U.S. patent application number 12/575560 was filed with the patent office on 2010-07-15 for thienopyrimidines useful as aurora kinase inhibitors.
This patent application is currently assigned to Sunesis Pharmaceuticals, Inc.. Invention is credited to Subramanian Baskaran, Willard Lew, Johan D. Oslob, Joshua C. Yoburn, Min Zhong.
Application Number | 20100179123 12/575560 |
Document ID | / |
Family ID | 35527256 |
Filed Date | 2010-07-15 |
United States Patent
Application |
20100179123 |
Kind Code |
A1 |
Lew; Willard ; et
al. |
July 15, 2010 |
THIENOPYRIMIDINES USEFUL AS AURORA KINASE INHIBITORS
Abstract
The present invention provides compounds having the formula:
##STR00001## wherein R.sup.1, R.sup.2, X.sup.1, X.sup.2, L.sup.1,
L.sup.2, Y and Z are as defined in classes and subclasses herein,
and pharmaceutical compositions thereof, as described generally and
in subclasses herein, which compounds are useful as inhibitors of
protein kinase (e.g., Aurora), and thus are useful, for example,
for the treatment of Aurora mediated diseases.
Inventors: |
Lew; Willard; (San Mateo,
CA) ; Baskaran; Subramanian; (Foster City, CA)
; Oslob; Johan D.; (Sunnyvale, CA) ; Yoburn;
Joshua C.; (San Francisco, CA) ; Zhong; Min;
(Foster City, CA) |
Correspondence
Address: |
CHOATE, HALL & STEWART LLP
TWO INTERNATIONAL PLACE
BOSTON
MA
02110
US
|
Assignee: |
Sunesis Pharmaceuticals,
Inc.
South San Francisco
CA
|
Family ID: |
35527256 |
Appl. No.: |
12/575560 |
Filed: |
October 8, 2009 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11182215 |
Jul 15, 2005 |
7601725 |
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12575560 |
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60632568 |
Dec 1, 2004 |
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60588718 |
Jul 16, 2004 |
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Current U.S.
Class: |
514/210.21 ;
435/375; 514/234.2; 514/252.16; 514/260.1; 544/117; 544/278 |
Current CPC
Class: |
A61P 43/00 20180101;
C07D 495/04 20130101; A61P 31/12 20180101; A61P 29/00 20180101;
A61P 37/02 20180101; A61P 25/28 20180101; A61P 19/08 20180101; A61P
35/00 20180101; A61P 9/00 20180101; A61P 37/04 20180101; A61P 1/16
20180101; A61P 7/00 20180101; A61P 3/10 20180101; A61P 37/06
20180101 |
Class at
Publication: |
514/210.21 ;
544/278; 514/260.1; 514/252.16; 544/117; 514/234.2; 435/375 |
International
Class: |
A61K 31/519 20060101
A61K031/519; C07D 495/04 20060101 C07D495/04; A61K 31/5377 20060101
A61K031/5377; A61P 3/10 20060101 A61P003/10; A61P 37/04 20060101
A61P037/04; A61P 31/12 20060101 A61P031/12; A61P 7/00 20060101
A61P007/00; A61P 1/16 20060101 A61P001/16; A61P 37/06 20060101
A61P037/06; A61P 29/00 20060101 A61P029/00; C12N 5/00 20060101
C12N005/00 |
Claims
1-46. (canceled)
47. A compound having the structure: ##STR00714## or
pharmaceutically acceptable derivative thereof; wherein one of is a
double bond, as valency permits; one of X.sup.1 and X.sup.2 is S,
the other is --C(R.sup.X1)--; wherein R.sup.X1 is hydrogen,
halogen, cyano, nitro, or an aliphatic, heteroaliphatic, alicyclic,
heteroalicyclic, aromatic or heteroaromatic moiety; W.sup.1 is O,
S, NR.sup.W1 or --C(.dbd.O)NR.sup.W1 where R.sup.W1 is hydrogen,
lower alkyl, C.sub.3-6cycloalkyl, lower heteroalkyl, heterocyclyl,
aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl or acyl; or
R.sup.W1 together with a carbon atom present on Alk.sub.1 forms an
optionally substituted 5- to 6-membered heterocyclic ring;
Alk.sub.1 is a substituted or unsubstituted C.sub.1-6alkylene or
C.sub.2-6alkenylene chain wherein up to two non-adjacent methylene
units are independently optionally replaced by --C(.dbd.O)--,
--CO.sub.2--, --C(.dbd.O)C(.dbd.O)--, --C(.dbd.O)NR.sup.L1A--,
--OC(.dbd.O)--, --OC(.dbd.O)NR.sup.L1A--, --NR.sup.L1ANR.sup.L1B--,
--NR.sup.L1ANR.sup.L1BC(.dbd.O)--, --NR.sup.L1AC(.dbd.)--,
--NR.sup.L1ACO.sub.2--, --NR.sup.L1AC(.dbd.)NR.sup.L1B--,
--S(.dbd.O)--, --SO.sub.2--, --NR.sup.L1ASO.sub.2--,
--SO.sub.2NR.sup.L1A--, --NR.sup.L1ASO.sub.2NR.sup.L1B--, --O--,
--S--, or --NR.sup.L1A--; wherein each occurrence of R.sup.L1A and
R.sup.L1B is independently hydrogen, lower alkyl, lower
heteroalkyl, heterocyclyl, aryl, heteroaryl or acyl; L.sup.2 is
--NR.sup.W2--, --N(R.sup.W2)C(.dbd.O)G.sub.2-,
--N(R.sup.W2)C(.dbd.O)N(R.sup.W2)CR.sup.W3R.sup.W4-- or
--CR.sup.W3R.sup.W4C(.dbd.O)N(R.sup.W2)--; wherein G.sub.2 is
absent, O or NR.sup.G2; and R.sup.W2, R.sup.W3, R.sup.W4 and
R.sup.G2 are independently hydrogen, lower alkyl, lower
heteroalkyl, heterocyclyl, aryl, heteroaryl, -(alkyl)aryl,
-(alkyl)heteroaryl or acyl; Y is an optionally substituted phenyl
or thiazolyl ring; Z is an aliphatic, heteroaliphatic, alicyclic,
heteroalicyclic, aromatic or heteroaromatic moiety.
48. The compound of claim 47 wherein X.sup.1 is S and X.sup.2 is
CH.
49. The compound of claim 47 wherein X.sup.1 is CH and X.sup.2 is
S.
50. The compound of claim 47 wherein L.sup.2 is NH,
--NHC(.dbd.O)--, --NHC(.dbd.O)O--, --NHC(.dbd.O)NH--,
--NHC(.dbd.O)NHCH.sub.2--, or --CH.sub.2C(.dbd.O)NH--.
51. The compound of claim 47 having the structure: ##STR00715##
wherein q is 1-4; one of X.sup.1 and X.sup.2 is S and the other is
--CH--; and each occurrence of R.sup.Y1 is independently hydrogen,
alkyl, heteroalkyl, aryl, heteroaryl, -(alkyl)aryl or
-(alkyl)heteroaryl, --OR.sup.Y3, --SR.sup.Y3, --NR.sup.Y2R.sup.Y3,
--SO.sub.2NR.sup.Y2R.sup.Y3, --C(.dbd.O)NR.sup.Y2R.sup.Y3, halogen,
--CN, --NO.sub.2, --C(.dbd.O)OR.sup.Y3,
--N(R.sup.Y2)C(.dbd.O)R.sup.Y3, wherein each occurrence of R.sup.Y2
and R.sup.Y3 is independently hydrogen, lower alkyl, lower
heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl or
acyl, or R.sup.Y2 and R.sup.Y3 taken together with the nitrogen
atom to which they are attached form a 5-6 membered heterocyclic
ring.
52. The compound of claim 51 having the structure: ##STR00716##
wherein W.sup.1 is O or NR.sup.W1, where R.sup.W1 is hydrogen,
lower alkyl, C.sub.3-6cycloalkyl, lower heteroalkyl, heterocyclyl,
aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl or acyl; and
Alk.sub.1 is a C.sub.1-6alkylene or C.sub.2-6alkenylene moiety; and
each occurrence of R.sup.Y1 is independently hydrogen, halogen or
lower alkyl.
53. The compound of claim 52 having the structure: ##STR00717##
wherein L.sup.2 is NH, --NHC(.dbd.O)--, --NHC(.dbd.O)O--,
--NHC(.dbd.O)NH--, --NHC(.dbd.O)NHCH.sub.2--, or
--CH.sub.2C(.dbd.O)NH--.
54. The compound of claim 53 wherein Z is a branched alkyl,
alkenyl, alkynyl, heteroalkyl or heteroalkenyl moiety.
55. The compound of claim 53 wherein Z is one of: ##STR00718##
wherein each occurrence of R.sup.Z1 is independently hydrogen,
lower alkyl, lower alkenyl, aryl, heteroaryl or acyl.
56. The compound of claim 53 wherein Z is cycloalkyl, cycloalkenyl,
or a heterocyclyl, aryl or heteroaryl moiety having one of the
structures: ##STR00719## wherein the "A" cyclic moiety is a 6- to
10-membered mono- or fused bicyclic aromatic ring comprising from
0-4 nitrogen atoms; the "Het" moiety represents a fully or
partially saturated or unsaturated 5- to 8-membered mono- or fused
bicyclic ring comprising 1-4 heteroatoms selected from N, O and S;
m is an integer from 0-6; and each occurrence of R.sup.Z1 is
independently hydrogen, alkyl, cycloalkyl, heteroalkyl,
heterocyclyl, aryl, heteroaryl, -(alkyl)heterocyclyl, -(alkyl)aryl,
-(alkyl)heteroaryl, --OR.sup.Z2, --SR.sup.Z2, --N(R.sup.Z2).sub.2,
--SO.sub.2N(R.sup.Z2).sub.2, --SO.sub.2R.sup.Z4,
--C(.dbd.O)N(R.sup.Z2).sub.2, halogen, --CN, --NO.sub.2,
--C(.dbd.O)OR.sup.Z2, --N(R.sup.Z2)C(.dbd.O)R.sup.Z3 or
--N(R.sup.Z2)SO.sub.2R.sup.Z4; wherein each occurrence of R.sup.Z2
and R.sup.Z3 is independently hydrogen, lower alkyl, lower
heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl,
acyl; or any two occurrences of R.sup.Z2, taken together with the
nitrogen atom to which they are attached (e.g., N(R.sup.Z2).sub.2),
form a substituted or unsubstituted heterocyclic moiety; and
R.sup.Z4 is alkyl, heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, or
-(alkyl)heteroaryl; and wherein any two adjacent occurrence of
R.sup.Z1 may form a fused 5- to 6-membered aryl, heteroaryl or
heterocyclic ring.
57. The compound of claim 53 wherein Z is one of: ##STR00720##
wherein m is an integer from 0 to 3; r is an integer from 1 to 4;
X.sup.3 is N or CR.sup.Z1; each occurrence of R.sup.Z1 is
independently hydrogen, alkyl, heteroalkyl, aryl, heteroaryl,
-(alkyl)aryl or -(alkyl)heteroaryl, --OR.sup.Z2, --SR.sup.Z2,
--NR.sup.Z2R.sup.Z3, --SO.sub.2NR.sup.Z2R.sup.Z3,
--SO.sub.2R.sup.Z1, --C(.dbd.O)NR.sup.Z2R.sup.Z3, halogen, --CN,
--NO.sub.2, --C(.dbd.O)OR.sup.Z3, --N(R.sup.Z2)C(.dbd.O)R.sup.Z3,
wherein each occurrence of R.sup.Z2 and R.sup.Z3 is independently
hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl,
-(alkyl)aryl, -(alkyl)heteroaryl or acyl, or R.sup.Z2 and R.sup.Z3
taken together with the nitrogen or carbon atom to which they are
attached form a 5-6 membered heterocyclic, aryl or heteroaryl ring;
and R.sup.Z4 is hydrogen, lower alkyl, lower heteroalkyl, aryl,
heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl or acyl.
58. The compound of claim 57 wherein Z is one of: ##STR00721##
wherein X.sup.3 is N or CR.sup.Z1; R.sup.Z1 is hydrogen, halogen,
lower alkyl, lower hydroxyalkyl or lower haloalkyl; R.sup.Z2 and
R.sup.Z3 are independently hydrogen, lower alkyl, lower
heteroalkyl, acyl, or R.sup.Z2 and R.sup.Z3 taken together with the
nitrogen atom to which they are attached form a 5-6 membered
heterocyclic ring; and R.sup.Z4 is hydrogen or lower alkyl.
59. The compound of claim 57 wherein Z is one of: ##STR00722##
##STR00723## wherein X.sup.3 is N or CR.sup.Z1; R.sup.Z1 is
hydrogen, halogen, lower alkyl or lower haloalkyl; and R.sup.Z2 and
R.sup.Z3 are independently hydrogen, lower alkyl, lower
heteroalkyl, acyl, or R.sup.Z2 and R.sup.Z3 taken together with the
nitrogen atom to which they are attached form a 5-6 membered
heterocyclic ring; X is halogen, R.sup.Z1A is hydrogen, halogen,
--CN, lower alkyl, lower alkoxy, lower haloalkyl or
--SO.sub.2R.sup.Z4; wherein R.sup.Z4 is lower alkyl; and R.sup.Z2A
is hydrogen or lower alkyl.
60. The compound of claim 57 wherein Z is one of: ##STR00724##
##STR00725## wherein each occurrence of R.sup.Z1 is independently
Cl, F, methyl or CF.sub.3; R.sup.Z2 and R.sup.Z3 are each methyl or
ethyl, or taken together with the nitrogen atom to which they are
attached form a saturated or unsaturated pyrrolidinyl ring; and
R.sup.Z2A is hydrogen or methyl.
61. The compound of claim 60 wherein Z is one of: ##STR00726##
wherein R.sup.Z1 is Cl, F, methyl or CF.sub.3.
62. The compound of claim 47 having the structure: ##STR00727##
wherein X.sup.1 and X.sup.2 are as defined in claim 47; Z is an
aryl, heteroaryl or heterocyclic moiety; W.sup.1 is O or NR.sup.W1,
where R.sup.W1 is hydrogen, lower alkyl, lower heteroalkyl, aryl,
heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl or acyl; Alk.sub.1 is
a substituted or unsubstituted C.sub.1-6alkylene or
C.sub.2-6alkenylene chain wherein up to two non-adjacent methylene
units are independently optionally replaced by --C(.dbd.O)--,
--CO.sub.2--, --C(.dbd.O)C(.dbd.O)--, --C(.dbd.O)NR.sup.L1A--,
--OC(.dbd.O)--, --OC(.dbd.O)NR.sup.L1A--, --NR.sup.L1ANR.sup.L1B--,
--NR.sup.L1ANR.sup.L1BC(.dbd.O)--, --NR.sup.L1AC(.dbd.)--,
--NR.sup.L1ACO.sub.2--, --NR.sup.L1AC(.dbd.O)NR.sup.L1B--,
--S(.dbd.O)--, --SO.sub.2--, --NR.sup.L1ASO.sub.2--,
--SO.sub.2NR.sup.L1A--, --NR.sup.L1ASO.sub.2NR.sup.L1A--, --O--,
--S--, or --NR.sup.L1A--; wherein each occurrence of R.sup.L1A and
R.sup.L1B is independently hydrogen, lower alkyl, lower
heteroalkyl, heterocyclyl, aryl, heteroaryl or acyl.
63. The compound of claim 62 having the structure: ##STR00728##
wherein m is an integer from 0 to 3; and each occurrence of
R.sup.Z1 is independently hydrogen, alkyl, heteroalkyl, aryl,
heteroaryl, -(alkyl)aryl or -(alkyl)heteroaryl, --OR.sup.Z2,
--SR.sup.Z2, --NR.sup.Z2R.sup.Z3, --SO.sub.2NR.sup.Z2R.sup.Z3,
--SO.sub.2R.sup.Z1, --C(.dbd.O)NR.sup.Z2R.sup.Z3, halogen, --CN,
--NO.sub.2, --C(.dbd.O)OR.sup.Z3, --N(R.sup.Z2)C(.dbd.O)R.sup.Z3,
wherein each occurrence of R.sup.Z2 and R.sup.Z3 is independently
hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl,
-(alkyl)aryl, -(alkyl)heteroaryl or acyl, or R.sup.Z2 and R.sup.Z3
taken together with the nitrogen or carbon atom to which they are
attached form a 5-6 membered heterocyclic, aryl or heteroaryl
ring.
64. The compound of claim 63 having the structure: ##STR00729##
wherein R.sup.Z1 is halogen, lower alkyl or lower haloalkyl.
##STR00730##
65. The compound of claim 63 having the structure: wherein R.sup.X1
is hydrogen, lower alkyl or heterocyclyl; and R.sup.Z1 is halogen,
lower alkyl or lower haloalkyl.
66. The compound of claim 64 wherein R.sup.Z1 is Cl, F, methyl or
--CF.sub.3.
67. The compound of claim 62 having the structure: ##STR00731##
wherein m is an integer from 0 to 3; and each occurrence of
R.sup.Z1 is independently hydrogen, alkyl, heteroalkyl, aryl,
heteroaryl, -(alkyl)aryl or -(alkyl)heteroaryl, --OR.sup.Z2,
--SR.sup.Z2, --NR.sup.Z2R.sup.Z3, --SO.sub.2NR.sup.Z2R.sup.Z3,
--SO.sub.2R.sup.Z1, --C(.dbd.O)NR.sup.Z2R.sup.Z3, halogen, --CN,
--NO.sub.2, --C(.dbd.O)OR.sup.Z3, --N(R.sup.Z2)C(.dbd.O)R.sup.Z3,
wherein each occurrence of R.sup.Z2 and R.sup.Z3 is independently
hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl,
-(alkyl)aryl, -(alkyl)heteroaryl or acyl, or R.sup.Z2 and R.sup.Z3
taken together with the nitrogen or carbon atom to which they are
attached form a 5-6 membered heterocyclic, aryl or heteroaryl
ring.
68. The compound of claim 67 having the structure: ##STR00732##
wherein R.sup.Z1 is halogen, lower alkyl or lower haloalkyl.
69. The compound of claim 67 having the structure: ##STR00733##
wherein R.sup.X1 is hydrogen, lower alkyl or heterocyclyl; and
R.sup.Z1 is halogen, lower alkyl or lower haloalkyl.
70. The compound of claim 68 wherein R.sup.Z1 is Cl, F, methyl or
--CF.sub.3.
71. The compound of claim 51 wherein --W.sup.1-Alk.sub.1- is
--NH--C.sub.1-6alkyl- or --O--C.sub.1-6 alkyl-; wherein the
C.sub.1-6alkyl moiety may be substituted or unsubstituted.
72. The compound of claim 71 wherein --W.sup.1-Alk.sub.1- is
--NHCH.sub.2CH.sub.2--, --OCH.sub.2CH.sub.2-- or
--NH--CH.sub.2CH(CH.sub.2OH)--, or represents one of the
structures: ##STR00734##
73. A composition comprising an effective amount of compound of
claim 47, and a pharmaceutically acceptable carrier, adjuvant, or
vehicle.
74. The composition of claim 73, wherein the compound is in an
amount to detectably inhibit Aurora protein kinase activity.
75. The composition of claim 73, additionally comprising a
therapeutic agent selected from a chemotherapeutic or
anti-proliferative agent, an anti-inflammatory agent, an
immunomodulatory or immunosuppressive agent, a neurotrophic factor,
an agent for treating cardiovascular disease, an agent for treating
destructive bone disorders, an agent for treating liver disease, an
anti-viral agent, an agent for treating blood disorders, an agent
for treating diabetes, or an agent for treating immunodeficiency
disorders.
76. A method of inhibiting Aurora kinase activity in: (a) a
subject; or (b) a biological sample; which method comprises
administering to said patient, or contacting said biological sample
with a compound of claim 47.
77. The method of claim 76, wherein the method comprises inhibiting
Aurora kinase activity.
78. A method of treating or lessening the severity of a disease of
condition selected from a proliferative disorder, a cardiac
disorder, a neurodegenerative disorder, an autoimmune disorder, a
condition associated with organ transplant, an inflammatory
disorder, an immunologically mediated disorder, a viral disease, or
a bone disorder, comprising the step of administering to said
patient a compound of claim 47.
79. The method according to claim 78, comprising the additional
step of administering to said patient an additional therapeutic
agent selected from a chemotherapeutic or anti-proliferative agent,
an anti-inflammatory agent, an immunomodulatory or
immunosuppressive agent, a neurotrophic factor, an agent for
treating cardiovascular disease, an agent for treating destructive
bone disorders, an agent for treating liver disease, an anti-viral
agent, an agent for treating blood disorders, an agent for treating
diabetes, or an agent for treating immunodeficiency disorders,
wherein: said additional therapeutic agent is appropriate for the
disease being treated; and said additional therapeutic agent is
administered together with said composition as a single dosage form
or separately from said composition as part of a multiple dosage
form.
Description
PRIORITY
[0001] This application is a Divisional of co-pending U.S. patent
application Ser. No. 11/182,215, filed Jul. 15, 2005, which claims
priority to U.S. provisional application Ser. No. 60/632,568, filed
Dec. 1, 2004, and U.S. provisional application Ser. No. 60/588,718,
filed Jul. 16, 2004, the entire contents of each of which are
incorporated herein by reference.
BACKGROUND OF THE INVENTION
[0002] The search for new therapeutic agents has been greatly aided
in recent years by a better understanding of the structure of
enzymes and other biomolecules associated with diseases. One
important class of enzymes that has been the subject of extensive
study is protein kinases.
[0003] Protein kinases constitute a large family of structurally
related enzymes that are responsible for the control of a variety
of signal transduction processes within the cell. (See, Hardie, G.
and Hanks, S. The Protein Kinase Facts Book, I and II, Academic
Press, San Diego, Calif.: 1995). Protein kinases are thought to
have evolved from a common ancestral gene due to the conservation
of their structure and catalytic function. Almost all kinases
contain a similar 250-300 amino acid catalytic domain. The kinases
may be categorized into families by the substrates they
phosphorylate (e.g., protein-tyrosine, protein-serine/threonine,
lipids, etc.). Sequence motifs have been identified that generally
correspond to each of these kinase families (See, for example,
Hanks, S. K., Hunter, T., FASEB J. 1995, 9, 576-596; Knighton et
al., Science 1991, 253, 407-414; Hiles et al., Cell 1992, 70,
419-429; Kunz et al., Cell 1993, 73, 585-596; Garcia-Bustos et al.,
EMBO J. 1994, 13, 2352-2361).
[0004] In general, protein kinases mediate intracellular signaling
by effecting a phosphoryl transfer from a nucleoside triphosphate
to a protein acceptor that is involved in a signaling pathway.
These phosphorylation events act as molecular on/off switches that
can modulate or regulate the target protein biological function.
These phosphorylation events are ultimately triggered in response
to a variety of extracellular and other stimuli. Examples of such
stimuli include environmental and chemical stress signals (e.g.,
osmotic shock, heat shock, ultraviolet radiation, bacterial
endotoxin, and H.sub.2O.sub.2), cytokines (e.g., interleukin-1
(IL-1) and tumor necrosis factor .alpha. (TNF-.alpha.)), and growth
factors (e.g., granulocyte macrophage-colony-stimulating factor
(GM-CSF), and fibroblast growth factor (FGF)). An extracellular
stimulus may affect one or more cellular responses related to cell
growth, migration, differentiation, secretion of hormones,
activation of transcription factors, muscle contraction, glucose
metabolism, control of protein synthesis, and regulation of the
cell cycle.
[0005] Many diseases are associated with abnormal cellular
responses triggered by protein kinase-mediated events as described
above. These diseases include, but are not limited to, autoimmune
diseases, inflammatory diseases, bone diseases, metabolic diseases,
neurological and neurodegenerative diseases, cancer, cardiovascular
diseases, allergies and asthma, Alzheimer's disease, and
hormone-related diseases. Accordingly, there has been a substantial
effort in medicinal chemistry to find protein kinase inhibitors
that are effective as therapeutic agents.
[0006] The Aurora family of serine/threonine kinases plays an
important role in cell proliferation. The three known mammalian
family members, Aurora-A ("1"), B ("2") and C ("3"), are highly
homologous proteins responsible for chromosome segregation, mitotic
spindle function and cytokinesis. Aurora expression is low or
undetectable in resting cells, with expression and activity peaking
during the G2 and mitotic phases in cycling cells. Elevated levels
of all Aurora family members are observed in a wide variety of
tumor cell lines. For example, the Aurora-2 protein has been found
to be overexpressed in human colon cancer tissue [Bischoff et al.,
EMBO J. 1998, 17, 3052-3065; Schumacher et al., J. Cell Biol. 1998,
143, 1635-1646; Kimura et al., J. Biol. Chem. 1997, 272,
13766-13771]. Aurora-2 has been implicated in human cancer, such as
colon, breast and other solid tumors. This kinase is involved in
protein phosphorylation events that regulate the cell cycle.
Specifically, Aurora-2 plays a role in controlling the accurate
segregation of chromosomes during mitosis. Thus, Aurora inhibitors
have an important role in the treatment of Aurora-mediated
diseases.
[0007] Accordingly, there is a great need to develop compounds
useful as inhibitors of protein kinases. In particular, it would be
desirable to develop compounds that are useful as inhibitors of
Aurora, particularly given the inadequate treatments currently
available for the majority of the disorders implicated in their
activation.
SUMMARY OF THE INVENTION
[0008] As discussed above, there remains a need for the development
of novel therapeutic agents and agents useful for treating
disorders mediated by Aurora. In certain embodiments, the present
invention provides novel compounds having the structure:
##STR00002##
[0009] wherein R.sup.1, R.sup.2, X.sup.1, X.sup.2, L.sup.1,
L.sup.2, Y and Z are as defined in classes and subclasses herein,
and pharmaceutical compositions thereof, as described generally and
in subclasses herein, which compounds are useful as inhibitors of
protein kinase (e.g., Aurora), and thus are useful, for example,
for the treatment of Aurora mediated diseases.
[0010] In certain other embodiments, the invention provides
pharmaceutical compositions comprising an inventive compound,
wherein the compound is present in an amount effective to inhibit
Aurora activity. In certain other embodiments, the invention
provides pharmaceutical compositions comprising an inventive
compound and optionally further comprising an additional
therapeutic agent. In yet other embodiments, the additional
therapeutic agent is an agent for the treatment of cancer.
[0011] In yet another aspect, the present invention provides
methods for inhibiting kinase activity (e.g., Aurora) activity in a
patient or a biological sample, comprising administering to said
patient, or contacting said biological sample with an effective
inhibitory amount of a compound of the invention. In still another
aspect, the present invention provides methods for treating any
disorder involving Aurora activity, comprising administering to a
subject in need thereof a therapeutically effective amount of a
compound of the invention.
BRIEF DESCRIPTION OF THE DRAWING
[0012] FIG. 1 depicts exemplary histograms of G2/M phase cell
growth arrest experiments using four compounds of the
invention.
[0013] FIG. 2 depicts results of Histone H3 phosphorylation
inhibition experiments in HCT-116 cells. A compound of the
invention, cultured with HCT-116 cells, exhibits a
concentration-related inhibition of histone H3 serine
phosphorylation.
[0014] FIG. 3 depicts results of Histone H3 phosphorylation
inhibition experiments in a HCT-116 tumor xenograft model. A
compound of the invention was administered intra-peritoneally
(single dose, 75 mg/kg) to mice implanted with HCt-116 tumors. The
compound inhibits histone H3 serine phosphorylation in HCT-116
tumors for up to 10 hours after administration to implanted
mice.
[0015] FIG. 4 depicts results of tumor growth inhibition
experiments in a HCT-116 tumor xenograft model. A compound of the
invention was administered intra-peritoneally (IP) to mice
implanted with HCt-116 tumors. The compound inhibits tumor growth
following a dosing regimen of 75 mg/kg, once a week, for 3
weeks.
[0016] FIG. 5 depicts results of phosphorylated Histone H3
modulation experiments in a HCT-116 tumor xenograft model. A
compound of the invention was administered intravenously as a
single dose at 6 h (50 mg/kg) and 10 h (75 mg/kg).
DEFINITIONS
[0017] It is understood that the compounds, as described herein,
may be substituted with any number of substituents or functional
moieties. In general, the term "substituted" whether preceded by
the term "optionally" or not, and substituents contained in
formulas of this invention, refer to the replacement of hydrogen
radicals in a given structure with the radical of a specified
substituent. When more than one position in any given structure may
be substituted with more than one substituent selected from a
specified group, the substituent may be either the same or
different at every position. As used herein, the term "substituted"
is contemplated to include all permissible substituents of organic
compounds. In a broad aspect, the permissible substituents include
acyclic and cyclic, branched and unbranched, carbocyclic and
heterocyclic, aromatic and non-aromatic, carbon and heteroatom
substituents of organic compounds. For purposes of this invention,
heteroatoms such as nitrogen may have hydrogen substituents and/or
any permissible substituents of organic compounds described herein
which satisfy the valencies of the heteroatoms. Furthermore, this
invention is not intended to be limited in any manner by the
permissible substituents of organic compounds. Combinations of
substituents and variables envisioned by this invention are
preferably those that result in the formation of stable compounds
useful in the treatment and prevention, for example of disorders,
as described generally above. Examples of substituents include, but
are not limited to aliphatic; heteroaliphatici; alicyclic;
heteroalicyclic; aromatic, heteroaromatic; aryl; heteroaryl;
alkylaryl; alkylheteroaryl; alkoxy; aryloxy; heteroalkoxy;
heteroaryloxy; alkylthio; arylthio; heteroalkylthio;
heteroarylthio; F; Cl; Br; I; --NO.sub.2; --CN; --CF.sub.3;
--CH.sub.2CF.sub.3; --CHCl.sub.2; --CH.sub.2OH;
--CH.sub.2CH.sub.2OH; --CH.sub.2NH.sub.2; --CH.sub.2SO.sub.2
CH.sub.3; -- or -GR.sup.G1 wherein G is --O--, --S--,
--NR.sup.G2--, --C(.dbd.O)--, --S(.dbd.O)--, --SO.sub.2--,
--C(.dbd.O)O--, --C(.dbd.O)NR.sup.G2--, --OC(.dbd.O)--,
--NR.sup.G2C(.dbd.O)--, --OC(.dbd.O)O--, --OC(.dbd.O)NR.sup.G2--,
--NR.sup.G2C(.dbd.O)O--, --NR.sup.G2C(.dbd.O)NR.sup.G2--,
--C(.dbd.S)--, --C(.dbd.S)S--, --SC(.dbd.S)--, --SC(.dbd.S)S--,
--C(.dbd.NR.sup.G2)O--, --C(.dbd.NR.sup.G2)O--,
--C(.dbd.NR.sup.G2)NR.sup.G3--, OC(.dbd.NR.sup.G2)--,
--NR.sup.G2C(.dbd.NR.sup.G3)--, --NR.sup.G2SO.sub.2--,
--NR.sup.G2SO.sub.2NR.sup.G3--, or --SO.sub.2NR.sup.G2--, wherein
each occurrence of R.sup.G1, R.sup.G2 and R.sup.G3 independently
includes, but is not limited to, hydrogen, halogen, or an
optionally substituted aliphatic, heteroaliphatic, alicyclic,
heteroalicyclic, aromatic, heteroaromatic, aryl, heteroaryl,
alkylaryl, or alkylheteroaryl moiety. Additional examples of
generally applicable substituents are illustrated by the specific
embodiments shown in the Examples that are described herein.
[0018] The term "stable", as used herein, preferably refers to
compounds which possess stability sufficient to allow manufacture
and which maintain the integrity of the compound for a sufficient
period of time to be detected and preferably for a sufficient
period of time to be useful for the purposes detailed herein.
[0019] The term "aliphatic", as used herein, includes both
saturated and unsaturated, straight chain (i.e., unbranched) or
branched aliphatic hydrocarbons, which are optionally substituted
with one or more functional groups. As will be appreciated by one
of ordinary skill in the art, "aliphatic" is intended herein to
include, but is not limited to, alkyl, alkenyl, alkynyl moieties.
Thus, as used herein, the term "alkyl" includes straight and
branched alkyl groups. An analogous convention applies to other
generic terms such as "alkenyl", "alkynyl" and the like.
Furthermore, as used herein, the terms "alkyl", "alkenyl",
"alkynyl" and the like encompass both substituted and unsubstituted
groups. In certain embodiments, as used herein, "lower alkyl" is
used to indicate those alkyl groups (substituted, unsubstituted,
branched or unbranched) having about 1-6 carbon atoms.
[0020] In certain embodiments, the alkyl, alkenyl and alkynyl
groups employed in the invention contain about 1-20 aliphatic
carbon atoms. In certain other embodiments, the alkyl, alkenyl, and
alkynyl groups employed in the invention contain about 1-10
aliphatic carbon atoms. In yet other embodiments, the alkyl,
alkenyl, and alkynyl groups employed in the invention contain about
1-8 aliphatic carbon atoms. In still other embodiments, the alkyl,
alkenyl, and alkynyl groups employed in the invention contain about
1-6 aliphatic carbon atoms. In yet other embodiments, the alkyl,
alkenyl, and alkynyl groups employed in the invention contain about
1-4 carbon atoms. Illustrative aliphatic groups thus include, but
are not limited to, for example, methyl, ethyl, n-propyl,
isopropyl, allyl, n-butyl, sec-butyl, isobutyl, tert-butyl,
n-pentyl, sec-pentyl, isopentyl, tert-pentyl, n-hexyl, sec-hexyl,
moieties and the like, which again, may bear one or more
substituents. Alkenyl groups include, but are not limited to, for
example, ethenyl, propenyl, butenyl, 1-methyl-2-buten-1-yl, and the
like. Representative alkynyl groups include, but are not limited
to, ethynyl, 2-propynyl (propargyl), 1-propynyl and the like.
[0021] The term "alicyclic", as used herein, refers to compounds
which combine the properties of aliphatic and cyclic compounds and
include but are not limited to cyclic, or polycyclic aliphatic
hydrocarbons and bridged cycloalkyl compounds, which are optionally
substituted with one or more functional groups. As will be
appreciated by one of ordinary skill in the art, "alicyclic" is
intended herein to include, but is not limited to, cycloalkyl,
cycloalkenyl, and cycloalkynyl moieties, which are optionally
substituted with one or more functional groups. Illustrative
alicyclic groups thus include, but are not limited to, for example,
cyclopropyl, --CH.sub.2-cyclopropyl, cyclobutyl,
--CH.sub.2-cyclobutyl, cyclopentyl, --CH.sub.2-cyclopentyl-n,
cyclohexyl, --CH.sub.2-cyclohexyl, cyclohexenylethyl,
cyclohexanylethyl, norborbyl moieties and the like, which again,
may bear one or more substituents.
[0022] The term "cycloalkyl", as used herein, refers specifically
to cyclic alkyl groups having three to seven, preferably three to
ten carbon atoms. Suitable cycloalkyls include, but are not limited
to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl
and the like, which, as in the case of aliphatic, heteroaliphatic
or heterocyclic moieties, may optionally be substituted. An
analogous convention applies to other generic terms such as
"cycloalkenyl", "cycloalkynyl" and the like.
[0023] The term "heteroaliphatic", as used herein, refers to
aliphatic moieties in which one or more carbon atoms in the main
chain have been substituted with a heteroatom. Thus, a
heteroaliphatic group refers to an aliphatic chain which contains
one or more oxygen, sulfur, nitrogen, phosphorus or silicon atoms,
i.e., in place of carbon atoms. Thus, a 1-6 atom heteroaliphatic
linker having at least one N atom in the heteroaliphatic main
chain, as used herein, refers to a C.sub.1-6 aliphatic chain
wherein at least one carbon atom is replaced with a nitrogen atom,
and wherein any one or more of the remaining 5 carbon atoms may be
replaced by an oxygen, sulfur, nitrogen, phosphorus or silicon
atom. As used herein, a 1-atom heteroaliphatic linker having at
least one N atom in the heteroaliphatic main chain refers to --NH--
or --NR-- where R is aliphatic, heteroaliphatic, acyl, aromatic,
heteroaromatic or a nitrogen protecting group. Heteroaliphatic
moieties may be branched or linear unbranched. In certain
embodiments, heteroaliphatic moieties are substituted by
independent replacement of one or more of the hydrogen atoms
thereon with one or more moieties including, any of the
substituents described above.
[0024] The term "heteroalicyclic", "heterocycloalkyl" or
"heterocyclic", as used herein, refers to compounds which combine
the properties of heteroaliphatic and cyclic compounds and include
but are not limited to saturated and unsaturated mono- or
polycyclic heterocycles such as morpholino, pyrrolidinyl, furanyl,
thiofuranyl, pyrrolyl etc., which are optionally substituted with
one or more functional groups, as defined herein. In certain
embodiments, the term "heterocyclic" refers to a non-aromatic 5-,
6- or 7-membered ring or a polycyclic group, including, but not
limited to a bi- or tri-cyclic group comprising fused six-membered
rings having between one and three heteroatoms independently
selected from oxygen, sulfur and nitrogen, wherein (i) each
5-membered ring has 0 to 2 double bonds and each 6-membered ring
has 0 to 2 double bonds, (ii) the nitrogen and sulfur heteroatoms
may optionally be oxidized, (iii) the nitrogen heteroatom may
optionally be quaternized, and (iv) any of the above heterocyclic
rings may be fused to an aryl or heteroaryl ring. Representative
heterocycles include, but are not limited to, pyrrolidinyl,
pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl,
piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl,
morpholinyl, thiazolidinyl, isothiazolidinyl, and
tetrahydrofuryl.
[0025] Additionally, it will be appreciated that any of the
alicyclic or heteroalicyclic moieties described above and herein
may comprise an aryl or heteroaryl moiety fused thereto. Additional
examples of generally applicable substituents are illustrated by
the specific embodiments shown in the Examples that are described
herein.
[0026] In general, the term "aromatic moiety", as used herein,
refers to stable substituted or unsubstituted unsaturated mono- or
polycyclic hydrocarbon moieties having preferably 3-14 carbon
atoms, comprising at least one ring satisfying the Huckel rule for
aromaticity. Examples of aromatic moieties include, but are not
limited to, phenyl, indanyl, indenyl, naphthyl, phenanthryl and
anthracyl.
[0027] In general, the term "heteroaromatic moiety", as used
herein, refers to stable substituted or unsubstituted unsaturated
mono-heterocyclic or polyheterocyclic moieties having preferably
3-14 carbon atoms, comprising at least one ring satisfying the
Huckel rule for aromaticity. Examples of heteroaromatic moieties
include, but are not limited to, pyridyl, quinolinyl,
dihydroquinolinyl, isoquinolinyl, quinazolinyl, dihydroquinazolyl,
and tetrahydroquinazolyl.
[0028] It will also be appreciated that aromatic and heteroaromatic
moieties, as defined herein, may be attached via an aliphatic
(e.g., alkyl) or heteroaliphatic (e.g., heteroalkyl) moiety and
thus also include moieties such as -(aliphatic)aromatic,
-(heteroaliphatic)aromatic, -(aliphatic)heteroaromatic,
-(heteroaliphatic)heteroaromatic, -(alkyl)aromatic,
-(heteroalkyl)aromatic, -(alkyl)heteroaromatic, and
-(heteroalkyl)heteroaromatic moieties. Thus, as used herein, the
phrases "aromatic or heteroaromatic moieties" and "aromatic,
heteroaromatic, -(alkyl)aromatic, -(heteroalkyl)aromatic,
-(heteroalkyl)heteroaromatic, and -(heteroalkyl)heteroaromatic" are
interchangeable. Substituents include, but are not limited to, any
of the previously mentioned substituents resulting in the formation
of a stable compound.
[0029] In general, the term "aryl" refers to aromatic moieties, as
described above, excluding those attached via an aliphatic (e.g.,
alkyl) or heteroaliphatic (e.g., heteroalkyl) moiety. In certain
embodiments of the present invention, "aryl" refers to a mono- or
bicyclic carbocyclic ring system having one or two rings satisfying
the Huckel rule for aromaticity, including, but not limited to,
phenyl, naphthyl, tetrahydronaphthyl, indanyl, indenyl and the
like.
[0030] Similarly, the term "heteroaryl" refers to heteroaromatic
moieties, as described above, excluding those attached via an
aliphatic (e.g., alkyl) or heteroaliphatic (e.g., heteroalkyl)
moiety. In certain embodiments of the present invention, the term
"heteroaryl", as used herein, refers to a cyclic unsaturated
radical having from about five to about ten ring atoms of which one
ring atom is selected from S, O and N; zero, one or two ring atoms
are additional heteroatoms independently selected from S, O and N;
and the remaining ring atoms are carbon, the radical being joined
to the rest of the molecule via any of the ring atoms, such as, for
example, pyridyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl,
imidazolyl, thiazolyl, oxazolyl, isooxazolyl, thiadiazolyl,
oxadiazolyl, thiophenyl, furanyl, quinolinyl, isoquinolinyl, and
the like.
[0031] Substituents for aryl and heteroaryl moieties include, but
are not limited to, any of the previously mentioned substitutents,
i.e., the substituents recited for aliphatic moieties, or for other
moieties as disclosed herein, resulting in the formation of a
stable compound.
[0032] The terms "alkoxy" (or "alkyloxy"), and "thioalkyl" as used
herein refers to an alkyl group, as previously defined, attached to
the parent molecular moiety through an oxygen atom ("alkoxy") or
through a sulfur atom ("thioalkyl"). In certain embodiments, the
alkyl group contains about 1-20 aliphatic carbon atoms. In certain
other embodiments, the alkyl group contains about 1-10 aliphatic
carbon atoms. In yet other embodiments, the alkyl group contains
about 1-8 aliphatic carbon atoms. In still other embodiments, the
alkyl group contains about 1-6 aliphatic carbon atoms. In yet other
embodiments, the alkyl group contains about 1-4 aliphatic carbon
atoms. Examples of alkoxy groups, include but are not limited to,
methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, tert-butoxy,
neopentoxy and n-hexoxy. Examples of thioalkyl groups include, but
are not limited to, methylthio, ethylthio, propylthio,
isopropylthio, n-butylthio, and the like.
[0033] The term "amine" refers to a group having the structure
--N(R).sub.2 wherein each occurrence of R is independently
hydrogen, or an aliphatic, heteroaliphatic, aromatic or
heteroaromatic moiety, or the R groups, taken together, may form a
heterocyclic moiety.
[0034] The term "alkylamino" refers to a group having the structure
--NHR' wherein R' is alkyl, as defined herein. The term
"aminoalkyl" refers to a group having the structure NH.sub.2R'--,
wherein R' is alkyl, as defined herein. In certain embodiments, the
alkyl group contains about 1-aliphatic carbon atoms. In certain
other embodiments, the alkyl group contains about 1-10 aliphatic
carbon atoms. In yet other embodiments, the alkyl, alkenyl, and
alkynyl groups employed in the invention contain about 1-8
aliphatic carbon atoms. In still other embodiments, the alkyl group
contains about 1-6 aliphatic carbon atoms. In yet other
embodiments, the alkyl group contains about 1-4 aliphatic carbon
atoms. Examples of alkylamino include, but are not limited to,
methylamino, ethylamino, iso-propylamino and the like.
[0035] The terms "halo" and "halogen" as used herein refer to an
atom selected from fluorine, chlorine, bromine and iodine.
[0036] The term "halogenated" denotes a moiety having one, two, or
three halogen atoms attached thereto.
[0037] The term "haloalkyl" denotes an alkyl group, as defined
above, having one, two, or three halogen atoms attached thereto and
is exemplified by such groups as chloromethyl, bromoethyl,
trifluoromethyl, and the like.
[0038] The term "acyloxy", as used herein, does not substantially
differ from the common meaning of this term in the art, and refers
to a moiety of structure --OC(O)R.sub.X, wherein R.sub.X is a
substituted or unsubstituted aliphatic, alicyclic, heteroaliphatic,
heteroalicyclic, aryl or heteroaryl moiety.
[0039] The term "acyl", as used herein, does not substantially
differ from the common meaning of this term in the art, and refers
to a moiety of structure --C(O)R.sub.X, wherein R.sub.X is a
substituted or unsubstituted, aliphatic, alicyclic,
heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety.
[0040] The term "imino", as used herein, does not substantially
differ from the common meaning of this term in the art, and refers
to a moiety of structure --C(.dbd.NR.sub.X)R.sub.Y, wherein R.sub.X
is hydrogen or an optionally substituted aliphatic, alicyclic,
heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety; and
R.sub.Y is an optionally substituted aliphatic, alicyclic,
heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety.
[0041] The term "C.sub.1-6alkylene", as used herein, refers to a
substituted or unsubstituted, linear or branched saturated divalent
radical consisting solely of carbon and hydrogen atoms, having from
one to six carbon atoms, having a free valence "-" at both ends of
the radical.
[0042] The term "C.sub.2-6alkenylene", as used herein, refers to a
substituted or unsubstituted, linear or branched unsaturated
divalent radical consisting solely of carbon and hydrogen atoms,
having from two to six carbon atoms, having a free valence "-" at
both ends of the radical, and wherein the unsaturation is present
only as double bonds and wherein a double bond can exist between
the first carbon of the chain and the rest of the molecule.
[0043] As used herein, the terms "aliphatic", "heteroaliphatic",
"alkyl", "alkenyl", "alkynyl", "heteroalkyl", "heteroalkenyl",
"heteroalkynyl", and the like encompass substituted and
unsubstituted, saturated and unsaturated, and linear and branched
groups. Similarly, the terms "alicyclic", "heterocyclic",
"heterocycloalkyl", "heterocycle" and the like encompass
substituted and unsubstituted, and saturated and unsaturated
groups. Additionally, the terms "cycloalkyl", "cycloalkenyl",
"cycloalkynyl", "heterocycloalkyl", "heterocycloalkenyl",
"heterocycloalkynyl", "aromatic", "heteroaromatic", "aryl",
"heteroaryl" and the like, used alone or as part of a larger
moiety, encompass both substituted and unsubstituted groups.
[0044] As used herein, the term "isolated", when applied to the
compounds of the present invention, refers to such compounds that
are (i) separated from at least some components with which they are
associated in nature or when they are made and/or (ii) produced,
prepared or manufactured by the hand of man.
[0045] The phrase, "pharmaceutically acceptable derivative", as
used herein, denotes any pharmaceutically acceptable salt, ester,
or salt of such ester, of such compound, or any other adduct or
derivative which, upon administration to a patient, is capable of
providing (directly or indirectly) a compound as otherwise
described herein, or a metabolite or residue thereof.
Pharmaceutically acceptable derivatives thus include among others
pro-drugs. A pro-drug is a derivative of a compound, usually with
significantly reduced pharmacological activity, which contains an
additional moiety that is susceptible to removal in vivo yielding
the parent molecule as the pharmacologically active species. An
example of a pro-drug is an ester which is cleaved in vivo to yield
a compound of interest. Pro-drugs of a variety of compounds, and
materials and methods for derivatizing the parent compounds to
create the pro-drugs, are known and may be adapted to the present
invention. Certain exemplary pharmaceutical compositions and
pharmaceutically acceptable derivatives will be discussed in more
detail herein below.
[0046] The term "Aurora-mediated disease" or "Aurora-mediated
condition", as used herein, means any disease or other deleterious
condition in which Aurora is known to play a role. The terms
"Aurora-mediated disease" or "Aurora-mediated condition" also mean
those diseases or conditions that are alleviated by treatment with
an Aurora inhibitor. Such conditions include, without limitation,
colon, breast, stomach, and ovarian cancer. The term
"Aurora-mediated disease", as used herein, means any disease or
other deleterious condition or disease in which Aurora is known to
play a role. Such diseases or conditions include, without
limitation, cancers such as colon and breast cancer.
[0047] The term "treating", as used herein generally means that the
compounds of the invention can be used in humans or animals with at
least a tentative diagnosis of disease. In certain embodiments,
compounds of the invention will delay or slow the progression of
the disease thereby giving the individual a longer life span.
[0048] The term "preventing" as used herein means that the
compounds of the present invention are useful when administered to
a patient who has not been diagnosed as possibly having the disease
at the time of administration, but who would normally be expected
to develop the disease or be at increased risk for the disease. The
compounds of the invention will slow the development of disease
symptoms, delay the onset of disease, or prevent the individual
from developing the disease at all. Preventing also includes
administration of the compounds of the invention to those
individuals thought to be predisposed to the disease due to
familial history, genetic or chromosomal abnormalities, and/or due
to the presence of one or more biological markers for the
disease.
[0049] As used herein the term "biological sample" includes,
without limitation, cell cultures or extracts thereof; biopsied
material obtained from an animal (e.g., mammal) or extracts
thereof; and blood, saliva, urine, feces, semen, tears, or other
body fluids or extracts thereof. For example, the term "biological
sample" refers to any solid or fluid sample obtained from, excreted
by or secreted by any living organism, including single-celled
micro-organisms (such as bacteria and yeasts) and multicellular
organisms (such as plants and animals, for instance a vertebrate or
a mammal, and in particular a healthy or apparently healthy human
subject or a human patient affected by a condition or disease to be
diagnosed or investigated). The biological sample can be in any
form, including a solid material such as a tissue, cells, a cell
pellet, a cell extract, cell homogenates, or cell fractions; or a
biopsy, or a biological fluid. The biological fluid may be obtained
from any site (e.g. blood, saliva (or a mouth wash containing
buccal cells), tears, plasma, serum, urine, bile, cerebrospinal
fluid, amniotic fluid, peritoneal fluid, and pleural fluid, or
cells therefrom, aqueous or vitreous humor, or any bodily
secretion), a transudate, an exudate (e.g. fluid obtained from an
abscess or any other site of infection or inflammation), or fluid
obtained from a joint (e.g. a normal joint or a joint affected by
disease such as rheumatoid arthritis, osteoarthritis, gout or
septic arthritis). The biological sample can be obtained from any
organ or tissue (including a biopsy or autopsy specimen) or may
comprise cells (whether primary cells or cultured cells) or medium
conditioned by any cell, tissue or organ. Biological samples may
also include sections of tissues such as frozen sections taken for
histological purposes. Biological samples also include mixtures of
biological molecules including proteins, lipids, carbohydrates and
nucleic acids generated by partial or complete fractionation of
cell or tissue homogenates. Although the sample is preferably taken
from a human subject, biological samples may be from any animal,
plant, bacteria, virus, yeast, etc. The term animal, as used
herein, refers to humans as well as non-human animals, at any stage
of development, including, for example, mammals, birds, reptiles,
amphibians, fish, worms and single cells. Cell cultures and live
tissue samples are considered to be pluralities of animals. In
certain exemplary embodiments, the non-human animal is a mammal
(e.g., a rodent, a mouse, a rat, a rabbit, a monkey, a dog, a cat,
a sheep, cattle, a primate, or a pig). An animal may be a
transgenic animal or a human clone. If desired, the biological
sample may be subjected to preliminary processing, including
preliminary separation techniques.
DETAILED DESCRIPTION OF CERTAIN PREFERRED EMBODIMENTS OF THE
INVENTION
[0050] As noted above, there has been increasing interest in recent
years in the development of protein kinase inhibitors, particularly
Aurora inhibitors, as therapeutic agents for the treatment of
diseases/conditions involving protein kinase-mediated events. In
one aspect, the present invention provides Aurora inhibitors.
[0051] Compounds of this invention include those generally set
forth above and described specifically herein, and are illustrated
in part by the various classes, subgenera and species disclosed
herein. Additionally, the present invention provides
pharmaceutically acceptable derivatives of the inventive compounds,
and methods of treating a subject using these compounds,
pharmaceutical compositions thereof, or either of these in
combination with one or more additional therapeutic agents.
[0052] 1) General Description of Compounds of the Invention
[0053] In certain embodiments, the compounds of the invention
include compounds of the general formula (I) as further defined
below:
##STR00003##
[0054] and pharmaceutically acceptable derivatives thereof;
[0055] wherein one of is a double bond, as valency permits;
[0056] R.sup.1 and R.sup.2 are independently hydrogen, halogen,
cyano, nitro, or an aliphatic, heteroaliphatic, alicyclic,
heteroalicyclic, aromatic or heteroaromatic moiety;
[0057] one of X.sup.1 and X.sup.2 is S, the other is
--C(R.sup.X1)--; wherein R.sup.X1 is hydrogen, halogen, cyano,
nitro, or an aliphatic, heteroaliphatic, alicyclic,
heteroalicyclic, aromatic or heteroaromatic moiety;
[0058] L.sup.1 is a 2-8 atom heteroaliphatic linker having at least
one N, O or S atom in the heteroaliphatic main chain;
[0059] L.sup.2 is a 1-6 atom heteroaliphatic linker having at least
one N atom in the heteroaliphatic main chain;
[0060] Y is an alicyclic, heteroalicyclic, aromatic or
heteroaromatic moiety; and
[0061] Z is an aliphatic, heteroaliphatic, alicyclic,
heteroalicyclic, aromatic or heteroaromatic moiety.
[0062] In certain embodiments, the following groups do not occur
simultaneously as defined: L.sup.1 is --OCH.sub.2--, --CH.sub.2O--,
--N(R)CH.sub.2-- or --CH.sub.2N(R)--, wherein R is H or
C.sub.1-8alkyl; Y is phenyl; and Z is a 5-10-membered cycloalkyl,
heterocyclyl, aryl or heteroaryl.
[0063] In certain embodiments, the following groups do not occur
simultaneously as defined: L.sup.1-Y is --NHCH.sub.2CH.sub.2-phenyl
or --OCH.sub.2CH.sub.2-phenyl; L.sup.2 is --C(R).dbd.N--O--,
wherein R is H, C.sub.1-4alkyl, C.sub.1-4haloalkyl or
C.sub.3-6cycloalkyl; and R.sup.1 and R.sup.X1 (or R.sup.1 and
R.sup.X2, when X.sup.1 is S) are independently hydrogen, halogen or
C.sub.1-4alkyl.
[0064] In certain embodiments, the following groups do not occur
simultaneously as defined: L.sup.1 is --OCH(R)--,
--OCH(R)--C.sub.1-6alkylO-- or
--OCH(R)--C.sub.1-6alkylC(.dbd.NR.sub.x)-- where R is H,
C.sub.1-4alkyl, C.sub.1-4haloalkyl or C.sub.3-6cycloalkyl and
R.sub.x is H, aliphatic, heteroaliphatic, alicyclic,
heteroalicyclic, aromatic or heteroaromatic; Y and Z are each
optionally substituted phenyl; and L.sup.2 is --OCH.sub.2-- or
--OSO.sub.2--; and R.sup.1 and R.sup.X1 (or R.sup.1 and R.sup.X2,
when X.sup.1 is S) are independently hydrogen, halogen or
alkyl.
[0065] In certain embodiments, the following groups do not occur
simultaneously as defined: X.sup.1 is CR.sup.X1 wherein R.sup.X1 is
Q.sub.4; X.sup.2 is S; R.sup.1 is Q.sub.5; Y and Z are
independently optionally substituted aryl, carbocycle or 5-membered
monocyclic heterocycle; and L.sup.1 s --W--N.dbd.CH-- wherein W is
O or NR, wherein R is H, C.sub.1-6alk(en/yn)yl,
C.sub.3-8cycloalk(en)yl, aryl, hydroxyC.sub.1-6alk(en/yn)yl,
C.sub.3-8cycloalk(en)yl-C.sub.1-6alk(en/yn)yl or acyl; wherein
Q.sub.4 is hydrogen, halogen, cyano, nitro, C.sub.1-6alk(en/yn)yl,
C.sub.1-6alk(en/yn)yloxy,
C.sub.1-6alk(en/yn)yloxy-C.sub.1-6alk(en/yn)yl,
C.sub.1-6alk(en/yn)ylsulfanyl, hydroxy,
hydroxy-C.sub.1-6alk(en/yn)yl, halo-C.sub.1-6 alk(en/yn)yl,
halo-C.sub.1-6alk(en/yn)yloxy, C.sub.3-8cycloalk(en)yl,
C.sub.3-8cycloalk(en)yl-C.sub.1-6 alk(en/yn)yl, acyl,
C.sub.1-6alk(en/yn)yloxycarbonyl, C.sub.1-6alk(en/yn)ylsulfonyl,
--NR.sup.X1AR.sup.X1B or R.sup.X1AR.sup.X1BNC.sub.1-6alk(en/yn)yl;
and Q5 is hydrogen, halogen, C.sub.1-6alk(en/yn)yl,
C.sub.1-6alk(en/yn)yloxy,
C.sub.1-6alk(en/yn)yloxy-C.sub.1-6alk(en/yn)yl,
C.sub.1-6alk(en/yn)ylsulfanyl, acyl, hydroxy,
hydroxy-C.sub.1-6alk(en/yn)yl, C.sub.3-8cycloalk(en/yn)yl,
C.sub.3-8cycloalk(en/yn)yloxy, aryl, heterocyclyl,
--NR.sup.X1AR.sup.X1B or R.sup.X1AR.sup.X1BNC.sub.1-6alk(en/yn)yl,
where R.sup.X1A and R.sup.X1B are independently hydrogen or
C.sub.1-6alk(en/yn)yl.
[0066] In certain embodiments, neither R.sup.1 nor R.sup.X1 (or
neither R.sup.1 nor R.sup.X2, when X.sup.1 is S) is Q.sup.1,
Q.sup.2 or Q.sup.3, wherein
[0067] Q.sup.1 is
--(CR.sup.1AR.sup.1B).sub.mC.ident.C--(CR.sup.1AR.sup.1B).sub.tR.sup.1C,
--(CR.sup.1AR.sup.1B).sub.mC.dbd.C--(CR.sup.1AR.sup.1B).sub.tR.sup.1C,
--C.dbd.NOR.sup.1D, or --X.sup.3R.sup.1D wherein m is an integer
from 0 to 3, t is an integer from 0 to 5, and X.sup.3 is a divalent
group derived from azetidine, oxetane or a C.sub.3-4carbocyclic
group;
[0068] Q.sup.2 is
--(CR.sup.1AR.sup.1B).sub.mC.ident.C--(CR.sup.1AR.sup.1B).sub.kR.sup.1E,
--(CR.sup.1AR.sup.1B).sub.mC.dbd.C--(CR.sup.1AR.sup.1B).sub.kR.sup.1E
wherein k is an integer from 1 to 3 and m is an integer from 0 to
3; and
[0069] Q.sup.3 is --(CR.sup.1AR.sup.1B).sub.tR.sup.1C, wherein t is
an integer from 0 to 5 and the attachment point to R.sup.1C is
through a carbon atom of the R.sup.1C group; wherein R.sup.1A and
R.sup.1B are independently H or C.sub.1-6alkyl; R.sup.1C is an
optionally substituted non-aromatic monocyclic ring, a fused or
bridged bycyclic ring or a spirocyclic ring; R.sup.1E is
--NR.sup.1AR.sup.1D or --OR.sup.1D; R.sup.1D is R.sup.1F,
--C(.dbd.O)R.sup.1F, --SO.sub.2R.sup.1F,
--C(.dbd.O)N(R.sup.1F).sub.2, --SO.sub.2N(R.sup.1F).sub.2, or
--CO.sub.2R.sup.1F, wherein R.sup.1F is H, C.sub.1-6alkyl,
--(CR.sup.1AR.sup.1B).sub.t(C.sub.6-10aryl) or
--(CR.sup.1AR.sup.1B).sub.t(4-10 membered heterocyclic).
[0070] In certain embodiments, the following groups do not occur
simultaneously as defined: one of R.sup.1 and R.sup.X1 (or one of
R.sup.1 and R.sup.X2, when X.sup.1 is S) is hydrogen, the other is
hydrogen, halogen, C.sub.1-4alkyl or C.sub.1-4alkoxy; L.sup.1 is
--NHC.sub.1-6alkyl, --OC.sub.1-6alkyl, --NHC.sub.1-6heteroalkyl or
--OC.sub.1-6heteroalkyl; Y is cycloalkyl, aryl, heteroaryl or
heterocyclyl; L.sup.2-Z is --X--R.sup.x where X is --NR--,
--C(.dbd.O)NH--, --NHC(.dbd.O)--, --SO.sub.2NH-- or --NHSO.sub.2--
and R.sup.x is C.sub.3-10cycloalkyl, morpholinyl, phenyl,
phenylC.sub.1-4alkyl or phenylC.sub.2-3alkenyl.
[0071] In certain embodiments, the following groups do not occur
simultaneously as defined: one of X.sup.1 and X.sup.2 is CH, the
other is S; L.sup.1 is --NR(CR.sup.x).sub.1-2-- or
--O(CR.sup.x).sub.1-2-- wherein R is hydrogen, C.sub.1-4alkyl,
C.sub.1-4alkoxy, OH, NH.sub.2 or --C.sub.1-4alkylNH; and R.sup.x is
H or C.sub.1-4alkyl; Y is phenyl, thienyl, furanyl, pyrrolyl,
pyridyl, pyrimidyl, imidazolyl, pyrazinyl, oxazolyl, thiazolyl,
naphthyl, benzothienyl, benzofuranyl, indolyl, quinolinyl,
isoquinolinyl or quinazolinyl; L.sup.2-Z is
--SO.sub.2NHC.sub.3-8cycloalkyl,
--SO.sub.2N(C.sub.3-8cycloalkyl).sub.2,
--C(.dbd.O)NHC.sub.3-8cycloalkyl or
--C(.dbd.O)N(C.sub.3-8cycloalkyl).sub.2.
[0072] In certain embodiments, the following groups do not occur
simultaneously as defined: R.sup.1 is hydrogen, halogen, nitro or
C.sub.1-4alkyl; one of X.sup.1 and X.sup.2 is S, the other is
CR.sup.XA wherein R.sup.XA is hydrogen, C.sub.1-4alkyl or phenyl
optionally substituted with halogen, (halo)C.sub.1-4alkyl or
(halo)C.sub.1-4alkoxy; L.sup.1 is --NRC.sub.1-6alkyl-,
--OC.sub.1-6alkyl- or --SC.sub.1-6alkyl- wherein R is hydrogen,
C.sub.1-4alkyl, C.sub.1-4acyl; Y is phenyl; L.sup.2-Z is a
C.sub.1-12alkyl saturated or unsaturated hydrocarbon chain
including --NR-- and optionally substituted with
haloC.sub.1-4alkoxy, C.sub.3-8cycloalkyl, C.sub.3-8cycloalkenyl,
C.sub.1-4acyl, phenoxy, phenyl or phenylthio.
[0073] In certain embodiments, compounds specifically and/or
generically disclosed in Japanese Application Nos.: JP 3-173872 and
JP 3-063271 (which are incorporated herein by reference) are
excluded.
[0074] In certain embodiments, the present invention defines
particular classes of compounds which are of special interest. For
example, one class of compounds of special interest includes
compounds of formula (I.sup.A):
##STR00004##
[0075] Another class of compounds of special interest includes
compounds of formula (I.sup.B):
##STR00005##
[0076] Another class of compounds of special interest includes
compounds of formula (I.sup.C):
##STR00006##
[0077] Another Class of Compounds of Special Interest Includes
Compounds of Formula (I.sup.D):
##STR00007##
[0078] Another class of compounds of special interest includes
compounds of formula (I.sup.E):
##STR00008##
[0079] wherein W.sup.1 is O or NR.sup.W1, where R.sup.W1 is
hydrogen, aliphatic, heteroaliphatic, alicyclic, heteroalicyclic,
aromatic, heteroaromatic, or acyl; and Alk.sub.1 is a
C.sub.1-6alkylene or C.sub.2-6alkenylene moiety.
[0080] Another class of compounds of special interest includes
compounds of formula (I.sup.F):
##STR00009##
[0081] wherein R.sup.W1 is hydrogen, aliphatic, heteroaliphatic,
alicyclic, heteroalicyclic, aromatic, heteroaromatic, or acyl;
Alk.sub.1 is a C.sub.1-6alkylene or C.sub.2-6alkenylene moiety; or
R.sup.W1 taken together with a carbon atom present on Alk.sub.1 may
form a heterocyclic moiety.
[0082] Another class of compounds of special interest includes
compounds of formula (I.sup.G):
##STR00010##
[0083] wherein W.sup.2 and W.sup.3 are independently absent, O,
NR.sup.W, CR.sup.W1R.sup.W2 or NR.sup.WCR.sup.W1R.sup.W2, where
R.sup.W is hydrogen, aliphatic, heteroaliphatic, alicyclic,
heteroalicyclic, aromatic, heteroaromatic, or acyl; and R.sup.W1
and R.sup.W2 are independently hydrogen, aliphatic,
heteroaliphatic, alicyclic, heteroalicyclic, aromatic or
heteroaromatic; with the proviso that W.sup.2 and W.sup.3 are not
each absent and at least one of W.sup.2 and W.sup.3 is NR.sup.W or
NR.sup.WCR.sup.W1R.sup.W2.
[0084] A number of important subclasses of each of the foregoing
classes deserve separate mention; these subclasses include
subclasses of the foregoing classes in which:
[0085] i) neither R.sup.1 nor R.sup.X1 (or neither R.sup.1 nor
R.sup.X2, when X.sup.1 is S) is
--(CR.sup.1AR.sup.1B).sub.mC.ident.C--(CR.sup.1AR.sup.1B).sub.tR.sup.1C,
--(CR.sup.1AR.sup.1B).sub.mC.dbd.C--(CR.sup.1AR.sup.1B).sub.tR.sup.1C,
--C.dbd.NOR.sup.1D, or --X.sup.3R.sup.1D wherein m is an integer
from 0 to 3, t is an integer from 0 to 5, and X.sup.3 is a divalent
group derived from azetidine, oxetane or a C.sub.3-4carbocyclic
group; wherein R.sup.1A and R.sup.1B are independently H or
C.sub.1-6alkyl; R.sup.1C is an optionally substituted non-aromatic
monocyclic ring, a fused or bridged bycyclic ring or a spirocyclic
ring; R.sup.1E is --NR.sup.1AR.sup.1D or --OR.sup.1D; R.sup.1D is
R.sup.1F, --C(.dbd.O)R.sup.1F, --SO.sub.2R.sup.1F,
--C(.dbd.O)N(R.sup.1F).sub.2, --SO.sub.2N(R.sup.1F).sub.2, or
--CO.sub.2R.sup.1F, wherein R.sup.1F is H, C.sub.1-6alkyl,
--(CR.sup.1AR.sup.1B).sub.t(C.sub.6-10aryl) or
--(CR.sup.1AR.sup.1B).sub.t(4-10 membered heterocyclic);
[0086] ii) neither R.sup.1 nor R.sup.X1 (or neither R.sup.1 nor
R.sup.X2, when X.sup.1 is S) is
--(CR.sup.1AR.sup.1B).sub.mC.ident.C--(CR.sup.1AR.sup.1B).sub.kR.sup.1E,
--(CR.sup.1AR.sup.1B).sub.mC.dbd.C--(CR.sup.1AR.sup.1B).sub.kR.sup.1E
wherein k is an integer from 1 to 3 and m is an integer from 0 to
3;
[0087] iii) neither R.sup.1 nor R.sup.X1 (or neither R.sup.1 nor
R.sup.X2, when X.sup.1 is S) is
--(CR.sup.1AR.sup.1B).sub.tR.sup.1C, wherein t is an integer from 0
to 5 and the attachment point to R.sup.1C is through a carbon atom
of the R.sup.1C group;
[0088] iv) R.sup.1 is hydrogen, halogen, --CN, --NO.sub.2,
--C(.dbd.O)R.sup.1A, --C(.dbd.O)OR.sup.1A,
--C(.dbd.O)NR.sup.1AR.sup.1B, --S(.dbd.O).sub.2R.sup.1C,
--P(.dbd.O)(R.sup.1C).sub.2, alkyl, alkenyl, alkynyl, cycloalkyl,
cycloalkenyl, heteroalkyl, heteroalkenyl, heteroalkynyl,
heterocyclyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl,
-(heteroalkyl)aryl or -(heteroalkyl)heteroaryl; wherein R.sup.1A
and R.sup.1B are independently hydrogen, alkyl, alkenyl, alkynyl,
cycloalkyl, cycloalkenyl, heteroalkyl, heteroalkenyl,
heteroalkynyl, heterocyclyl, aryl, heteroaryl, -(alkyl)aryl,
-(alkyl)heteroaryl, -(heteroalkyl)aryl or -(heteroalkyl)heteroaryl;
or taken together with the nitrogen atom to which they are attached
form a 5-6-membered heterocyclic ring; and each occurrence of
R.sup.1C is independently alkyl, alkenyl, alkynyl, cycloalkyl,
cycloalkenyl, heteroalkyl, heteroalkenyl, heteroalkynyl,
heterocyclyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl,
-(heteroalkyl)aryl or -(heteroalkyl)heteroaryl;
[0089] v) R.sup.1 is hydrogen, halogen, --NO.sub.2, --CN,
--C(.dbd.O)OR.sup.1A, --S(.dbd.O).sub.2R.sup.1C,
--P(.dbd.O)(R.sup.1C).sub.2, alkyl, alkenyl, alkynyl, heteroalkyl,
heteroalkenyl, heteroalkynyl, heterocyclyl, aryl or heteroaryl;
wherein R.sup.1A is hydrogen or C.sub.1-6alkyl; and each occurrence
of R.sup.1C is independently C.sub.1-6 alkyl;
[0090] vi) R.sup.1 is hydrogen, halogen, --NO.sub.2, --CN,
C.sub.1-5alkyl or C.sub.1-5alkoxy;
[0091] vii) R.sup.1 is hydrogen;
[0092] viii) R.sup.1 is F, Cl, Br or I;
[0093] ix) R.sup.1 is alkyl, alkenyl, alkynyl, heteroalkyl,
heteroalkenyl or heteroalkynyl;
[0094] x) R.sup.1 is one of:
##STR00011##
[0095] wherein V is O, S or R.sup.1B; p is an integer from 0 to 6;
and R.sup.1A is hydrogen, alkyl, heteroalkyl, aryl, heteroaryl,
-(alkyl)aryl, -(alkyl)heteroaryl, --C(.dbd.O)N(R.sup.1B).sub.2,
--C(.dbd.O)OR.sup.1B; wherein each occurrence of R.sup.1B and
R.sup.1C is independently hydrogen, lower alkyl, lower heteroalkyl,
aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl or acyl; or
R.sup.1B and R.sup.1C, taken together with the nitrogen atom to
which they are attached, form a substituted or unsubstituted
heterocyclic moiety;
[0096] xi) R.sup.1 is --CN, lower alkyl, lower alkynyl,
--CO.sub.2R.sup.1D, or one of:
##STR00012##
[0097] wherein p is an integer from 1 to 4; and R.sup.1A is
hydrogen, alkyl, heteroalkyl, aryl, heteroaryl, -(alkyl)aryl,
-(alkyl)heteroaryl, --C(.dbd.O)N(R.sup.1B).sub.2,
--C(.dbd.O)OR.sup.1B; wherein each occurrence of R.sup.1B and
R.sup.1C is independently hydrogen, lower alkyl, lower heteroalkyl,
aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl or acyl; or
R.sup.1B and R.sup.1C, taken together with the nitrogen atom to
which they are attached, form a substituted or unsubstituted
heterocyclic moiety; and R.sup.1D is hydrogen or lower alkyl;
##STR00013##
[0098] xii) R.sup.1 is --CN, --C.ident.CH, methyl, --CO.sub.2H,
--CO.sub.2Me, or one of:
[0099] xiii) R.sup.1 is aryl, heteroaryl or heterocyclyl;
[0100] xiv) R.sup.1 is an aryl, heteroaryl or heterocyclyl moiety
having one of the structures:
##STR00014##
[0101] wherein the "A" cyclic moiety is a 6-membered aromatic ring
comprising from 0-4 nitrogen atoms; the "Het" moiety represents a
fully or partially saturated or unsaturated 5- to 6-membered ring
comprising 1-4 heteroatoms selected from N, O and S; n is an
integer from 0-6; and each occurrence of R.sup.1A is independently
hydrogen, alkyl, cycloalkyl, heteroalkyl, heterocyclyl, aryl,
heteroaryl, -(alkyl)heterocyclyl, -(alkyl)aryl, -(alkyl)heteroaryl,
--OR.sup.1B, --SR.sup.1B, --N(R.sup.1B).sub.2,
--SO.sub.2N(R.sup.1B).sub.2, --SO.sub.2R.sup.1E,
--C(.dbd.O)N(R.sup.1B).sub.2, halogen, --CN, --NO.sub.2,
--C(.dbd.O)OR.sup.1B, --N(R.sup.1B)C(.dbd.O)R.sup.1C or
--N(R.sup.1B)SO.sub.2R.sup.1E; wherein each occurrence of R.sup.1B
and R.sup.1C is independently hydrogen, lower alkyl, lower
heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl,
acyl; or any two occurrences of R.sup.1B, taken together with the
nitrogen atom to which they are attached (e.g., N(R.sup.1B).sub.2),
form a substituted or unsubstituted heterocyclic moiety; R.sup.1E
is alkyl, heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, or
-(alkyl)heteroaryl; and wherein any two adjacent occurrence of
R.sup.1A may form a fused 5- to 6-membered aryl, heteroaryl or
heterocyclic ring;
[0102] xv) R.sup.1 is one of:
##STR00015## ##STR00016##
[0103] wherein each occurrence of R.sup.1A is independently
hydrogen, alkyl, cycloalkyl, heteroalkyl, heterocyclyl, aryl,
heteroaryl, -(alkyl)heterocyclyl, -(alkyl)aryl, -(alkyl)heteroaryl,
--OR.sup.1B, --SR.sup.1B, --N(R.sup.1B).sub.2,
--SO.sub.2N(R.sup.1B).sub.2, --SO.sub.2R.sup.1E,
--C(.dbd.O)N(R.sup.1B).sub.2, halogen, --CN, --NO.sub.2,
--C(.dbd.O)OR.sup.1B, --N(R.sup.1B)C(.dbd.O)R.sup.1C or
--N(R.sup.1B)SO.sub.2R.sup.1E; wherein each occurrence of R.sup.1B
and R.sup.1C is independently hydrogen, lower alkyl, lower
heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl,
acyl; or R.sup.1B and R.sup.1C, taken together with the atoms to
which they are attached, form a substituted or unsubstituted
heterocyclic moiety; R.sup.1D is hydrogen, alkyl, cycloalkyl,
heteroalkyl, heterocyclyl, aryl, heteroaryl, -(alkyl)heterocyclyl,
-(alkyl)aryl, -(alkyl)heteroaryl, acyl or a nitrogen protecting
group; and R.sup.1E is lower alkyl, lower heteroalkyl, aryl,
heteroaryl, -(alkyl)aryl, or -(alkyl)heteroaryl; wherein n is an
integer from 0 to 3 and r is an integer from 1 to 6;
[0104] xvi) R.sup.1 is one of:
##STR00017##
[0105] wherein n, R.sup.1A and R.sup.1D are as defined in xiv)
above;
[0106] xvii) R.sup.1 is one of:
##STR00018##
[0107] wherein n is 0-2; R.sup.1A is hydrogen or lower alkyl; each
occurrence of R.sup.1B and R.sup.1C is independently hydrogen,
lower alkyl, or R.sup.1B and R.sup.1C, taken together with the
nitrogen atom to which they are attached, form a substituted or
unsubstituted 5-6 membered heterocyclic moiety; R.sup.1D is
hydrogen, or lower alkyl; R.sup.1E is hydrogen, or lower alkyl;
[0108] xviii) R.sup.1 is one of:
##STR00019##
[0109] wherein each occurrence of R.sup.1A is independently
hydrogen or lower alkyl; each occurrence of R.sup.1B and R.sup.1C
is independently hydrogen, lower alkyl, or R.sup.1B and R.sup.1C,
taken together with the nitrogen atom to which they are attached,
form a substituted or unsubstituted 5-6 membered heterocyclic
moiety; R.sup.1D is hydrogen, or lower alkyl; R.sup.1E is hydrogen,
or lower alkyl;
[0110] xix) R.sup.1 is one of:
##STR00020## ##STR00021##
[0111] wherein p is 1 or 3;
[0112] xx) R.sup.2 is hydrogen, halogen, cyano, nitro, or an alkyl,
alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heteroalkyl,
heteroalkenyl, heteroalkynyl, heterocyclyl, aryl, heteroaryl,
-(alkyl)aryl, -(alkyl)heteroaryl, -(heteroalkyl)aryl or
-(heteroalkyl)heteroaryl moiety;
[0113] xxi) R.sup.2 is C.sub.1-3alkyl or C.sub.1-3alkoxy;
[0114] xxii) R.sup.2 is methyl or --CF.sub.3;
[0115] xxiii) R.sup.2 is halogen;
[0116] xxiv) R.sup.2 is hydrogen;
[0117] xxv) one of X.sup.1 and X.sup.2 is S, the other is
--C(R.sup.XA)--; wherein R.sup.XA is hydrogen, halogen, cyano,
nitro, or an alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,
heteroalkyl, heteroalkenyl, heteroalkynyl, heterocyclyl, aryl,
heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl, -(heteroalkyl)aryl or
-(heteroalkyl)heteroaryl moiety;
[0118] xxvi) one of X.sup.1 and X.sup.2 is S, the other is
--C(R.sup.XA)--; wherein R.sup.XA is hydrogen, halogen, or an
alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heteroalkyl,
heteroalkenyl, heteroalkynyl, heterocyclyl, aryl or heteroaryl
moiety;
[0119] xxvii) one of X.sup.1 and X.sup.2 is S, the other is
--C(R.sup.XA)--; wherein R.sup.XA is hydrogen, halogen, or a lower
alkyl, cycloalkyl, cycloalkenyl, lower heteroalkyl, heterocyclyl,
aryl or heteroaryl moiety;
[0120] xxviii) one of X.sup.1 and X.sup.2 is S, the other is
--C(R.sup.XA)--; wherein R.sup.XA is hydrogen, halogen, or a lower
alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl moiety;
[0121] xxix) one of X.sup.1 and X.sup.2 is S, the other is
--C(R.sup.XA)--; wherein R.sup.XA is hydrogen, halogen,
C.sub.1-5alkyl, C.sub.1-5alkoxy, --CO.sub.2H,
--CO.sub.2C.sub.1-5alkyl, --CN or --NO.sub.2;
[0122] xxx) X.sup.1 is S and X.sup.2 is CH;
[0123] xxxi) X.sup.2 is S and X.sup.1 is --C(R.sup.X1)--; wherein
R.sup.X1 is hydrogen, halogen, --CN, --NO.sub.2,
--C(.dbd.O)R.sup.1A, --C(.dbd.O)OR.sup.1A,
--C(.dbd.O)NR.sup.1AR.sup.1B, --S(.dbd.O).sub.2R.sup.1C,
--P(.dbd.O)(R.sup.1C).sub.2, alkyl, alkenyl, alkynyl, cycloalkyl,
cycloalkenyl, heteroalkyl, heteroalkenyl, heteroalkynyl,
heterocyclyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl,
-(heteroalkyl)aryl or -(heteroalkyl)heteroaryl; wherein R.sup.1A
and R.sup.1B are independently hydrogen, alkyl, alkenyl, alkynyl,
cycloalkyl, cycloalkenyl, heteroalkyl, heteroalkenyl,
heteroalkynyl, heterocyclyl, aryl, heteroaryl, -(alkyl)aryl,
-(alkyl)heteroaryl, -(heteroalkyl)aryl or -(heteroalkyl)heteroaryl;
or taken together with the nitrogen atom to which they are attached
form a 5-6-membered heterocyclic ring; and each occurrence of
R.sup.1C is independently alkyl, alkenyl, alkynyl, cycloalkyl,
cycloalkenyl, heteroalkyl, heteroalkenyl, heteroalkynyl,
heterocyclyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl,
-(heteroalkyl)aryl or -(heteroalkyl)heteroaryl;
[0124] xxxii) X.sup.2 is S and X.sup.1 is --C(R.sup.X1)--; wherein
R.sup.X1 is hydrogen, halogen, --NO.sub.2, --CN,
--C(.dbd.O)OR.sup.1A, --S(.dbd.O).sub.2R.sup.1C,
--P(.dbd.O)(R.sup.1C).sub.2, alkyl, alkenyl, alkynyl, heteroalkyl,
heteroalkenyl, heteroalkynyl, heterocyclyl, aryl or heteroaryl;
wherein R.sup.1A is hydrogen or C.sub.1-6alkyl; and each occurrence
of R.sup.1C is independently C.sub.1-6alkyl;
[0125] xxxiii) X.sup.2 is S and X.sup.1 is --C(R.sup.X1)--; wherein
R.sup.X1 is hydrogen, halogen, --NO.sub.2, --CN, C.sub.1-5alkyl or
C.sub.1-5alkoxy;
[0126] xxxiv) X.sup.2 is S and X.sup.1 is CH;
[0127] xxxv) X.sup.2 is S and X.sup.1 is --C(R.sup.X1)--; wherein
R.sup.X1 is F, Cl, Br or I;
[0128] xxxvi) X.sup.2 is S and X.sup.1 is --C(R.sup.X1)--; wherein
R.sup.X1 is alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl or
heteroalkynyl;
[0129] xxxvii) X.sup.2 is S and X.sup.1 is --C(R.sup.X1)--; wherein
R.sup.X1 is one of:
##STR00022##
[0130] wherein V is O, S or R.sup.1B; p is an integer from 0 to 6;
and R.sup.1A is hydrogen, alkyl, heteroalkyl, aryl, heteroaryl,
-(alkyl)aryl, -(alkyl)heteroaryl, --C(.dbd.O)N(R.sup.1B).sub.2,
--C(.dbd.O)OR.sup.1B; wherein each occurrence of R.sup.1B and
R.sup.1C is independently hydrogen, lower alkyl, lower heteroalkyl,
aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl or acyl; or
R.sup.1B and R.sup.1C, taken together with the nitrogen atom to
which they are attached, form a substituted or unsubstituted
heterocyclic moiety;
[0131] xxxviii) X.sup.2 is S and X.sup.1 is --C(R.sup.X1)--;
wherein R.sup.X1 is --CN, lower alkyl, lower alkynyl,
--CO.sub.2R.sup.1D, or one of:
##STR00023##
[0132] wherein p is an integer from 1 to 4; and R.sup.1A is
hydrogen, alkyl, heteroalkyl, aryl, heteroaryl, -(alkyl)aryl,
-(alkyl)heteroaryl, --C(.dbd.O)N(R.sup.1B).sub.2,
--C(.dbd.O)OR.sup.1B; wherein each occurrence of R.sup.1B and
R.sup.1C is independently hydrogen, lower alkyl, lower heteroalkyl,
aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl or acyl; or
R.sup.1B and R.sup.1C, taken together with the nitrogen atom to
which they are attached, form a substituted or unsubstituted
heterocyclic moiety; and R.sup.1D is hydrogen or lower alkyl;
[0133] xxxix) X.sup.2 is S and X.sup.1 is --C(R.sup.X1)--; wherein
R.sup.X1 is --CN, --C.ident.CH, methyl, --CO.sub.2H, --CO.sub.2Me,
or one of:
##STR00024##
[0134] xl) X.sup.2 is S and X.sup.1 is --C(R.sup.X1)--; wherein
R.sup.X1 is aryl, heteroaryl or heterocyclyl;
[0135] xli) X.sup.2 is S and X.sup.1 is --C(R.sup.X1)--; wherein
R.sup.X1 is an aryl, heteroaryl or heterocyclyl moiety having one
of the structures:
##STR00025##
[0136] wherein the "A" cyclic moiety is a 6-membered aromatic ring
comprising from 0-4 nitrogen atoms; the "Het" moiety represents a
fully or partially saturated or unsaturated 5- to 6-membered ring
comprising 1-4 heteroatoms selected from N, O and S; n is an
integer from 0-6; and each occurrence of R.sup.1A is independently
hydrogen, alkyl, cycloalkyl, heteroalkyl, heterocyclyl, aryl,
heteroaryl, -(alkyl)heterocyclyl, -(alkyl)aryl, -(alkyl)heteroaryl,
--OR.sup.1B, --SR.sup.1B, --N(R.sup.1B).sub.2,
--SO.sub.2N(R.sup.1B).sub.2, --SO.sub.2R.sup.1E,
--C(.dbd.O)N(R.sup.1B).sub.2, halogen, --CN, --NO.sub.2,
--C(.dbd.O)OR.sup.1B, --N(R.sup.1B)C(.dbd.O)R.sup.1C or
--N(R.sup.1B)SO.sub.2R.sup.1E; wherein each occurrence of R.sup.1B
and R.sup.1C is independently hydrogen, lower alkyl, lower
heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl,
acyl; or any two occurrences of R.sup.1B, taken together with the
nitrogen atom to which they are attached (e.g., N(R.sup.1B).sub.2),
form a substituted or unsubstituted heterocyclic moiety; R.sup.1E
is alkyl, heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, or
-(alkyl)heteroaryl; and wherein any two adjacent occurrence of
R.sup.1A may form a fused 5- to 6-membered aryl, heteroaryl or
heterocyclic ring;
[0137] xlii) X.sup.2 is S and X.sup.1 is --C(R.sup.X1)--; wherein
R.sup.X1 is one of:
##STR00026## ##STR00027##
[0138] wherein each occurrence of R.sup.1A is independently
hydrogen, alkyl, cycloalkyl, heteroalkyl, heterocyclyl, aryl,
heteroaryl, -(alkyl)heterocyclyl, -(alkyl)aryl, -(alkyl)heteroaryl,
--OR.sup.1B, --SR.sup.1B, --N(R.sup.1B).sub.2,
--SO.sub.2N(R.sup.1B).sub.2, --SO.sub.2R.sup.1E,
--C(.dbd.O)N(R.sup.1B).sub.2, halogen, --CN, --NO.sub.2,
--C(.dbd.O)OR.sup.1B, --N(R.sup.1B)C(.dbd.O)R.sup.1C or
--N(R.sup.1B)SO.sub.2R.sup.1E; wherein each occurrence of R.sup.1B
and R.sup.1C is independently hydrogen, lower alkyl, lower
heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl,
acyl; or R.sup.1B and R.sup.1C, taken together with the atoms to
which they are attached, form a substituted or unsubstituted
heterocyclic moiety; R.sup.1D is hydrogen, alkyl, cycloalkyl,
heteroalkyl, heterocyclyl, aryl, heteroaryl, -(alkyl)heterocyclyl,
-(alkyl)aryl, -(alkyl)heteroaryl, acyl or a nitrogen protecting
group; and R.sup.1E is lower alkyl, lower heteroalkyl, aryl,
heteroaryl, -(alkyl)aryl, or -(alkyl)heteroaryl; wherein n is an
integer from 0 to 3 and r is an integer from 1 to 6;
[0139] xliii) X.sup.2 is S and X.sup.1 is --C(R.sup.X1)--; wherein
R.sup.X1 is one of:
##STR00028##
[0140] wherein n, R.sup.1A and R.sup.1D are as defined in xlii)
above;
[0141] xliv) X.sup.2 is S and X.sup.1 is --C(R.sup.X1)--; wherein
R.sup.X1 is one of:
##STR00029##
[0142] wherein n is 0-2; R.sup.1A is hydrogen or lower alkyl; each
occurrence of R.sup.1B and R.sup.1C is independently hydrogen,
lower alkyl, or R.sup.1B and R.sup.1C, taken together with the
nitrogen atom to which they are attached, form a substituted or
unsubstituted 5-6 membered heterocyclic moiety; R.sup.1D is
hydrogen, or lower alkyl; R.sup.1E is hydrogen, or lower alkyl;
[0143] xlv) X.sup.2 is S and X.sup.1 is --C(R.sup.X1)--; wherein
R.sup.X1 is one of:
##STR00030##
[0144] wherein each occurrence of R.sup.1A is independently
hydrogen or lower alkyl; each occurrence of R.sup.1B and R.sup.1C
is independently hydrogen, lower alkyl, or R.sup.1B and R.sup.1C,
taken together with the nitrogen atom to which they are attached,
form a substituted or unsubstituted 5-6 membered heterocyclic
moiety; R.sup.1D is hydrogen, or lower alkyl; R.sup.1E is hydrogen,
or lower alkyl;
[0145] xlvi) X.sup.2 is S and X.sup.1 is --C(R.sup.X1)--; wherein
R.sup.X1 is one of:
##STR00031## ##STR00032##
[0146] xlvii) L.sup.1 is --W.sup.1-Alk.sub.1-; wherein W.sup.1 is
O, S, NR.sup.w1 or --C(.dbd.O)NR.sup.w1 where R.sup.W1 is hydrogen,
alkyl, cycloalkyl, heteroalkyl, heterocyclyl, aryl, heteroaryl,
-(alkyl)aryl, -(alkyl)heteroaryl or acyl; and Alk.sub.1 is a
substituted or unsubstituted C.sub.1-6alkylene or
C.sub.2-6alkenylene chain wherein up to two non-adjacent methylene
units are independently optionally replaced by --C(.dbd.O)--,
--CO.sub.2--, --C(.dbd.O)C(.dbd.O)--, --C(.dbd.O)NR.sup.L1A--,
--OC(.dbd.O)--, --OC(.dbd.O)NR.sup.L1A--, --NR.sup.L1ANR.sup.L1B--,
--NR.sup.L1ANR.sup.L1BC(.dbd.O)--, --NR.sup.L1AC(.dbd.O)--,
--NR.sup.L1ACO.sub.2--, --NR.sup.L1AC(.dbd.O)NR.sup.L1B--,
--S(.dbd.O)--, --SO.sub.2--, --NR.sup.L1ASO.sub.2--,
--SO.sub.2NR.sup.L1A--, --NR.sup.L1ASO.sub.2NR.sup.L1B--, --O--,
--S--, or --NR.sup.L1A--; wherein each occurrence of R.sup.L1A and
R.sup.L1B is independently hydrogen, alkyl, heteroalkyl,
heterocyclyl, aromatic, heteroaromatic or acyl;
[0147] xlviii) L.sup.1 is --W.sup.1-Alk.sub.1-; wherein W.sup.1 is
O, S, NR.sup.w1 or --C(.dbd.O)NR.sup.W1 where R.sup.W1 is hydrogen,
lower alkyl, C.sub.3-6cycloalkyl, lower heteroalkyl, heterocyclyl,
aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl or acyl; and
Alk.sub.1 is a substituted or unsubstituted C.sub.1-6alkylene or
C.sub.2-6alkenylene chain wherein up to two non-adjacent methylene
units are independently optionally replaced by --C(.dbd.O)--,
--CO.sub.2--, --C(.dbd.O)C(.dbd.O)--, --C(.dbd.O)NR.sup.L1A--,
--OC(.dbd.O)--, --OC(.dbd.O)NR.sup.L1A--, --NR.sup.L1ANR.sup.L1B--,
--NR.sup.L1ANR.sup.L1BC(.dbd.)--, --NR.sup.L1AC(.dbd.)--,
--NR.sup.L1ACO.sub.2--, --NR.sup.L1AC(.dbd.O)NR.sup.L1B--,
--S(.dbd.O)--, --SO.sub.2--, --NR.sup.L1ASO.sub.2--,
--SO.sub.2NR.sup.L1A--, --NR.sup.L1ASO.sub.2NR.sup.L1B--, --O--,
--S--, or --NR.sup.L1A--; wherein each occurrence of R.sup.L1A and
R.sup.L1B is independently hydrogen, lower alkyl, lower
heteroalkyl, heterocyclyl, aryl, heteroaryl or acyl;
[0148] xlix) Compounds of subset xlviii) above wherein W.sup.1 is
S;
[0149] l) Compounds of subset xlviii) above wherein W.sup.1 is O or
NR.sup.W1;
[0150] li) L.sup.1 is --O-Alk.sub.1-; wherein Alk.sub.1 is a
substituted or unsubstituted C.sub.2 alkylene chain;
[0151] lii) L.sup.1 is --O-cyclopropyl-;
[0152] liii) L.sup.1 is --O--CH.sub.2CH.sub.2--;
[0153] iv) L.sup.1 is --NR.sup.W1-Alk.sub.1-; wherein R.sup.W1 is
hydrogen, lower alkyl, C.sub.3-6cycloalkyl, lower heteroalkyl,
aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl or acyl; and
Alk.sub.1 is a substituted or unsubstituted C.sub.2-6alkylene chain
wherein up to two non-adjacent methylene units are independently
optionally replaced by --C(.dbd.O)--, --S(.dbd.O)--, --SO.sub.2--,
--O--, --S--, or --NR.sup.L1A--; wherein R.sup.L1A is hydrogen or
lower alkyl;
[0154] Iv) L.sup.1 is --NR.sup.W1-Alk.sub.1-; wherein R.sup.W1 is
hydrogen, lower alkyl or lower heteroalkyl; and Alk.sub.1 is a
substituted or unsubstituted C.sub.2alkylene chain;
[0155] lvi) L.sup.1 is --NH-cyclopropyl-;
[0156] lvii) L.sup.1 is --NH--CH.sub.2CH.sub.2--;
[0157] lviii) L.sup.1 is --NH--CH.sub.2CF.sub.2--;
[0158] lix) L.sup.1 is
--NH--CH.sub.2CH[(CH.sub.2).sub.pOR.sup.W2]--; wherein p is 1 or 2
and R.sup.W2 is hydrogen or lower alkyl;
[0159] lx) L.sup.1 is --NH--CH.sub.2CH(CH.sub.2OH)--;
[0160] lxi) L.sup.1 is --NH--CH.sub.2CH(CH.sub.2CH.sub.2OH)--;
[0161] xii) L.sup.1 is --NR.sup.W1-Alk.sub.1-; wherein R.sup.W1 is
lower heteroalkyl; and Alk.sub.1 is a substituted or unsubstituted
C.sub.2 alkylene chain;
[0162] lxiii) L.sup.1 is --NR.sup.W1-Alk.sub.1-; wherein R.sup.W1
is --(CH.sub.2).sub.2NR.sup.W2R.sup.W3; Alk.sub.1 is a substituted
or unsubstituted C.sub.2 alkylene chain; and R.sup.W2 and R.sup.W3
are independently hydrogen or lower alkyl;
[0163] lxiv) L.sup.1 is --NR.sup.W1--(CH.sub.2).sub.2--; wherein
R.sup.W1 is --(CH.sub.2).sub.2NR.sup.W2R.sup.W3; and R.sup.W2 and
R.sup.W3 are independently hydrogen or lower alkyl;
[0164] lxv) L.sup.1 is --NR.sup.W1--(CH.sub.2).sub.2--; wherein
R.sup.W1 is --(CH.sub.2).sub.2NMe.sub.2;
[0165] lxvi) L.sup.1 is --NR.sup.W1-Alk.sub.1-; wherein R.sup.W1
together with a carbon atom present on Alk.sub.1 forms an
optionally substituted 5- to 6-membered heterocyclic moiety;
[0166] xvii) L.sup.1 has the structure:
##STR00033##
[0167] wherein R.sup.Alk1 is hydrogen, halohen, hydroxy, CN, nitro,
lower alkyl, lower alkoxy, aryl, or heteroaryl;
[0168] lxviii) L.sup.1 has the structure:
##STR00034##
lxix) L.sup.1 has the structure:
##STR00035##
[0169] wherein R.sup.Alk1 is hydrogen, halohen, hydroxy, CN, nitro,
lower alkyl, lower alkoxy, aryl, or heteroaryl;
[0170] lxx) L.sup.1 has the structure:
##STR00036##
[0171] lxxi) L.sup.1 is --C(.dbd.O)NR.sup.W1-Alk.sub.1-; wherein
R.sup.W1 is hydrogen or lower alkyl; and Alk.sub.1 is a substituted
or unsubstituted C.sub.1alkylene moiety;
[0172] lxxii) L.sup.1 is --C(.dbd.O)NH--CH.sub.2--;
[0173] lxxiii) Y is a saturated or unsaturated cyclic ring system
optionally comprising one or more heteroatoms selected from S, N
and O;
[0174] lxxiv) Y is a saturated or unsaturated monocyclic cyclic
ring system optionally comprising one or more heteroatoms selected
from S, N and O;
[0175] lxxv) Y is a cycloalkyl, cycloalkenyl, heterocylic, aryl or
heteroaryl moiety;
[0176] lxxvi) Y is a 5-6 membered cycloalkyl, 5-6 membered
cycloalkenyl, 5-6 membered heterocylic, 6-membered aryl or
6-membered heteroaryl moiety;
[0177] lxxvii) Y is one of:
##STR00037##
[0178] wherein q is an integer from 0 to 3; each occurrence of
R.sup.Y1 is independently hydrogen, alkyl, heteroalkyl, aryl,
heteroaryl, -(alkyl)aryl or -(alkyl)heteroaryl, --OR.sup.Y3,
--SR.sup.Y3, --NR.sup.Y2R.sup.Y3, --SO.sub.2NR.sup.Y2R.sup.Y3,
--C(.dbd.O)NR.sup.Y2R.sup.Y3, halogen, --CN, --NO.sub.2,
--C(.dbd.O)OR.sup.Y3, --N(R.sup.Y2)C(.dbd.O)R.sup.Y3, wherein each
occurrence of R.sup.Y2 and R.sup.Y3 is independently hydrogen,
lower alkyl, lower heteroalkyl, aryl, heteroaryl, -(alkyl)aryl,
-(alkyl)heteroaryl or acyl, or R.sup.Y2 and R.sup.Y3 taken together
with the nitrogen atom to which they are attached form a 5-6
membered heterocyclic ring;
[0179] lxxviii) Y is one of:
##STR00038##
[0180] wherein q and R.sup.Y1 are as defined directly above;
[0181] lxxix) Y is one of:
##STR00039##
[0182] wherein q is 0-3; and R.sup.Y1 is hydrogen, halogen or lower
alkyl;
[0183] lxxx) Y is one of:
##STR00040##
[0184] lxxxi) Y is one of:
##STR00041##
[0185] lxxxii) Y is:
##STR00042##
[0186] lxxxii) Y is:
##STR00043##
[0187] lxxxiii) Y is:
##STR00044##
[0188] wherein at least one R.sup.Y1 is halogen, the other is
hydrogen or halogen;
[0189] lxxxiv) Y is:
##STR00045##
[0190] wherein at least one R.sup.Y1 is fluoro, the other is
hydrogen or fluoro;
[0191] lxxxv) L.sup.2 is --NR.sup.L2A-- or a substituted or
unsubstituted C.sub.1-6alkylene or C.sub.2-6alkenylene chain
interrupted with at least one nitrogen atom wherein up to two
non-adjacent methylene units are independently optionally replaced
by --C(.dbd.O)--, --CO.sub.2--, --C(.dbd.O)C(.dbd.O)--,
--C(.dbd.O)NR.sup.L2A--, OC(.dbd.O)--, --OC(.dbd.O)NR.sup.L2A--,
--NR.sup.L2ANR.sup.L2B--, --NR.sup.L2ANR.sup.L2BC(.dbd.)--,
--NR.sup.L2AC(.dbd.)--, --NR.sup.L2ACO.sub.2--,
--NR.sup.L2AC(.dbd.O)NR.sup.L2B--, --S(.dbd.O)--, --SO.sub.2--,
--NR.sup.L2ASO.sub.2--, --SO.sub.2NR.sup.L2A--,
--NR.sup.L2ASO.sub.2NR.sup.L2B--, --O--, --S--, or --NR.sup.L2A--;
wherein each occurrence of R.sup.L2A, R.sup.L2B, R.sup.L2C and
R.sup.L2D is independently hydrogen, alkyl, heteroalkyl,
heterocyclyl, aromatic, heteroaromatic or acyl;
[0192] lxxxvi) L.sup.2 is --NR.sup.L2A-- or a substituted or
unsubstituted C.sub.1-6alkylene or C.sub.2-6alkenylene chain
interrupted with at least one nitrogen atom wherein up to two
non-adjacent methylene units are independently optionally replaced
by --C(.dbd.O)--, --CO.sub.2--, --C(.dbd.O)C(.dbd.O)--,
--C(.dbd.O)NR.sup.L2A--, --OC(.dbd.O)--, --OC(.dbd.O)NR.sup.L2A--,
--NR.sup.L2ANR.sup.L2B--, --NR.sup.L2ANR.sup.L2BC(.dbd.)--,
--NR.sup.L2AC(.dbd.)--, --NR.sup.L2ACO.sub.2--,
--NR.sup.L2AC(.dbd.O)NR.sup.L2B--, --S(.dbd.O)--, --SO.sub.2--,
--NR.sup.L2ASO.sub.2--, --SO.sub.2NR.sup.L2A--,
--NR.sup.L2ASO.sub.2NR.sup.L2B--, --O--, --S--, or --NR.sup.L2A--;
wherein each occurrence of R.sup.L2A, R.sup.L2B, R.sup.L2C and
R.sup.L2D is independently hydrogen, lower alkyl, lower
heteroalkyl, heterocyclyl, aryl, heteroaryl or acyl;
[0193] lxxxvii) L.sup.2 is
--(CH.sub.2).sub.mNR.sup.L2A(CH.sub.2).sub.m--,
--(CH.sub.2).sub.mC(.dbd.O)NR.sup.L2A(CH.sub.2).sub.m--,
--(CH.sub.2).sub.mOC(.dbd.O)NR.sup.L2A(CH.sub.2).sub.m--,
--(CH.sub.2).sub.mNR.sup.L2ANR.sup.L2B(CH.sub.2).sub.m--,
(CH.sub.2).sub.mNR.sup.L2ANR.sup.L2BC(.dbd.O)(CH.sub.2).sub.m--,
--(CH.sub.2).sub.mNR.sup.L2AC(.dbd.O)(CH.sub.2).sub.m--,
(CH.sub.2).sub.mNR.sup.L2AC(.dbd.O)O(CH.sub.2).sub.m--,
--(CH.sub.2).sub.mNR.sup.L2AC(.dbd.O)NR.sup.L2B(CH.sub.2).sub.m--,
(CH.sub.2).sub.mNR.sup.L2AC(.dbd.O)NR.sup.L2BCR.sup.L2CR.sup.L2D(CH.sub.2-
).sub.m--,
--(CH.sub.2).sub.mCR.sup.L2CR.sup.L2DC(.dbd.O)NR.sup.L2B(CH.sub-
.2).sub.m, --(CH.sub.2).sub.mNR.sup.L2ASO.sub.2(CH.sub.2).sub.m--,
--(CH.sub.2).sub.mSO.sub.2NR.sup.L2A(CH.sub.2).sub.m--,
--(CH.sub.2).sub.mNR.sup.L2ASO.sub.2NR.sup.L2B(CH.sub.2).sub.m--;
wherein each occurrence of m is independently 0-4; and each
occurrence of R.sup.L2A, R.sup.L2B, R.sup.L2C and R.sup.L2D is
independently hydrogen, lower alkyl, lower heteroalkyl,
heterocyclyl, aryl, heteroaryl or acyl;
[0194] lxxxviii) L.sup.2 is --NR.sup.L2A--,
--C(.dbd.O)NR.sup.L2A--, --OC(.dbd.O)NR.sup.L2A--,
--NR.sup.L2ANR.sup.L2B--, NR.sup.L2ANR.sup.L2BC(.dbd.O)--,
--NR.sup.L2AC(.dbd.O)--, --NR.sup.L2ACO.sub.2--,
--NR.sup.L2AC(.dbd.O)NR.sup.L2B--,
--NR.sup.L2AC(.dbd.O)NR.sup.L2BCR.sup.L2CR.sup.L2D,
--CR.sup.L2CR.sup.L2DC(.dbd.O)NR.sup.L2B, --NR.sup.L2ASO.sub.2--,
--SO.sub.2NR.sup.L2A--, --NR.sup.L2ASO.sub.2NR.sup.L2B--, wherein
each occurrence of R.sup.L2A, R.sup.L2B, R.sup.L2C and R.sup.L2D is
independently hydrogen, lower alkyl, lower heteroalkyl,
heterocyclyl, aryl, heteroaryl or acyl;
[0195] lxxxix) L.sup.2 is --NR.sup.L2A--, --C(.dbd.O)NR.sup.L2A--,
--NR.sup.L2AC(.dbd.O)--, --OC(.dbd.O)NR.sup.L2A--,
--NR.sup.L2ACO.sub.2--, --NR.sup.L2AC(.dbd.O)NR.sup.L2B--,
--NR.sup.L2AC(.dbd.O)NR.sup.L2BCR.sup.L2CR.sup.L2D or
--CR.sup.L2CR.sup.L2DC(.dbd.O)NR.sup.L2B, wherein each occurrence
of R.sup.L2A, R.sup.L2B, R.sup.L2C and R.sup.L2D is independently
hydrogen, lower alkyl, lower heteroalkyl, heterocyclyl, aryl,
heteroaryl or acyl;
[0196] xc) L.sup.2 is --NR.sup.L2A--, --NR.sup.L2AC(.dbd.)--,
--NR.sup.L2AC(.dbd.O)NR.sup.L2B--,
--NR.sup.L2AC(.dbd.O)NR.sup.L2BCR.sup.L2CR.sup.L2D or
--CR.sup.L2CR.sup.L2DC(.dbd.O)NR.sup.L2B, wherein each occurrence
of R.sup.L2A, R.sup.L2B, R.sup.L2C and R.sup.L2D is independently
hydrogen, lower alkyl, lower heteroalkyl, heterocyclyl, aryl,
heteroaryl or acyl;
[0197] xci) L.sup.2 is --NH--, --NHC(.dbd.O)--, --NHC(.dbd.O)O--,
--NHC(.dbd.O)NH--, --CH.sub.2--C(.dbd.O)NH-- or
--NHC(.dbd.O)NHCH.sub.2--;
[0198] xcii) L.sup.2 is --NH--;
[0199] xciii) L.sup.2 is --NHC(.dbd.O)NH--;
[0200] xciv) L.sup.2 is --CH.sub.2--C(.dbd.O)NH--;
[0201] xcv) L.sup.2 is --NHC(.dbd.O)NHCH.sub.2--;
[0202] xcvi) Z is an alkyl, alkenyl, alkynyl, cycloalkyl,
cycloalkenyl, heteroalkyl, heteroalkenyl, heteroalkynyl,
heterocyclyl, aryl or heteroaryl moiety;
[0203] xcvii) Z is a branched alkyl, alkenyl, alkynyl, heteroalkyl
or heteroalkenyl moiety;
[0204] xcviii) Z is one of:
##STR00046##
[0205] wherein each occurrence of R.sup.Z1 is independently
hydrogen, lower alkyl, lower alkenyl, aryl, heteroaryl or acyl;
[0206] xcix) Z is a cycloalkyl, cycloalkenyl, heterocyclyl, aryl or
heteroaryl moiety;
[0207] c) Z is cycloalkyl, cycloalkenyl, or a heterocyclyl, aryl or
heteroaryl moiety having one of the structures:
##STR00047##
[0208] wherein the "A" cyclic moiety is a 6- to 10-membered mono-
or fused bicyclic aromatic ring comprising from 0-4 nitrogen atoms;
the "Het" moiety represents a fully or partially saturated or
unsaturated 5- to 8-membered mono- or fused bicyclic ring
comprising 1-4 heteroatoms selected from N, O and S; m is an
integer from 0-6; and each occurrence of R.sup.Z1 is independently
hydrogen, alkyl, cycloalkyl, heteroalkyl, heterocyclyl, aryl,
heteroaryl, -(alkyl)heterocyclyl, -(alkyl)aryl, -(alkyl)heteroaryl,
--OR.sup.Z2, --SR.sup.Z2, --N(R.sup.Z2).sub.2,
--SO.sub.2N(R.sup.Z2).sub.2, --SO.sub.2R.sup.Z4,
--C(.dbd.O)N(R.sup.Z2).sub.2, halogen, --CN, --NO.sub.2,
--C(.dbd.O)OR.sup.Z2, --N(R.sup.Z2)C(.dbd.O)R.sup.Z3 or
--N(R.sup.Z2)SO.sub.2R.sup.Z4; wherein each occurrence of R.sup.Z2
and R.sup.Z3 is independently hydrogen, lower alkyl, lower
heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl,
acyl; or any two occurrences of R.sup.Z2, taken together with the
nitrogen atom to which they are attached (e.g., N(R.sup.Z2).sub.2),
form a substituted or unsubstituted heterocyclic moiety; and
R.sup.Z4 is alkyl, heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, or
-(alkyl)heteroaryl; and wherein any two adjacent occurrence of
R.sup.Z1 may form a fused 5- to 6-membered aryl, heteroaryl or
heterocyclic ring;
[0209] ci) Z is one of:
##STR00048## ##STR00049##
[0210] wherein m is an integer from 0 to 3; r is an integer from 1
to 4; X.sup.3 is N or CR.sup.Z1; each occurrence of R.sup.Z1 is
independently hydrogen, alkyl, heteroalkyl, aryl, heteroaryl,
-(alkyl)aryl or -(alkyl)heteroaryl, --OR.sup.Z2, --SR.sup.Z2,
--NR.sup.Z2R.sup.Z3, --SO.sub.2NR.sup.Z2R.sup.Z3,
--SO.sub.2R.sup.Z1, --C(.dbd.O)NR.sup.Z2R.sup.Z3, halogen, --CN,
--NO.sub.2, --C(.dbd.O)OR.sup.Z3, --N(R.sup.Z2)C(.dbd.O)R.sup.Z3,
wherein each occurrence of R.sup.Z2 and R.sup.Z3 is independently
hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl,
-(alkyl)aryl, -(alkyl)heteroaryl or acyl, or R.sup.Z2 and R.sup.Z3
taken together with the nitrogen or carbon atom to which they are
attached form a 5-6 membered heterocyclic, aryl or heteroaryl ring;
and R.sup.Z4 is hydrogen, lower alkyl, lower heteroalkyl, aryl,
heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl or acyl;
[0211] cii) Z is one of:
##STR00050##
[0212] ciii) Z is one of:
##STR00051##
[0213] wherein X.sup.3 is N or CR.sup.Z1; R.sup.Z1 is hydrogen,
halogen, lower alkyl, lower hydroxyalkyl or lower haloalkyl;
R.sup.Z2 and R.sup.Z3 are independently hydrogen, lower alkyl,
lower heteroalkyl, acyl, or R.sup.Z2 and R.sup.Z3 taken together
with the nitrogen atom to which they are attached form a 5-6
membered heterocyclic ring; and R.sup.Z4 is hydrogen or lower
alkyl;
[0214] civ) Z is one of:
##STR00052## ##STR00053##
[0215] wherein X.sup.3 is N or CR.sup.Z1; R.sup.Z1 is hydrogen,
halogen, lower alkyl or lower haloalkyl; and R.sup.Z2 and R.sup.Z3
are independently hydrogen, lower alkyl, lower heteroalkyl, acyl,
or R.sup.Z2 and R.sup.Z3 taken together with the nitrogen atom to
which they are attached form a 5-6 membered heterocyclic ring; X is
halogen, R.sup.Z1A is hydrogen, halogen, --CN, lower alkyl, lower
alkoxy, lower haloalkyl or --SO.sub.2R.sup.Z4; wherein R.sup.Z4 is
lower alkyl; R.sup.Z1B is hydrogen or halogen; and R.sup.Z2A is
hydrogen or lower alkyl;
[0216] cv) Z is one of:
##STR00054##
[0217] wherein X is halogen; R.sup.Z1A is lower alkyl; R.sup.Z1 is
halogen, lower alkyl or lower haloalkyl; and R.sup.Z2 and R.sup.Z3
are independently lower alkyl, or R.sup.Z2 and R.sup.Z3 taken
together with the nitrogen atom to which they are attached form a
5-6 membered heterocyclic ring;
[0218] cvi) Z is one of:
##STR00055## ##STR00056##
[0219] wherein R.sup.Z1 is Cl, F, methyl or CF.sub.3; R.sup.Z2 and
R.sup.Z3 are each methyl or ethyl, or taken together with the
nitrogen atom to which they are attached form a saturated or
unsaturated pyrrolidinyl ring; and R.sup.Z2A is hydrogen or
methyl;
[0220] cvii) Z is one of:
##STR00057##
[0221] wherein R.sup.Z1 is Cl, F, methyl or CF.sub.3;
[0222] cviii) -L.sup.2-Z together represent a moiety having one of
the following structures:
##STR00058##
[0223] wherein s is 0 or 1; X is --C(R.sup.Z1).sub.2, --C(.dbd.O)--
or --SO.sub.2--; J.sup.1, J.sup.2 and J.sup.3 are independently N,
S, O, NR.sup.Z1 or CR.sup.Z1; each occurrence of R.sup.Z1 is
independently hydrogen, alkyl, heteroalkyl, aryl, heteroaryl,
-(alkyl)aryl or -(alkyl)heteroaryl, --OR.sup.Z2, --SR.sup.Z2,
--NR.sup.Z2R.sup.Z3, --SO.sub.2NR.sup.Z2R.sup.Z3,
--SO.sub.2R.sup.Z1, --C(.dbd.O)NR.sup.Z2R.sup.Z3, halogen, --CN,
--NO.sub.2, --C(.dbd.O)OR.sup.Z3, --N(R.sup.Z2)C(.dbd.O)R.sup.Z3,
wherein each occurrence of R.sup.Z2 and R.sup.Z3 is independently
hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl,
-(alkyl)aryl, -(alkyl)heteroaryl or acyl, or R.sup.Z2 and R.sup.Z3
taken together with the nitrogen or carbon atom to which they are
attached form a 5-6 membered heterocyclic, aryl or heteroaryl
ring;
[0224] cix) -L.sup.2-Z together represent --CH.sub.2-Cy or --NH-Cy
where Cy is an optionally substituted bicyclic heterocycle;
[0225] cx) -L.sup.2-Z together represent a moiety having one of the
following structures:
##STR00059##
[0226] wherein the "A" cyclic moiety is a 6-membered aromatic ring
comprising from 0-4 nitrogen atoms; each "Het" moiety independently
represents a fully or partially saturated or unsaturated 5- to
6-membered ring comprising 1-4 heteroatoms selected from N, O and
S; m is an integer from 0-6; and each occurrence of R.sup.Z1 is
independently hydrogen, alkyl, heteroalkyl, aryl, heteroaryl,
-(alkyl)aryl, -(alkyl)heteroaryl, --OR.sup.Z2, --SR.sup.Z2,
--N(R.sup.Z2).sub.2, --SO.sub.2N(R.sup.Z2).sub.2,
--SO.sub.2R.sup.Z4, --C(.dbd.O)N(R.sup.Z2).sub.2, halogen, --CN,
--NO.sub.2, --C(.dbd.O)OR.sup.Z2, --N(R.sup.Z2)C(.dbd.)R.sup.Z3 or
--N(R.sup.Z2)SO.sub.2R.sup.Z4; wherein each occurrence of R.sup.Z2
and R.sup.Z3 is independently hydrogen, lower alkyl, lower
heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl,
acyl; or any two occurrences of R.sup.Z2, taken together with the
nitrogen atom to which they are attached (e.g., N(R.sup.Z2).sub.2),
form a substituted or unsubstituted heterocyclic moiety; and
R.sup.Z4 is alkyl, heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, or
-(alkyl)heteroaryl; and wherein any two adjacent occurrence of
R.sup.Z1 may form a fused 5- to 6-membered aryl, heteroaryl or
heterocyclic ring;
[0227] cxi) -L.sup.2-Z together represent a moiety having one of
the following structures:
##STR00060##
[0228] wherein the "A" cyclic moiety is a 6-membered aromatic ring
comprising from 0-4 nitrogen atoms; each "Het" moiety independently
represents a fully or partially saturated or unsaturated 5- to
6-membered ring comprising 1-4 heteroatoms selected from N, O and
S; m is an integer from 0-6; and each occurrence of R.sup.Z1 is
independently hydrogen, lower alkyl, lower alkoxy,
--SO.sub.2R.sup.Z4, halogen or --CN; wherein R.sup.Z4 is lower
alkyl;
[0229] cxii) -L.sup.2-Z together represent a moiety having one of
the following structures:
##STR00061##
[0230] wherein m is an integer from 0-4; each occurrence of
R.sup.Z1 is independently hydrogen, alkyl, heteroalkyl, aryl,
heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl, --OR.sup.Z2,
--SR.sup.Z2, --N(R.sup.Z2).sub.2, --SO.sub.2N(R.sup.Z2).sub.2,
--SO.sub.2R.sup.Z4, --C(.dbd.O)N(R.sup.Z2).sub.2, halogen, --CN,
--NO.sub.2, --C(.dbd.O)OR.sup.Z2, --N(R.sup.Z2)C(.dbd.O)R.sup.Z3 or
--N(R.sup.Z2)SO.sub.2R.sup.Z4; wherein each occurrence of R.sup.Z2
is hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl,
-(alkyl)aryl, -(alkyl)heteroaryl or acyl; and wherein any two
adjacent occurrence of R.sup.Z1 may form a fused 5- to 6-membered
aryl, heteroaryl or heterocyclic ring;
[0231] cxiii) -L.sup.2-Z together represent a moiety having one of
the following structures:
##STR00062##
[0232] wherein R.sup.Z2 is hydrogen or lower alkyl; each occurrence
of R.sup.Z1 is independently hydrogen, halogen, --CN, lower alkyl,
lower alkoxy, lower haloalkyl or --SO.sub.2R.sup.Z4; wherein
R.sup.Z4 is lower alkyl;
[0233] cxiv) -L.sup.2-Z together represent a moiety having one of
the following structures:
##STR00063##
[0234] wherein X is halogen, R.sup.Z1A is hydrogen, halogen, --CN,
lower alkyl, lower alkoxy, lower haloalkyl or --SO.sub.2R.sup.Z4;
wherein R.sup.Z4 is lower alkyl; and R.sup.Z2 is hydrogen or lower
alkyl;
[0235] cxv) -L.sup.2-Z together represent a moiety having one of
the following structures:
##STR00064##
[0236] wherein R.sup.Z1 is Cl, F, methyl or CF.sub.3; and R.sup.Z2
is hydrogen or methyl; and/or
[0237] cxvi) -L.sup.2-Z together represent a moiety having one of
the following structures:
##STR00065##
[0238] wherein R.sup.Z1 is Cl, F, methyl or CF.sub.3.
[0239] It will be appreciated that for each of the classes and
subclasses described above and herein, any one or more occurrences
of aliphatic or heteroaliphatic may independently be substituted or
unsubstituted, cyclic or acyclic, linear or branched, saturated or
unsaturated and any one or more occurrences of aryl, heteroaryl,
cycloaliphatic, cycloheteroaliphatic may be substituted or
unsubstituted.
[0240] The reader will also appreciate that any and all possible
combinations of the variables described in i)- through cxvi) above
(e.g., R.sup.1, R.sup.2, L.sup.1, L.sup.2, X.sup.1, X.sup.2, Y and
Z, among others) are considered part of the invention. Thus, the
invention encompasses any and all compounds of formula I generated
by taking any possible permutation of variables R.sup.1, R.sup.2,
L.sup.1, L.sup.2, X.sup.1, X.sup.2, Y and Z, and other
variables/substituents (e.g., R.sup.X1, R.sup.X2, R.sup.Y1,
R.sup.Z1 etc.) as further defined for R.sup.1, R.sup.2, L.sup.1,
L.sup.2, X.sup.1, X.sup.2, Y and Z, described in i)- through lii)
above.
[0241] For example, an exemplary combination of variables described
in i)- through cxvi) above includes those compounds of Formula I
wherein:
[0242] R.sup.1 is H, halogen, cyano, nitro, alkyl, alkenyl,
alkynyl, cycloalkyl, cycloalkenyl, heteroalkyl, heteroalkenyl,
heteroalkynyl, heterocyclyl, aryl, heteroaryl, -(alkyl)aryl,
-(alkyl)heteroaryl, -(heteroalkyl)aryl or
-(heteroalkyl)heteroaryl;
[0243] R.sup.2 is hydrogen, halogen, cyano, nitro, or an alkyl,
alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heteroalkyl,
heteroalkenyl, heteroalkynyl, heterocyclyl, aryl, heteroaryl,
-(alkyl)aryl, -(alkyl)heteroaryl, -(heteroalkyl)aryl or
-(heteroalkyl)heteroaryl moiety;
[0244] X.sup.1 is S;
[0245] X.sup.2 is --C(R.sup.X2)--; wherein R.sup.X2A is hydrogen,
halogen, cyano, nitro, or an alkyl, alkenyl, alkynyl, cycloalkyl,
cycloalkenyl, heteroalkyl, heteroalkenyl, heteroalkynyl,
heterocyclyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl,
-(heteroalkyl)aryl or -(heteroalkyl)heteroaryl moiety;
[0246] L.sup.1 is --W.sup.1-Alk.sub.1-; wherein W.sup.1 is O or
NR.sup.W1, where R.sup.W1 is hydrogen, alkyl, heteroalkyl, aryl,
heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl or acyl; and Alk.sub.1
is a substituted or unsubstituted C.sub.1-6 alkylene or
C.sub.2-6alkenylene chain wherein up to two non-adjacent methylene
units are independently optionally replaced by --C(.dbd.O)--,
--CO.sub.2--, --C(.dbd.O)C(.dbd.O)--, --C(.dbd.O)NR.sup.L1A-,
--OC(.dbd.O)--, --OC(.dbd.O)NR.sup.L1A--, --NR.sup.L1ANR.sup.L1B--,
--NR.sup.L1ANR.sup.L1BC(.dbd.)--, --NR.sup.L1AC(.dbd.)--,
--NR.sup.L1ACO.sub.2--, --NR.sup.L1AC(.dbd.O)NR.sup.L1B--,
--S(.dbd.O)--, --SO.sub.2--, --NR.sup.L1ASO.sub.2--,
--SO.sub.2NR.sup.L1A--, --NR.sup.L1ASO.sub.2NR.sup.L1B--, --O--,
--S--, or --NR.sup.L1A--; wherein each occurrence of R.sup.L1A and
R.sup.L1B is independently hydrogen, alkyl, heteroalkyl,
heterocyclyl, aromatic, heteroaromatic or acyl;
[0247] L.sup.2 is --C(.dbd.O)NR.sup.L2A--,
--OC(.dbd.O)NR.sup.L2A--, --NR.sup.L2ANR.sup.L2B--,
--NR.sup.L2ANR.sup.L2BC(.dbd.O)--, --NR.sup.L2AC(.dbd.O)--,
--NR.sup.L2ACO.sub.2--, --NR.sup.L2AC(.dbd.O)NR.sup.L2B--,
--NR.sup.L2ASO.sub.2--, --SO.sub.2NR.sup.L2A--,
--NR.sup.L2ASO.sub.2NR.sup.L2B, or a substituted or unsubstituted
C.sub.1-6alkylene or C.sub.2-6alkenylene chain interrupted with at
least one nitrogen atom wherein up to two non-adjacent methylene
units are independently optionally replaced by --C(.dbd.O)--,
--CO.sub.2--, --C(.dbd.O)C(.dbd.O)--, --C(.dbd.O)NR.sup.L2A--,
--OC(.dbd.O)--, --OC(.dbd.O)NR.sup.L2A--, NR.sup.L2ANR.sup.L2B--,
--NR.sup.L2ANR.sup.L2BC(.dbd.O)--, --NR.sup.L2AC(.dbd.O)--,
--NR.sup.L2ACO.sub.2--, --NR.sup.L2AC(.dbd.O)NR.sup.L2B--,
S(.dbd.O)--, --SO.sub.2--, --NR.sup.L2ASO.sub.2--,
--SO.sub.2NR.sup.L2A--, --NR.sup.L2ASO.sub.2NR.sup.L2B--, --O--,
--S--, or --NR.sup.L2A--; wherein each occurrence of R.sup.L2A and
R.sup.L2B is independently hydrogen, alkyl, heteroalkyl,
heterocyclyl, aromatic, heteroaromatic or acyl;
[0248] Y is a saturated or unsaturated cyclic ring system
optionally comprising one or more heteroatoms selected from S, N
and O;
[0249] Z is an alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,
heteroalkyl, heteroalkenyl, heteroalkynyl, heterocyclyl, aryl or
heteroaryl moiety.
[0250] Other exemplary combinations are illustrated by compounds of
the following subgroups I through XVI:
[0251] I. Compounds Having the Structure (and Pharmaceutically
Acceptable Derivatives Thereof):
##STR00066##
[0252] wherein R.sup.1, L.sup.2, Y and Z are as defined generally
and in classes and subclasses herein; W.sup.1 is O or NR.sup.W1,
where R.sup.W1 is hydrogen, lower alkyl, lower heteroalkyl, aryl,
heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl or acyl; and Alk.sub.1
is a substituted or unsubstituted C.sub.1-6alkylene or
C.sub.2-6alkenylene chain wherein up to two non-adjacent methylene
units are independently optionally replaced by --C(.dbd.O)--,
--CO.sub.2--, --C(.dbd.O)C(.dbd.O)--, --C(.dbd.O)NR.sup.L1A--,
--OC(.dbd.O)--, --OC(.dbd.O)NR.sup.L1A--, --NR.sup.L1ANR.sup.L1B--,
--NR.sup.L1ANR.sup.L1BC(.dbd.O)--, --NR.sup.L1AC(.dbd.O)--,
--NR.sup.L1ACO.sub.2--, --NR.sup.L1AC(.dbd.O)NR.sup.L1B--,
--S(.dbd.O)--, --SO.sub.2--, --NR.sup.L1ASO.sub.2--,
--SO.sub.2NR.sup.L1A--, --NR.sup.L1ASO.sub.2NR.sup.L1B--, --O--,
--S--, or --NR.sup.L1A--; wherein each occurrence of R.sup.L1A and
R.sup.L1B is independently hydrogen, lower alkyl, lower
heteroalkyl, heterocyclyl, aryl, heteroaryl or acyl. In certain
embodiments, the invention encompasses the compounds described
directly above with the proviso that:
[0253] (i) R.sup.1 is not Q.sup.1, Q.sup.2 or Q.sup.3;
[0254] (ii) for compounds of formula (2), the following groups do
not occur simultaneously as defined: R.sup.1 is Q.sub.5; Y and Z
are independently optionally substituted aryl, carbocyle or
5-membered monocyclic heterocycle; Alk.sub.1 is --N.dbd.CH--.
[0255] (iii) the following groups do not occur simultaneously as
defined: Y and Z are each optionally substituted phenyl; L.sup.2 is
--OCH.sub.2-- or --OSO.sub.2--; W.sup.1Alk.sub.1 is --OCH(R)--,
--OCH(R)--C.sub.1-6alkylO-- or
--OCH(R)--C.sub.1-6alkylC(.dbd.NR.sub.x)-- where R is H,
C.sub.1-4alkyl, C.sub.1-4haloalkyl or C.sub.3-6cycloalkyl and
R.sub.x is H, aliphatic, heteroaliphatic, alicyclic,
heteroalicyclic, aromatic or heteroaromatic; and R.sup.1 is
hydrogen, halogen or alkyl;
[0256] (iv) the following groups do not occur simultaneously as
defined: W.sup.1Alk.sub.1 is --NHCH.sub.2CH.sub.2-- or
--OCH.sub.2CH.sub.2--; Y is phenyl or L.sup.2 is --C(R).dbd.N--O--,
wherein R is H, C.sub.1-4alkyl, C.sub.1-4haloalkyl or
C.sub.3-6cycloalkyl; and R.sup.1 is hydrogen, halogen or
C.sub.1-4alkyl;
[0257] (v) the following groups do not occur simultaneously as
defined: W.sup.1Alk.sub.1 is --OCH.sub.2--, or --N(R)CH.sub.2--,
wherein Ris H or C.sub.1-8alkyl; Y is phenyl, or Z is a
5-10-membered cycloalkyl, heterocyclyl, aryl or heteroaryl;
[0258] (vi) R.sup.1 is hydrogen, halogen, C.sub.1-4alkyl or
C.sub.1-4alkoxy; L.sup.1 is --NHC.sub.1-6alkyl, --OC.sub.1-6alkyl,
--NHC.sub.1-6heteroalkyl or --OC.sub.1-6heteroalkyl; Y is
cycloalkyl, aryl, heteroaryl or heterocyclyl; L.sup.2-Z is
--X--R.sup.x where X is --NR--, --C(.dbd.O)NH--, --NHC(.dbd.O)--,
--SO.sub.2NH-- or --NHSO.sub.2-- and R.sup.x is
C.sub.3-10cycloalkyl, morpholinyl, phenyl, phenylC.sub.1-4alkyl or
phenylC.sub.2-3alkenyl;
[0259] (vii) the following groups do not occur simultaneously as
defined: L.sup.1 is --NR(CR.sup.x).sub.1-2-- or
--O(CR.sup.X).sub.1-2-- wherein R is hydrogen, C.sub.1-4alkyl,
C.sub.1-4alkoxy, OH, NH.sub.2 or --C.sub.1-4alkylNH; and R.sup.x is
H or C.sub.1-4alkyl; Y is phenyl, thienyl, furanyl, pyrrolyl,
pyridyl, pyrimidyl, imidazolyl, pyrazinyl, oxazolyl, thiazolyl,
naphthyl, benzothienyl, benzofuranyl, indolyl, quinolinyl,
isoquinolinyl or quinazolinyl; L.sup.2-Z is
--SO.sub.2NHC.sub.3-8cycloalkyl,
--SO.sub.2N(C.sub.3-8cycloalkyl).sub.2,
--C(.dbd.O)NHC.sub.3-8cycloalkyl or
--C(.dbd.O)N(C.sub.3-8cycloalkyl).sub.2; and
[0260] (viii) the following groups do not occur simultaneously as
defined: R.sup.1 is hydrogen, halogen, nitro or C.sub.1-4alkyl;
L.sup.1 is --NRC.sub.1-6alkyl- or --OC.sub.1-6alkyl- wherein R is
hydrogen, C.sub.1-4alkyl, C.sub.1-4acyl; Y is phenyl; L.sup.2-Z is
a C.sub.1-12alkyl saturated or unsaturated hydrocarbon chain
optionally including --NR-- and optionally substituted with
haloC.sub.1-4alkoxy, C.sub.3-8cycloalkyl, C.sub.3-8cycloalkenyl,
C.sub.1-4acyl, phenoxy, phenyl or phenylthio.
[0261] In certain embodiments, compounds of the invention have the
structure (1.sup.A) or (2.sup.A) below:
##STR00067##
[0262] wherein the C.sub.1-6 alkyl moiety may be substituted or
unsubstituted.
[0263] In certain embodiments, compounds of the invention have the
structure (1.sup.B) or (2.sup.B) below:
##STR00068##
[0264] In certain embodiments, for compounds of formulae (1.sup.A),
(1.sup.B), (2.sup.A) and (2.sup.B), the C.sub.1-6alkyl moiety is a
substituted or unsubstituted C.sub.2 alkyl moiety. In certain
exemplary embodiments, the C.sub.1-6alkyl moiety is
--CH.sub.2CH.sub.2--.
[0265] II. Compounds Having the Structure (and Pharmaceutically
Acceptable Derivatives Thereof):
##STR00069##
[0266] wherein R.sup.1, L, Y and Z are as defined generally and in
classes and subclasses herein; G.sub.2 is absent, O or NR.sup.G2;
and R.sup.W2 and R.sup.G2 are independently hydrogen, lower alkyl,
lower heteroalkyl, aryl, heteroaryl, -(alkyl)aryl,
-(alkyl)heteroaryl or acyl. In certain embodiments, the invention
encompasses the compounds described directly above with the proviso
that:
[0267] (i) R.sup.1 is not Q.sup.1, Q.sup.2 or Q3;
[0268] (ii) the following groups do not occur simultaneously as
defined: G.sub.2 is absent; L.sup.1 is --OCH.sub.2--,
--CH.sub.2O--, --N(R)CH.sub.2-- or --CH.sub.2N(R)--, wherein R is H
or C.sub.1-8alkyl; Y is phenyl; and Z is a 5-10-membered
cycloalkyl, heterocyclyl, aryl or heteroaryl; and
[0269] (iii) the following groups do not occur simultaneously as
defined: R.sup.1 is hydrogen, halogen, C.sub.1-4alkyl or
C.sub.1-4alkoxy; L.sup.1 is --NHC.sub.1-6alkyl, --OC.sub.1-6alkyl,
--NHC.sub.1-6heteroalkyl or --OC.sub.1-6heteroalkyl; Y is
cycloalkyl, aryl, heteroaryl or heterocyclyl; G.sup.2 is absent and
Z is C.sub.3-10cycloalkyl, morpholinyl, phenyl,
phenylC.sub.1-4alkyl or phenylC.sub.2-3alkenyl.
[0270] In certain embodiments, --N(R.sup.w2)C(.dbd.O)G.sub.2- is
--NHC(.dbd.O)--, --NHC(.dbd.O)O--, or --NHC(.dbd.O)NH--. In certain
embodiments, compounds of the invention have the structure
(3.sup.A) or (4.sup.A) below:
##STR00070##
[0271] III. Compounds Having the Structure (and Pharmaceutically
Acceptable Derivatives Thereof):
##STR00071##
[0272] wherein R.sup.1, L, Y and Z are as defined generally and in
classes and subclasses herein; and R.sup.w2, R.sup.W3 and R.sup.W4
are independently hydrogen, lower alkyl, lower heteroalkyl,
heterocyclyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl or
acyl. In certain embodiments, the invention encompasses the
compounds described directly above with the proviso that:
[0273] (i) R.sup.1 is not Q.sup.1, Q.sup.2 or Q.sup.3; and
[0274] (ii) the following groups do not occur simultaneously as
defined: (R.sup.W3, R.sup.W4) is (H,H), (F,F) or (H,
C.sub.1-4alkyl); L.sup.1 is --OCH.sub.2--, --CH.sub.2O--,
--N(R)CH.sub.2-- or --CH.sub.2N(R)--, wherein R is H or
C.sub.1-8alkyl; Y is phenyl; and Z is a 5-10-membered cycloalkyl,
heterocyclyl, aryl or heteroaryl.
[0275] In certain embodiments, compounds of the invention have the
structure (5.sup.A) or (6.sup.A) below:
##STR00072##
[0276] IV. Compounds Having the Structure (and Pharmaceutically
Acceptable Derivatives Thereof):
##STR00073##
[0277] wherein q is an integer from 0-2; R.sup.1, L.sup.2 and Z are
as defined generally and in classes and subclasses herein; and
J.sup.1, J.sup.2 and J.sup.3 are independently O, S, N, NR.sup.Y1
or CR.sup.Y1; wherein each occurrence of R.sup.Y1 is independently
hydrogen, alkyl, heteroalkyl, aryl, heteroaryl, -(alkyl)aryl or
-(alkyl)heteroaryl, --OR.sup.Y3, --SR.sup.Y3, --NR.sup.Y2R.sup.Y3,
--SO.sub.2NR.sup.Y2R.sup.Y3, --C(.dbd.O)NR.sup.Y2R.sup.Y3, halogen,
--CN, --NO.sub.2, --C(.dbd.O)OR.sup.Y3,
--N(R.sup.Y2)C(.dbd.O)R.sup.Y3, wherein each occurrence of R.sup.Y2
and R.sup.Y3 is independently hydrogen, lower alkyl, lower
heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl or
acyl, or R.sup.Y2 and R.sup.Y3 taken together with the nitrogen
atom to which they are attached form a 5-6 membered heterocyclic
ring. In certain embodiments, the invention encompasses the
compounds described directly above with the proviso that:
[0278] (i) R.sup.1 is not Q.sup.1, Q.sup.2 or Q.sup.3;
[0279] (ii) for compounds of formula (8), the following groups do
not occur simultaneously as defined: R.sup.1 is Q.sub.5; Z is
optionally substituted aryl, carbocyle or 5-membered monocyclic
heterocycle; L.sup.1 is --W--N.dbd.CH--, where W is O or NR,
wherein R is H, C.sub.1-6alk(en/yn)yl, C.sub.3-8cycloalk(en)yl,
aryl, hydroxyC.sub.1-6alk(en/yn)yl,
C.sub.3-8cycloalk(en)yl-C.sub.1-6alk(en/yn)yl or acyl.
[0280] (iii) the following groups do not occur simultaneously as
defined: L.sup.1 is --NR(CR.sup.x).sub.1-2-- or
--O(CR.sup.X).sub.1-2-- wherein R is hydrogen, C.sub.1-4alkyl,
C.sub.1-4alkoxy, OH, NH.sub.2 or --C.sub.1-4alkylNH; and R.sup.x is
H or C.sub.1-4alkyl;
##STR00074##
is thienyl, furanyl, pyrrolyl, imidazolyl, oxazolyl or thiazolyl;
L.sup.2-Z is --SO.sub.2NHC.sub.3-8cycloalkyl,
--SO.sub.2N(C.sub.3-8cycloalkyl).sub.2,
--C(.dbd.O)NHC.sub.3-8cycloalkyl or
--C(.dbd.O)N(C.sub.3-8cycloalkyl).sub.2.
[0281] In certain embodiments, compounds of the invention have the
structure (7.sup.A) or (8.sup.A) below:
##STR00075##
[0282] V. Compounds Having the Structure (and Pharmaceutically
Acceptable Derivatives Thereof):
##STR00076##
[0283] wherein q is an integer from 0-3; R.sup.1, L.sup.1, L.sup.2
and Z are as defined generally and in classes and subclasses
herein; and J.sup.4, J.sup.5 and J.sup.6 are independently N or
CR.sup.Y1; wherein each occurrence of R.sup.Y1 is independently
hydrogen, alkyl, heteroalkyl, aryl, heteroaryl, -(alkyl)aryl or
-(alkyl)heteroaryl, --OR.sup.3, --SR.sup.Y3, --NR.sup.Y2R.sup.Y3,
--SO.sub.2NR.sup.Y2R.sup.Y3, --C(.dbd.O)NR.sup.Y2R.sup.Y3, halogen,
--CN, --NO.sub.2, --C(.dbd.O)OR.sup.Y3,
--N(R.sup.Y2)C(.dbd.O)R.sup.3, wherein each occurrence of R.sup.Y2
and R.sup.Y3 is independently hydrogen, lower alkyl, lower
heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl or
acyl, or R.sup.Y2 and R.sup.Y3 taken together with the nitrogen
atom to which they are attached form a 5-6 membered heterocyclic
ring. In certain embodiments, the invention encompasses the
compounds described directly above with the proviso that:
[0284] (i) R.sup.1 is not Q.sup.1, Q.sup.2 or Q.sup.3;
[0285] (ii) the following groups do not occur simultaneously as
defined: L.sup.1 is --OCH.sub.2--, --CH.sub.2O--, --N(R)CH.sub.2--
or --CH.sub.2N(R)--, wherein R is H or C.sub.1-8alkyl; J.sup.4,
J.sup.5 and J.sup.6 are each CR.sup.1; and Z is a 5-10-membered
cycloalkyl, heterocyclyl, aryl or heteroaryl;
[0286] (iii) the following groups do not occur simultaneously as
defined: J.sup.4, J.sup.5 and J.sup.6 are each CH; L.sup.1 is
--NHCH.sub.2CH.sub.2-- or --OCH.sub.2CH.sub.2--; and L.sup.2 is
--C(R).dbd.N--O--, wherein R is H, C.sub.1-4alkyl,
C.sub.1-4haloalkyl or C.sub.3-6cycloalkyl; and R.sup.1 is hydrogen,
halogen or C.sub.1-4alkyl.
[0287] (iv) the following groups do not occur simultaneously as
defined: J.sup.4, J.sup.5 and J.sup.6 are each CH; L.sup.1 is
--OCH(R)--, --OCH(R)--C.sub.1-6alkylO-- or
--OCH(R)--C.sub.1-6alkylC(.dbd.NR.sub.x)-- where R is H,
C.sub.1-4alkyl, C.sub.1-4haloalkyl or C.sub.3-6cycloalkyl and
R.sup.x is H, aliphatic, heteroaliphatic, alicyclic,
heteroalicyclic, aromatic or heteroaromatic; Z is optionally
substituted phenyl; L.sup.2 is --OCH.sub.2-- or --OSO.sub.2--; and
R.sup.1 is hydrogen, halogen or alkyl;
[0288] (v) for compounds of formula (10), the following groups do
not occur simultaneously as defined: R.sup.1 is Q.sub.5; J.sup.4,
J.sup.5 and J.sup.6 are each CR.sup.Y1; Z is optionally substituted
aryl, carbocyle or 5-membered monocyclic heterocycle; and L.sup.1
is --W--N.dbd.CH-- wherein W is O or NR, wherein R is H,
C.sub.1-6alk(en/yn)yl, C.sub.3-8cycloalk(en)yl, aryl,
hydroxyC.sub.1-6alk(en/yn)yl,
C.sub.3-8cycloalk(en)yl-C.sub.1-6alk(en/yn)yl or acyl;
[0289] (vi) the following groups do not occur simultaneously as
defined: R.sup.1 is hydrogen, halogen, C.sub.1-4alkyl or
C.sub.1-4alkoxy; L.sup.1 is --NHC.sub.1-6alkyl, --OC.sub.1-6alkyl,
--NHC.sub.1-6heteroalkyl or --OC.sub.1-6heteroalkyl; L.sup.2-Z is
--X--R.sup.x where X is --NR--, --C(.dbd.O)NH--, --NHC(.dbd.O)--,
--SO.sub.2NH-- or --NHSO.sub.2-- and R.sup.x is
C.sub.3-10cycloalkyl, morpholinyl, phenyl, phenylC.sub.1-4alkyl or
phenylC.sub.2-3alkenyl;
[0290] (vii) the following groups do not occur simultaneously as
defined: L.sup.1 is --NR(CR.sup.x).sub.1-2-- or
--O(CR.sup.X).sub.1-2-- wherein R is hydrogen, C.sub.1-4alkyl,
C.sub.1-4alkoxy, OH, NH.sub.2 or --C.sub.1-4alkylNH; and R.sup.x
is
[0291] H or C.sub.1-4alkyl;
##STR00077##
is phenyl, pyridyl, pyrimidyl or pyrazinyl; L.sup.2-Z is
--SO.sub.2NHC.sub.3-8cycloalkyl,
--SO.sub.2N(C.sub.3-8cycloalkyl).sub.2,
--C(.dbd.O)NHC.sub.3-8cycloalkyl or
--C(.dbd.O)N(C.sub.3-8cycloalkyl).sub.2; and/or
[0292] (ix) the following groups do not occur simultaneously as
defined: R.sup.1 is hydrogen, halogen, nitro or C.sub.1-4alkyl;
L.sup.1 is --NRC.sub.1-6alkyl- or --OC.sub.1-6alkyl- wherein R is
hydrogen, C.sub.1-4alkyl, C.sub.1-4acyl; J.sup.4, J.sup.5 and
J.sup.6 are each CH; L.sup.2-Z is a C.sub.1-12alkyl saturated or
unsaturated hydrocarbon chain optionally including --NR-- and
optionally substituted with haloC.sub.1-4alkoxy,
C.sub.3-8cycloalkyl, C.sub.3-8cycloalkenyl, C.sub.1-4acyl, phenoxy,
phenyl or phenylthio.
[0293] In certain embodiments, compounds of the invention have the
structure (9.sup.A) or (10.sup.A) below:
##STR00078##
[0294] In certain embodiments, compounds of the invention have the
structure (9.sup.B) or (10.sup.B) below:
##STR00079##
[0295] VI. Compounds Having the Structure (and Pharmaceutically
Acceptable Derivatives Thereof):
##STR00080##
[0296] wherein R.sup.1, L.sup.2 and Z are as defined generally and
in classes and subclasses herein; W.sup.1 is O or NR.sup.W1, where
R.sup.W1 is hydrogen, lower alkyl, lower heteroalkyl, aryl,
heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl or acyl; Alk.sub.1 is
a substituted or unsubstituted C.sub.1-6alkylene or
C.sub.2-6alkenylene chain wherein up to two non-adjacent methylene
units are independently optionally replaced by --C(.dbd.O)--,
--CO.sub.2--, --C(.dbd.O)C(.dbd.O)--, --C(.dbd.O)NR.sup.L1A--,
--OC(.dbd.O)--, --OC(.dbd.O)NR.sup.L1A--, --NR.sup.L1ANR.sup.L1B--,
NR.sup.L1ANR.sup.L1BC(.dbd.)--, --NR.sup.L1AC(.dbd.)--,
--NR.sup.L1ACO.sub.2--, --NR.sup.L1AC(.dbd.O)NR.sup.L1B--,
--S(.dbd.O)--, --SO.sub.2--, --NR.sup.L1ASO.sub.2--,
--SO.sub.2NR.sup.L1A--, --NR.sup.L1ASO.sub.2NR.sup.L1B--, --O--,
--S--, or --NR.sup.L1A--; wherein each occurrence of R.sup.L1A and
R.sup.L1B is independently hydrogen, lower alkyl, lower
heteroalkyl, heterocyclyl, aryl, heteroaryl or acyl; q is an
integer from 0-3; J.sup.1, J.sup.2 and J.sup.3 are independently O,
S, N, NR.sup.Y1 or CR.sup.Y1; J.sup.4, J.sup.5 and J.sup.6 are
independently N or CR.sup.Y1; wherein each occurrence of R.sup.Y1
is independently hydrogen, alkyl, heteroalkyl, aryl, heteroaryl,
-(alkyl)aryl or -(alkyl)heteroaryl, --OR.sup.Y3, --SR.sup.Y3,
--NR.sup.Y2R.sup.Y3, --SO.sub.2NR.sup.Y2R.sup.Y3,
--C(.dbd.O)NR.sup.Y2R.sup.Y3, halogen, --CN, --NO.sub.2,
--C(.dbd.O)OR.sup.Y3, N(R.sup.Y2)C(.dbd.O)R.sup.Y3, wherein each
occurrence of R.sup.Y2 and R.sup.Y3 is independently hydrogen,
lower alkyl, lower heteroalkyl, aryl, heteroaryl, -(alkyl)aryl,
-(alkyl)heteroaryl or acyl, or R.sup.Y2 and R.sup.Y3 taken together
with the nitrogen atom to which they are attached form a 5-6
membered heterocyclic ring. In certain embodiments, the invention
encompasses the compounds described directly above with the proviso
that:
[0297] (i) R.sup.1 is not Q.sup.1, Q.sup.2 or Q3;
[0298] (ii) for compounds of formula (12), the following groups do
not occur simultaneously as defined: R.sup.1 is Q.sub.5; Z is
optionally substituted aryl, carbocyle or 5-membered monocyclic
heterocycle; Alk.sub.1 is --N.dbd.CH--.
[0299] (iii) for compounds of formula (14), the following groups do
not occur simultaneously as defined: R.sup.1 is Q.sub.5; J.sup.4,
J.sup.5 and J.sup.6 are each CR.sup.Y1; Z is optionally substituted
aryl, carbocyle or 5-membered monocyclic heterocycle; Alk.sub.1 is
--N.dbd.CH--.
[0300] (iv) for compounds of formula (13) and (14), the following
groups do not occur simultaneously as defined: Z is optionally
substituted phenyl; L.sup.2 is --OCH.sub.2-- or --OSO.sub.2--;
W.sup.1Alk.sub.1 is --OCH(R)--, --OCH(R)--C.sub.1-6alkylO-- or
--OCH(R)--C.sub.1-6alkylC(.dbd.NR.sub.x)-- where R is H,
C.sub.1-4alkyl, C.sub.1-4haloalkyl or C.sub.3-6cycloalkyl and
R.sub.x is H, aliphatic, heteroaliphatic, alicyclic,
heteroalicyclic, aromatic or heteroaromatic; and R.sup.1 is
hydrogen, halogen or alkyl;
[0301] (v) for compounds of formula (13) and (14), the following
groups do not occur simultaneously as defined: W.sup.1Alk.sub.1 is
--NHCH.sub.2CH.sub.2-- or --OCH.sub.2CH.sub.2--; and L.sup.2 is
--C(R).dbd.N--O--,
[0302] wherein R is H, C.sub.1-4alkyl, C.sub.1-4haloalkyl or
C.sub.3-6cycloalkyl; and R.sup.1 is hydrogen, halogen or
C.sub.1-4alkyl;
[0303] (vi) for compounds of formula (13) and (14), the following
groups do not occur simultaneously as defined: W.sup.1Alk.sub.1 is
--OCH.sub.2--, or --N(R)CH.sub.2--, wherein R is H or
C.sub.1-8alkyl; and Z is not a 5-10-membered cycloalkyl,
heterocyclyl, aryl or heteroaryl;
[0304] (vii) the following groups do not occur simultaneously as
defined: R.sup.1 is hydrogen, halogen, C.sub.1-4alkyl or
C.sub.1-4alkoxy; W.sup.1Alk.sub.1 is --NHC.sub.1-6alkyl,
--OC.sub.1-6alkyl, --NHC.sub.1-6heteroalkyl or
--OC.sub.1-6heteroalkyl; L.sup.2-Z is --X--R.sup.x where X is
--NR--, --C(.dbd.O)NH--, --NHC(.dbd.O)--, --SO.sub.2NH-- or
--NHSO.sub.2-- and R.sup.x is C.sub.3-10cycloalkyl, morpholinyl,
phenyl, phenylC.sub.1-4alkyl or phenylC.sub.2-3alkenyl.
[0305] (viii) the following groups do not occur simultaneously as
defined: W.sup.1Alk.sub.1 is --NR(CR.sup.x).sub.1-2-- or
--O(CR.sup.X).sub.1-2-- wherein R is hydrogen, C.sub.1-4alkyl,
C.sub.1-4alkoxy, OH, NH.sub.2 or --C.sub.1-4alkylNH; and R.sup.x is
H or C.sub.1-4alkyl;
##STR00081##
is thienyl, furanyl, pyrrolyl, imidazolyl, oxazolyl or
thiazolyl;
##STR00082##
is phenyl, pyridyl, pyrimidyl or pyrazinyl; L.sup.2-Z is
--SO.sub.2NHC.sub.3-8cycloalkyl,
--SO.sub.2N(C.sub.3-8cycloalkyl).sub.2,
--C(.dbd.O)NHC.sub.3-8cycloalkyl or
--C(.dbd.O)N(C.sub.3-8cycloalkyl).sub.2; and/or
[0306] (ix) the following groups do not occur simultaneously as
defined: R.sup.1 is hydrogen, halogen, nitro or C.sub.1-4alkyl;
W.sup.1Alk.sub.1 is --NRC.sub.1-6alkyl- or --OC.sub.1-6alkyl-
wherein R is hydrogen, C.sub.1-4alkyl, C.sub.1-4acyl;
##STR00083##
is phenyl; L.sup.2-Z is a C.sub.1-12alkyl saturated or unsaturated
hydrocarbon chain optionally including --NR-- and optionally
substituted with haloC.sub.1-4alkoxy, C.sub.3-8cycloalkyl,
C.sub.3-8cycloalkenyl, C.sub.1-4acyl, phenoxy, phenyl or
phenylthio.
[0307] In certain embodiments, in compounds of the formulae (11)
and (12) the 5-membered ring having the structure:
##STR00084##
[0308] has the structure:
##STR00085##
[0309] In certain embodiments, in compounds of the formulae (13)
and (14) the 6-membered ring having the structure:
##STR00086##
[0310] has one of the following structures:
##STR00087##
[0311] In certain embodiments, --W.sup.1-Alk.sub.1- is
--NHC.sub.1-6alkyl- or --OC.sub.1-6alkyl-. In certain embodiments,
--W.sup.1-Alk.sub.1- is --NHC.sub.2alkyl- or --OC.sub.2alkyl-. In
certain embodiments, --W.sup.1-Alk.sub.1- is
--NHCH.sub.2CH.sub.2--, --OCH.sub.2CH.sub.2-- or
--NH--CH.sub.2CH(CH.sub.2OH)--.
[0312] VII. Compounds Having the Structure (and Pharmaceutically
Acceptable Derivatives Thereof):
##STR00088##
[0313] wherein R.sup.1, L.sup.1 and Z are as defined generally and
in classes and subclasses herein; q is an integer from 0-3;
J.sup.1, J.sup.2 and J.sup.3 are independently O, S, N, NR.sup.Y1
or CR.sup.Y1; J.sup.4, J.sup.5 and J.sup.6 are independently N or
CR.sup.Y%; wherein each occurrence of R.sup.Y1 is independently
hydrogen, alkyl, heteroalkyl, aryl, heteroaryl, -(alkyl)aryl or
-(alkyl)heteroaryl, --OR.sup.Y3, --SR.sup.Y3, --NR.sup.Y2R.sup.Y3,
--SO.sub.2NR.sup.Y2R.sup.Y3, --C(.dbd.O)NR.sup.Y2R.sup.Y3, halogen,
--CN, --NO.sub.2, --C(.dbd.O)OR.sup.Y3,
--N(R.sup.Y2)C(.dbd.)R.sup.Y3, wherein each occurrence of R.sup.Y2
and R.sup.Y3 is independently hydrogen, lower alkyl, lower
heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl or
acyl, or R.sup.Y2 and R.sup.Y3 taken together with the nitrogen
atom to which they are attached form a 5-6 membered heterocyclic
ring; G.sub.2 is absent, O or NR.sup.G2; and R.sup.W2 and R.sup.G2
are independently hydrogen, lower alkyl, lower heteroalkyl,
heterocyclyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl or
acyl. In certain embodiments, the invention encompasses the
compounds described directly above with the proviso that:
[0314] (i) R.sup.1 is not Q.sup.1, Q.sup.2 or Q.sup.3;
[0315] (ii) for compounds of formula (16) and (18), the following
groups do not occur simultaneously as defined: G.sub.2 is absent;
L.sup.1 is --OCH.sub.2--, --CH.sub.2O--, --N(R)CH.sub.2-- or
--CH.sub.2N(R)--, wherein R is H or C.sub.1-8alkyl; and Z is a
5-10-membered cycloalkyl, heterocyclyl, aryl or heteroaryl;
[0316] (iii) the following groups do not occur simultaneously as
defined: G.sup.2 is absent; R.sup.1 is hydrogen, halogen, C.sub.1-4
alkyl or C.sub.1-4alkoxy; L.sup.1 is --NHC.sub.1-6 alkyl,
--OC.sub.1-6alkyl, --NHC.sub.1-6heteroalkyl or
--OC.sub.1-6heteroalkyl; and Z is C.sub.3-10cycloalkyl,
morpholinyl, phenyl, phenylC.sub.1-4alkyl or
phenylC.sub.2-3alkenyl; and/or
[0317] (iv) the following groups do not occur simultaneously as
defined: G.sup.2 is absent; L.sup.1 is --NR(CR.sup.x).sub.1-2-- or
--O(CR.sup.X).sub.1-2-- wherein R is hydrogen, C.sub.1-4alkyl,
C.sub.1-4alkoxy, OH, NH.sub.2 or --C.sub.1-4alkylNH; and R.sup.x is
H or C.sub.1-4alkyl;
##STR00089##
is thienyl, furanyl, pyrrolyl, imidazolyl, oxazolyl or
thiazolyl;
##STR00090##
is phenyl, pyridyl, pyrimidyl or pyrazinyl; R.sup.W2 is H or
C.sub.3-8cycloalkyl; and Z is C.sub.3-8cycloalkyl.
[0318] In certain embodiments, in compounds of the formulae (15)
and (16) the 5-membered ring having the structure:
##STR00091##
[0319] has the structure:
##STR00092##
[0320] In certain embodiments, in compounds of the formulae (17)
and (18) the 6-membered ring having the structure:
##STR00093##
[0321] has one of the following structures:
##STR00094##
[0322] In certain embodiments, --N(R.sup.W2)C(.dbd.O)G.sub.2- is
--NHC(.dbd.O)--, --NHC(.dbd.O)O--, or --NHC(.dbd.O)NH--.
[0323] VIII. Compounds Having the Structure (and Pharmaceutically
Acceptable Derivatives Thereof):
##STR00095## ##STR00096##
[0324] wherein R.sup.1, L.sup.1 and Z are as defined generally and
in classes and subclasses herein; q is an integer from 0-3;
J.sup.1, J.sup.2 and J.sup.3 are independently O, S, N, NR.sup.Y1
or CR.sup.Y1; J.sup.4, J.sup.5 and J.sup.6 are independently N or
CR.sup.Y1; wherein each occurrence of R.sup.Y1 is independently
hydrogen, alkyl, heteroalkyl, aryl, heteroaryl, -(alkyl)aryl or
-(alkyl)heteroaryl, --OR.sup.Y3, --SR.sup.Y3, --NR.sup.Y2R.sup.Y3,
--SO.sub.2NR.sup.Y2R.sup.Y3, --C(.dbd.O)NR.sup.Y2R.sup.Y3, halogen,
--CN, --NO.sub.2, --C(.dbd.O)OR.sup.Y3,
--N(R.sup.Y2)C(.dbd.O)R.sup.Y3, wherein each occurrence of R.sup.Y2
and R.sup.Y3 is independently hydrogen, lower alkyl, lower
heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl or
acyl, or R.sup.Y2 and R.sup.Y3 taken together with the nitrogen
atom to which they are attached form a 5-6 membered heterocyclic
ring; R.sup.W3 and R.sup.W4 are independently hydrogen, lower
alkyl, lower heteroalkyl, heterocyclyl, aryl, heteroaryl or acyl;
and R.sup.W2 is hydrogen, lower alkyl, lower heteroalkyl,
heterocyclyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl or
acyl. In certain embodiments, the invention encompasses the
compounds described directly above with the proviso that:
[0325] (i) R.sup.1 is not Q.sup.1, Q.sup.2 or Q.sup.3; and
[0326] (ii) for compounds of formula 20.sup.A-B and 22.sup.A-B, if
(R.sup.W3, R.sup.W4) is (H,H), (F,F) or (H, C.sub.1-4alkyl), then
--W.sup.1-Alk.sub.1- is not --OCH.sub.2-- or --N(R)CH.sub.2--,
wherein R is H or C.sub.1-8alkyl.
[0327] In certain embodiments, in compounds of the formulae (19)
and (20) the 5-membered ring having the structure:
##STR00097##
[0328] has the structure:
##STR00098##
[0329] In certain embodiments, in compounds of the formulae (21)
and (22) the 6-membered ring having the structure:
##STR00099##
[0330] has one of the following structures:
##STR00100##
[0331] In certain embodiments,
--N(R.sup.W2)C(.dbd.O)N(R.sup.W2)CR.sup.W3R.sup.W4-- is
--NHC(.dbd.O)NHCH.sub.2--, and
--CR.sup.W3R.sup.W4C(.dbd.O)N(R.sup.W2)-- is
--CH.sub.2C(.dbd.O)NH--.
[0332] IX. Compounds Having the Structure (and Pharmaceutically
Acceptable Derivatives Thereof):
##STR00101##
[0333] wherein R.sup.1 and Z are as defined generally and in
classes and subclasses herein; W.sup.1 is O or NR.sup.W1, where
R.sup.W1 is hydrogen, lower alkyl, lower heteroalkyl, aryl,
heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl or acyl; Alk.sub.1 is
a substituted or unsubstituted C.sub.1-6alkylene or
C.sub.2-6alkenylene chain wherein up to two non-adjacent methylene
units are independently optionally replaced by --C(.dbd.O)--,
--CO.sub.2--, --C(.dbd.O)C(.dbd.O)--, --C(.dbd.O)NR.sup.L1A--,
--OC(.dbd.O)--, --OC(.dbd.O)NR.sup.L1A--, --NR.sup.L1ANR.sup.L1B--,
NR.sup.L1ANR.sup.L1BC(.dbd.O)--, --NR.sup.L1AC(.dbd.O)--,
--NR.sup.L1ACO.sub.2--, --NR.sup.L1AC(.dbd.O)NR.sup.L1B--,
--S(.dbd.O)--, --SO.sub.2--, --NR.sup.L1ASO.sub.2--,
--SO.sub.2NR.sup.L1A--, --NR.sup.L1ASO.sub.2NR.sup.L1B--, --O--,
--S--, or --NR.sup.L1A--; wherein each occurrence of R.sup.L1A and
R.sup.L1B is independently hydrogen, lower alkyl, lower
heteroalkyl, heterocyclyl, aryl, heteroaryl or acyl; q is an
integer from 0-3; J.sup.1, J.sup.2 and J.sup.3 are independently O,
S, N, NR.sup.Y1 or CR.sup.Y1; wherein each occurrence of R.sup.Y1
is independently hydrogen, alkyl, heteroalkyl, aryl, heteroaryl,
-(alkyl)aryl or -(alkyl)heteroaryl, --OR.sup.Y3, --SR.sup.Y3,
--NR.sup.Y2R.sup.Y3, --SO.sub.2NR.sup.Y2R.sup.Y3,
C(.dbd.O)NR.sup.Y2R.sup.Y3, halogen, --CN, --NO.sub.2,
--C(.dbd.O)OR.sup.Y3, --N(R.sup.Y2)C(.dbd.O)R.sup.Y3, wherein each
occurrence of R.sup.Y2 and R.sup.Y3 is independently hydrogen,
lower alkyl, lower heteroalkyl, aryl, heteroaryl, -(alkyl)aryl,
-(alkyl)heteroaryl or acyl, or R.sup.Y2 and R.sup.Y3 taken together
with the nitrogen atom to which they are attached form a 5-6
membered heterocyclic ring; G.sub.2 is absent, O or NR.sup.G2; and
R.sup.W2 and R.sup.G2 are independently hydrogen, lower alkyl,
lower heteroalkyl, heterocyclyl, aryl, heteroaryl, -(alkyl)aryl,
-(alkyl)heteroaryl or acyl. In certain embodiments, the invention
encompasses the compounds described directly above with the proviso
that:
[0334] (i) R.sup.1 is not Q.sup.1, Q.sup.2 or Q.sup.3;
[0335] (ii) for compounds of formula (23) and (24), the following
groups do not occur
[0336] simultaneously as defined: G.sub.2 is absent; L.sup.1 is
--OCH.sub.2--, --CH.sub.2O--, --N(R)CH.sub.2-- or --CH.sub.2N(R)--,
wherein R is H or C.sub.1-8alkyl; and Z is not a 5-10-membered
cycloalkyl, heterocyclyl, aryl or heteroaryl;
[0337] (iii) the following groups do not occur simultaneously as
defined: G.sup.2 is absent; R.sup.1 is hydrogen, halogen,
C.sub.1-4alkyl or C.sub.1-4alkoxy; W.sup.1Alk.sub.1 is
--NHC.sub.1-6alkyl, --OC.sub.1-6alkyl, --NHC.sub.1-6heteroalkyl or
--OC.sub.1-6heteroalkyl; and Z is C.sub.3-10cycloalkyl,
morpholinyl, phenyl, phenylC.sub.1-4alkyl or
phenylC.sub.2-3alkenyl; and/or
[0338] (iv) the following groups do not occur simultaneously as
defined: G.sup.2 is absent; W.sup.1Alk.sub.1 is
--NR(CR.sup.x).sub.1-2-- or --O(CR.sup.X).sub.1-2-- wherein R is
hydrogen, C.sub.1-4alkyl, C.sub.1-4alkoxy, OH, NH.sub.2 or
--C.sub.1-4alkylNH; and R.sup.x is H or C.sub.1-4alkyl;
##STR00102##
is thienyl, furanyl, pyrrolyl, imidazolyl, oxazolyl or thiazolyl;
R.sup.W2 is H or C.sub.3-8cycloalkyl; and Z is
C.sub.3-8cycloalkyl.
[0339] In certain embodiments, compounds of this class have the
structure (23.sup.A), (23.sup.B), (24.sup.A) or (24.sup.B)
below:
##STR00103##
[0340] wherein the C.sub.1-6alkyl moiety may be substituted or
unsubstituted.
[0341] In certain embodiments, for compounds of formulae (23) and
(24), --W.sup.1-Alk.sub.1- is --NHC.sub.2alkyl- or
--OC.sub.2alkyl-. In certain embodiments, --W.sup.1-Alk.sub.1- is
--NHCH.sub.2CH.sub.2--, --OCH.sub.2CH.sub.2-- or
--NH--CH.sub.2CH(CH.sub.2OH)--.
[0342] In certain embodiments, for compounds of formulae (23),
(24), (23.sup.A), (23.sup.B), (24.sup.A) and (24.sup.B) the
C.sub.1-6alkyl moiety is a substituted or unsubstituted C.sub.2
alkyl moiety. In certain exemplary embodiments, the C.sub.1-6alkyl
moiety is --CH.sub.2CH.sub.2--.
[0343] In certain embodiments, in compounds of the formulae (23),
(24), (23.sup.A), (23.sup.B), (24.sup.A) and (24.sup.B) the
5-membered ring having the structure:
##STR00104##
[0344] has the structure:
##STR00105##
[0345] In certain embodiments, --N(R.sup.W2)C(.dbd.O)G.sub.2- is
--NHC(.dbd.O)--, --NHC(.dbd.O)O--, or --NHC(.dbd.O)NH--.
[0346] X. Compounds Having the Structure (and Pharmaceutically
Acceptable Derivatives Thereof):
##STR00106##
[0347] wherein R.sup.1 and Z are as defined generally and in
classes and subclasses herein; W.sup.1 is O or NR.sup.W1, where
R.sup.W1 is hydrogen, lower alkyl, lower heteroalkyl, aryl,
heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl or acyl; Alk.sub.1 is
a substituted or unsubstituted C.sub.1-6alkylene or
C.sub.2-6alkenylene chain wherein up to two non-adjacent methylene
units are independently optionally replaced by --C(.dbd.O)--,
--CO.sub.2--, --C(.dbd.O)C(.dbd.O)--, --C(.dbd.O)NR.sup.L1A--,
--OC(.dbd.O)--, --OC(.dbd.O)NR.sup.L1A--, --NR.sup.L1ANR.sup.L1B--,
NR.sup.L1ANR.sup.L1BC(.dbd.O)--, --NR.sup.L1AC(.dbd.O)--,
--NR.sup.L1ACO.sub.2--, --NR.sup.L1AC(.dbd.O)NR.sup.L1B--,
--S(.dbd.O)--, --SO.sub.2--, --NR.sup.L1A SO.sub.2--,
--SO.sub.2NR.sup.L1A--, --NR.sup.L1ASO.sub.2NR.sup.L1B--, --O--,
--S--, or --NR.sup.L1A--; wherein each occurrence of R.sup.L1A and
R.sup.L1B is independently hydrogen, lower alkyl, lower
heteroalkyl, heterocyclyl, aryl, heteroaryl or acyl; q is an
integer from 0-3; J.sup.1, J.sup.2 and J.sup.3 are independently O,
S, N, NR.sup.Y1 or CR.sup.Y1; wherein each occurrence of R.sup.Y1
is independently hydrogen, alkyl, heteroalkyl, aryl, heteroaryl,
-(alkyl)aryl or -(alkyl)heteroaryl, --OR.sup.Y3, --SR.sup.Y3,
--NR.sup.Y2R.sup.Y3, --SO.sub.2NR.sup.Y2R.sup.Y3,
C(.dbd.O)NR.sup.Y2R.sup.Y3, halogen, --CN, --NO.sub.2,
--C(.dbd.O)OR.sup.Y3, --N(R.sup.Y2)C(.dbd.O)R.sup.Y3, wherein each
occurrence of R.sup.Y2 and R.sup.Y3 is independently hydrogen,
lower alkyl, lower heteroalkyl, aryl, heteroaryl, -(alkyl)aryl,
-(alkyl)heteroaryl or acyl, or R.sup.Y2 and R.sup.Y3 taken together
with the nitrogen atom to which they are attached form a 5-6
membered heterocyclic ring; R.sup.W3 and R.sup.W4 are independently
hydrogen, lower alkyl, lower heteroalkyl, heterocyclyl, aryl,
heteroaryl or acyl; and R.sup.W2 is hydrogen, lower alkyl, lower
heteroalkyl, heterocyclyl, aryl, heteroaryl, -(alkyl)aryl,
-(alkyl)heteroaryl or acyl. In certain embodiments, the invention
encompasses the compounds described directly above with the proviso
that:
[0348] (i) R.sup.1 is not Q.sup.1, Q.sup.2 or Q.sup.3.
[0349] In certain embodiments, --W.sup.1-Alk.sub.1- is
--NHC.sub.1-6alkyl- or --OC.sub.1-6alkyl-. In certain embodiments,
--W.sup.1-Alk.sub.1- is --NHC.sub.2alkyl- or --OC.sub.2alkyl-. In
certain embodiments, --W.sup.1-Alk.sub.1- is
--NHCH.sub.2CH.sub.2--, --OCH.sub.2CH.sub.2-- or
--NH--CH.sub.2CH(CH.sub.2OH)--.
[0350] In certain embodiments, in compounds of the formulae (25),
(26), (27) and (28), the 5-membered ring having the structure:
##STR00107##
[0351] has the structure:
##STR00108##
[0352] In certain embodiments,
--N(R.sup.W2)C(.dbd.O)N(R.sup.W2)CR.sup.W3R.sup.W4-- is
--NHC(.dbd.O)NHCH.sub.2--, and
--CR.sup.W3R.sup.W4C(.dbd.O)N(R.sup.W2)-- is
--CH.sub.2C(.dbd.O)NH--.
[0353] XI. Compounds Having the Structure (and Pharmaceutically
Acceptable Derivatives Thereof):
##STR00109##
[0354] wherein R.sup.1 and Z are as defined generally and in
classes and subclasses herein; W.sup.1 is O or NR.sup.W1, where
R.sup.W1 is hydrogen, lower alkyl, lower heteroalkyl, aryl,
heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl or acyl; Alk.sub.1 is
a substituted or unsubstituted C.sub.1-6alkylene or
C.sub.2-6alkenylene chain wherein up to two non-adjacent methylene
units are independently optionally replaced by --C(.dbd.O)--,
--CO.sub.2--, --C(.dbd.O)C(.dbd.O)--, --C(.dbd.O)NR.sup.L1A--,
--OC(.dbd.O)--, --OC(.dbd.O)NR.sup.L1A--, --NR.sup.L1ANR.sup.L1B--,
NR.sup.L1ANR.sup.L1BC(.dbd.O)--, --NR.sup.L1AC(.dbd.O)--,
--NR.sup.L1ACO.sub.2--, --NR.sup.L1AC(.dbd.O)NR.sup.L1B--,
--S(.dbd.O)--, --SO.sub.2--, --NR.sup.L1ASO.sub.2--,
--SO.sub.2NR.sup.L1A--, --NR.sup.L1ASO.sub.2NR.sup.L1B--, --O--,
--S--, or --NR.sup.L1A--; wherein each occurrence of R.sup.L1A and
R.sup.L1B is independently hydrogen, lower alkyl, lower
heteroalkyl, heterocyclyl, aryl, heteroaryl or acyl; q is an
integer from 0-3; J.sup.4, J.sup.5 and J.sup.6 are independently N
or CR.sup.Y1; wherein each occurrence of R.sup.Y1 is independently
hydrogen, alkyl, heteroalkyl, aryl, heteroaryl, -(alkyl)aryl or
-(alkyl)heteroaryl, --OR.sup.Y3, --SR.sup.Y3, --NR.sup.Y2R.sup.Y3,
--SO.sub.2NR.sup.Y2R.sup.Y3, --C(.dbd.O)NR.sup.Y2R.sup.Y3, halogen,
--CN, --NO.sub.2, --C(.dbd.O)OR.sup.Y3,
--N(R.sup.Y2)C(.dbd.O)R.sup.Y3, wherein each occurrence of R.sup.Y2
and R.sup.Y3 is independently hydrogen, lower alkyl, lower
heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl or
acyl, or R.sup.Y2 and R.sup.Y3 taken together with the nitrogen
atom to which they are attached form a 5-6 membered heterocyclic
ring; G.sub.2 is absent, O or NR.sup.G2; and R.sup.W2 and R.sup.G2
are independently hydrogen, lower alkyl, lower heteroalkyl,
heterocyclyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl or
acyl. In certain embodiments, the invention encompasses the
compounds described directly above with the proviso that:
[0355] (i) R.sup.1 is not Q.sup.1, Q.sup.2 or Q3;
[0356] (ii) the following groups do not occur simultaneously as
defined: G.sub.2 is absent; W.sup.1Alk.sub.1 is --OCH.sub.2-- or
--N(R)CH.sub.2--, wherein R is H or C.sub.1-8alkyl; and Z is a
5-10-membered cycloalkyl, heterocyclyl, aryl or heteroaryl;
[0357] (iii) the following groups do not occur simultaneously as
defined: G.sup.2 is absent; R.sup.1 is hydrogen, halogen,
C.sub.1-4alkyl or C.sub.1-4alkoxy; W.sup.1Alk.sub.1 is
--NHC.sub.1-6alkyl, --OC.sub.1-6alkyl, --NHC.sub.1-6heteroalkyl or
--OC.sub.1-6 heteroalkyl; and Z is C.sub.3-10cycloalkyl,
morpholinyl, phenyl, phenylC.sub.1-4alkyl or
phenylC.sub.2-3alkenyl; and/or
[0358] (iv) the following groups do not occur simultaneously as
defined: G.sup.2 is absent; W.sup.1Alk.sub.1 is
--NR(CR.sup.x).sub.1-2-- or --O(CR.sup.X).sub.1-2-- wherein R is
hydrogen, C.sub.1-4alkyl, C.sub.1-4alkoxy, OH, NH.sub.2 or
--C.sub.1-4alkylNH; and R.sup.x is H or C.sub.1-4alkyl;
##STR00110##
is phenyl, pyridyl, pyrimidyl or pyrazinyl; R.sup.W2 is H or
C.sub.3-8cycloalkyl; and Z is C.sub.3-8cycloalkyl.
[0359] In certain embodiments, the compounds have the following
structures:
##STR00111##
[0360] wherein the C.sub.1-6alkyl moiety may be substituted or
unsubstituted.
[0361] In certain embodiments, for compounds of formulae (XX) and
(XXI), --W.sup.1-Alk.sub.1- is --NHC.sub.2alkyl- or
--OC.sub.2alkyl-. In certain embodiments, --W.sup.1-Alk.sub.1- is
--NHCH.sub.2CH.sub.2--, --OCH.sub.2CH.sub.2-- or
--NH--CH.sub.2CH(CH.sub.2OH)--.
[0362] In certain embodiments, for compounds of formulae (29),
(30), (29.sup.A), (29.sup.B), (30.sup.A) and (30.sup.B) the
C.sub.1-6alkyl moiety is a substituted or unsubstituted C.sub.2
alkyl moiety. In certain exemplary embodiments, the C.sub.1-6 alkyl
moiety is --CH.sub.2CH.sub.2--.
[0363] In certain embodiments, in compounds of the formulae (29)
and (30) the 6-membered ring having the structure:
##STR00112##
[0364] has one of the following structures:
##STR00113##
[0365] In certain embodiments, --N(R.sup.W2)C(.dbd.O)G.sub.2- is
--NHC(.dbd.O)--, --NHC(.dbd.O)O--, or --NHC(.dbd.O)NH--.
[0366] XII. Compounds Having the Structure (and Pharmaceutically
Acceptable Derivatives Thereof):
##STR00114##
[0367] wherein R.sup.1 and Z are as defined generally and in
classes and subclasses herein; W.sup.1 is O or NR.sup.W1, where
R.sup.W1 is hydrogen, lower alkyl, lower heteroalkyl, aryl,
heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl or acyl; Alk.sub.1 is
a substituted or unsubstituted C.sub.1-6alkylene or
C.sub.2-6alkenylene chain wherein up to two non-adjacent methylene
units are independently optionally replaced by --C(.dbd.O)--,
--CO.sub.2--, --C(.dbd.O)C(.dbd.O)--, --C(.dbd.O)NR.sup.L1A--,
--OC(.dbd.O)--, --OC(.dbd.O)NR.sup.L1A--, --NR.sup.L1ANR.sup.L1B--,
NR.sup.L1ANR.sup.L1BC(.dbd.O)--, --NR.sup.L1AC(.dbd.O)--,
--NR.sup.L1ACO.sub.2--, --NR.sup.L1AC(.dbd.O)NR.sup.L1B--,
--S(.dbd.O)--, --SO.sub.2--, --NR.sup.L1A SO.sub.2--,
--SO.sub.2NR.sup.L1A--, --NR.sup.L1ASO.sub.2NR.sup.L1B--, --O--,
--S--, or --NR.sup.L1A--; wherein each occurrence of R.sup.L1A and
R.sup.L1B is independently hydrogen, lower alkyl, lower
heteroalkyl, heterocyclyl, aryl, heteroaryl or acyl; q is an
integer from 0-3; J.sup.4, J.sup.5 and J.sup.6 are independently N
or CR.sup.Y1; wherein each occurrence of R.sup.Y1 is independently
hydrogen, alkyl, heteroalkyl, aryl, heteroaryl, -(alkyl)aryl or
-(alkyl)heteroaryl, --OR.sup.Y3, --SR.sup.Y3, --NR.sup.Y2R.sup.Y3,
--SO.sub.2NR.sup.Y2R.sup.Y3, --C(.dbd.O)NR.sup.Y2R.sup.Y3, halogen,
--CN, --NO.sub.2, --C(.dbd.O)OR.sup.Y3,
--N(R.sup.Y2)C(.dbd.O)R.sup.Y3, wherein each occurrence of R.sup.Y2
and R.sup.Y3 is independently hydrogen, lower alkyl, lower
heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl or
acyl, or R.sup.Y2 and R.sup.Y3 taken together with the nitrogen
atom to which they are attached form a 5-6 membered heterocyclic
ring; R.sup.W3 and R.sup.W4 are independently hydrogen, lower
alkyl, lower heteroalkyl, heterocyclyl, aryl, heteroaryl or acyl;
and R.sup.W2 is hydrogen, lower alkyl, lower heteroalkyl,
heterocyclyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl or
acyl. In certain embodiments, the invention encompasses the
compounds described directly above with the proviso that:
[0368] (i) R.sup.1 is not Q.sup.1, Q.sup.2 or Q.sup.3; and
[0369] (ii) for compounds of structure (32) or (34), if (R.sup.W3,
R.sup.W4) is (H,H), (F,F) or (H, C.sub.1-4alkyl), then
--W.sup.1-Alk.sub.1- is not --OCH.sub.2-- or --N(R)CH.sub.2--,
wherein R is H or C.sub.1-8alkyl.
[0370] In certain embodiments, --W.sup.1-Alk.sub.1- is
--NHC.sub.1-6alkyl- or --OC.sub.1-6alkyl-. In certain embodiments,
--W.sup.1-Alk.sub.1- is --NHC.sub.2alkyl- or --OC.sub.2alkyl-. In
certain embodiments, --W.sup.1-Alk.sub.1- is
--NHCH.sub.2CH.sub.2--, --OCH.sub.2CH.sub.2-- or
--NH--CH.sub.2CH(CH.sub.2OH)--.
[0371] In certain embodiments, in compounds of the formulae
(31)-(34) the 6-membered ring having the structure:
##STR00115##
[0372] has one of the following structures:
##STR00116##
[0373] In certain embodiments, --N(R.sup.W2)C(.dbd.O)G.sub.2- is
--NHC(.dbd.O)--, --NHC(.dbd.O)O--, or --NHC(.dbd.O)NH--.
[0374] In certain embodiments,
--N(R.sup.W2)C(.dbd.O)N(R.sup.W2)CR.sup.W3R.sup.W4-- is
--NHC(.dbd.O)NHCH.sub.2--, and
--CR.sup.W3R.sup.W4C(.dbd.O)N(R.sup.W2)-- is
--CH.sub.2C(.dbd.O)NH--.
[0375] XIII. Compounds Having the Structure (and Pharmaceutically
Acceptable Derivatives Thereof):
##STR00117##
[0376] wherein R.sup.1 and R.sup.X1 are as defined generally and in
classes and subclasses herein; Z is an aryl, heteroaryl or
heterocyclic moiety; W.sup.1 is O or NR.sup.W1, where R.sup.W1 is
hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl,
-(alkyl)aryl, -(alkyl)heteroaryl or acyl; Alk.sub.1 is a
substituted or unsubstituted C.sub.1-6alkylene or
C.sub.2-6alkenylene chain wherein up to two non-adjacent methylene
units are independently optionally replaced by --C(.dbd.O)--,
--CO.sub.2--, --C(.dbd.O)C(.dbd.O)--, --C(.dbd.O)NR.sup.L1A--,
--OC(.dbd.O)--, --OC(.dbd.O)NR.sup.L1A--, --NR.sup.L1ANR.sup.L1B--,
--NR.sup.L1ANR.sup.L1BC(.dbd.)--, --NR.sup.L1AC(.dbd.O)--,
--NR.sup.L1ACO.sub.2--, --NR.sup.L1AC(.dbd.O)NR.sup.L1B--,
--S(.dbd.O)--, --SO.sub.2--, --NR.sup.L1ASO.sub.2--,
--SO.sub.2NR.sup.L1A--, --NR.sup.L1ASO.sub.2NR.sup.L1A--, --O--,
--S--, or --NR.sup.L1A--; wherein each occurrence of R.sup.L1A and
R.sup.L1B is independently hydrogen, lower alkyl, lower
heteroalkyl, heterocyclyl, aryl, heteroaryl or acyl; m is an
integer from 0 to 3; r is an integer from 1 to 4; each occurrence
of R.sup.Z1 is independently hydrogen, alkyl, heteroalkyl, aryl,
heteroaryl, -(alkyl)aryl or -(alkyl)heteroaryl, --OR.sup.Z2,
--SR.sup.Z2, --NR.sup.Z2R.sup.Z3, --SO.sub.2NR.sup.Z2R.sup.Z3,
--SO.sub.2R.sup.Z1, --C(.dbd.O)NR.sup.Z2R.sup.Z3, halogen, --CN,
--NO.sub.2, --C(.dbd.O)OR.sup.Z3, --N(R.sup.Z2)C(.dbd.O)R.sup.Z3,
wherein each occurrence of R.sup.Z2 and R.sup.Z3 is independently
hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl,
-(alkyl)aryl, -(alkyl)heteroaryl or acyl, or R.sup.Z2 and R.sup.Z3
taken together with the nitrogen or carbon atom to which they are
attached form a 5-6 membered heterocyclic, aryl or heteroaryl ring;
and R.sup.Z4 is hydrogen, lower alkyl, lower heteroalkyl, aryl,
heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl or acyl. In certain
embodiments, the invention encompasses the compounds described
directly above with the proviso that:
[0377] (i) neither R.sup.1 nor R.sup.X1 is Q.sup.1, Q.sup.2 or
Q.sup.3.
[0378] In certain embodiments, --W.sup.1-Alk.sub.1- is
--NH--C.sub.1-6alkyl- or --O--C.sub.1-6alkyl-; wherein the
C.sub.1-6alkyl moiety may be substituted or unsubstituted. In
certain embodiments, --W-Alk.sub.1- is --NHC.sub.2alkyl- or
--OC.sub.2alkyl-. In certain embodiments, --W.sup.1-Alk1- is
--NHCH.sub.2CH.sub.2--, --OCH.sub.2CH.sub.2-- or
--NH--CH.sub.2CH(CH.sub.2OH)--.
[0379] XIV. Compounds Having the Structure (and Pharmaceutically
Acceptable Derivatives Thereof):
##STR00118##
[0380] wherein R.sup.1 and R.sup.X1 are as defined generally and in
classes and subclasses herein; W.sup.1 is O or NR.sup.W1, where
R.sup.W1 is hydrogen, lower alkyl, lower heteroalkyl, aryl,
heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl or acyl; Alk.sub.1 is
a substituted or unsubstituted C.sub.1-6alkylene or
C.sub.2-6alkenylene chain wherein up to two non-adjacent methylene
units are independently optionally replaced by --C(.dbd.O)--,
--CO.sub.2--, --C(.dbd.O)C(.dbd.O)--, --C(.dbd.O)NR.sup.L1A--,
--OC(.dbd.O)--, --OC(.dbd.O)NR.sup.L1A--, --NR.sup.L1ANR.sup.L1B--,
NR.sup.L1ANR.sup.L1BC(.dbd.O)--, --NR.sup.L1AC(.dbd.O)--,
--NR.sup.L1ACO.sub.2--, --NR.sup.L1AC(.dbd.O)NR.sup.L1B--,
--S(.dbd.O)--, --SO.sub.2--, --NR.sup.L1ASO.sub.2--,
--SO.sub.2NR.sup.L1A--, --NR.sup.L1ASO.sub.2NR.sup.L1B--, --O--,
--S--, or --NR.sup.L1A--; wherein each occurrence of R.sup.L1A and
R.sup.L1B is independently hydrogen, lower alkyl, lower
heteroalkyl, heterocyclyl, aryl, heteroaryl or acyl; m is an
integer from 0 to 3; r is an integer from 1 to 4; each occurrence
of R.sup.Z1 is independently hydrogen, alkyl, heteroalkyl, aryl,
heteroaryl, -(alkyl)aryl or -(alkyl)heteroaryl, --OR.sup.Z2,
--SR.sup.Z2, --NR.sup.Z2R.sup.Z3, --SO.sub.2NR.sup.Z2R.sup.Z3,
--SO.sub.2R.sup.Z1, --C(.dbd.O)NR.sup.Z2R.sup.Z3, halogen, --CN,
--NO.sub.2, --C(.dbd.O)OR.sup.Z3, --N(R.sup.Z2)C(.dbd.O)R.sup.Z3,
wherein each occurrence of R.sup.Z2 and R.sup.Z3 is independently
hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl,
-(alkyl)aryl, -(alkyl)heteroaryl or acyl, or R.sup.Z2 and R.sup.Z3
taken together with the nitrogen or carbon atom to which they are
attached form a 5-6 membered heterocyclic, aryl or heteroaryl ring;
and R.sup.Z4 is hydrogen, lower alkyl, lower heteroalkyl, aryl,
heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl or acyl. In certain
embodiments, the invention encompasses the compounds described
directly above with the proviso that:
[0381] (i) neither R.sup.1 nor R.sup.X1 is Q.sup.1, Q.sup.2 or
Q.sup.3.
[0382] In certain embodiments, for compounds of groups XIII and
XIV, --W.sup.1-Alk.sub.1- is --NHC.sub.1-6alkyl- or
--OC.sub.1-6alkyl-. In certain embodiments, --W.sup.1-Alk1- is
--NHC.sub.2alkyl- or --OC.sub.2alkyl-. In certain embodiments,
--W.sup.1-Alk- is --NHCH.sub.2CH.sub.2--, --OCH.sub.2CH.sub.2-- or
--NH--CH.sub.2CH(CH.sub.2OH)--.
[0383] In certain embodiments, for compounds of groups XIII and
XIV, R.sup.1 is hydrogen, halogen, heterocyclyl, aryl or
heteroaryl. In certain exemplary embodiments, R.sup.1 is
hydrogen.
[0384] In certain embodiments, for compounds of group XIV, R.sup.Z1
is hydrogen, halogen, lower alkyl or lower haloalkyl. In certain
embodiments, m is 1 and R.sup.Z1 is halogen, lower alkyl or lower
haloalkyl.
[0385] In certain embodiments, compounds of group XIV have the
structure:
##STR00119##
[0386] wherein R.sup.Z1 is halogen, lower alkyl or lower haloalkyl.
In certain exemplary embodiments, R.sup.Z1 is Cl, F, methyl or
--CF.sub.3. In certain exemplary embodiments, R.sup.Z1 is Cl or
--CF.sub.3.
[0387] In certain embodiments, compounds of group XIV have the
structure:
##STR00120##
[0388] wherein R.sup.1 is hydrogen, lower alkyl or
--CO.sub.2R.sup.1A where R.sup.1A is hydrogen or lower alkyl;
R.sup.X1 is hydrogen, lower alkyl or heterocyclyl; and R.sup.Z1 is
halogen, lower alkyl or lower haloalkyl. In certain exemplary
embodiments, R.sup.1 is hydrogen, methyl, --CO.sub.2H or
--CO.sub.2Me; R.sup.X1 is hydrogen, methyl or thienyl; and R.sup.Z1
is Cl, F, methyl or --CF.sub.3.
[0389] XV. Compounds Having the Structure (and Pharmaceutically
Acceptable Derivatives Thereof):
##STR00121##
[0390] wherein R.sup.1 and R.sup.X1 are as defined generally and in
classes and subclasses herein; W.sup.1 is O or NR.sup.W1, where
R.sup.W1 is hydrogen, lower alkyl, lower heteroalkyl, aryl,
heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl or acyl; Alk.sub.1 is
a substituted or unsubstituted C.sub.1-6alkylene or
C.sub.2-6alkenylene chain wherein up to two non-adjacent methylene
units are independently optionally replaced by --C(.dbd.O)--,
--CO.sub.2--, --C(.dbd.O)C(.dbd.O)--, --C(.dbd.O)NR.sup.L1A--,
--OC(.dbd.O)--, --OC(.dbd.O)NR.sup.L1A--, --NR.sup.L1ANR.sup.L1B--,
NR.sup.L1ANR.sup.L1BC(.dbd.O)--, --NR.sup.L1AC(.dbd.O)--,
--NR.sup.L1ACO.sub.2--, --NR.sup.L1AC(.dbd.O)NR.sup.L1B--,
--S(.dbd.O)--, --SO.sub.2--, --NR.sup.L1A SO.sub.2--,
--SO.sub.2NR.sup.L1A--, --NR.sup.L1ASO.sub.2NR.sup.L1B--, --O--,
--S--, or --NR.sup.L1A--; wherein each occurrence of R.sup.L1A and
R.sup.L1B is independently hydrogen, lower alkyl, lower
heteroalkyl, heterocyclyl, aryl, heteroaryl or acyl; m is an
integer from 0 to 3; r is an integer from 1 to 4; each occurrence
of R.sup.Z1 is independently hydrogen, alkyl, heteroalkyl, aryl,
heteroaryl, -(alkyl)aryl or -(alkyl)heteroaryl, --OR.sup.Z2,
--SR.sup.Z2, --NR.sup.Z2R.sup.Z3, --SO.sub.2NR.sup.Z2R.sup.Z3,
--SO.sub.2R.sup.Z1, --C(.dbd.O)NR.sup.Z2R.sup.Z3, halogen, --CN,
--NO.sub.2, --C(.dbd.O)OR.sup.Z3, --N(R.sup.Z2)C(.dbd.O)R.sup.Z3,
wherein each occurrence of R.sup.Z2 and R.sup.Z3 is independently
hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl,
-(alkyl)aryl, -(alkyl)heteroaryl or acyl, or R.sup.Z2 and R.sup.Z3
taken together with the nitrogen or carbon atom to which they are
attached form a 5-6 membered heterocyclic, aryl or heteroaryl ring;
and R.sup.Z4 is hydrogen, lower alkyl, lower heteroalkyl, aryl,
heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl or acyl. In certain
embodiments, the invention encompasses the compounds described
directly above with the proviso that:
[0391] (i) neither R.sup.1 nor R.sup.X1 is Q.sup.1, Q.sup.2 or
Q.sup.3.
[0392] In certain embodiments, for compounds of group XV,
--W.sup.1-Alk.sub.1- is --NHC.sub.1-6alkyl- or --OC.sub.1-6alkyl-.
In certain embodiments, --W.sup.1-Alk.sub.1- is --NHC.sub.2alkyl-
or --OC.sub.2alkyl-. In certain embodiments, --W.sup.1-Alk1- is
--NHCH.sub.2CH.sub.2--, --OCH.sub.2CH.sub.2-- or
--NH--CH.sub.2CH(CH.sub.2OH)--.
[0393] In certain embodiments, for compounds of group XV, R.sup.1
is hydrogen, halogen, heterocyclyl, aryl or heteroaryl. In certain
exemplary embodiments, R.sup.1 is hydrogen.
[0394] In certain embodiments, for compounds of group XV, R.sup.Z1
is hydrogen, halogen, lower alkyl or lower haloalkyl. In certain
embodiments, m is 0.
[0395] In certain embodiments, compounds of group XV have the
structure:
##STR00122##
[0396] In certain embodiments, compounds of group XV have the
structure:
##STR00123##
[0397] wherein R.sup.1 is hydrogen, lower alkyl or
--CO.sub.2R.sup.1A where R.sup.1A is hydrogen or lower alkyl; and
R.sup.X1 is hydrogen, lower alkyl or heterocyclyl. In certain
exemplary embodiments, R.sup.1 is hydrogen, methyl, --CO.sub.2H or
--CO.sub.2Me; R.sup.X1 is hydrogen, methyl or thienyl.
[0398] XVI. Compounds Having the Structure (and Pharmaceutically
Acceptable Derivatives Thereof):
##STR00124##
[0399] wherein R.sup.1 and R.sup.X1 are as defined generally and in
classes and subclasses herein; W.sup.1 is O or NR.sup.W1, where
R.sup.W1 is hydrogen, lower alkyl, lower heteroalkyl, aryl,
heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl or acyl; Alk.sub.1 is
a substituted or unsubstituted C.sub.1-6alkylene or
C.sub.2-6alkenylene chain wherein up to two non-adjacent methylene
units are independently optionally replaced by --C(.dbd.O)--,
--CO.sub.2--, --C(.dbd.O)C(.dbd.O)--, --C(.dbd.O)NR.sup.L1A--,
--OC(.dbd.O)--, --OC(.dbd.O)NR.sup.L1A--, --NR.sup.L1ANR.sup.L1B--,
NR.sup.L1ANR.sup.L1BC(.dbd.O)--, --NR.sup.L1AC(.dbd.O)--,
--NR.sup.L1AC.sub.2--, --NR.sup.L1AC(.dbd.O)NR.sup.L1B--,
--S(.dbd.O)--, --SO.sub.2--, --NR.sup.L1ASO.sub.2--,
--SO.sub.2NR.sup.L1A--, --NR.sup.L1ASO.sub.2NR.sup.L1B--, --O--,
--S--, or --NR.sup.L1A--; wherein each occurrence of R.sup.L1A and
R.sup.L1B is independently hydrogen, lower alkyl, lower
heteroalkyl, heterocyclyl, aryl, heteroaryl or acyl; m is an
integer from 0 to 3; r is an integer from 1 to 4; each occurrence
of R.sup.Z1 is independently hydrogen, alkyl, heteroalkyl, aryl,
heteroaryl, -(alkyl)aryl or -(alkyl)heteroaryl, --OR.sup.Z2,
--SR.sup.Z2, --NR.sup.Z2R.sup.Z3, --SO.sub.2NR.sup.Z2R.sup.Z3,
--SO.sub.2R.sup.Z1, --C(.dbd.O)NR.sup.Z2R.sup.Z3, halogen, --CN,
--NO.sub.2, --C(.dbd.O)OR.sup.Z3, --N(R.sup.Z2)C(.dbd.O)R.sup.Z3,
wherein each occurrence of R.sup.Z2 and R.sup.Z3 is independently
hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl,
-(alkyl)aryl, -(alkyl)heteroaryl or acyl, or R.sup.Z2 and R.sup.Z3
taken together with the nitrogen or carbon atom to which they are
attached form a 5-6 membered heterocyclic, aryl or heteroaryl ring;
and R.sup.Z4 is hydrogen, lower alkyl, lower heteroalkyl, aryl,
heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl or acyl. In certain
embodiments, the invention encompasses the compounds described
directly above with the proviso that:
[0400] (i) neither R.sup.1 nor R.sup.X1 is Q.sup.1, Q.sup.2 or
Q.sup.3; and
[0401] (ii) --W.sup.1-Alk.sub.1- is not --OCH.sub.2-- or
--N(R)CH.sub.2--, wherein R is H or C.sub.1-8alkyl.
[0402] In certain embodiments, for compounds of group XVI,
--W.sup.1-Alk.sub.1- is --NHC.sub.1-6alkyl- or --OC.sub.1-6alkyl-.
In certain embodiments, --W.sup.1-Alk1- is --NHC.sub.2alkyl- or
--OC.sub.2alkyl-. In certain embodiments, --W.sup.1-Alk.sub.1- is
--NHCH.sub.2CH.sub.2--, --OCH.sub.2CH.sub.2-- or
--NH--CH.sub.2CH(CH.sub.2OH)--.
[0403] In certain embodiments, for compounds of group XVI, R.sup.1
is hydrogen, halogen, heterocyclyl, aryl or heteroaryl. In certain
exemplary embodiments, R.sup.1 is hydrogen.
[0404] In certain embodiments, for compounds of group XVI, R.sup.Z1
is hydrogen, halogen, lower alkyl or lower haloalkyl. In certain
embodiments, m is 1 and R.sup.Z1 is Cl, F, methyl or --CF.sub.3. In
certain embodiments, m is 1 and R.sup.Z1 is lower haloalkyl. In
certain embodiments, m is 1 and R.sup.Z1 is --CF.sub.3.
[0405] In certain embodiments, compounds of group XVI have the
structure:
##STR00125##
[0406] wherein R.sup.Z1 is halogen, lower alkyl or lower haloalkyl.
In certain exemplary embodiments, R.sup.Z1 is Cl, F, methyl or
--CF.sub.3.
[0407] In certain embodiments, compounds of group XVI have the
structure:
##STR00126##
[0408] wherein R.sup.1 is hydrogen, lower alkyl or
--CO.sub.2R.sup.1A where R.sup.1A is hydrogen or lower alkyl;
R.sup.X1 is hydrogen, lower alkyl or heterocyclyl; and R.sup.Z1 is
halogen, lower alkyl or lower haloalkyl. In certain exemplary
embodiments, R.sup.1 is hydrogen, methyl, --CO.sub.2H or
--CO.sub.2Me; R.sup.X1 is hydrogen, methyl or thienyl; and R.sup.Z1
is Cl, F, methyl or --CF.sub.3.
[0409] XVII. Compounds Having the Structure (and Pharmaceutically
Acceptable Derivatives Thereof):
##STR00127##
[0410] wherein R.sup.1, L.sup.2, Y and Z are as defined generally
and in classes and subclasses herein; and R.sup.W1 together with a
carbon atom present on Alk.sub.1 forms an optionally substituted 5-
to 6-membered heterocyclic ring.
[0411] In certain embodiments, compounds of the invention have the
structure (1.sup.A) or (2.sup.A) below:
##STR00128##
[0412] wherein m is 1 or 2 and R.sup.Alk1 is hydrogen, halohen,
hydroxy, CN, nitro, lower alkyl, lower alkoxy, aryl, or heteroaryl.
In certain embodiments, R.sup.Alk1 is hydrogen.
[0413] XVIII. Compounds Having the Structure (and Pharmaceutically
Acceptable Derivatives Thereof):
##STR00129##
[0414] wherein one of is a double bond, as valency permits;
[0415] one of X.sup.1 and X.sup.2 is S, the other is
--C(R.sup.X1)--; wherein R.sup.X1 is hydrogen, halogen, cyano,
nitro, or an aliphatic, heteroaliphatic, alicyclic,
heteroalicyclic, aromatic or heteroaromatic moiety;
[0416] W.sup.1 is O, S, NR.sup.W1 or --C(.dbd.O)NR.sup.W1 where
R.sup.W1 is hydrogen, lower alkyl, C.sub.3-6cycloalkyl, lower
heteroalkyl, heterocyclyl, aryl, heteroaryl, -(alkyl)aryl,
-(alkyl)heteroaryl or acyl; or R.sup.W1 together with a carbon atom
present on Alk.sub.1 forms an optionally substituted 5- to
6-membered heterocyclic ring;
[0417] Alk.sub.1 is a substituted or unsubstituted
C.sub.1-6alkylene or C.sub.2-6alkenylene chain wherein up to two
non-adjacent methylene units are independently optionally replaced
by --C(.dbd.O)--, --CO.sub.2--, --C(.dbd.O)C(.dbd.O)--,
--C(.dbd.O)NR.sup.L1A--, --OC(.dbd.O)--, --OC(.dbd.O)NR.sup.L1A--,
--NR.sup.L1ANR.sup.L1B--, --NR.sup.L1ANR.sup.L1BC(.dbd.O)--,
NR.sup.L1AC(.dbd.O)--, --NR.sup.L1ACO.sub.2--,
--NR.sup.L1AC(.dbd.O)NR.sup.L1B--, --S(.dbd.O)--, --SO.sub.2--,
--NR.sup.L1ASO.sub.2--, --SO.sub.2NR.sup.L1A--,
--NR.sup.L1ASO.sub.2NR.sup.L1B--, --O--, --S--, or --NR.sup.L1A--;
wherein each occurrence of R.sup.L1A and R.sup.L1B is independently
hydrogen, lower alkyl, lower heteroalkyl, heterocyclyl, aryl,
heteroaryl or acyl;
[0418] L.sup.2 is --NR.sup.W2--, --N(R.sup.W2)C(.dbd.O)G.sub.2-,
--N(R.sup.W2)C(.dbd.O)N(R.sup.W2)CR.sup.W3R.sup.W4-- or
--CR.sup.W3R.sup.W4C(.dbd.O)N(R.sup.W2)--; wherein G.sub.2 is
absent, O or NR.sup.G2; and R.sup.W2, R.sup.W3, R.sup.W4 and
R.sup.G2 are independently hydrogen, lower alkyl, lower
heteroalkyl, heterocyclyl, aryl, heteroaryl, -(alkyl)aryl,
-(alkyl)heteroaryl or acyl;
[0419] Y is an optionally substituted phenyl or thiazolyl ring;
[0420] Z is an aliphatic, heteroaliphatic, alicyclic,
heteroalicyclic, aromatic or heteroaromatic moiety;
[0421] with the proviso that (a) R.sup.X1 is not Q.sup.1, Q.sup.2
or Q.sup.3, wherein
[0422] Q.sup.1 is
--(CR.sup.1AR.sup.1B).sub.mC.ident.C--(CR.sup.1AR.sup.1B).sub.tR.sup.1C,
--(CR.sup.1AR.sup.1B).sub.mC.dbd.C--(CR.sup.1AR.sup.1B).sub.tR.sup.1C,
--C.dbd.NOR.sup.1D, or --X.sup.3R.sup.1D wherein m is an integer
from 0 to 3, t is an integer from 0 to 5, and X.sup.3 is a divalent
group derived from azetidine, oxetane or a C.sub.3-4carbocyclic
group;
[0423] Q.sup.2 is
--(CR.sup.1AR.sup.1B).sub.mC.dbd.C--(CR.sup.1AR.sup.1B).sub.kR.sup.1E,
--(CR.sup.1AR.sup.1B).sub.mC.dbd.C--(CR.sup.1AR.sup.1B).sub.kR.sup.1E
wherein k is an integer from 1 to 3 and m is an integer from 0 to
3; and
[0424] Q.sup.3 is --(CR.sup.1AR.sup.1B).sub.tR.sup.1C, wherein t is
an integer from 0 to 5 and the attachment point to R.sup.1C is
through a carbon atom of the R.sup.1C group; wherein R.sup.1A and
R.sup.1B are independently H or C.sub.1-6alkyl; R.sup.1C is an
optionally substituted non-aromatic monocyclic ring, a fused or
bridged bycyclic ring or a spirocyclic ring; R.sup.1E is
--NR.sup.1AR.sup.1D or --OR.sup.1D; R.sup.1D is R.sup.1F,
--C(.dbd.O)R.sup.1F, --SO.sub.2R.sup.1F,
C(.dbd.O)N(R.sup.1F).sub.2, --SO.sub.2N(R.sup.1F).sub.2, or
--CO.sub.2R.sup.1F, wherein R.sup.1F is H, C.sub.1-6alkyl,
--(CR.sup.1AR.sup.1B).sub.t(C.sub.6-10aryl) or
--(CR.sup.1AR.sup.1B).sub.t(4-10 membered heterocyclic); and
[0425] (b) in any one or more of the following groups, the recited
variables do not occur simultaneously as defined:
[0426] (i) --W.sup.1-Alk.sub.1- is --OCH.sub.2-- or
--N(R)CH.sub.2--, wherein R is H or C.sub.1-8alkyl; Y is phenyl;
and Z is a 5-10-membered cycloalkyl, heterocyclyl, aryl or
heteroaryl;
[0427] (ii) R.sup.X1 is hydrogen, halogen, C.sub.1-4alkyl or
C.sub.1-4alkoxy; --W.sup.1-Alk.sub.1- is --NHC.sub.1-6alkyl,
--OC.sub.1-6alkyl, --NHC.sub.1-6heteroalkyl or
--OC.sub.1-6heteroalkyl; L.sup.2-Z is --X--R.sup.x where X is
--NR-- or --NHC(.dbd.O)--, and R.sup.x is C.sub.3-10cycloalkyl,
morpholinyl, phenyl, phenylC.sub.1-4alkyl or phenylC.sub.2-3
alkenyl; and
[0428] (iii) one of X.sup.1 and X.sup.2 is S, the other is
CR.sup.XA wherein R.sup.XA is hydrogen, C.sub.1-4alkyl or phenyl
optionally substituted with halogen, (halo)C.sub.1-4alkyl or
(halo)C.sub.1-4alkoxy; --W.sup.1-Alk.sub.1- is --NRC.sub.1-6alkyl-,
--OC.sub.1-6alkyl- or --SC.sub.1-6alkyl- wherein R is hydrogen,
C.sub.1-4alkyl, C.sub.1-4acyl; Y is phenyl; L.sup.2-Z is a
C.sub.1-12alkyl saturated or unsaturated hydrocarbon chain
including --NR-- and optionally substituted with
haloC.sub.1-4alkoxy, C.sub.3-8cycloalkyl, C.sub.3-8cycloalkenyl,
C.sub.1-4acyl, phenoxy, phenyl or phenylthio.
[0429] In certain embodiments, X.sup.1 is S and X.sup.2 is CH. In
certain embodiments, X.sup.1 is CH and X.sup.2 is S. In certain
embodiments, L.sup.2 is NH, --NHC(.dbd.O)--, --NHC(.dbd.O)O--,
--NHC(.dbd.O)NH--, --NHC(.dbd.O)NHCH.sub.2--, or
--CH.sub.2C(.dbd.O)NH--.
[0430] In certain embodiments, compounds of subgroup XVIII have the
following structure:
##STR00130##
[0431] wherein q is 1-4; one of X.sup.1 and X.sup.2 is S and the
other is --CH--; and each occurrence of R.sup.Y is independently
hydrogen, alkyl, heteroalkyl, aryl, heteroaryl, -(alkyl)aryl or
-(alkyl)heteroaryl, --OR.sup.Y3, --SR.sup.Y3, --NR.sup.Y2R.sup.Y3,
--SO.sub.2NR.sup.Y2R.sup.Y3, --C(.dbd.O)NR.sup.Y2R.sup.Y3, halogen,
--CN, --NO.sub.2, --C(.dbd.O)OR.sup.Y3,
--N(R.sup.Y2)C(.dbd.O)R.sup.Y3, wherein each occurrence of R.sup.Y2
and R.sup.Y3 is independently hydrogen, lower alkyl, lower
heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl or
acyl, or R.sup.Y2 and R.sup.Y3 taken together with the nitrogen
atom to which they are attached form a 5-6 membered heterocyclic
ring.
[0432] In certain embodiments, compounds of subgroup XVIII have the
following structure:
##STR00131##
[0433] wherein W.sup.1 is O or NR.sup.W1, where R.sup.W1 is
hydrogen, lower alkyl, C.sub.3-6cycloalkyl, lower heteroalkyl,
heterocyclyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl or
acyl; and Alk.sub.1 is a C.sub.1-6alkylene or C.sub.2-6alkenylene
moiety; and each occurrence of R.sup.Y1 is independently hydrogen,
halogen or lower alkyl.
[0434] In certain embodiments, compounds of subgroup XVIII have the
following structure:
##STR00132##
[0435] wherein L.sup.2 is NH, --NHC(.dbd.O)--, --NHC(.dbd.O)O--,
--NHC(.dbd.O)NH--, --NHC(.dbd.O)NHCH.sub.2--, or
--CH.sub.2C(.dbd.O)NH--.
[0436] In certain embodiments for compounds as described in
subgroups I-XVII above, R.sup.1 is hydrogen.
[0437] In certain embodiments, for compounds as described in
subgroups I-XVIII above, R.sup.W1 together with a carbon atom
present on Alk.sub.1 forms an optionally substituted 5- to
6-membered heterocyclic ring.
[0438] In certain embodiments, for compounds as described in
subgroups I-XIII and XVII-XVIII above, Z is a branched alkyl,
alkenyl, alkynyl, heteroalkyl or heteroalkenyl moiety. In certain
exemplary embodiments, Z has one of the following structures:
##STR00133##
[0439] wherein each occurrence of R.sup.Z1 is independently
hydrogen, lower alkyl, lower alkenyl, aryl, heteroaryl or acyl. In
certain embodiments, Z has one of the following structures:
##STR00134##
[0440] In certain embodiments, for compounds as described in
subgroups I-XIII and XVII-XVIII above, Z is a cycloalkyl,
cycloalkenyl, heterocyclyl, aryl or heteroaryl moiety. In certain
exemplary embodiments, Z has one of the following structures:
##STR00135##
[0441] wherein R.sup.Z1 is Cl, F, methyl or CF.sub.3.
[0442] In certain embodiments, for compounds as described in
subgroups I, IV-VI and XVII-XVIII above, -L.sup.2-Z together
represent a moiety having one of the following structures:
##STR00136##
[0443] wherein R.sup.Z1 is Cl, F, methyl or CF.sub.3.
[0444] It will also be appreciated that for each of the subgroups
I-XVIII described above, a variety of other subclasses are of
special interest, including, but not limited to those classes
described above i)- cxvi) and classes, subclasses and species of
compounds described above and in the examples herein.
[0445] Some of the foregoing compounds can comprise one or more
asymmetric centers, and thus can exist in various isomeric forms,
e.g., stereoisomers and/or diastereomers. Thus, inventive compounds
and pharmaceutical compositions thereof may be in the form of an
individual enantiomer, diastereomer or geometric isomer, or may be
in the form of a mixture of stereoisomers. In certain embodiments,
the compounds of the invention are enantiopure compounds. In
certain other embodiments, mixtures of stereoisomers or
diastereomers are provided.
[0446] Furthermore, certain compounds, as described herein may have
one or more double bonds that can exist as either the Z or E
isomer, unless otherwise indicated. The invention additionally
encompasses the compounds as individual isomers substantially free
of other isomers and alternatively, as mixtures of various isomers,
e.g., racemic mixtures of stereoisomers. In addition to the
above-mentioned compounds per se, this invention also encompasses
pharmaceutically acceptable derivatives of these compounds and
compositions comprising one or more compounds of the invention and
one or more pharmaceutically acceptable excipients or
additives.
[0447] Compounds of the invention may be prepared by
crystallization of compound of formula (I) under different
conditions and may exist as one or a combination of polymorphs of
compound of general formula (I) forming part of this invention. For
example, different polymorphs may be identified and/or prepared
using different solvents, or different mixtures of solvents for
recrystallization; by performing crystallizations at different
temperatures; or by using various modes of cooling, ranging from
very fast to very slow cooling during crystallizations. Polymorphs
may also be obtained by heating or melting the compound followed by
gradual or fast cooling. The presence of polymorphs may be
determined by solid probe NMR spectroscopy, IR spectroscopy,
differential scanning calorimetry, powder X-ray diffractogram
and/or other techniques. Thus, the present invention encompasses
inventive compounds, their derivatives, their tautomeric forms,
their stereoisomers, their polymorphs, their pharmaceutically
acceptable salts their pharmaceutically acceptable solvates and
pharmaceutically acceptable compositions containing them.
[0448] 2) Synthetic Overview:
[0449] The practitioner has a well-established literature of
thienopyrimidine chemistry to draw upon, in combination with the
information contained herein, for guidance on synthetic strategies,
protecting groups, and other materials and methods useful for the
synthesis of the compounds of this invention, including compounds
containing the various R.sup.1 and R.sup.2 substituents and
L.sup.1, L.sup.2, Y and Z moieties.
[0450] The various patent documents and other references cited
herein provide helpful background information on preparing
compounds similar to the inventive compounds described herein or
relevant intermediates. Certain cited patent documents also contain
information on formulation, uses, and administration of such
compounds which may be of interest. For example, guidance may be
found in U.S. Pat. Nos. 6,169,091; 5,227,387; 5,654,307 and
5,859,020; European Patent Application No.: EP 452002 and
International Application Nos.: WO 97/09316, WO 01/32632 and WO
03/64428. Although U.S. Pat. No. 6,541,481 does not specifically
disclose thienopyrimidines, the synthetic guidance provided therein
may be adapted to generate compounds of the invention.
[0451] Moreover, the practitioner is directed to the specific
guidance and examples provided in this document relating to various
exemplary compounds and intermediates thereof.
[0452] As described above, the present invention provides novel
compounds, specifically compounds having the following general
structure:
##STR00137##
[0453] and pharmaceutically acceptable derivatives thereof;
[0454] wherein R.sup.1, R.sup.2, X.sup.1, X.sup.2, L.sup.1,
L.sup.2, Y and Z are as defined in classes and subclasses
herein.
[0455] It will be appreciated that for compounds as generally
described above, certain classes of compounds are of special
interest. For example, one class of compounds of special interest
includes thieno[3,2d]pyrimidines having the Formula (I.sup.A):
##STR00138##
[0456] In yet another aspect of the invention, methods for
producing intermediates useful for the preparation of compounds of
formulae (I) and (I.sup.A) are provided, embodiments of said
methods being depicted generally in Scheme A:
##STR00139##
[0457] where LG.sup.1 is a suitable leaving group and L.sup.1A is
adapted to displace LG.sup.1 upon reaction with
thieno[3,2d]pyrimidine (1).
[0458] In other embodiments, one class of compounds of special
interest includes thieno[2,3d]pyrimidines having the Formula
(I.sup.B):
##STR00140##
[0459] In yet another aspect of the invention, methods for
producing intermediates useful for the preparation of compounds of
formulae (I) and (I.sup.B) are provided, embodiments of said
methods being depicted generally in Scheme B:
##STR00141##
[0460] where LG.sup.1 is a suitable leaving group and L.sup.1A is
adapted to displace LG.sup.1 upon reaction with
thieno[2,3d]pyrimidine (2).
[0461] Numerous suitable prodrug moieties, and information
concerning their selection, synthesis and use are well known in the
art. Examples of prodrug moieties of interest include, among
others, prodrug moieties that can be attached to primary or
secondary amine-containing functionalities. For instance, prodrug
moieties of interest include those that can be attached to group
--NH.sub.2. Examples of such prodrug moieties include the
following:
##STR00142##
For the synthesis of the prodrug groups, see Borchardt, R. T. et
al., J. Org. Chem. 1997, 43, 3461-3562. R.sup.1=all natural,
unnatural amino acids
##STR00143##
For the synthesis of the prodrug groups, see Zhou, X-X. et al., PCT
WO 99/51613. R.sup.1=C.sub.1-C.sub.4 alkyl, cycloalkyl, oxyalkyl,
aminoalkyl, etc. R.sup.2=all natural, unnatural amino acids
##STR00144##
For the synthesis of the prodrug groups, see Ezra, A. et al., J.
Med. Chem. 2000, 43, 3641-3652. R.sup.1, R.sup.2=all natural,
unnatural amino acids
[0462] The present invention encompasses any prodrug form of the
compounds described herein. Although certain other exemplary
prodrug moieties generated from the inventive compounds amino group
are detailed herein, it will be appreciated that the present
invention is not intended to be limited to these prodrug moieties;
rather, a variety of additional prodrug moieties can be readily
identified by a person skilled in the relevant art.
[0463] Pharmaceutical Compositions
[0464] As discussed above, the present invention provides compounds
that are inhibitors of protein kinases (e.g., Aurora kinase), and
thus the present compounds are useful for the treatment of
diseases, disorders, and conditions including, but not limited to
melanoma, leukemia, or cancers such as colon, breast, gastric,
ovarian, cervical, renal, prostate, lymphoma, neuroblastoma,
pancreatic and blader cancer. Accordingly, in another aspect of the
present invention, pharmaceutically acceptable compositions are
provided, wherein these compositions comprise any of the compounds
as described herein, and optionally comprise a pharmaceutically
acceptable carrier, adjuvant or vehicle. In certain embodiments,
these compositions optionally further comprise one or more
additional therapeutic agents.
[0465] It will also be appreciated that certain of the compounds of
present invention can exist in free form for treatment, or where
appropriate, as a pharmaceutically acceptable derivative thereof.
According to the present invention, a pharmaceutically acceptable
derivative includes, but is not limited to, pharmaceutically
acceptable salts, esters, salts of such esters, or any other adduct
or derivative which upon administration to a patient in need is
capable of providing, directly or indirectly, a compound as
otherwise described herein, or a metabolite or residue thereof.
[0466] As used herein, the term "pharmaceutically acceptable salt"
refers to those salts which are, within the scope of sound medical
judgement, suitable for use in contact with the tissues of humans
and lower animals without undue toxicity, irritation, allergic
response and the like, and are commensurate with a reasonable
benefit/risk ratio. A "pharmaceutically acceptable salt" means any
non-toxic salt or salt of an ester of a compound of this invention
that, upon administration to a recipient, is capable of providing,
either directly or indirectly, a compound of this invention or an
inhibitorily active metabolite or residue thereof. As used herein,
the term "inhibitorily active metabolite or residue thereof" means
that a metabolite or residue thereof is also an inhibitor of a
Aurora kinase.
[0467] Pharmaceutically acceptable salts are well known in the art.
For example, S. M. Berge et al., describe pharmaceutically
acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66,
1-19, incorporated herein by reference. Pharmaceutically acceptable
salts of the compounds of this invention include those derived from
suitable inorganic and organic acids and bases. Examples of
pharmaceutically acceptable, nontoxic acid addition salts are salts
of an amino group formed with inorganic acids such as hydrochloric
acid, hydrobromic acid, phosphoric acid, sulfuric acid and
perchloric acid or with organic acids such as acetic acid, oxalic
acid, maleic acid, tartaric acid, citric acid, succinic acid or
malonic acid or by using other methods used in the art such as ion
exchange. Other pharmaceutically acceptable salts include adipate,
alginate, ascorbate, aspartate, benzenesulfonate, benzoate,
bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate,
cyclopentanepropionate, digluconate, dodecylsulfate,
ethanesulfonate, formate, fumarate, glucoheptonate,
glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate,
hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate,
laurate, lauryl sulfate, malate, maleate, malonate,
methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate,
oleate, oxalate, palmitate, pamoate, pectinate, persulfate,
3-phenylpropionate, phosphate, picrate, pivalate, propionate,
stearate, succinate, sulfate, tartrate, thiocyanate,
p-toluenesulfonate, undecanoate, valerate salts, and the like.
Salts derived from appropriate bases include alkali metal, alkaline
earth metal, ammonium and N.sup.+(C.sub.1-4alkyl).sub.4 salts. This
invention also envisions the quaternization of any basic
nitrogen-containing groups of the compounds disclosed herein. Water
or oil-soluble or dispersable products may be obtained by such
quaternization. Representative alkali or alkaline earth metal salts
include sodium, lithium, potassium, calcium, magnesium, and the
like. Further pharmaceutically acceptable salts include, when
appropriate, nontoxic ammonium, quaternary ammonium, and amine
cations formed using counterions such as halide, hydroxide,
carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and
aryl sulfonate.
[0468] As described above, the pharmaceutically acceptable
compositions of the present invention additionally comprise a
pharmaceutically acceptable carrier, adjuvant, or vehicle, which,
as used herein, includes any and all solvents, diluents, or other
liquid vehicle, dispersion or suspension aids, surface active
agents, isotonic agents, thickening or emulsifying agents,
preservatives, solid binders, lubricants and the like, as suited to
the particular dosage form desired. Remington's Pharmaceutical
Sciences, Sixteenth Edition, E. W. Martin (Mack Publishing Co.,
Easton, Pa., 1980) discloses various carriers used in formulating
pharmaceutically acceptable compositions and known techniques for
the preparation thereof. Except insofar as any conventional carrier
medium is incompatible with the compounds of the invention, such as
by producing any undesirable biological effect or otherwise
interacting in a deleterious manner with any other component(s) of
the pharmaceutically acceptable composition, its use is
contemplated to be within the scope of this invention. Some
examples of materials which can serve as pharmaceutically
acceptable carriers include, but are not limited to, ion
exchangers, alumina, aluminum stearate, lecithin, serum proteins,
such as human serum albumin, buffer substances such as phosphates,
glycine, sorbic acid, or potassium sorbate, partial glyceride
mixtures of saturated vegetable fatty acids, water, salts or
electrolytes, such as protamine sulfate, disodium hydrogen
phosphate, potassium hydrogen phosphate, sodium chloride, zinc
salts, colloidal silica, magnesium trisilicate, polyvinyl
pyrrolidone, polyacrylates, waxes,
polyethylene-polyoxypropylene-block polymers, wool fat, sugars such
as lactose, glucose and sucrose; starches such as corn starch and
potato starch; cellulose and its derivatives such as sodium
carboxymethyl cellulose, ethyl cellulose and cellulose acetate;
powdered tragacanth; malt; gelatin; talc; excipients such as cocoa
butter and suppository waxes; oils such as peanut oil, cottonseed
oil; safflower oil; sesame oil; olive oil; corn oil and soybean
oil; glycols; such a propylene glycol or polyethylene glycol;
esters such as ethyl oleate and ethyl laurate; agar; buffering
agents such as magnesium hydroxide and aluminum hydroxide; alginic
acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl
alcohol, and phosphate buffer solutions, as well as other non-toxic
compatible lubricants such as sodium lauryl sulfate and magnesium
stearate, as well as coloring agents, releasing agents, coating
agents, sweetening, flavoring and perfuming agents, preservatives
and antioxidants can also be present in the composition, according
to the judgment of the formulator.
[0469] Uses of Compounds and Pharmaceutically Acceptable
Compositions
[0470] Research Uses
[0471] According to the present invention, the inventive compounds
may be assayed in any of the available assays known in the art for
identifying compounds having protease inhibitory activity. For
example, the assay may be cellular or non-cellular, in vivo or in
vitro, high- or low-throughput format, etc.
[0472] In certain exemplary embodiments, compounds of this
invention were assayed for their ability to inhibit protein
kinases, more specifically Aurora.
[0473] Thus, in one aspect, compounds of this invention which are
of particular interest include those which: [0474] are inhibitors
of protein kinases; [0475] exhibit the ability to inhibit Aurora
kinase; [0476] are useful for treating mammals (e.g., humans) or
animals suffering from an Aurora-mediated disease or condition, and
for helping to prevent or delay the onset of such a
disease/condition; [0477] exhibit a favorable therapeutic profile
(e.g., safety, efficacy, and stability).
[0478] In certain embodiments, compounds of the invention are
Aurora kinase inhibitors. In certain exemplary embodiments,
inventive compounds are Aurora-A inhibitors. In certain exemplary
embodiments, inventive compounds have .sup.CellIC.sub.50
values<100 .mu.M. In certain other embodiments, inventive
compounds have .sup.CellIC.sub.50 values<75 .mu.M. In certain
other embodiments, inventive compounds have .sup.CellIC.sub.50
values<50 .mu.M. In certain other embodiments, inventive
compounds have .sup.CellIC.sub.50 values<25 .mu.M. In certain
other embodiments, inventive compounds have .sup.CellIC.sub.50
values<10 .mu.M. In certain other embodiments, inventive
compounds have .sup.CellIC.sub.50 values<7.5 .mu.M. In certain
other embodiments, inventive compounds have .sup.CellIC.sub.50
values<5 .mu.M. In certain other embodiments, inventive
compounds have .sup.CellIC.sub.50 values<2.5 .mu.M. In certain
other embodiments, inventive compounds have .sup.CellIC.sub.50
values<1 .mu.M. In certain other embodiments, inventive
compounds have .sup.CellIC.sub.50 values<800 nM. In certain
other embodiments, inventive compounds have .sup.CellIC.sub.50
values<600 nM. In certain other embodiments, inventive compounds
have .sup.CellIC.sub.50 values<500 nM. In certain other
embodiments, inventive compounds have .sup.CellIC.sub.50
values<300 nM. In certain other embodiments, inventive compounds
have .sup.CellIC.sub.50 values<200 nM. In certain other
embodiments, inventive compounds have .sup.CellIC.sub.50
values<100 nM.
[0479] In yet another aspect, a method for the treatment or
lessening the severity of an Aurora-mediated disease or condition
is provided comprising administering an effective amount of a
compound, or a pharmaceutically acceptable composition comprising a
compound to a subject in need thereof. In certain embodiments of
the present invention an "effective amount" of the compound or
pharmaceutically acceptable composition is that amount effective
for treating or lessening the severity of an Aurora-mediated
disease or condition. The compounds and compositions, according to
the method of the present invention, may be administered using any
amount and any route of administration effective for treating or
lessening the severity of an Aurora-mediated disease or condition.
The exact amount required will vary from subject to subject,
depending on the species, age, and general condition of the
subject, the severity of the infection, the particular agent, its
mode of administration, and the like. The compounds of the
invention are preferably formulated in dosage unit form for ease of
administration and uniformity of dosage. The expression "dosage
unit form" as used herein refers to a physically discrete unit of
agent appropriate for the patient to be treated. It will be
understood, however, that the total daily usage of the compounds
and compositions of the present invention will be decided by the
attending physician within the scope of sound medical judgment. The
specific effective dose level for any particular patient or
organism will depend upon a variety of factors including the
disorder being treated and the severity of the disorder; the
activity of the specific compound employed; the specific
composition employed; the age, body weight, general health, sex and
diet of the patient; the time of administration, route of
administration, and rate of excretion of the specific compound
employed; the duration of the treatment; drugs used in combination
or coincidental with the specific compound employed, and like
factors well known in the medical arts. The term "patient", as used
herein, means an animal, preferably a mammal, and most preferably a
human.
[0480] The pharmaceutically acceptable compositions of this
invention can be administered to humans and other animals orally,
rectally, parenterally, intracisternally, intravaginally,
intraperitoneally, topically (as by powders, ointments, or drops),
bucally, as an oral or nasal spray, or the like, depending on the
severity of the infection being treated. In certain embodiments,
the compounds of the invention may be administered orally or
parenterally at dosage levels of about 0.01 mg/kg to about 50 mg/kg
and preferably from about 1 mg/kg to about 25 mg/kg, of subject
body weight per day, one or more times a day, to obtain the desired
therapeutic effect.
[0481] Liquid dosage forms for oral administration include, but are
not limited to, pharmaceutically acceptable emulsions,
microemulsions, solutions, suspensions, syrups and elixirs. In
addition to the active compounds, the liquid dosage forms may
contain inert diluents commonly used in the art such as, for
example, water or other solvents, solubilizing agents and
emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl
carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate,
propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in
particular, cottonseed, groundnut, corn, germ, olive, castor, and
sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene
glycols and fatty acid esters of sorbitan, and mixtures thereof.
Besides inert diluents, the oral compositions can also include
adjuvants such as wetting agents, emulsifying and suspending
agents, sweetening, flavoring, and perfuming agents.
[0482] Injectable preparations, for example, sterile injectable
aqueous or oleaginous suspensions may be formulated according to
the known art using suitable dispersing or wetting agents and
suspending agents. The sterile injectable preparation may also be a
sterile injectable solution, suspension or emulsion in a nontoxic
parenterally acceptable diluent or solvent, for example, as a
solution in 1,3-butanediol. Among the acceptable vehicles and
solvents that may be employed are water, Ringer's solution, U.S.P.
and isotonic sodium chloride solution. In addition, sterile, fixed
oils are conventionally employed as a solvent or suspending medium.
For this purpose any bland fixed oil can be employed including
synthetic mono- or diglycerides. In addition, fatty acids such as
oleic acid are used in the preparation of injectables.
[0483] The injectable formulations can be sterilized, for example,
by filtration through a bacterial-retaining filter, or by
incorporating sterilizing agents in the form of sterile solid
compositions which can be dissolved or dispersed in sterile water
or other sterile injectable medium prior to use.
[0484] In order to prolong the effect of a compound of the present
invention, it is often desirable to slow the absorption of the
compound from subcutaneous or intramuscular injection. This may be
accomplished by the use of a liquid suspension of crystalline or
amorphous material with poor water solubility. The rate of
absorption of the compound then depends upon its rate of
dissolution that, in turn, may depend upon crystal size and
crystalline form. Alternatively, delayed absorption of a
parenterally administered compound form is accomplished by
dissolving or suspending the compound in an oil vehicle. Injectable
depot forms are made by forming microencapsule matrices of the
compound in biodegradable polymers such as
polylactide-polyglycolide. Depending upon the ratio of compound to
polymer and the nature of the particular polymer employed, the rate
of compound release can be controlled. Examples of other
biodegradable polymers include poly(orthoesters) and
poly(anhydrides). Depot injectable formulations are also prepared
by entrapping the compound in liposomes or microemulsions that are
compatible with body tissues.
[0485] Compositions for rectal or vaginal administration are
preferably suppositories which can be prepared by mixing the
compounds of this invention with suitable non-irritating excipients
or carriers such as cocoa butter, polyethylene glycol or a
suppository wax which are solid at ambient temperature but liquid
at body temperature and therefore melt in the rectum or vaginal
cavity and release the active compound.
[0486] Solid dosage forms for oral administration include capsules,
tablets, pills, powders, and granules. In such solid dosage forms,
the active compound is mixed with at least one inert,
pharmaceutically acceptable excipient or carrier such as sodium
citrate or dicalcium phosphate and/or a) fillers or extenders such
as starches, lactose, sucrose, glucose, mannitol, and silicic acid,
b) binders such as, for example, carboxymethylcellulose, alginates,
gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants
such as glycerol, d) disintegrating agents such as agar--agar,
calcium carbonate, potato or tapioca starch, alginic acid, certain
silicates, and sodium carbonate, e) solution retarding agents such
as paraffin, f) absorption accelerators such as quaternary ammonium
compounds, g) wetting agents such as, for example, cetyl alcohol
and glycerol monostearate, h) absorbents such as kaolin and
bentonite clay, and i) lubricants such as talc, calcium stearate,
magnesium stearate, solid polyethylene glycols, sodium lauryl
sulfate, and mixtures thereof. In the case of capsules, tablets and
pills, the dosage form may also comprise buffering agents.
[0487] Solid compositions of a similar type may also be employed as
fillers in soft and hard-filled gelatin capsules using such
excipients as lactose or milk sugar as well as high molecular
weight polyethylene glycols and the like. The solid dosage forms of
tablets, dragees, capsules, pills, and granules can be prepared
with coatings and shells such as enteric coatings and other
coatings well known in the pharmaceutical formulating art. They may
optionally contain opacifying agents and can also be of a
composition that they release the active ingredient(s) only, or
preferentially, in a certain part of the intestinal tract,
optionally, in a delayed manner. Examples of embedding compositions
that can be used include polymeric substances and waxes. Solid
compositions of a similar type may also be employed as fillers in
soft and hard-filled gelatin capsules using such excipients as
lactose or milk sugar as well as high molecular weight polethylene
glycols and the like.
[0488] The active compounds can also be in micro-encapsulated form
with one or more excipients as noted above. The solid dosage forms
of tablets, dragees, capsules, pills, and granules can be prepared
with coatings and shells such as enteric coatings, release
controlling coatings and other coatings well known in the
pharmaceutical formulating art. In such solid dosage forms the
active compound may be admixed with at least one inert diluent such
as sucrose, lactose or starch. Such dosage forms may also comprise,
as is normal practice, additional substances other than inert
diluents, e.g., tableting lubricants and other tableting aids such
a magnesium stearate and microcrystalline cellulose. In the case of
capsules, tablets and pills, the dosage forms may also comprise
buffering agents. They may optionally contain opacifying agents and
can also be of a composition that they release the active
ingredient(s) only, or preferentially, in a certain part of the
intestinal tract, optionally, in a delayed manner. Examples of
embedding compositions that can be used include polymeric
substances and waxes.
[0489] Dosage forms for topical or transdermal administration of a
compound of this invention include ointments, pastes, creams,
lotions, gels, powders, solutions, sprays, inhalants or patches.
The active component is admixed under sterile conditions with a
pharmaceutically acceptable carrier and any needed preservatives or
buffers as may be required. Ophthalmic formulation, ear drops, and
eye drops are also contemplated as being within the scope of this
invention. Additionally, the present invention contemplates the use
of transdermal patches, which have the added advantage of providing
controlled delivery of a compound to the body. Such dosage forms
can be made by dissolving or dispensing the compound in the proper
medium. Absorption enhancers can also be used to increase the flux
of the compound across the skin. The rate can be controlled by
either providing a rate controlling membrane or by dispersing the
compound in a polymer matrix or gel.
[0490] As described generally above, the compounds of the invention
are useful as inhibitors of protein kinases. In one embodiment, the
compounds and compositions of the invention are Aurora kinase
inhibitors, and thus, without wishing to be bound by any particular
theory, the compounds and compositions are particularly useful for
treating or lessening the severity of a disease, condition, or
disorder where activation of Aurora kinase is implicated in the
disease, condition, or disorder. When activation of Aurora kinase
is implicated in a particular disease, condition, or disorder, the
disease, condition, or disorder may also be referred to as
"Aurora-mediated disease" or disease symptom. Accordingly, in
another aspect, the present invention provides a method for
treating or lessening the severity of a disease, condition, or
disorder where activation of Aurora kinase is implicated in the
disease state.
[0491] The activity of a compound utilized in this invention as an
Aurora kinase inhibitor, may be assayed in vitro, in vivo or in a
cell line. In vitro assays include assays that determine inhibition
of either the phosphorylation activity or ATPase activity of
activated Aurora A, B and/or C. Alternate in vitro assays
quantitate the ability of the inhibitor to bind to Aurora A, B
and/or C. Inhibitor binding may be measured by radiolabelling the
inhibitor prior to binding, isolating the inhibitor/Aurora A, B
and/or C, complex and determining the amount of radiolabel bound.
Alternatively, inhibitor binding may be determined by running a
competition experiment where new inhibitors are incubated with
Aurora A, B and/or C bound to known radioligands.
[0492] The term "measurably inhibit", as used herein means a
measurable change in Aurora A, B and/or C activity between a sample
comprising said composition and a Aurora A, B and/or C kinase and
an equivalent sample comprising Aurora A, B and/or C kinase in the
absence of said composition.
[0493] The term "Aurora-mediated disease" or "Aurora-mediated
condition", as used herein, means any disease or other deleterious
condition in which Aurora is known to play a role. The terms
"Aurora-mediated disease" or "Aurora-mediated condition" also mean
those diseases or conditions that are alleviated by treatment with
an Aurora inhibitor. Such conditions include, without limitation,
colon, breast, stomach, and ovarian cancer. The term
"Aurora-mediated disease", as used herein, means any disease or
other deleterious condition or disease in which Aurora is known to
play a role. Such diseases or conditions include, without
limitation, cancers such as colon and breast cancer.
[0494] It will also be appreciated that the compounds and
pharmaceutically acceptable compositions of the present invention
can be employed in combination therapies, that is, the compounds
and pharmaceutically acceptable compositions can be administered
concurrently with, prior to, or subsequent to, one or more other
desired therapeutics or medical procedures. The particular
combination of therapies (therapeutics or procedures) to employ in
a combination regimen will take into account compatibility of the
desired therapeutics and/or procedures and the desired therapeutic
effect to be achieved. It will also be appreciated that the
therapies employed may achieve a desired effect for the same
disorder (for example, an inventive compound may be administered
concurrently with another agent used to treat the same disorder),
or they may achieve different effects (e.g., control of any adverse
effects). As used herein, additional therapeutic agents that are
normally administered to treat or prevent a particular disease, or
condition, are known as "appropriate for the disease, or condition,
being treated".
[0495] For example, other therapies, chemotherapeutic agents or
other anti-proliferative agents may be combined with the compounds
of this invention to treat proliferative diseases and cancer.
Examples of therapies or anticancer agents that may be used in
combination with the inventive anticancer agents of the present
invention include surgery, radiotherapy (in but a few examples,
gamma-radiation, neutron beam radiotherapy, electron beam
radiotherapy, proton therapy, brachytherapy, and systemic
radioactive isotopes, to name a few), endocrine therapy, biologic
response modifiers (interferons, interleukins, and tumor necrosis
factor (TNF) to name a few), hyperthermia and cryotherapy, agents
to attenuate any adverse effects (e.g., antiemetics), and other
approved chemotherapeutic drugs, including, but not limited to,
alkylating drugs (mechlorethamine, chlorambucil, Cyclophosphamide,
Melphalan, Ifosfamide), antimetabolites (Methotrexate), purine
antagonists and pyrimidine antagonists (6-Mercaptopurine,
5-Fluorouracil, Cytarabile, Gemcitabine), spindle poisons
(Vinblastine, Vincristine, Vinorelbine, Paclitaxel),
podophyllotoxins (Etoposide, Irinotecan, Topotecan), antibiotics
(Doxorubicin, Bleomycin, Mitomycin), nitrosoureas (Carmustine,
Lomustine), inorganic ions (Cisplatin, Carboplatin), enzymes
(Asparaginase), and hormones (Tamoxifen, Leuprolide, Flutamide, and
Megestrol), Gleevec.TM., adriamycin, dexamethasone, and
cyclophosphamide. For a more comprehensive discussion of updated
cancer therapies see, The Merck Manual, Seventeenth Ed. 1999, the
entire contents of which are hereby incorporated by reference. See
also the National Cancer Institute (CNI) website (www.nci.nih.gov)
and the Food and Drug Administration (FDA) website for a list of
the FDA approved oncology drugs
(www.fda.gov/cder/cancer/druglistframe--See Appendix).
[0496] Other examples of agents the inhibitors of this invention
may also be combined with include, without limitation: treatments
for Alzheimer's Disease such as Aricept.RTM. and Excelon.RTM.;
treatments for Parkinson's Disease such as L-DOPA/carbidopa,
entacapone, ropinrole, pramipexole, bromocriptine, pergolide,
trihexephendyl, and amantadine; agents for treating Multiple
Sclerosis (MS) such as beta interferon (e.g., Avonex.RTM. and
Rebif.RTM.), Copaxone.RTM., and mitoxantrone; treatments for asthma
such as albuterol and Singulair.RTM.; agents for treating
schizophrenia such as zyprexa, risperdal, seroquel, and
haloperidol; anti-inflammatory agents such as corticosteroids, TNF
blockers, IL-1 RA, azathioprine, cyclophosphamide, and
sulfasalazine; immunomodulatory and immunosuppressive agents such
as cyclosporin, tacrolimus, rapamycin, mycophenolate mofetil,
interferons, corticosteroids, cyclophosphamide, azathioprine, and
sulfasalazine; neurotrophic factors such as acetylcholinesterase
inhibitors, MAO inhibitors, interferons, anti-convulsants, ion
channel blockers, riluzole, and anti-Parkinsonian agents; agents
for treating cardiovascular disease such as beta-blockers, ACE
inhibitors, diuretics, nitrates, calcium channel blockers, and
statins; agents for treating liver disease such as corticosteroids,
cholestyramine, interferons, and anti-viral agents; agents for
treating blood disorders such as corticosteroids, anti-leukemic
agents, and growth factors; and agents for treating
immunodeficiency disorders such as gamma globulin.
[0497] The amount of additional therapeutic agent present in the
compositions of this invention will be no more than the amount that
would normally be administered in a composition comprising that
therapeutic agent as the only active agent. Preferably the amount
of additional therapeutic agent in the presently disclosed
compositions will range from about 50% to 100% of the amount
normally present in a composition comprising that agent as the only
therapeutically active agent.
[0498] The compounds of this invention or pharmaceutically
acceptable compositions thereof may also be incorporated into
compositions for coating implantable medical devices, such as
prostheses, artificial valves, vascular grafts, stents and
catheters. Accordingly, the present invention, in another aspect,
includes a composition for coating an implantable device comprising
a compound of the present invention as described generally above,
and in classes and subclasses herein, and a carrier suitable for
coating said implantable device. In still another aspect, the
present invention includes an implantable device coated with a
composition comprising a compound of the present invention as
described generally above, and in classes and subclasses herein,
and a carrier suitable for coating said implantable device.
[0499] Vascular stents, for example, have been used to overcome
restenosis (re-narrowing of the vessel wall after injury). However,
patients using stents or other implantable devices risk clot
formation or platelet activation. These unwanted effects may be
prevented or mitigated by pre-coating the device with a
pharmaceutically acceptable composition comprising a kinase
inhibitor. Suitable coatings and the general preparation of coated
implantable devices are described in U.S. Pat. Nos. 6,099,562;
5,886,026; and 5,304,121. The coatings are typically biocompatible
polymeric materials such as a hydrogel polymer,
polymethyldisiloxane, polycaprolactone, polyethylene glycol,
polylactic acid, ethylene vinyl acetate, and mixtures thereof. The
coatings may optionally be further covered by a suitable topcoat of
fluorosilicone, polysaccarides, polyethylene glycol, phospholipids
or combinations thereof to impart controlled release
characteristics in the composition.
[0500] Another aspect of the invention relates to inhibiting Aurora
A, B and/or C activity in a biological sample or a patient, which
method comprises administering to the patient, or contacting said
biological sample with a compound of formula I or a composition
comprising said compound. The term "biological sample", as used
herein, includes, without limitation, cell cultures or extracts
thereof; biopsied material obtained from a mammal or extracts
thereof; and blood, saliva, urine, feces, semen, tears, or other
body fluids or extracts thereof.
[0501] Inhibition of Aurora A, B and/or C kinase activity in a
biological sample is useful for a variety of purposes that are
known to one of skill in the art. Examples of such purposes
include, but are not limited to, blood transfusion,
organ-transplantation, biological specimen storage, and biological
assays.
Treatment Kit
[0502] In other embodiments, the present invention relates to a kit
for conveniently and effectively carrying out the methods in
accordance with the present invention. In general, the
pharmaceutical pack or kit comprises one or more containers filled
with one or more of the ingredients of the pharmaceutical
compositions of the invention. Such kits are especially suited for
the delivery of solid oral forms such as tablets or capsules. Such
a kit preferably includes a number of unit dosages, and may also
include a card having the dosages oriented in the order of their
intended use. If desired, a memory aid can be provided, for example
in the form of numbers, letters, or other markings or with a
calendar insert, designating the days in the treatment schedule in
which the dosages can be administered. Alternatively, placebo
dosages, or calcium dietary supplements, either in a form similar
to or distinct from the dosages of the pharmaceutical compositions,
can be included to provide a kit in which a dosage is taken every
day. Optionally associated with such container(s) can be a notice
in the form prescribed by a governmental agency regulating the
manufacture, use or sale of pharmaceutical products, which notice
reflects approval by the agency of manufacture, use or sale for
human administration.
EQUIVALENTS
[0503] The representative examples that follow are intended to help
illustrate the invention, and are not intended to, nor should they
be construed to, limit the scope of the invention. Indeed, various
modifications of the invention and many further embodiments
thereof, in addition to those shown and described herein, will
become apparent to those skilled in the art from the full contents
of this document, including the examples which follow and the
references to the scientific and patent literature cited herein. It
should further be appreciated that the contents of those cited
references are incorporated herein by reference to help illustrate
the state of the art.
[0504] The following examples contain important additional
information, exemplification and guidance that can be adapted to
the practice of this invention in its various embodiments and the
equivalents thereof.
EXEMPLIFICATION
[0505] The compounds of this invention and their preparation can be
understood further by the examples that illustrate some of the
processes by which these compounds are prepared or used. It will be
appreciated, however, that these examples do not limit the
invention. Variations of the invention, now known or further
developed, are considered to fall within the scope of the present
invention as described herein and as hereinafter claimed.
Example 1
[0506] This example describes the synthesis of
##STR00145##
[0507] Step 1: A solution of [2-(4-amino-phenyl)-ethyl]-carbamic
acid tert-butyl ester (compound 1.1; 1.0 mmol, prepared according
to the procedure of Hah, J. M. et. al J. Med. Chem. 46, 2003, 1661)
and triethylamine ("TEA"; 3.0 equivalents) in anhydrous
tetrahydrofuran ("THF"; 5.0 mL) is treated with the dropwise
addition of benzoyl chloride (1.1 equivalents) at 0.degree. C.
After completion of the reaction, the mixture is partitioned
between water and diethyl ether. The organic layer is separated,
washed with 1.0 N HCl, saturated sodium bicarbonate, brine and
dried. Purification by flash column chromatography on silica gel
provides [2-(4-benzoylamino-phenyl)-ethyl]-carbamic acid tert-butyl
ester (compound 1.2).
[0508] Step 2: Compound 1.2 (1.0 mmol), is treated with anhydrous
4.0 N HCl in dioxane (25 mL) at 0.degree. C., stirred at room
temperature for 2 hours and concentrated to dryness under reduced
pressure. The crude amine salt,
4-chloro-7-methylthieno[3,2-d]pyrimidine (1.0 equiv.) and
N,N-diisopropylethylamine ("DIEA"; 2.5 equivalents) is then heated
in n-butanol (10 mL) at 135.degree. C. for 2 hours. The reaction
mixture is cooled and then partitioned between dichloromethane and
water. The organic layer is separated, washed with brine, dried and
concentrated under reduced pressure. The titled compound is
precipitated from ethyl acetate ("EtOAc") and methanol ("MeOH")
with hexanes.
Example 2
[0509] This example describes the synthesis of
##STR00146##
where R.sup.1 is as described previously. These compounds are made
according to the procedures of Example 1 except that
##STR00147##
is used instead of 4-chloro-7-methylthieno[3,2-d]pyrimidine in step
2. Illustrative examples of R.sup.1's are found throughout this
disclosure as well as in Table 1.
TABLE-US-00001 TABLE 1 ##STR00148## Final Compound ##STR00149##
##STR00150## ##STR00151## ##STR00152## ##STR00153## ##STR00154##
##STR00155## ##STR00156## ##STR00157## ##STR00158## ##STR00159##
##STR00160##
Example 3
[0510] This example describes the synthesis of
##STR00161##
where R.sup.1 is as described previously. These compounds are made
according to the procedures of Example 1 except that
##STR00162##
is used instead of 4-chloro-7-methylthieno[3,2-d]pyrimidine in step
2. Illustrative examples of R.sup.1's are found throughout this
disclosure as well as in Table 2.
TABLE-US-00002 TABLE 2 ##STR00163## Final Compound ##STR00164##
##STR00165## ##STR00166## ##STR00167## ##STR00168##
##STR00169##
Example 4
[0511] This example describes the synthesis of
##STR00170##
where Z is as described previously. These compounds are made
according to the procedures of Example 1 except that
##STR00171##
is used instead of benzoyl chloride in step 1. Illustrative
examples of Z's are found throughout this disclosure as well as in
Table 3.
TABLE-US-00003 TABLE 3 ##STR00172## Final Compound ##STR00173##
##STR00174## ##STR00175## ##STR00176## ##STR00177## ##STR00178##
##STR00179## ##STR00180## ##STR00181## ##STR00182##
Example 5
[0512] This example describes the synthesis of
##STR00183##
[0513] A solution of di-tert-butyl dicarbonate (0.5 equivalents) in
anhydrous dioxane (3.0 mL) is added dropwise to a solution of
5-(2-amino-ethyl)-thiazol-2-ylamine (1.0 mmol, prepared according
to the procedure of Eriks, J. C. et. al. J. Med. Chem. 35, 1992,
3239) in anhydrous dioxane (3.0 mL) at room temperature. After
completion of the reaction, the solvents are removed under reduced
pressure and the desired product,
[2-(2-amino-thiazol-5-yl)-ethyl]-carbamic acid tert-butyl ester
(compound 5.1), is purified by flash column chromatography on
silica gel.
[0514] The titled compound is made according to the procedures of
Example 1 except that compound 5.1 is used in step 1 instead of
compound 1.1.
Example 6
[0515] This example describes the synthesis of
##STR00184##
[0516] Step 1: 4-(2-Amino-ethyl)-benzonitrile (compound 6.1 (1.0
mmol), 4-chloro-thieno[3,2-d]pyrimidine (compound 6.2; 1.0 equiv.)
and DIEA (2.5 equivalents) is heated in n-butanol (10 mL) at
135.degree. C. for 2 hours. The reaction mixture is cooled and then
partitioned between dichloromethane and water. The organic layer is
separated, washed with brine, dried and concentrated under reduced
pressure. The desired product,
4-[2-(thieno[3,2-d]pyrimidin-4-ylamino)-ethyl]-benzonitrile
(compound 5.3), is precipitated from EtOAc with hexanes.
[0517] Step 2: Compound 6.3 is treated with sodium methoxide
("NaOMe") in MeOH according to a procedure found in Lipinski, C. A.
et. al. J. Med. Chem. 28, 1985, 1628 to yield
4-[2-(thieno[3,2-d]pyrimidin-4-ylamino)-ethyl]-benzimidic acid
methyl ester (compound 6.4).
[0518] Step 3: The titled compound is obtained by the reaction of
compound 6.4 and 3-chloro-benzoic acid hydrazide by heating in
MeOH.
Example 7
[0519] This example describes the synthesis of
##STR00185##
[0520] Step 1: Compound 6.2 is reacted with potassium cyanide
according to a procedure in Miyashita, A. et. al. (Heterocycles 39,
1994, 345) to yield thieno[3,2-d]pyrimidine-4-carbonitrile
(compound 7.1).
[0521] Step 2: A solution of compound 7.1 (1.0 mmol) in
concentrated HCl (20 mL) is stirred at 80.degree. C. overnight. The
reaction mixture is then cooled and evaporated to dryness under
reduced pressure. The residue is dissolved in a saturated lithium
hydroxide ("LiOH"_solution (pH 9) and evaporated to dryness under
reduced pressure. The residue is then dissolved in 10% aqueous HCl
(pH 2), evaporated and dried under vacuum to provide
thieno[3,2-d]pyrimidine-4-carboxylic acid (compound 7.2).
[0522] Step 3: To a solution of compound 7.2 (1.0 mmol) and
4-nitrobenzyl amine (1.0 mmol) in dichloromethane (5.0 mL) is added
TEA (3.0 equivalents) and
O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluorophosphate ("HATU"; 1.1 equivalents). After completion of
the reaction, the reaction is partitioned between EtOAc and water.
The organic layer is separated, washed with 0.5 N HCl, saturated
sodium bicarbonate, brine and dried. Purification by flash column
chromatography on silica gel provides
thieno[3,2-d]pyrimidine-4-carboxylic acid 4-nitro-benzylamide
(compound 7.3).
[0523] Step 4: Compound 7.3 (1.0 mmol) and Pd/C (10 w/w %, 60 mg)
in MeOH--H.sub.2O (12 mL) is stirred under a hydrogen atmosphere at
room temperature until the reaction is complete. The catalyst is
removed by filtration and the filtrate is evaporated to dryness
under reduced pressure to provide
thieno[3,2-d]pyrimidine-4-carboxylic acid 4-amino-benzylamide
(compound 7.4).
[0524] Step 5: To a solution of compound 7.4 (1.0 mmol) and
5-methyl-2H-pyrazole-3-carboxylic acid (1.0 mmol) in
dichloromethane (5.0 mL) is added TEA (3.0 equiv.) and HATU (1.1
equiv.). After completion of the reaction, the reaction is
partitioned between EtOAc and water. The organic layer is
separated, washed with 0.5 N HCl, saturated sodium bicarbonate,
brine and dried. Purification by flash column chromatography on
silica gel provides the titled compound.
Example 8
[0525] This example describes the synthesis of
##STR00186##
[0526] Step 1: 2-Thiophenecarbonyl chloride (1.1 equiv) is added
dropwise to a solution of 2-(4-amino-phenyl)-ethanol (1.0 mmol) and
TEA (3.0 equiv) in anhydrous THF (5.0 mL) at 0.degree. C. After
completion of the reaction, the reaction mixture is poured into
water and extracted with dichloromethane. The organic layer is
separated, washed with saturated sodium bicarbonate, brine and
dried. The desired product, thiophene-2-carboxylic acid
[4-(2-hydroxy-ethyl)-phenyl]-amide (compound 8.1) is purified by
flash column chromatography on silica gel.
[0527] Step 2: To a solution of compound 8.1 (1.0 mmol) and
compound 6.2 (1.0 equiv.) in anhydrous THF (8.0 mL) is added NaH
(2.3 equiv.) at 0.degree. C. The reaction is warmed to room
temperature and stirred overnight. Saturated ammonium chloride is
added and the reaction mixture is extracted with EtOAc. The organic
layer is separated, washed with brine, dried and concentrated under
reduced pressure. The titled compound is precipitated from EtOAc
with hexanes.
Example 9
[0528] This example describes the synthesis of
##STR00187##
where Z is as described previously. These compounds are made
according to the procedures of Example 8 except that
##STR00188##
is used instead of 2-thiophenecarbonyl chloride in step 1.
Illustrative examples of suitable Z are found throughout this
disclosure as well as in Table 3.
Example 10
[0529] This example describes the synthesis of
##STR00189##
where Z is as described previously. These compounds are made
according to the procedures of Example 8 except that
HO--(CH.sub.2).sub.2--Y--NH.sub.2 is used instead of
2-(4-amino-phenyl)-ethanol in step 1. Illustrative examples of
suitable Y's are found throughout this disclosure as well as in
Table 4.
TABLE-US-00004 TABLE 4 HO--(CH.sub.2).sub.2--Y--NH.sub.2 Final
Compound ##STR00190## ##STR00191## ##STR00192## ##STR00193##
##STR00194## ##STR00195##
Example 11
[0530] This example describes the synthesis of
##STR00196##
[0531] Step 1: To a solution of 2-amino-5-methyl benzoic acid (1.0
mmol) dissolved in 10% MeOH in toluene (2.5 mL) is added dropwise
trimethylsilyl-diazomethane (2.0 M in hexanes, 0.75 mL). The
reaction mixture is stirred at room temperature for 1 hour and the
solvent is removed under reduced pressure. The resulting methyl
ester is dissolved in dichloromethane (3.0 mL) and then
4-chlorobenzoyl chloride (1.0 equivalent) and DIEA (1.0 equivalent)
is added sequentially. The reaction mixture is stirred for 3 hours
and the solvent is evaporated. The yellow residue is diluted with
EtOAc, washed with 1 M NaHSO.sub.4, brine, dried, filtered and
concentrated under reduced pressure to provide
2-(4-chloro-benzoylamino)-5-methyl-benzoic acid methyl ester
(compound 11.1) which is used without purification in the next
step.
[0532] Step 2: To a solution of compound 11.1 (1.0 mmol) in benzene
(2.0 mL) is added N-bromosuccinimide (1 equivalent) and benzoyl
peroxide (0.33 equivalent). The reaction mixture is refluxed
overnight under N.sub.2. After cooling to room temperature, the
solution is diluted with EtOAc, washed with H.sub.2O, brine, dried,
filtered and concentrated under reduced pressure. The crude product
is purified by flash column chromatography on silica gel to provide
5-bromomethyl-2-(4-chloro-benzoylamino)-benzoic acid methyl ester
(compound 11.2).
[0533] Step 3: Potassium cyanide (1.0 equivalent) is added to a
solution of compound 11.2 (1.0 mmol) in methyl sulfoxide ("DMSO";
24 mL) and stirred for 2 hours at room temperature. The reaction
mixture is diluted with EtOAc, washed with 1 M NaHSO.sub.4, brine,
filtered and evaporated under reduced pressure. The residue is
purified by flash column chromatography on silica gel to provide
the nitrile. To a solution of the nitrile (1.0 mmol) dissolved in
ethanol (5.0 mL) is added 4.0 N HCl in dioxane (0.25 mL) and
catalytic Pd/C. The reaction mixture is subjected to hydrogenolysis
at 50 psi for 12 hours. The solution is filtered over a pad of
celite followed by careful rinsing with ethanol. The combined
organic solution is concentrated under reduced pressure to provide
5-(2-amino-ethyl)-2-(4-chloro-benzoylamino)-benzoic acid methyl
ester (compound 11.3).
[0534] Step 4: Compound 11.3 (1.0 mmol), compound 6.2 (1.0
equivalent) and DIEA (2.5 equivalents) is heated in n-butanol (10
mL) at 135.degree. C. for 2 hours. The reaction mixture is cooled
and then partitioned between dichloromethane and water. The organic
layer is separated, washed with brine, dried and concentrated under
reduced pressure. The titled compound is precipitated from EtOAc
with hexanes.
Example 12
[0535] This example describes the synthesis of
##STR00197##
[0536] Step 1: A solution of 4-(2-amino-ethyl)-phenylamine
(compound 12.1; 0.1 mmol.), compound 6.2 (1.0 equivalent) and DIEA
(2.5 equivalents) was heated in n-butanol (2 mL) at 135.degree. C.
for 2 hours. The reaction mixture was cooled and partitioned
between dichloromethane and water. The organic layer was separated,
washed with brine, dried and concentrated under reduced pressure to
give crude
[2-(4-amino-phenyl)-ethyl]-thieno[3,2-d]pyrimidin-4-yl-amine
(compound 12.2) which was used without purification for the next
step.
[0537] Step 2: To a suspension of compound 12.2 (0.46 mmol) and TEA
(2.5 equivalents) in anhydrous THF (3.0 mL) cooled to 0.degree. C.
was added 3-(trifluoromethyl)phenyl chloroformate (1.1
equivalents). The reaction was warmed to room temperature and after
45 minutes, water was added and the reaction extracted with EtOAc.
The organic layer was separated, washed with brine, dried and
concentrated under reduced pressure. Purification by reverse-phase
HPLC (aqueous 0.1% trifluoroacetic acid ("TFA")/CH.sub.3CN)
provided the titled compound.
Example 13
[0538] This example describes the synthesis of
##STR00198##
[0539] Step 1: 3-Methoxyphenyl isocyanate and compound 1.1 are
reacted according to a procedure in Dhar, T. G. et. al. (Bioorg.
Med. Chem. Lett. 13, 2003, 3557) to yield
(2-{4-[3-(3-Methoxy-phenyl)-ureido]-phenyl}-ethyl)-carbamic acid
tert-butyl ester (compound 13.1).
[0540] Step 2: Compound 13.1 (1.0 mmol) is treated with anhydrous
4.0 N HCl in dioxane (25 mL) at 0.degree. C., stirred at room
temperature for 2 hours and concentrated to dryness under reduced
pressure. The crude amine salt, compound 6.2 (1.0 equivalent) and
DIEA (2.5 equivalents) is then heated in n-butanol (10 mL) at
135.degree. C. for 2 hours. The reaction mixture is cooled and then
partitioned between dichloromethane and water. The organic layer is
separated, washed with brine, dried and concentrated under reduced
pressure. The titled compound is precipitated from EtOAc with
hexanes.
Example 14
[0541] This example describes the synthesis of
##STR00199##
[0542] Step 1: [5-(2-Amino-ethyl)-thiazol-2-yl]-carbamic acid
tert-butyl ester (compound 14.1; 20.5 mmol), compound 6.2 (0.94
equivalent) and DIEA (1.0 equivalent) was heated in
N,N-dimethylformamide ("DMF"; 75 mL) at 90.degree. C. for 1.5
hours. The reaction mixture was cooled and diluted with EtOAc and
water. The organic layer was separated, washed with brine, dried,
concentrated and purified by flash column chromatography on silica
gel to provide
{5-[2-(thieno[3,2-d]pyrimidin-4-ylamino)-ethyl]-thiazol-2-yl}-carbamic
acid tert-butyl ester (compound 14.2) in 75% yield.
[0543] Step 2: To a solution of compound 14.2 (14.5 mmol) in
1,4-dioxane (30 mL) was added anhydrous HCl (20 mL of a 4 N
solution in 1,4-dioxane) after stirring at room temperature for 2
hours the reaction was concentrated to dryness, diluted with water
and the solution adjusted to pH 8 with saturated sodium
bicarbonate. The slurry was extracted several times with EtOAc and
the organic layers were combined, dried and concentrated to provide
[2-(2-amino-thiazol-5-yl)-ethyl]-thieno[3,2-d]pyrimidin-4-yl-amine
(compound 14.3) in 88% yield.
[0544] Step 3: To a suspension of compound 14.3 (10.8 mmol) in
anhydrous benzene (75 mL) was added 3-trifluoromethylphenyl
isocyanate (1.0 equivalent). The reaction mixture was heated at
90.degree. C. for 1 hour, cooled and concentrated to give a solid
that was washed with a mixture of dichloromethane and hexanes. The
solid was treated with MeOH followed by the addition of 1 N HCl and
water. The solution was then sonicated and lyophilized to give a
solid that was washed with ethanol and dried under vacuum to
provide the HCl salt of the titled compound in 86% yield. Anal.
Calcd for C.sub.19H.sub.16N.sub.6OS.sub.2F.sub.3Cl: C, 45.55; H,
3.22; N, 16.78. Found: C, 45.56; H, 3.27; N, 16.75.
Example 15
[0545] This example describes the synthesis of
##STR00200##
where R.sup.Z1 and m are as described previously. These compounds
are made according to the procedures of Example 14 except that
##STR00201##
is used instead of 3-trifluoromethylphenyl isocyanate in step 3.
Illustrative examples of suitable R.sup.Z1's are found throughout
this disclosure as well as in Table 5.
TABLE-US-00005 TABLE 5 ##STR00202## Final Compound ##STR00203##
##STR00204## ##STR00205## ##STR00206## ##STR00207## ##STR00208##
##STR00209## ##STR00210## ##STR00211## ##STR00212## ##STR00213##
##STR00214##
Example 16
[0546] This example describes an alternate synthesis of
##STR00215##
[0547] Step 1: To a suspension of compound 14.2 (23.7 mmol) in
1,4-dioxane (100 mL) was added HCl (70 mL of a 4.0 M in
1,4-dioxane) at 0.degree. C. The reaction was allowed to warm to
room temperature, stirred for 2 hours and concentrated to dryness
to give a tan solid. The crude solid was suspended in THF (200 mL)
and cooled to 0.degree. C. Triethylamine (33 mL) was added followed
by phenyl chloroformate (26.1 mmol). The reaction mixture was
allowed to slowly warm to room temperature and stirred for 2 hours.
Volatiles were removed under reduced pressure at room temperature,
water was added and the solid collected by vacuum filtration. The
solid was washed with ethyl ether and dried under vacuum to give
{5-[2-(thieno[3,2-d]pyrimidin-4-ylamino)-ethyl]-thiazol-2-yl}-carbamic
acid phenyl ester (compound 16.1) in 80% yield as a tan solid.
[0548] Step 2: To a suspension of compound 16.1 (0.63 mmol) in DMSO
(3.5 mL) was added 3,4-difluoroaniline (0.63 mmol) and
4-dimethylamino)pyridine ("DMAP"; catalytic amount or 1.0
equivalent). The reaction was heated in an 80.degree. C. oil bath
for 30 minutes, diluted with EtOAc and washed with water, 2.0 N
NaOH, water, brine, dried and concentrated to give a solid. The
solid was dissolved in hot EtOAc/MeOH and then hexanes/ethyl ether
was added to precipitate the titled compound as a tan powder in 81%
yield.
Example 17
[0549] This example describes the synthesis of
##STR00216##
where Z is as described previously. These compounds are made
according to Example 16 except that H.sub.2NZ is used instead of
3,4-difluoroaniline in step 2. Illustrative examples of suitable
Z's are found throughout this disclosure as well as in Table 6.
TABLE-US-00006 TABLE 6 H.sub.2NR 1. Final Compound ##STR00217##
##STR00218## ##STR00219## ##STR00220## ##STR00221## ##STR00222##
##STR00223## ##STR00224## ##STR00225## ##STR00226## ##STR00227##
##STR00228## ##STR00229## ##STR00230## ##STR00231## ##STR00232##
##STR00233## ##STR00234## ##STR00235## ##STR00236## ##STR00237##
##STR00238## ##STR00239## ##STR00240## ##STR00241## ##STR00242##
##STR00243## ##STR00244## ##STR00245## ##STR00246## ##STR00247##
##STR00248## ##STR00249## ##STR00250## ##STR00251## ##STR00252##
##STR00253## ##STR00254## ##STR00255## ##STR00256## ##STR00257##
##STR00258## ##STR00259## ##STR00260## ##STR00261## ##STR00262##
##STR00263## ##STR00264## ##STR00265## ##STR00266## ##STR00267##
##STR00268## ##STR00269## ##STR00270## ##STR00271## ##STR00272##
##STR00273## ##STR00274## ##STR00275## ##STR00276## ##STR00277##
##STR00278## ##STR00279## ##STR00280## ##STR00281## ##STR00282##
##STR00283## ##STR00284## ##STR00285## ##STR00286## ##STR00287##
##STR00288## ##STR00289## ##STR00290## ##STR00291## ##STR00292##
##STR00293## ##STR00294## ##STR00295## ##STR00296## ##STR00297##
##STR00298## ##STR00299## ##STR00300## ##STR00301## ##STR00302##
##STR00303## ##STR00304## ##STR00305## ##STR00306## ##STR00307##
##STR00308## ##STR00309## ##STR00310## ##STR00311## ##STR00312##
##STR00313## ##STR00314## ##STR00315## ##STR00316## ##STR00317##
##STR00318## ##STR00319## ##STR00320## ##STR00321## ##STR00322##
##STR00323## ##STR00324## ##STR00325## ##STR00326## ##STR00327##
##STR00328## ##STR00329## ##STR00330## ##STR00331## ##STR00332##
##STR00333## ##STR00334## ##STR00335## ##STR00336## ##STR00337##
##STR00338## ##STR00339## ##STR00340## ##STR00341## ##STR00342##
##STR00343## ##STR00344## ##STR00345## ##STR00346## ##STR00347##
##STR00348## ##STR00349## ##STR00350## ##STR00351## ##STR00352##
##STR00353## ##STR00354## ##STR00355## ##STR00356## ##STR00357##
##STR00358## ##STR00359## ##STR00360## ##STR00361## ##STR00362##
##STR00363## ##STR00364## ##STR00365## ##STR00366## ##STR00367##
##STR00368## ##STR00369## ##STR00370## ##STR00371## ##STR00372##
##STR00373## ##STR00374## ##STR00375## ##STR00376## ##STR00377##
##STR00378## ##STR00379## ##STR00380## ##STR00381## ##STR00382##
##STR00383## ##STR00384## ##STR00385## ##STR00386## ##STR00387##
##STR00388## ##STR00389## ##STR00390## ##STR00391## ##STR00392##
##STR00393## ##STR00394## ##STR00395## ##STR00396## ##STR00397##
##STR00398## ##STR00399## ##STR00400## ##STR00401## ##STR00402##
##STR00403## ##STR00404## ##STR00405## ##STR00406## ##STR00407##
##STR00408## ##STR00409## ##STR00410## ##STR00411## ##STR00412##
##STR00413## ##STR00414## ##STR00415## ##STR00416## ##STR00417##
##STR00418## ##STR00419## ##STR00420## ##STR00421## ##STR00422##
##STR00423## ##STR00424## ##STR00425## ##STR00426## ##STR00427##
##STR00428## ##STR00429## ##STR00430## ##STR00431## ##STR00432##
##STR00433## ##STR00434## ##STR00435## ##STR00436## ##STR00437##
##STR00438## ##STR00439## ##STR00440## ##STR00441## ##STR00442##
##STR00443## ##STR00444## ##STR00445## ##STR00446## ##STR00447##
##STR00448## ##STR00449## ##STR00450## ##STR00451## ##STR00452##
##STR00453## ##STR00454## ##STR00455## ##STR00456## ##STR00457##
##STR00458## ##STR00459## ##STR00460## ##STR00461##
##STR00462##
##STR00463## ##STR00464## ##STR00465## ##STR00466## ##STR00467##
##STR00468## ##STR00469## ##STR00470## ##STR00471## ##STR00472##
##STR00473## ##STR00474## ##STR00475## ##STR00476## ##STR00477##
##STR00478## ##STR00479## ##STR00480## ##STR00481## ##STR00482##
##STR00483## ##STR00484## ##STR00485## ##STR00486## ##STR00487##
##STR00488## ##STR00489## ##STR00490## ##STR00491## ##STR00492##
##STR00493## ##STR00494## ##STR00495## ##STR00496## ##STR00497##
##STR00498## ##STR00499## ##STR00500## ##STR00501## ##STR00502##
##STR00503## ##STR00504## ##STR00505## ##STR00506## ##STR00507##
##STR00508## ##STR00509## ##STR00510## ##STR00511## ##STR00512##
##STR00513## ##STR00514## ##STR00515## ##STR00516## ##STR00517##
##STR00518## ##STR00519## ##STR00520## ##STR00521## ##STR00522##
##STR00523## ##STR00524## ##STR00525## ##STR00526## ##STR00527##
##STR00528## ##STR00529## ##STR00530## ##STR00531## ##STR00532##
##STR00533## ##STR00534## ##STR00535## ##STR00536##
Example 18
[0550] This example describes the synthesis of
##STR00537##
where R.sup.1 is as described previously. These compounds are made
according to the procedures of Example 18 except that
##STR00538##
is used instead of 4-chloro-6-phenyl-thieno[3,2-d]pyrimidine in
step 1. Illustrative examples of R.sup.1's are found throughout
this disclosure as well as in Table 1.
Example 19
[0551] This example describes the synthesis of
##STR00539##
[0552] Step 1: (3-Methoxy-4-nitro-phenyl)-methanol (compound 19.1;
2.78 mmol), THF (14.0 mL), PPh.sub.3 (1.5 equivalents), and carbon
tetrabromide (1.5 equivalents) are combined and stirred at room
temperature for 2 hours. The reaction mixture was partitioned
between EtOAc and water. The organic layer was separated, washed
with brine, dried, filtered and concentrated under reduced
pressure. Purification by flash column chromatography on silica gel
using a gradient of EtOAc/hexanes provided the corresponding
bromide as a solid (87%). The resulting bromide (2.06 mmol) was
added to DMSO (10 mL) and potassium cyanide (2.27 mmol), stirred at
room temperature for 2.5 hours, hydrolyzed by the addition of 1.0 M
HCl and then partitioned between EtOAc and water. The organic layer
was separated, washed with brine, dried, filtered and concentrated
under reduced pressure. Purification by flash column chromatography
on silica gel using a gradient of EtOAc/hexanes provided
(3-methoxy-4-nitro-phenyl)-acetonitrile (compound 19.2) in 8%.
[0553] Step 2: Compound 19.2 (0.096 mmol), and catalytic Pd/C in
EtOAc (2 mL) were placed under an atmosphere of hydrogen for 3
hours. The reaction mixture was filtered, concentrated and taken on
crude to the next reaction. The crude compound (0.096 mmol),
dichloromethane (0.5 mL), 3-(trifluoromethyl)benzoyl chloride (1.05
mmol) and DIEA (1.10 mmol) was stirred at room temperature for 10
minutes. Water was added after which the mixture partitioned
between EtOAc and water. The organic layer was separated, washed
with brine, dried, filtered and concentrated under reduced
pressure. Purification by flash column chromatography on silica gel
using a gradient of EtOAc/hexanes provided
N-(4-cyanomethyl-2-methoxy-phenyl)-3-trifluoromethyl-benzamide
(compound 19.3) in 71%.
[0554] Step 3: Compound 19.3 (0.062 mmol), ethanol (1.5 mL), 4.0 M
HCl/dioxane (1 equivalent) and catalytic Pd/C are placed under an
atmosphere of hydrogen for 20 hours. The reaction mixture was
filtered, concentrated and taken on crude to the next reaction. The
crude compound (0.062 mmol), compound 6.2 (1.02 equiv), and DIEA
(3.4 equiv.) was heated in n-butanol (0.52 mL) at 135.degree. C.
for 2 hours. The reaction mixture was cooled and then partitioned
between dichlomethane and water. The organic layer was separated,
washed with brine, dried, filtered and concentrated under reduced
pressure. Purification by flash column chromatography on silica gel
using a gradient of EtOAc/hexanes provided the titled compound as a
pale yellow solid in 54%.
Example 20
[0555] This example describes the synthesis of
##STR00540##
[0556] Step 1: A solution of compound 1.1 (1.0 mmol) and TEA (3.0
equiv.) in anhydrous THF (5.0 mL) was treated with the dropwise
addition of 3-trifluoromethyl-benzoyl chloride (1.1 equivalents) at
0.degree. C. After completion of the reaction, the mixture was
partitioned between water and diethyl ether. The organic layer was
separated, washed with 1N HCl, saturated sodium bicarbonate, brine
and dried. Purification by flash column chromatography on silica
gel provided
{2-[4-(3-trifluoromethyl-benzoylamino)-phenyl]-ethyl}-carbamic acid
tert-butyl ester (compound 20.1).
[0557] Step 2: Compound 20.1 (1.0 mmol) was treated with anhydrous
4.0 N HCl in dioxane (25 mL) at 0.degree. C., stirred at room
temperature for 2 hours and concentrated to dryness under reduced
pressure. The crude amine salt, 4-chloro-6-bromo
thieno[3,2-d]pyrimidine (1.0 equivalent) and
N,N-diisopropylethylamine (2.5 equivalents) was then heated in
n-butanol (10 mL) at 135.degree. C. for 2 hours. The reaction
mixture was cooled and then partitioned between dichloromethane and
water. The organic layer was separated, washed with brine, dried
and concentrated under reduced pressure. The desired product,
N-{4-[2-(6-bromo-thieno[3,2-d]pyrimidin-4-ylamino)-ethyl]-phenyl}-3-trifl-
uoromethyl-benzamide (compound 20.2), was then precipitated from
EtOAc and hexanes to give a tan powder.
[0558] Step 3: Compound 20.2 (0.1 mmol), 4-pyridineboronic acid
(3.0 equivalents), Pd.sub.2(dba).sub.3 (16 mol %), AsPh.sub.3 (30
mol %) and K.sub.2HPO.sub.4 (3.0 equivalents) in DMF (3.0 mL) and
water (0.75 mL) was heated at 90.degree. C. for 3 hours. The
reaction was cooled and after aqueous work-up and purification by
flash column chromatography on silica gel, the titled compound is
obtained.
Example 21
[0559] This example describes the synthesis of
##STR00541##
where R.sup.1 is as described previously. These compounds are made
according to Example 20 except that R.sup.1B(OH).sub.2 is used
instead of 4-chloro-6-bromo thieno[3,2-d]pyrimidine in step 2.
Illustrative examples of suitable R.sup.1's are found throughout
this disclosure as well as in Table 7.
TABLE-US-00007 TABLE 7 R.sup.1B(OH).sub.2 Final Compound
##STR00542## ##STR00543## ##STR00544## ##STR00545## ##STR00546##
##STR00547## ##STR00548## ##STR00549## ##STR00550##
##STR00551##
Example 22
[0560] This example describes the synthesis of
##STR00552##
[0561] Step 1:
N-(4-{2-[6-(4-Formyl-phenyl)-thieno[3,2-d]pyrimidin-4-ylamino]-ethyl}-phe-
nyl)-3-trifluoromethyl-benzamide (compound 22.1) was prepared as
described in Example 21 using 4-formylphenylboronic acid.
[0562] Step 2: To a suspension of compound 22.1 (0.07 mmol) and
pyrrolidine (5.0 equivalents) in ethanol (3.0 ml) and AcOH (0.5 mL)
was added NaCNBH.sub.3 (1.4 equiv.) at room temperature. After 2
hours the reaction mixture was partitioned between EtOAc and
saturated sodium bicarbonate. The organic layer was separated,
dried and concentrated under reduced pressure. Purification by
preparative TLC provided the titled compound.
Example 23
##STR00553##
[0564] Step 1: To a nitrogen purged solution of compound 20.2 (0.79
mmol), 3-butyn-1-ol (2.5 equivalents), Pd(PhCN).sub.2Cl.sub.2 (0.2
equivalent) in piperidine was added CuI (0.5 equivalent) followed
by stirring at room temperature for 3 hours. The reaction mixture
was then subjected to an aqueous work-up and purified by flash
column chromatography on silica gel to provide
N-(4-{2-[6-(4-hydroxy-but-1-ynyl)-thieno[3,2-d]pyrimidin-4-ylamino]-ethyl-
}-phenyl)-3-trifluoromethyl-benzamide (compound 23.1).
[0565] Step 2: To a solution of compound 23.1 (0.27 mmol) in
dichloromethane was added sequentially TEA (3.0 equiv.) and
methanesulfonyl chloride (2.5 equivalents). After stirring at room
temperature for 2 hours, excess pyrrolidine (.about.5.0 equivalent)
was added and the reaction was heated at 40.degree. C. until
starting material is consumed. The reaction was cooled,
concentrated to dryness and purified by flash column chromatography
on silica gel to provide
N-(4-{2-[6-(4-pyrrolidin-1-yl-but-1-ynyl)-thieno[3,2-d]pyrimidin-4-ylamin-
o]-ethyl}-phenyl)-3-trifluoromethyl-benzamide (compound 23.2).
[0566] Step 3: A solution of compound 23.2 (0.06 mmol) and 10%
palladium on carbon (0.11 equivalent) in MeOH was stirred under an
atmosphere of hydrogen (via a balloon) until all starting material
was consumed. The reaction mixture was filtered, concentrated to
dryness and purified by flash column chromatography on silica gel
to provide the titled compound.
Example 24
[0567] This example describes the synthesis of
##STR00554##
[0568] Step 1:
N-(4-{2-[6-(2-Chloro-pyridin-4-yl)-thieno[3,2-d]pyrimidin-4-ylamino]-ethy-
l}-phenyl)-3-trifluoromethyl-benzamide (compound 21.1) was prepared
as described in Example 21 using 2-chloropyridine-4-boronic
acid.
[0569] Step 2: A solution of compound 21.1 (0.036 mmol) and
1-methylpiperazine (10 equiv.) in 1-methyl-2-pyrrolidinone (2.0 mL)
was heated overnight at 200.degree. C. in a screw-top reaction
vial. The reaction was cooled, concentrated and purified by
preparative TLC to give the titled compound.
Example 25
[0570] This example describes the synthesis of
##STR00555##
[0571] To a flame-dried round-bottom flask containing compound 20.2
(0.19 mmol) was added DMSO (1.0 mL) followed by
2-(methylamino)-ethanol (0.96 mmol). The reaction was stirred under
nitrogen at 150.degree. C. overnight and then cooled to room
temperature. Purification by reverse-phase HPLC (aqueous 0.1%
TFA/CH.sub.3CN) provided the titled compound as an off-white powder
(20 mg, 17%).
Example 26
[0572] This example describes the synthesis of
##STR00556##
[0573] Step 1: To a nitrogen purged solution of compound 20.2 (0.42
mmol), Pd(AcO).sub.2 (0.2 equivalent) and
1,3-bis(diphenylphosphino)propane ("Dppp"; 0.2 equivalent) in DMF
(10.0 mL) and MeOH (2.0 mL) was added DIEA (4.1 equivalents). CO
gas was bubbled through the reaction mixture for 20 minutes and the
reaction was then stirred for 3.5 hours under a CO atmosphere (via
a balloon) at 80.degree. C. After aqueous work-up and purification
by flash column chromatography on silica gel,
4-{2-[4-(3-trifluoromethyl-benzoylamino)-phenyl]-ethylamino}-thieno[3,2-d-
]pyrimidine-6-carboxylic acid methyl ester (compound 26.1) was
obtained.
[0574] Step 2: To a solution of compound 26.1 (0.72 mmol) in THF
(5.0 mL) was added aqueous 1.0 M LiOH (6.0 equivalents). The
reaction mixture was stirred at 70.degree. C. until all of the
starting material was consumed. The reaction was cooled,
neutralized with 10% HCl and concentrated to dryness under reduced
pressure to provide
4-{2-[4-(3-trifluoromethyl-benzoylamino)-phenyl]-ethylamino}-thieno[3,2-d-
]pyrimidine-6-carboxylic acid (compound 26.2).
[0575] Step 3: To a solution of compound 26.2 (0.08 mmol) in DMF
(1.0 mL) was added 1-methylpiperazine (2.1 equivalents), DIEA (3.5
equivalents), DMAP (0.5 equivalent) and HATU (1.2 equivalents) at
room temperature. After overnight stirring followed by aqueous
work-up, the titled compound was isolated after preparative TLC
purification.
Example 27
[0576] This example describes the synthesis of
##STR00557##
[0577] To a solution of compound 12.2 (0.37 mmol) in DMF (3.0 mL)
was added 5-phenyl-oxazole-4-carboxylic acid (1.0 equivalent), DIEA
(3.4 equivalents), and HATU (1.1 equivalents). After overnight
heating at 50.degree. C. the reaction was directly subjected to
purification by reverse-phase HPLC (aqueous 0.1% TFA/CH.sub.3CN) to
provide the titled compound after lyophilization.
Example 28
[0578] This example describes the synthesis of
##STR00558##
where Z is as previously described. These compounds are made
according to Example 27 except that ZCOOH is used instead of
5-phenyl-oxazole-4-carboxylic acid. Illustrative examples of
suitable Z's are found throughout this disclosure as well as in
Table 8.
TABLE-US-00008 TABLE 8 ZCOOH Final Compound ##STR00559##
##STR00560## ##STR00561## ##STR00562##
Example 29
[0579] This example describes the synthesis of
##STR00563##
[0580] Step 1: A sealed Pyrex tube was charged, under nitrogen,
with
{5-[2-(6-bromo-thieno[3,2-d]pyrimidin-4-ylamino)-ethyl]-thiazol-2-yl}-car-
bamic acid tert-butyl ester (compound 29.1; 0.2 mmol),
4-pyridineboronic acid (0.25 mmol), PdCl.sub.2 (PPh.sub.3).sub.2
(0.04 mmol), 2M Na.sub.2CO.sub.3 (0.6 mmol), water (0.5 mL), and
DMF (1.5 mL). The reaction mixture was heated subjected to
microwave irradiation at 50 watts for 5 minutes at 100.degree. C.
and then at 300 watts for 20 minutes at 120.degree. C. After
cooling, the reaction mixture was filtered and concentrated to
provide crude
[2-(2-amino-thiazol-5-yl)-ethyl]-(6-pyridin-4-yl-thieno[3,2-d]pyrimidin-4-
-yl)-amine (compound 29.2) which was used in the next step without
further purification.
[0581] Step 2: Compound 29.2 (0.15 mmol) and
3-trifluoromethylphenyl isocyanate (0.2 mmol) was heated in
acetonitrile (2 mL) at 70.degree. C. for 4 hours. The reaction
mixture was cooled, concentrated and purified by preparative TLC
chromatography (5% MeOH in dichloromethane) to provide the titled
compound.
Example 30
[0582] This example describes the synthesis of
##STR00564##
[0583] where R.sup.1 is as described previously. These compounds
are made according to Example 29 except that R.sup.1B(OH).sub.2 is
used instead of 4-pyridineboronic acid in step 1. Illustrative
examples of suitable R.sup.1's are found throughout this disclosure
as well as in Table 9.
TABLE-US-00009 TABLE 9 R.sup.1B(OH).sub.2 Final Compound
##STR00565## ##STR00566## ##STR00567## ##STR00568## ##STR00569##
##STR00570## ##STR00571## ##STR00572## ##STR00573## ##STR00574##
##STR00575## ##STR00576## ##STR00577## ##STR00578## ##STR00579##
##STR00580## ##STR00581## ##STR00582## ##STR00583## ##STR00584##
##STR00585## ##STR00586##
Example 31
[0584] This example describes the synthesis of
##STR00587##
[0585] Step 1: Compound 26.1 is converted to the corresponding
aldehyde via a two step reaction sequence. First, compound 26.1 is
reduced to the alcohol with diisobutylaluminum hydride ("DIBAL") at
-78.degree. C. Second, after standard work-up and purification, the
resulting alcohol is oxidized to
N-{4-[2-(6-formyl-thieno[3,2-d]pyrimidin-4-ylamino)-ethyl]-phenyl}-3-trif-
luoromethyl-benzamide (compound 31.1) using pyridinium dichromate
("PDC") under standard conditions. Such transformations are found,
for example, in Handbook of Reagents for Organic Synthesis
Oxidizing and Reducing Agents, Burke, S. D.; Danheiser, R. L., Ed.;
John Wiley and Sons Inc: New York.
[0586] Step 2: Compound 31.1 is reacted with the ylide generated
from (methoxymethyl)triphenylphosphonium chloride. The resulting
product is then hydrolyzed with aqueous HCl to yield
N-(4-{2-[6-(2-oxo-ethyl)-thieno[3,2-d]pyrimidin-4-ylamino]-ethyl}-phenyl)-
-3-trifluoromethyl-benzamide (compound 31.2). Such a transformation
is found, for example, in Stork, G. et. al. J. Am. Chem. Soc. 2001,
123, 3239.
[0587] Step 3: The titled compound is prepared according to Step 2
of Example 22 except for using compound 31.2 instead of compound
22.1 and for using 1-methylpiperazine instead of pyrrolidine.
Example 32
[0588] This example describes the synthesis of
##STR00588##
[0589] Step 1: Difluoro-(4-nitro-phenyl)-acetic acid ethyl ester
(compound 32.1) is reacted according to Sato, K. et. al. Chem.
Pharm. Bull. 1999, 47, 1013). Briefly, compound 32.1 and catalytic
Pd/C in EtOAc are placed under an atmosphere of hydrogen for 3
hours. The reaction mixture is filtered, concentrated and taken on
crude to the next reaction. The crude compound, dichloromethane,
3-(trifluoromethyl)benzoyl chloride and DIEA are stirred at room
temperature for 10 minutes. Water is added after which the mixture
partitioned between EtOAc and water. The organic layer is
separated, washed with brine, dried, filtered and concentrated
under reduced pressure. Purification by flash column chromatography
on silica gel using a gradient of EtOAc/hexanes provides
difluoro-[4-(3-trifluoromethyl-benzoylamino)-phenyl]-acetic acid
ethyl ester (compound 32.2).
[0590] Step 2: Compound 32.2 is reduced with DIBAL at -78.degree.
C. to the corresponding aldehyde according to a procedure found in
Ishikawa, T. et. al. J. Am. Chem. Soc. 2000, 122, 7633. The
resulting aldehyde is then converted into
N-[4-(2-amino-1,1-difluoro-ethyl)-phenyl]-3-trifluoromethyl-benzamide
(compound 32.3) via reductive amination using NH.sub.4OAc and
NaCNBH.sub.3 according to a procedure found in Aurelin, L. et. al.
J. Org. Chem. 2003, 68, 2652.
[0591] Step 3: Compound 32.3, compound 6.2 and DIEA are heated in
n-butanol at 135.degree. C. for 2 hours. The reaction mixture is
cooled and then partitioned between dichloromethane and water. The
organic layer is separated, washed with brine, dried, filtered and
concentrated under reduced pressure. Purification by flash column
chromatography on silica gel using a gardient of EtOAc/hexanes
provides the titled compound.
Example 33
[0592] This example describes the synthesis of
##STR00589##
[0593] Step 1: A flask was charged with compound 14.1 (200 mg, 100
mol %), tetrahydro-pyran-4-carbaldehyde (100 mol %), and
dichloroethane. To this was added NaBH(OAc).sub.3 (150 mol %) and
the resulting slurry was stirred at room temperature for 2 hours.
The solvents were removed in vacuo and the residue was re-suspended
in EtOAc and H.sub.2O. The organic layer was washed sequentially
with saturated sodium bicarbonate, H.sub.2O, and brine. The organic
layers were combined, dried over Na.sub.2SO.sub.4, and concentrated
to give
(5-{2-[(tetrahydro-pyran-4-ylmethyl)-amino]-ethyl}-thiazol-2-yl)-carbamic
acid tert-butyl ester (compound 33.1) as an oil which was used in
the next step without further purification.
[0594] Step 2: Compound 33.1, n-butanol (2 mL),
6-bromo-4-chloro-[3,2-d]thienopyrimidine (100 mol %), and DIEA (500
mol %) was stirred for 2 hours at 100.degree. C. and then
concentrated in vacuo. The resulting oil was treated with 4N HCl in
dioxane (10 mL) at room temperature for 1 hour. The reaction was
concentrated to a solid and lixiviated three times with cold ether
to provide
[2-(2-amino-thiazol-5-yl)-ethyl]-(6-bromo-thieno[3,2-d]pyrimidin-4-yl)-(t-
etrahydro-pyran-4-ylmethyl)-amine (compound 33.2) as a HCl salt
which was used in the next step without further purification.
[0595] Step 3: Crude 33.2 was suspended in DMF (2 mL) and DIEA (1
mL). To this solution was added trifluoromethylphenyl isocyanate
(120 mol %). The solution was stirred at room temperature for 5
minutes and then purified by reverse phase HPLC providing the
titled compound. LCMS [M+H].sup.+ m/z 643.1
Example 34
[0596] This example describes the synthesis of
##STR00590##
[0597] Step 1:
1-{5-[2-(6-Bromo-thieno[3,2-d]pyrimidin-4-ylamino)-ethyl]-thiazol-2-yl}-3-
-(3-trifluoromethyl-phenyl)-urea (compound 34.1) was prepared
according to Example 18 except that
6-bromo-4-chloro-[3,2-d]thienopyrimidine was used instead of
4-chloro-6-phenyl-thieno[3,2-d]pyrimidine in step 1.
[0598] Step 2: Compound 32.1 (100 mg, 100 mol %),
1-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole
(46 mg, 120 mole %) and PdCl.sub.2 (PPh.sub.3).sub.2 (20 mol %) was
placed in a 100 mL reaction vial and to this was added DMF/H.sub.2O
(4:1, 4 mL) along with 2N Na.sub.2CO.sub.3 (1 mL). The vial was
flushed with nitrogen, sealed and subjected to microwave
irradiation (10 minutes, 300 W, 100.degree. C.). The contents were
cooled, the solid precipitate was filtered and washed with cold
ether and recrystallized from MeOH/ether to provide the titled
compound. LCMS [M+H].sup.+ m/z 545.1
Example 35
[0599] This example describes the synthesis of
##STR00591##
where R.sup.1 is as previously described. These compounds are made
according to Example 34 except that
##STR00592##
is used instead of
1-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole
in step 2. Illustrative examples of suitable R.sup.1's are found
throughout this disclosure as well as in Table 10.
TABLE-US-00010 TABLE 10 ##STR00593## Final Compound ##STR00594##
##STR00595## ##STR00596## ##STR00597## ##STR00598## ##STR00599##
##STR00600## ##STR00601## ##STR00602## ##STR00603## ##STR00604##
##STR00605##
Example 36
[0600] This example describes an alternate synthesis of
##STR00606##
where R.sup.1 is as previously described. Illustrative examples of
suitable R.sup.1's are found throughout this disclosure as well as
in Table 10. These compounds are made according to Example 15
except that compound 34.1 and
##STR00607##
are used instead of compound 20.2 and 4-pyridineboronic acid in
step 3.
Example 37
[0601] This example describes the synthesis of
##STR00608##
[0602]
[2-(4-Amino-phenyl)-ethyl]-(6-bromo-thieno[3,2-d]pyrimidin-4-yl)-am-
ine (compound 37.1; 75 mg, 100 mol %) was suspended in
N-methyl-2-pyrrolidone (0.5 mL) and DIEA (150 uL, 400 mol %). To
this solution was added cyclohexyl isocyanate (110 mol %). The
reaction was heated at 95.degree. C. for 1 hour, cooled and
purified by reverse phase HPLC to provide the titled compound. LCMS
[M+H]+m/z 474.2
Example 38
[0603] This example describes the synthesis of
##STR00609##
[0604]
1-[5-(2-Amino-ethyl)-thiazol-2-yl]-3-(3-trifluoromethyl-phenyl)-ure-
a (compound 38.1; 200 mg, 100 mol %),
5-methyl-4-chloro-[2,3-d]thienopyrimidine (112 mg, 100 mol %) and
DIEA (500 mol %) in DMF (2 mL) was heated at 100.degree. C. for 15
min, cooled and purified by reverse phase HPLC to provide the
titled compound. LCMS [M+H].sup.+ m/z 479.1
Example 39
[0605] This example describes the synthesis of
##STR00610##
[0606] Step 1: A mixture of methanesulfonic acid
2-tert-butoxycarbonylamino-ethyl ester (compound 39.1; 2.04 g, 8.53
mmol, prepared according to the procedure of Hey, M. P. et. al J.
Med. Chem. 37, 1994, 381), 4-nitroimidazole (876 mg, 7.75 mmol),
K.sub.2CO.sub.3 (1.18 g, 8.53 mmol), in DMF is stirred at
110.degree. C. for 2 hours. After cooling to room temperature, the
mixture is diluted with EtOAc and washed with water. The aqueous
layer was extracted three times with EtOAc and the combined organic
phases were dried (Na.sub.2SO.sub.4) and concentrated. The crude
residue was purified by flash column chromatography (SiO.sub.2, 45
to 100% EtOAc in hexanes) to yield 634 mg (32%) of
[2-(4-nitro-imidazol-1-yl)-ethyl]-carbamic acid tert-butyl ester
(compound 39.2) as a solid, ES (+) MS m/e=257 (M+H.sup.+).
[0607] Step 2: A flask containing compound 39.2 (400 mg, 1.56 mmol)
and 10% (dry basis) palladium on activated carbon (.about.50% wet,
Deguessa, 664 mg, .about.0.312 mmol) in MeOH (6.0 mL) was sealed
with a septum and purged with nitrogen followed by hydrogen. The
mixture was stirred under hydrogen (balloon pressure) at ambient
temperature for 3 hours. After completion of the reaction, the
mixture was filtered through a plug of celite and concentrated. The
residue was dried under high-vacuum to yield 353 mg (quantitative)
of [2-(4-amino-imidazol-1-yl)-ethyl]-carbamic acid tert-butyl ester
(compound 39.3) as a solid, ES (+) MS m/e=227 (M+H.sup.+).
[0608] Step 3: To a solution of compound 39.3 in dichloromethane
under nitrogen was added 3-trifluoromethylphenyl isocyanate
dropwise. After about 0.1 hour, a white precipitate formed. The
precipitate was filtered off, washed with dichloromethane and dried
under high-vacuum to yield 485 mg (75%) of
(2-{4-[3-(3-trifluoromethyl-phenyl)-ureido]-imidazol-1-yl}-ethyl)-carbami-
c acid tert-butyl ester (compound 39.4) as a white solid, ES (+) MS
m/e=414 (M+H.sup.+).
[0609] Step 4: A mixture of compound 39.4 (485 mg, 1.17 mmol) and
4.0 N HCl in dioxane (10.0 mL) was stirred at room temperature for
0.25 hour. The solvent was then removed under reduced pressure and
the residue was dried under high-vacuum to yield 410 mg (91%) of a
HCl salt of
1-[1-(2-amino-ethyl)-1H-imidazol-4-yl]-3-(3-trifluoromethyl-phenyl)-urea
(compound 39.5) as a white solid, ES (+) MS m/e=314
(M+H.sup.+).
[0610] Step 5: A mixture of compound 39.5 (309 mg, 0.800 mmol) and
compound 6.2 (137 mg, 0.800 mmol) in DIEA/n-BuOH (1:1, 4.0 mL) was
heated at 100.degree. C. in a sealed tube behind a blast shield for
2 hours. After cooling to room temperature the mixture was
concentrated under reduced pressure. The residue thus obtained was
dried under high-vacuum and then purified by flash column
chromatography on silica gel (0 to 10% MeOH in dichloromethane) to
yield 222 mg (62%) of a solid, R.sub.f 0.32 (10% MeOH in
dichloromethane). ES (+) MS m/e=448 (M+H.sup.+). This material was
further purified on a C-18 column (10 g, 0 to 100% MeCN in aq. 0.01
N HCl). The fractions containing pure compound were pooled and
lyophilized to yield 157 mg (38%) of the titled compound as a white
solid. ES (+) MS m/e=448 (M+H.sup.+).
Example 40
[0611] This example describes the synthesis of
##STR00611##
[0612] Step 1: Compound 39.1 (2.0 g, 8.4 mmol) and
2-methyl-5-nitroimidazole (1.0 g, 8.4 mmol) in DMF (50 mL) were
heated to 110.degree. C. for 2 hours. The resulting reaction
mixture was cooled to room temperature and diluted with water and
EtOAc. The organic layer was separated and the aqueous layer
extracted with EtOAc. The combined organic layers were washed with
brine, dried over MgSO.sub.4, filtered, concentrated and purified
by flash column chromatography on silica gel using 40% EtOAc in
hexanes to afford
[2-(2-methyl-4-nitro-imidazol-1-yl)-ethyl]-carbamic acid tert-butyl
ester (compound 40.1; 0.44 g, 19%). ES (+) MS m/e=271 (M+1).
[0613] Step 2: 10% wt Pd/C (0.17 g 0.16 mmol) was added to a
solution of compound 40.1 (0.44 g, 1.6 mmol) in MeOH (10 mL). The
resulting reaction mixture was stirred under a hydrogen atmosphere
(1 atm via a balloon). After 2 hours, the reaction mixture was
filtered thru a plug of Celite and the resulting filtrate
concentrated to provide
[2-(4-amino-2-methyl-imidazol-1-yl)-ethyl]-carbamic acid tert-butyl
ester (compound 40.2; 0.3 g, 77%). ES (+) MS m/e=241 (M+1).
[0614] Step 3: 3-Trifluoromethylphenyl isocyanate (0.23 g, 1.2
mmol) was added to a solution of compound 40.2 (0.30 g, 1.2 mmol)
in dichloromethane (5 mL). The reaction mixture was stirred for 15
minutes, concentrated and purified by flash column chromatography
on silica gel using EtOAc to provide
(2-{2-methyl-4-[3-(3-trifluoromethyl-phenyl)-ureido]-imidazol-1-yl}-ethyl-
)-carbamic acid tert-butyl ester (compound 40.3; 0.11 g, 21%). ES
(+) MS m/e=428 (M+1).
[0615] Step 4: 4 N HCl in dioxanes (3 mL) was added to a solution
of compound 40.3 (0.11 g, 0.26 mmol) in dichloromethane (3 mL). The
reaction mixture stirred for 2 hours and concentrated to provide
1-[1-(2-amino-ethyl)-2-methyl-1H-imidazol-4-yl]-3-(3-trifluoromethyl-phen-
yl)-urea (compound 40.4; 0.10 g, 100%) as a HCl salt. ES (+) MS
m/e=328 (M+1).
[0616] Step 5: 4-chloro-thieno[3,2-d]pyrimidine (0.040 g, 0.25
mmol) was added to a solution of compound 40.4 (0.094 g, 0.25 mmol)
and DIEA (0.13 mL, 0.94 mmol) in n-butanol (3 mL). The resulting
reaction mixture was heated at 100.degree. C. for 2 hours, cooled
and concentrated to dryness. The resulting residue was purified by
reverse phase HPLC to provide the titled compound (0.011 g, 10%).
ES (+) MS m/e=462 (M+1).
Example 41
[0617] This example describes the synthesis of
##STR00612##
[0618] Step 1: A mixture of compound 39.5 (102 mg, 0.292 mmol) and
2-bromo-4-chloro-thieno[3,2-d]pyrimidine (73 mg, 0.292 mmol) in
DIEA/n-butanol (1:1, 1.0 mL) was heated at 100.degree. C. in a
sealed tube behind a blast shield for 2 hours. After cooling to
room temperature the mixture was concentrated under reduced
pressure. The residue thus obtained was dried under high-vacuum and
then purified by preparative TLC (SiO.sub.2, 10% MeOH in
dichloromethane) to yield 80 mg (52%) of
1-{1-[2-(6-bromo-thieno[3,2-d]pyrimidin-4-ylamino)-ethyl]-1H-imidazol-4-y-
l}-3-(3-trifluoromethyl-phenyl)-urea (compound 41.1) as a solid,
R.sub.f 0.34 (10% MeOH in dichloromethane). ES (+) MS m/e=528
(M+H.sup.+).
[0619] Step 2: To a degassed mixture of compound 41.1 (119 mg,
0.226 mmol), 4-pyridine boronic acid 83 mg, 0.677 mmol), 0.8 mL aq.
KH.sub.2PO.sub.4 (1.0 M, 0.8 mmol), in DMF at 100.degree. C. was
added Pd.sub.2 (dba).sub.3 (21 mg, 0.0226 mmol) and triphenylarsine
(17 mg, 0.0542 mmol). The resulting mixture was stirred at
100.degree. C. under nitrogen for 6 hours. After cooling to room
temperature, the mixture was partitioned between water and EtOAc
and filtered through a plug of celite. The aqueous layer was
extracted twice with EtOAc. The combined organic layers were dried
(Na.sub.2SO.sub.4) and concentrated. The crude residue was purified
preparative TLC (SiO.sub.2, 10% MeOH in dichloromethane) to yield a
solid, R.sub.f 0.27 (10% MeOH in dichloromethane). The solid was
taken up in MeOH/dichloromethane and treated with 2.0 M HCl in
ether. The resulting mixture was concentrated and the residue was
lyophilized under high-vacuum to yield 15.3 mg of the titled
compound as a white solid. ES (+) MS m/e=525 (M+H.sup.+).
Example 42
[0620] This example describes the synthesis of
##STR00613##
[0621] Step 1: To a mixture of 1-amino-propan-2-ol (compound 42.1;
3.53 g, 47.0 mmol) and TEA (25 mL) in MeOH (35 mL) was slowly added
a solution of di-tert-butyl dicarbonate (10.3 g, 47.0 mmol) in MeOH
(15 mL). The resulting solution was stirred at room temperature
over night. The mixture was then concentrated and the residue was
dried under high-vacuum to yield 8.23 g (quantitative) of a clear
oil. The oil thus obtained was dissolved in THF (100 mL) and
treated with TEA (13.1 mL, 94.0 mmol). To the resulting solution
was added methansulfonyl chloride (0.3.82 mL, 49.3 mmol) dropwise
at 0.degree. C. under nitrogen. After 1 hour, the mixture was
diluted with EtOAc and washed with aqueous 1 M HCl, aq sodium
bicarbonate, and brine. The organic phase was dried
(Na.sub.2SO.sub.4) and concentrated to yield 10.5 g (88%) of
(compound 42.2) as a clear oil which solidified upon standing, ES
(+) MS m/e=254 (M+H.sup.+).
[0622] Step 2: The titled compound was prepared according to
Example 39 except that compound 42.2 was used instead of compound
39.1 in step 1.
Example 43
[0623] This example describes the synthesis of
##STR00614##
[0624] Step 1: A 20 mL vial was charged with
4-chloro-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid methyl
ester (250 mg, 100 mol %), compound 38.1 (341 mg, 100 mole %), DIEA
(1 mL) and DMF (2 mL). The resulting suspension was heated at
110.degree. C. for 2 hours and cooled to room temperature.
Concentration in vacuo provided
5-methyl-4-(2-{2-[3-(3-trifluoromethyl-phenyl)-ureido]-thiazol-5-yl}-ethy-
lamino)-thieno[2,3-d]pyrimidine-6-carboxylic acid methyl ester;
compound with methane (compound 43.1) as a solid that was used in
the next reaction without further purification. LCMS [M+H].sup.+
m/z 537.2
[0625] Step 2: A 20 mL vial was charged with compound 43.1 (100
mg), DMF (1 mL), and 2N NaOH (2 mL). The reaction was stirred at
room temperature for 10 minutes and then purified by reverse phase
HPLC (aqueous 0.1% CF.sub.3COOH/MeCN gradient). The appropriate
fractions were pooled, concentrated in vacuo to .about.5 mL and
lyophilized to dryness to provide the titled compound. LCMS
[M+H].sup.+ m/z 523.1
Example 44
[0626] This example describes the synthesis of
##STR00615##
[0627] Step 1: To a solution of the HBr salt of
(2-amino-thiazol-5-yl)-acetic acid methyl ester (compound 44.1; 20
mmol) in DIEA (40 mmol) and DMF (100 mL) was added
3-trifluoromethylphenyl isocyanate (20 mmol) at room temperature.
After overnight stirring, the reaction mixture was concentrated and
purified by flash column chromatography on silica gel to provide
{2-[3-(3-trifluoromethyl-phenyl)-ureido]-thiazol-5-yl}-acetic acid
methyl ester (compound 44.2) in 60% yield. EIMS (m/z): calcd. for
C.sub.14H.sub.12F.sub.3N.sub.3O.sub.3S (M.sup.+)+H 360.06. found
360.10.
[0628] Step 2: To a solution of compound 44.2 (10 mmol) in dry THF
(50 mL) was added lithium aluminum hydride ("LAH"; 30 mmol; 1.0 M
in THF) at room temperature. After stirring for 30 minutes, the
reaction mixture was cooled and treated with the cautious addition
of ice water. The solvent was removed, diluted with saturated
sodium bicarbonate and extracted with EtOAc. The organic layers
were combined, dried, concentrated and purified by flash column
chromatography on silica gel to provide
1-[5-(2-hydroxy-ethyl)-thiazol-2-yl]-3-(3-trifluoromethyl-phenyl)-urea
(compound 44.3) in 95% yield. EIMS (m/z): calcd. for
C.sub.13H.sub.12F.sub.3N.sub.3O.sub.2S (M.sup.+)+H 332.06. found
332.10.
[0629] Step 3: To a solution of compound 44.3 (0.15 mmol) in dry
DMF (2 mL) was added NaH (0.45 mmol, 60% oil dispersion) at room
temperature and stirred for 30 minutes. Subsequently,
4-chlorothieno[3,-d]pyrimidine (0.15 mmol) was added and the
resulting mixture was stirred at 60.degree. C. for 1 hour and
quenched by the addition of several drops of saturated ammonium
chloride. The solvent was removed and the residue was purified by
flash column chromatography on silica gel to provide the titled
compound in 30% yield. EIMS (m/z): calcd. for
C.sub.19H.sub.14F.sub.3N.sub.5O.sub.2S.sub.2 (M.sup.+)+H 466.05.
found 466.90.
Example 45
[0630] This example describes the synthesis of
##STR00616##
[0631] Step 1: A mixture of compound 44.2 (2.0 mmol) and anhydrous
MgCl.sub.2 (2.0 mmol) in methylamine (10 mL of a 2.0 M solution in
THF) was stirred at room temperature for several hours. The mixture
was concentrated, diluted with EtOAC and filtered. The filtrate was
washed with brine, dried, concentrated and purified by flash column
chromatography on silica gel to provide the intermediate amide in
90% yield. EIMS (m/z): calcd. for
C.sub.14H.sub.13F.sub.3N.sub.4O.sub.2S (M.sup.+)+H 359.07. found
359.10. To a solution of the intermediate amide (1.0 mmol) in dry
THF (5.0 mL) was added LAH (3.0 mmol, 1.0 M in THF) at room
temperature. The resulting mixture was stirred at 60.degree. C. for
several hours, cooled to 0.degree. C. and hydrolyzed with the
addition of ice water. The mixture was concentrated, diluted with
saturated sodium bicarbonate and extracted with EtOAc. The organic
layer was then dried, concentrated and purified by flash column
chromatography on silica gel to provide
1-[5-(2-methylamino-ethyl)-thiazol-2-yl]-3-(3-trifluoromethyl-phe-
nyl)-urea (compound 45.1) in 85% yield. EIMS (m/z): calcd. for
C.sub.14H.sub.15F.sub.3N.sub.4OS (M.sup.+)+H 345.09. found
344.90.
[0632] Step 2: A mixture of compound 45.1 (0.15 mmol), compound 6.2
(0.15 mmol) and DIEA (0.15 mmol) in DMF (2.0 mL) was stirred at
100.degree. C. for 2 hours. The solvent was removed and the residue
purified by flash column chromatography on silica gel to provide
the titled compound in 20% yield. EIMS (m/z): calcd. for
C.sub.20H.sub.17F.sub.3N.sub.6OS.sub.2 (M.sup.+)+H 479.09. found
479.10.
Example 46
[0633] This example describes the synthesis of
##STR00617##
[0634] Step 1: To a solution of compound 44.3 (2.0 mmol) in dry
dichlorormethane (10 mL) was added TEA (2.0 mmol) and tosyl
chloride (2.2 mmol) at room temperature. The resulting mixture was
stirred at room temperature for several hours, concentrated and
purified by flash column chromatography on silica gel to provide
the intermediate tosylate in 32% yield. EIMS (m/z): calcd. for
C.sub.20H.sub.18F.sub.3N.sub.3O.sub.4S.sub.2 (M.sup.+)+H 486.07.
found 466.10. To a solution of the intermediate tosylate (0.5 mmol)
in DMF (2.0 mL) was added potassium thioacetate (1.0 mmol) and the
mixture was stirred at 90.degree. C. for 2 hours. The solvent was
removed and the residue was purified by flash column chromatography
on silica gel to provide thioacetic acid
S-(2-{2-[3-(3-trifluoromethyl-phenyl)-ureido]-thiazol-5-yl}-ethyl)ester
(compound 46.1) in 90% yield. EIMS (m/z): calcd. for
C.sub.15H.sub.14F.sub.3N.sub.3O.sub.2S.sub.2 (M.sup.+)+H 390.05.
found 390.00.
[0635] Step 2: A mixture of compound 46.1 (0.15 mmol), compound 6.2
(0.15 mmol), and K.sub.2CO.sub.3 (0.16 mmol) in DMF (2.0 mL) was
stirred at 90.degree. C. for 1 hour. The solvent was removed and
the residue purified by flash column chromatography on silica gel
to provide the titled compound in 42% yield. EIMS (m/z): calcd. for
C.sub.19H.sub.14F.sub.3N.sub.5O.sub.2S.sub.3 (M.sup.+)+H 482.03.
found 482.00.
Example 47
[0636] This example describes the synthesis of
##STR00618##
[0637] Step 1: To a suspension of compound 6.2 (5.0 mmol) in dry
THF (25.0 mL) was added lithium diisopropylamide ("LDA"; 6.0 mmol;
2.0 M in heptane/THF/ethylbenzene) at -78.degree. C. under an
atmosphere of N.sub.2. After stirring at -78.degree. C. for 30
minutes, the mixture was transferred to a pre-cooled solution of
TsCN (8.0 mmol) in dry THF (10 mL) at -78.degree. C. The resulting
mixture was slowly warmed to room temperature and stirred for
several hours. The reaction was quenched by the addition of several
drops of saturated ammonium chloride and then concentrated. The
residue was diluted with saturated sodium bicarbonate and extracted
with EtOAc. The organic layers was dried, concentrated and purified
by flash column chromatography on silica gel to provide
4-chloro-thieno[3,2-d]pyrimidine-6-carbonitrile c(compound 47.1) in
20% yield. EIMS (m/z): calcd. for C.sub.7H.sub.2CN.sub.3S
(M.sup.+)+H 195.97. found 196.00.
[0638] Step 2: A mixture 47.1 (0.15 mmol), compound 38.1 (0.15
mmol) and DIEA (0.15 mmol) in DMF (2.0 mL) was stirred at
100.degree. C. for 2 h. The solvent was removed and the residue
purified by reverse phase HPLC (aqueous 0.1% CF.sub.3COOH/MeCN
gradient) to provide the titled compound in 40% yield. EIMS (m/z):
calcd. for C.sub.20H.sub.14F.sub.3N.sub.7OS.sub.2 (M.sup.+)+H
490.07. found 490.90.
Example 48
[0639] This example describes the synthesis of
##STR00619##
[0640] Step 1: A mixture of
6-bromo-4-chloro-thieno[3,2-d]pyrimidine (10.0 mmol),
(trimethylsilyl)acetylene (12.0 mmol), Pd(PhCN).sub.2Cl.sub.2, (1.0
mmol), CuI (1.0 mmol) and TEA (2.0 mmol) in dry THF (60.0 mL) was
flushed with dry N.sub.2 for several minutes and stirred at
60.degree. C. for minutes under an atmosphere of N.sub.2. The
solvent was removed and the residue purified by flash column
chromatography on silica gel to provide
4-chloro-6-trimethylsilanylethynyl-thieno[3,2-d]pyrimidine
(compound 48.1) in 65% yield. EIMS (m/z): calcd. for
C.sub.11H.sub.11ClN.sub.2SSi (M.sup.+)+H 266.01. found 266.00.
[0641] Step 2: To a solution of compound 48.1 (5.0 mmol) in THF (50
mL) was tetrabutylammonium fluoride ("TBAF"; 5.0 mmol; 1.0 M in
THF) at 0.degree. C. After stirring at 0.degree. C. for 5 minutes,
the reaction mixture was concentrated, diluted with EtOAc, washed
with saturated sodium bicarbonate, brine and dried. The solvent was
removed and the residue purified by flash column chromatography on
silica gel to provide 4-chloro-6-ethynyl-thieno[3,2-d]pyrimidine
(compound 48.2) in 92% yield. EIMS (m/z): calcd. for
C.sub.8H.sub.3ClN.sub.2S (M.sup.+)+H 194.97. found 195.00
[0642] Step 3: A mixture of compound 48.2 (1.0 mmol),
trimethylsilylmethyl azide (5.0 mmol), CuI (0.2 mmol), and DIEA
(1.0 mmol) in DMF (10 mL) was stirred at room temperature for 24
hours. The solvent was removed and the residue was diluted with
water and extracted with EtOAc. The organic layer was washed with
dilute aqueous ammonium hydroxide, brine, dried, concentrated and
purified by flash column chromatography to provide
4-chloro-6-(1-trimethylsilanylmethyl-1H-[1,2,3]triazol-4-yl)-thieno[3,2-d-
]pyrimidine (compound 48.3) in 80% yield. EIMS (m/z): calcd. for
C.sub.12H.sub.14ClN.sub.5SSi (M.sup.+)+H 324.04. found 324.00.
[0643] Step 4: To a solution of compound 48.3 (0.5 mmol) in THF
(10.0 mL) was added several drops of water and TBAF (0.55 mmol; 1.0
M in THF) at 0.degree. C. The resulting mixture was stirred at
0.degree. C. for 15 minutes, concentrated and washed with hexanes.
The white solid that formed was suspended in ice water (10 mL),
filtered, washed with ice water and dried in vacuo to provide
4-chloro-6-(1-methyl-1H-[1,2,3]triazol-4-yl)-thieno[3,2-d]pyrimidine
(compound 48.4) in 95% yield. EIMS (m/z): calcd. for
C.sub.9H.sub.6ClN.sub.5S (M.sup.+)+H 252.00. found 252.00.
[0644] Step 5: A mixture of compound 48.4 (0.15 mmol), compound
38.1 (0.15 mmol) and DIEA (0.15 mmol) in DMF (2.0 mL) was stirred
at 100.degree. C. for 8 hours. The solvent was removed and the
residue was purified by flash column chromatography on silica gel
to provide the titled compound in 10% yield. EIMS (m/z): calcd. for
C.sub.22H.sub.18F.sub.3N.sub.9OS.sub.2 (M.sup.+)+H 546.10. found
545.85.
Example 49
[0645] This example describes the synthesis of
##STR00620##
[0646] A 100 mL vial was charged with compound 34.1 (125 mg, 100
mol %),
4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine--
1-carboxylic acid tert-butyl ester (86 mg, 120 mole %), and
PdCl.sub.2 (PPh.sub.3).sub.2 (33 mg, 20 mol %). To this was added
DMF/H.sub.2O (4:1, 1 mL) along with 2N Na.sub.2CO.sub.3 (0.3 mL).
The vial was flushed with nitrogen, sealed, and subjected to
microwave irradiation (10 minutes, 300 W, 100.degree. C.). The
contents were cooled and concentrated in vacuo. The resulting
residue was purified by reverse phase HPLC (aqueous 0.1%
CF.sub.3COOH/MeCN gradient) resulting in a 1:1 mixture of
1-{5-[2-(thieno[3,2-d]pyrimidin-4-ylamino)-ethyl]-thiazol-2-yl}-3-(3-trif-
luoromethyl-phenyl)-urea; compound with
3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester
(compound 50.1) and the titled compound. This mixture was dissolved
in 4N HCl/dioxane (2 mL), stirred at room temperature for 15
minutes, and concentrated in vacuo to provide exclusively the HCl
salt of the titled compound as a yellow powder LCMS [M+H].sup.+ m/z
546.1.
Example 50
[0647] This example describes the synthesis of
##STR00621##
where R.sup.1 is as described previously. These compounds are made
according to Example 29 except that R.sup.1B(OH).sub.2 is used
instead of 4-pyridineboronic acid in step 1 and 3-chlorophenyl
isocyanate is used instead of 3-trifluoromethylphenyl isocyanate in
step 2. Illustrative examples of suitable R.sup.1's are found
throughout this disclosure as well as in Table 9.
Example 51
[0648] This example describes the synthesis of
##STR00622##
where R.sup.1 is as described previously. These compounds are made
according to Example 29 except that R.sup.1B(OH).sub.2 is used
instead of 4-pyridineboronic acid in step 1 and 3-fluorophenyl
isocyanate is used instead of 3-trifluoromethylphenyl isocyanate in
step 2. Illustrative examples of suitable R.sup.1's are found
throughout this disclosure as well as in Table 9.
Example 52
[0649] This example describes the synthesis of
##STR00623##
[0650] Step 1: To a flame dried flask was placed a suspension of
compound 6.2 (5.92 mmol) in THF (50 mL). The reaction was cooled to
-78.degree. C. and a solution of LDA (3.25 mL of a 2.0 M solution
in heptane/THF/ethyl benzene) was slowly added. After stirring for
30 minutes, a -78.degree. C., a solution of (n-Bu).sub.3SnCL (1.9
mL) in THF (50 mL) was added via cannula over a 20 minute period at
-78.degree. C. and stirred for 2 hours. The reaction was warmed to
room temperature, hydrolyzed with saturated NH.sub.4Cl, extracted
with EtOAc, dried and concentrated. The crude product was purified
by flash column chromatography on silica gel (1:1
hexanes/dichloromethane then 10% EtOAc/dichloromethane) to provide
4-chloro-6-tributylstannanyl-thieno[3,2-d]pyrimidine (compound
52.1) in 92% yield.
[0651] Step 2: Compound 52.1 (22.58 mmol) and
4-iodo-1-(2-pyrrolidin-1-yl-ethyl)-1H-pyrazole (22.32 mmol) was
dissolved in DMF and degassed with nitrogen. To this was added
Pd.sub.2 (dba).sub.3 (0.23 mmol), Ph.sub.3As (0.46 mmol) and CuI
(1.16 mmol). The reaction mixture was heated at 80.degree. C. for 6
hours, concentrated to dryness and purified by flash column
chromatography on silica gel (10% MeOH in dichloromethane) to
provide
4-chloro-6-[1-(2-pyrrolidin-1-yl-ethyl)-1H-pyrazol-4-yl]-thieno[3,2-d]pyr-
imidine (compound 52.2).
[0652] Step 3: Compound 52.2 (3.04 mmol), compound 38.1 (3.03 mmol)
and DIEA (6.88 mmol) in DMF (10 mL) was heated at 100.degree. C.
for 2 hours. The reaction mixture was concentrated to dryness and
purified by column chromatography on C.sub.18 silica gel to provide
the titled compound.
Example 53
[0653] This example describes the synthesis of
##STR00624##
where 1A and R.sup.1A are as previously described. These compounds
are made according to Example 52 except that R.sup.1A-A-I is used
instead of 4-iodo-1-(2-pyrrolidin-1-yl-ethyl)-1H-pyrazole in step
2. Illustrative examples of suitable R.sup.1A 's and A's are found
throughout this disclosure as well as in Table 11.
TABLE-US-00011 TABLE 11 R.sup.1A-A-I Final Compound ##STR00625##
##STR00626## ##STR00627## ##STR00628## ##STR00629## ##STR00630##
##STR00631## ##STR00632## ##STR00633## ##STR00634## ##STR00635##
##STR00636##
Example 54
[0654] This example describes the synthesis of
##STR00637##
[0655] Step 1:
1-[5-(2-{6-[1-(4-Methoxy-benzyl)-1H-pyrazol-4-yl]-thieno[3,2-d]pyrimidin--
4-ylamino}-ethyl)-thiazol-2-yl]-3-(3-trifluoromethyl-phenyl)-urea
(compound 54.1) is synthesized according to Example 53.
[0656] Step 2: Compound 54.1 (0.19 mmol) is heated at 60.degree. C.
in neat TFA for 8 hours. The reaction was evaporated to dryness and
purified by column chromatography on C.sub.18 silica gel to provide
the titled compound.
Example 55
[0657] This example describes the synthesis of
##STR00638##
[0658] Step 1:
1-{5-[2-(6-{1-[2-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-ethyl]-1H-pyrazol--
4-yl}-thieno[3,2-d]pyrimidin-4-ylamino)-ethyl]-thiazol-2-yl}-3-(3-trifluor-
omethyl-phenyl)-urea (compound 55.1) is synthesized according to
Example 53.
[0659] Step 2: To a solution of compound 55.1 in ethanol was added
hydrazine (22 equivalents) and the reaction mixture was heated at
60.degree. C. for 2.5 hours. The reaction is concentrated to
dryness and the residue purified by preparative TLC (10% 7.0 M
NH.sub.3/MeOH in dichloromethane) to provide the titled
compound.
Example 56
[0660] This example describes the synthesis of
##STR00639##
[0661] Step 1:
1-[5-(2-{6-[1-(2-Hydroxy-ethyl)-1H-pyrazol-4-yl]-thieno[3,2-d]pyrimidin-4-
-ylamino}-ethyl)-thiazol-2-yl]-3-(3-trifluoromethyl-phenyl)-urea
(compound 56.1) is synthesized according to Example 33 or Example
53.
[0662] Step 2: To a solution of compound 56.1 (0.17 mmol) in THF
was added POCl.sub.3 (10.9 mmol) at room temperature. After 2
hours, an additional equivalent of POCl.sub.3 was added and the
reaction was stirred for 4 hours. Water was added and the reaction
mixture was stirred for an additional 1 hour. Volatiles were
removed under reduced pressure and the residue purified by reverse
phase HPLC to provide the titled compound along with recovered
compound 56.1.
Example 57
[0663] This example describes the synthesis of
##STR00640##
[0664] Step 1:
1-(5-{2-[6-(3-Hydroxy-phenyl)-thieno[3,2-d]pyrimidin-4-ylamino]-ethyl}-th-
iazol-2-yl)-3-(3-trifluoromethyl-phenyl)-urea (compound 57.1) was
synthesized according to Example 35.
[0665] Step 2: To a solution of compound 57.1 (0.20 mmol) in THF
(20 mL) was added 1-H-tetrazole (6.0 mL of a 3% w/w in CH.sub.3CN).
The reaction was purged with nitrogen and di-tert-butyl
diethylphosphoramidite (1.06 mmol) was added. After stirring at
room temperature for 3.5 hours, tert-butyl hydroperoxide (5 mL of
70% aqueous solution) was added. After stirring for 1 hour, the
reaction was cooled to 0.degree. C. followed by the addition of
NaHSO.sub.3 (15 mL of a 5% aqueous solution). After an additional 1
hour, the reaction mixture was extracted with dichloromethane,
washed with brine, dried and concentrated to give phosphoric acid
di-tert-butyl ester
3-[4-(2-{2-[3-(3-trifluoromethyl-penta-2,4-dienyl)-ureido]-thiazol-5-yl}--
ethylamino)-thieno[3,2-d]pyrimidin-6-yl]-phenyl ester (compound
57.2)
[0666] Step 3: Crude compound 57.2 from the previous reaction was
dissolved in dichloromethane and TFA (0.1 mL) was added. The
reaction was stirred at room temperature overnight, concentrated to
dryness and purified by reverse phase HPLC. The lyophilized product
was washed with EtOAc to give a beige precipitate. The precipitate
was stirred at room temperature with a suspension of .about.2 g of
Dowex cation exchange resin (Na+ form) in water and CH.sub.3CN for
2 hours. The resin was filtered and the filtrate lyophilized to
give the titled compound.
Example 58
[0667] This example describes the synthesis of
##STR00641##
[0668] Step 1: To a suspension of a HBr salt of
2-[2-(2-amino-thiazol-5-yl)-ethyl]-isoindole-1,3-dione (compound
58.1; 1.42 mmol) in dichloromethane was added TEA (4.30 mmol)
followed by the addition of phenyl chloroformate (1.43 mmol) at
room temperature. After 2 hours, the reaction was concentrated to
dryness to give a solid that was suspended in EtOAc, filtered,
washed with additional EtOAc and dried under vacuum to provide
{5-[2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-ethyl]-thiazol-2-yl}-carbamic
acid phenyl ester (compound 58.2, which is contaminated with
triethyl amine salts) which was used in the next reaction without
further purification.
[0669] Step 2: Compound 58.2 (0.64 mmol),
3-pyrrolidin-1-ylmethyl-phenylamine (0.64 mmol) and TEA (2.15 mmol)
are dissolved in DMF and heated at 75.degree. C. for 30 minutes.
The reaction is concentrated to dryness and purified by flash
column chromatography on silica gel (10% 7.0 M NH.sub.3/MeOH in
dichloromethane) to provide the desired urea. The urea was
dissolved in ethanol and treated with hydrazine (0.06 mL) at
70.degree. C. for 3 hours and concentrated. The residue is
suspended and sonicated in dichloromethane, filtered and
co-evaporated from MeOH/toluene four times to provide
1-[5-(2-amino-ethyl)-thiazol-2-yl]-3-(3-pyrrolidin-1-ylmethyl-phenyl)-ure-
a (compound 58.3).
[0670] Step 3: A mixture of
6-bromo-4-chloro-thieno[3,2-d]pyrimidine (4.0 mmol),
1-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyraz-
ole (4.4 mmol), Pd.sub.2 (dba).sub.3 (0.8 mmol), Ph.sub.3As (0.8
mmol) and K.sub.2HPO.sub.4 (8.0 mmol) in a DMF (40 mL) and water
(10 mL) are stirred at room temperature until the reaction was
complete. The reaction is partitioned between EtOAc and water,
washed with brine, dried, concentrated and purified by flash column
chromatography on silica gel to give
4-chloro-6-(1-methyl-1H-pyrazol-4-yl)-thieno[3,2-d]pyrimidine
(compound 58.4).
[0671] Step 4: Compound 58.3 (0.23 mmol), compound 58.4 (0.47 mmol)
and DIEA (0.2 mL) in N,N-dimethylacetamide ("DMA") are heated at
110.degree. C. for 5 hours. The reaction is concentrated to dryness
and purified by flash column chromatography on silica gel (10% 7.0
M NH.sub.3/MeOH in dichloromethane), and then is purified a second
time by preparative TLC to afford the titled compound.
Example 59
[0672] This example describes the synthesis of
##STR00642##
where R.sup.1 is as described previously. These compounds are made
according to the procedures of Example 58 except that
##STR00643##
is used instead of compound 58.4 in step 4. Illustrative examples
of R.sup.1's are found throughout this disclosure as well as in
Table 1.
Example 60
[0673] This example describes the synthesis of
##STR00644##
[0674] Step 1: A mixture of compound 58.1 (21.2 g) in
dichloromethane (1.0 L), saturated NaHCO.sub.3 (300 mL) and water
(100 mL) was rapidly stirred until the organic layer became clear.
The organic layer was separated and the aqueous layer was extracted
with dichloromethane several times. The organic layers were
combined, dried and concentrated to give the amine as a yellow
solid. A portion of the amine (5.3 g) was dissolved in
dichloromethane (80 mL) and treated with 3-fluorophenyl isocyante
(2.5 mL) at room temperature with overnight stirring. The solid
that formed was filtered, washed with dichloromethane and dried
under vacuum to provide
1-{5-[2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-ethyl]-thiazol-2-yl-
}-3-(3-fluoro-phenyl)-urea (compound 60.1; 2.6 g) as a colorless
solid.
[0675] Step 2: To a suspension of compound 60.1 (2.6 g) in ethanol
(64 mL) was added hydrazine (2.0 mL) and the reaction stirred at
65.degree. C. for 4 hours. The solid that formed was filtered off
and the filtrate was concentrated to give
1-[5-(2-amino-ethyl)-thiazol-2-yl]-3-(3-fluoro-phenyl)-urea
(compound 60.2; 1.6 g) as a yellow solid.
[0676] Step 3: A solution of compound 60.2 (1.48 mmol), compound
52.2 (1.67 mmol) and DIEA (3.44 mmol) in 1-methyl-2-pyrrolidinone
("NMP") was heated at 90.degree. C. overnight. The reaction was
cooled, diluted with EtOAc, washed with water, brine, dried and
concentrated. The residue was purified by column chromatography to
give the titled compound.
Example 61
[0677] This example describes the synthesis of
##STR00645##
where R.sup.Z1 and m are as described previously. These compounds
are made according to the procedures of Example 60 except that
##STR00646##
is used instead of 3-fluorophenyl isocyante in step 1. Illustrative
examples of suitable R.sup.Z1's are found throughout this
disclosure as well as in Table 5.
Example 62
[0678] This example describes the synthesis of
##STR00647##
where R.sup.Z1 and m are as described previously.
[0679] Step 1: To a suspension of
2-tert-butoxycarbonylamino-thiazole-5-carboxylic acid methyl ester
(compound 62.1; 21.7 mmol) in THF was slowly added LAH (25 mL of a
1.0 M solution in THF). After stirring for 1 hour at room
temperature the reaction is cautiously hydrolyzed with the
sequential addition of water (0.95 mL), 15% aqueous NaOH (0.95 mL)
and additional water (2.85 mL). After stirring for 30 minutes the
reaction is filtered through a pad of Celite and the filtrate is
dried and concentrated to give
(5-hydroxymethyl-thiazol-2-yl)-carbamic acid tert-butyl ester
(compound 62.2).
[0680] Step 2: To a solution of compound 62.2 (18.5 mmol) in
dichloromethane is added molecular sieves (4.0 g) and PDC (39.0
mmol) at room temperature (THF is added to help dissolve the
starting material). After 1.5 hours, an additional equivalent of
PDC is added and the reaction is stirred for 5.5 hours. The
reaction mixture is poured directly onto a silica gel column and is
eluted with a gradient of 100% dichloromethane to 100% EtOAc.
Fractions containing the desired product are pooled and
concentrated to afford (5-formyl-thiazol-2-yl)-carbamic acid
tert-butyl ester (compound 62.3).
[0681] Step 3: To a solution of compound 62.3 (4.5 mmol) in
dichloromethane is added trimethylsilyl cyanide ("TMSCN"; 2.1
equivalents) and ZnI.sub.2 (10% mol). After stirring at room
temperature overnight, the reaction is concentrated under vacuum.
The crude cyanohydrin is dissolved in THF and treated with
AlH.sub.3 (2.2 equivalents of a 0.5 M solution in THF). After
stirring for 15 minutes, the reaction is quenched with the addition
of saturated aqueous Na.sub.2SO.sub.4, is filtered through a pad of
Celite, is dried and concentrated. Purification by flash column
chromatography on silica gel (10% 7.0 M NH.sub.3/MeOH in
dichloromethane) provides
[5-(2-amino-1-hydroxy-ethyl)-thiazol-2-yl]-carbamic acid tert-butyl
ester (compound 62.4).
[0682] Step 4: Compound 62.4 (0.16 mmol),
4-chloro-thieno[3,2-d]pyrimidine (0.16 mmol.) and DIEA (0.28 mmol)
is heated in DMA at 90.degree. C. for 5 hours. The reaction mixture
is cooled, concentrated and purified by preparative TLC (10% MeOH
in EtOAc) to afford
{5-[1-hydroxy-2-(thieno[3,2-d]pyrimidin-4-ylamino)-ethyl]-thiazol-2-yl}-c-
arbamic acid tert-butyl ester (compound 62.5).
[0683] Step 5: To a solution of compound 62.5 (0.06 mmol) in
dichloromethane is added anhydrous HCl (31 equivalents of a 4.0 M
solution in 1,4-dioxane). After stirring for 1.5 hours at room
temperature the reaction is concentrated to dryness to give a
residue that is suspended in THF. To this suspension is added TEA
(5.6 equivalents) and
##STR00648##
(1.1 equivalents) and after stirring at room temperature for 1.5
hours, the reaction is concentrated and purified by preparative TLC
(10% MeOH in EtOAc) to give titled compound. Illustrative examples
of suitable R.sup.Z1's are found throughout this disclosure as well
as in Table 5.
Example 63
[0684] This example describes the synthesis of
##STR00649##
[0685] Step 1: To a suspension of compound 6.2 (5 mmol) in dry THF
(25 mL) was added LDA (6 mmol, 2.0 M in heptane/THF/ethylbenzene)
at -78.degree. C. under an atmosphere of N.sub.2. After stirring at
-78.degree. C. for 30 minutes, the mixture was transferred to a
pre-cooled solution of methyl methanethiosulfonate (8 mmol) in of
dry THF (10 mL) at -78.degree. C. The resulting mixture was slowly
warmed to room temperature and stirred for 2 hours. The reaction
was quenched by the addition of several portions of sat. aq.
NH.sub.4Cl, concentrated and partitioned between EtOAc and
saturated aqueous NaHCO.sub.3. The organic layer was separated,
dried and concentrated to give a residue that was purified by flash
column chromatography on silica gel to give
4-chloro-6-methylsulfanyl-thieno[3,2-d]pyrimidine (compound
63.1).
[0686] Step 2: A mixture of compound 63.1 (1 mmol) and
3-chloroperoxybenzoic acid ("m-CPBA"; 2 mmol) in dichloromethane
(10 mL) was stirred at room temperature for 2 hours. The reaction
mixture was then diluted with dichloromethane, washed with
saturated aqueous NaHCO.sub.3 several times, dried and concentrated
to give a residue that was purified by flash column chromatography
on silica gel to give
4-chloro-6-methanesulfonyl-thieno[3,2-d]pyrimidine (compound
63.2).
[0687] Step 3: A mixture of compound 63.2 (0.2 mmol), compound 38.1
(0.2 mmol) and DIEA in DMF (2 mL) was heated at 100.degree. C. for
2 hours. The reaction was concentrated to dryness and purified by
reverse phase HPLC to provide the titled compound.
Example 64
[0688] This example describes the synthesis of
##STR00650##
[0689] This compound is made according to Example 63 except that
only one equivalent of m-CPBA is used in step 2.
Example 65
[0690] This example describes the synthesis of
##STR00651##
[0691] This compound is made according to Example 63 except that
dimethylphosphine chloride is used instead of methyl
methanethiosulfonate in step 1.
Example 66
[0692] This example describes the synthesis of
##STR00652##
[0693] Step 1:
4-(2-{2-[3-(3-Trifluoromethyl-phenyl)-ureido]-thiazol-5-yl}-ethylamino)-t-
hieno[3,2-d]pyrimidine-6-carboxylic acid ethyl ester (compound
66.1) is prepared according to Example 38 except that
4-chloro-thieno[3,2-d]pyrimidine-6-carboxylic acid ethyl ester is
used instead of 5-methyl-4-chloro-[2,3-d]thienopyrimidine.
[0694] Step 2: A mixture of compound 66.1 (2 mmol) and
LiOH.H.sub.2O (4 mmol) in THF (20 mL) and H.sub.2O (5 mL) was
stirred at room temperature for 2 hours and then neutralized with
1.0 N HCl (4 mL). The reaction was concentrated to dryness to give
4-(2-{2-[3-(3-trifluoromethyl-phenyl)-ureido]-thiazol-5-yl}-ethylamino)-t-
hieno[3,2-d]pyrimidine-6-carboxylic acid (compound 66.2) which is
used without further purification in the next step.
[0695] Step 3: A mixture of compound 66.2 (0.05 mmol),
1-methylpiperazine (0.05 mmol), HATU (0.05 mmol) and DIEA (0.10
mmol) in DMF (1.0 mL) was stirred at room temperature overnight.
The reaction was concentrated to dryness and purified by reverse
phase HPLC to afford the titled compound.
Example 67
[0696] This example describes the synthesis of
##STR00653##
where R.sup.1B's are as described previously. These compounds are
made according to Example 66 except that (R.sup.1B).sub.2N is used
instead of 1-methylpiperazine in step 3. Illustrative examples of
suitable (R.sup.1B).sub.2N's are found throughout this disclosure
as well as in Table 12.
TABLE-US-00012 TABLE 12 (R.sup.1B).sub.2N 2. Final Compound
##STR00654## ##STR00655## ##STR00656## ##STR00657## ##STR00658##
##STR00659## ##STR00660## ##STR00661## ##STR00662## ##STR00663##
##STR00664## ##STR00665## ##STR00666## ##STR00667## ##STR00668##
##STR00669##
Example 68
[0697] This example describes the synthesis of
##STR00670##
[0698] A mixture of compound 48.2 (1.0 mmol),
1-(2-azido-ethyl)-piperidine (1.0 mmol), CuI (1.0 mmol) and DIEA
(2.0 mmol) in DMF (10 mL) was stirred at room temperature for 2 h.
Subsequently, compound 38.1 (1.0 mmol.) was added and the reaction
was heated at 100.degree. C. for 2 hours. The reaction was
concentrated and the residue diluted with aqueous NH.sub.4OH. The
resulting suspension was filtered and washed with water and EtOAc.
The solid was collected and dried under vacuum to provide the
titled compound.
Example 69
[0699] This example describes the synthesis of
##STR00671##
[0700] This compound is made according to Example 68 except that
4-(2-azido-ethyl)-morpholine is used instead of
1-(2-azido-ethyl)-piperidine.
Example 70
[0701] This example describes the synthesis of
##STR00672##
[0702] Step 1: To a solution of 3,5-difluoronitrobenzene (6.0 mmol)
and (S)-(+)-2,2-dimethyl-1,3-dioxolan-4-methanol (7.5 mmol) in DMF
(10 mL) is added NaH (2.3 equiv.) at room temperature. After
stirring for 2 hours, saturated NH.sub.4Cl is added and the
reaction is extracted with EtOAc. The organic layer is separated,
washed with brine, dried and concentrated to give a residue that
was purified by preparative TLC (30% EtOAC in hexanes). The
corresponding nitro compound thus obtained (1.0 mmol) is stirred at
room temperature for 12 hours under a hydrogen atmosphere over 10%
Pd/C (30 mg) in MeOH/EtOAc (15 mL). The reaction is filtered
through a Celite pad and concentrated to dryness to provide
3-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-5-fluoro-phenylamine
(compound 70.1) of sufficient purity to be used in the next
step.
[0703] Step 2: A solution of compound 70.1 (1.0 mmol), compound
16.1 (1.0 mmol) and DMAP (1.0 mmol) in DMSO (10 mL) is heated at
90.degree. C. for 30 minutes. The reaction is cooled, and
partitioned between EtOAC and 1.0 N NaOH. The organic layer is
separated, washed with brine, dried and concentrated to give a
residue that was purified by preparative TLC (6% MeOH in
dichoromethane) to provide
1-[3-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-5-fluoro-phenyl]-3-{5-[2-(t-
hieno[3,2-d]pyrimidin-4-ylamino)-ethyl]-thiazol-2-yl}-urea
(compound 70.2).
[0704] Step 3: To a solution of compound 70.2 (0.2 mmol) in MeOH
(1.0 mL) and dichloromethane (1.0 mL) is added trifluoroacetic acid
(5 equivalents). The reaction is stirred at room temperature for 12
hours and then directly purified by reverse phase HPLC to provide
the titled compound.
Example 71
[0705] This example describes the synthesis of
##STR00673##
[0706] This compound is made according to Example 70 except that
from (R)-(-)-2,2-dimethyl-1,3-dioxolan-4-methanol is used instead
of (S)-(+)-2,2-dimethyl-1,3-dioxolan-4-methanol in step 1.
Example 72
[0707] This example describes the synthesis of
##STR00674##
where R.sup.Z1 and m are as described previously.
[0708] Step 1:
2-[2-(2-Amino-4-methyl-thiazol-5-yl)-ethyl]-isoindole-1,3-dione is
(compound 72.1; 1.0 mmol) is prepared according to the procedure of
Ericks, J. C. et al; J. Med. Chem. 1992, 35, 3239. Compound 72.1 is
refluxed with 3
##STR00675##
(1 equivalent) in acetone (10 mL) for 30 minutes. The reaction is
cooled to room temperature and the solvent is removed under reduced
pressure. Trituration from dichloromethane and hexanes gives urea
product (compound 72.2).
[0709] Step 2: Compound 72.2 (0.7 mmol) is refluxed in EtOH (10 mL)
with hydrazine (3 equivalents) for 2 hours. The reaction mixture is
cooled to room temperature and the precipitate is filtered off and
the filtrate concentrated to dryness to give the corresponding
amine (compound 72.3).
[0710] Step 3: To a solution of compound 72.3 (0.35 mmol) in DMF
(1.0 mL) was added compound 6.2 (1 equivalent) and triethylamine (5
equivalents). The reaction is stirred at 90.degree. C. for 1 hour,
cooled, diluted with EtOAc, washed with water, brine, dried and
concentrated to provide the titled compound.
Example 73
[0711] This example describes the synthesis of
##STR00676##
[0712] Step 1: A mixture of
{2-[3-(3-trifluoromethyl-phenyl)-ureido]-thiazol-5-yl}-acetic acid
methyl ester (4.17 mmol), paraformaldehyde (0.95 equiv.) and
K.sub.2CO.sub.3 (0.95 equiv.) in DMSO (10.0 mL) was heated at
50.degree. C. for 1.5 hours. The reaction was cooled, diluted with
EtOAc, washed with water, dried and concentrated to give a residue
that was purified by flash column chromatography on silica gel (0
to 6% MeOH in EtOAc) to provide
3-hydroxy-2-{2-[3-(3-trifluoromethyl-phenyl)-ureido]-thiazol-5-yl}-propio-
nic acid methyl ester (compound 73.1).
[0713] Step 2: To a mixture of compound 73.1 (1.67 mmol) and
triethylamine (2.2 equivalent) in 1:1 dichloromethane/THF (12.0 mL)
was added triisopropylsilyl trifluoromethanesulfonate (2.2
equivalents) dropwise at 0.degree. C. After complete consumption of
the starting material (TLC 30% EtOAc in hexanes) the reaction
mixture is diluted with EtOAc and washed with 0.5 N HCl, saturated
sodium bicarbonate, dried and concentrated to give a residue that
was purified by flash column chromatography on silica gel (0 to 60%
EtOAc in hexanes) to provide
2-{2-[3-(3-trifluoromethyl-phenyl)-ureido]-thiazol-5-yl}-3-triisopropylsi-
lanyloxy-propionic acid methyl ester (compound 73.2) as a foam.
[0714] Step 3: To a solution of compound 73.2 (0.275 mmol) in THF
(2.5 mL) was added LAH (0.275 mL of a 1.0 M solution in THF)
dropwise at 0.degree. C. The reaction is allowed to warmed to room
temperature and stirred until the starting material was consumed.
The reaction is quenched by the dropwise addition of water and the
reaction mixture was extracted with EtOAc. The combined organic
layers were combined, dried and concentrated to give a residue that
was purified by flash column chromatography (20 to 100% EtOAc in
hexanes) to provide
1-[5-(2-hydroxy-1-triisopropylsilanyloxymethyl-ethyl)-thiazol-2-yl]-3-(3--
trifluoromethyl-phenyl)-urea (compound 73.3).
[0715] Step 4: To a suspension of NaH (0.12 mmol as a 60% oil
dispersion) in THF (0.20 mL) was added a solution of compound 73.3
(0.04 mmol) in THF (1.0 mL) at room temperature. After stirring for
1 hour, 4-chlorothieno[3,2-d]pyrimidine (0.04 mmol) was added and
the reaction mixture was heated at 60.degree. C. for 1 hour. The
reaction was cooled and quenched with the addition of saturated
NH.sub.4Cl. The reaction mixture was extracted with EtOAc, dried
and concentrated to give a residue that was purified by preparative
TLC (20% hexanes in EtOAc) to afford
1-{5-[2-(thieno[3,2-d]pyrimidin-4-yloxy)-1-triisopropylsilanyloxym-
ethyl-ethyl]-thiazol-2-yl}-3-(3-trifluoromethyl-phenyl)-urea
(compound 73.4).
[0716] Step 5: To a solution of compound 73.4 (70 mg) in ethanol
(4.0 mL) was added concentrated aqueous HCl (1.0 mL) and the
reaction was stirred at room temperature overnight. The reaction is
then diluted with water and methanol and directly purified by
reverse phase HPLC. The fractions containing the desired product
were pooled and lyophilized to afford the titled compound as a
colorless solid.
Example 74
[0717] This example describes the synthesis of
##STR00677##
[0718] Step 1: Ammonia gas is bubbled through a solution of
compound 73.1 (435 mg) in methanol (20.0 mL) for 10 minutes. The
reaction vessel is then sealed and heated at 80.degree. C. for 3
hours. The mixture is concentrated and the residue purified by
preparative TLC to give
3-hydroxy-2-{2-[3-(3-trifluoromethyl-phenyl)-ureido]-thiazol-5-yl}-propio-
namide (compound 74.1).
[0719] Step 2: To a solution of compound 74.1 (0.08 mmol) in THF
(1.0 mL) is added LAH (0.24 mL of 1.0 M solution in THF) and the
reaction mixture is heated at 50.degree. C. for 4 hours. The
reaction is quenched with the dropwise addition of saturated
NH.sub.4Cl, the volatiles are removed under reduced pressure and
then extracted with EtOAc. The combined organic layers are filtered
and concentrated to provide
1-[5-(2-amino-1-hydroxymethyl-ethyl)-thiazol-2-yl]-3-(3-trifluoromethyl-p-
henyl)-urea (compound 74.2) of sufficient purity for use in the
next step.
[0720] Step 3: A mixture of compound 74.2 (0.20 mmol),
4-chlorothieno[3,2-d]pyrimidine (0.20 mmol) and DIEA (1.0 mL) in
n-butanol (1.0 mL) are heated at 110.degree. C. for 2 hours. The
reaction mixture is concentrated to dryness to give a residue that
was purified by reverse phase HPLC. The product that is obtained
was dissolved in methanol, treated with solid Na.sub.2CO.sub.3,
filtered, concentrated and further purified by preparative TLC (10%
methanol in dichloromethane) to afford the titled compound.
Example 75
[0721] This example describes the synthesis of
##STR00678##
[0722] Step 1: A mixture of 4-nitrophenylethylamine (compound 75.1;
20 mmol), compound 6.2 (20 mmol) and DIEA (20 mmol) in DMF (100 mL)
was stirred at 100.degree. C. for 4 hours. The reaction mixture was
concentrated to dryness and diluted with 100 mL of water. The
resulting suspension was filtered and the solid collected was
washed with water and dried in vacuo to give the
nitro-intermediate. To the nitro-intermediate was added zinc powder
(100 mmol), saturated aqueous NH.sub.4Cl (20 mL) and MeOH (100 mL)
and the resulting mixture was stirred at 50.degree. C. for 8 hours.
The mixture was filtered through a short column of Celite.RTM.545
and washed with methanol. The filtrate was then concentrated and
diluted with 50 mL of 0.1 N HCl. The mixture was extracted with
EtOAc several times and the aqueous phase was adjusted to pH 10 by
the addition of 4N NaOH. Subsequently, the aqueous layer was back
extracted with EtOAc. The organic layers were combined, dried and
concentrated in vacuo to give
[2-(4-amino-phenyl)-ethyl]-thieno[3,2-d]pyrimidin-4-yl-amine
(compound 75.2) in 80% yield. .sup.1H NMR (CD.sub.3OD, 400 MHz):
.delta. 8.74 (s, 1H), 8.37 (d, J=5.4 Hz, 1H), 7.50 (d, J=5.4 Hz,
1H), 7.45 (d, J=8.3 Hz, 2H), 7.31 (d, J=7.8 Hz, 2H), 4.00 (t,
J=7.1, 2H), 3.11 (t, J=7.3 Hz, 2H) ppm; EIMS (m/z): 271.1
(M.sup.++H).
[0723] Step 2: A mixture of compound 1.2 (0.2 mmol) and
thiocarbonyldiimidazole (0.2 mmol) in dry THF (2.0 mL) was stirred
at room temperature for 30 minutes under an atmosphere of N.sub.2.
5-Trifluoromethyl-pyridine-2,3-diamine (0.2 mmol) was added and the
reaction stirred at room temperature until the reaction was deemed
complete. The reaction mixture was then treated with
N,N'-dicyclohexylcarbodiimide (0.2 mmol) and the resulting mixture
was stirred at 40-60.degree. C. for several hours. The solvent was
removed and the residue was purified by preparative HPLC to give
the titled compound. .sup.1H NMR (CD.sub.3OD, 400 MHz): .delta.
8.76 (s, 1H), 8.51 (s, 1H), 8.38 (s, 1H), 7.95 (s, 1H), 7.56 (d,
J=7.3 Hz, 2H), 7.48 (s, 1H), 7.38 (d, J=6.4 Hz, 2H), 4.03 (s, 2H),
3.09 (s, 2H) ppm; EIMS (m/z): 456.1 (M.sup.++H).
Example 76
[0724] This compound describes the synthesis of
##STR00679##
where A' is a 6-membered aryl or heteroaryl group and R.sup.Z1 and
m are as previously described. These compounds are made according
to Example 75 except that
##STR00680##
is used instead of 5-trifluoromethyl-pyridine-2,3-diamine in step
2. Illustrative examples of suitable R.sup.Z1 's are found
throughout this disclosure as well as in Table 13.
TABLE-US-00013 TABLE 13 ##STR00681## 3. Final Compound ##STR00682##
##STR00683## ##STR00684## ##STR00685## ##STR00686## ##STR00687##
##STR00688## ##STR00689## ##STR00690## ##STR00691## ##STR00692##
##STR00693## ##STR00694## ##STR00695## ##STR00696## ##STR00697##
##STR00698## ##STR00699## ##STR00700## ##STR00701## ##STR00702##
##STR00703## ##STR00704## ##STR00705## ##STR00706## ##STR00707##
##STR00708## ##STR00709##
Example 77
[0725] This example describes the synthesis of
##STR00710##
[0726] A mixture of compound 75.2 (0.2 mmol), 2-chlorobenzoxazole
(0.2 mmol), DIEA (0.4 mmol) and DMAP (0.02 mmol) in DMSO (2 mL) was
stirred at 110.degree. C. for several hours. The solvent was
removed and the residue was purified by preparative HPLC to give
the titled compound. .sup.1H NMR (CD.sub.3OD, 400 MHz): .delta.
8.74 (s, 1H), 8.38 (d, J=5.4 Hz, 1H), 7.58 (d, J=8.3 Hz, 2H), 7.48
(d, J=5.4 Hz, 1H), 7.39 (t, J=8.1 Hz, 2H), 7.28 (d, J=8.3 Hz, 2H),
7.23 (t, J=7.6 Hz, 1H), 7.14 (t, J=7.6 Hz, 1H), 4.03 (t, J=7.1 Hz,
2H), 3.05 (t, J=7.1 Hz, 2H) ppm; EIMS (m/z): 388.1 (M.sup.++H).
Example 78
[0727] This example describes the synthesis of
##STR00711##
[0728] This compound is prepared according to step 2 of Example 75
except that compound 14.3 is used instead of compound 75.2. .sup.1H
NMR (CD.sub.3OD, 400 MHz): .delta. 8.79 (s, 1H), 8.46 (s, 1H), 8.41
(d, J=5.9 Hz, 1H), 7.98 (s, 1H), 7.50 (d, J=5.4 Hz, 2H), 7.17 (s,
1H), 4.07 (t, J=6.8 Hz, 2H), 3.21 (t, J=6.6 Hz, 2H) ppm; EIMS
(m/z): 463.1 (M+H).
Example 79
[0729] This example describes the synthesis of
##STR00712##
[0730] Step 1: A solution of compound 1.1 (2.0 mmol) and
thiocarbonyldiimidazole (2.0 mmol) in dry THF (10.0 mL) was stirred
at room temperature for 30 minutes and then saturated with NH.sub.3
(gas). The resulting mixture was stirred at room temperature for 10
minutes and concentrated to give a residue that was purified by
preparative chromatography to give
[2-(4-thioureido-phenyl)-ethyl]-carbamic acid tert-butyl ester
(compound 79.2) in 95% yield. .sup.1H NMR (CD.sub.3OD, 400 MHz):
.delta. 7.25 (m, 4H), 3.26 (t, J=7.1 Hz, 2H), 2.76 (t, J=7.1 Hz,
2H), 1.43 (s, 9H) ppm; EIMS (m/z): 296.1 (M.sup.++H).
[0731] Step 2: A solution of compound 79.2 (1.5 mmol) and methyl
iodide (6.0 mmol) in acetone (15.0 mL) was stirred at 40.degree. C.
overnight. The solvent was removed and the residue was dried in
vacuo to give
{2-[4-(2-methyl-isothioureido)-phenyl]-ethyl}-carbamic acid
tert-butyl ester (compound 79.3) in quantitative yield. .sup.1H NMR
(CD.sub.3OD, 400 MHz): .delta. 7.40 (d, J=7.8 Hz, 2H), 7.28 (d,
J=8.3 Hz, 2H), 3.30 (t, J=7.1 Hz, 2H), 2.82 (t, J=7.1 Hz, 2H), 2.73
(s, 3H) ppm; EIMS (m/z): 310.1 (M.sup.++H).
[0732] Step 3: A mixture of compound 79.3 (1.5 mmol), isatoic
anhydride (1.5 mmol), and Na.sub.2CO.sub.3 (3.0 mmol) in dioxane
(15 mL) was stirred at 100.degree. C. for 8 hours. The solvent was
removed and the residue was diluted with 20 mL of water.
Subsequently, the suspension was filtered and the white solid was
washed sequentially with water and ether, and then dried in vacuo
to give
{2-[4-(4-oxo-1,4-dihydro-quinazolin-2-ylamino)-phenyl]-ethyl}-carbamic
acid tert-butyl ester (compound 79.4) in 52% yield. .sup.1H NMR
(d.sup.6-DMSO, 400 MHz): .delta. 10.77 (s, 1H), 8.60 (s, 1H), 7.92
(d, J=7.3 Hz, 1H), 7.59 (m, 3H), 7.35 (d, J=8.3 Hz, 1H), 7.12-7.20
(m, 3H), 6.86 (s, 1H), 3.09 (t, J=7.1 Hz, 2H), 2.62 (t, J=7.1 Hz,
2H), 1.34 (s, 9H) ppm; EIMS (m/z): 381.2 (M.sup.++H).
[0733] Step 4: A mixture of compound 79.4 (0.5 mmol) in anhydrous
HCl in dioxane (5.0 mL of a 4.0 N solution in dioxane) was stirred
at 60.degree. C. for 1 hour. The solvent was removed and the
residue dried in vacuo to give the amine intermediate. A mixture of
this intermediate (0.2 mmol), compound 6.2 (0.2 mmol) and DIEA (1.0
mmol) was stirred at 100.degree. C. for several hours. The solvent
was removed and the residue was purified by preparative HPLC to
give the titled compound. .sup.1H NMR (CD.sub.3OD, 400 MHz):
.delta. 8.75 (s, 1H), 8.39 (d, J=4.9 Hz, 1H), 8.12 (d, J=8.3 Hz,
1H), 7.75 (t, J=7.8 Hz, 1H), 7.45-7.52 (m, 4H), 7.37-7.41 (m, 3H),
4.05 (t, J=7.1 Hz, 2H), 3.11 (t, J=7.1 Hz, 2H) ppm; EIMS (m/z):
415.1 (M.sup.++H).
Example 80
[0734] This example describes the synthesis of
##STR00713##
[0735] Step 1:
[0736] A mixture of 1.0 mmol of
3-(4-amino-phenyl)-piperidine-1-carboxylic acid tert-butyl ester
and 1.0 mmol of thiocarbonyldiimidazole in 10 mL of dry THF was
stirred at room temperature for 30 minutes under an atmosphere of
N.sub.2. After stirring with 1.0 mmol of diaminobenzene at room
temperature for 30 minutes under an atmosphere of N.sub.2, the
reaction mixture was treated with 1.0 mmol of DCC and the resulting
mixture was stirred at 60.degree. C. for several hours. The solvent
was removed and the residue was purified by preparative TLC to give
3-(4-amino-phenyl)-piperidine-1-carboxylic acid tert-butyl ester
(compound 80.1) in 55% yield. EIMS (m/z): 393.2 (M.sup.++H).
[0737] Step 2:
[0738] A mixture of 0.5 mmol of compound 80.1 in 10 mL of 4.0N HCl
in dioxane was stirred at 60.degree. C. for 1 h. The solvent was
removed and the residue was dried in vacuo to give the free amine,
(1H-benzoimidazol-2-yl)-(4-piperidin-3-yl-phenyl)-amine (compound
80.2) in quantitative yield. EIMS (m/z): 293.1 (M+H).
[0739] Step 3:
[0740] A mixture of 0.2 mmol of compound 6.2, 0.2 mmol of compound
80.2, and 1 mmol of DIEA was stirred at 100.degree. C. for several
hours. The solvent was removed and the residue was purified by
preparative HPLC to give the titled compound. .sup.1H NMR
(CD.sub.3OD, 400 MHz): .delta. 8.72 (s, 1H), 8.46 (d, J=5.4 Hz,
1H), 7.57 (m, 3H), 7.49 (d, J=8.3 Hz, 2H), 7.43 (m, 2H), 7.34 (m,
2H), 5.16 (d, J=11.3 Hz, 2H), 3.58 (m, 2H), 3.10 (t, J=10.0 Hz,
1H), 2.04-2.17 (m, 3H), 1.92 (m, 1H) ppm; EIMS (m/z): 427.2
(M.sup.++H).
[0741] Formulation of Compounds
[0742] The solubility of poorly soluble compounds are improved by
making them as acid salts. Illustrative examples of such acids
include methane sulfonic acid and citric acid. Solubility of these
compounds can be additionally improved by the addition of
solubility enhancing agents such as Tween-80 and PEG-400.
Illustrative formulations of poorly soluble compounds of the
present invention include 10%/30%/60%, 5%/30%/65%, and
2.5%/30%/67.5% respectively of Tween-80, PEG-400 and water. The pH
of these formulations can also be varied to identify a range for
optimal solubility.
[0743] Target Modulation Studies.
[0744] Nu/nu mice were subcutaneously injected into their hind
flank with human HCT-116 cells and 50% Matrigel (Becton-Dickinson).
Human HCT-116 tumors were then allowed to grow to 400 mm.sup.3. The
tumor bearing mice were then either given an administration of SPD
or vehicle (Sigma-Aldrich) (orally, intravenously or
intraperitoneally). At prescribed time points post dose, mice were
anesthetized and blood taken via terminal cardiac puncture, and
sacrificed. The HCT-116 tumors were excised from the mice,
pulverized using liquid nitrogen-cooled mortar and pestle, and
flash-frozen in liquid nitrogen. Tumor lysates were made from the
pulverized samples by addition of lysis buffer.
[0745] For detection of response markers by Western blotting, the
protein concentration of the lysates was determined by colorimetric
detection. Twenty-five micrograms of protein was loaded per lane on
an SDS-PAGE gel. Proteins were separated by gel electrophoresis,
blotted onto nitrocellulose membranes, and probed using
anti-Histone H3 and anti-phosphorylated Histone H3 antibodies,
(both from Cell Signaling Technology)
[0746] Maximum Tolerated Dose Studies.
[0747] Maximum Tolerated Dose (MTD) is defined as the dose at which
the mouse is no longer able to function normally and is determined
by either significant toxicity (eg. body weight loss) or mortality.
Mice (nu/nu) were sorted according to weight and randomized into
groups prior to being dosed with a test compound, by oral,
intravenous or intraperitoneal routes. Escalating doses of a test
compound were used. Animal weights were measured daily for 5 days
and about every 3 days after that until the animal was removed from
the study due to body weight loss of >20% or any alterations in
physiological function that would affect normal function. Clinical
observations were performed throughout the study to note any
toxicity and mice were monitored until the end of the study.
[0748] Efficacy Studies.
[0749] Nu/nu mice were subcuntaneously injected into their hind
flank with human HCT-116 cells and 50% Matrigel (Becton-Dickinson).
Human HCT-116 tumors were allowed to grow to 150-200 mm.sup.3. The
tumor bearing mice were then either given an administration of a
test compound or a vehicle control. The tumor dimensions (length [1
mm] and width [w mm]) were measured by electronic calipers and the
tumor volume (mm.sup.3) determined from the equation
([w.sup.2.times.1]/2). Weights of the mice and their respective
tumor volumes were measured twice weekly until the animal was
removed from the study, either because there was a body weight loss
of greater than 20% or a tumor volume greater than 2000 mm.sup.3.
Clinical observations were performed throughout the study, which
usually lasted for up to 70 days after the initial implantation of
the tumor cells. Tumor volume increases were compared to negative
(vehicle) and positive controls. Percentage tumor growth inhibition
(TGI) was calculated from the equation [(tumor volume
T.gamma.-tumor volume)/tumor volume C].times.100, where T=treatment
group and C=control or vehicle group. The tumor volume for both
groups was usually determined at defined times after the
administration of the last dose of compound. Survival plots
(Kaplan-Maier) were also performed to examine the pattern of
survival.
[0750] While we have described a number of embodiments of this
invention, it is apparent that our basic examples may be altered to
provide other embodiments that utilize the compounds and methods of
this invention. Therefore, it will be appreciated that the scope of
this invention is to be defined by the appended claims rather than
by the specific embodiments that have been represented by way of
example.
* * * * *