sup.2 is C(R.sup.10) or N;
[0064] Z is --CR.sup.11.dbd.CR.sup.11--, --CR.sup.11.dbd.N--,
--N.dbd.CR.sup.11--, --CR.sup.11.dbd.CR.sup.11--C(.dbd.O)-- and
--C(.dbd.O)--CR.sup.11.dbd.CR.sup.11--;
[0065] n is 0, 1, 2 or 3;
[0066] R.sup.1 is a direct-bonded or oxygen-linked 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 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.1-4alkyl, OC.sub.1-4alkyl, OC.sub.1-4haloalkyl,
NHC.sub.1-4alkyl, N(C.sub.1-4alkyl)C.sub.1-4alkyl and
C.sub.1-4haloalkyl;
[0067] R.sup.2 is selected from halo, C.sub.1-4haloalkyl, 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.2-6alkylNR.sup.aR.sup.a, --OC.sub.2-6alkylOR.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.2-6alkylNR.sup.aR.sup.a and
--NR.sup.aC.sub.2-6alkylOR.sup.a; or R.sup.2 is selected from
C.sub.1-6alkyl, phenyl, benzyl, heteroaryl, heterocycle,
--(C.sub.1-3alkyl)heteroaryl, --(C.sub.1-3alkyl)heterocycle,
--O(C.sub.1-3alkyl)heteroaryl, --O(C.sub.1-3alkyl)hetero cycle,
--NR.sup.a(C.sub.1-3alkyl)hetero aryl,
--NR.sup.a(C.sub.1-3alkyl)hetero cycle, --(C.sub.1-3alkyl)phenyl,
--O(C.sub.1-3alkyl)phenyl and --NR.sup.a(C.sub.1-3alkyl)phenyl all
of which are substituted by 0, 1, 2 or 3 substituents selected from
C.sub.1-4haloalkyl, OC.sub.1-4alkyl, Br, Cl, F, I and
C.sub.1-4alkyl;
[0068] R.sup.3 is selected from H, halo, C.sub.1-4haloalkyl, 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.2-6alkylNR.sup.aR.sup.a, --OC.sub.2-6alkylOR.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.2-6alkylNR.sup.aR.sup.a,
--NR.sup.aC.sub.2-6alkylOR.sup.a, C.sub.1-6alkyl, phenyl, benzyl,
heteroaryl and heterocycle, wherein the C.sub.1-6alkyl, phenyl,
benzyl, heteroaryl and heterocycle are additionally substituted by
0, 1, 2 or 3 substituents selected from C.sub.1-6haloalkyl,
OC.sub.1-6alkyl, Br, Cl, F, I and C.sub.1-6alkyl;
[0069] R.sup.4 is, independently, in each instance, halo, nitro,
cyano, C.sub.1-4alkyl, OC.sub.1-4alkyl, OC.sub.1-4haloalkyl,
NHC.sub.1-4alkyl, N(C.sub.1-4alkyl)C.sub.1-4alkyl or
C.sub.1-4haloalkyl;
[0070] R.sup.5 is, independently, in each instance, H, halo,
C.sub.1-6alkyl, C.sub.1-4haloalkyl, or C.sub.1-6alkyl substituted
by 1, 2 or 3 substituents selected from halo, cyano, OH,
OC.sub.1-4alkyl, C.sub.1-4alkyl, C.sub.1-3haloalkyl,
OC.sub.1-4alkyl, NH.sub.2, NHC.sub.1-4alkyl,
N(C.sub.1-4alkyl)C.sub.1-4alkyl; or both R.sup.5 groups together
form a C.sub.3-6spiroalkyl substituted by 0, 1, 2 or 3 substituents
selected from halo, cyano, OH, OC.sub.1-4alkyl, C.sub.1-4alkyl,
C.sub.1-3haloalkyl, OC.sub.1-4alkyl, NH.sub.2, NHC.sub.1-4alkyl,
N(C.sub.1-4alkyl)C.sub.1-4alkyl;
[0071] R.sup.6 is selected from H, C.sub.1-6haloalkyl, Br, Cl, F,
I, OR.sup.a, NR.sup.aR.sup.a, C.sub.1-6alkyl, phenyl, benzyl,
heteroaryl and heterocycle, wherein the C.sub.1-6alkyl, phenyl,
benzyl, heteroaryl and heterocycle are additionally substituted by
0, 1, 2 or 3 substituents selected from C.sub.1-6haloalkyl,
OC.sub.1-6alkyl, Br, Cl, F, I and C.sub.1-6alkyl;
[0072] R.sup.7 is selected from H, C.sub.1-6haloalkyl, Br, Cl, F,
I, OR.sup.a, NR.sup.aR.sup.a, C.sub.1-6alkyl, phenyl, benzyl,
heteroaryl and heterocycle, wherein the C.sub.1-6alkyl, phenyl,
benzyl, heteroaryl and heterocycle are additionally substituted by
0, 1, 2 or 3 substituents selected from C.sub.1-6haloalkyl,
OC.sub.1-6alkyl, Br, Cl, F, I and C.sub.1-6alkyl;
[0073] R.sup.8 is selected from H, C.sub.1-6haloalkyl, Br, Cl, F,
I, OR.sup.a, NR.sup.aR.sup.a, C.sub.1-6alkyl, phenyl, benzyl,
heteroaryl and heterocycle, wherein the C.sub.1-6alkyl, phenyl,
benzyl, heteroaryl and heterocycle are additionally substituted by
0, 1, 2 or 3 substituents selected from C.sub.1-6haloalkyl,
OC.sub.1-6alkyl, Br, Cl, F, I and C.sub.1-6alkyl;
[0074] R.sup.9 is selected from H, halo, C.sub.1-4haloalkyl, 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.2-6alkylNR.sup.aR.sup.a, --OC.sub.2-6alkylOR.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.2-6alkylNR.sup.aR.sup.a,
--NR.sup.aC.sub.2-6alkylOR.sup.a, C.sub.1-6alkyl, phenyl, benzyl,
heteroaryl and heterocycle, wherein the C.sub.1-6alkyl, phenyl,
benzyl, heteroaryl and heterocycle are additionally substituted by
0, 1, 2 or 3 substituents selected from halo, C.sub.1-4haloalkyl,
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.2-6alkylNR.sup.aR.sup.a, --OC.sub.2-6alkylOR.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.2-6alkylNR.sup.aR.sup.a,
--NR.sup.aC.sub.2-6alkylOR.sup.a; or R.sup.9 is 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.1-4haloalkyl, 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.2-6alkylNR.sup.aR.sup.a, --OC.sub.2-6alkylOR.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.2-6alkylNR.sup.aR.sup.a and
--NR.sup.aC.sub.2-6alkylOR.sup.a;
[0075] R.sup.10 is H, C.sub.1-3alkyl, C.sub.1-3haloalkyl, cyano,
nitro, CO.sub.2R.sup.a, C(.dbd.O)NR.sup.aR.sup.a,
--C(.dbd.NR.sup.a)NR.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,
S(.dbd.O)R.sup.b, S(.dbd.O).sub.2R.sup.b or
S(.dbd.O).sub.2NR.sup.aR.sup.a;
[0076] R.sup.11 is selected from H, halo, C.sub.1-4haloalkyl,
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.2-6alkylNR.sup.aR.sup.a, --OC.sub.2-6alkylOR.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.2-6alkylNR.sup.aR.sup.a and
--NR.sup.aC.sub.2-6alkylOR.sup.a; or R.sup.11 is C.sub.1-9alkyl or
C.sub.1-4alkyl(phenyl) wherein either is substituted by 0, 1, 2, 3
or 4 substituents selected from halo, C.sub.1-4haloalkyl, 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.2-6alkylNR.sup.aR.sup.a, --OC.sub.2-6alkylOR.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.2-6alkylNR.sup.aR.sup.a and
--NR.sup.aC.sub.2-6alkylOR.sup.a; and additionally substituted by
0, 1, 2, 3, 4 or 5 substituents independently selected from Br, Cl,
F and I; or R.sup.11 is 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.1-4haloalkyl, 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.2-6alkylNR.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.2-6alkylNR.sup.aR.sup.a and
--NR.sup.aC.sub.2-6alkylOR.sup.a;
[0077] R.sup.a is independently, at each instance, H or R.sup.b;
and
[0078] R.sup.b is independently, at each instance, phenyl, benzyl
or C.sub.1-6alkyl, the phenyl, benzyl and C.sub.1-6alkyl being
substituted by 0, 1, 2 or 3 substituents selected from halo,
C.sub.1-4alkyl, C.sub.1-3haloalkyl, --OC.sub.1-4alkyl, --NH.sub.2,
--NHC.sub.1-4alkyl, --N(C.sub.1-4alkyl)C.sub.1-4alkyl.
[0079] Another aspect of the invention relates to compounds having
the structure:
##STR00005##
or any pharmaceutically-acceptable salt thereof, wherein:
[0080] X.sup.1 is C(R.sup.9) or N;
[0081] X.sup.2 is C(R.sup.10) or N;
[0082] Z is --CR.sup.11.dbd.CR.sup.11--, --CR.sup.11.dbd.N--,
--N.dbd.CR.sup.11--, --CR.sup.11--C(.dbd.O)-- and
--C(.dbd.O)--CR.sup.11.dbd.CR.sup.11--;
[0083] n is 0, 1, 2 or 3;
[0084] R.sup.1 is a direct-bonded or oxygen-linked 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 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.1-4alkyl, OC.sub.1-4alkyl, OC.sub.1-4haloalkyl,
NHC.sub.1-4alkyl, N(C.sub.1-4alkyl)C.sub.1-4alkyl and
C.sub.1-4haloalkyl;
[0085] R.sup.2 is selected from halo, C.sub.1-4haloalkyl, 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.2-6alkylNR.sup.aR.sup.a, --OC.sub.2-6alkylOR.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.2-6alkylNR.sup.aR.sup.a and
--NR.sup.aC.sub.2-6alkylOR.sup.a; or R.sup.2 is selected from
C.sub.1-6alkyl, phenyl, benzyl, heteroaryl, heterocycle,
--(C.sub.1-3alkyl)hetero aryl, --(C.sub.1-3alkyl)hetero cycle,
--O(C.sub.1-3alkyl)heteroaryl, --O(C.sub.1-3alkyl)hetero cycle,
--NR.sup.a(C.sub.1-3alkyl)hetero aryl,
--NR.sup.a(C.sub.1-3alkyl)hetero cycle, --(C.sub.1-3alkyl)phenyl,
--O(C.sub.1-3alkyl)phenyl and --NR.sup.a(C.sub.1-3alkyl)phenyl all
of which are substituted by 0, 1, 2 or 3 substituents selected from
C.sub.1-4haloalkyl, OC.sub.1-4alkyl, Br, Cl, F, I and
C.sub.1-4alkyl;
[0086] R.sup.3 is selected from H, halo, C.sub.1-4haloalkyl, 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.2-6alkylNR.sup.aR.sup.a, --OC.sub.2-6alkylOR.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.2-6alkylNR.sup.aR.sup.a,
--NR.sup.aC.sub.2-6alkylOR.sup.a, C.sub.1-6alkyl, phenyl, benzyl,
heteroaryl and heterocycle, wherein the C.sub.1-6alkyl, phenyl,
benzyl, heteroaryl and heterocycle are additionally substituted by
0, 1, 2 or 3 substituents selected from C.sub.1-6haloalkyl,
OC.sub.1-6alkyl, Br, Cl, F, I and C.sub.1-6alkyl;
[0087] R.sup.4 is, independently, in each instance, halo, nitro,
cyano, C.sub.1-4alkyl, OC.sub.1-4alkyl, OC.sub.1-4haloalkyl,
NHC.sub.1-4alkyl, N(C.sub.1-4alkyl)C.sub.1-4alkyl or
C.sub.1-4haloalkyl;
[0088] R.sup.5 is, independently, in each instance, H, halo,
C.sub.1-6alkyl, C.sub.1-4haloalkyl, or C.sub.1-6alkyl substituted
by 1, 2 or 3 substituents selected from halo, cyano, OH,
OC.sub.1-4alkyl, C.sub.1-4alkyl, C.sub.1-3haloalkyl,
OC.sub.1-4alkyl, NH.sub.2, NHC.sub.1-4alkyl,
N(C.sub.1-4alkyl)C.sub.1-4alkyl; or both R.sup.5 groups together
form a C.sub.3-6spiroalkyl substituted by 0, 1, 2 or 3 substituents
selected from halo, cyano, OH, OC.sub.1-4alkyl, C.sub.1-4alkyl,
C.sub.1-3haloalkyl, OC.sub.1-4alkyl, NH.sub.2, NHC.sub.1-4alkyl,
N(C.sub.1-4alkyl)C.sub.1-4alkyl;
[0089] R.sup.6 is selected from H, C.sub.1-6haloalkyl, Br, Cl, F,
I, OR.sup.a, NR.sup.aR.sup.a, C.sub.1-6alkyl, phenyl, benzyl,
heteroaryl and heterocycle, wherein the C.sub.1-6alkyl, phenyl,
benzyl, heteroaryl and heterocycle are additionally substituted by
0, 1, 2 or 3 substituents selected from C.sub.1-6haloalkyl,
OC.sub.1-6alkyl, Br, Cl, F, I and C.sub.1-6alkyl;
[0090] R.sup.7 is selected from H, C.sub.1-6haloalkyl, Br, Cl, F,
I, OR.sup.a, NR.sup.aR.sup.a, C.sub.1-6alkyl, phenyl, benzyl,
heteroaryl and heterocycle, wherein the C.sub.1-6alkyl, phenyl,
benzyl, heteroaryl and heterocycle are additionally substituted by
0, 1, 2 or 3 substituents selected from C.sub.1-6haloalkyl,
OC.sub.1-6alkyl, Br, Cl, F, I and C.sub.1-6alkyl;
[0091] R.sup.8 is selected from H, C.sub.1-6haloalkyl, Br, Cl, F,
I, OR.sup.a, NR.sup.aR.sup.a, C.sub.1-6alkyl, phenyl, benzyl,
heteroaryl and heterocycle, wherein the C.sub.1-6alkyl, phenyl,
benzyl, heteroaryl and heterocycle are additionally substituted by
0, 1, 2 or 3 substituents selected from C.sub.1-6haloalkyl,
OC.sub.1-6alkyl, Br, Cl, F, I and C.sub.1-6alkyl;
[0092] R.sup.9 is selected from H, halo, C.sub.1-4haloalkyl, 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.2-6alkylNR.sup.aR.sup.a, --OC.sub.2-6alkylOR.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.2-6alkylNR.sup.aR.sup.a,
--NR.sup.aC.sub.2-6alkylOR.sup.a, C.sub.1-6alkyl, phenyl, benzyl,
heteroaryl and heterocycle, wherein the C.sub.1-6alkyl, phenyl,
benzyl, heteroaryl and heterocycle are additionally substituted by
0, 1, 2 or 3 substituents selected from halo, C.sub.1-4haloalkyl,
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.2-6alkylNR.sup.aR.sup.a, --OC.sub.2-6alkylOR.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.2-6alkylNR.sup.aR.sup.a,
--NR.sup.aC.sub.2-6alkylOR.sup.a; or R.sup.9 is 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.1-4haloalkyl, 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.2-6alkylNR.sup.aR.sup.a, --OC.sub.2-6alkylOR.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.2-6alkylNR.sup.aR.sup.a and
--NR.sup.aC.sub.2-6alkylOR.sup.a;
[0093] R.sup.10 is H, C.sub.1-3alkyl, C.sub.1-3haloalkyl, cyano,
nitro, CO.sub.2R.sup.a, C(.dbd.O)NR.sup.aR.sup.a,
--C(.dbd.NR.sup.a)NR.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,
S(.dbd.O)R.sup.b, S(.dbd.O).sub.2R.sup.b or
S(.dbd.O).sub.2NR.sup.aR.sup.a;
[0094] R.sup.11 is selected from H, halo, C.sub.1-4haloalkyl,
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.2-6alkylNR.sup.aR.sup.a, --OC.sub.2-6alkylOR.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.2-6alkylNR.sup.aR.sup.a and
--NR.sup.aC.sub.2-6alkylOR.sup.a; or R.sup.11 is C.sub.1-9alkyl or
C.sub.1-4alkyl(phenyl) wherein either is substituted by 0, 1, 2, 3
or 4 substituents selected from halo, C.sub.1-4haloalkyl, 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.2-6alkylNR.sup.aR.sup.a, --OC.sub.2-6alkylOR.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.2-6alkylNR.sup.aR.sup.a and
--NR.sup.aC.sub.2-6alkylOR.sup.a; and additionally substituted by
0, 1, 2, 3, 4 or 5 substituents independently selected from Br, Cl,
F and I; or R.sup.11 is 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.1-4haloalkyl, 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.2-6alkylNR.sup.aR.sup.a, --OC.sub.2-6alkylOR.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.2-6alkylNR.sup.aR.sup.a and
--NR.sup.aC.sub.2-6alkylOR.sup.a;
[0095] R.sup.a is independently, at each instance, H or R.sup.b;
and
[0096] R.sup.b is independently, at each instance, phenyl, benzyl
or C.sub.1-6alkyl, the phenyl, benzyl and C.sub.1-6alkyl being
substituted by 0, 1, 2 or 3 substituents selected from halo,
C.sub.1-4alkyl, C.sub.1-3haloalkyl, --OC.sub.1-4alkyl, --NH.sub.2,
--NHC.sub.1-4alkyl, --N(C.sub.1-4alkyl)C.sub.1-4alkyl.
[0097] Another aspect of the invention relates to compounds having
the structure:
##STR00006##
or any pharmaceutically-acceptable salt or hydrate thereof,
wherein:
[0098] X.sup.1 is C(R.sup.9) or N;
[0099] X.sup.2 is C(R.sup.10) or N;
[0100] Z is --CR.sup.11.dbd.CR.sup.11--, --CR.sup.11.dbd.N--,
--N.dbd.CR.sup.11--, --CR.sup.11.dbd.CR.sup.11--C(.dbd.O)-- and
--C(.dbd.O)--CR.sup.11.dbd.CR.sup.11--;
[0101] n is 0, 1, 2 or 3;
[0102] R.sup.1 is 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 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.1-4alkyl, OC.sub.1-4alkyl,
OC.sub.1-4haloalkyl, NHC.sub.1-4alkyl,
N(C.sub.1-4alkyl)C.sub.1-4alkyl and C.sub.1-4haloalkyl;
[0103] R.sup.2 is selected from halo, C.sub.1-4haloalkyl, 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.2-6alkylNR.sup.aR.sup.a, --OC.sub.2-6alkylOR.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.2-6alkylNR.sup.aR.sup.a and
--NR.sup.aC.sub.2-6alkylOR.sup.a; or R.sup.2 is selected from
C.sub.1-6alkyl, phenyl, benzyl, heteroaryl and heterocycle, all of
which are substituted by 0, 1, 2 or 3 substituents selected from
C.sub.1-4haloalkyl, OC.sub.1-4alkyl, Br, Cl, F, I and
C.sub.1-4alkyl;
[0104] R.sup.3 is selected from H, halo, C.sub.1-4haloalkyl, 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.2-6alkylNR.sup.aR.sup.a, --OC.sub.2-6alkylOR.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.2-6alkylNR.sup.aR.sup.a,
--NR.sup.aC.sub.2-6alkylOR.sup.a, C.sub.1-6alkyl, phenyl, benzyl,
heteroaryl and heterocycle, wherein the C.sub.1-6alkyl, phenyl,
benzyl, heteroaryl and heterocycle are additionally substituted by
0, 1, 2 or 3 substituents selected from C.sub.1-6haloalkyl,
OC.sub.1-6alkyl, Br, Cl, F, I and C.sub.1-6alkyl;
[0105] R.sup.4 is, independently, in each instance, halo, nitro,
cyano, C.sub.1-4alkyl, OC.sub.1-4alkyl, OC.sub.1-4haloalkyl,
NHC.sub.1-4alkyl, N(C.sub.1-4alkyl)C.sub.1-4alkyl or
C.sub.1-4haloalkyl;
[0106] R.sup.5 is, independently, in each instance, H, halo,
C.sub.1-6alkyl, C.sub.1-4haloalkyl, or C.sub.1-6alkyl substituted
by 1, 2 or 3 substituents selected from halo, cyano, OH,
OC.sub.1-4alkyl, C.sub.1-4alkyl, C.sub.1-3haloalkyl,
OC.sub.1-4alkyl, NH.sub.2, NHC.sub.1-4alkyl,
N(C.sub.1-4alkyl)C.sub.1-4alkyl; or both R.sup.5 groups together
form a C.sub.3-6spiroalkyl substituted by 0, 1, 2 or 3 substituents
selected from halo, cyano, OH, OC.sub.1-4alkyl, C.sub.1-4alkyl,
C.sub.1-3haloalkyl, OC.sub.1-4alkyl, NH.sub.2, NHC.sub.1-4alkyl,
N(C.sub.1-4alkyl)C.sub.1-4alkyl;
[0107] R.sup.6 is selected from H, C.sub.1-6haloalkyl, Br, Cl, F,
I, OR.sup.a, NR.sup.aR.sup.a, C.sub.1-6alkyl, phenyl, benzyl,
heteroaryl and heterocycle, wherein the C.sub.1-6alkyl, phenyl,
benzyl, heteroaryl and heterocycle are additionally substituted by
0, 1, 2 or 3 substituents selected from C.sub.1-6haloalkyl,
OC.sub.1-6alkyl, Br, Cl, F, I and C.sub.1-6alkyl;
[0108] R.sup.7 is selected from H, C.sub.1-6haloalkyl, Br, Cl, F,
I, OR.sup.a, NR.sup.aR.sup.a, C.sub.1-6alkyl, phenyl, benzyl,
heteroaryl and heterocycle, wherein the C.sub.1-6alkyl, phenyl,
benzyl, heteroaryl and heterocycle are substituted by 0, 1, 2 or 3
substituents selected from C.sub.1-6haloalkyl, OC.sub.1-6alkyl, Br,
Cl, F, I and C.sub.1-6alkyl;
[0109] R.sup.8 is selected from H, halo, C.sub.1-4haloalkyl, 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.2-6alkylNR.sup.aR.sup.a, --OC.sub.2-6alkylOR.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.2-6alkylNR.sup.aR.sup.a and
--NR.sup.aC.sub.2-6alkylOR.sup.a; or R.sup.8 is C.sub.1-9alkyl or
C.sub.1-4alkyl(phenyl) wherein either is substituted by 0, 1, 2, 3
or 4 substituents selected from halo, C.sub.1-4haloalkyl, 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.2-6alkylNR.sup.aR.sup.a, --OC.sub.2-6alkylOR.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.2-6alkylNR.sup.aR.sup.a and
--NR.sup.aC.sub.2-6alkylOR.sup.a; and additionally substituted by
0, 1, 2, 3, 4 or 5 substituents independently selected from Br, Cl,
F and I; or R.sup.8 is 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.1-4haloalkyl, 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.2-6alkylNR.sup.aR.sup.a, --OC.sub.2-6alkylOR.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.2-6alkylNR.sup.aR.sup.a and
--NR.sup.aC.sub.2-6alkylOR.sup.a;
[0110] R.sup.9 is selected from H, halo, C.sub.1-4haloalkyl, 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.2-6alkylNR.sup.aR.sup.a, --OC.sub.2-6alkylOR.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.2-6alkylNR.sup.aR.sup.a,
--NR.sup.aC.sub.2-6alkylOR.sup.a, C.sub.1-6alkyl, phenyl, benzyl,
heteroaryl and heterocycle, wherein the C.sub.1-6alkyl, phenyl,
benzyl, heteroaryl and heterocycle are additionally substituted by
0, 1, 2 or 3 substituents selected from halo, C.sub.1-4haloalkyl,
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.2-6alkylNR.sup.aR.sup.a, --OC.sub.2-6alkylOR.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.2-6alkylNR.sup.aR.sup.a,
--NR.sup.aC.sub.2-6alkylOR.sup.a; or R.sup.9 is 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.1-4haloalkyl, 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.2-6alkylNR.sup.aR.sup.a, --OC.sub.2-6alkylOR.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.2-6alkylNR.sup.aR.sup.a and
--NR.sup.aC.sub.2-6alkylOR.sup.a;
[0111] R.sup.10 is H, C.sub.1-3alkyl, C.sub.1-3haloalkyl, cyano,
nitro, CO.sub.2R.sup.a, C(.dbd.O)NR.sup.aR.sup.a,
--C(.dbd.NR.sup.a)NR.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,
S(.dbd.O)R.sup.b, S(.dbd.O).sub.2R.sup.b or
S(.dbd.O).sub.2NR.sup.aR.sup.a;
[0112] R.sup.11 is selected from H, halo, C.sub.1-4haloalkyl,
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.2-6alkylNR.sup.aR.sup.a, --OC.sub.2-6alkylOR.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.2-6alkylNR.sup.aR.sup.a and
--NR.sup.aC.sub.2-6alkylOR.sup.a; or R.sup.11 is C.sub.1-9alkyl or
C.sub.1-4alkyl(phenyl) wherein either is substituted by 0, 1, 2, 3
or 4 substituents selected from halo, C.sub.1-4haloalkyl, 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.2-6alkylNR.sup.aR.sup.a, --OC.sub.2-6alkylOR.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.2-6alkylNR.sup.aR.sup.a and
--NR.sup.aC.sub.2-6alkylOR.sup.a; and additionally substituted by
0, 1, 2, 3, 4 or 5 substituents independently selected from Br, Cl,
F and I; or R.sup.11 is 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.1-4haloalkyl, 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.2-6alkylNR.sup.aR.sup.a, --OC.sub.2-6alkylOR.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,
--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.2-6alkylNR.sup.aR.sup.a and
--NR.sup.aC.sub.2-6alkylOR.sup.a;
[0113] R.sup.a is independently, at each instance, H or R.sup.b;
and
[0114] R.sup.b is independently, at each instance, phenyl, benzyl
or C.sub.1-6alkyl, the phenyl, benzyl and C.sub.1-6alkyl being
substituted by 0, 1, 2 or 3 substituents selected from halo,
C.sub.1-4alkyl, C.sub.1-3haloalkyl, --OC.sub.1-4alkyl, --NH.sub.2,
--NHC.sub.1-4alkyl, --N(C.sub.1-4alkyl)C.sub.1-4alkyl.
[0115] In another embodiment, in conjunction with any of the above
or below embodiments, X.sup.1 is C(R.sup.9) and X.sup.2 is N.
[0116] In another embodiment, in conjunction with any of the above
or below embodiments, X.sup.1 is C(R.sup.9) and X.sup.2
is)C(R.sup.10.
[0117] In another embodiment, in conjunction with any of the above
or below embodiments, R.sup.1 is phenyl substituted by 0 or 1
R.sup.2 substituents, and the phenyl is additionally substituted by
0, 1, 2 or 3 substituents independently selected from halo, nitro,
cyano, C.sub.1-4alkyl, OC.sub.1-4alkyl, OC.sub.1-4haloalkyl,
NHC.sub.1-4alkyl, N(C.sub.1-4alkyl)C.sub.1-4alkyl and
C.sub.1-4haloalkyl.
[0118] In another embodiment, in conjunction with any of the above
or below embodiments, R.sup.1 is phenyl.
[0119] In another embodiment, in conjunction with any of the above
or below embodiments, R.sup.1 is phenyl substituted by R.sup.2, and
the phenyl is additionally substituted by 0, 1, 2 or 3 substituents
independently selected from halo, nitro, cyano, C.sub.1-4alkyl,
OC.sub.1-4alkyl, OC.sub.1-4haloalkyl, NHC.sub.1-4alkyl,
N(C.sub.1-4alkyl)C.sub.1-4alkyl and C.sub.1-4haloalkyl.
[0120] In another embodiment, in conjunction with any of the above
or below embodiments, R.sup.1 is selected from 2-methylphenyl,
2-chlorophenyl, 2-trifluoromethylphenyl, 2-fluorophenyl and
2-methoxyphenyl.
[0121] In another embodiment, in conjunction with any of the above
or below embodiments, R.sup.1 is a direct-bonded or oxygen-linked
saturated, partially-saturated or unsaturated 5-, 6- or 7-membered
monocyclic ring containing 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 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.1-4alkyl, OC.sub.1-4alkyl, OC.sub.1-4haloalkyl,
NHC.sub.1-4alkyl, N(C.sub.1-4-alkyl)C.sub.1-4alkyl and
C.sub.1-4haloalkyl.
[0122] In another embodiment, in conjunction with any of the above
or below embodiments, R.sup.1 is an unsaturated 5- or 6-membered
monocyclic ring containing 1, 2, 3 or 4 atoms selected from N, O
and S, but containing no more than one O or S, wherein the ring is
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.1-4alkyl, OC.sub.1-4alkyl,
OC.sub.1-4haloalkyl, NHC.sub.1-4alkyl,
N(C.sub.1-4alkyl)C.sub.1-4alkyl and C.sub.1-4haloalkyl.
[0123] In another embodiment, in conjunction with any of the above
or below embodiments, R.sup.1 is an unsaturated 5- or 6-membered
monocyclic ring containing 1, 2, 3 or 4 atoms selected from N, O
and S, but containing no more than one O or S, wherein the ring is
substituted by 0 or 1 R.sup.2 substituents, and the ring is
additionally substituted by 1, 2 or 3 substituents independently
selected from halo, nitro, cyano, C.sub.1-4alkyl, OC.sub.1-4alkyl,
OC.sub.1-4haloalkyl, NHC.sub.1-4alkyl,
N(C.sub.1-4alkyl)C.sub.1-4alkyl and C.sub.1-4haloalkyl.
[0124] In another embodiment, in conjunction with any of the above
or below embodiments, R.sup.1 is an unsaturated 5- or 6-membered
monocyclic ring containing 1, 2, 3 or 4 atoms selected from N, O
and S.
[0125] In another embodiment, in conjunction with any of the above
or below embodiments, R.sup.1 is selected from pyridyl and
pyrimidinyl.
[0126] In another embodiment, in conjunction with any of the above
or below embodiments, R.sup.3 is selected from halo,
C.sub.1-4haloalkyl, 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.2-6alkylNR.sup.aR.sup.a, --OC.sub.2-6alkylOR.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.2-6alkylNR.sup.aR.sup.a,
--NR.sup.aC.sub.2-6alkylOR.sup.a, C.sub.1-6alkyl, phenyl, benzyl,
heteroaryl and heterocycle, wherein the C.sub.1-6alkyl, phenyl,
benzyl, heteroaryl and heterocycle are additionally substituted by
0, 1, 2 or 3 substituents selected from C.sub.1-6haloalkyl,
OC.sub.1-6alkyl, Br, Cl, F, I and C.sub.1-6alkyl.
[0127] In another embodiment, in conjunction with any of the above
or below embodiments, R.sup.3 is H.
[0128] In another embodiment, in conjunction with any of the above
or below embodiments, R.sup.3 is selected from F, Cl,
C.sub.1-6alkyl, phenyl, benzyl, heteroaryl and heterocycle, wherein
the C.sub.1-6alkyl, phenyl, benzyl, heteroaryl and heterocycle are
additionally substituted by 0, 1, 2 or 3 substituents selected from
C.sub.1-6haloalkyl, OC.sub.1-6alkyl, Br, Cl, F, I and
C.sub.1-6alkyl.
[0129] In another embodiment, in conjunction with any of the above
or below embodiments, R.sup.5 is, independently, in each instance,
H, halo, C.sub.1-6alkyl, C.sub.1-4haloalkyl, or C.sub.1-6alkyl
substituted by 1, 2 or 3 substituents selected from halo, cyano,
OH, OC.sub.1-4alkyl, C.sub.1-4alkyl, C.sub.1-3haloalkyl,
OC.sub.1-4alkyl, NH.sub.2, NHC.sub.1-4alkyl,
N(C.sub.1-4alkyl)C.sub.1-4alkyl; or both R.sup.5 groups together
form a C.sub.3-6spiroalkyl substituted by 0, 1, 2 or 3 substituents
selected from halo, cyano, OH, OC.sub.1-4alkyl, C.sub.1-4alkyl,
C.sub.1-3haloalkyl, OC.sub.1-4alkyl, NH.sub.2, NHC.sub.1-4alkyl,
N(C.sub.1-4alkyl)C.sub.1-4alkyl.
[0130] In another embodiment, in conjunction with any of the above
or below embodiments, R.sup.5 is H.
[0131] In another embodiment, in conjunction with any of the above
or below embodiments, one R.sup.5 is S-methyl, the other is H.
[0132] In another embodiment, in conjunction with any of the above
or below embodiments, at least one R.sup.5 is halo, C.sub.1-6alkyl,
C.sub.1-4haloalkyl, or C.sub.1-6alkyl substituted by 1, 2 or 3
substituents selected from halo, cyano, OH, OC.sub.1-4alkyl,
C.sub.1-4alkyl, C.sub.1-3haloalkyl, OC.sub.1-4alkyl, NH.sub.2,
NHC.sub.1-4alkyl, N(C.sub.1-4alkyl)C.sub.1-4alkyl.
[0133] In another embodiment, in conjunction with any of the above
or below embodiments, R.sup.6 is H.
[0134] In another embodiment, in conjunction with any of the above
or below embodiments, R.sup.6 is NR.sup.bR.sup.a.
[0135] In another embodiment, in conjunction with any of the above
or below embodiments, R.sup.6 is NH.sub.2.
[0136] In another embodiment, in conjunction with any of the above
or below embodiments, R.sup.6 is NHC.sub.1-6alkyl.
[0137] In another embodiment, in conjunction with any of the above
or below embodiments, R.sup.7 is selected from C.sub.1-6haloalkyl,
Br, Cl, F, I, OR.sup.a, NR.sup.aR.sup.a, C.sub.1-6alkyl, phenyl,
benzyl, heteroaryl and heterocycle, wherein the C.sub.1-6alkyl,
phenyl, benzyl, heteroaryl and heterocycle are substituted by 0, 1,
2 or 3 substituents selected from C.sub.1-6haloalkyl,
OC.sub.1-6alkyl, Br, Cl, F, I and C.sub.1-6alkyl.
[0138] In another embodiment, in conjunction with any of the above
or below embodiments, R.sup.7 is selected from C.sub.1-6haloalkyl,
Br, Cl, F, I and C.sub.1-6alkyl.
[0139] In another embodiment, in conjunction with any of the above
or below embodiments, R.sup.7 is H.
[0140] In another embodiment, in conjunction with any of the above
or below embodiments, R.sup.8 is H.
[0141] In another embodiment, in conjunction with any of the above
or below embodiments, R.sup.8 is selected from halo,
C.sub.1-4haloalkyl, 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.2-6alkylNR.sup.aR.sup.a, --OC.sub.2-6alkylOR.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.2-6alkylNR.sup.aR.sup.a and
--NR.sup.aC.sub.2-6alkylOR.sup.a.
[0142] In another embodiment, in conjunction with any of the above
or below embodiments, R.sup.8 is C.sub.1-9alkyl or
C.sub.1-4alkyl(phenyl) wherein either is substituted by 0, 1, 2, 3
or 4 substituents selected from halo, C.sub.1-4haloalkyl, 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.2-6alkylNR.sup.aR.sup.a, --OC.sub.2-6alkylOR.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.2-6alkylNR.sup.aR.sup.a and
--NR.sup.aC.sub.2-6alkylOR.sup.a; and additionally substituted by
0, 1, 2, 3, 4 or 5 substituents independently selected from Br, Cl,
F and I.
[0143] In another embodiment, in conjunction with any of the above
or below embodiments, R.sup.8 is 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.1-4haloalkyl, 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.2-6alkylNR.sup.aR.sup.a, --OC.sub.2-6alkylOR.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.2-6alkylNR.sup.aR.sup.a and
--NR.sup.aC.sub.2-6alkylOR.sup.a.
[0144] In another embodiment, in conjunction with any of the above
or below embodiments, R.sup.9 is H.
[0145] In another embodiment, in conjunction with any of the above
or below embodiments, R.sup.9 is selected from halo,
C.sub.1-4haloalkyl, 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.2-6alkylNR.sup.aR.sup.a, --OC.sub.2-6alkylOR.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.2-6alkylNR.sup.aR.sup.a,
--NR.sup.aC.sub.2-6alkylOR.sup.a, C.sub.1-6alkyl, phenyl, benzyl,
heteroaryl and heterocycle, wherein the C.sub.1-6alkyl, phenyl,
benzyl, heteroaryl and heterocycle are additionally substituted by
0, 1, 2 or 3 substituents selected from halo, C.sub.1-4haloalkyl,
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.2-6alkylNR.sup.aR.sup.a, --OC.sub.2-6alkylOR.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.2-6alkylNR.sup.aR.sup.a,
--NR.sup.aC.sub.2-6alkylOR.sup.a.
[0146] In another embodiment, in conjunction with any of the above
or below embodiments, R.sup.9 is 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.1-4haloalkyl, 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.2-6alkylNR.sup.aR.sup.a, --OC.sub.2-6alkylOR.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.2-6alkylNR.sup.aR.sup.a and
--NR.sup.aC.sub.2-6alkylOR.sup.a.
[0147] In another embodiment, in conjunction with any of the above
or below embodiments, R.sup.10 is H.
[0148] In another embodiment, in conjunction with any of the above
or below embodiments, R.sup.10 is cyano, nitro, CO.sub.2R.sup.a,
C(.dbd.O)NR.sup.aR.sup.a, --C(.dbd.NR.sup.a)NR.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,
S(.dbd.O)R.sup.b, S(.dbd.O).sub.2R.sup.b or
S(.dbd.O).sub.2NR.sup.aR.sup.a.
[0149] Another aspect of the invention relates to a method of
treating PI3K-mediated conditions or disorders.
[0150] 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.
[0151] 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.
[0152] 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.
[0153] 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.
[0154] 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.
[0155] 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.
[0156] Another aspect of the invention relates to the use of a
compound according to any of the above embodiments as a
medicament.
[0157] 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.
[0158] 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.
[0159] Unless otherwise specified, the following definitions apply
to terms found in the specification and claims:
"C.sub..alpha.-.beta.alkyl" means an alkyl 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 alkyl
groups described in this section may also contain one or two double
or triple bonds. Examples of C.sub.1-6alkyl include, but are not
limited to the following:
##STR00007##
"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. The terms "oxo" and "thioxo" represent the
groups .dbd.O (as in carbonyl) and .dbd.S (as in thiocarbonyl),
respectively. "Halo" or "halogen" means a halogen atoms selected
from F, Cl, Br and I. "C.sub.v-whaloalkyl" means an alkyl group, as
described above, wherein any number--at least one--of the hydrogen
atoms attached to the alkyl chain are replaced by F, Cl, Br or I.
"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:
##STR00008## ##STR00009##
"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. "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). "Saturated, partially saturated or
unsaturated" includes substituents saturated with hydrogens,
substituents completely unsaturated with hydrogens and substituents
partially saturated with hydrogens. "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. "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, aralkyl, substituted aralkyl, cycloalkenylalkyl and substituted
cycloalkenyl alkyl, allyl, substituted allyl, acyl, alkoxycarbonyl,
aralkoxycarbonyl, silyl and the like. Examples of aralkyl include,
but are not limited to, benzyl, ortho-methylbenzyl, trityl and
benzhydryl, which can be optionally substituted with halogen,
alkyl, 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 cycloalkenylalkyl or substituted cycloalkylenylalkyl
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 aralkyl 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 cycloalkyl 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, aralkyl groups. Alkyl groups are also
suitable groups for protecting hydroxy and mercapto groups, such as
tert-butyl. Silyl protecting groups are silicon atoms optionally
substituted by one or more alkyl, aryl and aralkyl 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. 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. 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'.dbd.O, S, NR), and the like, which are
illustrated in the following examples:
##STR00010##
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. 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 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.
[0160] 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.
EXPERIMENTAL
[0161] The following abbreviations are used: [0162] aq.--aqueous
[0163] BINAP--2,2'-bis(diphenylphosphino)-1,1'-binaphthyl [0164]
cond--concentrated [0165] DCM dichloromethane [0166]
DMF--N,N-dimethylformamide [0167] Et.sub.2O--diethyl ether [0168]
EtOAc--ethyl acetate [0169] EtOH--ethyl alcohol [0170] h--hour(s)
[0171] min--minutes [0172] MeOH--methyl alcohol [0173] rt room
temperature [0174] satd--saturated [0175] THF--tetrahydrofuran
General
[0176] 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:H.sub.2O 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.
Procedure A
##STR00011##
[0178] A mixture of 2-chloro-quinoline-3-carbaldehyde (1 eq),
arylboronic acid (1.1 eq), tetrakis(triphenylphosphine)palladium (5
mol %), and sodium carbonate (2M aq. Sol., 5.0 eq) in
CH.sub.3CN-water (3:1, 0.1 M) was heated at 100.degree. C. under
N.sub.2 for several hours. The mixture was partitioned between
EtOAc and H.sub.2O, the organic layer was separated, and the
aqueous layer was extracted with EtOAc. The combined organic layers
were dried over Na.sub.2SO.sub.4, filtered, concentrated under
reduced pressure, and purified by column chromatography on silica
gel using 0% to 25% gradient of EtOAc in hexane to provide
2-arylquinoline-3-carbaldehydes.
Procedure B
##STR00012##
[0180] Solid sodium borohydride (1.5 eq) was added to a solution of
2-arylquinoline-3-carbaldehyde (1 eq) in THF (0.5M) at 0.degree. C.
and the mixture was stirred at 0.degree. C. for 2 h. The reaction
was quenched by addition of water. The aqueous layer was extracted
with EtOAc (3 times). The combined organic layers were dried over
Na.sub.2SO.sub.4, filtered, and concentrated under reduced
pressure. The residue was purified by column chromatography on
silica gel using 50% of EtOAc in hexane to provide
(2-arylquinolin-3-yl)methanols.
Procedure C
##STR00013##
[0182] (2-Arylquinolin-3-yl)methanol (1 eq) in CHCl.sub.3 (0.25M)
was treated with SOCl.sub.2 (5 eq) at rt for 2 h. Solvents were
removed under reduced pressure and the residue was partitioned
between EtOAc and saturated aq. NaHCO.sub.3 solution. The organic
layer was separated, washed with water and brine, dried over
Na.sub.2SO.sub.4, filtered, and concentrated under reduced
pressure. The crude product was purified by column chromatography
on a Redi-Sep.TM. column using 0 to 100% gradient of EtOAc in
hexane to provide 3-(chloromethyl)-2-arylquinolines.
Procedure D
##STR00014##
[0184] To a solution of 3-(chloromethyl)-2-arylquinoline (1 eq) in
DMSO (0.25 M) was added NaN.sub.3 (3 eq) at rt and the mixture was
stirred for 4 h at rt. The mixture was diluted with water,
extracted with EtOAc (2 times) and the combined organic layers were
washed with water (2 times), dried over Na.sub.2SO.sub.4, filtered,
and concentrated under reduced pressure. The residue was dissolved
in MeOH and treated with 10% Pd--C (5 wt %) and the mixture was
then stirred under H.sub.2 balloon over night. The mixture was
filtered through a celite pad followed by removal of solvents to
give (2-arylquinolin-3-yl)methanamines.
Procedure E
##STR00015##
[0186] To a stirring solution of 3-(chloromethyl)-2-arylquinoline
(1 eq) in 16 mL of DMF was added NaN.sub.3 (2 eq) at rt. The
mixture was stirred at rt for 1 h. The mixture was partitioned
between EtOAc and H.sub.2O. The organic layer was dried over
MgSO.sub.4, filtered, and concentrated under reduced pressure to
provide 3-(azidomethyl)-2-arylquinolines. The crude product was
carried on without purification for the next step. To a stirring
solution of 3-(azidomethyl)-2-arylquinoline in THF--H.sub.2O (4:1,
0.21 M) was added dropwise PMe.sub.3 (1.0 M solution in THF, 1.2
eq) at rt and the mixture was stirred at rt for 1 h. To the mixture
was added EtOAc and the mixture was extracted with 1N HCl (2
times). The combined extracts were neutralized with solid sodium
bicarbonate, and extracted with EtOAc (2 times). The combined
organic extracts were dried over MgSO.sub.4, filtered, and
concentrated under reduced pressure to give dark syrup. The crude
product was purified by column chromatography on a Redi-Sep.TM.
column using 0 to 100% gradient of CH.sub.2Cl.sub.2:MeOH:NH.sub.4OH
(89:9:1) in CH.sub.2Cl.sub.2 as eluent to provide
(2-arylquinolin-3-yl)methanamines.
Procedure F
##STR00016##
[0188] A mixture of 2-arylquinoline-3-carbaldehyde (1 eq), DCE (0.2
M), and PMBNH.sub.2 (1.5 eq) was stirred at rt. After 1 h, to the
mixture was added NaBH(OAc).sub.3 (3 eq) and the mixture was
stirred at 50.degree. C. for 2 h. To the mixture was added
saturated aq. NaHCO.sub.3 and the mixture was stirred for 15 min.
The organic layer was separated and the aqueous layer was extracted
with CH.sub.2Cl.sub.2 (2 times). The combined organic layers were
washed with brine, dried over MgSO.sub.4, filtered, and
concentrated under reduced pressure. The residue was purified by
column chromatography on a Redi-Sep.TM. column using 0 to 100%
gradient of EtOAc in hexane to provide
N-(4-methoxybenzyl)(2-arylquinolin-3-yl)methanamines.
Procedures G
##STR00017##
[0190] A mixture of
N-(4-methoxybenzyl)(2-arylquinolin-3-yl)methanamine (1 eq) and
ammonium cerium(iv) nitrate (3.5 eq) in CH.sub.3CN--H.sub.2O (2:1,
0.22M) was stirred at rt for 24 h. To the mixture wad added 0.5M
HCl (12 eq) and the mixture was washed with CH.sub.2Cl.sub.2 (3
times) to remove 4-methoxybenzaldehyde produced. The organic
fraction was then extracted with 0.5M HCl (2 times). The combined
acidic aqueous layer was basified to pH 9.0 with 2N HaOH. The
resulting precipitate was collected by filtration. The crude
product was purified by column chromatography on a Redi-Sep.TM.
column using 0 to 100% gradient of CH.sub.2Cl.sub.2:MeOH:NH.sub.4OH
(89:9:1) in CH.sub.2Cl.sub.2 as eluent to provide provide
(2-arylquinolin-3-yl)methanamines.
Procedure I
##STR00018##
[0192] A solution of 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (1
eq) in DMF (0.3M) at 0.degree. C. was treated with NaH (60%, 2.2
eq) for 30 min before addition of a solution of
3-(chloromethyl)-2-arylquinolines (1 eq) in DMF (0.5M). The mixture
was stirred at room temperature overnight. The mixture was poured
onto ice-water. The resulting precipitate was collected by suction
filtration, washed with water, and air-dried. The crude product was
purified by column chromatography on a Redi-Sep.TM. column using 0
to 100% gradient of EtOAc in hexane and then 100% isocratic of
EtOAc as eluent to provide
3-iodo-1-((2-arylquinolin-3-yl)-methyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ami-
nes.
Procedure J
##STR00019##
[0194] A mixture of
3-iodo-1-((2-arylquinolin-3-yl)methyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amin-
e (1 eq), boronic acid (2.0 eq),
tetrakis(triphenylphosphine)-palladium (10 mol %), and sodium
carbonate (2M aq. Sol., 6 eq) in DMF (0.2M) was heated at
100.degree. C. under N.sub.2 for several hours. To the mixture was
added water. The resulting precipitate was collected by suction
filtration, washed with water, and air-dried. The crude product was
purified by column chromatography on a Redi-Sep.TM. column using 0
to 100% gradient of CH.sub.2Cl.sub.2:MeOH:NH.sub.4OH (89:9:1) in
CH.sub.2Cl.sub.2 over 14 min as eluent to provide
3-substituted-1-((2-phenylquinolin-3-yl)methyl)-1H-pyrazolo[3,4-d]pyrimid-
in-4-amines.
Procedure K
##STR00020##
[0196] To a mixture of 2-phenylquinoline-3-carbaldehyde (1.0 eq) in
THF (0.28M) at 0.degree. C. was added dropwise a solution of a
Grignard reagent (3 M, 2 eq) and the reaction was stirred overnight
before being quenched with NH.sub.4Cl saturated solution. The
mixture was extracted with EtOAc (2.times.10 mL) and the combined
organic layers were dried (Na.sub.2SO.sub.4) and concentrated under
reduced pressure. The residue was purified by column chromatography
on silica gel (eluent: EtOAc/hexane, 1/1) to provide
1-(2-phenylquinolin-3-yl)alcohols.
Procedure L
Preparation of
N-((5-Chloro-3-(2-chlorophenyl)quinoxalin-2-yl)methyl)-9H-purin-6-amine
3-Chlorobenzene-1,2-diamine
##STR00021##
[0198] To a solution of 3-chloro-2-nitroaniline (10.00 g, 57.95
mmol), 3 N aq. HCl (96.58 mL, 289.7 mmol), and ethyl alcohol (148.6
mL, 57.95 mmol) was added Tin(II) chloride dihydrate (65.96 g,
289.7 mmol) and the mixture was heated under reflux with stirring.
After 3 h, the mixture was cooled to room temperature and
concentrated under reduced pressure to give a brown syrup. The
mixture was cautiously treated with an excess of 10 M KOH (115.9
mL, 1159 mmol, 20 eqv.). The mixture was diluted with EtOAc (200
mL), filtered through Celite.TM. pad, and washed the pad well with
EtOAc (100 mL.times.2). The filtrate was extracted with EtOAc (100
mL.times.2). The combined organic layers were washed with water
(100 mL.times.1), dried over MgSO.sub.4, filtered, and concentrated
under reduced pressure to give 3-chlorobenzene-1,2-diamine as a red
oil: .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 6.43-6.53 (2H,
m), 6.38 (1H, t, J=7.8 Hz), 4.80 (2H, s), 4.60 (2H, s); LC-MS (ESI)
m/z 142.9 [M+H].sup.+. The crude product was carried on crude
without purification for the next step.
1-(2-Chlorophenyl)propane-1,2-dione
##STR00022##
[0200] To a solution of 2-chlorophenylacetone (10.800 g, 64.049
mmol) in 279 mL of CH.sub.2Cl.sub.2, pyridinium chlorochromate
(41.418 g, 192.15 mmol), and pyidine (16 mL) in three portions were
added over 2.5 hours and the mixture was refluxed under vigorous
stirring. After 22 h, he mixture was removed from heat. The mixture
was concentrated in vacuo to give a dark red syrup. The crude
mixture was purified by column chromatography on a 120 g of
Redi-Sep.TM. column using 0-10% gradient of EtOAc in hexane over 28
min as eluent to give 1-(2-chlorophenyl)propane-1,2-dione as yellow
liquid: .sup.1H NMR (400 MHz, choroform-d) .delta. ppm 7.66 (1H,
dd, J=7.6, 1.8 Hz), 7.49-7.54 (1H, m), 7.38-7.45 (2H, m), 2.58 (3H,
s); LC-MS: m/z 182.9 [M+H].sup.+.
3-Bromo-1-(2-chlorophenyl)propane-1,2-dione
##STR00023##
[0202] A mixture of 1-(2-chlorophenyl)propane-1,2-dione (4.2379 g,
23.208 mmol), bromine (1.1891 mL, 23.208 mmol), and glacial acetic
acid (0.67005 mL, 11.604 mmol) in chloroform (58.020 mL, 23.208
mmol) was heated at 60.degree. C. After 17 h of stirring at
60.degree. C., the mixture was removed from heat and concentrated
under reduced pressure to give
3-bromo-1-(2-chlorophenyl)propane-1,2-dione as an orange liquid:
LC-MS: a peak of m/z 261.0 [M+H(.sup.79Br)].sup.+ and 262.9 [M+H
(.sup.81Br)--].sup.+. The orange liquid was carried on crude
without purification for the next step.
Example 1
9-((2-(2-Chlorophenyl)-8-methylquinolin-3-yl)methyl)-9H-purin-6-amine
##STR00024##
[0204]
9-((2-(2-Chlorophenyl)-8-methylquinolin-3-yl)methyl)-9H-purin-6-ami-
ne. A mixture of
3-(bromomethyl)-2-(2-chlorophenyl)-8-methylquinoline (66 mg, 0.19
mmol), {prepared in a similar way as
3-(bromomethyl)-8-methyl-2-o-tolyl-quinoline, example 9} adenine
(39 mg, 0.29 mmol), and cesium carbonate (124 mg, 0.38 mmol) in DMF
(0.7 mL) was stirred at rt for 2 h. The crude mixture was
evaporated onto silica gel and purified by flash chromatography
(Biotage Si 25+M) eluting with MeOH/CH.sub.2Cl.sub.2 (5% to 10%).
The resulting white solid was further purified by HPLC (Berger SFC)
eluting with i-PrOH/CO.sub.2/DEA to provide a white solid
[PI3K.delta. IC.sub.50=2130 nM]. MS (ESI+) m/z=401.1 (M+1).
Example 2
Preparation of
4-Amino-8-((2-(2-chlorophenyl)-8-methyl-quinolin-3-yl)methyl)pyrido[2,3-d-
]pyrimidin-5(8H)-one
##STR00025##
[0206] To a mixture of 4-aminopyrido[2,3-d]pyrimidin-5(8H)-one (0.1
g, 0.616 mmol), Cs.sub.2CO.sub.3 (0.3013 g, 0.925 mmol, 1.5 eq),
and KI (0.0102 g, 0.0616 mmol, 0.1 eq) in DMF (2 mL) was added
3-(chloromethyl)-2-(2-chlorophenyl)-8-methyl-quinoline (0.2049 g,
0.678 mmol, 1.1 eq) and the mixture was stirred at 140.degree. C.
for 2.5 h. The mixture was concentrated under reduced pressure. The
crude product was purified by column chromatography on a 40 g of
Redi-Sep.TM. column using 0 to 100% gradient of EtOAc in hexane
over 14 min and then 100% isocratic of EtOAc for 10 min as eluent
to provide
4-amino-8-((2-(2-chlorophenyl)-8-methyl-quinolin-3-yl)methyl)pyrido[2,3-d-
]pyrimidin-5(8H)-one as white solid. The white solid was triturated
with EtOAc-Hexane (1:1) and filtered to provide
4-amino-8-((2-(2-chlorophenyl)-8-methylquinolin-3-yl)methyl)pyrido[2,3-d]-
pyrimidin-5(8H)-one [PI3K.delta. IC.sub.50=58 nM] as white solid.
.sup.1H NMR (DMSO-d.sub.6) .delta. ppm 9.53 (1H, d, J=4.7 Hz), 8.13
(1H, s), 8.04-8.11 (2H, m), 7.84 (1H, d, J=7.8 Hz), 7.78 (1H, d,
J=7.8 Hz), 7.64 (1H, d, J=7.0 Hz), 7.38-7.59 (5H, m), 6.12 (1H, d,
J=7.8 Hz), 5.40 (2H, d, J=6.3 Hz), 2.64 (3H, s). Mass Spectrum
(ESI) m/e=428.0 (M+1).
Example 3
3-Iodo-1-((8-methyl-2-(2-(trifluoromethyl)phenyl)quinolin-3-yl)-methyl)-1H-
-pyrazolo[3,4-d]pyrimidin-4-amine
3-(Chloromethyl)-8-methyl-2-(2-(trifluoromethyl)phenyl)quinoline
##STR00026##
[0208] Prepared according to Procedure B using
8-methyl-2-(2-(trifluoromethyl)phenyl)-quinoline-3-carbaldehyde
(1.6541 g, 5.25 mmol) and solid NaBH.sub.4 (0.2977 g, 7.87 mmol,
1.5 eq) in THF (26 mL) followed by Procedure C using the crude
(8-methyl-2-(2-(trifluoromethyl)phenyl)quinolin-3-yl)methanol and
SOCl.sub.2 (1.9 mL, 26.23 mmol, 5 eq) in CHCl.sub.3 (26 mL). After
purification,
3-(chloromethyl)-8-methyl-2-(2-(trifluoromethyl)phenyl)quinoline
was obtained as as yellow syrup. .sup.1H NMR (DMSO-d.sub.6) .delta.
ppm 8.60 (1H, s), 7.92 (2H, dd, J=11.5, 8.0 Hz), 7.72-7.85 (2H, m),
7.67 (2H, dd, J=14.3, 7.2 Hz), 7.54-7.62 (1H, m), 4.71 (2H, dd,
J=89.8, 11.9 Hz), 2.62 (3H, s). Mass Spectrum (ESI) m/e=336.1
(M+1).
3-Iodo-1-((8-methyl-2-(2-(trifluoromethyl)phenyl)quinolin-3-yl)methyl)-1H--
pyrazolo[3,4-d]pyrimidin-4-amine
##STR00027##
[0210] Prepared according to Procedure I using
3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.41 g, 1.6 mmol, 1 eq)
in DMF (5 mL), NaH (60%, 0.138 g, 3.5 mmol, 2.2 eq), and
3-(chloromethyl)-8-methyl-2-(2-(trifluoromethyl)phenyl)quinoline
(0.58 g, 1.7 mmol, 1 eq) in DMF (3 mL). After purification,
3-iodo-1-((8-methyl-2-(2-(trifluoromethyl)phenyl)quinolin-3-yl)methyl)-1H-
-pyrazolo[3,4-d]pyrimidin-4-amine was obtained as white solid.
.sup.1H NMR (DMSO-d.sub.6) .delta. ppm 8.27 (1H, s), 7.99 (1H, s),
7.88 (1H, d, J=7.8 Hz), 7.73-7.79 (1H, m), 7.65 (1H, d, J=6.7 Hz),
7.51-7.61 (3H, m), 7.28-7.35 (1H, m), 5.41-5.54 (2H, m), 2.60 (3H,
s). Mass Spectrum (ESI) m/e=561.0 (M+1).
Example 4
3-Iodo-1-((8-methyl-2-o-tolylquinolin-3-yl)methyl)-1H-pyrazolo[3,4-d]pyrim-
idin-4-amine
##STR00028##
[0212] Prepared according to Procedure I. A solution of
3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (400 mg, 1.5 mmol) in
DMF (5 mL) at 0.degree. C. was treated with NaH (60%, 67.4 mg, 1.1
eq) for 30 min before addition of a solution of
3-(chloro-methyl)-8-methyl-2-o-tolylquinoline (435 mg, 1 eq) in DMF
(2 mL). The mixture was stirred at room temperature over night. The
reaction mixture was partitioned between DCM (50 mL) and water (50
mL). The insoluble was filtered and washed with DCM and water. The
organic layer from the filtrate was separated, dried over
Na.sub.2SO.sub.4, concentrated and purified by column
chromatography on silica gel (eluent: DCM/MeOH, 25/1) to provide a
white solid [PI3K.delta. IC.sub.50=6 nM]. .sup.1H-NMR
(DMSO-d.sup.6) .delta. 7.96 (s, 1H), 7.85 (s, 1H), 7.63 (d, J=8.2
Hz, 1H), 7.44 (d, J=7.0 Hz, 1H), 7.31 (t, J=7.1 Hz, 1H), 6.94-6.99
(m, 4H), 5.26 (s, 2H), 2.45 (s, 3H), 1.79 (s, 3H). Mass Spectrum
(ESI) m/e=507 (M+1).
Example 5
Preparation of
1-((8-Chloro-2-(2-chlorophenyl)quinolin-3-yl)-methyl)-3-iodo-1H-pyrazolo[-
3,4-d]pyrimidin-4-amine
##STR00029##
[0214] Prepared according to Procedure I using
8-chloro-3-(chloromethyl)-2-(2-chloro-phenyl)quinoline (0.235 g,
0.73 mmol), NaH (0.047 g 60% in oil, 1.17 mmol, 1.6 eq) and
3-iodo-1H-pyrazolo{3,4-d}pyrimidin-4-amine (0.209 g, 0.8 mmol, 1.1
eq) in DMF.
1-((8-chloro-2-(2-chlorophenyl)quinolin-3-yl)methyl)-3-iodo-1H-pyraz-
olo[3,4-d]pyrimidin-4-amine was obtained after purification as a
white solid [PI3K.delta. IC.sub.50=14 nM]. 1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 8.42 (1H, s), 8.09 (1H, dd, J=8.6, 1.2
Hz), 7.98-8.05 (2H, m), 7.66 (1H, t), 7.48 (1H, dd, J=8.2, 0.8 Hz),
7.36 (1H, dt, J=7.8, 1.6 Hz), 7.25 (1H, dt, J=7.4, 1.2 Hz), 7.13
(1H, dd, J=7.4, 1.6 Hz), 5.53 (2H, s) Mass Spectrum (ESI) m/e=547.0
and 549.0 (M+1)
Example 6
Preparation of
1-((8-Chloro-2-(2-(trifluoromethyl)phenyl)-quinolin-3-yl)methyl)-3-iodo-1-
H-pyrazolo[3,4-d]pyrimidin-4-amine
8-Chloro-2-(2-(trifluoromethyl)phenyl)quinoline-3-carbaldehyde
##STR00030##
[0216] Prepared according to Procedure A using
2,8-dichloroquinoline 3-carbaldehyde (1.0 g, 4.42 mmol),
2-trifluoromethylphenyl boronic acid (0.924 g, 4.87 mmol, 1.1 eq),
tetrakis(triphenylphosphine)palladium (0.256 g, 0.221 mmol, 0.05
eq), and sodium carbonate (2.34 g, 22.1 mmol, 5 eq) in acetonitrile
(30 mL) and water (10 mL). After purification,
2-(2-trifluoromethylphenyl)-8-chloroquinoline-3-carb-aldehyde was
obtained as a yellow solid. 1H NMR (500 MHz, DMSO-d.sub.6) .delta.
ppm 9.95 (1H, s), 9.19 (1H, s), 8.33 (1H, dd, J=8.5, 1.2 Hz), 8.20
(1H, dd, J=7.3, 1.2 Hz), 7.95 (1H, d, J=7.3 Hz), 7.74-7.87 (2H, m),
7.63 (1H, d, J=7.3 Hz) Mass Spectrum (ESI) m/e=336.1 and 338.0
(M+1)
(8-Chloro-2-(2-(trifluoromethyl)phenyl)quinolin-3-yl)methanol
##STR00031##
[0218] Prepared according to Procedure B using
8-chloro-2-(2-trifluoromethylphenyl) quinoline-3-carbaldehyde (1.10
g, 3.28 mmol) and sodium borohydride (0.186 g, 4.91 mmol, 1.5 eq)
in THF (15 mL).
(8-chloro-2-(2-trifluoromethylphenyl)-quinolin-3-yl)methanol was
obtained as a white solid. 1H NMR (500 MHz, DMSO-d.sub.6) .delta.
ppm 8.57 (1H, s), 8.10 (1H, dd, J=7.9, 1.2 Hz), 7.94 (2H, t, J=6.4
Hz), 7.82 (1H, t, J=7.6 Hz), 7.76 (1H, t, J=7.6 Hz), 7.50-7.68 (4H,
m), 5.54 (1H, t, J=5.2 Hz), 4.45 (1H, br d), 4.28 (1H, br d) Mass
Spectrum (ESI) m/e=338.0 and 340.0 (M+1)
8-Chloro-3-(chloromethyl)-2-(2-(trifluoromethyl)phenyl)quinoline
##STR00032##
[0220] Prepared according to Procedure C using
(8-chloro-2-(2-trifluoromethylphenyl)-quinolin-3-yl)methanol (1.10
g, 3.26 mmol) and SOCl.sub.2 (1.19 mL, 16.3 mmol, 5 eq) in
dichloromethane (5 mL).
8-chloro-3-(chloromethyl)-2-(2-trifluoromethyl-phenyl)quinoline was
obtained as a yellow syrup. 1H NMR (400 MHz, DMSO-d.sub.6) .delta.
ppm 8.75 (1H, s), 8.10 (1H, d, J=8.2 Hz), 8.02 (1H, d, J=6.3 Hz),
7.95 (1 H, d, J=7.4 Hz), 7.72-7.87 (2H, m), 7.58-7.71 (2H, m), 4.71
(2H, dd, J=82.2, 12.1 Hz) Mass Spectrum (ESI) m/e=356.0 and 358.0
(M+1).
1-((8-Chloro-2-(2-(trifluoromethyl)phenyl)quinolin-3-yl)methyl)-3-iodo-1H--
pyrazolo[3,4-d]pyrimidin-4-amine
##STR00033##
[0222] Prepared according to Procedure I using
8-chloro-3-(chloromethyl)-2-(2-trifluoro-methylphenyl)quinoline
(0.356 g, 1.0 mmol), NaH (0.044 g 60% in oil, 1.1 mmol, 1.1 eq) and
3-iodo-1H-pyrazolo{3,4-d}pyrimidin-4-amine (0.287 g, 1.1 mmol, 1.1
eq) in 5 mL DMF.
1-((8-Chloro-2-(2-trifluoromethylphenyl)quinolin-3-yl)-methyl)--
3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine [PI3K.delta. IC.sub.50=7
nM] was obtained after purification as a white solid. 1H NMR (400
MHz, DMSO-d.sub.6) .delta. ppm 8.40 (1H, s), 8.08 (1H, d, J=8.2
Hz), 7.96-8.03 (2H, m), 7.74-7.84 (1H, m), 7.56-7.70 (3H, m),
7.26-7.37 (1H, m), 5.47 (2H, s) Mass Spectrum (ESI) m/e=580.9 and
583.0 (M+1)
Example 7
Preparation of
1-((2-(2-Fluorophenyl)-8-methylquinolin-3-yl)-methyl)-3-iodo-1H-pyrazolo[-
3,4-d]pyrimidin-4-amine
2-(2-Fluorophenyl)-8-methylquinoline-3-carbaldehyde
##STR00034##
[0224] Prepared according to Procedure A using
2-chloro-8-methylquinoline 3-carbaldehyde (1.0 g, 4.86 mmol),
2-fluorophenyl boronic acid (0.749 g, 5.35 mmol, 1.1 eq),
tetrakis(triphenylphosphine)palladium (0.281 g, 0.24 mmol, 0.05
eq), and sodium carbonate (2.58 g, 24 mmol, 5 eq) in acetonitrile
(36 mL) and water (12 mL). After purification,
2-(2-fluorophenyl)-8-methylquinoline-3-carbaldehyde was obtained as
a yellow solid. 1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 10.03
(1H, d, J=3.5 Hz), 8.99 (1H, s), 8.12 (1H, d, J=7.8 Hz), 7.85 (1H,
d, J=7.0 Hz), 7.76 (1H, td, J=7.5, 1.8 Hz), 7.58-7.70 (2H, m), 7.45
(2H, td, J=7.5, 1.0 Hz), 7.38 (2H, td, J=9.4, 1.2 Hz), 2.75 (3H, s)
Mass Spectrum (ESI) m/e=266.0 (M+1)
(2-(2-Fluorophenyl)-8-methylquinolin-3-yl)methanol
##STR00035##
[0226] Prepared according to Procedure B using
2-(2-fluorophenyl)-8-methylquinoline-3-carbaldehyde (0.725 g, 2.73
mmol), and sodium borohydride (0.155 g, 4.1 mmol, 1.5 eq) in THF
(15 mL). (2-(2-fluorophenyl)-8-methylquinolin-3-yl)methanol was
obtained as a yellow solid. 1H NMR (500 MHz, DMSO-d.sub.6) .delta.
ppm 8.46 (1H, s), 7.90 (1H, d, J=7.9 Hz), 7.63 (1H, d, J=6.7 Hz),
7.50-7.60 (3H, m), 7.38 (1H, d, J=7.9 Hz), 7.35-7.37 (1H, m), 5.42
(1H, t, J=5.5 Hz), 4.50 (2H, d, J=5.5 Hz), 2.69 (3H, s) Mass
Spectrum (ESI) m/e=268.1 (M+1)
3-(Chloromethyl)-2-(2-fluorophenyl)-8-methylquinoline
##STR00036##
[0228] Prepared according to Procedure C using
(2-(2-fluorophenyl)-8-methylquinolin-3-yl)methanol (0.700 g, 2.62
mmol) in SOCl.sub.2 (2 mL, 27.4 mmol, 10.5 eq).
3-(chloromethyl)-2-(2-fluorophenyl)-8-methyl-quinoline (0.665 g,
89%) was obtained after purification as a brown foam. 1H NMR (500
MHz, DMSO-d.sub.6) .delta. ppm 8.61 (1H, s), 7.92 (1H, d, J=7.9
Hz), 7.71 (1H, d, J=6.7 Hz), 7.53-7.66 (3H, m), 7.40 (2H, t, J=7.9
Hz), 4.81 (2H, s), 2.69 (3H, s) Mass Spectrum (ESI) m/e=286.1 and
288.1 (M+1)
1-((2-(2-Fluorophenyl)-8-methylquinolin-3-yl)methyl)-3-iodo-1H-pyrazolo[3,-
4-d]pyrimidin-4-amine
##STR00037##
[0230] Prepared according to Procedure I using
(2-(2-fluorophenyl)-8-methylquinolin-3-yl)methanamine (0.200 g, 0.7
mmol), NaH (0.031 g, 60% in oil, 0.77 mmol, 1.1 eq) and
3-iodo-1H-pyrazolo{3,4-d}pyrimidin-4-amine (0.201 g, 0.77 mmol, 1.1
eq) in DMF.
1-((2-(2-fluorophenyl)-8-methylquinolin-3-yl)methyl)-3-iodo-1H-py-
razolo[3,4-d]pyrimidin-4-amine [PI3K.delta. IC.sub.50=4 nM] was
obtained after purification as a white solid. 1H NMR (500 MHz,
DMSO-d.sub.6) .delta. ppm 8.09 (1H, s), 8.00 (1H, s), 7.96 (1H, s),
7.80 (1H, d, J=7.9 Hz), 7.63 (1H, d, J=7.3 Hz), 7.46-7.53 (1H, m),
7.30 (1H, dt), 7.08 (1H, dd, J=7.6, 1.5 Hz), 7.02 (1H, d, J=7.9
Hz), 6.91 (1H, t, J=7.3 Hz), 5.46-5.54 (2H, m), 2.90 (3H, s) Mass
Spectrum (ESI) m/e=511.0 (M+1)
Example 8
3-(4-Amino-1-((8-methyl-2-(2-(trifluoromethyl)phenyl)quinolin-3-yl)methyl)-
-1H-pyrazolo[3,4-d]pyrimidin-3-yl)phenol
##STR00038##
[0232] Prepared according to Procedure J using
3-iodo-1-((8-methyl-2-(2-(trifluoro-methyl)phenyl)quinolin-3-yl)methyl)-1-
H-pyrazolo[3,4-d]pyrimidin-4-amine (0.1 g, 0.1785 mmol, 1 eq),
3-hydroxyphenylboronic acid (0.0492 g, 0.357 mmol, 2.0 eq),
tetrakis(triphenylphosphine)palladium (0.0206 g, 0.0178 mmol, 10
mol %), and sodium carbonate (2M aq. sol, 0.535 mL, 1.07 mmol., 6
eq) in DMF (1 mL). After purification,
3-(4-amino-1-((8-methyl-2-(2-(trifluoromethyl)phenyl)-quinolin-3-yl)methy-
l)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)phenol was obtained as light
gray solid. The gray solid was suspended in CH.sub.2Cl.sub.2 and
filtered to provide
3-(4-amino-1-((8-methyl-2-(2-(trifluoromethyl)phenyl)quinolin-3-y-
l)methyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)phenol [PI3K.delta.
IC.sub.50=8 nM] as off-white solid. .sup.1H NMR (DMSO-d.sub.6)
.delta. ppm 9.65 (1H, s), 8.28 (1H, s), 8.04 (1H, s), 7.87 (1H, d,
J=7.8 Hz), 7.74-7.80 (1H, m), 7.64 (1H, d, J=7.0 Hz), 7.56-7.61
(2H, m), 7.50-7.56 (1H, m), 7.34-7.38 (1H, m), 7.30 (1H, t, J=7.8
Hz), 6.94-7.02 (2H, m), 6.80-6.87 (1H, m), 5.53 (2H, s), 2.60 (3H,
s). Mass Spectrum (ESI) m/e=527.2 (M+1).
Example 9
3-(4-Amino-1-((8-methyl-2-o-tolylquinolin-3-yl)methyl)-1H-pyrazolo[3,4-d]p-
yrimidin-3-yl)phenol
##STR00039##
[0234] Prepared according to Procedure J. A mixture of
3-iodo-1-((8-methyl-2-O-tolylquinolin-3-yl)methyl)-1H-pyrazolo[3,4-d]pyri-
midin-4-amine (51 mg, 0.1 mmol), 3-hydroxyphenylboronic acid (15.2
mg, 1.1 eq), sodium carbonate (55 mg, 5 eq),
tetrakis(triphenylphosphine)palladium (6 mg, 5% mmol) in DMF (1 mL)
and water (0.3 mL) was heated to 100.degree. C. under N.sub.2 for 4
h. The reaction mixture was cooled to room temperature, filtered
and purified by reverse HPLC (MeCN/H.sub.2O/0.1% TFA) on C18 to
give a white solid [PI3K.delta. IC.sub.50=7 nM]. .sup.1H-NMR
(DMSO-d.sup.6) .delta. 8.37 (s, 1H), 8.35 (s, 1H), 7.86 (d, J=8.2
Hz, 1H), 7.65 (d, J=7.0 Hz, 1H), 7.53 (t, J=7.4 Hz, 1H), 7.31 (t,
J=7.8 Hz, 1H), 7.14-7.17 (m, 4H), 6.87-6.97 (m, 4H), 5.63 (s, br,
2H), 2.63 (s, 3H), 1.91 (s, 3H). Mass Spectrum (ESI) m/e=473
(M+1).
Example 10
Preparation of
3-(4-Amino-1-((8-chloro-2-(2-chlorophenyl)-quinolin-3-yl)methyl)-1H-pyraz-
olo[3,4-d]pyrimidin-3-yl)phenol
##STR00040##
[0236] Prepared according to Procedure J using
1-((8-chloro-2-(2-chlorophenyl)quinolin-3-yl)methyl)-3-iodo-1H-pyrazolo[3-
,4-d]pyrimidin-4-amine (0.100 g, 0.18 mmol),
3-(hydroxyphenyl)boronic acid (0.050 g, 0.37 mmol, 2 eq),
tetrakis(triphenyl-phosphine)palladium (0.021 g, 0.018 mmol, 0.1
eq) and 2M aq sodium carbonate (0.54 mL, 1.08 mmol, 6 eq) in DMF (1
mL).
3-(4-Amino-1-((8-chloro-2-(2-chlorophenyl)quinolin-3-yl)methyl)-1H-pyrazo-
lo[3,4-d]pyrimidin-3-yl)phenol [PI3K.delta. IC.sub.50=14 nM] was
obtained after purification as a white solid. 1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 9.52 (1H, s), 8.31 (1H, s), 7.91-8.00
(2H, m), 7.86 (1H, dd, J=7.4, 1.2 Hz), 7.52 (1H, t, J=7.8 Hz), 7.35
(1H, d, J=8.2 Hz), 7.07-7.28 (3H, m), 6.97-7.05 (1H, m), 6.78-6.93
(2H, m), 6.70 (1H, dd, J=8.2, 1.6 Hz), 5.36-5.57 (2H, m) Mass
Spectrum (ESI) m/e=513.1 and 515.0 (M+1).
Example 11
1-((2-(2-Chlorophenyl)-8-methylquinolin-3-yl)methyl)-3-methyl-1H-pyrazolo[-
3,4-d]pyrimidin-4-amine
##STR00041##
[0238] To a stirred solution of
3-methyl-1H-pyrazole[3,4-d]pyrimidin-4-amine.sup.1 (59 mg, 0.397
mmol) in DMF (1.65 mL) at room temperature was added sodium hydride
(26.5 mg, 0.662 mmol) at once. After 25 minutes,
3-(chloromethyl)-2-(2-chloro-phenyl)-8-methylquinoline (100 mg,
0.331 mmol) was added, the mixture was stirred for several days.
The reaction mixture was poured into H.sub.2O and extracted with
Et.sub.2O washed with brine and dried over MgSO.sub.4 [PI3K.delta.
IC.sub.50=137 nM]. Chromatography:Gradient 89:9:1/DCM. .sup.1H NMR
(DMSO-d.sub.6) .delta. ppm 8.07 (1H, s), 7.96 (1H, s), 7.82 (1H, d,
J=7.8 Hz), 7.64 (1H, d, J=7.0 Hz), 7.48-7.55 (2H, d, m), 7.34-7.40
(1H, m), 7.24-7.30 (1H, m), 7.16-7.21 (1H, m), 5.40 (2H, s), 2.64
(3H, s), 2.44 (3H, s), 7.36-7.40 (2H, m), 7.30-7.36 (1H, m), 6.12
(1H, d, J=5.5 Hz), 4.41 (2H, d, J=4.7 Hz), 2.67 (3H, s), 2.14 (3H,
s). Mass Spectrum (ESI) m/e=415.1 (M+1).
Example 12
1-((8-Methyl-2-(2-(trifluoromethyl)phenyl)quinolin-3-yl)-methyl)-3-(1H-pyr-
azol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine
##STR00042##
[0240] Prepared according to Procedure J using
3-iodo-1-((8-methyl-2-(2-(tri-fluoromethyl)phenyl)quinolin-3-yl)methyl)-1-
H-pyrazolo[3,4-d]pyrimidin-4-amine (0.1000 g, 0.178 mmol, 1 eq),
pyrazole-4-boronic acid pinacol ester (0.0693 g, 0.357 mmol, 2.0
eq), tetrakis(triphenylphosphine)palladium(0) (0.0206 g, 0.0178
mmol, 10 mol %), and sodium carbonate (2M aq. sol, 0.535 mL, 1.07
mmol., 6 eq) in DMF (1 mL). After purification,
1-((8-methyl-2-(2-(trifluoromethyl)-phenyl)quinolin-3-yl)methyl)-3-(1H-py-
razol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine was obtained as
white solid. The white solid was suspended in CH.sub.2Cl.sub.2 and
filtered to give the desired product as white solid [PI3K.delta.
IC.sub.50=8 nM]. .sup.1H NMR (DMSO-d.sub.6) .delta. ppm 13.17 (1H,
s), 8.22 (1H, s), 7.97-8.08 (2H, m), 7.71-7.90 (3H, m), 7.56-7.66
(3H, m), 7.52 (1H, dd, J=7.8, 7.0 Hz), 7.35-7.44 (1H, m), 6.82 (2H,
br. s.), 5.42-5.55 (2H, m), 2.60 (3H, s). Mass Spectrum (ESI)
m/e=501.1 (M+1).
Example 13
3-Cyclopropyl-1-((8-methyl-2-(2-(trifluoromethyl)phenyl)-quinolin-3-yl)met-
hyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine
##STR00043##
[0242] To a solution of
3-iodo-1-((8-methyl-2-(2-(trifluoromethyl)phenyl)quinolin-3-yl)-methyl)-1-
H-pyrazolo[3,4-d]pyrimidin-4-amine (0.1000 g, 0.18 mmol),
cyclopropylboronic acid (0.020 g, 0.23 mmol, 1.3 eq), tripotassium
phosphate (0.13 g, 0.62 mmol, 3.5 eq), and tricyclohexylphosphine
(0.0050 g, 0.018 mmol, 0.1 eq) in toluene (2 mL) and water (0.1 mL)
under nitrogen atmosphere was added palladium acetate (0.0020 g,
0.0089 mmol, 5 mol %). The mixture was heated at 90.degree. C. for
62 h. To the mixture was added water (30 mL). The mixture was
extracted with EtOAc (30 mL.times.2). The combined organic layers
were washed with brine (50 mL.times.1), dried over MgSO.sub.4,
filtered, and concentrated under reduced pressure to provide a
yellow syrup. The yellow syrup was purified by column
chromatography on a 40 g of Redi-Sep.TM. column using 50 to 100%
gradient of EtOAc in hexane over 9 min, 100% isocratic of EtOAc for
8 min, and then 0 to 100% gradient of
CH.sub.2Cl.sub.2:MeOH:NH.sub.4OH (89:9:1) in CH.sub.2Cl.sub.2 over
14 min as eluent to provide
3-cyclopropyl-1-((8-methyl-2-(2-(trifluoromethyl)-phenyl)quinolin-3-yl)me-
thyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine [PI3K.delta.
IC.sub.50=149 nM] as yellow solid. .sup.1H NMR (DMSO-d.sub.6)
.delta. ppm 8.08 (1H, s), 7.98 (1H, s), 7.77-7.85 (2H, m),
7.59-7.68 (3H, m), 7.51 (1H, dd, J=7.8, 7.0 Hz), 7.37-7.44 (1H, m),
5.34 (2H, s), 2.59 (3H, s), 2.31-2.42 (1H, m), 0.84-0.93 (2H, m),
0.70-0.78 (2H, m). Mass Spectrum (ESI) m/e=475.1 (M+1).
Example 14
4-(4-Amino-1-((8-methyl-2-(2-(trifluoromethyl)phenyl)quinolin-3-yl)methyl)-
-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-methylbut-3-yn-2-ol
##STR00044##
[0244] A suspension of
3-iodo-1-((8-methyl-2-(2-(trifluoromethyl)phenyl)quinolin-3-yl)-methyl)-1-
H-pyrazolo[3,4-d]pyrimidin-4-amine (0.0569 g, 0.102 mmol) and
copper(i) iodide (0.00387 g, 0.0203 mmol, 0.2 eq) in DMF (2 mL) was
treated with 2-methyl-3-butyn-2-ol (0.0984 mL, 1.02 mmol, 10 eq),
triethylamine (0.0282 mL, 0.203 mmol, 2 eq) and
tetrakis(triphenylphosphine)palladium(0) (0.0117 g, 0.0102 mmol, 10
mol %) under Ar. The mixture was stirred under Ar at rt for 45 min.
The mixture was concentrated under reduced pressure. The residue
was purified by column chromatography on a 40 g of Redi-Sep.TM.
column using 0 to 100% gradient of CH.sub.2Cl.sub.2:MeOH:NH.sub.4OH
(89:9:1) in CH.sub.2Cl.sub.2 over 14 min as eluent to provide
4-(4-amino-1-((8-methyl-2-(2-(trifluoromethyl)phenyl)quinolin-3-yl)methyl-
)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-methylbut-3-yn-2-ol
[PI3K.delta. IC.sub.50=116 nM] as a tan solid. .sup.1H NMR
(DMSO-d.sub.6) .delta. ppm 8.21 (1H, s), 8.02 (1H, s), 7.87 (1H, d,
J=7.8 Hz), 7.77-7.82 (1H, m), 7.65 (1H, d, J=6.7 Hz), 7.57-7.62
(2H, m), 7.51-7.57 (1H, m), 7.26-7.32 (1H, m), 5.76 (1H, s), 5.44
(2H, s), 2.60 (3H, s), 1.46 (6H, s). Mass Spectrum (ESI) m/e=517.2
(M+1).
Examples 15 and 16
1-((3-(2-Chlorophenyl)-8-methylquinoxalin-2-yl)-methyl)-3-iodo-1H-pyrazolo-
[3,4-d]pyrimidin-4-amine and
1-((3-(2-Chlorophenyl)-5-methylquinoxalin-2-yl)methyl)-3-iodo-1H-pyrazolo-
[3,4-d]pyrimidin-4-amine
##STR00045##
[0246] To a solution of 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine
(0.8909 g, 3.41 mmol, 1 eq) 10 mL of DMF (10 mL) was added sodium
hydride, 60% dispersion in mineral oil (0.2730 g, 6.83 mmol, 2 eq)
at 0.degree. C. and the mixture was stirred at rt. After 10 min at
rt, to the mixture was added a solution of
3-(bromomethyl)-2-(2-chlorophenyl)-5-methylquinoxaline and
2-(bromomethyl)-3-(2-chlorophenyl)-5-methylquinoxaline (prepared
according to procedures shown in Example 15 and 16, 1.2458 g, 3.58
mmol) in DMF (5 mL) and the mixture was stirred at rt for 1 h. The
mixture was poured into ice-water (100 mL). The resulting
precipitate was collected by filtration to provide yellow solid.
The yellow solid was purified by column chromatography on a 80 g of
Redi-Sep.TM. column using 9% isocratic of
CH.sub.2Cl.sub.2:MeOH:NH.sub.4OH (89:9:1) in CH.sub.2Cl.sub.2 for
20 min and then 9% to 100% gradient of
CH.sub.2Cl.sub.2:MeOH:NH.sub.4OH (89:9:1) in CH.sub.2Cl.sub.2 over
20 min as eluent to provide a mixture of
1-((3-(2-chlorophenyl)-8-methylquinoxalin-2-yl)methyl)-3-iodo-1H-pyraz-
olo[3,4-d]pyrimidin-4-amine and
1-((3-(2-chlorophenyl)-5-methylquinoxalin-2-yl)methyl)-3-iodo-1H-pyrazolo-
[3,4-d]pyrimidin-4-amine as yellow foamy solid. The yellow foamy
solid (0.1 g) was dissolved in 5 mL of MeOH--CH.sub.3CN (0.1% of
TFA) and purified by semi-prep-HPLC on C18 column using 30-90%
gradient of CH.sub.3CN (0.1% of TFA) in water (0.1% of TFA) over 40
min as eluent to provide
1-((3-(2-chlorophenyl)-8-methylquinoxalin-2-yl)methyl)-3-iodo-1H--
pyrazolo[3,4-d]pyrimidin-4-amine [PI3K.delta. IC.sub.50=38 nM] as
white solid and
1-((3-(2-chlorophenyl)-5-methylquinoxalin-2-yl)methyl)-3-iodo-1-
H-pyrazolo[3,4-d]pyrimidin-4-amine [PI3K.delta. IC.sub.50=21 nM] as
a TFA salt. .sup.1H NMR (DMSO-d.sub.6) .delta. ppm 8.05 (1H, s),
7.93 (1H, dd, J=8.0, 1.0 Hz), 7.77-7.82 (1H, m), 7.72-7.77 (1H, m),
7.48 (1H, d, J=7.8 Hz), 7.33-7.39 (1H, m), 7.27-7.32 (2H, m), 5.74
(2H, s), 2.54 (3H, s); Mass Spectrum (ESI) m/e=528.0 (M+1); HPLC: a
peak at 7.834 min. .sup.1H NMR (DMSO-d.sub.6) .delta. ppm 8.02 (1H,
s), 7.93 (1H, d, J=8.5 Hz), 7.82 (1H, t, J=7.6 Hz), 7.75-7.79 (1H,
m), 7.43 (1H, d, J=7.9 Hz), 7.28-7.34 (1H, m), 7.19-7.26 (2H, m),
5.75 (2H, br. s.), 2.68 (3H, s); Mass Spectrum (ESI) m/e=528.0
(M+1); HPLC: a peak at 8.039 min.
Example 17 and 18
1-((3-(2-Chlorophenyl)-8-methylquinoxalin-2-yl)methyl)-3-(1H-pyrazol-4-yl)-
-1H-pyrazolo[3,4-d]pyrimidin-4-amine and
1-((3-(2-Chlorophenyl)-5-methylquinoxalin-2-yl)methyl)-3-(1H-pyrazol-4-yl-
)-1H-pyrazolo[3,4-d]pyrimidin-4-amine
##STR00046##
[0248] Prepared according to Procedure J using a mixture of
1-((3-(2-chlorophenyl)-8-methylquinoxalin-2-yl)methyl)-3-iodo-1H-pyrazolo-
[3,4-d]pyrimidin-4-amine and
1-((3-(2-chlorophenyl)-5-methylquinoxalin-2-yl)methyl)-3-iodo-1H-pyrazolo-
[3,4-d]pyrimidin-4-amine (0.2737 g, 0.52 mmol, 1 eq),
4-pyrazoleboronic acid pinacol ester (0.20 g, 1.0 mmol, 2.0 eq),
tetrakis(triphenylphosphine)palladium(0) (0.060 g, 0.052 mmol, 10
mol %), and sodium carbonate (2M aq. sol, 1.6 mL, 3.1 mmol, 6 eq)
in DMF (3.1 mL). After purification, a mixture of
1-((3-(2-chlorophenyl)-8-methylquinoxalin-2-yl)methyl)-3-(1H-pyrazol-4-yl-
)-1H-pyrazolo[3,4-d]pyrimidin-4-amine and
1-((3-(2-chlorophenyl)-5-methylquinoxalin-2-yl)methyl)-3-(1H-pyrazol-4-yl-
)-1H-pyrazolo[3,4-d]pyrimidin-4-amine was obtained as tan solid.
The tan solid (0.1566 g) was dissolved in DMSO (8 mL) and purified
by semi-prep-HPLC on C18 column using 20-70% gradient of CH.sub.3CN
(0.1% of TFA) in water (0.1% of TFA) over 40 min as eluent to
provide
1((3-(2-chlorophenyl)-8-methylquinoxalin-2-yl)methyl)-3-(1H-pyrazol-4-yl)-
-1H-pyrazolo[3,4-d]pyrimidin-4-amine [PI3K.delta. IC.sub.50=18 nM]
as white solid as a TFA salt and
1-((3-(2-chlorophenyl)-5-methylquinoxalin-2-yl)methyl)-3-(1H-pyrazol-4-yl-
)-1H-pyrazolo[3,4-d]pyrimidin-4-amine [PI3K.delta. IC.sub.50=30 nM]
as white solid as a TFA salt. .sup.1H NMR (DMSO-d.sub.6) .delta.
ppm 8.18 (1H, s), 7.88-7.96 (3H, m), 7.77-7.82 (1H, m), 7.72-7.77
(1H, m), 7.49 (1H, d, J=7.8 Hz), 7.27-7.38 (3H, m), 5.82 (2H, d,
J=18.4 Hz), 2.54 (3H, s); Mass Spectrum (ESI) m/e=468.1 (M+1);
HPLC: a peak at 6.522 min. .sup.1H NMR (DMSO-d.sub.6) .delta. ppm
8.15 (1H, s), 7.91-7.96 (1H, m), 7.89 (2H, s), 7.78-7.84 (1H, m),
7.74-7.78 (1H, m), 7.40-7.49 (1H, m), 7.18-7.34 (3H, m), 5.82 (2H,
d, J=27.4 Hz), 2.66 (3H, s); Mass Spectrum (ESI) m/e=468.1 (M+1);
HPLC: a peak at 6.700 min.
Example 19
7-((2-(2-Chlorophenyl)-8-methylquinolin-3-yl)methyl)-7H-pyrrolo[2,3-d]pyri-
midin-4-amine
##STR00047##
[0250] A solution of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (280 mg,
1.1 eq) in DMF (3 mL) was treated with NaH (1.2 eq, 80 mg, 60%) and
the reaction mixture was stirred at rt for 30 min before addition
of 3-(chloromethyl)-2-(2-chlorophenyl)-8-methylquinoline (500 mg,
1.7 mmol) in DMF (2 mL). After 2 h at rt, the mixture was
partitioned between EtOAc (50 mL) and H.sub.2O (30 mL), the layers
were separated, and the aqueous layer was extracted with EtOAc
(2.times.30 mL). The combined organic layers were dried
(Na.sub.2SO.sub.4), concentrated and purified by flash
chromatography (0% to 25% EtOAc/hexane) to provide
3-((4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-2-(2-chlorophenyl)-8-
-methylquinoline as a white foam. This material (60 mg, 0.14 mmol)
was dissolved in EtOH (4 mL) and treated with NH.sub.3 gas for 3
min. The sealed tube was heated at 80.degree. C. for 4 days. The
reaction mixture was concentrated and purified by column
chromatography on silica gel (eluent: DCM/MeOH, 20/1) to provide a
white solid [PI3K.delta. IC.sub.50=1968 nM]. .sup.1H-NMR
(DMSO-d.sup.6) .delta. 7.94 (s, 1H), 7.89 (s, 1H), 7.75 (t, J=7.8
Hz, 1H), 7.37-7.62 (m, 6H), 6.96 (s, 2H), 6.86 (d, J=3.6 Hz, 1H),
6.54 (d, J=3.5 Hz, 1H), 5.30 (d, J=5.9 Hz, 2H), 2.64 (s, 3H). Mass
Spectrum (ESI) m/e=400 (M+1).
Example 20
5-Chloro-7-((2-(2-chlorophenyl)-8-methylquinolin-3-yl)methyl)-7H-pyrrolo[2-
,3-d]pyrimidin-4-amine
##STR00048##
[0252]
5-Chloro-7-((2-(2-chlorophenyl)-8-methylquinolin-3-yl)methyl)-7H-py-
rrolo[2,3-d]pyrimidin-4-amine was prepared from
4,5-dichloro-7H-pyrrolo[2,3-d]pyrimidine according to the above
procedure (example 44) as a white solid [PI3K.delta. IC.sub.50=20
nM]. .sup.1H-NMR (CDCl.sub.3) .delta. 8.04 (s, 1H), 7.90 (s, 1H),
7.60 (d, J=8.3 Hz, 1H), 7.54 (d, J=7.0 Hz, 1H), 7.15-7.43 (m, 6H),
5.23-5.45 (m, 4H), 2.69 (s, 3H). Mass Spectrum (ESI) m/e=434
(M+1).
Example 21
Preparation of
4-Amino-8-((5-chloro-3-(2-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl-
)methyl)pyrido[2,3-d]pyrimidin-5(8H)-one
2-Amino-6-chloro-N-(2-methoxyphenyl)benzamide
##STR00049##
[0254] SO.sub.2Cl.sub.2 (5.4 mL, 74 mmol, 2.5 eq) was added to a
rapidly stirring solution of 2-amino-6-chlorobenzoic acid (5 g,
29.14 mmol) in benzene (146 mL) and the mixture was stirred at
reflux for 24 h. The mixture was concentrated under reduced
pressure, and stripped down twice with benzene to give brown oil.
The resulting oil was dissolved in CHCl.sub.3 (146 mL) and to that
solution was added o-anisidine and the mixture was stirred at
65.degree. C. for 2 h. The mixture was cooled to rt and the
resulting precipitate was removed by filtration. The filtrate was
concentrated under reduced pressure and purified by column
chromatography on a 120 g of Redi-Sep.TM. column using 0 to 100%
gradient of EtOAc in hexane over 20 min as eluent to provide
2-amino-6-chloro-N-(2-methoxyphenyl)benzamide as yellow solid.
.sup.1H NMR (DMSO-d.sub.6) .delta. ppm 9.44 (1H, s), 7.86 (1H, dd,
J=7.9, 1.3 Hz), 7.13-7.21 (1H, m), 7.04-7.11 (2H, m), 6.97 (1H, t,
J=7.6 Hz), 6.66 (2H, dd, J=28.0, 7.9 Hz), 5.37 (2H, s), 3.81 (3H,
s). Mass Spectrum (ESI) m/e=277.0 (M+1).
5-Chloro-2-(chloromethyl)-3-(2-methoxyphenyl)quinazolin-4(3H)-one
##STR00050##
[0256] To a solution of
2-amino-6-chloro-N-(2-methoxyphenyl)benzamide (4.0813 g, 14.75
mmol) in AcOH (39 mL) was added dropwise chloroacetyl chloride (3.6
mL, 45.2 mmol, 3 eq), and then the mixture was stirred at
110.degree. C. for 3 h. The mixture was cooled to rt and
concentrated under reduce pressure. The residue was dissolved in
H.sub.2O and neutralized with K.sub.2CO.sub.3. The oily product was
extracted with CH.sub.2Cl.sub.2 (3 times). The combined organic
layers were dried with K.sub.2CO.sub.3, filtered, and concentrated
under reduced pressure. The residue was purified by column
chromatography on a 120 g of Redi-Sep.TM. column using 0 to 100%
gradient of EtOAc in hexane over 20 min as eluent to provide
5-chloro-2-(chloromethyl)-3-(2-methoxyphenyl)quinazolin-4(3H)-one
as off-white solid. .sup.1H NMR (DMSO-d.sub.6) .delta. ppm 7.83
(1H, t, J=7.9 Hz), 7.69-7.74 (1H, m), 7.64 (1H, dd, J=7.9, 0.9 Hz),
7.51-7.58 (1H, m), 7.47 (1H, dd, J=7.7, 1.6 Hz), 7.26 (1H, d, J=8.3
Hz), 7.09-7.17 (1H, m), 4.28 (2H, dd, J=51.8, 12.5 Hz), 3.77 (3H,
s). Mass Spectrum (ESI) m/e=335.0 and 337.0 (M+1).
4-Amino-8-((5-chloro-3-(2-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)-
methyl)pyrido[2,3-d]pyrimidin-5(8H)-one
##STR00051##
[0258] To a mixture of 4-aminopyrido[2,3-d]pyrimidin-5(8H)-one (0.1
g, 0.616 mmol), Cs.sub.2CO.sub.3 (0.3013 g, 0.925 mmol, 1.5 eq),
and KI (0.0102 g, 0.0616 mmol, 0.1 eq) in DMF (2 mL) was added
5-chloro-2-(chloromethyl)-3-(2-methoxyphenyl)-quinazolin-4(3H)-one
(0.2273 g, 0.678 mmol, 1.1 eq) and the mixture was stirred at
100.degree. C. for 1 h. The mixture was concentrated under reduced
pressure. The crude product was purified by column chromatography
on a 40 g of Redi-Sep.TM. column using 0 to 100% gradient
of:MeOH:NH.sub.4OH (89:9:1) in CH.sub.2Cl.sub.2 over 14 min as
eluent to provide
4-amino-8-((5-chloro-3-(2-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl-
)methyl)pyrido[2,3-d]pyrimidin-5(8H)-one as yellow solid (0.1707 g,
60%). The yellow solid was triturated with MeOH and filtered to
provide
4-amino-8-((5-chloro-3-(2-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl-
)methyl)pyrido[2,3-d]pyrimidin-5(8H)-one [PI3K.delta. IC.sub.50=13
nM] as yellow solid. .sup.1H NMR (DMSO-d.sub.6) d ppm 9.53 (1H, d,
J=4.7 Hz), 8.20 (1H, s), 8.14 (1H, d, J=4.7 Hz), 7.88 (1H, d, J=7.8
Hz), 7.65-7.72 (1H, m), 7.49-7.59 (3H, m), 7.37 (1H, dd, J=8.2, 1.2
Hz), 7.31 (1H, dd, J=8.6, 1.2 Hz), 7.15-7.21 (1H, m), 6.20 (1H, d,
J=8.2 Hz), 4.91-5.13 (2H, m), 3.85 (3H, s). Mass Spectrum (ESI)
m/e=461.0 (M+1).
Example 22
Preparation of
4-Amino-8-((8-chloro-2-(2-chlorophenyl)-quinolin-3-yl)methyl)pyrido[2,3-d-
]pyrimidin-5(8H)-one
##STR00052##
[0260] To a mixture of 4-aminopyrido[2,3-d]pyrimidin-5(8H)-one
(0.05 g, 0.308 mmol), Cs.sub.2CO.sub.3 (0.1515 g, 0.46 mmol, 1.5
eq), and KI (0.0051 g, 0.0309 mmol, 0.1 eq) in DMF (1 mL) was added
8-chloro-3-(chloromethyl)-2-(2-chlorophenyl)quinoline (0.1 g, 0.309
mmol, 1.0 eq) and the mixture was stirred at 140.degree. C. for 1
h. The mixture was concentrated under reduced pressure. The crude
product was purified by column chromatography on a 40 g of
Redi-Sep.TM. column using 0 to 100% gradient of EtOAc in hexane
over 14 min and then 100% isocratic of EtOAc for 14 min as eluent
to provide
4-amino-8-((8-chloro-2-(2-chlorophenyl)-quinolin-3-yl)methyl)pyrido[2,3-d-
]pyrimidin-5(8H)-one [PI3K.delta. IC.sub.50=33 nM] as white solid.
.sup.1H NMR (DMSO-d.sub.6) .delta. ppm 9.52 (1H, d, J=4.7 Hz), 8.25
(1H, s), 8.11 (1H, d, J=4.7 Hz), 8.09 (1H, s), 8.04 (1H, dd, J=8.4,
1.4 Hz), 7.97 (1H, dd, J=7.6, 1.4 Hz), 7.81 (1H, d, J=7.8 Hz), 7.63
(1H, d, J=7.8 Hz), 7.57-7.61 (1H, m), 7.42-7.53 (3H, m), 6.14 (1H,
d, J=7.8 Hz), 5.40 (2H, s). Mass Spectrum (ESI) m/e=448.0 and 450.1
(M+1).
Example 23
##STR00053##
[0262] 1,3,5-Trichlorotriazine (94 mg, 510 .mu.mol) was added to
dimethylformamide (0.04 mL, 510 .mu.mol) at 25.degree. C. After the
formation of a white solid (10 min), DCM (3 mL) was added, followed
by 1-(8-chloro-2-(3-fluorophenyl)quinolin-3-yl)ethanol (140.0 mg,
464 .mu.mol), made from procedure K. After the addition, the
mixture was stirred at room temperature for 4 h. Water (10 mL) was
added, and then diluted with DCM (10 mL), the organic phase was
washed with 15 mL of a saturated solution of NaHCO.sub.3, followed
by water and brine. The organic layers were dried and concentrated.
Purification of the residue by flash chromatography over silica
gel, using 10% hexane in EtOAc, gave
8-chloro-3-(1-chloroethyl)-2-(3-fluorophenyl)quinoline, Mass
Spectrum (ESI) m/e=320.0 (M+1).
##STR00054##
[0263] To a solution of
3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine.sup.1 (28 mg, 187
mmol) in DMF (2 mL) was added sodium hydride, 60% dispersion in
mineral oil (15 mg, 375 .mu.mol) at 0.degree. C. and the mixture
was stirred at rt for 10 min. To the mixture was added a solution
of 8-chloro-3-(1-chloroethyl)-2-(3-fluorophenyl)-quinoline (60.0
mg, 187 .mu.mol) in DMF (1 mL) and the mixture was stirred at rt
for 24 hrs. The mixture was poured into ice-water and extracted
with Et.sub.2O. The organic layer was washed with brine, dried, and
concentrated. The residue was purified by flash chromatography over
silica gel, using DCM and MeOH (95:5), then Chiral HPLC (Chiralpak
IA column, 0.46.times.250 mm, 5 mm), using 15% isopropanol in
hexane as eluent, gave
1-((S)-1-(8-chloro-2-(3-fluorophenyl)-quinolin-3-yl)ethyl)-3-methyl-1H-py-
razolo[3,4-d]pyrimidin-4-amine, a fraction collected at 17 min, 99%
ee at 254 nm, .sup.1H NMR (DMSO-d.sub.6) .delta. ppm 8.62 (1H, s),
8.09 (1H, d, J=8.2 Hz), 7.97 (1H, d, J=8.2 Hz), 7.96 (1H, s), 7.63
(1H, t, J=8.0 Hz), 7.35-7.41 (1H, m), 7.13-7.22 (3H, m), 6.22-6.27
(1H, m), 2.47 (3H, s), 1.79 (3H, d, J=6.8 Hz). Mass Spectrum (ESI)
m/e=433.1 (M+1).
Example 24
[0264] Using the same or analogous synthetic techniques and
substituting with appropriate reagents as in Example 1, the
following compound was prepared:
##STR00055##
[0265]
1-((8-chloro-3-(4-fluorophenyl)quinoxalin-2-yl)methyl)-3-methyl-1H--
pyrazolo-[3,4-d]pyrimidin-4-amine, .sup.1H NMR (DMSO-d.sub.6)
.delta. ppm 8.08 (1H, dd, J=8.0, 1.2 Hz), 8.02 (1H, dd, J=8.0, 1.2
Hz), 8.01 (1H, s), 7.85 (1H, t, J=8.0 Hz), 7.58-7.64 (2H, m),
7.11-7.18 (3H, m), 2.38 (3H, s). Mass Spectrum (ESI) m/e=420.1
(M+1).
Example 25
1-((5-Chloro-2-(2-chlorophenyl)quinolin-3-yl)methyl)-3-iodo-1H-pyrazolo-[3-
,4-c]pyrimidin-4-amine
##STR00056##
[0267] Prepared according to Procedure I using
5-chloro-3-(chloromethyl)-2-(2-chloro-phenyl)quinoline (0.700 g,
2.17 mmol), 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.623 g,
2.39 mmol, 1.1 eq) and NaH (0.078 g, 3.26 mmol, 1.5 eq) in DMF (15
mL).
N-((8-chloro-2-(3-fluorophenyl)quinolin-3-yl)methyl)-9H-purin-6-amine
[PI3K.delta. IC.sub.50=35 nM] was obtained after purification as a
white solid. 1H-NMR (MeOD) .delta. ppm 8.62 (s, 1H), 8.00 (s, 1H),
7.89-7.91 (m, 1H), 7.82-7.85 (m, 1H), 7.43 (d, 1H, J=5.0 Hz),
7.29-7.32 (t, 1H), 7.18-7.22 (t, 1H), 7.06 (d, 1H, J=5.0 Hz), 5.63
(s, 2H), Mass Spectrum (ESI) m/e=548 (M+1).
Example 26
1-((5-chloro-2-(2-chlorophenyl)quinolin-3-yl)methyl)-3-(1-methyl-1H-pyrazo-
l-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine
##STR00057##
[0269] Prepared according to Procedure J using
1-((5-chloro-2-(2-chlorophenyl)quinolin-3-yl)methyl)-3-iodo-1H-pyrazolo[3-
,4-d]pyrimidin-4-amine (0.060 g, 0.110 mmol),
1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole
(0.032 g, 0.164 mmol, 1.5 eq),
tetrakis(triphenylphosphine)palladium (0.006 g, 10 mol %), and
sodium carbonate (2M aq. Sol., 6 eq) in DMF (0.2M)).
1-((5-chloro-2-(2-chlorophenyl)quinolin-3-yl)methyl)-3-(1-methyl-
-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine was obtained
after purification as a white solid. 1H-NMR (MeOD) .delta. ppm 8.56
(s, 1H), 8.01-8.05 (m, 3H), 7.87 (d, 1H, J=5.0), 7.80-7.83 (m, 1H),
7.65 (s, 1H), 7.47 (d, 1H, J=5.0), 7.34 (t, 1H, J=5.0), 7.24 (t,
1H, J=5.0 Hz), 7.15 (d, 1H), 5.63 (s, 2H), 3.89 (s, 3H), Mass
Spectrum (ESI) m/e=502 (M+1).
Example 27
Preparation of
1-((8-chloro-3-(2-chlorophenyl)quinoxalin-2-yl)-methyl)-3-(1H-pyrazol-4-y-
l)-1H-pyrazolo[3,4-d]pyrimidin-4-amine as a TFA salt and
1-((5-chloro-3-(2-chlorophenyl)quinoxalin-2-yl)methyl)-3-(1H-pyrazol-4-yl-
)-1H-pyrazolo[3,4-d]pyrimidin-4-amine as a TFA salt
1-((8-Chloro-3-(2-chlorophenyl)quinoxalin-2-yl)methyl)-3-iodo-1H-pyrazolo[-
3,4-d]pyrimidin-4-amine and
1-((5-chloro-3-(2-chlorophenyl)-quinoxalin-2-yl)methyl)-3-iodo-1H-pyrazol-
o[3,4-d]pyrimidin-4-amine
##STR00058##
[0271] To a solution of 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine
(0.7168 g, 2.746 mmol) in 6 mL of DMF was added sodium hydride, 60%
dispersion in mineral oil (0.2197 g, 5.492 mmol) at 0.degree. C.
and the mixture was stirred at room temperature. After 10 min, to
the mixture was added a solution of a mixture of
3-(bromomethyl)-5-chloro-2-(2-chlorophenyl)quinoxaline and
2-(bromomethyl)-5-chloro-3-(2-chlorophenyl)quinoxaline (1.061 g,
2.883 mmol) in 6 mL of DMF and the mixture was stirred at room
temperature. After 1 hr, the mixture was poured into ice-water (100
mL). The resulting precipitate was collected by filtration to give
yellow solid (1.2805 g). The yellow solid was purified by column
chromatography on a 40 g of Redi-Sep.TM. column using 0-100%
gradient of EtOAc in hexane over 14 min and then 100% isocratic of
EtOAc for 16 min as eluent to give a mixture of two regioisomers as
yellow solid. The yellow solid was suspended in EtOAc and filtered
to give
1-((8-chloro-3-(2-chlorophenyl)-quinoxalin-2-yl)methyl)-3-iodo-1H-pyrazol-
o[3,4-d]pyrimidin-4-amine and
1-((5-chloro-3-(2-chlorophenyl)quinoxalin-2-yl)methyl)-3-iodo-1H-pyrazolo-
[3,4-d]pyrimidin-4-amine as tan solid: LC-MS (ESI) m/z 547.9
[M+H].sup.+.
1-((8-Chloro-3-(2-chlorophenyl)quinoxalin-2-yl)methyl)-3-(1H-pyrazol-4-yl)-
-1H-pyrazolo[3,4-d]pyrimidin-4-amine as a TFA salt and
1-((5-Chloro-3-(2-chlorophenyl)quinoxalin-2-yl)methyl)-3-(1H-pyrazol-4-yl-
)-1H-pyrazolo[3,4-d]pyrimidin-4-amine as a TFA salt
##STR00059##
[0273] A solution of a mixture of
1-((8-chloro-3-(2-chlorophenyl)quinoxalin-2-yl)-methyl)-3-iodo-1H-pyrazol-
o[3,4-d]pyrimidin-4-amine and
1-((5-chloro-3-(2-chlorophenyl)quinoxalin-2-yl)methyl)-3-iodo-1H-pyrazolo-
[3,4-d]pyrimidin-4-amine in 3.2 mL of DMF was treated with
4-pyrazoleboronic acid pinacol ester (0.2124 g, 1.095 mmol),
tetrakis(triphenylphosphine)palladium(0) (0.06324 g, 0.05473 mmol),
and 2 M aq. sodium carbonate sol. (1.642 mL, 3.284 mmol). The
mixture was heated at 100.degree. C. After 3.5 hr, the mixture was
removed from the heat and poured onto ice-water (100 mL). The
resulting precipitate was collected by suction filtration, washed
with water, and air-dried to give tan solid. The tan solid was
purified by column chromatography on a 40 g of Redi-Sep.TM. column
using 0 to 100% gradient of CH.sub.2Cl.sub.2:MeOH:NH.sub.4OH
(89:9:1) in CH.sub.2Cl.sub.2 over 14 min and then 100% isocratic of
CH.sub.2Cl.sub.2:MeOH:NH.sub.4OH (89:9:1) for 8 min as eluent to
give a product mixture of two regioisomers as off-white solid. The
off-white solid was dissolved purified by semi-prep-HPLC on C18
column using 30-60% gradient of CH.sub.3CN (0.1% of TFA) in water
(0.1% of TFA) over 40 min as eluent to give two separated
regioisomers:
1-((8-chloro-3-(2-chlorophenyl)-quinoxalin-2-yl)methyl)-3-(1H-pyrazol-4-y-
l)-1H-pyrazolo[3,4-d]pyrimidin-4-amine as a TFA salt as white
solid: .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 8.14 (1H,
s), 8.12-8.13 (1H, m), 8.11 (1H, q, J=1.4 Hz), 7.85-7.94 (3H, m),
7.44 (1H, d, J=7.8 Hz), 7.22-7.33 (3H, m), 5.89 (1H, s), 5.85 (1H,
s); LC-MS: m/z 488.0 and 490.0 [M+1], (Exact Mass: 487.08) and
1-((5-chloro-3-(2-chlorophenyl)quinoxalin-2-yl)methyl)-3-(1H-pyrazol-4-yl-
)-1H-pyrazolo[3,4-d]pyrimidin-4-amine as a TFA salt as white solid:
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 8.16 (1H, s), 8.12
(1H, s), 8.10 (1H, s), 7.87-7.95 (3H, m), 7.44-7.50 (1H, m),
7.25-7.37 (3H, m), 5.87 (1H, s), 5.83 (1H, s); LC-MS: m/z 488.0 and
490.0 [M+1], (Exact Mass: 487.08).
Example 28
Preparation of
4-Amino-1-((3-(2-chlorophenyl)-8-methyl-quinoxalin-2-yl)methyl)-1H-pyrazo-
lo[3,4-d]pyrimidine-3-carbonitrile and
4-Amino-1-((3-(2-chlorophenyl)-5-methylquinoxalin-2-yl)methyl)-1H-pyrazol-
o[3,4-d]pyrimidine-3-carbonitrile
##STR00060##
[0275] A suspension of a mixture of
1-((3-(2-chlorophenyl)-8-methylquinoxalin-2-yl)-methyl)-3-iodo-1H-pyrazol-
o[3,4-d]pyrimidin-4-amine and
1-((3-(2-chloro-phenyl)-5-methylquinoxalin-2-yl)methyl)-3-iodo-1H-pyrazol-
o[3,4-d]pyrimidin-4-amine (Prepared in Example 15, 0.30000 g, 0.568
mmol) and copper(i) cyanide (0.305 g, 3.41 mmol) in 5 mL of
pyridine was stirred at 100.degree. C. After 8 hr, the mixture was
cooled to room temperature. The mixture was concentrated under
reduced pressure. The crude mixture was purified by column
chromatography on a 40 g of Redi-Sep.TM. column using 0-100%
gradient of EtOAc in hexane over 14 min and then 100% isocratic of
EtOAc for 10 min as eluent to give a mixture of two regioisomers.
The mixture was purified (1.5 mL (.about.50 mg).times.4 injections)
by semi-prep-HPLC on a Gemini.TM. 10.mu. C18 column (250.times.21.2
mm, 10 .mu.m) using 30-70% gradient of CH.sub.3CN (0.1% of TFA) in
water (0.1% of TFA) over 40 min as eluent to give two fractions:
each fraction was treated with saturated NaHCO.sub.3 (50 mL) and
extracted with CH.sub.2Cl.sub.2 (50 mL.times.1). The each organic
layer was washed with H.sub.2O (30 mL.times.2), dried over
Na.sub.2SO.sub.4, filtered, concentrated under reduced pressure to
give two separated regioisomers:
4-amino-1-((3-(2-chlorophenyl)-8-methylquinoxalin-2-yl)methyl)-1H-pyrazol-
o[3,4-d]pyrimidine-3-carbonitrile as an off-white solid: .sup.1H
NMR (500 MHz, DMF) .delta. ppm 8.16 (1H, s), 7.95 (1H, d, J=8.1
Hz), 7.78-7.83 (1H, m), 7.73-7.78 (1H, m), 7.50-7.56 (1H, m),
7.39-7.45 (2H, m), 7.32-7.38 (1H, m), 5.86 (2H, s), 2.50 (3H, s);
LC-MS (ESI) m/z 427.0 [M+H].sup.+ and
4-amino-1-((3-(2-chlorophenyl)-5-methylquinoxalin-2-yl)methyl)-1H-pyrazol-
o[3,4-d]pyrimidine-3-carbonitrile as a white solid: .sup.1H NMR
(500 MHz, DMSO-d.sub.6) .delta. ppm 8.13 (1H, s), 7.91 (1H, dd,
J=8.2, 0.9 Hz), 7.79-7.84 (1H, m), 7.76-7.80 (1H, m), 7.46-7.51
(1H, m), 7.33-7.40 (2H, m), 7.26-7.32 (1H, m), 5.87 (2H, s), 2.68
(3H, s); LC-MS (ESI) m/z 427.1 [M+H].sup.+.
Example 29
Preparation of
1-((3-(2-chlorophenyl)-8-methylquinoxalin-2-yl)-methyl)-3-(1-methyl-1H-py-
razol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine and
1-((3-(2-chlorophenyl)-5-methylquinoxalin-2-yl)methyl)-3-(1-methyl-1H-pyr-
azol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine
##STR00061##
[0277] A solution of a mixture of
1-((3-(2-chlorophenyl)-8-methylquinoxalin-2-yl)-methyl)-3-iodo-1H-pyrazol-
o[3,4-d]pyrimidin-4-amine and
1-((3-(2-chloro-phenyl)-5-methylquinoxalin-2-yl)methyl)-3-iodo-1H-pyrazol-
o[3,4-d]pyrimidin-4-amine (Prepared in Example 15, 0.3000 g, 0.5685
mmol) in 3.3 mL of DMF was treated with 1-methylpyrazole-4-boronic
acid pinacol ester (0.2366 g, 1.137 mmol),
tetrakis(triphenylphosphine)palladium(0) (0.06569 g, 0.05685 mmol),
and 2 M aq. sodium carbonate sol. (1.705 mL, 3.411 mmol). The
mixture was stirred at 100.degree. C. After 50 min, The mixture was
cooled to room temperature. To the mixture was added water (50 mL)
and the resulting precipitate was collected by filtration to give
the products as a brown solid. The brown solid was purified by
column chromatography on a 40 g of Redi-Sep.TM. column using 0 to
100% gradient of CH.sub.2Cl.sub.2:MeOH:NH.sub.4OH (89:9:1) in
CH.sub.2Cl.sub.2 over 14 min and then 100% isocratic of
CH.sub.2Cl.sub.2:MeOH:NH.sub.4OH (89:9:1) for 10 min as eluent to
give a mixture of two regioisomers as a dark brown solid. The dark
brown solid was purified (1.5 mL (.about.53 mg).times.5 injections)
by semi-prep-HPLC on a Gemini.TM. 10 .mu.C18 column (250.times.21.2
mm, 10 .mu.m) using 20-60% gradient of CH.sub.3CN (0.1% of TFA) in
water (0.1% of TFA) over 40 min as eluent to give two fractions:
each fraction was treated with saturated NaHCO.sub.3 (50 mL) and
extracted with CH.sub.2Cl.sub.2 (50 mL.times.2). The combined
organic layers were respectively washed with H.sub.2O (30
mL.times.2), dried over Na.sub.2SO.sub.4, filtered, concentrated
under reduced pressure to give two separated regioisomers:
1-((3-(2-chlorophenyl)-8-methylquinoxalin-2-yl)methyl)-3-(1-methyl-1H-pyr-
azol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine as an -off-white
solid: .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 8.04 (1H,
s), 7.99 (1H, s), 7.90-7.95 (1H, m), 7.76-7.81 (1H, m), 7.72-7.76
(1H, m), 7.63 (1H, d, J=0.8 Hz), 7.45 (1H, dd, J=7.4, 0.8 Hz),
7.28-7.33 (1H, m), 7.20-7.27 (2H, m), 6.83 (2H, br. s.), 5.62-5.93
(2H, m), 3.87 (3H, s), 2.57 (3H, s); LC-MS (ESI) m/z 482.0
[M+H].sup.+ and
1-((3-(2-chlorophenyl)-5-methylquinoxalin-2-yl)methyl)-3-(1-methyl-1H-pyr-
azol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine as a white solid:
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 8.01 (1H, s), 7.97
(1H, s), 7.94 (1H, dd, J=8.4, 1.0 Hz), 7.78-7.84 (1H, m), 7.74-7.78
(1H, m), 7.61 (1H, d, J=0.8 Hz), 7.38-7.43 (1H, m), 7.22-7.28 (1H,
m), 7.14-7.22 (2H, m), 6.81 (2H, br. s.), 5.59-5.95 (2H, m), 3.86
(3H, s), 2.66 (3H, s); LC-MS (ESI) m/z 482.0 [M+H].sup.+.
Example 30
Preparation of
1-((8-chloro-2-(2-(trifluoromethyl)phenyl)-quinolin-3-yl)methyl)-3-methyl-
-1H-pyrazolo[3,4-d]pyrimidin-4-amine
##STR00062##
[0279] To a solution of
3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.07385 g, 0.4951
mmol) in 1 mL of DMF was added Sodium hydride, 60% dispersion in
mineral oil (0.03960 g, 0.9902 mmol) at 0.degree. C. and the
mixture was stirred at room temperature. After 10 min at room
temperature, to the mixture was added a solution of
8-chloro-3-(chloromethyl)-2-(2-(trifluoromethyl)phenyl)quinoline
hydrochloride (Prepared in Example 6, 0.1944 g, 0.4951 mmol) in 2
mL of DMF and the mixture was stirred at room temperature. After 50
min, the mixture was poured into ice-water (100 mL). The resulting
precipitate was collected by filtration to give a brown solid
(0.2185 g). The aq. filtrate also contained the desired product.
The aq. filtrate was extracted with CH.sub.2Cl.sub.2 (50
mL.times.3). The combined organis layers were washed with brine (50
mL.times.1), dried over Na.sub.2SO.sub.4, filtered, and
concentrated under reduced pressure to give a colorless syrup
(0.0346 g). The brown solid and the colorless syrup were combined
and purified by column chromatography on a 40 g of Redi-Sep.TM.
column using 0-100% gradient of EtOAc in hexane over 14 min, then
100% isocratic of EtOAc for 10 min, and then 0% to 100% gradient of
CH.sub.2Cl.sub.2:MeOH:NH.sub.4OH (89:9:1) in CH.sub.2Cl.sub.2 over
14 min as eluent to give
1-((8-chloro-2-(2-(trifluoromethyl)phenyl)quinolin-3-yl)-methyl)-3-methyl-
-1H-pyrazolo[3,4-d]pyrimidin-4-amine as an off-white solid: .sup.1H
NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 8.24 (1H, s), 8.03 (1H, dd,
J=8.3, 1.3 Hz), 7.97 (1H, dd, J=7.5, 1.3 Hz), 7.95 (1H, s),
7.79-7.85 (1H, m), 7.57-7.67 (3H, m), 7.32-7.37 (1H, m), 7.24 (2H,
br. s.), 5.30-5.42 (2H, m), 2.46 (3H, s); LC-MS (ESI) m/z 469.1
[M+H].sup.+.
Example 31
Preparation of
1-((5-chloro-2-(2-(trifluoromethyl)phenyl)-quinolin-3-yl)methyl)-3-methyl-
-1H-pyrazolo[3,4-d]pyrimidin-4-amine
5-Chloro-2-(2-(trifluoromethyl)phenyl)quinoline-3-carbaldehyde
##STR00063##
[0281] A mixture of 2,5-dichloroquinoline-3-carbaldehyde (1.9948 g,
8.8243 mmol), 2-(trifluoromethyl)phenylboronic acid (1.8436 g,
9.7067 mmol), tetrakis(triphenyl-phosphine)palladium (0.50985 g,
0.44121 mmol), and sodium carbonate an-hydrous (4.6763 g, 44.121
mmol) in 88 mL of CH.sub.3CN--H.sub.2O (3:1) was stirred at
100.degree. C. After 5 hr, the mixture was cooled to room
temperature and partitioned between EtOAc (100 mL) and water (100
mL). The organic layer was washed with brine (50 mL.times.2), dried
over MgSO.sub.4, filtered, and concentrated under reduced pressure
to give a red syrup. The red syrup was purified by silica gel
column chromatography on a 80 g of Redi-Sep.TM. column using 0 to
50% gradient of EtOAc in hexane over 25 min and then 50% isocratic
of EtOAc for 30 min as eluent to give
5-chloro-2-(2-(trifluoromethyl)phenyl)quinoline-3-carbaldehyde as a
light-yellow solid: .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm
10.01 (1H, s), 9.19 (1H, d, J=1.0 Hz), 8.08-8.14 (1H, m), 7.97-8.03
(2H, m), 7.89-7.95 (1H, m), 7.73-7.84 (2H, m), 7.55-7.61 (1H, m);
LC-MS (ESI) m/z 336.1 [M+H].sup.+.
5-Chloro-3-(chloromethyl)-2-(2-(trifluoromethyl)phenyl)quinoline
hydrochloride
##STR00064##
[0283] To a solution of
5-chloro-2-(2-(trifluoromethyl)phenyl)quinoline-3-carbaldehyde
(2.1673 g, 6.456 mmol) in 32 mL of THF at 0.degree. C. was added
sodium borohydride (0.3664 g, 9.684 mmol) and the mixture was
stirred at 0.degree. C. After 1 hr at 0.degree. C., the mixture was
partitioned between EtOAc (100 mL) and H.sub.2O (100 mL), and the
organic layer was washed with brine (50 mL.times.3), dried over
Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure
to give
(5-chloro-2-(2-(trifluoromethyl)-phenyl)quinolin-3-yl)methanol as a
yellow syrup: .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm
8.68-8.73 (1H, m), 7.96-8.02 (1H, m), 7.90-7.95 (1H, m), 7.83-7.87
(1H, m), 7.68-7.83 (3H, m), 7.50-7.58 (1H, m), 5.63 (1H, t, J=5.3
Hz), 4.36 (2H, br. s.); LC-MS (ESI) m/z 338.0 [M+H].sup.+. The
product was carried on crude without purification for the next
step.
A solution of
(5-chloro-2-(2-(trifluoromethyl)phenyl)quinolin-3-yl)methanol
(2.180 g, 6.455 mmol) in 22 mL of CHCl.sub.3 was treated with
thionyl chloride (2.348 mL, 32.27 mmol) dropwise, and the reaction
mixture was stirred at room temperature. After 1.5 hr, the mixture
was concentrated under reduced pressure and co-evaporated three
times with CH.sub.2Cl.sub.2 to give
5-chloro-3-(chloromethyl)-2-(2-(trifluoromethyl)phenyl)quinoline
hydrochloride as a yellow solid: .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 8.86 (1H, d, J=0.6 Hz), 7.99-8.05 (1H,
m), 7.94 (1H, dd, J=7.4, 1.0 Hz), 7.88-7.92 (1H, m), 7.81-7.87 (2H,
m), 7.74-7.81 (1H, m), 7.61-7.66 (1H, m), 4.77 (2H, d, J=79.0 Hz);
LC-MS (ESI) m/z 356.0 and 358.0 [M+H].sup.+ (Exact Mass of neutral
form: 355.014). The yellow solid was carried on crude without
purification for the next step.
1-((5-Chloro-2-(2-(trifluoromethyl)phenyl)quinolin-3-yl)methyl)-3-methyl-1-
H-pyrazolo[3,4-d]pyrimidin-4-amine
##STR00065##
[0285] To a solution of
3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.0956 g, 0.641 mmol)
in 1 mL of DMF was added sodium hydride, 60% dispersion in mineral
oil (0.0513 g, 1.28 mmol) at 0.degree. C. and the mixture was
stirred at room temperature. After 5 min at room temperature, to
the mixture was added a solution of
5-chloro-3-(chloromethyl)-2-(2-(trifluoromethyl)phenyl)quinoline
hydrochloride (0.2767 g, 0.705 mmol) in 3 mL of DMF and the mixture
was stirred at room temperature. After 1.5 hr, the mixture was
poured into ice-water (100 mL). The resulting precipitate was
collected by filtration to give an off-white solid. The off white
solid was purified by column chromatography on a 40 g of
Redi-Sep.TM. column using 0-100% gradient of EtOAc in hexane over
14 min and then 0% to 100% gradient of
CH.sub.2Cl.sub.2:MeOH:NH.sub.4OH (89:9:1) in CH.sub.2Cl.sub.2 over
14 min as eluent to give an off-white solid. The off-white solid
was suspended in CH.sub.2Cl.sub.2-hexane (1:1) and filtered to give
1-((5-chloro-2-(2-(trifluoromethyl)phenyl)quinolin-3-yl)-methyl)-3-methyl-
-1H-pyrazolo[3,4-d]pyrimidin-4-amine as a white solid: .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. ppm 8.44 (1H, d, J=0.8 Hz),
7.96-8.02 (1H, m), 7.94 (1H, s), 7.84-7.88 (1H, m), 7.75-7.83 (2H,
m), 7.52-7.64 (2H, m), 7.05-7.49 (3H, m, J=6.7 Hz), 5.42 (2H, s),
2.45 (3H, s); LC-MS (ESI) m/z 469.1 [M+H].sup.+.
Example 32
Preparation of
1-((3-(2-chlorophenyl)-8-fluoroquinoxalin-2-yl)-methyl)-3-iodo-1H-pyrazol-
o[3,4-d]pyrimidin-4-amine and
1-((3-(2-chlorophenyl)-5-fluoroquinoxalin-2-yl)methyl)-3-iodo-1H-pyrazolo-
[3,4-d]pyrimidin-4-amine
3-(Bromomethyl)-2-(2-chlorophenyl)-5-fluoroquinoxaline and
2-(Bromo-methyl)-3-(2-chlorophenyl)-5-fluoroquinoxaline
##STR00066##
[0287] To a solution of 3-bromo-1-(2-chlorophenyl)propane-1,2-dione
(Prepared in Procedure L, 2.3832 g, 9.114 mmol) in 61 mL of EtOAc
was added a solution of 3-fluorobenzene-1,2-diamine (1.150 g, 9.114
mmol) at room temperature and the resulting red mixture was stirred
at room temperature. After 3 hr, the mixture was concentrated in
vacuo to give a mixture of two regioisomers as a black syrup. The
black syrup was purified by column chromatography on a 80 g of
Redi-Sep.TM. column using 0 to 50% gradient of EtOAc in hexane over
25 min and then 100% isocratic of EtOAc for 4 min as eluent to give
a mixture of 3-(bromomethyl)-2-(2-chlorophenyl)-5-fluoroquinoxaline
and 2-(bromomethyl)-3-(2-chlorophenyl)-5-fluoroquinoxaline as a red
syrup: LC-MS (ESI) two peaks of m/z 351.0 [M+H (.sup.79Br)].sup.+
and 352.9 [M+H (.sup.81Br)].sup.+. The red syrup was carried on
crude without further purification for the next step.
[0288]
1-((3-(2-Chlorophenyl)-8-fluoroquinoxalin-2-yl)methyl)-3-iodo-1H-py-
razolo[3,4-d]pyrimidin-4-amine and
1-((3-(2-Chlorophenyl)-5-fluoro-quinoxalin-2-yl)methyl)-3-iodo-1H-pyrazol-
o[3,4-d]pyrimidin-4-amine
##STR00067##
[0289] To a solution of 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine
(0.6330 g, 2.425 mmol) 5 mL of DMF was added Sodium hydride, 60%
dispersion in mineral oil (0.1940 g, 4.850 mmol) at 0.degree. C.
and the mixture was stirred at room temperature. After 10 min at
room temperature, to the mixture was added a solution of a mixture
of 3-(bromomethyl)-2-(2-chlorophenyl)-5-fluoroquinoxaline and
2-(bromomethyl)-3-(2-chlorophenyl)-5-fluoroquinoxaline (0.9379 g,
2.668 mmol) in 5 mL of DMF and the mixture was stirred at room
temperature. After 50 min, the mixture was poured into ice-water
(100 mL). The resulting precipitate was collected by filtration to
give a yellow solid. The yellow solid was purified by silica gel
column chromatography on a 40 g of Redi-Sep.TM. column using 0-100%
gradient of EtOAc in hexane over 14 min and then 100% isocratic of
EtOAc for 16 min as eluent to give a mixture of
1-((3-(2-chlorophenyl)-8-fluoroquinoxalin-2-yl)methyl)-3-iodo-1H-pyrazolo-
[3,4-d]pyrimidin-4-amine and 1-((3-(2-chlorophenyl)-5-fluoro
quinoxalin-2-yl)methyl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine
as a tan solid. The tan solid was separated by supercritical fluid
chromatography (SFC) to give two separated regioisomers:
1-((3-(2-chlorophenyl)-8-fluoroquinoxalin-2-yl)methyl)-3-iodo-1H-pyrazolo-
[3,4-d]pyrimidin-4-amine as a white solid: .sup.1H NMR (400 MHz,
chloroform-d) .delta. ppm 8.18 (1H, s), 7.92-7.98 (1H, m),
7.72-7.80 (1H, m), 7.46-7.55 (1H, m), 7.36 (1H, dd, J=8.0, 1.0 Hz),
7.19-7.24 (1H, m), 7.12-7.17 (1H, m), 7.05-7.10 (1H, m), 5.75-6.14
(4H, m); LC-MS (ESI) m/z 532.0 [M+H].sup.+ and
1-((3-(2-chlorophenyl)-5-fluoroquinoxalin-2-yl)methyl)-3-iodo-1H-pyrazolo-
[3,4-d]pyrimidin-4-amine as a white solid: .sup.1H NMR (400 MHz,
chloroform-d) .delta. ppm 8.20 (1H, s), 7.86-7.92 (1H, m),
7.70-7.78 (1H, m), 7.45-7.53 (1H, m), 7.37-7.42 (1H, m), 7.24-7.30
(1H, m), 7.16-7.23 (2H, m), 5.76-6.04 (4H, m); LC-MS (ESI) m/z
532.0 [M+H].sup.+.
Biological Assays
[0290] Recombinant expression of PI3Ks 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 hr 2 hr 2 hr 1 hr [Enzyme] 15 nM 40 nM 15 nM
50 nM
In Vitro Enzyme Assays.
[0291] Assays were performed in 25 .mu.L with the above final
concentrations of components in white polyproplyene plates (Costar
3355). Phospatidyl inositol phosphoacceptor, Ptdlns(4,5)P2 P4508,
was from Echelon Biosciences. The ATPase activity of the alpha and
gamma isozymes was not greatly stimulated by Ptdlns(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 room temperature, 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:
[0292] 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
[0293] 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.
TABLE-US-00002 Compound IC50
1-((8-chloro-2-(2-fluorophenyl)-3-quinolinyl)methyl)-3-(1H-
0.018171 pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine
4-amino-1-((3-(2-chlorophenyl)-8-methyl-2- 0.083816
quinoxalinyl)methyl)-1H-pyrazolo[3,4-d]pyrimidine- 3-carbonitrile
4-amino-1-((3-(2-chlorophenyl)-5-methyl-2- 0.001989
quinoxalinyl)methyl)-1H-pyrazolo [3,4-d]pyrimidine- 3-carbonitrile
1-((3-(2-chlorophenyl)-8-methyl-2-quinoxalinyl)methyl)-3-(1-
0.01979 methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-
amine 1-((3-(2-chlorophenyl)-5-methyl-2-quinoxalinyl)methyl)-3-(1-
0.037023 methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-
amine 1-((5-chloro-2-(2-chlorophenyl)-3-quinolinyl)methyl)-3-
0.093431 iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine
1-((8-chloro-2-(2-(trifluoromethyl)phenyl)-3- 0.044789
quinolinyl)methyl)-3-methyl-1H-pyrazolo[3,4-d]pyrimidin- 4-amine
1-((5-chloro-2-(2-(trifluoromethyl)phenyl)-3- 0.135691
quinolinyl)methyl)-3-methyl-1H-pyrazolo[3,4-d]pyrimidin- 4-amine
1-((3-(2-chlorophenyl)-8-fluoro-2-quinoxalinyl)methyl)- 0.817616
3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine
1-((3-(2-chlorophenyl)-5-fluoro-2-quinoxalinyl)methyl)- 0.55443
3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine
1-((5-chloro-2-(2-chlorophenyl)-3-quinolinyl)methyl)-3-(1- 0.046745
methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin- 4-amine
1-((1S)-1-(8-chloro-2-(3-fluorophenyl)-3-quinolinyl)ethyl)-3-
0.00157 methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine
2-((4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1- 0.512429
yl)methyl)-3-(3-fluorophenyl)-6-methyl-4H-
pyrido[1,2-a]pyrimidin-4-one
Human B Cells Proliferation Stimulate by IL-4
Isolate Human B Cells:
[0294] 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
[0295] 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
[0296] 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
[0297] 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)
[0298] 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)
[0299] Treat cells with compound in growth medium 1 h. Fix and
image.
Class III PI(3)P Assay (U2OS EGFP-2XFYVE Cells/GE Healthcare)
[0300] Wash cells with assay buffer. Treat with compounds in assay
buffer 1 h. Fix and image.
Control for all 3 Assays is 10 .mu.M Wortmannin:
[0301] AKT is cytoplasmic Forkhead is nuclear PI(3)P depleted from
endosomes
Biomarker Assay: B-Cell Receptor Stimulation of CD69 or B7.2 (CD86)
Expression
[0302] 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 minutes in the dark at room temperature. The blood was
then lysed and fixed using 450 .mu.L of FACS lysing solution (BD
Biosciences, #349202) for 15 minutes at room temperature. 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
[0303] 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 minutes 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 minutes at room temperature. 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 minutes. Plates were spun at 1500 rpm for
10 minutes, 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
minutes 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 minutes.
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 minutes 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
[0304] 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 minutes 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 minutes at room temperature. 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 minutes. Plates
were spun at 1500 rpm for 10 minutes. 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 minutes 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 minutes at room
temperature. After block, 50 .mu.L 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
minutes. 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 minutes
at rt with shaking Cells were then washed 1.times. in buffer and
suspended in 100 .mu.L 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 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 3X'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 3X'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.). Methanol 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
[0305] 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 minutes and spun at
10,000 rpm in serum microtainer tubes (Becton Dickinson) for 10
minutes. 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 minutes for 1
hour before immunization. On day 5, post-last treatment, mice were
CO.sub.2 sacrificed and cardiac punctured. Blood was allowed to
clot for 30 minutes and spun at 10,000 rpm in serum microtainer
tubes for 10 minutes. 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 minutes depending on the Ig
analyzed. The reaction was stopped with 2M sulfuric acid and plates
were read at an OD of 450 nm.
[0306] 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.
[0307] 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.
[0308] The dosage regimen for treating PI3K.delta.-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.
[0309] 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.
[0310] 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.
[0311] 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.
[0312] Injectable preparations, such as sterile injectable aqueous
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.
[0313] 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.
[0314] 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.
[0315] 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.
[0316] 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.
[0317] 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.
[0318] 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.
[0319] 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.
[0320] 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.
[0321] 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.
[0322] 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.
[0323] 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.
[0324] 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, iso-propoxyethyl, 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.
[0325] Further, the compounds of the invention may exist as
crystalline solids which can be crystallized from common solvents
such as ethanol, N,N-dimethyl-formamide, 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.
[0326] 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.
[0327] 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.
[0328] 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.
* * * * *