U.S. patent application number 13/311949 was filed with the patent office on 2012-03-29 for organic compounds.
This patent application is currently assigned to NOVARTIS AG. Invention is credited to Daniel Kaspar Baeschlin, Francois GESSIER, Kenji NAMOTO, Nils OSTERMANN, Finton SIROCKIN.
Application Number | 20120077787 13/311949 |
Document ID | / |
Family ID | 38235160 |
Filed Date | 2012-03-29 |
United States Patent
Application |
20120077787 |
Kind Code |
A1 |
Baeschlin; Daniel Kaspar ;
et al. |
March 29, 2012 |
ORGANIC COMPOUNDS
Abstract
New compounds of the Formula (I): ##STR00001## for the treatment
of non-insulin-dependent diabetes mellitus.
Inventors: |
Baeschlin; Daniel Kaspar;
(Arlesheim, CH) ; OSTERMANN; Nils; (Binzen,
DE) ; GESSIER; Francois; (Altkirch, FR) ;
SIROCKIN; Finton; (Blotzheim, FR) ; NAMOTO;
Kenji; (Basel, CH) |
Assignee: |
NOVARTIS AG
Basel
CH
|
Family ID: |
38235160 |
Appl. No.: |
13/311949 |
Filed: |
December 6, 2011 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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12295549 |
Sep 30, 2008 |
8097617 |
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PCT/EP2007/053064 |
Mar 29, 2007 |
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13311949 |
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60788294 |
Mar 31, 2006 |
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Current U.S.
Class: |
514/171 ;
514/228.2; 514/233.2; 514/248; 514/249; 514/252.11; 514/253.04;
514/278; 514/300; 514/303; 544/121; 544/127; 544/236; 544/295;
544/350; 544/357; 544/362; 544/58.2; 544/58.4; 544/61; 546/119;
546/121; 546/19 |
Current CPC
Class: |
A61P 9/04 20180101; A61P
27/02 20180101; A61P 19/02 20180101; A61P 35/00 20180101; A61P
43/00 20180101; A61P 1/04 20180101; A61P 5/28 20180101; A61P 9/14
20180101; A61P 25/16 20180101; A61P 25/20 20180101; A61P 13/08
20180101; A61P 1/02 20180101; A61P 3/04 20180101; A61P 25/22
20180101; A61P 19/10 20180101; A61P 25/00 20180101; A61P 31/00
20180101; A61P 3/00 20180101; A61P 9/10 20180101; A61P 3/10
20180101; A61P 37/06 20180101; A61P 13/12 20180101; C07D 471/04
20130101; C07D 519/00 20130101; A61P 1/18 20180101; A61P 9/12
20180101; A61P 3/06 20180101; A61P 5/50 20180101; A61P 5/02
20180101; A61P 5/24 20180101; A61P 9/00 20180101; A61P 35/04
20180101; A61P 25/28 20180101; A61P 1/00 20180101 |
Class at
Publication: |
514/171 ;
546/121; 514/300; 544/127; 514/233.2; 544/61; 514/228.2; 544/362;
514/253.04; 544/350; 514/249; 544/236; 514/248; 544/295; 544/357;
546/19; 514/278; 544/121; 546/119; 514/303; 544/58.4; 514/252.11;
544/58.2 |
International
Class: |
A61K 31/437 20060101
A61K031/437; A61K 31/5377 20060101 A61K031/5377; A61K 31/541
20060101 A61K031/541; A61K 31/496 20060101 A61K031/496; C07D 519/00
20060101 C07D519/00; A61K 31/4985 20060101 A61K031/4985; A61K
31/5025 20060101 A61K031/5025; A61K 31/506 20060101 A61K031/506;
A61K 31/438 20060101 A61K031/438; A61P 3/10 20060101 A61P003/10;
A61P 3/04 20060101 A61P003/04; A61P 9/12 20060101 A61P009/12; A61P
31/00 20060101 A61P031/00; A61P 19/02 20060101 A61P019/02; A61P
9/00 20060101 A61P009/00; A61P 25/16 20060101 A61P025/16; A61P
19/10 20060101 A61P019/10; A61P 1/00 20060101 A61P001/00; A61P
27/02 20060101 A61P027/02; A61P 25/28 20060101 A61P025/28; A61P
5/50 20060101 A61P005/50; A61P 3/00 20060101 A61P003/00; A61P 3/06
20060101 A61P003/06; A61P 1/18 20060101 A61P001/18; A61P 9/10
20060101 A61P009/10; A61P 13/12 20060101 A61P013/12; A61P 25/00
20060101 A61P025/00; A61P 5/24 20060101 A61P005/24; A61P 13/08
20060101 A61P013/08; A61K 31/444 20060101 A61K031/444; A61K 31/4545
20060101 A61K031/4545; A61K 31/56 20060101 A61K031/56; A61K 31/568
20060101 A61K031/568; C07D 471/04 20060101 C07D471/04 |
Claims
1. A compound of Formula (I): ##STR00332## wherein X is .dbd.N--; Y
is .dbd.N--; R.sup.1 and R.sup.2 are each independently selected
from R.sup.10, --OR.sup.10, --C(O)R.sup.10, --C(O)OR.sup.10 and
--S(O).sub.lR.sup.10; R.sup.3 and R.sup.4 are each independently
hydrogen or R.sup.13; or R.sup.3 and R.sup.4 taken together with
the carbon atom to which they are attached form carbocyclyl or
heterocyclyl, either of which is optionally substituted with 1, 2,
3, 4 or 5 R.sup.13; R.sup.5 is aryl or heteroaryl, either of which
is optionally substituted with 1, 2, 3, 4 or 5 R.sup.13; R.sup.6 is
selected from halogen, trifluoromethyl, cyano, nitro, R.sup.10,
--C(O)R.sup.10, --C(O)R.sup.10, --OC(O)R.sup.10,
--S(O).sub.lR.sup.11, --N(R.sup.11)(R.sup.12) and
--C(O)N(R.sup.11)(R.sup.12); R.sup.7, R.sup.8 and R.sup.9 are each
independently selected from hydrogen, halogen and moieties
comprising from 1 to 30 plural valent atoms selected from C, N, O
and S; for example R.sup.7, R.sup.8 and R.sup.9 are each
independently selected from halogen, trifluoromethyl, cyano, nitro,
R.sup.10, --OR.sup.10, --C(O)R.sup.10, --C(O)OR.sup.10,
--OC(O)R.sup.10, --S(O).sub.lR.sup.11, --N(R.sup.11)(R.sup.12) and
--C(O)N(R.sup.11)(R.sup.12); R.sup.10 is hydrogen, hydrocarbyl
optionally substituted with 1, 2, 3, 4 or 5 R.sup.13; or
--(CH.sub.2).sub.k-heterocyclyl optionally substituted with 1, 2,
3, 4 or 5 R.sup.13; R.sup.11 and R.sup.12 are each independently
selected from R.sup.10, --OR.sup.10, --C(O)R.sup.10,
--C(O)OR.sup.10, --(CH.sub.2).sub.k--R.sup.10,
--C(O)--(CH.sub.2).sub.k--R.sup.10 and --S(O).sub.lR.sup.10; or
R.sup.11 and R.sup.12 taken together with a nitrogen atom to which
they are attached form heterocyclyl optionally substituted with 1,
2, 3, 4 or 5 R.sup.13; each R.sup.13 is independently selected from
halogen, trifluoromethyl, cyano, nitro, oxo, .dbd.NR.sup.14,
--OR.sup.14, --C(O)R.sup.14, --C(O)OR.sup.14, --OC(O)R.sup.14,
--S(O).sub.lR.sup.14, --N(R.sup.14)R.sup.15,
--C(O)N(R.sup.14)R.sup.15 and R.sup.16; R.sup.14 and R.sup.16 are
each independently hydrogen or R.sup.16; R.sup.16 is selected from
a spiro group, hydrocarbyl, --(CH.sub.2).sub.k-hydrocarbyl,
--(CH.sub.2).sub.k-heterocyclyl and
--(CH.sub.2).sub.k--C(O)-heterocyclyl, either of which is
optionally substituted with 1, 2, 3, 4 or 5 substituents
independently selected from halogen, cyano, oxo, amino, hydroxy,
--C(O)--C.sub.1-6 alkyl, C.sub.1-6 alkyl and C.sub.1-6 alkoxy; j is
0, 1 or 2; k is 0, 1, 2, 3, 4, 5 or 6; and l is 0, 1, or 2; or a
pharmaceutically acceptable salt or prodrug thereof.
2. The compound according to claim 1, wherein; R.sup.11 and
R.sup.12 are each independently selected from R.sup.10,
--OR.sup.10, --C(O)R.sup.10, --C(O)OR.sup.10 and
--S(O).sub.lR.sup.10; or R.sup.11 and R.sup.12 taken together with
a nitrogen atom to which they are attached form heterocyclyl
optionally substituted with 1, 2, 3, 4 or 5 R.sup.13; and R.sup.16
is selected from hydrocarbyl and --(CH.sub.2).sub.k-heterocyclyl,
either of which is optionally substituted with 1, 2, 3, 4 or 5
substituents independently selected from halogen, cyano, amino,
hydroxy, C.sub.1-6 alkyl and C.sub.1-6 alkoxy; or a
pharmaceutically acceptable salt or prodrug thereof.
3. The compound according to claim 1, which is of the Formula (II):
##STR00333## or a pharmaceutically acceptable salt or prodrug
thereof.
4. The compound according to claim 3, wherein R.sup.8 is
hydrogen.
5. The compound according to claim 1, which is of the Formula
(III): ##STR00334## or a pharmaceutically acceptable salt or
prodrug thereof.
6. The compound according to claim 1, wherein R.sup.1 and R.sup.2
are each independently selected from hydrogen, C.sub.1-6 alkyl
optionally substituted with 1, 2, 3, 4 or 5 R.sup.13, and
--(CH.sub.2).sub.k-carbocyclyl optionally substituted with 1, 2, 3,
4 or 5 R.sup.13.
7. The compound according to claim 6, wherein R.sup.1 and R.sup.2
are each hydrogen.
8. The compound according to claim 1, wherein R.sup.3 and R.sup.4
are each independently selected from hydrogen, C.sub.1-6 alkyl
optionally substituted with 1, 2, 3, 4 or 5 R.sup.13, and
--(CH.sub.2).sub.k-carbocyclyl optionally substituted with 1, 2, 3,
4 or 5 R.sup.13.
9. The compound according to claim 8, wherein R.sup.3 and R.sup.4
are each hydrogen.
10. The compound according to claim 1, wherein R.sup.1, R.sup.2,
R.sup.3 and R.sup.4 are each hydrogen.
11. The compound according to claim 1, wherein R.sup.5 is aryl
optionally substituted with 1, 2, 3, 4 or 5 R.sup.13.
12. The compound according to claim 11, wherein R.sup.5 is phenyl
optionally substituted with 1, 2, 3, 4 or 5 R.sup.13.
13. The compound according to claim 12, wherein R.sup.5 is phenyl
optionally substituted with 1, 2 or 3 substituents independently
selected from halogen, cyano, amino, hydroxy, C.sub.1-6 alkyl and
C.sub.1-6 alkoxy.
14. The compound according to claim 13, wherein R.sup.5 is phenyl
comprising substituents at the 2- and 4-positions, wherein the
substituents are independently selected from halogen, methyl and
methoxy.
15. The compound according to claim 14, wherein R.sup.5 is
2,4-dichlorophenyl.
16-63. (canceled)
64. The compound according to claim 1, selected from: 12 13 14
##STR00335## ##STR00336## ##STR00337## ##STR00338## ##STR00339##
or, in each case, a pharmaceutically acceptable salt, free form or
prodrug thereof.
65-66. (canceled)
67. A pharmaceutical formulation, comprising; a compound of claim
1, and a pharmaceutically acceptable excipient or carrier.
68. (canceled)
69. A formulation according to claim 67, which further comprises a
therapeutic agent selected from anti-diabetic agents, hypolipidemic
agents, anti-obesity or appetite-regulating agents,
anti-hypertensive agents, HDL-increasing agents, cholesterol
absorption modulators, Apo-A1 analogues and mimetics, thrombin
inhibitors, aldosterone inhibitors, inhibitors of platelet
aggregation, estrogen, testosterone, selective estrogen receptor
modulators, selective androgen receptor modulators,
chemotherapeutic agents, and 5-HT.sub.3 or 5-HT.sub.4 receptor
modulators; or pharmaceutically acceptable salts or prodrugs
thereof.
70-74. (canceled)
75. A method of treating or preventing a disease or condition
selected from non-insulin-dependent diabetes mellitus, arthritis,
obesity, allograft transplantation, calcitonin-osteoporosis, heart
failure, impaired glucose metabolism or impaired glucose tolerance,
neurodegenerative diseases, cardiovascular or renal diseases, and
neurodegenerative or cognitive disorders (such as Alzheimer's
disease, Parkinson's disease, Crohn's disease or ulcerative
colitis), hyperglycemia, insulin resistance, lipid disorders,
dyslipidemia, hyperlipidennia, hypertriglyceridemia,
hypercholesterolemia, low HDL levels, high LDL levels,
atherosclerosis, vascular restenosis, irritable bowel syndrome,
inflammatory bowel disease, pancreatitis, retinopathy, nephropathy,
neuropathy, syndrome X, ovarian hyperandrogenism (polycystic
ovarian syndrome), type 2 diabetes, growth hormone deficiency,
neutropenia, neuronal disorders, tumor metastasis, benign prostatic
hypertrophy, gingivitis, diabetic cardiomyopathy, left or right
ventricular hypertrophy, hypertrophic medial thickening in arteries
and/or in large vessels, mesenteric vasculature hypertrophy,
mesanglial hypertrophy, hypertension and osteoporosis, for
producing a sedative or anxiolytic effect, attenuating
post-surgical catabolic changes or hormonal responses to stress,
reducing mortality and morbidity after myocardial infarction,
modulating hyperlipidemia or associated conditions, or lowering
VLDL, LDL or Lp(a) levels in a patient, comprising: administering a
therapeutically effective amount of the compound of claim 1.
76. (canceled)
Description
FIELD OF THE INVENTION
[0001] The present invention relates to compounds and their use in
therapy.
BACKGROUND TO THE INVENTION
[0002] Dipeptidylpeptidase-IV (DPP-IV) is a serine protease which
cleaves N-terminal dipeptides from a peptide chain containing, in
general, a proline residue in the penultimate position. DPP-IV is
widely expressed in mammalian tissue as a type II integral membrane
protein. The protease is expressed on the surface of differentiated
epithelial cells of the intestine, liver, kidney proximal tubules,
prostate, corpus luteum, and on leukocyte subsets such as
lymphocytes and macrophages. A soluble form of the enzyme is found
in serum that has structure and function identical to the
membrane-bound form of the enzyme but lacks the hydrophobic
transmembrane domain.
[0003] DPP-IV has many physiologically relevant substrates
including chemokines (e.g. eotaxin and macrophage-derived
chemokine), neuropeptides (e.g. neuropeptide Y and substance P),
vasoactive peptides, and incretins (e.g. GLP-1 and GIP). GLP-1
(glucagon-like peptide-1) is a hormone produced in the L cells of
the distal small intestine in response to ingested nutrients. GLP-1
receptor binding on various tissues stimulates insulin gene
expression, biosynthesis and glucose-dependent insulin secretion,
inhibits glucagon secretion, promotes satiety, slows gastric
emptying and promotes growth of pancreatic beta cells.
[0004] Although the biological role of DPP-IV in mammalian systems
has not been completely established, it is believed to play an
important role in neuropeptide metabolism, T-cell activation,
attachment of cancer cells to the endothelium and the entry of HIV
into lymphoid cells. It has also been discovered that DPP-IV is
responsible for inactivating glucagon-like peptide-1 (GLP-1). Since
GLP-1 is a major stimulator of pancreatic insulin secretion and has
direct beneficial effects on glucose disposal, DPP-IV inhibition
appears to represent an attractive approach for treating, for
example, non-insulin-dependent diabetes mellitus (NIDDM).
[0005] DPP-IV has also been shown to play a part in the immune
response. Expressed by T-CD4+ lymphocytes, where it is synonymous
with the antigen CD26, DPP-IV plays an important part in the
mechanism of transplant rejection (Transplantation 1997, 63 (10),
1495-500). By allowing more selective suppression of the immune
response, inhibition of DPP-IV accordingly represents an extremely
promising approach in the prevention of transplant rejection in
transplant patients.
[0006] Inhibitors of DPP-IV are described inter alia in
WO-A-2003/068748, WO-A-2003/068757, US-A-2006/0014764 and
US-A-2005/0272765.
SUMMARY OF THE INVENTION
[0007] A first aspect of the invention is a compound of the Formula
(I):
##STR00002##
wherein [0008] X is .dbd.N-- or .dbd.C(R.sup.8)--; [0009] Y is
.dbd.N-- or .dbd.C(R.sup.9)--; [0010] R.sup.1 and R.sup.2 are each
independently selected from R.sup.10, --OR.sup.10, --C(O)R.sup.10,
--C(O)OR.sup.10 and --S(O).sub.lR.sup.10; [0011] R.sup.3 and
R.sup.4 are each independently hydrogen or R.sup.13; or R.sup.3 and
R.sup.4 taken together with the carbon atom to which they are
attached form carbocyclyl or heterocyclyl, either of which is
optionally substituted with 1, 2, 3, 4 or 5 R.sup.13; [0012]
R.sup.5 is aryl or heteroaryl, either of which is optionally
substituted with 1, 2, 3, 4 or 5 R.sup.13; [0013] R.sup.6 is
selected from halogen, trifluoromethyl, cyano, nitro, oxo,
R.sup.10, --OR.sup.10, --C(O)R.sup.10, --C(O)OR.sup.10,
--OC(O)R.sup.10, --S(O).sub.lR.sup.11, --N(R.sup.11)(R.sup.12) and
--C(O)N(R.sup.11)(R.sup.12), [0014] R.sup.7, R.sup.8 and R.sup.9
are each independently selected from hydrogen, halogen and moieties
comprising from 1 to 30 plural valent atoms selected from C, N, O
and S; for example R.sup.7, R.sup.8 and R.sup.9 are each
independently selected from halogen, trifluoromethyl, cyano, nitro,
R.sup.10, --OR.sup.10, --C(O)R.sup.10, --C(O)OR.sup.10,
--OC(O)R.sup.10, --S(O).sub.lR.sup.11, --N(R.sup.11)(R.sup.12) and
--C(O)N(R.sup.11)(R.sup.12); [0015] R.sup.10 is hydrogen,
hydrocarbyl optionally substituted with 1, 2, 3, 4 or 5 R.sup.13;
or --(CH.sub.2).sub.k-heterocyclyl optionally substituted with 1,
2, 3, 4 or 5 R.sup.13; [0016] R.sup.11 and R.sup.12 are each
independently selected from R.sup.10, --OR.sup.10, --C(O)R.sup.10,
--C(O)OR.sup.10 and --S(O).sub.lR.sup.10; or R.sup.11 and R.sup.12
taken together with a nitrogen atom to which they are attached form
heterocyclyl optionally substituted with 1, 2, 3, 4 or 5 R.sup.13;
or [0017] R.sup.11 and R.sup.12 are each independently selected
from R.sup.10, --OR.sup.10, --C(O)R.sup.10, --C(O)OR.sup.10,
--(CH.sub.2).sub.k--R.sup.10, --C(O)--(CH.sub.2).sub.k--R.sup.10
and --S(O).sub.lR.sup.10; or R.sup.11 and R.sup.12 taken together
with a nitrogen atom to which they are attached form heterocyclyl
optionally substituted with 1, 2, 3, 4 or 5 R.sup.13; [0018] each
R.sup.13 is independently selected from halogen, trifluoromethyl,
cyano, nitro, oxo, .dbd.NR.sup.14, --OR.sup.14, --C(O)R.sup.14,
--C(O)OR.sup.14, --OC(O)R.sup.14, --S(O).sub.lR.sup.14,
--N(R.sup.14)R.sup.15, --C(O)N(R.sup.14)R.sup.15 and R.sup.16;
[0019] R.sup.14 and R.sup.15 are each independently hydrogen or
R.sup.16; [0020] R.sup.16 is selected from hydrocarbyl and
--(CH.sub.2).sub.k-heterocyclyl, either of which is optionally
substituted with 1, 2, 3, 4 or 5 substituents independently
selected from halogen, cyano, amino, hydroxy, C.sub.1-6 alkyl and
C.sub.1-6 alkoxy; or [0021] R.sup.16 is selected from a spiro
group, hydrocarbyl, --(CH.sub.2).sub.k-hydrocarbyl,
--(CH.sub.2).sub.k-heterocyclyl and
--(CH.sub.2).sub.k--C(O)-heterocyclyl, either of which is
optionally substituted with 1, 2, 3, 4 or 5 substituents
independently selected from halogen, cyano, oxo, amino, hydroxy,
--C(O)--C.sub.1-6 alkyl, Cl.sub.1-6 alkyl and C.sub.1-6 alkoxy.
[0022] j is 0, 1 or 2; [0023] k is 0, 1, 2, 3, 4, 5 or 6; and
[0024] l is 0, 1, or 2; [0025] or a pharmaceutically acceptable
salt or prodrug thereof.
[0026] A second aspect of the invention is a compound of the
invention for therapeutic use.
[0027] Another aspect of the invention is a pharmaceutical
formulation comprising a compound of the invention and, optionally,
a pharmaceutically acceptable diluent or carrier.
[0028] A further aspect of the invention is a product comprising a
compound of the invention and a therapeutic agent; as a combined
preparation for simultaneous, separate or sequential use in
therapy.
[0029] Another aspect of the invention is the use of a compound of
the invention for the manufacture of a medicament for the treatment
or prevention of a disease or condition selected from
non-insulin-dependent diabetes mellitus, arthritis, obesity,
allograft transplantation, calcitonin-osteoporosis, heart failure,
impaired glucose metabolism or impaired glucose tolerance,
neurodegenerative diseases, cardiovascular or renal diseases, and
neurodegenerative or cognitive disorders.
[0030] Another aspect of the invention is the use of a compound of
the invention for the manufacture of a medicament for producing a
sedative or anxiolytic effect, attenuating post-surgical catabolic
changes or hormonal responses to stress, reducing mortality and
morbidity after myocardial infarction, modulating hyperlipidemia or
associated conditions, or lowering VLDL, LDL or Lp(a) levels.
[0031] Another aspect of the invention is a method of treating or
preventing a disease or condition in a patient, which comprises
administering a therapeutically effective amount of a compound of
the invention.
[0032] The compounds of the invention can exist in different forms,
such as free acids, free bases, esters and other prodrugs, salts
and tautomers, for example, and the disclosure includes all variant
forms of the compounds.
[0033] The extent of protection includes counterfeit or fraudulent
products which contain or purport to contain a compound of the
invention irrespective of whether they do in fact contain such a
compound and irrespective of whether any such compound is contained
in a therapeutically effective amount.
[0034] Included in the scope of protection are packages which
include a description or instructions which indicate that the
package contains a species or pharmaceutical formulation of the
invention and a product which is or comprises, or purports to be or
comprise, such a formulation or species. Such packages may be, but
are not necessarily, counterfeit or fraudulent.
[0035] Features, integers, characteristics, compounds, chemical
moieties or groups described in conjunction with a particular
aspect, embodiment or example of the invention are to be understood
to be applicable to any other aspect, embodiment or example
described herein unless incompatible therewith.
DESCRIPTION OF VARIOUS EMBODIMENTS
Hydrocarbyl
[0036] The term "hydrocarbyl" as used herein includes reference to
a moiety consisting exclusively of hydrogen and carbon atoms; such
a moiety may comprise an aliphatic and/or an aromatic moiety. The
moiety may comprise 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14,
15, 16, 17, 18, 19 or 20 carbon atoms. Examples of hydrocarbyl
groups include alkyl such as C.sub.1-6 alkyl (e.g. C.sub.1,
C.sub.2, C.sub.3 or C.sub.4 alkyl, for example methyl, ethyl,
propyl, isopropyl, n-butyl, sec-butyl or tert-butyl); C.sub.1-6
alkyl substituted by aryl (e.g. benzyl) or by cycloalkyl (e.g
cyclopropylmethyl); cycloalkyl (e.g. cyclopropyl, cyclobutyl,
cyclopentyl or cyclohexyl); aryl (e.g. phenyl, naphthyl or
fluorenyl) and the like.
Alkyl
[0037] The terms "alkyl" and "C.sub.1-6 alkyl" as used herein
include reference to a straight or branched chain alkyl moiety
having 1, 2, 3, 4, 5 or 6 carbon atoms. This term includes
reference to groups such as methyl, ethyl, propyl (n-propyl or
isopropyl), butyl (n-butyl, sec-butyl or tert-butyl), pentyl, hexyl
and the like. In particular, alkyl may have 1, 2, 3 or 4 carbon
atoms.
Alkenyl
[0038] The terms "alkenyl" and "C.sub.2-6 alkenyl" as used herein
include reference to a straight or branched chain alkyl moiety
having 2, 3, 4, 5 or 6 carbon atoms and having, in addition, at
least one double bond, of either E or Z stereochemistry where
applicable. This term includes reference to groups such as ethenyl,
2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl,
2-pentenyl, 3-pentenyl, 1-hexenyl, 2-hexenyl and 3-hexenyl and the
like.
Alkynyl
[0039] The terms "alkynyl" and "C.sub.2-6 alkynyl" as used herein
include reference to a straight or branched chain alkyl moiety
having 2, 3, 4, 5 or 6 carbon atoms and having, in addition, at
least one triple bond. This term includes reference to groups such
as ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl,
3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 1-hexynyl, 2-hexynyl
and 3-hexynyl and the like.
Alkoxy
[0040] The terms "alkoxy" and "C.sub.1-6 alkoxy" as used herein
include reference to --O-alkyl, wherein alkyl is straight or
branched chain and comprises 1, 2, 3, 4, 5 or 6 carbon atoms. In
one class of embodiments, alkoxy has 1, 2, 3 or 4 carbon atoms.
This term includes reference to groups such as methoxy, ethoxy,
propoxy, isopropoxy, butoxy, tert-butoxy, pentoxy, hexoxy and the
like.
Cycloalkyl
[0041] The term "cycloalkyl" as used herein includes reference to
an alicyclic moiety having 3, 4, 5, 6, 7 or 8 carbon atoms. The
group may be a bridged or polycyclic ring system. More often
cycloalkyl groups are monocyclic. This term includes reference to
groups such as adamantly, cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl, norbornyl, bicyclo[2.2.2]octyl, bicyclo[2.2.1]heptyl
and the like.
Aryl
[0042] The term "aryl" as used herein includes reference to an
aromatic ring system comprising 6, 7, 8, 9, 10, 11, 12, 13, 14, 15
or 16 ring carbon atoms. Aryl is often phenyl but may be a
polycyclic ring system, having two or more rings, at least one of
which is aromatic. This term includes reference to groups such as
phenyl, naphthyl, fluorenyl, azulenyl, indenyl, anthryl and the
like.
Carbocyclyl
[0043] The term "carbocyclyl" as used herein includes reference to
a saturated (e.g. cycloalkyl) or unsaturated (e.g. aryl) ring
moiety having 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16
carbon ring atoms. In particular, carbocyclyl includes a 3- to
10-membered ring or ring system and, in particular, a 5- or
6-membered ring, which may be saturated or unsaturated. A
carbocyclic moiety is, for example, selected from cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl, norbornyl,
bicyclo[2.2.2]octyl, phenyl, naphthyl, fluorenyl, azulenyl,
indenyl, anthryl and the like.
Heterocyclyl
[0044] The term "heterocyclyl" as used herein includes reference to
a saturated (e.g. heterocycloalkyl) or unsaturated (e.g.
heteroaryl) heterocyclic ring moiety having from 3, 4, 5, 6, 7, 8,
9, 10, 11, 12, 13, 14, 15 or 16 ring atoms, at least one of which
is selected from nitrogen, oxygen, phosphorus, silicon and sulphur.
In particular, heterocyclyl includes a 3- to 10-membered ring or
ring system and more particularly a 5- or 6-membered ring, which
may be saturated or unsaturated.
[0045] A heterocyclic moiety is, for example, selected from
oxiranyl, azirinyl, 1,2-oxathiolanyl, imidazolyl, thienyl, furyl,
tetrahydrofuryl, pyranyl, thiopyranyl, thianthrenyl,
isobenzofuranyl, benzofuranyl, chromenyl, 2H-pyrrolyl, pyrrolyl,
pyrrolinyl, pyrrolidinyl, imidazolyl, imidazolidinyl,
benzimidazolyl, pyrazolyl, pyrazinyl, pyrazolidinyl, thiazolyl,
isothiazolyl, dithiazolyl, oxazolyl, isoxazolyl, pyridyl,
pyrazinyl, pyrimidinyl, piperidyl, piperazinyl, pyridazinyl,
morpholinyl, thiomorpholinyl, especially thiomorpholino,
indolizinyl, isoindolyl, 3H-indolyl, indolyl, benzimidazolyl,
cumaryl, indazolyl, triazolyl, tetrazolyl, purinyl,
4H-quinolizinyl, isoquinolyl, quinolyl, tetrahydroquinolyl,
tetrahydroisoquinolyl, decahydroquinolyl, octahydroisoquinolyl,
benzofuranyl, dibenzofuranyl, benzothiophenyl, dibenzothiophenyl,
phthalazinyl, naphthyridinyl, quinoxalyl, quinazolinyl,
quinazolinyl, cinnolinyl, pteridinyl, carbazolyl,
.beta.-carbolinyl, phenanthridinyl, acridinyl, perimidinyl,
phenanthrolinyl, furazanyl, phenazinyl, phenothiazinyl,
phenoxazinyl, chromenyl, isochromanyl, chromanyl,
tetrahydro-2H-pyridopyridazinyl e.g.
3,5,7,8-tetrahydro-2H-pyrido[4,3-c]pyridazine,
1-methyl-1H-pyridinyl-2-one and the like.
Heterocycloalkyl
[0046] The term "heterocycloalkyl" as used herein includes
reference to a saturated heterocyclic moiety having 3, 4, 5, 6 or 7
ring carbon atoms and 1, 2, 3, 4 or 5 ring heteroatoms selected
from nitrogen, oxygen, phosphorus and sulphur. The group may be a
polycyclic ring system but more often is monocyclic. This term
includes reference to groups such as azetidinyl, pyrrolidinyl,
tetrahydrofuranyl, piperidinyl, oxiranyl, pyrazolidinyl,
imidazolyl, indolizidinyl, piperazinyl, thiazolidinyl, morpholinyl,
thiomorpholinyl, quinolizidinyl and the like.
Heteroaryl
[0047] The term "heteroaryl" as used herein includes reference to
an aromatic heterocyclic ring system having 5, 6, 7, 8, 9, 10, 11,
12, 13, 14, 15 or 16 ring atoms, at least one of which is selected
from nitrogen, oxygen and sulphur. The group may be a polycyclic
ring system, having two or more rings, at least one of which is
aromatic, but is more often monocyclic. This term includes
reference to groups such as pyrimidinyl, furanyl,
benzo[b]thiophenyl, thiophenyl, pyrrolyl, imidazolyl, pyrrolidinyl,
pyridinyl, benzo[b]furanyl, pyrazinyl, purinyl, indolyl,
benzimidazolyl, quinolinyl, phenothiazinyl, triazinyl,
phthalazinyl, 2H-chromenyl, oxazolyl, isoxazolyl, thiazolyl,
isoindolyl, indazolyl, purinyl, isoquinolinyl, quinazolinyl,
pteridinyl and the like.
Halogen
[0048] The term "halogen" as used herein includes reference to F,
Cl, Br or I. In a particular, halogen may be F or Cl, of which F is
more common.
Spiro
[0049] The term "spiro" as used herein includes 5- to 6-cycloalkyl
or 5- to 6-heterocycloalkyl groups which can optionally be
substituted by 1, 2, 3 or 4, R.sup.13. Non limitative examples of
spiro groups are;
##STR00003##
Substituted
[0050] The term "alkoxycarbonyl" refers to alkyl-O--C(O)--.
[0051] In the present application, the terms "--N(C.sub.1-6
alkyl).sub.2" and "--N(C.sub.1-6 alkyl)(C.sub.1-6 alkyl)" have the
same meaning. For both terms the two alkyl groups may be the same
or different and cover e.g. N(CH.sub.3)(CH.sub.2CH.sub.3) or
N(CH.sub.3)(CH.sub.3).
[0052] The term "substituted" as used herein in reference to a
moiety means that one or more, especially up to 5, more especially
1, 2 or 3, of the hydrogen atoms in said moiety are replaced
independently of each other by the corresponding number of the
described substituents. The term "optionally substituted" as used
herein means substituted or unsubstituted.
[0053] It will, of course, be understood that substituents are only
at positions where they are chemically possible, the person skilled
in the art being able to decide (either experimentally or
theoretically) without inappropriate effort whether a particular
substitution is possible. For example, amino or hydroxy groups with
free hydrogen may be unstable if bound to carbon atoms with
unsaturated (e.g. olefinic) bonds. Additionally, it will of course
be understood that the substituents described herein may themselves
be substituted by any substituent, subject to the aforementioned
restriction to appropriate substitutions as recognised by the
skilled man.
Pharmaceutically Acceptable
[0054] The term "pharmaceutically acceptable" as used herein
includes reference to those compounds, materials, compositions,
and/or dosage forms which are, within the scope of sound medical
judgment, suitable for use in contact with the tissues of human
beings or animals without excessive toxicity, irritation, allergic
response, or other problem or complication, commensurate with a
reasonable benefit/risk ratio. This term includes acceptability for
both human and veterinary purposes.
Independently
[0055] Where two or more moieties are described as being "each
independently" selected from a list of atoms or groups, this means
that the moieties may be the same or different. The identity of
each moiety is therefore independent of the identities of the one
or more other moieties.
Compounds
[0056] The present invention provides compounds of the Formula
(I):
##STR00004## [0057] wherein X, Y, R.sup.1, R.sup.2, R.sup.3,
R.sup.4, R.sup.5, R.sup.6, R.sup.7 and j are as defined herein;
[0058] or a pharmaceutically acceptable salt or prodrug
thereof.
[0059] Embodiments of the invention are described below. It will be
appreciated that the features specified in each embodiment may be
combined with other specified features, to provide further
embodiments.
X & Y
[0060] In Formula (I), X is .dbd.N-- or .dbd.C(R.sup.8)--; and Y is
.dbd.N-- or .dbd.C(R.sup.9)--. The invention therefore includes
compounds of the following Formulae:
##STR00005## [0061] or, in each case, a pharmaceutically acceptable
salt or prodrug thereof.
[0062] Of particular mention are compounds of the Formula (II) and
compounds of the Formula (III), and pharmaceutically acceptable
salts or prodrugs thereof.
[0063] In the above Formulae, R.sup.8 and R.sup.9 are each
independently selected from hydrogen, halogen and moieties
comprising from 1 to 30 plural valent atoms selected from C, N, O
and S. For example, R.sup.8 and R.sup.9 may be each independently
selected from halogen, trifluoromethyl, cyano, nitro, R.sup.10,
--OR.sup.10, --C(O)R.sup.10, --C(O)OR.sup.10, --OC(O)R.sup.10,
--S(O).sub.lR.sup.11, --N(R.sup.11)(R.sup.12) and
--C(O)N(R.sup.11)(R.sup.12); wherein R.sup.10 is hydrogen,
hydrocarbyl optionally substituted with 1, 2, 3, 4 or 5 R.sup.13;
or --(CH.sub.2).sub.k-heterocyclyl optionally substituted with 1,
2, 3, 4 or 5 R.sup.13; and R.sup.11 and R.sup.12 are each
independently selected from R.sup.10, --OR.sup.10, --C(O)R.sup.10,
--C(O)OR.sup.10 and --S(O).sub.lR.sup.10; or R.sup.11 and R.sup.12
taken together with the nitrogen atom to which they are attached
form heterocyclyl optionally substituted with 1, 2, 3, 4 or 5
R.sup.13. Typically, R.sup.8 and/or R.sup.9 are each independently
hydrogen or C.sub.1-6 alkyl optionally substituted with 1, 2, 3, 4
or 5 R.sup.13.
R.sup.1 & R.sup.2
[0064] R.sup.1 and R.sup.2 are each independently selected from
R.sup.10, --OR.sup.10, --C(O)R.sup.10, --C(O)OR.sup.10 and
--S(O).sub.lR.sup.10, wherein R.sup.10 is hydrogen, hydrocarbyl
optionally substituted with 1, 2, 3, 4 or 5 R.sup.13; or
--(CH.sub.2).sub.k-heterocyclyl optionally substituted with 1, 2,
3, 4 or 5 R.sup.13. Where R.sup.10 is hydrocarbyl, it may be, for
example, C.sub.1-6 alkyl (e.g. C.sub.1, C.sub.2, C.sub.3 or C.sub.4
alkyl) or --(CH.sub.2).sub.k-carbocyclyl (e.g.
--(CH.sub.2).sub.k-cycloalkyl or --(CH.sub.2).sub.k-aryl), either
of which is optionally substituted with 1, 2, 3, 4 or 5 R.sup.13.
In particular, hydrocarbyl may be C.sub.1-6 alkyl (e.g. C.sub.1,
C.sub.2, C.sub.3 or C.sub.4 alkyl) or --(CH.sub.2).sub.k-aryl (e.g.
phenyl or benzyl), either of which is optionally substituted with
1, 2, 3, 4 or 5 R.sup.13. Where R.sup.10 is
--(CH.sub.2).sub.k-heterocyclyl, it may be, for example,
--(CH.sub.2).sub.k-heterocycloalkyl or
--(CH.sub.2).sub.k-heteroaryl, either of which is optionally
substituted with 1, 2, 3, 4 or 5 R.sup.13.
[0065] In one embodiment, R.sup.1 and R.sup.2 are each
independently selected from hydrogen; C.sub.1-6 alkyl optionally
substituted with 1, 2, 3, 4 or 5 R.sup.13; and
--(CH.sub.2).sub.k-carbocyclyl (e.g. --(CH.sub.2).sub.k-cycloalkyl
or --(CH.sub.2).sub.k-aryl) optionally substituted with 1, 2, 3, 4
or 5 R.sup.13.
[0066] In another embodiment, R.sup.1 is hydrogen; and R.sup.2 is
hydrogen or C.sub.1-6 alkyl (e.g. C.sub.1, C.sub.2, C.sub.3 or
C.sub.4 alkyl) optionally substituted with 1, 2, 3, 4 or 5
R.sup.13.
[0067] In another embodiment, R.sup.1 and R.sup.2 are each
hydrogen. The invention therefore includes compounds of the
following Formula:
##STR00006## [0068] or a pharmaceutically acceptable salt or
prodrug thereof.
R.sup.3 & R.sup.4
[0069] R.sup.3 and R.sup.4 are each independently hydrogen or
R.sup.13; or R.sup.3 and R.sup.4 taken together with the carbon
atom to which they are attached form carbocyclyl or heterocyclyl,
either of which is optionally substituted with 1, 2, 3, 4 or 5
R.sup.13.
[0070] Where R.sup.3 and/or R.sup.4 is R.sup.13, the or each
R.sup.13 is often independently selected from halogen (e.g.
fluorine, chlorine or bromine), hydroxy, cyano, amino, --C(O)OH,
C.sub.1-6 alkyl, C.sub.1-6 alkoxy (e.g. C.sub.1, C.sub.2, C.sub.3
or C.sub.4 alkoxy), --C(O)--C.sub.1-6 alkyl, --C(O)O--C.sub.1-6
alkyl, --S(O).sub.l--C.sub.1-6 alkyl, --NH(C.sub.1-6 alkyl) and
--N(C.sub.1-6 alkyl).sub.2, wherein any C.sub.1-6 alkyl group
present is optionally substituted with 1, 2, 3, 4 or 5 substituents
independently selected from halogen, cyano, amino, hydroxy and
C.sub.1-6 alkoxy, and wherein the alkyl groups of the di(C.sub.1-6
alkyl)amino group may be the same or different.
[0071] In one embodiment, R.sup.3 and R.sup.4 are each
independently selected from hydrogen, C.sub.1-6 alkyl optionally
substituted with 1, 2, 3, 4 or 5 R.sup.13, and
--(CH.sub.2).sub.k-carbocyclyl optionally substituted with 1, 2, 3,
4 or 5 R.sup.13.
[0072] In a further embodiment, R.sup.3 and R.sup.4 taken together
with the carbon atom to which they are attached form carbocyclyl
optionally substituted with 1, 2, 3, 4 or 5 R.sup.13. In this case,
carbocyclyl is often cycloalkyl, usually C.sub.3-6 cycloalkyl (e.g.
cyclopropyl or cyclohexyl), optionally substituted with 1, 2, 3, 4
or 5 R.sup.13.
[0073] In another embodiment, R.sup.3 and R.sup.4 are each
hydrogen. The invention therefore includes compounds of the
following Formula:
##STR00007## [0074] or a pharmaceutically acceptable salt or
prodrug thereof.
R.sup.5
[0075] R.sup.5 is aryl or heteroaryl, either of which is optionally
substituted with 1, 2, 3, 4 or 5 R.sup.13. Typically, the aryl or
heteroaryl ring is a 5- or 6-membered ring.
[0076] In one embodiment, R.sup.5 is heteroaryl, for example
pyrimidinyl, furanyl, benzo[b]thiophenyl, thiophenyl, pyrrolyl,
imidazolyl, pyrrolidinyl, pyridinyl, benzo[b]furanyl, pyrazinyl,
purinyl, indolyl, benzimidazolyl, quinolinyl, phenothiazinyl,
triazinyl, phthalazinyl, 2H-chromenyl, oxazolyl, isoxazolyl,
thiazolyl, isoindolyl, indazolyl, purinyl, isoquinolinyl,
quinazolinyl or pteridinyl, and is optionally substituted with 1,
2, 3, 4 or 5 R.sup.13.
[0077] In another embodiment, R.sup.5 is aryl, for example phenyl
or naphthyl, optionally substituted with 1, 2, 3, 4 or 5 R.sup.13.
The or each R.sup.13 may be independently selected from halogen,
cyano, amino, hydroxy, C.sub.1-6 alkyl and C.sub.1-6 alkoxy.
[0078] In a further embodiment, R.sup.5 is phenyl substituted with
0, 1, 2, 3, 4 or 5 (e.g. 0, 1, 2 or 3) R.sup.13. The invention
therefore includes compounds of the following Formula:
##STR00008## [0079] wherein p is 0, 1, 2, 3, 4 or 5; [0080] or a
pharmaceutically acceptable salt or prodrug thereof.
[0081] In a further embodiment, R.sup.5 is phenyl substituted with
0, 1, 2, 3, 4 or 5 (e.g. 0, 1, 2 or 3) substituents independently
selected from halogen, cyano, amino, hydroxy, C.sub.1-6 alkyl and
C.sub.1-6 alkoxy.
[0082] In a further embodiment, R.sup.5 is phenyl comprising
substituents at the 2- and 4-positions, wherein the substituents
are independently selected from halogen (e.g. fluorine or
chlorine), methyl and methoxy.
[0083] In a further embodiment, R.sup.5 is one of the following
groups:
##STR00009##
[0084] In a further embodiment, R.sup.5 is 2,4-dichlorophenyl. In
other embodiments, one of a Cl or F atom shown in the above groups
is exchanged for the other. Methyl and methoxy may be similarly
exchanged.
R.sup.6
[0085] R.sup.6 is present when j is 1 or 2, and is selected from
halogen, trifluoromethyl, cyano, nitro, oxo, R.sup.10, --OR.sup.10,
--C(O)R.sup.10, --C(O)OR.sup.10, --OC(O)R.sup.10,
--S(O).sub.lR.sup.11, --N(R.sup.11)(R.sup.12) and
--C(O)N(R.sup.11)(R.sup.12); wherein R.sup.10 is hydrogen,
hydrocarbyl optionally substituted with 1, 2, 3, 4 or 5 R.sup.13;
or --(CH.sub.2).sub.k-heterocyclyl optionally substituted with 1,
2, 3, 4 or 5 R.sup.13; and R.sup.11 and R.sup.12 are each
independently selected from R.sup.10, --OR.sup.10, --C(O)R.sup.10,
--C(O)OR.sup.10 and --S(O).sub.lR.sup.10; or R.sup.11 and R.sup.12
taken together with the nitrogen atom to which they are attached
form heterocyclyl optionally substituted with 1, 2, 3, 4 or 5
R.sup.13.
[0086] Where present, the or each R.sup.6 is often independently
selected from halogen (e.g. fluorine, chlorine or bromine),
hydroxy, cyano, amino, --C(O)OH, C.sub.1-6 alkyl, C.sub.1-6 alkoxy
(e.g. C.sub.1, C.sub.2, C.sub.3 or C.sub.4 alkoxy),
--C(O)--C.sub.1-6 alkyl, --C(O)O--C.sub.1-6 alkyl, --S(O),
--C.sub.1-6 alkyl, --NH(C.sub.1-6 alkyl) and --N(C.sub.1-6
alkyl).sub.2, wherein any C.sub.1-6 alkyl group present is
optionally substituted with 1, 2, 3, 4 or 5 substituents
independently selected from halogen, cyano, amino, hydroxy and
C.sub.1-6 alkoxy. Exemplary are halogen, methyl, methoxy, hydroxy
and cyano.
[0087] In one embodiment, j is 0 or 1.
[0088] More usually, j is 0. The invention therefore includes
compounds of the following Formula:
##STR00010## [0089] or a pharmaceutically acceptable salt or
prodrug thereof.
R.sup.7
[0090] R.sup.7 is selected from hydrogen, halogen and moieties
comprising from 1 to 30 (e.g. 1 to 20) plural valent atoms selected
from C, N, O and S.
[0091] Typically, R.sup.7 is selected from halogen,
trifluoromethyl, cyano, nitro, R.sup.10, --OR.sup.10,
--C(O)R.sup.10, --C(O)OR.sup.10, --OC(O)R.sup.10,
--S(O).sub.lR.sup.11, --N(R.sup.11)(R.sup.12) and
--C(O)N(R.sup.11)(R.sup.12), wherein R.sup.10 is hydrogen,
hydrocarbyl optionally substituted with 1, 2, 3, 4 or 5 R.sup.13;
or --(CH.sub.2).sub.k-heterocyclyl optionally substituted with 1,
2, 3, 4 or 5 R.sup.13; and R.sup.11 and R.sup.12 are each
independently selected from R.sup.10, --OR.sup.10, --C(O)R.sup.10,
--C(O)OR.sup.10 and --S(O).sub.lR.sup.10; or R.sup.11 and R.sup.12
taken together with the nitrogen atom to which they are attached
form heterocyclyl optionally substituted with 1, 2, 3, 4 or 5
R.sup.13. Where R.sup.10 is hydrocarbyl, it may be, for example, a
saturated or unsaturated aliphatic group having 1, 2, 3, 4, 5 or 6
carbon atoms and is unsubstituted or substituted with 1, 2, 3, 4 or
5 R.sup.13. Thus, R.sup.10 may be C.sub.1-6 alkyl (e.g. C.sub.1,
C.sub.2, C.sub.3 or C.sub.4 alkyl) or
--(CH.sub.2).sub.k-carbocyclyl (e.g. --(CH.sub.2).sub.k-cycloalkyl
or --(CH.sub.2).sub.k-aryl), either of which is optionally
substituted with 1, 2, 3, 4 or 5 R.sup.13. In particular,
hydrocarbyl may be C.sub.1-6 alkyl (e.g. C.sub.1, C.sub.2, C.sub.3
or C.sub.4 alkyl) or --(CH.sub.2).sub.k-aryl (e.g. phenyl or
benzyl), either of which is optionally substituted with 1, 2, 3, 4
or 5 R.sup.13. Where R.sup.10 is --(CH.sub.2).sub.k-heterocyclyl,
it may be, for example, --(CH.sub.2).sub.k-heterocycloalkyl or
--(CH.sub.2).sub.k-heteroaryl, either of which is optionally
substituted with 1, 2, 3, 4 or 5 R.sup.13.
[0092] In one embodiment, R.sup.7 is hydrogen.
[0093] In another embodiment, R.sup.7 is
--(CH.sub.2).sub.k-carbocyclyl (e.g. --(CH.sub.2).sub.k-cycloalkyl
or --(CH.sub.2).sub.k-aryl) optionally substituted with 1, 2, 3, 4
or 5 R.sup.13. In this case, k is usually 0 or 1, often 0. In
particular, carbocyclyl may be aryl (e.g. phenyl or naphthyl),
cycloalkenyl or cycloalkyl (e.g. C.sub.3-6 cycloalkyl), any of
which is optionally substituted with 1, 2, 3, 4 or 5 R.sup.13. The
carbocyclyl group may be mono- or bicyclic, e.g. C.sub.3-7
monocyclic or C.sub.8-12 bicyclic. More particularly, R.sup.7 may
be phenyl or cyclohexyl, either of which is optionally substituted
with 1, 2, 3, 4 or 5 (e.g. 1, 2 or 3) R.sup.13.
[0094] In a further embodiment, R.sup.7 is heterocyclyl optionally
substituted with 1, 2, 3, 4 or 5 R.sup.13. Of particular mention
are 5- or 6-membered heterocyclyl groups, especially 6-membered
heterocyclyl group, which are optionally substituted with 1, 2, 3,
4 or 5 (e.g. 1, 2 or 3) R.sup.13. In particular, R.sup.7 may be
imidazolyl, pyridinyl, pyrimidinyl, pyrazinyl, piperidinyl,
piperazinyl, morpholinyl, thiomorpholinyl or tetrahydropyranyl, any
of which is optionally substituted with 1, 2 or 3 R.sup.13.
[0095] In a further embodiment, R.sup.7 is --N(R.sup.11)(R.sup.12)
or --C(O)N(R.sup.11)(R.sup.12). In particular, R.sup.7 may be
--N(R.sup.11)(R.sup.12). In particular, R.sup.7 may be
C(O)N(R.sup.11)(R.sup.12). The invention therefore includes
compounds of the following Formulas (X) and (Xb):
##STR00011## [0096] or a pharmaceutically acceptable salt or
prodrug thereof. Where R.sup.7 is --N(R.sup.11)(R.sup.12) or
--C(O)N(R.sup.11)(R.sup.12), R.sup.11 and R.sup.12 may be each
independently hydrogen or C.sub.1-6 alkyl or
--(CH.sub.2).sub.k-carbocyclyl (e.g. --(CH.sub.2).sub.k-cycloalkyl
or --(CH.sub.2).sub.k-aryl), or --(CH.sub.2).sub.k-heterocyclyl, or
--C(O)--(CH.sub.2).sub.k-heterocyclyl,
--C(O)--(CH.sub.2).sub.k-cycloalkyl or --C(O)--C.sub.1-6 alkyl,
either of which is optionally substituted with 1, 2, 3, 4 or 5
R.sup.13. In particular, R.sup.11 and R.sup.12 may be each
independently hydrogen or C.sub.1-6 alkyl optionally substituted
with 1, 2, 3, 4 or 5 substituents independently selected from
--OR.sup.14, --C(O)R.sup.14 and --C(O)OR.sup.14; wherein R.sup.14
is usually hydrogen or selected from C.sub.1-6 alkyl optionally
substituted with 1, 2, 3, 4 or 5 R.sup.13. or Where R.sup.7 is
--N(R.sup.11)(R.sup.12) or --C(O)N(R.sup.11)(R.sup.12), R.sup.11
and R.sup.12 may be each independently hydrogen or C.sub.1-6 alkyl
or --(CH.sub.2).sub.k-carbocyclyl (e.g.
--(CH.sub.2).sub.k-cycloalkyl or --(CH.sub.2).sub.k-aryl), either
of which is optionally substituted with 1, 2, 3, 4 or 5 R.sup.13.
In particular, R.sup.11 and R.sup.12 may be each independently
hydrogen or C.sub.1-6 alkyl optionally substituted with 1, 2, 3, 4
or 5 substituents independently selected from --OR.sup.14,
--C(O)R.sup.14 and --C(O)OR.sup.14; wherein R.sup.14 is usually
hydrogen or selected from C.sub.1-6 alkyl optionally substituted
with 1, 2, 3, 4 or 5 R.sup.13.
[0097] In another embodiment, R.sup.11 is a R.sup.10 moiety; and
R.sup.12 is --C(O)R.sup.10. In this case, R.sup.11 may be hydrogen
or C.sub.1-6 alkyl optionally substituted with 1, 2, 3, 4 or 5
R.sup.13; and R.sup.12 may be --C(O)--C.sub.1-6 alkyl,
--C(O)--(CH.sub.2).sub.k-carbocyclyl-C(O)--(CH.sub.2).sub.k-heterocyclyl,
any of which is optionally substituted with 1, 2, 3, 4 or 5
R.sup.13.
[0098] The invention includes compounds in which R.sup.7 is
--N(R.sup.11)(R.sup.12) or --C(O)N(R.sup.11)(R.sup.12) and R.sup.7
includes two cyclic groups, for example a heterocycle, which may be
unsaturated but is more commonly saturated, and a carbocycle which,
independently of the identity of the heterocycle, may be saturated
or, more usually, unsaturated as in the case of aromatic
carbocycles. In some such compounds, the cyclic groups are
monocyclic, e.g. having 5 or 6 ring members.
[0099] To be mentioned are four sub-classes of the compounds in
which R.sup.7 is --C(O)N(R.sup.11)(R.sup.12) or, more particularly,
--N(R.sup.11)(R.sup.12) and R.sup.7 includes two cyclic groups,
namely: [0100] (i) compounds in which R.sup.11 and R.sup.12 taken
together with the nitrogen atom to which they are attached form
heterocyclyl (e.g. heterocycloalkyl or heteroaryl) substituted with
1, 2, 3, 4 or 5 R.sup.13 moieties of which at least one and often
exactly one is a moiety R.sup.17 and any additional R.sup.13
moieties are typically selected from halogen, hydroxy, amino,
C.sub.1-6 alkyl (e.g. C.sub.1-4 alkyl) and C.sub.1-6 alkoxy (e.g.
C.sub.1-4 alkoxy), wherein: [0101] R.sup.17 is selected from
.dbd.NR.sup.16, --OR.sup.16, --C(O)R.sup.16, --C(O)OR.sup.16,
--OC(O)R.sup.16, --S(O).sub.lR.sup.16, --N(R.sup.16)R.sup.15,
--C(O)N(R.sup.16)R.sup.15 and R.sup.16, wherein R.sup.15 is as
previously described, e.g. is H, and R.sup.16 is selected from
--(CH.sub.2).sub.k-carbocyclyl and --(CH.sub.2).sub.k-heterocyclyl,
wherein carbocyclyl and heterocyclyl are optionally substituted
with 1, 2, 3, 4 or 5 R.sup.13 moieties (e.g. selected from halogen,
hydroxy, amino, alkyl and alkoxy wherein alkyl and alkoxy have from
1 to 6 and often from 1 to 4 carbon atoms) and for example are
saturated or more particularly unsaturated monocyclic rings having
up to 7 ring members, e.g. having 6 ring members, and as in the
case of aromatic rings (e.g. phenyl); [0102] (ii) compounds in
which R.sup.11 is as previously described, e.g. is H, and R.sup.12
is selected from --C(O)--(CH.sub.2).sub.t-carbocyclyl and
--C(O)--(CH.sub.2).sub.t-heterocyclyl substituted with 1, 2, 3, 4
or 5 R.sup.13 moieties of which at least one and often exactly one
is a moiety R.sup.17 as described above and any additional R.sup.13
moieties are typically selected from halogen, hydroxy, amino,
C.sub.1-6 alkyl and C.sub.1-6 alkoxy, t being 0, 1, 2, 3, 4, 5 or
6; [0103] (iii) compounds in which R.sup.11 and R.sup.12 taken
together with the nitrogen atom to which they are attached form
heterocyclyl (e.g. heterocycloalkyl or heteroaryl) substituted with
1, 2, 3, 4 or 5 R.sup.13 moieties of which at least one and often
exactly one is a moiety R.sup.17 and any additional R.sup.13
moieties are typically selected from halogen, hydroxy, amino,
C.sub.1-6 alkyl (e.g. C.sub.1-4 alkyl) and C.sub.1-6 alkoxy (e.g.
C.sub.i alkoxy), wherein: [0104] R.sup.17 is selected from oxo,
spiro, .dbd.NR.sup.16, --OR.sup.16, --C(O)R.sup.16,
--C(O)OR.sup.16, --OC(O)R.sup.16, --S(O).sub.lR.sup.16,
--N(R.sup.16)R.sup.15, --C(O)N(R.sup.16)R.sup.15 and R.sup.16,
wherein R.sup.15 is as previously described, e.g. is H, and
R.sup.16 is selected from hydrocaryl,
--(CH.sub.2).sub.k-carbocyclyl, --(CH.sub.2).sub.k-heterocyclyl and
--(CH.sub.2).sub.k--C(O)-heterocyclyl, wherein carbocyclyl and
heterocyclyl are optionally substituted with 1, 2, 3, 4 or 5
R.sup.13 moieties (e.g. selected from halogen, hydroxy, oxo, amino,
alkyl and alkoxy wherein alkyl and alkoxy have from 1 to 6 and
often from 1 to 4 carbon atoms) and for example are saturated or
more particularly unsaturated monocyclic rings having up to 7 ring
members, e.g. having 6 ring members, and as in the case of aromatic
rings (e.g. phenyl); [0105] (iv) compounds in which R.sup.11 is as
previously described, e.g. is H, and R.sup.12 is selected from
--C(O)--(CH.sub.2).sub.t-carbocyclyl and
--C(O)--(CH.sub.2).sub.t-heterocyclyl unsubstituted or substituted
with 1, 2, 3, 4 or 5 R.sup.13 moieties of which at least one and
often exactly one is a moiety R.sup.17 as described above and any
additional R.sup.13 moieties are typically selected from halogen,
hydroxy, amino, oxo, --C(O)--O--(C.sub.1-6 alkyl), C.sub.1-6 alkyl
and C.sub.1-6 alkoxy, t being 0, 1, 2, 3, 4, 5 or 6;
[0106] In some compounds of sub-paragraph (i) above, R.sup.17 is
--C(O)OR.sup.16 and/or k is 1 or 2. In some compounds of
sub-paragraph (ii) above, R.sup.17 is R.sup.16 and/or k and t are
each independently 1 or 2.
[0107] In one class of compounds in which R.sup.7 is
--N(R.sup.11)(R.sup.12), R.sup.11 is H and R.sup.12 is not H; in
these compounds, R.sup.12 may be as described in the preceding
paragraphs. This applies also to a class of compounds in which
R.sup.7 is --C(O)N(R.sup.11)(R.sup.12).
[0108] Alternatively, R.sup.11 and R.sup.12 taken together with the
nitrogen atom to which they are attached may form heterocyclyl
(e.g. heterocycloalkyl or heteroaryl) optionally substituted with
1, 2, 3, 4 or 5 R.sup.13. Of particular mention are 5- or
6-membered heterocyclyl groups, especially 6-membered heterocyclyl
groups, which are optionally substituted with 1, 2, 3, 4 or 5 (e.g.
1, 2 or 3) R.sup.13. In particular, R.sup.11 and R.sup.12 taken
together with the attached nitrogen atom may form heterocycloalkyl
(e.g. piperidinyl, piperazinyl, morpholinyl or thiomorpholinyl)
optionally substituted with 1, 2, 3, 4 or 5 (e.g. 1, 2, or 3)
R.sup.13. In this case, the heterocycloalkyl ring is often a 5- or
6-membered ring, especially a 6-membered ring.
[0109] Alternatively, R.sup.11 and R.sup.12 taken together with the
nitrogen atom to which they are attached may form heterocyclyl
(e.g. heterocycloalkyl or heteroaryl) optionally substituted with
1, 2, 3, 4 or 5 R.sup.13. Of particular mention are 5- or
6-membered monocyclic heterocyclyl groups, especially 6-membered
heterocyclyl groups, 9- or 10-membered bicyclic heterocyclyl
groups, which are optionally substituted with 1, 2, 3, 4 or 5 (e.g.
1, 2 or 3) R.sup.13. In particular, R.sup.11 and R.sup.12 taken
together with the attached nitrogen atom may form heterocycloalkyl
(e.g. triazolopyrazinyl, piperidinyl, piperazinyl, morpholinyl or
thiomorpholinyl) optionally substituted with 1, 2, 3, 4 or 5 (e.g.
1, 2, or 3) R.sup.13. In this case, the heterocycloalkyl ring is
often a 5- or 6-membered ring, especially a 6-membered ring or 9-
or 10-membered bicyclic heterocyclyl groups.
[0110] In a further embodiment when R.sup.7 is
--N(R.sup.11)(R.sup.12) or --C(O)N(R.sup.11)(R.sup.12) and when
R.sup.11 and R.sup.12 taken together with the nitrogen atom to
which they are attached form heterocyclyl the formed heterocyclyl
can be selected from
##STR00012##
and can optionally be substituted with 1, 2 or 3 R.sup.13 moieties
preferably selected from oxo, trifluoromethyl, halogen, C.sub.1-6
alkyl and C.sub.1-6 alkoxy. In the above heterocyclyl formulas, the
arrows represent the bound to the rest of the compound i.e.
directly to the compound of formula (I) when R.sup.7 is
--N(R.sup.11)(R.sup.12) or indirectly throught the carbonyl group
when R.sup.7 is --C(O)N(R.sup.11)(R.sup.12).
[0111] R.sup.13a is hydrogen or is R.sup.13. R.sup.13a is
preferably selected from hydrogen, halogen, trifluoromethyl, cyano,
nitro, a spiro group, amino, oxo, alkyl (preferably C.sub.1-6
alkyl), --(CH.sub.2).sub.k-heterocyclyl, --(CH.sub.2).sub.k-aryl,
C.sub.1-6 alkoxy, --C(O)--C.sub.1-6 alkyl,
--C(O)--(CH.sub.2).sub.k-cycloalkyl,
--C(O)--(CH.sub.2).sub.k-heterocyclyl,
--C(O)O--(CH.sub.2).sub.k-aryl, --C(O)O--(C.sub.1-6 alkyl),
--(CH.sub.2).sub.k--C(O)-heterocyclyl, --S(O).sub.2--(C.sub.1-6
alkyl), --NH--(C.sub.1-6 alkyl), --N(C.sub.1-6 alkyl)(C.sub.1-6
alkyl), --C(O)NH--(C.sub.1-6 alkyl), --C(O)N(C.sub.1-6
alkyl)(C.sub.1-6 alkyl). When R.sup.13a contains a spiro group, a
heterocyclyl group, a cycloalkyl group, an aryl group, or an alkyl
group, such group is optionally substituted with 1, 2, 3, 4 or 5
substituents independently selected from halogen, cyano, oxo,
amino, hydroxy, --C(O)--C.sub.1-6 alkyl, C.sub.1-6 alkyl and
C.sub.1-6 alkoxy. When R.sup.13a contains a heterocyclyl group it
is a 5- or 6-membered monocyclic heterocycloalkyl group (in
particular piperidinyl, morpholinyl, tetrahydropyranyl,
tetrahydrofuranyl, imidazolidinyl) or a 9- or 10-membered bicyclic
heterocycloalkyl group, or 5- or 6-membered monocyclic heteroaryl
group (in particular pyridinyl, furanyl, pyrimidinyl, pyrazinyl,
imidazolyl, 1-methyl-1H-pyridinyl-2-one) or a 9- or 10-membered
bicyclic heteroaryl group. When R.sup.13 contains a cycloalkyl
group it is in particular a C.sub.3-6 cycloalkyl group e.g.
cyclopropane, cyclobutane, cyclopentane, cyclohexane. When
R.sup.13a contains an aryl group it is in particular a phenyl
group. When R.sup.13a contains a spiro group it is in particular a
5-membered heterocyclic group (in particular oxazolan or
azolan-2-one). When R.sup.13a is --S(O).sub.2--(C.sub.1-6 alkyl) it
is in particular --S(O).sub.2--CH.sub.3 or
--S(O).sub.2--CH.sub.2CH.sub.3.
[0112] In one family of compounds the only substituent is
R.sup.13a.
[0113] In a second family of compounds, R.sup.13a is different from
hydrogen and the heterocyclyl is substituted by one or two
substituents, selected independently from each other, from methyl,
methoxy and oxo.
[0114] In a third family of compounds, R.sup.13a is hydrogen and
the heterocyclyl is substituted by one or two substituents,
selected independently from each other, from methyl,
trifluoromethyl, methoxy and oxo.
[0115] In a further class of compounds R.sup.11 may be hydrogen or
C.sub.1-6 alkyl optionally substituted with 1, 2, 3, 4 or 5
R.sup.13 (preferably R.sup.13 is then selected from halogen, cyano,
amino, hydroxy and C.sub.1-6 alkoxy), and R.sup.12 may be hydrogen
or C.sub.1-6 alkyl or --(CH.sub.2).sub.k-cycloalkyl or
--(CH.sub.2).sub.k-aryl, or --(CH.sub.2).sub.k-heterocyclyl, or
--C(O)--(CH.sub.2).sub.k-heterocyclyl,
--C(O)--(CH.sub.2).sub.k-cycloalkyl or --C(O)--C.sub.1-6 alkyl,
either of which is optionally substituted with 1, 2, 3, 4 or 5
R.sup.13. Typically, each R.sup.13 is independently selected from
oxo, halogen (e.g. fluorine, chlorine or bromine), hydroxy, cyano,
amino, --C(O)OH, C.sub.1-6 alkyl, C.sub.1-6 alkoxy (e.g. C.sub.1,
C.sub.2, C.sub.3 or C.sub.4 alkoxy), --C(O)--C.sub.1-5 alkyl,
--C(O)O--C.sub.1-6 alkyl, --S(O).sub.l--C.sub.1-6 alkyl,
--NH(C.sub.1-6 alkyl) and --N(C.sub.1-6 alkyl).sub.2, benzyl,
phenyl, wherein any C.sub.1-6 alkyl group or aryl group, present is
optionally substituted with 1, 2, 3, 4 or 5 substituents
independently selected from halogen, cyano, amino, hydroxy and
C.sub.1-6 alkoxy. When R.sup.12 contains a heterocyclyl group it is
in particular a 5- or 6-membered monocyclic heterocycloalkyl group
(in particular piperidinyl, morpholinyl, tetrahydropyranyl,
tetrahydrofuranyl, imidazolidinyl) or a 9- or 10-membered bicyclic
heterocycloalkyl group, or 5- or 6-membered monocyclic heteroaryl
group (in particular pyridinyl, furanyl, pyrimidinyl, pyrazinyl,
imidazolyl, 1-methyl-1H-pyridinyl-2-one) or a 9- or 10-membered
bicyclic heteroaryl group. When R.sup.12 contains a cycloalkyl
group it is in particular a C.sub.3-6 cycloalkyl group (e.g.
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl) or a C.sub.7-10
bicyclic cycloalkyl (e.g. adamantly, bicycloheptyl). When R.sup.12
contains an aryl group it is in particular a phenyl group.
R.sup.13
[0116] Each R.sup.13 is independently selected from halogen,
trifluoromethyl, cyano, nitro, oxo, .dbd.NR.sup.14, --OR.sup.14,
--C(O)R.sup.14, --C(O)OR.sup.14, --OC(O)R.sup.14,
--S(O).sub.lR.sup.14, --N(R.sup.14)R.sup.15,
--C(O)N(R.sup.14)R.sup.15, and R.sup.16; wherein R.sup.14 and
R.sup.15 are each independently hydrogen or R.sup.16; and R.sup.16
is selected from a spiro group, hydrocarbyl,
--(CH.sub.2).sub.k-hydrocarbyl (in particular;
--(CH.sub.2).sub.k-aryl or --(CH.sub.2).sub.k-cycloalkyl),
--(CH.sub.2).sub.k-heterocyclyl and
--(CH.sub.2).sub.k--C(O)-heterocyclyl, either of which is
optionally substituted with 1, 2, 3, 4 or 5 substituents
independently selected from halogen, cyano, oxo, amino, hydroxy,
--C(O)--C.sub.1-6 alkyl, C.sub.1-6 alkyl and C.sub.1-6 alkoxy.
[0117] Each R.sup.13 is independently selected from halogen,
trifluoromethyl, cyano, nitro, oxo, .dbd.NR.sup.14, --OR.sup.14,
--C(O)R.sup.14, --C(O)OR.sup.14, --OC(O)R.sup.14,
--N(R.sup.14)R.sup.15, --C(O)N(R.sup.14)R.sup.15 and R.sup.16;
wherein R.sup.14 and R.sup.15 are each independently hydrogen or
R.sup.16; and R.sup.16 is selected from hydrocarbyl and
--(CH.sub.2).sub.k-heterocyclyl, either of which is optionally
substituted with 1, 2, 3, 4 or 5 substituents independently
selected from halogen, cyano, amino, hydroxy, C.sub.1-6 alkyl and
C.sub.1-6 alkoxy.
[0118] Typically, each R.sup.13 is independently selected from oxo,
halogen (e.g. fluorine, chlorine or bromine), hydroxy, cyano,
amino, --C(O)OH, C.sub.1-6 alkyl, C.sub.1-6 alkoxy (e.g. C.sub.1,
C.sub.2, C.sub.3 or C.sub.4 alkoxy), --C(O)--C.sub.1-6 alkyl,
--C(O)O--C.sub.1-6 alkyl, --S(O), --C.sub.1-6 alkyl, --NH(C.sub.1-6
alkyl) and --N(C.sub.1-6 alkyl).sub.2, wherein any C.sub.1-6 alkyl
group present is optionally substituted with 1, 2, 3, 4 or 5
substituents independently selected from halogen, cyano, amino,
hydroxy and C.sub.1-6 alkoxy.
[0119] When R.sup.13 is --S(O).sub.2--(C.sub.1-6 alkyl) it is in
particular --S(O).sub.2--CH.sub.3 or
--S(O).sub.2--CH.sub.2CH.sub.3.
[0120] For the avoidance of doubt, where a group is substituted
with more than one R.sup.13, each R.sup.13 is independently
selected from the range of substituents specified. The same applies
to compounds of the invention comprising more than one R.sup.13
substituent; each R.sup.13 is selected independently of any other
R.sup.13 substituent present in the compound. As previously
indicated, where R.sup.13 is halo, particularly fluoro, any number
of hydrogens may in principle be replaced.
[0121] A particular embodiment of the invention is a compound of
the Formula (XI):
##STR00013## [0122] wherein p is 0, 1, 2, 3, 4 or 5; [0123] or a
pharmaceutically acceptable salt or prodrug thereof.
[0124] Particular embodiments of Formula (XI) include the following
compounds:
##STR00014## [0125] or, in each case, a pharmaceutically acceptable
salt or prodrug thereof.
[0126] With regard to Formulae (XI) to (XV), j is usually 0.
[0127] With regard to Formulae (XI) to (XV), j is usually 0 or
1.
[0128] Also with regard to the above Formulae, R.sup.7 may be
--N(R.sup.11)(R.sup.12) or --C(O)N(R.sup.11)(R.sup.12).
[0129] In particular, R.sup.7 may be --N(R.sup.11)(R.sup.12). The
invention therefore includes compounds of the following
Formula:
##STR00015## [0130] or a pharmaceutically acceptable salt or
prodrug thereof.
[0131] Particular embodiments of Formula (XVI) include the
following compounds:
##STR00016## [0132] or, in each case, a pharmaceutically acceptable
salt or prodrug thereof.
[0133] With regard to Formulae (XVI) to (XX), R.sup.8 and/or
R.sup.9 is often hydrogen or C.sub.1-6 alkyl optionally substituted
with 1, 2, 3, 4 or 5 R.sup.13. In this case, the or each R.sup.11
is often independently selected from hydroxy, halogen (e.g.
fluorine or chlorine) or C.sub.1-6 (e.g. C.sub.1, C.sub.2, C.sub.3
or C.sub.4) alkoxy. More usually, R.sup.8 and/or R.sup.9 is
hydrogen.
[0134] With regard to Formulae (XVI) to (XX), R.sup.11 and R.sup.12
may be each independently hydrogen or C.sub.1-6 alkyl or
--(CH.sub.2).sub.k-carbocyclyl (e.g. --(CH.sub.2).sub.k-cycloalkyl
or --(CH.sub.2).sub.k-aryl), either of which is optionally
substituted with 1, 2, 3, 4 or 5 R.sup.13. In particular, R.sup.11
and R.sup.12 may be each independently hydrogen or C.sub.1-6 alkyl
optionally substituted with 1, 2, 3, 4 or 5 substituents
independently selected from --OR.sup.14, --C(O)R.sup.14 and
--C(O)OR.sup.14; wherein R.sup.14 is usually hydrogen or selected
from C.sub.1-6 alkyl optionally substituted with 1, 2, 3, 4 or 5
R.sup.13.
[0135] Alternatively, R.sup.11 and R.sup.12 taken together with the
nitrogen atom to which they are attached may form heterocyclyl
(e.g. heterocycloalkyl or heteroaryl) optionally substituted with
1, 2, 3, 4 or 5 R.sup.13. Of particular mention are 5- or
6-membered heterocyclyl groups, especially 6-membered heterocyclyl
groups, or a 9- or 10-membered ring, especially a 9-membered
heterocyclyl groups, which are optionally substituted with 1, 2, 3,
4 or 5 (e.g. 1, 2 or 3) R.sup.13. In particular, R.sup.11 and
R.sup.12 taken together with the attached nitrogen atom may form
heterocycloalkyl (e.g. pyrrolidinyl, piperidinyl, piperazinyl,
morpholinyl, thiomorpholinyl, or triazolopyrazinyl (e.g.
[1,2,4]triazolo[4,3-a]pyrazin-7-yl)) optionally substituted with 1,
2, 3, 4 or 5 (e.g. 1, 2, or 3) R.sup.13. In this case, the
heterocycloalkyl ring is often a 5- or 6-membered ring, especially
a 6-membered ring or a 9- or 10-membered ring, especially a
9-membered ring.
[0136] In another embodiment, R.sup.11 is R.sup.10; and R.sup.12 is
--C(O)R.sup.10. In this case, R.sup.11 may be hydrogen or C.sub.1-6
alkyl optionally substituted with 1, 2, 3, 4 or 5 R.sup.13; and
R.sup.12 may be --C(O)--C.sub.1-6 alkyl,
--C(O)--(CH.sub.2).sub.k-carbocyclyl-C(O)--(CH.sub.2).sub.k-heterocyclyl,
any of which is optionally substituted with 1, 2, 3, 4 or 5
R.sup.13.
[0137] In particular, R.sup.7 may be --C(O)N(R.sup.11)(R.sup.12).
The invention therefore includes compounds of the following
Formula:
##STR00017## [0138] or a pharmaceutically acceptable salt or
prodrug thereof.
[0139] Particular embodiments of Formula (XVIb) include the
following compounds:
##STR00018## [0140] or, in each case, a pharmaceutically acceptable
salt or prodrug thereof.
[0141] With regard to Formulae (XVIb) to (XXb), R.sup.8 and/or
R.sup.9 is often hydrogen or C.sub.1-6 alkyl optionally substituted
with 1, 2, 3, 4 or 5 R.sup.13. In this case, the or each R.sup.11
is often independently selected from hydroxy, halogen (e.g.
fluorine or chlorine) or C.sub.1-6 (e.g. C.sub.1, C.sub.2, C.sub.3
or C.sub.4) alkoxy. More usually, R.sup.8 and/or R.sup.9 is
hydrogen.
[0142] With regard to Formulae (XVIb) to (XXb), R.sup.11 and
R.sup.12 may be each independently hydrogen or C.sub.1-6 alkyl or
--(CH.sub.2).sub.k-carbocyclyl (e.g. --(CH.sub.2).sub.k-cycloalkyl
or --(CH.sub.2).sub.k-aryl), either of which is optionally
substituted with 1, 2, 3, 4 or 5 R.sup.13. In particular, R.sup.11
and R.sup.12 may be each independently hydrogen or C.sub.1-6 alkyl
optionally substituted with 1, 2, 3, 4 or 5 substituents
independently selected from --OR.sup.14, --C(O)R.sup.14 and
--C(O)OR.sup.14; wherein R.sup.14 is usually hydrogen or selected
from C.sub.1-6 alkyl optionally substituted with 1, 2, 3, 4 or 5
R.sup.13.
[0143] Alternatively, R.sup.11 and R.sup.12 taken together with the
nitrogen atom to which they are attached may form heterocyclyl
(e.g. heterocycloalkyl or heteroaryl) optionally substituted with
1, 2, 3, 4 or 5 R.sup.13. Of particular mention are 5- or
6-membered heterocyclyl groups, especially 6-membered heterocyclyl
groups, or a 9- or 10-membered ring, especially a 9-membered
heterocyclyl groups, which are optionally substituted with 1, 2, 3,
4 or 5 (e.g. 1, 2 or 3) R.sup.13. In particular, R.sup.11 and
R.sup.12 taken together with the attached nitrogen atom may form
heterocycloalkyl (e.g. pyrrolidinyl, piperidinyl, piperazinyl,
morpholinyl, thiomorpholinyl, or triazolopyrazinyl (e.g.
[1,2,4]triazolo[4,3-a]pyrazin-7-yl)) optionally substituted with 1,
2, 3, 4 or 5 (e.g. 1, 2, or 3) R.sup.13. In this case, the
heterocycloalkyl ring is often a 5- or 6-membered ring, especially
a 6-membered ring or a 9- or 10-membered ring, especially a
9-membered ring.
[0144] In another embodiment, R.sup.11 is R.sup.10; and R.sup.12 is
--C(O)R.sup.10. In this case, R.sup.11 may be hydrogen or C.sub.1-6
alkyl optionally substituted with 1, 2, 3, 4 or 5 R.sup.13; and
R.sup.12 may be --C(O)--C.sub.1-6 alkyl,
--C(O)--(CH.sub.2).sub.k-carbocyclyl-C(O)--(CH.sub.2).sub.k-heterocyclyl,
any of which is optionally substituted with 1, 2, 3, 4 or 5
R.sup.13.
[0145] Particular embodiments of Formula (XI) include the following
compounds:
##STR00019## [0146] or, in each case, a pharmaceutically acceptable
salt or prodrug thereof.
[0147] With regard to Formulae (XXI) to (XXIV), R.sup.13a is
R.sup.13. In a preferred embodiment the R.sup.13a substituents are
independently from each other selected from halogen (preferably
--Cl or --F) or C.sub.1-6 alkyl (preferably methyl or ethyl) or
C.sub.1-6 alkoxy (preferably methoxy or ethoxy).
[0148] In compounds of the above Formulae, p is 0, 1, 2 or 3.
[0149] In compounds of the above Formulae, the phenyl group
substituted with the R.sup.13a substituents is one of the following
groups:
##STR00020##
[0150] In other embodiments, one of a Cl or F atom shown in the
above groups is exchanged for the other. Methyl and methoxy may be
similarly exchanged.
[0151] In compounds of the above Formulae, R.sup.8 and/or R.sup.9
is often hydrogen or C.sub.1-6 alkyl optionally substituted with 1,
2, 3, 4 or 5 R.sup.13.
[0152] In a preferred embodiment R.sup.8 and/or R.sup.9 is
hydrogen.
[0153] With regard to Formulae (XCI) to (XXIV), R.sup.11 and
R.sup.12 may be each independently hydrogen or C.sub.1-6 alkyl or
--(CH.sub.2).sub.k-carbocyclyl (e.g. --(CH.sub.2).sub.k-cycloalkyl
or --(CH.sub.2).sub.k-aryl), or --(CH.sub.2).sub.k-heterocyclyl, or
--C(O)--(CH.sub.2).sub.k-heterocyclyl,
--C(O)--(CH.sub.2).sub.k-cycloalkyl or --C(O)--C.sub.1-6 alkyl,
either of which is optionally substituted with 1, 2, 3, 4 or 5
R.sup.13.
[0154] In particular, R.sup.11 and R.sup.12 may be each
independently hydrogen or C.sub.1-6 alkyl optionally substituted
with 1, 2, 3, 4 or 5 substituents independently selected from
--OR.sup.14, --C(O)R.sup.14 and --C(O)OR.sup.14; wherein R.sup.14
is usually hydrogen or selected from C.sub.1-6 alkyl optionally
substituted with 1, 2, 3, 4 or 5 R.sup.13.
[0155] In a further embodiment R.sup.11 may be hydrogen or
C.sub.1-6 alkyl optionally substituted with 1, 2, 3, 4 or 5
R.sup.13 (preferably R.sup.13 is then selected from halogen, cyano,
amino, hydroxy and C.sub.1-6 alkoxy), and R.sup.12 may be hydrogen
or C.sub.1-6 alkyl or --(CH.sub.2).sub.k-carbocyclyl (e.g.
--(CH.sub.2).sub.k-cycloalkyl or --(CH.sub.2).sub.k-aryl), or
--(CH.sub.2).sub.k-heterocyclyl, or
--C(O)--(CH.sub.2).sub.k-heterocyclyl,
--C(O)--(CH.sub.2).sub.k-cycloalkyl or --C(O)--C.sub.1-6 alkyl,
either of which is optionally substituted with 1, 2, 3, 4 or 5
R.sup.13. Typically, each R.sup.13 is independently selected from
oxo, halogen (e.g. fluorine, chlorine or bromine), hydroxy, cyano,
amino, --C(O)OH, C.sub.1-6 alkyl, C.sub.1-6 alkoxy (e.g. C.sub.1,
C.sub.2, C.sub.3 or C.sub.4 alkoxy), --C(O)--C.sub.1-6 alkyl,
--C(O)O--C.sub.1-6 alkyl, --S(O).sub.l--C.sub.1-6 alkyl,
--NH(C.sub.1-6 alkyl) and --N(C.sub.1-6 alkyl).sub.2, benzyl,
phenyl, wherein any C.sub.1-6 alkyl group or aryl group, present is
optionally substituted with 1, 2, 3, 4 or 5 substituents
independently selected from halogen, cyano, amino, hydroxy and
C.sub.1-6 alkoxy.
[0156] In particular, R.sup.11 may be hydrogen and R.sup.12 may be
each independently hydrogen or C.sub.1-6 alkyl optionally
substituted with 1, 2, 3, 4 or 5 substituents independently
selected from --OR.sup.14, --C(O)R.sup.14 and --C(O)OR.sup.14;
wherein R.sup.14 is usually hydrogen or selected from C.sub.1-6
alkyl optionally substituted with 1, 2, 3, 4 or 5 R.sup.13.
[0157] In a further embodiment R.sup.11 may be hydrogen or
C.sub.1-6 alkyl optionally substituted with 1, 2, 3, 4 or 5
R.sup.13 (preferably R.sup.13 is then selected from halogen, cyano,
amino, hydroxy and C.sub.1-6 alkoxy), and R.sup.12 may be hydrogen
or C.sub.1-6 alkyl or --(CH.sub.2).sub.k-cycloalkyl or
--(CH.sub.2).sub.k-aryl, or --(CH.sub.2).sub.k-heterocyclyl, or
--C(O)--(CH.sub.2).sub.k-heterocyclyl,
--C(O)--(CH.sub.2).sub.k-cycloalkyl or --C(O)--C.sub.1-6 alkyl,
either of which is optionally substituted with 1, 2, 3, 4 or 5
R.sup.13. Typically, each R.sup.13 is independently selected from
oxo, halogen (e.g. fluorine, chlorine or bromine), hydroxy, cyano,
amino, --C(O)OH, C.sub.1-6 alkyl, C.sub.1-6 alkoxy (e.g. C.sub.1,
C.sub.2, C.sub.3 or C.sub.4 alkoxy), --C(O)--C.sub.1-6 alkyl,
--C(O)O--C.sub.1-6 alkyl, --S(O).sub.rC.sub.1-6 alkyl,
--NH(C.sub.1-6 alkyl) and --N(C.sub.1-6 alkyl).sub.2, benzyl,
phenyl, wherein any C.sub.1-6 alkyl group or aryl group, present is
optionally substituted with 1, 2, 3, 4 or 5 substituents
independently selected from halogen, cyano, amino, hydroxy and
C.sub.1-6 alkoxy. When R.sup.12 contains a heterocyclyl group it is
in particular a 5- or 6-membered monocyclic heterocycloalkyl group
(in particular piperidinyl, morpholinyl, tetrahydropyranyl,
tetrahydrofuranyl, imidazolidinyl) or a 9- or 10-membered bicyclic
heterocycloalkyl group, or 5- or 6-membered monocyclic heteroaryl
group (in particular pyridinyl, furanyl, pyrimidinyl, pyrazinyl,
imidazolyl, 1-methyl-1H-pyridinyl-2-one) or a 9- or 10-membered
bicyclic heteroaryl group. When R.sup.12 contains a cycloalkyl
group it is in particular a C.sub.3-6 cycloalkyl group (e.g.
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl) or a C.sub.7-10
bicyclic cycloalkyl (e.g. adamantly, bicycloheptyl). When R.sup.12
contains an aryl group it is in particular a phenyl group.
[0158] Alternatively, R.sup.11 and R.sup.12 taken together with the
nitrogen atom to which they are attached may form heterocyclyl
(e.g. heterocycloalkyl or heteroaryl) optionally substituted with
1, 2, 3, 4 or 5 R.sup.13. Of particular mention are 5- or
6-membered heterocyclyl groups, especially 6-membered heterocyclyl
groups, or a 9- or 10-membered ring, especially a 9-membered ring,
which are optionally substituted with 1, 2, 3, 4 or 5 (e.g. 1, 2 or
3) R.sup.13. In particular, R.sup.11 and R.sup.12 taken together
with the attached nitrogen atom may form heterocycloalkyl (e.g.
pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl,
thiomorpholinyl, or triazolopyrazinyl (e.g.
[1,2,4]triazolo[4,3-a]pyrazin-7-yl)) optionally substituted with 1,
2, 3, 4 or 5 (e.g. 1, 2, or 3) R.sup.13. In this case, the
heterocycloalkyl ring is often a 5- or 6-membered ring, especially
a 6-membered ring or a 9- or 10-membered ring, especially a
9-membered ring. In particular each R.sup.13 is independently
selected from halogen, trifluoromethyl, cyano, nitro, a spiro
group, amino, oxo, alkyl (preferably C.sub.1-6 alkyl),
--(CH.sub.2).sub.k-heterocyclyl, --(CH.sub.2).sub.k-aryl, C.sub.1-6
alkoxy, --C(O)--C.sub.1-6 alkyl,
--C(O)--(CH.sub.2).sub.k-cycloalkyl,
--C(O)--(CH.sub.2).sub.k-heterocyclyl,
--C(O)O--(CH.sub.2).sub.k-aryl, --C(O)O--(C.sub.1-6 alkyl),
--(CH.sub.2).sub.k--C(O)-heterocyclyl, --S(O).sub.2--(C.sub.1-6
alkyl), --NH--(C.sub.1-6 alkyl), --N(C.sub.1-6 alkyl)(C.sub.1-6
alkyl), --C(O)NH--(C.sub.1-6 alkyl), --C(O)N(C.sub.1-6
alkyl)(C.sub.1-6 alkyl). When R.sup.13 contains a spiro group, a
heterocyclyl group, a cycloalkyl group, an aryl group, or an alkyl
group, such group is optionally substituted with 1, 2, 3, 4 or 5
substituents independently selected from halogen, cyano, oxo,
amino, hydroxy, --C(O)--C.sub.1-6 alkyl, C.sub.1-6 alkyl and
C.sub.1-6 alkoxy. When R.sup.13 contains a heterocyclyl group it is
a 5- or 6-membered monocyclic heterocycloalkyl group (in particular
piperidinyl, morpholinyl, tetrahydropyranyl, tetrahydrofuranyl,
imidazolidinyl) or a 9- or 10-membered bicyclic heterocycloalkyl
group, or 5- or 6-membered monocyclic heteroaryl group (in
particular pyridinyl, furanyl, pyrimidinyl, pyrazinyl, imidazolyl,
1-methyl-1H-pyridinyl-2-one) or a 9- or 10-membered bicyclic
heteroaryl group. When R.sup.13 contains a cycloalkyl group it is
in particular a C.sub.3-6 cycloalkyl group e.g. cyclopropane,
cyclobutane, cyclopentane, cyclohexane. When R.sup.13 contains an
aryl group it is in particular a phenyl group. When R.sup.13
contains a spiro group it is in particular a 5-membered
heterocyclic group (in particular oxazolan).
[0159] In a further embodiment when R.sup.11 and R.sup.12 taken
together with the nitrogen atom to which they are attached form
heterocyclyl the formed heterocyclyl can be selected from
##STR00021##
and can optionally be substituted with 1, 2 or 3 R.sup.13 moieties
preferably selected from oxo, trifluoromethyl, halogen, C.sub.1-6
alkyl and C.sub.1-6 alkoxy.
[0160] R.sup.13a is hydrogen or is R.sup.13. R.sup.13a is
preferably selected from hydrogen, halogen, trifluoromethyl, cyano,
nitro, a spiro group, amino, oxo, alkyl (preferably C.sub.1-6
alkyl), --(CH.sub.2).sub.k-heterocyclyl, --(CH.sub.2).sub.k-aryl,
C.sub.1-6 alkoxy, --C(O)--C.sub.1-6 alkyl,
--C(O)--(CH.sub.2).sub.k-cycloalkyl,
--C(O)--(CH.sub.2).sub.k-heterocyclyl,
--C(O)O--(CH.sub.2).sub.k-aryl, --C(O)O--(C.sub.1-6 alkyl),
--(CH.sub.2).sub.k--C(O)-heterocyclyl, --S(O).sub.2--(C.sub.1-6
alkyl), --NH--(C.sub.1-6 alkyl), --N(C.sub.1-6 alkyl)(C.sub.1-6
alkyl), --C(O)NH--(C.sub.i alkyl), --C(O)N(C.sub.1-6
alkyl)(C.sub.1-6 alkyl). When R.sup.13a contains a spiro group, a
heterocyclyl group, a cycloalkyl group, an aryl group, or an alkyl
group, such group is optionally substituted with 1, 2, 3, 4 or 5
substituents independently selected from halogen, cyano, oxo,
amino, hydroxy, --C(O)--C.sub.1-6 alkyl, C.sub.1-6 alkyl and
C.sub.1-6 alkoxy. When R.sup.13a contains a heterocyclyl group it
is a 5- or 6-membered monocyclic heterocycloalkyl group (in
particular piperidinyl, morpholinyl, tetrahydropyranyl,
tetrahydrofuranyl, imidazolidinyl) or a 9- or 10-membered bicyclic
heterocycloalkyl group, or 5- or 6-membered monocyclic heteroaryl
group (in particular pyridinyl, furanyl, pyrimidinyl, pyrazinyl,
imidazolyl, 1-methyl-1H-pyridinyl-2-one) or a 9- or 10-membered
bicyclic heteroaryl group. When R.sup.13 contains a cycloalkyl
group it is in particular a C.sub.3-6 cycloalkyl group e.g.
cyclopropane, cyclobutane, cyclopentane, cyclohexane. When
R.sup.13a contains an aryl group it is in particular a phenyl
group. When R.sup.13a contains a spiro group it is in particular a
5-membered heterocyclic group (in particular oxazolan or
azolan-2-one). When R.sup.13a is --S(O).sub.2--(C.sub.1-6 alkyl) it
is in particular --S(O).sub.2--CH.sub.3 or
--S(O).sub.2--CH.sub.2CH.sub.3.
[0161] In one family of compounds the only substituent is
R.sup.13a.
[0162] In a second family of compounds, R.sup.13a is different from
hydrogen and the heterocyclyl is substituted by one or two
substituents, selected independently from each other, from methyl,
methoxy and oxo.
[0163] In a third family of compounds, R.sup.13a is hydrogen and
the heterocyclyl is substituted by one or two substituents,
selected independently from each other, from methyl,
trifluoromethyl, methoxy and oxo.
[0164] In another embodiment, R.sup.11 is R.sup.10; and R.sup.12 is
--C(O)R.sup.10. In this case, R.sup.11 may be hydrogen or C.sub.1-6
alkyl optionally substituted with 1, 2, 3, 4 or 5 R.sup.13; and
R.sup.12 may be --C(O)--C.sub.1-6 alkyl,
--C(O)--(CH.sub.2).sub.k-carbocyclyl or
--C(O)--(CH.sub.2).sub.k-heterocyclyl, any of which is optionally
substituted with 1, 2, 3, 4 or 5 R.sup.13.
[0165] Particular embodiments of Formula (XVI) include the
following compounds:
##STR00022## [0166] or, in each case, a pharmaceutically acceptable
salt or prodrug thereof.
[0167] In compounds of the above Formulae (XXV to XXVIII), j is 0
or 1.
[0168] In compounds of the above Formulae, R.sup.13a is R.sup.13.
In a preferred embodiment the R.sup.13a substituents are
independently from each other selected from halogen (preferably
--Cl or --F) or C.sub.1-6 alkyl (preferably methyl or ethyl) or
C.sub.1-6 alkoxy (preferably methoxy or ethoxy).
[0169] In compounds of the above Formulae, p is 0, 1, 2 or 3.
[0170] In compounds of the above Formulae, the phenyl group
substituted with the R.sup.13a substituents is one of the following
groups:
##STR00023##
[0171] In other embodiments, one of a Cl or F atom shown in the
above groups is exchanged for the other. Methyl and methoxy may be
similarly exchanged.
[0172] In compounds of the above Formulae in a further embodiment
R.sup.6 is selected from halogen, trifluoromethyl, cyano, nitro,
amino, hydroxy, 5- or 6-membered heterocycloalkyl,
--(CH.sub.2).sub.k-heterocycloalkyl, --C(O)-heterocycloalkyl,
--C(O)--NH-heterocycloalkyl, --NH--C(O)--C.sub.1-6alkyl,
--NH--(CH.sub.2).sub.k-heterocycloalkyl, C.sub.1-6alkyl,
C.sub.1-6alkoxy, --NH--C.sub.1-6 alkyl, --N(C.sub.1-6
alkyl)(C.sub.1-6 alkyl), --NH--(C.sub.3-6 cycloalkyl),
--N(C.sub.3-6 cycloalkyl)(C.sub.5-6 cycloalkyl),
--(CH.sub.2).sub.k--(C.sub.3-6 cycloalkyl), --(CH.sub.2).sub.k-aryl
(preferably substituted or unsubstituted phenyl),
--NH--(CH.sub.2).sub.k--C.sub.3-6cycloalkyl or
--NH--(CH.sub.2).sub.k-aryl, wherein the alkyl, cycloalkyl,
heterocycloalkyl or aryl moieties can be substituted by 1, 2, 3 or
4 substituents selected from halogen, hydroxy, C.sub.1-6 alkoxy,
C.sub.1-6 alkyl, --CH.sub.2--NH.sub.2, or amino. Wherein the
heterocycloalkyl is preferably a 5- or 6 membered heterocycloalkyl
(e.g.
[0173] The compounds of the above Formulae wherein R.sup.6 is
hydrogen.
[0174] The compounds of the above Formulae wherein R.sup.6 is
amino.
[0175] The compounds of the above Formulae wherein R.sup.6 is
amino, --NH--C.sub.1-6 alkyl, --N(C.sub.1-6 alkyl)(C.sub.1-6
alkyl), --NH--(C.sub.3-6 cycloalkyl), C.sub.1-6alkoxy,
C.sub.1-6alkyl, optionally substituted by halogen, hydroxy,
C.sub.1-6 alkoxy, C.sub.1-6 alkyl, or amino.
[0176] In compounds of the above Formulae, R.sup.8 and/or R.sup.9
is often hydrogen or C.sub.1-6 alkyl optionally substituted with 1,
2, 3, 4 or 5 R.sup.13. In this case, the or each R.sup.13 is often
independently selected from hydroxy, halogen (e.g. fluorine or
chlorine) or C.sub.1-6 (e.g. C.sub.1, C.sub.2, C.sub.3 or C.sub.4)
alkoxy.
[0177] In a preferred embodiment R.sup.8 and/or R.sup.9 is
hydrogen.
[0178] With regard to Formulae (XXV) to (XXVIII), R.sup.11 and
R.sup.12 may be each independently hydrogen or C.sub.1-6 alkyl or
--(CH.sub.2).sub.k-carbocyclyl (e.g. --(CH.sub.2).sub.k-cycloalkyl
or --(CH.sub.2).sub.k-aryl), or --(CH.sub.2).sub.k-heterocyclyl, or
--C(O)--(CH.sub.2).sub.k-heterocyclyl,
--C(O)--(CH.sub.2).sub.k-cycloalkyl or --C(O)--C.sub.1-6 alkyl,
either of which is optionally substituted with 1, 2, 3, 4 or 5
R.sup.13.
[0179] In particular, R.sup.11 and R.sup.12 may be each
independently hydrogen or C.sub.1-6 alkyl optionally substituted
with 1, 2, 3, 4 or 5 substituents independently selected from
--OR.sup.14, --C(O)R.sup.14 and --C(O)OR.sup.14; wherein R.sup.14
is usually hydrogen or selected from C.sub.1-6 alkyl optionally
substituted with 1, 2, 3, 4 or 5 R.sup.13.
[0180] In a further embodiment R.sup.11 may be hydrogen or
C.sub.1-6 alkyl optionally substituted with 1, 2, 3, 4 or 5
R.sup.13 (preferably R.sup.13 is then selected from halogen, cyano,
amino, hydroxy and C.sub.1-6 alkoxy), and R.sup.12 may be hydrogen
or C.sub.1-6 alkyl or --(CH.sub.2).sub.k-carbocyclyl (e.g.
--(CH.sub.2).sub.k-cycloalkyl or --(CH.sub.2).sub.k-aryl), or
--(CH.sub.2).sub.k-heterocyclyl, or
--C(O)--(CH.sub.2).sub.k-heterocyclyl,
--C(O)--(CH.sub.2).sub.k-cycloalkyl or --C(O)--C.sub.1-6 alkyl,
either of which is optionally substituted with 1, 2, 3, 4 or 5
R.sup.13. Typically, each R.sup.13 is independently selected from
oxo, halogen (e.g. fluorine, chlorine or bromine), hydroxy, cyano,
amino, --C(O)OH, C.sub.1-6 alkyl, C.sub.1-6 alkoxy (e.g. C.sub.1,
C.sub.2, C.sub.3 or C.sub.4 alkoxy), --C(O)--C.sub.1-6 alkyl,
--C(O)O--C.sub.1-6 alkyl, --S(O).sub.l--C.sub.1-6 alkyl,
--NH(C.sub.1-6 alkyl) and --N(C.sub.1-6 alkyl).sub.2, benzyl,
phenyl, wherein any C.sub.1-6 alkyl group or aryl group, present is
optionally substituted with 1, 2, 3, 4 or 5 substituents
independently selected from halogen, cyano, amino, hydroxy and
C.sub.1-6 alkoxy.
[0181] In particular, R.sup.11 may be hydrogen and R.sup.12 may be
each independently hydrogen or C.sub.1-6 alkyl optionally
substituted with 1, 2, 3, 4 or 5 substituents independently
selected from --OR.sup.14, --C(O)R.sup.14 and --C(O)OR.sup.14;
wherein R.sup.14 is usually hydrogen or selected from C.sub.1-6
alkyl optionally substituted with 1, 2, 3, 4 or 5 R.sup.13.
[0182] In a further embodiment R.sup.11 may be hydrogen or
C.sub.1-6 alkyl optionally substituted with 1, 2, 3, 4 or 5
R.sup.13 (preferably R.sup.13 is then selected from halogen, cyano,
amino, hydroxy and C.sub.1-6 alkoxy), and R.sup.12 may be hydrogen
or C.sub.1-6 alkyl or --(CH.sub.2).sub.k-cycloalkyl or
--(CH.sub.2).sub.k-aryl, or --(CH.sub.2).sub.k-heterocyclyl, or
--C(O)--(CH.sub.2).sub.k-heterocyclyl,
--C(O)--(CH.sub.2).sub.k-cycloalkyl or --C(O)--C.sub.1-6 alkyl,
either of which is optionally substituted with 1, 2, 3, 4 or 5
R.sup.13. Typically, each R.sup.13 is independently selected from
oxo, halogen (e.g. fluorine, chlorine or bromine), hydroxy, cyano,
amino, --C(O)OH, C.sub.1-6 alkyl, C.sub.1-6 alkoxy (e.g. C.sub.1,
C.sub.2, C.sub.3 or C.sub.4 alkoxy), --C(O)--C.sub.1-6 alkyl,
--C(O)O--C.sub.1-6 alkyl, --S(O).sub.l--C.sub.1-6 alkyl,
--NH(C.sub.1-6 alkyl) and --N(C.sub.1-6 alkyl).sub.2, benzyl,
phenyl, wherein any C.sub.1-6 alkyl group or aryl group, present is
optionally substituted with 1, 2, 3, 4 or 5 substituents
independently selected from halogen, cyano, amino, hydroxy and
C.sub.1-6 alkoxy. When R.sup.12 contains a heterocyclyl group it is
in particular a 5- or 6-membered monocyclic heterocycloalkyl group
(in particular piperidinyl, morpholinyl, tetrahydropyranyl,
tetrahydrofuranyl, imidazolidinyl) or a 9- or 10-membered bicyclic
heterocycloalkyl group, or 5- or 6-membered monocyclic heteroaryl
group (in particular pyridinyl, furanyl, pyrimidinyl, pyrazinyl,
imidazolyl, 1-methyl-1H-pyridinyl-2-one) or a 9- or 10-membered
bicyclic heteroaryl group. When R.sup.12 contains a cycloalkyl
group it is in particular a C.sub.3-6 cycloalkyl group (e.g.
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl) or a C.sub.7-10
bicyclic cycloalkyl (e.g. adamantly, bicycloheptyl). When R.sup.12
contains an aryl group it is in particular a phenyl group.
[0183] Alternatively, R.sup.11 and R.sup.12 taken together with the
nitrogen atom to which they are attached may form heterocyclyl
(e.g. heterocycloalkyl or heteroaryl) optionally substituted with
1, 2, 3, 4 or 5 R.sup.13. Of particular mention are 5- or
6-membered heterocyclyl groups, especially 6-membered heterocyclyl
groups, or a 9- or 10-membered ring, especially a 9-membered ring,
which are optionally substituted with 1, 2, 3, 4 or 5 (e.g. 1, 2 or
3) R.sup.13. In particular, R.sup.11 and R.sup.12 taken together
with the attached nitrogen atom may form heterocycloalkyl (e.g.
pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl,
thiomorpholinyl, or triazolopyrazinyl (e.g.
[1,2,4]triazolo[4,3-a]pyrazin-7-yl)) optionally substituted with 1,
2, 3, 4 or 5 (e.g. 1, 2, or 3) R.sup.13. In this case, the
heterocycloalkyl ring is often a 5- or 6-membered ring, especially
a 6-membered ring or a 9- or 10-membered ring, especially a
9-membered ring. In particular each R.sup.13 is independently
selected from halogen, trifluoromethyl, cyano, nitro, a spiro
group, amino, oxo, alkyl (preferably C.sub.1-6 alkyl),
--(CH.sub.2).sub.k-heterocyclyl, --(CH.sub.2).sub.k-aryl, C.sub.1-6
alkoxy, --C(O)--C.sub.1-6 alkyl,
--C(O)--(CH.sub.2).sub.k-cycloalkyl,
--C(O)--(CH.sub.2).sub.k-heterocyclyl,
--C(O)O--(CH.sub.2).sub.k-aryl, --C(O)O--(C.sub.1-6 alkyl),
--(CH.sub.2).sub.k--C(O)-heterocyclyl, --S(O).sub.2--(C.sub.1-6
alkyl), --NH--(C.sub.1-6 alkyl), --N(C.sub.1-6 alkyl)(C.sub.1-6
alkyl), --C(O)NH--(C.sub.1-6 alkyl), --C(O)N(C.sub.1-6
alkyl)(C.sub.1-6 alkyl). When R.sup.13 contains a spiro group, a
heterocyclyl group, a cycloalkyl group, an aryl group, or an alkyl
group, such group is optionally substituted with 1, 2, 3, 4 or 5
substituents independently selected from halogen, cyano, oxo,
amino, hydroxy, --C(O)--C.sub.1-6 alkyl, C.sub.1-6 alkyl and
C.sub.1-6 alkoxy. When R.sup.13 contains a heterocyclyl group it is
a 5- or 6-membered monocyclic heterocycloalkyl group (in particular
piperidinyl, morpholinyl, tetrahydropyranyl, tetrahydrofuranyl,
imidazolidinyl) or a 9- or 10-membered bicyclic heterocycloalkyl
group, or 5- or 6-membered monocyclic heteroaryl group (in
particular pyridinyl, furanyl, pyrimidinyl, pyrazinyl, imidazolyl,
1-methyl-1H-pyridinyl-2-one) or a 9- or 10-membered bicyclic
heteroaryl group. When R.sup.13 contains a cycloalkyl group it is
in particular a C.sub.3-6 cycloalkyl group e.g. cyclopropane,
cyclobutane, cyclopentane, cyclohexane. When R.sup.13 contains an
aryl group it is in particular a phenyl group. When R.sup.13
contains a spiro group it is in particular a 5-membered
heterocyclic group (in particular oxazolan).
[0184] In a further embodiment when R.sup.11 and R.sup.12 taken
together with the nitrogen atom to which they are attached form
heterocyclyl the formed heterocyclyl can be selected from
##STR00024##
and can optionally be substituted with 1, 2 or 3 R.sup.13 moieties
preferably selected from halogen, oxo, trifluoromethyl, C.sub.1-6
alkyl and C.sub.1-6 alkoxy.
[0185] R.sup.13a is hydrogen or is R.sup.13. R.sup.13a is
preferably selected from hydrogen, halogen, trifluoromethyl, cyano,
nitro, a spiro group, amino, oxo, alkyl (preferably C.sub.1-6
alkyl), --(CH.sub.2).sub.k-heterocyclyl, --(CH.sub.2).sub.k-aryl,
C.sub.1-6 alkoxy, --C(O)--C.sub.1-6 alkyl,
--C(O)--(CH.sub.2).sub.k-cycloalkyl,
--C(O)--(CH.sub.2).sub.k-heterocyclyl,
--C(O)O--(CH.sub.2).sub.k-aryl, --C(O)O--(C.sub.1-6 alkyl),
--(CH.sub.2).sub.k--C(O)-heterocyclyl, --S(O).sub.2--(C.sub.1-6
alkyl), --NH--(C.sub.1-6 alkyl), --N(C.sub.1-6 alkyl)(C.sub.1-6
alkyl), --C(O)NH--(C.sub.1-6 alkyl), --C(O)N(C.sub.1-6
alkyl)(C.sub.1-6 alkyl). When R.sup.13a contains a spiro group, a
heterocyclyl group, a cycloalkyl group, an aryl group, or an alkyl
group, such group is optionally substituted with 1, 2, 3, 4 or 5
substituents independently selected from halogen, cyano, oxo,
amino, hydroxy, --C(O)--C.sub.1-6 alkyl, C.sub.1-6 alkyl and
C.sub.1-6 alkoxy. When R.sup.13a contains a heterocyclyl group it
is a 5- or 6-membered monocyclic heterocycloalkyl group (in
particular piperidinyl, morpholinyl, tetrahydropyranyl,
tetrahydrofuranyl, imidazolidinyl) or a 9- or 10-membered bicyclic
heterocycloalkyl group, or 5- or 6-membered monocyclic heteroaryl
group (in particular pyridinyl, furanyl, pyrimidinyl, pyrazinyl,
imidazolyl, 1-methyl-1H-pyridinyl-2-one) or a 9- or 10-membered
bicyclic heteroaryl group. When R.sup.13 contains a cycloalkyl
group it is in particular a C.sub.3-6 cycloalkyl group e.g.
cyclopropane, cyclobutane, cyclopentane, cyclohexane. When
R.sup.13a contains an aryl group it is in particular a phenyl
group. When R.sup.13a contains a spiro group it is in particular a
5-membered heterocyclic group (in particular oxazolan or
azolan-2-one). When R.sup.13a is --S(O).sub.2--(C.sub.1-6 alkyl) it
is in particular --S(O).sub.2--CH.sub.3 or
--S(O).sub.2--CH.sub.2CH.sub.3.
[0186] In one family of compounds the only substituent is
R.sup.13a.
[0187] In a second family of compounds, R.sup.13a is different from
hydrogen and the heterocyclyl is substituted by one or two
substituents, selected independently from each other, from methyl,
methoxy and oxo.
[0188] In a third family of compounds, R.sup.13a is hydrogen and
the heterocyclyl is substituted by one or two substituents,
selected independently from each other, from methyl,
trifluoromethyl, methoxy and oxo.
[0189] In another embodiment, R.sup.11 is R.sup.10; and R.sup.12 is
--C(O)R.sup.10. In this case, R.sup.11 may be hydrogen or C.sub.1-6
alkyl optionally substituted with 1, 2, 3, 4 or 5 R.sup.13; and
R.sup.12 may be --C(O)--C.sub.1-6 alkyl,
--C(O)--(CH.sub.2).sub.k-carbocyclyl-C(O)--(CH.sub.2).sub.k-heterocyclyl,
any of which is optionally substituted with 1, 2, 3, 4 or 5
R.sup.13. In particular, the carbocyclyl is a C.sub.5 to C.sub.12
cycloalkyl (e.g. cyclopentyl, cyclohexy, bicycloheptyl, adamantly),
or a phenyl. In particular the heterocyclyl is a 5- or 6-membered
monocyclic heterocyclyl (e.g. piperidinyl, piperazinyl,
tetrahydropyranyl) or a 9- or 10-membered bicyclic hererocyclyl
(e.g. tetrahydro-2H-pyridopyridazinyl).
[0190] Particular embodiments of Formula (XI) include the following
compounds:
##STR00025## [0191] or, in each case, a pharmaceutically acceptable
salt or prodrug thereof.
[0192] In compounds of the above Formulae (XXIX to XXXII), j is 0
or 1.
[0193] In compounds of the above Formulae, R.sup.13a is R.sup.13.
In a preferred embodiment the R.sup.13a substituents are
independently from each other selected from halogen (preferably
--Cl or --F) or C.sub.1-6 alkyl (preferably methyl or ethyl) or
C.sub.1-6 alkoxy (preferably methoxy or ethoxy).
[0194] In compounds of the above Formulae, p is 0, 1, 2 or 3.
[0195] In compounds of the above Formulae, the phenyl group
substituted with the R.sup.13a substituents is one of the following
groups:
##STR00026##
[0196] In other embodiments, one of a Cl or F atom shown in the
above groups is exchanged for the other. Methyl and methoxy may be
similarly exchanged.
[0197] In compounds of the above Formulae, R.sup.8 and/or R.sup.9
is often hydrogen or C.sub.1-6 alkyl optionally substituted with 1,
2, 3, 4 or 5 R.sup.13. In this case, the or each R.sup.13 is often
independently selected from hydroxy, halogen (e.g. fluorine or
chlorine) or C.sub.1-6 (e.g. C.sub.1, C.sub.2, C.sub.3 or C.sub.4)
alkoxy.
[0198] In a preferred embodiment, R.sup.8 and/or R.sup.9 is
hydrogen.
[0199] With regard to Formulae (XXIX) to (XXXII), R.sup.11 and
R.sup.12 may be each independently hydrogen or C.sub.1-6 alkyl or
--(CH.sub.2).sub.k-carbocyclyl (e.g. --(CH.sub.2).sub.k-cycloalkyl
or --(CH.sub.2).sub.k-aryl), or --(CH.sub.2).sub.k-heterocyclyl, or
--C(O)--(CH.sub.2).sub.k-heterocyclyl,
--C(O)--(CH.sub.2).sub.k-cycloalkyl or --C(O)--C.sub.1-6 alkyl,
either of which is optionally substituted with 1, 2, 3, 4 or 5
R.sup.13.
[0200] In particular, R.sup.11 and R.sup.12 may be each
independently hydrogen or C.sub.1-6 alkyl optionally substituted
with 1, 2, 3, 4 or 5 substituents independently selected from
--OR.sup.14, --C(O)R.sup.14 and --C(O)OR.sup.14; wherein R.sup.14
is usually hydrogen or selected from C.sub.1-6 alkyl optionally
substituted with 1, 2, 3, 4 or 5 R.sup.13.
[0201] In a further embodiment R.sup.11 may be hydrogen or
C.sub.1-6 alkyl optionally substituted with 1, 2, 3, 4 or 5
R.sup.13 (preferably R.sup.13 is then selected from halogen, cyano,
amino, hydroxy and C.sub.1-6 alkoxy), and R.sup.12 may be hydrogen
or C.sub.1-6 alkyl or --(CH.sub.2).sub.k-carbocyclyl (e.g.
--(CH.sub.2).sub.k-cycloalkyl or --(CH.sub.2).sub.k-aryl), or
--(CH.sub.2).sub.k-heterocyclyl, or
--C(O)--(CH.sub.2).sub.k-heterocyclyl,
--C(O)--(CH.sub.2).sub.k-cycloalkyl or --C(O)--C.sub.1-6 alkyl,
either of which is optionally substituted with 1, 2, 3, 4 or 5
R.sup.13. Typically, each R.sup.13 is independently selected from
oxo, halogen (e.g. fluorine, chlorine or bromine), hydroxy, cyano,
amino, --C(O)OH, C.sub.1-6 alkyl, C.sub.1-6 alkoxy (e.g. C.sub.1,
C.sub.2, C.sub.3 or C.sub.4 alkoxy), --C(O)--C.sub.1-6 alkyl,
--C(O)O--C.sub.1-6 alkyl, --S(O).sub.l--C.sub.1-6 alkyl,
--NH(C.sub.1-6 alkyl) and --N(C.sub.1-6 alkyl).sub.2, benzyl,
phenyl, wherein any C.sub.1-6 alkyl group or aryl group, present is
optionally substituted with 1, 2, 3, 4 or 5 substituents
independently selected from halogen, cyano, amino, hydroxy and
C.sub.1-6 alkoxy.
[0202] In particular, R.sup.11 may be hydrogen and R.sup.12 may be
each independently hydrogen or C.sub.1-6 alkyl optionally
substituted with 1, 2, 3, 4 or 5 substituents independently
selected from --OR.sup.14, --C(O)R.sup.14 and --C(O)OR.sup.14;
wherein R.sup.14 is usually hydrogen or selected from C.sub.1-6
alkyl optionally substituted with 1, 2, 3, 4 or 5 R.sup.13.
[0203] In a further embodiment R.sup.11 may be hydrogen or
C.sub.1-6 alkyl optionally substituted with 1, 2, 3, 4 or 5
R.sup.13 (preferably R.sup.13 is then selected from halogen, cyano,
amino, hydroxy and C.sub.1-6 alkoxy), and R.sup.12 may be hydrogen
or C.sub.1-6 alkyl or --(CH.sub.2).sub.k-cycloalkyl or
--(CH.sub.2).sub.k-aryl, or --(CH.sub.2).sub.k-heterocyclyl, or
--C(O)--(CH.sub.2).sub.k-heterocyclyl,
--C(O)--(CH.sub.2).sub.k-cycloalkyl or --C(O)--C.sub.1-6 alkyl,
either of which is optionally substituted with 1, 2, 3, 4 or 5
R.sup.13. Typically, each R.sup.13 is independently selected from
oxo, halogen (e.g. fluorine, chlorine or bromine), hydroxy, cyano,
amino, --C(O)OH, C.sub.1-6 alkyl, C.sub.1-6 alkoxy (e.g. C.sub.1,
C.sub.2, C.sub.3 or C.sub.4 alkoxy), --C(O)--C.sub.1-6 alkyl,
--C(O)O--C.sub.1-6 alkyl, --S(O).sub.l--C.sub.1-6 alkyl,
--NH(C.sub.1-6 alkyl) and --N(C.sub.1-6 alkyl).sub.2, benzyl,
phenyl, wherein any C.sub.1-6 alkyl group or aryl group, present is
optionally substituted with 1, 2, 3, 4 or 5 substituents
independently selected from halogen, cyano, amino, hydroxy and
C.sub.1-6 alkoxy. When R.sup.12 contains a heterocyclyl group it is
in particular a 5- or 6-membered monocyclic heterocycloalkyl group
(in particular piperidinyl, morpholinyl, tetrahydropyranyl,
tetrahydrofuranyl, imidazolidinyl) or a 9- or 10-membered bicyclic
heterocycloalkyl group, or 5- or 6-membered monocyclic heteroaryl
group (in particular pyridinyl, furanyl, pyrimidinyl, pyrazinyl,
imidazolyl, 1-methyl-1H-pyridinyl-2-one) or a 9- or 10-membered
bicyclic heteroaryl group. When R.sup.12 contains a cycloalkyl
group it is in particular a C.sub.3-6 cycloalkyl group (e.g.
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl) or a C.sub.7-10
bicyclic cycloalkyl (e.g. adamantly, bicycloheptyl). When R.sup.12
contains an aryl group it is in particular a phenyl group.
[0204] Alternatively, R.sup.11 and R.sup.12 taken together with the
nitrogen atom to which they are attached may form heterocyclyl
(e.g. heterocycloalkyl or heteroaryl) optionally substituted with
1, 2, 3, 4 or 5 R.sup.13. Of particular mention are 5- or
6-membered heterocyclyl groups, especially 6-membered heterocyclyl
groups, or a 9- or 10-membered ring, especially a 9-membered ring,
which are optionally substituted with 1, 2, 3, 4 or 5 (e.g. 1, 2 or
3) R.sup.13. In particular, R.sup.11 and R.sup.12 taken together
with the attached nitrogen atom may form heterocycloalkyl (e.g.
pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl,
thiomorpholinyl, or triazolopyrazinyl (e.g.
[1,2,4]triazolo[4,3-a]pyrazin-7-yl)) optionally substituted with 1,
2, 3, 4 or 5 (e.g. 1, 2, or 3) R.sup.13. In this case, the
heterocycloalkyl ring is often a 5- or 6-membered ring, especially
a 6-membered ring or a 9- or 10-membered ring, especially a
9-membered ring. In particular each R.sup.13 is independently
selected from halogen, trifluoromethyl, cyano, nitro, a spiro
group, amino, oxo, alkyl (preferably C.sub.1-6 alkyl),
--(CH.sub.2).sub.k-heterocyclyl, --(CH.sub.2).sub.k-aryl, C.sub.1-6
alkoxy, --C(O)--C.sub.1-6 alkyl,
--C(O)--(CH.sub.2).sub.k-cycloalkyl,
--C(O)--(CH.sub.2).sub.k-heterocyclyl,
--C(O)O--(CH.sub.2).sub.k-aryl, --C(O)O--(C.sub.1-6 alkyl),
--(CH.sub.2).sub.k--C(O)-heterocyclyl, --S(O).sub.2--(C.sub.1-6
alkyl), --NH--(C.sub.1-6 alkyl), --N(C.sub.1-6 alkyl)(C.sub.1-6
alkyl), --C(O)NH--(C.sub.1-6 alkyl), --C(O)N(C.sub.1-6
alkyl)(C.sub.1-6 alkyl). When R.sup.13 contains a spiro group, a
heterocyclyl group, a cycloalkyl group, an aryl group, or an alkyl
group, such group is optionally substituted with 1, 2, 3, 4 or 5
substituents independently selected from halogen, cyano, oxo,
amino, hydroxy, --C(O)--C.sub.1-6 alkyl, C.sub.1-6 alkyl and
C.sub.1-6 alkoxy. When R.sup.13 contains a heterocyclyl group it is
a 5- or 6-membered monocyclic heterocycloalkyl group (in particular
piperidinyl, morpholinyl, tetrahydropyranyl, tetrahydrofuranyl,
imidazolidinyl) or a 9- or 10-membered bicyclic heterocycloalkyl
group, or 5- or 6-membered monocyclic heteroaryl group (in
particular pyridinyl, furanyl, pyrimidinyl, pyrazinyl, imidazolyl,
1-methyl-1H-pyridinyl-2-one) or a 9- or 10-membered bicyclic
heteroaryl group. When R.sup.13 contains a cycloalkyl group it is
in particular a C.sub.3-6 cycloalkyl group e.g. cyclopropane,
cyclobutane, cyclopentane, cyclohexane. When R.sup.13 contains an
aryl group it is in particular a phenyl group. When R.sup.13
contains a spiro group it is in particular a 5-membered
heterocyclic group (in particular oxazolan).
[0205] In a further embodiment when R.sup.11 and R.sup.12 taken
together with the nitrogen atom to which they are attached form
heterocyclyl the formed heterocyclyl can be selected from
##STR00027##
and can optionally be substituted with 1, 2 or 3 R.sup.13 moieties
preferably selected from oxo, trifluoromethyl, halogen, C.sub.1-6
alkyl and C.sub.1-6 alkoxy.
[0206] R.sup.13a is hydrogen or is R.sup.13. R.sup.13a is
preferably selected from hydrogen, halogen, trifluoromethyl, cyano,
nitro, a spiro group, amino, oxo, alkyl (preferably C.sub.1-6
alkyl), --(CH.sub.2).sub.k-heterocyclyl, --(CH.sub.2).sub.k-aryl,
C.sub.1-6 alkoxy, --C(O)--C.sub.1-6 alkyl,
--C(O)--(CH.sub.2).sub.k-cycloalkyl,
--C(O)--(CH.sub.2).sub.k-heterocyclyl,
--C(O)O--(CH.sub.2).sub.k-aryl, --C(O)O--(C.sub.1-6 alkyl),
--(CH.sub.2).sub.k--C(O)-heterocyclyl, --S(O).sub.2--(C.sub.1-6
alkyl), --NH--(C.sub.1-6 alkyl), --N(C.sub.1-6 alkyl)(C.sub.1-6
alkyl), --C(O)NH--(C.sub.1-6 alkyl), --C(O)N(C.sub.1-6
alkyl)(C.sub.1-6 alkyl). When R.sup.13a contains a spiro group, a
heterocyclyl group, a cycloalkyl group, an aryl group, or an alkyl
group, such group is optionally substituted with 1, 2, 3, 4 or 5
substituents independently selected from halogen, cyano, oxo,
amino, hydroxy, --C(O)--C.sub.1-6 alkyl, C.sub.1-6 alkyl and
C.sub.1-6 alkoxy. When R.sup.13a contains a heterocyclyl group it
is a 5- or 6-membered monocyclic heterocycloalkyl group (in
particular piperidinyl, morpholinyl, tetrahydropyranyl,
tetrahydrofuranyl, imidazolidinyl) or a 9- or 10-membered bicyclic
heterocycloalkyl group, or 5- or 6-membered monocyclic heteroaryl
group (in particular pyridinyl, furanyl, pyrimidinyl, pyrazinyl,
imidazolyl, 1-methyl-1H-pyridinyl-2-one) or a 9- or 10-membered
bicyclic heteroaryl group. When R.sup.13 contains a cycloalkyl
group it is in particular a C.sub.3-6 cycloalkyl group e.g.
cyclopropane, cyclobutane, cyclopentane, cyclohexane. When
R.sup.13a contains an aryl group it is in particular a phenyl
group. When R.sup.13a contains a spiro group it is in particular a
5-membered heterocyclic group (in particular oxazolan or
azolan-2-one). When R.sup.13a is --S(O).sub.2--(C.sub.1-6 alkyl) it
is in particular --S(O).sub.2--CH.sub.3 or
--S(O).sub.2--CH.sub.2CH.sub.3.
[0207] In one family of compounds the only substituent is
R.sup.13a.
[0208] In a second family of compounds, R.sup.13a is different from
hydrogen and the heterocyclyl is substituted by one or two
substituents, selected independently from each other, from methyl,
methoxy and oxo.
[0209] In a third family of compounds, R.sup.13a is hydrogen and
the heterocyclyl is substituted by one or two substituents,
selected independently from each other, from methyl,
trifluoromethyl, methoxy and oxo.
[0210] In a further embodiment R.sup.11 may be hydrogen or
C.sub.1-6 alkyl optionally substituted with 1, 2, 3, 4 or 5
R.sup.13 (preferably R.sup.13 is then selected from halogen, cyano,
amino, hydroxy and C.sub.1-6 alkoxy), and R.sup.12 may be hydrogen
or C.sub.1-6 alkyl or --(CH.sub.2).sub.k-carbocyclyl (e.g.
--(CH.sub.2).sub.k-cycloalkyl or --(CH.sub.2).sub.k-aryl), either
of which is optionally substituted with 1, 2, 3, 4 or 5 R.sup.13.
Typically, each R.sup.13 is independently selected from oxo,
halogen (e.g. fluorine, chlorine or bromine), hydroxy, cyano,
amino, --C(O)OH, C.sub.1-6 alkyl, C.sub.1-6 alkoxy (e.g. C.sub.1,
C.sub.2, C.sub.3 or C.sub.4 alkoxy), --C(O)--C.sub.1-6 alkyl,
--C(O)O--C.sub.1-6 alkyl, --S(O), --C.sub.1-6 alkyl, --NH(C.sub.1-6
alkyl) and --N(C.sub.1-6 alkyl).sub.2, wherein any C.sub.1-6 alkyl
group present is optionally substituted with 1, 2, 3, 4 or 5
substituents independently selected from halogen, cyano, amino,
hydroxy and C.sub.1-6 alkoxy.
[0211] In particular, R.sup.11 may be hydrogen and R.sup.12 may be
each independently hydrogen or C.sub.1-6 alkyl optionally
substituted with 1, 2, 3, 4 or 5 substituents independently
selected from --OR.sup.14, --C(O)R.sup.14 and --C(O)OR.sup.14;
wherein R.sup.14 is usually hydrogen or selected from C.sub.1-6
alkyl optionally substituted with 1, 2, 3, 4 or 5 R.sup.13.
[0212] In a further embodiment R.sup.11 may be hydrogen or
C.sub.1-6 alkyl optionally substituted with 1, 2, 3, 4 or 5
R.sup.13 (preferably R.sup.13 is then selected from halogen, cyano,
amino, hydroxy and C.sub.1-6 alkoxy), and R.sup.12 may be hydrogen
or C.sub.1-6 alkyl or --(CH.sub.2).sub.k--C.sub.3-6 cycloalkyl or
--(CH.sub.2).sub.k-phenyl, either of which is optionally
substituted with 1, 2, 3, 4 or 5 R.sup.13. Typically, each R.sup.13
is independently selected from oxo, halogen (e.g. fluorine,
chlorine or bromine), hydroxy, cyano, amino, --C(O)OH, C.sub.1-6
alkyl, C.sub.1-6 alkoxy (e.g. C.sub.1, C.sub.2, C.sub.3 or C.sub.4
alkoxy), --C(O)--C.sub.1-6 alkyl, --C(O)O--C.sub.1-6 alkyl,
--S(O).sub.l--C.sub.1-6 alkyl, --NH(C.sub.1-6 alkyl) and
--N(C.sub.1-6 alkyl).sub.2, wherein any C.sub.1-6 alkyl group
present is optionally substituted with 1, 2, 3, 4 or 5 substituents
independently selected from halogen, cyano, amino, hydroxy and
C.sub.1-6 alkoxy.
[0213] In another embodiment, R.sup.11 is R.sup.10; and R.sup.12 is
--C(O)R.sup.10. In this case, R.sup.11 may be hydrogen or C.sub.1-6
alkyl optionally substituted with 1, 2, 3, 4 or 5 R.sup.13; and
R.sup.12 may be --C(O)--C.sub.1-6 alkyl,
--C(O)--(CH.sub.2).sub.k-carbocyclyl-C(O)--(CH.sub.2).sub.k-heterocyclyl,
any of which is optionally substituted with 1, 2, 3, 4 or 5
R.sup.13. In particular, the carbocyclyl is a C.sub.5 to C.sub.12
cycloalkyl (e.g. cyclopentyl, cyclohexy, bicycloheptyl, adamantly),
or a phenyl. In particular the heterocyclyl is a 5- or 6-membered
monocyclic heterocyclyl (e.g. piperidinyl, piperazinyl,
tetrahydropyranyl) or a 9- or 10-membered bicyclic hererocyclyl
(e.g. tetrahydro-2H-pyridopyridazinyl). Typically, each R.sup.13 is
independently selected from oxo, halogen (e.g. fluorine, chlorine
or bromine), hydroxy, cyano, amino, --C(O)OH, C.sub.1-4 alkyl,
C.sub.1-6 alkoxy (e.g. C.sub.1, C.sub.2, C.sub.3 or C.sub.4
alkoxy), --C(O)--C.sub.1-6 alkyl, --C(O)O--C.sub.1-6 alkyl,
--S(O).sub.l--C.sub.1-6 alkyl, --NH(C.sub.1-6 alkyl) and
--N(C.sub.1-6 alkyl).sub.2, wherein any C.sub.1-6 alkyl group
present is optionally substituted with 1, 2, 3, 4 or 5 substituents
independently selected from halogen, cyano, amino, hydroxy and
C.sub.1-6 alkoxy.
[0214] Particular embodiments of Formula (XI) include the following
compounds:
##STR00028## [0215] or, in each case, a pharmaceutically acceptable
salt or prodrug thereof.
[0216] In compounds of the above Formulae (XXXIII to XXXVI), j is 0
or 1.
[0217] In compounds of the above Formulae, R.sup.13a is R.sup.13.
In a preferred embodiment the R.sup.13a substituents are
independently from each other selected from halogen (preferably
--Cl or --F) or C.sub.1-6 alkyl (preferably methyl or ethyl) or
C.sub.1-6 alkoxy (preferably methoxy or ethoxy).
[0218] In compounds of the above Formulae, p is 0, 1, 2 or 3.
[0219] In compounds of the above Formulae, the phenyl group
substituted with the R.sup.13a substituents is one of the following
groups:
##STR00029##
[0220] In other embodiments, one of a Cl or F atom shown in the
above groups is exchanged for the other. Methyl and methoxy may be
similarly exchanged.
[0221] In compounds of the above Formulae in a further embodiment
R.sup.6 is selected from halogen, trifluoromethyl, cyano, nitro,
amino, hydroxy, 5- or 6-membered heterocycloalkyl, C.sub.1-6 alkyl,
C.sub.1-6 alkoxy, --NH--C.sub.1-6 alkyl, --N(C.sub.1-6
alkyl).sub.2, --NH--(C.sub.5-6 cycloalkyl),
--(CH.sub.2).sub.k--C.sub.3-6cycloalkyl or --(CH.sub.2).sub.k-aryl
(preferably substituted or unsubstituted phenyl),
--NH--(CH.sub.2).sub.k--C.sub.3-6cycloalkyl or
--NH--(CH.sub.2).sub.k-aryl, wherein the alkyl, cycloalkyl or aryl
moieties can be substituted by halogen, hydroxy, C.sub.1-6 alkoxy,
C.sub.1-6 alkyl, or amino.
[0222] In compounds of the above Formulae, R.sup.8 and/or R.sup.9
is often hydrogen or C.sub.1-6 alkyl optionally substituted with 1,
2, 3, 4 or 5 R.sup.13. In this case, the or each R.sup.13 is often
independently selected from hydroxy, halogen (e.g. fluorine or
chlorine) or C.sub.1-6 (e.g. C.sub.1, C.sub.2, C.sub.3 or C.sub.4)
alkoxy.
[0223] In a preferred embodiment R.sup.8 and/or R.sup.9 is
hydrogen.
[0224] In compounds of the above Formulae, R.sup.7 is a 5- or
6-membered heterocyclyl group, especially a 5- or 6-membered
heteroaryl groups, optionally substituted with 1, 2, 3, 4 or 5
R.sup.13. In particular, R.sup.7 may be imidazolyl, pyrazolyl,
pyridinyl, pyrimidinyl, or pyrazinyl, any of which is optionally
substituted with 1, 2 or 3 R.sup.13. Typically, each R.sup.13 is
independently selected from oxo, halogen (e.g. fluorine, chlorine
or bromine), hydroxy, cyano, amino, --C(O)OH, C.sub.1-6 alkyl,
C.sub.1-6 alkoxy (e.g. C.sub.1, C.sub.2, C.sub.3 or C.sub.4
alkoxy), --C(O)--C.sub.1-6 alkyl, --C(O)O--C.sub.1-6 alkyl,
--S(O).sub.l--C.sub.1-6 alkyl, --NH(C.sub.1-6 alkyl) and
--N(C.sub.1-6 alkyl).sub.2, --C(O)--(CH.sub.2).sub.k-heterocyclyl,
--(CH.sub.2).sub.k--C(O)-heterocyclyl, or a 5- or 6-membered
heterocyclyl group (in particular piperidinyl, morpholinyl,
thiomorpholinyl, tetrahydropyranyl), wherein any C.sub.1-6 alkyl
group present is optionally substituted with 1, 2, 3, 4 or 5
substituents independently selected from halogen, cyano, amino,
hydroxyl, C.sub.1-6 alkyl and C.sub.1-6 alkoxy, and wherein the
heterocyclyl group (which is in particular a 5- or 6-membered
heterocyclyl group such as imidazolyl, pyridinyl, pyrimidinyl,
pyrazinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl
or tetrahydropyranyl) is optionally substituted with 1, 2, 3, 4 or
5 substituents independently selected from halogen, cyano, oxo,
amino, hydroxy, C.sub.1-6 alkyl and C.sub.1-6 alkoxy.
[0225] Examples of compounds of the invention include those shown
below. It will of course be appreciated that where a salt is shown,
this is merely an illustrative example and non-limiting and other
forms may be contemplated. Each compound may, therefore, be in the
form of the free compound, an acid or base addition salt, or a
prodrug.
##STR00030## ##STR00031## ##STR00032## ##STR00033## ##STR00034##
##STR00035## ##STR00036## ##STR00037## ##STR00038## ##STR00039##
##STR00040## ##STR00041## ##STR00042## ##STR00043## ##STR00044##
##STR00045## ##STR00046## ##STR00047## ##STR00048## ##STR00049##
##STR00050## ##STR00051## ##STR00052## ##STR00053## ##STR00054##
##STR00055## ##STR00056## ##STR00057## ##STR00058## ##STR00059##
##STR00060## ##STR00061## ##STR00062## ##STR00063## ##STR00064##
##STR00065## ##STR00066## ##STR00067## ##STR00068## ##STR00069##
##STR00070## ##STR00071## ##STR00072## ##STR00073## ##STR00074##
##STR00075##
[0226] Compounds of the invention may be in the form of
pharmaceutically acceptable salts. The pharmaceutically acceptable
salts of the invention can be synthesized from the parent compound
which contains a basic or acidic moiety by conventional chemical
methods. Generally, such salts can be prepared by reacting the free
acid or base forms of these compounds with a stoichiometric amount
of the appropriate base or acid in water or in an organic solvent,
or in a mixture of the two; generally, nonaqueous media like ether,
ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred.
Lists of suitable salts are found in Remington's Pharmaceutical
Sciences, 17th ed., Mack Publishing Company, Easton, Pa., US, 1985,
p. 1418, the disclosure of which is hereby incorporated by
reference; see also Stahl et al, Eds, "Handbook of Pharmaceutical
Salts Properties Selection and Use", Verlag Helvetica Chimica Acta
and Wiley-VCH, 2002.
[0227] The disclosure thus includes pharmaceutically-acceptable
salts of the disclosed compounds wherein the parent compound is
modified by making acid or base salts thereof. For example the
conventional non-toxic salts or the quaternary ammonium salts which
are formed, e.g. from inorganic or organic acids or bases. Examples
of such acid addition salts include acetate, adipate, alginate,
aspartate, benzoate, benzenesulfonate, bisulfate, butyrate,
citrate, camphorate, camphorsulfonate, cyclopentanepropionate,
digluconate, dodecylsulfate, ethanesulfonate, fumarate,
glucoheptanoate, glycerophosphate, hemisulfate, heptanoate,
hexanoate, hydrochloride, hydrobromide, hydroiodide,
2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate,
2-naphthalenesulfonate, nicotinate, oxalate, pamoate, pectinate,
persulfate, 3-phenylpropionate, picrate, pivalate, propionate,
succinate, tartrate, thiocyanate, tosylate, and undecanoate. Base
salts include ammonium salts, alkali metal salts such as sodium and
potassium salts, alkaline earth metal salts such as calcium and
magnesium salts, salts with organic bases such as dicyclohexylamine
salts, N-methyl-D-glucamine, and salts with amino acids such as
arginine, lysine, and so forth. Also, the basic nitrogen-containing
groups may be quaternized with such agents as lower alkyl halides,
such as methyl, ethyl, propyl, and butyl chloride, bromides and
iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl; and
diamyl sulfates, long chain halides such as decyl, lauryl, myristyl
and stearyl chlorides, bromides and iodides, aralkyl halides like
benzyl and phenethyl bromides and others.
[0228] The invention includes prodrugs for the active
pharmaceutical species of the invention, for example in which one
or more functional groups are protected or derivatised but can be
converted in vivo to the functional group, as in the case of esters
of carboxylic acids convertible in vivo to the free acid, or in the
case of protected amines, to the free amino group. The term
"prodrug," as used herein, represents in particular compounds which
are rapidly transformed in vivo to the parent compound, for
example, by hydrolysis in blood. A thorough discussion is provided
in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems,
Vol. 14 of the A.C.S. Symposium Series, Edward B. Roche, ed.,
Bioreversible Carriers in Drug Design, American Pharmaceutical
Association and Pergamon Press, 1987; H Bundgaard, ed, Design of
Prodrugs, Elsevier, 1985; and Judkins, et al. Synthetic
Communications, 26(23), 4351-4367 (1996), each of which is
incorporated herein by reference.
[0229] Prodrugs therefore include drugs having a functional group
which has been transformed into a reversible derivative thereof.
Typically, such prodrugs are transformed to the active drug by
hydrolysis. As examples may be mentioned the following:
TABLE-US-00001 Functional Group Reversible derivative Carboxylic
acid Esters, including e.g. acyloxyalkyl esters, amides Alcohol
Esters, including e.g. sulfates and phosphates as well as
carboxylic acid esters Amine Amides, carbamates, imines, enamines,
Carbonyl (aldehyde, Imines, oximes, acetals/ketals, ketone) enol
esters, oxazolidines and thiazoxolidines
[0230] Prodrugs also include compounds convertible to the active
drug by an oxidative or reductive reaction. As examples may be
mentioned:
[0231] Oxidative Activation [0232] N- and O-dealkylation [0233]
Oxidative deamination [0234] N-oxidation [0235] Epoxidation
[0236] Reductive Activation [0237] Azo reduction [0238] Sulfoxide
reduction [0239] Disulfide reduction [0240] Bioreductive alkylation
[0241] Nitro reduction.
[0242] Also to be mentioned as metabolic activations of prodrugs
are nucleotide activation, phosphorylation activation and
decarboxylation activation. For additional information, see "The
Organic Chemistry of Drug Design and Drug Action", R B Silverman
(particularly Chapter 8, pages 497 to 546), incorporated herein by
reference.
[0243] The use of protecting groups is fully described in
`Protective Groups in Organic Chemistry`, edited by J W F McOmie,
Plenum Press (1973), and `Protective Groups in Organic Synthesis`,
2nd edition, T W Greene & P G M Wutz, Wiley-Interscience
(1991).
[0244] Thus, it will be appreciated by those skilled in the art
that, although protected derivatives of compounds of the disclosure
may not possess pharmacological activity as such, they may be
administered, for example parenterally or orally, and thereafter
metabolised in the body to form compounds of the invention which
are pharmacologically active. Such derivatives are therefore
examples of "prodrugs". All prodrugs of the described compounds are
included within the scope of the disclosure.
[0245] Many of the groups referred to or featured herein
(especially those containing heteroatoms and conjugated bonds) can
exist in tautomeric forms and all these tautomers are included in
the scope of the disclosure. More generally, many species may exist
in equilibrium, as for example in the case of organic acids and
their counterpart anions; a reference herein to a species
accordingly includes reference to all equilibrium forms
thereof.
[0246] The compounds of the disclosure may also contain one or more
asymmetric carbon atoms and may therefore exhibit optical and/or
diastereoisomerism. All diastereoisomers may be separated using
conventional techniques, e.g. chromatography or fractional
crystallisation. The various stereoisomers may be isolated by
separation of a racemic or other mixture of the compounds using
conventional, e.g. fractional crystallisation or HPLC, techniques.
Alternatively the desired optical isomers may be made by reaction
of the appropriate optically active starting materials under
conditions which will not cause racemisation or epimerisation, or
by derivatisation, for example with a homochiral acid followed by
separation of the diastereomeric derivatives by conventional means
(e.g. HPLC, chromatography over silica). All stereoisomers are
included within the scope of the disclosure.
[0247] Geometric isomers may also exist in the compounds of the
present disclosure. The present disclosure contemplates the various
geometric isomers and mixtures thereof resulting from the
arrangement of substituents around a carbon-carbon double bond and
designates such isomers as of the Z or E configuration, wherein the
term "Z" represents substituents on the same side of the
carbon-carbon double bond and the term "E" represents substituents
on opposite sides of the carbon-carbon double bond.
[0248] The disclosure therefore includes all variant forms of the
defined compounds, for example any tautomer or any pharmaceutically
acceptable salt, ester, acid or other variant of the defined
compounds and their tautomers as well as substances which, upon
administration, are capable of providing directly or indirectly a
compound as defined above or providing a species which is capable
of existing in equilibrium with such a compound.
Synthesis
[0249] Scheme A illustrates a general method of preparing compounds
of the invention:
##STR00076##
[0250] In Scheme A, reduction of the cyano group may be performed
either by hydrogenolysis using Pd/C and hydrogen or using a
BH.sub.3-THF complex. Selective Boc-protection of the benzilic
amine may be carried out by treatment with Boc.sub.2O in MeOH at
0.degree. C. in the presence of triethylamine. Selective
halogenation of the heteroaromatic system may be accomplished using
standard procedures such as NBS in DMF, at low temperature or RT.
The cyclization of appropriately functionalized 2-amino-pyridines
may be performed by condensation of the adequate reagent including,
but not limited to chloracetaldehyde,
1-chloro-4-methoxy-butan-2-one, 2-chloro-3-oxo-propionic acid ethyl
ester, or a reagent generated by the condensation of benzotriazole,
glyoxal, and any appropriate secondary amine, for example, as
disclosed by Katritzky et al. (J. Org. Chem., 2003, 68, 4935-4937
and J. Org. Chem., 1990, 55, 3209-3213). The Suzuki coupling may be
performed using an appropriate boronic acid and Pd(PPh.sub.3).sub.4
as a catalyst in a mixture of DME and aqueous Na.sub.2CO.sub.3
under reflux conditions or by heating in a microwave oven. Finally,
the Boc-protecting group may be removed by standard methods known
in the art, such as using TFA in DCM or HCl in dioxane.
[0251] Scheme B illustrates an alternative method for preparing
compounds of the invention:
##STR00077##
[0252] In Scheme B, selective bromation may be accomplished using
standard procedures such as NBS in DMF at low temperature. As
exemplified in the context of Scheme A, the
imidazolo[1,2-a]pyridine moiety may be obtained by cyclization of
the appropriate 2-amino-pyridine with the adequate reagent
including, but not limited to chloracetaldehyde,
1-chloro-4-methoxy-butan-2-one, or a reagent generated by the
condensation of benzotriazole, glyoxal, and any appropriate
secondary amine as disclosed by Katritzky et al. (J. Org. Chem.,
2003, 68, 4935-4937 and J. Org. Chem., 1990, 55, 3209-3213). The
Suzuki coupling may be performed using the appropriate boronic acid
and Pd(PPh.sub.3).sub.4 as a catalyst in a mixture of DME and
aqueous Na.sub.2CO.sub.3 under reflux conditions or by heating in a
microwave oven. The cyano group may be reduced using a BH.sub.3-THF
complex and the benzilic amine may be Boc-protected as described in
Scheme A. Selective halogenation of the imidazole part, followed by
Suzuki coupling and Boc-deprotection may be performed using similar
conditions as those described in respect of Scheme A.
[0253] Scheme C illustrates an alternative method for preparing
compounds of the invention:
##STR00078##
[0254] In Scheme C, Suzuki coupling on the appropriate
5-bromo-2-amino-pyridines may be performed prior to cyclization and
Boc-deprotection, to give the functionalized
imidazolo[1,2-a]pyridines. The conditions used are typically
identical to those described in Scheme B.
[0255] Scheme D illustrates an alternative method for preparing
compounds of the invention:
##STR00079##
[0256] In Scheme D, the Suzuki coupling may be performed using an
appropriate boronic acid and Pd(PPh.sub.3).sub.4 as a catalyst in a
mixture of DME and aqueous Na.sub.2CO.sub.3 under reflux conditions
or by heating in a microwave oven. The Sandmeyer reaction may be
carried out with NaNO.sub.2 and HCl at low temperature or RT, or
with tBuONO and CuCl.sub.2 with exclusion of light. Hydrazination
may be accomplished using standard procedures with hydrazine in
EtOH or dioxane under reflux conditions. The cyclization of
appropriately functionalized 2-hydrazino-pyridines may be performed
by condensation of the adequate reagent including, but not limited
to formic acid, or cyanogen bromide. The reduction of the cyano
group may be performed using a BH.sub.3-THF complex.
[0257] Scheme E illustrates an alternative method for preparing
compounds of the invention:
##STR00080##
[0258] In Scheme E, the conditions used are typically identical to
those described in Scheme D for the Sandmeyer reaction, the
hydrazination and the cyclization, and in Scheme A for the
deprotect ion.
[0259] Scheme F illustrates an alternative method for preparing
compounds of the invention:
##STR00081##
[0260] In Scheme F, amide bond may be formed from carboxylic acids
by standard methods known in the art, such as using HATU as a
coupling reagent. The Boc-deprotection may be performed using
similar conditions as those described in respect of Scheme A.
[0261] Scheme G illustrates an alternative method for preparing
compounds of the invention:
##STR00082##
[0262] In Scheme G, selective chlorination may be accomplished
using standard procedures such as NCS in DMF at 50.degree. C.
Substitution of the chlorine by primary or secondary amine may be
performed at high temperature, neat or in an appropriate solvent.
The reduction of the cyano group may be performed using similar
conditions as those described in respect of Scheme D.
[0263] Scheme H illustrates an alternative method for preparing
compounds of the invention:
##STR00083##
[0264] In Scheme H, selective chlorination may be accomplished
using standard procedures such as NCS in DMF at 50.degree. C. The
cyclization of appropriately functionalized 2-amino-pyridines may
be performed using similar conditions as those described in respect
of Scheme A. Substitution of the chlorine by primary and secondary
amine or alcools may be performed at high temperature in an
appropriate solvent, using respectively the free amine and the
alcoolat. The reduction of the cyano group may be performed using
similar conditions as those described in respect of Scheme D.
[0265] Unless otherwise noted, all non-aqueous reactions in the
above Schemes are usually carried out under an argon atmosphere
with commercial dry solvents.
[0266] It will be understood that the processes detailed above and
elsewhere herein are solely for the purpose of illustrating the
invention and should not be construed as limiting. A process
utilising similar or analogous reagents and/or conditions known to
one skilled in the art may also be used to obtain a compound of the
invention.
[0267] Any mixtures of final products or intermediates obtained can
be separated on the basis of the physico-chemical differences of
the constituents, in a known manner, into the pure final products
or intermediates, for example by chromatography, distillation,
fractional crystallisation, or by the formation of a salt if
appropriate or possible under the circumstances.
Administration and Pharmaceutical Formulations
[0268] The compounds of the invention will normally be administered
orally, intravenously, subcutaneously, buccally, rectally,
dermally, nasally, tracheally, bronchially, by any other parenteral
route, as an oral or nasal spray or via inhalation, The compounds
may be administered in the form of pharmaceutical preparations
comprising prodrug or active compound either as a free compound or,
for example, a pharmaceutically acceptable non-toxic organic or
inorganic acid or base addition salt, in a pharmaceutically
acceptable dosage form. Depending upon the disorder and patient to
be treated and the route of administration, the compositions may be
administered at varying doses.
[0269] Typically, therefore, the pharmaceutical compounds of the
invention may be administered orally or parenterally
("parenterally" as used herein, refers to modes of administration
which include intravenous, intramuscular, intraperitoneal,
intrasternal, subcutaneous and intraarticular injection and
infusion) to a host to obtain an protease-inhibitory effect. In the
case of larger animals, such as humans, the compounds may be
administered alone or as compositions in combination with
pharmaceutically acceptable diluents, excipients or carriers.
[0270] Actual dosage levels of active ingredients in the
pharmaceutical compositions of this invention may be varied so as
to obtain an amount of the active compound(s) that is effective to
achieve the desired therapeutic response for a particular patient,
compositions, and mode of administration. The selected dosage level
will depend upon the activity of the particular compound, the route
of administration, the severity of the condition being treated and
the condition and prior medical history of the patient being
treated. However, it is within the skill of the art to start doses
of the compound at levels lower than required for to achieve the
desired therapeutic effect and to gradually increase the dosage
until the desired effect is achieved.
[0271] In the treatment, prevention, control, amelioration, or
reduction of risk of conditions which require inhibition of DPP-IV
enzyme activity, an appropriate dosage level will generally be
about 0.01 to 500 mg per kg patient body weight per day which can
be administered in single or multiple doses. Preferably, the dosage
level will be about 0.1 to about 250 mg/kg per day; more preferably
about 0.5 to about 100 mg/kg per day. A suitable dosage level may
be about 0.01 to 250 mg/kg per day, about 0.05 to 100 mg/kg per
day, or about 0.1 to 50 mg/kg per day. Within this range the dosage
may be 0.05 to 0.5, 0.5 to 5 or 5 to 50 mg/kg per day. For oral
administration, the compositions are preferably provided in the
form of tablets containing 1.0 to 1000 milligrams of the active
ingredient, particularly 1.0, 5.0, 10.0, 15.0, 20.0, 25.0, 50.0,
75.0, 100.0, 150.0, 200.0, 250.0, 300.0, 400.0, 500.0, 600.0,
750.0, 800.0, 900.0 and 1000.0 milligrams of the active ingredient
for the symptomatic adjustment of the dosage to the patient to be
treated. The compounds may be administered on a regimen of 1 to 4
times per day, preferably once or twice per day. The dosage regimen
may be adjusted to provide the optimal therapeutic response.
[0272] According to a further aspect of the invention there is thus
provided a pharmaceutical composition including a compound of the
invention, in admixture with a pharmaceutically acceptable
adjuvant, diluent or carrier.
[0273] Pharmaceutical compositions of this invention for parenteral
injection suitably comprise pharmaceutically acceptable sterile
aqueous or nonaqueous solutions, dispersions, suspensions or
emulsions as well as sterile powders for reconstitution into
sterile injectable solutions or dispersions just prior to use.
Examples of suitable aqueous and nonaqueous carriers, diluents,
solvents or vehicles include water, ethanol, polyols (such as
glycerol, propylene glycol, polyethylene glycol and the like), and
suitable mixtures thereof, vegetable oils (such as olive oil) and
injectable organic esters such as ethyl oleate. Proper fluidity can
be maintained, for example, by the use of coating materials such as
lecithin, by the maintenance of the required particle size in the
case of dispersions and by the use of surfactants.
[0274] These compositions may also contain adjuvants such as
preservative, wetting agents, emulsifying agents and dispersing
agents. Prevention of the action of microorganisms may be ensured
by the inclusion of various antibacterial and antifungal agents,
for example, paraben, chlorobutanol or phenol sorbic acid. It may
also be desirable to include isotonic agents such as sugars or
sodium chloride, for example. Prolonged absorption of the
injectable pharmaceutical form may be brought about by the
inclusion of agents (for example aluminum monostearate and gelatin)
which delay absorption.
[0275] In some cases, in order to prolong the effect of the drug,
it is desirable to slow the absorption of the drug 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
drug then depends upon its rate of dissolution which, in turn, may
depend upon crystal size and crystalline form. Alternatively,
delayed absorption of a parenterally administered drug form is
accomplished by dissolving or suspending the drug in an oil
vehicle.
[0276] Injectable depot forms are suitably made by forming
microencapsule matrices of the drug in biodegradable polymers, for
example polylactide-polyglycolide. Depending upon the ratio of drug
to polymer and the nature of the particular polymer employed, the
rate of drug release can be controlled. Examples of other
biodegradable polymers include poly(orthoesters) and
poly(anhydrides). Depot injectable formulations may also prepared
by entrapping the drug in liposomes or microemulsions which are
compatible with body tissues. 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 media just
prior to use.
[0277] Solid dosage forms for oral administration include capsules,
tablets, pills, powders and granules. In such solid dosage forms,
the active compound is typically mixed with at least one inert,
pharmaceutically acceptable excipient or carrier such as sodium
citrate or dicalcium phosphate and/or one or more: a) fillers or
extenders such as starches, lactose, sucrose, glucose, mannitol and
silicic acid; b) binders such as carboxymethylcellulose, alginates,
gelatin, polyvinylpyrrolidone, 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 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. 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 glycol,
for example.
[0278] Suitably, oral formulations contain a dissolution aid. The
dissolution aid is not limited as to its identity so long as it is
pharmaceutically acceptable. Examples include nonionic surface
active agents, such as sucrose fatty acid esters, glycerol fatty
acid esters, sorbitan fatty acid esters (e.g. sorbitan trioleate),
polyethylene glycol, polyoxyethylene hydrogenated castor oil,
polyoxyethylene sorbitan fatty acid esters, polyoxyethylene alkyl
ethers, methoxypolyoxyethylene alkyl ethers, polyoxyethylene
alkylphenyl ethers, polyethylene glycol fatty acid esters,
polyoxyethylene alkylamines, polyoxyethylene alkyl thioethers,
polyoxyethylene polyoxypropylene copolymers, polyoxyethylene
glycerol fatty acid esters, pentaerythritol fatty acid esters,
propylene glycol monofatty acid esters, polyoxyethylene propylene
glycol monofatty acid esters, polyoxyethylene sorbitol fatty acid
esters, fatty acid alkylolamides, and alkylamine oxides; bile acid
and salts thereof (e.g. chenodeoxycholic acid, cholic acid,
deoxycholic acid, dehydrocholic acid and salts thereof, and glycine
or taurine conjugate thereof); ionic surface active agents, such as
sodium laurylsulfate, fatty acid soaps, alkylsulfonates,
alkylphosphates, ether phosphates, fatty acid salts of basic amino
acids; triethanolamine soap, and alkyl quaternary ammonium salts;
and amphoteric surface active agents, such as betaines and
aminocarboxylic acid salts.
[0279] 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 may also be of a composition such that they
release the active ingredient(s) only, or preferentially, in a
certain part of the intestinal tract, and/or in delayed fashion.
Examples of embedding compositions include polymeric substances and
waxes.
[0280] The active compounds may also be in micro-encapsulated form,
if appropriate, with one or more of the above-mentioned
excipients.
[0281] The active compounds may be in finely divided form, for
example it may be micronised.
[0282] Liquid dosage forms for oral administration include
pharmaceutically acceptable emulsions, 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 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, dimethyl formamide, 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 may also include
adjuvants such as wetting agents, emulsifying and suspending
agents, sweetening, flavoring and perfuming agents. Suspensions, in
addition to the active compounds, may contain suspending agents
such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol
and sorbitan esters, microcrystalline cellulose, aluminum
metahydroxide, bentonite, agar-agar, and tragacanth and mixtures
thereof.
[0283] 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 room temperature but liquid at
body temperature and therefore melt in the rectum or vaginal cavity
and release the active compound.
[0284] Compounds of the present invention can also be administered
in the form of liposomes. As is known in the art, liposomes are
generally derived from phospholipids or other lipid substances.
Liposomes are formed by mono- or multi-lamellar hydrated liquid
crystals which are dispersed in an aqueous medium. Any non-toxic,
physiologically acceptable and metabolisable lipid capable of
forming liposomes can be used. The present compositions in liposome
form can contain, in addition to a compound of the present
invention, stabilisers, preservatives, excipients and the like. The
preferred lipids are the phospholipids and the phosphatidyl
cholines (lecithins), both natural and synthetic. Methods to form
liposomes are known in the art, for example, Prescott, Ed., Methods
in Cell Biology, Volume XIV, Academic Press, New York, N.Y. (1976),
p 33 et seq.
[0285] Dosage forms for topical administration of a compound of
this invention include powders, sprays, ointments and inhalants.
The active compound is mixed under sterile conditions with a
pharmaceutically acceptable carrier and any needed preservatives,
buffers or propellants which may be required. Ophthalmic
formulations, eye ointments, powders and solutions are also
contemplated as being within the scope of this invention.
[0286] Advantageously, the compounds of the invention may be orally
active, have rapid onset of activity and low toxicity.
[0287] The compounds of the invention may have the advantage that
they are more efficacious, less toxic, longer acting, have a
broader range of activity, more potent, produce fewer side effects,
more easily absorbed than, or have other useful pharmacological
properties over, compounds known in the prior art.
Combination Therapies
[0288] Compounds of the invention may be administered in
combination with one or more therapeutic agents. Accordingly, the
invention provides a pharmaceutical composition comprising an
additional agent. The invention also provides a product comprising
a compound of the invention and an agent; as a combined preparation
for simultaneous, separate or sequential use in therapy.
[0289] In particular, a composition or product of the invention may
further comprise a therapeutic agent selected from anti-diabetic
agents, hypolipidemic agents, anti-obesity or appetite-regulating
agents, anti-hypertensive agents, HDL-increasing agents,
cholesterol absorption modulators, Apo-A1 analogues and mimetics,
thrombin inhibitors, aldosterone inhibitors, inhibitors of platelet
aggregation, estrogen, testosterone, selective estrogen receptor
modulators, selective androgen receptor modulators,
chemotherapeutic agents, and 5-HT.sub.3 or 5-HT.sub.4 receptor
modulators; or pharmaceutically acceptable salts or prodrugs
thereof.
[0290] Examples of anti-diabetic agents include insulin, insulin
derivatives and mimetics; insulin secretagogues, for example
sulfonylureas (e.g. glipizide, glyburide or amaryl); insulinotropic
sulfonylurea receptor ligands, for example meglitinides (e.g.
nateglinide or repaglinide); insulin sensitisers, for example
protein tyrosine phosphatase-1B (PTP-1B) inhibitors (e.g. PTP-112);
GSK3 (glycogen synthase kinase-3) inhibitors, for example
SB-517955, SB-4195052, SB-216763, N,N-57-05441 or N,N-57-05445; RXR
ligands, for example GW-0791 or AGN-194204; sodium-dependent
glucose cotransporter inhibitors, for example T-1095; glycogen
phosphorylase A inhibitors, for example BAY R3401; biguanides, for
example metformin; alpha-glucosidase inhibitors, for example
acarbose; GLP-1 (glucagon like peptide-1), GLP-1 analogues and
mimetics, for example exendin-4; DPPIV (dipeptidyl peptidase IV)
inhibitors, for example DPP728, LAF237 (vildagliptin), MK-0431,
saxagliptin or GSK23A; AGE breakers; and thiazolidone derivatives,
for example glitazone, pioglitazone, rosiglitazone or
(R)-1-{4-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmethoxy]-benze-
nesulfonyl}-2,3-dihydro-1H-indole-2-carboxylic acid (compound 4 of
Example 19 of WO 03/043985) or a non-glitazone type PPAR-agonist
(e.g. GI-262570); or pharmaceutically acceptable salts or prodrugs
thereof.
[0291] Examples of hypolipidemic agents include
3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase
inhibitors, for example lovastatin, pitavastatin, simvastatin,
pravastatin, cerivastatin, mevastatin, velostatin, fluvastatin,
dalvastatin, atorvastatin, rosuvastatin or rivastatin; squalene
synthase inhibitors; FXR (farnesoid X receptor) ligands; LXR (liver
X receptor) ligands; cholestyramine; fibrates; nicotinic acid; and
aspirin; or pharmaceutically acceptable salts or prodrugs
thereof.
[0292] Examples of anti-obesity/appetite-regulating agents include
phentermine, leptin, bromocriptine, dexamphetamine, amphetamine,
fenfluramine, dexfenfluramine, sibutramine, orlistat,
dexfenfluramine, mazindol, phentermine, phendimetrazine,
diethylpropion, fluoxetine, bupropion, topiramate, diethylpropion,
benzphetamine, phenylpropanolamine or ecopipam, ephedrine,
pseudoephedrine and cannabinoid receptor antagonists (rimonaban);
or pharmaceutically acceptable salts or prodrugs thereof.
[0293] Examples of anti-hypertensive agents include loop diuretics,
for example ethacrynic acid, furosemide or torsemide; diuretics,
for example thiazide derivatives, chlorithiazide,
hydrochlorothiazide or amiloride; angiotensin converting enzyme
(ACE) inhibitors, for example benazepril, captopril, enalapril,
fosinopril, lisinopril, moexipril, perinodopril, quinapril,
ramipril or trandolapril; Na--K-ATPase membrane pump inhibitors,
for example digoxin; neutralendopeptidase (NEP) inhibitors, for
example thiorphan, terteo-thiorphan or SQ29072; ECE inhibitors, for
example SLV306; dual ACE/NEP inhibitors, for example omapatrilat,
sampatrilat or fasidotril; angiotensin II antagonists, for example
candesartan, eprosartan, irbesartan, losartan, telmisartan or
valsartan; renin inhibitors, for example aliskiren, terlakiren,
ditekiren, RO-66-1132 or RO-66-1168; b-adrenergic receptor
blockers, for example acebutolol, atenolol, betaxolol, bisoprolol,
metoprolol, nadolol, propranolol, sotalol or timolol; inotropic
agents, for example digoxin, dobutamine or milrinone; calcium
channel blockers, for example amlodipine, bepridil, diltiazem,
felodipine, nicardipine, nimodipine, nifedipine, nisoldipine or
verapamil; aldosterone receptor antagonists; and aldosterone
synthase inhibitors; or pharmaceutically acceptable salts or
prodrugs thereof.
[0294] Examples of cholesterol absorption modulators include
Zetia.RTM. and KT6-971, or pharmaceutically acceptable salts or
prodrugs thereof.
[0295] Examples of aldosterone inhibitors include anastrazole,
fadrazole and eplerenone, or pharmaceutically acceptable salts or
prodrugs thereof.
[0296] Examples of inhibitors of platelet aggregation include
aspirin or clopidogrel bisulfate, or pharmaceutically acceptable
salts or prodrugs thereof.
[0297] Examples of chemotherapeutic agents include compounds
decreasing the protein kinase activity, for example PDGF receptor
tyrosine kinase inhibitors (e.g. imatinib or
4-methyl-N-[3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-phenyl]-3-(4-pyr-
idin-3-yl-pyrimidin-2-ylamino)-benzamide), or pharmaceutically
acceptable salts or prodrugs thereof.
[0298] Examples of 5-HT.sub.3 or 5-HT.sub.4 receptor modulators
include tegaserod, tegaserod hydrogen maleate, cisapride or
cilansetron, or pharmaceutically acceptable salts or prodrugs
thereof.
[0299] The weight ratio of the compound of the present invention to
the further active ingredient(s) may be varied and will depend upon
the effective dose of each ingredient. Generally, an effective dose
of each will be used. Thus, for example, when a compound of the
present invention is combined with another agent, the weight ratio
of the compound of the present invention to the other agent will
generally range from about 1000:1 to about 1:1000, preferably about
200:1 to about 1:200.
[0300] Combinations of a compound of the present invention and
other active ingredients will generally also be within the
aforementioned range, but in each case, an effective dose of each
active ingredient should be used.
[0301] In such combinations the compound of the present invention
and other active agents may be administered separately or in
conjunction. In addition, the administration of one element may be
prior to, concurrent to, or subsequent to the administration of
other agent(s).
Use
[0302] Compounds of the invention may be useful in the therapy of a
variety of diseases and conditions.
[0303] In particular, compounds of the invention may be useful in
the treatment or prevention of a disease or condition selected from
non-insulin-dependent diabetes mellitus, arthritis, obesity,
allograft transplantation, osteoporosis, heart failure, impaired
glucose metabolism or impaired glucose tolerance, neurodegenerative
diseases (for example Alzheimer's disease or Parkinson disease),
cardiovascular or renal diseases (for example diabetic
cardiomyopathy, left or right ventricular hypertrophy, hypertrophic
medial thickening in arteries and/or in large vessels, mesenteric
vasculature hypertrophy or mesanglial hypertrophy),
neurodegenerative or cognitive disorders, hyperglycemia, insulin
resistance, lipid disorders, dyslipidemia, hyperlipidemia,
hypertriglyceridemia, hypercholesterolemia, low HDL levels, high
LDL levels, atherosclerosis, vascular restenosis, irritable bowel
syndrome, inflammatory bowel disease (e.g. Crohn's disease or
ulcerative colitis), pancreatitis, retinopathy, nephropathy,
neuropathy, syndrome X, ovarian hyperandrogenism (polycystic
ovarian syndrome), type 2 diabetes, growth hormone deficiency,
neutropenia, neuronal disorders, tumor metastasis, benign prostatic
hypertrophy, gingivitis, hypertension and osteoporosis.
[0304] The compounds may also be useful in producing a sedative or
anxiolytic effect, attenuating post-surgical catabolic changes or
hormonal responses to stress, reducing mortality and morbidity
after myocardial infarction, modulating hyperlipidemia or
associated conditions; and lowering VLDL, LDL or Lp(a) levels.
EXAMPLES
[0305] The following Examples illustrate the invention.
Abbreviations:
[0306] AcOEt ethyl acetate [0307] BH.sub.3.THF borane
tetrahydrofuran complex [0308] Boc.sub.2O di-tert-butyl dicarbonate
[0309] BrCN cyanogen bromide [0310] CHCl.sub.3 chloroform [0311]
CuCl.sub.2 copper(II) chloride [0312] DCE 1,2-dichloroethane [0313]
DCM dichloromethane [0314] DIPEA N,N-diisopropylethylamine [0315]
DMAP 4-dimethylaminopyridine [0316] DME 1,2-dimethoxyethane [0317]
DMF N,N-dimethylformamide [0318] DMSO dimethylsulfoxide [0319]
EtMgBr ethylmagnesium bromide [0320] Et.sub.3N triethylamine [0321]
Et.sub.2O diethylether [0322] EtOH ethanol [0323] h hour [0324]
HATU O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluorophosphate [0325] HCl hydrochloric acid [0326] HNO.sub.3
nitric acid [0327] HPLC high pressure liquid chromatography [0328]
H.sub.2SO.sub.4 sulfuric acid [0329] KOH potassium hydroxide [0330]
LiBH.sub.4 lithium borohydride [0331] LiOH lithium hydroxide [0332]
mCPBA 3-chloroperbenzoic acid [0333] MeCN acetonitrile [0334] MeOH
methanol [0335] MnO.sub.2 manganese(IV) oxide [0336] MS mass
spectroscopy [0337] MW microwave [0338] Na.sub.2CO.sub.3 sodium
carbonate [0339] NaH sodium hydride [0340] NaHCO.sub.3 sodium
hydrogencarbonate [0341] NaIO.sub.4 sodium (meta)periodate [0342]
NaNO.sub.2 sodium nitrite [0343] NaOH sodium hydroxide [0344] NaOMe
sodium methoxide [0345] Na.sub.2SO.sub.4 sodium sulfate [0346] NBS
N-bromosuccinimide [0347] NCS N-chlorosuccinimide [0348] NH.sub.3
ammonia [0349] NH.sub.4Cl ammonium chloride [0350] Pd/C palladium
over charcoal [0351] PdCl.sub.2(PPh.sub.3).sub.2
dichloro-bis-triphenylphosphinepalladium(II) [0352]
Pd(PPh.sub.3).sub.4 tetrakis(triphenylphosphine)palladium [0353]
R.sub.F retention factor [0354] RT room temperature [0355]
SiO.sub.2 silica [0356] SnCl.sub.2 tin(II) chloride [0357] TBAF
tetrabutylammonium fluoride [0358] TBME tert-butyl-methylether
[0359] tBuOH tert-butanol [0360] tBuONO tert-butyl nitrite [0361]
TFA trifluoroacetic acid [0362] THF tetrahydrofuran [0363] TLC thin
layer chromatography [0364] ZnBr.sub.2 zinc bromide [0365]
prep-HPLC preparative high pressure liquid chromatography; Waters
system. Column: reversed phase SunFire.TM. Prep (100.times.30 mm),
C18 OBD, 5 .mu.M. Gradient elution (CH.sub.3CN/water with 0.1%
TFA), generally product obtained as a TFA salt after
lyophilization.
HPLC Conditions:
[0366] .sup.At.sub.Ret: retention time [min] for System A: Linear
gradient 5-100% CH.sub.3CN and H.sub.2O (0.1% TFA) in 4 min+0.5 min
100% CH.sub.3CN; PDA MaxPlot detection (210.0 nm to 400.0 nm), flow
rate 3 ml/min at 35.degree. C. Column: Sunfire.TM. (4.6.times.20
mm) C18, 3.5 .mu.m.
Example 1
C-(6-Phenyl-imidazo[1,2-a]pyridin-7-yl)-methylamine
[0367] Compound 1 was prepared according to Scheme 1:
##STR00084##
Step 1.1: 4-Aminomethyl-pyridin-2-ylamine
[0368] In a sealed flask, a well stirred mixture of
2-amino-isonicotinonitrile (12.6 g, 106.0 mmol), Et.sub.3N (98 mL)
and Pd/C 10% (15.0 g) in EtOH (400 mL) was placed under an H.sub.2
atmosphere (50 psi) and hydrogenated at RT for 12 h. The catalyst
was filtered through a Celite pad and washed with MeOH. The
filtrate was concentrated to dryness to yield the title compound
(11.6 g, 94.2 mmol, 89%) as a white solid, which was used without
further purification. MS: 122 [M-1].sup.+; HPLC:
.sup.At.sub.Ret=0.16.
Step 1.2: (2-Amino-pyridin-4-ylmethyl)-carbamic acid tert-butyl
ester
[0369] To a solution of 4-aminomethyl-pyridin-2-ylamine (11.36 g,
92.2 mmol) and Et.sub.3N (16.7 mL, 120.0 mmol) in MeOH (150 mL) was
added a solution of Boc.sub.2O (20.2 g, 92.2 mmol) in MeOH (20 mL)
at 0.degree. C. The reaction mixture was stirred at 0.degree. C.
for 1 h and concentrated under vacuum. The residue was dissolved in
AcOEt (800 mL) and washed with water (200 mL) and brine (100 mL).
The organic layer was dried over Na.sub.2SO.sub.4, filtered, and
evaporated to dryness to yield the crude title compound (17.55 g)
as a yellow foam, which was used without further purification. MS:
224 [M+1].sup.+; HPLC: .sup.At.sub.Ret=0.88.
Step 1.3: (2-Amino-5-bromo-pyridin-4-ylmethyl)-carbamic acid
tert-butyl ester
[0370] A solution of crude (2-amino-pyridin-4-ylmethyl)-carbamic
acid tert-butyl ester (17.55 g) in DMF (50 mL) was cooled to
-18.degree. C. (ice/MeOH bath), treated with NBS (12.6 g, 70.7
mmol), and stirred at -18.degree. C. for 1 h. The reaction mixture
was diluted in AcOEt (800 mL) and washed with water (2.times.100
mL) and brine (50 mL). The organic layer was dried over
Na.sub.2SO.sub.4, filtered and evaporated. The residue was purified
by Combi-Flash Companion.TM. (Isco Inc.) column chromatography
(SiO.sub.2; gradient elution, hexane/DCM/TBME 10:10:1.fwdarw.TBME
100%) to yield the title compound (13.95 g, 46.2 mmol, 50% for 2
steps) as a pale yellow solid. MS: 303 [M+1].sup.+; HPLC:
.sup.At.sub.Ret=1.10; TLC: R.sub.F 0.18 (hexane/DCM/TBME
1:1:2).
Step 1.4: (6-Bromo-imidazo[1,2-a]pyridin-7-ylmethyl)-carbamic acid
tert-butyl ester
[0371] A mixture of (2-amino-5-bromo-pyridin-4-ylmethyl)-carbamic
acid tert-butyl ester (1.0 g, 3.3 mmol), NaHCO.sub.3 (474 mg, 5.6
mmol) and chloracetaldehyde (2.2 mL, 15.0 mmol) was vigorously
stirred and refluxed for 14 h. The reaction mixture was cooled to
RT, concentrated under vacuum and the remaining residue was
suspended in DCM and brine. The aqueous layer was separated and
extracted with DCM (5.times.), and the combined organic fractions
were dried over Na.sub.2SO.sub.4, filtered, and evaporated. The
residue was purified by Combi-Flash Companion.TM. (Isco Inc.)
column chromatography (SiO.sub.2; gradient elution, hexane/DCM/TBME
10:10:1.fwdarw.1:1:18) to yield the title compound (860 mg, 2.6
mmol, 79%) as a pale yellow solid. MS: 327 [M+1].sup.+; HPLC:
.sup.At.sub.Ret=1.07; TLC: R.sub.F 0.16 (hexane/DCM/TBME
1:1:2).
Step 1.5
[0372] (1) In a sealed tube, a mixture of
(6-bromo-imidazo[1,2-a]pyridin-7-ylmethyl)-carbamic acid tert-butyl
ester (40 mg, 0.12 mmol), phenylboronic acid (22 mg, 0.18 mmol),
Pd(PPh.sub.3).sub.4 (7 mg, 0.006 mmol) and Na.sub.2CO.sub.3 (2.0 M
solution in water, 0.21 mL) in DME (0.50 mL) was heated at
150.degree. C. for 20 min in a microwave oven. The reaction mixture
was cooled to RT, filtered through a Florisil pad and the filter
cake was washed with AcOEt. The filtrate was dried over
Na.sub.2SO.sub.4, filtered, and evaporated.
[0373] (2) The residue was dissolved in DCM (2 mL) and TFA (1 mL)
and the solution was stirred at RT for 1 h. The reaction mixture
was concentrated to dryness and the remaining residue purified by
reverse phase prep-HPLC (Waters system) to give the title compound
(2TFA salt, 15 mg, 0.033 mmol, 28% for 2 steps) as a white solid.
MS: 224 [M+1].sup.+; HPLC: .sup.At.sub.Ret=0.44.
Example 2
[0374] Compounds 2a to 2e were obtained analogously to Example 1,
using various phenylboronic acid derivatives in Step 1.5. The
compounds are of the following general formula:
TABLE-US-00002 ##STR00085## HPLC Com- .sup.At.sub.Ret MS pound Name
R5 [min] [M + 1].sup.+ 2a C-[6-(2,4-Dimethyl- phenyl)-imidazo[1,2-
a]pyridin-7-yl]- methylamine ##STR00086## 0.78 252 2b
C-[6-(2-Chloro-4- methyl-phenyl)- imidazo[1,2- a]pyridin-
7-yl]-methylamine ##STR00087## 0.80 272 2c C-[6-(4-Chloro-2-
methyl-phenyl)- imidazo[1,2- a]pyridin- 7-yl]-methylamine
##STR00088## 0.83 272 2d C-[6-(4-Chloro-2- methoxy-phenyl)-
imidazo[1,2- a]pyridin- 7-yl]-methylamine ##STR00089## 0.81 288 2e
C-[6-(2,4,5- Trifluoro-phenyl)- imidazo[1,2- a]pyridin-7-yl]-
methylamine ##STR00090## 0.57 278
Example 3
C-[6-(2,4-Dichloro-phenyl)-3-m-tolyl-imidazo[1,2-a]pyridin-7-yl]-methylami-
ne
[0375] Compound 3 was prepared according to Scheme 2:
##STR00091## ##STR00092##
Step 2.1: 2-Amino-5-bromo-isonicotinonitrile
[0376] A solution of 2-amino-isonicotinonitrile (10.0 g, 83.9 mmol)
in DMF (20 mL) was cooled to -18.degree. C. (ice/MeOH bath),
treated with NBS (16.5 g, 92.3 mmol), and stirred at -18.degree. C.
for 1 h. The reaction mixture was diluted in AcOEt (500 mL) and
washed with water (200 mL). The aqueous phase was separated and
extracted with AcOEt (2.times.500 ml). The combined organic
fractions were dried over Na.sub.2SO.sub.4, filtered and
evaporated. The residue was purified by Combi-Flash Companion.TM.
(Isco Inc.) column chromatography (SiO.sub.2; gradient elution,
[hexane/DCM 1:1]/TBME 98:2.fwdarw.6:4) to yield the title compound
(13.0 g, 65.6 mmol, 78%) as a pale yellow solid. MS: 199
[M+1].sup.+; HPLC: .sup.At.sub.Ret=1.13; TLC: R.sub.F 0.39
(hexane/DCM/TBME 1:1:2).
Step 2.2: 6-Bromo-imidazo[1,2-a]pyridine-7-carbonitrile
[0377] A mixture of 2-amino-5-bromo-isonicotinonitrile (5.0 g, 25.3
mmol), NaHCO.sub.3 (3.6 g, 42.9 mmol) and chloracetaldehyde (17.0
mL, 114.0 mmol) in EtOH (160 mL) was vigorously stirred and
refluxed for 14 h. The reaction mixture was cooled to RT,
concentrated under vacuum and the remaining residue was suspended
in DCM (500 mL) and brine (100 mL). The aqueous layer was separated
and extracted with DCM (5.times.), and the combined organic
fractions were dried over Na.sub.2SO.sub.4, filtered, and
evaporated. The residue was purified by Combi-Flash Companion.TM.
(Isco Inc.) column chromatography (SiO.sub.2; gradient elution,
[hexane/DCM 1:1]/TBME 95:5.fwdarw.3:7) to yield the title compound
(2.97 g, 13.4 mmol, 53%) as an orange solid. MS: 223 [M+1].sup.+;
HPLC: .sup.At.sub.Ret=0.54; TLC: R.sub.F 0.17 (hexane/DCM/TBME
1:1:2).
Step 2.3:
6-(2,4-Dichloro-phenyl)-imidazo[1,2-a]pyridine-7-carbonitrile
[0378] A mixture of 6-bromo-imidazo[1,2-a]pyridine-7-carbonitrile
(1.5 g, 6.8 mmol), 2,4-dichloro-benzeneboronic acid (1.9 g, 10.1
mmol), Pd(PPh.sub.3).sub.4 (390 mg, 0.34 mmol) and Na.sub.2CO.sub.3
(2.0 M solution in water, 12 mL) in DME (30 mL) was refluxed for 14
h under an inert atmosphere of argon. The reaction mixture was
cooled to RT, diluted in AcOEt (200 mL) and washed with water (200
mL). The organic layer was dried over Na.sub.2SO.sub.4, filtered,
and evaporated. The residue was purified by Combi-Flash
Companion.TM. (Isco Inc.) column chromatography (SiO.sub.2;
gradient elution, [hexane/DCM 1:1]/TBME 95:5.fwdarw.1:1) to yield
the title compound (750 mg, 2.6 mmol, 39%) as an orange foam. MS:
289 [M+1].sup.+; HPLC: .sup.At.sub.Ret=1.50; TLC: R.sub.F 0.16
([hexane/DCM 1:1]/TBME 3:7).
Step 2.4:
[6-(2,4-Dichloro-phenyl)-imidazo[1,2-a]pyridin-7-ylmethyl]-carba-
mic acid tert-butyl ester
[0379] (1) In a sealed flask, a solution of
6-(2,4-dichloro-phenyl)-imidazo[1,2-a]pyridine-7-carbonitrile (750
mg, 2.6 mmol) in THF (20 mL) was cautiously added to well stirred
BH.sub.3.THF complex (1.0 M solution in THF, 13 mL, 13.0 mmol) at
0.degree. C. The reaction mixture was heated at 40.degree. C. for 1
h and cooled to RT. MeOH (large excess) and Amberlyst 15 (35 g)
were successively added and the resulting mixture was shaken at RT
for 30 min. The resin was filtered, washed with MeOH (500 mL), and
the desired compound was released with ammonia (1.0 M solution in
MeOH, 1.2 L). The NH.sub.3-MeOH fraction was evaporated to yield
the crude
C-[6-(2,4-dichloro-phenyl)-imidazo[1,2-a]pyridin-7-yl]-methylamine
(778 mg) as a yellow oil.
[0380] (2) To a solution of the crude (778 mg) and Et.sub.3N (0.47
mL, 3.4 mmol) in MeOH (20 mL) was added a solution of Boc.sub.2O
(599 mg, 2.7 mmol) in MeOH (2 mL) at RT. The reaction mixture was
stirred at RT for 1 h and concentrated under vacuum. The residue
was dissolved in AcOEt (125 mL) and washed with a 0.5 M aqueous HCl
solution (2.times.50 mL) and brine (50 mL). The organic layer was
dried over Na.sub.2SO.sub.4, filtered, and evaporated to dryness to
yield the crude title compound (671 mg, 1.7 mmol, 66%) as a
brownish foam, which was used without further purification. MS: 393
[M+1].sup.+; HPLC: .sup.At.sub.Ret=1.70.
Step 2.5:
[3-Bromo-6-(2,4-dichloro-phenyl)-imidazo[1,2-a]pyridin-7-ylmethy-
l]-carbamic acid tert-butyl ester
[0381] A solution of
[6-(2,4-dichloro-phenyl)-imidazo[1,2-a]pyridin-7-ylmethyl]-carbamic
acid tert-butyl ester (543 mg, 1.38 mmol) in DMF (5 mL) was cooled
to 0.degree. C., treated with NBS (222 mg, 1.25 mmol), and stirred
at 0.degree. C. for 1 h. The reaction mixture was diluted in AcOEt
and washed with water and brine. The organic layer was dried over
Na.sub.2SO.sub.4, filtered and evaporated. The residue was purified
by Combi-Flash Companion.TM. (Isco Inc.) column chromatography
(SiO.sub.2; gradient elution, [hexane/DCM 1:1]/TBME
95:5.fwdarw.6:4) to yield the title compound (435 mg, 0.92 mmol,
67%) as a beige foam. MS: 472 [M+1].sup.+; HPLC:
.sup.At.sub.Ret=1.93; TLC: R.sub.F 0.50 (hexane/DCM/TBME
1:1:2).
Step 2.6
[0382] (1) In a sealed tube, a mixture of
[3-bromo-6-(2,4-dichloro-phenyl)-imidazo[1,2-a]pyridin-7-ylmethyl]-carbam-
ic acid tert-butyl ester (40 mg, 0.08 mmol), m-tolylboronic acid
(17 mg, 0.13 mmol), Pd(PPh.sub.3).sub.4 (5 mg, 0.004 mmol) and
Na.sub.2CO.sub.3 (2.0 M solution in water, 0.15 mL) in DME (0.50
mL) was heated at 150.degree. C. for 20 min in a microwave oven.
The reaction mixture was cooled to RT, filtered through a Florisil
pad and the filter cake was washed with AcOEt. The filtrate was
dried over Na.sub.2SO.sub.4, filtered, and evaporated to
dryness.
[0383] (2) The residue was dissolved in DCM (2 mL) and TFA (1 mL)
and the solution was stirred at RT for 1 h. The reaction mixture
was concentrated to dryness and the remaining residue purified by
reverse phase prep-HPLC (Waters system) to give the title compound
(2TFA salt, 24 mg, 0.039 mmol, 49% for 2 steps) as a white solid.
MS: 383 [M+1].sup.+; HPLC: .sup.At.sub.Ret=1.45.
Example 4
[0384] Compounds 4a to 4k were obtained analogously to Example 3,
using various phenylboronic acid derivatives in Step 2.6. The
compounds are of the following general formula:
TABLE-US-00003 ##STR00093## HPLC .sup.At.sub.Ret MS Compound Name
R7 [min] [M + 1].sup.+ 4a C-[6-(2,4-Dichloro-phenyl)-3-
phenyl-imidazo[1,2-a]pyridin- 7-yl]-methylamine ##STR00094## 1.19
369 4b C-[6-(2,4-Dichloro-phenyl)-3- (3-fluoro-phenyl)-imidazo[1,2-
a]pyridin-7-yl]-methylamine ##STR00095## 1.40 387 4c
C-[6-(2,4-Dichloro-phenyl)-3- (4-fluoro-phenyl)-imidazo[1,2-
a]pyridin-7-yl]-methylamine ##STR00096## 1.37 387 4d
C-[6-(2,4-Dichloro-phenyl)-3- (3,4-difluoro-phenyl)-
imidazo[1,2-a]pyridin-7-yl]- methylamine ##STR00097## 1.44 405 4e
C-[6-(2,4-Dichloro-phenyl)-3- (3,4-dimethoxy-phenyl)-
imidazo[1,2-a]pyridin-7-yl]- methylamine ##STR00098## 1.30 429 4f
C-[6-(2,4-Dichloro-phenyl)-3- pyridin-4-yl-imidazo[1,2-
a]pyridin-7-yl]-methylamine ##STR00099## 0.83 370 4g
C-[6-(2,4-Dichloro-phenyl)-3- pyridin-3-yl-imidazo[1,2-
a]pyridin-7-yl] ##STR00100## 0.91 370 4h
C-[6-(2,4-Dichloro-phenyl)-3- (3,5-dimethoxy-phenyl)-
imidazo[1,2-a]pyridin-7-yl]- methylamine ##STR00101## 1.44 429 4i
C-[6-(2,4-Dichloro-phenyl)-3- (2-methoxy-phenyl)-
imidazo[1,2-a]pyridin-7-yl]- methylamine ##STR00102## 1.20 399 4j
C-[6-(2,4-Dichloro-phenyl)-3- (6-morpholin-4-yl-pyridin-3-
yl)-imidazo[1,2-a]pyridin-7-yl]- methylamine ##STR00103## 1.06 454
4k C-[6-(2,4-Dichloro-phenyl)-3- (2-morpholin-4-yl-pyridin-4-
yl)-imidazo[1,2-a]pyridin-7-yl]- methylamine ##STR00104## 0.98
454
Example 5
C-[6-(2,4-Dichloro-phenyl)-imidazo[1,2-a]pyridin-7-yl]-methylamine
[0385] A solution of
[6-(2,4-dichloro-phenyl)-imidazo[1,2-a]pyridin-7-ylmethyl]carbamic
acid tert-butyl ester (30 mg, 0.07 mmol) in DCM (2 mL) and TFA (1
mL) was stirred at RT for 30 min, then concentrated to dryness. The
remaining residue was purified by reverse phase prep-HPLC (Waters
system) to give the title compound (2TFA salt, 19 mg, 0.037 mmol,
52%) as a white solid. MS: 293 [M+1].sup.+; HPLC:
.sup.At.sub.Ret=0.84.
Example 6
[7-Aminomethyl-6-(2,4-dichloro-phenyl)-imidazo[1,2-a]pyridin-3-yl]-ethyl-m-
ethyl-amine
[0386] Compound 6 was prepared according to Scheme 3:
##STR00105##
Step 3.1:
1,2-Bis-benzotriazol-1-yl-N,N-diethyl-N,N'-dimethyl-ethane-1,2--
diamine
[0387] According to the procedure published by Katritzky and al.
(J. Org. Chem., 1990, 55, 3209-3213), a mixture of
ethyl-methyl-amine (0.10 mL, 1.2 mmol) and 1H-benzotriazole (144
mg, 1.2 mmol) in EtOH (2 mL) was stirred at RT for 5 min. Glyoxal
(40 wt. % in water, 0.07 mL, 0.6 mmol) was then added, the mixture
was stirred at RT for 14 h and evaporated to dryness to give the
crude title compound as a brown oil which was used without further
purification.
Step 3.2:
[2-amino-5-(2,4-dichloro-phenyl)-pyridin-4-ylmethyl]-carbamic acid
tert-butyl ester
[0388] In a sealed tube, a mixture of
(2-amino-5-bromo-pyridin-4-ylmethyl)-carbamic acid tert-butyl ester
(4.48 g, 14.8 mmol, prepared according to Example 1, Step 1.3),
2,4-dichloro-benzeneboronic acid (4.24 g, 22.2 mmol),
Pd(PPh.sub.3).sub.4 (855 mg, 0.74 mmol) and Na.sub.2CO.sub.3 (2.0 M
solution in water, 26 mL, 52.0 mmol) in DME (50 mL) was heated at
150.degree. C. for 17 min in a microwave oven. The reaction mixture
was cooled to RT, diluted in AcOEt and washed with water. The
organic layer was dried over Na.sub.2SO.sub.4, filtered and
evaporated. The residue was purified by Combi-Flash Companion.TM.
(Isco Inc.) column chromatography (SiO.sub.2; gradient elution,
[hexane/DCM 1:1]/TBME 95:5.fwdarw.100% TBME) to yield the title
compound (3.2 g, 8.7 mmol, 59%) as a white solid. MS: 368
[M-1].sup.+; HPLC: .sup.At.sub.Ret=1.69.
Step 3.3
[0389] (1) A mixture of
[2-amino-5-(2,4-dichloro-phenyl)-pyridin-4-ylmethyl]-carbamic acid
tert-butyl ester (50 mg, 0.14 mmol) and
1,2-bis-benzotriazol-1-yl-N,N'-diethyl-N,N'-dimethyl-ethane-1,2-diamine
(51 mg, 0.14 mmol) in DCE (1.5 mL) was refluxed for 2 h, then
cooled to RT. Powdered KOH (29.2 mg, 0.45 mmol) was added, the
mixture was stirred at RT for 30 min and filtered. The solid was
washed with CHCl.sub.3 and the filtrate was concentrated to
dryness. The remaining residue was purified by reverse phase
prep-HPLC (Waters system) to give the Boc-protected intermediate
(TFA salt) as a white solid. MS: 450 [M+1].sup.+; HPLC:
.sup.At.sub.Ret=2.00.
[0390] (2) The Boc-protected compound was dissolved in DCM (2 mL)
and TFA (1 mL) and the solution was stirred at RT for 1 h. The
reaction mixture was concentrated to dryness and the remaining
residue purified by reverse phase prep-HPLC (Waters system) to give
the title compound (2TFA salt, 23 mg, 0.040 mmol, 29% for 2 steps)
as a white solid. MS: 350 [M+1].sup.+; HPLC:
.sup.At.sub.Ret=1.27.
Example 7
[7-Aminomethyl-6-(2,4-dichloro-phenyl)-imidazo[1,2-a]pyridin-3-yl]-(2-meth-
oxy-ethyl)-methyl-amine
[0391] (1) The TFA salt was obtained analogously to Example 6 from
[2-amino-5-(2,4-dichloro-phenyl)-pyridin-4-ylmethyl]-carbamic acid
tert-butyl ester (50 mg, 0.14 mmol) and
1,2-bis-benzotriazol-1-yl-N,N'-bis-(2-methoxy-ethyl)-N,N'-dimethyl-ethane-
-1,2-diamine (59.5 mg, 0.14 mmol) and subsequent Boc-deprotection
and reverse phase prep-HPLC (Waters system) purification.
[0392] (2) The TFA salt was dissolved in HCl (2.0 M solution in
dioxane), stirred for 5 min at RT, and evaporated to dryness (the
sequence was performed twice). The remaining residue was dissolved
in t-BuOH and lyophilized to give the HCl salt of the title
compound (2HCl salt, 34 mg, 0.075 mmol, 55% for 2 steps) as an
off-white solid. MS: 380 [M+1].sup.+; HPLC:
.sup.At.sub.Ret=1.19.
Example 8
[0393] Compounds 8a to 8c' were obtained as TFA or HCl salts, using
procedures analogous to those of Examples 6 and 7. Adequate boronic
acid was used for the Suzuki coupling and adequate freshly prepared
bis-benzotriazol-1,2-diamine was used for the cyclization step.
TABLE-US-00004 ##STR00106## HPLC .sup.At.sub.Ret MS Compound Name
R.sup.5 R.sup.7 [min] [M + 1].sup.+ 8a [7-Aminomethyl-6-(2,4-
dichloro-phenyl)- imidazo[1,2-a]pyridin-3- yl]-dimethyl-amine
##STR00107## ##STR00108## 1.14 336 8b [7-Aminomethyl-6-(2,4-
dichloro-phenyl)- imidazo[1,2-a]pyridin-3- yl]-cyclopropylmethyl-
propyl-amine ##STR00109## ##STR00110## 1.63 404 8c
C-[6-(2,4-Dichloro- phenyl)-3-piperidin-1-yl-
imidazo[1,2-a]pyridin-7- yl]-methylamine ##STR00111## ##STR00112##
1.39 376 8d C-[6-(2,4-Dichloro- phenyl)-3- thiomorpholin-4-yl-
imidazo[1,2-a]pyridin-7- yl]-methylamine ##STR00113## ##STR00114##
1.30 394 8e C-[6-(2,4-Dichloro- phenyl)-3-(4-methyl-
piperazin-1-yl)- imidazo[1,2-a]pyridin-7- yl]-methylamine
##STR00115## ##STR00116## 0.74 391 8f C-[6-(2,4-Dichloro-
phenyl)-3-piperazin-1- yl-imidazo[1,2- a]pyridin-7-yl]- methylamine
##STR00117## ##STR00118## 0.71 377 8g C-[6-(2,4-Dichloro-
phenyl)-3-morpholin-4- yl-imidazo[1,2- a]pyridin-7-yl]- methylamine
##STR00119## ##STR00120## 1.09 378 8h 4-[7-Aminomethyl-6-
(2,4-dichloro-phenyl)- imidazo[1,2-a]pyridin-3- yl]-piperazin-2-one
##STR00121## ##STR00122## 0.88 391 8i {[7-Aminomethyl-6-
(2,4-dichloro-phenyl)- imidazo[1,2-a]pyridin-3- yl]-methyl-amino}-
acetic acid ethyl ester ##STR00123## ##STR00124## 1.29 408 8j
C-[6-(2-Chloro-4- methyl-phenyl)-3- morpholin-4-yl-
imidazo[1,2-a]pyridin-7- yl]-methylamine ##STR00125## ##STR00126##
1.04 357 8k C-[6-(2-Chloro-4- methyl-phenyl)-3- piperazin-1-yl-
imidazo[1,2-a]pyridin-7- yl]-methylamine ##STR00127## ##STR00128##
0.65 356 8l C-[6-(2-Chloro-4- methyl-phenyl)-3-(4-
methyl-piperazin-1-yl)- imidazo[1,2-a]pyridin-7- yl]-methylamine
##STR00129## ##STR00130## 0.68 370 8m C-[6-(4-Chloro-2-
methyl-phenyl)-3- morpholin-4-yl- imidazo[1,2-a]pyridin-7-
yl]-methylamine ##STR00131## ##STR00132## 1.08 357 8n
C-[6-(4-Chloro-2- methyl-phenyl)-3- piperazin-1-yl-
imidazo[1,2-a]pyridin-7- yl]-methylamine ##STR00133## ##STR00134##
0.69 356 8o C-[6-(4-Chloro-2- methyl-phenyl)-3-(4-
methyl-piperazin-1-yl)- imidazo[1,2-a]pyridin-7- yl]-methylamine
##STR00135## ##STR00136## 0.73 370 8p C-[6-(2,4-Dimethyl-
phenyl)-3-morpholin-4- yl-imidazo[1,2- a]pyridin-7-yl]- methylamine
##STR00137## ##STR00138## 1.05 337 8q C-[6-(2,4-Dimethyl-
phenyl)-3-piperazin-1- yl-imidazo[1,2- a]pyridin-7-yl]- methylamine
##STR00139## ##STR00140## 0.64 336 8r C-[6-(2,4-Dimethyl-
phenyl)-3-(4-methyl- piperazin-1-yl)- imidazo[1,2-a]pyridin-7-
yl]-methylamine ##STR00141## ##STR00142## 0.67 350 8s
4-[7-Aminomethyl-6- (2,4-dichloro-phenyl)- imidazo[1,2-a]pyridin-3-
yl]-piperazine-1- carboxylic acid benzyl ester ##STR00143##
##STR00144## 1.38 511 8t C-[6-(2,4-Dichloro- phenyl)-3-(3-
trifluoromethyl-5,6- dihydro-8H- [1,2,4]triazolo[4,3-
a]pyrazin-7-yl)- imidazo[1,2-a]pyridin-7- yl]-methylamine
##STR00145## ##STR00146## 1.03 483 8u 1-[7-Aminomethyl-6-
(2,4-dichloro-phenyl)- imidazo[1,2-a]pyridin-3- yl]-piperidine-2-
carboxylic acid ethyl ester ##STR00147## ##STR00148## 1.54 448 8v
1-[7-Aminomethyl-6- (2,4-dichloro-phenyl)- imidazo[1,2-a]pyridin-3-
yl]-piperidine-3- carboxylic acid ethyl ester ##STR00149##
##STR00150## 1.48 448 8w 1-[7-Aminomethyl-6- (2,4-dichloro-phenyl)-
imidazo[1,2-a]pyridin-3- yl]-piperidine-4- carboxylic acid ethyl
ester ##STR00151## ##STR00152## 1.46 448 8x C-[6-(2,4-Dichloro-
phenyl)-3-(2,6- dimethyl-morpholin-4- yl)-imidazo[1,2-
a]pyridin-7-yl]- methylamine ##STR00153## ##STR00154## 1.32 406 8y
{1-[7-Aminomethyl-6- (2,4-dichloro-phenyl)-
imidazo[1,2-a]pyridin-3- yl]-piperidin-4-yl}- dimethyl-amine
##STR00155## ##STR00156## 0.82 419 8z C-{6-(2,4-Dichloro-
phenyl)-3-[4-(1-methyl- piperidin-4-yl)- piperazin-1-yl]-
imidazo[1,2-a]pyridin-7- yl}-methylamine ##STR00157## ##STR00158##
0.72 474 8a' 2-{4-[7-Aminomethyl-6- (2,4-dichloro-phenyl)-
imidazo[1,2-a]pyridin-3- yl]-piperazin-1-yl}-1- morpholin-4-yl-
ethanone ##STR00159## ##STR00160## 0.78 504 8b' C-{6-(2,4-Dichloro-
phenyl)-3-[4-(4- methoxy-phenyl)- piperazin-1-yl]-
imidazo[1,2-a]pyridin-7- yl}-methylamine ##STR00161## ##STR00162##
1.31 483 8c' {4-[7-Aminomethyl-6- (2,4-dichloro-phenyl)-
imidazo[1,2-a]pyridin-3- yl]-piperazin-1-yl}-
(tetrahydro-furan-2-yl)- methanone ##STR00163## ##STR00164## 1.12
475
Example 9
2-{[7-Aminomethyl-6-(2,4-dichloro-phenyl)-imidazo[1,2-a]pyridin-3-yl]-meth-
yl-amino}-ethanol
[0394] Compound 9 was obtained by the following procedure.
[0395] (1) A mixture of
[2-amino-5-(2,4-dichloro-phenyl)-pyridin-4-ylmethyl]-carbamic acid
tert-butyl ester (100 mg, 0.27 mmol) and
1,2-bis-benzotriazol-1-yl-N,N-bis-[2-(tert-butyl-diphenyl-silanyloxy)-eth-
yl]-N,N'-dimethyl-ethane-1,2-diamine (241 mg, 0.27 mmol) in DCE (3
mL) was refluxed for 2 h then cooled to RT. The reaction mixture
was diluted in DCM (40 mL) and washed with a 2.0 M aqueous KOH
solution (10 mL). The organic layer was dried over
Na.sub.2SO.sub.4, filtered and evaporated. The remaining residue
was purified by reverse phase prep-HPLC (Waters system) to give the
Boc-protected intermediate (TFA salt, 43 mg, 19%) as a white solid.
MS: 704 [M+1].sup.+; HPLC: .sup.At.sub.Ret=2.92.
[0396] (2) The Boc-protected compound (43 mg, 0.053 mmol) was
dissolved in THF (0.1 mL), and TBAF (1.0 M solution in THF, 0.11
mL, 0.11 mmol) was added. The reaction mixture was stirred at RT
for 2 h and evaporated to dryness. The remaining residue was
dissolved in DCM (2 mL) and TFA (1 mL) and the solution was stirred
at RT for 30 min. The reaction mixture was concentrated to dryness
and the residue purified by reverse phase prep-HPLC (Waters system)
to give the title compound as a white solid (2TFA salt, 22 mg,
0.037 mmol, 70%). MS: 366 [M+1].sup.+; HPLC:
.sup.At.sub.Ret=0.96.
Example 10
[7-Aminomethyl-6-(2-chloro-4-methyl-phenyl)-imidazo[1,2-a]pyridin-3-yl]-(2-
-methoxy-ethyl)-methyl-amine
[0397] Compound 10 was prepared according to Scheme 4:
##STR00165##
Step 4.1:
[{6-Bromo-3-[(2-methoxy-ethyl)-methyl-amino]-imidazo[1,2-a]pyri-
din-7-ylmethyl}-carbamic acid tert-butyl ester
[0398] The cyclization was carried out as described for Example 6
from (2-amino-5-bromo-pyridin-4-ylmethyl)-carbamic acid tert-butyl
ester (600 mg, 2.0 mmol, prepared according to Example 1, Step 1.3)
and
1,2-bis-benzotriazol-1-yl-N,N'-bis-(2-methoxy-ethyl)-N,N'-dimethyl-ethane-
-1,2-diamine (871 mg, 2.0 mmol, prepared according to Example 6,
Step 3.1). After the work-up, the crude was purified by Combi-Flash
Companion.TM. (Isco Inc.) column chromatography (SiO.sub.2;
gradient elution, [hexane/DCM 1:1]/TBME (containing 0.5% of a 7.0 M
solution of NH.sub.3 in MeOH) 1:0.fwdarw.0:1) to yield the title
compound (546 mg, 1.32 mmol, 67%) as a brownish oil. MS: 414
[M-1].sup.+; HPLC: .sup.At.sub.Ret=1.40; TLC: R.sub.F 0.15
(hexane/DCM/TBME (containing 0.5% of a 7.0 M solution of NH.sub.3
in MeOH) 1:1:2).
Step 4.2
[0399] (1) The Suzuki coupling was carried out as described for
Example 1 from
{6-bromo-3-[(2-methoxy-ethyl)-methyl-amino]-imidazo[1,2-a]pyridin-7--
ylmethyl}-carbamic acid tert-butyl ester (60 mg, 0.15 mmol),
2-chloro-4-methylphenylboronic acid (29.7 mg, 0.17 mmol),
Pd(PPh.sub.3).sub.4 (8.4 mg, 0.007 mmol) and Na.sub.2CO.sub.3 (2.0
M solution in water, 0.25 mL, 0.5 mmol) in DME (0.5 mL). After the
work-up, the remaining residue was purified by reverse phase
prep-HPLC (Waters system) to give the Boc-protected intermediate
(TFA salt). MS: 459 [M+1].sup.+; HPLC: .sup.At.sub.Ret=1.89.
[0400] (2) The Boc-protected intermediate was dissolved in a 2.0 M
HCl solution in dioxane (2 mL), stirred at RT for 1 h, and
evaporated to dryness. The remaining residue was dissolved in
t-BuOH and lyophilized to give the title compound (2HCl salt, 29
mg, 0.067 mmol, 45% for 2 steps) as a redish solid. MS: 359
[M+1].sup.+; HPLC: .sup.At.sub.Ret=1.13.
Example 11
[0401] Compounds 11a and 11b were obtained analogously to Example
10, using various phenylboronic acid derivatives in Step 4.2. The
compounds are of the following general formula:
TABLE-US-00005 ##STR00166## HPLC .sup.At.sub.Ret MS Compound Name
R.sup.5 [min] [M + 1].sup.+ 11a [7- Aminomethyl- 6-(4-chloro-
2-methyl- phenyl)- imidazo[1,2- a]pyridin- 3-yl]- (2-methoxy-
ethyl)- methyl-amine ##STR00167## 1.17 359 11b [7- Aminomethyl-
6-(2,4- dimethyl- phenyl)- imidazo[1,2- a]pyridin- 3-yl]-
(2-methoxy- ethyl)- methyl-amine ##STR00168## 1.13 339
Example 12
C-[6-(2,4-Dichloro-phenyl)-2-(2-methoxy-ethyl)-imidazo[1,2-a]pyridin-7-yl]-
-methylamine
[0402] Compound 12 was prepared according to Scheme 5:
##STR00169##
[0403] (1) In a sealed tube, a mixture of
[2-amino-5-(2,4-dichloro-phenyl)-pyridin-4-ylmethyl]-carbamic acid
tert-butyl ester (50 mg, 0.14 mmol, prepared according to Example
6, Step 3.2), 1-chloro-4-methoxy-butan-2-one (37.1 mg, 0.27 mmol,
prepared according to a published procedure: M. Okahara and al., J.
Org. Chem., 1988, 53, 2737-2740), and NaHCO.sub.3 (19.4 mg, 0.23
mmol) in EtOH (1 mL) was heated at 75.degree. C. for 14 h. The
reaction mixture was cooled to RT and concentrated, then the
residue was diluted in DCM (20 mL) and washed with brine (10 mL).
The aqueous layer was extracted with DCM (2.times.) and the
combined organic fractions were dried over Na.sub.2SO.sub.4,
filtered, and evaporated. The remaining residue was purified by
reverse phase prep-HPLC (Waters system) to give the Boc-protected
intermediate (TFA salt). MS: 450 [M+1].sup.+; HPLC:
.sup.At.sub.Ret=1.79.
[0404] (2) The Boc-protected intermediate was dissolved in a 2.0 M
HCl solution in dioxane (2 mL), stirred at RT for 1 h, and
evaporated to dryness. The remaining residue was dissolved in
t-BuOH and lyophilized to give the title compound (2HCl salt, 21
mg, 0.050 mmol, 36% for 2 steps) as an off-white solid. MS: 351
[M+1].sup.+; HPLC: .sup.At.sub.Ret=0.96.
Example 13
C-[6-(2,4-Dichloro-phenyl)-3-(1-oxo-1lambda*4*-thiomorpholin-4-yl)-imidazo-
[1,2-a]pyridin-7-yl]-methylamine
[0405] Compound 13 was obtained by the following procedure.
[0406] (1) A solution of
[6-(2,4-dichloro-phenyl)-3-thiomorpholin-4-yl-imidazo[1,2-a]pyridin-7-ylm-
ethyl]-carbamic acid tert-butyl ester (50 mg, 0.10 mmol, prepared
according to Example 6, Step 3.3) in a mixture of EtOH (5 mL) and
water (1 mL) was cooled to 0.degree. C. (ice bath), then NaIO.sub.4
(22.7 mg, 0.105 mmol) was added. The reaction mixture was slowly
warmed to RT and stirred for 14 h. The suspension was diluted in
AcOEt (30 mL) then washed successively with water (10 mL) and brine
(10 mL). The organic layer was dried over Na.sub.2SO.sub.4,
filtered, and evaporated to give the crude Boc-protected
intermediate.
[0407] (2) The Boc-protected intermediate was dissolved in DCM (2
mL) and TFA (1 mL) and the solution was stirred at RT for 30 min.
The reaction mixture was concentrated to dryness and the remaining
residue purified by reverse phase prep-HPLC (Waters system) to give
the title compound (2TFA salt, 29.5 mg, 0.046 mmol, 46% for 2
steps) as a white solid. MS: 410 [M+1].sup.+; HPLC:
.sup.At.sub.Ret=0.95.
Example 14
C-[6-(2,4-Dichloro-phenyl)-3-(1,1-dioxo-1lambda*6*-thiomorpholin-4-yl)-imi-
dazo[1,2-a]pyridin-7-yl]-methylamine
[0408] Compound 14 was obtained by the following procedure.
[0409] (1) A solution of
[6-(2,4-dichloro-phenyl)-3-thiomorpholin-4-yl-imidazo[1,2-a]pyridin-7-ylm-
ethyl]carbamic acid tert-butyl ester (50 mg, 0.10 mmol, prepared
according to Example 6, Step 3.3) in DCM (7 mL) was cooled to
0.degree. C. (ice bath), then mCPBA (52.5 mg, 0.30 mmol) was added.
The reaction mixture was slowly warmed to RT, stirred for 14 h, and
diluted in DCM (20 mL). The mixture was washed successively with a
saturated aqueous NaHCO.sub.3 solution (10 mL) and brine (10 mL).
The organic layer was dried over Na.sub.2SO.sub.4, filtered, and
evaporated to give the crude Boc-protected intermediate.
[0410] (2) The Boc-protected intermediate was dissolved in DCM (2
mL) and TFA (1 mL) and the solution was stirred at RT for 30 min.
The reaction mixture was concentrated to dryness and the remaining
residue purified by reverse phase prep-HPLC (Waters system) to give
the title compound (2TFA salt, 13.5 mg, 0.021 mmol, 21% for 2
steps) as a white solid. MS: 426 [M+1].sup.+; HPLC:
.sup.At.sub.Ret=0.70.
Example 15
C-[6-(2,4-Dichloro-phenyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl]-methylamine
[0411] Compound 15 was prepared according to Scheme 6:
##STR00170## ##STR00171##
Step 6.1: 2-Amino-5-(2,4-dichloro-phenyl)-isonicotinonitrile
[0412] A mixture of 2-amino-5-bromo-isonicotinonitrile (1.0 g, 5.1
mmol, prepared according to Example 3, Step 2.1),
2,4-dichloro-benzeneboronic acid (1.45 g, 7.6 mmol),
Pd(PPh.sub.3).sub.4 (292 mg, 0.25 mmol) and Na.sub.2CO.sub.3 (2.0 M
solution in water, 8.8 mL) in DME (10 mL) was refluxed for 2 h
under an inert atmosphere of argon. The reaction mixture was cooled
to RT, diluted in AcOEt and washed with water. The organic layer
was dried over Na.sub.2SO.sub.4, filtered, and evaporated. The
residue was purified by Combi-Flash Companion.TM. (Isco Inc.)
column chromatography (SiO.sub.2; gradient elution, [hexane/DCM
1:1]/TBME 95:5.fwdarw.3:7) to yield the title compound (880 mg, 3.3
mmol, 66%). MS: 264 [M+1].sup.+; HPLC: .sup.At.sub.Ret=1.73; TLC:
R.sub.F 0.31 (hexane/DCM/TBME 1:1:2).
Step 6.2: 2-Chloro-5-(2,4-dichloro-phenyl)-isonicotinonitrile
[0413] A mixture of
2-amino-5-(2,4-dichloro-phenyl)-isonicotinonitrile (880 mg, 3.3
mmol) in HCl conc. (15 mL) was vigorously stirred and cooled to
-15.degree. C. (ice/MeOH bath). NaNO.sub.2 (4.6 g, 66.7 mmol) was
carefully added, then the reaction mixture was slowly warmed to RT
and stirred for 24 h. The formed precipitate was filtered, washed
with water, and purified by Combi-Flash Companion.TM. (Isco Inc.)
column chromatography (SiO.sub.2; gradient elution, [hexane/DCM
1:1]/TBME 95:5.fwdarw.5:95) to yield the title compound (453 mg,
1.6 mmol, 48%). MS: 284 [M+1].sup.+; HPLC:
.sup.At.sub.Ret=2.70.
Step 6.3:
5-(2,4-Dichloro-phenyl)-2-hydrazino-isonicotinonitrile
[0414] A solution of
2-chloro-5-(2,4-dichloro-phenyl)-isonicotinonitrile (453 mg, 1.6
mmol) and hydrazine monohydrate (7.76 mL, 160 mmol) in dioxane (9
mL) was heated at 90.degree. C. and stirred for 14 h. The reaction
mixture was cooled to RT, poured into water (50 mL) and extracted
with AcOEt (3.times.25 mL). The combined organic fractions were
dried over Na.sub.2SO.sub.4, filtered, and evaporated to provide
the crude title compound (520 mg, quant.) as a yellow solid, which
was used without further purification. MS: 279 [M+1].sup.+; HPLC:
.sup.At.sub.Ret=1.44.
Step 6.4:
6-(2,4-Dichloro-phenyl)-[1,2,4]triazolo[4,3-a]pyridine-7-carboni-
trile
[0415] A solution of the crude
5-(2,4-dichloro-phenyl)-2-hydrazino-isonicotinonitrile (520 mg) in
formic acid (15 mL) was stirred and refluxed for 1 h. The reaction
mixture was concentrated under vacuum, then the remaining residue
was diluted in AcOEt (50 mL) and washed with a 2.0 M aqueous
NaHCO.sub.3 solution (2.times.25 mL). The organic layer was dried
over Na.sub.2SO.sub.4, filtered, and evaporated. The residue was
purified by Combi-Flash Companion.TM. (Isco Inc.) column
chromatography (SiO.sub.2; gradient elution, DCM.fwdarw.DCM/MeOH
7:3) to yield the title compound (397 mg, 1.37 mmol, 86% over 2
steps). MS: 289 [M+1].sup.+; HPLC: .sup.At.sub.Ret=1.79; TLC:
R.sub.F 0.41 (DCM/MeOH 95:5).
Step 6.5
[0416] In a sealed flask, a solution of
6-(2,4-dichloro-phenyl)-[1,2,4]triazolo[4,3-a]pyridine-7-carbonitrile
(50 mg, 0.164 mmol) in THF (0.5 mL) was cooled to 0.degree. C. (ice
bath) then treated with BH.sub.3.THF complex (1.0 M solution in
THF, 0.82 mL, 0.82 mmol). The reaction mixture was heated at
40.degree. C. for 1 h, cooled to RT, and diluted in MeOH (large
excess). The mixture was concentrated under vacuum, and the
remaining residue was suspended in 2.0 M HCl, and shaken for 15
min. After evaporation to dryness, the remaining residue was
purified by reverse phase prep-HPLC (Waters system) to give the
title compound (2TFA salt, 1.9 mg, 0.004 mmol, 2%) as a white
solid. MS: 293 [M+1].sup.+; HPLC: .sup.At.sub.Ret=0.95.
Example 16
7-Aminomethyl-6-(2,4-dichloro-phenyl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylam-
ine
[0417] Compound 16 was prepared according to Scheme 7:
##STR00172##
Step 7.1:
[2-Chloro-5-(2,4-dichloro-phenyl)-pyridin-4-ylmethyl]-carbamic acid
tert-butyl ester
[0418] A mixture of
[2-amino-5-(2,4-dichloro-phenyl)-pyridin-4-ylmethyl]-carbamic acid
tert-butyl ester (1.78 g, 4.82 mmol, prepared according to Example
6, Step 3.2), tBuONO (1.05 mL, 8.0 mmol), and CuCl.sub.2 (1.01 g,
7.51 mmol) in CHCl.sub.3 (6 mL) was stirred at RT for 3 days with
exclusion of light. The reaction mixture was concentrated under
vacuum, then the remaining residue was suspended in a 2.0 M aqueous
Na.sub.2CO.sub.3 solution (200 mL) and extracted with AcOEt
(2.times.100 mL). The combined organic fractions were dried over
Na.sub.2SO.sub.4, filtered, and evaporated. The residue was
purified by Combi-Flash Companion.TM. (Isco Inc.) column
chromatography (SiO.sub.2; gradient elution, [hexane/DCM 1:1]/TBME
95:5.fwdarw.4:6) to yield the title compound (1.17 g, 3.0 mmol,
62%) as a colorless solid. MS: 388 [M+1].sup.+; HPLC:
.sup.At.sub.Ret=2.89; TLC: R.sub.F 0.36 ([hexane/DCM 1:1]/TBME
95:5).
Step 7.2:
[5-(2,4-Dichloro-phenyl)-2-hydrazino-pyridin-4-ylmethyl]-carbami- c
acid tert-butyl ester
[0419] A solution of
[2-chloro-5-(2,4-dichloro-phenyl)-pyridin-4-ylmethyl]-carbamic acid
tert-butyl ester (1.17 g, 3.0 mmol) and hydrazine monohydrate (14.6
mL, 300 mmol) in dioxane (8 mL) was heated at 90.degree. C. and
stirred for 3 days. The reaction mixture was cooled to RT, poured
into AcOEt (200 mL) and washed with a 2.0 M aqueous
Na.sub.2CO.sub.3 solution (2.times.100 mL). The organic layer was
dried over Na.sub.2SO.sub.4, filtered, and evaporated to provide
the crude title compound (1.66 g, quant.), which was used without
further purification. HPLC: .sup.At.sub.Ret=1.61.
Step 7.3:
[3-Amino-6-(2,4-dichloro-phenyl)-[1,2,4]triazolo[4,3-a]pyridin-7-
-ylmethyl]-carbamic acid tert-butyl ester
[0420] A mixture of the crude
[5-(2,4-dichloro-phenyl)-2-hydrazino-pyridin-4-ylmethyl]-carbamic
acid tert-butyl ester (1.66 g) and BrCN (638 mg, 6.0 mmol) in EtOH
(40 mL) was heated at 65.degree. C. and stirred for 2 h30. The
reaction mixture was cooled to RT, poured into AcOEt (100 mL) and
washed with a 2.0 M aqueous Na.sub.2CO.sub.3 solution (2.times.50
mL). The organic layer was dried over Na.sub.2SO.sub.4, filtered,
and evaporated. The residue was purified by Combi-Flash
Companion.TM. (Isco Inc.) column chromatography (SiO.sub.2;
gradient elution, DCM/MeOH 95:5.fwdarw.4:6) to yield the title
compound (908 mg, 2.22 mmol, 74% over 2 steps) as a brownish solid.
MS: 408 [M+1].sup.+; HPLC: .sup.At.sub.Ret=1.62; TLC: R.sub.F 0.16
(DCM/MeOH 95:5).
Step 7.4
[0421]
[3-Amino-6-(2,4-dichloro-phenyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl-
methyl]carbamic acid tert-butyl ester (17 mg, 0.042 mmol) was
dissolved in DCM (2 mL) and TFA (1 mL) and the solution was stirred
at RT for 30 min. The reaction mixture was concentrated to dryness
and the remaining residue purified by reverse phase prep-HPLC
(Waters system) to give the title compound (2TFA salt, 5.7 mg,
0.011 mmol, 26%) as a white solid. MS: 308 [M+1].sup.+; HPLC:
.sup.At.sub.Ret=0.77.
Example 17
Tetrahydro-pyran-4-carboxylic acid
[7-aminomethyl-6-(2,4-dichloro-phenyl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl-
]-amide
[0422] Compound 17 was prepared according to Scheme 8:
##STR00173##
[0423] (1) To a solution of
[3-amino-6-(2,4-dichloro-phenyl)-[1,2,4]triazolo[4,3-a]pyridin-7-ylmethyl-
]-carbamic acid tert-butyl ester (30 mg, 0.073 mmol, prepared
according to Example 16, Step 7.3), tetrahydro-pyran-4-carboxylic
acid (15.3 mg, 0.118 mmol) and DIPEA (0.031 mL, 0.220 mmol) in DMF
(0.5 mL) was added HATU (41.9 mg, 0.110 mmol) at RT. The reaction
mixture was heated at 50.degree. C. for 2 h, then poured into AcOEt
(10 mL) and washed with a 2.0 M aqueous Na.sub.2CO.sub.3 solution
(2.times.5 mL) and brine (5 mL). The organic layer was dried over
Na.sub.2SO.sub.4, filtered, and evaporated to give the crude
Boc-protected intermediate.
[0424] (2) The Boc-protected intermediate was dissolved in DCM (2
mL) and TFA (1 mL) and the solution was stirred at RT for 30 min.
The reaction mixture was concentrated to dryness and the remaining
residue purified by reverse phase prep-HPLC (Waters system) to give
the title compound (2TFA salt, 21.4 mg, 0.033 mmol, 45% for 2
steps) as a white solid. MS: 420 [M+1].sup.+; HPLC:
.sup.At.sub.Ret=1.11.
Example 18
[0425] Compounds 18a to 18i were obtained analogously to Example
17, using various carboxylic acid derivatives. The compounds are of
the following general formula:
TABLE-US-00006 ##STR00174## HPLC .sup.At.sub.Ret MS Compound Name R
[min] [M + 1].sup.+ 18a Piperidine-4-carboxylic acid
[7-aminomethyl-6-(2,4- dichloro-phenyl)-
[1,2,4]triazolo[4,3-a]pyridin-3- yl]-amide ##STR00175## 0.81 419
18b 1-Methyl-piperidine-4- carboxylic acid [7-
aminomethyl-6-(2,4-dichloro- phenyl)-[1,2,4]triazolo[4,3-
a]pyridin-3-yl]-amide ##STR00176## 0.82 433 18c
1-Acetyl-piperidine-4- carboxylic acid [7-
aminomethyl-6-(2,4-dichloro phenyl)-[1,2,4]triazolo[4,3-
a]pyridin-3-yl]-amide ##STR00177## 1.09 461 18d
N-[7-Aminomethyl-6-(2,4- dichloro-phenyl)-
[1,2,4]triazolo[4,3-a]pyridin-3- yl]-2-methoxy-acetamide
##STR00178## 1.10 380 18e N-[7-Aminomethyl-6-(2,4-
dichloro-phenyl)- [1,2,4]triazolo[4,3-a]pyridin-3-
yl]-3-methoxy-propionamide ##STR00179## 1.13 394 18f
N-[7-Aminomethyl-6-(2,4- dichloro-phenyl)-
[1,2,4]triazolo[4,3-a]pyridin-3- yl]-2-bicyclo[2.2.1]hept-2-yl-
acetamide ##STR00180## 1.70 444 18g N-[7-Aminomethyl-6-(2,4-
dichloro-phenyl)- [1,2,4]triazolo[4,3-a]pyridin-3-
yl]-2-((R)-3-benzyl-1-methyl- piperidin-4-yl)-acetamide
##STR00181## 1.22 537 18h 2-Adamantan-1-yl-N-[7-
aminomethyl-6-(2,4-dichloro- phenyl)-[1,2,4]triazolo[4,3-
a]pyridin-3-yl]-acetamide ##STR00182## 1.86 484 18i
8-{[7-Aminomethyl-6-(2,4- dichloro-phenyl)-
[1,2,4]triazolo[4,3-a]pyridin-3- ylcarbamoyl]-methyl}-3-oxo-
3,5,7,8-tetrahydro-2H- pyrido[4,3-c]pyridazine-6- carboxylic acid
ethyl ester NVP-BJV736-AI-1 ##STR00183## 1.21 571
Example 19
C-[6-(2,4-Dichloro-phenyl)-3-morpholin-4-yl-[1,2,4]triazolo[4,3-a]pyridin--
7-yl]-methylamine
[0426] Compound 19 was prepared according to Scheme 9:
##STR00184##
Step 9.1:
[3-Chloro-6-(2,4-dichloro-phenyl)-[1,2,4]triazolo[4,3-a]pyridin-
e-7-carbonitrile
[0427] A mixture of
6-(2,4-dichloro-phenyl)-[1,2,4]triazolo[4,3-a]pyridine-7-carbonitrile
(397 mg, 1.37 mmol, prepared according to Example 15, Step 6.4) and
NCS (275 mg, 2.06 mmol) in DMF (8 mL) was heated at 50.degree. C.
and stirred for 7 h. The reaction mixture was diluted in AcOEt (50
mL) and washed with water (2.times.25 mL). The organic layer was
dried over Na.sub.2SO.sub.4, filtered, and evaporated to give the
crude title compound (466 mg, quant.). MS: 323 [M+1].sup.+; HPLC:
.sup.At.sub.Ret=2.11.
Step 9.2
[0428] (1) A solution of the crude
[3-chloro-6-(2,4-dichloro-phenyl)-[1,2,4]triazolo[4,3-a]pyridine-7-carbon-
itrile (50 mg, 0.148 mmol) in morpholine (1.2 mL) was heated at
110.degree. C. and stirred for 5 h. The reaction mixture was
concentrated in vacuum, the remaining residue was suspended in
water (10 mL) and extracted with AcOEt (3.times.5 mL). The combined
organic fractions were dried over Na.sub.2SO.sub.4, filtered, and
evaporated to give the crude
6-(2,4-dichloro-phenyl)-3-morpholin-4-yl-[1,2,4]triazolo[4,3-a]pyridine-7-
-carbonitrile, which was used without further purification. MS: 374
[M+1].sup.+; HPLC: .sup.At.sub.Ret=1.94.
[0429] (2) In a sealed flask, a solution of the crude
6-(2,4-dichloro-phenyl)-3-morpholin-4-yl-[1,2,4]triazolo[4,3-a]pyridine-7-
-carbonitrile in THF (1 mL) was cooled to 0.degree. C. (ice bath)
then treated with BH.sub.3.THF complex (1.0 M solution in THF, 0.73
mL, 0.73 mmol). The reaction mixture was heated at 40.degree. C.
for 1 h, cooled to RT, and diluted in MeOH (large excess). The
mixture was concentrated under vacuum, and the remaining residue
was suspended in 2.0 M HCl, and shaken for 15 min. After
evaporation to dryness, the remaining residue was purified by
reverse phase prep-HPLC (Waters system) to give the title compound
(2TFA salt, 5 mg, 0.008 mmol, 5%) as a white solid. MS: 378
[M+1].sup.+; HPLC: .sup.At.sub.Ret=1.15.
Example 20
[6-(2,4-Dichloro-phenyl)-3-morpholin-4-yl-imidazo[1,2-a]pyridin-7-ylmethyl-
]-methyl-amine
[0430] Compound 20 was prepared according to Scheme 10:
##STR00185##
[0431] (1) A solution of
[6-(2,4-dichloro-phenyl)-3-morpholin-4-yl-imidazo[1,2-a]pyridin-7-ylmethy-
l]-carbamic acid tert-butyl ester (20 mg, 0.042 mmol, prepared
according to Example 6, Step 3.3) in DMF (0.5 mL) was treated with
NaH (60% in mineral oil, 2.0 mg, 0.050 mmol) and stirred at RT for
30 min. MeI (0.003 mL, 0.050 mmol) was added and the mixture was
stirred at RT for 2 h. The reaction mixture was poured into water
(10 mL) and extracted with DCM (20 mL). The organic layer was dried
over Na.sub.2SO.sub.4, filtered, and evaporated to dryness to yield
the crude Boc-protected intermediate.
[0432] (2) The Boc-protected intermediate was dissolved in DCM (1
mL), TFA (1 mL) was added and the solution was stirred at RT for 30
min. The reaction mixture was concentrated to dryness and the
remaining residue purified by reverse phase prep-HPLC (Waters
system) to give the title compound as a TFA salt.
[0433] (3) The TFA salt was dissolved in HCl (1.25 M solution in
MeOH), stirred for 5 min at RT, and evaporated to dryness (the
sequence was performed 3 times). The remaining residue was
dissolved in water and lyophilized to give the HCl salt of the
title compound (2HCl salt, 13 mg, 0.028 mmol, 70%). MS: 392
[M+1].sup.+; HPLC: .sup.At.sub.Ret=1.26.
Example 21
[0434] Compounds 21a to 21e were obtained analogously to Example
20, using various alkyl halides. The compounds are of the following
general formula:
TABLE-US-00007 ##STR00186## HPLC .sup.At.sub.Ret MS Compound Name
R.sup.1 [min] [M + 1].sup.+ 21a [6-(2,4- Dichlo- phenyl)-3-
morpholin- 4-yl- imidazo[1,2- a]pyridin- 7-ylmethyl]- isopropyl-
amine ##STR00187## 1.16 420 21b [6-(2,4- Dichloro- phenyl)-3-
morpholin- 4-yl- imidazo[1,2- a]pyridin-7- ylmethyl]- ethyl- amine
##STR00188## 1.11 406 21c [6-(2,4- Dichloro- phenyl)-3- morpholin-
4-yl-imidazo [1,2- a]pyridin-7- ylmethyl]- isobutyl- amine
##STR00189## 1.27 434 21d Benzyl- [6-(2,4- dichloro phenyl)-3-
morpholin- 4-yl- imidazo[1,2- a]pyridin-7- ylmethyl]- amine
##STR00190## 1.39 467 21e [6-(2,4- Dichloro- phenyl)-3- morpholin-
4-yl- imidazo[1,2- a]pyridin-7- ylmethyl]-(2- methoxy- ethyl)-
amine ##STR00191## 1.16 436
Example 22
N-[6-(2,4-Dichloro-phenyl)-3-morpholin-4-yl-imidazo[1,2-a]pyridin-7-ylmeth-
yl]-acetamide
[0435] Compound 22 was prepared according to Scheme 11:
##STR00192##
[0436] (1) A solution of
[6-(2,4-dichloro-phenyl)-3-morpholin-4-yl-imidazo[1,2-a]pyridin-7-ylmethy-
l]-carbamic acid tert-butyl ester (30 mg, 0.063 mmol, prepared
according to Example 6, Step 3.3) in DCM (1 mL) and TFA (1 mL) was
stirred at RT for 30 min. The reaction mixture was concentrated to
dryness, the remaining residue was diluted in AcOEt and washed with
a 2.0 M Na.sub.2CO.sub.3 solution in water (2.times.). The organic
layer was dried over Na.sub.2SO.sub.4, filtered and evaporated to
give the crude benzylic amine intermediate which was used in the
next step without further purification.
[0437] (2) To a solution of the previously obtained benzylic amine
in DCM (0.5 mL) were added successively pyridine (0.015 mL, 0.189
mmol), DMAP (0.8 mg, 0.006 mmol) and acetyl chloride (0.005 ml,
0.075 mmol) at RT. The reaction mixture was stirred for 14 h then
concentrated to dryness and the remaining residue was purified by
reverse phase prep-HPLC (Waters system) to give the title compound
(TFA salt, 11.7 mg, 0.022 mmol, 35% for 2 steps). MS: 420
[M+1].sup.+; HPLC: .sup.At.sub.Ret=1.34.
Example 23
[7-Aminomethyl-6-(2,4-dichloro-phenyl)-imidazo[1,2-a]pyridin-8-yl]-isobuty-
l-amine
[0438] Compound 23 was prepared according to Scheme 12:
##STR00193##
Step 12.1:
2-Amino-3-chloro-5-(2,4-dichloro-phenyl)-isonicotinonitrile
[0439] A mixture of
2-amino-5-(2,4-dichloro-phenyl)-isonicotinonitrile (300 mg, 1.14
mmol, prepared according to Example 15, Step 6.1) and NCS (159 mg,
1.19 mmol) in DMF (4 mL) was stirred and heated at 50.degree. C.
for 3 h. The reaction mixture was cooled to RT, poured into AcOEt
(40 mL) and washed with water (10 mL). The organic layer was dried
over Na.sub.2SO.sub.4, filtered and evaporated. The residue was
purified by Combi-Flash Companion.TM. (Isco Inc.) column
chromatography (SiO.sub.2; gradient elution, hexane/TBME
95:5.fwdarw.100% TBME) to yield the title compound (310 mg, 0.99
mmol, 87%) as a yellow solid. MS: 296 [M-1].sup.+; HPLC:
.sup.At.sub.Ret=2.43; TLC: R.sub.F 0.33 (hexane/TBME 1:1).
Step 12.2:
8-Chloro-6-(2,4-dichloro-phenyl)-imidazo[1,2-a]pyridine-7-carbo-
nitrile
[0440] In a sealed tube, a mixture of
2-amino-3-chloro-5-(2,4-dichloro-phenyl)-isonicotinonitrile (285
mg, 0.96 mmol) and 1,2-dichloro-1-ethoxy-ethane (0.64 mL, 5.25
mmol) was heated at 150.degree. C. for 17 min under microwave
irradiation. The reaction mixture was cooled to RT, poured into
AcOEt (75 mL) and washed with a 2.0 M Na.sub.2CO.sub.3 solution in
water (2.times.25 mL). The organic layer was dried over
Na.sub.2SO.sub.4, filtered and evaporated. The residue was purified
by Combi-Flash Companion.TM. (Isco Inc.) column chromatography
(SiO.sub.2; gradient elution, [hexane/DCM 1:1]/TBME
95:5.fwdarw.3:7) to yield the title compound (185 mg, 0.57 mmol,
60%) as a brownish solid. MS: 322 [M+1].sup.+; HPLC:
.sup.At.sub.Ret=2.17; TLC: R.sub.F 0.13 (hexane/DCM/TBME
1:1:2).
Step 12.3:
6-(2,4-Dichloro-phenyl)-8-isobutylamino-imidazo[1,2-a]pyridine--
7-carbonitrile
[0441] In a sealed tube, a mixture of
8-chloro-6-(2,4-dichloro-phenyl)-imidazo[1,2-a]pyridine-7-carbonitrile
(20 mg, 0.062 mmol) and isobutylamine (0.037 mL, 0.37 mmol) was
heated at 150.degree. C. for 14 h. The reaction mixture was cooled
to RT, poured into AcOEt (5 mL) and washed with a 2.0 M
Na.sub.2CO.sub.3 solution in water (2.times.2 mL). The organic
layer was dried over Na.sub.2SO.sub.4, filtered and evaporated. The
residue was purified by Combi-Flash Companion.TM. (Isco Inc.)
column chromatography (SiO.sub.2; gradient elution, [hexane/DCM
1:1]/TBME 95:5.fwdarw.8:2) to yield the title compound (19.1 mg,
0.053 mmol, 85%) as a reddish solid. MS: 359 [M+1].sup.+; HPLC:
.sup.At.sub.Ret=2.61; TLC: R.sub.F 0.64 (hexane/DCM/TBME
1:1:2).
Step 12.4
[0442] In a sealed flask, a solution of
6-(2,4-dichloro-phenyl)-8-isobutylamino-imidazo[1,2-a]pyridine-7-carbonit-
rile (19.1 mg, 0.053 mmol) in THF (0.5 mL) was cooled to 0.degree.
C. (ice bath), treated with BH.sub.3.THF complex (1.0 M solution in
THF, 0.48 mL, 0.48 mmol) and heated at 40.degree. C. After 1 h, the
reaction was not complete according to HPLC. 4.0 M HCl in dioxane
(2 drops) and additional BH.sub.3-THF complex (1.0 M solution in
THF, 0.16 mL, 0.16 mmol) were added, then the reaction mixture was
heated at 40.degree. C. for 14 h, cooled to 0.degree. C., and
diluted in MeOH (large excess). The resulting mixture was
concentrated under vacuum, and the remaining residue was dissolved
in TFA. After evaporation to dryness, the remaining residue was
purified by reverse phase prep-HPLC (Waters system) to give the
title compound (2TFA salt, 7.6 mg, 0.013 mmol, 24%). MS: 363
[M+1].sup.+HPLC: .sup.At.sub.Ret=1.47.
Example 24
[0443] Compounds 24a to 24n were obtained analogously to Example
23, using various amines in Step 12.3. The compounds are of the
following general formula:
TABLE-US-00008 ##STR00194## HPLC .sup.At.sub.Ret MS Compound Name
R.sup.6 [min] [M + 1].sup.+ 24a [7-Aminomethyl-6-(2,4-
dichloro-phenyl)-imidazo[1,2- a]pyridin-8-yl]-
cyclopropylmethyl-amine ##STR00195## 1.18 361 24b
[7-Aminomethyl-6-(2,4- dichloro-phenyl)-imidazo[1,2-
a]pyridin-8-yl]-benzyl-amine ##STR00196## 1.31 397 24c
[7-Aminomethyl-6-(2,4- dichloro-phenyl)-imidazo[1,2-
a]pyridin-8-yl]-ethyl-amine ##STR00197## 1.03 335 24d
[7-Aminomethyl-6-(2,4- dichloro-phenyl)-imidazo[1,2-
a]pyridin-8-yl]-dimethyl-amine ##STR00198## 0.91 335 24e
[7-Aminomethyl-6-(2,4- dichloro-phenyl)-imidazo[1,2-
a]pyridin-8-yl]-butyl-amine ##STR00199## 1.28 363 24f
[7-Aminomethyl-6-(2,4- dichloro-phenyl)-imidazo[1,2-
a]pyridin-8-yl]-(2-methoxy- ethyl)-amine ##STR00200## 1.01 365 24g
[7-Aminomethyl-6-(2,4- dichloro-phenyl)-imidazo[1,2-
a]pyridin-8-yl]-propyl-amine ##STR00201## 1.16 349 24h
2-[7-Aminomethyl-6-(2,4- dichloro-phenyl)-imidazo[1,2-
a]pyridin-8-ylamino]-ethanol ##STR00202## 0.91 351 24i
C-[6-(2,4-Dichloro-phenyl)-8- piperidin-1-yl-imidazo[1,2-
a]pyridin-7-yl]-methylamine ##STR00203## 1.05 375 24j
C-[6-(2,4-Dichloro-phenyl)-8- morpholin-4-yl-imidazo[1,2-
a]pyridin-7-yl]-methylamine ##STR00204## 0.93 377 24k
C-[6-(2,4-Dichloro-phenyl)-8- pyrrolidin-1-yl-imidazo[1,2-
a]pyridin-7-yl]-methylamine ##STR00205## 1.03 361 24l
[7-Aminomethyl-6-(2,4- dichloro-phenyl)-imidazo[1,2-
a]pyridin-8-yl]-cyclopentyl- amine ##STR00206## 1.29 375 24m
[7-Aminomethyl-6-(2,4- dichloro-phenyl)-imidazo[1,2-
a]pyridin-8-yl]-cyclohexyl- amine ##STR00207## 1.36 389 24n
[7-Aminomethyl-6-(2,4- dichloro-phenyl)-imidazo[1,2-
a]pyridin-8-yl]-methyl-amine ##STR00208## 0.97 321
Example 25
7-Aminomethyl-6-(2,4-dichloro-phenyl)-imidazo[1,2-a]pyridin-8-ylamine
[0444] Compound 25 was prepared according to Scheme 13:
##STR00209##
Step 13.1:
8-Azido-6-(2,4-dichloro-phenyl)-imidazo[1,2-a]pyridine-7-carbonitrile
[0445] A mixture of
8-chloro-6-(2,4-dichloro-phenyl)-imidazo[1,2-a]pyridine-7-carbonitrile
(80 mg, 0.25 mmol, prepared according to Example 23, Step 12.2) and
sodium azide (81 mg, 1.24 mmol) in DMF (1 mL) was stirred and
heated at 60.degree. C. for 3 h. The reaction mixture was cooled to
RT, poured into AcOEt and washed successively with water and brine.
The organic layer was dried over Na.sub.2SO.sub.4, filtered and
evaporated to yield the crude title compound (77.4 mg, 0.24 mmol,
95%) as a brownish solid, which was used in the next step without
further purification. MS: 329 [M+1].sup.+; HPLC:
.sup.At.sub.Ret=2.56.
Step 13.2:
8-Amino-6-(2,4-dichloro-phenyl)-imidazo[1,2-a]pyridine-7-carbon-
itrile
[0446] A mixture of crude
8-azido-6-(2,4-dichloro-phenyl)-imidazo[1,2-a]pyridine-7-carbonitrile
(68 mg, 0.21 mmol) and triphenylphosphine (83.7 mg, 0.32 mmol) in
MeOH (2.5 mL) was stirred and refluxed for 1 h. 2 M HCl in water (1
mL) was added and the reaction mixture was further refluxed for 1
h. The reaction mixture was cooled to RT, concentrated under vacuum
and the remaining residue was dissolved in water. The aqueous
solution was basified to pH 12 by the addition of 2 M NaOH in
water. The resulting slurry was extracted with DCM (2.times.) and
the combined organic fractions were dried over Na.sub.2SO.sub.4,
filtered and evaporated. The remaining residue was dissolved in hot
MeOH, then the solution was slowly cooled to RT and the formed
precipitate was filtered and washed with cold MeOH to yield the
title compound (32.5 mg, 0.11 mmol, 52%) as a brownish solid. MS:
303 [M+1].sup.+; HPLC: .sup.At.sub.Ret=1.72.
Step 13.3
[0447] To a solution of
8-amino-6-(2,4-dichloro-phenyl)-imidazo[1,2-a]pyridine-7-carbonitrile
(32.5 mg, 0.11 mmol) in THF (1 mL) was added a BH.sub.3-THF complex
(1.0 M solution in THF, 0.43 mL, 0.43 mmol) followed by 4 M HCl in
dioxane (2 drops). The reaction mixture was stirred and refluxed
for 4 h, then cooled to 0.degree. C. (ice bath) and poured into
MeOH. The mixture was concentrated under vacuum, then the remaining
residue was dissolved in TFA, evaporated to dryness and purified by
reverse phase prep-HPLC (Waters system) to give the title compound
(2TFA salt, 35.7 mg, 0.067 mmol, 62%). MS: 307 [M+1].sup.+; HPLC:
.sup.At.sub.Ret=0.99.
Example 26
1-{4-[7-Aminomethyl-6-(2,4-dichloro-phenyl)-imidazo[1,2-a]pyridine-3-carbo-
nyl]-piperazin-1-yl}-ethanone
[0448] Compound 26 was prepared according to Scheme 14:
##STR00210##
Step 14.1:
6-Bromo-7-(tert-butoxycarbonylamino-methyl)-imidazo[1,2-a]pyridine-3-carb-
oxylic acid ethyl ester
[0449] A solution of (2-amino-5-bromo-pyridin-4-ylmethyl)-carbamic
acid tert-butyl ester (3.5 g, 11.6 mmol, prepared according to
Example 1, Step 1.3) and freshly prepared 2-chloro-3-oxo-propionic
acid ethyl ester (8.97 g, 59.6 mmol, prepared according to a
patented procedure U.S. Pat. No. 5,559,158-A1) in dioxane (60 mL)
was stirred at RT for 14 h. The reaction mixture was diluted in
AcOEt (400 mL) and washed with a 2.0 M aqueous Na.sub.2CO.sub.3
solution (2.times.200 mL). The organic layer was dried over
Na.sub.2SO.sub.4, filtered, and evaporated. The residue was
purified by Combi-Flash Companion.TM. (Isco Inc.) column
chromatography (SiO.sub.2; gradient elution, [hexane/DCM 1:1]/TBME
95:5.fwdarw.2:8) to yield the title compound (1.31 g, 4.83 mmol,
41%) as a light yellow solid. MS: 398 [M+1].sup.+; HPLC:
.sup.At.sub.Ret=1.85; TLC: R.sub.F 0.47 (hexane/DCM/TBME
1:1:2).
Step 14.2:
7-(tert-Butoxycarbonylamino-methyl)-6-(2,4-dichloro-phenyl)-imi-
dazo[1,2-a]pyridine-3-carboxylic acid ethyl ester
[0450] In a sealed tube, a mixture of
6-bromo-7-(tert-butoxycarbonylamino-methyl)-imidazo[1,2-a]pyridine-3-carb-
oxylic acid ethyl ester (1.4 g, 3.52 mmol),
2,4-dichloro-benzeneboronic acid (1.01 g, 5.29 mmol),
Pd(PPh.sub.3).sub.4 (203 mg, 0.18 mmol) and Na.sub.2CO.sub.3 (2.0 M
solution in water, 6.2 mL) in DME (20 mL) was heated at 150.degree.
C. for 17 min under microwave irradiation. The reaction mixture was
cooled to RT, diluted in AcOEt (400 mL) and washed with a 2.0 M
aqueous Na.sub.2CO.sub.3 solution (2.times.200 mL). The organic
layer was dried over Na.sub.2SO.sub.4, filtered, and evaporated.
The residue was purified by Combi-Flash Companion.TM. (Isco Inc.)
column chromatography (SiO.sub.2; gradient elution, [hexane/DCM
1:1]/TBME 95:5.fwdarw.2:8) to yield the title compound (1.39 g,
2.81 mmol, 80%). MS: 464 [M+1].sup.+; HPLC: .sup.At.sub.Ret=2.31;
TLC: R.sub.F 0.47 (hexane/DCM/TBME 1:1:2).
Step 14.3:
7-(tert-Butoxycarbonylamino-methyl)-6-(2,4-dichloro-phenyl)-imi-
dazo[1,2-a]pyridine-3-carboxylic acid
[0451] To a suspension of
7-(tert-butoxycarbonylamino-methyl)-6-(2,4-dichloro-phenyl)-imidazo[1,2-a-
]pyridine-3-carboxylic acid ethyl ester (1.39 g, 2.99 mmol) in MeOH
(24 mL) and water (12 mL) was added LiOH.H.sub.2O (377 mg, 8.98
mmol) in one portion. The slurry was stirred at RT for 14 h then
the clear solution was acidified to pH 5 by the addition of 2.0 M
HCl in water. The resulting precipitate was filtered, the solid
washed with water and dried under vacuum to yield the title
compound (1.25 g, 2.76 mmol, 92%) as a colorless solid, which was
used in the next step without further purification. MS: 436
[M+1].sup.+; HPLC: .sup.At.sub.Ret=1.76.
Step 14.4
[0452] (1) To a mixture of
7-(tert-butoxycarbonylamino-methyl)-6-(2,4-dichloro-phenyl)-imidazo[1,2-a-
]pyridine-3-carboxylic acid (50 mg, 0.115 mmol),
1-piperazin-1-yl-ethanone (16.2 mg, 0.126 mmol) and DIPEA (0.040
mL, 0.229 mmol) in DMF (0.8 mL) was added HATU (47.9 mg, 0.126
mmol) at RT. The reaction mixture was heated at 50.degree. C. for 3
h30, then poured into AcOEt (20 mL) and washed successively with a
2.0 M aqueous Na.sub.2CO.sub.3 solution (2.times.10 mL) and brine
(10 mL). The organic layer was dried over Na.sub.2SO.sub.4,
filtered, and evaporated to give the crude Boc-protected
intermediate.
[0453] (2) The Boc-protected intermediate was dissolved in DCM (2
mL), TFA (1 mL) was added and the solution was stirred at RT for 30
min. The reaction mixture was concentrated to dryness and the
remaining residue purified by reverse phase prep-HPLC (Waters
system) to give the title compound as a TFA salt.
[0454] (3) The TFA salt was dissolved in HCl (1.25 M solution in
MeOH), stirred for 5 min at RT, and evaporated to dryness (the
sequence was performed 3 times). The remaining residue was
dissolved in water and lyophilized to give the HCl salt of the
title compound (2HCl salt, 39.8 mg, .times.mmol, 67%) as a yellow
solid. MS: 446 [M+1].sup.+; HPLC: .sup.At.sub.Ret=1.06.
Example 27
[0455] Compounds 27a to 27l' were obtained as TFA or HCl salts,
analogously to Example 26, using various boronic acid in Step 14.2
and various amines in Step 14.4. The compounds are of the following
general formula:
TABLE-US-00009 ##STR00211## HPLC .sup.At.sub.Ret MS Compound Name
R.sup.5 R.sup.7 [min] [M + 1].sup.+ 27a [7-Aminomethyl-6-(2,4-
dichloro-phenyl)- imidazo[1,2-a]pyridin-3- yl]-morpholin-4-yl-
methanone ##STR00212## ##STR00213## 1.58 405 27b
[7-Aminomethyl-6-(2,4- dichloro-phenyl)- imidazo[1,2-a]pyridin-3-
yl]-piperazin-1-yl- methanone ##STR00214## ##STR00215## 0.81 404
27c [7-Aminomethyl-6-(2,4- dichloro-phenyl)-
imidazo[1,2-a]pyridin-3- yl]-thiomorpholin-4-yl- methanone
##STR00216## ##STR00217## 1.30 421 27d 4-[7-Aminomethyl-6-(2,4-
dichloro-phenyl)- imidazo[1,2-a]pyridine-3- carbonyl]-piperazine-1-
carboxylic acid ethyl ester ##STR00218## ##STR00219## 1.33 476 27e
4-[7-Aminomethyl-6-(2,4- dichloro-phenyl)-
imidazo[1,2-a]pyridine-3- carbonyl]-piperazin-2-one ##STR00220##
##STR00221## 0.95 418 27f 1-{1-[7-Aminomethyl-6-
(2,4-dichloro-phenyl)- imidazo[1,2-a]pyridine-3-
carbonyl]-piperidin-4-yl}- imidazolidin-2-one ##STR00222##
##STR00223## 1.08 487 27g 6-{4-[7-Aminomethyl-6-
(2,4-dichloro-phenyl)- imidazo[1,2-a]pyridine-3-
carbonyl]-piperazin-1-yl}- 1-methyl-1H-pyridin-2-one ##STR00224##
##STR00225## 1.22 511 27h [7-Aminomethyl-6-(2,4- dichloro-phenyl)-
imidazo[1,2-a]pyridin-3- yl]-[4-(furan-2-carbonyl)-
piperazin-1-yl]-methanone ##STR00226## ##STR00227## 1.26 498 27i
[7-Aminomethyl-6-(2,4- dichloro-phenyl)- imidazo[1,2-a]pyridin-3-
yl]-(4-pyrimidin-2-yl- piperazin-1-yl)-methanone ##STR00228##
##STR00229## 1.26 482 27j [7-Aminomethyl-6-(2,4- dichloro-phenyl)-
imidazo[1,2-a]pyridin-3- yl]-(2,3,5,6-tetrahydro-
[1,2']bipyrazinyl-4-yl)- methanone ##STR00230## ##STR00231## 1.24
482 27k [7-Aminomethyl-6-(2,4- dichloro-phenyl)-
imidazo[1,2-a]pyridin-3- yl]-(2,6-dimethyl- morpholin-4-yl)-
methanone ##STR00232## ##STR00233## 1.30 433 27l
2-{4-[7-Aminomethyl-6- (2,4-dichloro-phenyl)-
imidazo[1,2-a]pyridine-3- carbonyl]-piperazin-1-yl}-
1-morpholin-4-yl-ethanone ##STR00234## ##STR00235## 0.92 531 27m
8-[7-Aminomethyl-6-(2,4- dichloro-phenyl)-
imidazo[1,2-a]pyridine-3- carbonyl]-1-oxa-3,8-diaza-
spiro[4.5]decan-2-one ##STR00236## ##STR00237## 1.07 474 27n
7-Aminomethyl-6-(2,4- dichloro-phenyl)- imidazo[1,2-a]pyridine-3-
carboxylic acid (2- methoxy-ethyl)-methyl- amide ##STR00238##
##STR00239## 1.14 407 27o [7-Aminomethyl-6-(2,4- dichloro-phenyl)-
imidazo[1,2-a]pyridin-3- yl]-(3-trifluoromethyl-5,6- dihydro-8H-
[1,2,4]triazolo[4,3- a]pyrazin-7-yl)-methanone ##STR00240##
##STR00241## 1.32 510 27p 7-Aminomethyl-6-(2,4- dichloro-phenyl)-
imidazo[1,2-a]pyridine-3- carboxylic acid pyridin-4- ylamide
##STR00242## ##STR00243## 1.05 412 27q 7-Aminomethyl-6-(2,4-
dichloro-phenyl)- imidazo[1,2-a]pyridine-3- carboxylic acid
pyridin-3- ylamide ##STR00244## ##STR00245## 1.03 412 27r
[7-Aminomethyl-6-(2,4- dichloro-phenyl)- imidazo[1,2-a]pyridin-3-
yl]-(4-methyl-piperazin-1- yl)-methanone ##STR00246## ##STR00247##
0.84 418 27s 7-Aminomethyl-6-(2,4- dichloro-phenyl)-
imidazo[1,2-a]pyridine-3- carboxylic acid (tetrahydro-pyran-4-yl)-
amide ##STR00248## ##STR00249## 1.21 419 27t 7-Aminomethyl-6-(2,4-
dichloro-phenyl)- imidazo[1,2-a]pyridine-3- carboxylic acid
(tetrahydro-pyran-3-yl)- amide ##STR00250## ##STR00251## 1.25 419
27u 1-{4-[7-Aminomethyl-6- (2,4-dichloro-phenyl)-
imidazo[1,2-a]pyridine-3- carbonyl]-piperazin-1-yl}- propan-1-one
##STR00252## ##STR00253## 1.16 460 27v [7-Aminomethyl-6-(2,4-
dichloro-phenyl)- imidazo[1,2-a]pyridin-3- yl]-(4-methanesulfonyl-
piperazin-1-yl)-methanone ##STR00254## ##STR00255## 1.18 482 27w
4-[7-Aminomethyl-6-(2,4- dichloro-phenyl)-
imidazo[1,2-a]pyridine-3- carbonyl]-piperazine-1- carboxylic acid
dimethylamide ##STR00256## ##STR00257## 1.17 475 27x
7-Aminomethyl-6-(2,4- dichloro-phenyl)- imidazo[1,2-a]pyridine-3-
carboxylic acid methyl- (tetrahydro-pyran-4-yl)- amide ##STR00258##
##STR00259## 1.17 433 27y 7-Aminomethyl-6-(2,4- dichloro-phenyl)-
imidazo[1,2-a]pyridine-3- carboxylic acid ethyl-
(tetrahydro-pyran-4-yl)- amide ##STR00260## ##STR00261## 1.28 447
27z 3-{[7-Aminomethyl-6-(2,4- dichloro-phenyl)-
imidazo[1,2-a]pyridine-3- carbonyl]-amino}- piperidine-1-carboxylic
acid ethyl ester ##STR00262## ##STR00263## 1.45 490 27a'
3-{[7-Aminomethyl-6-(2,4- dichloro-phenyl)-
imidazo[1,2-a]pyridine-3- carbonyl]-methyl-amino}-
piperidine-1-carboxylic acid ethyl ester ##STR00264## ##STR00265##
1.42 504 27b' [7-Aminomethyl-6-(2,4- dichloro-phenyl)-
imidazo[1,2-a]pyridin-3- yl]-(1,1-dioxo-1lambda*6*-
thiomorpholin-4-yl)- methanone ##STR00266## ##STR00267## 1.11 453
27c' [7-Aminomethyl-6-(2,4- dimethyl-phenyl)-
imidazo[1,2-a]pyridin-3- yl]-morpholin-4-yl- methanone ##STR00268##
##STR00269## 1.34 365 27d' [7-Aminomethyl-6-(2,4- dimethyl-phenyl)-
imidazo[1,2-a]pyridin-3- yl]-(4-methanesulfonyl-
piperazin-1-yl)-methanone ##STR00270## ##STR00271## 1.11 442 27e'
[7-Aminomethyl-6-(2,4- dimethyl-phenyl)- imidazo[1,2-a]pyridin-3-
yl]-(4-pyrimidin-2-yl- piperazin-1-yl)-methanone ##STR00272##
##STR00273## 1.19 442 27f' [7-Aminomethyl-6-(2,4- dimethyl-phenyl)-
imidazo[1,2-a]pyridin-3- yl]-(3-trifluoromethyl-5,6- dihydro-8H-
[1,2,4]triazolo(4,3- a]pyrazin-7-yl)-methanone ##STR00274##
##STR00275## 1.22 470 27g' 1-{4-[7-Aminomethyl-6-
(2,4-dimethyl-phenyl)- imidazo[1,2-a]pyridine-3-
carbonyl]-piperazin-1-yl}- ethanone ##STR00276## ##STR00277## 0.97
406 27h' [7-Aminomethyl-6-(4- chloro-2-methyl-phenyl)-
imidazo[1,2-a]pyridin-3- yl]-morpholin-4-yl- methanone ##STR00278##
##STR00279## 1.09 385 27i' [7-Aminomethyl-6-(4-
chloro-2-methyl-phenyl)- imidazo[1,2-a]pyridin-3-
yl]-(4-methanesulfonyl- piperazin-1-yl)-methanone ##STR00280##
##STR00281## 1.16 462 27j' [7-Aminomethyl-6-(4-
chloro-2-methyl-phenyl)- imidazo[1,2-a]pyridin-3-
yl]-(4-pyrimidin-2-yl- piperazin-1-yl)-methanone ##STR00282##
##STR00283## 1.24 462 27k' [7-Aminomethyl-6-(4-
chloro-2-methyl-phenyl)- imidazo[1,2-a]pyridin-3-
yl]-(3-trifluoromethyl-5,6- dihydro-8H- [1,2,4]triazolo[4,3-
a]pyrazin-7-yl)-methanone ##STR00284## ##STR00285## 1.31 490 27l'
1-{4-[7-Aminomethyl-6-(4- chloro-2-methyl-phenyl)-
imidazo[1,2-a]pyridine-3- carbonyl]-piperazin-1-yl}- ethanone
##STR00286## ##STR00287## 1.03 426
Example 28
1-[6-(2,4-Dichloro-phenyl)-imidazo[1,2-a]pyridin-7-yl]-ethylamine
[0456] Compound 28 was prepared according to Scheme 15:
##STR00288## ##STR00289##
Step 15.1: 2-Amino-5-bromo-isonicotinic acid methyl ester
[0457] A solution of 2-amino-isonicotinic acid methyl ester (5.58
g, 36.7 mmol) in DMF (56 mL) was cooled to -18.degree. C. (ice/MeOH
bath), treated with NBS (7.21 g, 38.5 mmol), and stirred at
-18.degree. C. for 1 h. The reaction mixture was diluted in AcOEt
(500 mL) and washed with water (2.times.250 mL). The organic layer
was dried over Na.sub.2SO.sub.4, filtered and evaporated to yield
the crude title compound (3.0 g, 13.0 mmol, 35%) as a yellow solid,
which was used in the next step without further purification. MS:
231 [M+1].sup.+; HPLC: .sup.At.sub.Ret=0.70.
Step 15.2: 6-Bromo-imidazo[1,2-a]pyridine-7-carboxylic acid methyl
ester
[0458] A mixture of 2-amino-5-bromo-isonicotinic acid methyl ester
(500 mg, 2.16 mmol), NaHCO.sub.3 (309 mg, 3.68 mmol) and
chloracetaldehyde (1.16 mL, 9.8 mmol) in EtOH (15 mL) was
vigorously stirred and refluxed for 14 h. The reaction mixture was
cooled to RT, concentrated under vacuum and the remaining residue
was suspended in AcOEt (100 mL). The organic fraction was washed
with water (2.times.50 mL), then dried over Na.sub.2SO.sub.4,
filtered, and evaporated. The residue was purified by Combi-Flash
Companion.TM. (Isco Inc.) column chromatography (SiO.sub.2;
gradient elution, [hexane/DCM 1:1]/TBME 95:5.fwdarw.100% TBME) to
yield the title compound (505 mg, 1.98 mmol, 91%). MS: 255
[M+1].sup.+; HPLC: .sup.At.sub.Ret=0.58; TLC: R.sub.F 0.16
(hexane/DCM/TBME 1:1:2).
Step 15.3:
6-(2,4-Dichloro-phenyl)-imidazo[1,2-a]pyridine-7-carboxylic acid
methyl ester
[0459] In a sealed tube, a mixture of
6-bromo-imidazo[1,2-a]pyridine-7-carboxylic acid methyl ester (505
mg, 1.98 mmol), 2,4-dichlorobenzeneboronic acid (416 mg, 2.18
mmol), Pd(PPh.sub.3).sub.4 (114 mg, 0.10 mmol) and Na.sub.2CO.sub.3
(2.0 M solution in water, 3.5 mL) in DME (5 mL) was heated at
150.degree. C. for 17 min in a microwave oven. The reaction mixture
was cooled to RT, poured into AcOEt and washed with water. The
organic layer was dried over Na.sub.2SO.sub.4, filtered, and
evaporated. The remaining residue was purified by Combi-Flash
Companion.TM. (Isco Inc.) column chromatography (SiO.sub.2;
gradient elution, [hexane/DCM 1:1]/TBME 95:5.fwdarw.100% TBME) to
yield the title compound (488 mg, 1.52 mmol, 77%). MS: 321
[M+1].sup.+; HPLC: .sup.At.sub.Ret=1.43; TLC: R.sub.F 0.16
(hexane/DCM/TBME 1:1:2).
Step 15.4:
[6-(2,4-Dichloro-phenyl)-imidazo[1,2-a]pyridin-7-yl]-methanol
[0460] A solution of
6-(2,4-dichloro-phenyl)-imidazo[1,2-a]pyridine-7-carboxylic acid
methyl ester (394 mg, 1.23 mmol) and MeOH (0.15 mL, 3.68 mmol) in
THF (8 mL) was cooled to 0.degree. C. (ice bath) then LiBH.sub.4 (2
M solution in THF, 1.8 mL, 3.6 mmol) was added dropwise and the
resulting mixture was heated at 50.degree. C. and stirred for 4 h.
The reaction mixture was cooled to RT, quenched by the addition of
a saturated NH.sub.4Cl solution in water, diluted in water and
extracted with AcOEt (2.times.). The combined organic fractions
were dried over Na.sub.2SO.sub.4, filtered and evaporated to
dryness. The remaining residue was purified by Combi-Flash
Companion.TM. (Isco Inc.) column chromatography (SiO.sub.2;
gradient elution, DCM/MeOH 99:1.fwdarw.8:2) to yield the title
compound (156 mg, 0.53 mmol, 43%). MS: 293 [M+1].sup.+; HPLC:
.sup.At.sub.Ret=1.20; TLC: R.sub.F 0.20 (DCM/MeOH 95:5).
Step 15.5:
6-(2,4-Dichloro-phenyl)-imidazo[1,2-a]pyridine-7-carbaldehyde
[0461] A mixture of
[6-(2,4-dichloro-phenyl)-imidazo[1,2-a]pyridin-7-yl]methanol (125
mg, 0.43 mmol) and MnO.sub.2 (371 mg, 4.27 mmol) in CHCl.sub.3 (2
mL) was stirred at 60.degree. C. for 2 h, then cooled to RT and
filtered through a Celite pad. The solid was washed with AcOEt and
the filtrate was evaporated to dryness to give the crude title
compound (104 mg, 0.36 mmol, 84%) which was used in the next step
without further purification. HPLC: .sup.At.sub.Ret=1.22.
Step 15.6: 2-Methyl-propane-2-sulfinic acid
1-[6-(2,4-dichloro-phenyl)-imidazo[1,2-a]pyridin-7-yl]-meth-(E)-ylideneam-
ide
[0462] To a solution of
6-(2,4-dichloro-phenyl)-imidazo[1,2-a]pyridine-7-carbaldehyde (104
mg, 0.36 mmol) in DCM (5 mL) were successively added
2-methyl-2-propane-sulfinamide (47.6 mg, 0.39 mmol) and titanium
tetraisopropoxyde (0.21 mL, 0.72 mmol) at RT, then the mixture was
heated at 45.degree. C. and stirred for 14 h. The reaction mixture
was cooled to RT, quenched by the successive addition of MeOH (2
mL) and several drops of a saturated NaHCO.sub.3 solution in water.
The resulting precipitate was filtered through a Na.sub.2SO.sub.4
pad, the solid was washed with AcOEt and the filtrate was
evaporated to dryness. The remaining residue was purified by
Combi-Flash Companion.TM. (Isco Inc.) column chromatography
(SiO.sub.2; gradient elution, [hexane/DCM 1:1]/TBME
95:5.fwdarw.100% TBME) to yield the title compound (101 mg, 0.26
mmol, 72%). MS: 394 [M+1].sup.+; HPLC: .sup.At.sub.Ret=1.58; TLC:
R.sub.F 0.33 (hexane/DCM/TBME 1:1:6).
Step 15.7
[0463] (1) To a solution of 2-methyl-propane-2-sulfinic acid
1-[6-(2,4-dichloro-phenyl)-imidazo[1,2-a]pyridin-7-yl]-meth-(E)-ylideneam-
ide (20 mg, 0.045 mmol) in anhydrous THF (0.5 mL) was added
methylmagnesium bromide (3 M solution in Et.sub.2O, 0.045 mL, 0.14
mmol) at RT. The reaction mixture was stirred for 3 h30 then poured
into a saturated solution of NH.sub.4Cl in water and extracted with
AcOEt. The organic layer was dried over Na.sub.2SO.sub.4, filtered
and evaporated to dryness to give the crude
2-methyl-propane-2-sulfinic acid
{1-[6-(2,4-dichloro-phenyl)-imidazo[1,2-a]pyridin-7-yl]-ethyl}-amide
intermediate.
[0464] (2) The previously obtained intermediate was dissolved in a
1.25 M HCl solution in MeOH (2 mL) at RT, the resulting solution
was stirred for 30 min then evaporated to dryness. The remaining
residue was purified by reverse phase prep-HPLC Waters system) to
give the title compound (2TFA salt, 8.6 mg, 0.016 mmol, 36% for 2
steps). MS: 306 [M+1].sup.+; HPLC: .sup.At.sub.Ret=0.75 and 0.92
(two different conformers).
Example 29
1-[6-(2,4-Dichloro-phenyl)-imidazo[1,2-a]pyridin-7-yl]-propylamine
[0465] The title compound was obtained analogously to Example 28
from 2-methyl-propane-2-sulfinic acid
1-[6-(2,4-dichloro-phenyl)-imidazo[1,2-a]pyridin-7-yl]-meth-(E)-ylideneam-
ide (101 mg, 0.26 mmol, prepared according to Example 28, Step
15.6) and ethylmagnesium bromide (1M THF solution, 0.77 mL, 0.77
mmol), followed by subsequent sulfonamide deprotection and reverse
phase prep-HPLC (Waters system) purification (58.2 mg, 0.158 mmol,
62% for 2 steps). MS: 320 [M+1].sup.+; HPLC: .sup.At.sub.Ret=0.87
and 1.05 (two different conformers).
Example 30
[7-Aminomethyl-6-(2,4-dichloro-phenyl)-3-morpholin-4-yl-imidazo[1,2-a]pyri-
din-8-yl]-isobutyl-amine
[0466] Compound 30 was prepared according to Scheme 16:
##STR00290##
Step 16.1:
8-Chloro-6-(2,4-dichloro-phenyl)-3-morpholin-4-yl-imidazo[1,2-a]pyridine--
7-carbonitrile
[0467] A well stirred mixture of
2-amino-3-chloro-5-(2,4-dichloro-phenyl)-isonicotinonitrile (312
mg, 1.05 mmol, prepared according to Example 23, Step 12.1),
ZnBr.sub.2 (588 mg, 2.61 mmol) and
(1,2-bis-benzotriazol-1-yl-1,2-bis-morpholin-4-yl-ethyl)-1,2-diamine
(1.14 g, 2.62 mmol, freshly prepared according to Example 6, Step
3.1) in DCE (6 mL) was refluxed for 14 h, then cooled to RT and
diluted into DCM (100 mL). The resulting slurry was filtered
through a Celite pad and the filter cake washed with DCM. The
filtrate was washed with a 2M KOH solution in water (3.times.50
mL), dried over Na.sub.2SO.sub.4, filtered and evaporated to
dryness. The remaining residue was purified by Combi-Flash
Companion.TM. (Isco Inc.) column chromatography (SiO.sub.2;
gradient elution, [hexane/DCM 1:1]/[TBME/MeOH--NH.sub.3 98:2]
95:5.fwdarw.4:6) to yield the title compound (167 mg, 0.41 mmol,
39%). MS: 407 [M+1].sup.+; HPLC: .sup.At.sub.Ret=2.40; TLC: R.sub.F
0.24 (DCM/hexane/MeOH containing 1% MeOH--NH.sub.3 1/1/2).
Step 16.2
[0468] (1) In a sealed tube, a solution of
8-chloro-6-(2,4-dichloro-phenyl)-3-morpholin-4-yl-imidazo[1,2-a]pyridine--
7-carbonitrile (30 mg, 0.074 mmol) and isobutylamine (0.044 mL,
0.44 mmol) in dioxane (1 mL) was heated at 110.degree. C. for 14 h.
The reaction mixture was cooled to RT, then frozen at -44.degree.
C. (dry ice) and lyophilized to give the crude
6-(2,4-dichloro-phenyl)-8-isobutylamino-3-morpholin-4-yl-imidazo[1,2-a]py-
ridine-7-carbonitrile intermediate. HPLC: .sup.At.sub.Ret=2.77.
[0469] (2) To a solution of the previously obtained crude
intermediate in THF (1 mL) were added slowly a 1M BH.sub.3 solution
in THF (0.29 mL, 0.29 mmol) followed by 2 drops of a 4M HCl
solution in dioxane. The reaction mixture was refluxed for 2 h then
cooled to RT and additional 1M BH.sub.3 solution in THF (0.29 mL,
0.29 mmol) followed by 2 drops of a 4M HCl solution in dioxane were
added. The reaction mixture was refluxed for further 3 h30, then
cooled to RT and poured carefully into MeOH at 0.degree. C. The
resulting solution was concentrated to dryness, the remaining
residue was dissolved in TFA, and evaporated under vacuum. The
remaining residue was purified by reverse phase prep-HPLC (Waters
system) to give the title compound (2TFA salt, 20 mg, 0.030 mmol,
40%). MS: 448 [M+1].sup.+; HPLC: .sup.At.sub.Ret=1.38.
Example 31
7-Aminomethyl-6-(2,4-dichloro-phenyl)-3-morpholin-4-yl-imidazo[1,2-a]pyrid-
in-8-ylamine
[0470] Compound 31 was prepared according to Scheme 17:
##STR00291##
Step 17.1:
8-Azido-6-(2,4-dichloro-phenyl)-3-morpholin-4-yl-imidazo[1,2-a]pyridine-7-
-carbonitrile
[0471] A mixture of
8-chloro-6-(2,4-dichloro-phenyl)-3-morpholin-4-yl-imidazo[1,2-a]pyridine--
7-carbonitrile (135 mg, 0.33 mmol, prepared according to Example
30, Step 16.1) and sodium azide (108 mg, 1.66 mmol) in DMF (1 mL)
was heated at 60.degree. C. and stirred for 4 h. The reaction
mixture was cooled to RT, poured into AcOEt and washed successively
with water and brine. The organic layer was dried over
Na.sub.2SO.sub.4, filtered and evaporated to dryness to yield the
crude title compound (144 mg, 0.33 mmol, quant.) as a brownish
solid, which was used in the next step without further
purification. HPLC: .sup.At.sub.Ret=2.77.
Step 17.2:
8-Amino-6-(2,4-dichloro-phenyl)-3-morpholin-4-yl-imidazo[1,2-a]-
pyridine-7-carbonitrile
[0472] A mixture of crude
8-azido-6-(2,4-dichloro-phenyl)-3-morpholin-4-yl-imidazo[1,2-a]pyridine-7-
-carbonitrile (144 mg, 0.33 mmol) and triphenylphosphine (133 mg,
0.51 mmol) in MeOH (4 mL) was stirred and refluxed for 1 h. 2M HCl
in water (1 mL) was added and the reaction mixture was further
refluxed for 1 h. The reaction mixture was cooled to RT,
concentrated under vacuum and the remaining residue was dissolved
in water. The aqueous solution was basified to pH 12 by the
addition of a 2M NaOH solution in water. The resulting slurry was
extracted with DCM (3.times.) and the combined organic fractions
were dried over Na.sub.2SO.sub.4, filtered and evaporated. The
remaining residue was purified by Combi-Flash Companion.TM. (Isco
Inc.) column chromatography (SiO.sub.2; gradient elution, DCM/MeOH
99:1.fwdarw.92:8) to yield the title compound (112 mg, 0.29 mmol,
87%). MS: 388 [M+1].sup.+; HPLC: .sup.At.sub.Ret=1.91; TLC: R.sub.F
0.56 (DCM/MeOH 95:5).
Step 17.3
[0473] To a solution of
8-amino-6-(2,4-dichloro-phenyl)-3-morpholin-4-yl-imidazo[1,2-a]pyridine-7-
-carbonitrile (112 mg, 0.29 mmol) in THF (4 mL) was added a
BH.sub.3.THF complex (1.0 M solution in THF, 1.2 mL, 1.2 mmol)
followed by a 4M HCl solution in dioxane (2 drops). The reaction
mixture was stirred and refluxed for 3 h, then cooled to 0.degree.
C. (ice bath) and poured into MeOH. The mixture was concentrated
under vacuum, the remaining residue was dissolved in a 2M HCl
solution in water, and the mixture was washed with Et.sub.2O
(2.times.). The aqueous layer was frozen and lyophilized. The
remaining residue was purified by recrystallization in a mixture of
MeOH/AcOEt to yield the title compound (2HCl salt, 36 mg, 0.077
mmol, 27%). MS: 392 [M+1].sup.+; HPLC: .sup.At.sub.Ret=1.13.
Example 32
C-[6-(2,4-Dichloro-phenyl)-8-methoxy-3-morpholin-4-yl-imidazo[1,2-a]pyridi-
n-7-yl]-methylamine
[0474] Compound 32 was prepared according to Scheme 18:
##STR00292##
[0475] A mixture of
8-chloro-6-(2,4-dichloro-phenyl)-3-morpholin-4-yl-imidazo[1,2-a]pyridine--
7-carbonitrile (20 mg, 0.05 mmol, prepared according to Example 30,
Step 16.1) and NaOMe (8.2 mg, 0.15 mmol) in MeOH (0.5 mL) was
refluxed and stirred for 1 h. The reaction mixture was cooled to
RT, poured into water (20 ml) and extracted with DCM (3.times.10
mL). The combined organic fractions were dried over
Na.sub.2SO.sub.4, filtered, and evaporated. The remaining residue
was dissolved in THF and a BH.sub.3.THF complex (1.0 M solution in
THF, 0.2 mL, 0.2 mmol) followed by a 4M HCl solution in dioxane (2
drops) were added. The reaction mixture was stirred and refluxed
for 2 h30, then cooled to 0.degree. C. (ice bath) and poured into
MeOH. The resulting solution was evaporated to dryness and the
remaining residue was purified by reverse phase prep-HPLC (Waters
system) to give the title compound (2TFA salt, 3.3 mg, 0.005 mmol,
9% for 2 steps). MS: 407 [M+1].sup.+; HPLC:
.sup.At.sub.Ret=1.09.
Example 33
[0476] Compounds 33a to 33j were obtained analogously to Example
30, using the adequate cyclization reagent in Step 16.1 and various
amines in Step 16.2, or analogously to Example 32, using various
sodium alkoxydes, or analogously to Example 31 from the adequate
starting material. The compounds are of the following general
formula:
TABLE-US-00010 ##STR00293## HPLC .sup.At.sub.Ret MS Compound Name
R.sup.6 R.sup.7 [min] [M + 1].sup.+ 33a [7-Aminomethyl-6-(2,4-
dichloro-phenyl)-3-morpholin- 4-yl-imidazo[1,2-a]pyridin-8-
yl]-methyl-amine ##STR00294## ##STR00295## 1.13 406 33b
[7-Aminomethyl-6-(2,4- dichloro-phenyl)-3-morpholin-
4-yl-imidazo[1,2-a]pyridin-8- yl]-ethyl-amine ##STR00296##
##STR00297## 1.21 420 33c [7-Aminomethyl-6-(2,4-
dichloro-phenyl)-3-morpholin- 4-yl-imidazo[1,2-a]pyridin-8-
yl]-isopropyl-amine ##STR00298## ##STR00299## 1.26 434 33d
[7-Aminomethyl-6-(2,4- dichloro-phenyl)-3-morpholin-
4-yl-imidazo[1,2-a]pyridin-8- yl]-cyclopentyl-amine ##STR00300##
##STR00301## 1.39 460 33e [7-Aminomethyl-6-(2,4-
dichloro-phenyl)-3-piperazin-1- yl-imidazo[1,2-a]pyridin-8-yl]-
isobutyl-amine ##STR00302## ##STR00303## 1.38 447 33f
[7-Aminomethyl-6-(2,4- dichloro-phenyl)-3- thiomorpholin-4-yl-
imidazo[1,2-a]pyridin-8-yl]- isobutyl-amine ##STR00304##
##STR00305## 1.56 464 33g C-[6-(2,4-Dichloro-phenyl)-8-
isobutoxy-3-morpholin-4-yl- imidazo[1,2-a]pyridin-7-yl]-
methylamine ##STR00306## ##STR00307## 1.35 449 33h
7-Aminomethyl-6-(2,4- dichloro-phenyl)-3- thiomorpholin-4-yl-
imidazo[1,2-a]pyridin-8- ylamine ##STR00308## ##STR00309## 1.35 408
33i.sup.(*.sup.) [7-Aminomethyl-6-(2,4- dichloro-phenyl)-3-(1-oxo-
1lambda*4*-thiomorpholin-4- yl)-imidazo[1,2-a]pyridin-8-yl]-
isobutyl-amine ##STR00310## ##STR00311## 1.21 480 33j.sup.(*.sup.)
7-Aminomethyl-6-(2,4- dichloro-phenyl)-3-(1-oxo-
1lambda*4*-thiomorpholin-4- yl)-imidazo[1,2-a]pyridin-8- ylamine
##STR00312## ##STR00313## 0.96 424
[0477] Compounds 33i and 33j were obtained respectively from 33f
and 33h using the following procedure.
[0478] A solution of
[7-aminomethyl-6-(2,4-dichloro-phenyl)-3-thiomorpholin-4-yl-imidazo[1,2-a-
]pyridin-8-4-isobutyl-amine (30 mg, 0.065 mmol) in EtOH (3 mL) was
treated with NaIO.sub.4 (29.0 mg, 0.136 mmol) at 0.degree. C.,
warmed to RT before water (0.6 mL) was added. The reaction mixture
was stirred at RT for 24 h then poured into AcOEt (20 mL) and
washed successively with water (10 mL) and brine (10 mL). The
organic layer was dried over Na.sub.2SO.sub.4, filtered, and
evaporated to dryness. The remaining residue was purified by
reverse phase prep-HPLC (Waters system) to give the title compound
(2TFA salt, 2.3 mg, 0.003 mmol, 5%). MS: 480 [M+1].sup.+; HPLC:
.sup.At.sub.Ret=1.21.
Example 34
Tetrahydro-pyran-4-carboxylic acid
[7-aminomethyl-6-(2,4-dichloro-phenyl)-imidazo[1,2-a]pyridin-3-yl]-amide
[0479] Compound 34 was prepared according to Scheme 19:
##STR00314##
Step 19.1:
3-Amino-6-(2,4-dichloro-phenyl)-imidazo[1,2-a]pyridine-7-carbonitrile
[0480] (1) To a solution of
6-(2,4-dichloro-phenyl)-imidazo[1,2-a]pyridine-7-carbonitrile (3.07
g, 6.10 mmol, prepared according to Example 3, Step 2.3) in
concentrated H.sub.2SO.sub.4 (55 mL) was added a freshly prepared
mixture of fuming HNO.sub.3 in H.sub.2SO.sub.4 (1:2, v/v, 2.55 mL)
at RT. The reaction mixture was stirred at RT for 2 h then
cautiously added to cold water (300 mL) and extracted with DCM
(5.times.). The combined organic fractions were dried over
Na.sub.2SO.sub.4, filtered, and evaporated to dryness to give the
crude
6-(2,4-dichloro-phenyl)-3-nitro-imidazo[1,2-a]pyridine-7-carbonitrile
as a brown solid (533 mg). MS: 333 [M+1].sup.+; HPLC:
.sup.At.sub.Ret=1.57.
[0481] (2) A mixture of the previously obtained
6-(2,4-dichloro-phenyl)-3-nitro-imidazo[1,2-a]pyridine-7-carbonitrile
and Tin(II) chloride dihydrate (3.61 g, 15.7 mmol) in absolute EtOH
(10 mL) was refluxed for 10 min, then cooled to RT and concentrated
under vacuum. The residue was suspended into a 2M NaOH solution in
water (100 mL) and extracted with DCM (4.times.50 mL). The combined
organic fractions were washed with brine, dried over
Na.sub.2SO.sub.4, filtered, and evaporated to dryness. The
remaining residue was purified by Combi-Flash Companion.TM. (Isco
Inc.) column chromatography (SiO.sub.2; gradient elution,
DCM/MeOH--NH.sub.3 99:1.fwdarw.95:5) to yield the title compound
(517 mg, 1.71 mmol, 28% for 2 steps). HPLC: .sup.At.sub.Ret=1.34;
TLC: R.sub.F 0.47 (DCM/7N NH.sub.3 in MeOH 95:5).
Step 19.2:
[3-Amino-6-(2,4-dichloro-phenyl)-imidazo[1,2-a]pyridin-7-ylmeth-
yl]-carbamic acid tert-butyl ester
[0482] (1) A solution of
3-amino-6-(2,4-dichloro-phenyl)-imidazo[1,2-a]pyridine-7-carbonitrile
(517 mg, 1.71 mmol) in anhydrous THF (10 mL) was cooled to
0.degree. C. (ice bath), treated with a 1M BH.sub.3 solution in THF
(8.5 mL, 8.5 mmol) and stirred at 40.degree. C. for 1 h. The
reaction mixture was cooled to 0.degree. C. (ice bath), quenched by
the cautious addition of MeOH until gas evolution ceased and
concentrated to dryness. The residue was suspended into a 2M HCl
solution in water, stirred at RT for 10 min and evaporated to
dryness. The resulting HCl salt was suspended into a 2M NaOH
solution in water then extracted with DCM and AcOEt. The combined
organic fractions were dried over Na.sub.2SO.sub.4, filtered, and
evaporated under vacuum to give the crude
7-aminomethyl-6-(2,4-dichloro-phenyl)-imidazo[1,2-a]pyridin-3-ylamine
(277 mg). HPLC: .sup.At.sub.Ret=0.81.
[0483] (2) To a solution of the crude
7-aminomethyl-6-(2,4-dichloro-phenyl)-imidazo[1,2-a]pyridin-3-ylamine
(277 mg) in MeOH (2.5 ml) were successively added Et.sub.3N (0.24
mL, 1.70 mmol) and a solution of Boc.sub.2O (197 mg, 0.90 mmol) in
MeOH (2.5 mL). The reaction mixture was stirred at RT for 30 min
and concentrated under vacuum. The residue was dissolved in AcOEt,
washed with a 2M Na.sub.2CO.sub.3 solution in water, dried over
Na.sub.2SO.sub.4, filtered, and evaporated to dryness to yield the
crude title compound (327 mg, 0.80 mmol, 47% for 2 steps) as an
orange solid, which was used in the next step without further
purification. An analytical sample was purified by Combi-Flash
Companion.TM. (Isco Inc.) column chromatography (SiO.sub.2;
gradient elution, DCM/MeOH--NH.sub.3 99:1.fwdarw.94:6) to give pure
material as a white solid. MS: 407 [M+1].sup.+; HPLC:
.sup.At.sub.Ret=1.57.
Step 19.3:
{6-(2,4-Dichloro-phenyl)-3-[(tetrahydro-pyran-4-carbonyl)-amino-
]-imidazo[1,2-a]pyridin-7-ylmethyl}-carbamic acid tert-butyl
ester
[0484] To a mixture of
[3-amino-6-(2,4-dichloro-phenyl)-imidazo[1,2-a]pyridin-7-ylmethyl]-carbam-
ic acid tert-butyl ester (100 mg, 0.25 mmol),
tetrahydro-pyran-4-carboxylic acid (192 mg, 1.47 mmol) and DIPEA
(0.52 mL, 2.95 mmol) in DMF (3 mL) was added HATU (560 mg, 1.47
mmol) at RT. The reaction mixture was heated at 80.degree. C. and
stirred for 24 h, then poured into AcOEt (50 mL) and washed with a
2.0 M aqueous Na.sub.2CO.sub.3 solution (2.times.25 mL). The
organic layer was dried over Na.sub.2SO.sub.4, filtered, and
evaporated to dryness. The remaining residue was purified by
Combi-Flash Companion.TM. (Isco Inc.) column chromatography
(SiO.sub.2; gradient elution, DCM/MeOH 99:1.fwdarw.84:16) to yield
the title compound (79.5 mg, 0.153 mmol, 62%). MS: 519 [M+1].sup.+;
HPLC: .sup.At.sub.Ret=1.49; TLC: R.sub.F 0.14 (DCM/MeOH 95:5).
Step 19.4
[0485] To a solution of
{6-(2,4-dichloro-phenyl)-3-[(tetrahydro-pyran-4-carbonyl)-amino]-imidazo[-
1,2-a]pyridin-7-ylmethyl}-carbamic acid tert-butyl ester (79.5 mg,
0.153 mmol) in dioxane (3 mL) was added a 4M HCl solution in
dioxane (2 mL) and the mixture was stirred at RT for 15 min. The
formed precipitate was filtered and dried under vacuum to yield the
title compound (2HCl salt, 58 mg, 0.118 mmol, 48%) as a brownish
solid. MS: 419 [M+1].sup.+; HPLC: .sup.At.sub.Ret=0.83.
Example 35
C-[6-(2,4-Dichloro-phenyl)-8-isobutoxy-3-(6-morpholin-4-yl-pyridin-3-yl)-i-
midazo[1,2-a]pyridin-7-yl]-methylamine
[0486] Compound 35 was prepared according to Scheme 20:
##STR00315##
Step 20.1:
3-Bromo-8-chloro-6-(2,4-dichloro-phenyl)-imidazo[1,2-a]pyridine-7-carboni-
trile
[0487] A solution of
8-chloro-6-(2,4-dichloro-phenyl)-imidazo[1,2-a]pyridine-7-carbonitrile
(1.5 g, 4.65 mmol, prepared according to Example 23, Step 12.2) in
DMF (19 mL) was treated with NBS (910 mg, 5.12 mmol) at RT and
stirred for 1 h. The reaction mixture was diluted in AcOEt and
washed with water. The organic layer was dried over
Na.sub.2SO.sub.4, filtered and evaporated to yield the crude title
compound (1.92 g, 4.65 mmol, quant.), which was used in the next
step without further purification. MS: 400 [M+1].sup.+; HPLC:
.sup.At.sub.Ret=2.67.
Step 20.2:
3-Bromo-6-(2,4-dichloro-phenyl)-8-isobutoxy-imidazo[1,2-a]pyrid-
ine-7-carbonitrile
[0488] NaH (60% in mineral oil, 149 mg, 3.7 mmol) was carefully
added to 2-methyl-1-propanol (10 mL) at 0.degree. C. (ice bath).
The mixture was stirred at RT for 10 min before
3-bromo-8-chloro-6-(2,4-dichloro-phenyl)-imidazo[1,2-a]pyridine-7-carboni-
trile (500 mg, 1.25 mmol) was added in one portion. The reaction
mixture was heated at 70.degree. C. and stirred for 1 h, then
cooled to RT and poured into water (100 mL). The formed slurry was
extracted successively with DCM (2.times.50 mL) and AcOEt (50 mL),
and the combined organic fractions were dried over
Na.sub.2SO.sub.4, filtered, and evaporated to dryness. The
remaining residue was purified by Combi-Flash Companion.TM. (Isco
Inc.) column chromatography (SiO.sub.2; gradient elution,
hexane/TBME 95:5.fwdarw.100% TBME) to yield the title compound (348
mg, 0.79 mmol, 63%). MS: 438; HPLC: .sup.At.sub.Ret=3.36; TLC:
R.sub.F 0.81 (hexane/TBME 1:1).
Step 20.3:
6-(2,4-Dichloro-phenyl)-3-(6-fluoro-pyridin-3-yl)-8-isobutoxy-i-
midazo[1,2-a]pyridine-7-carbonitrile
[0489] In a sealed tube, a mixture of
3-bromo-6-(2,4-dichloro-phenyl)-8-isobutoxy-imidazo[1,2-a]pyridine-7-carb-
onitrile (115 mg, 0.25 mmol), 2-fluoro-5-pyridine-boronic acid
(38.4 mg, 0.27 mmol), PdCl.sub.2(PPh.sub.3).sub.2 (8.7 mg, 0.01
mmol) and Na.sub.2CO.sub.3 (2.0 M solution in water, 0.43 mL) in
DME (1 mL) was heated at 150.degree. C. for 17 min in a microwave
oven. The reaction mixture was cooled to RT, diluted in AcOEt (20
mL) and washed with water (2.times.10 mL). The organic layer was
dried over Na.sub.2SO.sub.4, filtered, and evaporated to dryness.
The remaining residue was purified by Combi-Flash Companion.TM.
(Isco Inc.) column chromatography (SiO.sub.2; gradient elution,
hexane/TBME 95:5.fwdarw.7:3) to yield the title compound (64 mg,
0.14 mmol, 56%) as a white solid. MS: 455 [M+1].sup.+; HPLC:
.sup.At.sub.Ret=3.14; TLC: R.sub.F 0.34 (hexane/TBME 1:1).
Step 20.4
[0490] (1) A mixture of
6-(2,4-dichloro-phenyl)-3-(6-fluoro-pyridin-3-yl)-8-isobutoxy-imidazo[1,2-
-a]pyridine-7-carbonitrile (64 mg, 0.14 mmol) and morpholine (0.06
mL, 0.70 mmol) in DMSO (1 mL) was heated at 180.degree. C. and
stirred for 30 min. The reaction mixture was cooled to RT, diluted
in AcOEt (20 mL) and washed with water (2.times.10 ml). The organic
layer was dried over Na.sub.2SO.sub.4, filtered, and evaporated to
dryness to yield the crude
6-(2,4-dichloro-phenyl)-8-isobutoxy-3-(6-morpholin-4-yl-pyridin-3-yl)-imi-
dazo[1,2-a]pyridine-7-carbonitrile intermediate (67.8 mg) as a
brown solid.
[0491] (2) To a solution of the crude intermediate (67.8 mg) in
anhydrous THF (1 mL) in THF was slowly added a BH.sub.3.THF complex
(1.0 M solution in THF, 0.56 mL, 0.56 mmol) at RT. The reaction
mixture was stirred and refluxed for 3 h, then cooled to RT and
quenched by the careful addition of MeOH until gas evolution
ceased. The resulting solution was concentrated under vacuum then a
2M HCl solution in water was added and the formed slurry was
evaporated to dryness. The remaining residue was purified by
reverse phase prep-HPLC (Waters system) to give the title compound
(2TFA salt, 7.3 mg, 0.010 mmol, 7% for 2 steps). MS: 526
[M+1].sup.+; HPLC: .sup.At.sub.Ret=1.42.
Example 36
C-[6-(2,4-Dichloro-phenyl)-8-isobutoxy-3-(2-morpholin-4-yl-pyridin-4-yl)-i-
midazo[1,2-a]pyridin-7-yl]-methylamine
[0492] Compound 36 was prepared according to Scheme 21:
##STR00316##
Step 21.1:
6-(2,4-Dichloro-phenyl)-3-(2-fluoro-pyridin-4-yl)-8-isobutoxy-imidazo[1,2-
-a]pyridine-7-carbonitrile
[0493] In a sealed tube, a mixture of
3-bromo-6-(2,4-dichloro-phenyl)-8-isobutoxy-imidazo[1,2-a]pyridine-7-carb-
onitrile (115 mg, 0.25 mmol, prepared according to Example 35, Step
20.2), 2-fluoro-4-pyridine-boronic acid (45.3 mg, 0.32 mmol),
PdCl.sub.2(PPh.sub.3).sub.2 (9.6 mg, 0.014 mmol) and
Na.sub.2CO.sub.3 (2.0 M solution in water, 0.43 mL) in DME (1 mL)
was heated at 150.degree. C. for 25 min in a microwave oven. The
reaction mixture was cooled to RT, diluted in AcOEt (20 mL) and
washed with water (2.times.10 mL). The organic layer was dried over
Na.sub.2SO.sub.4, filtered, and evaporated to dryness. The
remaining residue was purified by Combi-Flash Companion.TM. (Isco
Inc.) column chromatography (SiO.sub.2; gradient elution,
hexane/TBME 95:5.fwdarw.6:4) to yield the title compound (46.6 mg,
0.10 mmol, 41%) as a white solid. MS: 455 [M+1].sup.+; HPLC:
.sup.At.sub.Ret=3.18; TLC: R.sub.F 0.25 (hexane/TBME 1:1).
Step 21.2
[0494] (1) A mixture of
6-(2,4-dichloro-phenyl)-3-(2-fluoro-pyridin-4-yl)-8-isobutoxy-imidazo[1,2-
-a]pyridine-7-carbonitrile (46.6 mg, 0.10 mmol) and morpholine
(0.045 mL, 0.51 mmol) in DMSO (0.8 mL) was heated at 180.degree. C.
and stirred for 30 min. The reaction mixture was cooled to RT,
diluted in AcOEt (20 mL) and washed with water (2.times.10 ml). The
organic layer was dried over Na.sub.2SO.sub.4, filtered, and
evaporated to dryness to yield the crude
6-(2,4-dichloro-phenyl)-8-isobutoxy-3-(2-morpholin-4-yl-pyridin-4-yl)-imi-
dazo[1,2-a]pyridine-7-carbonitrile intermediate.
[0495] (2) To a solution of the crude intermediate in anhydrous THF
(1 mL) in THF was slowly added a BH.sub.3.THF complex (1.0 M
solution in THF, 0.41 mL, 0.41 mmol) at RT. The reaction mixture
was stirred and refluxed for 3 h, then cooled to RT and quenched by
the careful addition of MeOH until gas evolution ceased. The
resulting solution was concentrated under vacuum then a 2M HCl
solution in water was added and the formed slurry was evaporated to
dryness. The remaining residue was purified by reverse phase
prep-HPLC (Waters system) to give the title compound (2TFA salt,
8.1 mg, 0.011 mmol, 10% for 2 steps). MS: 526 [M+1].sup.+; HPLC:
.sup.At.sub.Ret=1.36.
Example 37
[7-Aminomethyl-6-(2,4-dichloro-phenyl)-8-isobutoxy-imidazo[1,2-a]pyridin-3-
-yl]-morpholin-4-yl-methanone
[0496] Compound 37 was prepared according to Scheme 22:
##STR00317##
Step 22.1:
[3-Bromo-6-(2,4-dichloro-phenyl)-8-isobutoxy-imidazo[1,2-a]pyridin-7-ylme-
thyl]-carbamic acid tert-butyl ester
[0497] (1) To a solution of
3-bromo-6-(2,4-dichloro-phenyl)-8-isobutoxy-imidazo[1,2-a]pyridine-7-carb-
onitrile (477 mg, 1.0 mmol, prepared according to Example 35, Step
20.2) in anhydrous THF (12 mL) were added a BH.sub.3.THF complex
(1.0 M solution in THF, 4.5 mL, 4.5 mmol) followed by a 4M HCl
solution in dioxane (10 drops) at RT. The reaction mixture was
heated at 50.degree. C. and stirred for 3 h, then cooled to
0.degree. C. (ice bath), quenched by the cautious addition of a 2M
HCl solution in water (10 mL) and poured into water (100 mL). The
aqueous mixture was washed with Et.sub.2O (2.times.30 mL) then
basified to pH 10 by the addition of a 2M Na.sub.2CO.sub.3 solution
in water and extracted with DCM (2.times.30 mL). The combined
organic fractions were dried over Na.sub.2SO.sub.4, filtered, and
evaporated to dryness to yield the crude
C-[3-bromo-6-(2,4-dichloro-phenyl)-8-isobutoxy-imidazo[1,2-a]pyridin-7-yl-
]-methylamine intermediate.
[0498] (2) To a solution of the crude intermediate in MeOH (3 mL)
were successively added Et.sub.3N (0.28 mL, 1.99 mmol) and
Boc.sub.2O (239.1 mg, 1.10 mmol) at RT. The reaction mixture was
stirred for 30 min then concentrated under vacuum and the resulting
residue was dissolved in AcOEt and washed successively with a 2M
Na.sub.2CO.sub.3 solution in water and brine. The organic layer was
dried over Na.sub.2SO.sub.4, filtered, and evaporated to dryness.
The remaining residue was purified by Combi-Flash Companion.TM.
(Isco Inc.) column chromatography (SiO.sub.2; gradient elution,
hexane/TBME 95:5.fwdarw.1:1) to yield the title compound (80.1 mg,
0.15 mmol, 15%) as a white solid. MS: 542 [M+1].sup.+; HPLC:
.sup.At.sub.Ret=3.24; TLC: R.sub.F 0.77 (hexane/TBME 1:1).
Step 22.2:
[3-Bromo-6-(2,4-dichloro-phenyl)-8-isobutoxy-imidazo[1,2-a]pyri-
din-7-ylmethyl]-carbamic acid bis-tert-butyl ester
[0499] A solution of
[3-bromo-6-(2,4-dichloro-phenyl)-8-isobutoxy-imidazo[1,2-a]pyridin-7-ylme-
thyl]-carbamic acid tert-butyl ester (80 mg, 0.15 mmol), DMAP (7.2
mg, 0.059 mmol) and Boc.sub.2O (354 mg, 1.62 mmol) in MeCN (1 mL)
was heated at 50.degree. C. and stirred for 24 h. The reaction
mixture was cooled to RT, concentrated under vacuum, diluted in
AcOEt (20 mL) and washed with a 2M Na.sub.2CO.sub.3 solution in
water (2.times.10 mL). The organic layer was dried over
Na.sub.2SO.sub.4, filtered, and evaporated to dryness. The
remaining residue was purified by Combi-Flash Companion.TM. (Isco
Inc.) column chromatography (SiO.sub.2; isocratic, hexane/TBME
95:5) to yield the title compound (74 mg, 0.12 mmol, 78%). MS: 642
[M+1].sup.+; HPLC: .sup.At.sub.Ret=3.79; TLC: R.sub.F 0.83
(hexane/TBME 1:1).
Step 22.3
[0500] (1) To a solution of
[3-bromo-6-(2,4-dichloro-phenyl)-8-isobutoxy-imidazo[1,2-a]pyridin-7-ylme-
thyl]-carbamic acid bis-tert-butyl ester (64 mg, 0.10 mmol) in DCM
(1 mL) was added dropwise EtMgBr (1M THF solution, 0.99 mL, 0.99
mmol) at RT. The clear solution was stirred for 30 min before a
large excess of dry ice was added in one portion. The heavy slurry
was stirred until the temperature raised to RT (15 min) then
diluted in DCM (20 mL) and washed with water (10 mL). The organic
layer was concentrated under vacuum, dissolved in AcOEt (20 mL) and
washed with a saturated aqueous NH.sub.4Cl solution (2.times.10
mL). The aqueous phase was reextracted with AcOEt (2.times.10 mL)
and the combined organic fractions were dried over
Na.sub.2SO.sub.4, filtered, and evaporated to dryness to yield the
crude carboxylic acid intermediate (50 mg).
[0501] (2) To a mixture of the crude carboxylic acid intermediate
(50 mg), morpholine (0.010 mL, 0.11 mmol) and DIPEA (0.035 mL, 0.20
mmol) in DMF (0.5 mL) was added HATU (41.6 mg, 0.11 mmol) at RT.
The reaction mixture was heated at 50.degree. C. and stirred for 30
min, then poured into AcOEt (10 mL) and washed with a 2.0 M aqueous
Na.sub.2CO.sub.3 solution (2.times.5 mL). The organic layer was
dried over Na.sub.2SO.sub.4, filtered, and evaporated to dryness.
The remaining residue was dissolved in DCM (2 mL) and TFA (1 mL)
and the solution was stirred at RT for 30 min. The reaction mixture
was concentrated to dryness and the remaining residue purified by
reverse phase prep-HPLC (Waters system) to give the title compound
(2TFA salt, 11.4 mg, 0.016 mmol, 16% for 3 steps) as a white solid.
MS: 477 [M+1].sup.+; HPLC: .sup.At.sub.Ret=1.57.
Example 38
1-{4-[7-Aminomethyl-6-(2,4-dichloro-phenyl)-imidazo[1,2-a]pyridin-3-yl]-pi-
perazin-1-yl}-ethanone
[0502] Compound 38 was prepared according to Scheme 23:
##STR00318##
Step 23.1:
[6-(2,4-Dichloro-phenyl)-3-piperazin-1-yl-imidazo[1,2-a]pyridin-7-ylmethy-
l]-carbamic acid tert-butyl ester
[0503] A mixture of
{6-(2,4-dichloro-phenyl)-3-[4-(2-nitro-benzenesulfonyl)-piperazin-1-yl]-i-
midazo[1,2-a]pyridin-7-ylmethyl}-carbamic acid tert-butyl ester
(2.9 g, 4.38 mmol, prepared following the procedure described for
Example 6, Step 3.3 using the adequate cyclisation reagent),
LiOH.H.sub.2O (1.11 g, 26.3 mmol) and mercaptoacetic acid (0.94 mL,
13.2 mmol) in DMF (20 mL) was stirred at RT for 30 min then poured
into a saturated aqueous NaHCO.sub.3 solution (200 mL) and
extracted with AcOEt (4.times.200 mL). The combined organic
fractions were washed with brine (100 mL), dried over
Na.sub.2SO.sub.4, filtered and evaporated to dryness. The remaining
residue was purified by Combi-Flash Companion.TM. (Isco Inc.)
column chromatography (SiO.sub.2; gradient elution,
DCM/[DCM/MeOH--NH.sub.3 9:1] 95:5.fwdarw.100% [DCM/MeOH--NH.sub.3
9:1]) to yield the title compound (1.61 g, 3.38 mmol, 77%) as a
yellow foam. MS: 477 [M+1].sup.+; HPLC: .sup.At.sub.Ret=1.45; TLC:
R.sub.F 0.33 (DCM/MeOH--NH.sub.3 9:1).
Step 23.2
[0504] To a solution of
[6-(2,4-dichloro-phenyl)-3-piperazin-1-yl-imidazo[1,2-a]pyridin-7-ylmethy-
l]-carbamic acid tert-butyl ester (30 mg, 0.06 mmol) in DCM (0.5
mL) were added successively acetyl chloride (6 mg, 0.07 mmol),
pyridine (0.015 mL, 0.19 mmol) and DMAP (1 mg, 0.006 mmol). The
reaction mixture was stirred at RT for 14 h then evaporated to
dryness. The resulting residue was dissolved in DCM (2 mL) then TFA
(1 mL) was added and the mixture was stirred at RT for 30 min. The
reaction mixture was concentrated to dryness and the remaining
residue purified by reverse phase prep-HPLC (Waters system) to give
the title compound (2TFA salt, 22 mg, 0.034 mmol, 57% for 2 steps)
as a white solid. MS: 419 [M+1].sup.+; HPLC:
.sup.At.sub.Ret=1.00.
Example 39
1-{4-[7-Aminomethyl-6-(2,4-dichloro-phenyl)-imidazo[1,2-a]pyridin-3-yl]-pi-
perazin-1-yl}-ethanone
[0505] To a mixture of
[6-(2,4-dichloro-phenyl)-3-piperazin-1-yl-imidazo[1,2-a]pyridin-7-ylmethy-
l]-carbamic acid tert-butyl ester (30 mg, 0.06 mmol, prepared
according to Example 38, Step 23.1), cyclobutanecarboxylic acid
(0.007 mL, 0.07 mmol) and NMM (0.035 mL, 0.32 mmol) in DMF (0.5 mL)
was added HATU (35.9 mg, 0.095 mmol). The reaction mixture was
stirred at RT for 14 h, then poured into AcOEt (20 mL) and washed
with a 2.0 M aqueous Na.sub.2CO.sub.3 solution (10 mL) and brine
(10 mL). The organic layer was dried over Na.sub.2SO.sub.4,
filtered, and evaporated to dryness. The remaining residue was
dissolved in DCM (2 mL) and TFA (1 mL) and the solution was stirred
at RT for 30 min. The reaction mixture was concentrated to dryness
and the remaining residue purified by reverse phase prep-HPLC
(Waters system) to give the title compound (2TFA salt, 20 mg, 0.029
mmol, 46% for 2 steps). MS: 459 [M+1].sup.+; HPLC:
.sup.At.sub.Ret=1.29.
Example 40
[0506] Compounds 40a to 401 were obtained analogously to Examples
38 and 39, using the adequate acyl chloride or carboxylic acid in
Step 23.2. The compounds are of the following general formula:
TABLE-US-00011 ##STR00319## HPLC .sup.At.sub.Ret MS Compound Name
R.sup.7 [min] [M + 1].sup.+ 40a 1-{4-[7-Aminomethyl-6-(2,4-
dichloro-phenyl)-imidazo[1,2- a]pyridin-3-yl]-piperazin-1-yl}-
propan-1-one ##STR00320## 1.10 433 40b 1-{4-[7-Aminomethyl-6-(2,4-
dichloro-phenyl)-imidazo[1,2- a]pyridin-3-yl]-piperazin-1-yl}-2-
methyl-propan-1-one ##STR00321## 1.20 447 40c
{4-[7-Aminomethyl-6-(2,4- dichloro-phenyl)-imidazo[1,2-
a]pyridin-3-yl]-piperazin-1-yl}- cyclopropyl-methanone ##STR00322##
1.14 445 40d 1-{4-[7-Aminomethyl-6-(2,4-
dichloro-phenyl)-imidazo[1,2- a]pyridin-3-yl]-piperazin-1-yl}-2-
methoxy-ethanone ##STR00323## 1.02 449 40e
1-(4-{4-[7-Aminomethyl-6-(2,4- dichloro-phenyl)-imidazo[1,2-
a]pyridin-3-yl]-piperazine-1- carbonyl}-piperidin-1-yl)- ethanone
##STR00324## 1.09 530 40f {4-[7-Aminomethyl-6-(2,4-
dichloro-phenyl)-imidazo[1,2- a]pyridin-3-yl]-piperazin-1-yl}-
cyclopentyl-methanone ##STR00325## 1.33 473 40g
1-{4-[7-Aminomethyl-6-(2,4- dichloro-phenyl)-imidazo[1,2-
a]pyridin-3-yl]-piperazin-1-yl}-2- cyclopropyl-ethanone
##STR00326## 1.21 459 40h {4-[7-Aminomethyl-6-(2,4-
dichloro-phenyl)-imidazo[1,2- a]pyridin-3-yl]-piperazin-1-yl}-
(tetrahydro-pyran-4-yl)- methanone ##STR00327## 1.11 489 40i
1-{4-[7-Aminomethyl-6-(2,4- dichloro-phenyl)-imidazo[1,2-
a]pyridin-3-yl]-piperazin-1-yl}-3- methoxy-propan-1-one
##STR00328## 1.09 463 40j 1-{4-[7-Aminomethyl-6-(2,4-
dichloro-phenyl)-imidazo[1,2- a]pyridin-3-yl]-piperazin-1-yl}-2-
(tetrahydro-pyran-4-yl)-ethanone ##STR00329## 1.16 503 40k
{4-[7-Aminomethyl-6-(2,4- dichloro-phenyl)-imidazo[1,2-
a]pyridin-3-yl]-piperazin-1-yl}-(1- methyl-1H-imidazol-4-yl)-
methanone ##STR00330## 0.91 485 40l {4-[7-Aminomethyl-6-(2,4-
dichloro-phenyl)-imidazo[1,2- a]pyridin-3-yl]-piperazin-1-yl}-
pyrazin-2-yl-methanone ##STR00331## 1.08 483
Example 41
Activity Assay
[0507] Some of Compounds 1 to 40 were tested for their inhibitory
activity to human DPP-IV.
Materials
[0508] Human DPP-IV consisting of amino acids 39 to 766 followed by
a C-terminal Streptavidin-tag was expressed using the baculovirus
system and purified to >80% purity. The enzyme was stored in 25
mM Tris buffer, pH 9.0, containing 300 mM NaCl at -80.degree.
C.
[0509] The fluorogenic substrates H-Gly-Pro-AMC was purchased from
Bachem AG (Bubendorf, Switzerland). The substrate was kept as a 5
mM stock solution in DMSO at -20.degree. C. All other chemicals
were purchased from Sigma (Buchs, Switzerland).
[0510] The assay buffer for the DPP-IV reaction was 25 mM Tris/HCl,
pH 7.5, containing 140 mM NaCl, 10 mM KCl and 0.05% (w/v)
CHAPS.
Compound and Liquid Handling
[0511] The test compounds were dissolved in 90% DMSO/10% H2O (v/v).
Serial dilutions of the compounds from 3 mM to 0.03 .mu.M in 90%
DMSO/10% H2O (v/v) followed by a 1:33.3 dilution in assay buffer
was done in 96-well polypropylene plates using a CyBio Dilus
8-channel pipettor (CyBio AG, Jena, Germany) with tip change after
each pipetting step. The compound solutions as well as the
substrate and the enzyme solutions were transferred to the assay
plates (384-well black Cliniplate; cat. no. 95040020 Labsystems Oy,
Finland) by means of a CyBi-Well 96-channel pipettor (CyBio AG,
Jena, Germany).
Kinetic Measurements
[0512] Enzyme kinetics were measured by mixing 10 .mu.l of a 3-fold
concentrated substrate solution in assay buffer (final substrate
concentration was 10 .mu.M) with 10 .mu.l of the corresponding
compound solution. The reactions were initiated by addition of 10
.mu.l of a 3-fold concentrated solution of the enzyme in assay
buffer. Final enzyme (active site) concentrations in the assay was
10 pM for DPP-IV. Fluorescence product (AMC) formation was
monitored for 1 hour at room temperature at 35 second intervals by
measuring the fluorescence emission at 500 nm using an exitation
wavelength of 350 nm in a TECAN Ultra fluorescence reader (TECAN,
Maennedorf, Switzerland). The fluorescence in each well was excited
by one flash per measurement. The Origin software package (Origin
7.5 Mircocal, Northampton, Mass., USA) was used to generate all
graphs and to perform the IC50 calculations.
Results
[0513] The inhibitory activities (IC.sub.50 values) of the
compounds to human DPP-IV were found to be 7.7 .mu.M or less and in
many cases 0.1 .mu.M or less. In the case of exemplary compounds,
their IC.sub.50 values were found to be between 7.7 .mu.M and 0.007
.mu.M.
[0514] Table 1 shows the inhibitory activity (IC.sub.50 values) of
representative compounds to human DPP-4.
TABLE-US-00012 Example IC.sub.50 (.mu.M) 7 0.023 4d 0.023 18b 0.025
27a 0.022
* * * * *