U.S. patent application number 15/680045 was filed with the patent office on 2018-03-08 for phosphatidylinositol 3-kinase inhibitors.
The applicant listed for this patent is Gilead Sciences, Inc.. Invention is credited to Jerry Evarts, Joshua A. Kaplan, Musong Kim, Devan Naduthambi, Leena Patel, Stephane Perreault, Gary Phillips, Lafe J. Purvis, II, Kirk L. Stevens, Jennifer Anne Treiberg.
Application Number | 20180065953 15/680045 |
Document ID | / |
Family ID | 53674285 |
Filed Date | 2018-03-08 |
United States Patent
Application |
20180065953 |
Kind Code |
A1 |
Evarts; Jerry ; et
al. |
March 8, 2018 |
PHOSPHATIDYLINOSITOL 3-KINASE INHIBITORS
Abstract
The present disclosure provides phosphatidylinositol 3-kinase
(PI3K) inhibitors of formula (J), ##STR00001## or pharmaceutically
acceptable salts thereof, in which A, n, m, R.sup.1, R.sup.2,
R.sup.3, R.sup.4, R.sup.5, R.sup.6 and R.sup.7 are as defined
herein. These compounds are useful for treatment of conditions
mediated by one or more PI3K isoforms. The present disclosure
further provides pharmaceutical compositions that include a
compound of formula (J), or pharmaceutically acceptable salts
thereof, and methods of using these compounds and compositions to
treat conditions mediated by one or more PI3K isoforms.
Inventors: |
Evarts; Jerry; (Seattle,
WA) ; Kaplan; Joshua A.; (Foster City, CA) ;
Kim; Musong; (Bellevue, WA) ; Naduthambi; Devan;
(San Bruno, CA) ; Patel; Leena; (Seattle, WA)
; Perreault; Stephane; (Brier, WA) ; Phillips;
Gary; (Issaquah, WA) ; Purvis, II; Lafe J.;
(Minneapolis, MN) ; Stevens; Kirk L.; (Bothell,
WA) ; Treiberg; Jennifer Anne; (Redmond, WA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Gilead Sciences, Inc. |
Foster City |
CA |
US |
|
|
Family ID: |
53674285 |
Appl. No.: |
15/680045 |
Filed: |
August 17, 2017 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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14747931 |
Jun 23, 2015 |
9765060 |
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15680045 |
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62016194 |
Jun 24, 2014 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61P 37/02 20180101;
C07D 403/14 20130101; C07D 403/12 20130101; A61P 35/02 20180101;
C07D 401/14 20130101; A61P 37/00 20180101; A61P 21/04 20180101;
A61P 11/06 20180101; A61P 17/06 20180101; A61P 17/00 20180101; A61P
11/00 20180101; A61P 19/02 20180101; A61P 25/00 20180101; A61P
43/00 20180101; A61P 7/06 20180101; C07D 413/14 20130101; A61P
35/00 20180101; A61P 29/00 20180101; C07D 491/107 20130101; C07D
409/14 20130101 |
International
Class: |
C07D 403/12 20060101
C07D403/12; C07D 491/107 20060101 C07D491/107; C07D 409/14 20060101
C07D409/14; C07D 413/14 20060101 C07D413/14; C07D 401/14 20060101
C07D401/14; C07D 403/14 20060101 C07D403/14 |
Claims
1-20. (canceled)
21. A method for treating a human, who has or is suspected of
having a disease or condition responsive or believed to be
responsive to the inhibition of PI3K.delta. activity, comprising
administering to the human a compound having the structure of
formula (J): ##STR00167## wherein: A is N or CH; n is 0, 1, 2, 3,
or 4; m is 0, 1, 2, 3, or 4; each R.sup.1 is independently selected
from optionally substituted alkyl, optionally substituted
haloalkyl, optionally substituted aryl, optionally substituted
heteroaryl, halo, cyano, NHC(.dbd.O)alkylene-N(R.sup.1x).sub.2,
NO.sub.2, OR.sup.1x, N(R.sup.1x).sub.2, OC(.dbd.O)R.sup.1x,
C(.dbd.O)R.sup.1x, C(.dbd.O)OR.sup.1x, aryl-OR.sup.1y, optionally
substituted cycloalkyl, optionally substituted heterocycloalkyl,
NR.sup.1xC(.dbd.O)alkylene-C(.dbd.O)OR.sup.1x,
aryl-O-alkylene-N(R.sup.1x).sub.2, aryl-O--C(.dbd.O)R.sup.1x,
alkylene-C(.dbd.O)OR.sup.1x, alkylene-C(.dbd.O)N(R.sup.1x).sub.2,
alkylene-C(.dbd.O)--Het, O-alkylene-C(.dbd.O)OR.sup.1x,
alkylene-O-alkylene-C(.dbd.O)OR.sup.1x
C(.dbd.O)NR.sup.1xSO.sub.2R.sup.1x, alkylene-N(R.sup.1x).sub.2,
alkenylene-N(R.sup.1x).sub.2,
C(.dbd.O)NR.sup.1x-alkylene-OR.sup.1x,
C(.dbd.O)NR.sup.1xalkylene-Het, O-alkylene-N(R.sup.1x).sub.2,
O-alkylene-CH(OR.sup.1y)CH.sub.2N(R.sup.1x).sub.2, O-alkylene-Het,
O-alkylene-C(.dbd.O)OR.sup.1x, O-alkylene-C(.dbd.O)--Het,
S-alkylene-OR.sup.1x, O-alkylene-OR.sup.1x,
O--C.sub.1-6alkylene-CH(OR.sup.1y)C.sub.1-6alkylene-OR.sup.1x,
O-alkylene-NR.sup.1xC(.dbd.O)OR.sup.1x,
NR.sup.1x-alkylene-N(R.sup.1x).sub.2, NR.sup.1xC(.dbd.O)R.sup.1x,
NR.sup.1xC(.dbd.O)N(R.sup.1x).sub.2, N(SO.sub.2-alkyl).sub.2,
NR.sup.1x(SO.sub.2-alkyl), SO.sub.2R.sup.1z,
SO.sub.2N(R.sup.1x).sub.2, alkylene-aryl, alkylene-Het,
alkylene-OR.sup.1y, alkylene-N(R.sup.1x).sub.2,
C(.dbd.O)N(R.sup.1x).sub.2, NHC(.dbd.O)alkylene-aryl,
aryl-O-alkylene-N(R.sup.1x).sub.2, aryl-OC(.dbd.O)R.sup.1y,
NHC(.dbd.O)alkylene-heterocycloalkyl, NHC(.dbd.O)alkylene-Het,
O-alkylene-O-alkylene-C(.dbd.O)OR.sup.1y, C(.dbd.O)alkylene-Het,
and NHC(.dbd.O)halo-alkyl, wherein Het is optionally substituted
heteroaryl or optionally substitutedheterocycloalkyl, wherein
R.sup.1x is independently hydrogen, optionally substituted alkyl,
optionally substituted haloalkyl, optionally substituted
cycloalkyl, optionally substituted heterocycloalkyl, or optionally
substituted aryl, wherein R.sup.1y is independently hydrogen,
optionally substituted alkyl, optionally substituted haloalkyl,
optionally substituted aryl, or optionally substituted heteroaryl,
and wherein R.sup.1z is independently optionally substituted alkyl,
optionally substituted haloalkyl, optionally substituted
cycloalkyl, optionally substituted heterocycloalkyl, or optionally
substituted aryl; each R.sup.2 is independently selected from halo,
cyano, optionally substituted alkyl, haloalkyl,
SO.sub.2N(R.sup.2x).sub.2, and optionally substituted alkoxy,
wherein R.sup.2x is hydrogen, optionally substituted alkyl, or
optionally substituted haloalkyl; R.sup.3 is hydrogen, optionally
substituted alkyl, optionally substituted haloalkyl, optionally
substituted cycloalkyl, optionally substituted aryl, optionally
substituted heteroaryl, or optionally substituted heterocycloalkyl;
R.sup.5 is hydrogen or alkyl, or R.sup.5 and R.sup.3 together with
the atoms to which they are attached optionally form an optionally
substituted four-, five- or six-membered heterocyclic ring; R.sup.4
is cyano, C(.dbd.O)NR.sup.4xR.sup.4y, SO.sub.2-alkyl, halo,
haloalkyl, or C(.dbd.O)R.sup.4x, wherein each R.sup.4x and R.sup.4y
is independently hydrogen, optionally substituted alkyl, or
optionally substituted haloalkyl; R.sup.6 is NH.sub.2, halo,
optionally substituted alkyl, or optionally substituted haloalkyl;
and R.sup.7 is NH.sub.2, halo, optionally substituted alkyl, or
optionally substituted haloalkyl; provided that when R.sup.5 and
R.sup.3 form a 5-membered heterocyclic ring that is optionally
substituted with hydroxyl, halo, or methoxy, R.sup.4 is cyano,
R.sup.6 is amino, and R.sup.7 is amino, or a pharmaceutically
acceptable salt, isomer, or a mixture thereof.
22. The method of claim 21, wherein the disease is selected from
the group consisting of acute lymphocytic leukemia (ALL), acute
myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), small
lymphocytic lymphoma (SLL), myelodysplastic syndrome (MDS),
myeloproliferative disease (MPD), chronic myeloid leukemia (CML),
juvenile myelomonocytic leukemia (JMML), multiple myeloma (MM),
Hodgkin lymphoma, indolent non-Hodgkin's lymphoma (iNHL),
refractory iNHL, non-Hodgkin's lymphoma (NHL), mantle cell lymphoma
(MCL), follicular lymphoma, Waldestrom's macroglobulinemia (WM),
minimal residual disease (MRD), T-cell lymphoma, B-cell lymphoma,
diffuse large B-cell lymphoma (DLBCL), T-cell acute lymphoblastic
leukemia (T-ALL), B-cell acute lymphoblastic leukemia (B-ALL),
lymphoplasmacytic lymphoma, marginal zone lymphoma, Burkitt
lymphoma, pancreatic cancer, bladder cancer, colorectal cancer,
breast cancer, prostate cancer, renal cancer, hepatocellular
cancer, lung cancer, ovarian cancer, cervical cancer, gastric
cancer, esophageal cancer, head and neck cancer, melanoma,
neuroendocrine cancers, CNS cancers, brain tumors, bone cancer,
soft tissue sarcoma, systemic lupus erythematosus (SLE), myestenia
gravis, rheumatoid arthritis (RA), psoriasis, acute disseminated
encephalomyelitis, idiopathic thrombocytopenic purpura, multiple
sclerosis (MS), Sjoegren's syndrome, psoriasis, autoimmune
hemolytic anemia, asthma, and chronic obstructive pulmonary disease
(COPD).
23. A method of inhibiting the activity of a phosphatidylinositol
3-kinase polypeptide by contacting the polypeptide with a compound
having the structure of formula (J): ##STR00168## wherein: A is N
or CH; n is 0, 1, 2, 3, or 4; m is 0, 1, 2, 3, or 4; each R.sup.1
is independently selected from optionally substituted alkyl,
optionally substituted haloalkyl, optionally substituted aryl,
optionally substituted heteroaryl, halo, cyano,
NHC(.dbd.O)alkylene-N(R.sup.1x).sub.2, NO.sub.2, OR.sup.1x,
N(R.sup.1x).sub.2, OC(.dbd.O)R.sup.1x, C(.dbd.O)R.sup.1x,
C(.dbd.O)OR.sup.1x, aryl-OR.sup.1y, optionally substituted
cycloalkyl, optionally substituted heterocycloalkyl,
NR.sup.1xC(.dbd.O)alkylene-C(.dbd.O)OR.sup.1x,
aryl-O-alkylene-N(R.sup.1x).sub.2, aryl-O--C(.dbd.O)R.sup.1x,
alkylene-C(.dbd.O)OR.sup.1x, alkylene-C(.dbd.O)N(R.sup.1x).sub.2,
alkylene-C(.dbd.O)--Het, O-alkylene-C(.dbd.O)OR.sup.1x,
alkylene-O-alkylene-C(.dbd.O)OR.sup.1xC(.dbd.O)NR.sup.1xSO.sub.2R.sup.1x,
alkylene-N(R.sup.1x).sub.2, alkenylene-N(R.sup.1x).sub.2,
C(.dbd.O)NR.sup.1x-alkylene-OR.sup.1x,
C(.dbd.O)NR.sup.1xalkylene-Het, O-alkylene-N(R.sup.1x).sub.2,
O-alkylene-CH(OR.sup.1y)CH.sub.2N(R.sup.1x).sub.2,
--O-alkylene-Het, O-alkylene-C(.dbd.O)OR.sup.1x,
O-alkylene-C(.dbd.O)--Het, S-alkylene-OR.sup.1x,
O-alkylene-OR.sup.1x,
O--C.sub.1-6alkylene-CH(OR.sup.1y)C.sub.1-6alkylene-OR.sup.1x,
O-alkylene-NR.sup.1xC(.dbd.O)OR.sup.1x,
NR.sup.1x-alkylene-N(R.sup.1x).sub.2, NR.sup.1xC(.dbd.O)R.sup.1x,
NR.sup.1xC(.dbd.O)N(R.sup.1x).sub.2, N(SO.sub.2-alkyl).sub.2,
NR.sup.1x(SO.sub.2-alkyl), SO.sub.2R.sup.1z,
SO.sub.2N(R.sup.1x).sub.2, alkylene-aryl, alkylene-Het,
alkylene-OR.sup.1y, alkylene-N(R.sup.1x).sub.2,
C(.dbd.O)N(R.sup.1x).sub.2, NHC(.dbd.O)alkylene-aryl,
aryl-O-alkylene-N(R.sup.1x).sub.2, aryl-OC(.dbd.O)R.sup.1y,
NHC(.dbd.O)alkylene-heterocycloalkyl, NHC(.dbd.O)alkylene-Het,
O-alkylene-O-alkylene-C(.dbd.O)OR.sup.1y, C(.dbd.O)alkylene-Het,
and NHC(.dbd.O)halo-alkyl, wherein Het is optionally substituted
heteroaryl or optionally substitutedheterocycloalkyl, wherein
R.sup.1x is independently hydrogen, optionally substituted alkyl,
optionally substituted haloalkyl, optionally substituted
cycloalkyl, optionally substituted heterocycloalkyl, or optionally
substituted aryl, wherein R.sup.1y is independently hydrogen,
optionally substituted alkyl, optionally substituted haloalkyl,
optionally substituted aryl, or optionally substituted heteroaryl,
and wherein R.sup.1z is independently optionally substituted alkyl,
optionally substituted haloalkyl, optionally substituted
cycloalkyl, optionally substituted heterocycloalkyl, or optionally
substituted aryl; each R.sup.2 is independently selected from halo,
cyano, optionally substituted alkyl, haloalkyl,
SO.sub.2N(R.sup.2x).sub.2, and optionally substituted alkoxy,
wherein R.sup.2x is hydrogen, optionally substituted alkyl, or
optionally substituted haloalkyl; R.sup.3 is hydrogen, optionally
substituted alkyl, optionally substituted haloalkyl, optionally
substituted cycloalkyl, optionally substituted aryl, optionally
substituted heteroaryl, or optionally substituted heterocycloalkyl;
R.sup.5 is hydrogen or alkyl, or R.sup.5 and R.sup.3 together with
the atoms to which they are attached optionally form an optionally
substituted four-, five- or six-membered heterocyclic ring; R.sup.4
is cyano, C(.dbd.O)NR.sup.4xR.sup.4y, SO.sub.2-alkyl, halo,
haloalkyl, or C(.dbd.O)R.sup.4x, wherein each R.sup.4x and R.sup.4y
is independently hydrogen, optionally substituted alkyl, or
optionally substituted haloalkyl; R.sup.6 is NH.sub.2, halo,
optionally substituted alkyl, or optionally substituted haloalkyl;
and R.sup.7 is NH.sub.2, halo, optionally substituted alkyl, or
optionally substituted haloalkyl; provided that when R.sup.5 and
R.sup.3 form a 5-membered heterocyclic ring that is optionally
substituted with hydroxyl, halo, or methoxy, R.sup.4 is cyano,
R.sup.6 is amino, and R.sup.7 is amino, or a pharmaceutically
acceptable salt, isomer, or a mixture thereof.
24. A method of inhibiting excessive or destructive immune
reactions or growth or a proliferation of cancer cells, comprising
administering an effective amount of a compound having the
structure of formula (J): ##STR00169## wherein: A is N or CH; n is
0, 1, 2, 3, or 4; m is 0, 1, 2, 3, or 4; each R.sup.1 is
independently selected from optionally substituted alkyl,
optionally substituted haloalkyl, optionally substituted aryl,
optionally substituted heteroaryl, halo, cyano,
NHC(.dbd.O)alkylene-N(R.sup.1x).sub.2, NO.sub.2, OR.sup.1x,
N(R.sup.1x).sub.2, OC(.dbd.O)R.sup.1x, C(.dbd.O)R.sup.1x,
C(.dbd.O)OR.sup.1x, aryl-OR.sup.1y, optionally substituted
cycloalkyl, optionally substituted heterocycloalkyl,
NR.sup.1xC(.dbd.O)alkylene-C(.dbd.O)OR.sup.1x,
aryl-O-alkylene-N(R.sup.1x).sub.2, aryl-O--C(.dbd.O)R.sup.1x,
alkylene-C(.dbd.O)OR.sup.1x, alkylene-C(.dbd.O)N(R.sup.1x).sub.2,
alkylene-C(.dbd.O)--Het, O-alkylene-C(.dbd.O)OR.sup.1x,
alkylene-O-alkylene-C(.dbd.O)OR.sup.1xC(.dbd.O)NR.sup.1xSO.sub.2R.sup.1x,
alkylene-N(R.sup.1x).sub.2, alkenylene-N(R.sup.1x).sub.2,
C(.dbd.O)NR.sup.1x-alkylene-OR.sup.1x,
C(.dbd.O)NR.sup.1xalkylene-Het, O-alkylene-N(R.sup.1x).sub.2,
O-alkylene-CH(OR.sup.1y)CH.sub.2N(R.sup.1x).sub.2, O-alkylene-Het,
O-alkylene-C(.dbd.O)OR.sup.1x, O-alkylene-C(.dbd.O)--Het,
S-alkylene-OR.sup.1x, O-alkylene-OR.sup.1x,
O--C.sub.1-6alkylene-CH(OR.sup.1y)C.sub.1-6alkylene-OR.sup.1x,
O-alkylene-NR.sup.1xC(.dbd.O)OR.sup.1x,
NR.sup.1x-alkylene-N(R.sup.1x).sub.2, NR.sup.1xC(.dbd.O)R.sup.1x,
NR.sup.1xC(.dbd.O)N(R.sup.1x).sub.2, N(SO.sub.2-alkyl).sub.2,
NR.sup.1x(SO.sub.2-alkyl) SO.sub.2R.sup.1z,
SO.sub.2N(R.sup.1x).sub.2, alkylene-aryl, alkylene-Het,
alkylene-OR.sup.1y, alkylene-N(R.sup.1x).sub.2,
C(.dbd.O)N(R.sup.1x).sub.2, NHC(.dbd.O)alkylene-aryl,
aryl-O-alkylene-N(R.sup.1x).sub.2, aryl-OC(.dbd.O)R.sup.1y,
NHC(.dbd.O)alkylene-heterocycloalkyl, NHC(.dbd.O)alkylene-Het,
O-alkylene-O-alkylene-C(.dbd.O)OR.sup.1y, C(.dbd.O)alkylene-Het,
and NHC(.dbd.O)halo-alkyl, wherein Het is optionally substituted
heteroaryl or optionally substitutedheterocycloalkyl, wherein
R.sup.1x is independently hydrogen, optionally substituted alkyl,
optionally substituted haloalkyl, optionally substituted
cycloalkyl, optionally substituted heterocycloalkyl, or optionally
substituted aryl, wherein R.sup.1y is independently hydrogen,
optionally substituted alkyl, optionally substituted haloalkyl,
optionally substituted aryl, or optionally substituted heteroaryl,
and wherein R.sup.1z is independently optionally substituted alkyl,
optionally substituted haloalkyl, optionally substituted
cycloalkyl, optionally substituted heterocycloalkyl, or optionally
substituted aryl; each R.sup.2 is independently selected from halo,
cyano, optionally substituted alkyl, haloalkyl,
SO.sub.2N(R.sup.2x).sub.2, and optionally substituted alkoxy,
wherein R.sup.2x is hydrogen, optionally substituted alkyl, or
optionally substituted haloalkyl; R.sup.3 is hydrogen, optionally
substituted alkyl, optionally substituted haloalkyl, optionally
substituted cycloalkyl, optionally substituted aryl, optionally
substituted heteroaryl, or optionally substituted heterocycloalkyl;
R.sup.5 is hydrogen or alkyl, or R.sup.5 and R.sup.3 together with
the atoms to which they are attached optionally form an optionally
substituted four-, five- or six-membered heterocyclic ring; R.sup.4
is cyano, C(.dbd.O)NR.sup.4xR.sup.4y, SO.sub.2-alkyl, halo,
haloalkyl, or C(.dbd.O)R.sup.4x, wherein each R.sup.4x and R.sup.4y
is independently hydrogen, optionally substituted alkyl, or
optionally substituted haloalkyl; R.sup.6 is NH.sub.2, halo,
optionally substituted alkyl, or optionally substituted haloalkyl;
and R.sup.7 is NH.sub.2, halo, optionally substituted alkyl, or
optionally substituted haloalkyl; provided that when R.sup.5 and
R.sup.3 form a 5-membered heterocyclic ring that is optionally
substituted with hydroxyl, halo, or methoxy, R.sup.4 is cyano,
R.sup.6 is amino, and R.sup.7 is amino, or a pharmaceutically
acceptable salt, isomer, or a mixture thereof.
25-28. (canceled)
29. The method of claim 21, wherein the compound is a compound of
formula (I): ##STR00170## wherein: n is 1 or 2; m is 0, 1, or 2;
each R.sup.1 is independently C.sub.1-6alkyl, C.sub.1-6haloalkyl,
C.sub.3-8cycloalkyl, C.sub.2-8heterocycloalkyl,
C.sub.3-8heteroaryl, C.sub.6-10aryl, halo, cyano,
C.sub.6-10aryl-OR.sup.1y, C.sub.1-6alkylene-C.sub.6-10aryl,
C.sub.1-6alkylene-Het, C.sub.1-6alkylene-C.sub.3-8cycloalkyl,
C.sub.1-6alkylene-OR.sup.1y, C.sub.1-6alkylene-N(R.sup.1x).sub.2,
C.sub.2-6alkenylene-OR.sup.1y,
C.sub.2-6alkenylene-N(R.sup.1x).sub.2,
C.sub.1-6alkylene-C(.dbd.O)OR.sup.1x,
C.sub.1-6alkylene-C(.dbd.O)N(R.sup.1x).sub.2,
C.sub.1-6alkylene-C(.dbd.O)-Het,
O--C.sub.1-6alkylene-C(.dbd.O)OR.sup.1x,
C.sub.1-6alkylene-O--C.sub.1-6alkylene-C(.dbd.O)OR.sup.1x,
C.sub.1-6alkenylene-N(R.sup.1x).sub.2, OR.sup.1x,
O--C.sub.1-6alkylene-N(R.sup.1x).sub.2,
O--C.sub.1-6alkylene-CH(OR.sup.1y)CH.sub.2N(R.sup.1x).sub.2,
O--C.sub.1-6alkylene-Het, O--C.sub.1-6alkylene-C(.dbd.O)OR.sup.1x,
O--C.sub.1-6alkylene-C(.dbd.O)--Het,
O--C.sub.1-6alkylene-OR.sup.1x,
O--C.sub.1-6alkylene-CH(OR.sup.1y)C.sub.1-6alkylene-OR.sup.1x,
O--C.sub.2-6alkenylene-OR.sup.1y,
O--C.sub.2-6alkenylene-N(R.sup.1x).sub.2,
O--C.sub.1-6alkylene-NR.sup.1xC(.dbd.O)OR.sup.1x,
O--C.sub.1-6alkylene-O--C.sub.1-6alkylene-C(.dbd.O)OR.sup.1y,
SO.sub.2R.sup.1x, S--C.sub.1-6alkylene-OR.sup.1z, or
SO.sub.2N(R.sup.1x).sub.2, wherein Het is C.sub.3-8heteroaryl or
C.sub.2-8heterocycloalkyl, wherein R.sup.1x is independently
hydrogen, C.sub.1-6alkyl, C.sub.1-6haloalkyl, C.sub.3-8cycloalkyl,
C.sub.6-10aryl, C.sub.2-8heterocycloalkyl, or C.sub.3-8heteroaryl,
wherein R.sup.1y is independently hydrogen, C.sub.1-6alkyl,
C.sub.1-6haloalkyl, C.sub.6-10aryl, or C.sub.3-8heteroaryl, wherein
R.sup.1z is independently C.sub.1-6alkyl, C.sub.1-6haloalkyl,
C.sub.3-8cycloalkyl, C.sub.6-10aryl, C.sub.2-8heterocycloalkyl, or
C.sub.3-8heteroaryl, and wherein each of Het, R.sup.1x, R.sup.1y
and R.sup.1z is optionally substituted with one, two, three, or
four members independently selected from halo, oxo, C.sub.1-6alkyl,
and C.sub.6-10aryl; each R.sup.2 is independently halo, cyano,
C.sub.1-6alkyl, C.sub.1-6haloalkyl, or SO.sub.2N(R.sup.2x).sub.2,
wherein R.sup.2x is hydrogen, C.sub.1-6alkyl, or
C.sub.1-6haloalkyl; R.sup.3 is hydrogen, C.sub.1-6alkyl,
C.sub.1-6haloalkyl, C.sub.3-8cycloalkyl, or C.sub.6-10aryl, wherein
the C.sub.1-6alkyl moiety is optionally substituted with
--C(.dbd.O)NR.sup.3xR.sup.3y, wherein each R.sup.3x and R.sup.3y is
independently hydrogen, C.sub.1-6alkyl, or C.sub.1-6haloalkyl;
R.sup.5 is hydrogen or C.sub.1-6alkyl, or R.sup.5 and R.sup.3
together with the atoms to which they are attached optionally form
a four-, five- or six-membered heterocyclic ring, wherein the
heterocyclic ring is optionally substituted with one, two, or three
members independently selected from halo, C.sub.1-6alkyl,
C.sub.1-6haloalkyl, and NR.sup.5xC(O)R.sup.5y where R.sup.5x is
hydrogen or C.sub.1-6alkyl, and R.sup.5y is
C.sub.1-6alkylene-NH.sub.2, C.sub.1-6 alkylene-C.sub.3-8cycloalkyl,
or C.sub.1-6haloalkyl; R.sup.4 is cyano,
C(.dbd.O)NR.sup.4xR.sup.4y, SO.sub.2--C.sub.1-6alkyl, halo,
C.sub.1-6haloalkyl, or C(.dbd.O)R.sup.4x, wherein each R.sup.4x and
R.sup.4y is independently hydrogen, C.sub.1-6alkyl, or
C.sub.1-6haloalkyl; R.sup.6 is NH.sub.2, halo, C.sub.1-6alkyl, or
C.sub.1-6haloalkyl; and R.sup.7 is NH.sub.2, halo, C.sub.1-6alkyl,
or C.sub.1-6haloalkyl, or a pharmaceutically acceptable salt,
isomer, or a mixture thereof.
30. The method of claim 21, wherein each R.sup.1 is independently
methyl, chloro, fluoro, cyano, tetrahydropyridinyl,
--CH.sub.2--C(.dbd.O)OH, --C.sub.2H.sub.4--C(.dbd.O)OH,
--C.sub.3H.sub.6--C(.dbd.O)OH, --CH.sub.2--C(.dbd.O)NH.sub.2,
--CH.sub.2--C(.dbd.O)N(CH.sub.3).sub.2,
--C.sub.2H.sub.4--C(.dbd.O)NH.sub.2,
--C.sub.2H.sub.4--C(.dbd.O)N(CH.sub.3).sub.2,
--C.sub.3H.sub.6--C(.dbd.O)NH.sub.2,
--C.sub.3H.sub.6--C(.dbd.O)N(CH.sub.3).sub.2,
--CH.sub.2--C(.dbd.O)--Het, C.sub.2H.sub.4--C(.dbd.O)--Het,
--C.sub.3H.sub.6--C(.dbd.O)--Het,
O--CH.sub.2--C(.dbd.O)OC.sub.3H.sub.7,
O--C.sub.2H.sub.4--C(.dbd.O)OC.sub.3H.sub.7,
O--C.sub.3H.sub.6--C(.dbd.O)OC.sub.3H.sub.7, --CH.sub.2--Het,
--C.sub.2H.sub.4-Het, --C.sub.3H.sub.6-Het, --CH.sub.2-cyclopropyl,
--C.sub.2H.sub.4-cyclopropyl, --C.sub.3H.sub.6-cyclopropyl,
--CH.sub.2-cyclobutyl, --C.sub.2H.sub.4-cyclobutyl,
--C.sub.3H.sub.6-cyclobutyl, --CH.sub.2-- cyclopentyl,
--C.sub.2H.sub.4-cyclopentyl, --C.sub.3H.sub.6-cyclopentyl,
--CH.sub.2-cyclohexyl, --C.sub.2H.sub.4-cyclohexyl,
--C.sub.3H.sub.6-cyclohexyl, O--CH.sub.2--NH.sub.2,
O--C.sub.2H.sub.4--NH.sub.2, O--C.sub.3H.sub.6--NH.sub.2,
O--CH.sub.2--N(CH.sub.3).sub.2,
O--C.sub.2H.sub.4--N(CH.sub.3).sub.2,
O--C.sub.3H.sub.6--N(CH.sub.3).sub.2, O--CH.sub.2--Het,
O--C.sub.2H.sub.4-Het, O--C.sub.3H.sub.6-Het,
O--CH.sub.2--C(.dbd.O)OH, O--C.sub.2H.sub.4--C(.dbd.O)OH,
O--C.sub.3H.sub.6--C(.dbd.O)OH, O--CH.sub.2--C(.dbd.O)OCH.sub.3,
O--C.sub.2H.sub.4--C(.dbd.O)OCH.sub.3,
O--C.sub.3H.sub.6--C(.dbd.O)OCH.sub.3, O--CH.sub.2--C(.dbd.O)--Het,
O--CH.sub.2C(CH.sub.3)(CH.sub.2OH).sub.2, S--C.sub.2H.sub.4OH,
S--C.sub.3H.sub.6OH, SO.sub.2-phenyl, SO.sub.2-methylphenyl,
--SO.sub.2-- ethylphenyl, --SO.sub.2-cyclopropyl,
--SO.sub.2-cyclobutyl, --SO.sub.2-cyclopentyl,
--SO.sub.2C.sub.2H.sub.4-Het, --SO.sub.2CH.sub.3,
--SO.sub.2C.sub.2H.sub.5, --SO.sub.2C.sub.3H.sub.7,
--SO.sub.2C.sub.2H.sub.4OH, or --SO.sub.2C.sub.3H.sub.6OH; wherein
Het is independently selected from piperidinyl, morpholinyl,
piperazinyl, azepanyl, imidazolyl, oxetanyl, azetidinyl,
pyrrolidinyl, tetrahydropyridinyl, 2-oxa-7-azaspiro[3.5]nonanyl,
2-oxa-6-azaspiro[3.4]octanyl, and 6-oxa-1-azaspiro[3.3]heptanyl,
wherein each of the piperidinyl, morpholinyl, piperazinyl,
azepanyl, imidazolyl, oxetanyl, azetidinyl, pyrrolidinyl,
tetrahydropyridinyl, 2-oxa-7-azaspiro[3.5]nonanyl,
2-oxa-6-azaspiro[3.4]octanyl, 6-oxa-1-azaspiro[3.3]heptanyl,
cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl moieties is
optionally substituted with one, two, three, or four members
independently selected from fluoro, chloro, methyl, ethyl, propyl,
oxo, and phenyl.
31. The method of claim 21, wherein each R.sup.2 is independently
fluoro, chloro, bromo, iodo, cyano, methyl, ethyl, propyl,
fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl,
difluoroethyl, trifluoroethyl, or SO.sub.2NH.sub.2.
32. The method of claim 21, wherein R.sup.3 is methyl, ethyl,
propyl, --CH.sub.2--C(.dbd.O)NH.sub.2,
--C.sub.2H.sub.4--C(.dbd.O)NH.sub.2,
--C.sub.3H.sub.6--C(.dbd.O)NH.sub.2,
--CH.sub.2--C(.dbd.O)N(CH.sub.3).sub.2,
--C.sub.2H.sub.4--C(.dbd.O)N(CH.sub.3).sub.2,
--C.sub.3H.sub.6--C(.dbd.O)N(CH.sub.3).sub.2, cyclopropyl,
cyclobutyl, or phenyl.
33. The method of claim 21, wherein R.sup.3 is
--CH.sub.2--C(.dbd.O)NH.sub.2, --C.sub.2H.sub.4--C(.dbd.O)NH.sub.2,
--C.sub.3H.sub.6--C(.dbd.O)NH.sub.2,
--CH.sub.2--C(.dbd.O)N(CH.sub.3).sub.2,
--C.sub.2H.sub.4--C(.dbd.O)N(CH.sub.3).sub.2,
--C.sub.3H.sub.6--C(.dbd.O)N(CH.sub.3).sub.2, cyclopropyl,
cyclobutyl, or phenyl.
34. The method of claim 21, wherein, R.sup.3 is methyl, ethyl, or
cyclopropyl.
35. The method of claim 21, wherein R.sup.4 is cyano, chloro,
bromo, iodo, or C(.dbd.O)CH.sub.3.
36. The method of claim 21, wherein R.sup.5 is hydrogen, methyl,
ethyl, or propyl.
37. The method of claim 21, wherein R.sup.6 and R.sup.7 are
independently NH.sub.2, chloro, fluoro, methyl, ethyl, or
propyl.
38. The method of claim 21, wherein R.sup.5 and R.sup.3 together
with the atoms to which they are attached optionally form a
heterocyclic ring, wherein the heterocyclic ring is selected from
azetidinyl, morpholinyl, and pyrrolidinyl, wherein each of the
azetidinyl, morpholinyl, and pyrrolidinyl moieties is optionally
substituted with 1, 2 or 3 groups which are independently C.sub.1-4
alkyl, methoxy, ethoxy, halo, N(CH.sub.3)C(.dbd.O)CH.sub.2NH.sub.2,
N(CH.sub.3)C(.dbd.O)CHF.sub.2,
N(CH.sub.3)C(.dbd.O)CH.sub.2CF.sub.3,
N(CH.sub.3)C(.dbd.O)cyclopropyl, NHC(.dbd.O)CH.sub.2NH.sub.2,
NHC(.dbd.O)CHF.sub.2, NHC(.dbd.O)CH.sub.2CF.sub.3,
NHC(.dbd.O)CH.sub.2cyclopropyl, or NHC(.dbd.O)cyclopropyl.
39. The method of claim 38, wherein each R.sup.1 is independently
chloro, fluoro, cyano, methyl, SO.sub.2-phenyl, --SO.sub.2CH.sub.3,
or --C.sub.3H.sub.6--C(.dbd.O)OH.
40. The method of claim 21, wherein: R.sup.3 is methyl; n is 1 or
2; and one R.sup.1 is tetrahydropyridinyl, CH.sub.2--C(.dbd.O)OH,
--C.sub.2H.sub.4--C(.dbd.O)OH, --C.sub.3H.sub.6--C(.dbd.O)OH,
--CH.sub.2--C(.dbd.O)NH.sub.2,
--CH.sub.2--C(.dbd.O)N(CH.sub.3).sub.2,
--C.sub.2H.sub.4--C(.dbd.O)NH.sub.2,
--C.sub.2H.sub.4--C(.dbd.O)N(CH.sub.3).sub.2,
--C.sub.3H.sub.6--C(.dbd.O)NH.sub.2,
--C.sub.3H.sub.6--C(.dbd.O)N(CH.sub.3).sub.2,
--CH.sub.2--C(.dbd.O)--Het, C.sub.2H.sub.4--C(.dbd.O)--Het,
--C.sub.3H.sub.6--C(.dbd.O)--Het,
O--CH.sub.2--C(.dbd.O)OC.sub.3H.sub.7,
O--C.sub.2H.sub.4--C(.dbd.O)OC.sub.3H.sub.7,
O--C.sub.3H.sub.6--C(.dbd.O)OC.sub.3H.sub.7, --CH.sub.2--Het,
--C.sub.2H.sub.4-Het, --C.sub.3H.sub.6-Het, --CH.sub.2-cyclopropyl,
--C.sub.2H.sub.4-cyclopropyl, --C.sub.3H.sub.6-cyclopropyl,
--CH.sub.2-cyclobutyl, --C.sub.2H.sub.4-cyclobutyl,
--C.sub.3H.sub.6-cyclobutyl, --CH.sub.2-cyclopentyl,
--C.sub.2H.sub.4-cyclopentyl, --C.sub.3H.sub.6-cyclopentyl,
--CH.sub.2-cyclohexyl, --C.sub.2H.sub.4-cyclohexyl,
--C.sub.3H.sub.6-cyclohexyl, O--CH.sub.2--NH.sub.2,
O--C.sub.2H.sub.4--NH.sub.2, O--C.sub.3H.sub.6--NH.sub.2,
O--CH.sub.2--N(CH.sub.3).sub.2,
O--C.sub.2H.sub.4--N(CH.sub.3).sub.2,
O--C.sub.3H.sub.6--N(CH.sub.3).sub.2, O--CH.sub.2--Het,
O--C.sub.2H.sub.4-Het, O--C.sub.3H.sub.6-Het,
O--CH.sub.2--C(.dbd.O)OH, O--C.sub.2H.sub.4--C(.dbd.O)OH,
O--C.sub.3H.sub.6--C(.dbd.O)OH, O--CH.sub.2--C(.dbd.O)OCH.sub.3,
O--C.sub.2H.sub.4--C(.dbd.O)OCH.sub.3,
O--C.sub.3H.sub.6--C(.dbd.O)OCH.sub.3, O--CH.sub.2--C(.dbd.O)-Het,
O--CH.sub.2C(CH.sub.3)(CH.sub.2OH).sub.2, S--C.sub.2H.sub.4OH,
S--C.sub.3H.sub.6OH, SO.sub.2-phenyl, SO.sub.2-methylphenyl,
--SO.sub.2-- ethylphenyl, --SO.sub.2-cyclopropyl,
--SO.sub.2-cyclobutyl, --SO.sub.2-cyclopentyl,
--SO.sub.2C.sub.2H.sub.4-Het, --SO.sub.2CH.sub.3,
--SO.sub.2C.sub.2H.sub.5, --SO.sub.2C.sub.3H.sub.7,
--SO.sub.2C.sub.2H.sub.4OH, or --SO.sub.2C.sub.3H.sub.6OH; wherein
Het is independently selected from piperidinyl, morpholinyl,
piperazinyl, azepanyl, imidazolyl, oxetanyl, azetidinyl,
pyrrolidinyl, tetrahydropyridinyl, 2-oxa-7-azaspiro[3.5]nonanyl,
2-oxa-6-azaspiro[3.4]octanyl, and 6-oxa-1-azaspiro[3.3]heptanyl,
wherein each of the piperidinyl, morpholinyl, piperazinyl,
azepanyl, imidazolyl, oxetanyl, azetidinyl, pyrrolidinyl,
tetrahydropyridinyl, 2-oxa-7-azaspiro[3.5]nonanyl,
2-oxa-6-azaspiro[3.4]octanyl, 6-oxa-1-azaspiro[3.3]heptanyl,
cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl moieties is
optionally substituted with one, two, three, or four members
independently selected from fluoro, chloro, methyl, ethyl, propyl,
oxo, or phenyl.
41. The method of claim 21, wherein: each R.sup.1 is independently
methyl, chloro, fluoro, or cyano; R.sup.3 is methyl or ethyl;
R.sup.4 is cyano or halo; R.sup.6 is NH.sub.2, halo, or C.sub.1-4
alkyl; and R.sup.7 is NH.sub.2, halo, or C.sub.1-4 alkyl; wherein
only one of R.sup.6 and R.sup.7 is NH.sub.2.
42. The method of claim 21, wherein the compound is an
(S)-enantiomer or a pharmaceutically acceptable salt thereof.
43. The method of claim 21, wherein the compound is an
(R)-enantiomer or a pharmaceutically acceptable salt thereof.
44. The method of claim 21, wherein the compound is selected from
the group consisting of:
(S)-2-(cyclopropyl((2,6-diamino-5-cyanopyrimidin-4-yl)amino)methyl)-4-oxo-
-3-phenyl-3,4-dihydroquinazoline-5-carbonitrile;
(S)-2-(cyclopropyl((2,6-diamino-5-cyanopyrimidin-4-yl)amino)methyl)-8-flu-
oro-4-oxo-3-phenyl-3,4-dihydroquinazoline-5-carbonitrile;
(S)-2,4-diamino-6-(((5-chloro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)(-
phenyl)methyl)amino)pyrimidine-5-carbonitrile;
(S)-2-(cyclopropyl((2,6-diamino-5-cyanopyrimidin-4-yl)amino)methyl)-3-(3--
(difluoromethyl)-5-fluorophenyl)-4-oxo-3,4-dihydroquinazoline-5-carbonitri-
le;
(S)-2,4-diamino-6-((cyclopropyl(3-(3-fluorophenyl)-5-(methylsulfonyl)--
4-oxo-3,4-dihydroquinazolin-2-yl)methyl)amino)pyrimidine-5-carbonitrile;
(S)-2,4-diamino-6-((cyclopropyl(3-(2-fluorophenyl)-5-(methylsulfonyl)-4-o-
xo-3,4-dihydroquinazolin-2-yl)methyl)amino)pyrimidine-5-carbonitrile;
(S)-2,4-diamino-6-((cyclopropyl(3-(2-fluorophenyl)-5-(methylsulfonyl)-4-o-
xo-3,4-dihydroquinazolin-2-yl)methyl)amino)pyrimidine-5-carbonitrile;
(S)-2,4-diamino-6-((cyclopropyl(3-(2,6-difluorophenyl)-5-(methylsulfonyl)-
-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)amino)pyrimidine-5-carbonitrile;
(S)-2-(cyclopropyl((2,6-diamino-5-cyanopyrimidin-4-yl)amino)methyl)-6-flu-
oro-3-(3-fluorophenyl)-4-oxo-3,4-dihydroquinazoline-8-carbonitrile;
(S)-2-(cyclopropyl((2,6-diamino-5-cyanopyrimidin-4-yl)amino)methyl)-6-flu-
oro-4-oxo-3-phenyl-3,4-dihydroquinazoline-8-carbonitrile;
(S)-3-(5-chloro-3-(3,5-difluorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)--
3-((2,6-diamino-5-cyanopyrimidin-4-yl)amino)-N,N-dimethylpropanamide
(S)-3-(5-chloro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)-3-((2,6-diamin-
o-5-cyanopyrimidin-4-yl)amino)-N,N-dimethylpropanamide;
(S)-2,4-diamino-6-(((3-(3-cyano-5-fluorophenyl)-5-methyl-4-oxo-3,4-dihydr-
oquinazolin-2-yl)(cyclopropyl)methyl)amino)pyrimidine-5-carbonitrile;
(S)-2,4-diamino-6-((cyclopropyl(3-(3,5-difluorophenyl)-5-methyl-4-oxo-3,4-
-dihydroquinazolin-2-yl)methyl)amino)pyrimidine-5-carbonitrile;
(S)-2,4-diamino-6-(((5-chloro-3-(3,5-difluorophenyl)-4-oxo-3,4-dihydroqui-
nazolin-2-yl)(cyclopropyl)methyl)amino)pyrimidine-5-carbonitrile;
(S)-2,4-diamino-6-((cyclopropyl(3-(3,5-difluorophenyl)-5-fluoro-4-oxo-3,4-
-dihydroquinazolin-2-yl)methyl)amino)pyrimidine-5-carbonitrile;
(S)-2,4-diamino-6-((cyclopropyl(5-fluoro-3-(3-fluorophenyl)-4-oxo-3,4-dih-
ydroquinazolin-2-yl)methyl)amino)pyrimidine-5-carbonitrile;
(S)-2,4-diamino-6-((cyclopropyl(6-fluoro-3-(3-fluorophenyl)-4-oxo-3,4-dih-
ydroquinazolin-2-yl)methyl)amino)pyrimidine-5-carbonitrile;
(S)-2-(1-((5-acetyl-2,6-diaminopyrimidin-4-yl)amino)ethyl)-5-chloro-3-(3,-
5-difluorophenyl)quinazolin-4(3H)-one,
2,4-diamino-6-((2S)-2-(5-chloro-3-(3,5-difluorophenyl)-4-oxo-3,4-dihydroq-
uinazolin-2-yl)-4-methoxypyrrolidin-1-yl)pyrimidine-5-carbonitrile;
(S)-2-(1-((6-amino-5-bromo-2-methylpyrimidin-4-yl)amino)ethyl)-5-chloro-3-
-phenylquinazolin-4(3H)-one;
(S)-2-(1-((6-amino-5-bromo-2-methylpyrimidin-4-yl)amino)ethyl)-5-chloro-3-
-(3,5-difluorophenyl)quinazolin-4(3H)-one;
(S)-2,4-diamino-6-((1-(5-(2-morpholinoethoxy)-4-oxo-3-phenyl-3,4-dihydroq-
uinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;
(S)-2,4-diamino-6-((1-(5-(2-(azepan-1-yl)ethoxy)-4-oxo-3-phenyl-3,4-dihyd-
roquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;
(S)-2,4-diamino-6-((1-(4-oxo-3-phenyl-5-(2-(pyrrolidin-1-yl)ethoxy)-3,4-d-
ihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;
(S)-isopropyl
2-((2-(1-((2,6-diamino-5-cyanopyrimidin-4-yl)amino)ethyl)-4-oxo-3-phenyl--
3,4-dihydroquinazolin-5-yl)oxy)acetate;
(S)-2,4-diamino-6-((1-(4-oxo-5-(2-(2-oxopyrrolidin-1-yl)ethoxy)-3-phenyl--
3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;
(S)-2,4-diamino-6-((1-(5-(2-(dimethylamino)ethoxy)-4-oxo-3-phenyl-3,4-dih-
ydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;
(S)-2,4-diamino-6-((1-(4-oxo-5-(2-oxo-2-(piperidin-1-yl)ethoxy)-3-phenyl--
3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;
(S)-2,4-diamino-6-((1-(5-(3-hydroxy-2-(hydroxymethyl)-2-methylpropoxy)-4--
oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitr-
ile;
(S)-2,4-diamino-6-((1-(4-oxo-3-phenyl-5-(2-(piperidin-1-yl)ethoxy)-3,-
4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;
(S)-2,4-diamino-6-((1-(4-oxo-3-phenyl-5-(2-(4-phenylpiperazin-1-yl)ethoxy-
)-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;
(S)-2,4-diamino-6-((1-(5-(2-(2-methyl-1H-imidazol-1-yl)ethoxy)-4-oxo-3-ph-
enyl-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;
2,4-diamino-6-(((1S)-1-(5-(2-(1-methylpyrrolidin-2-yl)ethoxy)-4-oxo-3-phe-
nyl-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;
(S)-2,4-diamino-6-((1-(5-((3-methyloxetan-3-yl)methoxy)-4-oxo-3-phenyl-3,-
4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;
(S)-2,4-diamino-6-((1-(5-(2-morpholino-2-oxoethoxy)-4-oxo-3-phenyl-3,4-di-
hydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;
(S)-2,4-diamino-6-((1-(5-(2-(4-methylpiperidin-1-yl)-2-oxoethoxy)-4-oxo-3-
-phenyl-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;
(S)-3-(2-(1-((2,6-diamino-5-cyanopyrimidin-4-yl)amino)ethyl)-4-oxo-3-phen-
yl-3,4-dihydroquinazolin-5-yl)propanamide;
(S)-3-(2-(1-((2,6-diamino-5-cyanopyrimidin-4-yl)amino)ethyl)-8-fluoro-4-o-
xo-3-phenyl-3,4-dihydroquinazolin-5-yl)propanamide;
(S)-3-(2-(1-((2,6-diamino-5-cyanopyrimidin-4-yl)amino)ethyl)-3-(3,5-diflu-
orophenyl)-8-fluoro-4-oxo-3,4-dihydroquinazolin-5-yl)propanamide;
(S)-3-(2-(1-((2,6-diamino-5-cyanopyrimidin-4-yl)amino)ethyl)-3-(3,5-diflu-
orophenyl)-4-oxo-3,4-dihydroquinazolin-5-yl)propanamide;
(S)-3-(2-(1-((2,6-diamino-5-chloropyrimidin-4-yl)amino)ethyl)-3-(3,5-difl-
uorophenyl)-8-fluoro-4-oxo-3,4-dihydroquinazolin-5-yl)propanamide;
(S)-3-(2-(1-((2,6-diamino-5-chloropyrimidin-4-yl)amino)ethyl)-3-(3,5-difl-
uorophenyl)-4-oxo-3,4-dihydroquinazolin-5-yl)propanamide;
(S)-3-(2-(1-((2,6-diamino-5-chloropyrimidin-4-yl)amino)ethyl)-4-oxo-3-phe-
nyl-3,4-dihydroquinazolin-5-yl)propanamide;
(S)-3-(2-(1-((2,6-diamino-5-chloropyrimidin-4-yl)amino)ethyl)-8-fluoro-4--
oxo-3-phenyl-3,4-dihydroquinazolin-5-yl)propanamide;
(S)-2,4-diamino-6-((1-(4-oxo-3-phenyl-5-(3-(pyrrolidin-1-yl)propyl)-3,4-d-
ihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;
(S)-2,4-diamino-6-((1-(4-oxo-3-phenyl-5-(3-(piperidin-1-yl)propyl)-3,4-di-
hydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;
(S)-2,4-diamino-6-((1-(5-(3-(3,3-difluoropyrrolidin-1-yl)propyl)-4-oxo-3--
phenyl-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;
(S)-2,4-diamino-6-((1-(5-(3-(4,4-difluoropiperidin-1-yl)propyl)-4-oxo-3-p-
henyl-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;
2,4-diamino-6-(((1S)-1-(5-(3-(3,5-dimethylmorpholino)propyl)-4-oxo-3-phen-
yl-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;
(S)-2,4-diamino-6-((1-(8-fluoro-4-oxo-3-phenyl-5-(3-(pyrrolidin-1-yl)prop-
yl)-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;
(S)-2,4-diamino-6-((1-(3-(3,5-difluorophenyl)-4-oxo-5-(3-(pyrrolidin-1-yl-
)propyl)-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;
(S)-2,4-diamino-6-((1-(5-(3-(2,2-dimethylmorpholino)propyl)-4-oxo-3-pheny-
l-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;
(S)-2,4-diamino-6-((1-(5-(3-(3,3-dimethylmorpholino)propyl)-4-oxo-3-pheny-
l-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;
(S)-2,4-diamino-6-((1-(4-oxo-3-phenyl-5-(3-(2,2,6,6-tetrafluoromorpholino-
)propyl)-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;
(S)-2,4-diamino-6-((1-(5-(3-(3,3-difluoropyrrolidin-1-yl)propyl)-8-fluoro-
-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbon-
itrile;
(S)-2,4-diamino-6-((cyclopropyl(4-oxo-3-phenyl-5-(3-(pyrrolidin-1--
yl)propyl)-3,4-dihydroquinazolin-2-yl)methyl)amino)pyrimidine-5-carbonitri-
le;
(S)-2,4-diamino-6-((cyclopropyl(4-oxo-3-phenyl-5-(3-(piperidin-1-yl)pr-
opyl)-3,4-dihydroquinazolin-2-yl)methyl)amino)pyrimidine-5-carbonitrile;
(S)-2,4-diamino-6-((cyclopropyl(8-fluoro-4-oxo-3-phenyl-5-(3-(pyrrolidinn-
-1-yl)propyl)-3,4-dihydroquinazolin-2-yl)methyl)amino)pyrimidine-5-carboni-
trile;
(S)-2,4-diamino-6-((cyclopropyl(8-fluoro-4-oxo-3-phenyl-5-(3-(piper-
idin-1-yl)propyl)-3,4-dihydroquinazolin-2-yl)methyl)amino)pyrimidine-5-car-
bonitrile;
(S)-2-amino-4-chloro-6-((cyclopropyl(4-oxo-3-phenyl-5-(3-(pyrro-
lidin-1-yl)propyl)-3,4-dihydroquinazolin-2-yl)methyl)amino)pyrimidine-5-ca-
rbonitrile;
(S)-2,4-diamino-6-((1-(5-(3-morpholinopropyl)-4-oxo-3-phenyl-3,4-dihydroq-
uinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;
(S)-4-((1-(5-(3-(2-oxa-6-azaspiro[3.3]heptan-6-yl)propyl)-4-oxo-3-phenyl--
3,4-dihydroquinazolin-2-yl)ethyl)amino)-2,6-diaminopyrimidine-5-carbonitri-
le;
(S)-4-((1-(5-(3-(2-oxa-6-azaspiro[3.4]octan-6-yl)propyl)-4-oxo-3-pheny-
l-3,4-dihydroquinazolin-2-yl)ethyl)amino)-2,6-diaminopyrimidine-5-carbonit-
rile;
(S)-4-((1-(5-(3-(2-oxa-7-azaspiro[3.5]nonan-7-yl)propyl)-4-oxo-3-phe-
nyl-3,4-dihydroquinazolin-2-yl)ethyl)amino)-2,6-diaminopyrimidine-5-carbon-
itrile;
(S)-2,4-diamino-6-((1-(5-(3-cyclohexylpropyl)-4-oxo-3-phenyl-3,4-d-
ihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;
(S)-2-amino-4-chloro-6-((1-(5-chloro-8-fluoro-4-oxo-3-phenyl-3,4-dihydroq-
uinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;
(S)-2,4-diamino-6-(2-(5-chloro-3-(3,5-difluorophenyl)-4-oxo-3,4-dihydroqu-
inazolin-2-yl)azetidin-1-yl)pyrimidine-5-carbonitrile;
(S)-2,4-diamino-6-(2-(5-chloro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)-
azetidin-1-yl)pyrimidine-5-carbonitrile;
(S)-4-(2-(1-((2,6-diamino-5-cyanopyrimidin-4-yl)amino)ethyl)-4-oxo-3-phen-
yl-3,4-dihydroquinazolin-5-yl)butanoic acid;
(S)-4-(2-(1-(2,6-diamino-5-cyanopyrimidin-4-yl)pyrrolidin-2-yl)-4-oxo-3-p-
henyl-3,4-dihydroquinazolin-5-yl)butanoic acid;
(S)-4-(2-(1-((2,6-diamino-5-cyanopyrimidin-4-yl)amino)ethyl)-3-(3,5-diflu-
orophenyl)-4-oxo-3,4-dihydroquinazolin-5-yl)butanoic acid;
(S)-2,4-diamino-6-(2-(3-(3-fluorophenyl)-5-(methylsulfonyl)-4-oxo-3,4-dih-
ydroquinazolin-2-yl)pyrrolidin-1-yl)pyrimidine-5-carbonitrile;
(S)-2,4-diamino-6-(2-(3-(2-fluorophenyl)-5-(methylsulfonyl)-4-oxo-3,4-dih-
ydroquinazolin-2-yl)pyrrolidin-1-yl)pyrimidine-5-carbonitrile;
(S)-2,4-diamino-6-(2-(3-(2-fluorophenyl)-5-(methylsulfonyl)-4-oxo-3,4-dih-
ydroquinazolin-2-yl)pyrrolidin-1-yl)pyrimidine-5-carbonitrile;
(S)-2,4-diamino-6-(2-(3-(2,6-difluorophenyl)-5-(methylsulfonyl)-4-oxo-3,4-
-dihydroquinazolin-2-yl)pyrrolidin-1-yl)pyrimidine-5-carbonitrile;
(S)-2,4-diamino-6-((1-(3-(3-fluorophenyl)-4-oxo-5-(phenylsulfonyl)-3,4-di-
hydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;
(S)-2,4-diamino-6-(2-(3-(3-fluorophenyl)-5-(methylsulfonyl)-4-oxo-3,4-dih-
ydroquinazolin-2-yl)pyrrolidin-1-yl)pyrimidine-5-carbonitrile;
(S)-2,4-diamino-6-((1-(3-(3-fluorophenyl)-5-((2-hydroxyethyl)sulfonyl)-4--
oxo-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;
(S)-2,4-diamino-6-((1-(3-(3-fluorophenyl)-5-((2-hydroxyethyl)thio)-4-oxo--
3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;
(S)-2,4-diamino-6-((1-(5-(cyclopentylsulfonyl)-3-(3-fluorophenyl)-4-oxo-3-
,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;
(S)-2,4-diamino-6-((1-(3-(3-fluorophenyl)-4-oxo-5-(o-tolylsulfonyl)-3,4-d-
ihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;
(S)-2,4-diamino-6-((1-(3-(3-fluorophenyl)-4-oxo-5-((2-(pyrrolidin-1-yl)et-
hyl)sulfonyl)-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonit-
rile;
(S)-2,4-diamino-6-(2-(5-chloro-3-(3,5-difluorophenyl)-4-oxo-3,4-dihy-
droquinazolin-2-yl)pyrrolidin-1-yl)pyrimidine-5-carbonitrile;
(S)-2,4-diamino-6-(2-(5-chloro-3-(3,5-difluorophenyl)-8-methyl-4-oxo-3,4--
dihydroquinazolin-2-yl)pyrrolidin-1-yl)pyrimidine-5-carbonitrile;
(S)-2,4-diamino-6-(2-(8-chloro-3-(3,5-difluorophenyl)-4-oxo-3,4-dihydroqu-
inazolin-2-yl)pyrrolidin-1-yl)pyrimidine-5-carbonitrile;
(S)-2,4-diamino-6-(2-(3-(3,5-difluorophenyl)-8-methyl-4-oxo-3,4-dihydroqu-
inazolin-2-yl)pyrrolidin-1-yl)pyrimidine-5-carbonitrile;
(S)-2,4-diamino-6-(2-(3-(3,5-difluorophenyl)-5-fluoro-4-oxo-3,4-dihydroqu-
inazolin-2-yl)pyrrolidin-1-yl)pyrimidine-5-carbonitrile;
(S)-2,4-diamino-6-(2-(5-chloro-3-(3-cyano-5-fluorophenyl)-4-oxo-3,4-dihyd-
roquinazolin-2-yl)pyrrolidin-1-yl)pyrimidine-5-carbonitrile;
(S)-2-(1-(2,6-diamino-5-cyanopyrimidin-4-yl)pyrrolidin-2-yl)-4-oxo-3-phen-
yl-3,4-dihydroquinazoline-8-carbonitrile;
(S)-2-(1-(2,6-diamino-5-cyanopyrimidin-4-yl)pyrrolidin-2-yl)-3-(3-(difluo-
romethyl)phenyl)-4-oxo-3,4-dihydroquinazoline-8-carbonitrile
(S)-3-(5,8-dichloro-2-(1-(2,6-diamino-5-cyanopyrimidin-4-yl)pyrrolidin-2--
yl)-4-oxoquinazolin-3 (4H)-yl)benzenesulfonamide;
(S)-3-(5,8-dichloro-2-(1-(2,6-diamino-5-cyanopyrimidin-4-yl)pyrrolidin-2--
yl)-4-oxoquinazolin-3 (4H)-yl)benzenesulfonamide;
(S)-2,4-diamino-6-((1-(4-oxo-3-phenyl-5-(1,2,3,6-tetrahydropyridin-4-yl)--
3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;
2,4-diamino-6-((2S,4R)-2-(5-chloro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-
-yl)-4-methylpyrrolidin-1-yl)pyrimidine-5-carbonitrile;
2,4-diamino-6-((2S,4R)-2-(5-chloro-3-(3,5-difluorophenyl)-4-oxo-3,4-dihyd-
roquinazolin-2-yl)-4-fluoropyrrolidin-1-yl)pyrimidine-5-carbonitrile;
(S)-2-amino-4-((1-(5-chloro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)eth-
yl)amino)-6-methylpyrimidine-5-carbonitrile;
(S)-2-(1-((2-amino-5-iodo-6-methylpyrimidin-4-yl)amino)ethyl)-5-chloro-3--
phenylquinazolin-4(3H)-one;
(S)-4-amino-6-((1-(5-chloro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)eth-
yl)amino)-2-methylpyrimidine-5-carbonitrile;
(S)-4-amino-6-((1-(5-chloro-3-(3,5-difluorophenyl)-4-oxo-3,4-dihydroquina-
zolin-2-yl)ethyl)amino)-2-methylpyrimidine-5-carbonitrile
(R)-5-chloro-2-(4-(2,6-diamino-5-chloropyrimidin-4-yl)morpholin-3-yl)-3-p-
henylquinazolin-4(3H)-one (0);
(S)-2-amino-4-chloro-6-((1-(5-chloro-4-oxo-3-phenyl-3,4-dihydroquinazolin-
-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;
(S)-2-amino-4-chloro-6-((1-(3-(3,5-difluorophenyl)-5-fluoro-4-oxo-3,4-dih-
ydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;
(S)-2-amino-4-chloro-6-((1-(5-chloro-3-(3,5-difluorophenyl)-4-oxo-3,4-dih-
ydroquinazolin-2-yl)propyl)amino)pyrimidine-5-carbonitrile;
(S)-4-amino-2-chloro-6-((1-(5-chloro-4-oxo-3-phenyl-3,4-dihydroquinazolin-
-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;
(S)-2-amino-4-chloro-6-((1-(5-chloro-3-(3,5-difluorophenyl)-4-oxo-3,4-dih-
ydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile;
(S)-4-amino-6-((1-(5-chloro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)eth-
yl)amino)-2-fluoropyrimidine-5-carbonitrile;
N-((3R,5S)-5-(5-chloro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)-1-(2,6--
diamino-5-cyanopyrimidin-4-yl)pyrrolidin-3-yl)-2,2-difluoroacetamide;
N-((3S,5S)-5-(5-chloro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)-1-(2,6--
diamino-5-cyanopyrimidin-4-yl)pyrrolidin-3-yl)-2,2,2-trifluoroacetamide;
N-((3R,5S)-5-(5-chloro-3-(3,5-difluorophenyl)-4-oxo-3,4-dihydroquinazolin-
-2-yl)-1-(2,6-diamino-5-cyanopyrimidin-4-yl)pyrrolidin-3-yl)-2,2-difluoroa-
cetamide;
N-((3R,5S)-5-(5-chloro-3-(3-(difluoromethyl)-5-fluorophenyl)-4-o-
xo-3,4-dihydroquinazolin-2-yl)-1-(2,6-diamino-5-cyanopyrimidin-4-yl)pyrrol-
idin-3-yl)-2,2-difluoroacetamide;
N-((3R,5S)-1-(2,6-diamino-5-cyanopyrimidin-4-yl)-5-(3-(3,5-difluorophenyl-
)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)pyrrolidin-3-yl)-2,2-difluoroa-
cetamide;
N-((3R,5S)-1-(2,6-diamino-5-cyanopyrimidin-4-yl)-5-(3-(3-(difluo-
romethyl)-5-fluorophenyl)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)pyrrol-
idin-3-yl)-2,2-difluoroacetamide;
N-((3R,5S)-5-(5-chloro-3-(3,5-difluorophenyl)-4-oxo-3,4-dihydroquinazolin-
-2-yl)-1-(2,6-diamino-5-cyanopyrimidin-4-yl)pyrrolidin-3-yl)-2,2-difluoro--
N-methylacetamide;
N-((3R,5S)-5-(5-chloro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)-1-(2,6--
diamino-5-cyanopyrimidin-4-yl)pyrrolidin-3-yl)-2-cyclopropylacetamide;
2-amino-N-((3R,5S)-5-(5-chloro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)-
-1-(2,6-diamino-5-cyanopyrimidin-4-yl)pyrrolidin-3-yl)acetamide;
and
2-amino-N-((3R,5S)-5-(5-chloro-3-(3,5-difluorophenyl)-4-oxo-3,4-dihydroqu-
inazolin-2-yl)-1-(2,6-diamino-5-cyanopyrimidin-4-yl)pyrrolidin-3-yl)acetam-
ide, or a pharmaceutically acceptable salt thereof.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is a Division of application of Ser. No.
14/747,931 filed Jun. 23, 2015. application Ser. No. 14/747,931
claims priority to and the benefit under 35 U.S.C. 119(e) of U.S.
Provisional Patent Application Ser. No. 62/016,194, filed Jun. 24,
2014, the disclosure of which is hereby incorporated by reference
in its entirety.
FIELD
[0002] The present disclosure relates generally to inhibitors of
phosphatidylinositol 3-kinase (PI3K) activity and, more
specifically, to novel compounds that are selective inhibitors of
PI3K isoforms.
BACKGROUND
[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 generally Rameh et al., J. Biol. Chem., 274:8347-8350
(1999). The enzyme responsible for generating these phosphorylated
signaling products is phosphatidylinositol 3-kinase (PI 3-kinase;
PI3K). PI3K originally was identified as an activity associated
with viral oncoproteins and growth factor receptor tyrosine kinases
that phosphorylate phosphatidylinositol (PI) and its phosphorylated
derivatives at the 3'-hydroxyl of the inositol ring. See Panayotou
et al., Trends Cell Biol 2:358-60 (1992).
[0004] Presently, three classes of the PI 3-kinase (PI3K) enzymes
are distinguished, based on their substrate specificities. Class I
PI3Ks can phosphorylate phosphatidylinositol (PI),
phosphatidylinositol-4-phosphate, and
phosphatidylinositol-4,5-biphosphate (PIP.sub.2) to produce
phosphatidylinositol-3-phosphate (PIP),
phosphatidylinositol-3,4-biphosphate, and
phosphatidylinositol-3,4,5-triphosphate, respectively. Class II
PI3Ks phosphorylate PI and phosphatidylinositol-4-phosphate,
whereas Class III PI3Ks can only phosphorylate PI.
[0005] The initial purification and molecular cloning of PI
3-kinase revealed that it was a heterodimer consisting of p85 and
p110 subunits. See 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, i.e.,
p85, whereas p110.gamma. interacts with a distinct p101 regulatory
subunit. As described below, the patterns of expression of each of
these PI3Ks in human cells and tissues also are distinct.
[0006] Identification of the p1106 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, suggesting that the protein might
play a role in PI 3-kinase-mediated signaling in the immune system.
Details concerning the p1106 isoform also can be found in U.S. Pat.
Nos. 5,858,753; 5,822,910; and 5,985,589, each of which is
incorporated herein by reference. See also Vanhaesebroeck et al.,
Proc. Natl. Acad. Sci. USA, 94:4330-5 (1997); and WO 97/46688.
[0007] A need remains, however, for additional therapeutic agents
useful to treat proliferative disorders or diseases that are
mediated by PI3K. The present invention provides novel compounds
that are inhibitors of PI3K isoforms.
SUMMARY
[0008] The present application provides novel compounds that are
inhibitors of PI3K isoforms. The application also provides
compositions, including pharmaceutical compositions, kits that
include the compounds, and methods of using and making the
compounds. The compounds provided herein are useful in treating
diseases, disorders, or conditions that are mediated by PI3K
isoforms. The application also provides compounds for use in
therapy. The application further provides compounds for use in a
method of treating a disease, disorder, or condition that is
mediated by PI3K isoforms. Moreover, the application provides uses
of the compounds in the manufacture of a medicament for the
treatment of a disease, disorder or condition that is mediated by
PI3K isoforms.
[0009] In one aspect, provided is a compound having the structure
of formula (J):
##STR00002##
[0010] wherein:
[0011] A is N or CH;
[0012] n is 0, 1, 2, 3, or 4;
[0013] m is 0, 1, 2, 3, or 4;
[0014] each R.sup.1 is independently selected from optionally
substituted alkyl, optionally substituted haloalkyl, optionally
substituted aryl, optionally substituted heteroaryl, halo, cyano,
NHC(.dbd.O)alkylene-N(R.sup.1x).sub.2, NO.sub.2, OR.sup.1x,
N(R.sup.1x).sub.2, OC(.dbd.O)R.sup.1x, C(.dbd.O)R.sup.1x,
C(.dbd.O)OR.sup.1x, aryl-OR, optionally substituted cycloalkyl,
optionally substituted heterocycloalkyl,
NR.sup.1xC(.dbd.O)alkylene-C(.dbd.O)OR.sup.1x,
aryl-O-alkylene-N(R.sup.1x).sub.2, aryl-O--C(.dbd.O)R.sup.1x,
alkylene-C(.dbd.O)OR.sup.1x, alkylene-C(.dbd.O)N(R.sup.1x).sub.2,
alkylene-C(.dbd.O)--Het, O-alkylene-C(.dbd.O)OR.sup.1x,
alkylene-O-alkylene-C(.dbd.O)OR.sup.1X
C(.dbd.O)NR.sup.1xSO.sub.2R.sup.1x, alkylene-N(R.sup.1x).sub.2,
alkenylene-N(R.sup.1x).sub.2, C(.dbd.O)NR.sup.1x-alkylene-OR.sup.1x
C(.dbd.O)NR.sup.1xalkylene-Het, O-alkylene-N(R.sup.1x).sub.2,
O-alkylene-CH(OR.sup.1y)CH.sub.2N(R.sup.1x).sub.2, O-alkylene-Het,
O-alkylene-C(.dbd.O)OR.sup.1x, O-alkylene-C(.dbd.O)--Het,
S-alkylene-OR.sup.1x, O-alkylene-OR.sup.1x,
O--C.sub.1-6alkylene-CH(OR.sup.1y)C.sub.1-6alkylene-OR.sup.1x,
O-alkylene-NR.sup.1xC(.dbd.O)OR.sup.1x,
NR.sup.1x-alkylene-N(R.sup.1x).sub.2, NR.sup.1xC(.dbd.O)R.sup.1x,
NR.sup.1xC(.dbd.O)N(R.sup.1x).sub.2, N(SO.sub.2-alkyl).sub.2,
NR.sup.1x(SO.sub.2-alkyl), SO.sub.2R.sup.1z,
SO.sub.2N(R.sup.1z).sub.2, alkylene-aryl, alkylene-Het,
alkylene-OR.sup.1y, alkylene-N(R.sup.1x).sub.2,
C(.dbd.O)N(R.sup.1x).sub.2, NHC(.dbd.O)alkylene-aryl,
aryl-O-alkylene-N(R.sup.1x).sub.2, aryl-OC(.dbd.O)R.sup.1y,
NHC(.dbd.O)alkylene-heterocycloalkyl, NHC(.dbd.O)alkylene-Het,
O-alkylene-O-alkylene-C(.dbd.O)OR.sup.1y, C(.dbd.O)alkylene-Het,
and NHC(.dbd.O)halo-alkyl, [0015] wherein Het is optionally
substituted heteroaryl or optionally substituted heterocycloalkyl,
wherein R.sup.1x is independently hydrogen, optionally substituted
alkyl, optionally substituted haloalkyl, optionally substituted
cycloalkyl, optionally substituted heterocycloalkyl, and optionally
substituted aryl, wherein R.sup.1y is independently hydrogen,
optionally substituted alkyl, optionally substituted haloalkyl,
optionally substituted aryl, and optionally substituted heteroaryl,
and wherein R.sup.1z is independently optionally substituted alkyl,
optionally substituted haloalkyl, optionally substituted
cycloalkyl, optionally substituted heterocycloalkyl, and optionally
substituted aryl;
[0016] each R.sup.2 is independently selected from halo, cyano,
optionally substituted alkyl, haloalkyl, SO.sub.2N(R.sup.2x).sub.2,
and optionally substituted alkoxy, [0017] wherein R.sup.2x is
hydrogen, optionally substituted alkyl, or optionally substituted
haloalkyl;
[0018] R.sup.3 is hydrogen, optionally substituted alkyl,
optionally substituted haloalkyl, optionally substituted
cycloalkyl, optionally substituted aryl, optionally substituted
heteroaryl, or optionally substituted heterocycloalkyl;
[0019] R.sup.5 is hydrogen or alkyl, or R.sup.5 and R.sup.3
together with the atoms to which they are attached optionally form
an optionally substituted four-, five- or six-membered heterocyclic
ring;
[0020] R.sup.4 is cyano, C(.dbd.O)NR.sup.4xR.sup.4y,
SO.sub.2-alkyl, halo, haloalkyl, or C(.dbd.O)R.sup.4x [0021]
wherein each R.sup.4x and R.sup.4y is independently hydrogen,
optionally substituted alkyl, and optionally substituted
haloalkyl;
[0022] R.sup.6 is NH.sub.2, halo, optionally substituted alkyl, or
optionally substituted haloalkyl; and
[0023] R.sup.7 is NH.sub.2, halo, optionally substituted alkyl, or
optionally substituted haloalkyl;
[0024] or a pharmaceutically acceptable salt, isomer, or a mixture
thereof.
[0025] A compound having the structure of formula (J):
##STR00003##
A is N or CH;
[0026] n is 0, 1, 2, 3, or 4;
[0027] m is 0, 1, 2, 3, or 4;
[0028] each R.sup.1 is independently selected from optionally
substituted alkyl, optionally substituted haloalkyl, optionally
substituted aryl, optionally substituted heteroaryl, halo, cyano,
NHC(.dbd.O)alkylene-N(R.sup.1x).sub.2, NO.sub.2, OR.sup.1x,
N(R.sup.1x).sub.2, OC(.dbd.O)R.sup.1x, C(.dbd.O)R.sup.1x,
C(.dbd.O)OR.sup.1x, aryl-OR.sup.1y, optionally substituted
cycloalkyl, optionally substituted heterocycloalkyl,
NR.sup.1xC(.dbd.O)alkylene-C(.dbd.O)OR.sup.1x,
aryl-O-alkylene-N(R.sup.1x).sub.2, aryl-O--C(.dbd.O)R.sup.1x,
alkylene-C(.dbd.O)OR.sup.1x, alkylene-C(.dbd.O)N(R.sup.1x).sub.2,
alkylene-C(.dbd.O)--Het, O-alkylene-C(.dbd.O)OR.sup.1x,
alkylene-O-alkylene-C(.dbd.O)OR.sup.1xC(.dbd.O)NR.sup.1xSO.sub.2R.sup.1x,
alkylene-N(R.sup.1x).sub.2, alkenylene-N(R.sup.1x).sub.2,
C(.dbd.O)NR.sup.1x-alkylene-OR.sup.1x,
C(.dbd.O)NR.sup.1xalkylene-Het, O-alkylene-N(R.sup.1x).sub.2,
O-alkylene-CH(OR.sup.1y)CH.sub.2N(R.sup.1x).sub.2, O-alkylene-Het,
O-alkylene-C(.dbd.O)OR.sup.1x, O-alkylene-C(.dbd.O)--Het,
S-alkylene-OR.sup.1x, O-alkylene-OR.sup.1x,
O--C.sub.1-6alkylene-CH(OR.sup.1x)C.sub.1-6alkylene-OR.sup.1x,
O-alkylene-NR.sup.1xC(.dbd.O)OR.sup.1X,
NR.sup.1x-alkylene-N(R.sup.1x).sub.2, NR.sup.1xC(.dbd.O)R.sup.1x,
NR.sup.1xC(.dbd.O)N(R.sup.1x).sub.2, N(SO.sub.2-alkyl).sub.2,
NR.sup.1x(SO.sub.2-alkyl), SO.sub.2R.sup.1z,
SO.sub.2N(R.sup.1x).sub.2, alkylene-aryl, alkylene-Het,
alkylene-OR.sup.1y, alkylene-N(R.sup.1x).sub.2,
C(.dbd.O)N(R.sup.1x).sub.2, NHC(.dbd.O)alkylene-aryl,
aryl-O-alkylene-N(R.sup.1x).sub.2, aryl-OC(.dbd.O)R.sup.1y,
NHC(.dbd.O)alkylene-heterocycloalkyl, NHC(.dbd.O)alkylene-Het,
O-alkylene-O-alkylene-C(.dbd.O)OR.sup.1y, C(.dbd.O)alkylene-Het,
and NHC(.dbd.O)halo-alkyl, [0029] wherein Het is optionally
substituted heteroaryl or optionally substituted heterocycloalkyl,
wherein R.sup.1x is independently hydrogen, optionally substituted
alkyl, optionally substituted haloalkyl, optionally substituted
cycloalkyl, optionally substituted heterocycloalkyl, and optionally
substituted aryl, [0030] wherein R.sup.1y is independently
hydrogen, optionally substituted alkyl, optionally substituted
haloalkyl, optionally substituted aryl, and optionally substituted
heteroaryl, and wherein R.sup.1z is independently optionally
substituted alkyl, optionally substituted haloalkyl, optionally
substituted cycloalkyl, optionally substituted heterocycloalkyl,
and optionally substituted aryl;
[0031] each R.sup.2 is independently selected from halo, cyano,
optionally substituted alkyl, haloalkyl, SO.sub.2N(R.sup.2x).sub.2,
and optionally substituted alkoxy, [0032] wherein R.sup.2x is
hydrogen, optionally substituted alkyl, or optionally substituted
haloalkyl;
[0033] R.sup.3 is hydrogen, optionally substituted alkyl,
optionally substituted haloalkyl, optionally substituted
cycloalkyl, optionally substituted aryl, optionally substituted
heteroaryl, or optionally substituted heterocycloalkyl;
[0034] R.sup.5 is hydrogen or alkyl, or R.sup.5 and R.sup.3
together with the atoms to which they are attached optionally form
an optionally substituted four-, five- or six-membered heterocyclic
ring; [0035] R.sup.4 is cyano, C(.dbd.O)NR.sup.4xR.sup.4y,
SO.sub.2-alkyl, halo, haloalkyl, or C(.dbd.O)R.sup.4x wherein each
R.sup.4x and R.sup.4y is independently hydrogen, optionally
substituted alkyl, and optionally substituted haloalkyl;
[0036] R.sup.6 is NH.sub.2, halo, optionally substituted alkyl, or
optionally substituted haloalkyl; and
[0037] R.sup.7 is NH.sub.2, halo, optionally substituted alkyl, or
optionally substituted haloalkyl;
[0038] provided that when R.sup.5 and R.sup.3 form a 5-membered
heterocyclic ring that is optionally substituted with hydroxyl,
halo, or methoxy, R.sup.4 is cyano, R.sup.6 is amino, and R.sup.7
is amino;
[0039] or a pharmaceutically acceptable salt, isomer, or a mixture
thereof.
[0040] In one aspect, provided is a compound having the structure
of formula (I):
##STR00004##
[0041] wherein:
[0042] n is 0, 1, 2, 3, or 4;
[0043] m is 0, 1, 2, or 3;
[0044] each R.sup.1 is independently alkyl, haloalkyl, aryl,
heteroaryl, cycloalkyl, heterocycloalkyl halo, cyano,
aryl-OR.sup.1y, alkenylene-OR.sup.1y, alkenylene-N(R.sup.1x).sub.2,
alkylene-C(.dbd.O)OR.sup.1x, alkylene-C(.dbd.O)N(R.sup.1x).sub.2,
alkylene-C(.dbd.O)--Het, alkylene-O-alkylene-C(.dbd.O)OR.sup.1x,
alkylene-N(R.sup.1x).sub.2, alkylene-aryl, alkylene-Het,
alkylene-OR.sup.1y, alkylene-N(R.sup.1x).sub.2,
O-alkylene-O-alkylene-C(.dbd.O)OR.sup.1yOR.sup.1x,
O-alkylene-C(.dbd.O)OR.sup.1x,
O-alkylene-CH(OR.sup.1y)CH.sub.2N(R.sup.1x).sub.2,
O-alkenylene-OR.sup.1y, O-alkenylene-N(R.sup.1x).sub.2,
O-alkylene-OR.sup.1x, O-alkylene-N(R.sup.1x).sub.2,
O-alkylene-CH(OR.sup.1y)alkylene-OR.sup.1x,
O-alkylene-NR.sup.1xC(.dbd.O)OR.sup.1x, O-alkylene-Het,
O-alkylene-C(.dbd.O)--Het, S-alkylene-OR.sup.1x, SO.sub.2R.sup.1z,
and SO.sub.2N(R.sup.1x).sub.2 [0045] wherein Het is optionally
substituted heteroaryl or optionally substituted heterocycloalkyl,
wherein R.sup.1x is independently hydrogen, optionally substituted
alkyl, optionally substituted haloalkyl, optionally substituted
cycloalkyl, optionally substituted heterocycloalkyl, and optionally
substituted aryl, wherein R.sup.1y is independently hydrogen,
optionally substituted alkyl, haloalkyl, optionally substituted
aryl, and optionally substituted heteroaryl, and wherein R.sup.1z
is independently optionally substituted alkyl, optionally
substituted haloalkyl, optionally substituted cycloalkyl,
optionally substituted heterocycloalkyl, and optionally substituted
aryl;
[0046] each R.sup.2 is independently halo, cyano, optionally
substituted alkyl, optionally substituted haloalkyl, and
SO.sub.2N(R.sup.2x).sub.2, wherein R.sup.2x is hydrogen, and
optionally substituted alkyl;
[0047] R.sup.3 is hydrogen, alkyl, haloalkyl, cycloalkyl, aryl,
heteroaryl, or heterocycloalkyl, wherein each of the cycloalkyl,
aryl, heteroaryl, and heterocycloalkyl moieties is optionally
substituted with halo or alkyl, wherein the alkyl moiety is
optionally substituted with --C(.dbd.O)NR.sup.3xR.sup.3y wherein
each R.sup.3x and R.sup.3y is independently hydrogen, alkyl, or
haloalkyl;
[0048] R.sup.5 is hydrogen or alkyl, or R.sup.5 and R.sup.3
together with the atoms to which they are attached optionally form
a four-, five- or six-membered heterocyclic ring, wherein the
heterocyclic ring is optionally substituted with halo, alkyl,
haloalkyl, or NR.sup.5xC(.dbd.O)R.sup.5y, [0049] wherein R.sup.5x
is hydrogen or alkyl, and wherein R.sup.5y is alkyl, haloalkyl,
cycloalkyl, cycloalkylalkyl, or alkyl-NH.sub.2;
[0050] R.sup.4 is cyano, C(.dbd.O)NR.sup.4xR.sup.4y,
SO.sub.2R.sup.4x, halo, haloalkyl, or C(.dbd.O)R.sup.4x [0051]
wherein each R.sup.4x and R.sup.4y is independently hydrogen,
alkyl, and haloalkyl;
[0052] R.sup.6 is NH.sub.2, halo, alkyl, or haloalkyl; and
[0053] R.sup.7 is NH.sub.2, halo, alkyl, or haloalkyl;
[0054] or a pharmaceutically acceptable salt, isomer, or a mixture
thereof.
[0055] In additional embodiments, the PI3K inhibitors are compounds
having the structure of formulae (J) or (I) wherein:
[0056] n is 1 or 2;
[0057] m is 0, 1, or 2;
[0058] each R.sup.1 is independently C.sub.1-6alkyl,
C.sub.1-6haloalkyl, C.sub.3-8cycloalkyl, C.sub.2-8heterocycloalkyl,
C.sub.3-8heteroaryl, C.sub.6-10aryl, halo, cyano,
C.sub.6-10aryl-OR.sup.1y, C.sub.1-6alkylene-C.sub.6-10aryl,
C.sub.1-6alkylene-Het, C.sub.1-6alkylene-C.sub.3-8cycloalkyl,
C.sub.1-6alkylene-OR.sup.1y, C.sub.1-6alkylene-N(R.sup.1x).sub.2,
C.sub.2-6alkenylene-OR.sup.1y,
C.sub.2-6alkenylene-N(R.sup.1x).sub.2,
C.sub.1-6alkylene-C(.dbd.O)OR.sup.1x,
C.sub.1-6alkylene-C(.dbd.O)N(R.sup.1x).sub.2,
C.sub.1-6alkylene-C(.dbd.O)-Het,
O--C.sub.1-6alkylene-C(.dbd.O)OR.sup.1x,
C.sub.1-6alkylene-O--C.sub.1-6alkylene-C(.dbd.O)OR.sup.1x,
C.sub.1-6alkenylene-N(R.sup.1x).sub.2, OR.sup.1x,
O--C.sub.1-6alkylene-N(R.sup.1x).sub.2,
O--C.sub.1-6alkylene-CH(OR.sup.1x)CH.sub.2N(R.sup.1x).sub.2,
O--C.sub.1-6alkylene-Het, O--C.sub.1-6alkylene-C(.dbd.O)OR.sup.1x,
O--C.sub.1-6alkylene-C(.dbd.O)--Het,
O--C.sub.1-6alkylene-OR.sup.1x,
O--C.sub.1-6alkylene-CH(OR.sup.1y)C.sub.1-6alkylene-OR.sup.1x,
O--C.sub.2-6alkenylene-OR.sup.1y,
O--C.sub.2-6alkenylene-N(R.sup.1x).sub.2,
O--C.sub.1-6alkylene-NR.sup.1xC(.dbd.O)OR.sup.1x,
O--C.sub.1-6alkylene-O--C.sub.1-6alkylene-C(.dbd.O)OR.sup.1y,
SO.sub.2R.sup.1x, S--C.sub.1-6alkylene-OR.sup.1z, and
SO.sub.2N(R.sup.1x).sub.2, [0059] wherein Het is
C.sub.3-8heteroaryl or C.sub.2-8heterocycloalkyl, wherein R.sup.1x
is independently hydrogen, C.sub.1-6alkyl, C.sub.1-6haloalkyl,
C.sub.3-8cycloalkyl, C.sub.6-10aryl, C.sub.2-8heterocycloalkyl, and
C.sub.3-8heteroaryl, wherein R.sup.1y is independently hydrogen,
C.sub.1-6alkyl, C.sub.1-6haloalkyl, C.sub.6-10aryl, and
C.sub.3-8heteroaryl, wherein R.sup.1z is independently
C.sub.1-6alkyl, C.sub.1-6haloalkyl, C.sub.3-8cycloalkyl,
C.sub.6-10aryl, C.sub.2-8heterocycloalkyl, and C.sub.3-8heteroaryl,
and wherein each of Het, R.sup.1x, R.sup.1y and R.sup.1z is
optionally substituted with one, two, three, or four members
independently selected from halo, oxo, C.sub.1-6alkyl, and
C.sub.6-10aryl;
[0060] each R.sup.2 is independently halo, cyano, C.sub.1-6alkyl,
C.sub.1-6haloalkyl, SO.sub.2N(R.sup.2x).sub.2, wherein R.sup.2x is
hydrogen, C.sub.1-6alkyl, or C.sub.1-6haloalkyl;
[0061] R.sup.3 is hydrogen, C.sub.1-6alkyl, C.sub.1-6haloalkyl,
C.sub.3-8cycloalkyl, C.sub.6-10aryl, wherein the C.sub.1-6alkyl
moiety is optionally substituted with --C(.dbd.O)NR.sup.3xR.sup.3y,
wherein each R.sup.3x and R.sup.3y is independently hydrogen,
C.sub.1-6alkyl, or C.sub.1-6haloalkyl;
[0062] R.sup.5 is hydrogen or C.sub.1-6alkyl, or R.sup.5 and
R.sup.3 together with the atoms to which they are attached
optionally form a four-, five- or six-membered heterocyclic ring,
wherein the heterocyclic ring is optionally substituted with one,
two, or three members independently selected from halo,
C.sub.1-6alkyl, C.sub.1-6haloalkyl, and NR.sup.5xC(O)R.sup.5y where
R.sup.5x is hydrogen or C.sub.1-6alkyl, and R.sup.5y is
C.sub.1-6alkylene-NH.sub.2, C.sub.1-6 alkylene-C.sub.3-8cycloalkyl,
or C.sub.1-6haloalkyl;
[0063] R.sup.4 is cyano, C(.dbd.O)NR.sup.4xR.sup.4y,
SO.sub.2--C.sub.1-6alkyl, halo, C.sub.1-6haloalkyl, or
C(.dbd.O)R.sup.4x, wherein each R.sup.4x and R.sup.4y is
independently hydrogen, C.sub.1-6alkyl, or C.sub.1-6haloalkyl;
[0064] R.sup.6 is NH.sub.2, halo, C.sub.1-6alkyl, or
C.sub.1-6haloalkyl; and
[0065] R.sup.7 is NH.sub.2, halo, C.sub.1-6alkyl, or
C.sub.1-6haloalkyl;
[0066] or a pharmaceutically acceptable salt, isomer, or a mixture
thereof.
[0067] In other embodiments, the PI3K inhibitors are compounds
having the structure of formulae (J) or (I) wherein:
[0068] n is 1 or 2;
[0069] m is 0, 1, or 2;
[0070] each R.sup.1 is independently C.sub.1-6alkyl,
C.sub.1-6haloalkyl, C.sub.6-10aryl, C.sub.3-8heteroaryl, C.sub.3-8
cycloalkyl, C.sub.2-8heterocycloalkyl, halo, cyano,
C.sub.1-6alkylene-C(.dbd.O)OH,
C.sub.1-6alkylene-C(.dbd.O)OC.sub.1-6alkyl,
C.sub.1-6alkylene-C(.dbd.O)--C.sub.3-8heterocycloalkyl,
C.sub.1-6alkylene-C(.dbd.O)--C.sub.3-8cycloalkyl,
C.sub.1-6alkylene-C(.dbd.O)NH.sub.2,
C.sub.1-6alkylene-C(.dbd.O)N(C.sub.1-6alkyl).sub.2,
C.sub.1-6alkylene-C(.dbd.O)NHC.sub.1-6alkyl,
C.sub.1-6alkylene-O--C.sub.1-6alkylene-C(.dbd.O)OH,
C.sub.1-6alkylene-O--C.sub.1-6alkylene-C(.dbd.O)OC.sub.1-6alkyl,
C.sub.1-6alkylene-C.sub.6-10aryl,
C.sub.1-6alkylene-C.sub.2-8heteroaryl,
C.sub.1-6alkylene-C.sub.2-8heterocycloalkyl,
C.sub.1-6alkylene-C.sub.3-8cycloalkyl, C.sub.1-6alkylene-OH,
C.sub.1-6 alkylene-OC.sub.1-6alkyl,
O--C.sub.1-6alkylene-N(C.sub.1-6alky).sub.2,
O--C.sub.1-6alkylene-NHC.sub.1-6alky,
O--C.sub.1-6alkylene-NH.sub.2,
O--C.sub.1-6alkylene-CH(OH)C.sub.1-6alkylNH.sub.2,
O--C.sub.1-6alkylene-CH(OH)C.sub.1-6alkylN(C.sub.1-6alkyl).sub.2,
O--C.sub.1-6alkylene-CH(OH)C.sub.1-6alkylNHC.sub.1-6alkyl,
O--C.sub.1-6alkylene-CH(OC.sub.1-6alkyl)C.sub.1-6alkylNH.sub.2,
O--C.sub.1-6alkylene-CH(OC.sub.1-6alkyl)C.sub.1-6alkylN(C.sub.1-6alkyl).s-
ub.2,
O--C.sub.1-6alkylene-CH(OC.sub.1-6alkyl)C.sub.1-6alkylNHC.sub.1-6alk-
yl, O--C.sub.1-6alkylene-C.sub.2-8heterocycloalkyl,
O--C.sub.1-6alkylene-C.sub.3-8heteroaryl,
O--C.sub.1-6alkylene-C(.dbd.O)OH,
O--C.sub.1-6alkylene-C(.dbd.O)OC.sub.1-6alkyl,
O--C.sub.1-6alkylene-C(.dbd.O)--C.sub.2-8heterocycloalkyl,
O--C.sub.1-6alkylene-C(.dbd.O)OC.sub.3-8cycloalkyl,
O--C.sub.1-6alkylene-C(.dbd.O)OC.sub.6-10aryl,
O--C.sub.1-6alkylene-OH, O--C.sub.1-6alkylene-OC.sub.3-8cycloalkyl,
O--C.sub.1-6alkylene-OC.sub.1-6alkyl,
O--C.sub.1-6alkylene-CH(OH)C.sub.1-6alkylene-OH,
O--C.sub.1-6alkylene-NHC(.dbd.O)OH,
O--C.sub.1-6alkylene-O--C.sub.1-6alkylene-C(.dbd.O)OH,
OSO.sub.2CF.sub.3, S--C.sub.1-6alkylene-OH,
SO.sub.2C.sub.1-6alkylene-C.sub.2-8heterocycloalkyl,
SO.sub.2C.sub.6-10aryl, SO.sub.2C.sub.3-8cycloalkyl,
SO.sub.2C.sub.1-6alkylene-OH, SO.sub.2N(C.sub.1-6alkyl).sub.2, or
SO.sub.2NH.sub.2; [0071] wherein each of the C.sub.6-10aryl,
C.sub.3-8cycloalkyl, C.sub.2-8heterocycloalkyl, and
C.sub.3-8heteroaryl moieties is optionally substituted with one,
two, three, or four members independently selected from fluoro,
chloro, oxo, methyl, ethyl, fluoromethyl, difluoromethyl,
trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, and
phenyl;
[0072] each R.sup.2 is independently halo, cyano, C.sub.1-6alkyl,
C.sub.1-6haloalkyl, and SO.sub.2NH.sub.2;
[0073] R.sup.3 is C.sub.1-6alkyl, C.sub.1-6haloalkyl,
C.sub.3-8cycloalkyl, C.sub.6-10aryl,
C.sub.1-6alkylene-C(.dbd.O)NHC.sub.1-6alkyl,
C.sub.1-6alkylene-C(.dbd.O)NH.sub.2, or
C.sub.1-6alkylene-C(.dbd.O)N(C.sub.1-6alkyl).sub.2;
[0074] R.sup.5 is hydrogen or C.sub.1-6alkyl, or R.sup.5 and
R.sup.3 together with the atoms to which they are attached
optionally form a four-, five- or six-membered heterocyclic ring,
wherein the heterocyclic ring is optionally substituted with one or
two members independently selected from halo, C.sub.1-6alkyl,
NHC(.dbd.O)C.sub.1-6alkylene-NH.sub.2, NHC(.dbd.O)C.sub.1-6
alkylene-C.sub.3-8cycloalkyl, NHC(.dbd.O)C.sub.1-6haloalkyl,
NC.sub.1-6alkylC(.dbd.O)C.sub.1-6alkylene-NH.sub.2,
NC.sub.1-6alkylC(.dbd.O)C.sub.1-6 alkylene-C.sub.3-8cycloalkyl, and
NC.sub.1-6alkylC(.dbd.O)C.sub.1-6haloalkyl;
[0075] R.sup.4 is cyano, halo, C.sub.1-6haloalkyl, C(.dbd.O)H, or
C(.dbd.O)C.sub.1-6alkyl;
[0076] R.sup.6 is NH.sub.2, halo, or C.sub.1-6alkyl; and
[0077] R.sup.7 is NH.sub.2, halo, or C.sub.1-6alkyl;
[0078] or a pharmaceutically acceptable salt, isomer, or a mixture
thereof.
[0079] In some embodiments of formulae (J) or (I), each R.sup.1 is
independently methyl, chloro, fluoro, cyano, tetrahydropyridinyl,
--CH.sub.2--C(.dbd.O)OH, --C.sub.2H.sub.4--C(.dbd.O)OH,
--C.sub.3H.sub.6--C(.dbd.O)OH, --CH.sub.2--C(.dbd.O)NH.sub.2,
--CH.sub.2--C(.dbd.O)N(CH.sub.3).sub.2,
--C.sub.2H.sub.4--C(.dbd.O)NH.sub.2,
--C.sub.2H.sub.4--C(.dbd.O)N(CH.sub.3).sub.2,
--C.sub.3H.sub.6--C(.dbd.O)NH.sub.2,
--C.sub.3H.sub.6--C(.dbd.O)N(CH.sub.3).sub.2,
--CH.sub.2--C(.dbd.O)--Het, C.sub.2H.sub.4--C(.dbd.O)--Het,
--C.sub.3H.sub.6--C(.dbd.O)--Het,
O--CH.sub.2--C(.dbd.O)OC.sub.3H.sub.7,
O--C.sub.2H.sub.4--C(.dbd.O)OC.sub.3H.sub.7,
O--C.sub.3H.sub.6--C(.dbd.O)OC.sub.3H.sub.7, --CH.sub.2--Het,
--C.sub.2H.sub.4-Het, --C.sub.3H.sub.6-Het, --CH.sub.2-cyclopropyl,
--C.sub.2H.sub.4-cyclopropyl, --C.sub.3H.sub.6-cyclopropyl,
--CH.sub.2-cyclobutyl, --C.sub.2H.sub.4-cyclobutyl,
--C.sub.3H.sub.6-cyclobutyl, --CH.sub.2-cyclopentyl,
--C.sub.2H.sub.4-cyclopentyl, --C.sub.3H.sub.6-cyclopentyl,
--CH.sub.2-cyclohexyl, --C.sub.2H.sub.4-cyclohexyl,
--C.sub.3H.sub.6-cyclohexyl, O--CH.sub.2--NH.sub.2,
O--C.sub.2H.sub.4--NH.sub.2, O--C.sub.3H.sub.6--NH.sub.2,
O--CH.sub.2--N(CH.sub.3).sub.2,
O--C.sub.2H.sub.4--N(CH.sub.3).sub.2,
O--C.sub.3H.sub.6--N(CH.sub.3).sub.2, O--CH.sub.2--Het,
O--C.sub.2H.sub.4-Het, O--C.sub.3H.sub.6-Het,
O--CH.sub.2--C(.dbd.O)OH, O--C.sub.2H.sub.4--C(.dbd.O)OH,
O--C.sub.3H.sub.6--C(.dbd.O)OH, O--CH.sub.2--C(.dbd.O)OCH.sub.3,
O--C.sub.2H.sub.4--C(.dbd.O)OCH.sub.3,
O--C.sub.3H.sub.6--C(.dbd.O)OCH.sub.3, O--CH.sub.2--C(.dbd.O)--Het,
O--CH.sub.2C(CH.sub.3)(CH.sub.2OH).sub.2, S--C.sub.2H.sub.4OH,
S--C.sub.3H.sub.6OH, SO.sub.2-phenyl, SO.sub.2-methylphenyl,
--SO.sub.2-ethylphenyl, --SO.sub.2-cyclopropyl,
--SO.sub.2-cyclobutyl, --SO.sub.2-cyclopentyl, --SO.sub.2CH.sub.3,
--SO.sub.2C.sub.2H.sub.5, --SO.sub.2C.sub.3H.sub.7,
--SO.sub.2C.sub.2H.sub.4OH, or --SO.sub.2C.sub.3H.sub.6OH; wherein
Het is independently selected from piperidinyl, morpholinyl,
piperazinyl, azepanyl, imidazolyl, oxetanyl, azetidinyl,
pyrrolidinyl, tetrahydropyridinyl, 2-oxa-7-azaspiro[3.5]nonanyl,
2-oxa-6-azaspiro[3.4]octanyl, and 6-oxa-1-azaspiro[3.3]heptanyl,
wherein each of the piperidinyl, morpholinyl, piperazinyl,
azepanyl, imidazolyl, oxetanyl, azetidinyl, pyrrolidinyl,
tetrahydropyridinyl, 2-oxa-7-azaspiro[3.5]nonanyl,
2-oxa-6-azaspiro[3.4]octanyl, 6-oxa-1-azaspiro[3.3]heptanyl,
cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl moieties is
optionally substituted with one, two, three, or four members
independently selected from fluoro, chloro, methyl, ethyl, propyl,
oxo, or phenyl. In some other embodiments of formulae (0.1) or (1),
each R.sup.2 is independently fluoro, chloro, bromo, iodo, cyano,
methyl, ethyl, propyl, fluoromethyl, difluoromethyl,
trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, and
SO.sub.2NH.sub.2. In certain other embodiments of formulae (J) or
(I). R.sup.3 is methyl, ethyl, propyl,
--CH.sub.2--C(.dbd.O)NH.sub.2, --C.sub.2H.sub.4--C(.dbd.O)NH.sub.2,
--C.sub.3H.sub.6--C(.dbd.O)NH.sub.2,
--CH.sub.2--C(.dbd.O)N(CH.sub.3).sub.2,
--C.sub.2H.sub.4--C(.dbd.O)N(CH.sub.3).sub.2,
--C.sub.3H.sub.6--C(.dbd.O)N(CH.sub.3).sub.2, cyclopropyl,
cyclobutyl, or phenyl. In additional embodiments of formulae (J) or
(I), R.sup.5 is hydrogen, methyl, ethyl, or propyl. In other
additional embodiments, R.sup.5 and R.sup.3 together with the atoms
to which they are attached optionally form a heterocyclic ring,
wherein the heterocyclic ring is selected from azetidinyl,
morpholinyl, or pyrrolidinyl, wherein each of the azetidinyl,
morpholinyl, and pyrrolidinyl moieties is optionally substituted
with N(CH.sub.3)C(.dbd.O)CH.sub.2NH.sub.2,
N(CH.sub.3)C(.dbd.O)CHF.sub.2,
N(CH.sub.3)C(.dbd.O)CH.sub.2CF.sub.3,
N(CH.sub.3)C(.dbd.O)cyclopropyl, NHC(.dbd.O)CH.sub.2NH.sub.2,
NHC(.dbd.O)CHF.sub.2, NHC(.dbd.O)CH.sub.2CF.sub.3, or
NHC(.dbd.O)cyclopropyl. In another embodiments of formulae (J) or
(I), R.sup.4 is cyano, chloro, bromo, iodo, or C(.dbd.O)CH.sub.3.
In certain embodiments, R.sup.6 is NH.sub.2, chloro, fluoro,
methyl, ethyl, or propyl. In certain embodiments, R.sup.7 is
NH.sub.2, fluoro, chloro, methyl, ethyl, or propyl. In yet another
embodiments of formulae (J) or (I), R.sup.6 is NH.sub.2, chloro,
fluoro, methyl, ethyl, or propyl; and R.sup.7 is NH.sub.2, fluoro,
chloro, methyl, ethyl, or propyl.
[0080] Provided are also compounds selected from Table 1, or a
pharmaceutically acceptable salt, isomer, or a mixture thereof. In
one embodiment, the compound is an (S)-enantiomer. In another
embodiment, the compound is an (R)-enantiomer. In some additional
embodiment, the compound is an atropisomer.
[0081] Provided are also compounds selected from compounds 1-116,
or a pharmaceutically acceptable salt, isomer, or a mixture
thereof. In one embodiment, the compound is an (S)-enantiomer. In
another embodiment, the compound is an (R)-enantiomer. In some
additional embodiment, the compound is an atropisomer.
[0082] Also provided is a pharmaceutical composition that includes
a compound of the present application, or a pharmaceutically
acceptable salt, isomer, or a mixture thereof, together with at
least one pharmaceutically acceptable vehicle. Examples of
pharmaceutically acceptable vehicle may be selected from carriers,
adjuvants, and excipients.
[0083] Also provided is a method of treating a subject, who has or
is suspected of having a disease or condition responsive or
believed to be responsive to the inhibition of PI3K.delta. activity
by administering to the subject a compound described herein or a
pharmaceutically acceptable salt, isomer, or a mixture thereof. In
some embodiments, the subject is a human. In additional
embodiments, the disease or condition is leukemia, lymphoma,
cancer, or inflammation.
[0084] Also provided is a method of inhibiting kinase activity of a
phosphatidylinositol 3-kinase delta polypeptide by contacting the
polypeptide with a compound described herein or a pharmaceutically
acceptable salt, isomer, or a mixture thereof. Further provided is
a method of inhibiting excessive or destructive immune reactions,
such as asthma, rheumatoid arthritis, multiple sclerosis, and
lupus.
[0085] Also provided is a method of disrupting leukocyte function,
comprising contacting the leukocytes with an effective amount of a
compound of formula described herein or a pharmaceutically
acceptable salt, isomer, or a mixture thereof.
[0086] Also provided is a method of inhibiting a growth or a
proliferation of cancer cells, comprising contacting the cancer
cells with an effective amount of a compound described herein or a
pharmaceutically acceptable salt, isomer, or a mixture thereof. In
some embodiments, the cancers cells are of hematopoietic
origin.
[0087] Also provided is a kit that includes a compound described
herein or a pharmaceutically acceptable salt, isomer, or a mixture
thereof; and a label and/or instructions for use of the compound in
the treatment of a disease or condition mediated by PI3K.delta.
activity.
[0088] Also provided are articles of manufacture that include a
compound described herein or a pharmaceutically acceptable salt,
isomer, or a mixture thereof; and a container. In one embodiment,
the container may be a vial, jar, ampoule, preloaded syringe, or an
intravenous bag.
DETAILED DESCRIPTION
[0089] The following description sets forth exemplary methods,
parameters and the like. It should be recognized, however, that
such description is not intended as a limitation on the scope of
the present disclosure but is instead provided as a description of
exemplary embodiments.
[0090] As used in the present specification, the following words,
phrases and symbols are generally intended to have the meanings as
set forth below, except to the extent that the context in which
they are used indicates otherwise.
[0091] A dash ("-") that is not between two letters or symbols is
used to indicate a point of attachment for a substituent. For
example, --CONH.sub.2 is attached through the carbon atom. A dash
at the front or end of a chemical group is a matter of convenience;
chemical groups may be depicted with or without one or more dashes
without losing their ordinary meaning. A wavy line drawn through a
line in a structure indicates a point of attachment of a group.
Unless chemically or structurally required, no directionality is
indicated or implied by the order in which a chemical group is
written or named.
[0092] The prefix "C.sub.u-v" indicates that the following group
has from u to v carbon atoms. For example, "C.sub.1-6 alkyl"
indicates that the alkyl group has from 1 to 6 carbon atoms.
[0093] Reference to "about" a value or parameter herein includes
(and describes) embodiments that are directed to that value or
parameter per se. In certain embodiments, the term "about" includes
the indicated amount .+-.10%. In other embodiments, the term
"about" includes the indicated amount .+-.5%. In certain other
embodiments, the term "about" includes the indicated amount .+-.1%.
Also, to the term "about X" includes description of "X". Also, the
singular forms "a" and "the" include plural references unless the
context clearly dictates otherwise. Thus, e.g., reference to "the
compound" includes a plurality of such compounds and reference to
"the assay" includes reference to one or more assays and
equivalents thereof known to those skilled in the art.
[0094] "Alkyl" refers to an unbranched or branched saturated
hydrocarbon chain. As used herein, alkyl has 1 to 20 carbon atoms
(i.e., C.sub.1-20 alkyl), 1 to 8 carbon atoms (i.e., C.sub.1-s
alkyl), 1 to 6 carbon atoms (i.e., C.sub.1-6 alkyl), or 1 to 4
carbon atoms (i.e., C.sub.1-4 alkyl). Examples of alkyl groups
include methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl,
iso-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl,
hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl. When an alkyl residue
having a specific number of carbons is named by chemical name or
identified by molecular formula, all geometric isomers having that
number of carbons may be encompassed; thus, for example, "butyl"
includes n-butyl (i.e. --(CH.sub.2).sub.3CH.sub.3), sec-butyl (i.e.
--CH(CH.sub.3)CH.sub.2CH.sub.3), isobutyl (i.e.
--CH.sub.2CH(CH.sub.3).sub.2) and tert-butyl (i.e.
--C(CH.sub.3).sub.3); and "propyl" includes n-propyl (i.e.
--(CH.sub.2).sub.2CH.sub.3) and isopropyl (i.e.
--CH(CH.sub.3).sub.2).
[0095] "Alkenyl" refers to an aliphatic group containing at least
one carbon-carbon double bond and having from 2 to 20 carbon atoms
(i.e., C.sub.2-20 alkenyl), 2 to 8 carbon atoms (i.e., C.sub.2-8
alkenyl), 2 to 6 carbon atoms (i.e., C.sub.2-6 alkenyl), or 2 to 4
carbon atoms (i.e., C.sub.2-4 alkenyl). Examples of alkenyl groups
include ethenyl, propenyl, butadienyl (including 1,2-butadienyl and
1,3-butadienyl).
[0096] "Alkynyl" refers to an aliphatic group containing at least
one carbon-carbon triple bond and having from 2 to 20 carbon atoms
(i.e., C.sub.2-20 alkynyl), 2 to 8 carbon atoms (i.e., C.sub.2-8
alkynyl), 2 to 6 carbon atoms (i.e., C.sub.2-6 alkynyl), or 2 to 4
carbon atoms (i.e., (C.sub.2-4 alkynyl). The term "alkynyl" also
includes those groups having one triple bond and one double
bond.
[0097] "Alkoxy" refers to the group "alkyl-O--". Examples of alkoxy
groups include methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy,
tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and
1,2-dimethylbutoxy.
[0098] "Acyl" refers to a group --C(.dbd.O)R, wherein R is
hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroalkyl,
or heteroaryl; each of which may be optionally substituted, as
defined herein. Examples of acyl include formyl, acetyl,
cylcohexylcarbonyl, cyclohexylmethyl-carbonyl, and benzoyl.
[0099] "Amido" refers to both a "C-amido" group which refers to the
group --C(.dbd.O)NR.sup.yR.sup.z and an "N-amido" group which
refers to the group --NR.sup.yC(.dbd.O)R.sup.z, wherein R.sup.y and
R.sup.z are independently selected from the group consisting of
hydrogen, alkyl, aryl, haloalkyl, or heteroaryl; each of which may
be optionally substituted.
[0100] "Amino" refers to the group --NR.sup.yR.sup.z wherein
R.sup.y and R.sup.z are independently selected from the group
consisting of hydrogen, alkyl, haloalkyl, aryl, or heteroaryl; each
of which may be optionally substituted.
[0101] "Aryl" refers to an aromatic carbocyclic group having a
single ring (e.g. monocyclic) or multiple rings (e.g. bicyclic or
tricyclic) including fused systems. As used herein, aryl has 6 to
20 ring carbon atoms (i.e., C.sub.6-20 aryl), 6 to 12 carbon ring
atoms (i.e., C.sub.6-12aryl), or 6 to 10 carbon ring atoms (i.e.,
C.sub.6-10 aryl). Examples of aryl groups include phenyl, naphthyl,
fluorenyl, and anthryl. Aryl, however, does not encompass or
overlap in any way with heteroaryl defined below. If one or more
aryl groups are fused with a heteroaryl ring, the resulting ring
system is heteroaryl.
[0102] "Carboxyl" or "carboxy" refers to --COOH or salts
thereof.
[0103] "Carboxyl ester" or "carboxy ester" refers to the group
--C(O)OR, wherein R is hydrogen, alkyl, aryl, arylalkyl,
heteroalkyl, or heteroaryl, each of which may be optionally
substituted. In certain embodiments R is alkyl, aryl, arylalkyl,
heteroalkyl, or heteroaryl, each of which may be optionally
substituted.
[0104] "Cyano" or "carbonitrile" refers to the group --CN.
[0105] "Cycloalkyl" refers to a saturated or partially saturated
cyclic alkyl group having a single ring or multiple rings including
fused, bridged, and spiro ring systems. The term "cycloalkyl"
includes cycloalkenyl groups (i.e. the cyclic group having at least
one double bond). As used herein, cycloalkyl has from 3 to 20 ring
carbon atoms (i.e., C.sub.3-20 cycloalkyl), 3 to 12 ring carbon
atoms (i.e., C.sub.3-12cycloalkyl), 3 to 10 ring carbon atoms
(i.e., C.sub.3-10 cycloalkyl), 3 to 8 ring carbon atoms (i.e.,
C.sub.3-8 cycloalkyl), or 3 to 6 ring carbon atoms (i.e., C.sub.3-6
cycloalkyl). Examples of cycloalkyl groups include cyclopropyl,
cyclobutyl, cyclopentyl, and cyclohexyl.
[0106] "Halogen" or "halo" includes fluoro, chloro, bromo, and
iodo. "Haloalkyl" refers to an unbranched or branched alkyl group
as defined above, wherein one or more hydrogen atoms are replaced
by a halogen. For example, where a residue is substituted with more
than one halogen, it may be referred to by using a prefix
corresponding to the number of halogen moieties attached.
Dihaloalkyl and trihaloalkyl refer to alkyl substituted with two
("di") or three ("tri") halo groups, which may be, but are not
necessarily, the same halogen. Examples of haloalkyl include
difluoromethyl (--CHF.sub.2) and trifluoromethyl (--CF.sub.3).
[0107] "Heteroalkyl" refers to an alkyl group in which one or more
of the carbon atoms (and any associated hydrogen atoms) are each
independently replaced with the same or different heteroatomic
group. The term "heteroalkyl" includes unbranched or branched
saturated chain having carbon and heteroatoms. By way of example,
1, 2 or 3 carbon atoms may be independently replaced with the same
or different heteroatomic group. Heteroatomic groups include, but
are not limited to, --NR--, --O--, --S--, --S(O)--, --S(O).sub.2--,
and the like, where R is H, alkyl, aryl, cycloalkyl, heteroalkyl,
heteroaryl or heterocycloalkyl, each of which may be optionally
substituted. Examples of heteroalkyl groups include --OCH.sub.3,
--CH.sub.2OCH.sub.3, --SCH.sub.3, --CH.sub.2SCH.sub.3,
--NRCH.sub.3, and --CH.sub.2NRCH.sub.3, where R is hydrogen, alkyl,
aryl, arylalkyl, heteroalkyl, or heteroaryl, each of which may be
optionally substituted. As used herein, heteroalkyl include 1 to 10
carbon atoms, 1 to 8 carbon atoms, or 1 to 4 carbon atoms; and 1 to
3 heteroatoms, 1 to 2 heteroatoms, or 1 heteroatom.
[0108] "Heteroaryl" refers to an aromatic group having a single
ring, multiple rings, or multiple fused rings, with one or more
ring heteroatoms independently selected from nitrogen, oxygen, and
sulfur. As used herein, heteroaryl include 1 to 20 ring carbon
atoms (i.e., C.sub.1-20 heteroaryl), 3 to 12 ring carbon atoms
(i.e., C.sub.3-12 heteroaryl), or 3 to 8 carbon ring atoms (i.e.,
C.sub.3-8 heteroaryl); and 1 to 5 heteroatoms, 1 to 4 heteroatoms,
1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring
heteroatom independently selected from nitrogen, oxygen, and
sulfur. Examples of heteroaryl groups include pyrimidinyl, purinyl,
pyridyl, pyridazinyl, benzothiazolyl, and pyrazolyl. Heteroaryl
does not encompass or overlap with aryl as defined above.
[0109] "Heterocycloalkyl" refers to a saturated or unsaturated
cyclic alkyl group, with one or more ring heteroatoms independently
selected from nitrogen, oxygen and sulfur. The term
"heterocycloalkyl" includes heterocycloalkenyl groups (i.e. the
heterocycloalkyl group having at least one double bond). A
heterocycloalkyl may be a single ring or multiple rings wherein the
multiple rings may be fused, bridged, or spiro. As used herein,
heterocycloalkyl has 2 to 20 ring carbon atoms (i.e., C.sub.2-20
heterocycloalkyl), 2 to 12 ring carbon atoms (i.e., C.sub.2-12
heterocycloalkyl), 2 to 10 ring carbon atoms (i.e., C.sub.2-10
heterocycloalkyl), 2 to 8 ring carbon atoms (i.e., C.sub.2-8
heterocycloalkyl), 3 to 12 ring carbon atoms (i.e., C.sub.3-12
heterocycloalkyl), 3 to 8 ring carbon atoms (i.e., C.sub.3-8
heterocycloalkyl), or 3 to 6 ring carbon atoms (i.e., C.sub.3-6
heterocycloalkyl); having 1 to 5 ring heteroatoms, 1 to 4 ring
heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1
ring heteroatom independently selected from nitrogen, sulfur or
oxygen. Examples of heterocycloalkyl groups include pyrrolidinyl,
piperidinyl, piperazinyl, oxetanyl, dioxolanyl, azetidinyl, and
morpholinyl. As used herein, the term "bridged-heterocycloalkyl"
refers to a four- to ten-membered cyclic moiety connected at two
non-adjacent atoms of the heterocycloalkyl with one or more (e.g. 1
or 2) four- to ten-membered cyclic moiety having at least one
heteroatom where each heteroatom is independently selected from
nitrogen, oxygen, and sulfur. As used herein,
bridged-heterocycloalkyl includes bicyclic and tricyclic ring
systems. Also used herein, the term "spiro-heterocycloalkyl" refers
to a ring system in which a three- to ten-membered heterocycloalkyl
has one or more additional ring, wherein the one or more additional
ring is three- to ten-membered cycloalkyl or three- to ten-membered
heterocycloalkyl, where a single atom of the one or more additional
ring is also an atom of the three- to ten-membered
heterocycloalkyl. Examples of the spiro-heterocycloalkyl include
bicyclic and tricyclic ring systems, such as
2-oxa-7-azaspiro[3.5]nonanyl, 2-oxa-6-azaspiro[3.4]octanyl, and
6-oxa-1-azaspiro[3.3]heptanyl. The above definition also
encompasses "heterocyclic ring."
[0110] "Hydroxy" or "hydroxyl" refers to the group --OH.
[0111] "Oxo" refers to the group (.dbd.O) or (O).
[0112] "Sulfonyl" refers to the group --S(O).sub.2R, where R is
alkyl, haloalkyl, heterocycloalkyl, cycloalkyl, heteroaryl, or
aryl. Examples of sulfonyl are methylsulfonyl, ethylsulfonyl,
phenylsulfonyl, and toluenesulfonyl.
[0113] Certain commonly used alternative chemical names may be
used. For example, a divalent group such as a divalent "alkyl"
group, a divalent "aryl" group, etc., may also be referred to as an
"alkylene" group or an "alkylenyl" group, an "arylene" group or an
"arylenyl" group, respectively. Also, unless indicated explicitly
otherwise, where combinations of groups are referred to herein as
one moiety, e.g. arylalkyl, the last mentioned group contains the
atom by which the moiety is attached to the rest of the
molecule.
[0114] The terms "optional" or "optionally" means that the
subsequently described event or circumstance may or may not occur,
and that the description includes instances where said event or
circumstance occurs and instances in which it does not. Also, the
term "optionally substituted" refers to any one or more hydrogen
atoms on the designated atom or group may or may not be replaced by
a moiety other than hydrogen.
[0115] The term "substituted" means that any one or more hydrogen
atoms on the designated atom or group is replaced with one or more
substituents other than hydrogen, provided that the designated
atom's normal valence is not exceeded. The one or more substituents
include, but are not limited to, alkyl, alkenyl, alkynyl, alkoxy,
acyl, amino, amido, amidino, aryl, azido, carbamoyl, carboxyl,
carboxyl ester, cyano, guanidino, halo, haloalkyl, heteroalkyl,
heteroaryl, heterocycloalkyl, hydroxy, hydrazino, imino, oxo,
nitro, alkylsulfinyl, sulfonic acid, alkylsulfonyl, thiocyanate,
thiol, thione, or combinations thereof. Polymers or similar
indefinite structures arrived at by defining substituents with
further substituents appended ad infinitum (e.g., a substituted
aryl having a substituted alkyl which is itself substituted with a
substituted aryl group, which is further substituted by a
substituted heteroalkyl group, etc.) are not intended for inclusion
herein. Unless otherwise noted, the maximum number of serial
substitutions in compounds described herein is three. For example,
serial substitutions of substituted aryl groups with two other
substituted aryl groups are limited to ((substituted
aryl)substituted aryl) substituted aryl. Similarly, the above
definitions are not intended to include impermissible substitution
patterns (e.g., methyl substituted with 5 fluorines or heteroaryl
groups having two adjacent oxygen ring atoms). Such impermissible
substitution patterns are well known to the skilled artisan. When
used to modify a chemical group, the term "substituted" may
describe other chemical groups defined herein. For example, the
term "substituted aryl" includes, but is not limited to,
"alkylaryl." Unless specified otherwise, where a group is described
as optionally substituted, any substituents of the group are
themselves unsubstituted. One or more substituents may include, for
example, 1, 2, 3, 4, 5, or 6 substitutents, 1, 2, 3, 4, or 5
substitutents, 1, 2, 3, or 4 substitutents, 1, 2, or 3
substituents, 1 or 2 substituents, or 1 substituent.
[0116] In some embodiments, the term "substituted alkyl" refers to
an alkyl group having one or more substituents including hydroxyl,
halo, alkoxy, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl.
In additional embodiments, "substituted cycloalkyl" refers to a
cycloalkyl group having one or more substituents including alkyl,
haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxy,
halo, oxo, and hydroxyl; "substituted heterocycloalkyl" refers to a
heterocycloalkyl group having one or more substituents including
alkyl, haloalkyl, heterocycloalkyl, cycloalkyl, aryl, heteroaryl,
alkoxy, halo, oxo, and hydroxyl; "substituted aryl" refers to an
aryl group having one or more substituents including halo, alkyl,
haloalkyl, cycloalkyl, heterocycloalkyl, heteroaryl, alkoxy, and
cyano; "substituted heteroaryl" refers to an heteroaryl group
having one or more substituents including halo, alkyl, haloalkyl,
heterocycloalkyl, heteroaryl, alkoxy, and cyano and "substituted
sulfonyl" refers to a group --S(O).sub.2R, in which R is
substituted with one or more substituents including alkyl,
cycloalkyl, heterocycloalkyl, aryl, and heteroaryl. In other
embodiments, the one or more substituents may be further
substituted with halo, alkyl, haloalkyl, hydroxyl, alkoxy,
cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, each of which is
substituted. In other embodiments, the substituents may be further
substituted with halo, alkyl, haloalkyl, alkoxy, hydroxyl,
cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, each of which is
unsubstituted.
[0117] The terms "a compound of the present application," "a
compound described herein," "a compound of any of the formulae
described herein," or variant thereof refer to a compound having
the structure of any of the foregoing formulae (J), (I), (I-A1),
(IA-2), (I-A3), (IB-1), (IB-2), (IB-3), (IB-4), (IB-5), including
at least the compounds of Table 1, 2, or 3, and compounds 1-116 as
described herein.
[0118] PI3K Inhibitor Compounds
[0119] Provided herein are compounds that function as inhibitors of
PI3K isoforms, such as PI3K.delta.. In one aspect, provided is a
compound having structure of formula (J):
##STR00005##
[0120] wherein:
[0121] A is N or CH;
[0122] n is 0, 1, 2, 3, or 4;
[0123] m is 0, 1, 2, 3, or 4;
[0124] each R.sup.1 is independently selected from optionally
substituted alkyl, optionally substituted haloalkyl, optionally
substituted aryl, optionally substituted heteroaryl, halo, cyano,
NHC(.dbd.O)alkylene-N(R.sup.1x).sub.2, NO.sub.2, OR.sup.1x,
N(R.sup.1x).sub.2, OC(.dbd.O)R.sup.1x, C(.dbd.O)R.sup.1x,
C(.dbd.O)OR.sup.1x, aryl-OR, optionally substituted cycloalkyl,
optionally substituted heterocycloalkyl,
NR.sup.1xC(.dbd.O)alkylene-C(.dbd.O)OR.sup.1x,
aryl-O-alkylene-N(R.sup.1x).sub.2, aryl-O--C(.dbd.O)R.sup.1x,
alkylene-C(.dbd.O)OR.sup.1x, alkylene-C(.dbd.O)N(R.sup.1x).sub.2,
alkylene-C(.dbd.O)--Het, O-alkylene-C(.dbd.O)OR.sup.1x,
alkylene-O-alkylene-C(.dbd.O)OR.sup.1x,
C(.dbd.O)NR.sup.1xSO.sub.2R.sup.1x, alkylene-N(R.sup.1x).sub.2,
alkenylene-N(R.sup.1x).sub.2,
C(.dbd.O)NR.sup.1x-alkylene-OR.sup.1x,
C(.dbd.O)NR.sup.1xalkylene-Het, O-alkylene-N(R.sup.1x).sub.2,
O-alkylene-CH(OR.sup.1y)CH.sub.2N(R.sup.1x).sub.2, O-alkylene-Het,
O-alkylene-C(.dbd.O)OR.sup.1x, O-alkylene-C(.dbd.O)--Het,
S-alkylene-OR.sup.1x, O-alkylene-OR.sup.1x,
O--C.sub.1-6alkylene-CH(OR.sup.1y)C.sub.1-6alkylene-OR,
O-alkylene-NR.sup.1xC(.dbd.O)OR.sup.1x,
NR.sup.1x-alkylene-N(R.sup.1x).sub.2, NR.sup.1xC(.dbd.O)R.sup.1x,
NR.sup.1xC(.dbd.O)N(R.sup.1x).sub.2, N(SO.sub.2-alkyl).sub.2,
NR.sup.1x(SO.sub.2-alkyl), SO.sub.2R.sup.1z,
SO.sub.2N(R.sup.1x).sub.2, alkylene-aryl, alkylene-Het,
alkylene-OR.sup.1y, alkylene-N(R.sup.1x).sub.2,
C(.dbd.O)N(R.sup.1x).sub.2, NHC(.dbd.O)alkylene-aryl,
aryl-O-alkylene-N(R.sup.1x).sub.2, aryl-OC(.dbd.O)R.sup.1y,
NHC(.dbd.O)alkylene-heterocycloalkyl, NHC(.dbd.O)alkylene-Het,
O-alkylene-O-alkylene-C(.dbd.O)OR.sup.1y, C(.dbd.O)alkylene-Het,
and NHC(.dbd.O)halo-alkyl, [0125] wherein Het is optionally
substituted heteroaryl or optionally substituted heterocycloalkyl,
wherein R.sup.1x is independently hydrogen, optionally substituted
alkyl, optionally substituted haloalkyl, optionally substituted
cycloalkyl, optionally substituted heterocycloalkyl, and optionally
substituted aryl, wherein R.sup.1y is independently hydrogen,
optionally substituted alkyl, optionally substituted haloalkyl,
optionally substituted aryl, and optionally substituted heteroaryl,
and wherein R.sup.1z is independently optionally substituted alkyl,
optionally substituted haloalkyl, optionally substituted
cycloalkyl, optionally substituted heterocycloalkyl, and optionally
substituted aryl;
[0126] each R.sup.2 is independently selected from halo, cyano,
optionally substituted alkyl, haloalkyl, SO.sub.2N(R.sup.2x).sub.2,
and optionally substituted alkoxy, [0127] wherein R.sup.2x is
hydrogen, optionally substituted alkyl, or optionally substituted
haloalkyl;
[0128] R.sup.3 is hydrogen, optionally substituted alkyl,
optionally substituted haloalkyl, optionally substituted
cycloalkyl, optionally substituted aryl, optionally substituted
heteroaryl, or optionally substituted heterocycloalkyl;
[0129] R.sup.5 is hydrogen or alkyl, or R.sup.5 and R.sup.3
together with the atoms to which they are attached optionally form
an optionally substituted four-, five- or six-membered heterocyclic
ring;
[0130] R.sup.4 is cyano, C(.dbd.O)NR.sup.4xR.sup.4y,
SO.sub.2-alkyl, halo, haloalkyl, or C(.dbd.O)R.sup.4x [0131]
wherein each R.sup.4x and R.sup.4y is independently hydrogen,
optionally substituted alkyl, and optionally substituted
haloalkyl;
[0132] R.sup.6 is NH.sub.2, halo, optionally substituted alkyl, or
optionally substituted haloalkyl; and
[0133] R.sup.7 is NH.sub.2, halo, optionally substituted alkyl, or
optionally substituted haloalkyl;
or a pharmaceutically acceptable salt, isomer, or a mixture
thereof.
[0134] Provided herein are compounds that function as inhibitors of
PI3K isoforms, such as PI3K.delta.. In one aspect, provided is a
compound having structure of formula (J):
##STR00006##
[0135] wherein:
[0136] A is N or CH;
[0137] n is 0, 1, 2, 3, or 4;
[0138] m is 0, 1, 2, 3, or 4;
[0139] each R.sup.1 is independently selected from optionally
substituted alkyl, optionally substituted haloalkyl, optionally
substituted aryl, optionally substituted heteroaryl, halo, cyano,
NHC(.dbd.O)alkylene-N(R.sup.1x).sub.2, NO.sub.2, OR.sup.1x,
N(R.sup.1x).sub.2, OC(.dbd.O)R.sup.1x, C(.dbd.O)R.sup.1x,
C(.dbd.O)OR.sup.1x, aryl-OR.sup.1y, optionally substituted
cycloalkyl, optionally substituted heterocycloalkyl,
NR.sup.1xC(.dbd.O)alkylene-C(.dbd.O)OR.sup.1x,
aryl-O-alkylene-N(R.sup.1x).sub.2, aryl-O--C(.dbd.O)R.sup.1x,
alkylene-C(.dbd.O)OR.sup.1x, alkylene-C(.dbd.O)N(R.sup.1x).sub.2,
alkylene-C(.dbd.O)--Het, O-alkylene-C(.dbd.O)OR.sup.1x,
alkylene-O-alkylene-C(.dbd.O)OR.sup.1xC(.dbd.O)NR.sup.1xSO.sub.2R.sup.1x,
alkylene-N(R.sup.1x).sub.2, alkenylene-N(R.sup.1x).sub.2,
C(.dbd.O)NR.sup.1x-alkylene-OR.sup.1x,
C(.dbd.O)NR.sup.1xalkylene-Het, O-alkylene-N(R.sup.1x).sub.2,
O-alkylene-CH(OR.sup.1y)CH.sub.2N(R.sup.1x).sub.2, O-alkylene-Het,
O-alkylene-C(.dbd.O)OR.sup.1x, O-alkylene-C(.dbd.O)--Het,
S-alkylene-OR.sup.1x, O-alkylene-OR.sup.1x,
O--C.sub.1-6alkylene-CH(OR.sup.1y)C.sub.1-6alkylene-OR.sup.1x,
O-alkylene-NR.sup.1xC(.dbd.O)OR.sup.1x,
NR.sup.1z-alkylene-N(R.sup.1x).sub.2, NR.sup.1xC(.dbd.O)R.sup.1x,
NR.sup.1xC(.dbd.O)N(R.sup.1x).sub.2, N(SO.sub.2-alkyl).sub.2,
NR.sup.1x(SO.sub.2-alkyl), SO.sub.2R.sup.1z,
SO.sub.2N(R.sup.1x).sub.2, alkylene-aryl, alkylene-Het,
alkylene-OR.sup.1y, alkylene-N(R.sup.1x).sub.2,
C(.dbd.O)N(R.sup.1x).sub.2, NHC(.dbd.O)alkylene-aryl,
aryl-O-alkylene-N(R.sup.1x).sub.2, aryl-OC(.dbd.O)R.sup.1y,
NHC(.dbd.O)alkylene-heterocycloalkyl, NHC(.dbd.O)alkylene-Het,
O-alkylene-O-alkylene-C(.dbd.O)OR.sup.1y, C(.dbd.O)alkylene-Het,
and NHC(.dbd.O)halo-alkyl, [0140] wherein Het is optionally
substituted heteroaryl or optionally substituted heterocycloalkyl,
wherein R.sup.1x is independently hydrogen, optionally substituted
alkyl, optionally substituted haloalkyl, optionally substituted
cycloalkyl, optionally substituted heterocycloalkyl, and optionally
substituted aryl, wherein R.sup.1y is independently hydrogen,
optionally substituted alkyl, optionally substituted haloalkyl,
optionally substituted aryl, and optionally substituted heteroaryl,
and wherein R.sup.1z is independently optionally substituted alkyl,
optionally substituted haloalkyl, optionally substituted
cycloalkyl, optionally substituted heterocycloalkyl, and optionally
substituted aryl;
[0141] each R.sup.2 is independently selected from halo, cyano,
optionally substituted alkyl, haloalkyl, SO.sub.2N(R.sup.2x).sub.2,
and optionally substituted alkoxy, [0142] wherein R.sup.2x is
hydrogen, optionally substituted alkyl, or optionally substituted
haloalkyl;
[0143] R.sup.3 is hydrogen, optionally substituted alkyl,
optionally substituted haloalkyl, optionally substituted
cycloalkyl, optionally substituted aryl, optionally substituted
heteroaryl, or optionally substituted heterocycloalkyl;
[0144] R.sup.5 is hydrogen or alkyl, or R.sup.5 and R.sup.3
together with the atoms to which they are attached optionally form
an optionally substituted four-, five- or six-membered heterocyclic
ring; provided that when R.sup.5 and R.sup.3 form a 5-membered
heterocyclic ring that is optionally substituted with hydroxyl,
halo, or methoxy, R.sup.4 is cyano, R.sup.6 is amino, and R.sup.7
is amino R.sup.4 is cyano, C(.dbd.O)NR.sup.4xR.sup.4y,
SO.sub.2-alkyl, halo, haloalkyl, or C(.dbd.O)R.sup.4x [0145]
wherein each R.sup.4x and R.sup.4y is independently hydrogen,
optionally substituted alkyl, and optionally substituted
haloalkyl;
[0146] R.sup.6 is NH.sub.2, halo, optionally substituted alkyl, or
optionally substituted haloalkyl; and
[0147] R.sup.7 is NH.sub.2, halo, optionally substituted alkyl, or
optionally substituted haloalkyl;
or a pharmaceutically acceptable salt, isomer, or a mixture
thereof.
[0148] In one aspect, provided is a compound having the structure
of formula (I)
##STR00007##
[0149] wherein:
[0150] n is 1 or 2;
[0151] m is 0, 1, or 2;
[0152] each R.sup.1 is independently C.sub.1-6alkyl,
C.sub.1-6haloalkyl, C.sub.3-8cycloalkyl, C.sub.2-8heterocycloalkyl,
C.sub.3-8heteroaryl, C.sub.6-10aryl, halo, cyano,
C.sub.6-10aryl-OR.sup.1y, C.sub.1-6alkylene-C.sub.6-10aryl,
C.sub.1-6alkylene-Het, C.sub.1-6alkylene-C.sub.3-8cycloalkyl,
C.sub.1-6alkylene-OR.sup.1y, C.sub.1-6alkylene-N(R.sup.1x).sub.2,
C.sub.2-6alkenylene-OR.sup.1y,
C.sub.2-6alkenylene-N(R.sup.1x).sub.2,
C.sub.1-6alkylene-C(.dbd.O)OR.sup.1x,
C.sub.1-6alkylene-C(.dbd.O)N(R.sup.1x).sub.2,
C.sub.1-6alkylene-C(.dbd.O)-Het,
O--C.sub.1-6alkylene-C(.dbd.O)OR.sup.1x,
C.sub.1-6alkylene-O--C.sub.1-6alkylene-C(.dbd.O)OR.sup.1x,
C.sub.1-6alkenylene-N(R.sup.1x).sub.2, OR.sup.1x,
O--C.sub.1-6alkylene-N(R.sup.1x).sub.2,
O--C.sub.1-6alkylene-CH(OR.sup.1y)CH.sub.2N(R.sup.1x).sub.2,
O--C.sub.1-6alkylene-Het, O--C.sub.1-6alkylene-C(.dbd.O)OR.sup.1x,
O--C.sub.1-6alkylene-C(.dbd.O)--Het,
O--C.sub.1-6alkylene-OR.sup.1x,
O--C.sub.1-6alkylene-CH(OR.sup.1y)C.sub.1-6alkylene-OR.sup.1x,
O--C.sub.2-6alkenylene-OR.sup.1y,
O--C.sub.2-6alkenylene-N(R.sup.1x).sub.2,
O--C.sub.1-6alkylene-NR.sup.1xC(.dbd.O)OR.sup.1x,
O--C.sub.1-6alkylene-O--C.sub.1-6alkylene-C(.dbd.O)OR.sup.1y,
SO.sub.2R.sup.1x, S--C.sub.1-6alkylene-OR.sup.1z, and
SO.sub.2N(R.sup.1x).sub.2, [0153] wherein Het is
C.sub.3-8heteroaryl or C.sub.2-8heterocycloalkyl, wherein R.sup.1x
is independently hydrogen, C.sub.1-6alkyl, C.sub.1-6haloalkyl,
C.sub.3-8cycloalkyl, C.sub.6-10aryl, C.sub.2-8heterocycloalkyl, and
C.sub.3-8heteroaryl, wherein R.sup.1y is independently hydrogen,
C.sub.1-6alkyl, C.sub.1-6haloalkyl, C.sub.6-10aryl, and
C.sub.3-8heteroaryl, wherein R.sup.1z is independently
C.sub.1-6alkyl, C.sub.1-6haloalkyl, C.sub.3-8cycloalkyl,
C.sub.6-10aryl, C.sub.2-8heterocycloalkyl, and C.sub.3-8heteroaryl,
and wherein each of Het, R.sup.1x, R.sup.1y and R.sup.1z is
optionally substituted with one, two, three, or four members
independently selected from halo, oxo, C.sub.1-6alkyl, and
C.sub.6-10aryl;
[0154] each R.sup.2 is independently halo, cyano, C.sub.1-6alkyl,
C.sub.1-6haloalkyl, SO.sub.2N(R.sup.2x).sub.2, wherein R.sup.2x is
hydrogen, C.sub.1-6alkyl, or C.sub.1-6haloalkyl;
[0155] R.sup.3 is hydrogen, C.sub.1-6alkyl, C.sub.1-6haloalkyl,
C.sub.3-8cycloalkyl, C.sub.6-10aryl, wherein the C.sub.1-6alkyl
moiety is optionally substituted with --C(.dbd.O)NR.sup.3xR.sup.3y,
wherein each R.sup.3x and R.sup.3y is independently hydrogen,
C.sub.1-6alkyl, or C.sub.1-6haloalkyl;
[0156] R.sup.5 is hydrogen or C.sub.1-6alkyl, or R.sup.5 and
R.sup.3 together with the atoms to which they are attached
optionally form a four-, five- or six-membered heterocyclic ring,
wherein the heterocyclic ring is optionally substituted with one,
two, or three members independently selected from halo,
C.sub.1-6alkyl, C.sub.1-6alkoxy, C.sub.1-6haloalkyl, and
NR.sup.5xC(O)R.sup.5y where R.sup.5x is hydrogen or C.sub.1-6alkyl,
and R.sup.5y is C.sub.1-6alkylene-NH.sub.2, C.sub.1-6
alkylene-C.sub.3-8cycloalkyl, or C.sub.1-6haloalkyl;
[0157] R.sup.4 is cyano, C(.dbd.O)NR.sup.4xR.sup.4y,
SO.sub.2--C.sub.1-6alkyl, halo, C.sub.1-6haloalkyl, or
C(.dbd.O)R.sup.4x, wherein each R.sup.4x and R.sup.4y is
independently hydrogen, C.sub.1-6alkyl, or C.sub.1-6haloalkyl;
[0158] R.sup.6 is NH.sub.2, halo, C.sub.1-6alkyl, or
C.sub.1-6haloalkyl; and
[0159] R.sup.7 is NH.sub.2, halo, C.sub.1-6alkyl, or
C.sub.1-6haloalkyl; or a pharmaceutically acceptable salt, isomer,
or a mixture thereof.
[0160] In one aspect, provided is a compound having the structure
of formula (I):
##STR00008##
[0161] wherein:
[0162] n is 0, 1, 2, 3, or 4;
[0163] m is 0, 1, 2, or 3;
[0164] each R.sup.1 is independently alkyl, haloalkyl, aryl,
heteroaryl, cycloalkyl, heterocycloalkyl halo, cyano,
aryl-OR.sup.1y, alkenylene-OR.sup.1y, alkenylene-N(R.sup.1x).sub.2,
alkylene-C(.dbd.O)OR.sup.1x, alkylene-C(.dbd.O)N(R.sup.1x).sub.2,
alkylene-C(.dbd.O)--Het, alkylene-O-alkylene-C(.dbd.O)OR.sup.1x,
alkylene-N(R.sup.1x).sub.2, alkylene-aryl, alkylene-Het,
alkylene-OR.sup.1x, alkylene-N(R.sup.1x).sub.2,
O-alkylene-O-alkylene-C(.dbd.O)OR.sup.1yOR.sup.1x,
O-alkylene-C(.dbd.O)OR.sup.1x,
O-alkylene-CH(OR.sup.1y)CH.sub.2N(R.sup.1x).sub.2,
O-alkenylene-OR.sup.1y, O-alkenylene-N(R.sup.1x).sub.2,
O-alkylene-OR.sup.1x, O-alkylene-N(R.sup.1x).sub.2,
O-alkylene-CH(OR.sup.1y)alkylene-OR.sup.1x,
O-alkylene-NR.sup.1xC(.dbd.O)OR.sup.1x, O-alkylene-Het,
O-alkylene-C(.dbd.O)--Het, S-alkylene-OR.sup.1x, SO.sub.2R.sup.1z,
and SO.sub.2N(R.sup.1x).sub.2, [0165] wherein Het is optionally
substituted heteroaryl or optionally substituted heterocycloalkyl,
wherein R.sup.1x is independently hydrogen, optionally substituted
alkyl, optionally substituted haloalkyl, optionally substituted
cycloalkyl, optionally substituted heterocycloalkyl, and optionally
substituted aryl, wherein R.sup.1y is independently hydrogen,
optionally substituted alkyl, haloalkyl, optionally substituted
aryl, and optionally substituted heteroaryl, and wherein R.sup.1z
is independently optionally substituted alkyl, optionally
substituted haloalkyl, optionally substituted cycloalkyl,
optionally substituted heterocycloalkyl, and optionally substituted
aryl;
[0166] each R.sup.2 is independently halo, cyano, optionally
substituted alkyl, optionally substituted haloalkyl, and
SO.sub.2N(R.sup.2x).sub.2, wherein R.sup.2x is hydrogen, and
optionally substituted alkyl;
[0167] R.sup.3 is hydrogen, alkyl, haloalkyl, cycloalkyl, aryl,
heteroaryl, or heterocycloalkyl, wherein each of the cycloalkyl,
aryl, heteroaryl, and heterocycloalkyl moieties is optionally
substituted with halo or alkyl, wherein the alkyl moiety is
optionally substituted with --C(.dbd.O)NR.sup.3xR.sup.3y wherein
each R.sup.3x and R.sup.3y is independently hydrogen, alkyl, or
haloalkyl;
[0168] R.sup.5 is hydrogen or alkyl, or R.sup.5 and R.sup.3
together with the atoms to which they are attached optionally form
a four-, five- or six-membered heterocyclic ring, wherein the
heterocyclic ring is optionally substituted with halo, alkyl,
haloalkyl, or NR.sup.5xC(.dbd.O)R.sup.5y, [0169] wherein R.sup.5x
is hydrogen or alkyl, and wherein R.sup.5y is alkyl, haloalkyl,
cycloalkyl, cycloalkylalkyl, or alkyl-NH.sub.2;
[0170] R.sup.4 is cyano, C(.dbd.O)NR.sup.4xR.sup.4y,
SO.sub.2R.sup.4x, halo, haloalkyl, or C(.dbd.O)R.sup.4x [0171]
wherein each R.sup.4x and R.sup.4y is independently hydrogen,
alkyl, and haloalkyl;
[0172] R.sup.6 is NH.sub.2, halo, alkyl, or haloalkyl; and
[0173] R.sup.7 is NH.sub.2, halo, alkyl, or haloalkyl;
[0174] or a pharmaceutically acceptable salt, isomer, or a mixture
thereof.
[0175] In additional embodiments, the PI3K inhibitors are compounds
having the structure of formulae (J) or (I) wherein:
[0176] n is 1 or 2;
[0177] m is 0, 1, or 2;
[0178] each R.sup.1 is independently C.sub.1-6alkyl,
C.sub.1-6haloalkyl, C.sub.3-8cycloalkyl, C.sub.2-8heterocycloalkyl,
C.sub.3-8heteroaryl, C.sub.6-10aryl, halo, cyano,
C.sub.6-10aryl-OR.sup.1y, C.sub.1-6alkylene-C.sub.6-10aryl,
C.sub.1-6alkylene-Het, C.sub.1-6alkylene-C.sub.3-8cycloalkyl,
C.sub.1-6alkylene-OR.sup.1y, C.sub.1-6alkylene-N(R.sup.1x).sub.2,
C.sub.2-6alkenylene-OR.sup.1y,
C.sub.2-6alkenylene-N(R.sup.1x).sub.2,
C.sub.1-6alkylene-C(.dbd.O)OR.sup.1x,
C.sub.1-6alkylene-C(.dbd.O)N(R.sup.1x).sub.2,
C.sub.1-6alkylene-C(.dbd.O)-Het,
O--C.sub.1-6alkylene-C(.dbd.O)OR.sup.1x,
C.sub.1-6alkylene-O--C.sub.1-6alkylene-C(.dbd.O)OR.sup.1x,
C.sub.1-6alkenylene-N(R.sup.1x).sub.2, OR.sup.1x,
O--C.sub.1-6alkylene-N(R.sup.1x).sub.2,
O--C.sub.1-6alkylene-CH(OR.sup.1y)CH.sub.2N(R.sup.1x).sub.2,
O--C.sub.1-6alkylene-Het, O--C.sub.1-6alkylene-C(.dbd.O)OR.sup.1x,
O--C.sub.1-6alkylene-C(.dbd.O)--Het,
O--C.sub.1-6alkylene-OR.sup.1x,
O--C.sub.1-6alkylene-CH(OR.sup.1y)C.sub.1-6alkylene-OR.sup.1x,
O--C.sub.2-6alkenylene-OR.sup.1y,
O--C.sub.2-6alkenylene-N(R.sup.1x).sub.2,
O--C.sub.1-6alkylene-NR.sup.1xC(.dbd.O)OR.sup.1x,
O--C.sub.1-6alkylene-O--C.sub.1-6alkylene-C(.dbd.O)OR.sup.1y,
SO.sub.2R.sup.1x, S--C.sub.1-6alkylene-OR.sup.1z, and
SO.sub.2N(R.sup.1x).sub.2, [0179] wherein Het is
C.sub.3-8heteroaryl or C.sub.2-8heterocycloalkyl, wherein R.sup.1x
is independently hydrogen, C.sub.1-6alkyl, C.sub.1-6haloalkyl,
C.sub.3-8cycloalkyl, C.sub.6-10aryl, C.sub.2-8heterocycloalkyl, and
C.sub.3-8heteroaryl, wherein R.sup.1y is independently hydrogen,
C.sub.1-6alkyl, C.sub.1-6haloalkyl, C.sub.6-10aryl, and
C.sub.3-8heteroaryl, wherein R.sup.1z is independently
C.sub.1-6alkyl, C.sub.1-6haloalkyl, C.sub.3-8cycloalkyl,
C.sub.6-10aryl, C.sub.2-8heterocycloalkyl, and C.sub.3-8heteroaryl,
and wherein each of Het, R.sup.1x, R.sup.1y and R.sup.1z is
optionally substituted with one, two, three, or four members
independently selected from halo, oxo, C.sub.1-6alkyl, and
C.sub.6-10aryl;
[0180] each R.sup.2 is independently halo, cyano, C.sub.1-6alkyl,
C.sub.1-6haloalkyl, SO.sub.2N(R.sup.2x).sub.2, wherein R.sup.2x is
hydrogen, C.sub.1-6alkyl, or C.sub.1-6haloalkyl;
[0181] R.sup.3 is hydrogen, C.sub.1-6alkyl, C.sub.1-6haloalkyl,
C.sub.3-8cycloalkyl, C.sub.6-10aryl, wherein the C.sub.1-6alkyl
moiety is optionally substituted with --C(.dbd.O)NR.sup.3xR.sup.3y,
wherein each R.sup.3x and R.sup.3y is independently hydrogen,
C.sub.1-6alkyl, or C.sub.1-6haloalkyl;
[0182] R.sup.5 is hydrogen or C.sub.1-6alkyl, or R.sup.5 and
R.sup.3 together with the atoms to which they are attached
optionally form a four-, five- or six-membered heterocyclic ring,
wherein the heterocyclic ring is optionally substituted with one,
two, or three members independently selected from halo,
C.sub.1-6alkyl, C.sub.1-6haloalkyl, and NR.sup.5xC(O)R.sup.5y where
R.sup.5x is hydrogen or C.sub.1-6alkyl, and R.sup.5y is
C.sub.1-6alkylene-NH.sub.2, C.sub.1-6 alkylene-C.sub.3-8cycloalkyl,
or C.sub.1-6haloalkyl;
[0183] R.sup.4 is cyano, C(.dbd.O)NR.sup.4xR.sup.4y,
SO.sub.2--C.sub.1-6alkyl, halo, C.sub.1-6haloalkyl, or
C(.dbd.O)R.sup.4x, wherein each R.sup.4x and R.sup.4y is
independently hydrogen, C.sub.1-6alkyl, or C.sub.1-6haloalkyl;
[0184] R.sup.6 is NH.sub.2, halo, C.sub.1-6alkyl, or
C.sub.1-6haloalkyl; and
[0185] R.sup.7 is NH.sub.2, halo, C.sub.1-6alkyl, or
C.sub.1-6haloalkyl;
[0186] or a pharmaceutically acceptable salt, isomer, or a mixture
thereof.
[0187] In some embodiments, the PI3K inhibitors are compounds
having the structure of formulae (J) or (I) wherein:
[0188] n is 1 or 2;
[0189] m is 0, 1, or 2;
[0190] each R.sup.1 is independently C.sub.1-6alkyl,
C.sub.1-6haloalkyl, C.sub.6-10aryl, C.sub.5-8heteroaryl, C.sub.3-8
cycloalkyl, C.sub.2-8heterocycloalkyl, halo, cyano,
C.sub.1-6alkylene-C(.dbd.O)OH,
C.sub.1-6alkylene-C(.dbd.O)OC.sub.1-6alkyl,
C.sub.1-6alkylene-C(.dbd.O)--C.sub.3-8heterocycloalkyl,
C.sub.1-6alkylene-C(.dbd.O)--C.sub.3-8cycloalkyl,
C.sub.1-6alkylene-C(.dbd.O)NH.sub.2,
C.sub.1-6alkylene-C(.dbd.O)N(C.sub.1-6alkyl).sub.2,
C.sub.1-6alkylene-C(.dbd.O)NHC.sub.1-6alkyl,
C.sub.1-6alkylene-O--C.sub.1-6alkylene-C(.dbd.O)OH,
C.sub.1-6alkylene-O--C.sub.1-6alkylene-C(.dbd.O)OC.sub.1-6alkyl,
C.sub.1-6alkylene-C.sub.6-10aryl,
C.sub.1-6alkylene-C.sub.2-8heteroaryl,
C.sub.1-6alkylene-C.sub.2-8heterocycloalkyl,
C.sub.1-6alkylene-C.sub.3-8cycloalkyl, C.sub.1-6alkylene-OH,
C.sub.1-6 alkylene-OC.sub.1-6alkyl,
O--C.sub.1-6alkylene-N(C.sub.1-6alky).sub.2,
O--C.sub.1-6alkylene-NHC.sub.1-6alky,
O--C.sub.1-6alkylene-NH.sub.2,
O--C.sub.1-6alkylene-CH(OH)C.sub.1-6alkylNH.sub.2,
O--C.sub.1-6alkylene-CH(OH)C.sub.1-6alkylN(C.sub.1-6alkyl).sub.2,
O--C.sub.1-6alkylene-CH(OH)C.sub.1-6alkylNHC.sub.1-6alkyl,
O--C.sub.1-6alkylene-CH(OC.sub.1-6alkyl)C.sub.1-6alkylNH.sub.2,
O--C.sub.1-6alkylene-CH(OC.sub.1-6alkyl)C.sub.1-6alkylN(C.sub.1-6alkyl).s-
ub.2,
O--C.sub.1-6alkylene-CH(OC.sub.1-6alkyl)C.sub.1-6alkylNHC.sub.1-6alk-
yl, O--C.sub.1-6alkylene-C.sub.2-8heterocycloalkyl,
O--C.sub.1-6alkylene-C.sub.3-8heteroaryl,
O--C.sub.1-6alkylene-C(.dbd.O)OH,
O--C.sub.1-6alkylene-C(.dbd.O)OC.sub.1-6alkyl,
O--C.sub.1-6alkylene-C(.dbd.O)--C.sub.2-8heterocycloalkyl,
O--C.sub.1-6alkylene-C(.dbd.O)OC.sub.3-8cycloalkyl,
O--C.sub.1-6alkylene-C(.dbd.O)OC.sub.6-10aryl,
O--C.sub.1-6alkylene-OH, O--C.sub.1-6alkylene-OC.sub.3-8cycloalkyl,
O--C.sub.1-6alkylene-OC.sub.1-6alkyl,
O--C.sub.1-6alkylene-CH(OH)C.sub.1-6alkylene-OH,
O--C.sub.1-6alkylene-NHC(.dbd.O)OH,
O--C.sub.1-6alkylene-O--C.sub.1-6alkylene-C(.dbd.O)OH,
OSO.sub.2CF.sub.3, S--C.sub.1-6alkylene-OH,
SO.sub.2C.sub.1-6alkylene-C.sub.2-8heterocycloalkyl,
SO.sub.2C.sub.6-10aryl, SO.sub.2C.sub.3-8cycloalkyl,
SO.sub.2C.sub.1-6alkylene-OH, SO.sub.2N(C.sub.1-6alkyl).sub.2, or
SO.sub.2NH.sub.2; [0191] wherein each of the C.sub.6-10aryl,
C.sub.3-8cycloalkyl, C.sub.2-8heterocycloalkyl, and
C.sub.3-8heteroaryl moieties is optionally substituted with one,
two, three, or four members independently selected from fluoro,
chloro, oxo, methyl, ethyl, fluoromethyl, difluoromethyl,
trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, and
phenyl;
[0192] each R.sup.2 is independently halo, cyano, C.sub.1-6alkyl,
C.sub.1-6haloalkyl, and SO.sub.2NH.sub.2;
[0193] R.sup.3 is C.sub.1-6alkyl, C.sub.1-6haloalkyl,
C.sub.3-8cycloalkyl, C.sub.6-10aryl,
C.sub.1-6alkylene-C(.dbd.O)NHC.sub.1-6alkyl,
C.sub.1-6alkylene-C(.dbd.O)NH.sub.2, or
C.sub.1-6alkylene-C(.dbd.O)N(C.sub.1-6alkyl).sub.2;
[0194] R.sup.5 is hydrogen or C.sub.1-6alkyl, or R.sup.5 and
R.sup.3 together with the atoms to which they are attached
optionally form a four-, five- or six-membered heterocyclic ring,
wherein the heterocyclic ring is optionally substituted with one or
two members independently selected from halo, C.sub.1-6alkyl,
NHC(.dbd.O)C.sub.1-6alkylene-NH.sub.2, NHC(.dbd.O)C.sub.1-6
alkylene-C.sub.3-8cycloalkyl, NHC(.dbd.O)C.sub.1-6haloalkyl,
NC.sub.1-6alkylC(.dbd.O)C.sub.1-6alkylene-NH.sub.2,
NC.sub.1-6alkylC(.dbd.O)C.sub.1-6 alkylene-C.sub.3-8cycloalkyl, and
NC.sub.1-6alkylC(.dbd.O)C.sub.1-6haloalkyl;
[0195] R.sup.4 is cyano, halo, C.sub.1-6haloalkyl, C(.dbd.O)H, or
C(.dbd.O)C.sub.1-6alkyl;
[0196] R.sup.6 is NH.sub.2, halo, or C.sub.1-6alkyl; and
[0197] R.sup.7 is NH.sub.2, halo, or C.sub.1-6alkyl;
[0198] or a pharmaceutically acceptable salt, isomer, or a mixture
thereof.
[0199] In some embodiments of formulae (J) or (I), each R.sup.1 is
independently methyl, chloro, fluoro, cyano, tetrahydropyridinyl,
--CH.sub.2--C(.dbd.O)OH, --C.sub.2H.sub.4--C(.dbd.O)OH,
--C.sub.3H.sub.6--C(.dbd.O)OH, --CH.sub.2--C(.dbd.O)NH.sub.2,
--CH.sub.2--C(.dbd.O)N(CH.sub.3).sub.2,
--C.sub.2H.sub.4--C(.dbd.O)NH.sub.2,
--C.sub.2H.sub.4--C(.dbd.O)N(CH.sub.3).sub.2,
--C.sub.3H.sub.6--C(.dbd.O)NH.sub.2,
--C.sub.3H.sub.6--C(.dbd.O)N(CH.sub.3).sub.2,
--CH.sub.2--C(.dbd.O)--Het, C.sub.2H.sub.4--C(.dbd.O)--Het,
--C.sub.3H.sub.6--C(.dbd.O)--Het,
O--CH.sub.2--C(.dbd.O)OC.sub.3H.sub.7,
O--C.sub.2H.sub.4--C(.dbd.O)OC.sub.3H.sub.7,
O--C.sub.3H.sub.6--C(.dbd.O)OC.sub.3H.sub.7, --CH.sub.2--Het,
--C.sub.2H.sub.4-Het, --C.sub.3H.sub.6-Het, --CH.sub.2-cyclopropyl,
--C.sub.2H.sub.4-cyclopropyl, --C.sub.3H.sub.6-cyclopropyl,
--CH.sub.2-cyclobutyl, --C.sub.2H.sub.4-cyclobutyl,
--C.sub.3H.sub.6-cyclobutyl, --CH.sub.2-cyclopentyl,
--C.sub.2H.sub.4-cyclopentyl, --C.sub.3H.sub.6-cyclopentyl,
--CH.sub.2-cyclohexyl, --C.sub.2H.sub.4-cyclohexyl,
--C.sub.3H.sub.6-cyclohexyl, O--CH.sub.2--NH.sub.2,
O--C.sub.2H.sub.4--NH.sub.2, O--C.sub.3H.sub.6--NH.sub.2,
O--CH.sub.2--N(CH.sub.3).sub.2,
O--C.sub.2H.sub.4--N(CH.sub.3).sub.2,
O--C.sub.3H.sub.6--N(CH.sub.3).sub.2, O--CH.sub.2--Het,
O--C.sub.2H.sub.4-Het, O--C.sub.3H.sub.6-Het,
O--CH.sub.2--C(.dbd.O)OH, O--C.sub.2H.sub.4--C(.dbd.O)OH,
O--C.sub.3H.sub.6--C(.dbd.O)OH, O--CH.sub.2--C(.dbd.O)OCH.sub.3,
O--C.sub.2H.sub.4--C(.dbd.O)OCH.sub.3,
O--C.sub.3H.sub.6--C(.dbd.O)OCH.sub.3, O--CH.sub.2--C(.dbd.O)--Het,
O--CH.sub.2C(CH.sub.3)(CH.sub.2OH).sub.2, S--C.sub.2H.sub.4OH,
S--C.sub.3H.sub.6OH, SO.sub.2-phenyl, SO.sub.2-methylphenyl,
--SO.sub.2-ethylphenyl, --SO.sub.2-cyclopropyl,
--SO.sub.2-cyclobutyl, --SO.sub.2-cyclopentyl,
--SO.sub.2--C.sub.2H.sub.4-Het, --SO.sub.2CH.sub.3,
--SO.sub.2C.sub.2H.sub.5, --SO.sub.2C.sub.3H.sub.7,
--SO.sub.2C.sub.2H.sub.4OH, and --SO.sub.2C.sub.3H.sub.6OH; wherein
Het is independently selected from piperidinyl, morpholinyl,
piperazinyl, azepanyl, imidazolyl, oxetanyl, azetidinyl,
pyrrolidinyl, tetrahydropyridinyl, 2-oxa-7-azaspiro[3.5]nonanyl,
2-oxa-6-azaspiro[3.4]octanyl, and 6-oxa-1-azaspiro[3.3]heptanyl,
wherein each of the piperidinyl, morpholinyl, piperazinyl,
azepanyl, imidazolyl, oxetanyl, azetidinyl, pyrrolidinyl,
tetrahydropyridinyl, 2-oxa-7-azaspiro[3.5]nonanyl,
2-oxa-6-azaspiro[3.4]octanyl, 6-oxa-1-azaspiro[3.3]heptanyl,
cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl moieties is
optionally substituted with one, two, three, or four members
independently selected from fluoro, chloro, methyl, ethyl, propyl,
oxo, or phenyl. In some other embodiments of formulae (J) or (I),
each R.sup.2 is independently fluoro, chloro, bromo, iodo, cyano,
methyl, ethyl, propyl, fluoromethyl, difluoromethyl,
trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, and
SO.sub.2NH.sub.2. In certain other embodiments of formulae (J) or
(I), R.sup.3 is methyl, ethyl, propyl,
--CH.sub.2--C(.dbd.O)NH.sub.2, --C.sub.2H.sub.4--C(.dbd.O)NH.sub.2,
--C.sub.3H.sub.6--C(.dbd.O)NH.sub.2,
--CH.sub.2--C(.dbd.O)N(CH.sub.3).sub.2,
--C.sub.2H.sub.4--C(.dbd.O)N(CH.sub.3).sub.2,
--C.sub.3H.sub.6--C(.dbd.O)N(CH.sub.3).sub.2, cyclopropyl,
cyclobutyl, or phenyl. In certain embodiments, R.sup.3 is
--CH.sub.2--C(.dbd.O)NH.sub.2, --C.sub.2H.sub.4--C(.dbd.O)NH.sub.2,
--C.sub.3H.sub.6--C(.dbd.O)NH.sub.2,
--CH.sub.2--C(.dbd.O)N(CH.sub.3).sub.2,
--C.sub.2H.sub.4--C(.dbd.O)N(CH.sub.3).sub.2,
--C.sub.3H.sub.6--C(.dbd.O)N(CH.sub.3).sub.2, cyclopropyl,
cyclobutyl, or phenyl. In certain embodiments, R.sup.3 is methyl,
ethyl or cyclopropyl. In additional embodiments of formulae (J) or
(I), R.sup.5 is hydrogen, methyl, ethyl, or propyl. In other
additional embodiments, R.sup.5 and R.sup.3 together with the atoms
to which they are attached optionally form a heterocyclic ring,
wherein the heterocyclic ring is selected from azetidinyl,
morpholinyl, or pyrrolidinyl, wherein each of the azetidinyl,
morpholinyl, and pyrrolidinyl moieties is optionally substituted
with N(CH.sub.3)C(.dbd.O)CH.sub.2NH.sub.2,
N(CH.sub.3)C(.dbd.O)CHF.sub.2,
N(CH.sub.3)C(.dbd.O)CH.sub.2CF.sub.3,
N(CH.sub.3)C(.dbd.O)cyclopropyl, NHC(.dbd.O)CH.sub.2NH.sub.2,
NHC(.dbd.O)CHF.sub.2, NHC(.dbd.O)CH.sub.2CF.sub.3, or
NHC(.dbd.O)cyclopropyl. In certain embodiments. R.sup.5 and R.sup.3
together with the atoms to which they are attached optionally form
a heterocyclic ring, wherein the heterocyclic ring is selected from
azetidinyl, morpholinyl, or pyrrolidinyl, wherein each of the
azetidinyl, morpholinyl, and pyrrolidinyl moieties is optionally
substituted with C.sub.1-4 alkyl, halo,
N(CH.sub.3)C(.dbd.O)CH.sub.2NH.sub.2,
N(CH.sub.3)C(.dbd.O)CHF.sub.2,
N(CH.sub.3)C(.dbd.O)CH.sub.2CF.sub.3,
N(CH.sub.3)C(.dbd.O)cyclopropyl, NHC(.dbd.O)CH.sub.2NH.sub.2,
NHC(.dbd.O)CHF.sub.2, NHC(.dbd.O)CH.sub.2CF.sub.3,
NHC(.dbd.O)CH.sub.2cyclopropyl or NHC(.dbd.O)cyclopropyl. In
another embodiments of formulae (J) or (I), R.sup.4 is cyano,
chloro, bromo, iodo, or C(.dbd.O)CH.sub.3. In yet another
embodiments of formulae (J) or (I), R.sup.6 is NH.sub.2, chloro,
fluoro, methyl, ethyl, or propyl; and R.sup.7 is NH.sub.2, fluoro,
chloro, methyl, ethyl, or propyl.
[0200] In certain embodiments, R.sup.5 and R.sup.3 together with
the atoms to which they are attached optionally form a heterocyclic
ring, wherein the heterocyclic ring is selected from azetidinyl,
morpholinyl, or pyrrolidinyl, wherein each of the azetidinyl,
morpholinyl, and pyrrolidinyl moieties is optionally substituted
with 1, 2 or 3 groups which are independently C.sub.1-4 alkyl,
methoxy, ethoxy, halo, N(CH.sub.3)C(.dbd.O)CH.sub.2NH.sub.2,
N(CH.sub.3)C(.dbd.O)CHF.sub.2,
N(CH.sub.3)C(.dbd.O)CH.sub.2CF.sub.3,
N(CH.sub.3)C(.dbd.O)cyclopropyl, NHC(.dbd.O)CH.sub.2NH.sub.2,
NHC(.dbd.O)CHF.sub.2, NHC(.dbd.O)CH.sub.2CF.sub.3,
NHC(.dbd.O)CH.sub.2cyclopropyl or NHC(.dbd.O)cyclopropyl; and each
R.sup.1 is independently chloro, fluoro, cyano, methyl,
SO.sub.2-phenyl, --SO.sub.2CH.sub.3, or
--C.sub.3H.sub.6--C(.dbd.O)OH.
[0201] In certain embodiments. R.sup.5 and R.sup.3 together with
the atoms to which they are attached optionally form a heterocyclic
ring, wherein the heterocyclic ring is selected from azetidinyl,
morpholinyl, or pyrrolidinyl, wherein each of the azetidinyl,
morpholinyl, and pyrrolidinyl moieties is optionally substituted
with C.sub.1-4 alkyl, halo, N(CH.sub.3)C(.dbd.O)CH.sub.2NH.sub.2,
N(CH.sub.3)C(.dbd.O)CHF.sub.2,
N(CH.sub.3)C(.dbd.O)CH.sub.2CF.sub.3,
N(CH.sub.3)C(.dbd.O)cyclopropyl, NHC(.dbd.O)CH.sub.2NH.sub.2,
NHC(.dbd.O)CHF.sub.2, NHC(.dbd.O)CH.sub.2CF.sub.3,
NHC(.dbd.O)CH.sub.2cyclopropyl or NHC(.dbd.O)cyclopropyl; and each
R.sup.1 is independently chloro, fluoro, cyano, methyl,
SO.sub.2-phenyl, --SO.sub.2CH.sub.3, or
--C.sub.3H.sub.6--C(.dbd.O)OH.
[0202] In certain embodiments of a compound of the present
application, R.sup.3 is methyl; n is 1 or 2; and one R.sup.1 is
tetrahydropyridinyl, CH.sub.2--C(.dbd.O)OH,
--C.sub.2H.sub.4--C(.dbd.O)OH, --C.sub.3H.sub.6--C(.dbd.O)OH,
--CH.sub.2--C(.dbd.O)NH.sub.2,
--CH.sub.2--C(.dbd.O)N(CH.sub.3).sub.2,
--C.sub.2H.sub.4--C(.dbd.O)NH.sub.2,
--C.sub.2H.sub.4--C(.dbd.O)N(CH.sub.3).sub.2,
--C.sub.3H.sub.6--C(.dbd.O)NH.sub.2,
--C.sub.3H.sub.6--C(.dbd.O)N(CH.sub.3).sub.2,
--CH.sub.2--C(.dbd.O)--Het, C.sub.2H.sub.4--C(.dbd.O)--Het,
--C.sub.3H.sub.6--C(.dbd.O)--Het,
O--CH.sub.2--C(.dbd.O)OC.sub.3H.sub.7,
O--C.sub.2H.sub.4--C(.dbd.O)OC.sub.3H.sub.7,
O--C.sub.3H.sub.6--C(.dbd.O)OC.sub.3H.sub.7, --CH.sub.2--Het,
--C.sub.2H.sub.4-Het, --C.sub.3H.sub.6-Het, --CH.sub.2-cyclopropyl,
--C.sub.2H.sub.4-cyclopropyl, --C.sub.3H.sub.6-cyclopropyl,
--CH.sub.2-cyclobutyl, --C.sub.2H.sub.4-cyclobutyl,
--C.sub.3H.sub.6-cyclobutyl, --CH.sub.2-cyclopentyl,
--C.sub.2H.sub.4-cyclopentyl, --C.sub.3H.sub.6-cyclopentyl,
--CH.sub.2-- cyclohexyl, --C.sub.2H.sub.4-cyclohexyl,
--C.sub.3H.sub.6-cyclohexyl, O--CH.sub.2--NH.sub.2,
O--C.sub.2H.sub.4--NH.sub.2, O--C.sub.3H.sub.6--NH.sub.2,
O--CH.sub.2--N(CH.sub.3).sub.2,
O--C.sub.2H.sub.4--N(CH.sub.3).sub.2,
O--C.sub.3H.sub.6--N(CH.sub.3).sub.2, O--CH.sub.2--Het,
O--C.sub.2H.sub.4-Het, O--C.sub.3H.sub.6-Het,
O--CH.sub.2--C(.dbd.O)OH, O--C.sub.2H.sub.4--C(.dbd.O)OH,
O--C.sub.3H.sub.6--C(.dbd.O)OH, O--CH.sub.2--C(.dbd.O)OCH.sub.3,
O--C.sub.2H.sub.4--C(.dbd.O)OCH.sub.3,
O--C.sub.3H.sub.6--C(.dbd.O)OCH.sub.3, O--CH.sub.2--C(.dbd.O)--Het,
O--CH.sub.2C(CH.sub.3)(CH.sub.2OH).sub.2, S--C.sub.2H.sub.4OH,
S--C.sub.3H.sub.6OH, SO.sub.2-phenyl, SO.sub.2-methylphenyl,
--SO.sub.2-ethylphenyl, --SO.sub.2-cyclopropyl,
--SO.sub.2-cyclobutyl, --SO.sub.2-cyclopentyl,
SO.sub.2--C.sub.2H.sub.4-Het, --SO.sub.2CH.sub.3,
--SO.sub.2C.sub.2H.sub.5, --SO.sub.2C.sub.3H.sub.7,
--SO.sub.2C.sub.2H.sub.4OH, or --SO.sub.2C.sub.3H.sub.6OH; wherein
Het is independently selected from piperidinyl, morpholinyl,
piperazinyl, azepanyl, imidazolyl, oxetanyl, azetidinyl,
pyrrolidinyl, tetrahydropyridinyl, 2-oxa-7-azaspiro[3.5]nonanyl,
2-oxa-6-azaspiro[3.4]octanyl, and 6-oxa-1-azaspiro[3.3]heptanyl,
wherein each of the piperidinyl, morpholinyl, piperazinyl,
azepanyl, imidazolyl, oxetanyl, azetidinyl, pyrrolidinyl,
tetrahydropyridinyl, 2-oxa-7-azaspiro[3.5]nonanyl,
2-oxa-6-azaspiro[3.4]octanyl, 6-oxa-1-azaspiro[3.3]heptanyl,
cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl moieties is
optionally substituted with one, two, three, or four members
independently selected from fluoro, chloro, methyl, ethyl, propyl,
oxo or phenyl.
[0203] In certain embodiments of a compound of the present
application, R.sup.3 is methyl; n is 1 or 2; and one R.sup.1 is
tetrahydropyridinyl, CH.sub.2--C(.dbd.O)OH,
--C.sub.2H.sub.4--C(.dbd.O)OH, --C.sub.3H.sub.6--C(.dbd.O)OH,
--CH.sub.2--C(.dbd.O)NH.sub.2,
--CH.sub.2--C(.dbd.O)N(CH.sub.3).sub.2,
--C.sub.2H.sub.4--C(.dbd.O)NH.sub.2,
--C.sub.2H.sub.4--C(.dbd.O)N(CH.sub.3).sub.2,
--C.sub.3H.sub.6--C(.dbd.O)NH.sub.2,
--C.sub.3H.sub.6--C(.dbd.O)N(CH.sub.3).sub.2,
--CH.sub.2--C(.dbd.O)--Het, C.sub.2H.sub.4--C(.dbd.O)--Het,
--C.sub.3H.sub.6--C(.dbd.O)-Het, O--CH.sub.2--C(.dbd.O)OCH.sub.3,
O--C.sub.2H.sub.4--C(.dbd.O)OC.sub.3H.sub.7,
O--C.sub.3H.sub.6--C(.dbd.O)OC.sub.3H.sub.7, --CH.sub.2--Het,
--C.sub.2H.sub.4-Het, --C.sub.3H.sub.6-Het, --CH.sub.2-cyclopropyl,
--C.sub.2H.sub.4-cyclopropyl, --C.sub.3H.sub.6-cyclopropyl,
--CH.sub.2-cyclobutyl, --C.sub.2H.sub.4-cyclobutyl,
--C.sub.3H.sub.6-cyclobutyl, --CH.sub.2-cyclopentyl,
--C.sub.2H.sub.4-cyclopentyl, --C.sub.3H.sub.6-cyclopentyl,
--CH.sub.2-- cyclohexyl, --C.sub.2H.sub.4-cyclohexyl,
--C.sub.3H.sub.6-cyclohexyl, O--CH.sub.2--NH.sub.2,
O--C.sub.2H.sub.4--NH.sub.2, O--C.sub.3H.sub.6--NH.sub.2,
O--CH.sub.2--N(CH.sub.3).sub.2,
O--C.sub.2H.sub.4--N(CH.sub.3).sub.2,
O--C.sub.3H.sub.6--N(CH.sub.3).sub.2, O--CH.sub.2--Het,
O--C.sub.2H.sub.4-Het, O--C.sub.3H.sub.6-Het,
O--CH.sub.2--C(.dbd.O)OH, O--C.sub.2H.sub.4--C(.dbd.O)OH,
O--C.sub.3H.sub.6--C(.dbd.O)OH, O--CH.sub.2--C(.dbd.O)OCH.sub.3,
O--C.sub.2H.sub.4--C(.dbd.O)OCH.sub.3,
O--C.sub.3H.sub.6--C(.dbd.O)OCH.sub.3, O--CH.sub.2--C(.dbd.O)--Het,
O--CH.sub.2C(CH.sub.3)(CH.sub.2OH).sub.2, S--C.sub.2H.sub.4OH,
S--C.sub.3H.sub.6OH, SO.sub.2-phenyl, SO.sub.2-methylphenyl,
--SO.sub.2-ethylphenyl, --SO.sub.2C.sub.2H.sub.4OH, and
--SO.sub.2C.sub.3H.sub.6OH; wherein Het is independently selected
from piperidinyl, morpholinyl, piperazinyl azepanyl, imidazolyl,
oxetanyl, azetidinyl, pyrrolidinyl, tetrahydropyridinyl,
2-oxa-7-azaspiro[3.5]nonanyl, 2-oxa-6-azaspiro[3.4]octanyl, and
6-oxa-1-azaspiro[3.3]heptanyl, wherein each of the piperidinyl,
morpholinyl, piperazinyl, azepanyl, imidazolyl, oxetanyl,
azetidinyl, pyrrolidinyl, tetrahydropyridinyl,
2-oxa-7-azaspiro[3.5]nonanyl, 2-oxa-6-azaspiro[3.4]octanyl,
6-oxa-1-azaspiro[3.3]heptanyl, cyclopropyl, cyclobutyl,
cyclopentyl, and cyclohexyl moieties is optionally substituted with
one, two, three, or four members independently selected from
fluoro, chloro, methyl, ethyl, propyl, oxo or phenyl.
[0204] In certain embodiments, when n is 1, 2, 3, or 4, the R.sup.1
substituents may be listed individually as R.sup.1a, R.sup.1b,
R.sup.1c, or R.sup.1d respectively. In certain embodiments, when m
is 1, 2, 3, or 4, the R.sup.2 substituents may be listed
individually as R.sup.2a, R.sup.2b, R.sup.2c, or R.sup.2d
respectively
[0205] In certain embodiments of a compound of the present
application, R.sup.1 is independently methyl, chloro, fluoro, or
cyano; R.sup.3 is methyl or ethyl; R.sup.4 is cyano or halo;
R.sup.6 is NH.sub.2, halo, or C.sub.1-4 alkyl; and R.sup.7 is
NH.sub.2, halo, or C.sub.1-4 alkyl; wherein only one of R.sup.6 and
R.sup.7 is NH.sub.2.
[0206] In certain embodiments of the compounds of the present
application, each R.sup.1 is independently methyl, chloro, fluoro,
cyano, tetrahydropyridinyl, --CH.sub.2--C(.dbd.O)OH,
--C.sub.2H.sub.4--C(.dbd.O)OH, --C.sub.3H.sub.6--C(.dbd.O)OH,
--CH.sub.2--C(.dbd.O)NH.sub.2,
--CH.sub.2--C(.dbd.O)N(CH.sub.3).sub.2,
--C.sub.2H.sub.4--C(.dbd.O)NH.sub.2,
--C.sub.2H.sub.4--C(.dbd.O)N(CH.sub.3).sub.2,
--C.sub.3H.sub.6--C(.dbd.O)NH.sub.2,
--C.sub.3H.sub.6--C(.dbd.O)N(CH.sub.3).sub.2,
--CH.sub.2--C(.dbd.O)--Het, C.sub.2H.sub.4--C(.dbd.O)--Het,
--C.sub.3H.sub.6--C(.dbd.O)--Het,
O--CH.sub.2--C(.dbd.O)OC.sub.3H.sub.7,
O--C.sub.2H.sub.4--C(.dbd.O)OC.sub.3H.sub.7,
O--C.sub.3H.sub.6--C(.dbd.O)OC.sub.3H.sub.7, --CH.sub.2--Het,
--C.sub.2H.sub.4-Het, --C.sub.3H.sub.6-Het, --CH.sub.2-cyclopropyl,
--C.sub.2H.sub.4-cyclopropyl, --C.sub.3H.sub.6-cyclopropyl,
--CH.sub.2-- cyclobutyl, --C.sub.2H.sub.4-cyclobutyl,
--C.sub.3H.sub.6-cyclobutyl, --CH.sub.2-cyclopentyl,
--C.sub.2H.sub.4-cyclopentyl, --C.sub.3H.sub.6-cyclopentyl,
--CH.sub.2-cyclohexyl, --C.sub.2H.sub.4-cyclohexyl,
--C.sub.3H.sub.6-cyclohexyl, O--CH.sub.2--NH.sub.2,
O--C.sub.2H.sub.4--NH.sub.2, O--C.sub.3H.sub.6--NH.sub.2,
O--CH.sub.2--N(CH.sub.3).sub.2,
O--C.sub.2H.sub.4--N(CH.sub.3).sub.2,
O--C.sub.3H.sub.6--N(CH.sub.3).sub.2, O--CH.sub.2--Het,
O--C.sub.2H.sub.4- Het, O--C.sub.3H.sub.6-Het,
O--CH.sub.2--C(.dbd.O)OH, O--C.sub.2H.sub.4--C(.dbd.O)OH,
O--C.sub.3H.sub.6--C(.dbd.O)OH, O--CH.sub.2--C(.dbd.O)OCH.sub.3,
O--C.sub.2H.sub.4--C(.dbd.O)OCH.sub.3,
O--C.sub.3H.sub.6--C(.dbd.O)OCH.sub.3, O--CH.sub.2--C(.dbd.O)--Het,
O--CH.sub.2C(CH.sub.3)(CH.sub.2OH).sub.2, S--C.sub.2H.sub.4OH,
S--C.sub.3H.sub.6OH, SO.sub.2-phenyl, SO.sub.2-methylphenyl,
--SO.sub.2-ethylphenyl, --SO.sub.2-cyclopropyl,
--SO.sub.2-cyclobutyl, --SO.sub.2-cyclopentyl,
--SO.sub.2C.sub.2H.sub.4-Het, --SO.sub.2CH.sub.3,
--SO.sub.2C.sub.2H.sub.5, --SO.sub.2C.sub.3H.sub.7,
--SO.sub.2C.sub.2H.sub.4OH, and --SO.sub.2C.sub.3H.sub.6OH; wherein
Het is independently selected from piperidinyl, morpholinyl,
piperazinyl, azepanyl, imidazolyl, oxetanyl, azetidinyl,
pyrrolidinyl, tetrahydropyridinyl, 2-oxa-7-azaspiro[3.5]nonanyl,
2-oxa-6-azaspiro[3.4]octanyl, and 6-oxa-1-azaspiro[3.3]heptanyl,
wherein each of the piperidinyl, morpholinyl, piperazinyl,
azepanyl, imidazolyl, oxetanyl, azetidinyl, pyrrolidinyl,
tetrahydropyridinyl, 2-oxa-7-azaspiro[3.5]nonanyl,
2-oxa-6-azaspiro[3.4]octanyl, 6-oxa-1-azaspiro[3.3]heptanyl,
cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl moieties is
optionally substituted with one, two, three, or four members
independently selected from fluoro, chloro, methyl, ethyl, propyl,
oxo, or phenyl.
[0207] In one embodiment, n is 0. In other embodiments, n is 1, 2
or 3. In certain embodiments, n is 1 or 2. In one embodiment, n is
1 and the R.sup.1 moiety (e.g. R.sup.1a) may be located on any
position of the phenyl of the quinazolinone ring, as depicted
below.
##STR00009##
[0208] In another embodiment, n is 2. In embodiments where n is 2,
both R.sup.1 may be the same or different. Two R.sup.1 moieties may
be located of any two positions of the phenyl of the quinazolinone
ring as depicted below. For example, two R.sup.1 moieties (e.g.
R.sup.1a and R.sup.1b) may be in para-, meta- or ortho-positions to
each other.
##STR00010##
[0209] In yet another embodiment, n is 3. In embodiments where n is
3, all R.sup.1 may be the same or different, or two R.sup.1 may be
the same and different from the third R.sup.1. Three R.sup.1
moieties (e.g. R.sup.1a, R.sup.1b, and R.sup.1c) may be located on
any three positions of the phenyl of the quinazolinone ring as
depicted below. For example, the first R.sup.1 may be ortho to the
second R.sup.1, and the first R.sup.1 may be para to the third
R.sup.1.
##STR00011##
[0210] In embodiments where n is 4, all R.sup.1 (e.g. R.sup.1a,
R.sup.1b, R.sup.1c, and R.sup.1d) may be the same or different.
Also, three R.sup.1 moieties may be the same or different from the
fourth R.sup.1 moiety, or two R.sup.1 moieties may be the same or
different from the third or fourth R1 moieties. All four R.sup.1
moieties (e.g. R.sup.1a, R.sup.1b, R.sup.1c, and R.sup.1d) may be
located at any position of the phenyl of the quinazolinone ring. In
any of the foregoing embodiments, each of R.sup.1a, R.sup.1b,
R.sup.1c, and R.sup.1d is independently selected from the moieties
defined as R.sup.1 described herein.
[0211] In one embodiment, each R.sup.1 is independently
C.sub.1-6alkyl, C.sub.1-6haloalkyl, C.sub.3-8cycloalkyl,
C.sub.2-8heterocycloalkyl, C.sub.3-8heteroaryl, C.sub.6-10aryl,
halo, cyano, C.sub.6-10aryl-OR.sup.1y,
C.sub.1-6alkylene-C.sub.6-10aryl, C.sub.1-6alkylene-Het,
C.sub.1-6alkylene-C.sub.3-8cycloalkyl, C.sub.1-6alkylene-OR.sup.1y,
C.sub.1-6alkylene-N(R.sup.1x).sub.2, C.sub.2-6alkenylene-OR.sup.1y,
C.sub.2-6alkenylene-N(R.sup.1x).sub.2,
C.sub.1-6alkylene-C(.dbd.O)OR.sup.1x,
C.sub.1-6alkylene-C(.dbd.O)N(R.sup.1X).sub.2,
C.sub.1-6alkylene-C(.dbd.O)--Het,
O--C.sub.1-6alkylene-C(.dbd.O)OR.sup.1x,
C.sub.1-6alkylene-O--C.sub.1-6alkylene-C(.dbd.O)OR.sup.1x,
C.sub.1-6alkenylene-N(R.sup.1x).sub.2, OR.sup.1x,
O--C.sub.1-6alkylene-N(R.sup.1z).sub.2,
O--C.sub.1-6alkylene-CH(OR.sup.1y)CH.sub.2N(R.sup.1x).sub.2,
O--C.sub.1-6alkylene-Het, O--C.sub.1-6alkylene-C(.dbd.O)OR.sup.1x,
O--C.sub.1-6alkylene-C(.dbd.O)-Het, O--C.sub.1-6alkylene-OR.sup.1x,
O--C.sub.1-6alkylene-CH(OR.sup.1y)C.sub.1-6alkylene-OR.sup.1x,
O--C.sub.2-6alkenylene-OR.sup.1y,
O--C.sub.2-6alkenylene-N(R.sup.1x).sub.2,
O--C.sub.1-6alkylene-NR.sup.1xC(.dbd.O)OR.sup.1x,
O--C.sub.1-6alkylene-O--C.sub.1-6alkylene-C(.dbd.O)OR.sup.1y,
SO.sub.2R.sup.1z, S--C.sub.1-6alkylene-OR.sup.1x, and
SO.sub.2N(R.sup.1x).sub.2; wherein Het is heteroaryl or
heterocycloalkyl, wherein R.sup.1x is independently hydrogen,
C.sub.1-6alkyl, C.sub.1-6haloalkyl, C.sub.3-8cycloalkyl, aryl,
heterocycloalkyl, and C.sub.3-8heteroaryl, wherein R.sup.1y is
independently hydrogen, C.sub.1-6alkyl, C.sub.1-6haloalkyl, aryl,
and heteroaryl, wherein R.sup.1z is independently hydrogen,
C.sub.1-6alkyl, C.sub.1-6haloalkyl, C.sub.3-8cycloalkyl, aryl,
heterocycloalkyl, and C.sub.3-8heteroaryl, and wherein each of Het,
R.sup.1x, R.sup.1y, and R.sup.1z is optionally substituted with
one, two, three, or four members independently selected from halo,
oxo, C.sub.1-6alkyl, and C.sub.6-10aryl. In some embodiments, Het
is a seven- to nine-membered spiro-heterocycloalkyl which is
optionally substituted, wherein the spiro-heterocycloalkyl has at
least two heteroatoms which are independently selected from
nitrogen, oxygen, or sulfur. In some additional embodiments, Het is
a seven- to nine-membered spiro-heterocycloalkyl selected from the
group consisting of 2-oxa-7-azaspiro[3.5]nonanyl,
2-oxa-6-azaspiro[3.4]octanyl, and 6-oxa-1-azaspiro[3.3]heptanyl,
each of which is optionally substituted one, two, three, or four
members independently selected from halo, oxo, C.sub.1-6alkyl, and
C.sub.6-10aryl. In certain embodiments, Het is a four- to
seven-membered heterocycloalkyl which is optionally substituted,
wherein the heterocycloalkyl is a single ring having at least one
heteroatom which is independently selected from nitrogen, oxygen,
or sulfur. In certain other embodiments, Het is a four- to
eight-membered heterocycloalkyl selected from the group consisting
of piperidinyl, morpholinyl, piperazinyl, azepanyl, imidazolyl,
oxetanyl, azetidinyl, pyrrolidinyl, and tetrahydropyridinyl, each
of which is optionally substituted one, two, three, or four members
independently selected from halo, oxo, C.sub.1-6alkyl, and
C.sub.6-10aryl. In further embodiments, Het is independently
selected from 2-oxa-7-azaspiro[3.5]nonanyl,
2-oxa-6-azaspiro[3.4]octanyl, 6-oxa-1-azaspiro[3.3]heptanyl,
piperidinyl, morpholinyl, piperazinyl, azepanyl, imidazolyl,
oxetanyl, azetidinyl, pyrrolidinyl, and tetrahydropyridinyl,
wherein Het is optionally substituted with one, two, three, or four
members independently selected from fluoro, chloro, oxo, methyl,
ethyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl,
difluoroethyl, trifluoroethyl, and phenyl.
[0212] In certain embodiments of a compound of the present
application, n is 1 or 2, and one R.sup.1 is tetrahydropyridinyl,
CH.sub.2--C(.dbd.O)OH, --C.sub.2H.sub.4--C(.dbd.O)OH,
--C.sub.3H.sub.6--C(.dbd.O)OH, --CH.sub.2--C(.dbd.O)NH.sub.2,
--CH.sub.2--C(.dbd.O)N(CH.sub.3).sub.2,
--C.sub.2H.sub.4--C(.dbd.O)NH.sub.2,
--C.sub.2H.sub.4--C(.dbd.O)N(CH.sub.3).sub.2,
--C.sub.3H.sub.6--C(.dbd.O)NH.sub.2,
--C.sub.3H.sub.6--C(.dbd.O)N(CH.sub.3).sub.2,
--CH.sub.2--C(.dbd.O)--Het, C.sub.2H.sub.4--C(.dbd.O)--Het,
--C.sub.3H.sub.6--C(.dbd.O)--Het,
O--CH.sub.2--C(.dbd.O)OC.sub.3H.sub.7,
O--C.sub.2H.sub.4--C(.dbd.O)OC.sub.3H.sub.7,
O--C.sub.3H.sub.6--C(.dbd.O)OC.sub.3H.sub.7, --CH.sub.2--Het,
--C.sub.2H.sub.4-Het, --C.sub.3H.sub.6-Het, --CH.sub.2-cyclopropyl,
--C.sub.2H.sub.4-cyclopropyl, --C.sub.3H.sub.6-cyclopropyl,
--CH.sub.2-cyclobutyl, --C.sub.2H.sub.4-cyclobutyl,
--C.sub.3H.sub.6-cyclobutyl, --CH.sub.2-cyclopentyl,
--C.sub.2H.sub.4-cyclopentyl, --C.sub.3H.sub.6-cyclopentyl,
--CH.sub.2-cyclohexyl, --C.sub.2H.sub.4-cyclohexyl,
--C.sub.3H.sub.6-cyclohexyl, O--CH.sub.2--NH.sub.2,
O--C.sub.2H.sub.4--NH.sub.2, O--C.sub.3H.sub.6--NH.sub.2,
O--CH.sub.2--N(CH.sub.3).sub.2,
O--C.sub.2H.sub.4--N(CH.sub.3).sub.2,
O--C.sub.3H.sub.6--N(CH.sub.3).sub.2, O--CH.sub.2--Het,
O--C.sub.2H.sub.4-Het, O--C.sub.3H.sub.6-Het,
O--CH.sub.2--C(.dbd.O)OH, O--C.sub.2H.sub.4--C(.dbd.O)OH,
O--C.sub.3H.sub.6--C(.dbd.O)OH, O--CH.sub.2--C(.dbd.O)OCH.sub.3,
O--C.sub.2H.sub.4--C(.dbd.O)OCH.sub.3,
O--C.sub.3H.sub.6--C(.dbd.O)OCH.sub.3, O--CH.sub.2--C(.dbd.O)--Het,
O--CH.sub.2C(CH.sub.3)(CH.sub.2OH).sub.2, S--C.sub.2H.sub.4OH,
S--C.sub.3H.sub.6OH, SO.sub.2-phenyl, SO.sub.2-methylphenyl,
--SO.sub.2-ethylphenyl, --SO.sub.2-cyclopropyl,
--SO.sub.2-cyclobutyl, --SO.sub.2-cyclopentyl,
SO.sub.2--C.sub.2H.sub.4-Het, --SO.sub.2CH.sub.3,
--SO.sub.2C.sub.2H.sub.5, --SO.sub.2C.sub.3H.sub.7,
--SO.sub.2C.sub.2H.sub.4OH, or --SO.sub.2C.sub.3H.sub.6OH; wherein
Het is independently selected from piperidinyl, morpholinyl,
piperazinyl, azepanyl, imidazolyl, oxetanyl, azetidinyl,
pyrrolidinyl, tetrahydropyridinyl, 2-oxa-7-azaspiro[3.5]nonanyl,
2-oxa-6-azaspiro[3.4]octanyl, and 6-oxa-1-azaspiro[3.3]heptanyl,
wherein each of the piperidinyl, morpholinyl, piperazinyl,
azepanyl, imidazolyl, oxetanyl, azetidinyl, pyrrolidinyl,
tetrahydropyridinyl, 2-oxa-7-azaspiro[3.5]nonanyl,
2-oxa-6-azaspiro[3.4]octanyl, 6-oxa-1-azaspiro[3.3]heptanyl,
cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl moieties is
optionally substituted with one, two, three, or four members
independently selected from fluoro, chloro, methyl, ethyl, propyl,
oxo, or phenyl.
[0213] In certain embodiments of a compound of the present
application, n is 1 or 2, and one R.sup.1 is tetrahydropyridinyl,
CH.sub.2--C(.dbd.O)OH, --C.sub.2H.sub.4--C(.dbd.O)OH,
--C.sub.3H.sub.6--C(.dbd.O)OH, --CH.sub.2--C(.dbd.O)NH.sub.2,
--CH.sub.2--C(.dbd.O)N(CH.sub.3).sub.2,
--C.sub.2H.sub.4--C(.dbd.O)NH.sub.2,
--C.sub.2H.sub.4--C(.dbd.O)N(CH.sub.3).sub.2,
--C.sub.3H.sub.6--C(.dbd.O)NH.sub.2,
--C.sub.3H.sub.6--C(.dbd.O)N(CH.sub.3).sub.2,
--CH.sub.2--C(.dbd.O)--Het, C.sub.2H.sub.4--C(.dbd.O)-Het,
--C.sub.3H.sub.6--C(.dbd.O)-Het,
O--CH.sub.2--C(.dbd.O)OC.sub.3H.sub.7,
O--C.sub.2H.sub.4--C(.dbd.O)OC.sub.3H.sub.7,
O--C.sub.3H.sub.6--C(.dbd.O)OC.sub.3H.sub.7, --CH.sub.2--Het,
--C.sub.2H.sub.4-Het, --C.sub.3H.sub.6-Het, --CH.sub.2-cyclopropyl,
--C.sub.2H.sub.4-cyclopropyl, --C.sub.3H.sub.6-cyclopropyl,
--CH.sub.2-cyclobutyl, --C.sub.2H.sub.4-cyclobutyl,
--C.sub.3H.sub.6-cyclobutyl, --CH.sub.2-cyclopentyl,
--C.sub.2H.sub.4-cyclopentyl, --C.sub.3H.sub.6-cyclopentyl,
--CH.sub.2-cyclohexyl, --C.sub.2H.sub.4-cyclohexyl,
--C.sub.3H.sub.6-cyclohexyl, O--CH.sub.2--NH.sub.2,
O--C.sub.2H.sub.4--NH.sub.2, O--C.sub.3H.sub.6--NH.sub.2,
O--CH.sub.2--N(CH.sub.3).sub.2,
O--C.sub.2H.sub.4--N(CH.sub.3).sub.2,
O--C.sub.3H.sub.6--N(CH.sub.3).sub.2, O--CH.sub.2--Het,
O--C.sub.2H.sub.4-Het, O--C.sub.3H.sub.6-Het,
O--CH.sub.2--C(.dbd.O)OH, O--C.sub.2H.sub.4--C(.dbd.O)OH,
O--C.sub.3H.sub.6--C(.dbd.O)OH, O--CH.sub.2--C(.dbd.O)OCH.sub.3,
O--C.sub.2H.sub.4--C(.dbd.O)OCH.sub.3,
O--C.sub.3H.sub.6--C(.dbd.O)OCH.sub.3, O--CH.sub.2--C(.dbd.O)--Het,
O--CH.sub.2C(CH.sub.3)(CH.sub.2OH).sub.2, S--C.sub.2H.sub.4OH,
S--C.sub.3H.sub.6OH, SO.sub.2-phenyl, SO.sub.2-methylphenyl,
--SO.sub.2-ethylphenyl, --SO.sub.2-cyclopropyl,
--SO.sub.2-cyclobutyl, --SO.sub.2-cyclopentyl,
SO.sub.2--C.sub.2H.sub.4-Het, --SO.sub.2C.sub.2H.sub.4OH, or
--SO.sub.2C.sub.3H.sub.6OH; wherein Het is independently selected
from piperidinyl, morpholinyl, piperazinyl, azepanyl, imidazolyl,
oxetanyl, azetidinyl, pyrrolidinyl, tetrahydropyridinyl,
2-oxa-7-azaspiro[3.5]nonanyl, 2-oxa-6-azaspiro[3.4]octanyl, and
6-oxa-1-azaspiro[3.3]heptanyl, wherein each of the piperidinyl,
morpholinyl, piperazinyl, azepanyl, imidazolyl, oxetanyl,
azetidinyl, pyrrolidinyl, tetrahydropyridinyl,
2-oxa-7-azaspiro[3.5]nonanyl, 2-oxa-6-azaspiro[3.4]octanyl,
6-oxa-1-azaspiro[3.3]heptanyl, cyclopropyl, cyclobutyl,
cyclopentyl, and cyclohexyl moieties is optionally substituted with
one, two, three, or four members independently selected from
fluoro, chloro, methyl, ethyl, propyl, oxo, or phenyl.
[0214] In certain embodiments of a compound of the present
application, n is 1 or 2, and one R.sup.1 is tetrahydropyridinyl,
--C.sub.2H.sub.4--C(.dbd.O)OH, --C.sub.3H.sub.6--C(.dbd.O)OH,
--C.sub.2H.sub.4--C(.dbd.O)NH.sub.2,
O--CH.sub.2--C(.dbd.O)OC.sub.3H.sub.7, --C.sub.3H.sub.6-Het,
--C.sub.3H.sub.6-cyclohexyl, O--CH.sub.2--Het,
O--C.sub.2H.sub.4-Het, O--C.sub.3H.sub.6-Het,
O--CH.sub.2--C(.dbd.O)--Het,
O--CH.sub.2C(CH.sub.3)(CH.sub.2OH).sub.2, S--C.sub.2H.sub.4OH,
SO.sub.2-phenyl, SO.sub.2-methylphenyl, --SO.sub.2-- cyclopentyl,
and --SO.sub.2C.sub.2H.sub.4OH, wherein Het is independently
selected from piperidinyl, morpholinyl, piperazinyl, azepanyl,
imidazolyl, oxetanyl, pyrrolidinyl, 2-oxa-7-azaspiro[3.5]nonanyl,
2-oxa-6-azaspiro[3.4]octanyl, and 6-oxa-1-azaspiro[3.3]heptanyl,
wherein each of the piperidinyl, morpholinyl, piperazinyl,
azepanyl, imidazolyl, oxetanyl, pyrrolidinyl,
2-oxa-7-azaspiro[3.5]nonanyl, 2-oxa-6-azaspiro[3.4]octanyl,
6-oxa-1-azaspiro[3.3]heptanyl, cyclopentyl, and cyclohexyl moieties
is optionally substituted with one, two, or three members
independently selected from fluoro, chloro, methyl, ethyl, propyl,
oxo, or phenyl.
[0215] In some embodiments, each R.sup.1 is independently selected
from C.sub.1-6alkyl, C.sub.1-6haloalkyl, C.sub.6-10aryl, C.sub.3-8
heteroaryl, C.sub.3-8 cycloalkyl, C.sub.2-8heterocycloalkyl, halo,
cyano, C.sub.1-6alkylene-C(.dbd.O)OH,
C.sub.1-6alkylene-C(.dbd.O)OC.sub.1-6alkyl,
C.sub.1-6alkylene-C(.dbd.O)--C.sub.3-8heterocycloalkyl,
C.sub.1-6alkylene-C(.dbd.O)--C.sub.3-8cycloalkyl,
C.sub.1-6alkylene-C(.dbd.O)NH.sub.2,
C.sub.1-6alkylene-C(.dbd.O)N(C.sub.1-6alkyl).sub.2,
C.sub.1-6alkylene-C(.dbd.O)NHC.sub.1-6alkyl,
C.sub.1-6alkylene-O--C.sub.1-6alkylene-C(.dbd.O)OH,
C.sub.1-6alkylene-O--C.sub.1-6alkylene-C(.dbd.O)OC.sub.1-6alkyl,
C.sub.1-6alkylene-C.sub.6-10aryl,
C.sub.1-6alkylene-C.sub.2-8heteroaryl, C.sub.1-6alkylene-C.sub.2-8
heterocycloalkyl, C.sub.1-6alkylene-C.sub.3-8cycloalkyl,
C.sub.1-6alkylene-OH, C.sub.1-6 alkylene-OC.sub.1-6alkyl,
O--C.sub.1-6alkylene-N(C.sub.1-6alky).sub.2,
O--C.sub.1-6alkylene-NHC.sub.1-6alky,
O--C.sub.1-6alkylene-NH.sub.2,
O--C.sub.1-6alkylene-CH(OH)C.sub.1-6alkylNH.sub.2,
O--C.sub.1-6alkylene-CH(OH)C.sub.1-6alkylN(C.sub.1-6alkyl).sub.2,
O--C.sub.1-6alkylene-CH(OH)C.sub.1-6alkylNHC.sub.1-6alkyl,
O--C.sub.1-6alkylene-CH(OC.sub.1-6alkyl)C.sub.1-6alkylNH.sub.2,
O--C.sub.1-6alkylene-CH(OC.sub.1-6alkyl)C.sub.1-6alkylN(C.sub.1-6alkyl).s-
ub.2,
O--C.sub.1-6alkylene-CH(OC.sub.1-6alkyl)C.sub.1-6alkylNHC.sub.1-6alk-
yl, O--C.sub.1-6alkylene-C.sub.2-8heterocycloalkyl,
O--C.sub.1-6alkylene-C.sub.3-8heteroaryl,
O--C.sub.1-6alkylene-C(.dbd.O)OH,
O--C.sub.1-6alkylene-C(.dbd.O)OC.sub.1-6alkyl,
O--C.sub.1-6alkylene-C(.dbd.O)--C.sub.2-8heterocycloalkyl,
O--C.sub.1-6alkylene-C(.dbd.O)OC.sub.3-8cycloalkyl,
O--C.sub.1-6alkylene-C(.dbd.O)OC.sub.6-10aryl,
O--C.sub.1-6alkylene-OH, O--C.sub.1-6alkylene-OC.sub.3-8cycloalkyl,
O--C.sub.1-6alkylene-OC.sub.1-6alkyl,
O--C.sub.1-6alkylene-CH(OH)C.sub.1-6alkylene-OH,
O--C.sub.1-6alkylene-NHC(.dbd.O)OH,
O--C.sub.1-6alkylene-O--C.sub.1-6alkylene-C(.dbd.O)OH,
S--C.sub.1-6alkylene-OH,
SO.sub.2C.sub.1-6alkylene-C.sub.2-8heterocycloalkyl,
SO.sub.2C.sub.6-10aryl, SO.sub.2C.sub.3-8cycloalkyl,
SO.sub.2C.sub.1-6alkylene-OH, SO.sub.2N(C.sub.1-6alkyl).sub.2, or
SO.sub.2NH.sub.2; wherein each of the C.sub.6-10aryl,
C.sub.3-8cycloalkyl, C.sub.2-8heterocycloalkyl, and
C.sub.3-8heteroaryl moieties is optionally substituted with one,
two, three, or four members independently selected from fluoro,
chloro, oxo, methyl, ethyl, fluoromethyl, difluoromethyl,
trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, and
phenyl. In some additional embodiments, each R.sup.1 is
independently selected from C.sub.1-6alkyl, C.sub.1-6haloalkyl,
C.sub.6-10aryl, C.sub.5-8heteroaryl, C.sub.3-8 cycloalkyl,
C.sub.2-8heterocycloalkyl, halo, cyano,
C.sub.1-6alkylene-C(.dbd.O)OH,
C.sub.1-6alkylene-C(.dbd.O)--C.sub.3-8heterocycloalkyl,
C.sub.1-6alkylene-C(.dbd.O)NH.sub.2,
C.sub.1-6alkylene-C(.dbd.O)N(C.sub.1-6alkyl).sub.2,
C.sub.1-6alkylene-C.sub.2-8heterocycloalkyl,
C.sub.1-6alkylene-C.sub.3-8cycloalkyl,
O--C.sub.1-6alkylene-N(C.sub.1-6alky).sub.2,
O--C.sub.1-6alkylene-C.sub.2-8heterocycloalkyl,
O--C.sub.1-6alkylene-C.sub.3-8heteroaryl,
O--C.sub.1-6alkylene-C(.dbd.O)OC.sub.1-6alkyl,
O--C.sub.1-6alkylene-C(.dbd.O)--C.sub.2-8heterocycloalkyl,
O--C.sub.1-6alkylene-CH(OH)C.sub.1-6alkylene-OH,
S--C.sub.1-6alkylene-OH,
SO.sub.2C.sub.1-6alkylene-C.sub.2-8heterocycloalkyl,
SO.sub.2C.sub.6-10aryl, SO.sub.2C.sub.3-8cycloalkyl, and
SO.sub.2C.sub.1-6alkylene-OH; wherein each of the aryl, cycloalkyl,
and heterocycloalkyl moieties is optionally substituted with one,
two, three, or four members independently selected from fluoro,
chloro, oxo, methyl, ethyl, and phenyl. Each and every variation of
n and R.sup.1 may be combined with each and every variation of W,
m, R.sup.2, R.sup.3 R.sup.4, R.sup.5, R.sup.6, and R.sup.7 as
described for any of the foregoing formulae.
[0216] In some embodiments, m is 0. In other embodiments, m is 1,
2, 3, or 4. In yet other embodiments, m is 1 or 2. In the
embodiment where m is 1, the R.sup.2 moiety may be located on any
position of the phenyl ring, as depicted below.
##STR00012##
[0217] In the embodiment where m is 2, both R.sup.2 may be the same
or different. The two R.sup.2 moieties (e.g. R.sup.2a and R.sup.2b)
may be located on any two positions of the phenyl ring, as depicted
below.
##STR00013##
[0218] In embodiments where m is 3, all R.sup.2 may be the same or
different, or two R.sup.2 may be the same and different from the
third R.sup.2. The three R.sup.2 moieties (e.g. R.sup.2a, R.sup.2b,
and R.sup.2c) may be located on any three positions of the phenyl
ring. In embodiments where m is 4, all four R.sup.2 may be the same
or different, two R.sup.2 may be the same and different from the
third or fourth R.sup.2, or three R.sup.2 may be the same and
different from the fourth R.sup.2. The four R.sup.2 moieties (e.g.
R.sup.2a, R.sup.2bR.sup.2c, and R.sup.2d) may be located on any
three positions of the phenyl ring. In any of the foregoing
embodiments, each of R.sup.2a, R.sup.2b, R.sup.2c, and R.sup.2d is
independently selected from the moieties defined as R.sup.2
described herein.
[0219] In some embodiments, each R.sup.2 is independently halo,
cyano, C.sub.1-6alkyl, C.sub.1-6haloalkyl, and
SO.sub.2N(R.sup.2x).sub.2 where R.sup.2x is hydrogen,
C.sub.1-6alkyl, or C.sub.1-6haloalkyl. In some other embodiments,
each R.sup.2 is independently fluoro, chloro, bromo, iodo, cyano,
methyl, ethyl, propyl, fluoromethyl, difluoromethyl,
trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, and
SO.sub.2NH.sub.2. Accordingly, for compounds having m is 1, 2, 3,
or 4, each R.sup.2a, R.sup.2b, R.sup.2c, or R.sup.2d is
independently halo, cyano, C.sub.1-6alkyl, C.sub.1-6haloalkyl, and
SO.sub.2N(R.sup.2x).sub.2 where R.sup.2x is hydrogen,
C.sub.1-6alkyl, or C.sub.1-6haloalkyl. In certain embodiments where
m is 1, each R.sup.2a is independently selected from fluoro,
chloro, bromo, iodo, cyano, methyl, ethyl, propyl, fluoromethyl,
difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl,
trifluoroethyl, and SO.sub.2NH.sub.2. In some embodiments where m
is 2, each R.sup.2a and R.sup.2b is independently selected from
fluoro, chloro, bromo, iodo, cyano, methyl, ethyl, propyl,
fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl,
difluoroethyl, trifluoroethyl, and SO.sub.2NH.sub.2. In additional
embodiments where m is 3, each R.sup.2a, R.sup.2b, and R.sup.2c is
independently selected from fluoro, chloro, bromo, iodo, cyano,
methyl, ethyl, propyl, fluoromethyl, difluoromethyl,
trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, and
SO.sub.2NH.sub.2. In other embodiments where m is 4, each R.sup.2a,
R.sup.2b, R.sup.2c, and R.sup.2d is independently selected from
fluoro, chloro, bromo, iodo, cyano, methyl, ethyl, propyl,
fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl,
difluoroethyl, trifluoroethyl, and SO.sub.2NH.sub.2. Each and every
variation of m and R.sup.2 may be combined with each and every
variation of W, n, R.sup.1, R.sup.3, R.sup.4, R.sup.5, R.sup.6, and
R.sup.7 as described herein.
[0220] In other embodiments of formula (I) where n is 2 and m is 2,
the compound has the structure of formula (IA-1):
##STR00014##
wherein:
[0221] R.sup.1a and R.sup.1b are independently selected from the
moieties defined for R.sup.1 described herein;
[0222] R.sup.2a and R.sup.2b are independently selected from the
moieties defined for R.sup.2 described herein; and
[0223] R.sup.3, R.sup.4, R.sup.5, R.sup.6, and R.sup.7 are as
defined herein;
[0224] or a pharmaceutically acceptable salt, isomer, or a mixture
thereof.
[0225] In other embodiments of formula (I) where n is 2 and m is 2,
the compound is of formula (IA-2):
##STR00015##
[0226] wherein R.sup.1a, R.sup.1b, R.sup.2a, R.sup.2b, R.sup.3,
R.sup.4, R.sup.5, R.sup.6, and R.sup.7 are as defined herein;
[0227] or a pharmaceutically acceptable salt, isomer, or a mixture
thereof.
[0228] In other embodiments of formula (I) where n is 2 and m is 2,
the compound is of formula (IA-3):
##STR00016##
[0229] wherein R.sup.1a, R.sup.1b, R.sup.2a, R.sup.2b, R.sup.3,
R.sup.4, R.sup.5, R.sup.6, and R.sup.7 are as defined herein;
[0230] or a pharmaceutically acceptable salt, isomer, or a mixture
thereof.
[0231] In yet other embodiments of formula (I) where n is 1 and m
is 2, the compound has the structure of formula (IB-1):
##STR00017##
[0232] wherein R.sup.1a, R.sup.2a, R.sup.2b, R.sup.3, R.sup.4,
R.sup.5, R.sup.6, and R.sup.7 are as defined herein;
[0233] or a pharmaceutically acceptable salt, isomer, or a mixture
thereof.
[0234] In yet other embodiments of formula (I) where n is 1 and m
is 2, the compound has the structure of formula (IB-2):
##STR00018##
[0235] wherein R.sup.1a, R.sup.2a, R.sup.2b, R.sup.3, R.sup.4,
R.sup.5, R.sup.6, and R.sup.7 are as defined herein;
[0236] or a pharmaceutically acceptable salt, isomer, or a mixture
thereof.
[0237] In yet other embodiments of formula (I) where n is 1 and m
is 2, the compound is of formula (IB-3):
##STR00019##
[0238] wherein R.sup.1a, R.sup.2a, R.sup.2b, R.sup.3, R.sup.4,
R.sup.5, R.sup.6, and R.sup.7 are as defined herein;
[0239] or a pharmaceutically acceptable salt, isomer, or a mixture
thereof.
[0240] In yet other embodiments of formula (I) where n is 1 and m
is 2, the compound has the structure of formula (IB-4):
##STR00020##
[0241] wherein R.sup.1a, R.sup.2a, R.sup.2b, R.sup.3, R.sup.4,
R.sup.5, R.sup.6, and R.sup.7 are as defined herein;
[0242] or a pharmaceutically acceptable salt, isomer, or a mixture
thereof.
[0243] In yet other embodiments of formula (I) where n is 1 and m
is 2, the compound is of formula (IB-5):
##STR00021##
[0244] wherein R.sup.1a, R.sup.2a, R.sup.2b, R.sup.3, R.sup.4,
R.sup.5, R.sup.6, and R.sup.7 are as defined herein;
[0245] or a pharmaceutically acceptable salt, isomer, or a mixture
thereof.
[0246] In the embodiments, the compound has the structure of any of
the foregoing formulae (IA-1), (IA-2), (IA-3), (IB-1), (IB-2),
(IB-3), (IB-4), or (IB-5), wherein R.sup.1a is chloro, fluoro,
SO.sub.2-phenyl (i.e. SO.sub.2C.sub.6H.sub.6), SO.sub.2-methyl
(i.e. SO.sub.2CH.sub.3), SO.sub.2-methylphenyl,
SO.sub.2-cyclopentyl, SO.sub.2-ethylene-OH (i.e.
SO.sub.2C.sub.2H.sub.4OH), SC.sub.2H.sub.4OH,
SO.sub.2CH.sub.2--Het,
O--C.sub.2H.sub.4(CH.sub.3)(CH.sub.2OH).sub.2,
O--C.sub.2H.sub.4N(CH.sub.3).sub.2, O--CH.sub.2C(O)OC.sub.3H.sub.7,
O--CH.sub.2C(O)-Het, tetrahydropyridinyl, CH.sub.2COOH,
C.sub.2H.sub.4COOH, C.sub.3H.sub.6COOH, CH.sub.2C(O)NH.sub.2,
C.sub.2H.sub.4C(O)NH.sub.2, C.sub.3H.sub.6C(O)NH.sub.2,
CH.sub.2C(O)N(CH.sub.3).sub.2, C.sub.2H.sub.4C(O)N(CH.sub.3).sub.2,
C.sub.3H.sub.6C(O)N(CH.sub.3).sub.2, CH.sub.2C(O)-Het,
C.sub.2H.sub.4C(O)-Het, C.sub.3H.sub.6C(O)-Het, CH.sub.2--Het,
C.sub.2H.sub.4-Het, C.sub.3H.sub.6-Het, O--CH.sub.2--Het,
O--C.sub.2H.sub.4-Het, O--C.sub.3H.sub.6-Het; wherein Het is
azetidinyl, pyrrolidinyl, piperidinyl, azepanyl, piperazinyl,
imidazolyl, oxetanyl, morpholinyl, 2-oxa-7-azaspiro[3.5]nonanyl,
2-oxa-6-azaspiro[3.4]octanyl, 6-oxa-1-azaspiro[3.3]heptanyl, where
each of the Het moieties is optionally substituted with one, two,
three, or four members independently selected from oxo, fluoro,
methyl, and phenyl. In some other embodiments, the compound has the
structure of any of the foregoing formulae (IA-1), (IA-2), (IA-3),
(IB-1), (IB-2), (IB-3), (IB-4), or (IB-5), wherein R.sup.1b is
fluoro, chloro, methyl, or cyano. In certain embodiments, the
compound has the structure of any of the foregoing formulae (IA-1),
(IA-2), (IA-3), (IB-1), (IB-2), (IB-3), (IB-4), or (IB-5), wherein
R.sup.2a is fluoro, difluoromethyl, fluoromethyl, trifluoromethyl,
or SO.sub.2NH.sub.2. In certain other embodiments, the compound has
the structure of any of the foregoing formulae (IA-1), (IA-2),
(IA-3), (IB-1), (IB-2), (IB-3), (IB-4), or (IB-5), wherein R.sup.2b
is fluoro, or cyano. Each and every variation of R.sup.1a and
R.sup.1b may be combined with each and every variation of R.sup.2a,
R.sup.2b, R.sup.3, R.sup.4, R.sup.5, R.sup.6, and R.sup.7 as
described herein.
[0247] In the embodiments, the compound has the structure of any of
the foregoing formulae (IA-1), (IA-2), (IA-3), (IB-1), (IB-2),
(IB-3), (IB-4), or (IB-5), wherein R.sup.1a is methyl, chloro,
fluoro, cyano, tetrahydropyridinyl, --CH.sub.2--C(.dbd.O)OH,
--C.sub.2H.sub.4--C(.dbd.O)OH, --C.sub.3H.sub.6--C(.dbd.O)OH,
--CH.sub.2--C(.dbd.O)NH.sub.2,
--CH.sub.2--C(.dbd.O)N(CH.sub.3).sub.2,
--C.sub.2H.sub.4--C(.dbd.O)NH.sub.2,
--C.sub.2H.sub.4--C(.dbd.O)N(CH.sub.3).sub.2,
--C.sub.3H.sub.6--C(.dbd.O)NH.sub.2,
--C.sub.3H.sub.6--C(.dbd.O)N(CH.sub.3).sub.2,
--CH.sub.2--C(.dbd.O)--Het, C.sub.2H.sub.4--C(.dbd.O)--Het,
--C.sub.3H.sub.6--C(.dbd.O)--Het,
O--CH.sub.2--C(.dbd.O)OC.sub.3H.sub.7,
O--C.sub.2H.sub.4--C(.dbd.O)OC.sub.3H.sub.7,
O--C.sub.3H.sub.6--C(.dbd.O)OC.sub.3H.sub.7, --CH.sub.2--Het,
--C.sub.2H.sub.4-Het, --C.sub.3H.sub.6-Het, --CH.sub.2-cyclopropyl,
--C.sub.2H.sub.4-cyclopropyl, --C.sub.3H.sub.6-cyclopropyl,
--CH.sub.2-cyclobutyl, --C.sub.2H.sub.4-cyclobutyl,
--C.sub.3H.sub.6-cyclobutyl, --CH.sub.2-cyclopentyl,
--C.sub.2H.sub.4-cyclopentyl, --C.sub.3H.sub.6-cyclopentyl,
--CH.sub.2-cyclohexyl, --C.sub.2H.sub.4-cyclohexyl,
--C.sub.3H.sub.6-cyclohexyl, O--CH.sub.2--NH.sub.2,
O--C.sub.2H.sub.4--NH.sub.2, O--C.sub.3H.sub.6--NH.sub.2,
O--CH.sub.2--N(CH.sub.3).sub.2,
O--C.sub.2H.sub.4--N(CH.sub.3).sub.2,
O--C.sub.3H.sub.6--N(CH.sub.3).sub.2, O--CH.sub.2--Het,
O--C.sub.2H.sub.4-Het, O--C.sub.3H.sub.6-Het,
O--CH.sub.2--C(.dbd.O)OH, O--C.sub.2H.sub.4--C(.dbd.O)OH,
O--C.sub.3H.sub.6--C(.dbd.O)OH, O--CH.sub.2--C(.dbd.O)OCH.sub.3,
O--C.sub.2H.sub.4--C(.dbd.O)OCH.sub.3,
O--C.sub.3H.sub.6--C(.dbd.O)OCH.sub.3, O--CH.sub.2--C(.dbd.O)--Het,
O--CH.sub.2C(CH.sub.3)(CH.sub.2OH).sub.2, S--C.sub.2H.sub.4OH,
S--C.sub.3H.sub.6OH, SO.sub.2-phenyl, SO.sub.2-methylphenyl,
--SO.sub.2-ethylphenyl, --SO.sub.2-cyclopropyl,
--SO.sub.2-cyclobutyl, --SO.sub.2-cyclopentyl,
--SO.sub.2C.sub.2H.sub.4-Het, --SO.sub.2CH.sub.3,
--SO.sub.2C.sub.2H.sub.5, --SO.sub.2C.sub.3H.sub.7,
--SO.sub.2C.sub.2H.sub.4OH, or --SO.sub.2C.sub.3H.sub.6OH; wherein
Het is independently selected from piperidinyl, morpholinyl,
piperazinyl, azepanyl, imidazolyl, oxetanyl, azetidinyl,
pyrrolidinyl, tetrahydropyridinyl, 2-oxa-7-azaspiro[3.5]nonanyl,
2-oxa-6-azaspiro[3.4]octanyl, and 6-oxa-1-azaspiro[3.3]heptanyl,
wherein each of the piperidinyl, morpholinyl, piperazinyl,
azepanyl, imidazolyl, oxetanyl, azetidinyl, pyrrolidinyl,
tetrahydropyridinyl, 2-oxa-7-azaspiro[3.5]nonanyl,
2-oxa-6-azaspiro[3.4]octanyl, 6-oxa-1-azaspiro[3.3]heptanyl,
cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl moieties is
optionally substituted with one, two, three, or four members
independently selected from fluoro, chloro, methyl, ethyl, propyl,
oxo, or phenyl. In some other embodiments, the compound has the
structure of any of the foregoing formulae (IA-1), (IA-2), (IA-3),
(IB-1), (IB-2), (IB-3), (IB-4), or (IB-5), wherein R.sup.1b is
fluoro, chloro, methyl, or cyano. In certain embodiments, the
compound has the structure of any of the foregoing formulae (IA-1),
(IA-2), (IA-3), (IB-1), (IB-2), (IB-3), (IB-4), or (IB-5), wherein
R.sup.2a is fluoro, difluoromethyl, fluoromethyl, trifluoromethyl,
or SO.sub.2NH.sub.2. In certain other embodiments, the compound has
the structure of any of the foregoing formulae (IA-1), (IA-2),
(IA-3), (IB-1), (IB-2), (IB-3), (IB-4), or (IB-5), wherein R.sup.2b
is fluoro, or cyano. Each and every variation of R.sup.1a and
R.sup.1b may be combined with each and every variation of R.sup.2a,
R.sup.2b, R.sup.3, R.sup.4, R.sup.5, R.sup.6, and R.sup.7 as
described herein.
[0248] In the embodiments, the compound has the structure of any of
the foregoing formulae (IA-1), (IA-2), (IA-3), (IB-1), (IB-2),
(IB-3), (IB-4), or (IB-5), wherein R.sup.1a is tetrahydropyridinyl,
CH.sub.2--C(.dbd.O)OH, --C.sub.2H.sub.4--C(.dbd.O)OH,
--C.sub.3H.sub.6--C(.dbd.O)OH, --CH.sub.2--C(.dbd.O)NH.sub.2,
--CH.sub.2--C(.dbd.O)N(CH.sub.3).sub.2,
--C.sub.2H.sub.4--C(.dbd.O)NH.sub.2,
--C.sub.2H.sub.4--C(.dbd.O)N(CH.sub.3).sub.2,
--C.sub.3H.sub.6--C(.dbd.O)NH.sub.2,
--C.sub.3H.sub.6--C(.dbd.O)N(CH.sub.3).sub.2,
--CH.sub.2--C(.dbd.O)--Het, C.sub.2H.sub.4--C(.dbd.O)--Het,
--C.sub.3H.sub.6--C(.dbd.O)--Het,
O--CH.sub.2--C(.dbd.O)OC.sub.3H.sub.7,
O--C.sub.2H.sub.4--C(.dbd.O)OC.sub.3H.sub.7,
O--C.sub.3H.sub.6--C(.dbd.O)OC.sub.3H.sub.7, --CH.sub.2--Het,
--C.sub.2H.sub.4-Het, --C.sub.3H.sub.6-Het, --CH.sub.2-cyclopropyl,
--C.sub.2H.sub.4-cyclopropyl, --C.sub.3H.sub.6-cyclopropyl,
--CH.sub.2-cyclobutyl, --C.sub.2H.sub.4-cyclobutyl,
--C.sub.3H.sub.6-cyclobutyl, --CH.sub.2-cyclopentyl,
--C.sub.2H.sub.4-cyclopentyl, --C.sub.3H.sub.6-cyclopentyl,
--CH.sub.2-cyclohexyl, --C.sub.2H.sub.4-cyclohexyl,
--C.sub.3H.sub.6-cyclohexyl, O--CH.sub.2--NH.sub.2,
O--C.sub.2H.sub.4--NH.sub.2, O--C.sub.3H.sub.6--NH.sub.2,
O--CH.sub.2--N(CH.sub.3).sub.2,
O--C.sub.2H.sub.4--N(CH.sub.3).sub.2,
O--C.sub.3H.sub.6--N(CH.sub.3).sub.2, O--CH.sub.2--Het,
O--C.sub.2H.sub.4-Het, O--C.sub.3H.sub.6-Het,
O--CH.sub.2--C(.dbd.O)OH, O--C.sub.2H.sub.4--C(.dbd.O)OH,
O--C.sub.3H.sub.6--C(.dbd.O)OH, O--CH.sub.2--C(.dbd.O)OCH.sub.3,
O--C.sub.2H.sub.4--C(.dbd.O)OCH.sub.3,
O--C.sub.3H.sub.6--C(.dbd.O)OCH.sub.3, O--CH.sub.2--C(.dbd.O)--Het,
O--CH.sub.2C(CH.sub.3)(CH.sub.2OH).sub.2, S--C.sub.2H.sub.4OH,
S--C.sub.3H.sub.6OH, SO.sub.2-phenyl, SO.sub.2-methylphenyl,
--SO.sub.2-ethylphenyl, --SO.sub.2-cyclopropyl,
--SO.sub.2-cyclobutyl, --SO.sub.2-cyclopentyl,
--SO.sub.2C.sub.2H.sub.4-Het, --SO.sub.2CH.sub.3,
--SO.sub.2C.sub.2H.sub.5, --SO.sub.2C.sub.3H.sub.7,
--SO.sub.2C.sub.2H.sub.4OH, or --SO.sub.2C.sub.3H.sub.6OH; wherein
Het is independently selected from piperidinyl, morpholinyl,
piperazinyl, azepanyl, imidazolyl, oxetanyl, azetidinyl,
pyrrolidinyl, tetrahydropyridinyl, 2-oxa-7-azaspiro[3.5]nonanyl,
2-oxa-6-azaspiro[3.4]octanyl, and 6-oxa-1-azaspiro[3.3]heptanyl,
wherein each of the piperidinyl, morpholinyl, piperazinyl,
azepanyl, imidazolyl, oxetanyl, azetidinyl, pyrrolidinyl,
tetrahydropyridinyl, 2-oxa-7-azaspiro[3.5]nonanyl,
2-oxa-6-azaspiro[3.4]octanyl, 6-oxa-1-azaspiro[3.3]heptanyl,
cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl moieties is
optionally substituted with one, two, three, or four members
independently selected from fluoro, chloro, methyl, ethyl, propyl,
oxo, or phenyl. In some other embodiments, the compound has the
structure of any of the foregoing formulae (IA-1), (IA-2), (IA-3),
(IB-1), (IB-2), (IB-3), (IB-4), or (IB-5), wherein R.sup.1b is
fluoro, chloro, methyl, or cyano. In certain embodiments, the
compound has the structure of any of the foregoing formulae (IA-1),
(IA-2), (IA-3), (IB-1), (IB-2), (IB-3), (IB-4), or (IB-5), wherein
R.sup.2a is fluoro, difluoromethyl, fluoromethyl, trifluoromethyl,
or SO.sub.2NH.sub.2. In certain other embodiments, the compound has
the structure of any of the foregoing formulae (IA-1), (IA-2),
(IA-3), (IB-1), (IB-2), (IB-3), (IB-4), or (IB-5), wherein R.sup.2b
is fluoro, or cyano. Each and every variation of R.sup.1a and
R.sup.1b may be combined with each and every variation of R.sup.2a,
R.sup.2b, R.sup.3, R.sup.4, R.sup.5, R.sup.6, and R.sup.7 as
described herein.
[0249] In certain embodiments, R.sup.3 is hydrogen, optionally
substituted C.sub.1-6 alkyl, optionally substituted C.sub.3-8
cycloalkyl, or optionally substituted C.sub.6-10 aryl. In one
embodiment, R.sup.3 is C.sub.3-6 cycloalkyl, C.sub.6-10 aryl, or
C.sub.1-6 alkyl optionally substituted with hydroxy, C.sub.6-10
arylC.sub.1-6 alkoxy, C.sub.3-6 cycloalkyl, or
--C(.dbd.O)NR.sup.3xR.sup.3y wherein each R.sup.3x and R.sup.3y is
independently hydrogen, C.sub.1-6 alkyl, or C.sub.1-6 haloalkyl. In
some embodiments, R.sup.3 is methyl, ethyl, propyl, butyl, pentyl,
hexyl, cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl,
cyclobutylethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
--CH.sub.2OH, --C.sub.2H.sub.4OH, --C.sub.3H.sub.6OH, phenyl,
--CH.sub.2--C(.dbd.O)NH.sub.2, --C.sub.2H.sub.4--C(.dbd.O)NH.sub.2,
--C.sub.3H.sub.6--C(.dbd.O)NH.sub.2,
--CH.sub.2--C(.dbd.O)N(CH.sub.3).sub.2,
--C.sub.2H.sub.4--C(.dbd.O)N(CH.sub.3).sub.2, or
--C.sub.3H.sub.6--C(.dbd.O)N(CH.sub.3).sub.2. In some other
embodiments, R.sup.3 is methyl, ethyl, propyl, cyclopropyl,
cyclobutyl, phenyl, --CH.sub.2--C(.dbd.O)N(CH.sub.3).sub.2,
--C.sub.2H.sub.4--C(.dbd.O)N(CH.sub.3).sub.2, or
--C.sub.3H.sub.6--C(.dbd.O)N(CH.sub.3).sub.2.
[0250] In additional embodiments, R.sup.5 is hydrogen or optionally
substituted C.sub.1-6 alkyl. In some embodiments, R.sup.5 is
hydrogen or C.sub.1-4 alkyl. In certain embodiments, R.sup.5 is
hydrogen, methyl, ethyl, propyl or butyl. In certain other
embodiments, R.sup.5 is hydrogen.
[0251] In further embodiments, R.sup.3 and R.sup.5 with the atoms
to which they are attached (e.g. carbon and nitrogen, respectively)
optionally form a heterocyclic ring that is optionally substituted.
In other embodiments, the R.sup.3-R.sup.5 heterocyclic ring is an
optionally substituted three-to eight-membered heterocycloalkyl
(i.e. heterocycloalkyl having three to eight ring members and at
least one ring member is a heteroatom). In other embodiments, the
R.sup.3-R.sup.5 heterocyclic ring is an optionally substituted
four- to seven-membered heterocycloalkyl (i.e. heterocycloalkyl
having four to seven ring members and at least one ring member is a
heteroatom). In certain other embodiments, the R.sup.3-R.sup.5
heterocyclic ring is C.sub.3-8 heterocycloalkyl. In certain
embodiments, the R.sup.3-R.sup.5 heterocyclic ring is azepanyl,
azetidinyl, piperidinyl, pyrrolidinyl, or morpholinyl; where each
of the azepanyl, azetidinyl, piperidinyl, pyrrolidinyl, and
morpholinyl moieties is optionally substituted with one or two
members independently selected from halo, C.sub.1-6alkyl,
C.sub.1-6haloalkyl, and NR.sup.5xC(O)R.sup.5y where R.sup.5x is
hydrogen or C.sub.1-6alkyl, and R.sup.5y is
C.sub.1-6alkylene-NH.sub.2, C.sub.1-6 alkylene-C.sub.3-8cycloalkyl,
or C.sub.1-6haloalkyl. In further embodiments, the R.sup.3-R.sup.5
heterocyclic ring is selected from azetidinyl, morpholinyl, and
pyrrolidinyl, each of which is optionally substituted with one
member of fluoro, chloro, iodo, methyl, ethyl, propyl,
N(CH.sub.3)C(.dbd.O)CH.sub.2NH.sub.2,
N(CH.sub.3)C(.dbd.O)CHF.sub.2,
N(CH.sub.3)C(.dbd.O)CH.sub.2CF.sub.3,
N(CH.sub.3)C(.dbd.O)cyclopropyl, NHC(.dbd.O)CH.sub.2NH.sub.2,
NHC(.dbd.O)CHF.sub.2, NHC(.dbd.O)CH.sub.2CF.sub.3, or
NHC(.dbd.O)cyclopropyl.
[0252] In yet other embodiments, R.sup.4 is cyano, halo,
C.sub.1-6haloalkyl, C(.dbd.O)H, or C(.dbd.O)C.sub.1-6alkyl. In some
other embodiments, R.sup.4 is cyano, chloro, fluoro, bromo, iodo,
methyl, ethyl, propyl, fluoromethyl, difluoromethyl,
trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, or
C(.dbd.O)CH.sub.3. In yet some other embodiments, R.sup.4 is cyano,
chloro, fluoro, methyl, or C(.dbd.O)CH.sub.3. In certain
embodiments, R.sup.6 is NH.sub.2, halo, or C.sub.1-6alkyl. In
certain other embodiments, R.sup.6 is NH.sub.2, fluoro, chloro,
bromo, iodo, methyl, ethyl, or propyl. In yet certain other
embodiments, R.sup.6 is NH.sub.2, chloro, or methyl. In additional
embodiments, R.sup.7 is NH.sub.2, halo, or C.sub.1-6alkyl. In some
additional embodiments, R.sup.7 is NH.sub.2, fluoro, chloro,
methyl, ethyl, or propyl. In yet some additional embodiments,
R.sup.7 is NH.sub.2, chloro, or methyl. Each and every variation of
R.sup.4 may be combined with each and every variation of W, n, m,
R.sup.1, R.sup.2, R.sup.3, R.sup.5, R.sup.6, and R.sup.7 as
described herein.
[0253] In certain embodiments of the compounds of the present
application, when R.sup.5 and R.sup.3 form a 5-membered
heterocyclic ring that is optionally substituted with hydroxyl,
halo, or methoxy, R.sup.4 is cyano, R.sup.6 is amino, and R.sup.7
is amino;
[0254] For certain compounds described herein, each unique
stereoisomer has a compound number bearing a suffix "a", "b", etc.
As an example, Compound 1 bearing one chiral center can be resolved
into its individual enantiomers 1a and 1b.
##STR00022##
[0255] In any one of the foregoing embodiments, the compound
described herein or a pharmaceutically acceptable salt thereof is
the (S)-enantiomer. It is understood that each compound having a
chiral center has enantiomers that correspond with the "a" and "b"
example provided above.
[0256] A composition containing a mixture of enantiomers of the
compound described herein or a pharmaceutically acceptable salt
thereof, is also provided herein. In some embodiments, the
composition contains the (S)-enantiomer of the compound and is
substantially free of its corresponding (R)-enantiomer. In certain
embodiments, a composition substantially free of the (R)-enantiomer
has less than or about 40%, 35%, 30%, 25%, 20%, 15%, 10%, 5%, 1%,
0.05%, or 0.01% of the (R)-enantiomer. In other embodiments, the
composition containing the (S)-enantiomer of a described herein or
a pharmaceutically acceptable salt thereof, predominates over its
corresponding (R)-enantiomer by a molar ratio of at least or about
9:1, at least or about 19:1, at least or about 40:1, at least or
about 80:1, at least or about 160:1, or at least or about
320:1.
[0257] The composition containing a compound of formula described
herein or a pharmaceutically acceptable salt thereof, may also
contain the compound in enantiomeric excess (e.e.). For instance, a
compound with 95% (S)-isomer and 5% (R)-isomer will have an e.e. of
90%. In some embodiments, the compound has an e.e. of at least or
about 60%, 75%, 80%, 85%, 90%, 95%, 98% or 99%. In some of the
foregoing embodiments, the compound is enantiomerically-enriched in
the (S)-isomer of compound of formula described herein.
[0258] Provided is also a composition comprising a mixture of the
(S)-enantiomer and the (R)-enantiomer of a compound of formula
described herein or a pharmaceutically acceptable salt thereof. In
one embodiment, the mixture is a racemic mixture. In other
embodiments, the composition comprises the (S)-enantiomer of a
compound described herein or a pharmaceutically acceptable salt
thereof, wherein the (S)-enantiomer of the compound is present in
excess of over the corresponding the (R)-enantiomer of the
compound, or a pharmaceutically acceptable salt thereof.
[0259] In any one of the foregoing embodiments, the compound
described herein or a pharmaceutically acceptable salt thereof, is
an atropisomer. A composition containing a mixture of atropisomers
of the compound described herein or a pharmaceutically acceptable
salt thereof, is also provided herein. "Atropisomers" refers to
conformational stereoisomers which occur when rotation about a
single bond in the molecule is prevented, or greatly slowed, as a
result of steric interactions with other parts of the molecule and
the substituents at both ends of the single bond are asymmetrical,
i.e., they do not require a stereocenter. Where the rotational
barrier about the single bond is high enough, and interconversion
between conformations is slow enough, separation and isolation of
the isomeric species may be permitted. Atropisomers are enantiomers
without a single asymmetric atom. As an example, Compound 17 can be
resolved into its individual atropisomers as depicted below.
##STR00023##
[0260] Representative compounds of the invention are listed in
Table 1 below in its non-isomeric form. The compounds in Table 1
are named using ChemBioDraw Ultra. Similarly, the Compounds 1-116
(which include certain compounds of Table 1) are named iusing
ChemBioDraw Ultra. It is understood that other names may be used to
identify compounds of the same structure. Other compounds or
radicals may be named with common names, or systematic or
non-systematic names. The compounds may also be named using other
nomenclature systems and symbols that are commonly recognized in
the art of chemistry including, for example, Chemical Abstract
Service (CAS) and International Union of Pure and Applied Chemistry
(IUPAC). The naming and numbering of the compounds of the present
disclosure is illustrated with representative compounds shown in
Table 1 below. The compounds provided in Table 1 may be a single
enantiomer (e.g., (S)-enantiomer, (R)-enantiomer), or the compounds
may be present in a composition having an enantiomeric mixture.
TABLE-US-00001 TABLE 1 Representative Compounds # Structure Name 1.
##STR00024## 2-(cyclopropyl((2,6-diamino-5-cyanopyrimidin-4-
yl)amino)methyl)-4-oxo-3-phenyl-3,4-
dihydroquinazoline-5-carbonitrile a: (S)-enantiomer b:
(R)-enantiomer 2. ##STR00025##
2-(cyclopropyl((2,6-diamino-5-cyanopryimidin-4-
yl)amino)methyl)-8-fluoro-4-oxo-3-phenyl-3,4-
dihydroquinazoline-5-carbonitrile a: (S)-enantiomer b:
(R)-enantiomer 3. ##STR00026##
2,4-diamino-6-(((5-chloro-4-oxo-3-phenyl-3,4- dihydroquinazolin-2-
yl)(phenyl)methyl)amino)pyrimidine-5-carbonitrile a: (S)-enantiomer
b: (R)-enantiomer 4. ##STR00027##
2-(cyclopropyl((2,6-diamino-5-cyanopyrimidin-4-
yl)amino)methyl)-3-(3-(difluoromethyl)-5-
fluorophenyl)-4-oxo-3,4-dihydroquinazoline-5- carbonitrile a:
(S)-enantiomer b: (R)-enantiomer 5. ##STR00028##
2,4-diamino-6-((cyclopropyl(3-(3-fluorophenyl)-5-
(methylsulfonyl)-4-oxo-3,4-dihydroquinazolin-2-
yl)methyl)amino)pyrimidine-5-carbonitrile a: (S)-enantiomer b:
(R)-enantiomer 6. ##STR00029## 2,4-diamino-6-((cyclopropyl(3-(2,6-
difluorophenyl)-5-(methylsulfonyl)-4-oxo-3,4-
dihydroquinazolin-2-yl)methyl)amino)pyrimidine-5- carbonitrile a:
(S)-enantiomer b: (R)-enantiomer 7. ##STR00030##
2-(cyclopropyl((2,6-diamino-5-cyanopyrimidin-4-
yl)amino)methyl)-6-fluoro-3-(3-fluorophenyl)-4-
oxo-3,4-dihydroquinazoline-8-carbonitrile a: (S)-enantiomer b:
(R)-enantiomer 8. ##STR00031##
2-(cyclopropyl((2,6-diamino-5-cyanopyrimidin-4-
yl)amino)methyl)-6-fluoro-4-oxo-3-phenyl-3,4-
dihydroquinazoline-8-carbonitrile a: (S)-enantiomer b:
(R)-enantiomer 9. ##STR00032##
3-(5-chloro-3-(3,5-difluorophenyl)-4-oxo-3,4-
dihydroquinazolin-2-yl)-3-((2,6-diamino-5-
cyanopyrimidin-4-yl)amino)-N,N- dimethylpropanamide a:
(S)-enantiomer b: (R)-enantiomer 10. ##STR00033##
3-(5-chloro-4-oxo-3-phenyl-3,4-dihydroquinazolin-
2-yl)-3-((2,6-diamino-5-cyanopyrimidin-4-
yl)amino)-N,N-dimethylpropanamide a: (S)-enantiomer b:
(R)-enantiomer 11. ##STR00034##
2,4-diamino-6-(((3-(3-cyano-5-fluorophenyl)-5-
methyl-4-oxo-3,4-dihydroquinazolin-2-
yl)(cyclopropyl)methyl)amino)pyrimidine-5- carbonitrile a:
(S)-enantiomer b: (R)-enantiomer 12. ##STR00035##
2,4-diamino-6-((cyclopropyl(3-(3,5-
difluorophenyl)-5-methyl-4-oxo-3,4-
dihydroquinazolin-2-yl)methyl)amino)pyrimidine-5- carbonitrile a:
(S)-enantiomer b: (R)-enantiomer 13. ##STR00036##
2,4-diamino-6-(((5-chloro-3-(3,5-difluorophenyl)-4-
oxo-3,4-dihydroquinazolin-2-
yl)(cyclopropyl)methyl)amino)pyrimidine-5- carbonitrile a:
(S)-enantiomer b: (R)-enantiomer 14. ##STR00037##
2,4-diamino-6-((cyclopropyl(3-(3,5-
difluorophenyl)-5-fluoro-4-oxo-3,4-
dihydroquinazolin-2-yl)methyl)amino)pyrimidine-5- carbonitrile a:
(S)-enantiomer b: (R)-enantiomer 15. ##STR00038##
2,4-diamino-6-((cyclopropyl(5-fluoro-3-(3-
fluorophenyl)-4-oxo-3,4-dihydroquinazolin-2-
yl)methyl)amino)pyrimidine-5-carbonitrile a: (S)-enantiomer b:
(R)-enantiomer 16. ##STR00039##
2,4-diamino-6-((cyclopropyl(6-fluoro-3-(3-
fluorophenyl)-4-oxo-3,4-dihydroquinazolin-2-
yl)methyl)amino)pyrimdine-5-carbonitrile a: (S)-enantiomer b:
(R)-enantiomer 17. ##STR00040##
2,4-diamino-6-((cyclopropyl(3-(2-fluorophenyl)-5-
(methylsulfonyl)-4-oxo-3,4-dihydroquinazolin-2-
yl)methyl)amino)pyrimidine-5-carbonitrile a: (S)-enantiomer a-1 and
a-2: atropisomers b: (R)-enantiomer b-1 and b-2: atropisomers 18.
##STR00041## 2-(1-((5-acetyl-2,6-diaminopyrimidin-4-
yl)amino)ethyl)-5-chloro-3-(3,5-
difluorophenyl)quinazolin-4(3H)-one a: (S)-enantiomer b:
(R)-enantiomer
[0261] Provided are also compounds described herein or
pharmaceutically acceptable salts, isomer, or a mixture thereof, in
which from 1 to n hydrogen atoms attached to a carbon atom may be
replaced by a deuterium atom or D, in which n is the number of
hydrogen atoms in the molecule. As known in the art, the deuterium
atom is a non-radioactive isotope of the hydrogen atom. Such
compounds may increase resistance to metabolism, and thus may be
useful for increasing the half-life of the compounds described
herein or pharmaceutically acceptable salts, isomer, or a mixture
thereof when administered to a mammal. See, e.g., Foster,
"Deuterium Isotope Effects in Studies of Drug Metabolism", Trends
Pharmacol. Sci., 5(12):524-527 (1984). Such compounds are
synthesized by means well known in the art, for example by
employing starting materials in which one or more hydrogen atoms
have been replaced by deuterium.
[0262] Provided are also pharmaceutically acceptable salts,
hydrates, solvates, tautomeric forms, polymorphs, and prodrugs of
the compounds described herein. "Pharmaceutically acceptable" or
"physiologically acceptable" refer to compounds, salts,
compositions, dosage forms and other materials which are useful in
preparing a pharmaceutical composition that is suitable for
veterinary or human pharmaceutical use. "Pharmaceutically
acceptable salts" or "physiologically acceptable salts" include,
for example, salts with inorganic acids and salts with an organic
acid. In addition, if the compounds described herein are obtained
as an acid addition salt, the free base can be obtained by
basifying a solution of the acid salt. Conversely, if the product
is a free base, an addition salt, particularly a pharmaceutically
acceptable addition salt, may be produced by dissolving the free
base in a suitable organic solvent and treating the solution with
an acid, in accordance with conventional procedures for preparing
acid addition salts from base compounds. Those skilled in the art
will recognize various synthetic methodologies that may be used to
prepare nontoxic pharmaceutically acceptable addition salts.
[0263] A "solvate" is formed by the interaction of a solvent and a
compound. Solvates of salts of the compounds described herein are
also provided. Hydrates of the compounds described herein are also
provided.
[0264] A "prodrug" includes any compound that becomes a compound
described herein when administered to a subject, e.g., upon
metabolic processing of the prodrug.
[0265] In certain embodiments, provided are optical isomers,
racemates, or other mixtures thereof of the compounds described
herein or pharmaceutically acceptable salts or a mixture thereof.
In those situations, the single enantiomer or diastereomer, i.e.,
optically active form, can be obtained by asymmetric synthesis or
by resolution of the racemate. Resolution of racemates can be
accomplished, for example, by conventional methods such as
crystallization in the presence of a resolving agent, or
chromatography, using, for example a chiral high pressure liquid
chromatography (HPLC) column. In addition, provided are also Z- and
E-forms (or cis- and trans-forms) of the compounds described herein
with carbon-carbon double bonds. Provided are also all tautomeric
forms of the compounds of formula described herein.
[0266] Compositions provided herein that include a compound
described herein or pharmaceutically acceptable salts, isomer, or a
mixture thereof may include racemic mixtures, or mixtures
containing an enantiomeric excess of one enantiomer or single
diastereomers or diastereomeric mixtures. All such isomeric forms
of these compounds are expressly included herein the same as if
each and every isomeric form were specifically and individually
listed.
[0267] In certain embodiments, provided herein are also crystalline
and amorphous forms of the compounds described herein or
pharmaceutically acceptable salts, isomer, or a mixture
thereof.
[0268] In certain embodiments, provided are also chelates,
non-covalent complexes, and mixtures thereof, of the compounds
described herein or pharmaceutically acceptable salts, isomer, or a
mixture thereof. A "chelate" is formed by the coordination of a
compound to a metal ion at two (or more) points. A "non-covalent
complex" is formed by the interaction of a compound and another
molecule wherein a covalent bond is not formed between the compound
and the molecule. For example, complexation can occur through van
der Waals interactions, hydrogen bonding, and electrostatic
interactions (also called ionic bonding).
Therapeutic Uses of the Compounds
[0269] The compounds described herein or pharmaceutically
acceptable salts, isomer, or a mixture thereof may be used for the
treatment of diseases and/or conditions mediated by PI3K isomers,
such as PI3K.delta.. Thus, provided herein are methods for
inhibiting one or more PI3K isomers. In one embodiment, provided
are methods for inhibiting PI3K.delta. activity using a described
herein or pharmaceutically acceptable salts, isomer, or a mixture
thereof. The PI3K isomers may be selectively or specifically
inhibited. Additionally, the compounds may be used to inhibit PI3K
activity therapeutically or prophylactically.
[0270] In some embodiments, the methods include administering a
compound described herein or pharmaceutically acceptable salts,
isomer, or a mixture thereof in a therapeutically effective amount
to a subject (including a human) in need thereof. The method can be
employed to treat a subject who has or is believed to have a
disease or condition whose symptoms or pathology is mediated by
PI3K.delta. expression or activity.
[0271] In addition to the therapeutic uses described herein,
certain compounds of the present application have one or more
properties selected from: (i) selectivity to any PI3K isoforms,
such as PI3K.delta.; (ii) hepatocyte stability; and (iii) potency
in a cellular assay. In one embodiment, certain compounds described
herein or pharmaceutically acceptable salts, isomer, or a mixture
thereof have selectivity to any PI3K isoforms, such as PI3K.delta..
In other embodiments, certain compounds described have selectivity
to at least PI3K.delta.. In yet other embodiments, certain
compounds have one of the properties selected from: (i) selectivity
to PI3K.delta.; (ii) hepatocyte stability; and (iii) potency in a
cellular assay. In yet other embodiments, certain compounds have
selectivity to PI3K.delta. and hepatocyte stability; or selectivity
to PI3K.delta. and potency in a cellular assay; or hepatocyte
stability and potency in a cellular assay. In some embodiments,
certain compounds have selectivity to PI3K.delta., hepatocyte
stability, and potency in a cellular assay.
[0272] In another embodiment, certain compounds have hepatocyte
stability. Hepatocyte stability of a subject can be determined
using any methods currently known in the art, including the methods
described in the Examples below. For example, hepatocyte stability
may be characterized based on clearance or half-life. In some
embodiments, the half-life is greater than or about 3 hours, 4
hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11
hours, 12 hours, or 15 hours in human hepatocytes.
[0273] In yet another embodiment, certain compounds have potency in
a cellular assay. Potency in a cellular assay can be determined
using any methods currently known in the art, including the methods
described in the Examples below. In some embodiments, the activity
in the cellular assay is less than 10 nM, 9 nM, 8 nM, 7 nM, 6 nM, 5
nM, 4 nM, 3 nM, 2 nM, 1 nM, 0.1 nM, or 0.01 nM. For example,
certain compounds may have selectivity to at least one PI3K
isoform, including PI3K.delta., and have hepatocyte stability based
on a half-life of greater than 3 hours. As used herein, the term
"potency," "potent," or variants thereof refer to a compound
exhibiting an IC.sub.50 value that is less than 100 nM. When
comparing two compounds, the compound that exhibits a lower
IC.sub.50 value is referred to as a more potent inhibitor.
[0274] "Treatment" or "treating" is an approach for obtaining
beneficial or desired results including clinical results.
Beneficial or desired clinical results may include one or more of
the following: a) inhibiting the disease or condition (e.g.,
decreasing one or more symptoms resulting from the disease or
condition, and/or diminishing the extent of the disease or
condition); b) slowing or arresting the development of one or more
clinical symptoms associated with the disease or condition (e.g.,
stabilizing the disease or condition, preventing or delaying the
worsening or progression of the disease or condition, and/or
preventing or delaying the spread (e.g., metastasis) of the disease
or condition); and/or c) relieving the disease, that is, causing
the regression of clinical symptoms (e.g., ameliorating the disease
state, providing partial or total remission of the disease or
condition, enhancing effect of another medication, delaying the
progression of the disease, increasing the quality of life, and/or
prolonging survival.
[0275] "Prevention" or "preventing" means any treatment of a
disease or condition that causes the clinical symptoms of the
disease or condition not to develop. Compounds may, in some
embodiments, be administered to a subject (including a human) who
is at risk or has a family history of the disease or condition.
[0276] "Subject" refers to an animal, such as a mammal (including a
human), that has been or will be the object of treatment,
observation or experiment. The methods described herein may be
useful in human therapy and/or veterinary applications. In some
embodiments, the subject is a mammal. In one embodiment, the
subject is a human. "Human in need thereof" refers to a human who
may have or is suspect to have diseases, or disorders, or
conditions that would benefit from certain treatment; for example,
being treated with the PI3K inhibitor of the compounds according to
the present application. In certain embodiments, the subject may be
a human who (i) has not received any treatment including
chemotherapy treatment, (ii) is substantially refractory to at
least one chemotherapy treatment, (iii) is in relapse after
treatment with chemotherapy, or both (i) and (ii). In some of
embodiments, the subject is refractory to at least one, at least
two, at least three, or at least four chemotherapy treatments
(including standard or experimental chemotherapies).
[0277] The term "therapeutically effective amount" or "effective
amount" of a compound described herein or pharmaceutically
acceptable salts, isomer, or a mixture thereof means an amount
sufficient to effect treatment when administered to a subject, to
provide a therapeutic benefit such as amelioration of symptoms or
slowing of disease progression. For example, a therapeutically
effective amount may be an amount sufficient to decrease a symptom
of a disease or condition responsive to inhibition of PI3K.delta.
activity. The therapeutically effective amount may vary depending
on the subject, and disease or condition being treated, the weight
and age of the subject, the severity of the disease or condition,
and the manner of administering, which can readily be determined by
one or ordinary skill in the art.
[0278] The term "inhibition" indicates a decrease in the baseline
activity of a biological activity or process. "Inhibition of
activity of PI3K isoforms" or variants thereof refer to a decrease
in activity in any PI3K isoform (e.g., alpha, beta, gamma, or
delta) as a direct or indirect response to the presence of a
compound of the present application relative to the activity of
PI3K isoform in the absence of the compound of the present
application. "Inhibition of PI3K.delta. activity" or variants
thereof refer to a decrease in PI3K.delta. activity as a direct or
indirect response to the presence of a compound described herein
relative to the activity of PI3K.delta. in the absence of the
compound described herein. In some embodiments, the inhibition of
PI3K.delta. activity may be compared in the same subject prior to
treatment, or other subjects not receiving the treatment.
[0279] Without wishing to be bound to any theory, the decrease in
PI3K.delta. activity may be due to the direct interaction of the
compound with PI3K.delta., or due to the interaction of the
compounds described herein with one or more other factors that in
turn affect PI3K.delta. activity. For example, the presence of the
compounds of any of the foregoing formulae may decrease PI3K.delta.
activity by directly binding to the PI3K.delta., by causing
(directly or indirectly) another factor to decrease PI3K.delta.
activity, or by (directly or indirectly) decreasing the amount of
PI3K.delta. present in the cell or organism.
[0280] The terms "PI3K isoform selective inhibitor" generally
refers to a compound that inhibits the activity of one or more PI3K
isoforms more effectively than the other remaining PI3K isoforms.
By way of example, the term "PI3K.delta. selective inhibitor"
generally refers to a compound that inhibits the activity of the
PI3K.delta. isoform more effectively than other isoforms of the
PI3K family (e.g., PI3K .alpha., .beta., or .gamma.). The term
"PI3Ku selective inhibitor" generally refers to a compound that
inhibits the activity of the PI3Ku isoform more effectively than
other isoforms of the PI3K family (e.g., PI3K .beta., .delta., or
.gamma.). The term "PI3K selective inhibitor" generally refers to a
compound that inhibits the activity of the PI3K.beta. isoform more
effectively than other isoforms of the PI3K family (e.g., PI3K
.alpha., .delta., or .gamma.). The term "dual PI3K.alpha./.beta.
selective inhibitor generally refers to a compound that inhibits
the activity of the PI3K.alpha. and PI3K.beta. isoforms more
effectively than other isoforms of the PI3K family (e.g., PI3K
.delta. or .gamma.).
[0281] The relative efficacies of compounds as inhibitors of an
enzyme activity (or other biological activity) can be established
by determining the concentrations at which each compound inhibits
the activity to a predefined extent and then comparing the results.
In one embodiment, the efficacy of a compound as an inhibitor of
one or more PI3K isoforms can be measured by the concentration that
inhibits 50% of the activity in a biochemical assay, i.e., the 50%
inhibitory concentration or "IC.sub.50". IC.sub.50 determinations
can be accomplished using conventional techniques known in the art,
including the techniques describes in the Examples below. In
general, an IC.sub.50 can be determined by measuring the activity
of a given enzyme in the presence of a range of concentrations of
the compound under study. The experimentally obtained values of
enzyme activity may then be plotted against the compound
concentrations used. The concentration of the inhibitor that shows
50% enzyme activity (as compared to the activity in the absence of
any inhibitor) is taken as the IC.sub.50 value. Analogously, other
inhibitory concentrations can be defined through appropriate
determinations of activity. For example, in some settings it may be
desirable to establish a 90% inhibitory concentration, i.e.,
IC.sub.90.
[0282] In one embodiment, a PI3K.delta. selective inhibitor is a
compound that exhibits a 50% inhibitory concentration (IC.sub.50)
with respect to PI3K.delta. that is at least 10-fold, in another
aspect at least 20-fold, and in another aspect at least 30-fold,
lower than the IC.sub.50 value with respect to any or all of the
other Class I PI3K family members. In another embodiment, a
PI3K.delta. selective inhibitor is a compound that exhibits an
IC.sub.50 with respect to PI3K.delta. that is at least 50-fold, in
another aspect at least 100-fold, in an additional aspect at least
200-fold, and in yet another aspect at least 500-fold, lower than
the IC.sub.50 with respect to any or all of the other PI3K Class I
family members. A PI3K.delta. selective inhibitor is typically
administered in an amount such that it selectively inhibits
PI3K.delta. activity, as described above.
[0283] In one embodiment, a PI3Ku selective inhibitor is a compound
that exhibits a 50% inhibitory concentration (IC.sub.50) with
respect to PI3K.beta. that is at least 10-fold, in another aspect
at least 20-fold, and in another aspect at least 30-fold, lower
than the IC.sub.50 value with respect to any or all of the other
Class I PI3K family members. In another embodiment, a PI3Ku
selective inhibitor is a compound that exhibits an IC.sub.50 with
respect to PI3Ku that is at least 50-fold, in another aspect at
least 100-fold, in an additional aspect at least 200-fold, and in
yet another aspect at least 500-fold, lower than the IC.sub.50 with
respect to any or all of the other PI3K Class I family members. A
PI3Ku selective inhibitor is typically administered in an amount
such that it selectively inhibits PI3Ku activity, as described
above
[0284] In one embodiment, a PI3K.beta. selective inhibitor is a
compound that exhibits a 50% inhibitory concentration (IC.sub.50)
with respect to PI3K.beta. that is at least 10-fold, in another
aspect at least 20-fold, and in another aspect at least 30-fold,
lower than the IC.sub.50 value with respect to any or all of the
other Class I PI3K family members. In another embodiment, a
PI3K.beta. selective inhibitor is a compound that exhibits an
IC.sub.50 with respect to PI3K.beta. that is at least 50-fold, in
another aspect at least 100-fold, in an additional aspect at least
200-fold, and in yet another aspect at least 500-fold, lower than
the IC.sub.50 with respect to any or all of the other PI3K Class I
family members. A PI3K.beta. selective inhibitor is typically
administered in an amount such that it selectively inhibits
PI3K.beta. activity, as described above.
[0285] The methods described herein may be applied to cell
populations in vivo or ex vivo. "In vivo" means within a living
individual, as within an animal or human. In this context, the
methods described herein may be used therapeutically in an
individual. "Ex vivo" means outside of a living individual.
Examples of ex vivo cell populations include in vitro cell cultures
and biological samples including fluid or tissue samples obtained
from individuals. Such samples may be obtained by methods well
known in the art. Exemplary biological fluid samples include blood,
cerebrospinal fluid, urine, and saliva. Exemplary tissue samples
include tumors and biopsies thereof. In this context, the invention
may be used for a variety of purposes, including therapeutic and
experimental purposes. For example, the invention may be used ex
vivo to determine the optimal schedule and/or dosing of
administration of a PI3K.delta. selective inhibitor for a given
indication, cell type, individual, and other parameters.
Information gleaned from such use may be used for experimental
purposes or in the clinic to set protocols for in vivo treatment.
Other ex vivo uses for which the invention may be suited are
described below or will become apparent to those skilled in the
art. The selected compounds may be further characterized to examine
the safety or tolerance dosage in human or non-human subjects. Such
properties may be examined using commonly known methods to those
skilled in the art.
[0286] Compared to other PI3K isoforms, PI3K.delta. is generally
expressed in hematopoietic cells. Consequently, the direct effects
of selective inhibitors of PI3K.delta. can be observed in
hematopoietic cells. Hematopoietic cells typically differentiate
into either lymphoid progenitor cells or myeloid progenitor cells,
both of which ultimately differentiate into various mature cell
types including leukocytes. Aberrant proliferation of hematopoietic
cells of one type often interferes with the production or survival
of other hematopoietic cell types, which can result in compromised
immunity, anemia, and/or thrombocytopenia. The methods described
herein may treat aberrant proliferation of hematopoietic cells by
inhibiting aberrant proliferation of hematopoietic cells. As a
result, these methods may also ameliorate the symptoms and
secondary conditions that result from a primary effect such as
excessive system or localized levels of leukocytes or
lymphocytes.
[0287] In some embodiments, the compounds described herein may be
used to treat subjects having various disease states, disorders,
and conditions (also collectively referred to as "indications")
involving aberrant proliferation of hematopoietic cells (including
excessive production of lymphoid progenitor cell-derived cells
and/or myeloid progenitor cell-derived cells). Such indications may
include, for example, leukemias, lymphomas, myeloproliferative
disorders, myelodysplastic syndromes, and plasma cell neoplasms. In
certain embodiments, the compounds described herein may be used to
treat hematologic malignancies, inflammation, autoimmune disorders,
allergic conditions, cardiovascular disease, and autoimmune
diseases. In certain embodiments, allergic conditions may include
all forms of hypersensitivity.
[0288] In other embodiments, the compounds described herein may be
used to treat cancers that are mediated by, dependent on or
associated with PI3K activity, such as PI3K.delta. activity. In
certain embodiments, the disease is a hematologic malignancy. In
certain embodiments, the disease is lymphoma, multiple myeloma, or
leukemia. In particular embodiments, the hematologic malignancy is
leukemia or lymphoma. In specific embodiments, the disease is acute
lymphocytic leukemia (ALL), acute myeloid leukemia (AML), chronic
lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL),
myelodysplastic syndrome (MDS), myeloproliferative disease (MPD),
chronic myeloid leukemia (CML), juvenile myelomonocytic leukemia
(JMML), multiple myeloma (MM), Hodgkin lymphoma, indolent
non-Hodgkin's lymphoma (iNHL), refractory iNHL, non-Hodgkin's
lymphoma (NHL), mantle cell lymphoma (MCL), follicular lymphoma,
Waldestrom's macroglobulinemia (WM), minimal residual disease
(MRD), T-cell lymphoma, B-cell lymphoma, diffuse large B-cell
lymphoma (DLBCL), T-cell acute lymphoblastic leukemia (T-ALL),
B-cell acute lymphoblastic leukemia (B-ALL), lymphoplasmacytic
lymphoma, marginal zone lymphoma, or Burkitt lymphoma. In one
embodiment, the disease is T-cell acute lymphoblastic leukemia
(T-ALL), or B-cell acute lymphoblastic leukemia (B-ALL). It should
be understood that the non-Hodgkin lymphoma may, in certain
embodiments, encompass the indolent B-cell diseases that include,
for example, follicular lymphoma, lymphoplasmacytic lymphoma,
Waldenstrom macroglobulinemia, and marginal zone lymphoma, as well
as the aggressive lymphomas that include, for example, Burkitt
lymphoma, diffuse large B-cell lymphoma (DLBCL) and mantle cell
lymphoma (MCL).
[0289] In other embodiments, the disease is a solid tumor. In
particular embodiments, the solid tumor is from pancreatic cancer,
bladder cancer, colorectal cancer, breast cancer, prostate cancer,
renal cancer, hepatocellular cancer, lung cancer, ovarian cancer,
cervical cancer, gastric cancer, esophageal cancer, head and neck
cancer, melanoma, neuroendocrine cancers, CNS cancers, brain tumors
(e.g., glioma, anaplastic oligodendroglioma, adult glioblastoma
multiforme, and adult anaplastic astrocytoma), bone cancer, or soft
tissue sarcoma. In some embodiments, the solid tumor is from
non-small cell lung cancer, small-cell lung cancer, colon cancer,
CNS cancer, melanoma, ovarian cancer, renal cancer, prostate
cancer, or breast cancer.
[0290] In some embodiments, the disease is an autoimmune disease.
In particular embodiments, the autoimmune disease is systemic lupus
erythematosus (SLE), myestenia gravis, rheumatoid arthritis (RA),
acute disseminated encephalomyelitis, idiopathic thrombocytopenic
purpura, multiple sclerosis (MS), psoriasis, Sjoegren's syndrome,
psoriasis, autoimmune hemolytic anemia, asthma, or chronic
obstructive pulmonary disease (COPD). In other embodiments, the
disease is inflammation. In yet other embodiments, the disease is
excessive or destructive immune reactions, such as asthma,
rheumatoid arthritis, multiple sclerosis, chronic obstructive
pulmonary disease (COPD), and lupus.
[0291] Provided is a method for treating a subject, who has or is
suspected of having a disease or condition responsive or believed
to be responsive to the inhibition of PI3K.delta. activity by
administering to the subject the compound described herein or
pharmaceutically acceptable salts, isomer, or a mixture thereof.
Provided is also a method of inhibiting kinase activity of a
phosphatidylinositol 3-kinase delta polypeptide by contacting the
polypeptide with the compound described herein or pharmaceutically
acceptable salts, isomer, or a mixture thereof. Provided is also a
method of disrupting leukocyte function comprising contacting the
leukocytes with an effective amount of a compound described herein
or pharmaceutically acceptable salts, isomer, or a mixture thereof
in a subject in need thereof (e.g., a human). Provided is also a
method of inhibiting a growth or a proliferation of cancer cells of
hematopoietic origin comprising contacting the cancer cells with an
effective amount of a compound described herein or pharmaceutically
acceptable salts, isomer, or a mixture thereof.
Combination Therapies
[0292] The compounds according to the present application may be
used in combination with one or more additional therapeutic agents.
The therapeutic agents may be in the forms of compounds,
antibodies, polypeptides, or polynucleotides. The therapeutic agent
includes, but is not limited to, a chemotherapeutic agent, an
immunotherapeutic agent, a radiotherapeutic agent, an
anti-neoplastic agent, an anti-cancer agent, an anti-proliferation
agent, an anti-fibrotic agent, an anti-angiogenic agent, a
therapeutic antibody, or any combination thereof. In one
embodiment, the application provides a product comprising a
compound described herein and an additional therapeutic agent as a
combined preparation for simultaneous, separate or sequential use
in therapy, e.g. a method of treating a disease, disorder, or
condition that is mediated by PI3K isoforms.
[0293] In one embodiment, the compounds of the present application
may be used in combination with one or more additional therapeutic
agent that are being used and/or developed to treat cancers or
inflammatory disorders. The one or more additional therapeutic
agent may be an inhibitor to PI3K such as PI3K.gamma., PI3K.beta.,
and/or PI3K.alpha., Janus kinase (JAK) such as JAK1, JAK2 and/or
JAK3, spleen tyrosine kinase (SYK), Bruton's tyrosine kinase (BTK),
bromodomain containing protein inhibitor (BRD) such as BRD4, a
lysyl oxidase protein (LOX), lysyl oxidase-like protein (LOXL) such
as LOXL1-5, matrix metalloprotease (MMP) such as MMP 1-10,
adenosine A2B receptor (A2B), isocitrate dehydrogenase (IDH) such
as IDH1, apoptosis signal-regulating kinase (ASK) such as ASK1,
serine/threonine kinase TPL2, discoidin domain receptor (DDR) such
as DDR1 and DDR2, histone deacetylase (HDAC), protein kinase C
(PKC), or any combination thereof.
[0294] One, two, three, or more of the therapeutic agents (e.g. a
PI3K inhibitor, a JAK inhibitor, a SYK inhibitor, a BTK inhibitor,
a BRD4 inhibitor, a LOXL2 inhibitor, a MMP9 inhibitor, a A2B
inhibitor, an IDH inhibitor, an ASK inhibitor, a TPL2 inhibitor, a
DDR1 inhibitor, a TBK inhibitor, a HDAC inhibitor, a PKC inhibitor)
may be further used or combined with a chemotherapeutic agent, an
immunotherapeutic agent, a radiotherapeutic agent, an
anti-neoplastic agent, an anti-cancer agent, an anti-fibrotic
agent, an anti-angiogenic agent, a therapeutic antibody, or any
combination thereof.
[0295] Also, the therapeutic agents may be those that inhibit or
modulate the activities of Bruton's tyrosine kinase, spleen
tyrosine kinase, apoptosis signal-regulating kinase, Janus kinase,
lysyl oxidase, lysyl oxidase-like proteins, matrix
metallopeptidase, bromodomain-containing protein, adenosine A2B
receptor, isocitrate dehydrogenase, serine/threonine kinase TPL2,
discoidin domain receptor, serine/threonine-protein kinases, IKK,
MEK, EGFR, histone deacetylase, protein kinase C, or any
combination thereof. In certain embodiments, the therapeutic agent
may be selected from a PI3K (including PI3K.gamma., PI3K.delta.,
PI3K.beta., PI3K.alpha., and/or pan-PI3K) inhibitor, a JAK (Janus
kinase, including JAK1, JAK2, and/or JAK3) inhibitor, a SYK (spleen
tyrosine kinase) inhibitor, a BTK (Bruton's tyrosine kinase)
inhibitor, an A2B (adenosine A2B receptor) inhibitor, an ACK
(activated CDC kinase, including ACK1) inhibitor, an ASK (apoptosis
signal-regulating kinase, including ASK1) inhibitor, Auroa kinase,
a BRD (bromodomain-containing protein, including BRD4) inhibitor, a
Bcl (B-cell CLL/lymphoma, including Bcl-1 and/or Bcl-2) inhibitor,
a CAK (CDK-activating kinase) inhibitor, a CaMK
(calmodulin-dependent protein kinases) inhibitor, a CDK
(cyclin-dependent kinases, including CDK1, 2, 3, 4, and/or 6)
inhibitor, a CK (casein kinase, including CK1 and/or CK2)
inhibitor, a DDR (discoidin domain receptor, including DDR1 and/or
DDR2) inhibitor, a EGFR inhibitor, a FXR (farnesoid x receptor)
inhibitor, a FAK (focal adhesion kinase) inhibitor, a GSK (glycogen
synthase kinase) inhibitor, a HDAC (histone deacetylase) inhibitor,
an IDO (indoleamine 2,3-dioxygenase) inhibitor, an IDH (isocitrate
dehydrogenase, including IDH1) inhibitor, an IKK (1-Kappa-B kinase)
inhibitor, a KDM5 (lysine demethylase) inhibitor, a LCK
(lymphocyte-specific protein tyrosine kinase) inhibitor, a LOX
(lysyl oxidase) inhibitor, a LOXL (lysyl oxidase like protein,
including LOXL1, LOXL2, LOXL3, LOXL4, and/or LOXL5) inhibitor, a
MTH (mut T homolog) inhibitor, a MEK (mitogen-activated protein
kinase kinase) inhibitor, a matrix metalloprotease (MMP, including
MMP2 and/or MMP9) inhibitor, a mitogen-activated protein kinases
(MAPK) inhibitor, a PD-1 (programmed cell death protein 1)
inhibitor, a PD-L1 (programmed death-ligand 1) inhibitor, a PDGF
(platelet-derived growth factor) inhibitor, a phosphorylase kinase
(PK) inhibitor, a PLK (polo-like kinase, including PLK1, 2, 3)
inhibitor, a protein kinase (PK, including protein kinase A, B, C)
inhibitor, a STK (serine/threonine kinase) inhibitor, a STAT
(signal transduction and transcription) inhibitor, a
serine/threonine-protein kinase inhibitor, a TBK (tank-binding
kinase) inhibitor, a TLR (toll-like receptor modulators, including
TLR-1, TLR-2, TLR-3, TLR-4, TLR-5, TLR-6, TLR-7, TLR-8, TLR-9,
TLR-10, TLR-11, TLR-12, and/or TLR-13) inhibitor, a TK (tyrosine
kinase) inhibitor, a TPL2 (serine/threonine kinase) inhibitor, a
NEK9 inhibitor, an Abl inhibitor, a p38 kinase inhibitor, a PYK
inhibitor, a PYK inhibitor, a c-Kit inhibitor, a NPM-ALK inhibitor,
a Flt-3 inhibitor, a c-Met inhibitor, a KDR inhibitor, a TIE-2
inhibitor, a VEGFR inhibitor, a SRC inhibitor, a HCK inhibitor, a
LYN inhibitor, a FYN inhibitor, a YES inhibitor, a chemotherapeutic
agent, an immunotherapeutic agent, a radiotherapeutic agent, an
anti-neoplastic agent, an anti-cancer agent, an anti-proliferation
agent, an anti-fibrotic agent, an anti-angiogenic agent, a
therapeutic antibody, or any combination thereof. In some
embodiments, the JAK inhibitor is
N-(cyanomethyl)-4-[2-(4-morpholinoanilino)pyrimidin-4-yl]benzamide
as named by ChemDraw (may also be referred to as CYT0387 or
momelotinib) and may be synthesized by the methods described in
U.S. Pat. No. 8,486,941. In certain embodiment, the SyK inhibitor
is
6-(1H-indazol-6-yl)-N-(4-morpholinophenyl)imidazo[1,2-a]pyrazin-8-amine
as named by ChemDraw (may also be referred to as
6-(1H-indazol-6-yl)-N-[4-(morpholin-4-yl)phenyl]imidazo[1,2-a]pyrazin-8-a-
mine) and may be synthesized by the methods described in U.S. Pat.
No. 8,450,321. In other embodiments, the BTK inhibitor is
(S)-6-amino-9-(1-(but-2-ynoyl)pyrrolidin-3-yl)-7-(4-phenoxyphenyl)-7H-pur-
in-8(9H)-one as named by ChemDraw (may also be
6-amino-9-[(3R)-1-(2-butynoyl)-3-pyrrolidinyl]-7-(4-phenoxyphenyl)-7,9-di-
hydro-8H-purin-8-one) and may be synthesized by the methods in U.S.
Pat. No. 8,557,803.
[0296] Chemotherapeutic agents may be categorized by their
mechanism of action into, for example, the following groups:
anti-metabolites/anti-cancer agents, such as pyrimidine analogs
(floxuridine, capecitabine, and cytarabine); purine analogs, folate
antagonists and related inhibitors, antiproliferative/antimitotic
agents including natural products such as vinca alkaloid
(vinblastine, vincristine) and microtubule such as taxane
(paclitaxel, docetaxel), vinblastin, nocodazole, epothilones and
navelbine, epidipodophyllotoxins (etoposide, teniposide); DNA
damaging agents (actinomycin, amsacrine, busulfan, carboplatin,
chlorambucil, cisplatin, cyclophosphamide, Cytoxan, dactinomycin,
daunorubicin, doxorubicin, epirubicin, iphosphamide, melphalan,
merchlorehtamine, mitomycin, mitoxantrone, nitrosourea,
procarbazine, taxol, taxotere, teniposide, etoposide,
triethylenethiophosphoramide); antibiotics such as dactinomycin
(actinomycin D), daunorubicin, doxorubicin (adriamycin),
idarubicin, anthracyclines, mitoxantrone, bleomycins, plicamycin
(mithramycin) and mitomycin; enzymes (L-asparaginase which
systemically metabolizes L-asparagine and deprives cells which do
not have the capacity to synthesize their own asparagine);
antiplatelet agents; antiproliferative/antimitotic alkylating
agents such as nitrogen mustards cyclophosphamide and analogs,
melphalan, chlorambucil), and (hexamethylmelamine and thiotepa),
alkyl nitrosoureas (BCNU) and analogs, streptozocin),
trazenes-dacarbazinine (DTIC); antiproliferative/antimitotic
antimetabolites such as folic acid analogs (methotrexate); platinum
coordination complexes (cisplatin, oxiloplatinim, carboplatin),
procarbazine, hydroxyurea, mitotane, aminoglutethimide; hormones,
hormone analogs (estrogen, tamoxifen, goserelin, bicalutamide,
nilutamide) and aromatase inhibitors (letrozole, anastrozole);
anticoagulants (heparin, synthetic heparin salts and other
inhibitors of thrombin); fibrinolytic agents (such as tissue
plasminogen activator, streptokinase and urokinase), aspirin,
dipyridamole, ticlopidine, clopidogrel; antimigratory agents;
antisecretory agents (breveldin); immunosuppressives tacrolimus
sirolimus azathioprine, mycophenolate; compounds (TNP-470,
genistein) and growth factor inhibitors (vascular endothelial
growth factor inhibitors, fibroblast growth factor inhibitors);
angiotensin receptor blocker, nitric oxide donors; anti-sense
oligonucleotides; antibodies (trastuzumab, rituximab); cell cycle
inhibitors and differentiation inducers (tretinoin); inhibitors,
topoisomerase inhibitors (doxorubicin (adriamycin), daunorubicin,
dactinomycin, eniposide, epirubicin, etoposide, idarubicin,
irinotecan and mitoxantrone, topotecan, irinotecan, camptothesin),
corticosteroids (cortisone, dexamethasone, hydrocortisone,
methylpednisolone, prednisone, and prenisolone); growth factor
signal transduction kinase inhibitors; dysfunction inducers, toxins
such as Cholera toxin, ricin, Pseudomonas exotoxin, Bordetella
pertussis adenylate cyclase toxin, or diphtheria toxin, and caspase
activators; and chromatin.
[0297] As used herein the term "chemotherapeutic agent" or
"chemotherapeutic" (or "chemotherapy," in the case of treatment
with a chemotherapeutic agent) is meant to encompass any
non-proteinaceous (i.e, non-peptidic) chemical compound useful in
the treatment of cancer. Examples of chemotherapeutic agents
include alkylating agents such as thiotepa and cyclophosphamide
(CYTOXAN); alkyl sulfonates such as busulfan, improsulfan and
piposulfan; aziridines such as benzodopa, carboquone, meturedopa,
and uredopa; emylerumines and memylamelamines including
alfretamine, triemylenemelamine, triethylenephosphoramide,
triethylenethiophosphoramide and trimemylolomelamine; acetogenins
(especially bullatacin and bullatacinone); a camptothecin
(including synthetic analogue topotecan); bryostatin; callystatin;
CC-1065 (including its adozelesin, carzelesin and bizelesin
synthetic analogues); cryptophycins (articularly cryptophycin 1 and
cryptophycin 8); dolastatin; duocarmycin (including the synthetic
analogues, KW-2189 and CBI-TMI); eleutherobin; pancratistatin; a
sarcodictyin; spongistatin; nitrogen mustards such as chlorambucil,
chlornaphazine, cholophosphamide, estramustine, ifosfamide,
mechlorethamine, mechlorethamine oxide hydrochloride, melphalan,
novembichin, phenesterine, prednimustine, trofosfamide, uracil
mustard; nitrosoureas such as carmustine, chlorozotocin,
foremustine, lomustine, nimustine, ranimustine; antibiotics such as
the enediyne antibiotics (e.g., calicheamicin, especially
calicheamicin gammall and calicheamicin philI, see, e.g., Agnew,
Chem. Intl. Ed. Engl, 33:183-186 (1994); dynemicin, including
dynemicin A; bisphosphonates, such as clodronate; an esperamicin;
as well as neocarzinostatin chromophore and related chromoprotein
enediyne antibiotic chromomophores), aclacinomysins, actinomycin,
authramycin, azaserine, bleomycins, cactinomycin, carabicin,
carrninomycin, carzinophilin, chromomycins, dactinomycin,
daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin
(including morpholino-doxorubicin, cyanomorpholino-doxorubicin,
2-pyrrolino-doxorubicin and deoxydoxorubicin), epirubicin,
esorubicin, idarubicin, marcellomycin, mitomycins such as mitomycin
C, mycophenolic acid, nogalamycin, olivomycins, peplomycin,
potfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin,
streptozocin, tubercidin, ubenimex, zinostatin, zorubicin;
anti-metabolites such as methotrexate and 5-fluorouracil (5-FU);
folic acid analogues such as demopterin, methotrexate, pteropterin,
trimetrexate; purine analogs such as fludarabine, 6-mercaptopurine,
thiamiprine, thioguanine; pyrimidine analogues such as ancitabine,
azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine,
doxifluridine, enocitabine, floxuridine; androgens such as
calusterone, dromostanolone propionate, epitiostanol, mepitiostane,
testolactone; anti-adrenals such as aminoglutethimide, mitotane,
trilostane; folic acid replinisher such as frolinic acid;
aceglatone; aldophosphamide glycoside; aminolevulinic acid;
eniluracil; amsacrine; hestrabucil; bisantrene; edatraxate;
defofamine; demecolcine; diaziquone; elformthine; elliptinium
acetate; an epothilone; etoglucid; gallium nitrate; hydroxyurea;
lentinan; leucovorin; lonidamine; maytansinoids such as maytansine
and ansamitocins; mitoguazone; mitoxantrone; mopidamol; nitracrine;
pentostatin; phenamet; pirarubicin; losoxantrone; fluoropyrimidine;
folinic acid; podophyllinic acid; 2-ethylhydrazide; procarbazine;
PSK.RTM.; razoxane; rhizoxin; sizofiran; spirogermanium; tenuazonic
acid; triaziquone; 2,2',2''-tricUorotriemylamine; trichothecenes
(especially T-2 toxin, verracurin A, roridin A and anguidine);
urethane; vindesine; dacarbazine; mannomustine; mitobronitol;
mitolactol; pipobroman; gacytosine; arabinoside ("Ara-C");
cyclophosphamide; thiopeta; taxoids, e.g., paclitaxel (TAXOL.RTM.
and docetaxel (TAXOTERE.RTM.); chlorambucil; gemcitabine
(Gemzar.RTM.); 6-thioguanine; mercaptopurine; methotrexate;
platinum analogs such as cisplatin and carboplatin; vinblastine;
platinum; etoposide (VP-16); ifosfamide; mitroxantrone;
vancristine; vinorelbine (Navelbine.RTM.); novantrone; teniposide;
edatrexate; daunomycin; aminopterin; xeoloda; ibandronate; CPT-11;
topoisomerase inhibitor RFS 2000; difluoromethylornithine (DMFO);
retinoids such as retinoic acid; capecitabine; FOLFIRI
(fluorouracil, leucovorin, and irinotecan) and pharmaceutically
acceptable salts, acids or derivatives of any of the above. One or
more chemotherapeutic agent are used or included in the present
application.
[0298] Also included in the definition of "chemotherapeutic agent"
are anti-hormonal agents that act to regulate or inhibit hormone
action on tumors such as anti-estrogens and selective estrogen
receptor modulators (SERMs), including, for example, tamoxifen
(including Nolvadex.TM.), raloxifene, droloxifene,
4-hydroxytamoxifen, trioxifene, keoxifene, LY 117018, onapristone,
and toremifene (Fareston.RTM.); inhibitors of the enzyme aromatase,
which regulates estrogen production in the adrenal glands, such as,
for example, 4(5)-imidazoles, aminoglutethimide, megestrol acetate
(Megace.RTM.), exemestane, formestane, fadrozole, vorozole
(Rivisor.RTM.), letrozole (Femara.RTM.), and anastrozole
(Arimidex.RTM.); and anti-androgens such as flutamide, nilutamide,
bicalutamide, leuprohde, and goserelin; and pharmaceutically
acceptable salts, acids or derivatives of any of the above.
[0299] The anti-angiogenic agents include, but are not limited to,
retinoid acid and derivatives thereof, 2-methoxyestradiol,
ANGIOSTATIN.RTM., ENDOSTATIN.RTM., suramin, squalamine, tissue
inhibitor of metalloproteinase-1, tissue inhibitor of
metalloproternase-2, plasminogen activator inhibitor-1, plasminogen
activator inbibitor-2, cartilage-derived inhibitor, paclitaxel
(nab-paclitaxel), platelet factor 4, protamine sulphate (clupeine),
sulphated chitin derivatives (prepared from queen crab shells),
sulphated polysaccharide peptidoglycan complex (sp-pg),
staurosporine, modulators of matrix metabolism, including for
example, proline analogs ((1-azetidine-2-carboxylic acid (LACA),
cishydroxyproline, d,I-3,4-dehydroproline, thiaproline,
.alpha.-dipyridyl, beta-aminopropionitrile fumarate,
4-propyl-5-(4-pyridinyl)-2(3h)-oxazolone; methotrexate,
mitoxantrone, heparin, interferons, 2 macroglobulin-serum, chimp-3,
chymostatin, beta-cyclodextrin tetradecasulfate, eponemycin;
fumagillin, gold sodium thiomalate, d-penicillamine (CDPT),
beta-1-anticollagenase-serum, alpba-2-antiplasmin, bisantrene,
lobenzarit disodium, n-2-carboxyphenyl-4-chloroanthronilic acid
disodium or "CCA", thalidomide; angiostatic steroid,
cargboxynaminolmidazole; metalloproteinase inhibitors such as BB94.
Other anti-angiogenesis agents include antibodies, preferably
monoclonal antibodies against these angiogenic growth factors:
beta-FGF, alpha-FGF, FGF-5, VEGF isoforms, VEGF-C, HGF/SF and
Ang-1/Ang-2. See Ferrara N. and Alitalo, K. "Clinical application
of angiogenic growth factors and their inhibitors" (1999) Nature
Medicine 5:1359-1364.
[0300] The anti-fibrotic agents include, but are not limited to,
the compounds such as beta-aminoproprionitrile (BAPN), as well as
the compounds disclosed in U.S. Pat. No. 4,965,288 to Palfreyman,
et al., issued Oct. 23, 1990, entitled "Inhibitors of lysyl
oxidase," relating to inhibitors of lysyl oxidase and their use in
the treatment of diseases and conditions associated with the
abnormal deposition of collagen; U.S. Pat. No. 4,997,854 to Kagan,
et al., issued Mar. 5, 1991, entitled "Anti-fibrotic agents and
methods for inhibiting the activity of lysyl oxidase in situ using
adjacently positioned diamine analogue substrate," relating to
compounds which inhibit LOX for the treatment of various
pathological fibrotic states, which are herein incorporated by
reference. Further exemplary inhibitors are described in U.S. Pat.
No. 4,943,593 to Palfreyman, et al., issued Jul. 24, 1990, entitled
"Inhibitors of lysyl oxidase," relating to compounds such as
2-isobutyl-3-fluoro-, chloro-, or bromo-allylamine; as well as,
e.g., U.S. Pat. No. 5,021,456; U.S. Pat. No. 5,5059,714; U.S. Pat.
No. 5,120,764; U.S. Pat. No. 5,182,297; U.S. Pat. No. 5,252,608
(relating to 2-(1-naphthyloxymemyl)-3-fluoroallylamine); and U.S.
Patent Application No. 2004/0248871, which are herein incorporated
by reference. Exemplary anti-fibrotic agents also include the
primary amines reacting with the carbonyl group of the active site
of the lysyl oxidases, and more particularly those which produce,
after binding with the carbonyl, a product stabilized by resonance,
such as the following primary amines: emylenemamine, hydrazine,
phenylhydrazine, and their derivatives, semicarbazide, and urea
derivatives, aminonitriles, such as beta-aminopropionitrile (BAPN),
or 2-nitroethylamine, unsaturated or saturated haloamines, such as
2-bromo-ethylamine, 2-chloroethylamine, 2-trifluoroethylamine,
3-bromopropylamine, p-halobenzylamines, selenohomocysteine lactone.
Also, the anti-fibrotic agents are copper chelating agents,
penetrating or not penetrating the cells. Exemplary compounds
include indirect inhibitors such compounds blocking the aldehyde
derivatives originating from the oxidative deamination of the lysyl
and hydroxylysyl residues by the lysyl oxidases, such as the
thiolamines, in particular D-penicillamine, or its analogues such
as 2-amino-5-mercapto-5-methylhexanoic acid,
D-2-amino-3-methyl-3-((2-acetamidoethyl)dithio)butanoic acid,
p-2-amino-3-methyl-3-((2-aminoethyl)dithio)butanoic acid,
sodium-4-((p-1-dimethyl-2-amino-2-carboxyethyl)dithio)butane
sulphurate, 2-acetamidoethyl-2-acetamidoethanethiol sulphanate,
sodium-4-mercaptobutanesulphinate trihydrate.
[0301] The immunotherapeutic agents include and are not limited to
therapeutic antibodies suitable for treating patients; such as
abagovomab, adecatumumab, afutuzumab, alemtuzumab, altumomab,
amatuximab, anatumomab, arcitumomab, bavituximab, bectumomab,
bevacizumab, bivatuzumab, blinatumomab, brentuximab, cantuzumab,
catumaxomab, cetuximab, citatuzumab, cixutumumab, clivatuzumab,
conatumumab, daratumumab, drozitumab, duligotumab, dusigitumab,
detumomab, dacetuzumab, dalotuzumab, ecromeximab, elotuzumab,
ensituximab, ertumaxomab, etaracizumab, farietuzumab, ficlatuzumab,
figitumumab, flanvotumab, futuximab, ganitumab, gemtuzumab,
girentuximab, glembatumumab, ibritumomab, igovomab, imgatuzumab,
indatuximab, inotuzumab, intetumumab, ipilimumab, iratumumab,
labetuzumab, lexatumumab, lintuzumab, lorvotuzumab, lucatumumab,
mapatumumab, matuzumab, milatuzumab, minretumomab, mitumomab,
moxetumomab, narnatumab, naptumomab, necitumumab, nimotuzumab,
nofetumomabn, ocaratuzumab, ofatumumab, olaratumab, onartuzumab,
oportuzumab, oregovomab, panitumumab, parsatuzumab, patritumab,
pemtumomab, pertuzumab, pintumomab, pritumumab, racotumomab,
radretumab, rilotumumab, rituximab, robatumumab, satumomab,
sibrotuzumab, siltuximab, simtuzumab, solitomab, tacatuzumab,
taplitumomab, tenatumomab, teprotumumab, tigatuzumab, tositumomab,
trastuzumab, tucotuzumab, ublituximab, veltuzumab, vorsetuzumab,
votumumab, zalutumumab, CC49 and 3F8. The exemplified therapeutic
antibodies may be further labeled or combined with a radioisotope
particle, such as indium In 111, yttrium Y 90, iodine I-131.
Obinutuzumab is also an example of an immunotherapeutic agent.
[0302] The application also provides method for treating a subject
who is undergoing one or more standard therapies, such as
chemotherapy, radiotherapy, immunotherapy, surgery, or combination
thereof. Accordingly, one or more therapeutic agent or inhibitors
may be administered before, during, or after administration of
chemotherapy, radiotherapy, immunotherapy, surgery or combination
thereof.
[0303] In certain embodiments, the subject may be a human who is
(i) substantially refractory to at least one chemotherapy
treatment, or (ii) in relapse after treatment with chemotherapy, or
both (i) and (ii). In some of embodiments, the subject is
refractory to at least two, at least three, or at least four
chemotherapy treatments (including standard or experimental
chemotherapies).
[0304] In certain embodiments, the subject is refractory to at
least one, at least two, at least three, or at least four
chemotherapy treatment (including standard or experimental
chemotherapy) selected from fludarabine, rituximab, obinutuzumab,
alkylating agents, alemtuzumab and other chemotherapy treatments
such as CHOP (cyclophosphamide, doxorubicin, vincristine,
prednisone); R-CHOP (rituximab-CHOP); hyperCVAD (hyperfractionated
cyclophosphamide, vincristine, doxorubicin, dexamethasone,
methotrexate, cytarabine); R-hyperCVAD (rituximab-hyperCVAD); FCM
(fludarabine, cyclophosphamide, mitoxantrone); R-FCM (rituximab,
fludarabine, cyclophosphamide, mitoxantrone); bortezomib and
rituximab; temsirolimus and rituximab; temsirolimus and
Velcade.RTM.; Iodine-131 tositumomab (Bexxaro) and CHOP; CVP
(cyclophosphamide, vincristine, prednisone); R-CVP (rituximab-CVP);
ICE (iphosphamide, carboplatin, etoposide); R-ICE (rituximab-ICE);
FCR (fludarabine, cyclophosphamide, rituximab); FR (fludarabine,
rituximab); and D.T. PACE (dexamethasone, thalidomide, cisplatin,
Adriamycin.RTM., cyclophosphamide, etoposide).
[0305] Other examples of chemotherapy treatments (including
standard or experimental chemotherapies) are described below. In
addition, treatment of certain lymphomas is reviewed in Cheson, B.
D., Leonard, J. P., "Monoclonal Antibody Therapy for B-Cell
Non-Hodgkin's Lymphoma" The New England Journal of Medicine 2008,
359(6), p. 613-626; and Wierda, W. G., "Current and Investigational
Therapies for Patients with CLL" Hematology 2006, p. 285-294.
Lymphoma incidence patterns in the United States is profiled in
Morton, L. M., et al. "Lymphoma Incidence Patterns by WHO Subtype
in the United States, 1992-2001" Blood 2006, 107(1), p.
265-276.
[0306] Examples of immunotherapeutic agents treating lymphoma or
leukemia include, but are not limited to, rituximab (such as
Rituxan), alemtuzumab (such as Campath, MabCampath), anti-CD19
antibodies, anti-CD20 antibodies, anti-MN-14 antibodies,
anti-TRAIL, Anti-TRAIL DR4 and DR5 antibodies, anti-CD74
antibodies, apolizumab, bevacizumab, CHIR-12.12, epratuzumab (hLL2-
anti-CD22 humanized antibody), galiximab, ha20, ibritumomab
tiuxetan, lumiliximab, milatuzumab, ofatumumab, PRO131921, SGN-40,
WT-1 analog peptide vaccine, WT1 126-134 peptide vaccine,
tositumomab, autologous human tumor-derived HSPPC-96, and
veltuzumab. Additional immunotherapy agents includes using cancer
vaccines based upon the genetic makeup of an individual patient's
tumor, such as lymphoma vaccine example is GTOP-99
(MyVax.RTM.).
[0307] Examples of chemotherapy agents for treating lymphoma or
leukemia include aldesleukin, alvocidib, antineoplaston AS2-1,
antineoplaston A10, anti-thymocyte globulin, amifostine trihydrate,
aminocamptothecin, arsenic trioxide, beta alethine, Bcl-2 family
protein inhibitor ABT-263, BMS-345541, bortezomib (Velcade.RTM.),
bryostatin 1, busulfan, carboplatin, campath-1H, CC-5103,
carmustine, caspofungin acetate, clofarabine, cisplatin, Cladribine
(Leustarin), Chlorambucil (Leukeran), Curcumin, cyclosporine,
Cyclophosphamide (Cyloxan, Endoxan, Endoxana, Cyclostin),
cytarabine, denileukin diftitox, dexamethasone, DT PACE, docetaxel,
dolastatin 10, Doxorubicin (Adriamycin.RTM., Adriblastine),
doxorubicin hydrochloride, enzastaurin, epoetin alfa, etoposide,
Everolimus (RAD001), fenretinide, filgrastim, melphalan, mesna,
Flavopiridol, Fludarabine (Fludara), Geldanamycin (17-AAG),
ifosfamide, irinotecan hydrochloride, ixabepilone, Lenalidomide
(Revlimid.RTM., CC-5013), lymphokine-activated killer cells,
melphalan, methotrexate, mitoxantrone hydrochloride, motexafin
gadolinium, mycophenolate mofetil, nelarabine, oblimersen
(Genasense) Obatoclax (GX15-070), oblimersen, octreotide acetate,
omega-3 fatty acids, oxaliplatin, paclitaxel, PD0332991, PEGylated
liposomal doxorubicin hydrochloride, pegfilgrastim, Pentstatin
(Nipent), perifosine, Prednisolone, Prednisone, R-roscovitine
(Selicilib, CYC202), recombinant interferon alfa, recombinant
interleukin-12, recombinant interleukin-11, recombinant flt3
ligand, recombinant human thrombopoietin, rituximab, sargramostim,
sildenafil citrate, simvastatin, sirolimus, Styryl sulphones,
tacrolimus, tanespimycin, Temsirolimus (CC1-779), Thalidomide,
therapeutic allogeneic lymphocytes, thiotepa, tipifarnib,
Velcade.RTM. (bortezomib or PS-341), Vincristine (Oncovin),
vincristine sulfate, vinorelbine ditartrate, Vorinostat (SAHA),
vorinostat, and FR (fludarabine, rituximab), CHOP
(cyclophosphamide, doxorubicin, vincristine, prednisone), CVP
(cyclophosphamide, vincristine and prednisone), FCM (fludarabine,
cyclophosphamide, mitoxantrone), FCR (fludarabine,
cyclophosphamide, rituximab), hyperCVAD (hyperfractionated
cyclophosphamide, vincristine, doxorubicin, dexamethasone,
methotrexate, cytarabine), ICE (iphosphamide, carboplatin and
etoposide), MCP (mitoxantrone, chlorambucil, and prednisolone),
R-CHOP (rituximab plus CHOP), R-CVP (rituximab plus CVP), R-FCM
(rituximab plus FCM), R-ICE (rituximab-ICE), and R-MCP (R-MCP). An
additional example includes ABT-199.
[0308] The therapeutic treatments can be supplemented or combined
with any of the abovementioned therapies with stem cell
transplantation or treatment. One example of modified approach is
radioimmunotherapy, wherein a monoclonal antibody is combined with
a radioisotope particle, such as indium In 111, yttrium Y 90,
iodine I-131. Examples of combination therapies include, but are
not limited to, Iodine-131 tositumomab (Bexxar.RTM.), Yttrium-90
ibritumomab tiuxetan (Zevalin.RTM.), Bexxar.RTM. with CHOP.
[0309] Other therapeutic procedures include peripheral blood stem
cell transplantation, autologous hematopoietic stem cell
transplantation, autologous bone marrow transplantation, antibody
therapy, biological therapy, enzyme inhibitor therapy, total body
irradiation, infusion of stem cells, bone marrow ablation with stem
cell support, in vitro-treated peripheral blood stem cell
transplantation, umbilical cord blood transplantation, immunoenzyme
technique, pharmacological study, low-LET cobalt-60 gamma ray
therapy, bleomycin, conventional surgery, radiation therapy, and
nonmyeloablative allogeneic hematopoietic stem cell
transplantation.
Kits
[0310] Provided herein are also kits that include a compound of the
present application or a pharmaceutically acceptable salt,
stereoisomer, prodrug, or solvate thereof, and suitable packaging.
Provided herein are also kits that include a compound of formula
(J), (I), (J-1), (J-1a), (J-1b), (IA-1), (IA-2), (IB-1), (IB-2),
(IB-3), or (IB-4), or a pharmaceutically acceptable salt,
stereoisomer, prodrug, or solvate thereof, and suitable packaging.
In one embodiment, a kit further includes instructions for use. In
one aspect, a kit includes a compound of formula (J-1), (J-1a),
(J-1b), (IA-1), (IA-2), (IB-1), (IB-2), (IB-3), or (IB-4), or a
pharmaceutically acceptable salt, stereoisomer, prodrug, or solvate
thereof, and a label and/or instructions for use of the compounds
in the treatment of the indications, including the diseases or
conditions, described herein. In one aspect, a kit includes a
compound selected from Compound 1 to 116, or a pharmaceutically
acceptable salt, stereoisomer, prodrug, or solvate thereof, and a
label and/or instructions for use of the compounds in the treatment
of the indications, including the diseases or conditions, described
herein.
[0311] Provided herein are also articles of manufacture that
include a compound described herein or pharmaceutically acceptable
salts, isomer, or a mixture thereof in a suitable container. The
container may be a vial, jar, ampoule, preloaded syringe, and
intravenous bag.
Pharmaceutical Compositions and Modes of Administration
[0312] Compounds provided herein are usually administered in the
form of pharmaceutical compositions. Thus, provides herein are also
pharmaceutical compositions that contain one or more of the
compounds described herein or pharmaceutically acceptable salts,
isomer, or a mixture thereof and one or more pharmaceutically
acceptable vehicles selected from carriers, adjuvants and
excipients. Suitable pharmaceutically acceptable vehicles may
include, for example, inert solid diluents and fillers, diluents,
including sterile aqueous solution and various organic solvents,
permeation enhancers, solubilizers and adjuvants. Such compositions
are prepared in a manner well known in the pharmaceutical art. See,
e.g., Remington's Pharmaceutical Sciences, Mace Publishing Co.,
Philadelphia, Pa. 17th Ed. (1985); and Modern Pharmaceutics, Marcel
Dekker, Inc. 3rd Ed. (G. S. Banker & C. T. Rhodes, Eds.).
[0313] The pharmaceutical compositions may be administered in
either single or multiple doses. The pharmaceutical composition may
be administered by various methods including, for example, rectal,
buccal, intranasal and transdermal routes. In certain embodiments,
the pharmaceutical composition may be administered by
intra-arterial injection, intravenously, intraperitoneally,
parenterally, intramuscularly, subcutaneously, orally, topically,
or as an inhalant.
[0314] One mode for administration is parenteral, for example, by
injection. The forms in which the pharmaceutical compositions
described herein may be incorporated for administration by
injection include, for example, aqueous or oil suspensions, or
emulsions, with sesame oil, corn oil, cottonseed oil, or peanut
oil, as well as elixirs, mannitol, dextrose, or a sterile aqueous
solution, and similar pharmaceutical vehicles.
[0315] Oral administration may be another route for administration
of the compounds described herein. Administration may be via, for
example, capsule or enteric coated tablets. In making the
pharmaceutical compositions that include at least one compound
described herein or pharmaceutically acceptable salts, isomer, or a
mixture thereof, the active ingredient is usually diluted by an
excipient and/or enclosed within such a carrier that can be in the
form of a capsule, sachet, paper or other container. When the
excipient serves as a diluent, it can be in the form of a solid,
semi-solid, or liquid material, which acts as a vehicle, carrier or
medium for the active ingredient. Thus, the compositions can be in
the form of tablets, pills, powders, lozenges, sachets, cachets,
elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a
solid or in a liquid medium), ointments containing, for example, up
to 10% by weight of the active compound, soft and hard gelatin
capsules, sterile injectable solutions, and sterile packaged
powders.
[0316] Some examples of suitable excipients include lactose,
dextrose, sucrose, sorbitol, mannitol, starches, gum acacia,
calcium phosphate, alginates, tragacanth, gelatin, calcium
silicate, microcrystalline cellulose, polyvinylpyrrolidone,
cellulose, sterile water, syrup, and methyl cellulose. The
formulations can additionally include lubricating agents such as
talc, magnesium stearate, and mineral oil; wetting agents;
emulsifying and suspending agents; preserving agents such as methyl
and propylhydroxy-benzoates; sweetening agents; and flavoring
agents.
[0317] The compositions that include at least one compound
described herein or pharmaceutically acceptable salts, isomer, or a
mixture thereof can be formulated so as to provide quick, sustained
or delayed release of the active ingredient after administration to
the subject by employing procedures known in the art. Controlled
release drug delivery systems for oral administration include
osmotic pump systems and dissolutional systems containing
polymer-coated reservoirs or drug-polymer matrix formulations.
Examples of controlled release systems are given in U.S. Pat. Nos.
3,845,770; 4,326,525; 4,902,514; and 5,616,345. Another formulation
for use in the methods of the present invention employs transdermal
delivery devices ("patches"). Such transdermal patches may be used
to provide continuous or discontinuous infusion of the compounds
described herein in controlled amounts. The construction and use of
transdermal patches for the delivery of pharmaceutical agents is
well known in the art. See, e.g., U.S. Pat. Nos. 5,023,252,
4,992,445 and 5,001,139. Such patches may be constructed for
continuous, pulsatile, or on demand delivery of pharmaceutical
agents.
[0318] For preparing solid compositions such as tablets, the
principal active ingredient may be mixed with a pharmaceutical
excipient to form a solid preformulation composition containing a
homogeneous mixture of a compound described herein or
pharmaceutically acceptable salts, isomer, or a mixture thereof.
When referring to these preformulation compositions as homogeneous,
the active ingredient may be dispersed evenly throughout the
composition so that the composition may be readily subdivided into
equally effective unit dosage forms such as tablets, pills and
capsules.
[0319] The tablets or pills of the compounds described herein may
be coated or otherwise compounded to provide a dosage form
affording the advantage of prolonged action, or to protect from the
acid conditions of the stomach. For example, the tablet or pill can
include an inner dosage and an outer dosage component, the latter
being in the form of an envelope over the former. The two
components can be separated by an enteric layer that serves to
resist disintegration in the stomach and permit the inner component
to pass intact into the duodenum or to be delayed in release. A
variety of materials can be used for such enteric layers or
coatings, such materials including a number of polymeric acids and
mixtures of polymeric acids with such materials as shellac, cetyl
alcohol, and cellulose acetate.
[0320] Compositions for inhalation or insufflation may include
solutions and suspensions in pharmaceutically acceptable, aqueous
or organic solvents, or mixtures thereof, and powders. The liquid
or solid compositions may contain suitable pharmaceutically
acceptable excipients as described supra. In some embodiments, the
compositions are administered by the oral or nasal respiratory
route for local or systemic effect. In other embodiments,
compositions in pharmaceutically acceptable solvents may be
nebulized by use of inert gases. Nebulized solutions may be inhaled
directly from the nebulizing device or the nebulizing device may be
attached to a facemask tent, or intermittent positive pressure
breathing machine. Solution, suspension, or powder compositions may
be administered, preferably orally or nasally, from devices that
deliver the formulation in an appropriate manner.
Dosing
[0321] The specific dose level of a compound of the present
application for any particular subject will depend upon a variety
of factors including the activity of the specific compound
employed, the age, body weight, general health, sex, diet, time of
administration, route of administration, and rate of excretion,
drug combination and the severity of the particular disease in the
subject undergoing therapy. For example, a dosage may be expressed
as a number of milligrams of a compound described herein per
kilogram of the subject's body weight (mg/kg). Dosages of between
about 0.1 and 150 mg/kg may be appropriate. In some embodiments,
about 0.1 and 100 mg/kg may be appropriate. In other embodiments a
dosage of between 0.5 and 60 mg/kg may be appropriate. Normalizing
according to the subject's body weight is particularly useful when
adjusting dosages between subjects of widely disparate size, such
as occurs when using the drug in both children and adult humans or
when converting an effective dosage in a non-human subject such as
dog to a dosage suitable for a human subject.
[0322] The daily dosage may also be described as a total amount of
a compound described herein administered per dose or per day. Daily
dosage of a compound of formula (J), (J1-a), (J1-b), (IA-1),
(IA-2), (IB-1), (IB-2), (IB-3), or (IB-4)) may be between about 1
mg and 4,000 mg, between about 2,000 to 4,000 mg/day, between about
1 to 2,000 mg/day, between about 1 to 1,000 mg/day, between about
10 to 500 mg/day, between about 20 to 500 mg/day, between about 50
to 300 mg/day, between about 75 to 200 mg/day, or between about 15
to 150 mg/day. Daily dosage of a compound of the present
application (e.g. compounds of formula (J), (I), (IA-1), (IA-2),
(IB-1), (IB-2), (IB-3), or (IB-4)) also falls within the ranges
described above. Daily dosage of a compound selected from Compounds
1 to 116 also falls within the ranges described above.
[0323] When administered orally, the total daily dosage for a human
subject may be between 1 mg and 1,000 mg, between about 10-500
mg/day, between about 50-300 mg/day, between about 75-200 mg/day,
or between about 100-150 mg/day.
[0324] The compounds of the present application or the compositions
thereof may be administered once, twice, three, or four times
daily, using any suitable mode described above. Also,
administration or treatment with the compounds may be continued for
a number of days; for example, commonly treatment would continue
for at least 7 days, 14 days, or 28 days, for one cycle of
treatment. Treatment cycles are well known in cancer chemotherapy,
and are frequently alternated with resting periods of about 1 to 28
days, commonly about 7 days or about 14 days, between cycles. The
treatment cycles, in other embodiments, may also be continuous.
[0325] In a particular embodiment, the method comprises
administering to the subject an initial daily dose of about 1 to
500 mg of a compound described herein and increasing the dose by
increments until clinical efficacy is achieved. Increments of about
5, 10, 25, 50, or 100 mg can be used to increase the dose. The
dosage can be increased daily, every other day, twice per week, or
once per week.
Synthesis of the Compounds
[0326] The compounds may be prepared using the methods disclosed
herein and routine modifications thereof, which will be apparent
given the disclosure herein and methods well known in the art.
Conventional and well-known synthetic methods may be used in
addition to the teachings herein. The synthesis of typical
compounds described herein may be accomplished as described in the
following examples. If available, reagents may be purchased
commercially, e.g., from Sigma Aldrich or other chemical
suppliers.
General Synthesis
[0327] Typical embodiments of compounds described herein may be
synthesized using the general reaction schemes described below. It
will be apparent given the description herein that the general
schemes may be altered by substitution of the starting materials
with other materials having similar structures to result in
products that are correspondingly different. Descriptions of
syntheses follow to provide numerous examples of how the starting
materials may vary to provide corresponding products. Given a
desired product for which the substituent groups are defined, the
necessary starting materials generally may be determined by
inspection. Starting materials are typically obtained from
commercial sources or synthesized using published methods. For
synthesizing compounds which are embodiments described in the
present disclosure, inspection of the structure of the compound to
be synthesized will provide the identity of each substituent group.
The identity of the final product will generally render apparent
the identity of the necessary starting materials by a simple
process of inspection, given the examples herein. In general,
compounds described herein are typically stable and isolatable at
room temperature and pressure.
Synthetic Reaction Parameters
[0328] The terms "solvent", "inert organic solvent", or "inert
solvent" refer to a solvent inert under the conditions of the
reaction being described in conjunction therewith (including, for
example, benzene, toluene, acetonitrile, tetrahydrofuran ("THF"),
dimethylformamide ("DMF"), chloroform, methylene chloride (or
dichloromethane), diethyl ether, methanol, and the like). Unless
specified to the contrary, the solvents used in the reactions of
the present invention are inert organic solvents, and the reactions
are carried out under an inert gas, preferably nitrogen.
[0329] The term "q.s." means adding a quantity sufficient to
achieve a stated function, e.g., to bring a solution to the desired
volume (i.e., 100%).
[0330] After synthesis, the compounds may be isolated in the form
of a free base or a trifluoroacetic acid salt and further
characterized by NMR. The resulting compounds and their NMR
characterizations may represent either the free base or salt form.
The ratio of parent compound and corresponding salt is not
determined.
Compounds of Formula I
[0331] One method of preparing compounds of formula (I) is shown in
Reaction Scheme
##STR00042## ##STR00043##
[0332] Step 1--Preparation of a Compound of Formula (1)
[0333] The compound of formula (1) can be made by combining
compounds (A), (B) and (C) in the presence of a dehydrating agent.
Compounds (A), (B) and (C) are commercially available or can be
made by methods known in the art. With respect to compound (A),
R.sup.1 is as defined herein. With respect to compound (B), R.sup.3
and R.sup.5 are as defined herein. With respect to compound (C),
R.sup.2 is as defined herein. Compound (A) can be mixed with
Compound (B) in the presence of a coupling agent such as diphenyl
phosphite in a solvent such as pyridine. After stirring at a
temperature between ambient and 100.degree. C. for between 1 and 5
hours, compound (C) is added. After further stirring at a
temperature between ambient and 100.degree. C. for between 5 and 24
hours, the reaction mixture is allowed to cool to room temperature.
To extract the compound of formula (1), an organic solvent such as
ethyl acetate (EtOAc) may be added, followed by washing with, mild
acid, water, and brine. The organic phase can be concentrated to
obtain the compound of formula (1). Additional compounds may be
prepared by alkylation of compounds of formula (1) in which R.sup.1
is OH. For example a compound of formula (1), R.sup.1.dbd.OH, is
mixed with a reagent containing a leaving group, such as a halide
or mesylate, in the presence of a base, such as Cs.sub.2CO.sub.3 or
K.sub.2CO.sub.3, in a solvent such as DMF or DMSO. After stirring
at a temperature between ambient and 110.degree. C. for between 5
and 24 hours, the reaction mixture is allowed to cool to room
temperature and worked up under standard conditions. Additional
compounds may be prepared by coupling reactions with compounds of
formula (1) in which R.sup.1 is halo, such as iodo, bromo, or
chloro. For example a compound of formula (1), R.sup.1.dbd.Br, may
be mixed with a double bond containing compound, such as
acrylamide, allyl alcohol, allylcyclohexane, or acrolein, in the
presence of a base, such as Hunig's base, Cs.sub.2CO.sub.3 or
K.sub.2CO.sub.3, and metal catalyst such as
chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-
-amino-1,1'-biphenyl)]palladium(II) in a solvent such as DMF. After
stirring at a temperature between ambient and 110.degree. C. for
between 5 and 24 hours, the reaction mixture is allowed to cool to
room temperature and worked up under standard conditions. If
R.sup.1 contains a double bond, it can be reduced under standard
conditions such as hydrogenation in the presence of a catalyst,
such as Pd/C or Pt in a solvent such as EtOAc, EtOH, or MeOH under
ambient or elevated pressure. If R.sup.1 contains an aldehyde, it
can be converted to an amine under standard conditions such as
reaction with a primary or secondary amine in the presence of
sodium cyanoborohydride or sodium triacetoxyborohydride, in a
solvent such as DCM, EtOAc, EtOH, or MeOH under ambient or elevated
temperature. Compounds where R.sup.1 is SO.sub.2R may be prepared
by reaction of a compound (1) where R.sup.1 is halo, such as Br,
with sodium alkyl or aryl sulfinate in the presence of a base, such
as Cs.sub.2CO.sub.3 or K.sub.2CO.sub.3, and a catalyst such as CuI,
in a solvent such as DMSO, and heated at a temperature between
ambient and 120.degree. C. Further, compounds where R.sup.1 is
SO.sub.2R may be prepared by first reacting a compound (1) where
R.sup.1 is halo, such as Br, with a thiol in the presence of a base
such as Hunig's base, a catalyst such as Pd(dba).sub.2, a ligand
such as Xantphos, and (S)-proline in a solvent such as dioxane, and
heated at a temperature between ambient and 140.degree. C. The
resulting thiol can be oxidized by treatment with an oxidizing
agent, such as oxone in an aqueous solvent such as a mixture of THF
and water. Additionally for compounds that have a latent amine
which is desired to be acylated, the amine may be reacted with an
acid in the presence of base, such as Hunig's base or triethylamine
and a coupling agent such as HATU or HOBT to give the amide. The
compound of formula (1) may be purified by any suitable methods
known in the art, such as chromatography on silica gel.
Alternatively, the compound of formula (1) may be used in the next
step without purification.
[0334] Step 2--Preparation of a Compound of Formula (2)
[0335] The compound of formula (2) can be made by removing the
protecting group(s) from the compound of formula (1). The compound
of formula (1) is dissolved in a suitable solvent and treated with
a suitable acid. Suitable solvents may include, for example,
dichloromethane, -dioxane, or other suitable solvents. Suitable
acids may include, for example, trifluoroacetic acid, hydrochloric
acid, or boron tribromide (BBr.sub.3). The reaction can be carried
out at temperatures between -78.degree. C. to ambient temperature.
On reaction completion, solvent is removed to obtain the compound
of formula (2). In the case of a reaction using BBr.sub.3 the
reaction may first be treated with MeOH before an aqueous work-up
to obtain a compound of formula (2).
[0336] Step 3--Preparation of a Compound of Formula (3)
[0337] The compound of formula (3) can be made by treating
5-substituted-2,4,6-trihalopyrimidine with ammonium hydroxide in a
suitable solvent such as dioxane, where the halo is either chloro
or fluoro. The reaction is carried out at an elevated temperature
between 30 and 80.degree. C. for a suitable time, typically between
2 and 8 hours or when the reaction is complete. Upon completion,
water is added to the cooled solution, and the precipitate is
collected by filtration. The nitrile can be converted to the
carboxamide under standard conditions.
[0338] Step 4--Preparation of a Compound of Formula (I)
[0339] The compound of formula (I) can generally be prepared by
coupling compound of formula (2) and compound of formula (3) in the
presence of a suitable base in a suitable solvent. An example of a
suitable base is diisopropylethylamine. An example of a suitable
solvent is N-methylpyrrolidone (NMP), DMF, DMSO, isopropanol, or
ethanol. The reaction is typically performed at a temperature
between 30.degree. C. to 150.degree. C. for about 30 minutes to 120
hours. Alternatively the reaction can be performed in a microwave
at a temperature between 100.degree. C. to 150.degree. C. for about
30 minutes to 24 hours. Water can be added to quench the reaction
upon completion, and the precipitate may be filtered and then
dissolved in an organic solvent such as dichloromethane (DCM). The
product can be isolated by methods known in the art, for example by
removal of solvent under reduced pressure. The product can be
purified using any suitable methods known in the art, for example,
chromatography of the residue on a silica column.
[0340] It should be understood that the compounds of formula (I)
can be prepared according to the methods provided in Reaction
Scheme 1, starting from materials known to one of skill in the
art.
Example 1a. Preparation of a Compound of Formula (1)
[0341] A. Preparation of a Compound of Formula (1) in which n is 1,
R.sup.1 is fluoro, m is 1, R.sup.2 is fluoro, R.sup.5 is hydrogen,
and R.sup.3 is cyclopropyl
##STR00044##
[0342] Diphenyl phosphite (1.6 mL, 9 mmol) was added to a solution
of 2-amino-6-fluorobenzoic acid (380 mg, 2 mmol) and
(S)-2-(tert-butoxycarbonylamino)-2-cyclopropylacetic acid (680 mg,
3 mmol) in pyridine (2 mL). The reaction mixture was stirred at
40.degree. C. for 1 hour. 3-Fluoroaniline (330 mg, 3 mmol) was then
added to the reaction mixture, which was then stirred at 50.degree.
C. for 16 hours. The reaction mixture was cooled to room
temperature. This mixture was purified by column chromatography on
SiO.sub.2 eluting with EtOAc in hexanes (0-75%) to afford
(S)-tert-butyl
(cyclopropyl(5-fluoro-3-(3-fluorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl-
)methyl)carbamate.
[0343] B. Following the procedure described in Example 1A and
Reaction Scheme I, below compounds of formula (1) were prepared:
[0344] (S)-tert-butyl
((5-chloro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)(phenyl)methyl)carba-
mate; [0345] (S)-tert-butyl
((5-cyano-3-(3-(difluoromethyl)-5-fluorophenyl)-4-oxo-3,4-dihydroquinazol-
in-2-yl)(cyclopropyl)methyl)carbamate; [0346] (S)-tert-butyl
(cyclopropyl(3-(3-fluorophenyl)-5-(methylsulfonyl)-4-oxo-3,4-dihydroquina-
zolin-2-yl)methyl)carbamate; [0347] (S)-tert-butyl
(cyclopropyl(3-(2,6-difluorophenyl)-5-(methylsulfonyl)-4-oxo-3,4-dihydroq-
uinazolin-2-yl)methyl)carbamate; [0348] (S)-tert-butyl
(cyclopropyl(3-(2-fluorophenyl)-5-(methylsulfonyl)-4-oxo-3,4-dihydroquina-
zolin-2-yl)methyl)carbamate; [0349] (S)-tert-butyl
(cyclopropyl(6-fluoro-3-(3-fluorophenyl)-8-iodo-4-oxo-3,4-dihydroquinazol-
in-2-yl)methyl)carbamate; [0350] (S)-tert-butyl
(cyclopropyl(6-fluoro-3-phenyl-8-iodo-4-oxo-3,4-dihydroquinazolin-2-yl)me-
thyl)carbamate; [0351] (S)-tert-butyl
(1-(5-chloro-3-(3,5-difluorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)-3-(-
dimethylamino)-3-oxopropyl)carbamate; [0352] (S)-tert-butyl
(1-(5-chloro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)-3-(dimethylamino)-
-3-oxopropyl)carbamate; [0353] (S)-tert-butyl
((3-(3-cyano-5-fluorophenyl)-5-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)(c-
yclopropyl)methyl)carbamate; [0354] (S)-tert-butyl
(cyclopropyl(3-(3,5-difluorophenyl)-5-methyl-4-oxo-3,4-dihydroquinazolin--
2-yl)methyl)carbamate; [0355] (S)-tert-butyl
((5-chloro-3-(3,5-difluorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)(cyclo-
propyl)methyl)carbamate; [0356] (S)-tert-butyl
((5-fluoro-3-(3,5-difluorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)(cyclo-
propyl)methyl)carbamate; [0357] (S)-tert-butyl
(cyclopropyl(6-fluoro-3-(3-fluorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl-
)methyl)carbamate; [0358] (2S,4S)-tert-butyl
2-(5-chloro-3-(3,5-difluorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)-4-me-
thoxypyrrolidine-1-carboxylate; [0359] (S)-tert-butyl
2-(5-chloro-3-(3,5-difluorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)azeti-
dine-1-carboxylate; [0360] (S)-tert-butyl
2-(5-chloro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)azetidine-1-carboxy-
late; [0361] (S)-tert-butyl
2-(5-bromo-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)pyrrolidine-1-carbox-
ylate; [0362] (S)-tert-butyl
2-(5-chloro-3-(3,5-difluorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)pyrro-
lidine-1-carboxylate; [0363] (S)-tert-butyl
2-(5-chloro-3-(3,5-difluorophenyl)-8-methyl-4-oxo-3,4-dihydroquinazolin-2-
-yl)pyrrolidine-1-carboxylate; [0364] (S)-tert-butyl
2-(8-chloro-3-(3,5-difluorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)pyrro-
lidine-1-carboxylate; [0365] (S)-tert-butyl
2-(3-(3,5-difluorophenyl)-8-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)pyrro-
lidine-1-carboxylate; [0366] (S)-tert-butyl
2-(3-(3,5-difluorophenyl)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)pyrro-
lidine-1-carboxylate; [0367] (S)-tert-butyl
2-(5-chloro-3-(3-cyano-5-fluorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)p-
yrrolidine-1-carboxylate; [0368] (S)-tert-butyl
2-(5,8-dichloro-4-oxo-3-(3-sulfamoylphenyl)-3,4-dihydroquinazolin-2-yl)py-
rrolidine-1-carboxylate; [0369] (S)-tert-butyl
2-(3-(3-(difluoromethyl)phenyl)-8-iodo-4-oxo-3,4-dihydroquinazolin-2-yl)p-
yrrolidine-1-carboxylate; [0370] (S)-tert-butyl
2-(8-iodo-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)pyrrolidine-1-carboxy-
late; [0371] (2S,4R)-tert-butyl
2-(5-chloro-3-(3,5-difluorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)-4-fl-
uoropyrrolidine-1-carboxylate; [0372] (2S,4R)-tert-butyl
2-(5-chloro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)-4-methylpyrrolidin-
e-1-carboxylate; [0373] (S)-tert-butyl
(1-(5-chloro-3-(3,5-difluorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethy-
l)carbamate; [0374] (S)-tert-butyl
(1-(5-chloro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethyl)carbamate;
[0375] (R)-tert-butyl
3-(5-chloro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)morpholine-4-carbox-
ylate; [0376] (S)-tert-butyl
(1-(3-(3,5-difluorophenyl)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)ethy-
l)carbamate; [0377] (2S,4R)-tert-butyl
4-amino-2-(5-chloro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)pyrrolidine-
-1-carboxylate; [0378] (2S,4R)-tert-butyl
4-amino-2-(5-chloro-3-(3,5-difluorophenyl)-4-oxo-3,4-dihydroquinazolin-2--
yl)pyrrolidine-1-carboxylate; [0379] (2S,4R)-tert-butyl
4-amino-2-(3-(3,5-difluorophenyl)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2--
yl)pyrrolidine-1-carboxylate; [0380] (2S,4R)-tert-butyl
4-amino-2-(3-(3-(difluoromethyl)-5-fluorophenyl)-5-fluoro-4-oxo-3,4-dihyd-
roquinazolin-2-yl)pyrrolidine-1-carboxylate; [0381]
(2S,4R)-tert-butyl
4-amino-2-(5-chloro-3-(3-(difluoromethyl)-5-fluorophenyl)-4-oxo-3,4-dihyd-
roquinazolin-2-yl)pyrrolidine-1-carboxylate; and [0382]
(2S,4R)-tert-butyl
4-amino-2-(5-chloro-3-(3-(difluoromethyl)-5-fluorophenyl)-4-oxo-3,4-dihyd-
roquinazolin-2-yl)pyrrolidine-1-carboxylate.
Example 1b. Preparation of Compound of Formula (1b)
[0383] A. Preparation of a Compound of Formula (1) in which n is 1,
R.sup.1 is cyano, m is 0, R.sup.5 is hydrogen, and R.sup.3 is
cyclopropyl
##STR00045##
[0384] (S)-tert-butyl
(1-(chloro-bromo-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)(cyclopropyl)m-
ethyl)carbamate (230 mg, 0.5 mmol), zinc cyanide (70 mg, 0.6 mmol),
and tetrakis(triphenylphosphine)Pd(0) (63 mg, 0.05 mmol) were
combined in NMP (2 mL). The mixture was degassed under Ar and
heated to 80.degree. C. for 72 h. The reaction was poured into
EtOAc, washed with aqueous NaHCO.sub.3 (2.times.) and brine. The
solvent was removed in vacuo and the residue was purified by
chromatography to give (S)-tert-butyl
((5-cyano-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)(cyclopropyl)methyl)c-
arbamate. ES/MS 417.1 (M+H.sup.+).
[0385] B. Following the procedure described in Example 1b and
Reaction Scheme I, below compound of formula (1) were prepared:
[0386] (S)-tert-butyl
((5-cyano-8-fluoro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)(cyclopropyl-
)methyl)carbamate.
Example 1c. Preparation of Compound of Formula (1c)
[0387] A. Preparation of a Compound of Formula (1) in which n is 1,
R.sup.1 is 2-(morpholin-4-yl)ethoxy, m is 0, R.sup.5 is hydrogen,
and R.sup.3 is methyl
##STR00046##
[0388] To a suspension of (S)-tert-butyl
(1-(5-hydroxy-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethyl)carbamate
(75 mg, 0.197 mmol) and cesium carbonate (256 mg, 0.786 mmol) in
DMF (0.75 mL) was added 4-(2-chloroethyl)morpholine hydrochloride
(52 mg, 0.279 mmol). The reaction was heated to 50.degree. C. and
stirred for 18 hours, then poured into EtOAc and washed with
H.sub.2O (3.times.). The organic phase was dried over
Na.sub.2SO.sub.4, filtered, and concentrated to give (S)-tert-butyl
(1-(5-(2-morpholinoethoxy)-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethy-
l)carbamate, which was taken on without further purification.
[0389] B. Following the procedure described in Example 1c and
Reaction Scheme I, below compound of formula (1) were prepared:
[0390] (S)-tert-butyl
(1-(5-(2-morpholinoethoxy)-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethy-
l)carbamate; [0391] (S)-tert-butyl
(1-(5-(2-(azepan-1-yl)ethoxy)-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)e-
thyl)carbamate; [0392] (S)-tert-butyl
(1-(4-oxo-3-phenyl-5-(2-(pyrrolidin-1-yl)ethoxy)-3,4-dihydroquinazolin-2--
yl)ethyl)carbamate; [0393] (S)-isopropyl
2-((2-(1-((tert-butoxycarbonyl)amino)ethyl)-4-oxo-3-phenyl-3,4-dihydroqui-
nazolin-5-yl)oxy)acetate; [0394] (S)-tert-butyl
(1-(4-oxo-5-(2-(2-oxopyrrolidin-1-yl)ethoxy)-3-phenyl-3,4-dihydroquinazol-
in-2-yl)ethyl)carbamate; [0395] (S)-tert-butyl
(1-(5-(2-(dimethylamino)ethoxy)-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl-
)ethyl)carbamate; [0396] (S)-tert-butyl
(1-(4-oxo-5-(2-oxo-2-(piperidin-1-yl)ethoxy)-3-phenyl-3,4-dihydroquinazol-
in-2-yl)ethyl)carbamate; [0397] (S)-tert-butyl
(1-(5-(3-hydroxy-2-(hydroxymethyl)-2-methylpropoxy)-4-oxo-3-phenyl-3,4-di-
hydroquinazolin-2-yl)ethyl)carbamate; [0398] (S)-tert-butyl
(1-(4-oxo-3-phenyl-5-(2-(piperidin-1-yl)ethoxy)-3,4-dihydroquinazolin-2-y-
l)ethyl)carbamate; [0399] (S)-tert-butyl
(1-(4-oxo-3-phenyl-5-(2-(4-phenylpiperazin-1-yl)ethoxy)-3,4-dihydroquinaz-
olin-2-yl)ethyl)carbamate; [0400] (S)-tert-butyl
(1-(5-(2-(2-methyl-1H-imidazol-1-yl)ethoxy)-4-oxo-3-phenyl-3,4-dihydroqui-
nazolin-2-yl)ethyl)carbamate; [0401] tert-butyl
((1S)-1-(5-(2-(1-methylpyrrolidin-2-yl)ethoxy)-4-oxo-3-phenyl-3,4-dihydro-
quinazolin-2-yl)ethyl)carbamate; and [0402] (S)-tert-butyl
(1-(5-((3-methyloxetan-3-yl)methoxy)-4-oxo-3-phenyl-3,4-dihydroquinazolin-
-2-yl)ethyl)carbamate.
Example 1d. Preparation of Compound of Formula (1d)
[0403] A. Preparation of a Compound of Formula (1) in which n is 1,
R.sup.1 is 2-(morpholin-4-yl)-2-oxoethoxy, m is 0, R.sup.5 is
hydrogen, and R.sup.3 is methyl
##STR00047##
[0404] To a solution of (S)-tert-butyl
(1-(5-fluoro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethyl)carbamate
(500 mg, 1.30 mmol) in DMF (2 mL) was added
2-hydroxy-1-(morpholin-4-yl)ethan-1-one (283 mg, 1.95 mmol) and
freshly ground K.sub.2CO.sub.3 (198 mg, 1.43 mmol). The mixture was
heated to 80.degree. C. and allowed to stir for 12 days. The
reaction was adsorbed directly onto isolute and purified on ISCO
(40 g silica, 0-100% EtOAc/hexane) to give (S)-tert-butyl
(1-(5-(2-morpholino-2-oxoethoxy)-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-y-
l)ethyl)carbamate.
Example 1e. Preparation of Compound of Formula (1e)
[0405] A. Preparation of a Compound of Formula (1) in which n is 1,
R.sup.1 is 2-(4-methylpiperidin-4-yl)-2-oxoethoxy, m is 0, R.sup.5
is hydrogen, and R.sup.3 is methyl
##STR00048##
[0406] To a suspension of (S)-tert-butyl
(1-(5-hydroxy-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethyl)carbamate
(150 mg, 0.393 mmol),
2-hydroxy-1-(4-methylpiperidin-1-yl)ethan-1-one (124 mg, 0.787
mmol), and triphenyl phosphine (206 mg, 0.787 mmol) in DCM (2 mL)
was added di-tert-butyl azodicarboxylate (181 mg, 0.787 mmol). The
reaction was stirred at ambient temperature, with more reagents
added as needed to drive the reaction. The reaction was poured into
H.sub.2O (20 mL), extracted into DCM (3.times.10 mL), and the
combined extracts were purified by flash chromatography (12 g
silica, 0-50% EtOAc/DCM) to give (S)-tert-butyl
(1-(5-(2-(4-methylpiperidin-1-yl)-2-oxoethoxy)-4-oxo-3-phenyl-3,4-dihydro-
quinazolin-2-yl)ethyl)carbamate.
Example 1f. Preparation of Compound of Formula (1f)
[0407] A. Preparation of a Compound of Formula (1) in which n is 1,
R.sup.1 is 3-amino-3-oxopropyl, m is 0, R.sup.5 is hydrogen, and
R.sup.3 is methyl
##STR00049##
[0408] To a solution of (S)-tert-butyl
(1-(5-bromo-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethyl)carbamate
(300 mg, 0.675 mmol) in DMF (3 mL) was added
chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)
[2-(2'-amino-1,1'-biphenyl)]palladium(II) (16 mg, 0.023 mmol),
acrylamide (72 mg, 1.01 mmol) and DIEA (0.35 mL, 2.03 mmol). The
mixture was degassed and heated to 80.degree. C. for 6 hours. The
reaction was poured into EtOAc and washed with H.sub.2O. The
resulting solution was dried over Na.sub.2SO.sub.4, filtered, and
concentrated to an orange oil. Purification by flash chromatography
(25 g silica, 0-100% EtOAc/DCM) provided the unsaturated
intermediate as a white solid. This material was dissolved in EtOAc
(5 mL) and hydrogenated over 10% Pd/C to give (S)-tert-butyl
(1-(5-(3-amino-3-oxopropyl)-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)eth-
yl)carbamate.
[0409] B. Following the procedure described in Example 1f and
Reaction Scheme I, below compound of formula (1) were prepared:
[0410] (S)-tert-butyl
(1-(5-(3-amino-3-oxopropyl)-8-fluoro-4-oxo-3-phenyl-3,4-dihydroquinazolin-
-2-yl)ethyl)carbamate; [0411] (S)-tert-butyl
(1-(5-(3-amino-3-oxopropyl)-3-(3,5-difluorophenyl)-8-fluoro-4-oxo-3,4-dih-
ydroquinazolin-2-yl)ethyl)carbamate; [0412] (S)-tert-butyl
(1-(5-(3-amino-3-oxopropyl)-3-(3,5-difluorophenyl)-4-oxo-3,4-dihydroquina-
zolin-2-yl)ethyl)carbamate.
Example 1g. Preparation of Compound of Formula (1g)
[0413] A. Preparation of a Compound of Formula (1) in which n is 1,
R.sup.1 is 3-oxopropenyl, m is 0, R.sup.5 is hydrogen, and R.sup.3
is methyl
##STR00050##
[0414] To a solution of (S)-tert-butyl
(1-(5-bromo-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethyl)carbamate
(250 mg, 0.563 mmol) in DMF (3 mL) was
chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)
[2-(2'-amino-1,1'-biphenyl)]palladium(II) (38 mg, 0.055 mmol) and
DIEA (0.29 mL, 1.69 mmol). The mixture was degassed under Ar.sub.2.
Acrolein (0.076 mL, 1.13 mmol) was added, and the mixture heated to
80.degree. C. for 10 hours. The reaction was poured into EtOAc and
washed with H.sub.2O (2.times.). Purified by flash chromatography
(25 g silica, 0-30% EtOAc/hexane) to provide (S,E)-tert-butyl
(1-(4-oxo-5-(3-oxoprop-1-en-1-yl)-3-phenyl-3,4-dihydroquinazolin-2-yl)eth-
yl)carbamate.
Example 1h. Preparation of Compound of Formula (1h)
[0415] A. Preparation of a Compound of Formula (1) in which n is 1,
R.sup.1 is 3-(pyrrolidin-1-yl)propyl, m is 0, R.sup.5 is hydrogen,
and R.sup.3 is methyl
##STR00051##
[0416] A solution of (S,E)-tert-butyl
(1-(4-oxo-5-(3-oxoprop-1-en-1-yl)-3-phenyl-3,4-dihydroquinazolin-2-yl)eth-
yl)carbamate (84 mg, 0.200 mmol) and pyrrolidine (excess) in EtOAc
(1.5 mL) was charged to a flask containing 10% Pd/C. The mixture
was hydrogenated under ambient pressure for 1.5 hours. The catalyst
was removed by filtration and the filtrate purified by flash
chromatography (12 g silica column, 0-100% EtOAc/hexane followed by
0-50% MeOH/DCM) to provide (S)-tert-butyl
(1-(4-oxo-3-phenyl-5-(3-(pyrrolidin-1-yl)propyl)-3,4-dihydroquinazolin-2--
yl)ethyl)carbamate.
Example 1i. Preparation of Compound of Formula (1i)
[0417] A. Preparation of a Compound of Formula (1) in which n is 1,
R.sup.1 is 3-oxopropyl, m is 0, R.sup.5 is hydrogen, and R.sup.3 is
methyl
##STR00052##
[0418] To a solution of (S)-tert-butyl
(1-(5-bromo-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethyl)carbamate
(1.5 g, 3.38 mmol) in DMF (10 mL) was added
chloro(2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl)[2-(2'-amino-
-1,1'-biphenyl)]palladium(II) (205 mg, 0.284 mmol) and DIEA (0.88
mL, 5.07 mmol). The mixture was degassed under Ar.sub.2. Allyl
alcohol (0.25 mL, 3.71 mmol) was added, and the mixture heated to
120.degree. C. in microwave for 2 hours. The reaction was poured
into EtOAc and washed with aq. NaCl (3.times.). Purification by
flash chromatography (0-40% EtOAc/hexane) provided (S)-tert-butyl
(1-(4-oxo-5-(3-oxopropyl)-3-phenyl-3,4-dihydroquinazolin-2-yl)ethyl)carba-
mate.
Example 1j. Preparation of Compound of Formula (1j)
[0419] A. Preparation of a Compound of Formula (1) in which n is 1,
R.sup.1 is 3-(3,3-difluoroazetidin-1-yl)propyl, m is 0, R.sup.5 is
hydrogen, and R.sup.3 is methyl
##STR00053##
[0420] To a solution of (S)-tert-butyl
(1-(4-oxo-5-(3-oxopropyl)-3-phenyl-3,4-dihydroquinazolin-2-yl)ethyl)carba-
mate (99 mg, 0.235 mmol) in DCM (3 mL) was added
3,3-difluoroazetidine hydrochloride (40 mg, 0.305 mmol). Allowed to
stir at ambient temperature for one hour, then sodium
triacetoxyborohydride (65 mg, 0.305 mmol) was added. Additional
sodium triacetoxyborohydride added as necessary until reaction was
deemed complete by LCMS. Aq. NaHCO.sub.3 was added, and the mixture
extracted into DCM (3.times.). The combined organics were
concentrated in vacuo and purified by flash chromatography (4 g
silica column, 0-100% EtOAc/hexane) to provide (S)-tert-butyl
(1-(5-(3-(3,3-difluoroazetidin-1-yl)propyl)-4-oxo-3-phenyl-3,4-dihydroqui-
nazolin-2-yl)ethyl)carbamate.
[0421] B. Following the procedure described in Example 1j and
Reaction Scheme I, below compound of formula (1) were prepared:
[0422] (S)-tert-butyl
(1-(4-oxo-3-phenyl-5-(3-(piperidin-1-yl)propyl)-3,4-dihydroquinazolin-2-y-
l)ethyl)carbamate; [0423] (S)-tert-butyl
(1-(5-(3-(3,3-difluoropyrrolidin-1-yl)propyl)-4-oxo-3-phenyl-3,4-dihydroq-
uinazolin-2-yl)ethyl)carbamate; [0424] (S)-tert-butyl
(1-(5-(3-(4,4-difluoropiperidin-1-yl)propyl)-4-oxo-3-phenyl-3,4-dihydroqu-
inazolin-2-yl)ethyl)carbamate; [0425] tert-butyl
((1S)-1-(5-(3-(3,5-dimethylmorpholino)propyl)-4-oxo-3-phenyl-3,4-dihydroq-
uinazolin-2-yl)ethyl)carbamate; [0426] (S)-tert-butyl
(1-(3-(3,5-difluorophenyl)-4-oxo-5-(3-(pyrrolidin-1-yl)propyl)-3,4-dihydr-
oquinazolin-2-yl)ethyl)carbamate; [0427] (S)-tert-butyl
(1-(5-(3-(2,2-dimethylmorpholino)propyl)-4-oxo-3-phenyl-3,4-dihydroquinaz-
olin-2-yl)ethyl)carbamate; [0428] (S)-tert-butyl
(1-(5-(3-(3,3-dimethylmorpholino)propyl)-4-oxo-3-phenyl-3,4-dihydroquinaz-
olin-2-yl)ethyl)carbamate; [0429] (S)-tert-butyl
(1-(8-fluoro-4-oxo-3-phenyl-5-(3-(pyrrolidin-1-yl)propyl)-3,4-dihydroquin-
azolin-2-yl)ethyl)carbamate; [0430] (S)-tert-butyl
(1-(4-oxo-3-phenyl-5-(3-(2,2,6,6-tetrafluoromorpholino)propyl)-3,4-dihydr-
oquinazolin-2-yl)ethyl)carbamate; [0431] (S)-tert-butyl
(1-(5-(3-(3,3-difluoropyrrolidin-1-yl)propyl)-8-fluoro-4-oxo-3-phenyl-3,4-
-dihydroquinazolin-2-yl)ethyl)carbamate; [0432] (S)-tert-butyl
(cyclopropyl(4-oxo-3-phenyl-5-(3-(piperidin-1-yl)propyl)-3,4-dihydroquina-
zolin-2-yl)methyl)carbamate; [0433] (S)-tert-butyl
(cyclopropyl(4-oxo-3-phenyl-5-(3-(pyrrolidin-1-yl)propyl)-3,4-dihydroquin-
azolin-2-yl)methyl)carbamate; [0434] (S)-tert-butyl
(cyclopropyl(8-fluoro-4-oxo-3-phenyl-5-(3-(piperidin-1-yl)propyl)-3,4-dih-
ydroquinazolin-2-yl)methyl)carbamate; [0435] (S)-tert-butyl
(cyclopropyl(8-fluoro-4-oxo-3-phenyl-5-(3-(pyrrolidin-1-yl)propyl)-3,4-di-
hydroquinazolin-2-yl)methyl)carbamate.
Example 1k. Preparation of Compound of Formula (1k)
[0436] A. Preparation of a Compound of Formula (1) in which n is 1,
R.sup.1 is 3-cyclohexylprop-1-en-1-yl, m is 0, R.sup.5 is hydrogen,
and R.sup.3 is methyl
##STR00054##
[0437] To a solution of (S)-tert-butyl
(1-(5-bromo-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethyl)carbamate
(300 mg, 0.675 mmol) in DMF (3 mL) was added
Chloro(2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl)[2-(2'-amino-
-1,1'-biphenyl)]palladium(II) (50 mg, 0.0.069 mmol) and DIEA (0.59
mL, 3.38 mmol). The mixture was degassed under Ar.sub.2. Allyl
cyclohexane (0.21 mL, 1.35 mmol) was added, and the mixture heated
to 80.degree. C. for 18 hours. The reaction was poured into EtOAc
and washed with aq. NaCl (3.times.). The organic phase was adsorbed
to isolute and purified by flash chromatography (25 g silica, 0-30%
EtOAc/hexane) to provide (S,E)-tert-butyl
(1-(5-(3-cyclohexylprop-1-en-1-yl)-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-
-yl)ethyl)carbamate.
[0438] B. Following the procedure described in Example 1k and
Reaction Scheme I, below compound of formula (1k) were prepared:
[0439] (S,E)-tert-butyl
4-(2-(1-((tert-butoxycarbonyl)amino)ethyl)-4-oxo-3-phenyl-3,4-dihydroquin-
azolin-5-yl)but-3-enoate; [0440] (S,E)-tert-butyl
2-(5-(4-(tert-butoxy)-4-oxobut-1-en-1-yl)-4-oxo-3-phenyl-3,4-dihydroquina-
zolin-2-yl)pyrrolidine-1-carboxylate; [0441] (S,E)-tert-butyl
4-(2-(1-((tert-butoxycarbonyl)amino)ethyl)-3-(3,5-difluorophenyl)-4-oxo-3-
,4-dihydroquinazolin-5-yl)but-3-enoate.
Example 1l. Preparation of Compound of Formula (1l)
[0442] A. Preparation of a Compound of Formula (1) in which n is 1,
R.sup.1 is 3-cyclohexylpropyl, m is 0, R.sup.5 is hydrogen, and
R.sup.3 is methyl
##STR00055##
[0443] A solution of (S,E)-tert-butyl
(1-(5-(3-cyclohexylprop-1-en-1-yl)-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-
-yl)ethyl)carbamate (274 mg, 0.562 mmol) in EtOAc (5 mL) was added
to a flask charged with 10% Pd/C. The mixture was hydrogenated at
atmospheric pressure for 10 hours. Filtration provided
(S)-tert-butyl
(1-(5-(3-cyclohexylpropyl)-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethy-
l)carbamate.
[0444] B. Following the procedure described in Example 1l and
Reaction Scheme I, below compound of formula (1) were prepared:
[0445] (S)-tert-butyl
4-(2-(1-((tert-butoxycarbonyl)amino)ethyl)-4-oxo-3-phenyl-3,4-dihydroquin-
azolin-5-yl)butanoate; [0446] (S)-tert-butyl
2-(5-(4-(tert-butoxy)-4-oxobutyl)-4-oxo-3-phenyl-3,4-dihydroquinazolin-2--
yl)pyrrolidine-1-carboxylate; [0447] (S)-tert-butyl
4-(2-(1-((tert-butoxycarbonyl)amino)ethyl)-3-(3,5-difluorophenyl)-4-oxo-3-
,4-dihydroquinazolin-5-yl)butanoate.
Example 1m. Preparation of Compound of Formula (1m)
[0448] A. Preparation of a Compound of Formula (1) in which n is 1,
R.sup.1 is SO.sub.2Me, m is 1, R.sup.2 is F, R.sup.5 and R.sup.3
together with the atoms to which they are attached optionally form
a pyrrolidine
##STR00056##
[0449] To a solution of (S)-tert-butyl
2-(5-bromo-3-(3-fluorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)pyrrolidin-
e-1-carboxylate (460 mg, 0.94 mmol) in DMSO (5 mL) was added sodium
methanesulfinate (375 mg, 3.7 mmol), cesium carbonate (153 mg, 0.47
mmol), copper iodide (72 mg, 0.38 mmol) and (S)-proline (87 mg,
0.75 mmol). The resulting mixture was degassed under Ar, sealed,
and heated to 95.degree. C. After 18 hours the reaction was cooled,
poured into EtOAc, and washed with H.sub.2O (3.times.). The organic
phase was dried over MgSO4, concentrated, and purified by column
chromatography on silica eluting with EtOAc in hexanes (5-80%) to
afford (S)-tert-butyl
2-(3-(3-fluorophenyl)-5-(methylsulfonyl)-4-oxo-3,4-dihydroquinazolin-2-yl-
)pyrrolidine-1-carboxylate. ES/MS m/z=488.1 (M+H.sup.+).
[0450] B. Following the procedure described in Example 1g and
Reaction Scheme I, below compound of formula (1) were prepared:
[0451] (S)-tert-butyl
2-(3-(2-fluorophenyl)-5-(methylsulfonyl)-4-oxo-3,4-dihydroquinazolin-2-yl-
)pyrrolidine-1-carboxylate [0452] (S)-tert-butyl
2-(3-(2,6-difluorophenyl)-5-(methylsulfonyl)-4-oxo-3,4-dihydroquinazolin--
2-yl)pyrrolidine-1-carboxylate [0453] (S)-tert-butyl
(1-(3-(3-fluorophenyl)-4-oxo-5-(phenylsulfonyl)-3,4-dihydroquinazolin-2-y-
l)ethyl)carbamate [0454] (S)-tert-butyl
2-(3-(3-fluorophenyl)-4-oxo-5-(phenylsulfonyl)-3,4-dihydroquinazolin-2-yl-
)pyrrolidine-1-carboxylate
Example 1n. Preparation of Compound of Formula (1n)
[0455] A. Preparation of a Compound of Formula (1) in which n is 1,
R.sup.1 is S(CH.sub.2).sub.2OH, m is 1, R.sup.2 is F, R.sup.5 is H,
and R.sup.3 is Me
##STR00057##
[0456] To a solution of (S)-tert-butyl
(1-(5-bromo-3-(3-fluorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)car-
bamate (1100 mg, 2.38 mmol) and mercaptoethanol (0.20 mL, 2.9 mmol)
in dioxane (12 mL) was added diisopropylethylamine (1.25 mL, 7.1
mmol), Xantphos (193 mg, 0.34 mmol), Pd(dba).sub.2 (96 mg, 0.17
mmol) and (S)-proline (87 mg, 0.75 mmol). The resulting mixture was
sealed and heated to 100.degree. C. After 18 hours the reaction was
cooled, poured into EtOAc, and washed with H.sub.2O. The organic
phase was dried over MgSO4, concentrated, and purified by column
chromatography on silica eluting with EtOAc in hexanes (5-100%) to
afford (S)-tert-butyl
(1-(3-(3-fluorophenyl)-5-((2-hydroxyethyl)thio)-4-oxo-3,4-dihydroquinazol-
in-2-yl)ethyl)carbamate. ES/MS m/z=460.1 (M+H.sup.+).
[0457] B. Following the procedure described in Example 1n and
Reaction Scheme I, below compound of formula (1) were prepared:
[0458] (S)-tert-butyl
(1-(5-(cyclopentylthio)-3-(3-fluorophenyl)-4-oxo-3,4-dihydroquinazolin-2--
yl)ethyl)carbamate [0459] (S)-tert-butyl
(1-(3-(3-fluorophenyl)-4-oxo-5-(o-tolylthio)-3,4-dihydroquinazolin-2-yl)e-
thyl)carbamate
Example 1o. Preparation of Compound of Formula (1o)
[0460] A. Preparation of a Compound of Formula (1) in which n is 1,
R.sup.1 is SO.sub.2(CH.sub.2).sub.2OH, m is 1, R.sup.2 is F,
R.sup.5 is H, and R.sup.3 is Me
##STR00058##
[0461] To a solution of (S)-tert-butyl
(1-(3-(3-fluorophenyl)-5-((2-hydroxyethyl)thio)-4-oxo-3,4-dihydroquinazol-
in-2-yl)ethyl)carbamate (1050 mg, 2.29 mmol) in THF (12 mL) and
water (6 mL) was added Oxone (4.9 g). The resulting mixture was
stirred at room temperature overnight. The reaction was poured into
EtOAc and washed with H.sub.2O. The organic phase was dried over
MgSO4 and concentrated to afford (S)-tert-butyl
(1-(3-(3-fluorophenyl)-5-((2-hydroxyethyl)thio)-4-oxo-3,4-dihydroquinazol-
in-2-yl)ethyl)carbamate. ES/MS m/z=492.1 (M+H.sup.+).
[0462] B. Following the procedure described in Example 1o and
Reaction Scheme I, below compound of formula (1) were prepared:
[0463] (S)-tert-butyl
(1-(5-(cyclopentylsulfonyl)-3-(3-fluorophenyl)-4-oxo-3,4-dihydroquinazoli-
n-2-yl)ethyl)carbamate [0464] (S)-tert-butyl
(1-(3-(3-fluorophenyl)-4-oxo-5-(o-tolylsulfonyl)-3,4-dihydroquinazolin-2--
yl)ethyl)carbamate
Example 1p. Preparation of Compound of Formula (1p)
[0465] A. Preparation of a Compound of Formula (1) in which n is 1,
R.sup.1 is Cl, m is 0, R.sup.3 and R.sup.5 together are
4-(2,2-difluoroacetamido)pyrrolidine-1-yl attached at the
2-position of the pyrrolidine to the quinazolinone
##STR00059##
[0466] HATU (724 mg, 1.9 mmol), difluoroacetic acid (0.11 mL, 1.75
mmol), and DIEA (0.83 mL, 4.77 mmol) were added to a stirring
solution of (2S,4R)-tert-butyl
4-amino-2-(5-chloro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)pyrrolidine-
-1-carboxylate (700 mg, 1.59 mmol) in ACN (15 mL) at rt. After
stirring for 3 h the resulting mixture was quenched with
NaHCO.sub.3 (sat) and the aqueous layer was extracted with. The
combined organic layers were washed with brine, dried over
Na.sub.2SO.sub.4, and concentrated to give crude acetamide.
Chromatography (1:1, Hexanes/EtOAc) afforded the pure acetamide
(2S,4R)-tert-butyl
2-(5-chloro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)-4-(2,2-difluoroace-
tamido)pyrrolidine-1-carboxylate.
[0467] B. Following the procedure described in Example 1p and
Reaction Scheme I, below compound of formula (1) were prepared:
[0468] (2S,4R)-tert-butyl
2-(5-chloro-3-(3,5-difluorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)-4-(2-
,2-difluoroacetamido)pyrrolidine-1-carboxylate; [0469]
(2S,4S)-tert-butyl
2-(5-chloro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)-4-(2,2,2-trifluoro-
acetamido)pyrrolidine-1-carboxylate; [0470] (2S,4R)-tert-butyl
2-(5-chloro-3-(3-(difluoromethyl)-5-fluorophenyl)-4-oxo-3,4-dihydroquinaz-
olin-2-yl)-4-(2,2-difluoroacetamido)pyrrolidine-1-carboxylate;
[0471] (2S,4R)-tert-butyl
4-(2,2-difluoroacetamido)-2-(3-(3,5-difluorophenyl)-5-fluoro-4-oxo-3,4-di-
hydroquinazolin-2-yl)pyrrolidine-1-carboxylate; [0472]
(2S,4R)-tert-butyl
4-(2,2-difluoroacetamido)-2-(3-(3-(difluoromethyl)-5-fluorophenyl)-5-fluo-
ro-4-oxo-3,4-dihydroquinazolin-2-yl)pyrrolidine-1-carboxylate;
[0473] (2S,4R)-tert-butyl
2-(5-chloro-3-(3-(difluoromethyl)-5-fluorophenyl)-4-oxo-3,4-dihydroquinaz-
olin-2-yl)-4-(2,2-difluoroacetamido)pyrrolidine-1-carboxylate;
[0474] (2S,4R)-tert-butyl
2-(5-chloro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)-4-(2-cyclopropylac-
etamido)pyrrolidine-1-carboxylate;
Example 1q. Preparation of Compound of Formula (1q)
[0475] A. Preparation of a Compound of Formula (1) in which n is 1,
R.sup.1 is Cl, m is 0, R.sup.3 and R.sup.5 together are
4-(2,2-difluoro-N-methylacetamido)pyrrolidine-1-yl attached at the
2-position of the pyrrolidine to the quinazolinone
##STR00060##
[0476] Solid NaH (60%, 29 mg, 0.72 mmol) was added to a stirring
solution of (2S,4R)-tert-butyl
2-(5-chloro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)-4-(2,2-difluoroace-
tamido)pyrrolidine-1-carboxylate (200 mg, 0.36 mmol) in THF (5 mL)
at 0.degree. C. After stirring for 5 min., iodomethane (77 mg, 0.54
mmol) was added. The resulting solution was allowed to warm to rt
and stirred for an additional 4 d. The reaction mixture was
quenched with NaHCO.sub.3 (sat) and the aqueous layer was extracted
with EtOAc. The combined organic layers were washed with brine,
dried over Na.sub.2SO.sub.4, and concentrated to give
(2S,4R)-tert-butyl
2-(5-chloro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)-4-(2,2-difluoro-N--
methylacetamido)pyrrolidine-1-carboxylate that was used in the next
step without further purification.
Example 2. Preparation of a Compound of Formula (2)
[0477] A. Preparation of a Compound of Formula (2) in which n is 1,
R.sup.1 is fluoro, m is 1, R.sup.2 is fluoro, R.sup.5 is hydrogen,
and R.sup.3 is cyclopropyl
##STR00061##
[0478] Trifluoroacetic acid (2 mL) was added to a solution of
(S)-tert-butyl
(cyclopropyl(5-fluoro-3-(3-fluorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl-
)methyl)carbamate (0.5 g, 1 mmol) in dichloromethane (2 mL). The
resulting solution was stirred at room temperature for 2 hours. The
mixture was poured into saturated aqueous NaHCO.sub.3 and extracted
with DCM. The organic layer was dried (Na.sub.2SO.sub.4) and the
solvent was removed in vacuo to afford
(S)-2-(amino(cyclopropyl)methyl)-5-fluoro-3-(3-fluorophenyl)quinazolin-4(-
3H)-one.
[0479] B. Following the procedure described in Example 2A and
Reaction Scheme I, below compounds of formula (2) were prepared:
[0480]
(S)-2-(amino(cyclopropyl)methyl)-4-oxo-3-phenyl-3,4-dihydroquinazoline-5--
carbonitrile; [0481]
(S)-2-(amino(cyclopropyl)methyl)-8-fluoro-4-oxo-3-phenyl-3,4-dihydroquina-
zoline-5-carbonitrile; [0482]
(S)-2-(amino(phenyl)methyl)-5-chloro-3-phenylquinazolin-4(3H)-one;
[0483]
(S)-2-(amino(cyclopropyl)methyl)-3-(3-(difluoromethyl)-5-fluorophenyl)-4--
oxo-3,4-dihydroquinazoline-5-carbonitrile; [0484]
(S)-2-(amino(cyclopropyl)methyl)-3-(3-fluorophenyl)-5-(methylsulfonyl)qui-
nazolin-4(3H)-one; [0485]
(S)-2-(amino(cyclopropyl)methyl)-3-(2,6-difluorophenyl)-5-(methylsulfonyl-
)quinazolin-4(3H)-one; [0486]
(S)-2-(amino(cyclopropyl)methyl)-3-(2-fluorophenyl)-5-(methylsulfonyl)qui-
nazolin-4(3H)-one; [0487]
(S)-2-(amino(cyclopropyl)methyl)-6-fluoro-3-(3-fluorophenyl)-8-iodoquinaz-
olin-4(3H)-one; [0488]
(S)-2-(amino(cyclopropyl)methyl)-6-fluoro-3-phenyl-8-iodoquinazolin-4(3H)-
-one; [0489]
(S)-3-amino-3-(5-chloro-3-(3,5-difluorophenyl)-4-oxo-3,4-dihydroquinazoli-
n-2-yl)-N,N-dimethylpropanamide; [0490]
(S)-3-amino-3-(5-chloro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)-N,N-di-
methylpropanamide; [0491]
(S)-3-(2-(amino(cyclopropyl)methyl)-5-methyl-4-oxoquinazolin-3(4H)-yl)-5--
fluorobenzonitrile; [0492]
(S)-2-(amino(cyclopropyl)methyl)-3-(3,5-difluorophenyl)-5-methylquinazoli-
n-4(3H)-one; [0493]
(S)-2-(amino(cyclopropyl)methyl)-5-chloro-3-(3,5-difluorophenyl)quinazoli-
n-4(3H)-one; [0494]
(S)-2-(amino(cyclopropyl)methyl)-5-fluoro-3-(3,5-difluorophenyl)quinazoli-
n-4(3H)-one; [0495]
(S)-2-(amino(cyclopropyl)methyl)-6-fluoro-3-(3-fluorophenyl)quinazolin-4(-
3H)-one. [0496]
5-chloro-3-(3,5-difluorophenyl)-2-((2S,4S)-4-methoxypyrrolidin-2-yl)quina-
zolin-4(3H)-one; [0497]
(S)-2-(1-aminoethyl)-5-(2-morpholinoethoxy)-3-phenylquinazolin-4(3H)-one;
[0498]
(S)-2-(1-aminoethyl)-5-(2-(azepan-1-yl)ethoxy)-3-phenylquinazolin--
4(3H)-one; [0499]
(S)-2-(1-aminoethyl)-3-phenyl-5-(2-(pyrrolidin-1-yl)ethoxy)quinazolin-4(3-
H)-one; [0500] (S)-isopropyl
2-((2-(1-aminoethyl)-4-oxo-3-phenyl-3,4-dihydroquinazolin-5-yl)oxy)acetat-
e; [0501]
(S)-2-(1-aminoethyl)-5-(2-(2-oxopyrrolidin-1-yl)ethoxy)-3-phenyl-
quinazolin-4(3H)-one; [0502]
(S)-2-(1-aminoethyl)-5-(2-(dimethylamino)ethoxy)-3-phenylquinazolin-4(3H)-
-one; [0503]
(S)-2-(1-aminoethyl)-5-(2-oxo-2-(piperidin-1-yl)ethoxy)-3-phenylquinazoli-
n-4(3H)-one; [0504]
(S)-2-(1-aminoethyl)-5-(3-hydroxy-2-(hydroxymethyl)-2-methylpropoxy)-3-ph-
enylquinazolin-4(3H)-one; [0505]
(S)-2-(1-aminoethyl)-3-phenyl-5-(2-(piperidin-1-yl)ethoxy)quinazolin-4(3H-
)-one; [0506]
(S)-2-(1-aminoethyl)-3-phenyl-5-(2-(4-phenylpiperazin-1-yl)ethoxy)quinazo-
lin-4(3H)-one; [0507]
(S)-2-(1-aminoethyl)-5-(2-(2-methyl-1H-imidazol-1-yl)ethoxy)-3-phenylquin-
azolin-4(3H)-one; [0508]
2-((S)-1-aminoethyl)-5-(2-(1-methylpyrrolidin-2-yl)ethoxy)-3-phenylquinaz-
olin-4(3H)-one; [0509]
(S)-2-(1-aminoethyl)-5-((3-methyloxetan-3-yl)methoxy)-3-phenylquinazolin--
4(3H)-one; [0510]
(S)-2-(1-aminoethyl)-5-(2-morpholino-2-oxoethoxy)-3-phenylquinazolin-4(3H-
)-one; [0511]
(S)-2-(1-aminoethyl)-5-(2-(4-methylpiperidin-1-yl)-2-oxoethoxy)-3-phenylq-
uinazolin-4(3H)-one; [0512]
(S)-3-(2-(1-aminoethyl)-4-oxo-3-phenyl-3,4-dihydroquinazolin-5-yl)propana-
mide; [0513]
(S)-3-(2-(1-aminoethyl)-8-fluoro-4-oxo-3-phenyl-3,4-dihydroquinazolin-5-y-
l)propanamide; [0514]
(S)-3-(2-(1-aminoethyl)-3-(3,5-difluorophenyl)-8-fluoro-4-oxo-3,4-dihydro-
quinazolin-5-yl)propanamide; [0515]
(S)-3-(2-(1-aminoethyl)-3-(3,5-difluorophenyl)-4-oxo-3,4-dihydroquinazoli-
n-5-yl)propanamide; [0516]
(S)-2-(1-aminoethyl)-3-phenyl-5-(3-(pyrrolidin-1-yl)propyl)quinazolin-4(3-
H)-one; [0517]
(S)-2-(1-aminoethyl)-5-(3-(3,3-difluoroazetidin-1-yl)propyl)-3-phenylquin-
azolin-4(3H)-one; [0518]
(S)-2-(1-aminoethyl)-3-phenyl-5-(3-(piperidin-1-yl)propyl)quinazolin-4(3H-
)-one; [0519]
(S)-2-(1-aminoethyl)-5-(3-(3,3-difluoropyrrolidin-1-yl)propyl)-3-phenylqu-
inazolin-4(3H)-one; [0520]
(S)-2-(1-aminoethyl)-5-(3-(4,4-difluoropiperidin-1-yl)propyl)-3-phenylqui-
nazolin-4(3H)-one; [0521]
2-((S)-1-aminoethyl)-5-(3-(3,5-dimethylmorpholino)propyl)-3-phenylquinazo-
lin-4(3H)-one; [0522]
(S)-2-(1-aminoethyl)-3-(3,5-difluorophenyl)-5-(3-(pyrrolidin-1-yl)propyl)-
quinazolin-4(3H)-one; [0523]
(S)-2-(1-aminoethyl)-5-(3-(2,2-dimethylmorpholino)propyl)-3-phenylquinazo-
lin-4(3H)-one; [0524]
(S)-2-(1-aminoethyl)-5-(3-(3,3-dimethylmorpholino)propyl)-3-phenylquinazo-
lin-4(3H)-one; [0525]
(S)-2-(1-aminoethyl)-8-fluoro-3-phenyl-5-(3-(pyrrolidin-1-yl)propyl)quina-
zolin-4(3H)-one; [0526]
(S)-2-(1-aminoethyl)-3-phenyl-5-(3-(2,2,6,6-tetrafluoromorpholino)propyl)-
quinazolin-4(3H)-one; [0527]
(S)-2-(amino(cyclopropyl)methyl)-3-phenyl-5-(3-(piperidin-1-yl)propyl)qui-
nazolin-4(3H)-one; [0528]
(S)-2-(amino(cyclopropyl)methyl)-3-phenyl-5-(3-(pyrrolidin-1-yl)propyl)qu-
inazolin-4(3H)-one; [0529]
(S)-2-(1-aminoethyl)-5-(3-(3,3-difluoropyrrolidin-1-yl)propyl)-8-fluoro-3-
-phenylquinazolin-4(3H)-one; [0530]
(S)-2-(amino(cyclopropyl)methyl)-8-fluoro-3-phenyl-5-(3-(piperidin-1-yl)p-
ropyl)quinazolin-4(3H)-one; [0531]
(S)-2-(amino(cyclopropyl)methyl)-8-fluoro-3-phenyl-5-(3-(pyrrolidin-1-yl)-
propyl)quinazolin-4(3H)-one; [0532]
(S)-2-(1-aminoethyl)-5-(3-cyclohexylpropyl)-3-phenylquinazolin-4(3H)-one
[0533]
(S)-2-(azetidin-2-yl)-5-chloro-3-(3,5-difluorophenyl)quinazolin-4(-
3H)-one; [0534]
(S)-2-(azetidin-2-yl)-5-chloro-3-phenylquinazolin-4(3H)-one; [0535]
(S)-4-(2-(1-aminoethyl)-4-oxo-3-phenyl-3,4-dihydroquinazolin-5-yl)butanoi-
c acid; [0536]
(S)-4-(4-oxo-3-phenyl-2-(pyrrolidin-2-yl)-3,4-dihydroquinazolin-5-yl)buta-
noic acid; [0537]
(S)-4-(2-(1-aminoethyl)-3-(3,5-difluorophenyl)-4-oxo-3,4-dihydroquinazoli-
n-5-yl)butanoic acid; [0538]
(S)-2-(1-aminoethyl)-3-(3-fluorophenyl)-5-(phenylsulfonyl)quinazolin-4(3H-
)-one; [0539]
(S)-3-(2,6-difluorophenyl)-5-(methylsulfonyl)-2-(pyrrolidin-2-yl)quinazol-
in-4(3H)-one; [0540]
(S)-3-(2-fluorophenyl)-5-(methylsulfonyl)-2-(pyrrolidin-2-yl)quinazolin-4-
(3H)-one; [0541]
(S)-3-(3-fluorophenyl)-5-(methylsulfonyl)-2-(pyrrolidin-2-yl)quinazolin-4-
(3H)-one; [0542]
(S)-3-(3-fluorophenyl)-5-(phenylsulfonyl)-2-(pyrrolidin-2-yl)quinazolin-4-
(3H)-one; [0543]
(S)-2-(1-aminoethyl)-3-(3-fluorophenyl)-5-((2-hydroxyethyl)sulfonyl)quina-
zolin-4(3H)-one; [0544]
(S)-2-(1-aminoethyl)-3-(3-fluorophenyl)-5-((2-hydroxyethyl)thio)quinazoli-
n-4(3H)-one; [0545]
(S)-2-(1-aminoethyl)-3-(3-fluorophenyl)-5-(o-tolylsulfonyl)quinazolin-4(3-
H)-one; [0546]
(S)-2-(1-aminoethyl)-5-(cyclopentylsulfonyl)-3-(3-fluorophenyl)quinazolin-
-4(3H)-one; [0547]
(S)-5-chloro-3-(3,5-difluorophenyl)-2-(pyrrolidin-2-yl)quinazolin-4(3H)-o-
ne; [0548]
(S)-5-chloro-3-(3,5-difluorophenyl)-8-methyl-2-(pyrrolidin-2-yl-
)quinazolin-4(3H)-one; [0549]
(S)-8-chloro-3-(3,5-difluorophenyl)-2-(pyrrolidin-2-yl)quinazolin-4(3H)-o-
ne; [0550]
(S)-3-(3,5-difluorophenyl)-8-methyl-2-(pyrrolidin-2-yl)quinazol-
in-4(3H)-one; [0551]
(S)-3-(3-(difluoromethyl)phenyl)-8-iodo-2-(pyrrolidin-2-yl)quinazolin-4(3-
H)-one; [0552]
(S)-8-iodo-3-phenyl-2-(pyrrolidin-2-yl)quinazolin-4(3H)-one; [0553]
(S)-3-(5-chloro-4-oxo-2-(pyrrolidin-2-yl)quinazolin-3
(4H)-yl)-5-fluorobenzonitrile; [0554]
(S)-3-(3,5-difluorophenyl)-5-fluoro-2-(pyrrolidin-2-yl)quinazolin-4(3H)-o-
ne; [0555]
(S)-3-(5,8-dichloro-4-oxo-2-(pyrrolidin-2-yl)quinazolin-3
(4H)-yl)benzenesulfonamide; [0556]
5-chloro-2-((2S,4R)-4-methylpyrrolidin-2-yl)-3-phenylquinazolin-4(3H)-one-
; [0557]
5-chloro-3-(3,5-difluorophenyl)-2-((2S,4R)-4-fluoropyrrolidin-2-y-
l)quinazolin-4(3H)-one; [0558]
(S)-2-(1-aminoethyl)-5-chloro-3-(3,5-difluorophenyl)quinazolin-4(3H)-one;
[0559] (S)-2-(1-aminoethyl)-5-chloro-3-phenylquinazolin-4(3H)-one;
[0560]
(R)-5-chloro-2-(morpholin-3-yl)-3-phenylquinazolin-4(3H)-one;
[0561]
(S)-2-(1-aminoethyl)-3-(3,5-difluorophenyl)-5-fluoroquinazolin-4(3H)-one;
N-((3R,5S)-5-(5-chloro-3-(3,5-difluorophenyl)-4-oxo-3,4-dihydroquinazolin-
-2-yl)pyrrolidin-3-yl)-2,2-difluoroacetamide; [0562]
N-((3R,5S)-5-(5-chloro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)pyrrolid-
in-3-yl)-2,2-difluoroacetamide; [0563] N-((3
S,5S)-5-(5-chloro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)pyrrolidin-3--
yl)-2,2,2-trifluoroacetamide; [0564]
N-((3R,5S)-5-(3-(3,5-difluorophenyl)-5-fluoro-4-oxo-3,4-dihydroquinazolin-
-2-yl)pyrrolidin-3-yl)-2,2-difluoroacetamide; [0565]
N-((3R,5S)-5-(3-(3-(difluoromethyl)-5-fluorophenyl)-5-fluoro-4-oxo-3,4-di-
hydroquinazolin-2-yl)pyrrolidin-3-yl)-2,2-difluoroacetamide; [0566]
N-((3R,5S)-5-(5-chloro-3-(3-(difluoromethyl)-5-fluorophenyl)-4-oxo-3,4-di-
hydroquinazolin-2-yl)pyrrolidin-3-yl)-2,2-difluoroacetamide; [0567]
N-((3R,5S)-5-(5-chloro-3-(3,5-difluorophenyl)-4-oxo-3,4-dihydroquinazolin-
-2-yl)pyrrolidin-3-yl)-2,2-difluoro-N-methylacetamide; [0568]
N-((3R,5S)-5-(5-chloro-3-(3-(difluoromethyl)-5-fluorophenyl)-4-oxo-3,4-di-
hydroquinazolin-2-yl)pyrrolidin-3-yl)-2,2-difluoroacetamide; and
[0569]
N-((3R,5S)-5-(5-chloro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)pyrrolid-
in-3-yl)-2-cyclopropylacetamide.
Example 3. Preparation of a Compound of Formula (3)
[0570] A. Preparation of a Compound of Formula (3) in which R.sup.4
is CN, R.sup.6 and R.sup.7 are NH.sub.2, and X is Cl
(2,4-diamino-6-chloropyrimidine-5-carbonitrile)
##STR00062##
[0571] Ammonium hydroxide (20 mL) was added to a solution of
2,4,6-trichloropyrimidine-5-carbonitrile (5.0 g, 24 mmol) in
dioxane (20 mL) at room temperature. The solution was warmed to
50.degree. C. and stirred for 3 hrs. The reaction mixture was
cooled to 10.degree. C. and water (50 mL) was added. The resulting
solid was filtered, washed with water, and dried under high vacuum
to afford the above compound. .sup.13H NMR (100 MHz, DMSO) 164.8,
162.6, 161.9, 115.8, 77.6. ES/MS m/z=169.9 (M+H).sup.+.
[0572] B. Following the procedure described in Example 3 and
Reaction Scheme I, below compounds of formula (3) were prepared:
[0573] 5-chloro-6-fluoropyrimidine-2,4-diamine; [0574]
6-chloro-5-(methylsulfonyl)pyrimidine-2,4-diamine; [0575]
2-amino-4,6-dichloropyrimidine-5-carbonitrile; [0576]
2-amino-4-chloro-6-methylpyrimidine-5-carbonitrile; [0577]
4-amino-2,6-dichloropyrimidine-5-carbonitrile; [0578]
4-amino-6-chloro-2-methylpyrimidine-5-carbonitrile; [0579]
4-chloro-5-iodo-6-methylpyrimidin-2-amine; [0580]
6-chloro-5-(trifluoromethyl)pyrimidine-2,4-diamine; and [0581]
2,4-diamino-6-chloropyrimidine-5-carboxamide.
[0582] C. Preparation of a Compound of Formula (3) in which R.sup.4
is Cl, R.sup.6 and R.sup.7 are NH.sub.2, and X is F
##STR00063##
[0583] To 2,4,6-trifluoropyrimidine (10 g, 75 mmol) in acetonitrile
(100 mL) cooled to 0.degree. C. is added conc NH.sub.4OH (50 mL) in
three portions. Remove the cooling bath and allow to stir at room
temperature for 6 h followed by heating at 40.degree. C. overnight.
Remove the solvent in vacuo to give 2,4-diamino-6-fluoropyrimidine.
MeOH/EtOH (250 mL, 1:1) is added to the
2,4-diamino-6-fluoropyrimidine and the mixture is cooled with an
ice bath. NCS (13 g, 97 mmol) was added in portions. The ice bath
was removed and the mixture stirred for 6 h, followed by heating to
50.degree. C. overnight. Approximately 75 mL of the solvent is
removed in vacuo and the reaction vessel is cooled to -10.degree.
C. The solid is collected by filtration and added to water (100 mL)
and stirred. The solid is collected by filtration and added to 0.1M
NaOH (100 mL) and stirred. The solid is collected by filtration to
give 2,4-diamino-5-chloro-6-fluoropyrimidine.
Example 4. Preparation of a Compound of Formula (I)
[0584] A. Preparation of a Compound of Formula (I) in which n is 1,
R.sup.1 is fluoro, m is 1, R.sup.2 is fluoro, R.sup.3 is
cyclopropyl, R.sup.4 is cyano, R.sup.5 is hydrogen, R.sup.6 is
NH.sub.2, and R.sup.7 is NH.sub.2
##STR00064## [0585]
(S)-2-(amino(cyclopropyl)methyl)-5-fluoro-3-(3-fluorophenyl)quinazolin-4(-
3H)-one (270 mg, 0.8 mmol) and
2,4-diamino-6-chloropyrimidine-5-carbonitrile (120 mg, 0.7 mmol)
were dissolved in diisopropylethylamine (0.7 mL, 4.0 mmol) and iPA
(2 mL). The resultant mixture was heated using a microwave to
130.degree. C. for 14 hours, after which time the reaction was
cooled to room temperature, and the solvent removed in vacuo. The
residue was purified by chromatography eluting with 0-100%
EtOAc/hexanes followed by 0-20% MeOH in EtOAc to afford
2,4-diamino-6-((cyclopropyl(5-fluoro-3-(3-fluorophenyl)-4-oxo-3,4--
dihydroquinazolin-2-yl)methyl)amino)pyrimidine-5-carbonitrile
(Compound 15a). .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
7.96-7.68 (m, 2H), 7.64-7.04 (m, 3H), 6.72-6.33 (m, 2H), 6.16 (s,
2H), 4.61 (dt, J=21.5, 7.6 Hz, 1H), 1.49-1.21 (m, 1H), 0.39 (dtd,
J=11.7, 7.0, 2.0 Hz, 3H), 0.12 (m, 1H). ES/MS 461.2
(M+H.sup.+).
[0586] B. Following the procedure described in Example 4 and
Reaction Scheme I, below compounds of formula (I) were prepared:
[0587]
(S)-2-(cyclopropyl((2,6-diamino-5-cyanopyrimidin-4-yl)amino)methyl)-4-oxo-
-3-phenyl-3,4-dihydroquinazoline-5-carbonitrile (Compound 1a).
[0588] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.13-7.94 (m,
2H), 7.62-7.37 (m, 4H), 6.59 (s, 2H), 6.46 (d, J=7.6 Hz, 1H), 6.20
(s, 2H), 4.74-4.55 (m, 1H), 1.36-1.22 (m, 1H), 0.49-0.30 (m, 3H),
0.07--0.07 (m, 1H). ES/MS 450.1 (M+H.sup.+). [0589]
(S)-2-(cyclopropyl((2,6-diamino-5-cyanopyrimidin-4-yl)amino)methyl)-8-flu-
oro-4-oxo-3-phenyl-3,4-dihydroquinazoline-5-carbonitrile (Compound
2a).
[0590] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.16 (dd, J=8.4,
4.5 Hz, 1H), 7.99 (dd, J=9.6, 8.4 Hz, 1H), 7.93-7.58 (m, 4H),
7.57-7.49 (m, 2H), 7.48-7.33 (m, 2H), 7.33-7.23 (m, 1H), 4.65 (t,
J=8.0 Hz, 1H), 1.48 (ddt, J=13.0, 7.9, 4.0 Hz, 1H), 0.57-0.35 (m,
3H), 0.16-0.03 (m, 1H). ES/MS 468.1 (M+H.sup.+). [0591]
(S)-2,4-diamino-6-(((5-chloro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)(-
phenyl)methyl)amino)pyrimidine-5-carbonitrile (Compound 3a).
[0592] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 7.99-6.97 (m,
14H), 6.60-6.51 (m, 1H), 5.91 (dd, J=6.8, 1.2 Hz, 1H), 4.54-3.39
(br m, 4H). ES/MS 495.1 (M+H)+; [0593]
(S)-2-(cyclopropyl((2,6-diamino-5-cyanopyrimidin-4-yl)amino)methyl)-3-(3--
(difluoromethyl)-5-fluorophenyl)-4-oxo-3,4-dihydroquinazoline-5-carbonitri-
le (Compound 4a):
[0594] .sup.1H NMR (400 MHz, DMSO) .delta. 8.17-8.00 (m, 3H),
7.95-7.47 (m, 6H), 7.47-7.28 (m, 2H), 7.26-6.79 (m, 1H), 4.60 (q,
J=8.3 Hz, 1H), 1.65-1.44 (m, 1H), 0.65-0.40 (m, 3H), 0.31-0.07 (m,
1H). ES/MS 518.1 (M+H.sup.+); [0595]
(S)-2,4-diamino-6-((cyclopropyl(3-(3-fluorophenyl)-5-(methylsulfonyl)-4-o-
xo-3,4-dihydroquinazolin-2-yl)methyl)amino)pyrimidine-5-carbonitrile
(Compound 5a):
[0596] .sup.1H NMR (400 MHz, DMSO) .delta. 8.36-8.30 (m, 1H),
8.14-8.08 (m, 2H), 7.91 (br s, 4H), 7.61-7.47 (m, 1H), 7.47-7.31
(m, 1H), 7.24-7.14 (m, 1H), 7.13-7.05 (m, 1H), 4.65-4.66 (m, 1H),
3.49 (s, 3H), 1.60-1.48 (m, 1H), 0.60-0.38 (m, 3H), 0.23-0.12 (m,
1H). ES/MS 521.1 (M+H.sup.+); [0597]
(S)-2,4-diamino-6-((cyclopropyl(3-(2-fluorophenyl)-5-(methylsulfon-
yl)-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)amino)pyrimidine-5-carbonitril-
e (Compound 17a-1):
[0598] .sup.1H NMR (400 MHz, DMSO) .delta. 8.34 (dd, J=6.7, 2.3 Hz,
1H), 8.16-8.08 (m, 2H), 7.90-7.56 (m, 4H), 7.50-7.38 (m, 4H), 7.21
(ddd, J=8.2, 6.3, 2.3 Hz, 1H), 4.55-4.48 (m, 1H), 3.49 (s, 3H),
1.46 (dt, J=8.9, 5.0 Hz, 1H), 0.59-0.50 (m, 1H), 0.49-0.35 (m, 2H),
-0.04--0.12 (m, 1H). ES/MS 521.1 (M+H.sup.+); [0599]
(S)-2,4-diamino-6-((cyclopropyl(3-(2-fluorophenyl)-5-(methylsulfonyl)-4-o-
xo-3,4-dihydroquinazolin-2-yl)methyl)amino)pyrimidine-5-carbonitrile
(Compound 17a-2):
[0600] .sup.1H NMR (400 MHz, DMSO) .delta. 8.44 (br s, 2H),
8.36-8.32 (m, 2H), 8.20-8.06 (m, 2H), 7.85 (br s, 2H), 7.65 (tt,
J=7.6, 1.4 Hz, 1H), 7.39-7.22 (m, 2H), 7.13 (ddt, J=9.5, 8.0, 1.3
Hz, 1H), 4.78-4.56 (m, 1H), 3.48 (s, 3H), 1.65 (qt, J=8.9, 5.0 Hz,
1H), 0.62 (tt, J=8.7, 4.9 Hz, 1H), 0.44 (ddp, J=13.1, 9.0, 4.7 Hz,
2H), 0.30 (dq, J=10.1, 4.9 Hz, 1H). ES/MS 521.1 (M+H.sup.+); [0601]
(S)-2,4-diamino-6-((cyclopropyl(3-(2,6-difluorophenyl)-5-(methylsulfonyl)-
-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)amino)pyrimidine-5-carbonitrile
(Compound 6a):
[0602] .sup.1H NMR (400 MHz, DMSO) .delta. 8.46 (br s, 1H), 8.36
(dd, J=5.1, 3.7 Hz, 1H), 8.19-8.13 (m, 2H), 7.71 (br s, 3H),
7.46-7.38 (m, 1H), 7.28 (t, J=9.1 Hz, 1H), 7.08 (t, J=8.8 Hz, 1H),
4.62 (t, J=8.7 Hz, 1H), 3.49 (s, J=3H), 1.74-1.62 (m, 1H),
0.72-0.63 (m, 1H), 0.46 (m, 2H), 0.14 (m, 1H). ES/MS 539.1
(M+H.sup.+); [0603]
(S)-2,4-diamino-6-((cyclopropyl(6-fluoro-3-(3-fluorophenyl)-8-iodo-4-oxo--
3,4-dihydroquinazolin-2-yl)methyl)amino)pyrimidine-5-carbonitrile;
[0604]
(S)-2,4-diamino-6-((cyclopropyl(6-fluoro-3-phenyl-8-iodo-4-oxo-3,4-dihydr-
oquinazolin-2-yl)methyl)amino)pyrimidine-5-carbonitrile; [0605]
(S)-3-(5-chloro-3-(3,5-difluorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)--
3-((2,6-diamino-5-cyanopyrimidin-4-yl)amino)-N,N-dimethylpropanamide
(Compound 9a):
[0606] .sup.1H NMR (400 MHz, DMSO) .delta. 7.89 (bs, 1H), 7.82 (t,
J=8 Hz, 1H), 7.66-7.62 (m, 2H), 7.38-7.32 (m, 1H), 7.29-7.26 (m,
1H), 7.18-7.14 (m, 1H), 5.26 (m, 1H), 3.02 (s, 3H), 2.76 (s, 3H),
2.69 (d, J=4.4 Hz, 2H), 2.65 (d, J=4.8 Hz, 2H). ES/MS 540.2
(M+H.sup.+); [0607]
(S)-3-(5-chloro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)-3-((2,6-diamin-
o-5-cyanopyrimidin-4-yl)amino)-N,N-dimethylpropanamide (Compound
10a):
[0608] .sup.1H NMR (400 MHz, DMSO) .delta. 7.89 (bs, 1H), 7.80 (t,
J=8 Hz, 1H), 7.65-7.59 (m, 2H), 7.55-7.51 (m, 1H), 7.42-7.31 (m,
4H), 5.25 (m, 1H), 3.00 (s, 3H), 2.75 (s, 3H), 2.66 (d, J=4.8 Hz,
2H), 2.62 (d, J=4.8 Hz, 2H). ES/MS 504.2 (M+H.sup.+); [0609]
(S)-2,4-diamino-6-(((3-(3-cyano-5-fluorophenyl)-5-methyl-4-oxo-3,4-dihydr-
oquinazolin-2-yl)(cyclopropyl)methyl)amino)pyrimidine-5-carbonitrile
(Compound 1a).
[0610] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.33-7.94 (m,
3H), 7.98-7.70 (m, 3H), 7.68-7.59 (m, 1H), 7.55-7.43 (m, 1H),
7.45-7.29 (m, 1H), 4.44 (dt, J=20.0, 8.2 Hz, 1H), 2.72 (d, J=1.1
Hz, 3H), 1.56 (dt, J=13.3, 6.5 Hz, 1H), 0.64-0.38 (m, 3H),
0.30-0.16 (m, 1H). ES/MS 482.3 (M+H.sup.+). [0611]
(S)-2,4-diamino-6-((cyclopropyl(3-(3,5-difluorophenyl)-5-methyl-4-oxo-3,4-
-dihydroquinazolin-2-yl)methyl)amino)pyrimidine-5-carbonitrile
(Compound 12a).
[0612] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 7.73 (dd, J=8.1,
7.4 Hz, 2H), 7.68-7.52 (m, 2H), 7.48-7.29 (m, 1H), 7.32-7.09 (m,
2H), 6.99 (d, J=9.4 Hz, 2H), 4.55 (t, J=8.0 Hz, 1H), 2.72 (d, J=0.8
Hz, 3H), 1.53 (d, J=8.8 Hz, 1H), 0.68-0.38 (m, 3H), 0.33-0.11 (m,
1H). ES/MS 475.6 (M+H.sup.+); [0613]
(S)-2,4-diamino-6-(((5-chloro-3-(3,5-difluorophenyl)-4-oxo-3,4-dihydroqui-
nazolin-2-yl)(cyclopropyl)methyl)amino)pyrimidine-5-carbonitrile
(Compound 13a).
[0614] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 7.89-7.78 (m,
1H), 7.71 (dd, J=8.2, 1.2 Hz, 1H), 7.62 (dd, J=7.8, 1.2 Hz, 1H),
7.55-7.36 (m, 1H), 7.22 (tt, J=9.3, 2.4 Hz, 1H), 6.98 (dd, J=9.0,
2.6 Hz, 1H), 4.54 (t, J=8.1 Hz, 1H), 1.52 (dq, J=8.1, 4.2, 3.3 Hz,
1H), 0.64-0.36 (m, 3H), 0.34-0.06 (m, 1H). ES/MS 495.9 (M+H.sup.+);
[0615]
(S)-2,4-diamino-6-((cyclopropyl(3-(3,5-difluorophenyl)-5-fluoro-4-oxo-3,4-
-dihydroquinazolin-2-yl)methyl)amino)pyrimidine-5-carbonitrile
(Compound 14a).
[0616] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 7.91 (td, J=8.2,
5.5 Hz, 1H), 7.86-7.52 (m, 2H), 7.52-7.33 (m, 2H), 7.24 (tt, J=9.3,
2.4 Hz, 1H), 7.13-6.87 (m, 1H), 4.58 (t, J=8.0 Hz, 1H), 1.53 (ddd,
J=13.1, 8.8, 5.2 Hz, 1H), 0.66-0.29 (m, 3H), 0.31-0.17 (m, 1H).
ES/MS 479.2 (M+H.sup.+); and [0617]
(S)-2,4-diamino-6-((cyclopropyl(6-fluoro-3-(3-fluorophenyl)-4-oxo-3,4-dih-
ydroquinazolin-2-yl)methyl)amino)pyrimidine-5-carbonitrile
(Compound 16a).
[0618] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.01-7.63 (m,
3H), 7.61-7.43 (m, 2H), 7.43-7.24 (m, 2H), 7.27-6.81 (m, 3H), 4.55
(dt, J=18.0, 8.0 Hz, 1H), 1.47 (dd, J=15.0, 7.8 Hz, 1H), 0.64-0.23
(m, 3H), 0.23-0.04 (m, 1H). ES/MS 461.1 (M+H.sup.+);
(S)-2-(1-((5-acetyl-2,6-diaminopyrimidin-4-yl)amino)ethyl)-5-chloro-3-(3,-
5-difluorophenyl)quinazolin-4(3H)-one (Compound 18a).
##STR00065## [0619]
2,4-diamino-6-((2S)-2-(5-chloro-3-(3,5-difluorophenyl)-4-oxo-3,4-dihydroq-
uinazolin-2-yl)-4-methoxypyrrolidin-1-yl)pyrimidine-5-carbonitrile
(Compound 19)
[0620] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 7.73-7.69 (m,
3H), 7.54-7.47 (m, 3H), 7.21 (broad s, 2H), 4.67 (br s, 1H),
4.34-4.29 (m, 1H), 3.99-3.94 (m, 1H), 3.72-3.70 (m, 1H), 3.19 (s,
3H) 2.18-2.13 (m, 1H), 1.97-1.92 (m, 1H). ES/MS 525.3
(M+H.sup.+)
##STR00066## [0621]
(S)-2-(1-((6-amino-5-bromo-2-methylpyrimidin-4-yl)amino)ethyl)-5-chloro-3-
-phenylquinazolin-4(3H)-one (Compound 20).
[0622] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 7.82-7.75 (m,
1H), 7.65 (dd, J=8.2, 1.2 Hz, 1H), 7.61-7.55 (m, 3H), 7.49-7.39 (m,
3H), 4.91 (d, J=7.3 Hz, 1H), 2.19 (s, 3H), 1.37 (d, J=6.7 Hz,
3H).
##STR00067## [0623]
(S)-2-(1-((6-amino-5-bromo-2-methylpyrimidin-4-yl)amino)ethyl)-5-chloro-3-
-(3,5-difluorophenyl)quinazolin-4(3H)-one (Compound 21).
[0624] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 7.85-7.78 (m,
1H), 7.69 (dd, J=8.2, 1.2 Hz, 1H), 7.62 (dd, J=7.8, 1.2 Hz, 1H),
7.57-7.51 (m, 1H), 7.43-7.33 (m, 1H), 7.16-7.10 (m, 1H), 5.09 (dd,
J=7.8, 6.4 Hz, 1H), 2.20 (s, 3H), 1.42 (d, J=6.7 Hz, 3H).
##STR00068## [0625]
(S)-2,4-diamino-6-((1-(5-(2-morpholinoethoxy)-4-oxo-3-phenyl-3,4-dihydroq-
uinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile (Compound
22).
[0626] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 9.59 (s, 1H),
7.82 (t, J=8.2 Hz, 1H), 7.60-7.12 (br m, 2H), 7.57-7.39 (m, 5H),
7.35 (dd, J=8.2, 0.9 Hz, 1H), 7.21 (dd, J=8.3, 1.0 Hz, 1H),
7.09-6.74 (br m, 2H), 4.89-4.75 (m, 1H), 4.46 (q, J=4.9 Hz, 2H),
3.87 (d, J=12.9 Hz, 2H), 3.62-3.41 (m, 6H), 3.27-3.10 (m, 2H), 1.30
(d, J=6.6 Hz, 3H). ES/MS 528.2 (M+H.sup.+).
##STR00069## [0627]
(S)-2,4-diamino-6-((1-(5-(2-(azepan-1-yl)ethoxy)-4-oxo-3-phenyl-3,4-dihyd-
roquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile (Compound
23).
[0628] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 9.12 (s, 1H),
7.82 (t, J=8.2 Hz, 1H), 7.63-7.22 (br m, 2H), 7.56-7.37 (m, 5H),
7.34 (dd, J=8.2, 1.0 Hz, 1H), 7.21-6.84 (br m, 2H), 7.19 (dd,
J=8.3, 1.0 Hz, 1H), 4.90-4.78 (m, 1H), 4.46 (q, J=5.1, 4.5 Hz, 2H),
3.54 (q, J=4.8 Hz, 2H), 3.52-3.40 (m, 2H), 3.35-3.21 (m, 2H),
1.81-1.67 (m, 2H), 1.67-1.53 (m, 2H), 1.53-1.40 (m, 4H), 1.31 (d,
J=6.6 Hz, 3H). ES/MS 540.3 (M+H.sup.+).
##STR00070## [0629]
(S)-2,4-diamino-6-((1-(4-oxo-3-phenyl-5-(2-(pyrrolidin-1-yl)ethoxy)-3,4-d-
ihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile
(Compound 24).
[0630] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 9.56 (s, 1H),
7.80 (t, J=8.3 Hz, 1H), 7.59-7.08 (br m, 2H), 7.55-7.38 (m, 5H),
7.32 (d, J=8.3 Hz, 1H), 7.20-7.14 (m, 1H), 7.02-6.64 (br m, 2H),
4.85-4.74 (m, 1H), 4.44-4.30 (m, 2H), 3.64-3.53 (m, 4H), 3.23-3.08
(m, 2H), 2.01-1.85 (m, 2H), 1.83-1.65 (m, 2H), 1.29 (d, J=6.6 Hz,
3H). ES/MS 512.2 (M+H.sup.+).
##STR00071## [0631] (S)-isopropyl
2-((2-(1-((2,6-diamino-5-cyanopyrimidin-4-yl)amino)ethyl)-4-oxo-3-phenyl--
3,4-dihydroquinazolin-5-yl)oxy)acetate (Compound 25).
[0632] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 7.70 (t, J=8.2
Hz, 1H), 7.57-7.31 (m, 7H), 7.24 (dd, J=8.2, 1.0 Hz, 1H), 6.91 (dd,
J=8.4, 1.1 Hz, 1H), 5.02-4.89 (m, 1H), 4.83-4.74 (m, 3H), 1.29 (d,
J=6.6 Hz, 3H), 1.18 (d, J=6.2 Hz, 6H). ES/MS 515.2 (M+H.sup.+).
##STR00072## [0633]
(S)-2,4-diamino-6-((1-(4-oxo-5-(2-(2-oxopyrrolidin-1-yl)ethoxy)-3-phenyl--
3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile
(Compound 26).
[0634] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 7.97-7.12 (br m,
4H), 7.72 (t, J=8.2 Hz, 1H), 7.55-7.35 (m, 5H), 7.21 (dd, J=8.1,
0.9 Hz, 1H), 7.07 (dd, J=8.4, 1.1 Hz, 1H), 4.87-4.75 (m, 1H), 4.13
(t, J=5.3 Hz, 2H), 3.55-3.47 (m, 4H), 2.14 (t, J=8.1 Hz, 2H), 1.81
(p, J=7.5 Hz, 2H), 1.30 (d, J=6.5 Hz, 3H). ES/MS 526.2
(M+H.sup.+).
##STR00073## [0635]
(S)-2,4-diamino-6-((1-(5-(2-(dimethylamino)ethoxy)-4-oxo-3-phenyl-3,4-dih-
ydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile (Compound
27).
[0636] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 9.49 (br s, 1H),
7.79 (t, J=8.2 Hz, 1H), 7.58-7.38 (m, 5H), 7.48-7.16 (br m, 2H),
7.30 (dd, J=8.1, 0.9 Hz, 1H), 7.14 (dd, J=8.4, 1.0 Hz, 1H), 6.90
(br s, 2H), 4.84-4.71 (m, 1H), 4.44-4.36 (m, 2H), 3.50 (q, J=4.6
Hz, 2H), 2.89 (s, 3H), 2.88 (s, 3H), 1.29 (d, J=6.8 Hz, 3H). ES/MS
486.2 (M+H.sup.+).
##STR00074## [0637]
(S)-2,4-diamino-6-((1-(4-oxo-5-(2-oxo-2-(piperidin-1-yl)ethoxy)-3-phenyl--
3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile
(Compound 28).
[0638] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 7.91-6.81 (br m,
4H), 7.69 (ddd, J=8.2, 7.4, 1.0 Hz, 1H), 7.45 (dt, J=21.8, 9.9 Hz,
5H), 7.20 (dt, J=8.1, 1.1 Hz, 1H), 6.90 (d, J=8.3 Hz, 1H), 4.88 (s,
2H), 4.85-4.77 (m, 1H), 3.44-3.33 (m, 4H), 1.58-1.34 (m, 6H), 1.30
(d, J=6.5 Hz, 3H). ES/MS 540.2 (M+H.sup.+).
##STR00075## [0639]
(S)-2,4-diamino-6-((1-(5-(3-hydroxy-2-(hydroxymethyl)-2-methylpropoxy)-4--
oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitr-
ile (Compound 29).
[0640] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 7.93-6.91 (br m,
4H), 7.73 (t, J=8.2 Hz, 1H), 7.55-7.36 (m, 5H), 7.19 (dd, J=8.2,
0.9 Hz, 1H), 7.04 (dd, J=8.5, 1.1 Hz, 1H), 4.84-4.72 (m, 1H), 3.88
(s, 2H), 3.46-3.31 (m, 4H), 1.30 (d, J=6.6 Hz, 3H), 0.87 (s, 3H).
ES/MS 517.2 (M+H.sup.+).
##STR00076## [0641]
(S)-2,4-diamino-6-((1-(4-oxo-3-phenyl-5-(2-(piperidin-1-yl)ethoxy)-3,4-di-
hydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile
(Compound 30).
[0642] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 9.06 (br s, 1H),
7.82 (t, J=8.2 Hz, 1H), 7.63-7.24 (br m, 2H), 7.56-7.39 (m, 5H),
7.34 (dd, J=8.2, 0.9 Hz, 1H), 7.20 (dd, J=8.3, 1.0 Hz, 1H), 7.01
(br s, 2H), 4.90-4.78 (m, 1H), 4.50-4.38 (m, 2H), 3.56 (d, J=12.2
Hz, 2H), 3.48 (q, J=4.9 Hz, 2H), 2.99 (q, J=11.3 Hz, 2H), 1.70 (d,
J=14.3 Hz, 2H), 1.62-1.41 (m, 3H), 1.37-1.26 (m, 1H), 1.31 (d,
J=6.7 Hz, 3H). ES/MS 526.3 (M+H.sup.+).
##STR00077## [0643]
(S)-2,4-diamino-6-((1-(4-oxo-3-phenyl-5-(2-(4-phenylpiperazin-1-yl)ethoxy-
)-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile
(Compound 31).
[0644] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 9.50 (s, 1H),
7.85 (t, J=8.2 Hz, 1H), 7.79-7.29 (m, 8H), 7.29-7.19 (m, 3H), 7.03
(br s, 2H), 6.92 (dd, J=8.4, 1.2 Hz, 2H), 6.87 (t, J=7.3 Hz, 1H),
4.91-4.79 (m, 1H), 4.58-4.44 (m, 2H), 3.77-3.56 (m, 6H), 3.38-3.21
(m, 2H), 2.90-2.74 (m, 2H), 1.31 (d, J=6.8 Hz, 3H). ES/MS 603.3
(M+H.sup.+).
##STR00078## [0645]
(S)-2,4-diamino-6-((1-(5-(2-(2-methyl-1H-imidazol-1-yl)ethoxy)-4-oxo-3-ph-
enyl-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile
(Compound 32).
[0646] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 7.87 (d, J=2.1
Hz, 1H), 7.84-7.55 (br m, 2H), 7.77 (t, J=8.2 Hz, 1H), 7.55-7.38
(m, 6H), 7.40-7.08 (br m, 2H), 7.26 (dd, J=8.2, 0.9 Hz, 1H), 7.04
(dd, J=8.5, 1.0 Hz, 1H), 4.88-4.76 (m, 1H), 4.56-4.47 (m, 2H),
4.45-4.36 (m, 2H), 2.62 (s, 3H), 1.30 (d, J=6.6 Hz, 3H). ES/MS
523.2 (M+H.sup.+).
##STR00079## [0647]
2,4-diamino-6-(((1S)-1-(5-(2-(1-methylpyrrolidin-2-yl)ethoxy)-4-oxo-3-phe-
nyl-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile
(Compound 33).
[0648] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 9.54-9.30 (m,
1H), 7.83-7.69 (m, 1H), 7.57-7.39 (m, 5H), 7.29-6.51 (br m, 4H),
7.27-7.08 (m, 2H), 5.13-4.93 (m, 1H), 4.86-4.71 (m, 1H), 3.84-3.29
(m, 2H), 3.29-3.13 (m, 1H), 3.13-2.96 (m, 1H), 2.76-2.70 (m, 3H),
2.29-1.57 (m, 6H), 1.34-1.24 (m, 3H). ES/MS 526.3 (M+H.sup.+).
##STR00080## [0649]
(S)-2,4-diamino-6-((1-(5-((3-methyloxetan-3-yl)methoxy)-4-oxo-3-phenyl-3,-
4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile
(Compound 34).
[0650] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 7.70 (t, J=8.2
Hz, 1H), 7.55-7.39 (m, 5H), 7.16 (dd, J=8.2, 0.9 Hz, 1H), 7.06 (d,
J=8.1 Hz, 1H), 6.74 (d, J=7.0 Hz, 1H), 6.53 (s, 2H), 6.23 (s, 2H),
4.68-4.58 (m, 1H), 4.46 (d, J=5.7 Hz, 2H), 4.21 (dd, J=5.7, 1.0 Hz,
2H), 4.11 (s, 2H), 1.34 (s, 3H), 1.22 (d, J=6.7 Hz, 3H). ES/MS
499.2 (M+H.sup.+).
##STR00081## [0651]
(S)-2,4-diamino-6-((1-(5-(2-morpholino-2-oxoethoxy)-4-oxo-3-phenyl-3,4-di-
hydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile
(Compound 35).
[0652] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 7.97 (br s, 1H),
7.77 (br s, 1H), 7.74-7.64 (m, 1H), 7.63-7.09 (br m, 2H), 7.62-7.26
(m, 5H), 7.25-7.15 (m, 1H), 6.97-6.88 (m, 1H), 4.98-4.88 (m, 2H),
4.89-4.45 (m, 1H), 3.61-3.31 (m, 8H), 1.36-1.16 (m, 3H). ES/MS
542.2 (M+H.sup.+).
##STR00082## [0653]
(S)-2,4-diamino-6-((1-(5-(2-(4-methylpiperidin-1-yl)-2-oxoethoxy)-4-oxo-3-
-phenyl-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile
(Compound 36).
[0654] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.02-7.54 (br m,
2H), 7.69 (t, J=8.2 Hz, 1H), 7.58-7.31 (m, 5H), 7.49-6.92 (br m,
2H), 7.20 (dd, J=8.1, 0.9 Hz, 1H), 6.89 (dd, J=8.5, 1.0 Hz, 1H),
4.89 (s, 2H), 4.86-4.78 (m, 1H), 4.23 (d, J=13.0 Hz, 1H), 3.82 (d,
J=13.6 Hz, 1H), 2.96 (t, J=12.8 Hz, 1H), 2.59-2.49 (m, 1H),
1.64-1.48 (m, 3H), 1.30 (d, J=6.6 Hz, 3H), 1.16-0.88 (m, 2H), 0.85
(d, J=6.1 Hz, 3H). ES/MS 554.3 (M+H.sup.+).
##STR00083## [0655]
(S)-3-(2-(1-((2,6-diamino-5-cyanopyrimidin-4-yl)amino)ethyl)-4-oxo-3-phen-
yl-3,4-dihydroquinazolin-5-yl)propanamide (Compound 37).
[0656] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.04-6.99 (br m,
4H), 7.73 (dd, J=8.1, 7.4 Hz, 1H), 7.55 (dd, J=8.2, 1.2 Hz, 1H),
7.53-7.37 (m, 5H), 7.34 (dd, J=7.6, 1.3 Hz, 1H), 7.15 (s, 1H), 6.69
(s, 1H), 4.94-4.82 (m, 1H), 3.34 (t, J=7.6 Hz, 2H), 2.37-2.28 (m,
2H), 1.33 (d, J=6.6 Hz, 3H). ES/MS 470.2 (M+H.sup.+).
##STR00084## [0657]
(S)-3-(2-(1-((2,6-diamino-5-cyanopyrimidin-4-yl)amino)ethyl)-8-fluoro-4-o-
xo-3-phenyl-3,4-dihydroquinazolin-5-yl)propanamide (Compound
38).
[0658] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 7.89-7.45 (br m,
3H), 7.62 (dd, J=10.0, 8.4 Hz, 2H), 7.52-7.44 (m, 2H), 7.44-7.33
(m, 3H), 7.30 (dd, J=8.4, 5.0 Hz, 1H), 7.13 (s, 1H), 6.67 (s, 1H),
4.93-4.82 (m, 1H), 3.27 (t, J=7.5 Hz, 2H), 2.33-2.24 (m, 2H), 1.32
(d, J=6.7 Hz, 3H). ES/MS 488.2 (M+H.sup.+).
##STR00085## [0659]
(S)-3-(2-(1-((2,6-diamino-5-cyanopyrimidin-4-yl)amino)ethyl)-3-(3,5-diflu-
orophenyl)-8-fluoro-4-oxo-3,4-dihydroquinazolin-5-yl)propanamide
(Compound 39).
[0660] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 7.76-6.79 (br m,
4H), 7.65 (dd, J=10.0, 8.4 Hz, 1H), 7.44 (d, J=9.2 Hz, 1H),
7.36-7.23 (m, 2H), 7.21-7.07 (m, 2H), 6.68 (s, 1H), 5.03-4.91 (m,
1H), 3.27 (t, J=7.6 Hz, 2H), 2.30 (t, J=7.6 Hz, 3H), 1.37 (d, J=6.5
Hz, 3H). ES/MS 524.1 (M+H.sup.+).
##STR00086## [0661]
(S)-3-(2-(1-((2,6-diamino-5-cyanopyrimidin-4-yl)amino)ethyl)-3-(3,5-diflu-
orophenyl)-4-oxo-3,4-dihydroquinazolin-5-yl)propanamide (Compound
40).
[0662] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 7.95-6.82 (br m,
4H), 7.77-7.67 (m, 1H), 7.59-7.52 (m, 1H), 7.44 (d, J=9.0 Hz, 1H),
7.34 (dd, J=7.7, 1.3 Hz, 1H), 7.27 (tt, J=9.2, 2.5 Hz, 1H),
7.21-7.09 (m, 2H), 6.68 (s, 1H), 5.03-4.89 (m, 1H), 3.32 (t, J=7.6
Hz, 2H), 2.31 (t, J=7.6 Hz, 2H), 1.36 (d, J=6.6 Hz, 3H). ES/MS
506.1 (M+H.sup.+).
##STR00087## [0663]
(S)-3-(2-(1-((2,6-diamino-5-chloropyrimidin-4-yl)amino)ethyl)-3-(3,5-difl-
uorophenyl)-8-fluoro-4-oxo-3,4-dihydroquinazolin-5-yl)propanamide
(Compound 41).
[0664] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 11.39 (br s,
1H), 7.76 (s, 1H), 7.70 (dd, J=10.0, 8.4 Hz, 1H), 7.57-7.41 (m,
3H), 7.39-7.23 (br m, 1H), 7.38 (dd, J=8.5, 5.0 Hz, 1H), 7.31 (tt,
J=9.3, 2.4 Hz, 1H), 7.18 (s, 1H), 7.07 (d, J=8.8 Hz, 1H), 6.73 (s,
1H), 5.08-4.95 (m, 1H), 3.37-3.25 (m, 2H), 2.34 (dd, J=8.5, 6.8 Hz,
2H), 1.44 (d, J=6.6 Hz, 3H). ES/MS 533.1 (M+H.sup.+).
##STR00088## [0665]
(S)-3-(2-(1-((2,6-diamino-5-chloropyrimidin-4-yl)amino)ethyl)-3-(3,5-difl-
uorophenyl)-4-oxo-3,4-dihydroquinazolin-5-yl)propanamide (Compound
42).
[0666] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 11.54 (br s,
1H), 7.86-7.71 (m, 2H), 7.62 (dd, J=8.1, 1.3 Hz, 1H), 7.52 (s, 2H),
7.51-7.47 (m, 1H), 7.39 (dd, J=7.5, 1.3 Hz, 1H), 7.31 (tt, J=9.4,
2.4 Hz, 1H), 7.19 (s, 1H), 7.14-7.02 (m, 1H), 6.73 (s, 1H),
5.08-4.93 (m, 1H), 2.54-2.48 (m, 2H), 2.42-2.29 (m, 2H), 2.08 (s,
OH), 1.43 (d, J=6.6 Hz, 3H). ES/MS 515.1 (M+H.sup.+).
##STR00089## [0667]
(S)-3-(2-(1-((2,6-diamino-5-chloropyrimidin-4-yl)amino)ethyl)-4-oxo-3-phe-
nyl-3,4-dihydroquinazolin-5-yl)propanamide (Compound 43).
[0668] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 11.38 (s, 1H),
7.79 (d, J=7.3 Hz, 1H), 7.75 (dd, J=8.1, 7.4 Hz, 1H), 7.59 (dd,
J=8.2, 1.2 Hz, 1H), 7.57-7.45 (m, 4H), 7.45-7.38 (m, 3H), 7.36 (dd,
J=7.6, 1.3 Hz, 1H), 7.17 (s, 1H), 6.71 (s, 1H), 4.95-4.83 (m, 1H),
3.42-3.29 (m, 2H), 2.34 (dd, J=8.4, 6.8 Hz, 2H), 1.37 (d, J=6.7 Hz,
3H). ES/MS 479.2 (M+H.sup.+).
##STR00090## [0669]
(S)-3-(2-(1-((2,6-diamino-5-chloropyrimidin-4-yl)amino)ethyl)-8-fluoro-4--
oxo-3-phenyl-3,4-dihydroquinazolin-5-yl)propanamide (Compound
44).
[0670] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 7.71-7.63 (m,
2H), 7.59-7.51 (m, 2H), 7.51-7.38 (m, 5H), 7.35 (dd, J=8.4, 5.0 Hz,
1H), 7.25 (br s, 2H), 7.18 (s, 1H), 6.72 (s, 1H), 4.95-4.85 (m,
1H), 3.37-3.19 (m, 2H), 2.38-2.29 (m, 2H), 1.38 (d, J=6.6 Hz, 3H).
ES/MS 497.1 (M+H.sup.+).
##STR00091## [0671]
(S)-2,4-diamino-6-((1-(4-oxo-3-phenyl-5-(3-(pyrrolidin-1-yl)propyl)-3,4-d-
ihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile
(Compound 45).
[0672] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 9.37 (br s, 1H),
7.78 (dd, J=8.2, 7.4 Hz, 1H), 7.69-7.35 (br m, 2H), 7.59 (dd,
J=8.1, 1.2 Hz, 1H), 7.57-7.40 (m, 5H), 7.37 (dd, J=7.5, 1.2 Hz,
1H), 7.20-6.84 (br m, 2H), 4.92-4.80 (m, 1H), 3.55-3.43 (m, 2H),
3.25-3.09 (m, 4H), 2.99-2.85 (m, 2H), 2.03-1.69 (m, 6H), 1.32 (d,
J=6.6 Hz, 3H). ES/MS 510.2 (M+H.sup.+).
##STR00092## [0673]
(S)-2,4-diamino-6-((1-(4-oxo-3-phenyl-5-(3-(piperidin-1-yl)propyl)-3,4-di-
hydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile
(Compound 46).
[0674] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.82 (br s, 1H),
7.78 (dd, J=8.1, 7.4 Hz, 1H), 7.58 (dd, J=8.2, 1.2 Hz, 1H),
7.56-7.40 (m, 5H), 7.37 (d, J=7.5 Hz, 1H), 7.35-6.49 (br m, 4H),
4.90-4.76 (m, 1H), 3.38 (d, J=12.2 Hz, 2H), 3.24-3.10 (m, 2H),
3.10-2.98 (m, 2H), 2.88-2.73 (m, 2H), 1.98-1.83 (m, 2H), 1.74 (d,
J=13.6 Hz, 2H), 1.69-1.44 (m, 4H), 1.30 (d, J=6.6 Hz, 3H). ES/MS
524.3 (M+H.sup.+).
##STR00093## [0675]
(S)-2,4-diamino-6-((1-(5-(3-(3,3-difluoropyrrolidin-1-yl)propyl)-4-oxo-3--
phenyl-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile
(Compound 47).
[0676] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 7.71 (t, J=7.8
Hz, 1H), 7.60-7.43 (m, 6H), 7.30 (dd, J=7.6, 1.3 Hz, 1H), 6.78 (d,
J=7.2 Hz, 1H), 6.55 (s, 2H), 6.25 (s, 2H), 4.78-4.66 (m, 1H),
3.19-3.08 (m, 2H), 2.80 (t, J=13.5 Hz, 2H), 2.61 (t, J=6.9 Hz, 2H),
2.40 (t, J=7.3 Hz, 2H), 2.25-2.08 (m, 2H), 1.73-1.59 (m, 2H), 1.26
(d, J=6.6 Hz, 3H). ES/MS 546.2 (M+H.sup.+).
##STR00094## [0677]
(S)-2,4-diamino-6-((1-(5-(3-(4,4-difluoropiperidin-1-yl)propyl)-4-oxo-3-p-
henyl-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile
(Compound 48).
[0678] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 9.34 (s, 1H),
7.80 (d, J=7.8 Hz, 1H), 7.59 (dd, J=8.2, 1.2 Hz, 1H), 7.57-7.40 (m,
5H), 7.37 (dd, J=7.5, 1.2 Hz, 1H), 7.40-6.52 (br m, 4H), 4.91-4.80
(m, 1H), 3.64-3.51 (m, 2H), 3.28-3.00 (m, 6H), 2.38-2.23 (m, 2H),
2.23-2.00 (m, 2H), 1.98-1.85 (m, 2H), 1.31 (d, J=6.6 Hz, 3H). ES/MS
560.2 (M+H.sup.+).
##STR00095## [0679]
2,4-diamino-6-(((1S)-1-(5-(3-(3,5-dimethylmorpholino)propyl)-4-oxo-3-phen-
yl-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile
(Compound 49).
[0680] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 9.70-9.12 (br m,
1H), 7.79 (dd, J=8.2, 7.4 Hz, 1H), 7.72-7.26 (m, 9H), 7.08 (br s,
2H), 4.88 (t, J=6.8 Hz, 1H), 4.29-3.62 (m, 2H), 3.51-2.91 (m, 6H),
2.65-2.53 (m, 2H), 2.03-1.82 (m, 2H), 1.40-1.18 (m, 3H), 1.13-0.96
(m, 6H). ES/MS 554.3 (M+H.sup.+).
##STR00096## [0681]
(S)-2,4-diamino-6-((1-(8-fluoro-4-oxo-3-phenyl-5-(3-(pyrrolidin-1-yl)prop-
yl)-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile
(Compound 50).
[0682] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 9.36 (s, 1H),
7.67 (dd, J=9.9, 8.3 Hz, 1H), 7.59-7.37 (m, 5H), 7.33 (dd, J=8.4,
4.9 Hz, 1H), 7.30-6.61 (m, 4H), 4.92-4.78 (m, 1H), 3.55-3.39 (m,
2H), 3.20-3.03 (m, 4H), 2.97-2.83 (m, 2H), 2.03-1.65 (m, 6H), 1.31
(d, J=6.7 Hz, 3H). ES/MS 528.2 (M+H.sup.+).
##STR00097## [0683]
(S)-2,4-diamino-6-((1-(3-(3,5-difluorophenyl)-4-oxo-5-(3-(pyrrolidin-1-yl-
)propyl)-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile
(Compound 51).
[0684] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 9.37 (br s, 1H),
7.78 (dd, J=8.2, 7.4 Hz, 1H), 7.69-6.65 (br m, 4H), 7.60 (dd,
J=8.1, 1.2 Hz, 1H), 7.48-7.41 (m, 1H), 7.37 (dd, J=7.5, 1.3 Hz,
1H), 7.29 (tt, J=9.3, 2.3 Hz, 1H), 7.15 (d, J=9.0 Hz, 1H),
5.00-4.90 (m, 1H), 3.54-3.40 (m, 2H), 3.24-3.06 (m, 4H), 2.99-2.84
(m, 2H), 2.02-1.67 (m, 6H), 1.36 (d, J=6.5 Hz, 3H). ES/MS 546.2
(M+H.sup.+).
##STR00098## [0685]
(S)-2,4-diamino-6-((1-(5-(3-(2,2-dimethylmorpholino)propyl)-4-oxo-3-pheny-
l-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile
(Compound 52).
[0686] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 9.11 (br s, 1H),
7.76 (dd, J=8.2, 7.4 Hz, 1H), 7.68-7.31 (m, 7H), 7.57 (dd, J=8.2,
1.2 Hz, 1H), 7.35 (dd, J=7.5, 1.3 Hz, 1H), 7.09 (br s, 2H),
4.92-4.78 (m, 1H), 3.78-3.63 (m, 2H), 3.45-3.15 (m, 3H), 3.15-2.93
(m, 3H), 2.93-2.77 (m, 1H), 2.77-2.65 (m, 1H), 1.98-1.81 (m, 2H),
1.37-1.26 (m, 3H), 1.22-1.13 (m, 3H), 1.08 (s, 3H). ES/MS 554.3
(M+H.sup.+).
##STR00099## [0687]
(S)-2,4-diamino-6-((1-(5-(3-(3,3-dimethylmorpholino)propyl)-4-oxo-3-pheny-
l-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile
(Compound 53).
[0688] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 9.26 (s, 1H),
7.91-7.60 (m, 3H), 7.61-7.53 (m, 1H), 7.53-7.12 (m, 8H), 4.94-4.81
(m, 1H), 3.94-3.84 (m, 1H), 3.65-3.48 (m, 2H), 3.40 (d, J=12.6 Hz,
1H), 3.37-2.99 (m, 5H), 2.92-2.76 (m, 1H), 2.02-1.74 (m, 2H),
1.34-1.28 (m, 3H), 1.26 (s, 3H), 1.20 (s, 3H). ES/MS 554.3
(M+H.sup.+).
##STR00100## [0689]
(S)-2,4-diamino-6-((1-(4-oxo-3-phenyl-5-(3-(2,2,6,6-tetrafluoromorpholino-
)propyl)-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile
(Compound 54).
[0690] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.04 (br s, 2H),
7.90 (br s, 3H), 7.72 (t, J=7.8 Hz, 1H), 7.53 (dd, J=8.2, 1.2 Hz,
1H), 7.52-7.34 (m, 5H), 7.31 (dd, J=7.5, 1.3 Hz, 1H), 4.93-4.82 (m,
1H), 3.20-3.02 (m, 6H), 2.51 (t, J=7.3 Hz, 2H), 1.69 (p, J=7.6 Hz,
2H), 1.31 (d, J=6.6 Hz, 3H). ES/MS 598.2 (M+H.sup.+).
##STR00101## [0691]
(S)-2,4-diamino-6-((1-(5-(3-(3,3-difluoropyrrolidin-1-yl)propyl)-8-fluoro-
-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbon-
itrile (Compound 55).
[0692] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 10.46 (br s,
1H), 7.72 (dd, J=9.9, 8.3 Hz, 1H), 7.63-7.41 (m, 6H), 7.41-7.13 (br
m, 2H), 7.37 (dd, J=8.4, 4.9 Hz, 1H), 7.09 (br m, 2H), 4.96-4.84
(m, 1H), 4.09 (s, 1H), 3.71 (s, 3H), 3.46-2.98 (m, 4H), 2.79-2.35
(m, 2H), 1.94-1.73 (m, 2H), 1.35 (d, J=6.6 Hz, 3H). ES/MS 564.2
(M+H.sup.+).
##STR00102## [0693]
(S)-2,4-diamino-6-((cyclopropyl(4-oxo-3-phenyl-5-(3-(pyrrolidin-1-yl)prop-
yl)-3,4-dihydroquinazolin-2-yl)methyl)amino)pyrimidine-5-carbonitrile
(Compound 56).
[0694] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 9.45 (s, 1H),
7.81 (t, J=7.8 Hz, 1H), 7.63 (dd, J=8.2, 1.2 Hz, 1H), 7.59-7.33 (m,
5H), 7.32-6.73 (br m, 5H), 4.68 (t, J=7.7 Hz, 1H), 3.47-3.26 (m,
2H), 3.25-3.08 (m, 4H), 2.94 (br p, J=8.0 Hz, 2H), 2.06-1.69 (m,
6H), 1.44-1.29 (m, 1H), 0.51-0.31 (m, 3H), 0.08-0.01 (m, 1H). ES/MS
536.3 (M+H.sup.+).
##STR00103## [0695]
(S)-2,4-diamino-6-((cyclopropyl(4-oxo-3-phenyl-5-(3-(piperidin-1-yl)propy-
l)-3,4-dihydroquinazolin-2-yl)methyl)amino)pyrimidine-5-carbonitrile
(Compound 57).
[0696] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 9.22 (s, 1H),
7.79 (t, J=7.8 Hz, 1H), 7.64-7.43 (m, 6H), 7.39 (d, J=7.4 Hz, 1H),
6.63 (s, 2H), 6.45 (d, J=7.9 Hz, 1H), 6.24 (br s, 2H), 4.72 (t,
J=7.5 Hz, 1H), 3.46-3.30 (m, 2H), 3.18 (t, J=7.8 Hz, 2H), 3.04 (s,
2H), 2.89-2.74 (m, 2H), 2.03-1.86 (m, 2H), 1.82-1.47 (m, 5H),
1.43-1.18 (m, 2H), 0.44-0.29 (m, 3H), 0.04--0.08 (m, 1H). ES/MS
550.3 (M+H.sup.+)
##STR00104## [0697]
(S)-2,4-diamino-6-((cyclopropyl(8-fluoro-4-oxo-3-phenyl-5-(3-(pyrrolidin--
1-yl)propyl)-3,4-dihydroquinazolin-2-yl)methyl)amino)pyrimidine-5-carbonit-
rile (Compound 58).
[0698] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 9.43 (s, 1H),
7.69 (d, J=8.8 Hz, 1H), 7.62-7.15 (m, 7H), 6.94 (br s, 2H),
4.71-4.58 (m, 1H), 3.99-3.30 (m, 2H); 3.11 (s, 4H), 2.99-2.82 (m,
2H), 2.03-1.67 (m, 6H), 1.47-1.30 (m, 1H), 0.52-0.29 (m, 3H),
0.12--0.08 (m, 1H). ES/MS 554.3 (M+H.sup.+).
##STR00105## [0699]
(S)-2,4-diamino-6-((cyclopropyl(8-fluoro-4-oxo-3-phenyl-5-(3-(piperidin-1-
-yl)propyl)-3,4-dihydroquinazolin-2-yl)methyl)amino)pyrimidine-5-carbonitr-
ile (Compound 59).
[0700] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 9.05-8.90 (m,
1H), 7.75-7.65 (m, 1H), 7.65-7.41 (m, 6H), 7.35 (s, 2H), 7.28 (s,
1H), 7.13 (br s, 2H), 4.70-4.58 (m, 1H), 3.42-3.30 (m, 2H),
3.22-2.94 (m, 4H), 2.85-2.68 (m, 2H), 1.93-1.78 (m, 2H), 1.78-1.66
(m, 2H), 1.66-1.12 (m, 6H), 0.52-0.31 (m, 3H), 0.11--0.02 (m, 1H).
ES/MS 568.3 (M+H.sup.+).
##STR00106## [0701]
(S)-2-amino-4-chloro-6-((cyclopropyl(4-oxo-3-phenyl-5-(3-(pyrrolidin-1-yl-
)propyl)-3,4-dihydroquinazolin-2-yl)methyl)amino)pyrimidine-5-carbonitrile
(Compound 60).
[0702] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 9.38 (s, 1H),
7.77 (dd, J=8.2, 7.4 Hz, 1H), 7.64-7.58 (m, 2H), 7.43 (tddd, J=7.9,
5.9, 3.4, 1.5 Hz, 3H), 7.36 (dd, J=7.5, 1.3 Hz, 1H), 7.32-7.18 (m,
3H), 7.08 (s, 1H), 4.59 (t, J=7.9 Hz, 1H), 3.96-3.62 (m, 2H),
3.23-3.07 (m, 4H), 2.97-2.83 (m, 2H), 2.01-1.69 (m, 6H), 1.51-1.35
(m, 1H), 0.53-0.33 (m, 3H), 0.10--0.01 (m, 1H). ES/MS 555.2
(M+H.sup.+).
##STR00107## [0703]
(S)-2,4-diamino-6-((1-(5-(3-cyclohexylpropyl)-4-oxo-3-phenyl-3,4-dihydroq-
uinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile (Compound
65).
[0704] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.13 (br s, 2H),
7.98 (br s, 2H), 7.77-7.69 (m, 1H), 7.57-7.47 (m, 3H), 7.47-7.36
(m, 3H), 7.32 (dd, J=7.5, 1.3 Hz, 1H), 4.91 (p, J=6.7 Hz, 1H), 3.12
(t, J=7.7 Hz, 2H), 1.68-1.46 (m, 7H), 1.34 (d, J=6.6 Hz, 3H),
1.24-1.00 (m, 6H), 0.88-0.72 (m, 2H). ES/MS 523.3 (M+H.sup.+).
##STR00108## [0705]
(S)-2-amino-4-chloro-6-((1-(5-chloro-8-fluoro-4-oxo-3-phenyl-3,4-dihydroq-
uinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile (Compound
66).
[0706] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 7.83 (d, J=6.9
Hz, 1H), 7.76 (dd, J=9.6, 8.7 Hz, 1H), 7.60 (dd, J=8.8, 4.5 Hz,
1H), 7.56-7.46 (m, 2H), 7.46-7.33 (m, 3H), 7.26 (s, 1H), 4.94-4.84
(m, 1H), 1.37 (d, J=6.6 Hz, 3H). ES/MS 470.0 (M+H.sup.+).
##STR00109## [0707]
(S)-2,4-diamino-6-(2-(5-chloro-3-(3,5-difluorophenyl)-4-oxo-3,4-dihydroqu-
inazolin-2-yl)azetidin-1-yl)pyrimidine-5-carbonitrile (Compound
67).
[0708] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 7.86-7.73 (m,
1H), 7.65 (d, J=8.2 Hz, 1H), 7.56 (dd, J=22.3, 9.1 Hz, 2H),
7.45-7.22 (m, 2H), 4.10 (s, 5H), 2.56-2.50 (m, 2H), 2.34-2.08 (m,
2H). ES/MS 481.1 (M+H.sup.+).
##STR00110## [0709]
(S)-2,4-diamino-6-(2-(5-chloro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)-
azetidin-1-yl)pyrimidine-5-carbonitrile (Compound 68).
[0710] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.02-7.65 (m,
2H), 7.72-7.49 (m, 4H), 7.42 (s, 2H), 5.25-5.20 (m, 1H), 4.45-4.15
(m, 4H), 2.79-2.49 (m, 1H), 2.39-1.70 (m, 1H). ES/MS 445.1
(M+H.sup.+).
##STR00111## [0711]
(S)-4-(2-(1-((2,6-diamino-5-cyanopyrimidin-4-yl)amino)ethyl)-4-oxo-3-phen-
yl-3,4-dihydroquinazolin-5-yl)butanoic acid (Compound 69).
[0712] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.02 (s, 1H),
7.84 (s, 1H), 7.77-7.65 (m, 1H), 7.61-7.40 (m, 4H), 7.29 (dd,
J=7.3, 1.3 Hz, 1H), 4.87 (p, J=6.7 Hz, 2H), 3.13 (dd, J=8.8, 6.4
Hz, 2H), 2.17 (t, J=7.6 Hz, 2H), 1.73 (p, J=7.7 Hz, 3H), 1.32 (d,
J=6.6 Hz, 3H). (ES/MS 485.1 (M+H.sup.+).
##STR00112## [0713]
(S)-4-(2-(1-(2,6-diamino-5-cyanopyrimidin-4-yl)pyrrolidin-2-yl)-4-oxo-3-p-
henyl-3,4-dihydroquinazolin-5-yl)butanoic acid (Compound 70).
[0714] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 7.84 (d, J=7.7
Hz, 1H), 7.79-7.35 (m, 5H), 7.30-6.77 (m, 1H), 4.70 (s, 3H),
4.27-3.60 (m, 4H), 3.11 (dtd, J=28.3, 13.0, 7.5 Hz, 3H), 2.30-1.95
(m, 3H), 1.98-1.28 (m, 4H). ES/MS 511.1 (M+H.sup.+).
##STR00113## [0715]
(S)-4-(2-(1-((2,6-diamino-5-cyanopyrimidin-4-yl)amino)ethyl)-3-(3,5-diflu-
orophenyl)-4-oxo-3,4-dihydroquinazolin-5-yl)butanoic acid (Compound
71).
[0716] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.15-7.66 (m,
4H), 7.57 (dd, J=8.2, 1.2 Hz, 1H), 7.49-7.40 (m, 1H), 7.36-7.20 (m,
2H), 7.17-6.91 (m, 2H), 4.96 (p, J=6.7 Hz, 1H), 3.14 (dd, J=8.8,
6.0 Hz, 3H), 2.18 (t, J=7.6 Hz, 2H), 1.74 (p, J=7.6 Hz, 2H), 1.37
(d, J=6.6 Hz, 3H). ES/MS 521.1 (M+H.sup.+).
##STR00114## [0717]
(S)-2,4-diamino-6-(2-(3-(3-fluorophenyl)-5-(methylsulfonyl)-4-oxo-3,4-dih-
ydroquinazolin-2-yl)pyrrolidin-1-yl)pyrimidine-5-carbonitrile
(Compound 72):
[0718] .sup.1H NMR (400 MHz, DMSO) .delta. 8.27 (dd, J=7.6, 1.4 Hz,
1H), 8.04-7.88 (m, 3H), 7.79-7.39 (m, 4H), 4.84-4.66 (m, 1H), 4.05
(br s, 1H), 3.90 (dt, J=10.1, 7.5 Hz, 1H), 3.48 (s, 3H), 2.09 (br
s, 2H), 1.91 (br s, 1H), 1.85-1.70 (m, 1H). ES/MS 521.1
(M+H.sup.+);
##STR00115## [0719]
(S)-2,4-diamino-6-(2-(3-(2-fluorophenyl)-5-(methylsulfonyl)-4-oxo-3,4-dih-
ydroquinazolin-2-yl)pyrrolidin-1-yl)pyrimidine-5-carbonitrile
(Compound 73):
[0720] .sup.1H NMR (400 MHz, DMSO) .delta. 8.27 (dd, J=7.6, 1.5 Hz,
1H), 8.05-7.94 (m, 2H), 7.77-7.56 (m, 3H), 7.46 (td, J=7.6, 1.6 Hz,
1H), 7.25 (br s, 2H), 4.69-4.60 (m, 1H), 4.14-4.02 (m, 1H),
3.95-3.83 (m, 1H), 3.48 (s, 3H), 2.29-2.18 (m, 2H), 2.03-1.90 (m,
2H). ES/MS 521.1 (M+H.sup.+);
##STR00116## [0721]
(S)-2,4-diamino-6-(2-(3-(2-fluorophenyl)-5-(methylsulfonyl)-4-oxo-3,4-dih-
ydroquinazolin-2-yl)pyrrolidin-1-yl)pyrimidine-5-carbonitrile
(Compound 74):
[0722] .sup.1H NMR (400 MHz, DMSO) .delta. 8.29 (dd, J=7.6, 1.4 Hz,
1H), 8.06-7.94 (m, 3H), 7.73-7.64 (m, 1H), 7.56 (ddd, J=9.9, 8.4,
1.3 Hz, 1H), 7.48 (td, J=7.7, 1.3 Hz, 1H), 4.93 (br s, 1H), 4.01
(br s, 1H), 3.94-3.85 (m, 1H), 3.48 (s, 3H), 1.98-1.66 (m, 4H).
ES/MS 521.1 (M+H.sup.+);
##STR00117## [0723]
(S)-2,4-diamino-6-(2-(3-(2,6-difluorophenyl)-5-(methylsulfonyl)-4-oxo-3,4-
-dihydroquinazolin-2-yl)pyrrolidin-1-yl)pyrimidine-5-carbonitrile
(Compound 75):
[0724] .sup.1H NMR (400 MHz, DMSO) .delta. 8.29 (dd, J=7.6, 1.4 Hz,
1H), 8.06 (dd, J=8.2, 7.6 Hz, 1H), 7.99 (dd, J=8.2, 1.4 Hz, 1H),
7.78 (ddd, J=15.0, 8.6, 6.4 Hz, 1H), 7.58-7.47-7.18 (m, 3H), 7.18
(br s, 2H) 4.89-4.84 (m, 1H), 4.05-3.97 (m, 1H), 3.94-3.83 (m, 1H),
3.48 (s, 3H), 2.25-2.09 (m, 1H), 2.09-1.82 (m, 3H). ES/MS 539.1
(M+H.sup.+);
##STR00118## [0725]
(S)-2,4-diamino-6-((1-(3-(3-fluorophenyl)-4-oxo-5-(phenylsulfonyl)-3,4-di-
hydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile
(Compound 76):
[0726] .sup.1H NMR (400 MHz, DMSO) .delta. 8.54 (dt, J=7.6, 1.3 Hz,
1H), 8.18-8.04 (m, 2H), 7.72-7.67 (m, 2H), 7.59-7.32 (m, 5H),
7.27-7.01 (m, 3H), 4.89 (q, J=6.7 Hz, 1H), 1.32 (d, J=6.6 Hz, 3H).
ES/MS 567.1 (M+H.sup.+);
##STR00119## [0727]
(S)-2,4-diamino-6-(2-(3-(3-fluorophenyl)-5-(methylsulfonyl)-4-oxo-3,4-dih-
ydroquinazolin-2-yl)pyrrolidin-1-yl)pyrimidine-5-carbonitrile
(Compound 77):
[0728] .sup.1H NMR (400 MHz, DMSO) .delta. 8.47 (dt, J=7.7, 1.1 Hz,
1H), 8.08-7.99 (m, 1H), 7.94 (dq, J=8.3, 1.1 Hz, 1H), 7.84-7.67 (m,
3H), 7.67-7.19 (m, 8H), 4.70-4.59 (m, 1H), 4.06-3.95 (m, 1H),
3.99-3.81 (m, 1H), 2.13-1.93 (m, 2H), 1.92-1.80 (m, 1H), 1.72-1.61
(m, 1H). ES/MS 583.1 (M+H.sup.+);
##STR00120## [0729]
(S)-2,4-diamino-6-((1-(3-(3-fluorophenyl)-5-((2-hydroxyethyl)sulfonyl)-4--
oxo-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile
(Compound 78):
[0730] .sup.1H NMR (400 MHz, DMSO) .delta. 8.44-8.34 (m, 1H),
8.22-8.13 (m, 2H), 7.75-7.59 (m, 2H), 7.57-7.48 (m, 1H), 7.41
(dddd, J=17.5, 8.9, 6.1, 2.4 Hz, 1H), 7.03 (dd, J=11.3, 7.1 Hz,
1H), 6.66 (br s, 2H), 6.44-6.32 (m, 2H), 4.99 (td, J=7.1, 5.9 Hz,
1H), 4.93 (td, J=5.5, 1.1 Hz, 1H), 4.09-3.97 (m, 2H), 3.84 (q,
J=6.0 Hz, 2H), 1.50-1.46 (m, 3H). ES/MS 525.1 (M+H.sup.+);
##STR00121## [0731]
(S)-2,4-diamino-6-((1-(3-(3-fluorophenyl)-5-((2-hydroxyethyl)thio)-4-oxo--
3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile
(Compound 79):
[0732] .sup.1H NMR (400 MHz, DMSO) .delta. 7.88-7.82 (m, 1H),
7.71-7.60 (m, 2H), 7.59-7.34 (m, 4H), 6.96 (dd, J=15.5, 7.0 Hz,
1H), 6.70-6.63 (m, 2H), 6.45-6.31 (m, 2H), 5.10 (td, J=5.6, 0.7 Hz,
1H), 4.94-4.81 (m, 1H), 3.76 (q, J=6.5 Hz, 2H), 3.15 (t, J=6.7 Hz,
2H), 1.45-1.41 (m, 3H). ES/MS 493.1 (M+H.sup.+);
##STR00122## [0733]
(S)-2,4-diamino-6-((1-(5-(cyclopentylsulfonyl)-3-(3-fluorophenyl)-4-oxo-3-
,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile
(Compound 80):
[0734] .sup.1H NMR (400 MHz, DMSO) .delta. 8.31-8.25 (m, 1H),
8.06-8.02 (m, 2H), 7.94-7.36 (m, 6H), 7.27-7.21 (m, 2H), 4.97 (q,
J=6.8 Hz, 1H), 4.76 (tt, J=8.9, 6.3 Hz, 1H), 1.98-1.43 (m, 9H),
1.37 (d, J=6.7 Hz, 3H). ES/MS 549.1 (M+H.sup.+);
##STR00123## [0735]
(S)-2,4-diamino-6-((1-(3-(3-fluorophenyl)-4-oxo-5-(o-tolylsulfonyl)-3,4-d-
ihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile
(Compound 81):
[0736] .sup.1H NMR (400 MHz, DMSO) .delta. 8.55 (dt, J=7.6, 1.3 Hz,
1H), 8.20-8.10 (m, 2H), 7.82 (dt, J=8.1, 1.8 Hz, 1H), 7.51-7.37 (m,
3H), 7.37-7.02 (m, 4H), 4.96-4.87 (m, 1H), 2.30 (s, 3H), 1.36 (d,
J=6.7 Hz, 3H). ES/MS 571.1 (M+H.sup.+);
##STR00124## [0737]
(S)-2,4-diamino-6-(2-(5-chloro-3-(3,5-difluorophenyl)-4-oxo-3,4-dihydroqu-
inazolin-2-yl)pyrrolidin-1-yl)pyrimidine-5-carbonitrile (Compound
83).
[0738] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 7.83 (m, 1H),
7.76 (t, J=8.0 Hz, 1H), 7.59 (m, 1H), 7.58 (m, 1H), 7.56-7.51 (m,
2H), 7.44 (bs, 2H), 7.03 (bs, 2H), 4.68 (m, 1H), 4.07 (d, J=7.5 Hz,
1H), 3.94 (m, 1H), 2.26-2.05 (m, 2H), 2.00 (m, 1H), 1.92-1.80 (m,
1H). ES/MS 495.2 (M+H.sup.+);
##STR00125## [0739]
(S)-2,4-diamino-6-(2-(5-chloro-3-(3,5-difluorophenyl)-8-methyl-4-oxo-3,4--
dihydroquinazolin-2-yl)pyrrolidin-1-yl)pyrimidine-5-carbonitrile
(Compound 84).
[0740] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 7.83 (m, 1H),
7.67 (dd, J=8.0, 1.0 Hz, 1H), 7.55 (m, 2H), 7.48 (d, J=8.0 Hz, 1H),
7.45 (bs, 2H), 7.01 (bs, 2H), 4.77 (m, 1H), 4.07 (m, 1H), 4.00 (m,
1H), 2.42 (s, 3H), 2.30-2.06 (m, 2H), 2.06-1.94 (m, 1H), 1.88 (m,
8.7 Hz, 1H). ES/MS 509.1 (M+H.sup.+);
##STR00126## [0741]
(S)-2,4-diamino-6-(2-(8-chloro-3-(3,5-difluorophenyl)-4-oxo-3,4-dihydroqu-
inazolin-2-yl)pyrrolidin-1-yl)pyrimidine-5-carbonitrile (Compound
85).
[0742] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.09 (dd, J=8.0,
1.4 Hz, 1H), 8.00 (dd, J=7.8, 1.4 Hz, 1H), 7.82 (d, J=9.0 Hz, 1H),
7.66-7.44 (m, 3H), 7.08 (bs, 2H), 4.75 (m, 1H), 4.06 (m, 1H), 3.98
(m, 1H), 2.21 (m, 1H), 2.15-2.05 (m, 1H), 1.98 (m, 1H), 1.86 (m,
1H). ES/MS 495.1 (M+H.sup.+);
##STR00127## [0743]
(S)-2,4-diamino-6-(2-(3-(3,5-difluorophenyl)-8-methyl-4-oxo-3,4-dihydroqu-
inazolin-2-yl)pyrrolidin-1-yl)pyrimidine-5-carbonitrile (Compound
86).
[0744] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 7.99 (ddd,
J=8.0, 1.6, 0.7 Hz, 1H), 7.86 (d, J=9.1 Hz, 1H), 7.74 (m, 1H), 7.78
(bs, 2H), 7.56 (m, 2H), 7.46 (t, J=7.6 Hz, 1H), 7.21 (bs, 2H), 4.84
(m, 1H), 4.11 (m, 1H), 4.02 (m, 1H), 2.49 (s, 3H), 2.21 (m, 1H),
2.17-2.08 (m, 1H), 2.01 (m, 1H), 1.89 (m, 1H). ES/MS 475.2
(M+H.sup.+);
##STR00128## [0745]
(S)-2,4-diamino-6-(2-(3-(3,5-difluorophenyl)-5-fluoro-4-oxo-3,4-dihydroqu-
inazolin-2-yl)pyrrolidin-1-yl)pyrimidine-5-carbonitrile (Compound
87).
[0746] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 7.96-7.79 (m,
2H), 7.72 (bs, 2H), 7.56 (m, 2H), 7.46 (m, 1H), 7.34 (m, 1H), 7.25
(bs, 2H), 4.69 (m, 1H), 4.08 (m, 1H), 3.95 (m, 1H), 2.25-2.06 (m,
2H), 1.98 (m, 1H), 1.89 (m, 1H). ES/MS 479.1 (M+H.sup.+);
##STR00129## [0747]
(S)-2,4-diamino-6-(2-(5-chloro-3-(3-cyano-5-fluorophenyl)-4-oxo-3,4-dihyd-
roquinazolin-2-yl)pyrrolidin-1-yl)pyrimidine-5-carbonitrile
(Compound 88).
[0748] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.38 (m, 0.5H),
8.32 (dt, J=9.3, 2.2 Hz, 0.5H), 8.24-8.15 (m, 1H), 8.12 (m, 0.5H),
8.08 (dt, J=9.3, 2.1 Hz, 0.5H), 7.78 (t, J=8.0 Hz, 1H), 7.60 (m,
2H), 7.58 (bs, 2H), 7.17 (bs, 2H), 4.61 (m, 1H), 4.07 (m, 1H),
4.00-3.87 (m, 1H), 2.24-2.04 (m, 2H), 1.98 (m, 1H), 1.86 (m, 1H).
ES/MS 502.1 (M+H.sup.+); [0749]
(S)-2,4-diamino-6-(2-(3-(3-(difluoromethyl)phenyl)-8-iodo-4-oxo-3,-
4-dihydroquinazolin-2-yl)pyrrolidin-1-yl)pyrimidine-5-carbonitrile;
[0750]
(S)-2,4-diamino-6-(2-(8-iodo-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)py-
rrolidin-1-yl)pyrimidine-5-carbonitrile;
[0750] ##STR00130## [0751]
(S)-3-(5,8-dichloro-2-(1-(2,6-diamino-5-cyanopyrimidin-4-yl)pyrrolidin-2--
yl)-4-oxoquinazolin-3(4H)-yl)benzenesulfonamide, mixture of
atropisomers (Compound 91).
[0752] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.31 (td, J=1.8,
0.7 Hz, 0.1H), 8.26 (s, 0.1H), 8.25-8.21 (m, 0.1H), 8.14 (m, 0.2H),
8.11-8.08 (m, 0.2H), 8.08-8.02 (m, 0.75H), 8.00 (s, 0.1H),
7.99-7.95 (m, 0.4H), 7.94 (s, 0.1H), 7.91-7.81 (m, 0.75H), 7.62 (s,
0.8H), 7.60-7.55 (m, 0.5H), 7.24-7.15 (m, 0.4H), 6.96 (bs, 2H),
6.82-6.75 (m, 0.5H), 6.52 (bs, 2H), 4.79-4.42 (m, 1H), 4.27-4.05
(m, 0.5H), 4.05-3.93 (m, 0.5H), 3.93-3.75 (m, 0.5H), 3.70-3.53 (m,
0.5H), 2.34-2.05 (m, 2H), 2.05-1.66 (m, 2H). ES/MS 572.1
(M+H.sup.+);
##STR00131## [0753]
(S)-3-(5,8-dichloro-2-(1-(2,6-diamino-5-cyanopyrimidin-4-yl)pyrrolidin-2--
yl)-4-oxoquinazolin-3(4H)-yl)benzenesulfonamide, single atropisomer
of unknown configuration (Compound 92).
[0754] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.26 (s, 1H),
8.14 (ddd, J=7.9, 2.1, 1.1 Hz, 1H), 8.11-8.02 (m, 2H), 7.98 (dd,
J=8.5, 6.0 Hz, 1H), 7.92-7.84 (m, 2H), 7.64 (s, 2H), 7.58 (dd,
J=8.5, 3.4 Hz, 1H), 7.48 (bs, 1H), 7.14 (bs, 1H), 4.73 (m, 1H),
4.15 (m, 1H), 3.99 (m, 1H), 2.35-2.17 (m, 1H), 2.17-2.06 (m, 1H),
2.00 (m, 1H), 1.90-1.73 (m, 1H). ES/MS 572.0 (M+H.sup.+);
##STR00132## [0755]
2,4-diamino-6-((2S,4R)-2-(5-chloro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-
-yl)-4-methylpyrrolidin-1-yl)pyrimidine-5-carbonitrile (Compound
94).
[0756] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 7.90-7.83 (m,
1H), 7.75-7.66 (m, 1H), 7.64-7.45 (m, 10H), 7.11 (brs, 2H), 4.68
(d, J=8.5 Hz, 1H), 4.22 (t, J=8.8 Hz, 1H), 2.64 (s, 1H), 2.23-2.13
(m, 1H), 1.41 (td, J=11.9, 8.8 Hz, 1H), 0.96 (d, J=6.6 Hz, 3H).
ES/MS 473.1 (M+H.sup.+).
##STR00133## [0757]
2,4-diamino-6-((2S,4R)-2-(5-chloro-3-(3,5-difluorophenyl)-4-oxo-3,4-dihyd-
roquinazolin-2-yl)-4-fluoropyrrolidin-1-yl)pyrimidine-5-carbonitrile
(Compound 95).
[0758] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 7.85-7.69 (m,
2H), 7.65-7.41 (m, 3H), 7.10 (brs, 4H), 5.51 (d, J=4.1 Hz, 1H),
5.38 (s, 1H), 4.72 (s, 2H), 2.41 (m, 1H), 2.33 (m, 1H), 2.13 (m,
2H). ES/MS 513.1 (M+H.sup.+).
##STR00134## [0759]
(S)-2-amino-4-((1-(5-chloro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)eth-
yl)amino)-6-methylpyrimidine-5-carbonitrile (Compound 96).
[0760] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.14 (s, 1H),
7.85-7.31 (m, 10H), 7.21 (s, 1H), 4.95-4.83 (m, 1H), 2.40-2.29 (m,
3H), 1.37 (dt, J=6.7, 1.6 Hz, 3H). ES/MS 532.1 (M+H.sup.+).
##STR00135## [0761]
(S)-2-(1-((2-amino-5-iodo-6-methylpyrimidin-4-yl)amino)ethyl)-5-chloro-3--
phenylquinazolin-4(3H)-one (Compound 97).
[0762] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.09 (s, 1H),
7.89-7.80 (m, 1H), 7.77 (s, 1H), 7.74-7.49 (m, 6H), 7.49-7.40 (m,
3H), 4.96-4.84 (m, 1H), 2.41 (d, J=1.2 Hz, 3H), 1.36 (d, J=6.5 Hz,
3H). ES/MS 533.1 (M+H.sup.+).
##STR00136## [0763]
(S)-4-amino-6-((1-(5-chloro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)eth-
yl)amino)-2-methylpyrimidine-5-carbonitrile (Compound 98).
[0764] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.00 (d, J=7.2
Hz, 1H), 7.79 (td, J=8.0, 1.1 Hz, 1H), 7.73-7.62 (m, 3H), 7.62-7.52
(m, 3H), 7.49-7.37 (m, 3H), 5.03-4.91 (m, 1H), 2.16 (d, J=1.1 Hz,
3H), 1.38 (d, J=6.7 Hz, 3H). ES/MS 432.1 (M+H.sup.+).
##STR00137## [0765]
(S)-4-amino-6-((1-(5-chloro-3-(3,5-difluorophenyl)-4-oxo-3,4-dihydroquina-
zolin-2-yl)ethyl)amino)-2-methylpyrimidine-5-carbonitrile (Compound
99).
[0766] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 7.89-7.45 (m,
7H), 7.33 (tt, J=9.3, 2.5 Hz, 1H), 7.16-7.08 (m, 1H), 5.19-5.07 (m,
1H), 2.13 (d, J=1.2 Hz, 3H), 1.41 (d, J=6.4 Hz, 3H). ES/MS 468.1
(M+H.sup.+).
##STR00138## [0767]
(R)-5-chloro-2-(4-(2,6-diamino-5-chloropyrimidin-4-yl)morpholin-3-yl)-3-p-
henylquinazolin-4(3H)-one (Compound 100).
[0768] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 9.47 (brs, 1H),
8.14-7.20 (m, 12H), 4.66 (m, 1H), 4.27-3.08 (m, 6H). ES/MS 484.1
(M+H.sup.+).
##STR00139## [0769]
(S)-2-amino-4-chloro-6-((1-(5-chloro-4-oxo-3-phenyl-3,4-dihydroquinazolin-
-2-yl)ethyl)amino)pyrimidine-5-carbonitrile (Compound 101).
[0770] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.01-7.11 (m,
12H), 4.86 (p, J=6.7 Hz, 1H), 1.36 (d, J=6.6 Hz, 3H). ES/MS 452.1
(M+H.sup.+).
##STR00140## [0771]
(S)-2-amino-4-chloro-6-((1-(3-(3,5-difluorophenyl)-5-fluoro-4-oxo-3,4-dih-
ydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile (Compound
102).
[0772] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.08-7.00 (m,
9H), 6.30-5.09 (brs, 2H), 5.12-4.86 (m, 1H), 1.41 (dd, J=6.4, 1.2
Hz, 3H). ES/MS 472.1 (M+H.sup.+).
##STR00141## [0773]
(S)-2-amino-4-chloro-6-((1-(5-chloro-3-(3,5-difluorophenyl)-4-oxo-3,4-dih-
ydroquinazolin-2-yl)propyl)amino)pyrimidine-5-carbonitrile
(Compound 103).
[0774] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 7.95-7.07 (m,
7H), 5.97-4.93 (brs, 2H), 4.80 (td, J=7.4, 5.3 Hz, 1H), 2.02 (ddd,
J=13.5, 7.5, 5.7 Hz, 1H), 1.82 (dp, J=14.5, 7.3 Hz, 1H), 0.96-0.76
(m, 3H). ES/MS 502.1 (M+H.sup.+).
##STR00142## [0775]
(S)-4-amino-2-chloro-6-((1-(5-chloro-4-oxo-3-phenyl-3,4-dihydroquinazolin-
-2-yl)ethyl)amino)pyrimidine-5-carbonitrile (Compound 104).
[0776] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.36 (d, J=6.7
Hz, 1H), 7.88-7.33 (m, 10H), 4.57-4.42 (m, 1H), 1.40-1.18 (m, 3H).
ES/MS 452.1 (M+H.sup.+)
##STR00143## [0777]
(S)-2-amino-4-chloro-6-((1-(5-chloro-3-(3,5-difluorophenyl)-4-oxo-3,4-dih-
ydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile (Compound
105).
[0778] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 7.99-6.55 (m,
10H), 5.34-4.64 (m, 1H), 1.42 (dd, J=6.5, 1.1 Hz, 3H). ES/MS 488.1
(M+H.sup.+).
##STR00144## [0779]
(S)-4-amino-6-((1-(5-chloro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)eth-
yl)amino)-2-(methylthio)pyrimidine-5-carbonitrile.
[0779] ##STR00145## [0780]
N-((3R,5S)-5-(5-chloro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)-1-(2,6--
diamino-5-cyanopyrimidin-4-yl)pyrrolidin-3-yl)-2,2-difluoroacetamide
(Compound 107).
[0781] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 9.09 (d, J=7.3
Hz, 1H), 7.92-7.66 (m, 4H), 7.65-7.43 (m, 7H), 7.23 (brs, 2H),
6.38-5.94 (m, 1H), 4.76 (s, 1H), 4.66 (d, J=10.9 Hz, 1H), 4.29 (d,
J=9.0 Hz, 1H), 3.90-3.81 (m, 1H), 2.42-2.31 (m, 1H), 1.82 (dt,
J=12.9, 8.4 Hz, 1H). ES/MS 552.2 (M+H.sup.+).
##STR00146## [0782]
N-((3S,5S)-5-(5-chloro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)-1-(2,6--
diamino-5-cyanopyrimidin-4-yl)pyrrolidin-3-yl)-2,2,2-trifluoroacetamide
(Compound 108).
[0783] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 9.39 (d, J=6.9
Hz, 1H), 7.88 (dt, J=8.1, 1.7 Hz, 1H), 7.77-7.37 (m, 8H), 7.37-7.15
(m, 3H), 4.69 (t, J=7.0 Hz, 1H), 4.40 (q, J=6.7 Hz, 1H), 4.25 (dd,
J=10.6, 6.9 Hz, 1H), 4.04 (dd, J=10.6, 5.8 Hz, 1H), 2.27-2.04 (m,
3H). ES/MS 570.1 (M+H.sup.+).
##STR00147## [0784]
N-((3R,5S)-5-(5-chloro-3-(3,5-difluorophenyl)-4-oxo-3,4-dihydroquinazolin-
-2-yl)-1-(2,6-diamino-5-cyanopyrimidin-4-yl)pyrrolidin-3-yl)-2,2-difluoroa-
cetamide (Compound 109).
[0785] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 9.12 (d, J=7.3
Hz, 1H), 8.02-7.66 (m, 4H), 7.63-7.44 (m, 5H), 7.26 (brs, 2H), 6.18
(td, J=53.6, 1.2 Hz, 1H), 4.88-4.51 (m, 2H), 4.29 (t, J=8.6 Hz,
1H), 3.86 (dd, J=10.4, 5.9 Hz, 1H), 2.39 (dt, J=11.6, 5.2 Hz, 1H),
1.92 (dt, J=12.8, 8.2 Hz, 1H). ES/MS 588.1 (M+H.sup.+).
##STR00148## [0786] N-((3R,5
S)-5-(5-chloro-3-(3-(difluoromethyl)-5-fluorophenyl)-4-oxo-3,4-dihydroqui-
nazolin-2-yl)-1-(2,6-diamino-5-cyanopyrimidin-4-yl)pyrrolidin-3-yl)-2,2-di-
fluoroacetamide (Compound 110).
[0787] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 9.10 (t, J=6.8
Hz, 1H), 8.08 (d, J=14.9 Hz, 1H), 7.86-7.62 (m, 4H), 7.57 (m, 4H),
7.12 (td, J=55.4, 8.6 Hz, 3H), 6.17 (td, J=53.6, 5.8 Hz, 1H), 4.68
(d, J=13.6 Hz, 2H), 4.39-4.18 (m, 1H), 3.83 (q, J=8.0, 7.5 Hz, 1H),
2.40 (p, J=6.6, 6.0 Hz, 1H), 1.88 (ddt, J=28.3, 12.5, 8.3 Hz, 1H).
ES/MS 620.1 (M+H.sup.+).
##STR00149## [0788]
N-((3R,5S)-1-(2,6-diamino-5-cyanopyrimidin-4-yl)-5-(3-(3,5-difluorophenyl-
)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)pyrrolidin-3-yl)-2,2-difluoroa-
cetamide (Compound 111).
[0789] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 9.10 (d, J=7.3
Hz, 1H), 7.92-7.69 (m, 2H), 7.64-7.39 (m, 4H), 7.31 (dd, J=10.9,
8.2 Hz, 1H), 7.09 (brs, 4H), 6.41-5.91 (m, 1H), 4.70 (dd, J=22.0,
8.5 Hz, 2H), 4.28 (t, J=8.8 Hz, 1H), 3.84 (dd, J=10.3, 5.8 Hz, 1H),
2.38 (dt, J=11.5, 5.4 Hz, 1H), 1.92 (dt, J=12.7, 8.3 Hz, 1H). ES/MS
572.2 (M+H.sup.+).
##STR00150## [0790]
N-((3R,5S)-1-(2,6-diamino-5-cyanopyrimidin-4-yl)-5-(3-(3-(difluoromethyl)-
-5-fluorophenyl)-5-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)pyrrolidin-3-yl-
)-2,2-difluoroacetamide (Compound 112).
[0791] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 9.10 (t, J=6.7
Hz, 1H), 8.07 (d, J=14.5 Hz, 1H), 7.88-7.62 (m, 3H), 7.62-7.38 (m,
3H), 7.38-7.21 (m, 1H), 7.05 (m, 4H), 6.36-5.94 (m, 1H), 4.67 (m,
2H), 4.27 (m, 1H), 3.91-3.70 (m, 1H), 2.39 (m, 1H), 1.95-1.71 (m,
1H). ES/MS 604.2 (M+H.sup.+)
##STR00151## [0792] N-((3R,5
S)-5-(5-chloro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)-1-(2,6-diamino--
5-cyanopyrimidin-4-yl)pyrrolidin-3-yl)-2-cyclopropylacetamide
(Compound 114).
[0793] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 7.96 (d, J=7.2
Hz, 1H), 7.86 (d, J=7.5 Hz, 1H), 7.72 (t, J=8.0 Hz, 1H), 7.64-7.46
(m, 8H), 6.69 (m, 1H), 4.58 (m, 1H), 4.24 (m, 1H), 3.68 (s, 1H),
2.70-2.62 (m, 1H), 2.33 (d, J=3.5 Hz, 1H), 2.26 (m, 1H), 1.89 (dd,
J=10.1, 7.0 Hz, 2H), 1.73 (m, 1H), 1.24 (s, 1H), 1.14 (d, J=0.7 Hz,
1H), 0.86 (s, 1H), 0.42-0.30 (m, 2H). ES/MS 556.1 (M+H.sup.+).
Example 5. Preparation of a Compound of Formula (I)
[0794] A. Preparation of a Compound of Formula (I) in which n is 2,
R.sup.1a is F, R.sup.1b.dbd.CN, m is 1, R.sup.2.dbd.F, R.sup.3 is
cyclopropyl, R.sup.4 is cyano, R.sup.5 is hydrogen, R.sup.6 is
NH.sub.2, and R.sup.7 is NH.sub.2
##STR00152##
[0795] To a solution of
(S)-2,4-diamino-6-((cyclopropyl(6-fluoro-3-(3-fluorophenyl)-8-iodo-4-oxo--
3,4-dihydroquinazolin-2-yl)methyl)amino)pyrimidine-5-carbonitrile
(720 mg, 1.2 mmol) in NMP (4 mL) was added cuprous cyanide (220 mg,
2.4 mmol) and tetrakis(triphenylphosphine)Pd(0) (140 mg, 0.12
mmol). The mixture was irradiated in microwave reactor at
150.degree. C. for one hour. Purification by flash chromatography
(40 g flash silica, 30% EtOAc/Hexanes to 20% MeOH/EtOAc), followed
by HPLC eluting with 5%-95% water/acetonitrile (0.1% v/v
trifluoroacetic acid) provided
(S)-2-(cyclopropyl((2,6-diamino-5-cyanopyrimidin-4-yl)amino)methyl)-6-flu-
oro-3-(3-fluorophenyl)-4-oxo-3,4-dihydroquinazoline-8-carbonitrile
(Compound 7a). .sup.1H NMR (400 MHz, DMSO) .delta. 8.56 (dd, J=3.2,
8.4 Hz, 1H), 8.20 (dd, J=3.2, 8.0 Hz, 1H), 7.80 (bs, 4H), 7.57-7.02
(m, 5H), 4.70 (m, 1H), 1.59 (m, 1H), 0.54 (m, 3H), 0.22 (m, 1H).
ES/MS 486.2 (M+H.sup.+).
[0796] B. Following the procedure described in Example 5 and
Reaction Scheme I, below compound of formula (I) were prepared:
[0797]
(S)-2-(cyclopropyl((2,6-diamino-5-cyanopyrimidin-4-yl)amino)methyl)-6-flu-
oro-4-oxo-3-phenyl-3,4-dihydroquinazoline-8-carbonitrile (Compound
8a):
[0798] .sup.1H NMR (400 MHz, DMSO) .delta. 8.55 (dd, J=3.2, 8.4 Hz,
1H), 8.19 (dd, J=2.8, 8.0 Hz, 1H), 7.73 (bs, 4H), 7.50 (m, 2H),
7.32 (m, 2H), 7.23 (m, 1H), 4.71 (m, 1H), 1.57 (m, 1H), 0.52 (m,
3H), 0.19 (m, 1H). ES/MS 468.1 (M+H.sup.+)
##STR00153## [0799]
(S)-2-(1-(2,6-diamino-5-cyanopyrimidin-4-yl)pyrrolidin-2-yl)-4-oxo-3-phen-
yl-3,4-dihydroquinazoline-8-carbonitrile (Compound 89).
[0800] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.38 (dd, J=8.0,
1.5 Hz, 1H), 8.34 (dd, J=7.6, 1.5 Hz, 1H), 7.89 (m, 1H), 7.63 (m,
2H), 7.60 (bs, 2H), 7.57 (m, 3H), 7.07 (bs, 2H), 4.75 (m, 1H), 4.06
(m, 1H), 3.99 (m, 1H), 2.19 (m, 1H), 2.10 (m, 1H), 1.97 (m, 1H),
1.76 (m, 1H). ES/MS 450.1 (M+H.sup.+);
##STR00154## [0801]
(S)-2-(1-(2,6-diamino-5-cyanopyrimidin-4-yl)pyrrolidin-2-yl)-3-(3-(difluo-
romethyl)phenyl)-4-oxo-3,4-dihydroquinazoline-8-carbonitrile
(Compound 90).
[0802] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.42 (ddd,
J=8.0, 3.5, 1.5 Hz, 1H), 8.39 (dt, J=7.6, 1.3 Hz, 1H), 8.22 (d,
J=1.7 Hz, 0.5H), 8.12 (m, 0.5H), 7.89 (d, J=1.6 Hz, 0.5H),
7.85-7.78 (m, 2.5H), 7.70 (t, J=7.8 Hz, 1H), 7.60 (bs, 2H), 7.18
(td, J=55.7, 14.4 Hz, 1H), 7.09 (bs, 2H), 4.70 (m, 1H), 4.11 (m,
1H), 4.07-3.99 (m, 1H), 2.35-2.09 (m, 2H), 2.02 (m, 1H), 1.80 (m,
1H). ES/MS 500.1 (M+H.sup.+);
Example 6. Preparation of a Compound of Formula (I)
[0803] A. Preparation of a Compound of Formula (I) in which n is 1,
R.sup.1 is 3-oxopropyl, m is 0, R.sup.3 is methyl, R.sup.4 is
cyano, R.sup.5 is hydrogen, R.sup.6 is NH.sub.2, and R.sup.7 is
NH.sub.2
##STR00155##
[0804] To a solution of
(S)-2,4-diamino-6-((1-(5-bromo-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)-
ethyl)amino)pyrimidine-5-carbonitrile (50 mg, 0.105 mmol) in DMF
(0.5 mL) was added
chloro(2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl)[2-
-(2'-amino-1,1'-biphenyl)]palladium(II) (8 mg, 0.011 mmol) and
dicyclohexylmethylamine (67 uL, 0.315 mmol). The mixture was
degassed under Ar. Allyl alcohol (9 uL, 0.126 mmol) was added, and
the mixture heated to 120.degree. C. in microwave for 1 hour. The
reaction was poured into EtOAc and washed with H.sub.2O (2.times.).
Purified by flash chromatography (4 g silica, 0-100% EtOAc/hexane)
to provide
(S)-2,4-diamino-6-((1-(4-oxo-5-(3-oxopropyl)-3-phenyl-3,4-dihydroquinazol-
in-2-yl)ethyl)amino)pyrimidine-5-carbonitrile.
Example 7. Preparation of a Compound of Formula (I)
[0805] A. Preparation of a Compound of Formula (I) in which n is 1,
R.sup.1 is 3-morpholinopropyl, m is 0, R.sup.3 is methyl, R.sup.4
is cyano, R.sup.5 is hydrogen, R.sup.6 is NH.sub.2, and R.sup.7 is
NH.sub.2
##STR00156##
[0806] A solution of
(S)-2,4-diamino-6-((1-(4-oxo-5-(3-oxopropyl)-3-phenyl-3,4-dihydroquinazol-
in-2-yl)ethyl)amino)pyrimidine-5-carbonitrile (99 mg, 0.24 mmol) in
DCM (2 mL) was treated with morpholine and sodium
triacetoxyborohydride. The reaction was filtered and the filtrate
purified by prep LC to give
(S)-2,4-diamino-6-((1-(5-(3-morpholinopropyl)-4-oxo-3-phenyl-3,4-dihydroq-
uinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile. (Compound
61). .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 9.47 (s, 1H), 7.79
(dd, J=8.1, 7.4 Hz, 1H), 7.59 (dd, J=8.2, 1.2 Hz, 4H), 7.58-7.40
(m, 5H), 7.38 (dd, J=7.5, 1.2 Hz, 1H), 6.99 (s, 4H), 4.92-4.80 (m,
1H), 3.91 (d, J=12.6 Hz, 2H), 3.54 (t, J=12.7 Hz, 2H), 3.38 (d,
J=12.3 Hz, 2H), 3.26-3.08 (m, 4H), 3.07-2.93 (m, 2H), 1.96-1.84 (m,
2H), 1.32 (d, J=6.6 Hz, 3H). ES/MS 526.3 (M+H.sup.+).
[0807] B. Following the procedure described in Example 7 and
Reaction Scheme I, below compound of formula (I) were prepared:
##STR00157## [0808]
(S)-4-((1-(5-(3-(2-oxa-6-azaspiro[3.3]heptan-6-yl)propyl)-4-oxo-3-phenyl--
3,4-dihydroquinazolin-2-yl)ethyl)amino)-2,6-diaminopyrimidine-5-carbonitri-
le (Compound 62).
[0809] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 7.71-7.64 (m,
1H), 7.58-7.40 (m, 6H), 7.24 (dd, J=7.5, 1.3 Hz, 1H), 6.76 (d,
J=7.2 Hz, 1H), 6.52 (s, 2H), 6.23 (s, 2H), 4.76-4.65 (m, 1H), 4.51
(s, 4H), 3.18 (br s, 4H), 3.10-3.03 (m, 2H), 2.54-2.47 (m, 2H),
1.52-1.38 (m, 2H), 1.24 (d, J=6.7 Hz, 3H). ES/MS 538.2
(M+H.sup.+).
##STR00158## [0810]
(S)-4-((1-(5-(3-(2-oxa-6-azaspiro[3.4]octan-6-yl)propyl)-4-oxo-3-phenyl-3-
,4-dihydroquinazolin-2-yl)ethyl)amino)-2,6-diaminopyrimidine-5-carbonitril-
e (Compound 63).
[0811] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 7.68 (t, J=7.8
Hz, 1H), 7.56-7.40 (m, 6H), 7.31-7.24 (m, 1H), 6.76 (d, J=7.1 Hz,
1H), 6.52 (s, 2H), 6.22 (s, 2H), 4.75-4.65 (m, 1H), 4.39 (s, 4H),
3.11 (t, J=7.6 Hz, 2H), 2.63 (s, 2H), 2.41-2.24 (m, 4H), 2.01-1.89
(m, 2H), 1.71-1.55 (m, 2H), 1.24 (d, J=6.6 Hz, 3H). ES/MS 552.2
(M+H.sup.+).
##STR00159## [0812]
(S)-4-((1-(5-(3-(2-oxa-7-azaspiro[3.5]nonan-7-yl)propyl)-4-oxo-3-phenyl-3-
,4-dihydroquinazolin-2-yl)ethyl)amino)-2,6-diaminopyrimidine-5-carbonitril-
e (Compound 64).
[0813] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 9.63 (s, 1H),
7.75-7.68 (m, 1H), 7.64-7.42 (m, 6H), 7.40-7.15 (m, 2H), 7.15-6.60
(br m, 3H), 4.61-4.50 (m, 1H), 3.87 (dd, J=10.6, 6.4 Hz, 2H),
3.78-3.69 (m, 2H), 3.45 (t, J=5.2 Hz, 2H), 3.37 (t, J=5.3 Hz, 2H),
3.21-3.02 (m, 4H), 1.66 (dt, J=11.1, 5.8 Hz, 6H), 1.19 (d, J=6.8
Hz, 3H). ES/MS 566.3 (M+H.sup.+).
Example 8. Preparation of a Compound of Formula (I)
[0814] A. Preparation of a Compound of Formula (I) in which n is 1,
R.sup.1 is vinylsulfonyl, m is 1, R.sup.2 is F, R.sup.3 is methyl,
R.sup.4 is cyano, R.sup.5 is hydrogen, R.sup.6 is NH.sub.2, and
R.sup.7 is NH.sub.2
##STR00160##
[0815] To a solution of
(S)-2,4-diamino-6-((1-(3-(3-fluorophenyl)-5-((2-hydroxyethyl)sulfonyl)-4--
oxo-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile
(127 mg, 0.24 mmol) in dichloromethane (1 mL) was added
p-toluenesulfonyl chloride (55 mg, 0.29 mmol),
4-dimethylaminopyridine (3 mg, 0.024 mmol) and triethylamine (0.051
mL, 0.36 mmol). The resulting mixture was stirred at room
temperature for 2 days. The reaction was poured into saturated
NaHCO3 and extracted with EtOAc (2.times.). The organic phase was
dried over MgSO4, concentrated, and purified by column
chromatography on silica eluting with EtOAc in hexanes (10-100%) to
afford
(S)-2,4-diamino-6-((1-(3-(3-fluorophenyl)-4-oxo-5-(vinylsulfonyl)-3,4-dih-
ydroquinnazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile. ES/MS
m/z=507.1 (M+H.sup.+).
Example 9. Preparation of a Compound of Formula (I)
[0816] A. Preparation of a Compound of Formula (I) in which n is 1,
R.sup.1 is 2-(pyrrolidin-1-yl)ethyl)sulfonyl, m is 1, R.sup.2 is F,
R.sup.3 is methyl, R.sup.4 is cyano, R.sup.5 is hydrogen, R.sup.6
is NH.sub.2, and
##STR00161##
[0817] To a solution of
(S)-2,4-diamino-6-((1-(3-(3-fluorophenyl)-4-oxo-5-(vinylsulfonyl)-3,4-dih-
ydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile (33 mg,
0.065 mmol) in THF (1 mL) was added pyrrolidine (0.021 mL, 0.26
mmol). The resulting mixture was stirred at room temperature for 1
h. The reaction was concentrated followed by lyophilization in
acetonitrile-water to afford
(S)-2,4-diamino-6-((1-(3-(3-fluorophenyl)-4-oxo-5-((2-(pyrrolidin--
1-yl)ethyl)sulfonyl)-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-c-
arbonitrile (Compound 82): .sup.1H NMR (400 MHz, DMSO) .delta.
8.34-8.27 (m, 1H), 8.15-8.05 (m, 2H), 7.65-7.55 (m, 2H), 7.47-7.29
(m, 2H), 6.99-6.90 (m, 1H), 6.59 (br s, 2H), 6.27 (br s, 2H),
4.97-4.88 (m, 1H), 4.07-3.90 (m, 2H), 2.81-2.70 (m, 2H), 2.39-2.20
(m, 4H), 1.55-1.48 (m, 4H), 1.41 (d, J=6.8 Hz, 3H). ES/MS 578.2
(M+H.sup.+).
Example 10. Preparation of a Compound of Formula (I)
[0818] A. Preparation of a Compound of Formula (I) in which n is 1,
R.sup.1 is 1,2,3,6-tetrahydropyridin-4-yl, m is 0, R.sup.3 is
methyl, R.sup.4 is cyano, R.sup.5 is hydrogen, R.sup.6 is NH.sub.2,
and R.sup.7 is NH.sub.2
##STR00162##
[0819] Tert-butyl
4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-
-carboxylate (0.29 g, 0.93 mmol),
(S)-2,4-diamino-6-((1-(5-bromo-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)-
ethyl)amino)pyrimidine-5-carbonitrile (0.22 g, 0.47 mmol),
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II)
dichloromethane complex (34 mg, 10 mol %) were taken up in
1,4-dioxanes (5 mL). A solution of saturated aqueous sodium
hydrogen carbonate (2.5 mL) was added. The mixture was heated with
magnetic stirring for 90 minutes at 120.degree. C. before being
allowed to cool to room temperature. The mixture, diluted with
dichloromethane and water, was filtered through a pad of Celite
diatomaceous earth. The aqueous phase was extracted twice with
dichloromethane. The combined organics were dried over anhydrous
magnesium sulfate, filtered, and concentrated under reduced
pressure to provide (S)-tert-butyl
4-(2-(1-((2,6-diamino-5-cyanopyrimidin-4-yl)amino)ethyl)-4-oxo-3-phenyl-3-
,4-dihydroquinazolin-5-yl)-5,6-dihydropyridine-1(2H)-carboxylate,
which was carried forward without further purification. ES/MS 580.3
(M+H.sup.+). A solution of crude (S)-tert-butyl
4-(2-(1-((2,6-diamino-5-cyanopyrimidin-4-yl)amino)ethyl)-4-oxo-3-phenyl-3-
,4-dihydroquinazolin-5-yl)-5,6-dihydropyridine-1(2H)-carboxylate
(assumed 0.47 mmol) in dichloromethane (5 mL) was treated with
trifluoroacetic acid (0.89 mL, 12 mmol). After stirring overnight,
the mixture was concentrated to dryness under reduced pressure. The
residue was purified on a Gilson HPLC system, eluting 5%
acetonitrile/95% water (0.1% TFA modifier in both solvents) to 70%
acetonitrile over 30 minutes. Fractions were concentrated to
furnish
(S)-2,4-diamino-6-((1-(4-oxo-3-phenyl-5-(1,2,3,6-tetrahydropyridin-4-yl)--
3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile,
trifluoroacetic acid salt (Compound 93). .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 8.90 (s, 2H), 7.90 (dd, J=8.2, 7.3 Hz, 1H),
7.75 (dd, J=8.3, 1.2 Hz, 1H), 7.65 (bs, 2H), 7.59-7.49 (m, 5H),
7.47 (m, 1H), 7.23 (dd, J=7.4, 1.3 Hz, 1H), 7.19 (bs, 2H), 5.49 (s,
1H), 4.92 (m, 1H), 3.72 (m, 2H), 3.27 (m, 2H), 2.47 (m, 2H), 1.39
(d, J=6.6 Hz, 3H). ES/MS 480.2 (M+H.sup.+).
Example 11. Preparation of a Compound of Formula (I)
[0820] A. Preparation of a Compound of Formula (I) in which n is 1,
R.sup.1 is Cl, m is 0, R.sup.3 is methyl, R.sup.4 is cyano, R.sup.5
is hydrogen, R.sup.6 is NH.sub.2, and R.sup.7 is F
##STR00163##
[0821] To
(S)-4-amino-6-((1-(5-chloro-4-oxo-3-phenyl-3,4-dihydroquinazolin-
-2-yl)ethyl)amino)-2-(methylthio)pyrimidine-5-carbonitrile (0.98 g)
and sodium bicarbonate (1.6 g, 1.9 mmol) in THF (10 mL) was added
potassium peroxymonosulfate (0.91 g, 1 mmol) in water (10 mL)
dropwise. When the reaction is complete, water and methylene
chloride are added. The layers are separated and the solvent was
removed in vacuo to give
4-amino-6-(((S)-1-(5-chloro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)eth-
yl)amino)-2-(methylsulfinyl)pyrimidine-5-carbonitrile. To
4-amino-6-(((S)-1-(5-chloro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)eth-
yl)amino)-2-(methylsulfinyl)pyrimidine-5-carbonitrile in THF (5 mL)
was added tetrabutylammonium fluoride in THF (1 M THF, 46 mg, 0.19
mmol). After stirring for 24 h, a few drops of water were added,
the reaction was filtered, the solvent was removed in vacuo, and
the residue was purified on a Gilson HPLC system, eluting with
acetonitrile/water (0.1% TFA modifier). Fractions were concentrated
to furnish
(S)-4-amino-6-((1-(5-chloro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)eth-
yl)amino)-2-fluoropyrimidine-5-carbonitrile Compound 106).
Example 12. Preparation of a Compound of Formula (I)
[0822] A. Preparation of a Compound of Formula (I) in which n is 1,
R.sup.1 is Cl, m is 0, R.sup.3 and R.sup.5 together are
4-(2-aminoacetamido)pyrrolidine-1-yl attached at the 2-position of
the pyrrolidine to the quinazolinone, R.sup.4 is cyano, R.sup.6 is
NH.sub.2, and R.sup.7 is NH.sub.2
##STR00164##
[0823] Solid K.sub.2CO.sub.3 (39 mg, 0.28 mmol) was added to
stirring solution of
N-((3R,5S)-5-(5-chloro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)-1-(2,6--
diamino-5-cyanopyrimidin-4-yl)pyrrolidin-3-yl)-2,2,2-trifluoroacetamide
(160 mg, 0.28 mmol) in MeOH/Water (2:1, 15 mL) at rt. After
stirring overnight the resulting mixture was concentrated then
purified on a silica column to give
2,4-diamino-6-((2S,4R)-4-amino-2-(5-chloro-4-oxo-3-phenyl-3,4-dihydroquin-
azolin-2-yl)pyrrolidin-1-yl)pyrimidine-5-carbonitrile. HATU (60 mg,
0.16 mmol), DMAP (1 mg, 0.01 mmol), and DIEA (0.028 mL, 0.16 mmol)
were added to a stirring solution of N-Boc glycine (18 mg, 0.16
mmol) in NMP (2 mL) at rt. After 5 min
2,4-diamino-6-((2S,4R)-4-amino-2-(5-chloro-4-oxo-3-phenyl-3,4-dihydroquin-
azolin-2-yl)pyrrolidin-1-yl)pyrimidine-5-carbonitrile (50 mg, 0.11
mmol) was added and stirred for an additional 15 min. The resulting
mixture was loaded directly on to silica column and purified to
give tert-butyl
(2-(((3R,5S)-5-(5-chloro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)-1-(2,-
6-diamino-5-cyanopyrimidin-4-yl)pyrrolidin-3-yl)amino)-2-oxoethyl)carbamat-
e. TFA (2 mL) was added to a stirring solution of tert-butyl
(2-(((3R,5S)-5-(5-chloro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)-1-(2,-
6-diamino-5-cyanopyrimidin-4-yl)pyrrolidin-3-yl)amino)-2-oxoethyl)carbamat-
e (67 mg, 0.11 mmol) in DCM (2 mL) at rt. After 30 min the reaction
mixture was concentrated and purified by HPLC to give
2-amino-N-((3R,5S)-5-(5-chloro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)-
-1-(2,6-diamino-5-cyanopyrimidin-4-yl)pyrrolidin-3-yl)acetamide
(Compound 115). .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.53
(d, J=7.2 Hz, 1H), 7.86 (d, J=24.0 Hz, 4H), 7.68 (t, J=8.0 Hz, 1H),
7.63-7.43 (m, 5H), 6.74 (m, 1H), 6.42 (m, 1H), 4.85-4.47 (m, 2H),
4.11-3.28 (m, 5H), 2.67-2.60 (m, 1H), 2.44-2.24 (m, 1H), 1.67 (s,
1H). ES/MS 531.1 (M+H.sup.+).
[0824] B. Following the procedure described in Example 12 and
Reaction Scheme I, below compound of formula (I) was prepared:
##STR00165## [0825]
2-amino-N-((3R,5S)-5-(5-chloro-3-(3,5-difluorophenyl)-4-oxo-3,4-dihydroqu-
inazolin-2-yl)-1-(2,6-diamino-5-cyanopyrimidin-4-yl)pyrrolidin-3-yl)acetam-
ide (Compound 116).
[0826] 1H NMR (400 MHz, DMSO-d6) .delta. 8.56 (d, J=7.3 Hz, 1H),
7.91 (s, 3H), 7.77 (d, J=9.0 Hz, 1H), 7.70 (t, J=8.0 Hz, 1H),
7.56-7.40 (m, 4H), 6.89-6.70 (m, 2H), 4.77-4.54 (m, 2H), 4.28-4.12
(m, 1H), 3.80-3.65 (m, 1H), 3.52-3.39 (m, 2H), 2.43-2.23 (m, 2H),
1.84-1.69 (m, 1H). ES/MS 567.1 (M+H.sup.+).
Biological Examples
[0827] Activity testing was conducted in the Examples below using
methods described herein and those well known in the art. Enzymatic
activity of PI3K isoforms were measured to compare the PI3K isoform
activity and selectivity of the compounds tested, including
selectivity to PI3K.delta.. A cellular assay measuring basophil
activation was used to assess the potency of the compounds
tested.
[0828] Enzymatic activity of the class I PI3K isoforms in the
presence of certain compounds of the present application and
compounds X and Y was measured using a time-resolved fluorescence
resonance energy transfer (TR-FRET) assay. Compounds X and Y have
the following structures:
##STR00166##
[0829] TR-FRET monitored the formation of 3,4,5-inositol
triphosphate molecule that competed with fluorescently labeled PIP3
for binding to the GRP-1 pleckstrin homology domain protein. An
increase in phosphatidylinositide 3-phosphate product resulted in a
decrease in TR-FRET signal as the labeled fluorophore was displaced
from the GRP-1 protein binding site. Class I PI3K isoforms were
expressed and purified as heterodimeric recombinant proteins. All
assay reagents and buffers for the TR-FRET assay were purchased
from Millipore. PI3K isoforms were assayed under initial rate
conditions in the presence of 25 mM Hepes (pH 7.4), and 2.times.Km
ATP (75-500 .mu.M), 2 .mu.M PIP2, 5% glycerol, 5 mM MgCl.sub.2, 50
mM NaCl, 0.05% (v/v) Chaps, 1 mM dithiothreitol, and 1% (v/v) DMSO
at the following concentrations for each isoform: PI3K.alpha.,
PI3K.beta., and PI3K.delta. between 25 and 50 .mu.M, and
PI3K.gamma. at 2 nM. The compounds of Table 1, Compound X
((S)-2-(1-((9H-purin-6-yl)amino)ethyl)-5-chloro-3-phenylquinazolin-4(3H)--
one) and Compound Y
((S)-4-amino-6-((1-(5-chloro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)et-
hyl)amino)pyrimidine-5-carbonitrile), were added to the assay
solution and incubated for 30 minutes at 25.degree. C.
Additionally, compounds 19 to 116 were added to the assay solution
and incubated for 30 minutes at 25.degree. C. The reactions were
terminated with a final concentration of 10 mM EDTA, 10 nM
labeled-PIP3, and 35 nM Europium labeled GRP-1 detector protein
before reading TR-FRET on an Envision plate reader (Ex: 340 nm; Em:
615/665 nm; 100 s delay and 500 s read window).
[0830] The results were normalized based on positive (1 .mu.M
wortmanin) and negative (DMSO) controls, and the IC.sub.50 values
for PI3K .alpha., .beta., .delta., and .gamma. were calculated from
the fit of the dose-response curves to a four-parameter equation.
These assays generally produced results within 3-fold of the
reported mean.
[0831] Table 2 summarizes the IC.sub.50 (nM) values for PI3K
isoform .delta. (IC.sub.50 for PI3K .beta., .alpha., and .gamma.
are not shown). Table 3 summarizes the IC.sub.50 (nM) values for
PI3K isoform .delta. (IC.sub.50 for PI3K .beta., .alpha., and
.gamma. are not shown). The results indicate that certain compounds
of present application inhibit PI3K.delta..
TABLE-US-00002 TABLE 2 The IC.sub.50 values (nM) for PI3K isoform
.delta.. Compound IC.sub.50 (nM) 1a 5 2a 10 3a 0.3 4a 49 5a 5 6a 41
7a 6 8a 2 9a 61 10a 2 11a 14 12a 1 13a 1 14a 19 15a 6 16a 4 17a-1 6
17a-2 8 18a 6 X 1 Y 0.4
TABLE-US-00003 TABLE 3 The IC.sub.50 values (nM) for PI3K isoform
.delta.. Compound IC.sub.50 (nM) 19 9 20 21 21 30 22 22 23 10 24 10
25 36 26 21 27 57 28 2 29 220 30 6 31 4 32 85 33 24 34 46 35 7 36 2
37 0.5 38 0.5 39 2 40 4 41 25 42 20 43 9 44 15 45 0.7 46 0.4 47 2
48 0.5 49 1.4 50 1.3 51 3 52 0.7 53 0.7 54 0.5 55 0.4 56 3 57 1.4
58 3 59 2 60 6 61 0.6 62 0.8 63 0.8 64 30 65 15 66 0.7 67 110 68 30
69 1 70 3 71 2 72 4 73 4 74 3 75 1.2 76 1.3 77 2 78 9 79 51 80 61
81 6 82 2 83 2 84 4 85 10 86 12 87 23 88 17 89 2 90 5 91 17 92 7 93
17 94 2 95 160 96 0.1 97 0.6 98 10 99 14 100 8400 101 1 102 30 103
9 104 4 105 2 106 0.8 107 0.4 108 2 109 0.7 110 2 111 9 112 17 113
7 114 0.9 115 64 116 7
[0832] All of the U.S. patents, U.S. patent application
publications, U.S. patent applications, foreign patents, foreign
patent applications and non-patent publications referred to in this
specification are incorporated herein by reference, in their
entirety to the extent not inconsistent with the present
description. From the foregoing it will be appreciated that,
although specific embodiments of the invention have been described
herein for purposes of illustration, various modifications may be
made without deviating from the spirit and scope of the present
application.
* * * * *