U.S. patent application number 15/809011 was filed with the patent office on 2018-03-29 for mnk inhibitors and methods related thereto.
This patent application is currently assigned to eFFECTOR Therapeutics, Inc.. The applicant listed for this patent is eFFECTOR Therapeutics, Inc.. Invention is credited to Justin T. Ernst, Siegfried H. Reich, Paul A. Sprengeler, Stephen E. Webber, Alan X. Xiang.
Application Number | 20180085368 15/809011 |
Document ID | / |
Family ID | 53724447 |
Filed Date | 2018-03-29 |
United States Patent
Application |
20180085368 |
Kind Code |
A1 |
Reich; Siegfried H. ; et
al. |
March 29, 2018 |
MNK INHIBITORS AND METHODS RELATED THERETO
Abstract
The present invention relates to compounds according to Formula
(I): ##STR00001## or a stereoisomer, tautomer or pharmaceutically
acceptable salt thereof, wherein R.sup.1, R.sup.2, R.sup.3,
R.sup.4a, R.sup.4b, R.sup.5, R.sup.6, R.sup.7, R.sup.8, W.sup.1,
W.sup.2, Y and n are as defined herein. Also described are
pharmaceutically acceptable compositions of Formula I compounds as
well as methods for utilizing the compounds of Formula I and the
pharmaceutically acceptable compositions of Formula I compounds as
inhibitors of Mnk as well as therapeutics for the treatment of
diseases such as cancer.
Inventors: |
Reich; Siegfried H.; (La
Jolla, CA) ; Sprengeler; Paul A.; (Escondido, CA)
; Webber; Stephen E.; (San Diego, CA) ; Xiang;
Alan X.; (Irvine, CA) ; Ernst; Justin T.; (San
Diego, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
eFFECTOR Therapeutics, Inc. |
San Diego |
CA |
US |
|
|
Assignee: |
eFFECTOR Therapeutics, Inc.
Schiphol
NL
|
Family ID: |
53724447 |
Appl. No.: |
15/809011 |
Filed: |
November 10, 2017 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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15611966 |
Jun 2, 2017 |
9814718 |
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15809011 |
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15187854 |
Jun 21, 2016 |
9669031 |
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15611966 |
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14748990 |
Jun 24, 2015 |
9382248 |
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15187854 |
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62017112 |
Jun 25, 2014 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C07D 487/04 20130101;
C07D 471/10 20130101; C07D 491/20 20130101; A61K 31/506 20130101;
C07D 471/20 20130101; C07D 519/00 20130101; A61P 35/00 20180101;
A61K 31/519 20130101; A61P 35/02 20180101; C07D 473/34 20130101;
A61P 43/00 20180101; A61K 31/52 20130101; A61K 31/551 20130101;
C07D 495/20 20130101; C07D 471/04 20130101 |
International
Class: |
A61K 31/506 20060101
A61K031/506; A61K 31/551 20060101 A61K031/551; C07D 473/34 20060101
C07D473/34; C07D 487/04 20060101 C07D487/04; C07D 471/10 20060101
C07D471/10; C07D 471/20 20060101 C07D471/20; C07D 471/04 20060101
C07D471/04; C07D 495/20 20060101 C07D495/20; C07D 519/00 20060101
C07D519/00; A61K 31/519 20060101 A61K031/519; A61K 31/52 20060101
A61K031/52; C07D 491/20 20060101 C07D491/20 |
Claims
1. A method for treating a disease or condition in a mammal in need
thereof, the method comprising administering to the mammal a
therapeutically effective amount of at least one MAP kinase
interacting kinase (Mnk) inhibitor and at least one other
therapeutic agent, wherein the at least one other therapeutic agent
is other than the at least one Mnk inhibitor.
2. The method of claim 1, wherein the mammal is a human.
3. The method of claim 1, wherein the at least one other
therapeutic agent is an anti-cancer agent.
4. The method of claim 3, wherein the anti-cancer agent is a
chemo-therapeutic drug.
5. The method of claim 3, wherein the anti-cancer agent is selected
from folate antagonists, antiproliferative agents, antimitotic
agents, microtubule inhibiting agents, DNA damaging agents, DNA
synthesis inhibitors, DNA interactive agents, DNA repair
inhibitors, antiplatelet agents, antimetabolites, hormones, hormone
analogs, aromatase inhibitors, fibrinolytic agents, antimigratory
agents, antisecretory agents, immunosuppressives, anti-angiogenic
compounds, growth factor inhibitors, angiotensin receptor blocker,
nitric oxide donors, anti-sense oligonucleotides, antibodies,
chimeric antigen receptors, cell cycle inhibitors, differentiation
inducers, mTOR inhibitors, topoisomerase inhibitors,
corticosteroids, growth factor signal transduction kinase
inhibitors, mitochondrial dysfunction inducers, caspase activators,
and inhibitors of chromatin function.
6. The method of claim 1, wherein the Mnk inhibitor is a compound
according to Formula (I): ##STR00540## or a stereoisomer, tautomer,
solvate, or pharmaceutically acceptable salt thereof, wherein:
W.sup.1 and W.sup.2 are independently O, S or N--OR', wherein R' is
lower alkyl; Y is --N(R.sup.5)--, --O--, --S--, --C(O)--,
--S.dbd.O, --S(O).sub.2--, or --CHR.sup.9--, wherein R.sup.5 is
hydrogen, cyano, or lower alkyl; R.sup.1 is hydrogen, lower alkyl,
cycloalkyl or heterocyclyl, wherein any lower alkyl, cycloalkyl or
heterocyclyl is optionally substituted with 1, 2 or 3 J groups; n
is 1, 2 or 3; R.sup.2 and R.sup.3 are each independently hydrogen,
alkyl, alkenyl, alkynyl, aryl, araalkylene, heteroaryl,
heteroarylalkylene, cycloalkyl, cycloalkylalkylene, heterocyclyl,
or heterocyclylalkylene, wherein any alkyl, aryl, araalkylene,
heteroaryl, heteroarylalkylene, cycloalkyl, cycloalkylalkylene,
heterocyclyl, or heterocyclylalkylene is optionally substituted
with 1, 2 or 3 J groups; or R.sup.2 and R.sup.3 taken together with
the carbon atom to which they are attached form a cycloalkyl or
heterocyclyl, wherein any cycloalkyl or heterocyclyl is optionally
substituted with 1, 2 or 3 J groups; R.sup.4a and R.sup.4b are each
independently hydrogen, halogen, hydroxyl, thiol, hydroxyalkylene,
cyano, alkyl, alkoxy, acyl, thioalkyl, alkenyl, alkynyl,
cycloalkyl, aryl, or heterocyclyl; R.sup.6, R.sup.7 and R.sup.8 are
each independently hydrogen, hydroxy, halogen, cyano, amino, alkyl,
alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkylene,
cycloalkylalkenylene, alkylaminyl, alkylcarbonylaminyl,
cycloalkylcarbonylaminyl, cycloalkylaminyl, heterocyclylaminyl,
heteroaryl, or heterocyclyl, and wherein any amino, alkyl, alkenyl,
alkynyl, alkoxy, cycloalkyl, cycloalkylalkylene,
cycloalkylalkenylene, amino, alkylaminyl, alkylcarbonylaminyl,
cycloalkylcarbonylaminyl, cycloalkylaminyl, heterocyclylaminyl,
heteroaryl, or heterocyclyl is optionally substituted with 1, 2 or
3 J groups; or R.sup.5 and R.sup.8 taken together with the atoms to
which they are attached form a fused heterocyclyl optionally
substituted with 1, 2 or 3 J groups; or R.sup.7 and R.sup.8 taken
together with the atoms to which they are attached form a fused
heterocyclyl or heteroaryl optionally substituted with 1, 2 or 3 J
groups; wherein each J group is independently --SH, --SR.sup.9,
--S(O)R.sup.9, --S(O).sub.2R.sup.9, --S(O)NH.sub.2,
--S(O)NR.sup.9R.sup.9, --NH.sub.2, --NR.sup.9R.sup.9, --COOH,
--C(O)OR.sup.9, --C(O)R.sup.9, --C(O)--NH.sub.2,
--C(O)--NR.sup.9R.sup.9, hydroxy, cyano, halogen, acetyl, alkyl,
lower alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, thioalkyl,
cyanoalkylene, alkylaminyl, NH.sub.2--C(O)-alkylene,
NR.sup.9R.sup.9--C(O)-alkylene, --CHR.sup.9--C(O)-lower alkyl,
--C(O)-lower alkyl, alkylcarbonylaminyl, cycloalkyl, cycloalkyl
alkylene, cycloalkylalkenylene, cycloalkylcarbonylaminyl,
cycloalkylaminyl, --CHR.sup.9--C(O)-cycloalkyl, --C(O)--
cycloalkyl, --CHR.sup.9--C(O)-aryl, --CHR.sup.9-aryl, --C(O)-aryl,
--CHR.sup.9--C(O)-heterocycloalkyl, --C(O)-heterocycloalkyl,
heterocyclylaminyl, or heterocyclyl; or any two J groups bound to
the same carbon or hetero atom may be taken together to form oxo;
and R.sup.9 is hydrogen, lower alkyl or --OH.
7. The method of claim 6, wherein n is 1.
8. The method of claim 6, wherein R.sup.2 and R.sup.3 taken
together with the carbon atom to which they are attached form a
cycloalkyl or heterocyclyl, wherein any cycloalkyl or heterocyclyl
is optionally substituted with 1, 2 or 3 J groups selected from the
group consisting of halogen, --CN, methyl, difluoroethylene,
trifluoroethylene, and methylenenitrile.
9. The method of claim 8, wherein R.sup.2 and R.sup.3 taken
together with the carbon atom to which they are attached form a
cyclohexyl or piperidine ring.
10. The method of claim 6, wherein: R.sup.4a and R.sup.4b are each
independently hydrogen, halogen, or alkyl; R.sup.6 and R.sup.8 are
hydrogen; and R.sup.7 is amino, cycloalkyl carbonylaminyl,
heterocyclylaminyl, or cycloalkyl alkylene.
11. The method of claim 6, wherein and W is O or S, and Y is
--N(R.sup.5)--, wherein R.sup.5 is hydrogen.
12. The method of claim 6, wherein the compound according to
Formula (I) is selected from the group consisting of: ##STR00541##
##STR00542## ##STR00543## ##STR00544## ##STR00545## or a
stereoisomer, tautomer, solvate, or pharmaceutically acceptable
salt thereof.
13. The method of claim 1, wherein the disease or condition is
associated with overexpression or hyperactivation of eukaryotic
initiation factor 4E (eIF4E).
14. The method of claim 1, wherein the disease or condition is
cancer.
15. The method of claim 14, wherein the cancer is selected from a
solid tumor and a hematological cancer.
16. The method of claim 14, wherein the cancer is selected from
colorectal cancer, bladder cancer, gastric cancer, esophageal
cancer, head and neck cancer, CNS cancer, malignant glioma,
glioblastoma, hepatocellular cancers, thyroid cancer, lung cancer,
non-small cell cancer, small cell lung cancer, melanoma, myeloma,
pancreatic cancer, pancreatic carcinoma, renal cell carcinoma,
cervical cancer, urothelial cancer, prostate cancer,
castration-resistant prostate cancer, ovarian cancer, breast
cancer, triple-negative breast cancer, leukemia, Hodgkins lymphoma,
non-Hodgkins lymphoma, B-cell lymphoma, T-cell lymphoma, hairy cell
lymphoma, diffuse large B-cell lymphoma, Burkitts lymphoma,
multiple myeloma, and myelodysplastic syndrome.
17. The method of claim 14, wherein the mammal exhibits resistance
to cancer therapy with an mTOR inhibitor.
18. The method of claim 1, wherein the disease or condition is
selected from an inflammatory disease.
19. The method of claim 18, wherein the disease or condition is an
inflammatory disease selected from inflammatory arthritis,
rheumatoid arthritis, psoriatic arthritis, osteoarthritis, juvenile
rheumatoid arthritis, Reiter's syndrome, rheumatoid traumatic
arthritis, rubella arthritis, acute synovitis and gouty arthritis;
sunburn, psoriasis, erythrodermic psoriasis, pustular psoriasis,
eczema, dermatitis, acute or chronic graft formation, atopic
dermatitis, contact dermatitis, urticaria and scleroderma;
inflammatory bowel disease, Crohn's disease, ulcerative colitis,
colitis, and diverticulitis; nephritis, urethritis, salpingitis,
oophoritis, endomyometritis, spondylitis, systemic lupus
erythematosus, multiple sclerosis, asthma, meningitis, myelitis,
encephalomyelitis, encephalitis, phlebitis, thrombophlebitis,
asthma, bronchitis, chronic obstructive pulmonary disease (COPD),
inflammatory lung disease, adult respiratory distress syndrome,
allergic rhinitis; endocarditis, osteomyelitis, rheumatic fever,
rheumatic pericarditis, rheumatic endocarditis, rheumatic
myocarditis, rheumatic mitral valve disease, rheumatic aortic valve
disease, prostatitis, prostatocystitis, spondoarthropathies
ankylosing spondylitis, synovitis, tenosynovotis, myositis,
pharyngitis, polymyalgia rheumatica, shoulder tendonitis or
bursitis, gout, pseudo gout, vasculitides, granulomatous
thyroiditis, lymphocytic thyroiditis, invasive fibrous thyroiditis,
acute thyroiditis; Hashimoto's thyroiditis, Kawasaki's disease,
Raynaud's phenomenon, Sjogren's syndrome, neuroinflammatory
disease, sepsis, conjunctivitis, keratitis, iridocyclitis, optic
neuritis, otitis, lymphoadenitis, nasopaharingitis, sinusitis,
pharyngitis, tonsillitis, laryngitis, epiglottitis, bronchitis,
pneumonitis, stomatitis, gingivitis, oesophagitis, gastritis,
peritonitis, hepatitis, cholelithiasis, cholecystitis,
glomerulonephritis, goodpasture's disease, crescentic
glomerulonephritis, pancreatitis, endomyometritis, myometritis,
metritis, cervicitis, endocervicitis, exocervicitis, parametritis,
tuberculosis, vaginitis, vulvitis, silicosis, sarcoidosis,
pneumoconiosis, pyresis, inflammatory polyarthropathies, psoriatric
arthropathies, intestinal fibrosis, bronchiectasis and enteropathic
arthropathies.
Description
CROSS-REFERENCE TO RELATED PATENT APPLICATIONS
[0001] The present application is a continuation of U.S. patent
application Ser. No. 15/611,966, filed Jun. 2, 2017, which is a
continuation of U.S. patent application Ser. No. 15/187,854, filed
Jun. 21, 2016, now U.S. Pat. No. 9,669,031, which is a divisional
of U.S. patent application Ser. No. 14/748,990, filed Jun. 24,
2015, now U.S. Pat. No. 9,382,248, which claims the benefit of U.S.
provisional application No. 62/017,112, filed Jun. 25, 2014, all of
which are herein incorporated by reference in their entirety.
FIELD
[0002] The present invention generally relates to compounds having
activity as inhibitors of MAP kinase interacting kinase (Mnk), as
well as to related compositions and methods containing or utilizing
the same. Such compounds find utility in any number of therapeutic
applications, including the treatment of cancer.
BACKGROUND
[0003] Eukaryotic initiation factor 4E (eIF4E) is a general
translation factor, but it has the potential to enhance
preferentially the translation of messenger RNAs (mRNAs) that lead
to production of malignancy-associated proteins. This selectivity
may relate to an increased requirement for eIF4E and its binding
partners for the translation of mRNAs containing extensive
secondary structure in their 5'-untranslated regions (5'-UTRs).
These mRNAs include those encoding certain proteins that control
cell cycle progression and tumorigenesis. Under normal cellular
conditions the translation of these malignancy-associated mRNAs is
suppressed as the availability of active eIF4E is limited; however,
their levels can increase when eIF4E is over-expressed or
hyperactivated. Elevated levels of eIF4E have been found in many
types of tumors and cancer cell lines including cancers of the
colon, breast, bladder, lung, prostate, gastrointestinal tract,
head and neck, Hodgkin's lymphomas and neuroblastomas.
[0004] Initiation of cap-dependent translation is thought to depend
on the assembly of eIF4F, an initiation factor complex including
eIF4E, the scaffold protein eIF4G, and the RNA helicase eIF4A.
Because eIF4E is the only one of these proteins that binds directly
to the mRNA cap structure, it is the key factor for the assembly of
eIF4F at the 5' cap. The scaffold protein, eIF4G, also recruits the
40S ribosomal subunit to the mRNA via its interaction with eIF3 and
binds eIF4B, a protein that aids the RNA-helicase function of
eIF4A, thus facilitating the translation of mRNAs that contain
structured 5'-UTRs. The availability of eIF4E as part of the eIF4F
complex is a limiting factor in controlling the rate of
translation, and therefore eIF4E is an important regulator of mRNA
translation.
[0005] Regulation of eIF4E activity forms a node of convergence of
the PI3K/Akt/mTOR and Ras/Raf/MAPK signaling pathways. The PI3K
(phosphoinositide 3-kinase)/PTEN (phosphatase and tensin homologue
deleted on chromosome ten)/Akt/mTOR (mammalian target of rapamycin)
pathway is often involved in tumorgenesis and in sensitivity and
resistance to cancer therapy. Deregulated signaling through the
PI3K/PTEN/Akt/mTOR pathway is often the result of genetic
alterations in critical components of this pathway and/or mutations
at upstream growth factor receptors or signaling components. PI3K
initiates a cascade of events when activated by, for example,
extracellular growth factors, mitogens, cytokines and/or receptors,
PDK1 activates Akt, which in turn phosphorylates and inactivates
the tumor suppressor complex comprising TSC1 and 2 (tuberous
sclerosis complex 1/2), resulting in the activation of mTORC1
(target of rapamycin complex 1) by Rheb-GTP. Activation of PDK1 and
Akt by PI3Ks is negatively regulated by PTEN.
[0006] PTEN is a critical tumor suppressor gene and is often
mutated or silenced in human cancers. Its loss results in
activation of Akt and increases downstream mTORC1 signaling. The
involvement of mTOR complex1 (mTORC1) in neoplastic transformation
appears to depend on its regulatory role toward the eIF4F complex;
overexpression of eIF4E can confer resistance to rapamycin. mTORC1
regulates the eIF4F complex assembly that is critical for the
translation of mRNAs associated with cell growth, prevention of
apoptosis and transformation. mTORC1 achieves this by
phosphorylation and inactivation of 4E-BPs and the subsequent
dissociation of 4E-BPs from eIF4E. This then enables eIF4E to
interact with the scaffold protein eIF4G, permitting assembly of
the eIF4F complex for the translation of structured mRNAs. mTORC1
also promotes activation of the translational activator, S6K, which
phosphorylates the ribosomal protein S6 and other substrates,
including eIF4B. mTORC1 signaling is inhibited by rapamycin and its
analogues (rapalogs), although these compounds act allosterically,
rather than directly inhibiting mTOR kinase activity.
[0007] Given the importance of the PI3K/Akt/mTOR pathway in
regulating mRNA translation of genes that encode for pro-oncogenic
proteins and activated mTORC1 signaling in a high proportion of
cancers, these kinases have been actively pursued as oncology drug
targets. A number of pharmacological inhibitors have been
identified, some of which have reached advanced clinical stages.
However, it has recently become clear that the mTOR pathway
participates in a complicated feedback loop that can impair
activation of Akt. It has been shown that prolonged treatment of
cancer cells or patients with mTOR inhibitors causes elevated PI3K
activity that leads to phosphorylation of Akt and eIF4E, and
promotes cancer cell survival. eIF4E, acting downstream of Akt and
mTOR, recapitulates Akt's action in tumorigenesis and drug
resistance, and Akt signaling via eIF4E is an important mechanism
of oncogenesis and drug resistance in vivo.
[0008] In addition to the PI3K/Akt/mTOR pathway, eIF4E is also the
target of the Ras/Raf/MAP signaling cascade which is activated by
growth factors and for the stress-activated p38 MAP kinase pathway.
Erk1/2 and p38 then phosphorylate MAP kinase-interacting kinase 1
(Mnk1) and MAP kinase-interacting kinase 2 (Mnk2). The Erk pathway
is also activated in many cancers, reflecting, for example,
activating mutations in Ras (found in around 20% of tumors) or loss
of function of the Ras GTPase-activator protein NF 1. Mnk1 and Mnk2
are threonine/serine protein kinases and specifically phosphorylate
serine 209 (Ser209) of eIF4E within the eIF4F complex, by virtue of
the interaction between eIF4E and the Mnks, which serves to recruit
Mnks to act on eIF4E. Mice with mutated eIF4E, in which Ser209 is
replaced by alanine, show no eIF4E phosphorylation and
significantly attenuated tumor growth. Significantly, while Mnk
activity is necessary for eIF4E-mediated oncogenic transformation,
it is dispensable for normal development. Pharmacologically
inhibiting Mnks thus presents an attractive therapeutic strategy
for cancer.
[0009] Despite increased understanding of Mnk structure and
function, little progress has been made with regard to the
discovery of pharmacological Mnk inhibitors and relatively few Mnk
inhibitors have been reported: CGP052088 (Tschopp et al., Mol Cell
Biol Res Commun. 3(4):205-211, 2000); CGP57380 (Rowlett et al., Am
J Physiol Gastrointest Liver Physiol. 294(2):G452-459, 2008); and
Cercosporamide (Konicek et al., Cancer Res. 71(5):1849-1857, 2011).
These compounds, however, have mainly been used for the purpose of
Mnk target validation. More recently, investigators have proposed
further compounds for treating diseases influenced by the
inhibition of kinase activity of Mnk1 and/or Mnk2, including, for
example, the compounds disclosed in WO 2014/044691 and the various
patent documents cited therein and the
4-(dihydropyridinon-3-yl)amino-5-methylthieno[2,3,-d]pyrimidines
disclosed by Yu et al., European Journal of Med. Chem., 95:
116-126, 2015.
[0010] Accordingly, while advances have been made in this field
there remains a significant need in the art for compounds that
specifically inhibit Mnk kinase activity, particularly with regard
to Mnk's role in regulation of cancer pathways, as well as for
associated composition and methods. The present invention fulfills
this need and provides further related advantages.
SUMMARY
[0011] The present invention is directed to compounds that inhibit
or modulate the activity of Mnk, as well as stereoisomers,
tautomers and pharmaceutically acceptable salts of such compounds
as candidate therapeutic agents. The present invention also is
directed to compositions containing such compounds and associated
methods for treating conditions that would benefit from Mnk
inhibition, such as cancer.
[0012] In one embodiment, the invention is directed to compounds
that conform to Formula I as well as to a stereoisomer, tautomer or
pharmaceutically acceptable salt of such compounds.
##STR00002##
[0013] For Formula I compounds, R.sup.1, R.sup.2, R.sup.3,
R.sup.4a, R.sup.4b, R.sup.6, R.sup.7, R.sup.8, W.sup.2, Y and "n"
are as defined below.
[0014] In another embodiment, compositions are disclosed comprising
a compound of structure (I) in combination with a pharmaceutically
acceptable carrier, diluent or excipient.
[0015] In a further embodiment, methods are provided for treating a
Mnk dependent condition in a mammal in need thereof. Such methods
comprise administering an effective amount of a compound of
structure (I), or compositions comprising the same, to the mammal.
Such conditions include, but are not limited to, various forms of
cancer as discussed in more detail below.
[0016] These and other aspects of the invention will be apparent
upon reference to the following detailed description. To this end,
various references are set forth herein which describe in more
detail certain background information, procedures, compounds and/or
compositions, and are each hereby incorporated by reference in
their entirety.
FIGURES
[0017] FIG. 1 illustrates XRPD data for the hydrogen chloride salt
form of an exemplary Formula I compound.
DETAILED DESCRIPTION
[0018] In the following description, certain specific details are
set forth in order to provide a thorough understanding of various
embodiments of the invention. However, one skilled in the art will
understand that the invention may be practiced without these
details. Unless the context requires otherwise, throughout the
present specification and claims, the word "comprise" and
variations thereof, such as, "comprises" and "comprising" are to be
construed in an open, inclusive sense (i.e., as "including, but not
limited to").
[0019] Reference throughout this specification to "one embodiment"
or "an embodiment" means that a particular feature, structure or
characteristic described in connection with the embodiment is
included in at least one embodiment of the present invention. Thus,
the appearances of the phrases "in one embodiment" or "in an
embodiment" in various places throughout this specification are not
necessarily all referring to the same embodiment. Furthermore, the
particular features, structures, or characteristics may be combined
in any suitable manner in one or more embodiments.
Definitions
[0020] As used herein, and unless noted to the contrary, the
following terms and phrases have the meaning noted below.
[0021] "Amino" refers to the --NH.sub.2 substituent.
[0022] "Aminocarbonyl" refers to the --C(O)NH.sub.2
substituent.
[0023] "Carboxyl" refers to the --CO.sub.2H substituent.
[0024] "Carbonyl" refers to a --C(O)-- or --C(.dbd.O)-- group. Both
notations are used interchangeably within the specification.
[0025] "Cyano" refers to the --C.ident.N substituent.
[0026] "Cyanoalkylene" refers to the -(alkylene)C.ident.N
substituent.
[0027] "Acetyl" refers to the --C(O)CH.sub.3 substituent.
[0028] "Hydroxy" or "hydroxyl" refers to the --OH substituent.
[0029] "Hydroxyalkylene" refers to the -(alkylene)OH
substituent.
[0030] "Oxo" refers to an oxygen of --O-- substituent.
[0031] "Thio" or "thiol" refer to a --SH substituent.
[0032] The phrase "MAP kinase interacting kinase" or the term "Mnk"
refers to all isoforms of the MAP kinase interacting kinase protein
including Mnk-1 and Mnk-2.
[0033] "Alkyl" refers to a saturated, straight or branched
hydrocarbon chain radical consisting solely of carbon and hydrogen
atoms, having from one to twelve carbon atoms (C.sub.1-C.sub.12
alkyl), from one to eight carbon atoms (C.sub.1-C.sub.8 alkyl) or
from one to six carbon atoms (C.sub.1-C.sub.6 alkyl), and which is
attached to the rest of the molecule by a single bond. Exemplary
alkyl groups include methyl, ethyl, n-propyl, 1-methylethyl
(iso-propyl), n-butyl, n-pentyl, 1,1-dimethylethyl (t-butyl),
3-methylhexyl, 2-methylhexyl, and the like.
[0034] "Lower alkyl" has the same meaning as alkyl defined above
but having from one to four carbon atoms (C.sub.1-C.sub.4
alkyl).
[0035] "Alkenyl" refers to an unsaturated alkyl group having at
least one double bond and from two to twelve carbon atoms
(C.sub.2-C.sub.12 alkenyl), from two to eight carbon atoms
(C.sub.2-C.sub.8 alkenyl) or from two to six carbon atoms
(C.sub.2-C.sub.6 alkenyl), and which is attached to the rest of the
molecule by a single bond, e.g., ethenyl, propenyl, butenyl,
pentenyl, hexenyl, and the like.
[0036] "Alkynyl" refers to an unsaturated alkyl group having at
least one triple bond and from two to twelve carbon atoms
(C.sub.2-C.sub.12 alkynyl), from two to ten carbon atoms
(C.sub.2-C.sub.10 alkynyl) from two to eight carbon atoms
(C.sub.2-C.sub.8 alkynyl) or from two to six carbon atoms
(C.sub.2-C.sub.6 alkynyl), and which is attached to the rest of the
molecule by a single bond, e.g., ethynyl, propynyl, butynyl,
pentynyl, hexynyl, and the like.
[0037] "Alkylene" or "alkylene chain" refers to a straight or
branched divalent hydrocarbon (alkyl) chain linking the rest of the
molecule to a radical group, consisting solely of carbon and
hydrogen, respectively. Alkylenes can have from one to twelve
carbon atoms, e.g., methylene, ethylene, propylene, n-butylene, and
the like. The alkylene chain is attached to the rest of the
molecule through a single or double bond. The points of attachment
of the alkylene chain to the rest of the molecule can be through
one carbon or any two carbons within the chain. "Optionally
substituted alkylene" refers to alkylene or substituted
alkylene.
[0038] "Alkenylene" refers to divalent alkene. Examples of
alkenylene include without limitation, ethenylene (--CH.dbd.CH--)
and all stereoisomeric and conformational isomeric forms thereof.
"Substituted alkenylene" refers to divalent substituted alkene.
"Optionally substituted alkenylene" refers to alkenylene or
substituted alkenylene.
[0039] "Alkynylene" refers to divalent alkyne. Examples of
alkynylene include without limitation, ethynylene, propynylene.
"Substituted alkynylene" refers to divalent substituted alkyne.
[0040] "Alkoxy" refers to a radical of the formula --OR.sub.a where
R.sub.a is an alkyl having the indicated number of carbon atoms as
defined above. Examples of alkoxy groups include without limitation
--O-methyl (methoxy), --O-ethyl (ethoxy), --O-propyl (propoxy),
--O-- isopropyl (iso propoxy) and the like.
[0041] "Acyl" refers to a radical of the formula --C(O)R.sub.a
where R.sub.a is an alkyl having the indicated number of carbon
atoms.
[0042] "Alkylaminyl" refers to a radical of the formula --NHR.sub.a
or --NR.sub.aR.sub.a where each R.sub.a is, independently, an alkyl
radical having the indicated number of carbon atoms as defined
above.
[0043] "Cycloalkylaminyl" refers to a radical of the formula
--NHR.sub.a where R.sub.a is a cycloalkyl radical as defined
herein.
[0044] "Alkylcarbonylaminyl" refers to a radical of the formula
--NHC(O)R.sub.a, where R.sub.a is an alkyl radical having the
indicated number of carbon atoms as defined herein.
[0045] "Cycloalkylcarbonylaminyl" refers to a radical of the
formula --NHC(O)R.sub.a, where R.sub.a is a cycloalkyl radical as
defined herein.
[0046] "Alkylaminocarbonyl" refers to a radical of the formula
--C(O)NHR.sub.a or --C(O)NR.sub.aR.sub.a, where each R.sub.a is
independently, an alkyl radical having the indicated number of
carbon atoms as defined herein.
[0047] "Cyclolkylaminocarbonyl" refers to a radical of the formula
--C(O)NHR.sub.a, where R.sub.a is a cycloalkyl radical as defined
herein.
[0048] "Aryl" refers to a hydrocarbon ring system radical
comprising hydrogen, 6 to 18 carbon atoms and at least one aromatic
ring. Exemplary aryls are hydrocarbon ring system radical
comprising hydrogen and 6 to 9 carbon atoms and at least one
aromatic ring; hydrocarbon ring system radical comprising hydrogen
and 9 to 12 carbon atoms and at least one aromatic ring;
hydrocarbon ring system radical comprising hydrogen and 12 to 15
carbon atoms and at least one aromatic ring; or hydrocarbon ring
system radical comprising hydrogen and 15 to 18 carbon atoms and at
least one aromatic ring. For purposes of this invention, the aryl
radical may be a monocyclic, bicyclic, tricyclic or tetracyclic
ring system, which may include fused or bridged ring systems. Aryl
radicals include, but are not limited to, aryl radicals derived
from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene,
azulene, benzene, chrysene, fluoranthene, fluorene, as-indacene,
s-indacene, indane, indene, naphthalene, phenalene, phenanthrene,
pleiadene, pyrene, and triphenylene. "Optionally substituted aryl"
refers to an aryl group or a substituted aryl group.
[0049] "Arylene" denotes divalent aryl, and "substituted arylene"
refers to divalent substituted aryl.
[0050] "Aralkyl" or "araalkylene" may be used interchangeably and
refer to a radical of the formula --R.sub.b--R.sub.c, where R.sub.b
is an alkylene chain as defined herein and R.sub.c is one or more
aryl radicals as defined herein, for example, benzyl,
diphenylmethyl and the like.
[0051] "Cycloalkyl" refers to a stable non-aromatic monocyclic or
polycyclic hydrocarbon radical consisting solely of carbon and
hydrogen atoms, which may include fused or bridged ring systems,
having from three to fifteen carbon atoms, preferably having from
three to ten carbon atoms, three to nine carbon atoms, three to
eight carbon atoms, three to seven carbon atoms, three to six
carbon atoms, three to five carbon atoms, a ring with four carbon
atoms, or a ring with three carbon atoms. The cycloalkyl ring may
be saturated or unsaturated and attached to the rest of the
molecule by a single bond. Monocyclic radicals include, for
example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
cycloheptyl, and cyclooctyl. Polycyclic radicals include, for
example, adamantyl, norbornyl, decalinyl,
7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like.
[0052] "Cycloalkylalkylene" or "cycloalkylalkyl" may be used
interchangeably and refer to a radical of the formula
--R.sub.bR.sub.e where R.sub.b is an alkylene chain as defined
herein and R.sub.e is a cycloalkyl radical as defined herein. In
certain embodiments, R.sub.b is further substituted with a
cycloalkyl group, such that the cycloalkylalkylene comprises two
cycloalkyl moieties. Cyclopropylalkylene and cyclobutylalkylene are
exemplary cycloalkylalkylene groups, comprising at least one
cyclopropyl or at least one cyclobutyl group, respectively.
[0053] "Fused" refers to any ring structure described herein which
is fused to an existing ring structure in the compounds of the
invention. When the fused ring is a heterocyclyl ring or a
heteroaryl ring, any carbon atom on the existing ring structure
which becomes part of the fused heterocyclyl ring or the fused
heteroaryl ring may be replaced with a nitrogen atom.
[0054] "Halo" or "halogen" refers to bromo (bromine), chloro
(chlorine), fluoro (fluorine), or iodo (iodine).
[0055] "Haloalkyl" refers to an alkyl radical having the indicated
number of carbon atoms, as defined herein, wherein one or more
hydrogen atoms of the alkyl group are substituted with a halogen
(halo radicals), as defined above. The halogen atoms can be the
same or different. Exemplary haloalkyls are trifluoromethyl,
difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl,
1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and
the like.
[0056] "Heterocyclyl", heterocycle", or "heterocyclic ring" refers
to a stable 3- to 18-membered saturated or unsaturated radical
which consists of two to twelve carbon atoms and from one to six
heteroatoms, for example, one to five heteroatoms, one to four
heteroatoms, one to three heteroatoms, or one to two heteroatoms
selected from the group consisting of nitrogen, oxygen and sulfur.
Exemplary heterocycles include without limitation stable 3-15
membered saturated or unsaturated radicals, stable 3-12 membered
saturated or unsaturated radicals, stable 3-9 membered saturated or
unsaturated radicals, stable 8-membered saturated or unsaturated
radicals, stable 7-membered saturated or unsaturated radicals,
stable 6-membered saturated or unsaturated radicals, or stable
5-membered saturated or unsaturated radicals.
[0057] Unless stated otherwise specifically in the specification,
the heterocyclyl radical may be a monocyclic, bicyclic, tricyclic
or tetracyclic ring system, which may include fused or bridged ring
systems; and the nitrogen, carbon or sulfur atoms in the
heterocyclyl radical may be optionally oxidized; the nitrogen atom
may be optionally quaternized; and the heterocyclyl radical may be
partially or fully saturated. Examples of non-aromatic heterocyclyl
radicals include, but are not limited to, azetidinyl, dioxolanyl,
thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl,
imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl,
octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl,
2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl,
piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl,
quinuclidinyl, thiazolidinyl, tetrahydrofuryl, thietanyl,
trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl,
1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. Heterocyclyls
include heteroaryls as defined herein, and examples of aromatic
heterocyclyls are listed in the definition of heteroaryls
below.
[0058] "Heterocyclylalkyl" or "heterocyclylalkylene" refers to a
radical of the formula --R.sub.bR.sub.f where R.sub.b is an
alkylene chain as defined herein and R.sub.f is a heterocyclyl
radical as defined above, and if the heterocyclyl is a
nitrogen-containing heterocyclyl, the heterocyclyl may be attached
to the alkyl radical at the nitrogen atom.
[0059] "Heteroaryl" or "heteroarylene" refers to a 5- to
14-membered ring system radical comprising hydrogen atoms, one to
thirteen carbon atoms, one to six heteroatoms selected from the
group consisting of nitrogen, oxygen and sulfur, and at least one
aromatic ring. For purposes of this invention, the heteroaryl
radical may be a stable 5-12 membered ring, a stable 5-10 membered
ring, a stable 5-9 membered ring, a stable 5-8 membered ring, a
stable 5-7 membered ring, or a stable 6 membered ring that
comprises at least 1 heteroatom, at least 2 heteroatoms, at least 3
heteroatoms, at least 4 heteroatoms, at least 5 heteroatoms or at
least 6 heteroatoms. Heteroaryls may be a monocyclic, bicyclic,
tricyclic or tetracyclic ring system, which may include fused or
bridged ring systems; and the nitrogen, carbon or sulfur atoms in
the heteroaryl radical may be optionally oxidized; the nitrogen
atom may be optionally quaternized. The heteroatom may be a member
of an aromatic or non-aromatic ring, provided at least one ring in
the heteroaryl is aromatic. Examples include, but are not limited
to, azepinyl, acridinyl, benzimidazolyl, benzothiazolyl,
benzindolyl, benzodioxolyl, benzofuranyl, benzooxazolyl,
benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl,
1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl,
benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl,
benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl),
benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl,
cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl,
isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl,
isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl,
isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl,
oxiranyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl,
1-oxidopyridazinyl, 1-phenyl-1H-pyrrolyl, phenazinyl,
phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl,
pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl,
pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl,
isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl,
triazolyl, tetrazolyl, triazinyl, and thiophenyl (i.e.
thienyl).
[0060] "Heteroarylalkyl" or "heteroarylalkylene" refers to a
radical of the formula --R.sub.bR.sub.g where R.sub.b is an
alkylene chain as defined above and R.sub.g is a heteroaryl radical
as defined above.
[0061] "Thioalkyl" refers to a radical of the formula --SR.sub.a
where R.sub.a is an alkyl radical as defined above containing one
to twelve carbon atoms, at least 1-10 carbon atoms, at least 1-8
carbon atoms, at least 1-6 carbon atoms, or at least 1-4 carbon
atoms.
[0062] "Heterocyclylaminyl" refers to a radical of the formula
--NHR.sub.f where R.sub.f is a heterocyclyl radical as defined
above.
[0063] "Thione" refers to a .dbd.S group attached to a carbon atom
of a saturated or unsaturated (C.sub.3-C.sub.8)cyclic or a
(C.sub.1-C.sub.8)acyclic moiety.
[0064] "Sulfoxide" refers to a --S(O)-- group in which the sulfur
atom is covalently attached to two carbon atoms.
[0065] "Sulfone" refers to a --S(O).sub.2-- group in which a
hexavalent sulfur is attached to each of the two oxygen atoms
through double bonds and is further attached to two carbon atoms
through single covalent bonds.
[0066] The term "oxime" refers to a --C(R.sub.a).dbd.N--OR.sub.a
radical where R.sub.a is hydrogen, lower alkyl, an alkylene or
arylene group as defined above.
[0067] The compound of the invention can exist in various isomeric
forms, as well as in one or more tautomeric forms, including both
single tautomers and mixtures of tautomers. The term "isomer" is
intended to encompass all isomeric forms of a compound of this
invention, including tautomeric forms of the compound.
[0068] Some compounds described here can have asymmetric centers
and therefore exist in different enantiomeric and diastereomeric
forms. A compound of the invention can be in the form of an optical
isomer or a diastereomer. Accordingly, the invention encompasses
compounds of the invention and their uses as described herein in
the form of their optical isomers, diastereoisomers and mixtures
thereof, including a racemic mixture. Optical isomers of the
compounds of the invention can be obtained by known techniques such
as asymmetric synthesis, chiral chromatography, or via chemical
separation of stereoisomers through the employment of optically
active resolving agents.
[0069] Unless otherwise indicated, "stereoisomer" means one
stereoisomer of a compound that is substantially free of other
stereoisomers of that compound. Thus, a stereomerically pure
compound having one chiral center will be substantially free of the
opposite enantiomer of the compound. A stereomerically pure
compound having two chiral centers will be substantially free of
other diastereomers of the compound. A typical stereomerically pure
compound comprises greater than about 80% by weight of one
stereoisomer of the compound and less than about 20% by weight of
other stereoisomers of the compound, for example greater than about
90% by weight of one stereoisomer of the compound and less than
about 10% by weight of the other stereoisomers of the compound, or
greater than about 95% by weight of one stereoisomer of the
compound and less than about 5% by weight of the other
stereoisomers of the compound, or greater than about 97% by weight
of one stereoisomer of the compound and less than about 3% by
weight of the other stereoisomers of the compound.
[0070] If there is a discrepancy between a depicted structure and a
name given to that structure, then the depicted structure controls.
Additionally, if the stereochemistry of a structure or a portion of
a structure is not indicated with, for example, bold or dashed
lines, the structure or portion of the structure is to be
interpreted as encompassing all stereoisomers of it. In some cases,
however, where more than one chiral center exists, the structures
and names may be represented as single enantiomers to help describe
the relative stereochemistry. Those skilled in the art of organic
synthesis will know if the compounds are prepared as single
enantiomers from the methods used to prepare them.
[0071] In this description, a "pharmaceutically acceptable salt" is
a pharmaceutically acceptable, organic or inorganic acid or base
salt of a compound of the invention. Representative
pharmaceutically acceptable salts include, e.g., alkali metal
salts, alkali earth salts, ammonium salts, water-soluble and
water-insoluble salts, such as the acetate, amsonate
(4,4-diaminostilbene-2,2-disulfonate), benzenesulfonate, benzonate,
bicarbonate, bisulfate, bitartrate, borate, bromide, butyrate,
calcium, calcium edetate, camsylate, carbonate, chloride, citrate,
clavulariate, dihydrochloride, edetate, edisylate, estolate,
esylate, fiunarate, gluceptate, gluconate, glutamate,
glycollylarsanilate, hexafluorophosphate, hexylresorcinate,
hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate,
iodide, isothionate, lactate, lactobionate, laurate, malate,
maleate, mandelate, mesylate, methylbromide, methylnitrate,
methylsulfate, mucate, napsylate, nitrate, N-methylglucamine
ammonium salt, 3-hydroxy-2-naphthoate, oleate, oxalate, palmitate,
pamoate (1,1-methene-bis-2-hydroxy-3-naphthoate, einbonate),
pantothenate, phosphate/diphosphate, picrate, polygalacturonate,
propionate, p-toluenesulfonate, salicylate, stearate, subacetate,
succinate, sulfate, sulfosaliculate, suramate, tannate, tartrate,
teoclate, tosylate, triethiodide, and valerate salts. A
pharmaceutically acceptable salt can have more than one charged
atom in its structure. In this instance the pharmaceutically
acceptable salt can have multiple counterions. Thus, a
pharmaceutically acceptable salt can have one or more charged atoms
and/or one or more counterions.
[0072] The terms "treat", "treating" and "treatment" refer to the
amelioration or eradication of a disease or symptoms associated
with a disease. In certain embodiments, such terms refer to
minimizing the spread or worsening of the disease resulting from
the administration of one or more prophylactic or therapeutic
agents to a patient with such a disease.
[0073] The term "effective amount" refers to an amount of a
compound of the invention or other active ingredient sufficient to
provide a therapeutic or prophylactic benefit in the treatment or
prevention of a disease or to delay or minimize symptoms associated
with a disease. Further, a therapeutically effective amount with
respect to a compound of the invention means that amount of
therapeutic agent alone, or in combination with other therapies,
that provides a therapeutic benefit in the treatment or prevention
of a disease. Used in connection with a compound of the invention,
the term can encompass an amount that improves overall therapy,
reduces or avoids symptoms or causes of disease, or enhances the
therapeutic efficacy or synergies with another therapeutic
agent.
[0074] The terms "modulate", "modulation" and the like refer to the
ability of a compound to increase or decrease the function, or
activity of, for example, MAP kinase interacting kinase (Mnk).
"Modulation", in its various forms, is intended to encompass
inhibition, antagonism, partial antagonism, activation, agonism
and/or partial agonism of the activity associated with Mnk. Mnk
inhibitors are compounds that bind to, partially or totally block
stimulation, decrease, prevent, delay activation, inactivate,
desensitize, or down regulate signal transduction. The ability of a
compound to modulate Mnk activity can be demonstrated in an
enzymatic assay or a cell-based assay.
[0075] A "patient" or subject" includes an animal, such as a human,
cow, horse, sheep, lamb, pig, chicken, turkey, quail, cat, dog,
mouse, rat, rabbit or guinea pig. The animal can be a mammal such
as a non-primate and a primate (e.g., monkey and human). In one
embodiment, a patient is a human, such as a human infant, child,
adolescent or adult.
[0076] The term "prodrug" refers to a precursor of a drug that is a
compound which upon administration to a patient must undergo
chemical conversion by metabolic processes before becoming an
active pharmacological agent. Exemplary prodrugs of compounds in
accordance with Formula I are esters, acetamides, and amides.
[0077] Compounds of the Invention
[0078] The present invention is generally directed to compounds
encompassed by the genus of Formula I
##STR00003##
or a stereoisomer, tautomer or pharmaceutically acceptable salt
thereof wherein:
[0079] W.sup.1 and W.sup.2 are independently O, S or N--OR', where
R' is lower alkyl;
[0080] Y is --N(R.sup.5)--, --O--, --S--, --C(O)--, --S.dbd.O,
--S(O).sub.2--, or --CHR.sup.9--;
[0081] R.sup.1 is hydrogen, lower alkyl, cycloalkyl or heterocyclyl
wherein any lower alkyl, cycloalkyl or heterocyclyl is optionally
substituted with 1, 2 or 3 J groups;
[0082] n is 1, 2 or 3;
[0083] R.sup.2 and R.sup.3 are each independently hydrogen, alkyl,
alkenyl, alkynyl, aryl, araalkylene, heteroaryl,
heteroarylalkylene, cycloalkyl, cycloalkylalkylene, heterocyclyl,
or heterocyclylalkylene, wherein any alkyl, aryl, araalkylene,
heteroaryl, heteroarylalkylene, cycloalkyl, cycloalkylalkylene,
heterocyclyl, or heterocyclylalkylene, is optionally substituted
with 1, 2 or 3 J groups;
[0084] or R.sup.2 and R.sup.3 taken together with the carbon atom
to which they are attached form a cycloalkyl or heterocyclyl,
wherein any cycloalkyl or heterocyclyl is optionally substituted
with 1, 2 or 3 J groups;
[0085] R.sup.4a and R.sup.4b are each independently hydrogen,
halogen, hydroxyl, thiol, hydroxyalkylene, cyano, alkyl, alkoxy,
acyl, thioalkyl, alkenyl, alkynyl, cycloalkyl, aryl, or
heterocyclyl;
[0086] R.sup.5 is hydrogen, cyano, or lower alkyl;
[0087] or R.sup.5 and R.sup.8 taken together with the atoms to
which they are attached form a fused heterocyclyl optionally
substituted with 1, 2 or 3 J groups;
[0088] R.sup.6, R.sup.7 and R.sup.8 are each independently
hydrogen, hydroxy, halogen, cyano, amino, alkyl, alkenyl, alkynyl,
alkoxy, cycloalkyl, cycloalkylalkylene, cycloalkylalkenylene,
alkylaminyl, alkylcarbonylaminyl, cycloalkylcarbonylaminyl,
cycloalkylaminyl, heterocyclylaminyl, heteroaryl, or heterocyclyl,
and wherein any amino, alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl,
cycloalkylalkylene, cycloalkylalkenylene, amino, alkylaminyl,
alkylcarbonylaminyl, cycloalkylcarbonylaminyl, cycloalkylaminyl,
heterocyclylaminyl, heteroaryl, or heterocyclyl is optionally
substituted with 1, 2 or 3 J groups;
[0089] or R.sup.7 and R.sup.8 taken together with the atoms to
which they are attached form a fused heterocyclyl or heteroaryl
optionally substituted with 1, 2 or 3 J groups;
[0090] J is --SH, --SR.sup.9, --S(O)R.sup.9, --S(O).sub.2R.sup.9,
--S(O)NH.sub.2, --S(O)NR.sup.9R.sup.9, --NH.sub.2,
--NR.sup.9R.sup.9, --COOH, --C(O)OR.sup.9, --C(O)R.sup.9,
--C(O)--NH.sub.2, --C(O)--NR.sup.9R.sup.9, hydroxy, cyano, halogen,
acetyl, alkyl, lower alkyl, alkenyl, alkynyl, alkoxy, haloalkyl,
thioalkyl, cyanoalkylene, alkylaminyl, NH.sub.2--C(O)-alkylene,
NR.sup.9R.sup.9--C(O)-alkylene, --CHR.sup.9--C(O)-lower alkyl,
--C(O)-lower alkyl, alkylcarbonylaminyl, cycloalkyl,
cycloalkylalkylene, cycloalkylalkenylene, cycloalkylcarbonylaminyl,
cycloalkylaminyl, --CHR.sup.9--C(O)-cycloalkyl, --C(O)-cycloalkyl,
--CHR.sup.9--C(O)-aryl, --CHR.sup.9-aryl, --C(O)-aryl,
--CHR.sup.9--C(O)-heterocycloalkyl, --C(O)-heterocycloalkyl,
heterocyclylaminyl, or heterocyclyl; or any two J groups bound to
the same carbon or hetero atom may be taken together to form oxo;
and
[0091] R.sup.9 is hydrogen, lower alkyl or --OH.
[0092] In one embodiment of structure (I), the present disclosure
provides a compound having the following structure (Ia), as well as
stereoisomers, tautomers or pharmaceutically acceptable salts
thereof.
##STR00004##
[0093] For Formula Ia compounds, substituent R.sup.1 is hydrogen or
lower alkyl and subscript n is 1, 2 or 3. Substituents R.sup.2 and
R.sup.3 in Formula Ia are each independently hydrogen, alkyl,
cycloalkyl, cycloalkylalkylene, heterocyclyl or heterocyclylalkyl,
and any such alkyl, cycloalkyl, cycloalkylalkylene, heterocyclyl or
heterocyclylalkyl can optionally be substituted with 1, 2 or 3 J
groups.
[0094] Substitutents R.sup.2 and R.sup.3 in Formula Ia when taken
together with the carbon atom to which they are attached can form a
cycloalkyl or heterocyclyl, wherein any such cycloalkyl or
heterocyclyl is optionally substituted with 1, 2 or 3 J groups. In
Formula Ia, R.sup.4a is hydrogen, halogen, hydroxy, alkyl, alkoxy,
thioalkyl, alkenyl or cycloalkyl and substituent R.sup.5 is
hydrogen or lower alkyl.
[0095] Alternatively, substituent groups R.sup.5 and R.sup.8 taken
together with the atoms to which they are attached form a fused
heterocyclyl that is optionally substituted with 1, 2 or 3 J
groups.
[0096] In one embodiment, substituents R.sup.6, R.sup.7 and R.sup.8
are independently and at each occurrence hydrogen, halogen, alkyl,
alkenyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, amino,
alkylaminyl, alklycarbonylaminyl, cycloalkylcarbonylaminyl,
alkylaminyl or cycloalkylaminyl, and any such alkyl, alkenyl,
cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, amino, alkylaminyl,
alklycarbonylaminyl, cycloalkylcarbonylaminyl, alkylaminyl or
cycloalkylaminyl is optionally substituted with 1, 2 or 3 J groups.
For some compounds in accordance with Formula Ia, R.sup.7 and
R.sup.8 taken together with the atoms to which they are attached
form a fused heterocyclyl unsubstituted or substituted with 1, 2 or
3 J groups.
[0097] Variable J in Formula Ia is --SH, --SR.sup.9, --S(O)
R.sup.9, --S(O).sub.2 R.sup.9, --S(O)NH.sub.2,
--S(O)NR.sup.9R.sup.9, --NH.sub.2, --NR.sup.9R.sup.9, --COOH,
--C(O)OR.sup.9, --C(O)R.sup.9, --C(O)-- NH.sub.2,
--C(O)--NR.sup.9R.sup.9, hydroxy, cyano, halogen, acetyl, alkyl,
lower alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, thioalkyl,
cyanoalkylene, alkylaminyl, NH.sub.2--C(O)-alkylene,
NR.sup.9R.sup.9--C(O)-alkylene, --CHR.sup.9--C(O)-lower alkyl,
--C(O)-lower alkyl, alkylcarbonylaminyl, cycloalkyl,
cycloalkylalkylene, cycloalkylalkenylene, cycloalkyl
carbonylaminyl, cycloalkylaminyl, --CHR.sup.9--C(O)-cycloalkyl,
--C(O)-cycloalkyl, --CHR.sup.9--C(O)-aryl, --CHR.sup.9-aryl,
--C(O)-aryl, --CHR.sup.9--C(O)-heterocycloalkyl,
--C(O)-heterocycloalkyl, heterocyclylaminyl, or heterocyclyl. For
some of the inventive compounds according to Formula Ia, any two J
groups bound to the same carbon or hetero atom may be taken
together to form an oxo group.
[0098] In some embodiments, variable J in Formula Ia is halogen,
amino, alkyl, haloalkyl, alkylaminyl, cycloalkyl or heterocyclyl.
Alternatively, for certain Formula Ia compounds, any two J groups
when bound to the same carbon or hetero atom may be taken together
to form oxo group.
[0099] The present invention is further directed to compounds
according to Formula IIa, illustrated below, where variable Y is
--N(R.sup.5)-- and subscript "n" is 1.
##STR00005##
[0100] According to one embodiment, variable Y in Formula I is
--O--, --S--, --C(O)--, sulfoxide, sulfone, --CHR.sup.9-- or
--CH.sub.2--, subscript "n" is 1 and the inventive compounds
conform to Formula IIb. When "Y" is --CHR.sup.9-- in Formula IIb,
substituent R.sup.9 is hydrogen, lower alkyl or hydroxy.
##STR00006##
[0101] In another embodiment of the invention, variable "Y" in
Formula I is --N(R.sup.5)--, subscript "n" is 2 or 3 and the
inventive compounds conform to Formula IIa or Formula IVa,
respectively:
##STR00007##
[0102] Alternatively, in certain embodiments variable "Y" in
Formula I is --O--, --S--, --C(O)--, sulfoxide, sulfone,
--CHR.sup.9-- or --CH.sub.2--, "n" is 2 or 3 and the inventive
compounds conform to Formula IIIb and Formula IVb, respectively:
When "Y" is --CHR.sup.9-- in Formula IIIb or Formula IVb,
substituent R.sup.9 is either hydrogen, lower alkyl or hydroxy.
##STR00008##
[0103] For compounds according to Formulae IIa, IIb, IIIa, IIIb,
IVa and IVb, variables W.sup.1 and W.sup.2 are both oxo. In certain
embodiments for compounds according to Formulae IIa, IIb, IIa,
IIIb, IVa and IVb, W.sup.1 is oxo and W.sup.2 is thione group.
According to one embodiment, Formulae IIa, IIb, IIIa, IIIb, IVa and
IVb compounds comprise an oxo at W.sup.1 and a .dbd.N--OR' group at
W.sup.2. Also encompassed within the scope of the present invention
are Formulae IIa, IIb, IIIa, IIIb, IVa and IVb compounds having a
thione group at W.sup.1 and an oxo group at W.sup.2.
[0104] For Formulae IIa, IIb, IIIa, IIIb, IVa and IVb compounds,
each of substituents R.sup.2 and R.sup.3 can be the same in which
case the carbon atom which R.sup.2 and R.sup.3 are attached is not
a chiral carbon. In certain embodiments, however, substituents
R.sup.2 and R.sup.3 are different. Thus, the carbon atom which
R.sup.2 and R.sup.3 are attached is chiral and the resulting
compound will have stereoisomers.
[0105] In an embodiment of the invention, each R.sup.2 and R.sup.3
in Formulae IIa, IIb, IIIa, IIIb, IVa and IVb is hydrogen.
Alternatively, one of R.sup.2 or R.sup.3 groups in Formulae IIa,
IIb, IIIa, IIIb, IVa and IVb is hydrogen and the other group is
alkyl optionally substituted with 1, 2 or 3 J groups. For certain
compounds according to Formulae IIa, IIb, IIIa, IIIb, IVa and IVb,
R.sup.2 and R.sup.3 are both alkyl groups that are optionally
substituted with 1, 2 or 3 J groups.
[0106] For some compounds in accordance with Formula IIa or Formula
IIb, R.sup.2 is alkyl and R.sup.3 is alkyl substituted with 1, 2 or
3 J groups. Exemplary of this category of Formula IIa and Formula
IIb compounds are the following--compounds with substituent R.sup.2
as alkyl and R.sup.3 is haloalkyl; compounds with substituent
compounds with substituent R.sup.2 as alkyl and R.sup.3 is
cycloalkyl optionally substituted with 1, 2 or 3 J groups;
compounds with substituent R.sup.2 as alkyl and R.sup.3 is
cyclopentyl optionally substituted with 1, 2 or 3 J groups;
compounds with substituent R.sup.2 as alkyl and R.sup.3 is aryl
optionally substituted with 1, 2 or 3 J groups; compounds with
substituent R.sup.2 as alkyl and R.sup.3 is phenyl optionally
substituted with 1, 2 or 3 J groups; compounds with substituent
R.sup.2 as alkyl and R.sup.3 is cycloalkylalkylene optionally
substituted with 1, 2 or 3 J groups; compounds with substituent
R.sup.2 as alkyl and R.sup.3 is aralkylene optionally substituted
with 1, 2 or 3 J groups; compounds with substituent R.sup.2 as
alkyl and R.sup.3 is benzyl optionally substituted with 1, 2 or 3 J
groups; compounds with substituent R.sup.2 as alkyl and R.sup.3 is
heterocyclyl optionally substituted with 1, 2 or 3 J groups;
compounds with substituent R.sup.2 as alkyl and R.sup.3 is
heteroaryl optionally substituted with 1, 2 or 3 J groups;
compounds with substituent R.sup.2 as alkyl and R.sup.3 is
thiophenyl, thiazolyl or pyridinyl; compounds with substituent
R.sup.2 as alkyl and R.sup.3 is heterocyclylalkylene substituted or
substituted with 1, 2 or 3 J groups; or compounds with substituent
R.sup.2 as alkyl and R.sup.3 is heteroarylalkylene optionally
substituted with 1, 2 or 3 J groups.
[0107] In one embodiment, for compounds according to Formulae IIa,
IIb, IIIa, IIIb, IVa and IVb each R.sup.2 and R.sup.3 are
independently hydrogen, alkyl, cycloalkyl, cycloalkylalkylene,
heterocyclyl or heterocyclylalkylene, and any such alkyl,
cycloalkyl, cycloalkylalkylene, heterocyclyl or
heterocyclylalkylene can optionally be substituted with 1, 2 or 3 J
groups, independently selected from the group consisting of
halogen, amino, alkylaminyl and alkyl.
[0108] For certain Formulae IIIa, IIIb, IVa and IVb compounds,
R.sup.2 and R.sup.3 together with the carbon atom to which they are
attached form a cycloalkyl or heterocyclyl ring.
[0109] Also contemplated are Formula I compounds where Y is
--N(R.sup.5)--, subscript "n" is 1 and R.sup.2 and R.sup.3 together
with the carbon atom to which they are attached form a cycloalkyl
or heterocyclyl ring "A". Such compounds conform to Formula Va and
the cycloalkyl or heterocyclyl ring "A" may optionally be
substituted with 1, 2 or 3 J groups.
##STR00009##
[0110] Alternatively, in some embodiments Y in Formula I is --O--,
--S--, --C(O)--, sulfoxide, sulfone, --CHR.sup.9-- or --CH.sub.2--,
"n" is 1 and R.sup.2 and R.sup.3 together with the carbon atom to
which they are attached form a cycloalkyl or heterocyclyl ring A.
Such compounds conform to Formula Vb and the cycloalkyl or
heterocyclyl ring "A" may optionally be substituted with 1, 2 or 3
J groups. When "Y" is --CHR.sup.9-- in Formula Vb, substituent
R.sup.9 is either hydrogen, lower alkyl or hydroxy.
##STR00010##
[0111] For Formula Va and Formula Vb compounds W.sup.1 and W.sup.2
are both oxo and ring A is a cycloalkyl optionally substituted with
1, 2 or 3 J groups. Also contemplated are Formula Va and Formula Vb
compounds for which ring A is a fused cycloalkyl optionally
substituted with 1, 2 or 3 J groups; ring A is a cycloalkyl
optionally substituted with 1, 2 or 3 J groups; ring A is a
cyclobutyl, cyclopentyl or cyclohexyl optionally substituted with
1, 2 or 3 J groups, for example, J groups selected from the group
consisting of halogen, amino, alkylaminyl and alkyl.
[0112] For some embodiments, ring A of a Formula Va or a Formula Vb
is a heterocyclyl optionally substituted with 1, 2 or 3 J groups.
Exemplary of such heterocyclyl groups are pyrrolidinyl,
piperidinyl, tetrahydropyranyl, thietanyl or azetidinyl. In one
embodiment, each of the above exemplified heterocyclyl may
optionally be substituted with 1, 2 or 3 J groups. For certain
Formula Va or a Formula Vb compounds ring A is a cycloalkyl
substituted with at least 2J groups attached to the same carbon
atom of the cycloalkyl, and the two J groups attached to the same
carbon taken together form oxo group. In another embodiment, ring A
of a Formula Va or a Formula Vb is a heterocyclyl substituted with
at least 2J groups that are attached to the same hetero atom and
wherein such 2 J groups taken together to form oxo. For some
Formula Va or a Formula Vb compounds the cycloalkyl or heterocyclyl
ring A is substituted with J groups selected from the group
consisting of halogen, cyano, hydroxy, trifluoromethyl, N-methyl
amino, methyl, difluoroethylene, and methylenenitrile.
[0113] The present invention also provides compounds in accordance
with Formula VI or its stereoisomers, tautomers or pharmaceutically
acceptable salts. Formula VI is a sub-genus of Formula I in which Y
is --N(R.sup.5)-- and substituent groups R.sup.5 and R.sup.8
together with the atoms to which they are attached form a
heterocycle ring B which may optionally be substituted with 1, 2 or
3 J groups.
##STR00011##
[0114] Also encompassed within the scope of the present invention
are Formula I compounds in which variable "Y" is --N(R.sup.5)--,
and substituent groups R.sup.7 and R.sup.8 together with the atoms
to which they are attached form a fused ring C. Such compounds or
the stereoisomer, tautomer or pharmaceutically acceptable salt
conform to Formula VIIa. For Formula VIIa compounds ring C may
optionally be substituted with 1, 2 or 3 J groups.
##STR00012##
[0115] According to one embodiment, variable "Y" in Formula I is
--O--, --S--, --C(O)--, sulfoxide, sulfone, --CHR.sup.9-- or
--CH.sub.2--, and substituent groups R.sup.7 and R.sup.8 together
with the atoms to which they are attached form a fused ring C. Such
compounds and their stereoisomers, tautomers or pharmaceutically
acceptable salts conform to Formula VIIb. For Formula VIIb
compounds where "Y" is --CHR.sup.9--, substituent R.sup.9 can be
hydrogen, lower alkyl or hydroxy.
##STR00013##
[0116] For Formula VIIb compounds fused ring C may optionally be
substituted with 1, 2 or 3 J groups. In one embodiment of the
invention, W.sup.1 and W.sup.2 are both oxo for Formula VI, Formula
VIIa and Formula VIIb compounds.
[0117] The present invention is further directed to Formulae I, Ia,
IIa, IIb, IIIa, IIIb, IVa, IVb, Va, Vb, VI, VIIa and VIIb compounds
where R.sup.1 is hydrogen or a lower alkyl group selected from
methyl, ethyl, propyl, butyl, iso-propyl, sec-butyl, or tert-butyl,
for example, compounds with R.sup.1 as methyl.
[0118] For certain Formulae I, Ia, IIa, IIb, IIIa, IIIb, IVa, IVb,
Va, Vb, VI, VIIa and VIIb compounds, R.sup.4a is selected from the
group consisting of hydrogen, halogen, alkyl, alkoxy, thioalkyl,
alkenyl, and cycloalkyl while substituent R.sup.4b is hydrogen or
halogen. R.sup.5 in Formulae I, Ia, IIa, IIb, IIIa, IIIb, IVa, IVb,
Va, Vb, VI, VIIa and VIIb is hydrogen or lower alkyl, while
substituents R.sup.6, R.sup.7 and R.sup.8 are hydrogen.
[0119] In an embodiment of the invention, R.sup.6 and R.sup.7 in
Formula VI are both hydrogen, while for certain Formula VIIa and
Formula VIIb compounds R.sup.6 is hydrogen.
[0120] The present invention is further directed to Formulae I, Ia,
IIa, IIb, IIIa, IIIb, IVa, IVb, Va, and Vb compounds where
substituent groups R.sup.6 and R.sup.8 are both hydrogen, and
R.sub.7 is selected from the group consisting of hydroxy, halogen,
cyano, alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl
cycloalkylalkylene, cycloalkylalkenylene, amino, alkylaminyl,
alkylcarbonylaminyl, cycloalkylcarbonylaminyl, cycloalkylaminyl,
heterocyclylaminyl, heteroaryl, and heterocyclyl. For these
inventive compounds any alkyl, alkenyl, alkynyl, alkoxy,
cycloalkyl, cycloalkylalkylene, cycloalkylalkenylene, amino,
alkylaminyl, alkylcarbonylaminyl, cycloalkylcarbonylaminyl,
cycloalkylaminyl, heterocyclylaminyl, heteroaryl, or heterocyclyl
is optionally substituted with 1, 2 or 3 J groups. In one
embodiment R.sub.7 is selected from the group consisting of alkyl,
cycloalkyl, cycloalkylalkylene, cycloalkylalkenylene, amino,
alkylaminyl, alklycarbonylaminyl, cycloalkylcarbonylaminyl,
heterocyclylaminyl, heteroaryl, heterocyclyl and cycloalkylaminyl.
For such compounds any alkyl, alkenyl, cycloalkyl,
cycloalkylalkylene, cycloalkylalkenylene, amino, alkylaminyl,
alklycarbonylaminyl, cycloalkylcarbonylaminyl, heterocyclylaminyl,
heteroaryl, heterocyclyl or cycloalkylaminyl may optionally be
substituted with 1, 2 or 3 J groups. Thus, the invention provides
Formulae I, Ia, IIa, IIb, IIIa, IIIb, IVa, IVb, Va, and Vb
compounds where substituent groups R.sup.6 and R.sup.8 are both
hydrogen, and R.sub.7 is amino; substituent groups R.sup.6 and
R.sup.8 are both hydrogen, and R.sub.7 is alkylaminyl; substituent
groups R.sup.6 and R.sup.8 are both hydrogen, and R.sub.7 is
--NHCH.sub.3; substituent groups R.sup.6 and R.sup.8 are both
hydrogen, and R.sub.7 is cycloalkyl, for example cyclopropyl;
substituent groups R.sup.6 and R.sup.8 are both hydrogen, and
R.sub.7 is cycloalkylaminyl substituted with 1 to 3 J groups, for
instance halogens.
[0121] In one embodiment, for compounds in accordance with Formulae
I, Ia, IIa, IIb, IIIa, IIIb, IVa, IVb, Va, and Vb, substituent
groups R.sup.6 and R.sup.8 are both hydrogen, and R.sub.7 is
selected from the group consisting of --NHCH(CF.sub.3)cyclopropyl,
cycloalkylcarbonylaminyl, --NHC(O)cyclopropyl,
cycloalkylalkenylene, and CH.dbd.CHcyclopropyl.
[0122] For any compound in accordance with Formulae I, Ia, IIa,
IIb, IIIa, IIIb, IVa, IVb, Va, Vb, VI, VIIa, and VIIb, J is --SH,
--SR.sup.9, --S(O)R.sup.9, --S(O).sub.2 R.sup.9, --S(O)NH.sub.2,
--S(O)NR.sup.9R.sup.9, --NH.sub.2, --NR.sup.9R.sup.9, --COOH,
--C(O)OR.sup.9, --C(O)R.sup.9, --C(O)--NH.sub.2,
--C(O)--NR.sup.9R.sup.9, hydroxy, cyano, halogen, acetyl, alkyl,
lower alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, thioalkyl,
cyanoalkylene, alkylaminyl, NH.sub.2--C(O)-alkylene,
NR.sup.9R.sup.9--C(O)-alkylene, --CHR.sup.9--C(O)-lower alkyl,
--C(O)-lower alkyl, alkylcarbonylaminyl, cycloalkyl,
cycloalkylalkylene, cycloalkylalkenylene, cycloalkylcarbonylaminyl,
cycloalkylaminyl, --CHR.sup.9--C(O)-cycloalkyl, --C(O)-cycloalkyl,
--CHR.sup.9--C(O)-aryl, --CHR.sup.9-aryl, --C(O)-aryl,
--CHR.sup.9--C(O)-heterocycloalkyl, --C(O)-heterocycloalkyl,
heterocyclylaminyl, or heterocyclyl and R.sup.9 is hydrogen, lower
alkyl or --OH. Additionally, when two J groups bound to the same
carbon or hetero atom they may be taken together to form oxo.
[0123] For certain compounds according to Formulae I, Ia, IIa, IIb,
IIIa, IIIb, IVa, IVb, Va, Vb, VI, VIIa, and VIIb, J is halogen,
hydroxy, alkyl, alkenyl, alkynyl or cyanoalkylene. Illustrative
alkyl or alkylene chains are those having C.sub.1-C.sub.10 carbon
atoms, C.sub.1-C.sub.8 carbon atoms, C.sub.1-C.sub.6 carbon atoms,
C.sub.1-C.sub.4 carbon atoms, C.sub.1-C.sub.3 carbon atoms as well
as ethyl and methyl groups. Alternatively, when J is alkenyl, or
alkynyl, the carbon chain has at least one double or triple bond
respectively and C.sub.2-C.sub.10 carbon atoms, C.sub.2-C.sub.8
carbon atoms, C.sub.2-C.sub.6 carbon atoms, C.sub.2-C.sub.4 carbon
atoms, or C.sub.2-C.sub.3 carbon atoms.
[0124] The inventive compounds according to Formula I, as well as
Formulae Ia, IIa, IIb, IIa, IIIb, IVa, IVb, Va, Vb VI, VIIa and
VIIb may be isotopically-labelled by having one or more atoms
replaced by an atom having a different atomic mass or mass number.
Examples of isotopes that can be incorporated into compounds of
according to Formula I include isotopes of hydrogen, carbon,
nitrogen, oxygen, phosphorous, fluorine, chlorine, or iodine.
Illustrative of such isotopes are .sup.2H, .sup.3H, .sup.11C,
.sup.13C, .sup.14C, .sup.13N, .sup.15N, .sup.15O, .sup.17O,
.sup.18O, .sup.31P, .sup.32P, .sup.35S, .sup.18F, .sup.36Cl,
.sup.123I, and .sup.125I, respectively. These radiolabelled
compounds can be used to measure the biodistribution, tissue
concentration and the kinetics of transport and excretion from
biological tissues including a subject to which such a labelled
compound is administered. Labeled compounds are also used to
determine therapeutic effectiveness, the site or mode of action,
and the binding affinity of a candidate therapeutic to a
pharmacologically important target. Certain radioactive-labelled
compounds according to Formula I, therefore, are useful in drug
and/or tissue distribution studies. The radioactive isotopes
tritium, i.e. .sup.3H, and carbon-14, i.e. .sup.14C, are
particularly useful for this purpose in view of their ease of
incorporation and ready means of detection.
[0125] Substitution with heavier isotopes such as deuterium, i.e.
.sup.2H, affords certain therapeutic advantages resulting from the
greater metabolic stability, for example, increased in vivo
half-life of compounds containing deuterium. Substitution of
hydrogen with deuterium may reduce dose required for therapeutic
effect, and hence may be preferred in a discovery or clinical
setting.
[0126] Substitution with positron emitting isotopes, such as
.sup.11C, .sup.18F, .sup.15O and .sup.13N, provides labeled analogs
of the inventive compounds that are useful in Positron Emission
Tomography (PET) studies, e.g., for examining substrate receptor
occupancy. Isotopically-labeled compounds according to Formula I,
as well as Formulae Ia, IIa, IIb, IIIa, IIIb, IVa, IVb, Va, Vb VI,
VIIa and VIIb can generally be prepared by conventional techniques
known to those skilled in the art or by processes analogous to
those described in the Preparations and Examples section as set out
below using an appropriate isotopic-labeling reagent.
[0127] Embodiments of the invention disclosed herein are also meant
to encompass the in vivo metabolic products of compounds according
to Formulae I, Ia, IIa, IIb, IIIa, IIIb, IVa, IVb, Va, Vb VI, VIIa
and VIIb. Such products may result from, for example, the
oxidation, reduction, hydrolysis, amidation, esterification, and
like processes primarily due to enzymatic activity upon
administration of a compound of the invention. Accordingly, the
invention includes compounds that are produced as by-products of
enzymatic or non-enzymatic activity on an inventive compound
following the administration of such a compound to a mammal for a
period of time sufficient to yield a metabolic product. Metabolic
products, particularly pharmaceutically active metabolites are
typically identified by administering a radiolabelled compound of
the invention in a detectable dose to a subject, such as rat,
mouse, guinea pig, monkey, or human, for a sufficient period of
time during which metabolism occurs, and isolating the metabolic
products from urine, blood or other biological samples that are
obtained from the subject receiving the radiolabelled compound.
[0128] The invention also provides pharmaceutically acceptable salt
forms of Formulae I, Ia, IIa, IIb, IIIa, IIIb, IVa, IVb, Va, Vb VI,
VIIa and VIIb compounds. Encompassed within the scope of the
invention are both acid and base addition salts that are formed by
contacting a pharmaceutically suitable acid or a pharmaceutically
suitable base with a compound of the invention.
[0129] To this end, a "pharmaceutically acceptable acid addition
salt" refers to those salts which retain the biological
effectiveness and properties of the free bases, which are not
biologically or otherwise undesirable, and which are formed with
inorganic acids such as, but are not limited to, hydrochloric acid,
hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and
the like, and organic acids such as, but not limited to, acetic
acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic
acid, aspartic acid, benzenesulfonic acid, benzoic acid,
4-acetamidobenzoic acid, camphoric acid, camphor-10-sulfonic acid,
capric acid, caproic acid, caprylic acid, carbonic acid, cinnamic
acid, citric acid, cyclamic acid, dodecyl sulfuric acid,
ethane-1,2-disulfonic acid, ethanesulfonic acid,
2-hydroxyethanesulfonic acid, formic acid, fumaric acid, galactaric
acid, gentisic acid, glucoheptonic acid, gluconic acid, glucuronic
acid, glutamic acid, glutaric acid, 2-oxo-glutaric acid,
glycerophosphoric acid, glycolic acid, hippuric acid, isobutyric
acid, lactic acid, lactobionic acid, lauric acid, maleic acid,
malic acid, malonic acid, mandelic acid, methanesulfonic acid,
mucic acid, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic
acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, oleic acid,
orotic acid, oxalic acid, palmitic acid, pamoic acid, propionic
acid, pyroglutamic acid, pyruvic acid, salicylic acid,
4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid,
tartaric acid, thiocyanic acid, p-toluenesulfonic acid,
trifluoroacetic acid, undecylenic acid, and the like.
[0130] Similarly, a "pharmaceutically acceptable base addition
salt" refers to those salts which retain the biological
effectiveness and properties of the free acids, which are not
biologically or otherwise undesirable. These salts are prepared by
addition of an inorganic base or an organic base to the free acid.
Salts derived from inorganic bases include, but are not limited to,
the sodium, potassium, lithium, ammonium, calcium, magnesium, iron,
zinc, copper, manganese, aluminum salts and the like. Preferred
inorganic salts are the ammonium, sodium, potassium, calcium, and
magnesium salts. Salts derived from organic bases include, but are
not limited to, salts of primary, secondary, and tertiary amines,
substituted amines including naturally occurring substituted
amines, cyclic amines and basic ion exchange resins, such as
ammonia, isopropylamine, trimethylamine, diethylamine,
triethylamine, tripropylamine, diethanolamine, ethanolamine,
deanol, 2-dimethylaminoethanol, 2-diethylaminoethanol,
dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine,
hydrabamine, choline, betaine, benethamine, benzathine,
ethylenediamine, glucosamine, methylglucamine, theobromine,
triethanolamine, tromethamine, purines, piperazine, piperidine,
N-ethylpiperidine, polyamine resins and the like. Particularly
preferred organic bases are isopropylamine, diethylamine,
ethanolamine, trimethylamine, dicyclohexylamine, choline and
caffeine.
[0131] Often crystallizations produce a solvate of the compound of
the invention. As used herein, the term "solvate" refers to an
aggregate that comprises one or more molecules of a compound of the
invention with one or more molecules of solvent. The solvent may be
water, in which case the solvate may be a hydrate. Alternatively,
the solvent may be an organic solvent. Thus, the compounds of the
present invention may exist as a hydrate, including a monohydrate,
dihydrate, hemihydrate, sesquihydrate, trihydrate, tetrahydrate and
the like, as well as the corresponding solvated forms. The
compounds of the invention may be true solvates, while in other
cases, the compounds of the invention may merely retain
adventitious water or be a mixture of water plus some adventitious
solvent.
[0132] A "stereoisomer" refers to a compound made up of the same
atoms bonded by the same bonds but having different
three-dimensional structures, which are not interchangeable. The
present invention contemplates various stereoisomers and mixtures
thereof and includes "enantiomers", which refers to two
stereoisomers whose molecules are nonsuperimposeable mirror images
of one another.
[0133] Compounds of the invention, or their pharmaceutically
acceptable salts may contain one or more asymmetric centers and may
thus give rise to enantiomers, diastereomers, and other
stereoisomeric forms that may be defined, in terms of absolute
stereochemistry, as (R)- or (S)- or, as (D)- or (L)- for amino
acids. The present invention is meant to include all such possible
isomers, as well as their racemic and optically pure forms.
Optically active (+) and (-), (R)- and (S)-, or (D)- and
(L)-isomers may be prepared using chiral synthons or chiral
reagents, or resolved using conventional techniques, for example,
chromatography and fractional crystallization. Conventional
techniques for the preparation/isolation of individual enantiomers
include chiral synthesis from a suitable optically pure precursor
or resolution of the racemate (or the racemate of a salt or
derivative) using, for example, chiral high pressure liquid
chromatography (HPLC). When the compounds described herein contain
olefinic double bonds or other centers of geometric asymmetry, and
unless specified otherwise, it is intended that the compounds
include both E and Z geometric isomers. Likewise, all tautomeric
forms are also intended to be included.
[0134] The term "tautomer" refers to a proton shift from one atom
of a molecule to another atom of the same molecule. For example,
when W' is oxo and R.sup.1 is H, the present invention provides
tautomers of a Formula I compound as illustrated below:
##STR00014##
[0135] Similar tautomers exists for Formulae I, Ia, IIa, IIb, IIIa,
IIIb, IVa, IVb, Va, Vb VI, VIIa and VIIb compounds. The inventive
compounds are synthesized using conventional synthetic methods, and
more specifically using the general methods noted below. Specific
synthetic protocols for several compounds in accordance with the
present invention are described in the Examples.
General Synthetic Methods
Method 1:
##STR00015##
[0137] Formation of IXa, when n=1 and X=halogen or other leaving
group, such as --OTf, --OTs or --OMs, was accomplished by exposing
intermediate VIIIa to an aldehyde or ketone Xa, or an aldehyde or
ketone equivalent Xb-d under acidic conditions where
R.sup.2-R.sup.3 are as previously defined and R.sup.m=H, CH.sub.3,
CH.sub.2CH.sub.3, or alkyl. More specifically, exposing VIIIa where
X is Cl or Br to an aldehyde or ketone Xa in 1,4-dioxane and
concentrated sulfuric acid with heating yields intermediated IXa
(n=1).
##STR00016##
[0138] Pyrimidine-type compounds according to Formula XIIa or XIIb
where Y is N(R.sup.5), O, or S and P is a protecting group can be
purchased or prepared from XIa by various methods, for example, by
displacing the leaving group X of compound XIa with an appropriate
N, O, or S nucleophile. The resulting compound XIIb can be
deprotected to give XIIa.
##STR00017##
[0139] Inventive compounds according to Formula I when Y is
N(R.sup.5), O, or S were synthesized by contacting intermediate IXa
with a pyrimidine compound XIIa where R.sup.6-R.sup.8 are as
previously defined, under appropriate reaction conditions as
further described below.
##STR00018##
[0140] More specifically, Formula I compounds when Y is N(R.sup.5),
O, or S were synthesized using Buchwald-Hartwig coupling,
Ullmann-type coupling, or nucleophilic aromatic substitution. Thus,
contacting intermediate IXa where X=Cl or Br and n=1 with a
compound of Formula XIIa where Y is N(R.sup.5), O, or S under
conditions suitable for coupling, or nucleophilic aromatic
substitution gave Formula I compounds.
[0141] Alternatively, the leaving group X of intermediate IXa may
be displaced with an appropriate N, O, or S nucleophile under
conditions similar to those described above for synthesis of XIIa
so as to afford intermediate XIIIa or protected intermediate XIIIb
where Y is N(R.sup.5), O, or S. XIIIb may be deprotected to yield
XIIIa.
##STR00019##
[0142] Formula I compounds when Y is N(R.sup.5), O, or S are
readily synthesized by contacting intermediate XIIIa where Y is
N(R.sup.5), O, or S with a pyrimidine compound XIa where X=halogen
or other leaving group such as --OTf, --OTs or --OMs under the
conditions of Buchwald-Hartwig coupling, Ullmann-type coupling, or
nucleophilic aromatic substitution.
##STR00020##
[0143] More specific synthetic methods for several Formula I
compounds are set forth below. It is understood that if protecting
groups are used during the synthesis of intermediates, or if a
Formula I compound contains one or more protecting groups, then
such protecting groups are removed by methods known in the chemical
art. Other transformations, such as the displacement of a halogen,
for example, the conversion of R.sup.4a, or R.sup.4b=Cl to
R.sup.4a, or R.sup.4b=OMe, SMe, CH.dbd.CH.sub.2 or Me, the
conversion of W.sup.1, or W.sup.2 or both groups from O to S; the
formation of an oxime by converting W.sup.1, or W.sup.2 or both
groups from an oxo (.dbd.O) group to a .dbd.NHOR' group, the
conversion of Y from S to S.dbd.O or S(.dbd.O).sub.2, and the
conversion of an intermediate or a Formula I compound to a
pharmaceutically acceptable salt are carried out using conventional
methods known in the chemical art.
Method 2:
##STR00021##
[0145] Formation of IXa or IXb, when n=2 or 3, variable "X" is a
halogen or another leaving group such as --OTf, --OTs or --OMs, and
variable "V" is O or N can be accomplished by contacting
intermediate VIIIb to a 1,2-difunctionalized ethyl intermediate
XIVa, or a 1,3-difunctionalized propyl intermediate XIVb under
conditions suitable for the synthesis of compounds IXa and IXb
respectively. Variables Z.sup.1 and Z.sup.2 in XIVa and XIVb can be
a halogen or other leaving groups such as --OTf, --OTs or --OMs, or
OH, NHR.sup.1 or NHP, where P is an appropriate protecting
group.
##STR00022##
[0146] According to this synthetic strategy, intermediate VIIIb
where variable "X" is Cl or Br and variable "V" is O is contacted
with XIVa where R.sup.2 and R.sup.3 are H, Z.sup.1 is OH and
Z.sup.2 is NH-(4-methoxybenzyl) in acetonitrile in the presence of
an amide bond forming reagent such as HATU. The reaction mixture is
heated to promote coupling and yields intermediated IXb where n=2
and P is 4-methoxybenzyl.
[0147] The inventive Formula I compounds when Y is N(R.sup.5), O,
or S are synthesized by contacting intermediates IXa or IXb (n=2 or
3 and X=halogen or other leaving group such as --OTf, --OTs or
--OMs), with pyrimidine XIIa where Y is N(R.sup.5), O, or S and
R.sup.6-R.sup.8 are as previously defined, under appropriate
conditions followed by deprotection of the resultant Formula I
compound if required.
##STR00023##
[0148] Thus, contacting intermediate DO where n=2, X is Cl or Br
and P is 4-methoxybenzyl with pyrimidine XIIa, where Y is
N(R.sup.5), O, or S, under the conditions suitable for
Buchwald-Hartwig coupling, Ullmann-type coupling, or nucleophilic
aromatic substitution results in a 4-methoxybenzyl protected
Formula I compound. The therapeutically active Formula I compound
can readily be obtained by deprotection of the 4-methoxybenzyl
group with trifluoroacetic acid.
[0149] Alternatively, certain Formula I compounds were synthesized
by displacing the leaving group "X" of intermediate IXa with
suitable N, O, or S nucleophiles under similar conditions similar
to those described in Method 1 to give XIIIa or protected
intermediate XIIIb which can be deprotected to yield XIIIa. The
leaving group "X" of intermediate IXa can be halogen, --OTf, --OTs
or --OMs and subscript n is either 2 or 3.
##STR00024##
[0150] As described above, the inventive Formula I compounds are
readily synthesized by contacting intermediate XIIIa when
Y=N(R.sup.5), O, S and n=2 or 3 with pyrimidine XIa where
X=halogen, --OTf, --OTs or --OMs under conditions suitable for
Buchwald-Hartwig coupling, Ullmann-type coupling, or nucleophilic
aromatic substitution.
##STR00025##
[0151] The synthesis of some Formula I compounds was carried out by
contacting the protected intermediate IXb (n=2 or 3), with an
appropriate N, O, or S nucleophile to give XIIIc under similar
conditions described above with IXa.
##STR00026##
[0152] Intermediate XIIIc, thus obtained, was then contacted with
pyrimidine XIa where X is either halogen or a leaving group
selected from the group consisting of --OTf, --OTs and --OMs under
conditions suitable for Buchwald-Hartwig coupling, Ullmann-type
coupling, or nucleophilic aromatic substitution. Deprotection by
methods known in the chemical art gave the candidate MnK inhibitor
Formula I compounds.
##STR00027##
Method 3:
##STR00028##
[0154] Synthesis of Formula VI compounds, where n=1, 2, or 3 was
accomplished by contacting intermediates IXa or IXb where variable
"X" is a leaving group selected from the group consisting of
halogen, --OTf, --OTs and --OMs, and P is a protecting group with a
bicyclic intermediate XV in the presence of a homogeneous
palladium-phosphine catalyst and a base such as cesium carbonate or
sodium t-butoxide using 1,4-dioxane as a solvent. The reaction
mixture was heated to promote coupling, followed by deprotection if
needed. Illustrative of intermediate XV compounds without
limitation are substituted or unsubstituted
6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine,
7H-pyrrolo[2,3-d]pyrimidine, 9H-purine,
1H-pyrazolo[3,4-d]pyrimidine, and
5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine).
##STR00029##
[0155] Alternatively, Formula VI compounds where B is an
unsaturated 5-membered ring and n=1, 2 or 3 may be synthesized by
contacting intermediates IXa or IXb with a
5-ethynyl-4-amino-pyrimidine intermediate XIIc (where R.sup.a is a
J group as defined herein) in the presence of a homogeneous
palladium-phosphine catalyst and a base such as cesium carbonate or
sodium t-butoxide using 1,4-dioxane as solvent for the coupling
reaction. The reaction mixture may be heated to promote coupling,
followed by deprotection if required. The
5-Ethynyl-4-amino-pyrimidine intermediates XIIc synthesized by a
cross-coupling reaction between XIIa where Y=N(R.sup.5) and R.sup.8
is a leaving group such as halogen or --OTf and a suitable alkyne
using copper and/or homogeneous palladium catalysts.
##STR00030##
Method 4:
##STR00031##
[0157] Compounds according to Formula VIIa or Formula VIIb, where
Y=N(R.sup.5), O, or S and n is 1, 2 or 3 can be synthesized by
contacting intermediates IXa or IXb where X is a leaving group such
as halogen, --OTf, --OTs or --OMs, and P is a protecting group with
the bicyclic intermediate XVIa under the conditions of
Buchwald-Hartwig coupling, Ullmann-type coupling, or nucleophilic
aromatic substitution. Ring C of bicyclic intermediate is as
defined above and variable Y can be --N(R.sup.5), O, or S.
Representative examples of XVIa intermediates include without
limitation substituted or unsubstituted 6-amino-purine,
4-amino-1H-pyrazolo[3,4-d]pyrimidine,
4-amino-7H-pyrrolo[2,3-d]pyrimidine,
4-amino-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine,
7-amino-3H-[1,2,3]triazolo[4,5-d]pyrimidine, 4-aminoquinazoline,
4-amino-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine, various
4-amino-pyrido[d]pyrimidines, pyrimido[5,4-d]pyrimidin-4-amine, and
7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine).
[0158] Bicyclic pyrimidine-type intermediate compounds according to
Formula XVIa where Y=N(R.sup.5), O, or S can be purchased or
prepared from XVI by displacing the leaving group X with an
appropriate N, O, or S nucleophile using methods known in the
chemical art. The protecting group "P" in an intermediate according
to XVIb can be removed to give intermediate XVIa.
##STR00032##
[0159] Alternatively intermediates XIIIa or XIIIb may be contacted
with the fused pyrimidine XVI where X=halogen or other leaving
group such as --OTf, --OTs or --OMs under conditions suitable for
Buchwald-Hartwig or Ullmann-type couplings, or conditions suitable
for nucleophilic aromatic substitution followed by deprotection if
necessary to give Formula VIIa or Formula VIIb compounds.
##STR00033##
Method 5:
##STR00034##
[0161] Methods for synthesizing a Formula I, when Y is --C(O) and
n=1, 2 or 3 comprise contacting intermediate IXa or intermediate DO
(where X is a leaving group, such as halogen, --OTf, --OTs or
--OMs, and P is a protecting group) with the intermediate XIId in
the presence of a base such as n-butyllithium. The resultant
product may be deprotected if required to provide Formula I
compounds.
[0162] Formation of Formula I, where Y=CH and n=1, 2 or 3 may be
carried out by reducing the carbonyl (--C(O)) at "Y" under
Wolff-Kishner reduction conditions.
Method 6:
##STR00035##
[0164] Synthesis of Formula VIIb compounds, when Y=C(O), n=1, 2 or
3 and C is as defined previously is carried out by contacting
intermediate IXa or intermediate IXb (where X is a leaving group,
such as halogen, --OTf, --OTs or --OMs, and P is a protecting
group) with the intermediate XVIc in the presence of a base such as
n-butyllithium. The resultant product may be deprotected if
required to provide Formula VIIb compounds.
[0165] Formation of VIIb, when Y=CH and n=1, 2 or 3 may be
accomplished by reducing the carbonyl (--C(O)) at "Y" under
Wolff-Kishner reduction conditions.
Pharmaceuticals Formulations
[0166] In one embodiment, a compounds according Formulae I through
VII, are formulated as pharmaceutically acceptable compositions
that contain a Formulae I-VII compound in an amount effective to
treat a particular disease or condition of interest upon
administration of the pharmaceutical composition to a mammal.
Pharmaceutical compositions in accordance with the present
invention can comprise a Formulae I-VII compound in combination
with a pharmaceutically acceptable carrier, diluent or
excipient.
[0167] In this regard, a "pharmaceutically acceptable carrier,
diluent or excipient" includes without limitation any adjuvant,
carrier, excipient, glidant, sweetening agent, diluent,
preservative, dye/colorant, flavor enhancer, surfactant, wetting
agent, dispersing agent, suspending agent, stabilizer, isotonic
agent, solvent, or emulsifier which has been approved by the United
States Food and Drug Administration as being acceptable for use in
humans or domestic animals.
[0168] Further, a "mammal" includes humans and both domestic
animals such as laboratory animals and household pets (e.g., cats,
dogs, swine, cattle, sheep, goats, horses, rabbits), and
non-domestic animals such as wildlife and the like.
[0169] The pharmaceutical compositions of the invention can be
prepared by combining a compound of the invention with an
appropriate pharmaceutically acceptable carrier, diluent or
excipient, and may be formulated into preparations in solid,
semi-solid, liquid or gaseous forms, such as tablets, capsules,
powders, granules, ointments, solutions, suppositories, injections,
inhalants, gels, microspheres, and aerosols. Typical routes of
administering such pharmaceutical compositions include, without
limitation, oral, topical, transdermal, inhalation, parenteral,
sublingual, buccal, rectal, vaginal, and intranasal. The term
parenteral as used herein includes subcutaneous injections,
intravenous, intramuscular, intrasternal injection or infusion
techniques. Pharmaceutical compositions of the invention are
formulated so as to allow the active ingredients contained therein
to be bioavailable upon administration of the composition to a
patient. Compositions that will be administered to a subject or
patient take the form of one or more dosage units, where for
example, a tablet may be a single dosage unit, and a container of a
compound of the invention in aerosol form may hold a plurality of
dosage units. Actual methods of preparing such dosage forms are
known, or will be apparent, to those skilled in this art; for
example, see Remington: The Science and Practice of Pharmacy, 20th
Edition (Philadelphia College of Pharmacy and Science, 2000). The
composition to be administered will, in any event, contain a
therapeutically effective amount of a compound of the invention, or
a pharmaceutically acceptable salt thereof, for treatment of a
disease or condition of interest in accordance with the teachings
of this invention.
[0170] A pharmaceutical composition of the invention may be in the
form of a solid or liquid. In one aspect, the carrier(s) are
particulate, so that the compositions are, for example, in tablet
or powder form. The carrier(s) may be liquid, with the compositions
being, for example, an oral syrup, injectable liquid or an aerosol,
which is useful in, for example, inhalatory administration. When
intended for oral administration, the pharmaceutical composition is
preferably in either solid or liquid form, where semi-solid,
semi-liquid, suspension and gel forms are included within the forms
considered herein as either solid or liquid.
[0171] As a solid composition for oral administration, the
pharmaceutical composition may be formulated into a powder,
granule, compressed tablet, pill, capsule, chewing gum, wafer or
the like form. Such a solid composition will typically contain one
or more inert diluents or edible carriers. In addition, one or more
of the following may be present: binders such as
carboxymethylcellulose, ethyl cellulose, microcrystalline
cellulose, gum tragacanth or gelatin; excipients such as starch,
lactose or dextrins, disintegrating agents such as alginic acid,
sodium alginate, Primogel, corn starch and the like; lubricants
such as magnesium stearate or Sterotex; glidants such as colloidal
silicon dioxide; sweetening agents such as sucrose or saccharin; a
flavoring agent such as peppermint, methyl salicylate or orange
flavoring; and a coloring agent.
[0172] When the pharmaceutical composition is in the form of a
capsule, for example, a gelatin capsule, it may contain, in
addition to materials of the above type, a liquid carrier such as
polyethylene glycol or oil.
[0173] The pharmaceutical composition may be in the form of a
liquid, for example, an elixir, syrup, solution, emulsion or
suspension. The liquid may be for oral administration or for
delivery by injection, as two examples. When intended for oral
administration, preferred composition contain, in addition to the
present compounds, one or more of a sweetening agent,
preservatives, dye/colorant and flavor enhancer. In a composition
intended to be administered by injection, one or more of a
surfactant, preservative, wetting agent, dispersing agent,
suspending agent, buffer, stabilizer and isotonic agent may be
included.
[0174] The liquid pharmaceutical compositions of the invention,
whether they be solutions, suspensions or other like form, may
include one or more of the following adjuvants: sterile diluents
such as water for injection, saline solution, preferably
physiological saline, Ringer's solution, isotonic sodium chloride,
fixed oils such as synthetic mono or diglycerides which may serve
as the solvent or suspending medium, polyethylene glycols,
glycerin, propylene glycol or other solvents; antibacterial agents
such as benzyl alcohol or methyl paraben; antioxidants such as
ascorbic acid or sodium bisulfate; chelating agents such as
ethylenediaminetetraacetic acid; buffers such as acetates, citrates
or phosphates and agents for the adjustment of tonicity such as
sodium chloride or dextrose. The parenteral preparation can be
enclosed in ampoules, disposable syringes or multiple dose vials
made of glass or plastic. Physiological saline is a preferred
adjuvant. An injectable pharmaceutical composition is preferably
sterile.
[0175] A liquid pharmaceutical composition of the invention
intended for either parenteral or oral administration should
contain an amount of a compound of the invention such that a
suitable dosage will be obtained.
[0176] The pharmaceutical composition of the invention may be
intended for topical administration, in which case the carrier may
suitably comprise a solution, emulsion, ointment or gel base. The
base, for example, may comprise one or more of the following:
petrolatum, lanolin, polyethylene glycols, bee wax, mineral oil,
diluents such as water and alcohol, and emulsifiers and
stabilizers. Thickening agents may be present in a pharmaceutical
composition for topical administration. If intended for transdermal
administration, the composition may include a transdermal patch or
iontophoresis device.
[0177] The pharmaceutical composition of the invention may be
intended for rectal administration, in the form, for example, of a
suppository, which will melt in the rectum and release the drug.
The composition for rectal administration may contain an oleaginous
base as a suitable nonirritating excipient. Such bases include,
without limitation, lanolin, cocoa butter and polyethylene
glycol.
[0178] The pharmaceutical composition of the invention may include
various materials, which modify the physical form of a solid or
liquid dosage unit. For example, the composition may include
materials that form a coating shell around the active ingredients.
The materials that form the coating shell are typically inert, and
may be selected from, for example, sugar, shellac, and other
enteric coating agents. Alternatively, the active ingredients may
be encased in a gelatin capsule.
[0179] The pharmaceutical composition of the invention in solid or
liquid form may include an agent that binds to the compound of the
invention and thereby assists in the delivery of the compound.
Suitable agents that may act in this capacity include a monoclonal
or polyclonal antibody, a protein or a liposome.
[0180] The pharmaceutical composition of the invention may consist
of dosage units that can be administered as an aerosol. The term
aerosol is used to denote a variety of systems ranging from those
of colloidal nature to systems consisting of pressurized packages.
Delivery may be by a liquefied or compressed gas or by a suitable
pump system that dispenses the active ingredients. Aerosols of
compounds of the invention may be delivered in single phase,
bi-phasic, or tri-phasic systems in order to deliver the active
ingredient(s). Delivery of the aerosol includes the necessary
container, activators, valves, subcontainers, and the like, which
together may form a kit. One skilled in the art, without undue
experimentation may determine preferred aerosols.
[0181] The pharmaceutical compositions of the invention may be
prepared by any methodology well known in the pharmaceutical art.
For example, a pharmaceutical composition intended to be
administered by injection can be prepared by combining a compound
of the invention with sterile, distilled water so as to form a
solution. A surfactant may be added to facilitate the formation of
a homogeneous solution or suspension. Surfactants are compounds
that non-covalently interact with the compound of the invention so
as to facilitate dissolution or homogeneous suspension of the
compound in the aqueous delivery system.
[0182] In certain embodiments a pharmaceutical composition
comprising a compound of Formula I is administered to a mammal in
an amount sufficient to inhibit Mnk activity upon administration,
and preferably with acceptable toxicity to the same. Mnk activity
of Formula I compounds can be determined by one skilled in the art,
for example, as described in the Examples below. Appropriate
concentrations and dosages can be readily determined by one skilled
in the art.
Therapeutic Use
[0183] The compounds of the invention, or their pharmaceutically
acceptable salts, are administered in a therapeutically effective
amount, which will vary depending upon a variety of factors
including the activity of the specific compound employed; the
metabolic stability and length of action of the compound; the age,
body weight, general health, sex, and diet of the patient; the mode
and time of administration; the rate of excretion; the drug
combination; the severity of the particular disorder or condition;
and the subject undergoing therapy.
[0184] "Effective amount" or "therapeutically effective amount"
refers to that amount of a compound of the invention which, when
administered to a mammal, preferably a human, is sufficient to
effect treatment, as defined below, of a Mnk related condition or
disease in the mammal, preferably a human. The amount of a compound
of the invention which constitutes a "therapeutically effective
amount" will vary depending on the compound, the condition and its
severity, the manner of administration, and the age of the mammal
to be treated, but can be determined routinely by one of ordinary
skill in the art having regard to his own knowledge and to this
disclosure.
[0185] Compounds of the invention, or pharmaceutically acceptable
salt thereof, may also be administered simultaneously with, prior
to, or after administration of one or more other therapeutic
agents. Such combination therapy includes administration of a
single pharmaceutical dosage formulation which contains a compound
of the invention and one or more additional active agents, as well
as administration of the compound of the invention and each active
agent in its own separate pharmaceutical dosage formulation. For
example, a compound of the invention and the other active agent can
be administered to the patient together in a single oral dosage
composition such as a tablet or capsule, or each agent administered
in separate oral dosage formulations. Where separate dosage
formulations are used, the compounds of the invention and one or
more additional active agents can be administered at essentially
the same time, i.e., concurrently, or at separately staggered
times, i.e., sequentially; combination therapy is understood to
include all these regimens.
[0186] In certain embodiments, the disclosed compounds are useful
for inhibiting the activity of Mnk and/or can be useful in
analyzing Mnk signaling activity in model systems and/or for
preventing, treating, or ameliorating a symptom associated with a
disease, disorder, or pathological condition involving Mnk,
preferably one afflicting humans. A compound which inhibits the
activity of Mnk will be useful in preventing, treating,
ameliorating, or reducing the symptoms or progression of diseases
of uncontrolled cell growth, proliferation and/or survival,
inappropriate cellular immune responses, or inappropriate cellular
inflammatory responses or diseases which are accompanied with
uncontrolled cell growth, proliferation and/or survival,
inappropriate cellular immune responses, or inappropriate cellular
inflammatory responses, particularly in which the uncontrolled cell
growth, proliferation and/or survival, inappropriate cellular
immune responses, or inappropriate cellular inflammatory responses
is mediated by Mnk, such as, for example, haematological tumors,
solid tumors, and/or metastases thereof, including leukaemias and
myelodysplastic syndrome, malignant lymphomas, for example, B-cell
lymphoma, T-cell lymphoma, hairy cell lymphoma, Hodgkins lymphoma,
non-Hodgins lymphoma and Burkitts lymphoma, head and neck tumors
including brain tumors and brain metastases, tumors of the thorax
including non-small cell and small cell lung tumors,
gastrointestinal tumors, endocrine tumors, mammary and other
gynecological tumors, urological tumors including renal, bladder
and prostate tumors, skin tumors, and sarcomas, and/or metastases
thereof.
[0187] Furthermore, the inventive compounds and their
pharmaceutical compositions are candidate theraputics for the
prophylaxis and/or therapy of cytokine related diseases, such as
inflammatory diseases, allergies, or other conditions associated
with proinflammatory cytokines. Exemplary inflammatory diseases
include without limitation, chronic or acute inflammation,
inflammation of the joints such as chronic inflammatory arthritis,
rheumatoid arthritis, psoriatic arthritis, osteoarthritis, juvenile
rheumatoid arthritis, Reiter's syndrome, rheumatoid traumatic
arthritis, rubella arthritis, acute synovitis and gouty arthritis;
inflammatory skin diseases such as sunburn, psoriasis,
erythrodermic psoriasis, pustular psoriasis, eczema, dermatitis,
acute or chronic graft formation, atopic dermatitis, contact
dermatitis, urticaria and scleroderma; inflammation of the
gastrointestinal tract such as inflammatory bowel disease, Crohn's
disease and related conditions, ulcerative colitis, colitis, and
diverticulitis; nephritis, urethritis, salpingitis, oophoritis,
endomyometritis, spondylitis, systemic lupus erythematosus and
related disorders, multiple sclerosis, asthma, meningitis,
myelitis, encephalomyelitis, encephalitis, phlebitis,
thrombophlebitis, respiratory diseases such as asthma, bronchitis,
chronic obstructive pulmonary disease (COPD), inflammatory lung
disease and adult respiratory distress syndrome, and allergic
rhinitis; endocarditis, osteomyelitis, rheumatic fever, rheumatic
pericarditis, rheumatic endocarditis, rheumatic myocarditis,
rheumatic mitral valve disease, rheumatic aortic valve disease,
prostatitis, prostatocystitis, spondoarthropathies ankylosing
spondylitis, synovitis, tenosynovotis, myositis, pharyngitis,
polymyalgia rheumatica, shoulder tendonitis or bursitis, gout,
pseudo gout, vasculitides, inflammatory diseases of the thyroid
selected from the group consisting of granulomatous thyroiditis,
lymphocytic thyroiditis, invasive fibrous thyroiditis, acute
thyroiditis; Hashimoto's thyroiditis, Kawasaki's disease, Raynaud's
phenomenon, Sjogren's syndrome, neuroinflammatory disease, sepsis,
conjunctivitis, keratitis, iridocyclitis, optic neuritis, otitis,
lymphoadenitis, nasopaharingitis, sinusitis, pharyngitis,
tonsillitis, laryngitis, epiglottitis, bronchitis, pneumonitis,
stomatitis, gingivitis. oesophagitis, gastritis, peritonitis,
hepatitis, cholelithiasis, cholecystitis, glomerulonephritis,
goodpasture's disease, crescentic glomerulonephritis, pancreatitis,
endomyometritis, myometritis, metritis, cervicitis, endocervicitis,
exocervicitis, parametritis, tuberculosis, vaginitis, vulvitis,
silicosis, sarcoidosis, pneumoconiosis, pyresis, inflammatory
polyarthropathies, psoriatric arthropathies, intestinal fibrosis,
bronchiectasis and enteropathic arthropathies.
[0188] Although inflammation is the unifying pathogenic process of
these diseases, current therapies only treat the symptoms of the
disease and not the underlying cause of inflammation. The
compositions of the present invention are useful for the treatment
and/or prophylaxis of inflammatory diseases and related
complications and disorders.
[0189] Accordingly, certain embodiments are directed to a method
for treating a Mnk dependent condition in a mammal in need thereof,
the method comprising administering an effective amount of a
pharmaceutical composition as described above (i.e., a
pharmaceutical composition comprising any one or more compounds of
Formula I) to a mammal.
[0190] "Treating" or "treatment" as used herein covers the
treatment of the disease or condition of interest in a mammal,
preferably a human, having the disease or condition of interest,
and includes: [0191] (i) preventing the disease or condition from
occurring in a mammal, in particular, when such mammal is
predisposed to the condition but has not yet been diagnosed as
having it; [0192] (ii) inhibiting the disease or condition, i.e.,
arresting its development; [0193] (iii) relieving the disease or
condition, i.e., causing regression of the disease or condition; or
[0194] (iv) relieving the symptoms resulting from the disease or
condition, i.e., relieving pain without addressing the underlying
disease or condition. As used herein, the terms "disease" and
"condition" may be used interchangeably or may be different in that
the particular malady or condition may not have a known causative
agent (so that etiology has not yet been worked out) and it is
therefore not yet recognized as a disease but only as an
undesirable condition or syndrome, wherein a more or less specific
set of symptoms have been identified by clinicians.
[0195] As described above deregulation of protein synthesis is a
common event in human cancers. A key regulator of translational
control is eIF4E whose activity is a key determinant of
tumorigenicity. Because activation of eIF4E involves
phosphorylation of a key serine (Ser209) specifically by MAP kinase
interacting kinases (Mnk), inhibitors of Mnk are suitable candidate
therapeutics for treating cell proliferative disorders such as
cancer. A wide variety of cancers, including solid tumors,
lymphomas and leukemias, are amenable to the compositions and
methods disclosed herein. Types of cancer that may be treated
include, but are not limited to adenocarcinoma of the breast,
prostate, and colon; all forms of bronchogenic carcinoma of the
lung; myeloid; melanoma; hepatoma; neuroblastoma; papilloma;
apudoma; choristoma; branchioma; malignant carcinoid syndrome;
carcinoid heart disease; and carcinoma (e.g., Walker, basal cell,
basosquamous, Brown-Pearce, ductal, Ehrlich tumor, Krebs 2, merkel
cell, mucinous, non-small cell lung, oat cell, papillary,
scirrhous, bronchiolar, bronchogenic, squamous cell, and
transitional cell). Additional types of cancers that may be treated
include histiocytic disorders; leukemia; histiocytosis malignant;
Hodgkin's disease; immunoproliferative small; non-Hodgkin's
lymphoma; diffuse large B cell lymphoma, T-cell lymphoma, B-cell
lymphoma, hairy cell lymphoma, Burkitts lymphoma, plasmacytoma;
reticuloendotheliosis; melanoma; chondroblastoma; chondroma;
chondrosarcoma; fibroma; fibrosarcoma; giant cell tumors;
histiocytoma; lipoma; liposarcoma; mesothelioma; myxoma;
myxosarcoma; osteoma; osteosarcoma; chordoma; craniopharyngioma;
dysgerminoma; hamartoma; mesenchymoma; mesonephroma; myosarcoma;
ameloblastoma; cementoma; odontoma; teratoma; thymoma;
trophoblastic tumor.
[0196] Other cancers that can be treated using the inventive
compounds include without limitation adenoma; cholangioma;
cholesteatoma; cyclindroma; cystadenocarcinoma; cystadenoma;
granulosa cell tumor; gynandroblastoma; hepatoma; hidradenoma;
islet cell tumor; Leydig cell tumor; papilloma; sertoli cell tumor;
theca cell tumor; leimyoma; leiomyosarcoma; myoblastoma; myomma;
myosarcoma; rhabdomyoma; rhabdomyosarcoma; ependymoma;
ganglioneuroma; glioma; medulloblastoma; meningioma; neurilemmoma;
neuroblastoma; neuroepithelioma; neurofibroma; neuroma;
paraganglioma; paraganglioma nonchromaffin.
[0197] In one embodiment the inventive compounds are candidate
therapeutic agents for the treatment of cancers such as
angiokeratoma; angiolymphoid hyperplasia with eosinophilia; angioma
sclerosing; angiomatosis; glomangioma; hemangioendothelioma;
hemangioma; hemangiopericytoma; hemangiosarcoma; lymphangioma;
lymphangiomyoma; lymphangiosarcoma; pinealoma; carcinosarcoma;
chondrosarcoma; cystosarcoma phyllodes; fibrosarcoma;
hemangiosarcoma; leiomyosarcoma; leukosarcoma; liposarcoma;
lymphangiosarcoma; myosarcoma; myxosarcoma; ovarian carcinoma;
rhabdomyosarcoma; sarcoma; neoplasms; nerofibromatosis; and
cervical dysplasia.
[0198] In a particular embodiment, the present disclosure provides
methods for treating solid tumor, colon cancer, rectal cancer,
colorectalcancer, bladder cancer, gastric cancer, esophageal
cancer, head and neck cancer, myelodysplastic syndrome, brain
cancer, CNS cancer, malignant glioma, glioblastoma, hepatocellular
cancers, hepatocellular carcinoma, thyroid cancer, lung cancer,
non-small cell lung cancer, a hematological cancer, leukemia,
B-cell lymphoma, T-cell lymphoma, hairy cell lymphoma, diffuse
large B cell lymphoma, Hodgkins lymphoma, non-Hodgkins lymphoma,
Burkitt lymphoma, pancreatic cancer, melanoma, myeloma, multiple
myeloma, pancreatic carcinoma, renal cell carcinoma, renal cancer,
cervical cancer, urothelial cancer, prostate cancer,
castration-resistant prostate cancer, ovarian cancer, breast cancer
or triple-negative breast cancer. According to such a method, a
therapeutically effective amount of at least one compound according
to Formula I or a stereoisomer, tautomer or pharmaceutically
acceptable salt thereof can be administered to a subject who has
been diagnosed with a cell proliferative disease, such as a cancer.
Alternatively, a pharmaceutical composition comprising at least one
compound according to Formula I or a stereoisomer, tautomer or
pharmaceutically acceptable salt thereof can be administered to a
subject who has been diagnosed with cancer.
[0199] In certain embodiments, the compounds in accordance with the
invention are administered to a subject with cancer in conjunction
with other conventional cancer therapies such as radiation
treatment or surgery. Radiation therapy is well-known in the art
and includes X-ray therapies, such as gamma-irradiation, and
radiopharmaceutical therapies.
[0200] In certain embodiments, the inventive Mnk inhibitor
compounds are used with at least one anti-cancer agent. Anti-cancer
agents include chemotherapeutic drugs. A chemotherapeutic agent
includes, but is not limited to, an inhibitor of chromatin
function, a topoisomerase inhibitor, a microtubule inhibiting drug,
a DNA damaging agent, an antimetabolite (such as folate
antagonists, pyrimidine analogs, purine analogs, and sugar-modified
analogs), a DNA synthesis inhibitor, a DNA interactive agent (such
as an intercalating agent), and a DNA repair inhibitor.
[0201] Illustrative chemotherapeutic agents include, without
limitation, the following groups: anti-metabolites/anti-cancer
agents, such as pyrimidine analogs (5-fluorouracil, floxuridine,
capecitabine, gemcitabine and cytarabine) and purine analogs,
folate antagonists and related inhibitors (mercaptopurine,
thioguanine, pentostatin and 2-chlorodeoxyadenosine (cladribine));
antiproliferative/antimitotic agents including natural products
such as vinca alkaloids (vinblastine, vincristine, and
vinorelbine), microtubule disruptors such as taxane (paclitaxel,
docetaxel), vincristin, vinblastin, nocodazole, epothilones and
navelbine, epidipodophyllotoxins (etoposide, teniposide), DNA
damaging agents (actinomycin, amsacrine, anthracyclines, bleomycin,
busulfan, camptothecin, carboplatin, chlorambucil, cisplatin,
cyclophosphamide, Cytoxan, dactinomycin, daunorubicin, doxorubicin,
epirubicin, hexamethylmelamineoxaliplatin, iphosphamide, melphalan,
merchlorehtamine, mitomycin, mitoxantrone, nitrosourea, plicamycin,
procarbazine, taxol, taxotere, temozolamide, teniposide,
triethylenethiophosphoramide and etoposide (VP 16)); antibiotics
such as dactinomycin (actinomycin D), daunorubicin, doxorubicin
(adriamycin), idarubicin, anthracyclines, mitoxantrone, bleomycins,
plicamycin (mithramycin) and mitomycin; enzymes (L-asparaginase
which systemically metabolizes L-asparagine and deprives cells
which do not have the capacity to synthesize their own asparagine);
antiplatelet agents; antiproliferative/antimitotic alkylating
agents such as nitrogen mustards (mechlorethamine, cyclophosphamide
and analogs, melphalan, chlorambucil), ethylenimines and
methylmelamines (hexamethylmelamine and thiotepa), alkyl
sulfonates-busulfan, nitrosoureas (carmustine (BCNU) and analogs,
streptozocin), trazenes--dacarbazinine (DTIC);
antiproliferative/antimitotic antimetabolites such as folic acid
analogs (methotrexate); platinum coordination complexes (cisplatin,
carboplatin), procarbazine, hydroxyurea, mitotane,
aminoglutethimide; hormones, hormone analogs (estrogen, tamoxifen,
goserelin, bicalutamide, nilutamide) and aromatase inhibitors
(letrozole, anastrozole); anticoagulants (heparin, synthetic
heparin salts and other inhibitors of thrombin); fibrinolytic
agents (such as tissue plasminogen activator, streptokinase and
urokinase), aspirin, dipyridamole, ticlopidine, clopidogrel,
abciximab; antimigratory agents; antisecretory agents (breveldin);
immunosuppressives (cyclosporine, tacrolimus (FK-506), sirolimus
(rapamycin), azathioprine, mycophenolate mofetil); anti-angiogenic
compounds (TNP470, genistein) and growth factor inhibitors
(vascular endothelial growth factor (VEGF) inhibitors, fibroblast
growth factor (FGF) inhibitors); angiotensin receptor blocker;
nitric oxide donors; anti-sense oligonucleotides; antibodies
(trastuzumab, rituximab); chimeric antigen receptors; cell cycle
inhibitors and differentiation inducers (tretinoin); mTOR
inhibitors, topoisomerase inhibitors (doxorubicin (adriamycin),
amsacrine, camptothecin, daunorubicin, dactinomycin, eniposide,
epirubicin, etoposide, idarubicin, irinotecan (CPT-11) and
mitoxantrone, topotecan, irinotecan), corticosteroids (cortisone,
dexamethasone, hydrocortisone, methylpednisolone, prednisone, and
prenisolone); growth factor signal transduction kinase inhibitors;
mitochondrial dysfunction inducers, toxins such as Cholera toxin,
ricin, Pseudomonas exotoxin, Bordetella pertussis adenylate cyclase
toxin, or diphtheria toxin, and caspase activators; and chromatin
disruptors.
[0202] In certain embodiments, an Mnk inhibitor in accordance with
the present invention is used simultaneously, in the same
formulation or in separate formulations, or sequentially with an
additional agent(s) as part of a combination therapy regimen.
[0203] Mnk inhibitors according to Formula I, Ia, IIa, IIb, IIIa,
IIIb, IVa, IVb, Va, Vb, VI, VIIa, and VIIb including their
corresponding salts and pharmaceutical compositions of Formula I,
Ia, IIa, IIb, IIIa, IIIb, IVa, IVb, Va, Vb, VI, VIIa, and VIIb
compounds are also effective as therapeutic agents for treating or
preventing cytokine mediated disorders, such as inflammation in a
patient, preferably in a human. In one embodiment, a compound or
composition in accordance with the invention is particularly useful
for treating or preventing a disease selected from the group
consisting of chronic or acute inflammation, chronic inflammatory
arthritis, rheumatoid arthritis, psoriasis, COPD, inflammatory
bowel disease, septic shock, Crohn's disease, ulcerative colitis,
multiple sclerosis and asthma.
[0204] In a further aspect of the invention, the inventive
compounds or pharmaceutically acceptable formulations of the
inventive compounds are provided as inhibitors of Mnk activity.
Such inhibition is achieved by contacting a cell expressing Mnk
with a compound or a pharmaceutically acceptable formulation, to
lower or inhibit Mnk activity, to provide therapeutic efficacy for
a Mnk dependent condition in a mammal in need thereof.
[0205] Therapeutically effective dosages of a compound according to
Formula I or a composition of a Formula I compound will generally
range from about 1 to 2000 mg/day, from about 10 to about 1000
mg/day, from about 10 to about 500 mg/day, from about 10 to about
250 mg/day, from about 10 to about 100 mg/day, or from about 10 to
about 50 mg/day. The therapeutically effective dosages may be
administered in one or multiple doses. It will be appreciated,
however, that specific doses of the compounds of the invention for
any particular patient will depend on a variety of factors such as
age, sex, body weight, general health condition, diet, individual
response of the patient to be treated, time of administration,
severity of the disease to be treated, the activity of particular
compound applied, dosage form, mode of application and concomitant
medication. The therapeutically effective amount for a given
situation will readily be determined by routine experimentation and
is within the skills and judgment of the ordinary clinician or
physician. In any case the compound or composition will be
administered at dosages and in a manner which allows a
therapeutically effective amount to be delivered based upon
patient's unique condition.
Synthesis
[0206] The following examples are provided for purpose of
illustration and not limitation.
Example 1
Synthesis of
7-(pyrimidin-4-ylamino)-3,4-dihydro-1H-pyrido[1,2-a]pyrazine-1,6(2H)-dion-
e (Cpd. No. 1)
##STR00036##
##STR00037##
[0207] Synthesis of
7-chloro-2-(4-methoxybenzyl)-3,4-dihydro-1H-pyrido[1,2-a]pyrazine-1,6-(2H-
)-dione (3)
[0208] To a solution of
5-chloro-6-oxo-1,6-dihydropyridine-2-carboxylic acid (1, 0.25 g,
1.44 mmol) in acetonitrile (10 mL),
2-((4-methoxybenzyl)amino)ethanol (2, 0.31 g, 1.73 mmol) followed
by cesium carbonate (1.18 g, 3.61 mmol) and HATU (1.26 g, 3.32
mmol) were added and the reaction mixture was stirred at 50.degree.
C. for 16 h. The reaction mixture was diluted with water and the
compound was extracted in ethyl acetate. The organic layer was
washed with brine, separated, dried over sodium sulphate and
concentrated under reduced pressure. The residue obtained was
purified via column chromatography (silica, ethyl
acetate/hexanes=60%) to afford
7-chloro-2-(4-methoxybenzyl)-3,4-dihydro-1H-pyrido[1,2-a]pyrazine-1,6-(2H-
)-dione (3). Yield: 0.24 g, 52%; MS (ESI) m/z 319 [M+1].sup.+.
Synthesis of
2-(4-methoxybenzyl)-7-(pyrimidin-4-ylamino)-3,4-dihydro-1H-pyrido[1,2-a]p-
yrazine-1,6(2H)-dione (5)
[0209] To a solution of
7-chloro-2-(4-methoxybenzyl)-3,4-dihydro-1H-pyrido[1,2-a]pyrazine-1,6-(2H-
)-dione (3, 0.45 g, 1.41 mmol) in dioxane (10 mL),
pyrimidin-4-amine (4, 0.13 g, 1.41 mmol), sodium tert-butoxide
(0.41 g, 4.2 mmol) followed by X-Phos (0.14 g, 0.28 mmol) were
added and the reaction mixture was degassed with argon for 5 min.
Tris(dibenzylideneacetone)dipalladium(0) (0.13 g, 0.14 mmol) was
added and the reaction mixture was degassed with argon for another
5 min and stirred at 110.degree. C. for 16 h. The reaction mixture
was diluted with water and the compound was extracted in ethyl
acetate. The organic layer was washed with brine, separated, dried
over sodium sulphate and concentrated under reduced pressure. The
residue obtained was purified via column chromatography (silica,
methanol/dichloromethane=5%) to afford
2-(4-methoxybenzyl)-7-(pyrimidin-4-ylamino)-3,4-dihydro-1H-pyrido[1,2-a]p-
yrazine-1,6(2H)-dione (5) as a yellow solid. Yield: 0.42 g, 79%; MS
(ESI) m/z 378 [M+1].sup.+.
Synthesis of
7-(pyrimidin-4-ylamino)-3,4-dihydro-1H-pyrido[1,2-a]pyrazine-1,6(2H)-dion-
e (Cpd. No. 1)
[0210] A solution of
2-(4-methoxybenzyl)-7-(pyrimidin-4-ylamino)-3,4-dihydro-1H-pyrido[1,2-a]p-
yrazine-1,6(2H)-dione (5, 0.3 g, 0.79 mmol) in trifluoroacetic acid
(5 mL) was heated at 90.degree. C. for 48 h. The reaction mixture
was cooled to room temperature and concentrated under reduced
pressure. The residue was neutralized with saturated solution of
sodium bicarbonate and the compound was extracted in 10% methanol
in ethyl acetate. The organic layer was separated, dried over
sodium sulphate, concentrated under reduced pressure and the
residue obtained was purified via column chromatography (silica,
methanol/dichloromethane=10%) to afford
7-(pyrimidin-4-ylamino)-3,4-dihydro-1H-pyrido[1,2-a]pyrazine-1,6(2H)-dion-
e (Cpd. No. 1) as a beige solid. Yield: 0.12 g, 59%; MS (ESI) m/z
258 [M+1].sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 9.45
(s, 1H), 8.79-8.64 (m, 2H), 8.48 (s, 1H), 8.38 (d, J=5.9 Hz, 1H),
7.41 (dd, J=6.0, 1.3 Hz, 1H), 7.11 (d, J=7.9 Hz, 1H), 4.23-4.16 (m,
2H), 3.55-3.48 (m, 2H).
Example 2
Synthesis of
3,3-dimethyl-6-(pyrimidin-4-ylamino)-2,3-dihydroimidazo
[1,5-a]pyridine-1,5-dione (Cpd. No. 2)
##STR00038##
##STR00039##
[0211] Synthesis of
5-chloro-6-oxo-1,6-dihydropyridine-2-carboxamide (2)
[0212] Aqueous ammonia (15 mL, 30% solution) was added to ethyl
5-chloro-6-oxo-1,6-dihydropyridine-2-carboxylate (1, 0.65 g, 3.2
mmol) at 0.degree. C. and the reaction mixture was allowed to stir
at room temperature for 16 h. The reaction mixture was concentrated
under reduced pressure and the residue was triturated with diethyl
ether, filtered and dried to afford
5-chloro-6-oxo-1,6-dihydropyridine-2-carboxamide (2). Yield: 0.43
g, 75%; MS (ESI) m/z 173[M+1].sup.+.
Synthesis of
6-chloro-3,3-dimethyl-2,3-dihydroimidazo[1,5-a]pyridine-1,5-dione
(4)
[0213] Procedure A: To a solution of
5-chloro-6-oxo-1,6-dihydropyridine-2-carboxamide (2, 1.4 g, 7.9
mmol) in 1,4-dioxane (20 mL), acetone (3, 4.6 g, 79 mmol) and
concentrated sulfuric acid (0.038 g, 0.39 mmol) were added at room
temperature and the reaction mixture was allowed to heat at
100.degree. C. for 8 h. The reaction mixture was concentrated under
reduced pressure and the residue was triturated with diethyl ether
and hexane, filtered and dried to afford
6-chloro-3,3-dimethyl-2,3-dihydroimidazo[1,5-a]pyridine-1,5-dione
(4). Yield: 1.4 g, 83%; MS (ESI) m/z 213[M+1].sup.+.
Synthesis of
3,3-dimethyl-6-(pyrimidin-4-ylamino)-2,3-dihydroimidazo[1,5-a]pyridine-1,-
5-dione (Cpd. No. 2)
[0214] Procedure B: To a solution of
6-chloro-3,3-dimethyl-2,3-dihydroimidazo[1,5-c]pyridine-1,5-dione
(4, 0.25 g, 1.18 mmol) in 1,4-dioxane (8 mL), pyrimidin-4-amine (5,
0.14 g, 1.41 mmol), Brettphos (0.19 g, 0.23 mmol) and cesium
carbonate (0.76 g, 2.36 mmol) were added and the reaction mixture
was degassed with argon for 5 min. Tris dibenzylideneacetone
dipalladium (0) (0.11 g, 0.12 mmol) was added. The reaction was
degassed with argon for another 5 min and then stirred at
100.degree. C. for 10 h. The reaction mixture was cooled to room
temperature, filtered through celite and the filtrate was
concentrated under reduced pressure. The residue was purified by
silica gel column chromatography using 5% methanol in
dichloromethane to afford
3,3-dimethyl-6-(pyrimidin-4-ylamino)-2,3-dihydroimidazo[1,5-a]pyridine-1,-
5-dione (Cpd. No. 2) as a light yellow solid. Yield: 0.036 g, 11%;
MS (ESI) m/z 272[M+1].sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. 9.70 (s, 1H), 9.42 (s, 1H), 8.81-8.73 (m, 2H), 8.37 (d,
J=5.9 Hz, 1H), 7.40-7.34 (m, 1H), 6.87 (d, J=7.7 Hz, 1H), 1.82 (s,
6H).
Example 3
Synthesis of
3-(4-fluorobenzyl)-3-methyl-6-(pyrimidin-4-ylamino)-2,3-dihydroimidazo[1,-
5-a]pyridine-1,5-dione (Cpd. No. 3)
##STR00040##
##STR00041##
[0215] Synthesis of
6-chloro-3-(4-fluorobenzyl)-3-methyl-2,3-dihydroimidazo[1,5-a]pyridine-1,-
5-dione (3)
[0216] The synthesis of intermediate 3 was carried out as described
above using the general protocol of Procedure A. Yield: 0.17 g,
49%; MS (ESI) m/z 307[M+1].sup.+.
Synthesis of
3-(4-fluorobenzyl)-3-methyl-6-(pyrimidin-4-ylamino)-2,3-dihydroimidazo-[1-
,5-a]pyridine-1,5-dione (Cpd. No. 3)
[0217] The synthesis of compound 3 was carried out as described
above using the general protocol of Procedure B. White solid;
Yield: 0.012 g, 40%; MS (ESI) m/z 366[M+1].sup.+; .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. 9.66 (s, 1H), 9.50 (s, 1H), 8.75 (s,
1H), 8.68 (d, J=7.6 Hz, 1H), 8.40 (d, J=5.9 Hz, 1H), 7.41 (d, J=5.9
Hz, 1H), 7.04-6.92 (m, 4H), 6.57 (d, J=7.7 Hz, 1H), 3.99 (d, J=13.9
Hz, 1H), 3.07 (d, J=13.9 Hz, 1H), 1.97 (s, 3H).
Example 4
Synthesis of
3-(4-chlorobenzyl)-3-methyl-6-(pyrimidin-4-ylamino)-2,3-dihydroimidazo[1,-
5-a]pyridine-1,5-dione (Cpd. No. 4)
##STR00042##
##STR00043##
[0218] Synthesis of
6-chloro-3-(4-chlorobenzyl)-3-methyl-2,3-dihydroimidazo[1,5-a]pyridine-1,-
5-dione (3)
[0219] The synthesis of intermediate 3 was carried out as described
above using the general protocol of Procedure A. Yield: 0.278 g,
59%; MS (ESI) m/z 323 [M+1].sup.+.
Synthesis of
3-(4-chlorobenzyl)-3-methyl-6-(pyrimidin-4-ylamino)-2,3-dihydroimidazo-[1-
,5-a]pyridine-1,5-dione (Cpd. No. 4)
[0220] The synthesis of compound 4 was carried out as described
above using the general protocol of Procedure B. Tan solid; Yield:
0.18 g, 59%; MS (ESI) m/z 382[M+1].sup.+; .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 9.68 (s, 1H), 9.51 (s, 1H), 8.75 (s, 1H),
8.68 (d, J=7.6 Hz, 1H), 8.40 (d, J=5.9 Hz, 1H), 7.41 (d, J=6.1 Hz,
1H), 7.20-7.01 (m, 1H), 6.99-6.92 (m, 2H), 6.77 (dd, J=8.6, 5.0 Hz,
1H), 6.58 (d, J=7.6 Hz, 1H), 4.02 (d, J=13.8 Hz, 1H), 3.12 (d,
J=13.8 Hz, 1H), 1.98 (s, 3H).
Example 5
Synthesis of
3-(3-fluorobenzyl)-3-methyl-6-(pyrimidin-4-ylamino)-2,3-dihydroimidazo[1,-
5-a]pyridine-1,5-dione (Cpd. No. 5)
##STR00044##
##STR00045##
[0221] Synthesis of
6-chloro-3-(3-fluorobenzyl)-3-methyl-2,3-dihydroimidazo[1,5-a]pyridine-1,-
5-dione (3)
[0222] The synthesis of intermediate 3 was carried out as described
above using the general protocol of Procedure A. Yield: 0.265 g,
59%; MS (ESI) m/z 307 [M+1].sup.+.
Synthesis of
3-(3-fluorobenzyl)-3-methyl-6-(pyrimidin-4-ylamino)-2,3-dihydroimidazo-[1-
,5-a]pyridine-1,5-dione (Cpd. No. 5)
[0223] The synthesis of compound 5 was carried out as described
above using the general protocol of Procedure B. Beige solid;
Yield: 0.17 g, 56%; MS (ESI) m/z 366[M+1].sup.+; .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. 9.68 (s, 1H), 9.51 (s, 1H), 8.75 (s,
1H), 8.68 (d, J=7.6 Hz, 1H), 8.40 (d, J=5.9 Hz, 1H), 7.41 (d, J=6.1
Hz, 1H), 7.2-7.08 (m, 1H), 6.99-6.91 (m, 1H), 6.77 (dd, J=8.6, 5.0
Hz, 2H), 6.58 (d, J=7.6 Hz, 1H), 4.02 (d, J=13.8 Hz, 1H), 3.12 (d,
J=13.8 Hz, 1H), 1.98 (s, 3H).
Example 6
Synthesis of
6'-(pyrimidin-4-ylamino)-1H-spiro[cyclopentane-1,3'-imidazo[1,5-a]pyridin-
e]-1',5'(2'H)-dione (Cpd. No. 6)
##STR00046##
##STR00047##
[0224] Synthesis of
6'-chloro-1'H-spiro[cyclopentane-1,3'-imidazo[1,5-a]pyridine]-1',5'(2'H)--
dione (3)
[0225] The synthesis of intermediate 3 was carried out as described
above using the general protocol of Procedure A. Yield: 0.18 g,
42%; MS (ESI) m/z 239[M+1].sup.+.
Synthesis of
6'-(pyrimidin-4-ylamino)-1'H-spiro[cyclopentane-1,3'-imidazo[1,5-a]-pyrid-
ine]-1',5'(2'H)-dione (Cpd. No. 6)
[0226] The synthesis of compound 6 was carried out as described
above using the general protocol of Procedure B. Light brown solid;
Yield: 0.1 g, 45%; MS (ESI) m/z 298.10[M+1].sup.+; .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. 10.01 (s, 1H), 9.43 (s, 1H), 8.82-8.73
(m, 2H), 8.37 (d, J=5.9 Hz, 1H), 7.37 (d, J=5.9 Hz, 1H), 6.88 (d,
J=7.6 Hz, 1H), 2.89-2.81 (m, 2H), 2.08-1.92 (m, 2H), 1.96-1.70 (m,
4H).
Example 7
Synthesis of
3-methyl-6-(pyrimidin-4-ylamino)-3-(2,2,2-trifluoroethyl)-2,3-dihydroimid-
azo[1,5-a]pyridine-1,5-dione (Cpd. No. 7)
##STR00048##
##STR00049##
[0227] Synthesis of
6-chloro-3-methyl-3-(2,2,2-trifluoroethyl)-2,3-dihydroimidazo[1,5-a]pyrid-
ine-1,5-dione (3)
[0228] The synthesis of intermediate 3 was carried out as described
above using the general protocol of Procedure A. Yield: 0.12 g,
22%.
Synthesis of
3-methyl-6-(pyrimidin-4-ylamino)-3-(2,2,2-trifluoroethyl)-2,3-dihydroimid-
azo[1,5-a]pyridine-1,5-dione (Cpd. No. 7)
[0229] The synthesis of compound 7 was carried out as described
above using the general protocol of Procedure B. Green-yellow
solid; Yield: 0.020 g, 15%; MS (ESI) m/z 340[M+1].sup.+; .sup.1H
NMR (400 MHz, DMSO-d.sub.6) .delta. 10.69 (s, 1H), 9.42 (s, 1H),
8.70 (dd, J=4.5, 1.7 Hz, 1H), 8.79 (s, 1H), 8.30-8.20 (m, 1H), 7.73
(d, J=1.1 Hz, 1H), 7.32 (dd, J=9.2, 4.4 Hz, 1H), 3.38-3.75 (m, 1H),
3.19-3.08 (m, 1H), 1.81 (s, 3H).
Example 8
Synthesis of
3-isopropyl-3-methyl-6-(pyrimidin-4-ylamino)-2,3-dihydroimidazo[1,5-a]pyr-
idine-1,5-dione (Cpd. No. 8)
##STR00050##
##STR00051##
[0230] Synthesis of
6-chloro-3-isopropyl-3-methyl-2,3-dihydroimidazo[1,5-a]pyridine-1,5-dione
(3)
[0231] The synthesis of intermediate 3 was carried out as described
above using the general protocol of Procedure A. Yield: 0.32 g,
77%.
Synthesis of
3-isopropyl-3-methyl-6-(pyrimidin-4-ylamino)-2,3-dihydroimidazo[1,5-a]pyr-
idine-1,5-dione (Cpd. No. 8)
[0232] The synthesis of compound 8 was carried out as described
above using the general protocol of Procedure B. Off-white solid;
Yield: 0.036 g, 19%; MS (ESI) m/z 300[M+1].sup.+; .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. 9.67 (s, 1H), 9.41 (s, 1H), 8.83-8.73
(m, 2H), 8.37 (d, J=5.9 Hz, 1H), 7.37 (d, J=5.9 Hz, 1H), 6.87 (d,
J=7.6 Hz, 1H), 3.1-2.90 (m, 1H), 1.83 (s, 3H), 1.05 (d, J=7.0 Hz,
3H), 0.46 (d, J=6.6 Hz, 3H).
Example 9
Synthesis of
3-cyclopentyl-3-methyl-6-(pyrimidin-4-ylamino)-2,3-dihydroimidazo[1,5-a]p-
yridine-1,5-dione (Cpd. No. 9)
##STR00052##
##STR00053##
[0233] Synthesis of
6-chloro-3-cyclopentyl-3-methyl-2,3-dihydroimidazo[1,5-a]pyridine-1,5-dio-
ne (3)
[0234] The synthesis of intermediate 3 was carried out as described
above using the general protocol of Procedure A. Yield: 0.2 g, 47%;
MS (ESI) m/z 267[M+1].sup.+.
Synthesis of
3-cyclopentyl-3-methyl-6-(pyrimidin-4-ylamino)-2,3-dihydroimidazo[1,5-a]p-
yridine-1,5-dione (Cpd. No. 9)
[0235] The synthesis of compound 9 was carried out as described
above using the general protocol of Procedure B. Beige solid;
Yield: 0.12 g, 47%; MS (ESI) m/z 326[M+1].sup.+; .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. 9.72 (s, 1H), 9.39 (s, 1H), 8.81-8.73
(m, 2H), 8.37 (d, J=5.9 Hz, 1H), 7.39-7.32 (m, 1H), 6.86 (d, J=7.7
Hz, 1H), 3.45-3.40 (m, 1H), 1.84 (s, 3H), 1.68-1.35 (m, 4H),
1.18-1.1 (m, 1H), 0.85-0.80 (m, 1H).
Example 10
Synthesis of
N-(6-((3,3-dimethyl-1,5-dioxo-1,2,3,5-tetrahydroimidazo[1,5-a]pyridin-6-y-
l)amino)pyrimidin-4-yl)cyclopropanecarboxamide (Cpd. No. 10)
##STR00054##
##STR00055##
[0236] Synthesis of
N-(6-((3,3-dimethyl-1,5-dioxo-1,2,3,5-tetrahydroimidazo[1,5-a]pyridin-6-y-
l)-amino)pyrimidin-4-yl)cyclopropanecarboxamide (Cpd. No. 10)
[0237] The synthesis of compound 10 was carried out as described
above using the general protocol of Procedure B. Beige solid;
Yield: 0.075 g, 15%; MS (ESI) m/z 355[M+1].sup.+; .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. 10.87 (s, 1H), 9.68 (s, 1H), 9.20 (s,
1H), 8.64 (d, J=7.7 Hz, 1H), 8.51 (s, 1H), 7.88 (d, J=1.0 Hz, 1H),
6.85 (d, J=7.6 Hz, 1H), 2.02 (m, J=6.2 Hz, 1H), 1.80 (s, 6H), 0.84
(d, J=6.1 Hz, 4H).
Example 11
Synthesis of
3-(4-fluorophenyl)-3-methyl-6-(pyrimidin-4-ylamino)-2,3-dihydroimidazo[1,-
5-a]pyridine-1,5-dione (Cpd. No. 11)
##STR00056##
##STR00057##
[0238] Synthesis of
6-chloro-3-(4-fluorophenyl)-3-methyl-2,3-dihydroimidazo[1,5-a]pyridine-1,-
5-dione (3)
[0239] The synthesis of intermediate 3 was carried out as described
above using the general protocol of Procedure A. Yield: 0.216 g,
52%; MS (ESI) m/z 293 [M+1].sup.+.
Synthesis of
3-(4-fluorophenyl)-3-methyl-6-(pyrimidin-4-ylamino)-2,3-dihydroimidazo-[1-
,5-a]pyridine-1,5-dione (Cpd. No. 11)
[0240] The synthesis of compound 11 was carried out as described
above using the general protocol of Procedure B. Brown solid;
Yield: 0.14 g, 41%; MS (ESI) m/z 252.15 [M+1].sup.+; .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 10.05 (s, 1H), 9.35 (s, 1H),
8.83-8.73 (m, 2H), 8.35 (d, J=5.9 Hz, 1H), 7.44 (dd, J=8.5, 5.2 Hz,
2H), 7.31-7.16 (m, 3H), 6.99 (d, J=7.6 Hz, 1H), 2.26 (s, 3H).
Example 12
Synthesis of
3-(3-fluorophenyl)-3-methyl-6-(pyrimidin-4-ylamino)-2,3-dihydroimidazo[1,-
5-a]pyridine-1,5-dione (Cpd. No. 12)
##STR00058##
##STR00059##
[0241] Synthesis of
6-chloro-3-(3-fluorophenyl)-3-methyl-2,3-dihydroimidazo[1,5-a]pyridine-1,-
5-dione (3)
[0242] The synthesis of intermediate 3 was carried out as described
above using the general protocol of Procedure A. Yield: 0.208 g,
50%; MS (ESI) m/z 293 [M+1].sup.+.
Synthesis of
3-(3-fluorophenyl)-3-methyl-6-(pyrimidin-4-ylamino)-2,3-dihydroimidazo-[1-
,5-a]pyridine-1,5-dione (Cpd. No. 12)
[0243] The synthesis of compound 12 was carried out as described
above using the general protocol of Procedure B. Yellow solid;
Yield: 0.08 g, 34%; MS (ESI) m/z 252.25 [M+1].sup.+; .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 10.07 (s, 1H), 9.34 (s, 1H),
8.84-8.73 (m, 2H), 8.35 (d, J=5.9 Hz, 1H), 7.43 (m, 1H), 7.32-7.12
(m, 4H), 7.00 (d, J=7.6 Hz, 1H), 2.26 (s, 3H).
Example 13
Synthesis of
3-(4-chlorophenyl)-3-methyl-6-(pyrimidin-4-ylamino)-2,3-dihydroimidazo[1,-
5-a]pyridine-1,5-dione (Cpd. No. 13)
##STR00060##
##STR00061##
[0244] Synthesis of
6-chloro-3-(4-chlorophenyl)-3-methyl-2,3-dihydroimidazo[1,5-a]pyridine-1,-
5-dione (3)
[0245] The synthesis of intermediate 3 was carried out as described
above using the general protocol of Procedure A. Yield: 0.17 g,
31%; MS (ESI) m/z 309 [M+1].sup.+.
Synthesis of
3-(4-chlorophenyl)-3-methyl-6-(pyrimidin-4-ylamino)-2,3-dihydroimidazo-[1-
,5-a]pyridine-1,5-dione (Cpd. No. 13)
[0246] The synthesis of compound 13 was carried out as described
above using the general protocol of Procedure B. Yellow solid;
Yield: 0.11 g, 55%; MS (ESI) m/z 368.15 [M+1].sup.+; .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 10.05 (s, 1H), 9.32 (s, 1H),
8.84-8.73 (m, 2H), 8.35 (d, J=5.9 Hz, 1H), 7.42 (m, 4H), 7.27 (dd,
J=5.9, 1.3 Hz, 1H), 7.00 (d, J=7.7 Hz, 1H), 2.25 (s, 3H).
Example 14
Synthesis of
3-methyl-6-(pyrimidin-4-ylamino)-3-(trifluoromethyl)-2,3-dihydroimidazo[1-
,5-a]pyridine-1,5-dione (Cpd. No. 14)
##STR00062##
##STR00063##
[0247] Synthesis of
6-chloro-3-methyl-3-(trifluoromethyl)-2,3-dihydroimidazo[1,5-a]pyridine-1-
,5-dione (3)
[0248] The synthesis of intermediate 3 was carried out as described
above using the general protocol of Procedure A. Yield: 0.255 g,
66%; MS (ESI) m/z 267 [M+1].sup.+
Synthesis of
3-methyl-6-(pyrimidin-4-ylamino)-3-(trifluoromethyl)-2,3-dihydroimidazo-[-
1,5-a]pyridine-1,5-dione (Cpd. No. 14)
[0249] The synthesis of compound 14 was carried out as described
above using the general protocol of Procedure B. Off-white solid;
Yield: 0.06 g, 19%; MS (ESI) m/z 326 [M+1].sup.+; .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. 10.50 (s, 1H), 9.58 (s, 1H), 8.84-8.76
(m, 2H), 8.41 (d, J=5.9 Hz, 1H), 7.40 (dd, J=5.9, 1.4 Hz, 1H), 7.02
(d, J=7.7 Hz, 1H), 2.14 (s, 3H).
Example 15
Synthesis of
3-(aminomethyl)-3-methyl-6-(pyrimidin-4-ylamino)-2,3-dihydroimidazo[1,5-a-
]pyridine-1,5-dione (Cpd. No. 15)
##STR00064##
##STR00065##
[0250] Synthesis of
6-chloro-3-((1,3-dioxoisoindolin-2-yl)methyl)-3-methyl-2,3-dihydroimidazo-
-[1,5-a]pyridine-1,5-dione (3)
[0251] The synthesis of intermediate 3 was carried out as described
above using the general protocol of Procedure A. Yield: 0.5 g, 50%;
MS (ESI) m/z 358 [M+1].sup.+.
Synthesis of
3-((1,3-dioxoisoindolin-2-yl)methyl)-3-methyl-6-(pyrimidin-4-ylamino)-2,3-
-dihydroimidazo[1,5-a]pyridine-1,5-dione (5)
[0252] The synthesis of intermediate 5 was carried out as described
above using the general protocol of Procedure B. Yield: 0.09 g,
26%; MS (ESI) m/z 417[M+1].sup.+.
Synthesis of
3-(aminomethyl)-3-methyl-6-(pyrimidin-4-ylamino)-2,3-dihydroimidazo[1,5-a-
]pyridine-1,5-dione (Cpd. No. 15)
[0253] Procedure C: To a solution of
3-((1,3-dioxoisoindolin-2-yl)methyl)-3-methyl-6-(pyrimidin-4-ylamino)-2,3-
-dihydroimidazo[1,5-a]pyridine-1,5-dione (5, 0.085 g, 0.29 mmol) in
methanol (20 mL), hydrazine hydrate (2 mL) was added and the
reaction mixture was stirred at room temperature for 16 h. The
reaction mixture was filtered and the filtrate was concentrated
under reduced pressure. The residue was dissolved in
dichloromethane and washed with water, separated, dried over sodium
sulphate and concentrated under reduced pressure, which was
purified by repeated washing with diethyl ether and hexane to
obtain
3-(aminomethyl)-3-methyl-6-(pyrimidin-4-ylamino)-2,3-dihydroimidazo[1,5-a-
]pyridine-1,5-dione (Cpd. No. 15) as an off-white solid. Yield:
0.008 g, 9%; MS (ESI) m/z 287.05[M+1].sup.+; .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 9.35 (s, 1H), 8.76 (d, J=7.8 Hz, 2H), 8.36
(d, J=5.9 Hz, 1H), 7.36 (d, J=6.0 Hz, 1H), 6.83 (d, J=7.6 Hz, 1H),
3.55 (d, J=13.6 Hz, 1H), 2.92 (d, J=13.7 Hz, 1H), 1.75 (s, 3H),
1.44 (s, 1H), 1.41-1.34 (m, 2H).
Example 16
Synthesis of
3-methyl-6-(pyrimidin-4-ylamino)-3-(thiophen-3-yl)-2,3-dihydroimidazo[1,5-
-a]pyridine-1,5-dione (Cpd. No. 16)
##STR00066##
##STR00067##
[0254] Synthesis of
6-chloro-3-methyl-3-(thiophen-3-yl)-2,3-dihydroimidazo[1,5-a]pyridine-1,5-
-dione (3)
[0255] To a solution of
5-chloro-6-oxo-1,6-dihydropyridine-2-carboxamide (1, 0.1 g, 0.58
mmol) in acetonitrile (4 mL), 1-(thiophen-3-yl)ethanone (2, 0.37 g,
2.9 mmol) and ferric chloride (0.094 g, 0.58 mmol) were added and
the reaction mixture was allowed to heat at 90.degree. C. for 18 h.
The reaction mixture was filtered and the filtrate was concentrated
under reduced pressure. The residue was purified by column
chromatography (silica, ethyl acetate/hexanes=50%) to afford
6-chloro-3-methyl-3-(thiophen-3-yl)-2,3-dihydroimidazo[1,5-a]pyridine-1,5-
-dione (3). Yield: 0.021 g, 13%; MS (ESI) m/z 281[M+1].sup.+.
Synthesis of
3-methyl-6-(pyrimidin-4-ylamino)-3-(thiophen-3-yl)-2,3-dihydroimidazo[1,5-
-a]pyridine-1,5-dione (Cpd. No. 16)
[0256] The synthesis of compound 16 was carried out as described
above using the general protocol of Procedure B. Beige solid;
Yield: 0.008 g, 12%; MS (ESI) m/z 340[M+1].sup.+; .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. 10.05 (s, 1H), 9.35 (s, 1H), 8.81-8.73
(m, 2H), 8.35 (d, J=5.9 Hz, 1H), 7.74-7.68 (m, 1H), 7.49 (dd,
J=5.1, 2.9 Hz, 1H), 7.29 (d, J=5.9 Hz, 1H), 7.00-6.92 (m, 2H), 2.25
(s, 3H).
Example 17
Synthesis of
3-methyl-6-(pyrimidin-4-ylamino)-3-(thiazol-4-yl)-2,3-dihydroimidazo[1,5--
a]pyridine-1,5-dione (Cpd. No. 17)
##STR00068##
##STR00069##
[0257] Synthesis of
6-chloro-3-methyl-3-(thiazol-4-yl)-2,3-dihydroimidazo[1,5-a]pyridine-1,5--
dione (3)
[0258] The synthesis of intermediate 3 was carried out as described
above using the general protocol of Procedure A. Yield: 0.2 g, 49%;
MS (ESI) m/z 282[M+1].sup.+.
Synthesis of
3-methyl-6-(pyrimidin-4-ylamino)-3-(thiazol-4-yl)-2,3-dihydroimidazo[1,5--
a]-pyridine-1,5-dione (Cpd. No. 17)
[0259] The synthesis of compound 17 was carried out as described
above using the general protocol of Procedure B. Yellow solid.
Yield: 0.013 g, 21%; MS (ESI) m/z 341[M+1].sup.+; .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. 9.97 (s, 1H), 9.43 (s, 1H), 8.99 (d,
J=1.8 Hz, 1H), 8.83-8.71 (m, 2H), 8.35 (d, J=6.0 Hz, 1H), 8.07 (d,
J=1.9 Hz, 1H), 7.27 (d, J=6.0 Hz, 1H), 6.94 (d, J=7.6 Hz, 1H), 2.30
(s, 3H).
Example 18
Synthesis of
3-(3-chlorophenyl)-3-methyl-6-(pyrimidin-4-ylamino)-2,3-dihydroimidazo[1,-
5-a]pyridine-1,5-dione (Cpd. No. 18)
##STR00070##
##STR00071##
[0260] Synthesis of
6-chloro-3-(3-chlorophenyl)-3-methyl-2,3-dihydroimidazo[1,5-a]pyridine-1,-
5-dione (3)
[0261] The synthesis of intermediate 3 was carried out as described
above using the general protocol of Procedure A. Yield: 0.210 g,
39%; MS (ESI) m/z 309 [M+1].sup.+.
Synthesis of
3-(3-chlorophenyl)-3-methyl-6-(pyrimidin-4-ylamino)-2,3-dihydroimidazo-[1-
,5-a]pyridine-1,5-dione (Cpd. No. 18)
[0262] The synthesis of compound 18 was carried out as described
above using the general protocol of Procedure B. Light yellow
solid; Yield: 0.053 g, 22%; MS (ESI) m/z 368 [M+1]+; .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 10.07 (s, 1H), 9.35 (s, 1H),
8.86-8.73 (m, 2H), 8.35 (d, J=5.9 Hz, 1H), 7.51-7.34 (m, 3H),
7.34-7.23 (m, 2H), 7.09 (s, 1H), 7.01 (d, J=7.6 Hz, 1H), 2.25 (s,
3H).
Example 19
Synthesis of
3-(3-chlorobenzyl)-3-methyl-6-(pyrimidin-4-ylamino)-2,3-dihydroimidazo[1,-
5-a]pyridine-1,5-dione (Cpd. No. 19)
##STR00072##
##STR00073##
[0263] Synthesis of
6-chloro-3-(3-chlorobenzyl)-3-methyl-2,3-dihydroimidazo[1,5-a]pyridine-1,-
5-dione (3)
[0264] The synthesis of intermediate 3 was carried out as described
above using the general protocol of Procedure A. Yield: 0.4 g, 70%;
MS (ESI) m/z 324 [M+1].sup.+
Synthesis of
3-(3-chlorobenzyl)-3-methyl-6-(pyrimidin-4-ylamino)-2,3-dihydroimidazo-[1-
,5-a]pyridine-1,5-dione (Cpd. No. 19)
[0265] The synthesis of compound 19 was carried out as described
above using the general protocol of Procedure B. White solid;
Yield: 0.2 g, 56%; MS (ESI) m/z 382 [M+1].sup.+; .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. 9.67 (s, 1H), 9.49 (s, 1H), 8.75 (s,
1H), 8.68 (d, J=7.7 Hz, 1H), 8.39 (d, J=5.9 Hz, 1H), 7.41 (d, J=5.9
Hz, 1H), 7.24-7.12 (m, 2H), 7.04 (d, J=2.3 Hz, 1H), 6.87 (dd,
J=6.8, 2.1 Hz, 1H), 6.58 (d, J=7.7 Hz, 1H), 4.00 (d, J=13.8 Hz,
1H), 3.11 (d, J=13.8 Hz, 1H), 1.97 (s, 3H).
Example 20
Synthesis of 6-(pyrimidin-4-ylamino)-1H-spiro[imidazo[1,5-a]
pyridine-3,3'-piperidine]-1,5(2H)-dione (Cpd. No. 20)
##STR00074##
##STR00075##
[0266] Synthesis of
6-chloro-2H-spiro[imidazo[1,5-a]pyridine-3,3'-piperidine]-1,5-dione
(3)
[0267] The synthesis of intermediate 3 was carried out as described
above using the general protocol of Procedure A. Yield: 0.504 g,
crude; MS (ESI) m/z 254 [M+1].sup.+.
Synthesis of tert-butyl
6-chloro-1,5-dioxo-2,5-dihydro-1H-spiro[imidazo[1,5-a]pyridine-3,3'-piper-
idine]-1'-carboxylate (4)
[0268] To a solution of
1'-benzyl-6-chloro-1H-spiro[imidazo[1,5-a]pyridine-3,3'-piperidine]-1,5(2-
H)-dione (3, 0.5 g, 1.9 mmol) in tetrahydrofuran (8 mL) and water
(4 mL), sodium bicarbonate (0.66 g, 7.8 mmol) and di-tertiarybutyl
dicarbonate (1.31 mL, 5.9 mmol) were added at 0.degree. C. and the
reaction mixture was allowed to stir at room temperature for 2 h.
The reaction mixture was diluted with water and the compound was
extracted in ethyl acetate. The organic layer was separated, dried
over sodium sulphate and concentrated under reduced pressure. The
residue was purified by column chromatography (silica,
methanol/dichloromethane=2%) to afford tert-butyl
6-chloro-1,5-dioxo-2,5-dihydro-1H-spiro[imidazo[1,5-a]pyridine-3,3'-piper-
idine]-1'-carboxylate 4. Yield: 0.33 g, 47%; MS (ESI) m/z 354
[M+1].sup.+.
Synthesis of tert-butyl
1,5-dioxo-6-(pyrimidin-4-ylamino)-1,5-dihydro-2H-spiro[imidazo[1,5-a]pyri-
dine-3,3'-piperidine]-1'-carboxylate (6)
[0269] The synthesis of intermediate 6 was carried out as described
above using the general protocol of Procedure B. Yield: 0.126 g,
31%; MS (ESI) m/z 413 [M+1].sup.+.
Synthesis of
6-(pyrimidin-4-ylamino)-1H-spiro[imidazo[1,5-a]pyridine-3,3'-piperidine]--
1,5(2H)-dione (Cpd. No. 20)
[0270] Procedure D: To a stirred solution of
1'-benzyl-6-(pyrimidin-4-ylamino)-1H-spiro[imidazo[1,5-a]pyridine-3,3'-pi-
peridine]-1,5(2H)-dione (5, 0.12 g, 0.29 mmol) in dioxane (1 mL), 4
M hydrogenchloride in dioxane (2 mL) was added at 0.degree. C. and
the reaction mixture was stirred at room temperature for 3 h. The
solvent was removed under reduced pressure and the residue was
purified by repeated washing with pentane. Compound was dissolved
in water and passed through strata column to obtain
6-(pyrimidin-4-ylamino)-1H-spiro[imidazo[1,5-a]pyridine-3,3'-piperidine]--
1,5(2H)-dione (Cpd. No. 20) as a light brown solid. Yield: 0.062 g,
67%; MS (ESI) m/z 313.15 [M+1].sup.+; .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 10.13 (s, 1H), 9.40 (s, 1H), 8.80-8.73 (m,
2H), 8.38 (d, J=5.9 Hz, 1H), 7.37 (dd, J=5.9, 1.3 Hz, 1H), 6.89 (d,
J=7.7 Hz, 1H), 3.94 (d, J=12.5 Hz, 1H), 3.16-3.12 (m, 1H), 2.95 (d,
J=13.1 Hz, 1H), 2.74-2.65 (m, 1H), 2.60 (s, 1H), 2.46 (d, J=11.7
Hz, 1H), 1.72 (d, J=8.2 Hz, 2H), 1.61 (d, J=13.0 Hz, 1H).
Example 21
Synthesis of
N-[6-[(1,5-dioxospiro[2H-imidazo[1,5-a]pyridine-3,1'-cyclopentane]-6-yl)a-
mino]pyrimidin-4-yl]cyclopropanecarboxamide (Cpd. No. 21)
##STR00076##
##STR00077##
[0271] Synthesis of
6-chlorospiro[2H-imidazo[1,5-a]pyridine-3,1'-cyclopentane]-1,5-dione
(3)
[0272] The synthesis of intermediate 3 was carried out as described
above using the general protocol of Procedure A. Off white solid;
Yield: 0.8 g, 58%; MS (ESI) m/z 237 [M-1].sup.-; .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. 10.33 (s, 1H), 7.94 (m, 1H), 6.72 (m,
1H), 2.76 (m, 2H), 1.95 (m, 2H), 1.82 (m, 2H), 1.70 (m, 2H).
Synthesis of
N-[6[(1,5-dioxospiro[2H-imidazo[1,5-a]pyridine-3,1'-cyclopentane]-6-yl)am-
ino]pyrimidin-4-yl]cyclopropanecarboxamide (Cpd. No. 21)
[0273] The synthesis of compound 21 was carried out as described
above using the general protocol of Procedure B. Off white solid;
Yield: 0.12 g, 15%; MS (ESI) m/z 381.13 [M+1].sup.+; .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 10.87 (s, 1H), 10.01 (s, 1H), 9.24
(s, 1H), 8.65 (d, J=7.6 Hz, 1H), 8.50 (s, 1H), 7.87 (s, 1H), 6.85
(d, J=7.6 Hz, 1H), 2.80 (m, 2H), 2.01 (m, 3H), 1.86 (s, 2H), 1.72
(m, 2H), 0.83 (m, 4H).
Example 22
Synthesis of
N-(6-((3-methyl-1,5-dioxo-3-(2,2,2-trifluoroethyl)-1,2,3,5-tetrahydroimid-
azo[1,5-a]pyridin-6-yl)amino)pyrimidin-4-yl)cyclopropanecarboxamide
(Cpd. No. 22)
##STR00078##
##STR00079##
[0274] Synthesis of
6-chloro-3-methyl-3-(2,2,2-trifluoroethyl)-2H-imidazo[1,5-a]pyridine-1,5--
dione (3)
[0275] The synthesis of intermediate 3 was carried out as described
above using the general protocol of Procedure A. Brown solid;
Yield: 0.35 g, 43%; MS (ESI) m/z 279.1 [M-1].sup.-; .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 10.15 (bs, 1H), 7.99 (d, J=4 Hz,
1H), 6.79 (d, J=4 Hz, 1H), 3.74-3.65 (m, 1H), 3.17-3.01 (m, 1H),
1.84 (s, 3H).
Synthesis of
N-[6-[[3-methyl-1,5-dioxo-3-(2,2,2-trifluoroethyl)-2H-imidazo[1,5-a]pyrid-
in-6-yl]amino]pyrimidin-4-yl]cyclopropanecarboxamide (Cpd. No.
22)
[0276] The synthesis of compound 22 was carried out as described
above using the general protocol of Procedure B. Brown solid;
Yield: 0.2 g, 28%; MS (ESI) m/z 423.1[M+1].sup.+; .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. 10.88 (s, 1H), 9.80 (s, 1H), 9.29 (s,
1H), 8.69 (d, J=7.6 Hz, 1H), 8.51 (s, 1H), 7.90 (s, 1H), 6.93 (d,
J=7.6 Hz, 1H), 3.82-3.70 (m, 1H), 3.16-3.04 (m, 1H), 2.07-1.99 (m,
1H), 1.80 (s, 3H), 0.84 (d, J=6.0 Hz, 4H).
Example 23
Synthesis of
N-[6-[(3-cyclopentyl-3-methyl-1,5-dioxo-2H-imidazo[1,5-a]pyridin-6-yl)ami-
no]pyrimidin-4-yl]cyclopropanecarboxamide (Cpd. No. 23)
##STR00080##
##STR00081##
[0277] Synthesis of
6-chloro-3-cyclopentyl-3-methyl-2H-imidazo[1,5-a]pyridine-1,5-dione
(3)
[0278] The synthesis of intermediate 3 was carried out as described
above using the general protocol of Procedure A. Off-white solid;
Yield: 1.61 g, 52%; MS (ESI) m/z 267.0 [M+1].sup.+; .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. 8.61 (s, 1H), 7.71 (d, J=7.2 Hz, 1H),
6.77 (d, J=7.2 Hz, 1H), 3.54 (m, 1H), 2.01 (m, 1H), 1.98 (s, 3H),
1.68 (m, 2H), 1.55 (m, 2H), 1.34 (m, 2H), 0.91 (m, 1H).
Synthesis of
N-[6[(3-cyclopentyl-3-methyl-1,5-dioxo-2H-imidazo[1,5-a]pyridin-6-yl)-ami-
no]pyrimidin-4-yl]cyclopropanecarboxamide (Cpd. No. 23)
[0279] The synthesis of compound 23 was carried out as described
above using the general protocol of Procedure B. Off-white solid;
Yield: 1.4 g, 57%; MS (ESI) m/z 409.36 [M+1].sup.+; .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 10.88 (s, 1H), 9.69 (s, 1H), 9.17
(s, 1H), 8.63 (d, J=7.6 Hz, 1H), 8.50 (s, 1H), 7.85 (s, 1H), 6.83
(d, J=7.6 Hz, 1H), 3.39 (m, 1H), 2.02 (m, 1H), 1.83 (s, 3H), 1.82
(m, 1H), 1.51 (m, 5H), 1.10 (m, 1H), 0.83 (d, J=6.0 Hz, 4H), 0.78
(m, 1H).
Example 24
Synthesis of
N-[6-[[3-methyl-1,5-dioxo-3-(trifluoromethyl)-2H-imidazo[1,5-a]pyridin-6--
yl]amino]pyrimidin-4-yl]cyclopropanecarboxamide (Cpd. No. 24)
##STR00082##
##STR00083##
[0280] Synthesis of
6-chloro-3-methyl-3-(trifluoromethyl)-2H-imidazo[1,5-a]pyridine-1,5-dione
(3)
[0281] The synthesis of intermediate 3 was carried out as described
above using the general protocol of Procedure A. Off-white solid;
Yield: 6.50 g, 84%; MS (ESI) m/z 267.11 [M+1].sup.+; .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 10.84 (s, 1H), 8.10 (d, J=7.2 Hz,
1H), 6.85 (d, J=7.2 Hz, 1H), 2.09 (s, 3H).
Synthesis of
N-[6-[[3-methyl-1,5-dioxo-3-(trifluoromethyl)-2H-imidazo[1,5-a]pyridin-6--
yl]amino]pyrimidin-4-yl]cyclopropanecarboxamide (Cpd. No. 24)
[0282] The synthesis of compound 24 was carried out as described
above using the general protocol of Procedure B. Light yellow
solid; Yield: 1.75 g, 64%; MS (ESI) m/z 409.29 [M+1].sup.+; .sup.1H
NMR (400 MHz, DMSO-d.sub.6) .delta. 10.90 (s, 1H), 10.48 (s, 1H),
9.43 (s, 1H), 8.68 (d, J=7.6 Hz, 1H), 8.53 (s, 1H), 7.94 (s, 1H),
6.97 (d, J=8.0 Hz, 1H), 2.17 (s, 3H), 2.02 (m, 1H), 0.84 (d, J=6.0
Hz, 4H).
Example 25
Synthesis of
3-methyl-3-((methylamino)methyl)-6-(pyrimidin-4-ylamino)-2,3-dihydroimida-
zo[1,5-a]pyridine-1,5-dione (Cpd. No. 25)
##STR00084##
##STR00085##
[0283] Synthesis of
6-chloro-3-methyl-3-((methylamino)methyl)-2,3-dihydroimidazo[1,5-a]pyridi-
ne-1,5-dione (3)
[0284] The synthesis of intermediate 3 was carried out as described
above using the general protocol of Procedure A. Yield: 0.56 g,
crude; MS (ESI) m/z 242 [M+1].sup.+.
Synthesis of tert-butyl
((6-chloro-3-methyl-1,5-dioxo-1,2,3,5-tetrahydroimidazo[1,5-a]pyridin-3-y-
l)methyl)(methyl)carbamate (4)
[0285] To a stirred solution of
6-chloro-3-methyl-3-((methylamino)methyl)-2,3-dihydroimidazo[1,5-a]pyridi-
ne-1,5-dione (3, 0.56 g, 2.3 mmol) in tetrahydrofuran (2 mL),
sodium bicarbonate (2.91 g, 34.0 mmol) followed by di-tertiary
butyl dicarbonate (2.58 mL, 11.0 mmol) were added and the reaction
mixture was heated at 100.degree. C. for 16 h. The reaction mixture
was quenched with water and the compound was extracted in ethyl
acetate. The organic layer was washed with 0.5 M hydrochloric acid
and brine, separated, dried over sodium sulphate and concentrated
under reduced pressure, and the residue was purified by repeated
washing with pentane to obtain tert-butyl
((6-chloro-3-methyl-1,5-dioxo-1,2,3,5-tetrahydroimidazo[1,5-c]pyridin-3-y-
l)methyl)(methyl)carbamate (4). Yield: 0.67 g, crude; MS (ESI) m/z
343[M+1].sup.+.
Synthesis of tert-butyl
methyl((3-methyl-1,5-dioxo-6-(pyrimidin-4-ylamino)-1,2,3,5-tetrahydroimid-
azo[1,5-a]pyridin-3-yl)methyl)carbamate (6)
[0286] The synthesis of intermediate 6 was carried out as described
above using the general protocol of Procedure B. Yield: 0.340 g,
72%; MS (ESI) m/z 401 [M+1].sup.+.
Synthesis of
3-methyl-3-((methylamino)methyl)-6-(pyrimidin-4-ylamino)-2,3-dihydroimida-
zo[1,5-a]pyridine-1,5-dione (Cpd. No. 25)
[0287] The synthesis of compound 25 was carried out as described
above using the general protocol of Procedure D. Light yellow
solid; Yield: 0.11 g, 44%; MS (ESI) m/z 301.20 [M+1].sup.+; .sup.1H
NMR (400 MHz, DMSO-d.sub.6) .delta. 9.37 (s, 2H), 8.75 (d, J=6.8
Hz, 2H), 8.36 (d, J=5.8 Hz, 1H), 7.36 (d, J=5.9 Hz, 1H), 6.82 (d,
J=7.1 Hz, 1H), 3.58 (d, J=13.1 Hz, 1H), 2.82 (d, J=13.1 Hz, 1H),
2.16 (s, 3H), 1.76 (s, 3H).
Example 26
Synthesis of
6-(pyrimidin-4-ylamino)-1H-spiro[imidazo[1,5-a]pyridine-3,3'-pyrrolidine]-
-1,5(2H)-dione (Cpd. No. 26)
##STR00086##
##STR00087##
[0288] Synthesis of benzyl
6-chloro-1,5-dioxo-2,5-dihydro-1H-spiro[imidazo[1,5-a]pyridine-3,3'-pyrro-
lidine]-1'-carboxylate (3)
[0289] The synthesis of intermediate 3 was carried out as described
above using the general protocol of Procedure A. Yield: 0.4 g, 37%;
MS (ESI) m/z 374 [M+1].sup.+.
Synthesis of benzyl
1,5-dioxo-6-(pyrimidin-4-ylamino)-2,5-dihydro-1H-spiro[imidazo[1,5-a]pyri-
dine-3,3'-pyrrolidine]-1'-carboxylate (5)
[0290] The synthesis of intermediate 5 was carried out as described
above using the general protocol of Procedure B. Yield: 0.1 g, 34%;
MS (ESI) m/z 432 [M+1].sup.+.
Synthesis of
6-(pyrimidin-4-ylamino)-1H-spiro[imidazo[1,5-a]pyridine-3,3'-pyrrolidine]-
-1,5(2H)-dione (Cpd. No. 26)
[0291] To a stirred solution of benzyl
1,5-dioxo-6-(pyrimidin-4-ylamino)-2,5-dihydro-1H-spiro[imidazo[1,5-a]pyri-
dine-3,3'-pyrrolidine]-1'-carboxylate (5, 0.06 g, 0.138 mmol) in
ethyl acetate: methanol (10:1, 33 mL), 20% palladium hydroxide
(0.03 g) was added. The reaction mixture was hydrogenated under
balloon pressure for 4 h. The progress of the reaction was
monitored by TLC. After complete consumption of starting material,
the reaction mixture was filtered through a pad of celite and the
filtrate was concentrated under reduced pressure. The residue was
purified by preparative TLC and repeated washing with ether to
afford
6-(pyrimidin-4-ylamino)-1H-spiro[imidazo[1,5-a]pyridine-3,3'-pyrrolidine]-
-1,5(2H)-dione (Cpd. No. 26) as a white solid. Yield: 0.025 g, 60%;
MS (ESI) m/z 299.20 [M+1].sup.+; .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 9.47 (s, 1H), 8.83-8.74 (m, 2H), 8.38 (d,
J=5.9 Hz, 1H), 7.37 (d, J=5.9 Hz, 1H), 6.92 (d, J=7.7 Hz, 1H), 3.67
(d, J=12.6 Hz, 1H), 3.19-3.03 (m, 2H), 2.95-2.75 (m, 2H), 2.05-1.88
(m, 1H).
Example 27
Synthesis of
3-(3,5-difluorophenyl)-3-methyl-6-(pyrimidin-4-ylamino)-2,3-dihydroimidaz-
o[1,5-a]pyridine-1,5-dione (Cpd. No. 27)
##STR00088##
##STR00089##
[0292] Synthesis of
6-chloro-3-(3,5-difluorophenyl)-3-methyl-2,3-dihydroimidazo[1,5-a]pyridin-
e-1,5-dione (3)
[0293] The synthesis of intermediate 3 was carried out as described
above using the general protocol of Procedure A. White solid;
Yield: 0.21 g, 23%; MS (ESI) m/z 311 [M+1].sup.+.
Synthesis of
3-(3,5-difluorophenyl)-3-methyl-6-(pyrimidin-4-ylamino)-2,3-dihydroimidaz-
o[1,5-a]pyridine-1,5-dione (Cpd. No. 27)
[0294] The synthesis of compound 27 was carried out as described
above using the general protocol of Procedure B. Yellow solid;
Yield: 0.12 g, 50%; MS (ESI) m/z 370 [M+1].sup.+; .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. 10.09 (s, 1H), 9.37 (s, 1H), 8.85-8.74
(m, 2H), 8.36 (d, J=5.9 Hz, 1H), 7.33-7.23 (m, 2H), 7.13 (d, J=8.0
Hz, 2H), 7.01 (d, J=7.7 Hz, 1H), 2.23 (s, 3H).
Example 28
Synthesis of
3-(3-chloro-5-fluorophenyl)-3-methyl-6-(pyrimidin-4-ylamino)-2,3-dihydroi-
midazo[1,5-a]pyridine-1,5-dione (Cpd. No. 28)
##STR00090##
##STR00091##
[0295] Synthesis of
6-chloro-3-(3-chloro-5-fluorophenyl)-3-methyl-2,3-dihydroimidazo[1,5-a]py-
ridine-1,5-dione (3)
[0296] The synthesis of intermediate 3 was carried out as described
above using the general protocol of Procedure A. Yield: 0.2 g, 21%;
MS (ESI) m/z 326[M+1].sup.+.
Synthesis of
3-(3-chloro-5-fluorophenyl)-3-methyl-6-(pyrimidin-4-ylamino)-2,3-dihydroi-
midazo[1,5-a]pyridine-1,5-dione (Cpd. No. 28)
[0297] The synthesis of compound 28 was carried out as described
above using the general protocol of Procedure B. Yellow solid;
Yield: 0.065 g, 27%; MS (ESI) m/z 286.25[M+1].sup.+; .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 10.10 (s, 1H), 9.39 (s, 1H),
8.86-8.74 (m, 2H), 8.36 (d, J=5.8 Hz, 1H), 7.53-7.45 (m, 1H),
7.33-7.24 (m, 3H), 7.22 (s, 1H), 2.23 (s, 3H).
Example 29
Synthesis of
N-[6-[(3-isopropyl-3-methyl-1,5-dioxo-2H-imidazo[1,5-a]pyridin-6-yl)amino-
]pyrimidin-4-yl]cyclopropanecarboxamide (Cpd. No. 29)
##STR00092##
##STR00093##
[0298] Synthesis of
6-chloro-3-isopropyl-3-methyl-2H-imidazo[1,5-a]pyridine-1,5-dione
(3)
[0299] The synthesis of intermediate 3 was carried out as described
above using the general protocol of Procedure A. Off-white solid.
Yield: 0.80 g, 82%; MS (ESI) m/z 241.08 [M+1].sup.+; .sup.1H NMR
(400 MHz, DMSO-d.sub.6): .delta. 9.94 (s, 1H), 7.95 (d, J=8.0 Hz,
1H), 6.71 (m, 1H), 3.01 (m, 1H), 1.79 (s, 3H), 1.03 (d, J=6.8 Hz,
3H), 0.42 (d, J=6.4 Hz, 3H).
Synthesis of
N-[6[(3-isopropyl-3-methyl-1,5-dioxo-2H-imidazo[1,5-a]pyridin-6-yl)-amino-
]pyrimidin-4-yl]cyclopropanecarboxamide (Cpd. No. 29)
[0300] The synthesis of compound 29 was carried out as described
above using the general protocol of Procedure B. Off-white solid;
Yield: 0.060 g, 13%; MS (ESI) m/z 383.30 [M+1].sup.+; .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 10.88 (s, 1H), 9.65 (s, 1H), 9.20
(s, 1H), 8.66 (d, J=7.6 Hz, 1H), 8.51 (s, 1H), 7.87 (s, 1H), 6.84
(d, J=7.6 Hz, 1H), 3.08 (m, 1H), 2.02 (m, 1H), 1.82 (s, 3H), 1.04
(d, J=6.8 Hz, 3H), 0.83 (d, J=6.0 Hz, 4H), 0.46 (d, J=6.4 Hz,
3H).
Example 30
Synthesis of
N-[6-[[3-(3-fluorophenyl)-3-methyl-1,5-dioxo-2H-imidazo[1,5-a]pyridin-6-y-
l]amino]pyrimidin-4-yl]cyclopropanecarboxamide (Cpd. No. 30)
##STR00094##
##STR00095##
[0301] Synthesis of
6-chloro-3-methyl-3-(trifluoromethyl)-2H-imidazo[1,5-a]pyridine-1,5-dione
(3)
[0302] The synthesis of intermediate 3 was carried out as described
above using the general protocol of Procedure A. White solid;
Yield: 300 mg, 59%; MS (ESI) m/z 293.13 [M+1].sup.+.
Synthesis of
N-[6-[[3-(3-fluorophenyl)-3-methyl-1,5-dioxo-2H-imidazo[1,5-a]pyridin-6-y-
l]amino]pyrimidin-4-yl]cyclopropanecarboxamide (Cpd. No. 30)
[0303] The synthesis of compound 30 was carried out as described
above using the general protocol of Procedure B. White solid;
Yield: 100 mg, 22%; MS (ESI) m/z 435.28 [M+1]+; .sup.1H NMR (400
MHz, DMSO-d6) .delta. 10.86 (s, 1H), 10.03 (s, 1H), 9.17 (s, 1H),
8.69 (d, J=7.6 Hz, 1H), 8.50 (s, 1H), 7.81 (s, 1H), 7.43 (m, 1H),
7.23 (m, 2H), 7.14 (m, 1H), 6.85 (d, J=7.6 Hz, 1H), 2.24 (s, 3H),
2.01 (m, 1H), 0.82 (d, J=6.0 Hz, 4H).
Example 31
Synthesis of
6-[[6-[(E)-2-cyclopropylvinyl]pyrimidin-4-yl]amino]-3-methyl-3-(trifluoro-
methyl)-2H-imidazo[1,5-a]pyridine-1,5-dione (Cpd. No. 31)
##STR00096##
##STR00097##
[0304] Synthesis of tert-butyl
N-[6-[(E)-2-cyclopropylvinyl]pyrimidin-4-yl]carbamate (3)
[0305] A mixture of [(E)-2-cyclopropylvinyl]boronic acid (1, 1.0 g,
8.93 mmol), tert-butyl
N-tert-butoxycarbonyl-N-(6-chloropyrimidin-4-yl)carbamate (2, 3.24
g, 9.83 mmol), sodium carbonate (2.84 g, 26.8 mmol), 1,4-dioxane
(10 mL) and water (3 mL) in a microwave vial was degassed with
argon for 10 minutes. To this mixture
1,1-bis(diphenylphosphino)ferrocene-palladium(II)dichloride
dichloromethane complex (0.73 g, 0.89 mmol) was added and purged
with argon for 5 minutes. After sealing, the vial was irradiated in
a microwave reactor at 130.degree. C. for 45 minutes. The reaction
mixture was diluted with water (20 mL) and extracted with ethyl
acetate (3.times.30 mL). The organics were washed with water
(2.times.10 mL) and saturated brine solution (1.times.10 mL). The
organics were then separated, dried with sodium sulfate, and
filtered before concentration to dryness. The crude residue was
purified by column chromatography (silica, ethyl
acetate/hexanes=25%) to obtain tert-butyl
N-[6-[(E)-2-cyclopropylvinyl]pyrimidin-4-yl]carbamate (3) as a
light brown solid. Yield: 370 mg, 16%; MS (ESI) m/z 262.22
[M+1-Boc].sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 10.23
(s, 1H), 8.60 (s, 1H), 7.63 (s, 1H), 6.50 (m, 2H), 1.48 (s, 9H),
0.91 (m, 2H), 0.64 (m, 2H)
Synthesis of 6-[(E)-2-cyclopropylvinyl]pyrimidin-4-amine (4)
[0306] A solution of tert-butyl
N-[6-[(E)-2-cyclopropylvinyl]pyrimidin-4-yl]carbamate (3, 350 mg,
1.34 mmol) in dichloromethane (10 mL) at 0.degree. C.,
trifluoroacetic acid (1.5 mL, 1.34 mmol) was added and stirred at
25.degree. C. for 16 h. The solvent was removed under reduced
pressure and the mixture made basic with the residue with aqueous
ammonia. Filtration and washing with diethyl ether provided
(6-[(E)-2-cyclopropylvinyl]pyrimidin-4-amine (4) as a brown solid.
Yield: 170 mg, 79%; MS (ESI) m/z 162.10 [M+1].sup.+; .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 8.19 (s, 1H), 6.70 (brs, 2H),
6.32-6.27 (m, 2H), 6.17 (s, 1H), 1.60 (m, 1H), 0.84 (m, 2H), 0.55
(m, 2H).
Synthesis of
6-[[6-[(E)-2-cyclopropylvinyl]pyrimidin-4-yl]amino]-3-methyl-3-(trifluoro-
methyl)-2H-imidazo[1,5-a]pyridine-1,5-dione (Cpd. No. 31)
[0307] The synthesis of compound 31 was carried out as described
above using the general protocol of Procedure B. Light brown solid;
Yield: 70 mg, 19%; MS (ESI) m/z 392.26 [M+1].sup.+; .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 10.50 (brs, 1H), 9.42 (s, 1H), 8.78
(d, J=7.6 Hz, 1H), 8.63 (s, 1H), 7.19 (s, 1H), 7.00 (d, J=8.0 Hz,
1H), 6.46 (m, 2H), 2.13 (s, 3H), 1.69 (m, 1H), 0.90 (m, 2H), 0.62
(m, 2H).
Example 32
Synthesis of
3,3-dimethyl-6-(7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,3-dihydroimidazo[1,5-a-
]pyridine-1,5-dione (Cpd. No. 32)
##STR00098##
##STR00099##
[0308] Synthesis of
3,3-dimethyl-6-(7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,3-dihydroimidazo[1,5-a-
]pyridine-1,5-dione (Cpd. No. 32)
[0309] The synthesis of compound 32 was carried out as described
above using the general protocol of Procedure B. Yellow solid;
Yield: 0.13 g, 42%; MS (ESI) m/z 296[M+1].sup.+; .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. 10.1 (s, 1H), 9.15 (s, 1H), 8.83 (s,
1H), 8.18-8.27 (m, 1H), 7.98-7.87 (m, 1H), 6.99 (d, J=5.9 Hz, 1H),
6.87 (d, J=7.7 Hz, 1H), 1.88 (s, 6H).
Example 33
Synthesis of
3-(3,5-dichlorophenyl)-3-methyl-6-(pyrimidin-4-ylamino)-2,3-dihydroimidaz-
o[1,5-a]pyridine-1,5-dione (Cpd. No. 33)
##STR00100##
##STR00101##
[0310] Synthesis of
6-chloro-3-(3,5-dichlorophenyl)-3-methyl-2,3-dihydroimidazo[1,5-a]pyridin-
e-1,5-dione (3)
[0311] The synthesis of intermediate 3 was carried out as described
above using the general protocol of Procedure A. Yield: 0.21 g,
21%.
Synthesis of
3-(3,5-dichlorophenyl)-3-methyl-6-(pyrimidin-4-ylamino)-2,3-dihydroimidaz-
o[1,5-a]pyridine-1,5-dione (Cpd. No. 33)
[0312] The synthesis of compound 33 was carried out as described
above using the general protocol of Procedure B. Yellow solid;
Yield: 0.042 g, 17%; MS (ESI) m/z 402[M+1].sup.+; .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. 10.09 (s, 1H), 9.38 (s, 1H), 8.85-8.74
(m, 2H), 8.36 (d, J=5.9 Hz, 1H), 7.66 (t, J=1.9 Hz, 1H), 7.44 (d,
J=1.9 Hz, 2H), 7.29 (d, J=6.0 Hz, 1H), 7.02 (d, J=7.7 Hz, 1H), 2.23
(s, 3H).
Example 34
Synthesis of
3-methyl-3-(pyridin-2-yl)-6-(pyrimidin-4-ylamino)-2,3-dihydroimidazo[1,5--
a]pyridine-1,5-dione (Cpd. No. 34)
##STR00102##
##STR00103##
[0313] Synthesis of
6-chloro-3-methyl-3-(pyridin-2-yl)-2,3-dihydroimidazo[1,5-a]pyridine-1,5--
dione (3)
[0314] The synthesis of intermediate 3 was carried out as described
above using the general protocol of Procedure A. Yield: 0.26 g,
33%; MS (ESI) m/z 276[M+1].sup.+.
Synthesis of
3-methyl-3-(pyridin-2-yl)-6-(pyrimidin-4-ylamino)-2,3-dihydroimidazo[1,5--
a]pyridine-1,5-dione (Cpd. No. 34)
[0315] The synthesis of compound 34 was carried out as described
above using the general protocol of Procedure B. Off-white solid;
Yield: 0.012 g, 5%; MS (ESI) m/z 335.10[M+1].sup.+; .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 9.96 (s, 1H), 9.28 (s, 1H),
8.83-8.73 (m, 2H), 8.55-8.48 (m, 1H), 8.34 (d, J=5.9 Hz, 1H),
7.88-7.84 (m, 1H), 7.57 (d, J=8.0 Hz, 1H), 7.37 (dd, J=7.6, 4.7 Hz,
1H), 7.25 (d, J=5.9 Hz, 1H), 6.97 (d, J=7.6 Hz, 1H), 2.29 (s,
3H).
Example 35
Synthesis of
8-chloro-3-methyl-6-(pyrimidin-4-ylamino)-3-(trifluoromethyl)-2H-imidazo[-
1,5-a]pyridine-1,5-dione (Cpd. No. 35)
##STR00104##
##STR00105##
[0316] Synthesis of
6-bromo-8-chloro-3-methyl-3-(trifluoromethyl)-2H-imidazo[1,5-a]pyridine-1-
,5-dione (3)
[0317] The synthesis of intermediate 3 was carried out as described
above using the general protocol of Procedure A. Off white solid;
Yield: 1.8 g, 66%; MS (ESI) m/z 346.6 [M+1].sup.+; .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. 10.90 (s, 1H), 8.36 (s, 1H), 2.06 (s,
3H).
Synthesis of
8-chloro-3-methyl-6-(pyrimidin-4-ylamino)-3-(trifluoromethyl)-2H-imidazo--
[1,5-a]pyridine-1,5-dione (Cpd. No. 35)
[0318] The synthesis of compound 35 was carried out as described
above using the general protocol of Procedure B. Off-white solid;
Yield: 0.52 g, 35%; MS (ESI) m/z 360.22 [M+1].sup.+; .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 10.60 (s, 1H), 9.82 (s, 1H), 8.87
(s, 1H), 8.81 (m, 1H), 8.47 (d, J=6.0 Hz, 1H), 7.46 (d, J=6.0 Hz,
1H), 2.12 (s, 3H).
Example 36
Synthesis of
2',2'-dimethyl-6-(pyrimidin-4-ylamino)spiro[2H-imidazo[1,5-a]pyridine-3,1-
'-cyclopentane]-1,5-dione (Cpd. No. 36)
##STR00106##
##STR00107##
[0319] Synthesis of
6-chloro-2',2'-dimethyl-spiro[2H-imidazo[1,5-a]pyridine-3,1'-cyclopentane-
]-1,5-dione (3)
[0320] The synthesis of intermediate 3 was carried out as described
above using the general protocol of Procedure A. Cream colored
solid; Yield: 0.12 g, 16%; MS (ESI) m/z 267.15 [M+1].sup.+.
Synthesis of
2',2'-dimethyl-6-(pyrimidin-4-ylamino)spiro[2H-imidazo[1,5-a]pyridine-3,1-
'-cyclopentane]-1,5-dione (Cpd. No. 36)
[0321] The synthesis of compound 36 was carried out as described
above using the general protocol of Procedure B. Off-white solid;
Yield: 17 mg, 9%; MS (ESI) m/z 326.30[M+1].sup.+; 1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 9.66 (s, 1H), 9.48 (s, 1H), 8.78 (d, J=7.6
Hz, 1H), 8.76 (s, 1H), 8.37 (d, J=6.0 Hz, 1H), 7.40 (d, J=6.06 Hz,
1H), 6.87 (d, J=7.6 Hz, 1H), 2.94 (m, 1H), 2.50-1.66 (m, 6H), 1.03
(s, 3H), 0.72 (s, 3H).
Example 37
Synthesis of
6-[(8-cyclopropyl-9H-purin-6-yl)amino]-3-methyl-3-(trifluoromethyl)-2H-im-
idazo[1,5-a]pyridine-1,5-dione (Cpd. No. 37)
##STR00108##
##STR00109##
[0322] Synthesis of 6-chloro-8-cyclopropyl-9H-purine (3)
[0323] To a solution of 6-chloropyrimidine-4,5-diamine (1, 2.0 g,
13.84 mmol) and cyclopropanecarbaldehyde (2, 1.16 g, 16.6 mmol) in
methanol (100 mL), acetic acid (1.0 mL) was added and stirred at
room temperature for 2 h. To this mixture was added iron(III)
chloride (11.22 g, 69.18 mmol) and stirring was continued for 24 h.
The solvents were removed under reduced pressure and the crude
residue was purified via column chromatography (silica, ethyl
acetate/hexanes=70%) to afford 6-chloro-8-cyclopropyl-9H-purine (3)
as a white solid. Yield: 1.2 g, 45%; MS (ESI) m/z 195.14
[M+1].sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 13.65 (s,
1H), 8.60 (s, 1H), 2.19 (m, 1H), 1.18 (m, 4H).
Synthesis of
2-[(6-chloro-8-cyclopropyl-purin-9-yl)methoxy]ethyl-trimethyl-silane
(5)
[0324] To a stirred suspension of sodium hydride (0.18 g, 7.71
mmol) in dimethylformamide (10 mL) at 0.degree. C.,
6-chloro-8-cyclopropyl-9H-purine (3, 1.0 g, 5.14 mmol) was added
and stirred for 30 m. To this mixture,
2-(chloromethoxy)ethyl-trimethyl-silane (4, 2.0 mL, 6.17 mmol) was
added dropwise and allowed to stir at room temperature for 16 h.
The reaction mixture was quenched with ice cold water (20 mL) and
extracted with ethyl acetate (3.times.50 mL). The combined organic
layers were separated and dried with magnesium sulfate before
concentration to dryness. The crude residue was purified via column
chromatography ethyl acetate/hexanes=70%) to afford
2-[(6-chloro-8-cyclopropyl-purin-9-yl)methoxy]ethyl-trimethyl-s-
ilane (5) as an off-white solid. Yield: 0.84 g, 50%; MS (ESI) m/z
325.30 [M+1].sup.+; .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.65
(s, 1H), 5.73 (s, 2H), 3.61 (m, 2H), 2.44 (m, 1H), 1.43 (m, 2H),
1.26 (m, 2H), 0.88 (m, 2H), 0.05 (s, 9H).
Synthesis of
8-cyclopropyl-9-(2-trimethylsilylethoxymethyl)purin-6-amine (6)
[0325] In a sealed tube a stirred suspension of
2-[(6-chloro-8-cyclopropyl-purin-9-yl)methoxy]ethyl-trimethyl-silane
(5, 0.8 g, 2.46 mmol) and 30% aqueous ammonia (10 mL) in ethanol
(10 mL) was heated at 120.degree. C. for 14 h. After TLC showed
consumption of 5, ethanol was removed under reduced pressure and
the residue was washed with water (10 mL) and diethyl ether (10 mL)
to obtain
8-cyclopropyl-9-(2-trimethylsilylethoxymethyl)purin-6-amine (6) as
a white solid. Yield: 703 mg, 93%; MS (ESI) m/z 306.30 [M+1].sup.+;
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.00 (s, 1H), 7.10 (s,
2H), 5.64 (s, 2H), 3.57 (m, 2H), 2.24 (m, 1H), 1.08 (m, 4H), 0.83
(m, 2H), 0.09 (s, 9H).
Synthesis of
6-[[8-cyclopropyl-9-(2-trimethylsilylethoxymethyl)purin-6-yl]amino]-3-met-
hyl-3-(trifluoromethyl)-2H-imidazo[1,5-a]pyridine-1,5-dione (8)
[0326] The synthesis of intermediate 8 was carried out as described
above using the general protocol of Procedure B. Yellow solid;
Yield: 300 mg, 50%; MS (ESI) m/z 536.26 [M+1].sup.+.
Synthesis of
6-[(8-cyclopropyl-9H-purin-6-yl)amino]-3-methyl-3-(trifluoromethyl)-2H-im-
idazo[1,5-a]pyridine-1,5-dione (Cpd. No. 37)
[0327] To a solution of
6-[[8-cyclopropyl-9-(2-trimethylsilylethoxymethyl)purin-6-yl]amino]-3-met-
hyl-3-(trifluoromethyl)-2H-imidazo[1,5-a]pyridine-1,5-dione (8,
0.25 g, 0.47 mmol) in tetrahydrofuran (50 mL) was added
tetrabutylammonium fluoride hydrate (0.61 g, 2.33 mmol). The
mixture was heated at 70.degree. C. for 4 h. After TLC showed
consumption of 8, the reaction mixture was diluted with water (50
mL) and extracted with ethyl acetate (2.times.50 mL). The combined
organic layers were dried over sodium sulfate and concentrated
under reduced pressure. The crude mixture was purified via column
chromatography (silica, methanol/dichloromethane=2%) to afford
6-[(8-cyclopropyl-9H-purin-6-yl)amino]-3-methyl-3-(trifluoromet-
hyl)-2H-imidazo[1,5-a]pyridine-1,5-dione (Cpd. No. 37) as yellow
solid. Yield: 135 mg, 71%; MS (ESI) m/z 406.29 [M+1].sup.+; .sup.1H
NMR (400 MHz, DMSO-d.sub.6) .delta. 13.24 (s, 1H), 10.55 (s, 1H),
8.80 (d, J=7.6 Hz, 1H), 8.64 (s, 1H), 8.49 (s, 1H), 7.10 (d, J=7.6
Hz, 1H), 2.16 (m, 1H), 2.15 (s, 3H), 1.12 (m, 4H).
Example 38
Synthesis of
N-[6-[(8-chloro-1,5-dioxo-spiro[2H-imidazo[1,5-a]pyridine-3,1'-cyclopenta-
ne]-6-yl)amino]pyrimidin-4-yl]cyclopropanecarboxamide (Cpd. No.
38)
##STR00110##
##STR00111##
[0328] Synthesis of ethyl 5-bromo-3-chloro-pyridine-2-carboxylate
(2)
[0329] To a stirred solution of
5-bromo-3-chloro-pyridine-2-carboxylic acid (1, 150.0 g, 634.38
mmol) in ethanol (1.5 L) was added sulfuric acid (93.26 g, 951.58
mmol) at room temperature. The reaction mass was stirred at
80.degree. C. overnight. After consumption of starting material as
indicated by TLC, the reaction mixture was cooled to room
temperature and solvent was removed under reduced pressure. The
resulting residue was neutralized with saturated aqueous sodium
bicarbonate solution and extracted with ethyl acetate (2.times.1
L). The organic layers were then separated, combined, dried with
magnesium sulfate and concentrated to dryness in vacuum to afford
ethyl 5-bromo-3-chloro-pyridine-2-carboxylate (2) as an off white
solid. Yield: 163 g, 97%; .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. 8.69 (m, 1H), 8.08 (m, 1H), 7.81 (m, 1H), 4.47 (m, 2H),
1.43 (t, J=7.2 Hz, 3H).
Synthesis of ethyl
5-bromo-3-chloro-1-oxido-pyridin-1-ium-2-carboxylate (3)
[0330] To a stirred solution of ethyl
5-bromo-3-chloro-pyridine-2-carboxylate (2, 151.0 g, 570.89 mmol)
in dichloromethane (1.73 L) was added trifluoroacetic anhydride
(30.0 mL, 1.14 mol) and urea hydrogen peroxide (112.69 g, 1.20 mol)
at 0.degree. C. The reaction was stirred overnight at room
temperature. After completion of the reaction, the reaction mixture
was neutralized with a potassium phosphate dibasic solution. A
sodium bisulfite solution was added followed by extraction with
dichloromethane (2.times.100 mL). The organic layers were
separated, combined, dried with magnesium sulfate, filtered and
concentrated to dryness under vacuum to afford ethyl
5-bromo-3-chloro-1-oxido-pyridin-1-ium-2-carboxylate 3 as an off
white solid. Yield: 150.5 g, 94%; MS (ESI) m/z 281.8 [M+1].sup.+;
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.26 (d, J=1.2 Hz, 1H),
7.48 (d, J=1.2 Hz, 1H), 4.50 (q, J=7.12 Hz, 2H), 1.42 (t, J=12.12
Hz, 3H).
Synthesis of ethyl 5-bromo-3-chloro-6-oxo-1H-pyridine-2-carboxylate
(4)
[0331] To a stirred solution of ethyl
5-bromo-3-chloro-1-oxido-pyridin-1-ium-2-carboxylate (3, 150 g,
534.8 mmol) in dimethylformamide (900 mL) at 0.degree. C. was added
trifluoroacetic anhydride (224.63 g, 1.07 mmol). The temperature of
the reaction mixture was raised to 50.degree. C. and stirring was
continued for 1 h. After the oxidation was complete, the reaction
mass was quenched with a saturated aqueous sodium bicarbonate
solution and product was extracted with dichloromethane
(2.times.100 mL). The organic layers were separated, combined,
dried with magnesium sulfate and concentrated to dryness under
vacuum to afford ethyl
5-bromo-3-chloro-6-oxo-1H-pyridine-2-carboxylate (4) as a yellow
solid. Yield: 75 g, 50%; MS (ESI) m/z 281.8 [M+1].sup.+; .sup.1H
NMR (400 MHz, DMSO-d.sub.6) .delta. 10.44-10.02 (m, 1H), 7.86 (s,
1H), 4.47 (q, J=7.2 Hz, 2H), 1.43 (t, J=5.6 Hz, 3H).
Synthesis of 5-bromo-3-chloro-6-oxo-1H-pyridine-2-carboxamide
(5)
[0332] In a round bottom flask containing ethyl
5-bromo-3-chloro-6-oxo-1H-pyridine-2-carboxylate (4, 75.0 g, 267.38
mmol) was added liquid ammonia (150.0 mL, 267.38 mmol) in ethanol
(100 mL) at 0.degree. C. The reaction mixture was stirred at
45.degree. C. for 2 h. At this time the mixture was concentrated to
remove the ethanolic ammonia. The crude solids were washed with
diethyl ether (500 mL) and dissolved in refluxing methanol (1 L)
and filtered hot. The filtrate was concentrated under reduced
pressure until 1/3 of solvent volume remained. Diethyl ether was
added until all solids precipitated. The solid was filtered and
dried under vacuum to afford
5-bromo-3-chloro-6-oxo-1H-pyridine-2-carboxamide (5) as a light
brown solid. Yield: 45 g, 69%; MS (ESI) m/z 248.9 [M-1].sup.-;
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 7.92-7.82 (m, 1H),
7.61-7.59 (m, 1H), 7.36 (s, 1H).
Synthesis
6-bromo-8-chloro-spiro[2H-imidazo[1,5-a]pyridine-3,1'-cyclopenta-
ne]-1,5-dione (7)
[0333] The synthesis of intermediate 7 was carried out as described
above using the general protocol of Procedure A. Off-white solid;
Yield: 450 mg, 87%; MS (ESI) m/z 317.03 [M+1].sup.+; .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 10.39 (s, 1H), 8.25 (s, 1H), 2.73
(m, 4H), 2.21 (m, 2H), 1.93 (m, 2H).
Synthesis of
N-[6-[(8-chloro-1,5-dioxo-spiro[2H-imidazo[1,5-a]pyridine-3,1'-cyclopenta-
ne]-6-yl)amino]pyrimidin-4-yl]cyclopropanecarboxamide (Cpd. No.
38)
[0334] The synthesis of compound 38 was carried out as described
above using the general protocol of Procedure B. White solid;
Yield: 50 mg, 17%; MS (ESI) m/z 415.32 [M+1].sup.+; .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 10.92 (s, 1H), 10.08 (s, 1H), 9.52
(s, 1H), 8.72 (s, 1H), 8.59 (s, 1H), 7.98 (s, 1H), 2.78 (m, 2H),
2.02 (m, 3H), 1.83 (m, 2H), 1.72 (m, 2H), 0.84 (d, J=6.0 Hz,
4H).
Example 39
Synthesis of
8'-chloro-6'-(pyrimidin-4-ylamino)-2'H-spiro[cyclopentane-1,3'-imidazo[1,-
5-a]pyridine]-1',5'-dione (Cpd. No. 39)
##STR00112##
##STR00113##
[0335] Synthesis of
8'-chloro-6'-(pyrimidin-4-ylamino)-2'H-spiro[cyclopentane-1,3'-imidazo[1,-
5-a]pyridine]-1',5'-dione (Cpd. No. 39)
[0336] The synthesis of compound 39 was carried out as described
above using the general protocol of Procedure B. Off white solid;
Yield: 0.07 g, 30%; MS (ESI) m/z 332.28 [M+1]; .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. 10.11 (s, 1H), 9.67 (s, 1H), 8.84 (s,
1H), 8.79 (s, 1H), 8.43 (d, J=5.6 Hz, 1H), 7.43 (d, J=5.6, 1H),
2.77 (m, 2H), 1.98 (m, 2H), 1.82 (m, 2H), 1.74 (m, 2H).
Example 40
Synthesis of
3,3-dimethyl-6-(5H-pyrrolo[2,3-d]pyrimidin-7(6H)-yl)-2,3-dihydroimidazo[1-
,5-a]pyridine-1,5-dione (Cpd. No. 40)
##STR00114##
##STR00115##
[0337] Synthesis of
3,3-dimethyl-6-(5H-pyrrolo[2,3-d]pyrimidin-7(6H)-yl)-2,3-dihydroimidazo-[-
1,5-a]pyridine-1,5-dione (Cpd. No. 40)
[0338] To a stirred solution of 3, 3-dimethyl-6-(7H-pyrrolo [2,
3-d] pyrimidin-7-yl)-2, 3-dihydroimidazo[1,5-a]pyridine-1,5-dione
(1, 0.095 g, 0.32 mmol) in methanol (25 ml), 10% palladium on
carbon (25 mg) was added. The reaction mixture was hydrogenated
under balloon pressure hydrogen gas for 24 h. The progress of the
reaction was monitored by TLC. After complete consumption of
starting material, reaction mixture was filtered through a pad of
celite and the filtrate was concentrated under reduced pressure to
obtain a crude residue. The residue was purified by prep HPLC to
afford the product as a light yellow solid. Yield: 8.0 mg, 8%; MS
(ESI) m/z 298.20 [M+1].sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. 8.35 (s, 1H), 8.15 (s, 1H), 7.96 (d, J=7.4 Hz, 1H), 6.81
(d, J=7.5 Hz, 1H), 4.17 (t, J=8.6 Hz, 2H), 3.13 (t, J=8.6 Hz, 2H),
2.59 (s, 2H), 1.79 (s, 6H).
Example 41
Synthesis of
3-(2-aminoethyl)-3-methyl-6-(pyrimidin-4-ylamino)-2H-imidazo[1,5-a]pyridi-
ne-1,5-dione (Cpd. No. 41)
##STR00116##
##STR00117##
[0339] Synthesis of
6-chloro-3-[2-(1,3-dioxoisoindolin-2-yl)ethyl]-3-methyl-2H-imidazo[1,5-a]-
pyridine-1,5-dione (3)
[0340] The synthesis of intermediate 3 was carried out as described
above using the general protocol of Procedure A. Brown solid;
Yield: 3.01 g, 59%; MS (ESI) m/z 372.0 [M+1].sup.+.
Synthesis of
3-[2-(1,3-dioxoisoindolin-2-yl)ethyl]-3-methyl-6-(pyrimidin-4-ylamino)-2H-
-imidazo[1,5-a]pyridine-1,5-dione (5)
[0341] The synthesis of intermediate 5 was carried out as described
above using the general protocol of Procedure B. Yellow solid;
Yield: 1.03 g, 36%; MS (ESI) m/z 431.31 [M+1].sup.+.
Synthesis of
3-(2-aminoethyl)-3-methyl-6-(pyrimidin-4-ylamino)-2H-imidazo[1,5-a]pyridi-
ne-1,5-dione (Cpd. No. 41)
[0342] The synthesis of compound 41 was carried out as described
above using the general protocol of Procedure C. Cream-colored
solid; Yield: 300 mg, 54%; MS (ESI) m/z 301.32 [M+1].sup.+; .sup.1H
NMR (400 MHz, DMSO-d.sub.6) .delta. 9.41 (brs, 1H), 8.77 (d, J=7.6
Hz, 1H), 8.76 (s, 1H), 8.37 (d, J=6.0 Hz, 1H), 7.37 (d, J=5.6 Hz,
1H), 6.86 (d, J=7.6 Hz, 1H), 4.39 (brs, 2H), 2.59 (m, 1H), 2.41 (m,
1H), 2.22 (m, 1H), 2.15 (m, 1H), 1.80 (s, 3H).
Example 42
Synthesis of
N-[6-[(8-chloro-3-cyclopentyl-3-methyl-1,5-dioxo-2H-imidazo[1,5-a]pyridin-
-6-yl)amino]pyrimidin-4-yl]cyclopropanecarboxamide (Cpd. No.
42)
##STR00118##
##STR00119##
[0343] Synthesis of
6-bromo-8-chloro-3-cyclopentyl-3-methyl-2H-imidazo[1,5-a]pyridine-1,5-dio-
ne (3)
[0344] The synthesis of intermediate 3 was carried out as described
above using the general protocol of Procedure A. Light brown solid;
Yield: 605 mg, 54%; MS (ESI) m/z 346.98 [M+1].sup.+.
Synthesis of
N-[6[(8-chloro-3-cyclopentyl-3-methyl-1,5-dioxo-2H-imidazo[1,5-a]pyridin--
6-yl)amino]pyrimidin-4-yl]cyclopropanecarboxamide (Cpd. No. 42)
[0345] The synthesis of compound 42 was carried out as described
above using the general protocol of Procedure B. Off-white solid;
Yield: 16 mg, 5%; MS (ESI) m/z 443.35 [M+1].sup.+; .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. 10.93 (s, 1H), 9.78 (s, 1H), 9.46 (s,
1H), 8.70 (s, 1H), 8.59 (s, 1H), 7.97 (s, 1H), 3.39 (m, 1H), 2.01
(m, 1H), 1.82 (s, 3H), 1.77 (m, 1H), 1.57-1.37 (m, 5H), 1.14 (m,
1H), 0.83 (m, 5H).
Example 43
Synthesis of
N-[6-[(8-chloro-3,3-dimethyl-1,5-dioxo-2H-imidazo[1,5-a]pyridin-6-yl)amin-
o]pyrimidin-4-yl]cyclopropanecarboxamide (Cpd. No. 43)
##STR00120##
##STR00121##
[0346] Synthesis of
6-bromo-8-chloro-3,3-dimethyl-2H-imidazo[1,5-a]pyridine-1,5-dione
(3)
[0347] The synthesis of intermediate 3 was carried out as described
above using the general protocol of Procedure A. White solid;
Yield: 390 mg, 48%; MS (ESI) m/z 288.93 [M-1].sup.-; .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 10.03 (s, 1H), 8.24 (s, 1H), 1.75
(s, 6H).
Synthesis of
N-[6[(8-chloro-3,3-dimethyl-1,5-dioxo-2H-imidazo[1,5-a]pyridin-6-yl)-amin-
o]pyrimidin-4-yl]cyclopropanecarboxamide (Cpd. No. 43)
[0348] The synthesis of compound 43 was carried out as described
above using the general protocol of Procedure B. Light yellow
solid; Yield: 42 mg, 17%; MS (ESI) m/z 389.28 [M+1].sup.+; .sup.1H
NMR (400 MHz, DMSO-d.sub.6) .delta. 10.92 (s, 1H), 9.74 (s, 1H),
9.49 (s, 1H), 8.70 (s, 1H), 8.59 (s, 1H), 7.98 (s, 1H), 2.02 (m,
1H), 1.79 (s, 6H), 0.84 (d, J=6.0 Hz, 4H).
Example 44
Synthesis of
N-(6-((8'-chloro-1',5'-dioxo-1',5'-dihydro-2'H-spiro[cyclobutane-1,3'-imi-
dazo[1,5-a]pyridin]-6'-yl)amino)pyrimidin-4-yl)cyclopropanecarboxamide
(Cpd. No. 44)
##STR00122##
##STR00123##
[0349] Synthesis of
6'-bromo-8'-chloro-2'H-spiro[cyclobutane-1,3'-imidazo[1,5-a]pyridine]-1',-
5'-dione (3)
[0350] The synthesis of intermediate 3 was carried out as described
above using the general protocol of Procedure A. Brown solid;
Yield: 0.260 g, 72%; MS (ESI) m/z 300.94 [M-1].sup.-; .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 10.5 (s, 1H), 8.24 (s, 1H), 3.45
(m, 2H), 2.28 (m, 2H), 2.10 (m, 1H), 1.89 (m, 1H).
Synthesis of
N-(6-((8'-chloro-1',5'-dioxo-1',5'-dihydro-2'H-spiro[cyclobutane-1,3'-imi-
dazo-[1,5-a]pyridin]-6'-yl)amino)pyrimidin-4-yl)cyclopropanecarboxamide
(Cpd. No, 44)
[0351] The synthesis of compound 44 was carried out as described
above using the general protocol of Procedure B. Light yellow
solid; Yield: 0.110 g, 33%; MS (ESI) m/z 401.27 [M+1].sup.+;
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 10.94 (s, 1H), 10.24
(s, 1H), 9.59 (s, 1H), 8.71 (s, 1H), 8.59 (s, 1H), 8.00 (s, 1H),
3.26 (m, 2H), 2.34 (m, 2H), 2.15 (m, 1H), 2.04 (m, 1H), 1.89 (m,
1H), 0.82 (m, 4H).
Example 45
Synthesis of
N-(6-((8'-chloro-1',5'-dioxo-1',5'-dihydro-2'H-spiro[cyclohexane-1,3'-imi-
dazo[1,5-a]pyridin]-6'-yl)amino)pyrimidin-4-yl)cyclopropanecarboxamide
(Cpd. No. 45)
##STR00124##
##STR00125##
[0352] Synthesis of
6'-bromo-8'-chloro-2'H-spiro[cyclohexane-1,3'-imidazo[1,5-a]pyridine]-1',-
5'-dione (3)
[0353] The synthesis of intermediate 3 was carried out as described
above using the general protocol of Procedure A. Off white solid;
Yield: 1.93 g, 64%; MS (ESI) m/z 330.99 [M+1]; .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. 10.59 (s, 1H), 8.24 (s, 1H), 2.84 (t,
J=10.74, 2H), 1.74 (m, 2H), 1.63 (m, 3H), 1.53 (m, 2H), 1.20 (m,
1H).
Synthesis of
N-(6-((8'-chloro-1,5'-dioxo-1',5'-dihydro-2'H-spiro[cyclohexane-1,3'-imid-
azo[1,5-a]pyridin]-6'-yl)amino)pyrimidin-4-yl)cyclopropanecarboxamide
(Cpd. No. 45)
[0354] The synthesis of compound 45 was carried out as described
above using the general protocol of Procedure B. Yellow solid;
Yield: 0.051 g, 2.07%; MS (ESI) m/z 429.34 [M+1]+; .sup.1H NMR (400
MHz, DMSO-d6) .delta. 10.93 (s, 1H), 10.29 (s, 1H), 9.43 (s, 1H),
8.70 (s, 1H), 8.58 (s, 1H), 7.97 (s, 1H), 2.93 (t, J=11.16 Hz, 2H),
2.02 (m, 1H), 1.75 (m, 2H), 1.64 (m, 3H), 1.54 (m, 2H), 1.21 (m,
1H), 0.84 (m, 4H).
Example 46
Synthesis of
N-[6-[[8-chloro-3-methyl-1,5-dioxo-3-(2,2,2-trifluoroethyl)-2H-imidazo[1,-
5-a]pyridin-6-yl]amino]pyrimidin-4-yl]cyclopropanecarboxamide (Cpd.
No. 46)
##STR00126##
##STR00127##
[0355] Synthesis of
6-bromo-8-chloro-3-methyl-3-(2,2,2-trifluoroethyl)-2H-imidazo[1,5-a]-pyri-
dine-1,5-dione (3)
[0356] The synthesis of intermediate 3 was carried out as described
above using the general protocol of Procedure A. Brown solid;
Yield: 325 mg, 57%; MS (ESI) m/z 358.95 [M+1].sup.+.
Synthesis of
N-[6-[[8-chloro-3-methyl-1,5-dioxo-3-(2,2,2-trifluoroethyl)-2H-imidazo[1,-
5-a]pyridin-6-yl]amino]pyrimidin-4-yl]cyclopropanecarboxamide (Cpd.
No. 46)
[0357] The synthesis of compound 46 was carried out as described
above using the general protocol of Procedure B. Light brown solid;
Yield: 120 mg, 32%; MS (ESI) m/z 457.31 [M+1].sup.+; .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 10.95 (s, 1H), 9.92 (s, 1H), 9.59
(s, 1H), 8.75 (s, 1H), 8.60 (s, 1H), 8.01 (s, 1H), 3.69 (m, 1H),
3.12 (m, 1H), 2.02 (m, 1H), 1.87 (s, 3H), 0.84 (d, J=6.0 Hz,
4H).
Example 47
Synthesis of
8-chloro-3,3-dimethyl-6-(pyrimidin-4-ylamino)-2,3-dihydroimidazo[1,5-a]py-
ridine-1,5-dione (Cpd. No. 47)
##STR00128##
##STR00129##
[0358] Synthesis of
8-chloro-3,3-dimethyl-6-(pyrimidin-4-ylamino)-2,3-dihydroimidazo[1,5-a]py-
ridine-1,5-dione (Cpd. No. 47)
[0359] The synthesis of compound 47 was carried out as described
above using the general protocol of Procedure B. Off white solid;
Yield: 0.020 g, 10%; MS (ESI) m/z 306.25 [M+1].sup.+; .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 9.78 (s, 1H), 9.64 (s, 1H), 8.84
(s, 1H), 8.79 (s, 1H), 8.43 (d, J=5.6 Hz, 1H), 7.44 (d, J=5.2 Hz,
1H), 1.81 (s, 6H).
Example 48
Synthesis of
8-chloro-3-cyclopentyl-3-methyl-6-(pyrimidin-4-ylamino)-2H-imidazo[1,5-a]-
pyridine-1,5-dione (Cpd. No. 48)
##STR00130##
##STR00131##
[0360] Synthesis of
8-chloro-3-cyclopentyl-3-methyl-6-(pyrimidin-4-ylamino)-2H-imidazo[1,5-a]-
pyridine-1,5-dione (Cpd. No. 48)
[0361] The synthesis of compound 48 was carried out as described
above using the general protocol of Procedure B. Light yellow
solid; Yield: 0.019 g, 6%; MS (ESI) m/z 360.23 [M+1].sup.+; .sup.1H
NMR (400 MHz, DMSO-d.sub.6) .delta. 9.83 (s, 1H), 9.63 (s, 1H),
8.84 (s, 1H), 8.79 (s, 1H), 8.44 (d, J=5.7 Hz, 1H), 7.43 (d, J=5.6
Hz, 1H), 3.38 (m, 1H), 1.84 (s, 3H), 1.79 (m, 1H), 1.51 (m, 5H),
1.13 (m, 1H), 0.83 (m, 1H).
Example 49
Synthesis of
N-(6-((8-chloro-3-methyl-1,5-dioxo-3-(trifluoromethyl)-1,2,3,5-tetrahydro-
imidazo[1,5-a]pyridin-6-yl)amino)pyrimidin-4-yl)cyclopropanecarboxamide
(Cpd. No. 49)
##STR00132##
##STR00133##
[0362] Synthesis of
6-bromo-8-chloro-3-methyl-3-(trifluoromethyl)-2,3-dihydroimidazo[1,5-a]py-
ridine-1,5-dione (3)
[0363] The synthesis of intermediate 3 was carried out as described
above using the general protocol of Procedure A. Light brown solid;
Yield: 0.7 g, crude; MS (ESI) m/z 342.97 [M-1].sup.-
Synthesis of
N-(6-((8-chloro-3-methyl-1,5-dioxo-3-(trifluoromethyl)-1,2,3,5-tetrahydro-
imidazo[1,5-a]pyridin-6-yl)amino)pyrimidin-4-yl)cyclopropanecarboxamide
(Cpd. No. 49)
[0364] The synthesis of compound 49 was carried out as described
above using the general protocol of Procedure B. Light yellow
solid. Yield: 0.16 g, 42%; MS (ESI) m/z 443.27 [M+1].sup.+; .sup.1H
NMR (400 MHz, DMSO-d.sub.6) .delta. 10.95 (s, 1H), 10.55 (bs, 1H),
9.72 (s, 1H), 8.74 (s, 1H), 8.61 (s, 1H), 8.04 (s, 1H), 2.11 (s,
3H), 2.03 (m, 1H), 0.84 (d, J=6.0 Hz, 4H).
Example 50
Synthesis of
N-[6-[(8-chloro-4',4'-difluoro-1,5-dioxo-spiro[2H-imidazo[1,5-a]pyridine--
3,1'-cyclohexane]-6-yl)amino]pyrimidin-4-yl]cyclopropanecarboxamide
(Cpd. No. 50)
##STR00134##
##STR00135##
[0365] Synthesis of
6-bromo-8-chloro-4',4'-difluoro-spiro[2H-imidazo[1,5-a]pyridine-3,1'-cycl-
ohexane]-1,5-dione (3)
[0366] The synthesis of intermediate 3 was carried out as described
above using the general protocol of Procedure A. Off-white solid;
Yield: 0.41 g, 93%; MS (ESI) m/z 366.94 [M+1].sup.+; .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 9.79 (s, 1H), 7.89 (s, 1H), 2.12
(m, 6H), 1.66 (m, 2H).
Synthesis of
N-[6[(8-chloro-4',4'-difluoro-1,5-dioxo-spiro[2H-imidazo[1,5-a]pyridine-3-
,1'-cyclohexane]-6-yl)amino]pyrimidin-4-yl]cyclopropanecarboxamide
(Cpd. No. 50)
[0367] The synthesis of compound 50 was carried out as described
above using the general protocol of Procedure B. Light yellow
solid; Yield: 0.098 g, 39%; MS (ESI) m/z 465.16 [M+1].sup.+;
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 10.92 (s, 1H), 10.47
(s, 1H), 9.52 (s, 1H), 8.72 (s, 1H), 8.59 (s, 1H), 7.98 (s, 1H),
3.30-3.20 (m, 2H), 2.35-2.15 (m, 4H), 2.05-1.98 (m, 1H), 1.75-1.67
(m, 2H), 0.97-0.80 (m, 4H).
Example 51
Synthesis of
N-[6-[[8-chloro-3-(3-chlorophenyl)-3-methyl-1,5-dioxo-2H-imidazo[1,5-a]py-
ridin-6-yl]amino]pyrimidin-4-yl]cyclopropanecarboxamide (Cpd. No.
51)
##STR00136##
##STR00137##
[0368] Synthesis of
6-bromo-8-chloro-3-(3-chlorophenyl)-3-methyl-2H-imidazo[1,5-a]pyridine-1,-
5-dione (3)
[0369] The synthesis of intermediate 3 was carried out as described
above using the general protocol of Procedure A. White solid;
Yield: 0.13 g, 17%; MS (ESI) m/z 386.83 [M+1].sup.+; .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 10.38 (s, 1H), 8.32 (s, 1H), 7.52
(s, 1H), 7.43 (m, 2H), 7.34 (d, J=7.6 Hz, 1H), 2.18 (s, 3H).
Synthesis of
N-[6-[[8-chloro-3-(3-chlorophenyl)-3-methyl-1,5-dioxo-2H-imidazo[1,5-a]py-
ridin-6-yl]amino]pyrimidin-4-yl]cyclopropanecarboxamide (Cpd. No.
51)
[0370] The synthesis of compound 51 was carried out as described
above using the general protocol of Procedure B. Light yellow
solid; Yield: 0.04 g, 25%; MS (ESI) m/z 485.30 [M+1].sup.+; .sup.1H
NMR (400 MHz, DMSO-d.sub.6) .delta. 10.90 (s, 1H), 10.09 (s, 1H),
9.44 (s, 1H), 8.75 (s, 1H), 8.59 (s, 1H), 7.90 (s, 1H), 7.52 (s,
1H), 7.43 (m, 2H), 7.34 (d, J=7.2 Hz, 1H), 2.23 (s, 3H), 2.00 (m,
1H), 0.82 (m, 4H).
Example 52
Synthesis of
N-[6-[[8-chloro-3-(3-fluorophenyl)-3-methyl-1,5-dioxo-2H-imidazo[1,5-a]py-
ridin-6-yl]amino]pyrimidin-4-yl]cyclopropanecarboxamide (Cpd. No.
52)
##STR00138##
##STR00139##
[0371] Synthesis of
6-bromo-8-chloro-3-(3-fluorophenyl)-3-methyl-2H-imidazo[1,5-a]pyridine-1,-
5-dione (3)
[0372] The synthesis of intermediate 3 was carried out as described
above using the general protocol of Procedure A. White solid;
Yield: 0.18 g, 20%; MS (ESI) m/z 373.01 [M+1].sup.+; .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 10.38 (s, 1H), 8.31 (s, 1H), 7.43
(m, 1H), 7.31 (d, J=10.3 Hz, 1H), 7.22 (m, 2H), 2.19 (s, 3H).
Synthesis of
N-[6-[[8-chloro-3-(3-fluorophenyl)-3-methyl-1,5-dioxo-2H-imidazo[1,5-a]py-
ridin-6-yl]amino]pyrimidin-4-yl]cyclopropanecarboxamide (Cpd. No.
52)
[0373] The synthesis of compound 52 was carried out as described
above using the general protocol of Procedure B. White solid;
Yield: 0.035 g, 15%; MS (ESI) m/z 469.34 [M+1].sup.+; .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 10.91 (s, 1H), 10.10 (s, 1H), 9.44
(s, 1H), 8.75 (s, 1H), 8.59 (s, 1H), 7.90 (s, 1H), 7.42 (m, 1H),
7.32 (m, 1H), 7.23 (m, 2H), 2.23 (s, 3H), 2.00 (m, 1H), 0.823 (m,
4H).
Example 53
Synthesis of
(3'S)-3'-amino-6-(pyrimidin-4-ylamino)spiro[2H-imidazo[1,5-a]pyridine-3,1-
'-cyclohexane]-1,5-dione (Cpd. No. 53)
##STR00140##
##STR00141## ##STR00142##
[0374] Synthesis of
2-[(1S,3R)-3-hydroxycyclohexyl]isoindoline-1,3-dione (3)
[0375] To a solution of (1R,3S)-3-aminocyclohexanol hydrochloride
(2, 1.0 g, 6.57 mmol) in water (50 mL) at 0.degree. C., ethyl
1,3-dioxoisoindoline-2-carboxylate (1, 1.6 g, 7.3 mmol) was added.
The mixture was allowed to stir at 25.degree. C. for 3 hours while
monitoring by TLC. After completion, the suspension was filtered
and the residue was washed with water (50 mL) and dried to obtain
2-[(3R)-3-hydroxycyclohexyl]isoindoline-1,3-dione (3) as a white
solid. Yield: 1.45 g, 81%; .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. 7.83 (m, 4H), 4.77 (m, 1H), 3.99 (m, 1H), 2.04-1.29 (m,
9H).
Synthesis of (S)-2-(3-oxocyclohexyl)isoindoline-1,3-dione (4)
[0376] To a stirred solution of
2-[(3R)-3-hydroxycyclohexyl]isoindoline-1,3-dione (3, 1.4 g, 5.71
mmol) in dichloromethane (50 mL) at 0.degree. C., was added
pyridinium chlorochromate (3.69 g, 17.12 mmol). The mixture was
allowed to stir at 25.degree. C. for 5 hours while monitoring by
TLC. The reaction mixture was made basic (pH 8) with saturated
aqueous sodium bicarbonate solution and extracted with
dichloromethane (2.times.150 mL). The combined organic layers were
dried over sodium sulfate and concentrated under reduced pressure
to obtain 2-(3-oxocyclohexyl)isoindoline-1,3-dione (4) as a brown
solid. Yield: 1.31 g, 94%; MS (ESI) m/z 244.15 [M+1].sup.+.
Synthesis of
(3'S)-6-chloro-3'-(1,3-dioxoisoindolin-2-yl)spiro[2H-imidazo[1,5-a]pyridi-
ne-3,1'-cyclohexane]-1,5-dione (6)
[0377] The synthesis of intermediate 6 was carried out as described
above using the general protocol of Procedure A. Cream colored
solid; Yield: 1.51 g, 71%; MS (ESI) m/z 398.19 [M+1].sup.+.
Synthesis of
(3'S)-3'-(1,3-dioxoisoindolin-2-yl)-6-(pyrimidin-4-ylamino)spiro[2H-imida-
zo[1,5-a]pyridine-3,1'-cyclohexane]-1,5-dione (8)
[0378] The synthesis of intermediate 8 was carried out as described
above using the general protocol of Procedure B. Yellow solid;
Yield: 104 mg, 45%; MS (ESI) m/z 457.0 [M+1].sup.+; .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 10.54 (s, 1H), 9.47 (s, 1H), 8.76
(s, 2H), 8.37 (s, 1H), 7.84 (m, 4H), 7.38 (s, 1H), 6.91 (m, 1H),
4.60 (m, 1H), 3.96 (m, 1H), 3.32 (m, 1H), 3.06 (m, 1H), 2.32 (m,
1H), 1.99-1.56 (m, 5H).
Synthesis of
(3'S)-3'-amino-6-(pyrimidin-4-ylamino)spiro[2H-imidazo[1,5-a]pyridine-3,1-
'-cyclohexane]-1,5-dione (Cpd. No. 53)
[0379] The synthesis of compound 53 was carried out as described
above using the general protocol of Procedure C. Pale greenish
solid; Yield: 60.0 mg, 21%; MS (ESI) m/z 327.35 [M+1].sup.+;
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 9.37 (s, 1H), 8.78 (d,
J=7.6 Hz, 1H), 8.76 (s, 1H), 8.37 (d, J=6.0 Hz, 1H), 7.37 (d, J=5.6
Hz, 1H), 6.89 (d, J=7.6 Hz, 1H), 2.89 (m, 2H), 2.72 (m, 1H), 1.82
(m, 2H), 1.65 (m, 2H), 1.46 (m, 1H), 1.05 (m, 1H).
Example 54
Synthesis of
8-chloro-6-(pyrimidin-4-ylamino)spiro[2H-imidazo[1,5-a]pyridine-3,3'-pipe-
ridine]-1,5-dione hydrochloride (Cpd. No. 54)
##STR00143##
##STR00144##
[0380] Synthesis of tert-butyl
8-chloro-1,5-dioxo-6-(pyrimidin-4-ylamino)spiro[2H-imidazo[1,5-a]pyridine-
-3,3'-piperidine]-1'-carboxylate (3)
[0381] The synthesis of intermediate 3 was carried out as described
above using the general protocol of Procedure B. Light yellow
solid; Yield: 0.08 g, 50%; MS (ESI) m/z 447.17 [M+1].sup.+; .sup.1H
NMR (400 MHz, DMSO-d.sub.6) .delta. 10.51 (s, 1H), 9.63 (s, 1H),
8.85 (s, 1H), 8.79 (s, 1H), 8.44 (d, J=5.8 Hz, 1H), 7.45 (d, J=5.6
Hz, 1H), 4.14 (m, 2H), 3.89 (m, 1H), 3.05 (m, 1H), 2.90 (m, 1H),
1.93 (m, 3H), 1.41 (s, 9H).
Synthesis of
8-chloro-6-(pyrimidin-4-ylamino)spiro[2H-imidazo[1,5-a]pyridine-3,3'-pipe-
ridine]-1,5-dione hydrochloride (Cpd. No. 54)
[0382] The synthesis of compound 54 was carried out as described
above using the general protocol of Procedure D. Light brown solid;
Yield: 0.024 g, 35%; MS (ESI) m/z 347.31 [M+1].sup.+; .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 10.23 (s, 1H), 9.99 (s, 1H), 9.72
(bs, 1H), 9.48 (bs, 1H), 8.99 (bs, 1H), 8.78 (s, 1H), 8.53 (bs,
1H), 7.54 (bs, 1H), 4.15 (m, 1H), 3.52 (m, 1H), 3.38 (m, 1H), 3.03
(m, 1H), 2.92 (m, 1H), 2.17 (m, 1H), 2.04 (m, 1H), 1.84 (m,
1H).
Example 55
Synthesis of
8-chloro-3-methyl-6-(pyrimidin-4-ylamino)-3-(2,2,2-trifluoroethyl)-2H-imi-
dazo[1,5-a]pyridine-1,5-dione (Cpd. No. 55)
##STR00145##
##STR00146##
[0383] Synthesis of
8-chloro-3-methyl-6-(pyrimidin-4-ylamino)-3-(2,2,2-trifluoroethyl)-2H-imi-
dazo[1,5-a]pyridine-1,5-dione (Cpd. No. 55)
[0384] The synthesis of compound 55 was carried out as described
above using the general protocol of Procedure B. Light yellow
solid; Yield: 0.1 g, 30%; MS (ESI) m/z 374.25 [M+1].sup.+; .sup.1H
NMR (400 MHz, DMSO-d.sub.6) .delta. 9.95 (s, 1H), 9.70 (s, 1H),
8.86 (s, 1H), 8.83 (s, 1H), 8.45 (d, J=5.6 Hz, 1H), 7.45 (d, J=5.6
Hz, 1H), 3.73 (m, 1H), 3.14 (m, 1H), 1.89 (s, 3H).
Example 56
Synthesis of
N-(6-((8-chloro-1,5-dioxo-1,5-dihydro-2H-spiro[imidazo[1,5-a]pyridine-3,4-
'-piperidin]-6-yl)amino)pyrimidin-4-yl)cyclopropanecarboxamide
hydrochloride (Cpd. No. 56)
##STR00147##
##STR00148##
[0385] Synthesis of tert-butyl
6-bromo-8-chloro-1,5-dioxo-1,5-dihydro-2H-spiro[imidazo[1,5-a]pyridine-3,-
4'-piperidine]-1'-carboxylate (3)
[0386] Procedure E: To a stirred solution of
5-bromo-3-chloro-6-oxo-1H-pyridine-2-carboxamide (1, 0.4 g, 1.59
mmol) in 1,4-dioxane (12 mL) was added tert-butyl
4-oxopiperidine-1-carboxylate (2, 1.58 g, 7.95 mmol) in a vial at
room temperature. Concentrated sulfuric acid (0.16 g, 1.59 mmol)
was then added dropwise. The vial was sealed and heated to
120.degree. C. for 3 h. The reaction mixture was quenched with
water (20 mL) and extracted with ethyl acetate (2.times.15 mL). The
organic layers were separated and the aqueous layer was diluted
with 1,4-dioxane (30 mL), water (25 mL) and treated with
di-tert-butyl dicarbonate (0.44 g, 2.03 mmol) dropwise at 0.degree.
C. The reaction mixture was stirred at room temperature overnight.
After consumption of starting material the reaction was extracted
with 10% methanol in dichloromethane (2.times.25 mL). The organic
layers were dried with magnesium sulfate, filtered and concentrated
to dryness. The crude residue was then purified by flash column
chromatography using neutral alumina eluting with 2% methanol in
dichloromethane. The desired fractions were concentrated to dryness
in vacuo to afford tert-butyl
6-bromo-8-chloro-1,5-dioxo-1,5-dihydro-2H-spiro[imidazo[1,5-a]pyridine-3,-
4'-piperidine]-1'-carboxylate (3) as a yellow solid. Yield: 0.26 g,
44%; MS (ESI) m/z 430.11 [M-1].sup.-; .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 10.77 (s, 1H), 8.27 (m, 1H), 4.04 (s, 2H),
2.92 (m, 4H), 1.57 (m, 2H), 1.42 (s, 9H).
Synthesis of tert-butyl
8-chloro-6-((6-(cyclopropanecarboxamido)pyrimidin-4-yl)amino)-5-dihydro-2-
H-spiro[imidazo[1,5-a]pyridine-3, 4'-piperidine]-1'-carboxylate
(5)
[0387] The synthesis of intermediate 5 was carried out as described
above using the general protocol of Procedure B. Yellow solid;
Yield: 0.14 g, 44%; MS (ESI) m/z 530.36 [M+1].sup.+; .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 10.93 (s, 1H), 10.49 (s, 1H), 9.51
(s, 1H), 8.72 (s, 1H), 8.59 (s, 1H), 8.00 (s, 1H), 4.05 (m, 2H),
3.20 (m, 1H), 3.09 (m, 3H), 2.02 (m, 1H), 1.58 (m, 2H), 1.43 (s,
9H), 0.84 (m, 4H).
Synthesis of
N-(6-((8-chloro-1,5-dioxo-1,5-dihydro-2H-spiro[imidazo[1,5-a]pyridine-3,4-
'-piperidin]-6-yl)amino)pyrimidin-4-yl)cyclopropanecarboxamide
hydrochloride (Cpd. No. 56)
[0388] The synthesis of compound 56 was carried out as described
above using the general protocol of Procedure D. Yellow solid;
Yield: 0.10 g, 87%; MS (ESI) m/z 430.38 [M+1].sup.+; .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 10.98 (s, 1H), 10.54 (s, 1H), 9.43
(s, 1H), 9.33 (d, J=9.6 Hz, 1H), 8.77 (d, J=11.6 Hz, 1H), 8.73 (s,
1H), 8.60 (s, 1H), 8.00 (s, 1H), 3.48 (s, 2H), 3.32 (m, 2H), 3.18
(m, 2H), 2.02 (m, 1H), 1.86 (d, J=12.4 Hz, 2H), 0.84 (m, 4H).
Example 57
Synthesis of
8-chloro-3-(3-fluorophenyl)-3-methyl-6-(pyrimidin-4-ylamino)-2H-imidazo[1-
,5-a]pyridine-1,5-dione (Cpd. No. 57)
##STR00149##
##STR00150##
[0389] Synthesis of
8-chloro-3-(3-fluorophenyl)-3-methyl-6-(pyrimidin-4-ylamino)-2H-imidazo[1-
,5-a]pyridine-1,5-dione (Cpd. No. 57)
[0390] The synthesis of compound 57 was carried out as described
above using the general protocol of Procedure B. White solid;
Yield: 0.025 g, 10%; MS (ESI) m/z 386.31 [M+1].sup.+; .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 10.14 (s, 1H), 9.56 (s, 1H), 8.84
(s, 1H), 8.82 (s, 1H), 8.41 (d, J=5.9 Hz, 1H), 7.42 (m, 1H), 7.33
(m, 2H), 7.22 (m, 2H), 2.24 (s, 3H).
Example 58
Synthesis of
8-chloro-3-(3-chlorophenyl)-3-methyl-6-(pyrimidin-4-ylamino)-2H-imidazo[1-
,5-a]pyridine-1,5-dione (Cpd. No. 58)
##STR00151##
##STR00152##
[0391] Synthesis of
8-chloro-3-(3-chlorophenyl)-3-methyl-6-(pyrimidin-4-ylamino)-2H-imidazo[1-
,5-a]pyridine-1,5-dione (Cpd. No. 58)
[0392] The synthesis of compound 58 was carried out as described
above using the general protocol of Procedure B. Light yellow
solid; Yield: 0.07 g, 32%; MS (ESI) m/z 402.25 [M+1].sup.+; .sup.1H
NMR (400 MHz, DMSO-d.sub.6) .delta. 10.14 (s, 1H), 9.57 (s, 1H),
8.84 (s, 1H), 8.82 (s, 1H), 8.41 (d, J=5.9 Hz, 1H), 7.54 (s, 1H),
7.43 (m, 2H), 7.35 (m, 2H), 2.24 (s, 3H).
Example 59
Synthesis of
6-((6-((1-cyclopropyl-2,2,2-trifluoroethyl)amino)pyrimidin-4-yl)amino)-3--
methyl-3-(trifluoromethyl)-2,3-dihydroimidazo[1,5-a]pyridine-1,5-dione
(Cpd. No. 59)
##STR00153##
##STR00154##
[0393] Synthesis of tert-butyl
N-tert-butoxycarbonyl-N-[6[(1-cyclopropyl-2,2,2-trifluoroethyl)amino]pyri-
midin-4-yl]carbamate (3)
[0394] To a solution of tert-butyl
N-tert-butoxycarbonyl-N-(6-chloropyrimidin-4-yl)carbamate (1, 0.50
g, 1.52 mmol) and 1-cyclopropyl-2,2,2-trifluoro-ethanamine
hydrochloride (2, 0.40 g, 2.27 mmol) in monoglyme (15 mL) in a
vial, sodium tert-butoxide (0.729 g, 7.58 mmol) was added. After
purging with argon gas for 30 minutes, BINAP (0.14 g, 0.23 mmol)
and tris(dibenzylideneacetone)dipalladium(0) (69 mg, 0.080 mmol)
were added. The vial was sealed and the contents heated at
90.degree. C. for 24 h. Solvent was removed and the crude mixture
was by flash chromatography eluting with a 10-12% gradient of Ethyl
acetate in hexane. The desired fractions were concentrated under
pressure to obtain tert-butyl
N-tert-butoxycarbonyl-N-[6-[(1-cyclopropyl-2,2,2-trifluoro-ethyl)amino]py-
rimidin-4-yl]-carbamate (3) as an off-white solid. Yield: 110 mg,
17%; .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 9.78 (s, 1H), 8.15
(s, 1H), 7.79 (d, J=9.2 Hz, 1H), 7.10 (s, 1H), 4.47 (m, 1H), 1.46
(s, 1H), 0.61 (m, 1H), 0.49 (m, 2H), 0.39 (m, 1H).
Synthesis of
N.sup.4-(1-cyclopropyl-2,2,2-trifluoro-ethyl)pyrimidine-4,6-diamine
hydrochloride (4)
[0395] Procedure F: To a solution of tert-butyl
N-tert-butoxycarbonyl-N-[6-[(1-cyclopropyl-2,2,2-trifluoro-ethyl)amino]py-
rimidin-4-yl]-carbamate (3, 250 mg, 0.58 mmol) in dichloromethane
(2 mL) and methanol (2 mL) was added 4 M hydrogenchloride in
1,4-dioxane (5 mL). The reaction was stirred at room temperature
overnight. The solvents were evaporated under reduced pressure, the
resultant residue was triturated with dichloromethane. The solids
were placed in a round bottom flask and aqueous ammonia was added
adjusting the pH to 8-9. The solvent content was reduced added and
water was added. The solids were filtered and dried to afford
N.sup.4-(1-cyclopropyl-2,2,2-trifluoro-ethyl)pyrimidine-4,6-dia-
mine hydrochloride (4) as a light brown solid. Yield: 130 mg,
crude; MS (ESI) m/z 233 [M+1-HCl].sup.+.
Synthesis of
6-[[6-[(1-cyclopropyl-2,2,2-trifluoro-ethyl)amino]pyrimidin-4-yl]amino]-3-
-methyl-3-(trifluoromethyl)-2H-imidazo[1,5-a]pyridine-1,5-dione
(Cpd. No. 59)
[0396] The synthesis of compound 59 was carried out as described
above using the general protocol of Procedure B. Off-white solid;
Yield: 33 mg, 19%; MS (ESI) m/z 463.36 [M+1].sup.+; .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 10.44 (brs, 1H), 9.05 (s, 1H), 8.62
(d, J=7.6 Hz, 1H), 8.26 (s, 1H), 7.80 (d, J=8.8 Hz, 1H), 6.96 (d,
J=8.0 Hz, 1H), 6.43 (s, 1H), 4.36 (brs, 1H), 2.12 (s, 3H), 1.12 (m,
1H), 0.67 (m, 1H), 0.51 (m, 2H), 0.35 (m, 1H).
Example 60
Synthesis of
N-(6-((8-chloro-1,5-dioxo-1,5-dihydro-2H-spiro[imidazo[1,5-a]pyridine-3,3-
'-piperidin]-6-yl)amino)pyrimidin-4-yl)cyclopropanecarboxamide
hydrochloride (Cpd. No. 60)
##STR00155##
##STR00156##
[0397] Synthesis of tert-butyl
6-bromo-8-chloro-1,5-dioxo-spiro[2H-imidazo[1,5-a]pyridine-3,3'-piperidin-
e]-1'-carboxylate (3)
[0398] To a stirred solution of
5-bromo-3-chloro-6-oxo-1H-pyridine-2-carboxamide (1, 0.7 g, 2.78
mmol) in 1,4-dioxane (10 mL) in a vial, piperidin-3-one
hydrochloride (2, 1.13 g, 8.35 mmol) was added at room temperature.
To this solution concentrated sulfuric acid (0.27 g, 2.78 mmol) was
added dropwise. The reaction vial was sealed and heated to
100.degree. C. for 48 h. After completion the solvent was removed
under reduced pressure and the resultant reaction mass was diluted
with water (20 mL) and the aqueous layer was washed with ethyl
acetate (3.times.20 mL). The aqueous solution (20.0 mL) of
6-bromo-8-chloro-spiro[2H-imidazo[1,5-a]pyridine-3,3'-piperidine]-1,5-dio-
ne (.about.0.5 g) was treated with sodium hydroxide (90 mg, 2.26
mmol). di-tert-butyl dicarbonate (0.39 g, 1.80 mmol) in 1,4-dioxane
(20 mL) was added and the reaction mixture was stirred at
25.degree. C. for 6 h. Once completed the solvent was removed under
reduced pressure. The aqueous layer was extracted with ethyl
acetate (2.times.25 mL) and the organic layers were washed with
water (2.times.10 mL). The organic layers were separated and dried
with sodium sulfate, filtered and concentrated to dryness. The
crude residue was purified by flash column chromatography eluting
with 2% methanol in dichloromethane. The desired fractions were
concentrated to dryness to afford tert-butyl
6-bromo-8-chloro-1,5-dioxo-spiro[2H-imidazo[1,5-a]pyridine-3,3'-piperidin-
e]-1'-carboxylate (3) as white solid. Yield: 0.4 g; MS (ESI) m/z
432 [M+1].sup.+.
Synthesis of tert-butyl
8-chloro-6-((6-(cyclopropanecarboxamido)pyrimidin-4-yl)amino)-1,5-dioxo-1-
,5-dihydro-2H-spiro[imidazo[1,5-a]pyridine-3,
3'-piperidine]-1'-carboxylate (5)
[0399] The synthesis of intermediate 5 was carried out as described
above using the general protocol of Procedure B. Light yellow
solid; Yield: 0.07 g, 19%; MS (ESI) m/z 530.0 [M+1].sup.+; .sup.1H
NMR (400 MHz, DMSO-d.sub.6) .delta. 10.94 (s, 1H), 9.48 (s, 1H),
8.72 (s, 1H), 8.60 (s, 1H), 7.99 (s, 1H), 4.05 (m, 2H), 3.9 (m,
1H), 3.32 (m, 2H), 2.95 (m, 1H), 2.01 (m, 3H), 1.35 (s, 9H), 0.84
(m, 4H).
Synthesis of
N-(6-((8-chloro-1,5-dioxo-1,5-dihydro-2H-spiro[imidazo[1,5-a]pyridine-3,3-
'-piperidin]-6-yl)amino)pyrimidin-4-yl)cyclopropanecarboxamide
hydrochloride (Cpd. No. 60)
[0400] The synthesis of compound 60 was carried out as described
above using the general protocol of Procedure F. Light brown solid;
Yield: 22 mg, 35%; MS (ESI) m/z 430.39 [M+1].sup.+; .sup.1H NMR
(400 MHz, DMSO-d.sub.6): .delta. 10.98 (s, 1H), 10.04 (s, 1H), 9.55
(s, 1H), 9.19 (bs, 1H), 8.75 (s, 1H), 8.61 (s, 1H), 8.02 (s, 1H),
4.17 (m, 1H), 3.35 (m, 2H), 3.02 (m, 2H), 2.08 (m, 3H), 1.81 (m,
1H), 0.84 (s, 4H).
Example 61
Synthesis of
N-(6-((8-chloro-1,5-dioxo-1,2',3',5,5',6'-hexahydro-2H-spiro[imidazo[1,5--
a]pyridine-3,4'-pyran]-6-yl)amino)pyrimidin-4-yl)cyclopropanecarboxamide
(Cpd. No. 61)
##STR00157##
##STR00158##
[0401] Synthesis of
6-bromo-8-chloro-2',3',5',6'-tetrahydro-2H-spiro[imidazo[1,5-a]pyridine-3-
,4'-pyran]-1,5-dione (3)
[0402] The synthesis of intermediate 3 was carried out as described
above using the general protocol of Procedure A. Light brown solid;
Yield: 1.0 g, crude; MS (ESI) m/z 330.8 [M-1].sup.-; .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 10.84 (s, 1H), 8.28 (s, 1H), 3.92
(m, 2H), 3.64 (m, 2H), 3.09 (m, 2H), 1.52 (m, 2H).
Synthesis of
N-(6-((8-chloro-1,5-dioxo-1,2',3',5,5',6'-hexahydro-2H-spiro[imidazo[1,5--
a]pyridine-3,4'-pyran]-6-yl)amino)pyrimidin-4-yl)cyclopropanecarboxamide
(Cpd. No. 61)
[0403] The synthesis of compound 61 was carried out as described
above using the general protocol of Procedure B. Light yellow
solid; Yield: 0.11 g, 21%; MS (ESI) m/z 431.36 [M+1].sup.+; .sup.1H
NMR (400 MHz, DMSO-d.sub.6) .delta. 10.94 (s, 1H), 10.54 (s, 1H),
9.51 (s, 1H), 8.72 (s, 1H), 8.59 (s, 1H), 8.0 (s, 1H), 3.94 (m,
2H), 3.68 (t, J=12.4 Hz, 2H), 3.19 (m, 2H), 2.05 (m, 1H), 1.52 (d,
J=12.4 Hz, 2H), 0.81 (d, J=6.0 Hz, 4H).
Example 62
Synthesis of
N-[6-[(8-chloro-1',1'-difluoro-1,5-dioxo-spiro[2H-imidazo[1,5-a]pyridine--
3,3'-cyclobutane]-6-yl)amino]pyrimidin-4-yl]cyclopropanecarboxamide
(Cpd. No. 62)
##STR00159##
##STR00160##
[0404] Synthesis of
6-bromo-8-chloro-1',1'-difluoro-spiro[2H-imidazo[1,5-a]pyridine-3,3'-cycl-
obutane]-1,5-dione (3)
[0405] The synthesis of intermediate 3 was carried out as described
above using the general protocol of Procedure A. Brown solid;
Yield: 0.4 g, 59%; MS (ESI) m/z 337 [M+1].sup.+.
Synthesis of
N-[6[(8-chloro-1',1'-difluoro-1,5-dioxo-spiro[2H-imidazo[1,5-a]pyridine-3-
,3'-cyclobutane]-6-yl)amino]pyrimidin-4-yl]cyclopropanecarboxamide
(Cpd. No. 62)
[0406] The synthesis of compound 62 was carried out as described
above using the general protocol of Procedure B. White solid;
Yield: 0.025 g, 11%; MS (ESI) m/z 437.4 [M+1].sup.+; .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 10.92 (s, 1H), 10.39 (s, 1H), 9.74
(s, 1H), 8.74 (s, 1H), 8.59 (s, 1H), 8.03 (s, 1H), 4.22-4.15 (m,
1H), 3.13-2.90 (m, 1H), 2.07-1.96 (m, 1H), 0.85-0.77 (s, 4H).
Example 63
Synthesis of 8-chloro-2', 2'-dimethyl-6-(pyrimidin-4-ylamino) spiro
[2H-imidazo[1,5-a]pyridine-3,1'-cyclopentane]-1,5-dione (Cpd. No.
63)
##STR00161##
##STR00162##
[0407] Synthesis of
6-bromo-8-chloro-2',2'-dimethyl-spiro[2H-imidazo[1,5-a]pyridine-3,1'-cycl-
opentane]-1,5-dione (3)
[0408] The synthesis of intermediate 3 was carried out as described
above using the general protocol of Procedure A. Cream-colored
solid; Yield: 0.2 g, 14%; .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. 10.03 (s, 1H), 8.29 (s, 1H), 2.96-2.91 (m, 1H), 2.67 (m,
1H), 2.05-1.92 (m, 4H), 1.63-1.58 (m, 1H), 0.99 (s, 3H), 0.65 (s,
3H).
Synthesis of
8-chloro-2',2'-dimethyl-6-(pyrimidin-4-ylamino)spiro[2H-imidazo[1,5-a]pyr-
idine-3,1'-cyclopentane]-1,5-dione (Cpd. No. 63)
[0409] The synthesis of compound 63 was carried out as described
above using the general protocol of Procedure B. Microwave reactor
was used for heating in place of the conventional oil bath heating.
Off white solid; Yield: 0.03 g, 29%; MS (ESI) m/z 360.29
[M+1].sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 9.76 (s,
1H), 9.66 (s, 1H), 8.84 (s, 1H), 8.81 (s, 1H), 8.44 (d, 1H), 7.47
(d, 1H), 3.00-2.92 (m, 1H), 2.44-2.42 (m, 1H), 2.14-2.10 (m, 1H),
1.99-1.90 (m, 1H), 1.65-1.62 (m, 1H), 1.02 (s, 3H), 0.67, (s,
3H).
Example 64
Synthesis of
8-chloro-6-(pyrimidin-4-ylamino)-2',3',5',6'-tetrahydro-2H-spiro[imidazo[-
1,5-a]pyridine-3,4'-pyran]-1,5-dione (Cpd. No. 64)
##STR00163##
##STR00164##
[0410] Synthesis of
8-chloro-6-(pyrimidin-4-ylamino)-2',3',5',6'-tetrahydro-2H-spiro[imidazo[-
1,5-a]pyridine-3,4'-pyran]-1,5-dione (Cpd. No. 64)
[0411] The synthesis of compound 64 was carried out as described
above using the general protocol of Procedure B. Light yellow
solid; Yield: 0.10 g, 32%; MS (ESI) m/z 348.27 [M+1].sup.+; .sup.1H
NMR (400 MHz, DMSO-d.sub.6) .delta. 10.56 (s, 1H), 9.65 (s, 1H),
8.84 (d, J=12.0 Hz, 2H), 8.44 (s, 1H), 7.47 (s, 1H), 3.94 (m, 2H),
3.70 (m, 2H), 3.19 (m, 2H), 1.54 (d, J=11.4 Hz, 2H).
Example 65
Synthesis of
N-(6-((8-chloro-1,5-dioxo-1,5-dihydro-2H-spiro[imidazo[1,5-a]pyridine-3,3-
'-thietan]-6-yl)amino)pyrimidin-4-yl)cyclopropanecarboxamide (Cpd.
No. 65)
##STR00165##
##STR00166##
[0412] Synthesis of
6-bromo-8-chloro-2H-spiro[imidazo[1,5-a]pyridine-3,3'-thietane]-1,5-dione
(3)
[0413] The synthesis of intermediate 3 was carried out as described
above using the general protocol of Procedure A. Dark brown solid;
Yield: 0.25 g, 20%; MS (ESI) m/z 318.96 [M-1].sup.-; .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 11.10 (bs, 1H), 8.27 (s, 1H), 4.65
(s, 2H), 3.32 (s, 2H).
Synthesis of
N-(6-((8-chloro-1,5-dioxo-1,5-dihydro-2H-spiro[imidazo[1,5-a]pyridine-3,3-
'-thietan]-6-yl)amino)pyrimidin-4-yl)cyclopropanecarboxamide (Cpd.
No. 65)
[0414] The synthesis of compound 65 was carried out as described
above using the general protocol of Procedure B. Off white solid;
Yield: 0.05 g, 30%; MS (ESI) m/z 419.26 [M+1].sup.+; .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 10.95 (s, 1H), 10.80 (s, 1H), 9.65
(s, 1H), 8.69 (s, 1H), 8.59 (s, 1H), 8.02 (s, 1H), 4.66 (s, 2H),
3.32 (s, 2H), 2.03 (m, 1H), 0.85 (s, 4H).
Example 66
Synthesis of
8-chloro-2'-fluoro-6-(pyrimidin-4-ylamino)spiro[2H-imidazo[1,5-a]pyridine-
-3,1'-cyclohexane]-1,5-dione (Cpd. No. 66)
##STR00167##
##STR00168##
[0415] Synthesis of
6-bromo-8-chloro-2'-fluoro-spiro[2H-imidazo[1,5-a]pyridine-3,1'-cyclohexa-
ne]-1,5-dione (3)
[0416] The synthesis of intermediate 3 was carried out as described
above using the general protocol of Procedure A. Light brown solid;
Yield: 0.40 g, 57%; MS (ESI) m/z 349 [M-1].sup.-.
Synthesis of
8-chloro-2'-fluoro-6-(pyrimidin-4-ylamino)spiro[2H-imidazo[1,5-a]pyridine-
-3,1'-cyclohexane]-1,5-dione (Cpd. No. 66)
[0417] The synthesis of compound 66 was carried out as described
above using the general protocol of Procedure B. Off white solid;
Yield: 0.1 g, 38%; MS (ESI) m/z 364.29 [M+1].sup.+; .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 10.31 (s, 1H), 9.65 (s, 1H), 8.85
(d, J=12 Hz, 1H) 8.45 (d, J=4 Hz, 1H) 7.46 (d, J=8 Hz, 1H),
5.74-5.58 (m, 1H), 2.98-2.92 (m, 1H), 2.14-2.12 (m, 1H), 1.80-1.23
(m, 1H).
Example 67
Synthesis of
3,3,8-trimethyl-6-(pyrimidin-4-ylamino)-2H-imidazo[1,5-a]pyridine-1,5-dio-
ne (Cpd. No. 67)
##STR00169##
##STR00170##
[0418] Synthesis of
3,3,8-trimethyl-6-(pyrimidin-4-ylamino)-2H-imidazo[1,5-a]pyridine-1,5-dio-
ne (Cpd. No. 67)
[0419] Procedure G: A vial was charged with
8-chloro-3,3-dimethyl-6-(pyrimidin-4-ylamino)-2H-imidazo[1,5-a]pyridine-1-
,5-dione (1, 0.20 g, 0.65 mmol), trimethylboroxine (2, 0.16 g, 1.31
mmol) and potassium phosphate (0.28 g, 1.31 mmol) in 1,4-dioxane
(10 mL) at room temperature under argon. Then reaction mixture was
purged with argon for 10 min. followed by addition of
tris(dibenzylideneacetone)dipalladium(0) (60 mg, 0.07 mmol) and
tricyclohexylphosphine (18 mg, 0.07 mmol). The vial was sealed and
heated at 140.degree. C. in a microwave reactor for 1 h. The
reaction mixture was concentrated to dryness and the crude residue
was subjected to flash column chromatography using silica gel
100-200 mesh with a solvent gradient of 0.2-0.5% methanol in
dichloromethane. The desired fractions were collected and
concentrated to dryness under vacuum. The solid obtained was
stirred in n-pentane and filtered. The resulting product
3,3,8-trimethyl-6-(pyrimidin-4-ylamino)-2H-imidazo[1,5-a]pyridine-1,5-dio-
ne (Cpd. No. 67) was obtained as an off-white solid. Yield: 0.035
g, 18%; MS (ESI) m/z 286.3 [M+1].sup.+; .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 9.57 (s, 1H), 9.39 (s, 1H), 8.77 (s, 1H),
8.60 (s, 1H), 8.37 (d, J=5.76 Hz, 1H), 7.77 (d, J=5.64 Hz, 1H),
2.44 (s, 3H), 1.79 (s, 6H).
Example 68
Synthesis
8-cyclopropyl-3,3-dimethyl-6-(pyrimidin-4-ylamino)-2H-imidazo[1,-
5-a]pyridine-1,5-dione (Cpd. No. 68)
##STR00171##
##STR00172##
[0420] Synthesis
8-cyclopropyl-3,3-dimethyl-6-(pyrimidin-4-ylamino)-2H-imidazo[1,5-a]pyrid-
ine-1,5-dione (Cpd. No. 68)
[0421] The synthesis of compound 68 was carried out as described
above using the general protocol of Procedure G. Off white solid;
Yield: 0.032 g, 16%; MS (ESI) m/z 312.3 [M+1].sup.+; .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 9.57 (s, 1H), 9.40 (s, 1H), 8.75
(s, 1H), 8.37 (d, J=5.6 Hz, 1H), 8.26 (s, 1H), 7.35 (d, J=5.8 Hz,
1H), 3.17-3.15 (m, 1H), 1.80 (s, 6H), 1.10-0.98 (m, 2H), 0.69-0.68
(m, 2H).
Example 69
Synthesis of
8-fluoro-3,3-dimethyl-6-(pyrimidin-4-ylamino)-2H-imidazo[1,5-a]pyridine-1-
,5-dione (Cpd. No. 69)
##STR00173##
##STR00174##
[0422] Synthesis of ethyl 5-bromo-3-fluoro-pyridine-2-carboxylate
(2)
[0423] To a stirred solution of
5-bromo-3-fluoro-pyridine-2-carboxylic acid (1, 1.0 g, 4.55 mmol)
in ethanol (20 mL) was added sulfuric acid (0.67 g, 6.82 mmol) at
room temperature. The reaction mixture was stirred at reflux
overnight. After consumption of starting materials as indicated by
TLC, the reaction mixture was cooled to room temperature, and the
solvent was removed under vacuum. The residue was neutralized with
a saturated aqueous sodium bicarbonate solution and extracted with
ethyl acetate (2.times.100 mL). The organic layers were separated
and dried with magnesium sulfate, filtered and concentrated to
dryness under vacuum to afford ethyl
5-bromo-3-fluoro-pyridine-2-carboxylate (2) as an off-white solid.
Yield: 1.0 g, 89%; MS (ESI) m/z 249.9 [M+1].sup.+; .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. 8.61 (m, 1H), 7.77-7.75 (m, 1H), 4.51
(q, J=7.16 Hz, 2H), 1.43 (t, J=7.12 Hz, 3H).
Synthesis of ethyl
5-bromo-3-fluoro-1-oxido-pyridin-1-ium-2-carboxylate (3)
[0424] To a stirred solution of ethyl
5-bromo-3-fluoro-pyridine-2-carboxylate (2, 0.9 g, 3.63 mmol) in
dichloromethane (50 mL) at 0.degree. C. was added trifluoroacetic
anhydride (1.52 g, 7.26 mmol), urea hydrogen peroxide (0.72 g, 7.62
mmol). The reaction mixture was stirred at room temperature
overnight. After the oxidation was complete the reaction mixture
was neutralized with a dipotassium hydrogenphosphate solution and
quenched with a sodium bisulfite solution. The product was
extracted with dichloromethane (2.times.100 mL). The organic layers
were separated, dried with magnesium sulfate, filtered and
concentrated to dryness under vacuum to afford ethyl
5-bromo-3-fluoro-1-oxido-pyridin-1-ium-2-carboxylate (3) as an
off-white solid. Yield: 0.9 g, 89%; MS (ESI) m/z 265.95
[M+1].sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.: 8.22 (s,
1H), 7.30-7.26 (m, 1H), 4.50 (q, J=7.2 Hz, 2H), 1.42 (t, J=7.2 Hz,
3H).
Synthesis of ethyl 5-bromo-3-fluoro-6-oxo-1H-pyridine-2-carboxylate
(4)
[0425] To a stirred solution of ethyl
5-bromo-3-fluoro-1-oxido-pyridin-1-ium-2-carboxylate (3, 0.85 g,
3.21 mmol) in dimethylformamide (15 mL) was added trifluoroacetic
anhydride (1.35 g, 6.42 mmol) at 0.degree. C. The reaction mixture
was warmed to 50.degree. C. and stirred for 1 h, quenched with
saturated aqueous sodium bicarbonate solution and extracted with
dichloromethane (2.times.100 mL). The organic layers were
separated, dried with magnesium sulfate, filtered and concentrated
to dryness under vacuum to afford ethyl
5-bromo-3-fluoro-6-oxo-1H-pyridine-2-carboxylate (4) as a yellow
solid. Yield: 0.8 g, 94%; MS (ESI) m/z 264 [M+1].sup.+; .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 7.86 (m, 1H), 4.47 (q, J=7.2 Hz,
2H), 1.43 (t, J=7.2 Hz, 3H).
Synthesis of 5-bromo-3-fluoro-6-oxo-1H-pyridine-2-carboxamide
(5)
[0426] In a round bottom flask charged with ethyl
5-bromo-3-fluoro-6-oxo-1H-pyridine-2-carboxylate (4, 0.8 g, 3.03
mmol) at 0.degree. C. was added liquid ammonia (15 mL, 3.03 mmol)
in ethanol (5 mL). The stirred reaction mixture was warmed to
45.degree. C. for 2 h. After the ester was completely consumed
liquid ammonia and ethanol was evaporated under reduced pressure.
Methanol was added and the mixture was refluxed for 2 h and
filtered while hot. The volume of the filtrate was reduced by 2/3
and to the remaining methanol was added diethyl ether until solid
precipitated. The solid was filtered and dried under vacuum to
afford 5-bromo-3-fluoro-6-oxo-1H-pyridine-2-carboxamide (5) as a
light brown solid. Yield: 0.6 g, 85%; .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 7.88-7.86 (m, 1H), 7.67 (s, 1H), 7.50 (s,
1H).
Synthesis of
6-bromo-8-fluoro-3,3-dimethyl-2H-imidazo[1,5-a]pyridine-1,5-dione
(7)
[0427] The synthesis of intermediate 7 was carried out as described
above using the general protocol of Procedure A. Off-white solid;
Yield: 0.24 g, 34%; MS (ESI) m/z 275.07 [M+1].sup.+; .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 7.87 (d, J=7.44 Hz, 1H), 7.06 (s,
1H), 1.96 (s, 6H).
Synthesis of
8-fluoro-3,3-dimethyl-6-(pyrimidin-4-ylamino)-2H-imidazo[1,5-a]pyridine-1-
,5-dione (Cpd. No. 69)
[0428] The synthesis of compound 69 was carried out as described
above using the general protocol of Procedure B. Off-white solid;
Yield: 0.032 g, 13%; MS (ESI) m/z 290.32 [M+1].sup.+; .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 9.72 (s, 1H), 9.61 (s, 1H), 8.83
(d, J=5.1 Hz, 1H), 8.79 (s, 1H), 8.45 (d, J=5.7 Hz, 1H), 7.46 (d,
J=5.6 Hz, 1H), 1.82 (s, 6H).
Example 70
Synthesis of
6'-((6-aminopyrimidin-4-yl)amino)-8'-chloro-2'H-spiro[cyclohexane-1,3'-im-
idazo[1,5-a]pyridine]-1',5'-dione (Cpd. No. 70)
##STR00175##
##STR00176##
[0429] Synthesis of
6'-((6-aminopyrimidin-4-yl)amino)-8'-chloro-2'H-spiro[cyclohexane-1,3'-im-
idazo[1,5-a]pyridine]-1',5'-dione (Cpd. No. 70)
[0430] The synthesis of compound 70 was carried out as described
above using the general protocol of Procedure B. Yield: 22 mg; MS
(ESI) m/z 361.33 [M+1].sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. 10.22 (s, 1H), 8.90 (s, 1H), 8.63 (s, 1H), 8.20 (s, 1H),
6.61 (s, 2H), 6.24 (s, 1H), 2.94 (t, J=11.36 Hz, 2H), 1.65 (m, 5H),
1.51 (d, J=12.1 Hz, 2H), 1.21 (m, 1H).
Example 71
Synthesis of
8-ethyl-3,3-dimethyl-6-(pyrimidin-4-ylamino)-2H-imidazo[1,5-a]pyridine-1,-
5-dione (Cpd. No. 71)
##STR00177##
##STR00178##
[0431] Synthesis of
8-ethyl-3,3-dimethyl-6-(pyrimidin-4-ylamino)-2H-imidazo[1,5-a]pyridine-1,-
5-dione (Cpd. No. 71)
[0432] The synthesis of compound 71 was carried out as described
above using the general protocol of Procedure G. Off white solid;
Yield: 0.04 g, 12%; MS (ESI) m/z 300.3 [M+1].sup.+; .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 9.58 (s, 1H), 9.40 (s, 1H), 8.78
(s, 1H), 8.67 (s, 1H), 8.38 (d, J=5.84 Hz, 1H), 7.38 (d, J=5.36 Hz,
1H), 2.89 (q, J=7.76 Hz, 2H), 1.79 (s, 6H), 1.11 (t, J=7.36 Hz,
3H).
Example 72
Synthesis of
8-chloro-3-methyl-3-(3-pyridyl)-6-(pyrimidin-4-ylamino)-2H-imidazo[1,5-a]-
pyridine-1,5-dione (Cpd. No. 72)
##STR00179##
##STR00180##
[0433] Synthesis of
6-bromo-8-chloro-3-methyl-3-(3-pyridyl)-2H-imidazo[1,5-a]pyridine-1,5-dio-
ne (3)
[0434] The synthesis of intermediate 3 was carried out as described
above using the general protocol of Procedure A. Yellow solid;
Yield: 0.4 g, 57%; MS (ESI) m/z 354.02 [M+1].sup.+; .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 10.4 (bs, 1H), 8.70 (s, 1H), 8.57
(d, J=4 Hz, 1H), 8.31 (s, 1H), 7.82 (d, J=8.0 Hz, 1H), 7.42-7.39
(m, 1H), 2.22 (s, 3H).
Synthesis of
8-chloro-3-methyl-3-(3-pyridyl)-6-(pyrimidin-4-ylamino)-2H-imidazo[1,5-a]-
pyridine-1,5-dione (Cpd. No. 72)
[0435] Procedure H: To a solution of
6-bromo-8-chloro-3-methyl-3-(3-pyridyl)-2H-imidazo[1,5-a]pyridine-1,5-dio-
ne (100 mg, 0.28 mmol) and pyrimidin-4-amine (30 mg, 0.31 mmol) in
1,4-dioxane (12 mL) was added cesium carbonate (276 mg, 0.85 mmol).
The reaction was purged with argon for 15 min. XPhos (13 mg, 0.03
mmol), XantPhos (16 mg, 0.030 mmol), palladium acetate (6 mg, 0.030
mmol) and tris(dibenzylideneacetone)dipalladium(0) (26 mg, 0.030
mmol) were added and purging was continued for another 10 min. The
reaction was stirred at 100.degree. C. for 16 h. After completion
the reaction mass was diluted with 10% methanol in dichloromethane
and passed through celite pad. The crude filtrate was then purified
by flash column chromatography using 10% methanol in
dichloromethane. The desired fractions were concentrated to dryness
under vacuum to obtain
8-chloro-3-methyl-3-(3-pyridyl)-6-(pyrimidin-4-ylamino)-2H-imidazo[1,5-c]-
pyridine-1,5-dione as pale yellow solid. Yield: 0.059 g, 57%; MS
(ESI) m/z 369.29 [M+1].sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. 10.16 (s, 1H), 9.57 (s, 1H), 8.84 (d, J=6.2 Hz, 1H), 8.75
(d, J=2.24 Hz, 1H), 8.56-8.55 (m, 1H), 7.82 (d, J=8.2 Hz, 1H),
7.42-7.38 (m, 1H), 2.27 (s, 3H).
Example 73
Synthesis of
N-(6-((8-chloro-3-methyl-1,5-dioxo-3-(pyridin-4-yl)-1,2,3,5-tetrahydroimi-
dazo[1,5-a]pyridin-6-yl)amino)pyrimidin-4-yl)cyclopropanecarboxamide
(Cpd. No. 73)
##STR00181##
##STR00182##
[0436] Synthesis of
N-(6-((8-chloro-3-methyl-1,5-dioxo-3-(pyridin-4-yl)-1, 2,
3,5-tetrahydroimidazo[1,5-a]pyridin-6-yl)amino)pyrimidin-4-yl)cyclopro-
panecarboxamide (Cpd. No. 73)
[0437] The synthesis of compound 73 was carried out as described
above using the general protocol of Procedure B. Off-white solid;
Yield: 0.030 g, 16%; MS (ESI) m/z 352.34 [M+1].sup.+; .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 10.91 (brs, 1H), 10.15 (s, 1H),
9.45 (brs, 1H), 8.76 (s, 1H), 8.58 (m, 3H), 7.90 (s, 1H), 7.40
(brs, 2H), 2.21 (s, 3H), 2.05-1.95 (m, 1H), 0.90-0.75 (m, 4H).
Example 74
Synthesis of
8-chloro-3-methyl-3-(2-pyridyl)-6-(pyrimidin-4-ylamino)-2H-imidazo[1,5-a]-
pyridine-1,5-dione (Cpd. No. 74)
##STR00183##
##STR00184##
[0438] Synthesis of
6-bromo-8-chloro-3-methyl-3-(pyridin-2-yl)-2,3-dihydroimidazo[1,5-a]pyrid-
ine-1,5-dione (3)
[0439] The synthesis of intermediate 3 was carried out as described
above using the general protocol of Procedure A. White solid;
Yield: 0.30 g, 42%; MS (ESI) m/z 354 [M+1].sup.+.
Synthesis of
8-chloro-3-methyl-3-(2-pyridyl)-6-(pyrimidin-4-ylamino)-2H-imidazo[1,5-a]-
pyridine-1,5-dione (Cpd. No. 74)
[0440] The synthesis of compound 74 was carried out as described
above using the general protocol of Procedure H. Off-white solid;
Yield: 55 mg, 35%; .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
10.05 (bs, 1H), 9.51 (bs, 1H), 8.84 (d, J=11.1 Hz, 2H), 8.52 (d,
J=3.28 Hz, 1H), 8.40 (d, J=5.72 Hz, 1H), 7.88-7.84 (m, 1H), 7.66
(d, J=8.12 Hz, 1H), 7.38-7.35 (m, 1H), 7.24 (d, J=5.84 Hz, 1H),
2.26 (s, 3H).
Example 75
Synthesis of
8-chloro-3-methyl-3-(4-pyridyl)-6-(pyrimidin-4-ylamino)-2H-imidazo[1,5-a]-
pyridine-1,5-dione (Cpd. No. 75)
##STR00185##
##STR00186##
[0441] Synthesis of
6-bromo-8-chloro-3-methyl-3-(pyridin-4-yl)-2,3-dihydroimidazo[1,5-a]pyrid-
ine-1,5-dione (3)
[0442] The synthesis of intermediate 3 was carried out as described
above using the general protocol of Procedure A. Off-white solid;
Yield: 0.36 g, 51%; MS (ESI) m/z 354.02 [M+1].sup.+; .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 10.4 (bs, 1H), 8.57 (d, J=5.2 Hz,
2H), 8.33 (s, 1H), 7.40 (d, J=4.5 Hz, 2H), 2.17 (s, 3H).
Synthesis of
8-chloro-3-methyl-3-(4-pyridyl)-6-(pyrimidin-4-ylamino)-2H-imidazo[1,5-a]-
pyridine-1,5-dione (Cpd. No. 75)
[0443] The synthesis of compound 75 was carried out as described
above using the general protocol of Procedure B. Off-white solid;
Yield: 59 mg, 57%; MS (ESI) m/z 369.29 [M+1].sup.+; .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 10.18 (bs, 1H), 9.58 (s, 1H), 8.84
(d, J=2.88 Hz, 2H), 8.59 (d, J=5.64 Hz, 2H), 8.41 (d, J=5.88 Hz,
1H), 7.43 (d, J=5.76 Hz, 2H), 7.34 (d, J=5.76 Hz, 1H), 2.23 (s,
3H).
Example 76
Synthesis of
N-(6-((8-chloro-3-methyl-1,5-dioxo-3-(pyridin-2-yl)-1,2,3,5-tetrahydroimi-
dazo[1,5-a]pyridin-6-yl)amino)pyrimidin-4-yl)cyclopropanecarboxamide
(Cpd. No. 76)
##STR00187##
##STR00188##
[0444] Synthesis of
N-(6-((8-chloro-3-methyl-1,5-dioxo-3-(pyridin-2-yl)-1,2,3,5-tetrahydroimi-
dazo[1,5-a]pyridin-6-yl)amino)pyrimidin-4-yl)cyclopropanecarboxamide
(Cpd. No. 76)
[0445] The synthesis of compound 76 was carried out as described
above using the general protocol of Procedure H. Off-white solid;
Yield: 15 mg, 8%; MS (ESI) m/z 452.35 [M+1].sup.+; .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. 10.90 (s, 1H), 10.01 (s, 1H), 9.36 (s,
1H), 8.73 (s, 1H), 8.58 (s, 1H), 8.51 (d, J=4.32 Hz, 1H), 7.85 (m,
2H), 7.63 (d, J=7.96, 1H), 7.37 (m, 1H), 2.27 (s, 3H), 1.99 (m,
1H), 0.81 (m, 4H).
Example 77
Synthesis of
N-[6-[[8-chloro-3-methyl-1,5-dioxo-3-(3-pyridyl)-2H-imidazo[1,5-a]pyridin-
-6-yl]amino]pyrimidin-4-yl]cyclopropanecarboxamide (Cpd. No.
77)
##STR00189##
##STR00190##
[0446] Synthesis of
N-[6-[[8-chloro-3-methyl-1,5-dioxo-3-(3-pyridyl)-2H-imidazo[1,5-a]pyridin-
-6-yl]amino]pyrimidin-4-yl]cyclopropanecarboxamide (Cpd. No.
77)
[0447] The synthesis of compound 77 was carried out as described
above using the general protocol of Procedure H. Pale yellow solid;
Yield: 58 mg, 15%; MS (ESI) m/z 452.36 [M+1].sup.+; .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 10.99 (bs, 1H), 10.12 (bs, 1H),
9.44 (s, 1H), 8.75 (s, 1H), 8.73 (d, J=2.0 Hz, 1H), 8.58 (s, 1H),
8.56 (d, J=3.7 Hz, 1H), 7.90 (s, 1H), 7.42-7.38 (m, 1H), 2.26 (s,
3H), 2.02-1.96 (m, 1H), 0.82-0.81 (m, 4H).
Example 78
Synthesis of
N-(6-((8'-chloro-2-fluoro-1',5'-dioxo-1',5'-dihydro-2'H-spiro[cyclohexane-
-1,3'-imidazo[1,5-a]pyridin]-6'-yl)amino)pyrimidin-4-yl)cyclopropanecarbox-
amide (Cpd. No. 78)
##STR00191##
##STR00192##
[0448] Synthesis of
6'-bromo-8'-chloro-2-fluoro-2'H-spiro[cyclohexane-1,3'-imidazo[1,5-a]pyri-
dine]-1',5'-dione (3)
[0449] The synthesis of intermediate 3 was carried out as described
above using the general protocol of Procedure A. Off-white solid;
Yield: 0.31 g; MS (ESI) m/z 348.8 [M+1].sup.+.
Synthesis of
N-(6-((8'-chloro-2-fluoro-1',5'-dioxo-1',5'-dihydro-2'H-spiro[cyclohexane-
-1,3'-imidazo[1,5-a]pyridin]-6'-yl)amino)pyrimidin-4-yl)cyclopropanecarbox-
amide (Cpd. No. 78)
[0450] The synthesis of compound 78 was carried out as described
above using the general protocol of Procedure B. Light yellow
solid; Yield: 50 mg, 16%; MS (ESI) m/z 447.34 [M+1].sup.+; .sup.1H
NMR (400 MHz, DMSO-d.sub.6) .delta. 10.95 (s, 1H), 10.27 (s, 1H),
9.51 (s, 1H), 8.74 (s, 1H), 8.60 (s, 1H), 7.99 (s, 1H), 5.64 (m,
1H), 2.95 (m, 1H), 2.1 (m, 1H), 2.02 (m, 1H), 1.72 (m, 4H), 1.57
(m, 1H), 1.39 (m, 1H), 0.84 (d, J=5.12 Hz, 4H).
Example 79
Synthesis of
3,3-dimethyl-6-(pyrimidin-4-ylamino)-8-vinyl-2H-imidazo[1,5-a]pyridine-1,-
5-dione (Cpd. No. 79)
##STR00193##
##STR00194##
[0451] Synthesis of
3,3-dimethyl-6-(pyrimidin-4-ylamino)-8-vinyl-2H-imidazo[1,5-a]pyridine-1,-
5-dione (Cpd. No. 79)
[0452] The synthesis of compound 79 was carried out as described
above using the general protocol of Procedure G. Pale yellow solid;
Yield: 50 mg, 17%; MS (ESI) m/z 298.3 [M+1].sup.+; .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. 9.74 (s, 1H), 9.47 (s, 1H), 9.14 (s,
1H), 8.81 (s, 1H), 8.40 (d, J=5.88 Hz, 1H), 7.85 (dd, J=11.04 Hz,
1H), 7.40 (d, J=5.88 Hz, 1H), 5.75 (d, J=6.12 Hz, 1H), 5.37 (d,
J=11.24 Hz, 1H), 1.81 (s, 6H).
Example 80
Synthesis of
N-(6-((8-chloro-3-methyl-1,5-dioxo-3-(3-(trifluoromethyl)phenyl)-1,2,3,5--
tetrahydroimidazo[1,5-a]pyridin-6-yl)amino)pyrimidin-4-yl)cyclopropanecarb-
oxamide (Cpd. No. 80)
##STR00195##
##STR00196##
[0453] Synthesis of
6-bromo-8-chloro-3-methyl-3-(3-(trifluoromethyl)phenyl)-2,3-dihydroimidaz-
o[1,5-a]pyridine-1,5-dione (3)
[0454] The synthesis of intermediate 3 was carried out as described
above using the general protocol of Procedure A. Off-white solid;
Yield: 0.12 g, 14%; MS (ESI) m/z 419 [M-1].sup.-.
Synthesis of
N-(6-((8-chloro-3-methyl-1,5-dioxo-3-(3-(trifluoromethyl)phenyl)-1,
2,3,5-tetrahydroimidazo[1,5-a]pyridin-6-yl)amino)pyrimidin-4-yl)cycloprop-
anecarboxamide (Cpd. No. 80)
[0455] The synthesis of compound 80 was carried out as described
above using the general protocol of Procedure B. Off-white solid;
Yield: 16 mg, 11%; MS (ESI) m/z 519 [M+1].sup.+; .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. 8.75 (s, 1H), 8.58 (s, 1H), 7.90 (s,
1H), 7.82 (s, 1H), 7.75 (d, J=7.4 Hz, 1H), 7.68 (d, J=7.92 Hz, 1H),
7.62 (d, J=7.7 Hz, 1H), 2.27 (s, 3H), 1.98 (m, 1H), 0.81 (m,
4H).
Example 81
Synthesis of
8-methoxy-3,3-dimethyl-6-(pyrimidin-4-ylamino)-2H-imidazo[1,5-a]pyridine--
1,5-dione (Cpd. No. 81)
##STR00197##
##STR00198##
[0456] Synthesis of
6-bromo-8-methoxy-3,3-dimethyl-2H-imidazo[1,5-a]pyridine-1,5-dione
(3)
[0457] The synthesis of intermediate 3 was carried out as described
above using the general protocol of Procedure A. Light brown solid;
Yield: 0.5 g, 41%; .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 7.87
(s, 1H), 6.75 (bs, 1H), 3.94 (s, 3H), 1.93 (s, 6H).
Synthesis of
8-methoxy-3,3-dimethyl-6-(pyrimidin-4-ylamino)-2H-imidazo[1,5-a]pyridine--
1,5-dione (Cpd. No. 81)
[0458] The synthesis of compound 81 was carried out as described
above using the general protocol of Procedure B. Yellow solid;
Yield: 0.060 g, 15%; .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
9.50-9.41 (bs, 1H), 8.79 (s, 1H), 8.39 (d, J=4.0 Hz, 1H), 7.40 (d,
J=8.0 Hz, 1H), 7.13 (bs, 1H), 3.85 (s, 3H), 1.76 (s, 6H).
Example 82
Synthesis of
3,3-dimethyl-8-methylsulfanyl-6-(pyrimidin-4-ylamino)-2H-imidazo[1,5-a]py-
ridine-1,5-dione (Cpd. No. 82)
##STR00199##
##STR00200##
[0459] Synthesis of
3,3-dimethyl-8-methylsulfanyl-6-(pyrimidin-4-ylamino)-2H-imidazo[1,5-a]py-
ridine-1,5-dione (Cpd. No. 82)
[0460] To a vial was added
8-chloro-3,3-dimethyl-6-(pyrimidin-4-ylamino)-2H-imidazo[1,5-c]pyridine-1-
,5-dione (1, 0.30 g, 0.98 mmol) in dimethylformamide (5 mL). Sodium
thiomethoxide (0.14 g, 1.96 mmol) was added at room temperature,
the vial was sealed and heated at 110.degree. C. for 36 h. The
reaction mixture was quenched with an aqueous ammonium chloride
solution and extracted with 10% methanol in dichloromethane. The
organic layers were separated, combined, dried over sodium sulfate,
filtered and concentrated it to dryness. Solids were precipitated
by the addition of ice, filtered and dried. The solid material was
subjected to preparative HPLC to afford
3,3-dimethyl-8-methylsulfanyl-6-(pyrimidin-4-ylamino)-2H-imidazo[1,5-a]py-
ridine-1,5-dione (Cpd. No. 82) as a yellow solid. Yield: 0.060 g,
19%; MS (ESI) m/z 318.42 [M+1].sup.+; .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 10.02 (s, 1H), 9.66 (s, 1H), 8.92 (s, 1H),
8.84 (s, 1H), 8.45 (d, J=6.0 Hz, 1H), 7.47 (d, J=6.4 Hz, 1H), 2.47
(s, 3H), 1.80 (s, 6H).
Example 83
Synthesis of
N-(6-((8-chloro-3-methyl-1,5-dioxo-3-(m-tolyl)-1,2,3,5-tetrahydroimidazo[-
1,5-a]pyridin-6-yl)amino)pyrimidin-4-yl)cyclopropanecarboxamide
(Cpd. No. 83)
##STR00201##
##STR00202##
[0461] Synthesis of
6-bromo-8-chloro-3-methyl-3-(m-tolyl)-2,3-dihydroimidazo[1,5-a]pyridine-1-
,5-dione (3)
[0462] The synthesis of intermediate 3 was carried out as described
above using the general protocol of Procedure A. Off-white solid;
Yield: 0.30 g, 41%; MS (ESI) m/z 367 [M+1].sup.+; .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. 10.32 (s, 1H), 8.29 (s, 1H), 7.26 (m,
1H), 7.16 (m, 3H), 2.30 (s, 3H), 2.18 (s, 3H).
Synthesis of
N-(6-((8-chloro-3-methyl-1,5-dioxo-3-(m-tolyl)-1,2,3,5-tetrahydroimidazo--
[1,5-a]pyridin-6-yl)amino)pyrimidin-4-yl)cyclopropanecarboxamide
(Cpd. No. 83)
[0463] The synthesis of compound 83 was carried out as described
above using the general protocol of Procedure H. Pale yellow solid;
Yield: 60 mg, 16%; MS (ESI) m/z 465.49 [M+1].sup.+; .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 10.90 (s, 1H), 10.04 (s, 1H), 9.40
(s, 1H), 8.73 (s, 1H), 8.58 (s, 1H), 7.88 (s, 1H), 7.26 (m, 1H),
7.21 (m, 1H), 7.12 (m, 2H), 2.29 (s, 3H), 2.28 (s, 3H) 1.99 (m,
1H), 0.82 (m, 4H).
Example 84
Synthesis of
N-[6-[(3-tert-butyl-8-chloro-3-methyl-1,5-dioxo-2H-imidazo[1,5-a]pyridin--
6-yl)amino]pyrimidin-4-yl]cyclopropanecarboxamide (Cpd. No. 84)
##STR00203##
##STR00204##
[0464] Synthesis of
6-bromo-3-tert-butyl-8-chloro-3-methyl-2H-imidazo[1,5-a]pyridine-1,5-dion-
e (3)
[0465] The synthesis of intermediate 3 was carried out as described
above using the general protocol of Procedure A. Yellow solid;
Yield: 150 mg, 28%; MS (ESI) m/z 332.8 [M+1].sup.+.
Synthesis of
N-[6-[(3-tert-butyl-8-chloro-3-methyl-1,5-dioxo-2H-imidazo[1,5-a]pyridin--
6-yl)amino]pyrimidin-4-yl]cyclopropanecarboxamide (Cpd. No. 84)
[0466] The synthesis of compound 84 was carried out as described
above using the general protocol of Procedure H. Brown solid;
Yield: 0.060 g, 31%; MS (ESI) m/z 431.42 [M+1].sup.+; .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 10.91 (s, 1H), 9.73 (s, 1H), 9.49
(s, 1H), 8.67 (s, 1H), 8.58 (s, 1H), 7.98 (s, 1H), 2.02 (m, 1H),
1.92 (s, 1H), 0.98 (s, 9H), 0.83 (m, 4H).
Example 85
Synthesis of
N-[6-[[8-chloro-1,5-dioxo-3-(trifluoromethyl)-2,3-dihydroimidazo[1,5-a]py-
ridin-6-yl]amino]pyrimidin-4-yl]cyclopropanecarboxamide (Cpd. No.
85)
##STR00205##
##STR00206##
[0467] Synthesis of
6-bromo-8-chloro-3-(trifluoromethyl)-2,3-dihydroimidazo[1,5-a]pyridine-1,-
5-dione (3)
[0468] The synthesis of intermediate 3 was carried out as described
above using the general protocol of Procedure A. Brown solid;
Yield: 200 mg, 61%; .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
10.93 (s, 1H), 8.34 (m, 1H), 6.57 (m, 1H).
Synthesis of
N-[6-[[8-chloro-1,5-dioxo-3-(trifluoromethyl)-2,3-dihydroimidazo[1,5-a]py-
ridin-6-yl]amino]pyrimidin-4-yl]cyclopropanecarboxamide (Cpd. No.
85)
[0469] The synthesis of compound 85 was carried out as described
above using the general protocol of Procedure B. Pale yellow solid;
Yield: 0.035 g, 14%; MS (ESI) m/z 429.33 [M+1].sup.+; .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 10.95 (s, 1H), 10.58 (s, 1H), 9.80
(s, 1H), 8.76 (s, 1H), 8.61 (s, 1H), 8.06 (s, 1H), 6.61 (d, J=3.0
Hz, 1H), 2.02 (m, 1H), 0.84 (m, 4H).
Example 86
Synthesis of
N-[6-[(8-chloro-1,5-dioxo-spiro[2H-imidazo[1,5-a]pyridine-3, 3%
azetidine]-6-yl) amino] pyrimidin-4-yl] cyclopropanecarboxamide
hydrochloride (Cpd. No. 86)
##STR00207##
##STR00208##
[0470] Synthesis of tert-butyl
6-bromo-8-chloro-1,5-dioxo-spiro[2H-imidazo[1,5-a]pyridine-3,3'-azetidine-
]-1'-carboxylate (3)
[0471] To a stirred solution of
5-bromo-3-chloro-6-oxo-1H-pyridine-2-carboxamide (1, 1.0 g, 3.98
mmol) in 1,4-dioxane (12 mL) in a vial was added tert-butyl
3-oxoazetidine-1-carboxylate (2, 2.72 g, 15.91 mmol) at room
temperature. Concentrated sulfuric acid (0.39 g, 3.98 mmol) was
then added dropwise. The vial was sealed and heated to 95.degree.
C. for 16 h. The reaction mixture was concentrated, water (30 mL)
was added and extracted with ethyl acetate (2.times.30 mL). The
organic layers were separated and discarded.
[0472] To a stirred solution of
6-bromo-8-chloro-spiro[2H-imidazo[1,5-a]pyridine-3,3'-azetidine]-1,5-dion-
e (0.41 g, 1.35 mmol) in 1,4-dioxane (30 mL) and water (25 mL, 1.35
mmol) was added di-tert-butyl dicarbonate (0.59 g, 2.71 mmol). The
solution was cooled to 0.degree. C. and 2 M aqueous sodium
hydroxide solution was added dropwise with stirring. The reaction
mixture was stirred at room temperature overnight. After
consumption of starting material as indicated by TLC, the mixture
was extracted with 10% methanol in dichloromethane (2.times.25 mL).
The organic layers were separated and dried over magnesium sulfate,
filtered and concentrated to dryness. The crude residue was then
purified by flash column chromatography using neutral alumina with
2% methanol in dichloromethane. The desired fractions were
concentrated to dryness under vacuum to afford tert-butyl
6-bromo-8-chloro-1,5-dioxo-spiro [2H-imidazo[1,5-a]pyridine-3,
3'-azetidine]-1'-carboxylate (3) as a yellow solid. Yield: 180 mg,
33%; MS (ESI) m/z 404.03 [M+1].sup.+; .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 10.53 (s, 1H), 8.28 (s, 1H), 4.88-4.68 (m,
2H), 3.97-3.89 (m, 2H), 1.42 (s, 9H).
Synthesis of tert-butyl
8-chloro-6-[[6-(cyclopropanecarbonylamino)pyrimidin-4-yl]amino]-1,5-dioxo-
-spiro[2H-imidazo[1,5-a]pyridine-3,3'-azetidine]-1'-carboxylate
(5)
[0473] The synthesis of intermediate 5 was carried out as described
above using the general protocol of Procedure B. Yellow solid;
Yield: 0.065 g; 29%; .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
10.93 (s, 1H), 10.46 (s, 1H), 9.63 (s, 1H), 8.71 (s, 1H), 8.59 (s,
1H), 8.10 (s, 1H), 4.89-4.84 (m, 2H), 3.97-3.95 (m, 2H), 2.02-2.0
(m, 1H), 1.42 (s, 9H), 0.79-0.75 (m, 4H).
Synthesis of
N-[6[(8-chloro-1,5-dioxo-spiro[2H-imidazo[1,5-a]pyridine-3,3'-azetidine]--
6-yl)amino]pyrimidin-4-yl]cyclopropanecarboxamide hydrochloride
(Cpd. No. 86)
[0474] The synthesis of compound 86 was carried out as described
above using the general protocol of Procedure F. Light yellow
solid; Yield: 0.03 g; 61%; MS (ESI) m/z 402.34 [M+1].sup.+; .sup.1H
NMR (400 MHz, DMSO-d.sub.6) .delta. 11.04 (s, 1H), 10.41 (s, 1H),
9.67 (s, 1H) 9.5 (bs, 1H), 8.79 (s, 1H), 8.74 (s, 1H), 8.06 (s,
1H).
Example 87
Synthesis of 6-[(6-aminopyrimidin-4-yl)
amino]-8-chloro-3-(3-fluorophenyl)-3-methyl-2H-imidazo[1,5-a]pyridine-1,5-
-dione (Cpd. No. 87)
##STR00209##
##STR00210##
[0475] Synthesis of 6-[(6-aminopyrimidin-4-yl)
amino]-8-chloro-3-(3-fluorophenyl)-3-methyl-2H-imidazo[1,5-a]pyridine-1,5-
-dione (Cpd. No. 87)
[0476] Procedure I: In a vial containing
N-[6-[[8-chloro-3-(3-fluorophenyl)-3-methyl-1,5-dioxo-2H-imidazo[1,5-a]py-
ridin-6-yl]amino]pyrimidin-4-yl]cyclopropanecarboxamide (1, 0.23 g,
0.49 mmol) in tetrahydrofuran (5 mL), water (5 mL) and ethanol (10
mL) at room temperature was added a concentrated aqueous solution
of potassium hydroxide (0.14 g, 2.45 mmol). Then reaction mixture
was stirred for 16 h and was extracted with ethyl acetate
(3.times.50 mL). The organic layers were then separated and dried
over sodium sulfate, filtered and concentrated to dryness. The
crude residue was subjected to flash column chromatography with 2%
methanol in dichloromethane. The desired fractions were
concentrated to dryness. The resulting solid was washed with
pentane and diethyl ether to afford the product as a yellow solid.
Yield: 0.095 g, 48%; MS (ESI) m/z 401.40 [M+1].sup.+; .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 10.02 (brs, 1H), 8.86 (s, 1H), 8.68
(s, 1H), 8.19 (s, 1H), 7.45-7.38 (m, 1H), 7.30 (d, J=8.8 Hz, 1H),
7.23-7.15 (m, 2H), 6.58 (brs, 2H), 6.17 (s, 1H), 2.21 (s, 1H).
Example 88
Synthesis of
6-[(6-aminopyrimidin-4-yl)amino]-8-chloro-3,3-dimethyl-2H-imidazo[1,5-a]p-
yridine-1,5-dione (Cpd. No. 88)
##STR00211##
##STR00212##
[0477] Synthesis of
6-[(6-aminopyrimidin-4-yl)amino]-8-chloro-3,3-dimethyl-2H-imidazo[1,5-a]p-
yridine-1,5-dione (Cpd. No. 88)
[0478] The synthesis of compound 88 was carried out as described
above using the general protocol of Procedure I. Light yellow
solid; Yield: 0.14 g, 68%; MS (ESI) m/z 321.34 [M+1].sup.+; .sup.1H
NMR (400 MHz, DMSO-d.sub.6) .delta. 9.64 (s, 1H), 8.92 (s, 1H),
8.64 (s, 1H), 8.20 (s, 1H), 6.60 (s, 2H), 6.25 (s, 1H), 1.79 (s,
6H).
Synthesis of 6-[(6-aminopyrimidin-4-yl)
amino]-8-chloro-3,3-dimethyl-2H-imidazo[1,5-a]pyridine-1,5-dione
hydrogenchloride (hydrogenchloride salt of Cpd. No. 88)
[0479] To
6-[(6-aminopyrimidin-4-yl)amino]-8-chloro-3,3-dimethyl-2H-imidaz-
o[1,5-a]pyridine-1,5-dione (Cpd. No. 88, 0.55 g, 1.71 mmol), in
dichloromethane (10 mL), methanol (10 mL) a vial was added 4 M
hydrogenchloride in 1,4-dioxane (10 mL). After stirring overnight
at room temperature the reaction mixture was concentrated under
vacuum, filtered, washed with methanol then diethyl ether and dried
under vacuum to afford the product as a light yellow solid. Yield:
0.61 g, 100%; MS (ESI) m/z 319.43 [M+1].sup.+; .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. 9.83 (s, 1H), 9.77 (s, 1H), 8.48 (s,
1H), 8.42 (s, 1H), 7.75 (s, 2H), 6.49 (s, 1H), 1.79 (s, 6H).
Example 89
Synthesis of
8-chloro-3-(3-chlorophenyl)-3-methyl-6-[[6-(methylamino)pyrimidin-4-yl]am-
ino]-2H-imidazo[1,5-a]pyridine-1,5-dione (Cpd. No. 89)
##STR00213##
##STR00214##
[0480] Synthesis of
8-chloro-3-(3-chlorophenyl)-3-methyl-6-[[6-(methylamino)pyrimidin-4-yl]am-
ino]-2H-imidazo[1,5-a]pyridine-1,5-dione (Cpd. No. 89)
[0481] The synthesis of compound 89 was carried out as described
above using the general protocol of Procedure H. Yellow solid;
Yield: 50 mg, 16%; MS (ESI) m/z 431.32 [M+1].sup.+; .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 10.03 (s, 1H), 8.89 (s, 1H), 8.70
(s, 1H), 8.25 (s, 1H), 7.51 (s, 1H), 7.41 (m, 2H), 7.37 (m, 1H),
7.05 (s, 1H), 6.24 (s, 1H), 2.68 (s, 3H), 2.19 (s, 3H).
Example 90
Synthesis of
8-chloro-3-methyl-3-(6-methyl-2-pyridyl)-6-(pyrimidin-4-ylamino)-2H-imida-
zo[1,5-a]pyridine-1,5-dione (Cpd. No. 90)
##STR00215##
##STR00216##
[0482] Synthesis of
6-bromo-8-chloro-3-methyl-3-(6-methyl-2-pyridyl)-2H-imidazo[1,5-a]pyridin-
e-1,5-dione (3)
[0483] The synthesis of intermediate 3 was carried out as described
above using the general protocol of Procedure A. Brown solid;
Yield: 0.41 g, 56%; MS (ESI) m/z 370 [M+1].sup.+; .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. 10.28 (m, 1H), 8.30 (s, 1H), 7.73 (m,
1H), 7.39 (m, 1H), 7.24 (m, 1H), 2.29 (s, 3H), 2.20 (s, 3H).
Synthesis of
8-chloro-3-methyl-3-(6-methyl-2-pyridyl)-6-(pyrimidin-4-ylamino)-2H-imida-
zo[1,5-a]pyridine-1,5-dione (Cpd. No. 90)
[0484] The synthesis of compound 90 was carried out as described
above using the general protocol of Procedure B. Light yellow
solid; Yield: 0.15 g, 48%; MS (ESI) m/z 383.37 [M+1].sup.+; .sup.1H
NMR (400 MHz, DMSO-d.sub.6) .delta. 10.00 (s, 1H), 9.48 (s, 1H),
8.83 (s, 1H), 8.81 (s, 1H), 8.39 (d, J=11.92 Hz, 1H), 7.72 (t,
J=7.78 Hz, 1H), 7.37 (m, 1H), 7.31 (m, 1H), 7.22 (m, 1H), 2.38 (s,
3H), 2.25 (s, 3H).
Example 91
Synthesis of
N-[6-[[8-chloro-3-(3-fluorophenyl)-1,5-dioxo-2,3-dihydroimidazo[1,5-a]pyr-
idin-6-yl]amino]pyrimidin-4-yl]cyclopropanecarboxamide (Cpd. No.
91)
##STR00217##
##STR00218##
[0485] Synthesis of
6-bromo-8-chloro-3-(3-fluorophenyl)-2,3-dihydroimidazo[1,5-a]pyridine-1,5-
-dione (3)
[0486] A mixture of
5-bromo-3-chloro-6-oxo-1H-pyridine-2-carboxamide (1, 0.4 g, 1.59
mmol), 3-fluorobenzaldehyde (2, 0.69 g, 5.57 mmol), acetonitrile
(15 mL) and iron(III) chloride (1.81 g, 11.13 mmol) in a sealed
tube was heated at 90.degree. C. for 16 h. Once TLC showed
consumption of the starting material, the mixture was cooled and
filtered through a celite bed. The celite was washed with
acetonitrile and the filtrate was concentrated under vacuum. The
crude residue was subjected to flash column chromatography eluting
with 35% ethyl acetate in hexane. The desired fractions were
collected, concentrated and dried under high vacuum to afford
6-bromo-8-chloro-3-(3-fluorophenyl)-2,3-dihydroimidazo[1,5-c]pyridine-1,5-
-dione (3) as a yellow solid. Yield: 0.35 g, 61%; MS (ESI) m/z
357.20 [M+1].sup.+.
Synthesis of
N-[6-[[8-chloro-3-(3-fluorophenyl)-1,5-dioxo-2,3-dihydroimidazo[1,5-a]-py-
ridin-6-yl]amino]pyrimidin-4-yl]cyclopropanecarboxamide (Cpd. No.
91)
[0487] The synthesis of compound 91 was carried out as described
above using the general protocol of Procedure H. Yellow solid;
Yield: 46 mg, 18%. MS (ESI) m/z 455.33 [M+1].sup.+; .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 10.89 (s, 1H), 10.06 (s, 1H), 9.47
(s, 1H), 8.76 (s, 1H), 8.58 (s, 1H), 7.90 (s, 1H), 7.44 (m, 1H),
7.41 (m, 1H), 7.24 (m, 2H), 6.62 (s, 1H), 2.00 (t, J=5.68 Hz, 1H),
0.81 (m, 4H).
Example 92
Synthesis of
6-[(6-aminopyrimidin-4-yl)amino]-3-(3-chlorophenyl)-3,8-dimethyl-2H-imida-
zo[1,5-a]pyridine-1,5-dione (Cpd. No. 92)
##STR00219##
##STR00220##
[0488] Synthesis of
6-bromo-3-(3-chlorophenyl)-3,8-dimethyl-2H-imidazo[1,5-a]pyridine-1,5-dio-
ne (3)
[0489] The synthesis of intermediate 3 was carried out as described
above using the general protocol of Procedure A. Cream colored
solid; Yield: 0.25 g, 39%; MS (ESI) m/z 397.23 [M+1].sup.+.
Synthesis of tert-butyl
N-[6-[[3-(3-chlorophenyl)-3,8-dimethyl-1,5-dioxo-2H-imidazo[1,5-a]pyridin-
-6-yl]amino]pyrimidin-4-yl]carbamate (5)
[0490] The synthesis of intermediate 5 was carried out as described
above using the general protocol of Procedure H. Off-white
semi-solid; Yield: 0.26 g, 31%; MS (ESI) m/z 497.06[M+1].sup.+.
Synthesis of
6-[(6-aminopyrimidin-4-yl)amino]-3-(3-chlorophenyl)-3,8-dimethyl-2H-imida-
zo[1,5-a]pyridine-1,5-dione (Cpd. No. 92)
[0491] The synthesis of compound 92 was carried out as described
above using the general protocol of Procedure F. Yellow solid;
Yield: 0.077 g, 37%; MS (ESI) m/z 397.13 [M+1].sup.+; .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 9.80 (s, 1H), 8.57 (s, 1H), 8.46
(s, 1H), 8.15 (s, 1H), 7.41 (m, 3H), 7.27 (d, J=6.3 Hz, 1H), 6.50
(s, 2H), 6.10 (s, 1H), 2.47 (s, 3H), 2.20 (s, 3H).
Example 93
Synthesis of
6-[(6-aminopyrimidin-4-yl)amino]-8-chloro-3-(3-chlorophenyl)-3-methyl-2H--
imidazo[1,5-a]pyridine-1,5-dione (Cpd. No. 93)
##STR00221##
##STR00222##
[0492] Synthesis of
6-[(6-aminopyrimidin-4-yl)amino]-8-chloro-3-(3-chlorophenyl)-3-methyl-2H--
imidazo[1,5-a]pyridine-1,5-dione (Cpd. No. 93)
[0493] The synthesis of compound 93 was carried out as described
above using the general protocol of Procedure I. Yellow solid;
Yield: 0.17 g, 57%; MS (ESI) m/z 417.08 [M+1].sup.+; .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 8.55 (s, 1H), 8.15 (s, 1H),
7.39-7.35 (m, 3H), 6.08 (s, 1H), 2.17 (s, 3H).
Example 94
Synthesis of
6-[(6-aminopyrimidin-4-yl)amino]-8-chloro-spiro[2H-imidazo[1,5-a]pyridine-
-3,1'-cyclopentane]-1,5-dione (Cpd. No. 94)
##STR00223##
##STR00224##
[0494] Synthesis of
6-bromo-8-chloro-spiro[2H-imidazo[1,5-a]pyridine-3,1'-cyclopentane]-1,5-d-
ione (3)
[0495] The synthesis of intermediate 3 was carried out as described
above using the general protocol of Procedure A. Off-white solid;
Yield: 380 mg; 60%; MS (ESI) m/z 315.06 [M-1].sup.-.
Synthesis of tert-butyl
N-[6-[(8-chloro-1,5-dioxo-spiro[2H-imidazo[1,5-a]pyridine-3,1'-cyclopenta-
ne]-6-yl)amino]pyrimidin-4-yl]carbamate (5)
[0496] The synthesis of intermediate 5 was carried out as described
above using the general protocol of Procedure H. Light yellow
solid; Yield: 0.30 g, 71%. MS (ESI) m/z 447.03 [M+1].sup.+.
Synthesis of
6-[(6-aminopyrimidin-4-yl)amino]-8-chloro-spiro[2H-imidazo[1,5-a]pyridine-
-3,1'-cyclopentane]-1,5-dione (Cpd. No. 94)
[0497] The synthesis of compound 94 was carried out as described
above using the general protocol of Procedure F. Light yellow
solid; Yield: 0.07 g, 45%. MS (ESI) m/z 347.14 [M+1].sup.+; .sup.1H
NMR (400 MHz, DMSO-d.sub.6) .delta. 10.04 (s, 1H), 9.15 (s, 1H),
8.60 (s, 1H), 8.26 (s, 1H), 6.85 (s, 2H), 6.30 (s, 1H), 2.77 (s,
2H), 1.97 (s, 2H), 1.77 (m, 4H).
Example 95
Synthesis of
N-[6-[(8-chloro-1,1',5-trioxo-spiro[2H-imidazo[1,5-a]pyridine-3,3'-thieta-
ne]-6-yl)amino]pyrimidin-4-yl]cyclopropanecarboxamide (Cpd. No.
95)
##STR00225##
##STR00226##
[0498] Synthesis of
6-bromo-8-chloro-1'-oxo-spiro[2H-imidazo[1,5-a]pyridine-3,3'-thietane]-1,-
5-dione (2)
[0499] A 30% solution of hydrogen peroxide (0.53 g, 15.55 mmol) was
added dropwise to
6-bromo-8-chloro-spiro[2H-imidazo[1,5-a]pyridine-3,3'-thietane]-1,5-dione
(1, 1.0 g, 3.11 mmol) dissolved in acetone (15 mL). Acetic acid
(18.66 mg, 0.31 mmol) was added and the mixture was stirred at room
temperature for 16 h. After TLC showed consumption of starting
materials, the reaction mixture was concentrated under reduced
pressure. The solids were washed with diethyl ether and
dichloromethane. The solid was filtered and dried under vacuum to
afford 6-bromo-8-chloro-1'-oxo-spiro
[2H-imidazo[1,5-a]pyridine-3,3'-thietane]-1,5-dione (2) as an
off-white solid. Yield: 0.4 g, 38%; MS (ESI) m/z 335 [M+1].sup.+;
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.32 (s, 1H), 4.62 (d,
J=12 Hz, 2H), 3.54 (d, J=16 Hz, 2H).
Synthesis of
N-[6[(8-chloro-1,1',5-trioxo-spiro[2H-imidazo[1,5-a]pyridine-3,3'-thietan-
e]-6-yl)amino]pyrimidin-4-yl]cyclopropanecarboxamide (Cpd. No.
95)
[0500] The synthesis of compound 95 was carried out as described
above using the general protocol of Procedure H. Light yellow
solid; Yield: 0.08 g, 24%; MS (ESI) m/z 435.4 [M+1].sup.+; .sup.1H
NMR (400 MHz, DMSO-d.sub.6) .delta. 10.91 (bs, 1H), 10.45-10.32 (m,
1H), 8.76 (bs, 1H), 8.59 (bs, 1H), 8.04 (bs, 1H), 4.66-4.63 (m,
2H), 3.59-3.56 (m, 2H), 2.01 (bs, 1H), 0.84 (s, 4H).
Example 96
Synthesis of
8-chloro-1',1'-dimethyl-6-(pyrimidin-4-ylamino)spiro[2H-imidazo[1,5-a]pyr-
idine-3,2'-cyclohexane]-1,5-dione (Cpd. No. 96)
##STR00227##
##STR00228##
[0501] Synthesis of
6-bromo-8-chloro-1',1'-dimethyl-spiro[2H-imidazo[1,5-a]pyridine-3,2'-cycl-
ohexane]-1,5-dione (3)
[0502] The synthesis of intermediate 3 was carried out as described
above using the general protocol of Procedure A. Light brown solid;
Yield: 0.41 g, 57%; MS (ESI) m/z 360.8 [M+1].sup.+.
Synthesis of
8-chloro-1',1'-dimethyl-6-(pyrimidin-4-ylamino)spiro[2H-imidazo[1,5-a]pyr-
idine-3,2'-cyclohexane]-1,5-dione (Cpd. No. 96)
[0503] The synthesis of compound 96 was carried out as described
above using the general protocol of Procedure B. Off white solids;
Yield: 25 mg, 10%; MS (ESI) m/z 374.19[M+1].sup.+; .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. 9.98 (bs, 1H), 9.60 (s, 1H), 8.84 (s,
1H) 8.76 (s, 1H) 8.43 (d, J=4 Hz, 1H), 7.47 (d, J=4 Hz, 1H),
3.61-3.50 (m, 1H), 1.75-1.36 (m, 7H), 1.25 (s, 3H), 0.64 (s,
3H).
Example 97
Synthesis of
N-(6-((8-chloro-3-methyl-1,5-dioxo-3-phenyl-1,2,3,5-tetrahydroimidazo[1,5-
-a]pyridin-6-yl)amino)pyrimidin-4-yl)cyclopropanecarboxamide (Cpd.
No. 97)
##STR00229##
##STR00230##
[0504] Synthesis of
6-bromo-8-chloro-3-methyl-3-phenyl-2H-imidazo[1,5-a]pyridine-1,5-dione
(3)
[0505] The synthesis of intermediate 3 was carried out as described
above using the general protocol of Procedure A. Green solid;
Yield: 525 mg, 75%; MS (ESI) m/z 353.21 [M+1].sup.+.
Synthesis of
N-[6[(8-chloro-3-methyl-1,5-dioxo-3-phenyl-2H-imidazo[1,5-a]pyridin-6-yl)-
amino]pyrimidin-4-yl]cyclopropanecarboxamide (Cpd. No. 97)
[0506] The synthesis of compound 97 was carried out as described
above using the general protocol of Procedure H. Light yellow
solid; Yield: 97 mg, 15%. MS (ESI) m/z 451.13 [M+1].sup.+; .sup.1H
NMR (400 MHz, DMSO-d.sub.6) .delta. 10.89 (s, 1H), 10.06 (s, 1H),
9.39 (s, 1H), 8.73 (s, 1H), 8.58 (s, 1H), 7.88 (s, 1H), 7.39 (s,
5H), 2.24 (s, 3H), 1.99 (s, 1H), 0.81 (s, 4H).
Example 98
Synthesis of
6-[(6-aminopyrimidin-4-yl)amino]-8-methyl-spiro[2H-imidazo[1,5-a]pyridine-
-3,1'-cyclopentane]-1,5-dione hydrochloride (Cpd. No. 98)
##STR00231##
##STR00232##
[0507] Synthesis of
6-bromo-8-methyl-spiro[2H-imidazo[1,5-a]pyridine-3,1'-cyclopentane]-1,5-d-
ione (3)
[0508] The synthesis of intermediate 3 was carried out as described
above using the general protocol of Procedure A. Off-white solid;
Yield: 1.8 g, 70%; MS (ESI) m/z 297.15 [M+1].sup.+.
Synthesis of
N-[6[(8-methyl-1,5-dioxo-spiro[2H-imidazo[1,5-a]pyridine-3,1'-cyclopentan-
e]-6-yl)amino]pyrimidin-4-yl]cyclopropanecarboxamide (5)
[0509] The synthesis of intermediate 5 was carried out as described
above using the general protocol of Procedure H. White solid;
Yield: 1.30 g, 58%; MS (ESI) m/z 395.37 [M+1].sup.+; .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 10.86 (s, 1H), 9.88 (s, 1H), 9.20
(s, 1H), 8.51 (d, J=15.96 Hz, 2H), 7.86 (s, 1H), 2.81 (m, 2H), 2.45
(m, 3H), 2.09 (m, 3H), 1.82 (m, 2H), 1.67 (m, 2H), 0.72 (m,
4H).
Synthesis of
6-[(6-aminopyrimidin-4-yl)amino]-8-methyl-spiro[2H-imidazo[1,5-a]-pyridin-
e-3,1'-cyclopentane]-1,5-dione hydrochloride (Cpd. No. 98)
[0510] The synthesis of compound 98 was carried out as described
above using the general protocol of Procedure I. White solid;
Yield: 0.76 g, 87%; MS (ESI) m/z 327.49 [M+1].sup.+; .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 10.02 (s, 1H), 9.75 (s, 1H), 8.46
(s, 1H), 8.12 (s, 1H), 7.88 (s, 2H), 6.39 (s, 1H), 2.77 (m, 2H),
2.41 (s, 3H), 1.96 (m, 2H), 1.83 (m, 2H), 1.70 (m, 2H).
Example 99
Synthesis of
6-[(6-aminopyrimidin-4-yl)amino]-8-chloro-4',4'-difluoro-spiro[2H-imidazo-
[1,5-a]pyridine-3,1'-cyclohexane]-1,5-dione hydrochloride (Cpd. No.
99)
##STR00233##
##STR00234##
[0511] Synthesis of
6-bromo-8-chloro-4',4'-difluoro-spiro[2H-imidazo[1,5-a]pyridine-3,1'-cycl-
ohexane]-1,5-dione (3)
[0512] The synthesis of intermediate 3 was carried out as described
above using the general protocol of Procedure A. Off-white solid;
Yield: 5.9 g. 80%; MS (ESI) m/z 364.92 [M-1].sup.-.
Synthesis of
N-[6[(8-chloro-4',4'-difluoro-1,5-dioxo-spiro[2H-imidazo[1,5-a]pyridine-3-
,1'-cyclohexane]-6-yl)amino]pyrimidin-4-yl]cyclopropanecarboxamide
(5)
[0513] The synthesis of intermediate 5 was carried out as described
above using the general protocol of Procedure B. Off-white solid;
Yield: 4.71 g, 63%; MS (ESI) m/z 465.38 [M+1].sup.+; .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 10.92 (s, 1H), 10.47 (s, 1H), 9.51
(s, 1H), 8.71 (s, 1H), 8.59 (s, 1H), 7.98 (s, 1H), 3.32 (m, 2H),
2.24 (m, 4H), 2.02 (m, 1H), 1.71 (m, 2H), 0.64 (m, 4H).
Synthesis of
6-[(6-aminopyrimidin-4-yl)amino]-8-chloro-4',4'-difluoro-spiro[2H-imidazo-
[1,5-a]pyridine-3,1'-cyclohexane]-1,5-dione (6)
[0514] The synthesis of intermediate 6 was carried out as described
above using the general protocol of Procedure I. Light yellow
solid; Yield: 0.35 g, 41%; MS (ESI) m/z 397.33 [M+1].sup.+.
Synthesis of
6-[(6-aminopyrimidin-4-yl)amino]-8-chloro-4',4'-difluoro-spiro[2H-imidazo-
-[1,5-a]pyridine-3,1'-cyclohexane]-1,5-dione hydrochloride (Cpd.
No. 99)
[0515] The synthesis of compound 99 was carried out as described
above using the general protocol of Procedure F. Yellow solid;
Yield: 0.66 g, 92%; MS (ESI) m/z 397.17 [M+1].sup.+; .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 10.56 (s, 1H), 9.87 (s, 1H), 8.51
(s, 1H), 8.43 (s, 1H), 7.89 (s, 2H), 6.52 (s, 1H), 3.22 (m, 2H),
2.21 (m, 4H), 1.74 (d, J=12.12 Hz, 2H).
Example 100
Synthesis of
8-chloro-6-((7-cyclopropylpyrido[4,3-d]pyrimidin-4-yl)amino)-3,3-dimethyl-
-2,3-dihydroimidazo[1,5-a]pyridine-1,5-dione (Cpd. No. 100)
##STR00235##
##STR00236##
[0516] Synthesis of 4-amino-6-chloro-pyridine-3-carboxamide (2)
[0517] To a well stirred solution of
4,6-dichloropyridine-3-carboxamide (11.0 g, 57.59 mmol) in
1,4-dioxane (20 mL) in steel bomb was added the liquid ammonia (50
mL, 57.59 mmol). The steel bomb was closed and heated the reaction
to 100.degree. C. for 9 h. The progress of the displacement
reaction was monitored by TLC and LCMS. After completion the solid
formed was filtered. The filtrate was also concentrated as it also
contains 50% product. The combined solids were dried under vacuum
to afford 4-amino-6-chloro-pyridine-3-carboxamide (2) as a light
brown solid. Yield: 10.6 g, crude, 47%; .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 8.36 (s, 1H), 7.97 (s, 1H), 7.50 (s, 1H),
7.37 (s, 1H), 6.65 (s, 1H).
Synthesis of 7-chloro-3H-pyrido[4,3-d]pyrimidin-4-one (3)
[0518] 4-Amino-6-chloro-pyridine-3-carboxamide (2, 4.5 g, 26.23
mmol) was added to a pressure tube and triethylorthoformate (30 mL)
was added. The reaction vessel was sealed and heated to 140.degree.
C. for 11 h. After the cyclization was complete, the reaction
mixture was concentrated under reduced pressure, and to the solid
obtained was added diethyl ether. The solid was filtered, washed
with diethyl ether and dried in vacuum to afford
7-chloro-3H-pyrido[4,3-d]pyrimidin-4-one (3) as brown solid. MS
(ESI) m/z 181.90 [M+1].sup.+.
Synthesis of
7-chloro-3-(2-trimethylsilylethoxymethyl)pyrido[4,3-d]pyrimidin-4-one
(4)
[0519] In a dried round bottom flask under N.sub.2 atmosphere was
added 7-chloro-3H-pyrido[4,3-d]pyrimidin-4-one (3, 9.0 g, 49.56
mmol) to dimethylformamide (50 mL). The solution was stirred at
0.degree. C. and sodium hydride (1.78 g, 74.35 mmol) was added
portion-wise over 10 min. The anionic suspension was stirred for 1
h at 0.degree. C. followed by the addition of
2-(trimethylsilyl)ethoxymethyl chloride (12.4 g, 74.35 mmol) at
0.degree. C. The reaction mixture was stirred at room temperature
for 5 h. After consumption of starting materials as indicated by
TLC, the reaction mixture was quenched with ice. A solid
precipitates. It was filtered and washed with excess n-pentane. The
solid was dried under vacuum to afford
7-chloro-3-(2-trimethylsilylethoxymethyl)pyrido[4,3-d]pyrimidin-4-one
(4) as a brown solid. Yield: 9.1 g, 59%; .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 9.17 (s, 1H), 8.72 (s, 1H), 7.79 (s, 1H),
5.49 (s, 2H), 3.65 (t, J=16 Hz, 2H), 0.90 (t, J=16 Hz, 2H), -0.03
(s, 9H).
Synthesis of
7-cyclopropyl-3-(2-trimethylsilylethoxymethyl)pyrido[4,3-d]pyrimidin-4-on-
e (6)
[0520] The synthesis of intermediate 6 was carried out as described
above using the general protocol of Procedure G. Yellow liquid;
Yield: 2.1 g, 52%; MS (ESI) m/z 319 [M+1].sup.+; .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. 9.16 (s, 1H), 8.57 (s, 1H), 7.52 (s,
1H), 7.27 (s, 1H), 5.33 (s, 2H), 3.63-3.59 (m, 2H), 2.32-2.26 (m,
1H) 1.07-1.05 (m, 4H), 0.89 (t, J=8.0 Hz, 1H), 0.04 (s, 9H).
Synthesis of 7-cyclopropyl-3H-pyrido[4,3-d]pyrimidin-4-one (7)
[0521] To
7-cyclopropyl-3-(2-trimethylsilylethoxymethyl)pyrido[4,3-d]pyrim-
idin-4-one (6, 2.0 g, 6.3 mmol) in dichloromethane (10 mL) at
0.degree. C. was added a 20% trifluoroacteic acid solution in
dichloromethane (10 mL, 6.3 mmol). The reaction mixture was warmed
to room temperature and stirred for 3 h. After complete
deprotection as indicated by TLC the reaction mixture was
concentrated, taken up in dichloromethane and concentrated. This
process was repeated 2-3 times. Tetrahydrofuran (20 mL) was added
to the crude residue and cooled to 0.degree. C. 3 M potassium
hydroxide solution (10 mL, 6.3 mmol) was added to the solution
bringing the pH to 9-10. The suspension was stirred for 6-7 h. The
reaction was concentrated, the residue was diluted with 10%
methanol in dichloromethane and the organic layers were washed with
10 mL water and 10 mL of a saturated brine solution. The organic
layers were separated, dried over magnesium sulfate, filtered and
concentration to dryness to afford 7-cyclopropyl-3H-pyrido
[4,3-d]pyrimidin-4-one (7) as a brown solid. Yield: 1.00 g, 85%; MS
(ESI) m/z 188.18 [M+1].sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. 12.57 (bs, 1H), 9.15 (s, 1H), 8.32 (s, 1H), 7.38 (s, 1H),
2.27 (bs, 1H), 1.03 (bs, 4H).
Synthesis of 7-cyclopropylpyrido[4, 3-d]pyrimidin-4-amine (8)
[0522] To 7-cyclopropyl-3H-pyrido[4,3-d]pyrimidin-4-one (7, 1.0 g,
5.34 mmol) in a round bottom flask under a nitrogen atmosphere was
added N,N-diisopropylethylamine (9.45 mL, 53.42 mmol) at 0.degree.
C. To this stirred mixture was slowly added phosphorus(V)
oxychloride (7.48 mL, 80.13 mmol). The reaction mixture was stirred
at room temperature for 2-3 h until a clear solution was obtained.
The solution was concentrated under reduced pressure under inert
conditions, taken up in excess toluene and reconcentrated. This
process was repeated sev N,N-diisopropylethylamine eral times. The
residue was dissolved in acetonitrile to it was added 30% aqueous
ammonia (30 mL). The mixture was heated to 120.degree. C. for 16 h
in sealed tube. The reaction mixture was diluted with 10% methanol
in dichloromethane and extracted from the aqueous ammonia. The
organic layers were separated, dried over Sodium sulfate, filtered
and concentrated to dryness. The crude residue was given Methanol
washing. The solid obtained was dried to afford
7-cyclopropylpyrido[4,3-d]pyrimidin-4-amine (8) as a brown solid.
Yield: 0.60 g, 60%; MS (ESI) m/z 375.8 [M+1].sup.+; .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 9.34 (s, 1H), 8.43 (s, 1H),
8.26-7.99 (m, 2H), 7.39 (s, 1H), 1.75 (s, 1H), 1.01-0.84 (s,
4H).
Synthesis of
8-chloro-6-[(7-cyclopropylpyrido[4,3-d]pyrimidin-4-yl)amino]-3,3-dimethyl-
-2H-imidazo[1,5-a]pyridine-1,5-dione (Cpd. No. 100)
[0523] The synthesis of compound 100 was carried out as described
above using the general protocol of Procedure H. Pale yellow solid;
Yield: 0.37 g, 58%; MS (ESI) m/z 397.48 [M+1].sup.+; .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 9.46 (s, 1H), 8.85 (s, 1H), 8.75
(s, 1H), 7.58 (s, 1H), 2.32-2.29 (m, 1H), 1.82 (s, 6H), 1.08-1.02
(m, 4H).
Example 101
Synthesis of
6-((6-aminopyrimidin-4-yl)amino)-3-(3-fluorophenyl)-3,8-dimethyl-2,3-dihy-
droimidazo[1,5-a]pyridine-1,5-dione (Cpd. No. 101)
##STR00237##
##STR00238##
[0524] Synthesis of
6-bromo-3-(3-fluorophenyl)-3,8-dimethyl-2,3-dihydroimidazo[1,5-a]pyridine-
-1,5-dione (3)
[0525] The synthesis of intermediate 3 was carried out as described
above using the general protocol of Procedure A. Yellow solid;
Yield: 0.35 g, 46%; MS (ESI) m/z: 351.17 [M+1].sup.+; .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 10.17 (s, 1H), 8.08 (s, 1H), 7.42
(m, 1H), 7.21 (m, 2H), 7.13 (d, J=8.0 Hz, 1H), 2.43 (s, 3H), 2.1
(s, 3H).
Synthesis of tert-butyl
(6-((3-(3-fluorophenyl)-3,8-dimethyl-1,5-dioxo-1,2,3,5-tetrahydroimidazo[-
1,5-a]pyridin-6-yl)amino)pyrimidin-4-yl)carbamate (5)
[0526] The synthesis of intermediate 5 was carried out as described
above using the general protocol of Procedure H. Yellow solid;
Yield: 0.15 g, 34%; MS (ESI) m/z 481.47 [M+1].sup.+; .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 10.0-9.80 (brs, 2H), 9.01 (brs,
1H), 8.47 (s, 1H), 8.43 (s, 1H), 7.52 (s, 1H), 7.38 (m, 1H),
7.10-7.22 (m, 3H), 2.43 (s, 3H), 2.16 (s, 3H), 1.46 (s, 9H).
Synthesis of
6-((6-aminopyrimidin-4-yl)amino)-3-(3-fluorophenyl)-3,8-dimethyl-2,3-dihy-
droimidazo[1,5-a]pyridine-1,5-dione (Cpd. No. 101)
[0527] The synthesis of compound 101 was carried out as described
above using the general protocol of Procedure F. Off-white solid;
Yield: 0.09 g, 76%; MS (ESI) m/z 381.50 [M+1].sup.+; .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 9.82 (s, 1H), 8.60 (s, 1H), 8.45
(s, 1H), 8.17 (s, 1H), 7.42 (m, 1H), 7.25-7.10 (m, 3H), 6.54 (brs,
2H), 6.10 (s, 1H), 2.47 (s, 3H), 2.20 (s, 3H).
Example 102
Synthesis of
6-((6-aminopyrimidin-4-yl)amino)-3,3,8-trimethyl-2,3-dihydroimidazo[1,5-a-
]pyridine-1,5-dione hydrochloride (Cpd. No. 102)
##STR00239##
##STR00240##
[0528] Synthesis of
N-(6-((3,3,8-trimethyl-1,5-dioxo-1,2,3,5-tetrahydroimidazo[1,5-a]pyridin--
6-yl)amino)pyrimidin-4-yl)cyclopropanecarboxamide (3)
[0529] The synthesis of intermediate 3 was carried out as described
above using the general protocol of Procedure H. Yellow solid;
Yield: 0.85 g, 50%; MS (ESI) m/z 369.0 [M+1].sup.+; .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 10.86 (s, 1H), 9.52 (s, 1H), 9.16
(s, 1H), 8.53 (s, 1H), 8.47 (s, 1H), 7.86 (s, 1H), 5.75 (s, 1H),
2.42 (s, 3H), 2.02 (m, 1H), 1.77 (s, 6H), 0.88-0.80 (m, 4H).
Synthesis of
6-((6-aminopyrimidin-4-yl)amino)-3,3,8-trimethyl-2,3-dihydroimidazo[1,5-a-
]pyridine-1,5-dione (4)
[0530] The synthesis of intermediate 4 was carried out as described
above using the general protocol of Procedure I. Yellow solid;
Yield: 0.55 g, 80%; MS (ESI) m/z 301.29 [M+1].sup.+; .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 9.46 (s, 1H), 8.61 (s, 1H), 8.38
(s, 1H), 8.16 (s, 1H), 6.53 (brs, 2H), 6.16 (s, 1H), 2.40 (s, 3H),
1.77 (s, 6H).
Synthesis of
6-((6-aminopyrimidin-4-yl)amino)-3,3,8-trimethyl-2,3-dihydroimidazo[1,5-a-
]pyridine-1,5-dione hydrochloride (Cpd. No. 102)
[0531] The synthesis of compound 102 was carried out as described
above using the general protocol of Procedure F. Yellow solid;
Yield: 0.60 g, 97%; MS (ESI) m/z 301.25 [M+1].sup.+; .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 9.71 (s, 1H), 9.67 (s, 1H), 8.45
(s, 1H), 8.12 (s, 1H), 7.95-7.70 (brs, 2H), 6.39 (s, 1H), 2.41 (s,
3H), 1.77 (s, 6H).
Example 103
Synthesis of
6-[(6-aminopyrimidin-4-yl)amino]-4',4'-difluoro-8-methyl-spiro[2H-imidazo-
[1,5-a]pyridine-3,1'-cyclohexane]-1,5-dione hydrochloride (Cpd. No.
103)
##STR00241##
##STR00242##
[0532] Synthesis of
6-bromo-4',4'-difluoro-8-methyl-spiro[2H-imidazo[1,5-a]pyridine-3,1'-cycl-
ohexane]-1,5-dione (3)
[0533] The synthesis of intermediate 3 was carried out as described
above using the general protocol of Procedure A. Off-white solid;
Yield: 1.2 g, 53%; MS (ESI) m/z 346.99 [M+1].sup.+.
Synthesis of tert-butyl
N-[6-[(4',4'-difluoro-8-methyl-1,5-dioxo-spiro[2H-imidazo[1,5-a]pyridine--
3,1'-cyclohexane]-6-yl)amino]pyrimidin-4-yl]carbamate (5)
[0534] The synthesis of intermediate 5 was carried out as described
above using the general protocol of Procedure H. Yellow solid;
Yield: 0.8 g, 58%; MS (ESI) m/z 477.48 [M+1].sup.+.
Synthesis of
6-[(6-aminopyrimidin-4-yl)amino]-4',4'-difluoro-8-methyl-spiro[2H-imidazo-
[1,5-a]pyridine-3,1'-cyclohexane]-1,5-dione hydrochloride (Cpd. No.
103)
[0535] The synthesis of compound 103 was carried out as described
above using the general protocol of Procedure D. Yellow solid;
Yield: 0.75 g, 97%; MS (ESI) m/z 377.40 [M+1].sup.+; .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 10.40 (s, 1H), 9.73 (s, 1H), 8.46
(s, 1H), 8.15 (s, 1H), 7.87 (brs, 2H), 6.40 (s, 1H), 3.30 (m, 2H),
2.43 (s, 3H), 2.32-2.29 (m, 1H), 2.20-2.10 (m, 3H), 1.65 (m,
2H).
Example 104
Synthesis of
8-chloro-6-(pyrimidin-4-ylamino)spiro[2H-imidazo[1,5-a]pyridine-3,4'-pipe-
ridine]-1,5-dione hydrochloride (Cpd. No. 104)
##STR00243##
##STR00244##
[0536] Synthesis of tert-butyl
8-chloro-1,5-dioxo-6-(pyrimidin-4-ylamino)spiro[2H-imidazo[1,5-a]pyridine-
-3,4'-piperidine]-1'-carboxylate (3)
[0537] The synthesis of intermediate 3 was carried out as described
above using the general protocol of Procedure H. Yellow solid;
Yield: 0.8 g, 52%; MS (ESI) m/z 447 [M+1].sup.+.
Synthesis of
8-chloro-6-(pyrimidin-4-ylamino)spiro[2H-imidazo[1,5-a]pyridine-3,4'-pipe-
ridine]-1,5-dione hydrochloride (Cpd. No. 104)
[0538] The synthesis of compound 104 was carried out as described
above using the general protocol of Procedure F. Pale yellow solid;
Yield: 0.6 g, 93%; MS (ESI) m/z 347.37 [M+1].sup.+; .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 10.69 (s, 1H), 10.52 (brs, 1H),
9.46 (m, 1H), 8.72 (s, 1H), 8.52 (d, J=6.0 Hz, 1H), 7.57 (d, J=5.6
Hz, 1H), 3.50-3.45 (m, 2H), 3.36-3.12 (m, 4H), 1.91-1.86 (m,
2H).
Example 105
Synthesis of
6-[(6-aminopyrimidin-4-yl)amino]-3-tert-butyl-8-chloro-3-methyl-2H-imidaz-
o[1,5-a]pyridine-1,5-dione hydrochloride (Cpd. No. 105)
##STR00245##
##STR00246##
[0539] Synthesis of tert-butyl
N-[6-[(3-tert-butyl-8-chloro-3-methyl-1,5-dioxo-2H-imidazo[1,5-a]pyridin--
6-yl)amino]pyrimidin-4-yl]carbamate (3)
[0540] The synthesis of intermediate 3 was carried out as described
above using the general protocol of Procedure H. Yellow solid;
Yield: 0.21 g, 50%; MS (ESI) m/z 431.39 [M+1].sup.+; .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 10.04 (s, 1H), 9.73 (s, 1H), 9.50
(s, 1H), 8.57 (s, 1H), 8.51 (s, 1H), 7.77 (s, 1H), 1.92 (s, 3H),
1.48 (s, 9H), 0.99 (s, 9H).
Synthesis of
6-[(6-aminopyrimidin-4-yl)amino]-3-tert-butyl-8-chloro-3-methyl-2H-imidaz-
o[1,5-a]pyridine-1,5-dione hydrochloride (Cpd. No. 105)
[0541] The synthesis of compound 105 was carried out as described
above using the general protocol of Procedure F. Yellow solid;
Yield: 0.08 g, 54%; MS (ESI) m/z 363.46 [M+1].sup.+; .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 9.82 (s, 2H), 8.51 (s, 1H), 8.40
(s, 1H), 7.89 (brs, 2H), 6.54 (s, 1H), 1.92 (s, 3H), 0.99 (s,
9H).
Example 106
Synthesis of
6-((6-aminopyrimidin-4-yl)amino)-8-methyl-2H-spiro[imidazo[1,5-a]pyridine-
-3,4'-piperidine]-1,5-dione dihydrochloride (Cpd. No. 106)
##STR00247##
##STR00248##
[0542] Synthesis of tert-butyl
6-bromo-8-methyl-1,5-dioxo-1,5-dihydro-2H-spiro[imidazo[1,5-a]pyridine-3,-
4'-piperidine]-1'-carboxylate (3)
[0543] The synthesis of intermediate 3 was carried out as described
above using the general protocol of Procedure E. Off-white solid;
Yield: 1.7 g, 43%; MS (ESI) m/z 409.9 [M-1].sup.-; .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. 10.57 (s, 1H), 8.04 (s, 1H), 4.03 (brs,
2H), 3.56 (brs, 1H), 3.11 (brs, 4H), 2.23 (s, 3H), 1.42 (s,
9H).
Synthesis of tert-butyl
6-((6-((tert-butoxycarbonyl)amino)pyrimidin-4-yl)amino)-8-methyl-1,5-diox-
o-1,5-dihydro-2H-spiro[imidazo[1,5-a]pyridine-3,4'-piperidine]-1'-carboxyl-
ate (5)
[0544] The synthesis of intermediate 5 was carried out as described
above using the general protocol of Procedure H. Yellow solid;
Yield: 1.6 g, 60%; MS (ESI) m/z 542.2 [M+1].sup.+; .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. 10.27 (brs, 1H), 9.98 (s, 1H), 9.19 (s,
1H), 8.50-8.45 (m, 2H), 7.66 (s, 1H), 4.05 (brs, 1H), 3.32 (m, 2H),
2.24 (s, 3H), 1.48 (s, 9H), 1.43 (s, 9H).
Synthesis of
6-((6-aminopyrimidin-4-yl)amino)-8-methyl-2H-spiro[imidazo[1,5-a]-pyridin-
e-3,4'-piperidine]-1,5-dione dihydrochloride (Cpd. No. 106)
[0545] The synthesis of compound 106 was carried out as described
above using the general protocol of Procedure F. Pale yellow solid;
Yield: 1.02 g, 83%; MS (ESI) m/z 342.2 [M+1].sup.+; .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 10.42 (brs, 1H), 9.55 (brs, 1H),
9.24 (brs, 1H), 8.78 (brs, 1H), 8.41 (s, 1H), 8.16 (s, 1H), 7.58
(brs, 2H), 6.37 (s, 1H), 3.48-3.40 (m, 2H), 3.40-3.28 (m, 2H),
3.20-3.10 (m, 1H), 2.38 (s, 3H), 1.73 (m, 2H).
Example 107
Synthesis of
6'-((6-aminopyrimidin-4-yl)amino)-8'-methyl-2'H-spiro[cyclohexane-1,3'-im-
idazo[1,5-a]pyridine]-1',5'-dione hydrochloride (Cpd. No. 107)
##STR00249##
##STR00250##
[0546] Synthesis of
6'-bromo-8'-methyl-2'H-spiro[cyclohexane-1,3'-imidazo[1,5-a]pyridine]-1',-
5'-dione (3)
[0547] The synthesis of intermediate 3 was carried out as described
above using the general protocol of Procedure A. Off-white solid;
Yield: 2.4 g, 71%; MS (ESI) m/z 311.18 [M+1].sup.+.
Synthesis of tert-butyl
(6-((8'-methyl-1',5'-dioxo-1',5'-dihydro-2'H-spiro[cyclohexane-1,3'-imida-
zo[1,5-a]pyridin]-6'-yl)amino)pyrimidin-4-yl)carbamate (5)
[0548] The synthesis of intermediate 5 was carried out as described
above using the general protocol of Procedure H. Off-white solid;
Yield: 2.10 g, 30%.
Synthesis of
6'-((6-aminopyrimidin-4-yl)amino)-8'-methyl-2'H-spiro[cyclohexane-1,3'-im-
idazo[1,5-a]pyridine]-1',5'-dione hydrochloride (Cpd. No. 107)
[0549] The synthesis of compound 107 was carried out as described
above using the general protocol of Procedure F. Off-white solid;
Yield: 0.55 g, 64%; MS (ESI) m/z 341.50; [M+1].sup.+; .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 10.20 (s, 1H), 9.68 (s, 1H), 8.45
(s, 1H), 8.10 (s, 1H), 7.88 (brs, 2H), 6.39 (s, 1H), 3.00-2.90 (m,
2H), 2.42 (s, 3H), 1.80-1.60 (m, 5H), 1.42 (d, J=12 Hz, 2H),
1.25-1.12 (m, 1H).
Example 108
Synthesis of
6-((6-aminopyrimidin-4-yl)amino)-8-chloro-2H-spiro[imidazo[1,5-a]pyridine-
-3,4'-piperidine]-1,5-dione dihydrochloride (Cpd. No. 108)
##STR00251##
##STR00252##
[0550] Synthesis of tert-butyl
6-[[6-(tert-butoxycarbonylamino)pyrimidin-4-yl]amino]-8-chloro-1,5-dioxo--
spiro[2H-imidazo[1,5-a]pyridine-3,4'-piperidine]-1'-carboxylate
(3)
[0551] The synthesis of intermediate 3 was carried out as described
above using the general protocol of Procedure H. Off-white solid;
Yield: 1.6 g, 54%; MS (ESI) m/z 562.2 [M+1].sup.+; .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. 10.47 (s, 1H), 10.05 (s, 1H), 9.49 (s,
1H), 8.72 (s, 1H), 8.51 (s, 1H), 7.78 (s, 1H), 4.09 (brs, 1H), 3.33
(m, 4H), 1.74 (brs, 1H), 1.48 (s, 9H), 1.43 (s, 9H).
Synthesis of
6-((6-aminopyrimidin-4-yl)amino)-8-chloro-2H-spiro[imidazo[1,5-a]pyridine-
-3,4'-piperidine]-1,5-dione dihydrochloride (Cpd. No. 108)
[0552] The synthesis of compound 108 was carried out as described
above using the general protocol of Procedure F. Pale yellow solid;
Yield: 0.8 g, 96%; MS (ESI) m/z 362.16 [M+1].sup.+; .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 10.64 (s, 1H), 9.82 (s, 1H),
9.49-9.46 (m, 1H), 9.01-8.98 (m, 1H), 8.51 (s, 1H), 8.40 (s, 1H),
7.91 (brs, 2H), 6.54 (s, 1H), 3.54-3.47 (m, 2H), 3.38-3.18 (m, 4H),
1.88-1.85 (m, 2H).
Example 109
Synthesis of
8-chloro-6-(pyrimidin-4-ylamino)spiro[2H-imidazo[1,5-a]pyridine-3,1'-cycl-
ohexane]-1,5-dione hydrochloride (Cpd. No. 109)
##STR00253##
##STR00254##
[0553] Synthesis of
8-chloro-6-(pyrimidin-4-ylamino)spiro[2H-imidazo[1,5-a]pyridine-3,1'-cycl-
ohexane]-1,5-dione (3)
[0554] The synthesis of intermediate 3 was carried out as described
above using the general protocol of Procedure H. Off-white solid;
Yield: 0.8 g, 64%; MS (ESI) m/z 346.04 [M+1].sup.+; .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 10.32 (s, 1H), 9.61 (s, 1H), 8.84
(s, 1H), 8.43 (d, J=6.4 Hz, 1H), 7.45 (d, J=6.4 Hz, 1H), 2.9 (t,
J=9.2 Hz, 2H), 1.65-1.54 (m, 6H), 1.25-1.23 (m, 2H).
Synthesis of
8-chloro-6-(pyrimidin-4-ylamino)spiro[2H-imidazo[1,5-a]pyridine-3,1'-cycl-
ohexane]-1,5-dione hydrochloride (Cpd. No. 109)
[0555] The synthesis of compound 109 was carried out as described
above using the general protocol of Procedure F. Light yellow
solid; Yield: 0.6 g, 77%; MS (ESI) m/z 346.04 [M+1].sup.+; .sup.1H
NMR (400 MHz, DMSO-d.sub.6) .delta. 10.41 (s, 1H), 10.23 (s, 1H),
9.0 (s, 1H), 8.71 (s, 1H), 8.48 (d, J=6.4 Hz, 1H), 7.52 (d, J=6.4
Hz, 1H), 2.9 (t, J=9.2 Hz, 2H), 1.78-1.54 (m, 6H), 1.23-1.27 (m,
2H).
Example 110
Synthesis of
8-chloro-4',4'-difluoro-6-(pyrimidin-4-ylamino)spiro[2H-imidazo[1,5-a]pyr-
idine-3,1'-cyclohexane]-1,5-dione hydrochloride (Cpd. No. 110)
##STR00255##
##STR00256##
[0556] Synthesis of
8-chloro-4',4'-difluoro-6-(pyrimidin-4-ylamino)spiro[2H-imidazo[1,5-a]pyr-
idine-3,1'-cyclohexane]-1,5-dione (3)
[0557] The synthesis of intermediate 3 was carried out as described
above using the general protocol of Procedure H. Yellow solid;
Yield: 0.85 g, 35%; MS (ESI) m/z 382.36 [M+1].sup.+; .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 10.51 (s, 1H), 9.68 (s, 1H),
8.80-8.84 (m, 2H), 8.44 (d, J=6.8 Hz, 1H), 7.44 (d, J=6.4.0 Hz,
1H), 3.34-3.17 (m, 2H), 2.32-2.17 (m, 4H), 1.76-1.72 (m, 2H).
Synthesis of
8-chloro-4',4'-difluoro-6-(pyrimidin-4-ylamino)spiro[2H-imidazo[1,5-a]pyr-
idine-3,1'-cyclohexane]-1,5-dione hydrochloride (Cpd. No. 110)
[0558] The synthesis of compound 110 was carried out as described
above using the general protocol of Procedure F. Yellow solid;
Yield: 0.81 g, 87%; MS (ESI) m/z 382.4 [M+1].sup.+; .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 10.64 (s, 1H), 10.45 (s, 1H), 9.05
(s, 1H), 8.71 (s, 1H), 8.52 (d, J=6.8 Hz, 1H), 7.56 (d, J=6.4 Hz,
1H), 3.30-3.20 (m, 2H), 2.35-2.15 (m, 4H), 1.80-1.72 (m, 2H).
Example 111
Synthesis of
6-[(6-aminopyrimidin-4-yl)amino]-6',8-dichloro-spiro[2H-imidazo[1,5-a]pyr-
idine-3,1'-indane]-1,5-dione hydrochloride (Cpd. No. 111)
##STR00257##
##STR00258##
[0559] Synthesis of
6-bromo-6',8-dichloro-spiro[2H-imidazo[1,5-a]pyridine-3,1'-indane]-1,5-di-
one (3)
[0560] The synthesis of intermediate 3 was carried out as described
above using the general protocol of Procedure A. Off-white solid;
Yield: 0.52 g, 35%; MS (ESI) m/z: 399.23 [M+1].sup.+; .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 10.35 (s, 1H), 8.28 (s, 1H), 7.39
(m, 3H), 3.23 (m, 1H), 3.08 (m, 2H), 2.43 (m, 1H).
Synthesis of tert-butyl
N-[6-[(6',8-dichloro-1,5-dioxo-spiro[2H-imidazo[1,5-a]pyridine-3,1'-indan-
e]-6-yl)amino]pyrimidin-4-yl]carbamate (5)
[0561] The synthesis of intermediate 5 was carried out as described
above using the general protocol of Procedure H. Off-white solid;
Yield: 0.38 g, 56%; MS (ESI) m/z 529.2 [M+1].sup.+; .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 10.07 (s, 1H), 9.99 (s, 1H), 9.42
(s, 1H), 8.72 (s, 1H), 8.50 (s, 1H), 7.65 (s, 1H), 7.37 (m, 3H),
3.10 (m, 2H), 3.01 (m, 2H), 1.45 (s, 9H).
Synthesis of
6-[(6-aminopyrimidin-4-yl)amino]-6',8-dichloro-spiro[2H-imidazo[1,5-a]pyr-
idine-3,1'-indane]-1,5-dione hydrochloride (Cpd. No. 111)
[0562] The synthesis of compound 111 was carried out as described
above using the general protocol of Procedure F. Pale yellow solid;
Yield: 0.17 g, 55%; MS (ESI) m/z 429.3 [M+1].sup.+; .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 10.18 (s, 1H), 9.78 (s, 1H), 8.52
(s, 1H), 8.44 (s, 1H), 7.91 (brs, 2H), 7.38 (m, 3H), 6.42 (s, 1H),
3.30 (m, 1H), 3.21 (m, 1H), 2.96 (m, 1H), 2.47 (m, 1H).
Example 112
Synthesis of
8-chloro-6-[(5-fluoropyrimidin-4-yl)amino]spiro[2H-imidazo[1,5-a]pyridine-
-3,1'-cyclohexane]-1,5-dione (Cpd. No. 112)
##STR00259##
##STR00260##
[0563] Synthesis of
8-chloro-6-[(5-fluoropyrimidin-4-yl)amino]spiro[2H-imidazo[1,5-a]pyridine-
-3,1'-cyclohexane]-1,5-dione (Cpd. No. 112)
[0564] The synthesis of compound 112 was carried out as described
above using the general protocol of Procedure H. Yellow solid;
Yield: 0.14 g, 43%; MS (ESI) m/z 364.3 [M+1].sup.+; .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 10.41 (s, 1H), 8.73 (s, 1H), 8.62
(s, 2H), 8.54 (s, 1H), 2.95-2.87 (m, 2H), 1.80-1.54 (m, 7H),
1.30-1.18 (m, 1H).
Example 113
Synthesis of
8-chloro-6-(pyrimidin-4-ylamino)spiro[2H-imidazo[1,5-a]pyridine-3,2'-inda-
ne]-1,1',5-trione (Cpd. No. 113)
##STR00261##
##STR00262##
[0565] Synthesis of
6-bromo-8-chloro-spiro[2H-imidazo[1,5-a]pyridine-3,2'-indane]-1,1',5-trio-
ne (3)
[0566] The synthesis of intermediate 3 was carried out as described
above using the general protocol of Procedure A. Brown solid;
Yield: 0.12 g, 28%; MS (ESI) m/z 378.94 [M+1].sup.+; .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 10.40 (s, 1H), 8.40 (s, 1H),
7.88-7.81 (m, 2H), 7.70 (d, J 7.32, 1H), 7.57 (t, J=7.36, 1H), 4.12
(d, J=18.32, 1H), 3.43 (d, J=18.08, 1H).
Synthesis of
8-chloro-6-(pyrimidin-4-ylamino)spiro[2H-imidazo[1,5-a]pyridine-3,2'-inda-
ne]-1,1',5-trione (Cpd. No. 113)
[0567] The synthesis of compound 113 was carried out as described
above using the general protocol of Procedure H. Yellow solid;
Yield: 0.065 g, 26%; MS (ESI) m/z 394.06 [M+1].sup.+; .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 10.05 (brs, 1H), 9.64 (s, 1H), 8.85
(s, 2H), 8.41 (d, J=5.68 Hz, 1H), 7.86-7.80 (m, 2H), 7.69 (d,
J=7.44 Hz, 1H), 7.55 (t, J=7.44, 1H), 7.30 (d, J=5.92 Hz, 1H), 4.15
(d, J=18.2 Hz, 1H), 3.50 (d. J=18.44 Hz, 1H).
Example 114
Synthesis of
6-((6-aminopyrimidin-4-yl)amino)-8-chloro-6'-fluoro-2',3'-dihydro-2H-spir-
o[imidazo[1,5-a]pyridine-3,1'-indene]-1,5-dione hydrochloride (Cpd.
No. 114)
##STR00263##
##STR00264##
[0568] Synthesis of
6-bromo-8-chloro-6'-fluoro-2',3'-dihydro-2H-spiro[imidazo[1,5-a]pyridine--
3,1'-indene]-1,5-dione (3)
[0569] The synthesis of intermediate 3 was carried out as described
above using the general protocol of Procedure A. White solid;
Yield: 0.46 g, 32%; MS (ESI) m/z 381.19 [M+1].sup.+; .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 10.37 (s, 1H), 8.31-8.28 (s, 1H),
7.37-7.34 (m, 1H), 7.20-7.16 (m, 2H), 3.22 (m, 1H), 3.06-2.97 (m,
2H), 2.42-2.35 (m, 1H).
Synthesis of tert-butyl
(6-((8-chloro-6'-fluoro-1,5-dioxo-1,2',3',5-tetrahydro-2H-spiro[imidazo[1-
,5-a]pyridine-3,1'-inden]-6-yl)amino)pyrimidin-4-yl)carbamate
(5)
[0570] The synthesis of intermediate 5 was carried out as described
above using the general protocol of Procedure H. Off white solid;
Yield: 320 mg, 53%; MS (ESI) m/z 513.35 [M+1].sup.+.
Synthesis of
6-((6-aminopyrimidin-4-yl)amino)-8-chloro-6'-fluoro-2',3'-dihydro-2H-spir-
o[imidazo[1,5-a]pyridine-3,1'-indene]-1,5-dione hydrochloride (Cpd.
No. 114)
[0571] The synthesis of compound 114 was carried out as described
above using the general protocol of Procedure F. Yellow solid;
Yield: 0.089 g, 37%; MS (ESI) m/z 413.32 [M+1].sup.+; .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 10.16 (s, 1H), 9.72 (s, 1H),
8.49-8.46 (d, 2H), 7.86-7.69 (b s, 2H), 7.36 (m, 1H), 7.19 (m, 1H),
7.11 (m, 1H), 6.41 (s, 1H), 3.31-3.35 (m, 2H), 3.17-2.96 (m,
2H).
Example 115
Synthesis of
8-chloro-6-[(5-chloropyrimidin-4-yl)amino]spiro[2H-imidazo[1,5-a]pyridine-
-3,1'-cyclohexane]-1,5-dione (Cpd. No. 115)
##STR00265##
##STR00266##
[0572] Synthesis of
8-chloro-6-[(5-chloropyrimidin-4-yl)amino]spiro[2H-imidazo[1,5-a]pyridine-
-3,1'-cyclohexane]-1,5-dione (Cpd. No. 115)
[0573] The synthesis of compound 115 was carried out as described
above using the general protocol of Procedure H. Yellow solid;
Yield: 75 mg, 13%; MS (ESI) m/z 380.23 [M+1].sup.+; .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 10.44 (s, 1H), 8.85 (s, 1H), 8.80
(s, 1H), 8.72 (s, 1H), 8.66 (s, 1H), 2.93-2.88 (m, 2H), 1.77-1.74
(m, 2H), 1.65-1.61 (m, 3H), 1.57-1.57 (m, 2H), 1.04-1.02 (m,
1H).
Example 116
Synthesis of
8-chloro-6-[(6-methylpyrimidin-4-yl)amino]spiro[2H-imidazo[1,5-a]pyridine-
-3,1'-cyclohexane]-1,5-dione (Cpd. No. 116)
##STR00267##
##STR00268##
[0574] Synthesis of
8-chloro-6-[(6-methylpyrimidin-4-yl)amino]spiro[2H-imidazo[1,5-a]pyridine-
-3,1'-cyclohexane]-1,5-dione (Cpd. No. 116)
[0575] The synthesis of compound 116 was carried out as described
above using the general protocol of Procedure H. Yellow solid;
Yield: 190 mg, 58%; MS (ESI) m/z 359.81 [M+1].sup.+; .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 10.29 (s, 1H), 10.08 (s, 1H), 9.41
(s, 1H), 8.76 (s, 1H), 8.71 (s, 1H), 7.27 (s, 1H), 2.98-2.91 (m,
2H), 2.33 (s, 3H), 1.77-1.74 (m, 2H), 1.67-1.58 (m, 3H), 1.55-1.52
(m, 2H) 1.26-1.19 (m, 1H).
Example 117
Synthesis of
6'-((7H-purin-6-yl)amino)-8'-chloro-2'H-spiro[cyclohexane-1,3'-imidazo[1,-
5-a]pyridine]-1',5'-dione (Cpd. No. 117)
##STR00269##
##STR00270##
[0576] Synthesis of
N-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-purin-6-yl)isobutyramide
(2)
[0577] To a stirred solution of
2-methyl-N-(7H-purin-6-yl)propanamide (1, 5 g, 24.36 mmol) in
dimethylformamide (20 mL), sodium hydride (0.88 g, 36.55 mmol) was
added portion wise in 10 minutes at 0.degree. C. The above
suspension was stirred for 10 minutes at 0.degree. C. followed by
addition of 2-(trimethylsilyl)ethoxymethyl chloride (4.87 g, 29.24
mmol) slowly at 0.degree. C. under nitrogen atmosphere. The
reaction was stirred at room temperature for 16 h. After completion
of the reaction, the mixture was quenched with saturated aqueous
solution of ammonium chloride and product was extracted with
dichloromethane (2.times.50 mL). The organics were then separated,
dried (magnesium sulfate) and concentrated to dryness under vacuum
and the crude was purified by flash chromatography eluting with 2%
methanol in dichloromethane. Concentration of the desired fractions
afford
2-methyl-N-[7-(2-trimethylsilylethoxymethyl)purin-6-yl]propanamide
(2) as white solid. Yield: 2 g, 24%.
Synthesis of 7-((2-(trimethylsilyl)ethoxy)methyl)-7H-purin-6-amine
hydrochloride (3)
[0578] The synthesis of intermediate 3 was carried out as described
above using the general protocol of Procedure I. White solid;
Yield: 3.0 g, 73%; MS (ESI) m/z 266.31[M+1].sup.+; .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. 8.26 (s, 1H), 8.16 (s, 1H), 7.26 (brs,
2H), 5.50 (s, 2H), 3.52 (t, J=1.56 Hz, 2H), 0.835 (t, J=1.56 Hz,
2H), 0.088 (s, 9H).
Synthesis of
8'-chloro-6'-((7-((2-(trimethylsilyl)ethoxy)methyl)-7H-purin-6-yl)amino)--
2'H-spiro[cyclohexane-1,3'-imidazo[1,5-a]pyridine]-1',5'-dione
(5)
[0579] The synthesis of intermediate 5 was carried out as described
above using the general protocol of Procedure B. Yellow solid;
Yield: 0.10 g, 26%; MS (ESI) m/z 516.44 [M+1].sup.+; .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 10.42 (s, 1H), 9.07 (s, 1H), 9.03
(s, 1H), 8.71 (s, 1H), 8.58 (s, 1H), 5.74 (s, 2H), 3.61 (t, J=1.6
Hz, 2H), 0.852 (t, J=1.64 Hz, 2H), 0.081 (s, 9H).
Synthesis of
6'-((7H-purin-6-yl)amino)-8'-chloro-2'H-spiro[cyclohexane-1,3'-imidazo[1,-
5-a]pyridine]-1',5'-dione (Cpd. No. 117)
[0580]
8-Chloro-6-[[7-(2-trimethylsilylethoxy)purin-6-yl]amino]spiro[2H-im-
idazo[1,5-c]pyridine-3,1'-cyclohexane]-1,5-dione (5, 0.6 g, 1.2
mmol) was dissolved in dichloromethane (10 mL) in a flask and
trifluoroacetic acid (1.36 g, 11.95 mmol) was added dropwise and
stirred the mixture at room temperature overnight. After
completion, evaporated the solvent under reduced pressure and the
crude was basified by saturated aqueous solution of sodium
bicarbonate to pH 8 and extracted with dichloromethane (2.times.50
mL). The organic layer was dried over anhydrous. Sodium sulfate and
concentrated to afford crude. The crude was purified by flash
column chromatography eluting with 2.5% methanol in
dichloromethane. The desired fractions were concentrated to dryness
under vacuum to afford
8-chloro-6-(7H-purin-6-ylamino)spiro[2H-imidazo[1,5-a]pyridine-3,1'-cyclo-
hexane]-1,5-dione (Cpd. No. 117) as a yellow solid. Yield: 0.06 g,
13%; MS (ESI) m/z 386.39 [M+1].sup.+; .sup.1H NMR: (400 MHz,
DMSO-d.sub.6) .delta. 10.43 (m, 1H), 10.37 (s, 1H), 8.88 (s, 1H),
8.64 (s, 1H), 8.43 (s, 1H), 2.94 (t, J=2.32 Hz, 2H), 1.77 (m, 2H),
1.63 (m, 3H), 1.57 (d, J=12.8 Hz, 2H), 1.23 (m, 1H).
Example 118
Synthesis of
6-[(6-aminopyrimidin-4-yl)amino]-3-cyclopentyl-3-methyl-1,5-dioxo-imidazo-
[1,5-a]pyridine-2-carbonitrile (Cpd. No. 118)
##STR00271##
##STR00272##
[0581] Synthesis of
6-[(6-aminopyrimidin-4-yl)amino]-3-cyclopentyl-3-methyl-2H-imidazo[1,5-a]-
pyridine-1,5-dione (2)
[0582] The synthesis of intermediate 2 was carried out as described
above using the general protocol of Procedure I. Yellow solid;
Yield: 0.36 g, 71%; MS (ESI) m/z 341.16 [M+1].sup.+; .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 9.61 (s, 1H), 8.62 (s, 1H), 8.57
(d, J=7.64, 1H), 8.15 (s, 1H), 6.80 (d, J=7.68, 1H), 6.51 (s, 2H),
6.16 (s, 1H), 3.4 (m, 1H), 1.82 (s, 3H), 1.63-1.41 (m, 5H), 1.1 (m,
1H), 0.87-0.75 (m, 2H).
Synthesis of
6-[(6-aminopyrimidin-4-yl)amino]-3-cyclopentyl-3-methyl-1,5-dioxo-imidazo-
[1,5-a]pyridine-2-carbonitrile (Cpd. No. 118)
[0583] In a 2-neck round bottom flask
6-[(6-aminopyrimidin-4-yl)amino]-3-cyclopentyl-3-methyl-2H-imidazo[1,5-a]-
pyridine-1,5-dione (2, 0.28 g, 0.82 mmol) was taken in dry
tetrahydrofuran (15 mL). The reaction mixture was cooled to
0.degree. C. and sodium hydride (164 mg, 4.11 mmol) was added in
portions. After stirring for 10 min at room temperature, cyanogen
bromide (436 mg, 4.11 mmol) was added and the resulting reaction
mixture was stirred at room temperature for 20 h. The reaction
mixture was quenched with aqueous ammonium chloride solution and
then concentrated to get the crude mass. This crude was purified by
flash chromatography eluting with 2% methanol in dichloromethane.
The compound was washed with pentane and dried under vacuum to
afford
6-[(6-aminopyrimidin-4-yl)amino]-3-cyclopentyl-3-methyl-1,5-dioxo-imidazo-
[1,5-a]pyridine-2-carbonitrile (Cpd. No. 118) as yellow solid.
Yield: 0.018 g, 6%; MS (ESI) m/z 366.16 [M+1].sup.+; .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 9.08 (s, 1H), 8.71 (d, J=7.84, 1H),
8.19 (s, 1H), 7.28 (d, J=7.96, 1H), 6.65 (s, 2H), 6.29 (s, 1H),
3.49-3.43 (m, 1H), 2.21 (s, 3H), 1.94 (m, 1H), 1.7-1.58 (m, 4H),
1.48 (m, 1H), 1.23 (m, 1H), 1.06-1.02 (m, 1H).
Example 119
Synthesis of 6-[(6-aminopyrimidin-4-yl)
amino]-8-chloro-3-(3-fluorophenyl)-2,
3-dihydroimidazo[1,5-a]pyridine-1,5-dione (Cpd. No. 119)
##STR00273##
##STR00274##
[0584] Synthesis of
6-bromo-8-chloro-3-(3-fluorophenyl)-2,3-dihydroimidazo[1,5-a]pyridine-1,5-
-dione (3)
[0585] To a suspension of
5-bromo-3-chloro-6-oxo-1H-pyridine-2-carboxamide (1, 0.5 g, 1.99
mmol) in acetonitrile (15 mL), 3-fluorobenzaldehyde (0.86 g, 6.96
mmol) and ferric chloride (2.25 g, 13.92 mmol) were added in a
vial. The vial was sealed and heated the reaction mass to
85.degree. C. for 16 h. After completion, the reaction mass was
cooled to room temperature, filtered through celite bed, washed
with 5% methanol in dichloromethane followed by concentration to
get crude. The crude was then purified by column chromatography
eluting with 5% methanol in dichloromethane to afford
8-chloro-3-(3-fluorophenyl)-2,
3-dihydroimidazo[1,5-a]pyridine-1,5-dione as white solid. Yield:
0.45 g, 63%; MS (ESI) m/z 256.17 [M+1].sup.+.
Synthesis of tert-butyl
(6-((8-chloro-3-(3-fluorophenyl)-1,5-dioxo-1,2,3,5-tetrahydroimidazo[1,5--
a]pyridin-6-yl)amino)pyrimidin-4-yl)carbamate (5)
[0586] The synthesis of intermediate 5 was carried out as described
above using the general protocol of Procedure H. Yellow solid;
Yield: 0.15 g, 33%; MS (ESI) m/z 487.43 [M+1].sup.+.
Synthesis of 6-[(6-aminopyrimidin-4-yl)
amino]-8-chloro-3-(3-fluorophenyl)-2,
3-dihydroimidazo[1,5-a]pyridine-1,5-dione (Cpd. No. 119)
[0587] The synthesis of compound 119 was carried out as described
above using the general protocol of Procedure F. Off white solid;
Yield: 0.012 g, 10%; MS (ESI) m/z 387.29 [M+].sup.+; .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 9.98 (s, 1H), 8.90 (s, 1H), 8.70
(s, 1H), 8.20 (s, 1H), 7.43 (m, 1H), 7.33 (m, 1H), 7.19 (s, 2H),
6.61 (s, 1H), 6.58 (s, 2H), 6.17 (s, 1H).
Example 120
Synthesis of
8'-chloro-2,2-dimethyl-6'-(pyrimidin-4-ylamino)-2'H-spiro[cyclobutane-1,3-
'-imidazo[1,5-a]pyridine]-1',5'-dione (Cpd. No. 120)
##STR00275##
##STR00276##
[0588] Synthesis
6'-bromo-8'-chloro-2,2-dimethyl-2'H-spiro[cyclobutane-1,3'-imidazo[1,5-a]-
pyridine]-1',5'-dione (3)
[0589] The synthesis of intermediate 3 was carried out as described
above using the general protocol of Procedure A. Off white solid;
Yield: 0.51 g; 64%; MS (ESI) m/z 331.59 [M+1].sup.+.
Synthesis
8'-chloro-2,2-dimethyl-6'-(pyrimidin-4-ylamino)-2'H-spiro[cyclob-
utane-1,3'-imidazo[1,5-a]pyridine]-1',5'-dione (Cpd. No. 120)
[0590] The synthesis of compound 120 was carried out as described
above using the general protocol of Procedure H. Light yellow
solid; Yield: 0.12 g, 39%; MS (ESI) m/z 346.80 [M+1].sup.+; .sup.1H
NMR (400 MHz, DMSO-d.sub.6) .delta. 10.03 (s, 1H), 9.75 (s, 1H),
8.85 (s, 1H), 8.80 (s, 1H), 8.84 (d, J=16.88 Hz, 1H), 7.48 (d,
J=5.72 Hz, 2H), 3.13-3.08 (m, J=9.44 Hz, 1H), 2.66-2.59 (m, J=9.64
Hz, 1H), 1.20 (s, 3H), 0.98 (s, 3H).
Example 121
Synthesis of 6'-((6-Aminopyrimidin-4-yl)
amino)-8'-chloro-2,2-dimethyl-2'H-spiro[cyclobutane-1,3'-imidazo[1,5-a]py-
ridine]-1',5'-dione (Cpd. No. 121)
##STR00277##
##STR00278##
[0591] Synthesis of tert-butyl
(6-((8'-chloro-2,2-dimethyl-1',5'-dioxo-1',5'-dihydro-2'H-spiro[cyclobuta-
ne-1,3'-imidazo[1,5-a]pyridin]-6'-yl)amino)pyrimidin-4-yl)carbamate
(3)
[0592] The synthesis of intermediate 3 was carried out as described
above using the general protocol of Procedure H. Off white solid;
Yield: 0.31 g, crude; MS (ESI) m/z 461.90 [M+1].sup.+.
Synthesis of 6'-((6-aminopyrimidin-4-yl)
amino)-8'-chloro-2,2-dimethyl-2'H-spiro[cyclobutane-1,3'-imidazo[1,5-a]py-
ridine]-1',5'-dione (Cpd. No. 121)
[0593] The synthesis of compound 121 was carried out as described
above using the general protocol of Procedure F. Yellow solid;
Yield: 0.070 g, 30%; MS (ESI) m/z 361.92 [M+1].sup.+; .sup.1H NMR:
(400 MHz, DMSO-d.sub.6) .delta. 9.94 (s, 1H), 9.07 (s, 1H), 8.67
(s, 1H), 8.21 (s, 1H), 6.61 (s, 2H), 3.12-3.05 (m, J=2.48 Hz, 1H),
2.66-2.58 (m, J=5.4 Hz, 1H), 1.55-1.50 (m, J=3.0 Hz, 1H), 1.19 (s,
3H), 0.96 (s, 3H).
Example 122
Synthesis of
6-[(6-amino-5-chloro-pyrimidin-4-yl)amino]-8-chloro-spiro[2H-imidazo[1,5--
a]pyridine-3,1'-cyclohexane]-1,5-dione hydrochloride (Cpd. No.
122)
##STR00279##
##STR00280##
[0594] Synthesis tert-butyl
N-tert-butoxycarbonyl-N-(5,6-dichloropyrimidin-4-yl)carbamate
(2)
[0595] Procedure J: To a stirred solution of 5,
6-dichloropyrimidin-4-amine (1, 3.0 g, 18.29 mmol) in
tetrahydrofuran (30 mL), 4-dimethylaminopyridine (0.16 g, 1.31
mmol) and di-tert-butyl dicarbonate (8.77 g, 40.2 mmol) were added
at room temperature. The reaction mass was stirred at room
temperature for overnight. After completion, distilled out the
solvent. The above residue was diluted with water and extracted
with ethyl acetate (2.times.50 mL). The organics were then
separated and dried (magnesium sulfate) and concentrated to dryness
under vacuum to afford ethyl tert-butyl
N-tert-butoxycarbonyl-N-(5,6-dichloropyrimidin-4-yl)carbamate (2)
as white solid. Yield: 3.1 g, 47%; MS (ESI) m/z 364.3 [M+1].sup.+;
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 9.04 (s, 1H), 1.40 (s,
18H).
Synthesis of tert-butyl
N-tert-butoxycarbonyl-N-[5-chloro-6-[(8-chloro-1,5-dioxo-spiro[2H-imidazo-
[1,5-a]pyridine-3,1'-cyclohexane]-6-yl)amino]pyrimidin-4-yl]carbamate
(4)
[0596] The synthesis of intermediate 4 was carried out as described
above using the general protocol of Procedure B. Yellow solid;
Yield: 0.10 g, 26%; MS (ESI) m/z 595.45 [M+1].sup.+; .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 10.46 (s, 1H), 8.99 (s, 1H), 8.95
(s, 1H), 8.66 (s, 1H), 2.90 (m, 2H), 1.65 (m, 7H), 1.46 (s, 18H),
1.20 (m, 1H).
Synthesis of
6-[(6-amino-5-chloro-pyrimidin-4-yl)amino]-8-chloro-spiro[2H-imidazo[1,5--
a]pyridine-3,1'-cyclohexane]-1,5-dione hydrochloride (Cpd. No.
122)
[0597] The synthesis of compound 122 was carried out as described
above using the general protocol of Procedure F. Yellow solid;
Yield: 0.059 g, 81%; MS (ESI) m/z 395.35 [M+1].sup.+; .sup.1H NMR:
(400 MHz, DMSO-d.sub.6) .delta. 10.35 (s, 1H), 8.62 (s, 1H), 8.55
(s, 1H), 8.23 (s, 2H), 7.27 (s, 1H), 2.91 (t, J=2.28, 2H), 1.75 (m,
2H), 1.63 (m, 3H), 1.53 (d, J=12.8 Hz, 2H), 1.23 (m, 1H).
Example 123
Synthesis of
6'-((7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-8'-chloro-2'H-spiro[cyclohexa-
ne-1,3'-imidazo[1,5-a]pyridine]-1',5'-dione hydrochloride (Cpd. No.
123)
##STR00281##
##STR00282##
[0598] Synthesis of
6'-((7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-8'-chloro-2'H-spiro[cyclohexa-
ne-1,3'-imidazo[1,5-a]pyridine]-1',5'-dione (3)
[0599] The synthesis of intermediate 3 was carried out as described
above using the general protocol of Procedure H. Yellow solid;
Yield: 0.60 g, crude; MS (ESI) m/z 385.19 [M+1].sup.+
Synthesis of
6'-((7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-8'-chloro-2'H-spiro[cyclohexa-
ne-1,3'-imidazo[1,5-a]pyridine]-1',5'-dione hydrochloride (Cpd. No.
123)
[0600] To a stirred solution of
8-chloro-6-(7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)spiro[2H-imidazo[1,5-a]p-
yridine-3,1'-cyclohexane]-1,5-dione (3, 0.6 g, 1.56 mmol) in
methanol (6 mL) 4 M hydrogenchloride in dioxane (4 mL) was added
under cooling and stirred the reaction mixture at room temperature
for overnight. After completion filtered the reaction mass using
sintered funnel and washed with ethanol (10 mL). The solid obtained
was dried under high vacuum to afford
8-chloro-6-(7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)spiro[2H-imidazo[-
1,5-a]pyridine-3,1'-cyclohexane]-1,5-dione hydrochloride (Cpd. No.
123) as light yellow solid; Yield: 0.21 g, 32%; MS (ESI) m/z 385.31
[M+1].sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 12.24 (s,
1H), 10.39 (s, 1H), 9.12 (s, 1H), 8.75 (s, 1H), 8.50 (s, 1H), 7.43
(s, 1H), 6.88 (s, 1H), 2.95 (t, J=11.14 Hz, 2H), 1.76 (m, 2H), 1.62
(m, 5H), 1.22 (m, 1H).
Example 124
Synthesis of
8-chloro-3,3-dimethyl-6-(pyrido[4,3-d]pyrimidin-4-ylamino)-2,3-dihydroimi-
dazo[1,5-a]pyridine-1,5-dione (Cpd. No. 124)
##STR00283##
##STR00284##
[0601] Synthesis of 8-chloro-3, 3-dimethyl-6-(pyrido[4,
3-d]pyrimidin-4-ylamino)-2,
3-dihydroimidazo[1,5-a]pyridine-1,5-dione (Cpd. No. 124)
[0602] The synthesis of compound 124 was carried out as described
above using the general protocol of Procedure H. Yellow solid;
Yield: 0.060 g, 16%; MS (ESI) m/z 357.77 [M+1].sup.+; .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 9.91 (s, 2H), 9.69 (s, 1H), 8.96
(s, 1H), 8.90-8.86 (d, 1H), 8.87 (s, 1H), 7.73 (d, 1H), 1.84 (s,
6H).
Example 125
Synthesis of
8'-chloro-6'-((2-methylpyrimidin-4-yl)amino)-2'H-spiro[cyclohexane-1,3'-i-
midazo[1,5-a]pyridine]-1',5'-dione hydrochloride (Cpd. No. 125)
##STR00285##
##STR00286##
[0603] Synthesis of
8'-chloro-6'-((2-methylpyrimidin-4-yl)amino)-2'H-spiro[cyclohexane-1,3'-i-
midazo[1,5-a]pyridine]-1',5'-dione hydrochloride (Cpd. No. 125)
[0604] The synthesis of compound 125 was carried out as described
above using the general protocol of Procedure H. Off white solid;
Yield: 0.16 g, 45%; MS (ESI) m/z 360.38 [M+1].sup.+; .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 10.55 (s, 1H), 10.47 (s, 1H), 8.67
(s, 1H), 8.45 (m, 1H), 7.44 (d, J=4.8 Hz, 1H), 2.91 (t, J=11.74 Hz,
2H), 2.65 (s, 3H), 1.76 (m, 2H), 1.65 (m, 3H), 1.56 (m, 2H), 1.19
(m, 1H).
Example 126
Synthesis of
6-((6-aminopyrimidin-4-yl)amino)-8-chloro-2H-spiro[imidazo[1,5-a]pyridine-
-3,6'-[1,4]diazepane]-1,5-dione (Cpd. No. 126)
##STR00287##
##STR00288##
[0605] Synthesis of
6-bromo-8-chloro-1',4'-ditosyl-2H-spiro[imidazo[1,5-a]pyridine-3,6'-[1,4]-
diazepane]-1,5-dione (3)
[0606] The synthesis of intermediate 3 was carried out as described
above using the general protocol of Procedure A. White solid;
Yield: 1.7 g, 43%; MS (ESI) m/z 442.31 [M+1].sup.+.
Synthesis of
6-bromo-8-chloro-2H-spiro[imidazo[1,5-a]pyridine-3,6'-[1,4]diazepane]-1,5-
-dione (4)
[0607] To a stirred solution of hydrogenbromide (1.43 g, 15.24
mmol) in acetic acid in 1,4-dioxane (30 mL),
6-bromo-8-chloro-1',4'-ditosyl-2H-spiro[imidazo[1,5-a]pyridine-3,6'-[1,4]-
diazepane]-1,5-dione (1 g, 1.52 mmol) was added at room
temperature. The vial was sealed and heated the reaction mass to
100.degree. C. for 16 h. After completion, solvent was removed
under reduced pressure and crude was triturated with
dichloromethane to afford
6-bromo-8-chloro-2H-spiro[imidazo[1,5-a]pyridine-3,6'-[1,4]diazepane]-1,5-
-dione (4) as brown solid. Yield: 0.5 g, 94%; MS (ESI) m/z 362.28
[M+1].sup.+.
Synthesis of di-tert-butyl
6-bromo-8-chloro-1,5-dioxo-1,5-dihydro-2H-spiro[imidazo[1,5-a]pyridine-3,-
6'-[1,4]diazepane]-1',4'-dicarboxylate (5)
[0608] To a stirred solution of di-tert-butyl dicarbonate (0.94 g,
4.32 mmol) in dichloromethane (30 mL) in a vial at room
temperature,
6-bromo-8-chloro-2H-spiro[imidazo[1,5-a]pyridine-3,6'-[1,4]diazepane]-1,5-
-dione (4, 0.5 g, 1.44 mmol) and triethylamine (0.73 g, 7.19 mmol)
were added. The vial was sealed and stirred the reaction mass at
room temperature for 16 h. After completion, the solvent was
removed and the crude was triturated with hexane to afford
di-tert-butyl
6-bromo-8-chloro-1,5-dioxo-1,5-dihydro-2H-spiro[imidazo[1,5-a]pyridine-3,-
6'-[1,4]diazepane]-1',4'-dicarboxylate (5) as yellow solid. Yield:
0.45 g, 57%; MS (ESI) m/z 547.13 [M+1].sup.+.
Synthesis of di-tert-butyl
6-((6-((tert-butoxycarbonyl)amino)pyrimidin-4-yl)amino)-8-chloro-1,5-diox-
o-1,5-dihydro-2H-spiro[imidazo[1,5-a]pyridine-3,6'-[1,4]diazepane]-1',4'-d-
icarboxylate (7)
[0609] The synthesis of intermediate 7 was carried out as described
above using the general protocol of Procedure H. Yellow solid;
Yield: 0.41 g, 74%; MS (ESI) m/z 677.32 [M+1].sup.+.
Synthesis of
6-((6-aminopyrimidin-4-yl)amino)-8-chloro-2H-spiro[imidazo[1,5-a]pyridine-
-3,6'-[1,4]diazepane]-1,5-dione (Cpd. No. 126)
[0610] The synthesis of compound 126 was carried out as described
above using the general protocol of Procedure F. Off white solid;
Yield: 0.04 g, 18%; MS (ESI) m/z 377.32 [M+1].sup.+; .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 9.87 (s, 1H), 8.98 (s, 1H), 8.66
(s, 1H), 8.20 (s, 1H), 6.61 (s 2H), 6.25 (s, 1H), 3.61-3.58 (m,
2H), 2.95-2.91 (m, 2H), 2.82 (s, 4H), 2.66-2.61 (m, 2H).
Example 127
Synthesis of
6'-((1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)-8'-chloro-2'H-spiro
[cyclohexane-1,3'-imidazo[1,5-a]pyridine]-1',5'-dione (Cpd. No.
127)
##STR00289##
##STR00290##
[0611] Synthesis of
6'-((1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)-8'-chloro-2'H-spiro
[cyclohexane-1,3'-imidazo[1,5-a]pyridine]-1',5'-dione (Cpd. No.
127)
[0612] The synthesis of compound 127 was carried out as described
above using the general protocol of Procedure B. Yield: 0.037 g,
6%; MS (ESI) m/z 386.36 [M+1].sup.+; .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 10.39 (s, 1H), 9.55 (s, 1H), 8.91 (s, 1H),
8.61 (s, 2H), 2.97 (m, 2H), 1.76-1.56 (m, 7H), 1.23 (m, 1H).
Example 128
Synthesis of
6-[(6-aminopyrimidin-4-yl)amino]-8-chloro-1'-methyl-spiro[2H-imidazo[1,5--
a]pyridine-3,4'-piperidine]-1,5-dione hydrochloride (Cpd. No.
128)
##STR00291##
##STR00292##
[0613] Synthesis of
6-bromo-8-chloro-1'-methyl-spiro[2H-imidazo[1,5-a]pyridine-3,4'-piperidin-
e]-1,5-dione (3)
[0614] The synthesis of intermediate 3 was carried out as described
above using the general protocol of Procedure A. Light brown solid;
Yield: 1.0 g, 36%; MS (ESI) m/z 346.13 [M+1].sup.+.
Synthesis of tert-butyl
N-[6-[(8-chloro-1'-methyl-1,5-dioxo-spiro[2H-imidazo[1,5-a]pyridine-3,4'--
piperidine]-6-yl)amino]pyrimidin-4-yl]carbamate (5)
[0615] The synthesis of intermediate 5 was carried out as described
above using the general protocol of Procedure H. Off white solid;
Yield: 60 mg, 14%; .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
10.33 (s, 1H), 9.63 (s, 1H), 8.84 (s, 1H), 8.80 (s, 1H), 8.44-8.42
(d, J=8.0 Hz, 1H), 7.47-7.45 (d, J=8.0 Hz, 1H), 7.39-7.38 (m, 1H),
5.75 (s, 2H), 3.24-3.17 (m, 2H), 2.80-2.66 (m, 2H), 2.39-2.35 (m,
2H), 2.32 (s, 3H), 1.50-1.47 (m, 2H), 1.23 (s, 9H).
Synthesis of
6-[(6-aminopyrimidin-4-yl)amino]-8-chloro-1'-methyl-spiro[2H-imidazo[1,5--
a]pyridine-3,4'-piperidine]-1,5-dione hydrochloride (Cpd. No.
128)
[0616] The synthesis of compound 128 was carried out as described
above using the general protocol of Procedure F. Off white solid;
Yield: 0.032 g, 62%; MS (ESI) m/z 375.82 [M+1].sup.+; .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 10.72 (brs, 1H), 10.60 (s, 1H),
9.80 (s, 1H), 8.49 (s, 1H), 8.44 (s, 1H), 7.81 (brs, 2H), 6.53 (s,
1H), 3.66-3.33 (m, 6H), 2.78 (s, 3H), 1.91-1.88 (m, 2H).
Example 129
Synthesis of
8-chloro-1'-methyl-6-(pyrimidin-4-ylamino)spiro[2H-imidazo[1,5-a]pyridine-
-3,4'-piperidine]-1,5-dione (Cpd. No. 129)
##STR00293##
##STR00294##
[0617] Synthesis of
8-chloro-1'-methyl-6-(pyrimidin-4-ylamino)spiro[2H-imidazo[1,5-a]pyridine-
-3,4'-piperidine]-1,5-dione (Cpd. No. 129)
[0618] The synthesis of compound 129 was carried out as described
above using the general protocol of Procedure H. Off white solid;
Yield: 65 mg, 31%; MS (ESI) m/z 360.80 [M+1].sup.+; .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 10.32 (s, 1H), 9.62 (s, 1H),
8.43-8.42 (d, J=5.6 Hz, 1H), 7.47-7.45 (d, J=4.8 Hz, 1H), 3.25-3.17
(m, 2H), 2.80-2.78 (m, 2H), 2.39-2.33 (m, 2H), 2.24 (s, 3H),
1.50-1.47 (m, 2H).
Example 130
Synthesis of
1',8-dimethyl-6-(pyrimidin-4-ylamino)-2H-spiro[imidazo[1,5-a]pyridine-3,3-
'-piperidine]-1,5-dione (Cpd. No. 130)
##STR00295##
##STR00296##
[0619] Synthesis of
6-bromo-1',8-dimethyl-spiro[2H-imidazo[1,5-a]pyridine-3,3'-piperidine]-1,-
5-dione (3)
[0620] The synthesis of intermediate 3 was carried out as described
above using the general protocol of Procedure A. White solid;
Yield: 0.7 g, 25%; MS (ESI) m/z 326.19 [M+1].sup.+.
Synthesis of
1',8-dimethyl-6-(pyrimidin-4-ylamino)-2H-spiro[imidazo[1,5-a]pyridine-3,3-
'-piperidine]-1,5-dione (Cpd. No. 130)
[0621] The synthesis of compound 130 was carried out as described
above using the general protocol of Procedure H. Yellow solid;
Yield: 190 mg, 58%; MS (ESI) m/z 359.81 [M+1].sup.+; .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 9.93 (s, 1H), 9.35 (s, 1H), 8.77
(s, 1H), 8.59 (s, 1H), 8.37-8.38 (d, J=5.88 Hz, 1H), 7.35-7.36 (d,
J=5.88 Hz, 1H), 3.01 (m, 2H), 2.95 (m, 1H), 2.50 (s, 2H), 2.45 (s,
3H), 2.25 (s, 3H), 1.91-1.97 (m, 2H), 1.71-1.73 (m, 1H), 1.48-1.51
(m, 1H).
Example 131
Synthesis of
6'-(pyrimidin-4-ylamino)-1'-thioxo-1',2'-dihydro-5'H-spiro[cyclohexane-1,-
3'-imidazo[1,5-a]pyridin]-5'-one (Cpd. No. 131)
##STR00297##
##STR00298##
[0622] Synthesis of
6'-(pyrimidin-4-ylamino)-1'-thioxo-1',2'-dihydro-5'H-spiro[cyclohexane-1,-
3'-imidazo[1,5-a]pyridin]-5'-one (Cpd. No. 131)
[0623] A vial containing tetrahydrofuran (10 mL) was charged with
6-(pyrimidin-4-ylamino)spiro[2H-imidazo[1,5-a]pyridine-3,1'-cyclohexane]--
1,5-dione (1, 0.6 g, 1.93 mmol) and phosphorus pentasulfide (857
mg, 3.85 mmol). Seal the vial and heat the reaction mixture at
50.degree. C. for 16 h. After completion, the reaction mass was
diluted with 5% methanol in dichloromethane (100 mL), washed with
water (2.times.100 mL) and brine solution (100 mL), dried over
anhydrous sodium sulfate, concentrated under vacuum. Crude material
was purified by flash chromatography in silica gel in 3-4% methanol
in dichloromethane, fraction were combined concentrated under
reduced pressure. The product was triturated with methanol,
filtered washed with methanol (3 mL), ether (5 mL), dried under
high vacuum to obtain the desired product
6'-(pyrimidin-4-ylamino)-1'-thioxo-1',2'-dihydro-5'H-spiro[cyclohexane-1,-
3'-imidazo[1,5-a]pyridin]-5'-one (Cpd. No. 131) as light yellow
solid. Yield: 0.050 g, 8%; MS (ESI) m/z 328.41 [M+1].sup.+; .sup.1H
NMR (400 MHz, DMSO-d.sub.6) .delta. 12.26 (s, 1H), 9.46 (s, 1H),
8.80-8.77 (d, 2H), 8.39-8.38 (d, 1H), 7.39-7.38 (d, 1H), 7.07-7.06
(d, 1H), 2.97 (t, 2H), 1.78-1.72 (m, 5H), 1.59-1.56 (d, 1H), 1.26
(m, 1H).
Example 132
Synthesis of
8'-chloro-1'-(methoxyimino)-6'-(pyrimidin-4-ylamino)-1',2'-dihydro-5'H-sp-
iro[cyclohexane-1,3'-imidazo[1,5-a]pyridin]-5'-one (Cpd. No.
132)
##STR00299##
##STR00300##
[0624] Synthesis of
8'-chloro-1'-(methoxyimino)-6'-(pyrimidin-4-ylamino)-1',2'-dihydro-5'H-sp-
iro[cyclohexane-1,3'-imidazo[1,5-a]pyridin]-5'-one (Cpd. No.
132)
[0625] To a solution of
8'-chloro-6'-(pyrimidin-4-ylamino)-2'H-spiro[cyclohexane-1,3'-imidazo[1,5-
-a]pyridine]-1',5'-dione (1, 1 g, 2.89 mmol) in chloroform (30 mL)
was added triethylamine (1.21 mL, 8.67 mmol) and
O-methylhydroxylamine hydrochloride (241 mg, 2.89 mmol). The
reaction was stirred at reflux overnight. The resulting mixture was
cooled to room temperature and washed with water. The organic layer
was dried over magnesium sulfate, filtered and concentrated. The
crude was purified via flash column chromatography to afford
8'-chloro-1'-(methoxyimino)-6'-(pyrimidin-4-ylamino)-1',2'-dihydro-5'H-sp-
iro[cyclohexane-1,3'-imidazo[1,5-a]pyridin]-5'-one (Cpd. No.
132).
Example 133
Synthesis of
8'-chloro-6'-(pyrimidin-4-ylamino)-5'-thioxo-2'H-spiro[cyclohexane-1,3'-i-
midazo[1,5-a]pyridin]-1'(5'H)-one (Cpd. No. 133)
##STR00301##
##STR00302##
[0626] Synthesis of ethyl
3-chloro-6-oxo-5-(pyrimidin-4-ylamino)-1,6-dihydropyridine-2-carboxylate
(3)
[0627] The synthesis of intermediate 3 was carried out as described
above using the general protocol of Procedure H. Yellow solid;
Yield: 0.42 g, 20%; MS (ESI) m/z 295 [M+1].sup.+
Synthesis of ethyl
3-chloro-5-(pyrimidin-4-ylamino)-6-thioxo-1,6-dihydropyridine-2-carboxyla-
te (4)
[0628] A vial was charged with
3-chloro-6-oxo-5-(pyrimidin-4-ylamino)-1,6-dihydropyridine-2-carboxylate
(3, 0.35, 1.2 mmol) and pyridine (10 mL) was added. To the above
mixture phosphorus pentasulfide (0.53 g, 2.4 mmol) was added and
reaction was heated at 110.degree. C. for 16 h. TLC showed presence
of starting material and phosphorus pentasulfide (0.265 g, 1.2
mmol) was added again and heated the reaction to 115.degree. C. for
24 h. The pyridine was removed under reduced pressure and water (20
mL) was added and extracted with 5% methanol in dichloromethane
(100 mL). The organic layer was washed with sodium bicarbonate and
brine and layer was concentrated to dryness to afford ethyl
3-chloro-5-(pyrimidin-4-ylamino)-6-thioxo-1,6-dihydropyridine-2-carboxyla-
te (4) as brownish yellow solid and used directly without further
purification. Yield: 350 mg, crude; MS (ESI) m/z 310.94
[M+1].sup.+.
Synthesis of
3-chloro-5-(pyrimidin-4-ylamino)-6-thioxo-1,6-dihydropyridine-2-carboxami-
de (5)
[0629] Procedure K: A vial was charged with
3-chloro-5-(pyrimidin-4-ylamino)-6-thioxo-1,6-dihydropyridine-2-carboxyla-
te (4, 0.35 g, 1.2 mmol) and methanolic ammonia (12 mL) was added.
The mixture was slowly heated at 60-65.degree. C. for 40 h when TLC
showed complete conversion of starting material. The mixture was
cooled and concentrated under reduced pressure and triturated with
diethyl ether (10 mL) to afford
3-chloro-5-(pyrimidin-4-ylamino)-6-thioxo-1,6-dihydropyridine-2-carboxami-
de (5) as reddish brown solid. Yield: 350 mg, crude; MS (ESI) m/z
282.04 [M+1].sup.+.
Synthesis of
8'-chloro-6'-(pyrimidin-4-ylamino)-5'-thioxo-2'H-spiro[cyclohexane-1,3'-i-
midazo[1,5-a]pyridin]-1'(5'H)-one (Cpd. No. 133)
[0630] The synthesis of compound 133 was carried out as described
above using the general protocol of Procedure A. Yellow solid;
Yield: 17 mg, 4%; MS (ESI) m/z 362.06 [M+1].sup.+. .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. 10.64 (brs, 1H), 9.93 (s, 1H), 9.00 (s,
1H), 8.90 (s, 1H), 8.51 (d, J=5.6 Hz, 1H), 7.43 (d, J=6.0 Hz, 1H),
4.22-3.12 (m, 2H), 1.84-1.78 (m, 2H), 1.75-1.60 (m, 3H), 1.54-1.47
(m, 2H), 1.30-1.22 (m, 1H).
Example 134
Synthesis of
8'-chloro-5'-(methoxyimino)-6'-(pyrimidin-4-ylamino)-2'H-spiro[cyclohexan-
e-1,3'-imidazo[1,5-a]pyridin]-1'(5'H)-one (Cpd. No. 134)
##STR00303##
##STR00304##
[0631] Synthesis of
8'-chloro-5'-(methoxyimino)-6'-(pyrimidin-4-ylamino)-2'H-spiro[cyclohexan-
e-1,3'-imidazo[1,5-a]pyridin]-1'(5'H)-one (Cpd. No. 134)
[0632] To a solution of
8'-chloro-6'-(pyrimidin-4-ylamino)-2'H-spiro[cyclohexane-1,3'-imidazo[1,5-
-a]pyridine]-1',5'-dione (1, 1 g, 2.89 mmol) in chloroform (30 mL)
is added triethylamine (1.21 mL, 8.67 mmol) and
O-methylhydroxylamine hydrochloride (241 mg, 2.89 mmol). The
reaction is stirred at reflux overnight. The resulting mixture is
cooled to room temperature and washed with water. The organic layer
is dried over magnesium sulfate, filtered and concentrated. The
crude is purified via flash column chromatography to afford
8'-chloro-5'-(methoxyimino)-6'-(pyrimidin-4-ylamino)-2'H-spiro[-
cyclohexane-1,3'-imidazo[1,5-a]pyridin]-1'(5'H)-one (Cpd. No.
134).
Example 135
Synthesis of
8'-chloro-2'-cyclopropyl-6'-(pyrimidin-4-ylamino)-2'H-spiro[cyclohexane-1-
,3'-imidazo[1,5-a]pyridine]-1',5'-dione (Cpd. No. 135)
##STR00305##
##STR00306##
[0633] Synthesis of
6'-bromo-8'-chloro-2'-cyclopropyl-2'H-spiro[cyclohexane-1,3'-imidazo[1,5--
a]pyridine]-1',5'-dione (3)
[0634] To a solution of
6'-bromo-8'-chloro-2'H-spiro[cyclohexane-1,3'-imidazo[1,5-a]pyridine]-1',-
5'-dione (1, 1 g, 3.02 mmol) in 1,2-dichloroethane (15 mL) is added
cyclopropylboronic acid (2, 0.58 g, 6.80 mmol), copper(II) acetate
(0.59 g, 3.23 mmol), 2,2'-bi-pyridyl (0.50 g, 3.23 mmol) and sodium
carbonate (0.73 g, 6.86 mmol). The reaction is stirred at
70.degree. C. overnight. The reaction is cooled to room
temperature. The resulting mixture is quenched with saturated
aqueous ammonium chloride solution and extracted with
dichloromethane. The organic is dried over magnesium sulfate,
filtered and concentrated. The crude is purified via column
chromatography to afford
6'-bromo-8'-chloro-2'-cyclopropyl-2'H-spiro[cyclohexane-1,3'-imidazo[1,5--
a]pyridine]-1',5'-dione (3).
Synthesis of
8'-chloro-2'-cyclopropyl-6'-(pyrimidin-4-ylamino)-2'H-spiro[cyclohexane-1-
,3'-imidazo[1,5-a]pyridine]-1',5'-dione (Cpd. No. 135)
[0635] The synthesis of compound 135 is carried out as described
above using the general protocol of Procedure H.
Example 136
Synthesis of
8'-chloro-2'-(pyridin-3-yl)-6'-(pyrimidin-4-ylamino)-2'H-spiro[cyclohexan-
e-1,3'-imidazo[1,5-a]pyridine]-1',5'-dione (Cpd. No. 136)
##STR00307##
##STR00308##
[0636] Synthesis of
8'-chloro-2'-(pyridin-3-yl)-6'-(pyrimidin-4-ylamino)-2'H-spiro[cyclohexan-
e-1,3'-imidazo[1,5-a]pyridine]-1',5'-dione (Cpd. No. 136)
[0637] To a solution of
8'-chloro-6'-(pyrimidin-4-ylamino)-2'H-spiro[cyclohexane-1,3'-imidazo[1,5-
-a]pyridine]-1',5'-dione (1, 450 mg, 1.3 mmol) and 3-iodopyridine
(800 mg, 3.9 mmol) in dimethylformamide (10 mL) in a vial, cesium
carbonate (550 mg, 1.6 mmol) was added and the mixture was degassed
with argon for 15 min. To this mixture 1,10,-phenanthroline (37 mg,
0.2 mmol), copper(I) iodide (12 mg, 0.05 mmol), XantPhos (26 mg,
0.065 mmol) were added and the reaction was heated the mixture at
130.degree. C. for 26 h. TLC showed consumption of starting
material, the reaction mixture was filtered over celite bed and
washed with 5% methanol in dichloromethane followed by
concentration of the filtrate. Obtained solid was purified by
Combi-Flash chromatography on neutral alumina using 3%
methanol/dichloromethane as a eluent, appropriate fractions were
concentrated under reduced pressure to afford
8'-chloro-2'-(pyridin-3-yl)-6'-(pyrimidin-4-ylamino)-2'H-spiro[cyclohexan-
e-1,3'-imidazo[1,5-a]pyridine]-1',5'-dione (Cpd. No. 136) as yellow
solid. Yield: 0.025 g, 4.6%; MS (ESI) m/z 423.12 [M+1].sup.+;
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 10.59 (s, 1H), 8.61 (d,
J=2.0 Hz, 1H), 8.58 (s, 1H), 8.49 (d, J=4.8 Hz, 1H), 8.33 (d, J=6.0
Hz, 1H), 8.03 (s, 1H), 7.82 (d, J=8.8 Hz, 1H), 7.47 (dd, J=4.4, 8.8
Hz, 1H), 6.65 (d, J=6.0 Hz, 1H), 2.85-2.79 (m, 2H), 1.74-1.53 (m,
6H), 1.17-1.14 (m, 1H).
Example 137
Synthesis of
7'-fluoro-6'-(pyrimidin-4-ylamino)-2'H-spiro[cyclohexane-1,3'-imidazo[1,5-
-a]pyridine]-1',5'-dione (Cpd. No. 137)
##STR00309##
##STR00310##
[0638] Synthesis of methyl 4-fluoropicolinate (2)
[0639] To a solution of 4-fluoropicolinic acid (1, 1 g, 7.09 mmol)
in toluene (20 mL) and methanol (5 mL) at room temperature is added
(trimethylsilyl)diazomethane (2 M in hexanes, 5.32 mL, 10.64 mmol)
dropwise. The reaction is stirred at 80.degree. C. for 2 h. The
resulting mixture is concentrated and purified via flash
chromatography to afford methyl 4-fluoropicolinate (2).
Synthesis of 4-fluoro-2-(methoxycarbonyl)pyridine 1-oxide (3)
[0640] To a solution of methyl 4-fluoropicolinate (2, 1 g, 6.45
mmol) in dichloromethane (30 mL) is added urea hydrogen peroxide
(1.27 g, 13.54 mmol) and trifluoroacetic anhydride (1.79 mL, 12.9
mmol). The reaction is stirred at room temperature for 2 h. The
resulting mixture is pour into 0.5 M hydrochloric acid and
extracted with dichloromethane. The organic layer is washed with
saturated aqueous sodium bicarbonate solution, dried over magnesium
sulfate, filtered and concentrated. The crude is purified via flash
chromatography to afford methyl
4-fluoro-2-(methoxycarbonyl)pyridine 1-oxide (3).
Synthesis of methyl
4-fluoro-6-oxo-1,6-dihydropyridine-2-carboxylate (4)
[0641] To a solution of methyl 4-fluoro-2-(methoxycarbonyl)pyridine
1-oxide (3, 1 g, 5.84 mmol) in dimethylformamide (25 mL) is added
trifluoroacetic anhydride (1.62 mL, 11.68 mmol). The reaction is
stirred at 50.degree. C. for 3 h. The resulting mixture is
concentrated and purified via flash chromatography to afford methyl
4-fluoro-6-oxo-1,6-dihydropyridine-2-carboxylate (4).
Synthesis of methyl
5-bromo-4-fluoro-6-oxo-1,6-dihydropyridine-2-carboxylate (5)
[0642] To a solution of methyl
4-fluoro-6-oxo-1,6-dihydropyridine-2-carboxylate (4, 1 g, 5.84
mmol) in acetonitrile (25 mL) is added N-bromosuccinimide (1.56 g,
8.76 mmol). The reaction is stirred at reflux for 2 h. The
resulting mixture is pour into half saturated aqueous sodium
bisulfite and extracted with ethyl acetate. The organic layers are
combined, dried over magnesium sulfate, filtered and concentrated.
The crude is purified via flash chromatography to afford methyl
5-bromo-4-fluoro-6-oxo-1,6-dihydropyridine-2-carboxylate (5).
Synthesis of
5-bromo-4-fluoro-6-oxo-1,6-dihydropyridine-2-carboxamide (6)
[0643] The synthesis of intermediate 6 is carried out as described
above using the general protocol of Procedure K.
Synthesis of
6'-bromo-7'-fluoro-2'H-spiro[cyclohexane-1,3'-imidazo[1,5-a]pyridine]-1',-
5'-dione (8)
[0644] The synthesis of intermediate 8 is carried out as described
above using the general protocol of Procedure A.
Synthesis of
7'-fluoro-6'-(pyrimidin-4-ylamino)-2'H-spiro[cyclohexane-1,3'-imidazo[1,5-
-a]pyridine]-1',5'-dione (Cpd. No. 137)
[0645] The synthesis of compound 137 is carried out as described
above using the general protocol of Procedure H.
Example 138
Synthesis of
8-phenyl-6-(pyrimidin-4-ylamino)spiro[2H-imidazo[1,5-a]pyridine-3,1'-cycl-
ohexane]-1,5-dione (Cpd. No. 138)
##STR00311##
##STR00312##
[0646] Synthesis of
8-phenyl-6-(pyrimidin-4-ylamino)spiro[2H-imidazo[1,5-a]pyridine-3,1'-cycl-
ohexane]-1,5-dione (Cpd. No. 138)
[0647] The synthesis of compound 138 was carried out as described
above using the general protocol of Procedure G. Off white solid;
Yield: 0.15 g, 67%; MS (ESI) m/z 388.48 [M+1].sup.+; .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 10.16 (s, 1H), 9.49 (s, 1H), 8.74
(s, 1H), 8.71 (s, 1H), 8.38 (d, J=5.84 Hz, 1H), 7.47-7.35 (m, 6H),
3.10-3.04 (m, 2H), 1.76-1.49 (m, 7H), 1.04-1.02 (m, 1H).
Example 139
Synthesis of
8'-(oxetan-2-yl)-6'-(pyrimidin-4-ylamino)-2'H-spiro[cyclohexane-1,3'-imid-
azo[1,5-a]pyridine]-1',5'-dione (Cpd. No. 139)
##STR00313##
##STR00314## ##STR00315##
[0648] Synthesis of
8'-chloro-2'-(4-methoxybenzyl)-6'-((4-methoxybenzyl)(pyrimidin-4-yl)amino-
)-2'H-spiro[cyclohexane-1,3'-imidazo[1,5-a]pyridine]-1',5'-dione
(2)
[0649] To a solution of
8'-chloro-6'-(pyrimidin-4-ylamino)-2'H-spiro[cyclohexane-1,3'-imidazo[1,5-
-a]pyridine]-1',5'-dione (1, 1 g, 2.89 mmol) in dimethylformamide
(15 mL) is added sodium hydride (0.21 g, 8.67 mmol) and
4-methoxybenzyl chloride (1.57 mL, 11.56 mmol). The reaction is
stirred at room temperature overnight. The resulting mixture is
poured into iced water and extracted with dichloromethane. The
organic layer is dried over magnesium sulfate, filtered and
concentrated. The crude is purified via column chromatography to
afford
8'-chloro-2'-(4-methoxybenzyl)-6'-((4-methoxybenzyl)(pyrimidin-4-yl)amino-
)-2'H-spiro[cyclohexane-1,3'-imidazo[1,5-a]pyridine]-1',5'-dione
(2).
Synthesis of
2'-(4-methoxybenzyl)-6'-((4-methoxybenzyl)(pyrimidin-4-yl)amino)-1',5'-di-
oxo-1',5'-dihydro-2'H-spiro[cyclohexane-1,3'-imidazo[1,5-a]pyridine]-8'-ca-
rbonitrile (3)
[0650] To a solution of
8'-chloro-2'-(4-methoxybenzyl)-6'-((4-methoxybenzyl)(pyrimidin-4-yl)amino-
)-2'H-spiro[cyclohexane-1,3'-imidazo[1,5-a]pyridine]-1',5'-dione
(2, 1 g, 1.71 mmol)) in acetonitrile (20 mL) is added potassium
cyanide (0.17 g, 2.56 mmol), tributyltin chloride (0.038 mL, 0.14
mmol). The mixture is degassed and followed by the addition of
tris(dibenzylideneacetone)dipalladium(0) (64 mg, 0.07 mmol) and
tri-tert-butylphosphine (63 mg, 0.31 mmol). The mixture is degassed
two more times. The reaction is stirred at 80.degree. C. overnight.
The resulting mixture is cooled to room temperature and filtered
through a pad of celite. The filtrate is concentrated and purified
via column chromatography to afford
2'-(4-methoxybenzyl)-6'-((4-methoxybenzyl)(pyrimidin-4-yl)amino)-1',5'-di-
oxo-1',5'-dihydro-2'H-spiro[cyclohexane-1,3'-imidazo[1,5-a]pyridine]-8'-ca-
rbonitrile (3).
Synthesis of
2'-(4-methoxybenzyl)-6'-((4-methoxybenzyl)(pyrimidin-4-yl)amino)-1',5'-di-
oxo-1',5'-dihydro-2'H-spiro[cyclohexane-1,
3'-imidazo[1,5-a]pyridine]-8'-carbaldehyde (4)
[0651] To a solution of
2'-(4-methoxybenzyl)-6'-((4-methoxybenzyl)(pyrimidin-4-yl)amino)-1',5'-di-
oxo-1',5'-dihydro-2'H-spiro[cyclohexane-1,3'-imidazo[1,5-a]pyridine]-8'-ca-
rbonitrile (3, 1 g, 1.73 mmol) in dichloromethane (20 mL) at
0.degree. C. is added diisobutylaluminum hydride (1 M in
dichloromethane, 3.46 mL, 3.46 mmol) dropwise. The reaction is
stirred at 0.degree. C. for 2 h. The resulting mixture is poured
into saturated aqueous Rochelle's salt solution. The biphasic
mixture is stirred overnight and filtered. The filtrate is
extracted with dichloromethane. The organic is dried over magnesium
sulfate, filtered and concentrated. The crude is purified via
column chromatography to afford
2'-(4-methoxybenzyl)-6'-((4-methoxybenzyl)(pyrimidin-4-yl)amino)-1',5'-di-
oxo-1',5'-dihydro-2'H-spiro[cyclohexane-1,3'-imidazo[1,5-a]pyridine]-8'-ca-
rbaldehyde (4).
Synthesis of
2'-(4-methoxybenzyl)-6'-((4-methoxybenzyl)(pyrimidin-4-yl)amino)-8'-(oxir-
an-2-yl)-2'H-spiro[cyclohexane-1,3'-imidazo[1,5-a]pyridine]-1',5'-dione
(5)
[0652] A suspension of sodium hydride (50% dispersion washed free
of mineral oil, 90 mg, 1.87 mmol) in dimethylsulfoxide (2 mL) is
heated to 65.degree. C. under argon for 1 h. The oil bath is
removed and to the clear solution is added tetrahydrofuran (2 mL).
The solution is cooled to -15.degree. C. and treated with a
solution of trimethylsulfonium iodide (0.35 g, 1.72 mmol) in
dimethylsulfoxide (2 mL). After 3 min a solution of
2'-(4-methoxybenzyl)-6'-((4-methoxybenzyl)(pyrimidin-4-yl)amino)-1',5'-
-dioxo-1',5'-dihydro-2'H-spiro[cyclohexane-1,3'-imidazo[1,5-a]pyridine]-8'-
-carbaldehyde (4, 1 g, 1.72 mmol) in 3 ml. of tetrahydrofuran is
added. The reaction is stirred overnight. The resulting mixture is
poured into water and extracted with ethyl acetate. The extracts
are washed with water, dried and evaporated to afford
2'-(4-methoxybenzyl)-6'-((4-methoxybenzyl)(pyrimidin-4-yl)amino)-8'-(oxir-
an-2-yl)-2'H-spiro[cyclohexane-1,3'-imidazo[1,5-a]pyridine]-1',5'-dione
(5).
Synthesis of
2'-(4-methoxybenzyl)-6'-((4-methoxybenzyl)(pyrimidin-4-yl)amino)-8'-(oxet-
an-2-yl)-2'H-spiro[cyclohexane-1,3'-imidazo[1,5-a]pyridine]-1',5'-dione
(6)
[0653] Potassium tert-butoxide (0.23 g, 2.02 mmol) is added to a
solution of trimethylsulfoxonium iodide (0.44 g, 2.02 mmol) in
tert-butanol (10 mL) at room temperature. After 15 min, a solution
of
2'-(4-methoxybenzyl)-6'-((4-methoxybenzyl)(pyrimidin-4-yl)amino)-8'-(oxir-
an-2-yl)-2'H-spiro[cyclohexane-1,3'-imidazo[1,5-a]pyridine]-1',5'-dione
(5, 1 g, 1.68 mmol) in dimethylsulfoxide (5 mL) is added dropwise.
The reaction is stirred at 50.degree. C. overnight. The resulting
mixture is quenched with brine and extracted with ethyl acetate.
The combined extracts are dried over magnesium sulfate. After
filtration and concentration, the residue is purified by flash
column to afford
2'-(4-methoxybenzyl)-6'-((4-methoxybenzyl)(pyrimidin-4-yl)amino)-8'-(oxet-
an-2-yl)-2'H-spiro[cyclohexane-1,3'-imidazo[1,5-a]pyridine]-1',5'-dione
(6).
Synthesis of
8'-(oxetan-2-yl)-6'-(pyrimidin-4-ylamino)-2'H-spiro[cyclohexane-1,3'-imid-
azo[1,5-a]pyridine]-1',5'-dione (Cpd. No. 139)
[0654]
2'-(4-Methoxybenzyl)-6'-((4-methoxybenzyl)(pyrimidin-4-yl)amino)-8'-
-(oxetan-2-yl)-2'H-spiro[cyclohexane-1,3'-imidazo[1,5-a]pyridine]-1',5'-di-
one (6, 100 mg, 0.16 mmol) is dissolved in trifluoroacetic acid (5
mL). The reaction is stirred at room temperature overnight. The
resulting mixture is concentrated and purified via column
chromatography to afford
8'-(oxetan-2-yl)-6'-(pyrimidin-4-ylamino)-2'H-spiro[cyclohexane-1,3'-imid-
azo[1,5-a]pyridine]-1',5'-dione (Cpd. No. 139).
Example 140
Synthesis of
8-chloro-3-methyl-6-(pyrimidin-4-ylamino)-3-vinyl-2,3-dihydroimidazo[1,5--
a]pyridine-1,5-dione (Cpd. No. 140)
##STR00316##
##STR00317##
[0655] Synthesis of
6-bromo-8-chloro-3-methyl-3-vinyl-2,3-dihydroimidazo[1,5-a]pyridine-1,5-d-
ione (3)
[0656] The synthesis of intermediate 3 is carried out as described
above using the general protocol of Procedure A.
Synthesis of
8-chloro-3-methyl-6-(pyrimidin-4-ylamino)-3-vinyl-2,3-dihydroimidazo[1,5--
a]pyridine-1,5-dione (Cpd. No. 140)
[0657] The synthesis of compound 140 is carried out as described
above using the general protocol of Procedure H.
Example 141
Synthesis of
8-chloro-3-methyl-3-(prop-1-yn-1-yl)-6-(pyrimidin-4-ylamino)-2,3-dihydroi-
midazo[1,5-a]pyridine-1,5-dione (Cpd. No. 141)
##STR00318##
##STR00319##
[0658] Synthesis of
6-bromo-8-chloro-3-methyl-3-(prop-1-yn-1-yl)-2,3-dihydroimidazo[1,5-a]pyr-
idine-1,5-dione (3)
[0659] The synthesis of intermediate 3 is carried out as described
above using the general protocol of Procedure A.
Synthesis of
8-chloro-3-methyl-3-(prop-1-yn-1-yl)-6-(pyrimidin-4-ylamino)-2,3-dihydroi-
midazo[1,5-a]pyridine-1,5-dione (Cpd. No. 141)
[0660] The synthesis of compound 141 is carried out as described
above using the general protocol of Procedure H.
Example 142
Synthesis of
4-08'-chloro-1',5'-dioxo-1',5'-dihydro-2'H-spiro[cyclohexane-1,3'-imidazo-
[1,5-a]pyridin]-6'-yl)amino)pyrimidine-5-carbonitrile (Cpd. No.
142)
##STR00320##
##STR00321##
[0661] Synthesis of
4-((8'-chloro-1',5'-dioxo-1',5'-dihydro-2'H-spiro[cyclohexane-1,3'-imidaz-
o[1,5-a]pyridin]-6'-yl)amino)pyrimidine-5-carbonitrile (Cpd. No.
142)
[0662] The synthesis of compound 142 was carried out as described
above using the general protocol of Procedure H. Yellow solid;
Yield: 0.25 g, 76%; MS (ESI) m/z 371.38 [M+1].sup.+; .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 10.48 (s, 1H), 9.06 (s, 1H), 9.03
(s, 1H), 8.98 (s, 1H), 8.59 (s, 1H), 2.93-2.87 (m, 2H), 1.93-1.88
(m, 2H), 1.75-1.54 (m, 5H), 1.27-1.23 (m, 1H).
Example 143
Synthesis of
8'-chloro-6'-((5-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-2'H-spir-
o[cyclohexane-1,3'-imidazo[1,5-a]pyridine]-1',5'-dione (Cpd. No.
143)
##STR00322##
##STR00323##
[0663] Synthesis of 5-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine
(3)
[0664] To a solution of 5-iodopyrimidin-4-amine (1, 0.5 g, 2.26
mmol) and
1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole
(2, 0.56 g, 2.71 mmol) in dioxane/water (15 mL, 9:1.5) in a vial,
was added cesium carbonate (1.84 g, 5.66 mmol) and the mixture was
degassed with argon for 15 min. To this mixture was added
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II),
complex with dichloromethane (0.09 g, 0.11 mmol) and then heated to
110.degree. C. for 16 h. TLC showed consumption of starting
material, cooled the reaction mixture to ambient temperature,
filtered the mass over celite bed, washed with dichloromethane (30
mL) followed by concentration of filtrate. The crude compound was
purified by flash column chromatography eluting with 3% methanol in
dichloromethane. The desired fractions were concentrated to dryness
to afforded as 5-(1-methylpyrazol-4-yl)pyrimidin-4-amine (3) as off
white solid; Yield: 0.2 g, 50%; MS (ESI) m/z 176.08 [M+1].sup.+;
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.28 (s, 1H), 8.13 (s,
1H), 8.01 (s, 1H), 7.70 (s, 1H), 6.61 (s, 2H), 3.87 (s, 3H).
Synthesis of
8'-chloro-6'-((5-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-2'H-spir-
o[cyclohexane-1,3'-imidazo[1,5-a]pyridine]-1',5'-dione (Cpd. No.
143)
[0665] The synthesis of compound 143 was carried out as described
above using the general protocol of Procedure H. Pale yellow solid;
Yield: 0.14 g, 36%; MS (ESI) m/z 426.44 [M+1].sup.+; .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 10.35 (s, 1H), 8.83 (s, 1H),
8.76-8.73 (s, 2H), 8.46 (s, 1H), 8.17 (s, 1H), 7.85 (s, 1H), 3.96
(s, 3H), 2.86 (m, 2H), 1.74-1.49 (m, 7H), 1.25 (m, 1H).
Example 144
Synthesis of
8'-chloro-6'-((5-ethynylpyrimidin-4-yl)amino)-2'H-spiro[cyclohexane-1,3'--
imidazo[1,5-a]pyridine]-1',5'-dione (Cpd. No. 144)
##STR00324##
##STR00325##
[0666] Synthesis of 5-((trimethylsilyl)ethynyl)pyrimidin-4-amine
(3)
[0667] 5-Iodopyrimidin-4-amine (1, 1 g, 4.52 mmol), copper(I)
iodide (172 mg, 0.90 mmol), ethynyl(trimethyl) silane (2, 0.67 g,
6.79 mmol), triphenylphosphine (119 mg, 0.45 mmol), triethylamine
(0.914 mg, 9.04 mmol) and palladium(II) chloride (80 mg, 0.45 mmol)
were taken in a flask and tetrahydrofuran was added followed by
degassing with argon for 5 minutes. The reaction mixture was
stirred at 40.degree. C. for 16 h. After completion, reaction
mixture was filtered over celite bed and resulting filtrate was
concentrated to afford 5-(2-trimethylsilylethynyl)pyrimidin-4-amine
(3) as a brown solid. Yield: 0.76 g, 88%; MS (ESI) m/z 192.1
[M+1].sup.+.
Synthesis of
8'-chloro-6'-((5-((trimethylsilyl)ethynyl)pyrimidin-4-yl)amino)-2'H-spiro-
[cyclohexane-1,3'-imidazo[1,5-a]pyridine]-1',5'-dione (5)
[0668] The synthesis of intermediate 5 was carried out as described
above using the general protocol of Procedure B. Yellow solid.
Yield: 0.30 g, 45%; MS (ESI) m/z 441.99 [M+1].sup.+; .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 10.40 (s, 1H), 9.06 (s, 1H), 8.88
(s, 1H), 8.67 (m, 2H), 5.80 (m, 1H), 2.94-2.89 (m, 2H), 1.74-1.57
(m, 7H), 1.23 (m, 1H), 0.34 (s, 9H).
Synthesis of
8'-chloro-6'-((5-ethynylpyrimidin-4-yl)amino)-2'H-spiro[cyclohexane-1,3'--
imidazo[1,5-a]pyridine]-1',5'-dione (Cpd. No. 144)
[0669] A flask was charged with
8'-chloro-6'-((5-((trimethylsilyl)ethynyl)pyrimidin-4-yl)amino)-2'H-spiro-
[cyclohexane-1,3'-imidazo[1,5-a]pyridine]-1',5'-dione (5, 300 mg,
0.67 mmol) and methanol (20 mL) followed by addition of potassium
carbonate (469 mg, 3.39 mmol) at room temperature and reaction
mixture was stirred for 16 h. After completion, solvent was
concentrated under reduced pressure and the resulting residue was
further washed with water followed by diethyl ether and pentane to
afford
8'-chloro-6'-((5-ethynylpyrimidin-4-yl)amino)-2'H-spiro[cyclohexane-1,3'--
imidazo[1,5-a]pyridine]-1',5'-dione (Cpd. No. 144) as yellow solid.
Yield: 100 mg, 40%; MS (ESI) m/z 370.09 [M+1].sup.+; .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 10.42 (s, 1H), 8.99 (s, 1H), 8.90
(s, 1H), 8.70 (s, 2H), 5.22 (s, 1H), 2.90 (brs, 2H), 1.73-1.64 (m,
2H), 1.61-1.56 (m, 3H), 1.56-1.53 (m, 2H), 1.27 (m, 1H).
Example 145
Synthesis of
6'-((1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)-8'-chloro-2'H-spiro
[cyclohexane-1,3'-imidazo[1,5-a]pyridine]-1',5'-dione (Cpd. No.
145)
##STR00326##
##STR00327##
[0670] Synthesis of
6'-((1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)-8'-chloro-2'H-spiro
[cyclohexane-1,3'-imidazo[1,5-a]pyridine]-1',5'-dione (Cpd. No.
145)
[0671] To a suspension of
6-bromo-8-chloro-spiro[2H-imidazo[1,5-a]pyridine-3,1'-cyclohexane]-1,5-di-
one (1, 0.5 g, 1.51 mmol), 1H-pyrazolo[3,4-d]pyrimidin-4-amine (2,
0.2 g, 1.51 mmol) in tert-butanol (20 mL) in a vial, potassium
phosphate (0.96 g, 4.54 mmol) was added and the reaction mixture
was degassed with argon for 15 min. To this mixture XantPhos (4 mg,
0.08 mmol) and Pd.sub.2(dba).sub.3 (7 mg, 0.08 mmol) was added and
the reaction mixture was further degassed with argon for 5 min. The
reaction mixture was heated at 90.degree. C. for 18 h. TLC showed
consumption of starting material, the reaction mixture was filtered
over celite bed and washed with dichloromethane followed by
concentration of the filtrate. The crude was stirred with methanol
(10 mL) and filtered. The resulting solid was further washed with
diethyl ether (20 mL) and dried under vacuum to afford
8-chloro-6-(1H-pyrazolo[3,4-d]pyrimidin-4-ylamino)spiro[2H-imidazo-
[1,5-a]pyridine-3,1'-cyclohexane]-1,5-dione (Cpd. No. 145). Yield:
0.037 g, 6%; MS (ESI) m/z 386.36 [M+1].sup.+; .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 10.39 (s, 1H), 9.55 (s, 1H), 8.91 (s, 1H),
8.61 (s, 2H), 2.97 (m, 2H), 1.76-1.56 (m, 7H), 1.23 (m, 1H).
Example 146
Synthesis of
8-chloro-6-(3H-triazolo[4,5-d]pyrimidin-7-ylamino)spiro[2H-imidazo[1,5-a]-
pyridine-3,1'-cyclohexane]-1,5-dione (Cpd. No. 146)
##STR00328##
##STR00329##
[0672] Synthesis of
2-methyl-N-(3H-triazolo[4,5-d]pyrimidin-7-yl)propanamide (3)
[0673] To a vial 3H-triazolo[4,5-d]pyrimidin-7-amine (1, 2.0 g,
14.69 mmol) was added in dimethylformamide (20 mL) followed by
addition of 2-methylpropanoyl 2-methylpropanoate (2, 6.97 g, 44.08
mmol). The reaction mixture was stirred at 160.degree. C. for 1 h.
After completion, the reaction was cooled to room temperature and
diluted with water (100 mL). The precipitated white solid was
filtered and dried under vacuum to offer
2-methyl-N-(3H-triazolo[4,5-d]pyrimidin-7-yl)propanamide (3) as
white solid. Yield: 2.5 g, 82%; MS (ESI) m/z 205.2 [M+1].sup.+;
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 15.75 (m, 2H), 11.57
(s, 1H), 8.80 (s, 1H), 2.94-2.97 (m, 1H), 1.20 (d, J=6.8 Hz,
6H).
Synthesis of
N-((2-(trimethylsilyl)ethoxy)methyl)-N-(3-((2-(trimethylsilyl)ethoxy)meth-
yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-yl)isobutyramide (4)
[0674] To a stirred solution of
2-methyl-N-(3H-triazolo[4,5-d]pyrimidin-7-yl)propanamide (3, 1.5 g,
7.27 mmol) in dimethylformamide (20 mL), sodium hydride (0.26 g,
10.91 mmol) was added portion wise in 10 min at 0.degree. C. The
above suspension was stirred for 10 min at 0.degree. C. and
2-(trimethylsilyl)ethoxymethyl chloride (1.82 g, 10.91 mmol) was
added at the same temperature under nitrogen. The reaction was
stirred at room temperature for 6 h. After completion, the reaction
mass was quenched with saturated aqueous solution of ammonium
chloride and crude was extracted with dichloromethane (2.times.50
mL). The organics were then separated, dried (magnesium sulfate)
and concentrated to dryness under vacuum and the crude was purified
by flash chromatography eluting with 5% ethyl acetate in hexane.
Concentration of the desired fractions provides
2-methyl-N-(2-trimethylsilylethoxy)-N-[3-(2-trimethylsilylethoxy)triazolo-
[4,5-d]pyrimidin-7-yl]propanamide (4) as transparent viscous oil.
Yield: 1.1 g, 44%; MS (ESI) m/z 467.42 [M+1].sup.+.
Synthesis of
N,3-bis((2-(trimethylsilyl)ethoxy)methyl)-3H-[1,2,3]triazolo[4,5-d]pyrimi-
din-7-amine (5)
[0675] The synthesis of intermediate 5 was carried out as described
above using the general protocol of Procedure I. Yellow solid;
Yield: 0.8 g, 94%; MS (ESI) m/z 397 [M+1].sup.+.
Synthesis of
8'-chloro-6'-(((2-(trimethylsilyl)ethoxy)methyl)(3-((2-(trimethylsilyl)et-
hoxy)methyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-yl)amino)-2'H-spiro[cycl-
ohexane-1,3'-imidazo[1,5-a]pyridine]-1,5'-dione (7)
[0676] The synthesis of intermediate 7 was carried out as described
above using the general protocol of Procedure H. Brown solid;
Yield: 0.3 g, crude.
Synthesis of
8-chloro-6-(3H-triazolo[4,5-d]pyrimidin-7-ylamino)spiro[2H-imidazo[1,5-a]-
pyridine-3,1'-cyclohexane]-1,5-dione (Cpd. No. 146)
[0677] To a stirred solution of
8-chloro-6-[2-trimethylsilylethoxymethyl-[3-(2-trimethylsilylethoxymethyl-
)triazolo[4,5-d]pyrimidin-7-yl]amino]spiro[2H-imidazo[1,5-a]pyridine-3,1'--
cyclohexane]-1,5-dione (7, 0.3 g, 0.46 mmol) in dichloromethane (15
mL), trifluoroacetic acid (5 mL, 4.63 mmol) was added drop wise at
0.degree. C. The reaction mass was stirred for overnight at room
temperature. After completion, reaction mass was concentrated and
co-evaporated with diethyl ether. The crude was then dissolved in
tetrahydrofuran/ethanol solution and potassium hydroxide (5 mL,
0.46 mmol) solution (3 M in water) was added and stirred the
mixture for 16 h. After completion of the reaction the aqueous
layer was separated and organic layer was dried over sodium
sulfate, filtered and concentrated to get crude. The crude was
washed with methanol and n-pentane and dried to afford
8-chloro-6-(3H-triazolo[4,5-d]pyrimidin-7-ylamino)spiro[2H-imidazo[1,5-a]-
pyridine-3,1'-cyclohexane]-1,5-dione (Cpd. No. 146) as brown solid.
Yield: 70 mg, 39%; MS (ESI) m/z 387.39 [M+1].sup.+; .sup.1H NMR:
(400 MHz, DMSO-d.sub.6) .delta. 10.45 (brs, 1H), 9.29 (s, 1H), 8.88
(s, 1H), 7.77 (s, 1H), 2.94 (t, J=2.32, 2H), 1.79-1.76 (m, 2H),
1.67-1.51 (m, 5H), 1.27-1.23 (m, 1H).
Example 147
Synthesis of
8-((6-aminopyrimidin-4-yl)amino)-10-methyl-2,3,4,5-tetrahydropyrido[1,2-a-
][1,4]diazepine-1,7-dione (Cpd. No. 147)
##STR00330##
##STR00331## ##STR00332##
[0678] Synthesis of
N-benzyl-5-bromo-N-(3-((tert-butyldimethylsilyl)oxy)propyl)-3-methyl-6-ox-
o-1,6-dihydropyridine-2-carboxamide (3)
[0679] To a stirred solution of
N-benzyl-3-((tert-butyldimethylsilyl)oxy)propan-1-amine (2, 3.0 g,
12.9 mmol) in dimethylformamide (50 mL),
5-bromo-3-methyl-6-oxo-1,6-dihydropyridine-2-carboxylic acid (1,
3.6 g, 12.9 mmol), HBTU (6.4 g, 16.9 mmol) and
N,N-diisopropylethylamine (2.2 g, 16.9 mmol) were added in a vial
at room temperature and stirred the mixture for 16 h. TLC showed
completion of reaction, the reaction mixture was quenched with
aqueous sodium bicarbonate solution and extracted with ethyl
acetate (250 mL). The organic layer was dried over sodium sulfate
and solvent was removed under reduced pressure to afford
N-benzyl-5-bromo-N-(3-((tert-butyldimethylsilyl)oxy)propyl)-3-methyl-6-ox-
o-1, 6-dihydropyridine-2-carboxamide (3) as yellow liquid. Yield:
3.0 g, 47%; MS (ESI) m/z 495.24 [M-1].sup.-.
Synthesis of
N-benzyl-5-bromo-N-(3-hydroxypropyl)-3-methyl-6-oxo-1,6-dihydropyridine-2-
-carboxamide (4)
[0680] To a stirred solution of
N-benzyl-5-bromo-N-(3-((tert-butyldimethylsilyl)oxy)
propyl)-3-methyl-6-oxo-1,6-dihydropyridine-2-carboxamide (3, 3.0 g,
6.0 mmol) in dioxane (20 mL), hydrogenchloride in dioxane (20 mL)
was added at room temperature and the mixture was stirred for 16 h.
After completion, the solvent was removed and the reaction was
basified with aqueous sodium bicarbonate solution and extracted
with 5% methanol/dichloromethane (3.times.200 mL). The organic
layer was dried over sodium sulfate and solvent was removed under
reduced pressure to get
N-benzyl-5-bromo-N-(3-hydroxypropyl)-3-methyl-6-oxo-1,
6-dihydropyridine-2-carboxamide (4) as brown liquid. Yield: 2.2 g,
95%; MS (ESI) m/z 381.22 [M-1].sup.-.
Synthesis of 2-benzyl-8-bromo-10-methyl-2, 3, 4, 5-tetrahydropyrido
[1, 2-a][1,4]diazepine-1, 7-dione (5)
[0681] To a stirred solution of
N-benzyl-5-bromo-N-(3-hydroxypropyl)-3-methyl-6-oxo-1,6-dihydropyridine-2-
-carboxamide (4, 1.5 g, 3.9 mmol) in tetrahydrofuran (30 mL),
triphenylphosphine (1.5 g, 5.9 mmol) and diisopropyl
azodicarboxylate (1.2 g, 5.9 mmol) were added at 0.degree. C. The
reaction was stirred at room temperature for 16 h. After
completion, solvent was removed under reduced pressure and crude
was purified by flash chromatography eluting with 40% ethyl acetate
in hexane. Appropriate fractions were concentrated under reduced
pressure to afford
2-benzyl-8-bromo-10-methyl-2,3,4,5-tetrahydropyrido[1,2-a][1,4]diazepine--
1,7-dione (5) as yellow solid. Yield: 0.9 g, 64%; MS (ESI) m/z
361.18 [M+1].sup.+.
Synthesis of
8-((6-(di-(tert-butoxycarbonyl)-amino)pyrimidin-4-yl)amino)-2-benzyl-10-m-
ethyl-2,3,4,5-tetrahydropyrido[1,2-a][1,4]diazepine-1,7-dione
(7)
[0682] The synthesis of intermediate 7 was carried out as described
above using the general protocol of Procedure H. Yellow solid;
Yield: 0.9 g, 69%; MS (ESI) m/z 591.66 [M+1].sup.+.
Synthesis of
8-((6-aminopyrimidin-4-yl)amino)-2-benzyl-10-methyl-2,3,4,5-tetrahydropyr-
ido[1,2-a][1,4]diazepine-1,7-dione (8)
[0683] The synthesis of intermediate 8 was carried out as described
above using the general protocol of Procedure F. Yellow solid;
Yield: 0.59 g, 99%; MS (ESI) m/z 391.32 [M+1].sup.+.
Synthesis of
8-((6-aminopyrimidin-4-yl)amino)-10-methyl-2,3,4,5-tetrahydropyrido[1,2-a-
][1,4]diazepine-1,7-dione (Cpd. No. 147)
[0684] A vial was charged with
8-((6-aminopyrimidin-4-yl)amino)-2-benzyl-10-methyl-2,3,4,5-tetrahydropyr-
ido[1,2-a][1,4]diazepine-1,7-dione (8, 0.3 g, 76.9 mmol) and
trifluoroacetic acid (7.0 mL) was added and the reaction mixture
was heated under microwave at 150.degree. C. for 20 min. TLC showed
completion of the reaction and the mixture was cooled to ambient
temperature and this was then basified with aqueous sodium
bicarbonate solution and extracted with 5% methanol/dichloromethane
(3.times.200 mL). The organic layer was dried over sodium sulfate
and solvent was removed under reduced pressure to afford
8-((6-aminopyrimidin-4-yl)amino)-10-methyl-2,3,4,5-tetrahydropyrido[1,2-a-
][1,4]diazepine-1,7-dione (Cpd. No. 147) as a brown solid. Yield:
0.06 g, 26%; MS (ESI) m/z 301.15 [M+1].sup.+; .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 8.51 (s, 1H), 8.44 (m, 2H), 8.15 (s, 1H),
6.52 (m, 2H), 6.13 (s 1H), 5.05 (m, 1H), 3.17 (m, 2H), 2.95 (m,
1H), 2.13 (s, 3H), 1.87 (m, 2H).
Example 148
Synthesis of
3,3-di-tert-butyl-8-chloro-6-(pyrimidin-4-ylamino)-2,3-dihydroimidazo[1,5-
-a]pyridine-1,5-dione (Cpd. No. 148)
##STR00333##
##STR00334##
[0685] Synthesis of
6-bromo-3,3-di-tert-butyl-8-chloro-2,3-dihydroimidazo[1,5-a]pyridine-1,5--
dione (3)
[0686] The synthesis of intermediate 3 is carried out as described
above using the general protocol of Procedure A.
Synthesis of
3,3-di-tert-butyl-8-chloro-6-(pyrimidin-4-ylamino)-2,3-dihydroimidazo[1,5-
-a]pyridine-1,5-dione (Cpd. No. 148)
[0687] The synthesis of compound 148 is carried out as described
above using the general protocol of Procedure H.
Example 149
Synthesis of
8-chloro-6-(pyrimidin-4-ylamino)-3,3-di(thiophen-2-yl)-2,3-dihydroimidazo-
[1,5-a]pyridine-1,5-dione (Cpd. No. 149)
##STR00335##
##STR00336##
[0688] Synthesis of
6-bromo-8-chloro-3,3-di(thiophen-2-yl)-2,3-dihydroimidazo[1,5-a]pyridine--
1,5-dione (3)
[0689] The synthesis of intermediate 3 is carried out as described
above using the general protocol of Procedure A.
Synthesis of
8-chloro-6-(pyrimidin-4-ylamino)-3,3-di(thiophen-2-yl)-2,3-dihydroimidazo-
[1,5-a]pyridine-1,5-dione (Cpd. No. 149)
[0690] The synthesis of compound 149 is carried out as described
above using the general protocol of Procedure H.
Example 150
Synthesis of
8-chloro-6-(pyrimidin-4-ylamino)-3,3-di(thiophen-3-yl)-2,3-dihydroimidazo-
[1,5-a]pyridine-1,5-dione (Cpd. No. 150)
##STR00337##
##STR00338##
[0691] Synthesis of
6-bromo-8-chloro-3,3-di(thiophen-3-yl)-2,3-dihydroimidazo[1,5-a]pyridine--
1,5-dione (3)
[0692] The synthesis of intermediate 3 is carried out as described
above using the general protocol of Procedure A.
Synthesis of
8-chloro-6-(pyrimidin-4-ylamino)-3,3-di(thiophen-3-yl)-2,3-dihydroimidazo-
[1,5-a]pyridine-1,5-dione (Cpd. No. 150)
[0693] The synthesis of compound 150 is carried out as described
above using the general protocol of Procedure H.
Example 151
Synthesis of
8-chloro-3,3-dipropyl-6-(pyrimidin-4-ylamino)-2H-imidazo[1,5-a]pyridine-1-
,5-dione (Cpd. No. 151)
##STR00339##
##STR00340##
[0694] Synthesis of 6-bromo-8-chloro-3, 3-dipropyl-2,
3-dihydroimidazo[1,5-a]pyridine-1,5-dione (3)
[0695] The synthesis of intermediate 3 was carried out as described
above using the general protocol of Procedure A. Off white solid;
Yield: 0.23 g, 66%; MS (ESI) m/z 347.01 [M+1].sup.+.
Synthesis of
8-chloro-3,3-dipropyl-6-(pyrimidin-4-ylamino)-2H-imidazo[1,5-a]pyridine-1-
,5-dione (Cpd. No. 151)
[0696] The synthesis of compound 151 was carried out as described
above using the general protocol of Procedure H. Off white solid;
Yield: 0.14 g, 57%; MS (ESI) m/z 362.13 [M+1].sup.+; .sup.1H-NMR
(400 MHz, DMSO-d.sub.6) .delta. 9.64 (s, 1H), 9.59 (s, 1H), 8.85
(s, 1H), 8.81 (s, 1H), 8.44 (d, J=5.88 Hz, 1H), 7.42 (d, J=5.88,
1H), 2.54 (m, 2H), 1.86 (t, J=10.9 Hz, 2H), 1.15 (m, 2H), 0.82 (m,
8H).
Example 152
Synthesis of
3,3-bis(2-aminoethyl)-8-chloro-6-(pyrimidin-4-ylamino)-2,3-dihydroimidazo-
[1,5-a]pyridine-1,5-dione (Cpd. No. 152)
##STR00341##
##STR00342##
[0697] Synthesis of
2,2'-((6-bromo-8-chloro-1,5-dioxo-1,2,3,5-tetrahydroimidazo[1,5-a]pyridin-
e-3,3-diyl)bis(ethane-2,1-diyl))bis(isoindoline-1,3-dione) (3)
[0698] The synthesis of intermediate 3 is carried out as described
above using the general protocol of Procedure A.
Synthesis of
2,2'-((8-chloro-1,5-dioxo-6-(pyrimidin-4-ylamino)-1,2,3,5-tetrahydroimida-
zo[1,5-a]pyridine-3, 3-diyl)bis(ethane-2,1-di
yl))bis(isoindoline-1,3-dione) (5)
[0699] The synthesis of intermediate 5 is carried out as described
above using the general protocol of Procedure H.
Synthesis of
3,3-bis(2-aminoethyl)-8-chloro-6-(pyrimidin-4-ylamino)-2,3-dihydroimidazo-
[1,5-a]pyridine-1,5-dione (Cpd. No. 152)
[0700] The synthesis of compound 152 is carried out as described
above using the general protocol of Procedure C.
Example 153
Synthesis of
8-chloro-3,3-bis(2-hydroxyethyl)-6-(pyrimidin-4-ylamino)-2,3-dihydroimida-
zo[1,5-a]pyridine-1,5-dione (Cpd. No. 153)
##STR00343##
##STR00344##
[0701] Synthesis of dimethyl
2,2'-(6-bromo-8-chloro-1,5-dioxo-1,2,3,5-tetrahydroimidazo[1,5-a]pyridine-
-3,3-diyl)diacetate (3)
[0702] The synthesis of intermediate 3 was carried out as described
above using the general protocol of Procedure A. Off white solid;
Yield: 0.65 g, 27%; MS (ESI) m/z 407.18 [M-1].sup.-.
Synthesis of dimethyl
2,2'-(8-chloro-1,5-dioxo-6-(pyrimidin-4-ylamino)-1,2,3,5-tetrahydroimidaz-
o[1,5-a]pyridine-3,3-diyl)diacetate (5)
[0703] The synthesis of intermediate 5 was carried out as described
above using the general protocol of Procedure H. Off white solid;
Yield: 0.34 g, 51%; MS (ESI) m/z 422.49 [M+1].sup.+.
Synthesis of
8-chloro-3,3-bis(2-hydroxyethyl)-6-(pyrimidin-4-ylamino)-2,
3-dihydroimidazo[1,5-a]pyridine-1,5-dione (Cpd. No. 153)
[0704] To a slurry of lithium aluminum hydride (71 mg, 1.9 mmol) in
tetrahydrofuran (3 mL) at 0.degree. C. a solution of dimethyl
2,2'-(8-chloro-1,5-dioxo-6-(pyrimidin-4-ylamino)-1,2,3,5-tetrahydroimidaz-
o[1,5-a]pyridine-3,3-diyl)diacetate (5, 280 mg, 0.66 mmol) in
tetrahydrofuran (2 mL) was added slowly. After consumption of
starting material the reaction mixture was quenched with 10% sodium
hydroxide solution (1 mL), diluted with 10 ml of ethyl acetate. The
organic layer was separated and dried over anhydrous sodium sulfate
and concentrated under reduce pressure to afford the residue. The
residue was purified prep HPLC to afford
8-chloro-3,3-bis(2-hydroxyethyl)-6-(pyrimidin-4-ylamino)-2,3-dihydroimida-
zo[1,5-a]pyridine-1,5-dione (Cpd. No. 153) as yellow solid. Yield:
0.047 g, 19%; MS (ESI) m/z 366.09 [M+1].sup.+; .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. 9.58-9.57 (brs, 1H), 8.83 (s, 1H), 8.75
(s, 1H), 8.42 (d, J=5.6 Hz, 1H), 7.44-7.42 (d, J=5.6 Hz, 1H), 4.44
(brs, 2H), 3.34-3.26 (m, 4H), 2.79-3.73 (m, 2H), 2.11-2.08 (m,
2H).
Example 154
Synthesis of
3,3-bis(aminomethyl)-8-chloro-6-(pyrimidin-4-ylamino)-2,3-dihydroimidazo[-
1,5-a]pyridine-1,5-dione (Cpd. No. 154)
##STR00345##
##STR00346##
[0705] Synthesis of
2,2'-((6-bromo-8-chloro-1,5-dioxo-1,2,3,5-tetrahydroimidazo[1,5-a]pyridin-
e-3,3-diyl)bis(methylene))bis(isoindoline-1,3-dione) (3)
[0706] The synthesis of intermediate 3 is carried out as described
above using the general protocol of Procedure A.
Synthesis of
2,2'-((8-chloro-1,5-dioxo-6-(pyrimidin-4-ylamino)-1,2,3,5-tetrahydroimida-
zo[1,5-a]pyridine-3,
3-diyl)bis(methylene))bis(isoindoline-1,3-dione) (5)
[0707] The synthesis of intermediate 5 is carried out as described
above using the general protocol of Procedure H.
Synthesis of
3,3-bis(aminomethyl)-8-chloro-6-(pyrimidin-4-ylamino)-2,3-dihydroimidazo[-
1,5-a]pyridine-1,5-dione (Cpd. No. 154)
[0708] The synthesis of compound 154 is carried out as described
above using the general protocol of Procedure C.
Example 155
Synthesis of
8-chloro-1'-(2-hydroxyethyl)-6-(pyrimidin-4-ylamino)-2H-spiro[imidazo[1,5-
-a]pyridine-3,4'-piperidine]-1,5-dione (Cpd. No. 155)
##STR00347##
##STR00348##
[0709] Synthesis of
6-bromo-8-chloro-spiro[2H-imidazo[1,5-a]pyridine-3,4'-piperidine]-1,5-dio-
ne hydrochloride (2)
[0710] The synthesis of intermediate 2 was carried out as described
above using the general protocol of Procedure F. Off white solid;
Yield: 3.5 g, 95%; MS (ESI) m/z 332.1 [M+1].sup.+; .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. 10.89 (s, 1H), 9.45 (brs, 1H), 8.67
(brs, 1H), 8.30 (s, 1H), 3.70-3.36 (m, 4H), 2.59-2.57 (m, 2H),
1.89-1.85 (m, 2H).
Synthesis of
6-bromo-1'-[2-[tert-butyl(dimethyl)sily]oxyethyl]-8-chloro-spiro[2H-imida-
zo[1,5-a]pyridine-3,4'-piperidine]-1,5-dione (4)
[0711] A flask was charged with
6-bromo-8-chloro-spiro[2H-imidazo[1,5-a]pyridine-3,4'-piperidine]-1,5-dio-
ne hydrochloride (2, 0.5 g, 1.35 mmol) and acetonitrile (15 mL) was
added. The reaction mass was cooled to 0.degree. C. and potassium
carbonate (281 mg, 2.03 mmol) and
(2-bromoethoxy)(tert-butyl)dimethylsilane (3, 388 mg, 1.62 mmol)
were added and reaction mass was heated at 80.degree. C. for 2
days. After completion, the solvent was removed to get the crude
compound. The crude compound was purified by flash column with 0.2%
methanol in dichloromethane. The desired fractions were
concentrated to give
6-bromo-1'-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-8-chloro-spiro[2H-
-imidazo[1,5-a]pyridine-3,4'-piperidine]-1,5-dione (4) as a brown
solid. Yield: 0.3 g, 45%; MS (ESI) m/z 373.01 [M+1].sup.+; .sup.1H
NMR (400 MHz, DMSO-d.sub.6) .delta. 10.62 (s, 1H), 8.25 (s, 1H),
3.69-3.63 (m, 4H), 3.10-2.83 (m, 4H), 1.52 (m, 2H), 1.04 (s, 9H),
0.058 (s, 6H).
Synthesis of
1'-[2-[tert-butyl(dimethyl)sily]oxyethyl]-8-chloro-6-(pyrimidin-4-ylamino-
)spiro[2H-imidazo[1,5-a]pyridine-3,4'-piperidine]-1,5-dione (6)
[0712] The synthesis of intermediate 6 was carried out as described
above using the general protocol of Procedure H. Yellow solid;
Yield: 0.15 g, 49%; MS (ESI) m/z 505 [M+1].sup.+; .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. 10.37 (s, 1H), 9.63-9.60 (m, 1H),
8.84-8.75 (m, 2H), 8.43-8.36 (d, J=5.8 Hz, 1H), 7.47 (d, J=5.8 Hz,
1H), 3.72-3.70 (m, 2H), 3.26-3.22 (m, 4H), 2.98-2.90 (m, 4H),
1.53-1.46 (m, 2H), 1.33-1.29 (m, 2H), 0.95 (s, 9H), 0.058 (s,
6H).
Synthesis of
8-chloro-1'-(2-hydroxyethyl)-6-(pyrimidin-4-ylamino)spiro[2H-imidazo[1,5--
a]pyridine-3,4'-piperidine]-1,5-dione (Cpd. No. 155)
[0713] The synthesis of compound 155 was carried out as described
above using the general protocol of Procedure F. Yellow solid;
Yield: 0.035 g, 49%; MS (ESI) m/z 391.34 [M+1].sup.+; .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 10.50 (s, 1H), 9.59 (m, 1H), 8.84
(d, J=16.48 Hz, 2H), 8.43-8.36 (d, J=5.8 Hz, 1H), 7.47 (d, J=5.8
Hz, 1H), 4.43 (brs, 2H), 3.53 (brs, 2H), 3.21-3.16 (m, 2H),
2.98-2.90 (m, 2H), 2.46-2.41 (m, 2H), 1.48-1.46 (m, 2H).
Example 156
Synthesis of
8-chloro-1'-(2,2-difluoroethyl)-6-(pyrimidin-4-ylamino)spiro[2H-imidazo[1-
,5-a]pyridine-3,4'-piperidine]-1,5-dione (Cpd. No. 156)
##STR00349##
##STR00350##
[0714] Synthesis of
6-bromo-8-chloro-1'-(2,2-difluoroethyl)spiro[2H-imidazo[1,5-a]pyridine-3,-
4'-piperidine]-1,5-dione (3)
[0715] A flask was charged with
6-bromo-8-chloro-spiro[2H-imidazo[1,5-a]pyridine-3,4'-piperidine]-1,5-dio-
ne hydrochloride (1, 0.5 g, 1.35 mmol) and acetonitrile (15 mL) was
added. The reaction was cooled to 0.degree. C. and
N,N-diisopropylethylamine (1.17 mL, 6.77 mmol) was added drop wise
followed by addition of 2-bromo-1,1-difluoro-ethane (2, 589 mg,
4.06 mmol). The reaction was stirred at 60-110.degree. C. for 48 h.
After completion, the solvent was removed under reduced pressure to
get the crude. The crude was purified by flash column using 1-3%
methanol in dichloromethane. The desired fractions were
concentrated to get
6-bromo-8-chloro-1'-(2,2-difluoroethyl)spiro[2H-imidazo[1,5-a]pyridine-3,-
4'-piperidine]-1,5-dione (3) as brown solid. Yield: 0.27 g, 50%; MS
(ESI) m/z 396.11 [M+1].sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. 10.66 (s, 1H), 8.25 (s, 1H), 6.29 (t, J=55.68 Hz, 1H),
3.12-3.06 (m, 2H), 2.84-2.79 (m, 2H), 2.66-2.60 (m, 2H) 1.49-1.46
(m, 2H).
Synthesis of
8-chloro-1'-(2,2-difluoroethyl)-6-(pyrimidin-4-ylamino)spiro[2H-imidazo[1-
,5-a]pyridine-3,4'-piperidine]-1,5-dione (Cpd. No. 156)
[0716] The synthesis of compound 156 was carried out as described
above using the general protocol of Procedure H. Yellow solid;
Yield: 0.13 g, 50%; MS (ESI) m/z 411.38 [M+1].sup.+; .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 10.39 (s, 1H), 9.60 (s, 1H), 8.84
(s, 1H), 8.80 (s, 1H), 8.43-8.36 (d, J=6.28 Hz, 1H), 7.47 (d, J=5.8
Hz, 1H), 6.32 (t, J=56.0 Hz, 1H), 3.26-3.22 (m, 2H), 2.98-2.90 (m,
2H), 2.88-2.79 (m, 2H), 2.70-2.64 (m, 2H), 1.51-1.48 (m, 2H).
Example 157
Synthesis of
8-chloro-6-(pyrimidin-4-ylamino)-1'-(2,2,2-trifluoroethyl)-2H-spiro[imida-
zo[1,5-a]pyridine-3,4'-piperidine]-1,5-dione (Cpd. No. 157)
##STR00351##
##STR00352##
[0717] Synthesis of
6-bromo-8-chloro-1'-(2,2,2-trifluoroethyl)-2H-spiro[imidazo[1,5-a]pyridin-
e-3,4'-piperidine]-1,5-dione (3)
[0718] The synthesis of intermediate 3 was carried out as described
above using the general protocol of Procedure A. Off White solid;
Yield: 1.1 g, 50%; MS (ESI) m/z 414.28 [M-1].sup.-.
Synthesis of
8-chloro-6-(pyrimidin-4-ylamino)-1'-(2,2,2-trifluoroethyl)-2H-spiro[imida-
zo[1,5-a]pyridine-3,4'-piperidine]-1,5-dione (Cpd. No. 157)
[0719] The synthesis of compound 157 was carried out as described
above using the general protocol of Procedure B. Yellow solid;
Yield: 0.21 g, 41%; MS (ESI) m/z 429.24 [M+1].sup.+; .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 10.44 (s, 1H), 9.61 (s, 1H),
8.84-8.80 (m, 2H), 8.44-8.43 (m, 1H), 7.46-7.44 (m, 1H), 3.28-3.17
(m, 4H), 2.97-2.95 (m, 2H), 2.86-2.79 (m, 2H), 1.51-1.48 (d,
2H).
Example 158
Synthesis of
8'-chloro-8-methyl-6'-(pyrimidin-4-ylamino)-2'H-8-azaspiro[bicyclo[3.2.1]-
octane-3,3'-imidazo[1,5-a]pyridine]-1',5'-dione (Cpd. No. 158)
##STR00353##
##STR00354##
[0720] Synthesis of
6'-bromo-8'-chloro-8-methyl-2'H-8-azaspiro[bicyclo[3.2.1]octane-3,3'-imid-
azo[1,5-a]pyridine]-1',5'-dione (3)
[0721] The synthesis of intermediate 3 was carried out as described
above using the general protocol of Procedure A. Brown solid;
Yield: 0.15 g, 10%; MS (ESI) m/z 372.21 [M+1].sup.+.
Synthesis of
8'-chloro-8-methyl-6'-(pyrimidin-4-ylamino)-2'H-8-azaspiro[bicyclo[3.2.1]-
octane-3,3'-imidazo[1,5-a]pyridine]-1',5'-dione (Cpd. No. 158)
[0722] The synthesis of compound 158 was carried out as described
above using the general protocol of Procedure B. Yellow solid;
Yield: 0.029 g, 20%; MS (ESI) m/z 387.35 [M+1].sup.+; .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 9.64 (s, 1H), 9.53 (s, 1H), 8.84
(s, 1H), 8.80 (s, 1H), 8.43 (d, J=5.88 Hz, 1H), 7.46 (d, J=5.84 Hz,
1H), 3.23 (m, 4H), 2.59 (s, 3H), 1.94 (s, 4H). 1.40 (d, J=12.8 Hz,
2H).
Example 159
Synthesis of
8'-chloro-6'-(pyrimidin-4-ylamino)-2'H-8-azaspiro[bicyclo[3.2.1]octane-3,-
3'-imidazo[1,5-a]pyridine]-1',5'-dione (Cpd. No. 159)
##STR00355##
##STR00356##
[0723] Synthesis of tert-butyl
6'-bromo-8'-chloro-1',5'-dioxo-1',5'-dihydro-2'H-8-azaspiro[bicyclo[3.2.1-
]octane-3,3'-imidazo[1,5-a]pyridine]-8-carboxylate (3)
[0724] The synthesis of intermediate 3 is carried out as described
above using the general protocol of Procedure E.
Synthesis of tert-butyl
8'-chloro-1',5'-dioxo-6'-(pyrimidin-4-ylamino)-1',5'-dihydro-2'H-8-azaspi-
ro[bicyclo[3.2.1]octane-3,3'-imidazo[1,5-a]pyridine]-8-carboxylate
(5)
[0725] The synthesis of intermediate 5 is carried out as described
above using the general protocol of Procedure H.
Synthesis of
8'-chloro-6'-(pyrimidin-4-ylamino)-2'H-8-azaspiro[bicyclo[3.2.1]octane-3,-
3'-imidazo[1,5-a]pyridine]-1',5'-dione (Cpd. No. 159)
[0726] The synthesis of compound 159 is carried out as described
above using the general protocol of Procedure F.
Example 160
Synthesis of
2-(8-chloro-1,5-dioxo-6-(pyrimidin-4-ylamino)-1,5-dihydro-2H-spiro[imidaz-
o[1,5-a]pyridine-3,4'-piperidin]-1'-yl)acetonitrile (Cpd. No.
160)
##STR00357##
##STR00358##
[0727] Synthesis of
2-(6-bromo-8-chloro-1,5-dioxo-1,5-dihydro-2H-spiro[imidazo[1,5-a]pyridine-
-3,4'-piperidin]-1'-yl)acetonitrile (3)
[0728] A flask was charges with
6-bromo-8-chloro-spiro[2H-imidazo[1,5-a]pyridine-3,4'-piperidine]-1,5-dio-
ne hydrochloride (1, 0.5 g, 1.35 mmol) and acetonitrile (15 mL) was
added. The reaction mass was cooled to 0.degree. C. and potassium
carbonate (281 mg, 2.03 mmol) was added followed by addition of
2-bromoacetonitrile (2, 218 mg, 1.63 mmol). The reaction mass was
stirred at room temperature for 10 h. After completion, the solvent
was removed under reduced pressure to get the crude. The crude was
purified by Biotage snap using 1-3% methanol in dichloromethane.
The desired fractions were concentrated to get
3-(6-bromo-8-chloro-1,5-dioxo-spiro[2H-imidazo[1,5-a]pyridine-3,4'-piperi-
dine]-1'-yl)propanenitrile (3) as brown solid. Yield: 0.42 g, 83%;
MS (ESI) m/z 373.18 [M+1].sup.+; .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 10.83 (s, 1H), 8.25 (s, 1H), 3.75 (s, 2H),
3.15-3.10 (m, 2H), 2.87-2.72 (m, 2H), 2.66-2.60 (m, 2H) 1.57-1.54
(m, 2H).
Synthesis of
2-[8-chloro-1,5-dioxo-6-(pyrimidin-4-ylamino)spiro[2H-imidazo[1,5-a]pyrid-
ine-3,4'-piperidine]-1'-yl]acetonitrile (Cpd. No. 160)
[0729] The synthesis of compound 160 was carried out as described
above using the general protocol of Procedure H. Yellow solid;
Yield: 0.2 g, 49%; MS (ESI) m/z 385.97 [M+1].sup.+; .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 10.50 (s, 1H), 9.62 (s, 1H), 8.84
(s, 1H), 8.80 (s, 1H), 8.43-8.36 (d, J=6.28 Hz, 1H), 7.47 (d, J=5.8
Hz, 1H), 3.75 (s, 2H), 3.26-3.22 (m, 2H), 2.98-2.90 (m, 2H),
2.67-2.61 (m, 2H), 1.60-1.57 (m, 2H).
Example 161
Synthesis of
8-chloro-1'-(pyrimidin-4-yl)-6-(pyrimidin-4-ylamino)-2H-spiro[imidazo[1,5-
-a]pyridine-3,4'-piperidine]-1,5-dione (Cpd. No. 161)
##STR00359##
##STR00360##
[0730] Synthesis of
6-bromo-8-chloro-1'-(pyrimidin-4-yl)-2H-spiro[imidazo[1,5-a]pyridine-3,4'-
-piperidine]-1,5-dione (3)
[0731] The synthesis of intermediate 3 was carried out as described
above using the general protocol of Procedure A. Yellow solid.
Yield: 0.1 g, 61%; MS (ESI) m/z 410.02 [M+1].sup.+.
Synthesis of
8-chloro-1'-(pyrimidin-4-yl)-6-(pyrimidin-4-ylamino)-2H-spiro[imidazo[1,5-
-a]pyridine-3,4'-piperidine]-1,5-dione (Cpd. No. 161)
[0732] The synthesis of compound 161 was carried out as described
above using the general protocol of Procedure B. Yellow solid.
Yield: 0.06 g, 23%; MS (ESI) m/z 425.34 [M+1].sup.+; .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 10.65 (s, 1H), 9.59 (s, 1H), 8.83
(s, 1H), 8.79 (s, 1H), 8.56 (s, 1H), 8.41 (d, J=5.84 Hz, 1H), 8.25
(d, J=6.08 Hz, 1H), 7.39 (d, J=5.72 Hz, 1H), 7.00 (d, J=6.01 Hz,
1H), 4.53 (brs, 2H), 3.28 (m, 2H), 3.05 (m, 2H), 1.68 (d, J=12.6
Hz, 1H).
Example 162
Synthesis of
8-chloro-4'-(methylamino)-6-(pyrimidin-4-ylamino)spiro[2H-imidazo[1,5-a]p-
yridine-3,1'-cyclohexane]-1,5-dione hydrochloride (Cpd. No.
162)
##STR00361##
##STR00362##
[0733] Synthesis of
6'-bromo-4'-chloro-4-(methylamino)spiro[cyclohexane-1,1'-isoindole]-3',7'-
(2'H,7a'H)-dione (3)
[0734] The synthesis of intermediate 3 was carried out as described
above using the general protocol of Procedure A. Yield: 0.72 g,
crude; MS (ESI) m/z 359.65 [M-1].sup.-.
Synthesis of tert-butyl
N-(6-bromo-8-chloro-1,5-dioxo-spiro[2H-imidazo[1,5-a]pyridine-3,4'-cycloh-
exane]-1'-yl)-N-methyl-carbamate (4)
[0735] To a mixture of
6-bromo-8-chloro-4'-(methylamino)spiro[2H-imidazo[1,5-a]pyridine-3,1'-cyc-
lohexane]-1,5-dione (3, 0.72 g, 1.99 mmol) in 1,4-dioxane (10 mL)
and water (10 mL), potassium hydroxide (0.56 g, 9.94 mmol) was
added followed by addition of tert-butoxycarbonyl tert-butyl
carbonate (651 mg, 2.98 mmol) and stirred the mixture at room
temperature for 24 h. On completion of reaction, the resulting
mixture was filtered. The precipitate was dissolved it in 10%
methanol in dichloromethane. Organic layer was washed with water
and brine, dried over anhydrous sodium sulfate, filtered and
concentrated under reduced pressure to get tert-butyl
N-(6-bromo-8-chloro-1,5-dioxo-spiro[2H-imidazo[1,5-c]pyridine-3,4'-cycloh-
exane]-1'-yl)-N-methyl-carbamate (4) as white solid. Yield: 0.9 g,
98%; .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 10.76 (s, 1H),
8.26 (s, 1H), 4.00-3.97 (m, 1H), 2.98 (brs, 2H), 2.73 (s, 3H),
1.98-1.81 (m, 2H), 1.73-1.60 (m, 4H), 1.41 (s, 9H).
Synthesis of tert-butyl
N-[8-chloro-1,5-dioxo-6-(pyrimidin-4-ylamino)spiro[2H-imidazo[1,5-a]pyrid-
ine-3,4'-cyclohexane]-1'-yl]-N-methyl-carbamate (6)
[0736] The synthesis of intermediate 6 was carried out as described
above using the general protocol of Procedure H. Off white solid;
Yield: 0.11 g, 21%; MS (ESI) m/z 475.31 [M+1].sup.+; .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 10.51 (s, 1H), 9.67 (s, 1H), 8.84
(s, 1H), 8.80 (s, 1H), 8.44 (d, J=5.6, 1H), 7.46 (s, 1H), 3.94-3.87
(m, 1H), 3.12-3.06 (m, 2H) 2.75 (s, 3H), 1.89-1.85 (m, 3H),
1.66-1.64 (m, 4H), 1.41 (s, 3H).
Synthesis of
8-chloro-4'-(methylamino)-6-(pyrimidin-4-ylamino)spiro[2H-imidazo[1,5-a]p-
yridine-3,1'-cyclohexane]-1,5-dione hydrochloride (Cpd. No.
162)
[0737] The synthesis of compound 162 was carried out as described
above using the general protocol of Procedure F. Yellow solid;
Yield: 0.060 g, 69%; MS (ESI) m/z 375.26 [M+1].sup.+; .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 9.07 (s, 1H), 8.60 (s, 1H), 8.46
(d, J=6.8 Hz, 1H), 7.58 (d, J=6.0 Hz, 1H), 3.16-3.13 (m, 1H),
3.04-2.98 (m, 2H), 2.57 (s, 3H), 2.13-2.10 (m, 2H), 1.72-1.66 (m,
4H).
Example 163
Synthesis of
1'-acetyl-8-chloro-6-(pyrimidin-4-ylamino)-2H-spiro[imidazo[1,5-a]pyridin-
e-3, 4'-piperidine]-1,5-dione (Cpd. No. 163)
##STR00363##
##STR00364##
[0738] Synthesis of
1'-acetyl-6-bromo-8-chloro-2H-spiro[imidazo[1,5-a]pyridine-3,4'-piperidin-
e]-1,5-dione (3)
[0739] The synthesis of intermediate 3 was carried out as described
above using the general protocol of Procedure A. Off white solid;
Yield: 0.60 g, 81%; MS (ESI) m/z 375.41 [M+1].sup.+.
Synthesis
1'-acetyl-8-chloro-6-(pyrimidin-4-ylamino)-2H-spiro[imidazo[1,5--
a]pyridine-3,4'-piperidine]-1,5-dione (Cpd. No. 163)
[0740] The synthesis of compound 163 was carried out as described
above using the general protocol of Procedure H. Yellow solid;
Yield: 0.35 g, 43%; MS (ESI) m/z 389 [M+1].sup.+; .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. 10.55 (s, 1H), 9.66 (s, 1H), 8.84 (s,
1H), 8.79 (s, 1H), 8.43 (d, J=5.84 Hz, 1H), 7.43 (d, J=5.92 Hz,
1H), 4.50 (d, J=12.64 Hz, 1H), 3.96 (d, J=2.95 Hz, 1H), 3.10-3.07
(m, 1H), 3.06-3.03 (m, 1H), 2.06 (s, 3H), 1.68-1.59 (m, 2H).
Example 164
Synthesis of
8'-chloro-1',5'-dioxo-6'-(pyrimidin-4-ylamino)-1',5'-dihydro-2'H-spiro[cy-
clohexane-1,3'-imidazo[1,5-a]pyridine]-4-carbonitrile (Cpd. No.
164)
##STR00365##
##STR00366##
[0741] Synthesis of
6'-bromo-8'-chloro-1',5'-dioxo-1',5'-dihydro-2'H-spiro[cyclohexane-1,3'-i-
midazo[1,5-a]pyridine]-4-carbonitrile (3)
[0742] The synthesis of intermediate 3 was carried out as described
above using the general protocol of Procedure A. Off white solid;
Yield: 0.75 g, 53%; MS (ESI) m/z 354.08 [M-1].sup.-.
Synthesis of
8'-chloro-1',5'-dioxo-6'-(pyrimidin-4-ylamino)-1',5'-dihydro-2'H-spiro[cy-
clohexane-1,3'-imidazo[1,5-a]pyridine]-4-carbonitrile (Cpd. No.
164)
[0743] The synthesis of compound 164 was carried out as described
above using the general protocol of Procedure H. Yellow solid;
Yield: 0.21 g, 29%; MS (ESI) m/z 371.18 [M+1].sup.+; .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 10.36 (s, 1H), 9.58 (s, 1H),
8.84-8.78 (m, 2H), 8.44-8.39 (m, 1H), 7.44-7.43 (m, 1H), 3.00-2.94
(m, 2H), 2.82-2.76 (m, 1H), 2.15-2.12 (m, 2H), 1.99-1.90 (m, 3H),
1.67-1.64 (m, 2H).
Example 165
Synthesis of
8-chloro-3,3-dimethyl-6-(pyrido[3,4-d]pyrimidin-4-ylamino)-2,3-dihydroimi-
dazo[1,5-a]pyridine-1,5-dione (Cpd. No. 165)
##STR00367##
##STR00368##
[0744] Synthesis of
8-chloro-3,3-dimethyl-6-(pyrido[3,4-d]pyrimidin-4-ylamino)-2,3-dihydroimi-
dazo[1,5-a]pyridine-1,5-dione (Cpd. No. 165)
[0745] The synthesis of compound 165 was carried out as described
above using the general protocol of Procedure B. Yellow solid;
Yield: 25 mg, 8%; MS (ESI) m/z 357.34 [M+1].sup.+; .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. 10.05 (brs, 1H), 10.37 (s, 1H), 9.17 (s,
1H), 8.61 (m, 2H), 8.18 (d, J=5.24 Hz, 1H), 1.82 (s, 6H).
Example 166
Synthesis of
8-chloro-3,3-dimethyl-6-(pyrimido[5,4-c]pyridazin-8-ylamino)-2,3-dihydroi-
midazo[1,5-a]pyridine-1,5-dione (Cpd. No. 166)
##STR00369##
##STR00370##
[0746] Synthesis of
8-chloro-3,3-dimethyl-6-(pyrimido[5,4-c]pyridazin-8-ylamino)-2,3-dihydroi-
midazo[1,5-a]pyridine-1,5-dione (Cpd. No. 166)
[0747] The synthesis of compound 166 is carried out as described
above using the general protocol of Procedure H.
Example 167
Synthesis of
8-chloro-3,3-dimethyl-6-(pyrimido[5,4-d]pyrimidin-4-ylamino)-2,3-dihydroi-
midazo[1,5-a]pyridine-1,5-dione (Cpd. No. 167)
##STR00371##
##STR00372##
[0748] Synthesis of
8-chloro-3,3-dimethyl-6-(pyrimido[5,4-d]pyrimidin-4-ylamino)-2,3-dihydroi-
midazo[1,5-a]pyridine-1,5-dione (Cpd. No. 167)
[0749] The synthesis of compound 167 is carried out as described
above using the general protocol of Procedure H.
Example 168
Synthesis of
(Z)-8-chloro-6-((6-(2-cyclopropyl-3,3,3-trifluoroprop-1-en-1-yl)pyrimidin-
-4-yl)amino)-3-(3-fluorophenyl)-3-methyl-2,3-dihydroimidazo[1,5-a]pyridine-
-1,5-dione (Cpd. No. 168)
##STR00373##
##STR00374##
[0750] Synthesis of
(Z)-8-chloro-6-((6-(2-cyclopropyl-3,3,3-trifluoroprop-1-en-1-yl)pyrimidin-
-4-yl)amino)-3-(3-fluorophenyl)-3-methyl-2,3-dihydroimidazo[1,5-a]pyridine-
-1,5-dione (Cpd. No. 168)
[0751] The synthesis of compound 168 is carried out as described
above using the general protocol of Procedure H.
Example 169
Synthesis of
6'-((6-amino-5-fluoropyrimidin-4-yl)amino)-8'-chloro-2'H-spiro[cyclohexan-
e-1,3'-imidazo[1,5-a]pyridine]-1',5'-dione hydrochloride (Cpd. No.
169)
##STR00375##
##STR00376##
[0752] Synthesis of tert-butyl
N-tert-butoxycarbonyl-N-(6-chloro-5-fluoropyrimidin-4-yl)carbamate
(2)
[0753] The synthesis of intermediate 2 was carried out as described
above using the general protocol of Procedure J. Off white solid;
Yield: 2.3 g, 97%; MS (ESI) m/z 348 [M+1].sup.+.
Synthesis of tert-butyl
N-tert-butoxycarbonyl-N-[6-(cyclopropanecarbonylamino)-5-fluoro-pyrimidin-
-4-yl]carbamate (4)
[0754] The synthesis of intermediate 4 was carried out as described
above using the general protocol of Procedure H. Off white solid;
Yield: 0.9 g, 38%; MS (ESI) m/z 397.29 [M+1].sup.+; .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 8.6 (s, 1H), 7.83 (s, 1H), 2.41
(brs, 1H), 1.46 (s, 18H), 1.30 (m, 4H).
Synthesis of
N-(6-amino-5-fluoro-pyrimidin-4-yl)cyclopropanecarboxamide (5)
[0755] To a stirred solution of tert-butyl
N-tert-butoxycarbonyl-N-[6-(cyclopropanecarbonylamino)-5-fluoro-pyrimidin-
-4-yl]carbamate (4, 0.89 g, 2.25 mmol) in dichloromethane (20 mL),
trifluoroacetic acid (20 mL, 2.25 mmol) was added at 0.degree. C.
and stirred the reaction mass at room temperature for 16 h. After
completion the reaction, trifluoroacetic acid was distilled and the
crude compound was basified with liquid ammonia. The solid
precipitated out was filtered and dried to afford
N-(6-amino-5-fluoro-pyrimidin-4-yl)cyclopropanecarboxamide (5) as
off white solid. Yield: 0.4 g, 90%; MS (ESI) m/z 197.06
[M+1].sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 10.37 (s,
1H), 7.99 (s, 1H), 7.16 (s, 2H), 7.04 (s, 1H), 2.06 (m, 1H),
0.82-0.78 (m, 4H).
Synthesis of
N-[6[(8-chloro-1,5-dioxo-spiro[2H-imidazo[1,5-a]pyridine-3,1'-cyclohexane-
]-6-yl)amino]-5-fluoro-pyrimidin-4-yl]cyclopropanecarboxamide
(7)
[0756] The synthesis of intermediate 7 was carried out as described
above using the general protocol of Procedure H. Yellow solid;
Yield: 0.22 g, 40%; MS (ESI) m/z 447 [M+1].sup.+; .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. 10.87 (s, 1H), 10.45 (s, 1H), 8.59-8.53
(m, 1H), 8.50-8.42 (m, 2H), 2.90 (m, 2H), 1.98-1.98 (m, 1H),
1.77-1.53 (m, 8H), 0.82-0.84 (m, 4H).
Synthesis of
6'-((6-amino-5-fluoropyrimidin-4-yl)amino)-8'-chloro-2'H-spiro[cyclohexan-
e-1,3'-imidazo[1,5-a]pyridine]-1',5'-dione hydrochloride (Cpd. No.
169)
[0757] The synthesis of compound 169 was carried out as described
above using the general protocol of Procedure I. Off white solid;
Yield: 110 mg, 65%; MS (ESI) m/z 378.9 [M+1].sup.+; .sup.1H NMR:
(400 MHz, DMSO-d.sub.6) .delta. 10.34 (brs, 1H), 8.51 (s, 1H), 8.16
(s, 1H), 8.08 (s, 1H), 7.10 (s, 1H), 2.94 (t, J=2.32, 2H),
1.79-1.76 (m, 2H), 1.67-1.51 (m, 5H), 1.27-1.23 (m, 1H).
Example 170
Synthesis of
6-[(6-aminopyrimidin-4-yl)amino]-1',8-dimethyl-spiro[2H-imidazo[1,5-a]pyr-
idine-3,3'-piperidine]-1,5-dione (Cpd. No. 170)
##STR00377##
##STR00378##
[0758] Synthesis of
6-bromo-1',8-dimethyl-2H-spiro[imidazo[1,5-a]pyridine-3,3'-piperidine]-1,-
5-dione (3)
[0759] The synthesis of intermediate 3 was carried out as described
above using the general protocol of Procedure A. White solid;
Yield: 0.7 g, 25%; MS (ESI) m/z 326.19 [M+1].sup.+.
Synthesis of tert-butyl
(6-((1',8-dimethyl-1,5-dioxo-1,5-dihydro-2H-spiro[imidazo[1,5-a]pyridine--
3,3'-piperidin]-6-yl)amino)pyrimidin-4-yl)carbamate (5)
[0760] The synthesis of intermediate 5 was carried out as described
above using the general protocol of Procedure H. Yellow solid;
Yield: 0.25 g, 64%; .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
10.92 (s, 1H), 9.80 (s, 1H), 9.10 (s, 1H), 8.52-8.46 (m, 2H), 7.84
(m, 1H), 3.00-2.98 (m, 2H), 2.81-2.79 (m, 1H), 2.43 (s, 3H), 2.21
(s, 3H), 2.03-1.90 (m, 3H), 1.70 (m, 1H), 1.48-1.4 (s, 9H).
Synthesis of
6-[(6-aminopyrimidin-4-yl)amino]-1',8-dimethyl-spiro[2H-imidazo[1,5-a]pyr-
idine-3,3'-piperidine]-1,5-dione (Cpd. No. 170)
[0761] The synthesis of compound 170 was carried out as described
above using the general protocol of Procedure F. Yellow solid;
Yield: 0.1 g, 34%; MS (ESI) m/z 356.47 [M+1].sup.+; .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 9.82 (s, 1H), 8.59 (s, 1H), 8.38
(s, 1H), 8.16 (s, 1H), 6.52 (s, 2H), 6.14 (s, 1H), 3.32-3.30 (m,
1H), 2.98 (s, 1H), 2.80 (s, 1H), 2.50 (s, 1H), 2.41 (s, 3H), 2.20
(s, 3H), 1.91 (s, 2H), 1.76-1.69 (m, 1H), 1.48-1.45 (m, 1H).
Example 171
Synthesis of
8-chloro-6-(pyrimidin-4-ylamino)-2',3'-dihydro-1'H,2H-spiro[imidazo[1,5-a-
]pyridine-3,4'-isoquinoline]-1,5-dione (Cpd. No. 171)
##STR00379##
##STR00380##
[0762] Synthesis of tert-butyl
6-bromo-8-chloro-1,5-dioxo-1,5-dihydro-1'H,2H-spiro[imidazo[1,5-a]pyridin-
e-3,4'-isoquinoline]-2'(3'H)-carboxylate (3)
[0763] The synthesis of intermediate 3 is carried out as described
above using the general protocol of Procedure E.
Synthesis of tert-butyl
8-chloro-1,5-dioxo-6-(pyrimidin-4-ylamino)-1,5-dihydro-1'H,2H-spiro[imida-
zo[1,5-a]pyridine-3,4'-isoquinoline]-2'(3'H)-carboxylate (5)
[0764] The synthesis of intermediate 5 is carried out as described
above using the general protocol of Procedure H.
Synthesis of
8-chloro-6-(pyrimidin-4-ylamino)-2',3'-dihydro-1'H,2H-spiro[imidazo[1,5-a-
]pyridine-3,4'-isoquinoline]-1,5-dione (Cpd. No. 171)
[0765] The synthesis of compound 171 is carried out as described
above using the general protocol of Procedure F.
Example 172
Synthesis of
6-((6-aminopyrimidin-4-yl)amino)-8-chloro-2',3'-dihydro-1'H,2H-spiro[imid-
azo[1,5-a]pyridine-3,4'-isoquinoline]-1,5-dione (Cpd. No. 172)
##STR00381##
##STR00382##
[0766] Synthesis of tert-butyl
6-((6-((tert-butoxycarbonyl)amino)pyrimidin-4-yl)amino)-8-chloro-1,5-diox-
o-1,5-dihydro-1'H,2H-spiro[imidazo[1,5-a]pyridine-3,4'-isoquinoline]-2'(3'-
H)-carboxylate (3)
[0767] The synthesis of intermediate 3 is carried out as described
above using the general protocol of Procedure H.
Synthesis of
6-((6-aminopyrimidin-4-yl)amino)-8-chloro-2',3'-dihydro-1'H,2H-spiro[imid-
azo[1,5-a]pyridine-3,4'-isoquinoline]-1,5-dione (Cpd. No. 172)
[0768] The synthesis of compound 172 is carried out as described
above using the general protocol of Procedure F.
Example 173
Synthesis of
8-chloro-6'-fluoro-6-(pyrimidin-4-ylamino)-2',3'-dihydro-1'H,2H-spiro[imi-
dazo[1,5-a]pyridine-3,4'-isoquinoline]-1,5-dione (Cpd. No. 173)
##STR00383##
##STR00384##
[0769] Synthesis of tert-butyl
6-bromo-8-chloro-6'-fluoro-1,5-dioxo-1,5-dihydro-1'H,2H-spiro[imidazo[1,5-
-a]pyridine-3,4'-isoquinoline]-2'(3'H)-carboxylate (3)
[0770] The synthesis of intermediate 3 is carried out as described
above using the general protocol of Procedure E.
Synthesis of tert-butyl
8-chloro-6'-fluoro-1,5-dioxo-6-(pyrimidin-4-ylamino)-1,5-dihydro-1'H,2H-s-
piro[imidazo[1,5-a]pyridine-3,4'-isoquinoline]-2'(3'H)-carboxylate
(5)
[0771] The synthesis of intermediate 5 is carried out as described
above using the general protocol of Procedure H.
Synthesis of
8-chloro-6'-fluoro-6-(pyrimidin-4-ylamino)-2',3'-dihydro-1'H,2H-spiro[imi-
dazo[1,5-a]pyridine-3,4'-isoquinoline]-1,5-dione (Cpd. No. 173)
[0772] The synthesis of compound 173 is carried out as described
above using the general protocol of Procedure F.
Example 174
Synthesis of
6-((6-aminopyrimidin-4-yl)amino)-8-chloro-6'-fluoro-2',3'-dihydro-1'H,2H--
spiro[imidazo[1,5-a]pyridine-3,4'-isoquinoline]-1,5-dione (Cpd. No.
174)
##STR00385##
##STR00386##
[0773] Synthesis of tert-butyl
6-((6-((tert-butoxycarbonyl)amino)pyrimidin-4-yl)amino)-8-chloro-6'-fluor-
o-1,5-dioxo-1,5-dihydro-1'H,2H-spiro[imidazo[1,5-a]pyridine-3,4'-isoquinol-
ine]-2'(3'H)-carboxylate (3)
[0774] The synthesis of intermediate 3 is carried out as described
above using the general protocol of Procedure H.
Synthesis of
6-((6-aminopyrimidin-4-yl)amino)-8-chloro-6'-fluoro-2',3'-dihydro-1'H,2H--
spiro[imidazo[1,5-a]pyridine-3,4'-isoquinoline]-1,5-dione (Cpd. No.
174)
[0775] The synthesis of compound 174 is carried out as described
above using the general protocol of Procedure F.
Example 175
Synthesis of
8-chloro-6-(pyrimidin-4-ylamino)-2H-spiro[imidazo[1,5-a]pyridine-3,3'-ind-
oline]-1,5-dione (Cpd. No. 175)
##STR00387##
##STR00388##
[0776] Synthesis of tert-butyl
6-bromo-8-chloro-1,5-dioxo-1,5-dihydro-2H-spiro[imidazo[1,5-a]pyridine-3,-
3'-indoline]-1'-carboxylate (3)
[0777] The synthesis of intermediate 3 is carried out as described
above using the general protocol of Procedure E.
Synthesis of tert-butyl
8-chloro-1,5-dioxo-6-(pyrimidin-4-ylamino)-1,5-dihydro-2H-spiro[imidazo[1-
,5-a]pyridine-3,3'-indoline]-1'-carboxylate (5)
[0778] The synthesis of intermediate 5 is carried out as described
above using the general protocol of Procedure H.
Synthesis of
8-chloro-6-(pyrimidin-4-ylamino)-2H-spiro[imidazo[1,5-a]pyridine-3,3'-ind-
oline]-1,5-dione (Cpd. No. 175)
[0779] The synthesis of compound 175 is carried out as described
above using the general protocol of Procedure F.
Example 176
Synthesis of
8-chloro-5'-fluoro-6-(pyrimidin-4-ylamino)-2H-spiro[imidazo[1,5-a]pyridin-
e-3,3'-indoline]-1,5-dione (Cpd. No. 176)
##STR00389##
##STR00390##
[0780] Synthesis of tert-butyl
6-bromo-8-chloro-5'-fluoro-1,5-dioxo-1,5-dihydro-2H-spiro[imidazo[1,5-a]p-
yridine-3,3'-indoline]-1'-carboxylate (3)
[0781] The synthesis of intermediate 3 is carried out as described
above using the general protocol of Procedure E.
Synthesis of tert-butyl
8-chloro-5'-fluoro-1,5-dioxo-6-(pyrimidin-4-ylamino)-1,5-dihydro-2H-spiro-
[imidazo[1,5-a]pyridine-3,3'-indoline]-1'-carboxylate (5)
[0782] The synthesis of intermediate 5 is carried out as described
above using the general protocol of Procedure H.
Synthesis of
8-chloro-5'-fluoro-6-(pyrimidin-4-ylamino)-2H-spiro[imidazo[1,5-a]pyridin-
e-3,3'-indoline]-1,5-dione (Cpd. No. 176)
[0783] The synthesis of compound 176 is carried out as described
above using the general protocol of Procedure F.
Example 177
Synthesis of
8-chloro-4',4'-difluoro-6-(pyrimidin-4-ylamino)-2H-spiro[imidazo[1,5-a]py-
ridine-3,3'-piperidine]-1,5-dione (Cpd. No. 177)
##STR00391##
##STR00392##
[0784] Synthesis of tert-butyl
6-bromo-8-chloro-4',4'-difluoro-1,5-dioxo-1,5-dihydro-2H-spiro[imidazo[1,-
5-a]pyridine-3,3'-piperidine]-1'-carboxylate (3)
[0785] The synthesis of intermediate 3 is carried out as described
above using the general protocol of Procedure E.
Synthesis of tert-butyl
8-chloro-4',4'-difluoro-1,5-dioxo-6-(pyrimidin-4-ylamino)-1,5-dihydro-2H--
spiro[imidazo[1,5-a]pyridine-3,3'-piperidine]-1'-carboxylate
(5)
[0786] The synthesis of intermediate 5 is carried out as described
above using the general protocol of Procedure H.
Synthesis of
8-chloro-4',4'-difluoro-6-(pyrimidin-4-ylamino)-2H-spiro[imidazo[1,5-a]py-
ridine-3,3'-piperidine]-1,5-dione (Cpd. No. 177)
[0787] The synthesis of compound 177 is carried out as described
above using the general protocol of Procedure F.
Example 178
Synthesis of
6-((6-aminopyrimidin-4-yl)amino)-8-chloro-4',4'-difluoro-2H-spiro[imidazo-
[1,5-a]pyridine-3,3'-piperidine]-1,5-dione (Cpd. No. 178)
##STR00393##
##STR00394##
[0788] Synthesis of tert-butyl
6-((6-((tert-butoxycarbonyl)amino)pyrimidin-4-yl)amino)-8-chloro-4',4'-di-
fluoro-1,5-dioxo-1,5-dihydro-2H-spiro[imidazo[1,5-a]pyridine-3,3'-piperidi-
ne]-1'-carboxylate (3)
[0789] The synthesis of intermediate 3 is carried out as described
above using the general protocol of Procedure H.
Synthesis of
6-((6-aminopyrimidin-4-yl)amino)-8-chloro-4',4'-difluoro-2H-spiro[imidazo-
[1,5-a]pyridine-3,3'-piperidine]-1,5-dione (Cpd. No. 178)
[0790] The synthesis of compound 178 is carried out as described
above using the general protocol of Procedure F.
Example 179
Synthesis of
8'-chloro-2,2-dimethyl-6'-(pyrimidin-4-ylamino)-4,5-dihydro-2H,2'H-spiro[-
furan-3,3'-imidazo[1,5-a]pyridine]-1',5'-dione (Cpd. No. 179)
##STR00395##
##STR00396##
[0791] Synthesis of
6'-bromo-8'-chloro-2,2-dimethyl-4,5-dihydro-2H,2'H-spiro[furan-3,3'-imida-
zo[1,5-a]pyridine]-1',5'-dione (3)
[0792] The synthesis of intermediate 3 is carried out as described
above using the general protocol of Procedure A.
Synthesis of
8'-chloro-2,2-dimethyl-6'-(pyrimidin-4-ylamino)-4,5-dihydro-2H,2'H-spiro[-
furan-3,3'-imidazo[1,5-a]pyridine]-1',5'-dione (Cpd. No. 179)
[0793] The synthesis of compound 179 is carried out as described
above using the general protocol of Procedure H.
Example 180
Synthesis of
6'-((6-aminopyrimidin-4-yl)amino)-8'-chloro-2,2-dimethyl-4,5-dihydro-2H,2-
'H-spiro[furan-3,3'-imidazo[1,5-a]pyridine]-1',5'-dione (Cpd. No.
180)
##STR00397##
##STR00398##
[0794] Synthesis of tert-butyl
(6-((8'-chloro-2,2-dimethyl-1',5'-dioxo-1',4,5,5'-tetrahydro-2H,2'H-spiro-
[furan-3,3'-imidazo[1,5-a]pyridin]-6'-yl)amino)pyrimidin-4-yl)carbamate
(3)
[0795] The synthesis of intermediate 3 is carried out as described
above using the general protocol of Procedure H.
Synthesis of
6'-((6-aminopyrimidin-4-yl)amino)-8'-chloro-2,2-dimethyl-4,5-dihydro-2H,2-
'H-spiro[furan-3,3'-imidazo[1,5-a]pyridine]-1',5'-dione (Cpd. No.
180)
[0796] The synthesis of compound 180 is carried out as described
above using the general protocol of Procedure F.
Example 181
Synthesis of
3,3-dimethyl-1,5-dioxo-6-(pyrimidin-4-ylamino)-2H-imidazo[1,5-a]pyridine--
8-carbonitrile (Cpd. No. 181)
##STR00399##
##STR00400##
[0797] Synthesis of
3,3-dimethyl-1,5-dioxo-6-(pyrimidin-4-ylamino)-2H-imidazo[1,5-a]pyridine--
8-carbonitrile (Cpd. No. 181)
[0798] To a vial was added
8-chloro-3,3-dimethyl-6-(pyrimidin-4-ylamino)-2H-imidazo[1,5-c]pyridine-1-
,5-dione (1, 1000 mg, 3.27 mmol), copper(I) cyanide (293 mg, 3.27
mmol) and sodium cyanide (160 mg, 3.27 mmol) in 1,4-dioxane (10 mL)
at room temperature under argon. The reaction was purged with argon
for 5-10 min, followed by addition of tricyclohexylphosphine (92
mg, 0.33 mmol) and tris(dibenzylideneacetone)dipalladium(0) (299
mg, 0.33 mmol) under argon. The vial was then sealed and heated at
150.degree. C. for 48 h. After completion the reaction was quenched
with sat solution of potassium permanganate and extracted the crude
compound with 10% methanol in dichloromethane. The organic layer
was concentrated to dryness and crude was purified by flash column
chromatography (silica gel 100-200 mesh) using 2% methanol in
dichloromethane. The desired fractions were concentrated to dryness
under vacuum to obtain
3,3-dimethyl-1,5-dioxo-6-(pyrimidin-4-ylamino)-2H-imidazo[1,5-a]pyridine--
8-carbonitrile (Cpd. No. 181) as off white solid. Yield: 0.2 g,
20%; MS (ESI) m/z 297.36 [M+1].sup.+; .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 10.20 (s, 1H), 9.69 (s, 1H), 8.90 (s, 1H),
8.85 (s, 1H), 8.44 (d, J=5.84 Hz, 1H), 7.44 (d, J=5.36 Hz, 1H),
1.82 (s, 6H).
Example 182
Synthesis of
6'-((2-aminopyridin-4-yl)amino)-8'-methyl-2'H-spiro[cyclohexane-1,3'-imid-
azo[1,5-a]pyrazine]-1',5'-dione (Cpd. No. 182)
##STR00401##
##STR00402##
[0799] Synthesis of N,
N-ditertbutoxycarbonyl-2-chloropyridin-4-amine (2)
[0800] The synthesis of intermediate 2 was carried out as described
above using the general protocol of Procedure J. Light brown solid;
Yield: 5.3 g, 70%; MS (ESI) m/z 329.21 [M+1].sup.+.
Synthesis of N,
N-di-tertbutoxycarbonyl(2-(cyclopropanecarboxamido))pyridin-4-amine
(4)
[0801] The synthesis of intermediate 4 was carried out as described
above using the general protocol of Procedure B. Light brown solid;
Yield: 2.5 g, 51%; MS (ESI) m/z 378.61 [M+1].sup.+.
Synthesis of N-(4-aminopyridin-2-yl)cyclopropanecarboxamide
hydrochloride (5)
[0802] The synthesis of intermediate 5 was carried out as described
above using the general protocol of Procedure F. Off white solid;
Yield: 1.6 g, crude; MS (ESI) m/z 178.45 [M+1].sup.+.
Synthesis of methyl
5-((2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-3-methyl-6-oxo-1,6-dih-
ydropyrazine-2-carboxylate (7)
[0803] The synthesis of intermediate 7 was carried out as described
above using the general protocol of Procedure H. Yellow solid;
Yield: 1.5 g, 48%; MS (ESI) m/z 344.05 [M+1].sup.+.
Synthesis of
5-((2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-3-methyl-6-oxo-1,6-dih-
ydropyrazine-2-carboxamide (8)
[0804] The synthesis of intermediate 8 was carried out as described
above using the general protocol of Procedure K. Yield: 600 mg,
crude; MS (ESI) m/z 329.06 [M+1].sup.+.
Synthesis of
N-(4-((8'-methyl-1',5'-dioxo-1',5'-dihydro-2'H-spiro[cyclohexane-1,3'-imi-
dazo[1,5-a]pyrazin]-6'-yl)amino)pyridin-2-yl)cyclopropanecarboxamide
(10)
[0805]
5-((2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-3-methyl-6-oxo-1-
,6-dihydropyrazine-2-carboxamide (8, 600 mg, 1.83 mmol) and
cyclohexanone (538 mg, 5.48 mmol) were charged in acetonitrile in a
20 mL microwave vial. Iron(III) chloride (889 mg, 1.83 mmol) was
added and heated the reaction mixture at 80.degree. C. for 16 h. On
completion of the reaction, solvent was removed under vacuum and
purified the compound by silica gel (200-400 mesh) column
chromatography eluting with 5% methanol in dichloromethane.
Appropriate column fractions were concentrated under reduced
pressure to afford
N-(4-((8'-methyl-1',5'-dioxo-1',5'-dihydro-2'H-spiro[cyclohexane-1,3'-imi-
dazo[1,5-a]pyrazin]-6'-yl)amino)pyridin-2-yl)cyclopropanecarboxamide
(10, 100 mg, crude) as light brown crude solid which was directly
forwarded to next step. MS (ESI) m/z 409.43 [M+1].sup.+.
Synthesis of
6'-((2-aminopyridin-4-yl)amino)-8'-methyl-2'H-spiro[cyclohexane-1,3'-imid-
azo[1,5-a]pyrazine]-1',5'-dione (Cpd. No. 182)
[0806] The synthesis of compound 182 was carried out as described
above using the general protocol of Procedure I. Off white solid;
Yield: 2 mg; MS (ESI) m/z 341.21[M+1].sup.+; .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 12.59 (s, 1H), 10.36 (s, 1H), 10.18, (s, 1H),
8.09 (s, 1H), 7.79 (s, 1H), 7.77 (s, 2H), 7.27 (s, 1H), 2.82-2.76
(m, 2H), 2.50 (s, 3H), 1.77-1.74 (m, 2H), 1.70-1.60 (m, 3H),
1.55-1.52 (m, 2H), 1.23-1.19 (m, 1H).
Example 183
Synthesis of
3'-amino-6-((6-aminopyrimidin-4-yl)amino)-8-chloro-6'-fluoro-2',3'-dihydr-
o-2H-spiro[imidazo[1,5-a]pyridine-3,1'-indene]-1,5-dione (Cpd. No.
183)
##STR00403##
##STR00404##
[0807] Synthesis of
6-bromo-8-chloro-6'-fluoro-2H-spiro[imidazo[1,5-a]pyridine-3,1'-indene]-1-
,3',5(2'H)-trione (3)
[0808] The synthesis of intermediate 3 is carried out as described
above using the general protocol of Procedure A.
Synthesis of
N-(6-((8-chloro-6'-fluoro-1,3',5-trioxo-1,2',3',5-tetrahydro-2H-spiro[imi-
dazo[1,5-a]pyridine-3,1'-inden]-6-yl)amino)pyrimidin-4-yl)
cyclopropanecarboxamide (5)
[0809] The synthesis of intermediate 5 is carried out as described
above using the general protocol of Procedure H.
Synthesis of
N-(6-((3'-amino-8-chloro-6'-fluoro-1,5-dioxo-1,2',3',5-tetrahydro-2H-spir-
o[imidazo[1,5-a]pyridine-3,1'-inden]-6-yl)amino)pyrimidin-4-yl)cyclopropan-
ecarboxamide (6)
[0810] To a solution of
N-(6-((3'-amino-8-chloro-6'-fluoro-1,5-dioxo-1,2',3',5-tetrahydro-2H-spir-
o[imidazo[1,5-a]pyridine-3,1'-inden]-6-yl)amino)pyrimidin-4-yl)cyclopropan-
ecarboxamide (6, 1 g, 2.02 mmol) in 2-propanol (20 mL) was added
ammonium acetate (0.47 g, 6.06 mmol) and sodium cyanoborohydride
(1.02 g, 16.16 mmol). The reaction was stirred at 110.degree. C.
overnight. The resulting mixture was cooled to room temperature and
poured into saturated aqueous sodium bicarbonate solution. The
mixture was extracted with dichloromethane. The organic layer was
dried over magnesium sulfate, filtered and concentrated. The crude
was purified via column chromatography to afford
N-(6-((3'-amino-8-chloro-6'-fluoro-1,5-dioxo-1,2',3',5-tetrahydro-2H-spir-
o[imidazo[1,5-a]pyridine-3,1'-inden]-6-yl)amino)pyrimidin-4-yl)cyclopropan-
ecarboxamide (6).
Synthesis of
3'-amino-6-((6-aminopyrimidin-4-yl)amino)-8-chloro-6'-fluoro-2',3'-dihydr-
o-2H-spiro[imidazo[1,5-a]pyridine-3,1'-indene]-1,5-dione (Cpd. No.
183)
[0811] The synthesis of compound 183 is carried out as described
above using the general protocol of Procedure I.
Example 184
Synthesis of
N-(6-((8-chloro-3-(3-chlorophenyl)-3-methyl-1,5-dioxo-1,2,3,5-tetrahydroi-
midazo[1,5-a]pyridin-6-yl)amino)pyrimidin-4-yl)cyanamide (Cpd. No.
184)
##STR00405##
##STR00406##
[0812] Synthesis of
8-chloro-3-(3-chlorophenyl)-6-((6-fluoropyrimidin-4-yl)amino)-3-methyl-2,-
3-dihydroimidazo[1,5-a]pyridine-1,5-dione (3)
[0813] The synthesis of intermediate 3 is carried out as described
above using the general protocol of Procedure H.
Synthesis of
N-(6-((8-chloro-3-(3-chlorophenyl)-3-methyl-1,5-dioxo-1,2,3,5-tetrahydroi-
midazo[1,5-a]pyridin-6-yl)amino)pyrimidin-4-yl)cyanamide (Cpd. No.
184)
[0814] To a solution of
8-chloro-3-(3-chlorophenyl)-6-((6-fluoropyrimidin-4-yl)amino)-3-methyl-2,-
3-dihydroimidazo[1,5-a]pyridine-1,5-dione (3, 100 mg, 0.24 mmol) in
N-methyl-2-pyrrolidinone (4 mL) was added sodium hydrogencyanamide
(46 mg, 0.72 mmol). The reaction was stirred at 50.degree. C. for 2
h. The resulting mixture was cooled to room temperature, poured
into water and acidified to pH=5.5 with concentrated hydrochloric
acid. The mixture was filtered. The solid crude was purified via
HPLC to afford
N-(6-((8-chloro-3-(3-chlorophenyl)-3-methyl-1,5-dioxo-1,2,3,5-tetrahydroi-
midazo[1,5-a]pyridin-6-yl)amino)pyrimidin-4-yl)cyanamide (Cpd. No.
184).
Example 185
Synthesis of
8'-chloro-6'-(pyrimidin-4-ylamino)-2'H-spiro[bicyclo[2.2.1]heptane-7,3'-i-
midazo[1,5-a]pyridine]-1',5'-dione (Cpd. No. 185)
##STR00407##
##STR00408##
[0815] Synthesis of
6'-bromo-8'-chloro-2'H-spiro[bicyclo[2.2.1]heptane-7,3'-imidazo[1,5-a]pyr-
idine]-1',5'-dione (3)
[0816] The synthesis of intermediate 3 is carried out as described
above using the general protocol of Procedure A.
Synthesis of
8'-chloro-6'-(pyrimidin-4-ylamino)-2'H-spiro[bicyclo[2.2.1]heptane-7,3'-i-
midazo[1,5-a]pyridine]-1',5'-dione (Cpd. No. 185)
[0817] The synthesis of compound 185 is carried out as described
above using the general protocol of Procedure H.
Example 186
Synthesis of
6'-((6-aminopyrimidin-4-yl)amino)-8'-chloro-2'H-spiro[bicyclo[2.2.1]hepta-
ne-7,3'-imidazo[1,5-a]pyridine]-1',5'-dione (Cpd. No. 186)
##STR00409##
##STR00410##
[0818] Synthesis of
N-(6-((8'-chloro-1',5'-dioxo-1',5'-dihydro-2'H-spiro[bicyclo[2.2.1]heptan-
e-7,3'-imidazo[1,5-a]pyridin]-6'-yl)amino)pyrimidin-4-yl)cyclopropanecarbo-
xamide (3)
[0819] The synthesis of intermediate 3 is carried out as described
above using the general protocol of Procedure H.
Synthesis of
6'-((6-aminopyrimidin-4-yl)amino)-8'-chloro-2'H-spiro[bicyclo[2.2.1]hepta-
ne-7,3'-imidazo[1,5-a]pyridine]-1',5'-dione (Cpd. No. 186)
[0820] The synthesis of compound 186 is carried out as described
above using the general protocol of Procedure I.
Example 187
Synthesis of
8-chloro-6-[(5-methoxypyrimidin-4-yl)amino]spiro[2H-imidazo[1,5-a]pyridin-
e-3,1'-cyclohexane]-1,5-dione (Cpd. No. 187)
##STR00411##
##STR00412##
[0821] Synthesis of
8-chloro-6-[(5-methoxypyrimidin-4-yl)amino]spiro[2H-imidazo[1,5-a]pyridin-
e-3,1'-cyclohexane]-1,5-dione (Cpd. No. 187)
[0822] The synthesis of compound 187 was carried out as described
above using the general protocol of Procedure H. Grey solid; Yield:
0.052 g, 17%; MS (ESI) m/z 376.31 [M+1].sup.+; .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. 10.36 (s, 1H), 8.69 (s, 1H), 8.64 (s,
1H), 8.53 (s, 1H), 8.29 (s, 1H), 4.01 (s, 3H), 3.46-3.40 (m, 1H),
2.93-2.87 (m, 2H) 1.77-1.74 (m, 2H), 1.64-1.61 (m, 3H), 1.55-1.52
(m, 2H), 1.23 (m, 1H).
Example 188
Synthesis of
6'-((6-amino-5-ethylpyrimidin-4-yl)amino)-8'-chloro-2'H-spiro[cyclohexane-
-1,3'-imidazo[1,5-a]pyridine]-1',5'-dione hydrochloride (Cpd. No.
188)
##STR00413##
##STR00414##
[0823] Synthesis tert-butyl
N-tert-butoxycarbonyl-N-(6-chloro-5-ethyl-pyrimidin-4-yl)carbamate
(2)
[0824] The synthesis of intermediate 2 was carried out as described
above using the general protocol of Procedure J. Light brown solid.
Yield: 3.5 g, 96%; MS (ESI) m/z 358.5 [M+1].sup.+; .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. 8.71 (s, 1H), 2.70 (m, 3H), 1.4 (m,
18H), 1.20 (m, 3H).
Synthesis of tert-butyl
N-tert-butoxycarbonyl-N-[6[(8-chloro-1,5-dioxo-spiro[2H-imidazo[1,5-a]pyr-
idine-3,1'-cyclohexane]-6-yl)amino]-5-ethyl-pyrimidin-4-yl]carbamate
(4)
[0825] The synthesis of intermediate 4 was carried out as described
above using the general protocol of Procedure B. Yellow solid.
Yield: 0.48 g, 42%; MS (ESI) m/z 589.45 [M+1].sup.+; .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 10.40 (s, 1H), 8.75 (s, 1H), 8.71
(s, 1H), 8.54 (s, 1H), 2.94 (m, 2H), 2.59 (m, 2H), 1.74 (m, 2H),
1.65 (m, 2H), 1.57 (m, 2H), 1.14 (m, 18H), 1.25 (m, 1H), 1.22 (m,
4H).
Synthesis of
6'-((6-amino-5-ethylpyrimidin-4-yl)amino)-8'-chloro-2'H-spiro[cyclohexane-
-1,3'-imidazo[1,5-a]pyridine]-1',5'-dione hydrochloride (Cpd. No.
188)
[0826] The synthesis of compound 188 was carried out as described
above using the general protocol of Procedure F. Yellow solid.
Yield: 0.32 g, 94%; MS (ESI) m/z 389.06 [M+1].sup.+; .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 10.49 (s, 1H), 8.59 (s, 1H),
8.44-8.33 (m, 2H), 7.74 (brs, 2H), 2.93-2.90 (m, 2H), 2.66 (m, 2H),
1.77-1.74 (m, 3H), 1.55-1.52 (m, 2H), 1.25-1.22 (m, 1H), 1.10 (t,
J=14.8 Hz, 3H).
Example 189
Synthesis of
6'-((6-amino-5-isopropylpyrimidin-4-yl)amino)-8'-chloro-2'H-spiro[cyclohe-
xane-1,3'-imidazo[1,5-a]pyridine]-1',5'-dione (Cpd. No. 189)
##STR00415##
##STR00416##
[0827] Synthesis of tert-butyl
N-tert-butoxycarbonyl-N-(6-chloro-5-isopropyl-pyrimidin-4-yl)carbamate
(2)
[0828] The synthesis of intermediate 2 was carried out as described
above using the general protocol of Procedure J. White solid;
Yield: 4.5 g, 90%; MS (ESI) m/z 372.3 [M+1].sup.+; .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. 8.92 (s, 1H), 3.32-3.20 (m, 1H),
1.52-1.20 (m, 24H).
Synthesis of tert-butyl
N-tert-butoxycarbonyl-N-[6[(8-chloro-1,5-dioxo-spiro[2H-imidazo[1,5-a]pyr-
idine-3,1'-cyclohexane]-6-yl)amino]-5-isopropyl-pyrimidin-4-yl]carbamate
(4)
[0829] The synthesis of intermediate 4 was carried out as described
above using the general protocol of Procedure B. Yellow solid;
Yield: 0.41 g, 30%; MS (ESI) m/z 603.55 [M+1].sup.+; .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 10.40 (s, 1H), 8.75-8.72 (m, 2H),
8.67 (s, 1H), 3.32-3.19 (m, 1H), 2.94 (m, 2H), 1.74 (m, 2H), 1.65
(m, 3H), 1.57 (m, 2H), 1.14 (m, 24H), 1.20-1.00 (m, 1H).
Synthesis of
6'-((6-amino-5-isopropylpyrimidin-4-yl)amino)-8'-chloro-2'H-spiro[cyclohe-
xane-1,3'-imidazo[1,5-a]pyridine]-1',5'-dione hydrochloride (Cpd.
No. 189)
[0830] The synthesis of compound 189 was carried out as described
above using the general protocol of Procedure F. Yellow solid;
Yield: 0.30 g, 93%; MS (ESI) m/z 403.17 [M+1].sup.+; .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 10.38 (s, 1H), 9.51 (s, 1H), 8.45
(s, 2H), 7.69-7.68 (brs, 2H), 3.59-3.56 (m, 2H), 2.93-2.87 (m, 2H),
1.77-1.74 (m, 2H), 1.68-1.65 (m, 3H), 1.56 (m, 2H), 1.36 (m, 6H),
1.26 (m, 1H).
Example 190
Synthesis of
8'-chloro-6'-(7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2'H-spiro[cyclohexane-1,3'-
-imidazo[1,5-a]pyridine]-1',5'-dione (Cpd. No. 190)
##STR00417##
##STR00418##
[0831] Synthesis of
8'-chloro-6'-(7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2'H-spiro[cyclohexane-1,3'-
-imidazo[1,5-a]pyridine]-1',5'-dione (Cpd. No. 190)
[0832] The synthesis of compound 190 was carried out as described
above using the general protocol of Procedure B. Yellow solid.
Yield: 0.070 g, 7%; MS (ESI) m/z 370.09 [M+1].sup.+; .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 10.66 (s, 1H), 9.11 (s, 1H), 8.87
(s, 1H), 8.26 (s, 1H), 7.93 (d, J=3.56 Hz, 2H), 6.82 (d, J=3.56 Hz,
2H), 2.94-2.89 (m, 2H), 1.74-1.57 (m, 7H), 1.23 (m, 1H).
Example 191
Synthesis of
8'-chloro-6'-(pyrimidin-4-ylamino)-2-(trifluoromethyl)-2'H-spiro[cyclohex-
ane-1,3'-imidazo[1,5-a]pyridine]-1',5'-dione (Cpd. No. 191)
##STR00419##
##STR00420##
[0833] Synthesis of
6'-bromo-8'-chloro-2-(trifluoromethyl)-2'H-spiro[cyclohexane-1,3'-imidazo-
[1,5-a]pyridine]-1',5'-dione (3)
[0834] The synthesis of intermediate 3 was carried out as described
above using the general protocol of Procedure A. Off white solid;
Yield: 0.40 g, 43%; MS (ESI) m/z 400.59 [M+1].sup.+.
Synthesis of
8'-chloro-6'-(pyrimidin-4-ylamino)-2-(trifluoromethyl)-2'H-spiro[cyclohex-
ane-1,3'-imidazo[1,5-a]pyridine]-1',5'-dione (Cpd. No. 191)
[0835] The synthesis of compound 191 was carried out as described
above using the general protocol of Procedure B. White solid;
Yield: 0.030 g, 8%; MS (ESI) m/z 346.80 [M+1].sup.+; .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 10.53 (s, 1H), 9.66 (s, 1H), 8.84
(d, J=9.6 Hz, 2H), 8.45 (d, J=5.92 Hz, 1H), 7.44 (d, J=4.8 Hz, 1H),
4.03 (m, 1H), 2.88 (m, 1H), 2.04 (m, 1H), 1.80 (m, 3H), 1.67 (m,
1H), 1.41 (s, 1H).
Example 192
Synthesis of
8-chloro-3-methyl-3-(2-methylprop-1-enyl)-6-(pyrimidin-4-ylamino)-2H-imid-
azo[1,5-a]pyridine-1,5-dione (Cpd. No. 192)
##STR00421##
##STR00422##
[0836] Synthesis of
6-bromo-8-chloro-3-methyl-3-(2-methylprop-1-enyl)-2H-imidazo[1,5-a]pyridi-
ne-1,5-dione (3)
[0837] The synthesis of intermediate 3 was carried out as described
above using the general protocol of Procedure A. Light brown thick
liquid. Yield: 1.5 g, 28%; MS (ESI) m/z 329 [M-1].sup.-.
Synthesis of
8-chloro-3-methyl-3-(2-methylprop-1-enyl)-6-(pyrimidin-4-ylamino)-2H-imid-
azo[1,5-a]pyridine-1,5-dione (Cpd. No. 192)
[0838] The synthesis of compound 192 was carried out as described
above using the general protocol of Procedure H. White solid;
Yield: 65 mg, 31%; MS (ESI) m/z 360.80 [M+1].sup.+; .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 10.32 (s, 1H), 9.62 (s, 1H), 8.43
(d, J=5.6 Hz, 1H), 7.47 (d, J=4.8 Hz, 1H), 3.25-3.17 (m, 2H),
280-2.78 (m, 2H), 2.39-2.33 (m, 2H), 2.24 (s, 3H), 1.50-1.47 (m,
2H).
Example 193
Synthesis of
6'-((6-amino-5-methylpyrimidin-4-yl)amino)-8'-chloro-2'H-spiro[cyclohexan-
e-1,3'-imidazo[1,5-a]pyridine]-1',5'-dione hydrochloride (Cpd. No.
193)
##STR00423##
##STR00424##
[0839] Synthesis of tert-butyl
N-tert-butoxycarbonyl-N-(6-chloro-5-methyl-pyrimidin-4-yl)carbamate
(2)
[0840] The synthesis of intermediate 2 was carried out as described
above using the general protocol of Procedure J. White solid;
Yield: 1.1 g, 94%; MS (ESI) m/z 344.27 [M+1].sup.+; .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 8.90 (s, 1H), 2.22 (s, 1H), 1.38
(s, 18H).
Synthesis of tert-butyl
N-tert-butoxycarbonyl-N-[6-[(8-chloro-1,5-dioxo-spiro[2H-imidazo[1,5-a]py-
ridine-3,
1'-cyclohexane]-6-yl)amino]-5-methyl-pyrimidin-4-yl]carbamate
(4)
[0841] The synthesis of intermediate 4 was carried out as described
above using the general protocol of Procedure B. Yellow solid;
Yield: 0.20 g, 35%; MS (ESI) m/z 575.32 [M+1].sup.+; .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 10.41 (s, 1H), 8.73 (s, 2H), 8.46
(s, 1H), 2.14 (s, 3H), 1.77-1.66 (m, 7H), 1.46 (m, 18H), 1.20 (m,
1H).
Synthesis of
6'-((6-amino-5-methylpyrimidin-4-yl)amino)-8'-chloro-2'H-spiro[cyclohexan-
e-1,3'-imidazo[1,5-a]pyridine]-1',5'-dione hydrochloride (Cpd. No.
193)
[0842] The synthesis of compound 193 was carried out as described
above using the general protocol of Procedure F. Yellow solid;
Yield: 0.11 g, 80%; MS (ESI) m/z 375.26 [M+1].sup.+; .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 10.41 (s, 1H), 8.47 (s, 2H), 8.40
(s, 1H), 7.79 (brs, 2H), 2.93-2.87 (m, 1H), 2.07 (s, 1H), 1.77-1.74
(m, 2H), 1.65-1.56 (m, 3H), 1.56-1.53 (m, 2H), 1.09 (m, 1H).
Example 194
Synthesis of
8'-chloro-6'-((5-ethylpyrimidin-4-yl)amino)-2'H-spiro[cyclohexane-1,3'-im-
idazo[1,5-a]pyridine]-1',5'-dione (Cpd. No. 194)
##STR00425##
##STR00426##
[0843] Synthesis of
8'-chloro-6'-((5-ethylpyrimidin-4-yl)amino)-2'H-spiro[cyclohexane-1,3'-im-
idazo[1,5-a]pyridine]-1',5'-dione (Cpd. No. 194)
[0844] The synthesis of compound 194 was carried out as described
above using the general protocol of Procedure B. Yellow solid;
Yield: 0.026 g, 22%; MS (ESI) m/z 374.21 [M+1].sup.+; .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 10.37 (s, 1H), 8.78 (s, 1H), 8.72
(s, 1H), 8.39 (s, 1H), 8.34 (s, 1H), 2.95-2.89 (m, 2H), 2.70-2.64
(m, 2H), 1.77-1.74 (m, 2H), 1.69-1.65 (m, 3H), 1.57-1.54 (m, 2H),
1.26 (m, 4H).
Example 195
Synthesis of
6'-((6-amino-5-methoxypyrimidin-4-yl)amino)-8'-chloro-2'H-spiro[cyclohexa-
ne-1,3'-imidazo[1,5-a]pyridine]-1',5'-dione hydrochloride (Cpd. No.
195)
##STR00427##
##STR00428##
[0845] Synthesis of tert-butyl
N-tert-butoxycarbonyl-N-(6-chloro-5-methoxy-pyrimidin-4-yl)carbamate
(2)
[0846] The synthesis of intermediate 2 was carried out as described
above using the general protocol of Procedure J. Off white solid;
Yield: 092 g, 59%; MS (ESI) m/z 360.12 [M+1].sup.+; .sup.1H NMR
(400 MHz; DMSO-d.sub.6) .delta. 1.44 (s, 18H), 3.92 (s, 3H), 8.64
(s, 1H).
Synthesis of tert-butyl
N-tert-butoxycarbonyl-N-[6-[(8-chloro-1,5-dioxo-spiro[2H-imidazo[1,5-a]py-
ridine-3,1'-cyclohexane]-6-yl)amino]-5-methoxy-pyrimidin-4-yl]carbamate
(4)
[0847] The synthesis of intermediate 4 was carried out as described
above using the general protocol of Procedure B. Yellow solid;
Yield: 0.14 g; 23%; MS (ESI) m/z 591.23 [M+1].sup.+; .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 10.40 (s, 1H), 8.78 (s, 1H), 8.67
(s, 1H), 8.6 (s, 1H), 3.87 (s, 3H), 2.92 (m, 2H), 1.81-1.54 (m,
7H), 1.40 (s, 18H), 1.23 (m, 1H)
Synthesis of
6'-((6-amino-5-methoxypyrimidin-4-yl)amino)-8'-chloro-2'H-spiro[cyclohexa-
ne-1,3'-imidazo[1,5-a]pyridine]-1',5'-dione hydrochloride (Cpd. No.
195)
[0848] The synthesis of compound 195 was carried out as described
above using the general protocol of Procedure F. Off white solid;
Yield: 0.075 g, 80%; MS (ESI) m/z 391.12 [M+1].sup.+; .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 10.35 (s, 1H), 8.53 (s, 1H), 8.48
(s, 1H), 8.19 (s, 1H), 7.33 (brs, 2H), 3.74 (s, 3H), 2.91 (m, 2H),
1.76-1.52 (m, 7H), 1.26 (m, 1H).
Example 196
Synthesis of
8'-chloro-6'-((5-ethoxypyrimidin-4-yl)amino)-2'H-spiro[cyclohexane-1,3'-i-
midazo[1,5-a]pyridine]-1',5'-dione (Cpd. No. 196)
##STR00429##
##STR00430##
[0849] Synthesis of
8'-chloro-6'-((5-ethoxypyrimidin-4-yl)amino)-2'H-spiro[cyclohexane-1,3'-i-
midazo[1,5-a]pyridine]-1',5'-dione (Cpd. No. 196)
[0850] The synthesis of compound 196 was carried out as described
above using the general protocol of Procedure B. Yellow solid;
Yield: 0.055 g, 20%; MS (ESI) m/z 390.13 [M+1].sup.+; .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 10.42 (s, 1H), 8.82 (s, 1H), 8.75
(s, 1H), 8.62 (s, 1H), 8.33 (s, 1H), 4.30 (q, J=6.96 Hz, 2H), 2.90
(m, 2H), 1.74-1.53 (m, 7H), 1.43 (t, J=6.96 Hz, 3H), 1.25 (m,
1H).
Example 197
Synthesis of
8'-chloro-6'-((5-isopropoxypyrimidin-4-yl)amino)-2'H-spiro[cyclohexane-1,-
3'-imidazo[1,5-a]pyridine]-1',5'-dione (Cpd. No. 197)
##STR00431##
##STR00432##
[0851] Synthesis of N,N-di-boc-4-aminopyrimidin-5-ol (2)
[0852] The synthesis of intermediate 2 was carried out as described
above using the general protocol of Procedure J. Brown solid;
Yield: 1.2 g, 86%; MS (ESI) m/z 312.15 [M+1].sup.+; .sup.1H NMR
(400 MHz; CDCl.sub.3) .delta. 8.96 (s, 1H), 8.76 (s, 1H), 1.42 (s,
18H).
Synthesis of N,N-di-boc-5-isopropoxypyrimidin-4-amine (3)
[0853] To a solution of N,N-di-boc-4-aminopyrimidin-5-ol (2, 1.0 g,
3.21 mmol) in dimethylformamide (15 mL), potassium carbonate (1.11
g, 8.03 mmol) was added followed by addition of 2-iodo propane
(1.64 g, 9.64 mmol). The reaction mixture was stirred at 60.degree.
C. for 3 h. The reaction mixture was cooled, diluted with ethyl
acetate (50 mL) and washed with cold water (3.times.20 mL) and
brine, dried over sodium sulfate and concentrated under reduced
pressure to afford N,N-diboc-5-isopropoxypyrimidin-4-amine (3) as
white solid. Yield: 1.1 g, 97%; MS (ESI) m/z 354.20 [M+1].sup.+;
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.75 (s, 1H), 8.70 (s,
1H), 4.89 (m, 1H), 1.37 (s, 18H), 1.27 (d, J=6.0 Hz, 6H).
Synthesis of 5-isopropoxypyrimidin-4-amine hydrochloride (4)
[0854] The synthesis of intermediate 4 was carried out as described
above using the general protocol of Procedure F. Off white solid;
Yield: 0.55 g, 93%; MS (ESI) m/z 154.09 [M+1].sup.+; .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 14.32 (brs, 1H), 9.10-8.60 (m, 2H),
8.48 (s, 1H), 8.31 (brs, 1H), 8.06 (s, 1H), 4.72 (m, 1H), 1.32 (d,
J=6.0 Hz, 6H)
Synthesis of
8'-chloro-6'-((5-isopropoxypyrimidin-4-yl)amino)-2'H-spiro[cyclohexane-1,-
3'-imidazo[1,5-a]pyridine]-1',5'-dione (Cpd. No. 197)
[0855] The synthesis of compound 197 was carried out as described
above using the general protocol of Procedure H. Yellow solid;
Yield: 0.22 g, 61%; MS (ESI) m/z 404.14 [M+1].sup.+; .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 10.4 (s, 1H), 8.71 (s, 2H), 8.56
(s, 1H), 8.34 (s, 1H), 4.87 (m, 1H), 2.92 (m, 2H), 1.77-1.53 (m,
7H), 1.37 (d, J=6.0 Hz, 6H), 1.23 (m, 1H).
Example 198
Synthesis of
8'-chloro-2'-cyclopentyl-6'-(pyrimidin-4-ylamino)-2'H-spiro[cyclohexane-1-
,3'-imidazo[1,5-a]pyridine]-1',5'-dione (Cpd. No. 198)
##STR00433##
##STR00434##
[0856] Synthesis of
8'-chloro-2'-cyclopentyl-6'-(pyrimidin-4-ylamino)-2'H-spiro[cyclohexane-1-
,3'-imidazo[1,5-a]pyridine]-1',5'-dione (Cpd. No. 198)
[0857] In a vial
8'-chloro-6'-(pyrimidin-4-ylamino)-2'H-spiro[cyclohexane-1,3'-imidazo[1,5-
-a]pyridine]-1',5'-dione (0.5 g, 1.44 mmol), bromocyclopentane
(0.26 g, 1.73 mmol) and potassium phosphate (0.49 g, 3.62 mmol)
were taken in 1,4-dioxane (10 mL). The reaction mixture was purged
with argon for 10 min and copper(I) iodide (0.027 g, 0.14 mmol),
trans-N,N'-dimethylcyclohexane-1,2-diamine (0.041 g, 0.14 mmol)
were added and purging was continued for another 10 min. The
reaction was sealed and heated at 110.degree. C. for 24 h. After
completion, the reaction was diluted with 5% methanol in
dichloromethane (300 mL) and filtered through a celite bed. The
filtrate was concentrated. The crude compound was purified by
column chromatography using neutral alumina and the compound was
eluted with dichloromethane. The solvent was removed under reduced
pressure to get solid which was dried under high vacuum to afford
8'-chloro-2'-cyclopentyl-6'-(pyrimidin-4-ylamino)-2'H-spiro[cycloh-
exane-1,3'-imidazo[1,5-a]pyridine]-1',5'-dione (Cpd. No. 198) as an
off white solid. Yield: 0.035 g, 6%; MS (ESI) m/z 414.14
[M+1].sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 9.50 (s,
1H), 8.81 (s, 1H), 8.77 (s, 1H), 8.40 (d, J=5.84 Hz, 1H), 7.41 (d,
J=5.32 Hz, 1H), 5.33 (s, 1H), 2.93 (m, 2H), 1.92 (m, 12H), 1.62 (m,
2H), 1.37 (m, 2H).
Example 199
Synthesis of
6'-((6-aminopyrimidin-4-yl)amino)-8'-methyl-5'-thioxo-2'H-spiro[cyclopent-
ane-1,3'-imidazo[1,5-a]pyridin]-1'(5'H)-one (Cpd. No. 199)
##STR00435##
##STR00436##
[0858] Synthesis of n-butyl
5-((6-(cyclopropanecarboxamido)pyrimidin-4-yl)amino)-3-methyl-6-oxo-1,6-d-
ihydropyridine-2-carboxylate (3)
[0859] The synthesis of intermediate 3 is carried out as described
above using the general protocol of Procedure H.
Synthesis of
5-((6-aminopyrimidin-4-yl)amino)-3-methyl-6-oxo-1,6-dihydropyridine-2-car-
boxylic acid (4)
[0860] The synthesis of intermediate 3 is carried out as described
above using the general protocol of Procedure I.
Synthesis of
5-((6-aminopyrimidin-4-yl)amino)-3-methyl-6-thioxo-1,6-dihydropyridine-2--
carboxylic acid (5)
[0861] To a solution of
5-((6-aminopyrimidin-4-yl)amino)-3-methyl-6-oxo-1,6-dihydropyridine-2-car-
boxylic acid (4, 0.5 g, 1.91 mmol) in pyridine (10 mL) is added
phosphorus pentasulfide (1.27 g, 5.73 mmol). The reaction is
refluxed overnight. The resulting mixture is cooled to room
temperature and concentrated. The crude is purified via column
chromatography to afford
5-((6-aminopyrimidin-4-yl)amino)-3-methyl-6-thioxo-1,6-dihydropyridine-2--
carboxylic acid (5).
Synthesis of methyl
5-((6-aminopyrimidin-4-yl)amino)-3-methyl-6-thioxo-1,6-dihydropyridine-2--
carboxylate (6)
[0862] To a solution of
5-((6-aminopyrimidin-4-yl)amino)-3-methyl-6-thioxo-1,6-dihydropyridine-2--
carboxylic acid (5, 0.5 g, 1.72 mmol) in tetrahydrofuran (10 mL)
and methanol is added (trimethylsilyl)diazomethane (2 M in hexanes,
1.29 mL, 2.58 mmol). The reaction is stirred at room temperature
for 1 h. The resulting mixture is concentrated and purified via
column chromatography to afford methyl
5-((6-aminopyrimidin-4-yl)amino)-3-methyl-6-thioxo-1,6-dihydropyridine-2--
carboxylate (6).
Synthesis of
5-((6-aminopyrimidin-4-yl)amino)-3-methyl-6-thioxo-1,6-dihydropyridine-2--
carboxamide (7)
[0863] The synthesis of intermediate 7 is carried out as described
above using the general protocol of Procedure K.
Synthesis of
6'-((6-aminopyrimidin-4-yl)amino)-8'-methyl-5'-thioxo-2'H-spiro[cyclopent-
ane-1,3'-imidazo[1,5-a]pyridin]-1'(5'H)-one (Cpd. No. 199)
[0864] The synthesis of compound 199 is carried out as described
above using the general protocol of Procedure A.
Example 200
Synthesis of
6'-((6-aminopyrimidin-4-yl)(methyl)amino)-8'-chloro-2'H-spiro[cyclopentan-
e-1,3'-imidazo[1,5-a]pyridine]-1',5'-dione (Cpd. No. 200)
##STR00437##
##STR00438##
[0865] Synthesis of tert-butyl
(6-(cyclopropanecarboxamido)pyrimidin-4-yl)(methyl)carbamate
(3)
[0866] The synthesis of intermediate 3 was carried out as described
above using the general protocol of Procedure B. Yellow solid;
Yield: 2.5 g, 80%; MS (ESI) m/z 293.51 [M+1].sup.+; .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 11.06 (s, 1H), 8.63 (s, 1H), 8.59
(s, 1H), 2.05-1.99 (m, 1H), 1.49 (s, 9H), 0.85-0.83 (m, 4H).
Synthesis of
N-(6-(methylamino)pyrimidin-4-yl)cyclopropanecarboxamide
hydrochloride (4)
[0867] The synthesis of intermediate 4 was carried out as described
above using the general protocol of Procedure F. White solid;
Yield: 1.4 g, 90%; MS (ESI) m/z 193.30 [M+1].sup.+; .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 11.87 (brs, 1H), 9.10 (brs, 1H),
8.45 (s, 1H), 7.05 (brs, 1H), 2.91 (s, 3H), 2.01 (m, 1H), 0.93-0.89
(m, 4H).
Synthesis of
N-(6-((8'-chloro-1',5'-dioxo-1',5'-dihydro-2'H-spiro[cyclopentane-1,3'-im-
idazo[1,5-a]pyridin]-6'-yl)(methyl)amino)pyrimidin-4-yl)cyclopropanecarbox-
amide (6)
[0868] The synthesis of intermediate 6 was carried out as described
above using the general protocol of Procedure H. Yellow solid;
Yield: 120 mg, 18%; MS (ESI) m/z 427.01 [M-1].sup.-.
Synthesis of
6'-((6-aminopyrimidin-4-yl)(methyl)amino)-8'-chloro-2'H-spiro[cyclopentan-
e-1,3'-imidazo[1,5-a]pyridine]-1',5'-dione (Cpd. No. 200)
[0869] The synthesis of compound 200 was carried out as described
above using the general protocol of Procedure I. Light brown solid;
Yield: 27 mg, 32%; MS (ESI) m/z 361.12 [M+1].sup.+; .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 10.46 (s, 1H), 8.29 (s, 1H), 8.04
(s, 1H), 7.59 (brs, 2H), 5.72 (s, 1H), 3.27 (s, 3H), 2.76-2.69 (m,
2H), 1.91-1.84 (m, 2H), 1.82-1.79 (m, 2H), 1.74-1.69 (m, 2H).
Example 201
Synthesis of
6'-(pyrimidin-4-ylamino)-8'-(tetrahydro-2H-pyran-4-yl)-2'H-spiro[cyclohex-
ane-1,3'-imidazo[1,5-a]pyridine]-1',5'-dione (Cpd. No. 201)
##STR00439##
##STR00440##
[0870] Synthesis of
8'-(3,6-dihydro-2H-pyran-4-yl)-6'-(pyrimidin-4-ylamino)-2'H-spiro[cyclohe-
xane-1,3'-imidazo[1,5-a]pyridine]-1',5'-dione (3)
[0871] A vial was charged with
8'-chloro-6'-(pyrimidin-4-ylamino)-2'H-spiro[cyclohexane-1,3'-imidazo[1,5-
-a]pyridine]-1',5'-dione (1, 0.50 g, 1.44 mmol) and
2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane
(2, 0.36 g, 1.73 mmol) in 1,4-dioxane (10 mL). Sodium carbonate
(0.46 g, 4.33 mmol) was added followed by water (1.44 mL) and
purged the mixture with argon for 10 min.
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II),
complex with dichloromethane (0.11 g, 0.144 mmol) was then added
and purging was continued for 5 more min. The reaction was sealed
and heated at 110.degree. C. for 16 h. After completion of reaction
by TLC and LCMS. Water (100 mL) was added and extracted with 10%
methanol in dichloromethane (3.times.150 mL). The organics were
washed with brine (1.times.100 mL). The organics were then
separated and dried (sodium sulfate) before concentration to
dryness. The crude was then purified by flash column chromatography
eluting with 2-3% methanol in dichloromethane. The desired
fractions were concentrated to dryness under vacuum to afford
8'-(3,6-dihydro-2H-pyran-4-yl)-6'-(pyrimidin-4-ylamino)-2'H-spiro[cyclohe-
xane-1,3'-imidazo[1,5-a]pyridine]-1',5'-dione (3) as an off white
solid. Yield: 0.35 g, 61%; MS (ESI) m/z 394 [M+1].sup.+; .sup.1H
NMR (400 MHz, DMSO-d.sub.6) .delta. 10.24 (s, 1H), 9.41 (s, 1H),
8.78 (s, 1H), 8.61 (s, 1H), 8.43 (d, J=6.08 Hz, 1H), 7.44 (d,
J=5.72 Hz, 1H), 5.75 (s, 1H), 4.18 (s, 2H), 3.79 (s, 2H), 3.05 (m,
2H), 2.45 (m, 2H), 1.84 (m, 6H), 1.56 (s, 2H).
Synthesis of
6'-(pyrimidin-4-ylamino)-8'-(tetrahydro-2H-pyran-4-yl)-2'H-spiro[cyclohex-
ane-1,3'-imidazo[1,5-a]pyridine]-1',5'-dione (Cpd. No. 201)
[0872] A double neck round bottom flask was charged with
8'-(3,6-dihydro-2H-pyran-4-yl)-6'-(pyrimidin-4-ylamino)-2'H-spiro[cyclohe-
xane-1,3'-imidazo[1,5-a]pyridine]-1',5'-dione (3, 0.22 g, 0.57
mmol) in methanol (10 mL) and tetrahydrofuran (10 mL). Palladium on
carbon (0.10 g) was added followed by ammonium hydroxide (1.0 mL)
under nitrogen atmosphere. The reaction was filled with hydrogen
and stirred at room temperature for 3 d. After completion of
reaction monitored by TLC and LCMS, the reaction mass was diluted
with 5% methanol in dichloromethane (100 mL) and passed through
celite bed and washed with 10% methanol/dichloromethane (3.times.50
mL). Solvent was removed under vacuum and crude material was
purified by prep HPLC to afford
6'-(pyrimidin-4-ylamino)-8'-(tetrahydro-2H-pyran-4-yl)-2'H-spiro[cyclohex-
ane-1,3'-imidazo[1,5-a]pyridine]-1',5'-dione (Cpd. No. 201) as a
white solid. Yield: 0.11 g, 49%; MS (ESI) m/z 396.4 [M+1].sup.+;
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 10.16 (6, 1H), 9.40 (s,
1H), 8.85 (s, 1H), 8.81 (s, 1H), 8.38 (d, J=5.88 Hz, 1H), 7.37 (d,
J=5.88 Hz, 1H), 4.20 (m, 1H), 3.96 (m, 2H), 3.42 (t, J=11.3 Hz,
2H), 3.01 (m, 2H), 1.70 (m, 9H), 1.58 (m, 2H), 1.22 (m, 1H).
Example 202
Synthesis of
6'-((6-amino-5-hydroxypyrimidin-4-yl)amino)-8'-methyl-2'H-spiro[cyclohexa-
ne-1,3'-imidazo[1,5-a]pyridine]-1',5'-dione (Cpd. No. 202)
##STR00441##
##STR00442##
[0873] Synthesis of tert-butyl
N-tert-butoxycarbonyl-N-(5-methoxy-6-((8'-methyl-1',5'-dioxo-1',5'-dihydr-
o-2'H-spiro[cyclohexane-1,3'-imidazo[1,5-a]pyridin]-6'-yl)amino)pyrimidin--
4-yl)carbamate (3)
[0874] The synthesis of intermediate 3 was carried out as described
above using the general protocol of Procedure B. Yellow solid;
Yield: 0.45 g, 64%; MS (ESI) m/z 571.15 [M+1].sup.+.
Synthesis of
6'-((6-amino-5-hydroxypyrimidin-4-yl)amino)-8'-methyl-2'H-spiro[cyclohexa-
ne-1,3'-imidazo[1,5-a]pyridine]-1',5'-dione (Cpd. No. 202)
[0875] A flask was charged with tert-butyl
N-tert-butoxycarbonyl-N-(5-methoxy-6-((8'-methyl-1',5'-dioxo-1',5'-dihydr-
o-2'H-spiro[cyclohexane-1,3'-imidazo[1,5-a]pyridin]-6'-yl)amino)pyrimidin--
4-yl)carbamate (3, 0.40 g, 0.70 mmol) and dichloromethane (20 mL)
was added and mixture was cooled to -20.degree. C. boron tribromide
(0.87 g, 3.50 mmol) was then added to the mixture drop wise. The
reaction mass was stirred at room temperature overnight. After
completion, water was added to the reaction mixture and quenched
with saturated aqueous solution of sodium bicarbonate till pH 8.
Yellow solid was precipitated out, filtered and washed with water
(20 mL) followed by diethyl ether then finally dried under high
vacuum to afford
6'-((6-amino-5-hydroxypyrimidin-4-yl)amino)-8'-methyl-2'H-spiro[cyclohexa-
ne-1,3'-imidazo[1,5-a]pyridine]-1',5'-dione (Cpd. No. 202) as
yellow solid. Yield: 0.085 g, 34%; MS (ESI) m/z 357.16 [M+1].sup.+;
.sup.1H NMR: (400 MHz, DMSO-d.sub.6) .delta. 10.06 (s, 1H), 9.15
(brs, 1H), 8.50 (s, 1H), 8.40 (m, 1H), 8.08 (s, 1H), 6.65 (brs,
2H), 3.00-2.94 (m, 2H), 2.44 (s, 3H), 1.73-1.62 (m, 5H), 1.46-1.43
(m, 2H), 1.24-1.21 (m, 1H).
Example 203
Synthesis of
6'-((6-amino-2-hydroxypyrimidin-4-yl)amino)-8'-methyl-2'H-spiro[cyclohexa-
ne-1,3'-imidazo[1,5-a]pyridine]-1',5'-dione (Cpd. No. 203)
##STR00443##
##STR00444##
[0876] Synthesis of
6'-((6-(di-(tert-butoxycarbonyl)-amino)-2-methoxypyrimidin-4-yl)amino)-8'-
-methyl-2'H-spiro[cyclohexane-1,3'-imidazo[1,5-a]pyridine]-1',5'-dione
(3)
[0877] The synthesis of intermediate 3 was carried out as described
above using the general protocol of Procedure B. Yellow solid;
Yield: 0.77 g, 51%; MS (ESI) m/z 571.21 [M+1].sup.+.
Synthesis of
6'-((6-amino-2-hydroxypyrimidin-4-yl)amino)-8'-methyl-2'H-spiro[cyclohexa-
ne-1,3'-imidazo[1,5-a]pyridine]-1',5'-dione (Cpd. No. 203)
[0878] To a stirred solution of
6'-((6-(di-(tert-butoxycarbonyl)-amino)-2-methoxypyrimidin-4-yl)amino)-8'-
-methyl-2'H-spiro[cyclohexane-1,3'-imidazo[1,5-a]pyridine]-1',5'-dione
(3, 0.77 g, 1.35 mmol) in dichloromethane (15 mL) at -20.degree.
C., boron tribromide (1 mL) was added. The mixture was stirred for
another 20 min at the same temperature and then stirred for 48 h at
room temperature when TLC showed complete conversion of starting
material. The mixture was quenched by addition of methanol (2 mL)
and the solvent was removed under reduced pressure to afford the
crude. The crude was purified by washing with methanol (5 mL),
dichloromethane (5 mL) and pentane (25 mL) to afford
6'-((6-amino-2-hydroxypyrimidin-4-yl)amino)-8'-methyl-2'H-spiro[cy-
clohexane-1,3'-imidazo[1,5-a]pyridine]-1',5'-dione (Cpd. No. 203)
as pale yellow solid. Yield: 0.28 g, 58%; MS (ESI) m/z 357.16
[M+1].sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 10.03
(brs, 2H), 8.58 (brs, 1H), 8.47 (brs, 1H), 6.46 (brs, 2H), 5.39
(brs, 1H), 3.05-2.92 (m, 2H), 2.40 (s, 3H), 1.80-1.54 (m, 6H),
1.48-1.50 (m, 2H), 1.28-1.16 (m, 1H).
Example 204
Synthesis of
6'-((6-aminopyrimidin-4-yl)amino)-2-hydroxy-8'-methyl-2'H-spiro[cyclohexa-
ne-1,3'-imidazo[1,5-a]pyridine]-1',5'-dione (Cpd. No. 204)
##STR00445##
##STR00446##
[0879] Synthesis of
6'-bromo-2-hydroxy-8'-methyl-2'H-spiro[cyclohexane-1,3'-imidazo[1,5-a]pyr-
idine]-1',5'-dione (3)
[0880] The synthesis of intermediate 3 was carried out as described
above using the general protocol of Procedure A. Pale yellow solid;
Yield: 1.3 g, 62%; MS (ESI) m/z 326.97 [M+1].sup.+.
Synthesis of tert-butyl
(6-((2-hydroxy-8'-methyl-1',5'-dioxo-1',5'-dihydro-2'H-spiro[cyclohexane--
1,3'-imidazo[1,5-a]pyridin]-6'-yl)amino)pyrimidin-4-yl)carbamate
(5)
[0881] The synthesis of intermediate 5 was carried out as described
above using the general protocol of Procedure H. Pale yellow solid;
Yield: 1.1 g, 79%; MS (ESI) m/z 457.34 [M+1].sup.+.
Synthesis of
6'-((6-aminopyrimidin-4-yl)amino)-2-hydroxy-8'-methyl-2'H-spiro[cyclohexa-
ne-1,3'-imidazo[1,5-a]pyridine]-1',5'-dione (Cpd. No. 204)
[0882] The synthesis of compound 204 was carried out as described
above using the general protocol of Procedure F. Yellow solid;
Yield: 0.21 g, 25%; MS (ESI) m/z 357.16 [M+1].sup.+; .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 9.55 (s, 1H), 8.60 (brs, 1H), 8.30
(s, 1H), 8.19 (brs, 1H), 6.62 (brs, 2H), 6.17 (s, 1H), 5.00-4.95
(m, 1H), 4.70-4.62 (m, 1H), 3.10-3.00 (m, 1H), 1.82-1.48 (m, 6H),
1.38-1.28 (m, 1H).
Example 205
Synthesis of
6'-((6-aminopyrimidin-4-yl)amino)-3-hydroxy-8'-methyl-2'H-spiro[cyclohexa-
ne-1,3'-imidazo[1,5-a]pyridine]-1',5'-dione (Cpd. No. 205)
##STR00447##
##STR00448##
[0883] Synthesis of
6'-bromo-8'-methyl-2'H-spiro[cyclohexane-1,3'-imidazo[1,5-a]pyridine]-1',-
3,5'-trione (3)
[0884] The synthesis of intermediate 3 was carried out as described
above using the general protocol of Procedure A. Off white solid;
Yield: 1.6 g, 22%; MS (ESI) m/z 329.9 [M+1].sup.+.
Synthesis of
N-(6-((8'-methyl-1',3,5'-trioxo-1',5'-dihydro-2'H-spiro[cyclohexane-1,3'--
imidazo[1,5-a]pyridin]-6'-yl)amino)pyrimidin-4-yl)cyclopropanecarboxamide
(5)
[0885] The synthesis of intermediate 5 was carried out as described
above using the general protocol of Procedure H. Off white solid;
Yield: 0.40 g, 51%; MS (ESI) m/z 457.31 [M+1].sup.+.
Synthesis of
6'-((6-aminopyrimidin-4-yl)amino)-3-hydroxy-8'-methyl-2'H-spiro[cyclohexa-
ne-1,3'-imidazo[1,5-a]pyridine]-1',5'-dione (Cpd. No. 205)
[0886] A flask containing tetrahydrofuran and ethanol (1:1, 20 mL)
was charged with
N-(6-((8'-methyl-1',3,5'-trioxo-1',5'-dihydro-2'H-spiro[cyclohexane-1,3'--
imidazo[1,5-a]pyridin]-6'-yl)amino)pyrimidin-4-yl)cyclopropanecarboxamide
(5, 0.4 g, 0.9 mmol) and 3 M potassium hydroxide solution (8.0 mL)
was added to the above reaction. The reaction was stirred at room
temperature for 18 h. After complete hydrolysis, sodium borohydride
(0.18 g, 0.4 mmol) was added to the above reaction at room
temperature. The reaction mass was stirred for 2 h when TLC showed
completion of starting material. The solvents were removed under
reduced pressure and crude was dissolved in 10% methanol in
dichloromethane and neutralized with 10% citric acid. The organic
layer was separated and dried over sodium sulfate, filtered and
concentrated to obtain solid. The solid was filtered and washed
with methanol (5 mL) and pentane (20 mL) and dried under high
vacuum to afford
6'-((6-aminopyrimidin-4-yl)amino)-4-hydroxy-8'-methyl-2'H-spiro[cyclohexa-
ne-1,3'-imidazo[1,5-a]pyridine]-1',5'-dione (Cpd. No. 205) as
yellow solid as a mixture of diastereomers. Yield: 0.045 g, 13%; MS
(ESI) m/z 357.19 [M+1].sup.+; .sup.1H NMR: (400 MHz, DMSO-d.sub.6)
.delta. 9.89 & 8.48 (2 s, 1H each, isomer A & B), 8.59
& 8.57 (2 s, 1H each, isomer A & B), 8.42 (brs, 1H), 8.16
(brs, 1H), 6.52 (brs, 2H), 6.16 (brs, 1H), 5.16 & 4.85 (2 s, 1H
each, isomer A & B), 4.22 and 3.73 (2 m, 1H each, isomer A
& B), 2.99 & 2.88 (2 m, 2H each, isomer A & B), 2.42
(s, 3H), 1.98-1.11 (m, 6H).
Example 206
Synthesis of
6'-((6-aminopyrimidin-4-yl)amino)-4-hydroxy-8'-methyl-2'H-spiro[cyclohexa-
ne-1,3'-imidazo[1,5-a]pyridine]-1',5'-dione hydrochloride (Cpd. No.
206)
##STR00449##
##STR00450##
[0887] Synthesis of
6'-bromo-4-hydroxy-8'-methyl-2'H-spiro[cyclohexane-1,3'-imidazo[1,5-a]pyr-
idine]-1',5'-dione (3)
[0888] The synthesis of intermediate 3 was carried out as described
above using the general protocol of Procedure A. Off white solid;
Yield: 1.0 g, 35%; MS (ESI) m/z 326.91 [M+1].sup.+.
Synthesis of tert-butyl
(6-((4-hydroxy-8'-methyl-1',5'-dioxo-1',5'-dihydro-2'H-spiro[cyclohexane--
1,3'-imidazo[1,5-a]pyridin]-6'-yl)amino)pyrimidin-4-yl)carbamate
(5)
[0889] The synthesis of intermediate 5 was carried out as described
above using the general protocol of Procedure H. Off white solid;
Yield: 0.45 g, 81%; MS (ESI) m/z 457.31 [M+1].sup.+.
Synthesis of
6'-((6-aminopyrimidin-4-yl)amino)-4-hydroxy-8'-methyl-2'H-spiro[cyclohexa-
ne-1,3'-imidazo[1,5-a]pyridine]-1',5'-dione hydrochloride (Cpd. No.
206)
[0890] The synthesis of compound 206 was carried out as described
above using the general protocol of Procedure F. Yellow solid as a
mixture of diastereomers; Yield: 0.049 g, 12%; MS (ESI) m/z 357.09
[M+1].sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 10.04
& 9.97 (2 s, 1H each, isomer A & B), 8.58 & 8.56 (2 s,
1H each, isomer A & B), 8.38 & 8.35 (2 s, 1H each, isomer A
& B), 8.16 (s, 1H), 6.51 (brs, 2H), 6.15 & 6.14 (2 s, 1H
each, isomer A & B), 4.78 & 4.46 (2 brs, 1H each, isomer A
& B), 3.86 & 3.53 (2 m, 1H each, isomer A & B), 3.41
& 3.09 (2 m, 2H each, isomer A & B), 2.42 (s, 3H),
1.85-1.56 (m, 4H), 143 & 1.17 (2 m, 2H each, isomer A &
B).
Example 207
Synthesis of
6'-((6-aminopyrimidin-4-yl)amino)-8'-(hydroxymethyl)-2'H-spiro[cyclohexan-
e-1,3'-imidazo[1,5-a]pyridine]-1',5'-dione (Cpd. No. 207)
##STR00451##
##STR00452##
[0891] Synthesis of
N-(6-((1',5'-dioxo-8'-vinyl-1',5'-dihydro-2'H-spiro[cyclohexane-1,3'-imid-
azo[1,5-a]pyridin]-6'-yl)amino)pyrimidin-4-yl)cyclopropanecarboxamide
(3)
[0892] The synthesis of intermediate 3 was carried out as described
above using the general protocol of Procedure G. brown solid;
Yield: 1.5 g, 51%; MS (ESI) m/z 421.22 [M+1].sup.+; .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 10.88 (s, 1H), 10.25 (s, 1H), 9.20
(s, 1H), 8.99 (s, 1H), 8.56 (s, 1H), 7.92-7.84 (m, 2H), 5.70 (d,
J=17.6 Hz, 1H), 5.34 (d, J=11.6 Hz, 1H), 3.32 (m, 1H), 2.99-2.93
(m, 2H), 2.05-1.98 (m, 2H), 1.72-1.66 (m, 5H), 1.43-1.40 (m, 2H),
1.34-1.16 (m, 1H), 0.85 (m, 4H).
Synthesis of
N-(6-((8'-formyl-1',5'-dioxo-1',5'-dihydro-2'H-spiro[cyclohexane-1,3'-imi-
dazo[1,5-a]pyridin]-6'-yl)amino)pyrimidin-4-yl)cyclopropanecarboxamide
(4)
[0893] To a stirred solution of
N-(6-((1',5'-dioxo-8'-vinyl-1',5'-dihydro-2'H-spiro[cyclohexane-1,3'-imid-
azo[1,5-a]pyridin]-6'-yl)amino)pyrimidin-4-yl)cyclopropanecarboxamide
(3, 2.0 g, 4.75 mmol) and sodium periodate (3.05 g, 14.26 mmol) in
dioxane and water (2:1, 30 mL), a solution of osmium tetroxide in
butanol (0.60 g, 2.38 mmol) was added drop wise at 0.degree. C. The
reaction mass was stirred at room temperature overnight. After TLC
showed completion, the solvent was evaporated under reduced
pressure and water (100 mL) was added. The mixture was extracted
with 10% methanol in dichloromethane (2.times.50 mL). The organics
were then separated and dried (magnesium sulfate) and concentrated
to dryness under vacuum to afford
N-(6-((8'-formyl-1',5'-dioxo-1',5'-dihydro-2'H-spiro[cyclohexane-1,3'-imi-
dazo[1,5-a]pyridin]-6'-yl)amino)pyrimidin-4-yl)cyclopropanecarboxamide
(4) as brown solid. Yield: 1.2 g, 60%; MS (ESI) m/z 423.26
[M+1].sup.+.
Synthesis of
N-(6-((8'-(hydroxymethyl)-1',5'-dioxo-1',5'-dihydro-2'H-spiro[cyclohexane-
-1,3'-imidazo[1,5-a]pyridin]-6'-yl)amino)pyrimidin-4-yl)cyclopropanecarbox-
amide (5)
[0894] To a stirred solution of
N-(6-((8'-formyl-1',5'-dioxo-1',5'-dihydro-2'H-spiro[cyclohexane-1,3'-imi-
dazo[1,5-a]pyridin]-6'-yl)amino)pyrimidin-4-yl)cyclopropanecarboxamide
(1.2 g, 2.85 mmol) in methanol/tetrahydrofuran (1:2, 30 mL), sodium
borohydride was added portion wise at 0.degree. C. The reaction
mass was stirred at 0.degree. C. for 2 h. After completion, the
reaction mixture was diluted with water (100 mL) and the mixture
was extracted with 10% methanol in dichloromethane (2.times.50 mL).
The organics were then separated and dried (magnesium sulfate) and
concentrated to dryness under vacuum to afford
N-(6-((8'-(hydroxymethyl)-1',5'-dioxo-1',5'-dihydro-2'H-spiro[cyclohexane-
-1,3'-imidazo[1,5-a]pyridin]-6'-yl)amino)pyrimidin-4-yl)cyclopropanecarbox-
amide (5) as brown solid. Yield: 0.7 g, 62%; MS (ESI) m/z 423.43
[M-1].sup.-; .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 10.86 (s,
1H), 10.24-10.18 (m, 1H), 8.71-8.62 (m, 1H), 8.56-8.52 (m, 1H),
7.84 (s, 1H), 6.13-5.33 (m, 1H), 4.47-4.33 (m, 3H), 3.16-2.84 (m,
4H), 2.01-1.86 (m, 2H), 1.72-1.66 (m, 5H), 1.43-1.40 (m, 2H),
1.34-1.16 (m, 1H).
Synthesis of
6'-((6-aminopyrimidin-4-yl)amino)-8'-(hydroxymethyl)-2'H-spiro[cyclohexan-
e-1,3'-imidazo[1,5-a]pyridine]-1',5'-dione (Cpd. No. 207)
[0895] The synthesis of compound 207 was carried out as described
above using the general protocol of Procedure I. Brown solid;
Yield: 0.18 g, 29%; MS (ESI) m/z 357.35 [M+1].sup.+; .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 10.23 (s, 1H), 9.23 (m, 1H), 8.47
(m, 1H), 8.33 (s, 1H), 7.25 (brs, 2H), 6.27 (s, 1H), 5.18 (brs,
1H), 4.81 (s, 2H), 3.01 (m, 2H), 1.73-1.62 (m, 5H), 1.46-1.44 (m,
2H), 1.23 (m, 1H).
Example 208
Synthesis of
6'-((5-cyclopropylpyrimidin-4-yl)amino)-8'-methyl-2'H-spiro[cyclohexane-1-
,3'-imidazo[1,5-a]pyridine]-1',5'-dione (Cpd. No. 208)
##STR00453##
##STR00454##
[0896] Synthesis of 5-cyclopropylpyrimidin-4-amine (3)
[0897] The synthesis of intermediate 3 was carried out as described
above using the general protocol of Procedure G. Brown solid;
Yield: 0.41 g, 78%; MS (ESI) m/z 136.08 [M+1].sup.+; .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 8.02 (s, 1H), 7.81 (s, 1H), 6.75
(brs, 2H), 1.57-1.53 (m, 1H), 0.86-0.82 (m, 2H), 0.56-0.53 (m,
2H).
Synthesis of
6'-((5-cyclopropylpyrimidin-4-yl)amino)-8'-methyl-2'H-spiro[cyclohexane-1-
,3'-imidazo[1,5-a]pyridine]-1,5'-dione (Cpd. No. 208)
[0898] The synthesis of compound 208 was carried out as described
above using the general protocol of Procedure H. Off white solid;
Yield: 0.14 g, 24%; MS (ESI) m/z 366.20 [M+1].sup.+; .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 10.16 (s, 1H), 8.88 (s, 1H), 8.72
(s, 1H), 8.62 (s, 1H), 8.29 (s, 1H), 3.01-2.96 (m, 2H), 2.5 (s,
3H), 1.84-1.59 (m, 6H), 1.48-1.45 (m, 2H), 1.30-1.27 (m, 1H),
1.05-1.01 (m, 2H), 0.73-0.69 (m, 2H).
Example 209
Synthesis of
8'-methyl-6'-(pyrimidin-4-yloxy)-2'H-spiro[cyclohexane-1,3'-imidazo[1,5-a-
]pyridine]-1',5'-dione (Cpd. No. 209)
##STR00455##
##STR00456##
[0899] Synthesis of
6'-((4-methoxybenzyl)oxy)-8'-methyl-2'H-spiro[cyclohexane-1,3'-imidazo[1,-
5-a]pyridine]-1',5'-dione (2)
[0900] To a solution of
6'-bromo-8'-methyl-2'H-spiro[cyclohexane-1,3'-imidazo[1,5-a]pyridine]-1',-
5'-dione (2 g, 6.43 mmol) in dimethylformamide (30 mL) is added
sodium hydride (0.46 g, 19.29 mmol) and 4-methoxybenzyl alcohol
(3.19 mL, 25.72 mmol). The reaction is stirred at room temperature
overnight. The resulting mixture is poured into iced water and
extracted with dichloromethane. The organic layer is dried over
magnesium sulfate, filtered and concentrated. The crude is purified
via column chromatography to afford
6'-((4-methoxybenzyl)oxy)-8'-methyl-2'H-spiro[cyclohexane-1,3'-imidazo[1,-
5-a]pyridine]-1',5'-dione (2).
Synthesis of
6'-hydroxy-8'-methyl-2'H-spiro[cyclohexane-1,3'-imidazo[1,5-a]pyridine]-1-
',5'-dione (3)
[0901] To a solution of
6'-((4-methoxybenzyl)oxy)-8'-methyl-2'H-spiro[cyclohexane-1,3'-imidazo[1,-
5-a]pyridine]-1',5'-dione (2, 1.5 g, 4.07 mmol) in dichloromethane
(20 mL) is added 2,3-dichloro-5,6-dicyano-p-benzoquinone (1.38 g,
6.10 mmol). The reaction is stirred at room temperature for 2 h.
The resulting mixture is concentrated and purified via column
chromatography to afford
6'-hydroxy-8'-methyl-2'H-spiro[cyclohexane-1,3'-imidazo[1,5-a]pyridine]-1-
',5'-dione (3).
Synthesis of
8'-methyl-6'-(pyrimidin-4-yloxy)-2'H-spiro[cyclohexane-1,3'-imidazo[1,5-a-
]pyridine]-1',5'-dione (Cpd. No. 209)
[0902] To a solution of
6'-hydroxy-8'-methyl-2'H-spiro[cyclohexane-1,3'-imidazo[1,5-a]pyridine]-1-
',5'-dione (3, 1 g, 4.03 mmol) in dimethylacetamide (20 mL) is
added potassium carbonate (1.67 g, 12.09 mmol) and
4-bromopyrimidine (4, 0.77 g, 4.84 mmol). The reaction is stirred
at 130.degree. C. overnight. The resulting mixture is cooled to
room temperature, poured into water and extracted with
dichloromethane. The organic layer is dried over magnesium sulfate,
filtered and concentrated. The crude is purified via column
chromatography to afford
8'-methyl-6'-(pyrimidin-4-yloxy)-2'H-spiro[cyclohexane-1,3'-imidazo[1,5-a-
]pyridine]-1',5'-dione (Cpd. No. 209).
Example 210
Synthesis of
8'-methyl-6'-(pyrimidin-4-ylthio)-2'H-spiro[cyclohexane-1,3'-imidazo[1,5--
a]pyridine]-1',5'-dione (Cpd. No. 210)
##STR00457##
##STR00458##
[0903] Synthesis of
6'-((4-methoxybenzyl)thio)-8'-methyl-2'H-spiro[cyclohexane-1,3'-imidazo[1-
,5-a]pyridine]-1',5'-dione (3)
[0904] To a solution of
6'-bromo-8'-methyl-2'H-spiro[cyclohexane-1,3'-imidazo[1,5-a]pyridine]-1',-
5'-dione (1, 2 g, 6.43 mmol) in dimethylformamide (30 mL) is added
cesium carbonate (6.28 g, 19.29 mmol) and
(4-methoxyphenyl)methanethiol (2, 1.19 g, 7.72 mmol). The reaction
is stirred at 100.degree. C. overnight. The resulting mixture is
cooled to room temperature, poured into water and extracted with
dichloromethane. The organic layer is dried over magnesium sulfate,
filtered and concentrated. The crude is purified via column
chromatography to afford
6'-((4-methoxybenzyl)thio)-8'-methyl-TH-spiro[cyclohexane-1,3'-imidazo[1,-
5-a]pyridine]-1',5'-dione (3).
Synthesis of
6'-mercapto-8'-methyl-2'H-spiro[cyclohexane-1,3'-imidazo[1,5-a]pyridine]--
1',5'-dione (4)
[0905] To a solution of
6'-((4-methoxybenzyl)thio)-8'-methyl-2'H-spiro[cyclohexane-1,3'-imidazo[1-
,5-a]pyridine]-1',5'-dione (3, 3.3 g, 8.58 mmol) in chloroform (40
mL) is added methanesulfonic acid (3 mL, 46. 23 mmol). The reaction
is stirred at 50.degree. C. overnight. The resulting mixture is
cooled to room temperature, poured into water and extracted with
dichloromethane. The organic layer is dried over magnesium sulfate,
filtered and concentrated. The crude is purified via column
chromatography to afford
6'-mercapto-8'-methyl-2'H-spiro[cyclohexane-1,3'-imidazo[1,5-a]pyridine]--
1',5'-dione (4).
Synthesis of
6'-((2-chloropyrimidin-4-yl)thio)-8'-methyl-2'H-spiro[cyclohexane-1,3'-im-
idazo[1,5-a]pyridine]-1',5'-dione (6)
[0906] To a solution of
6'-mercapto-8'-methyl-2'H-spiro[cyclohexane-1,3'-imidazo[1,5-a]pyridine]--
1',5'-dione (4, 0.50 g, 1.89 mmol) in 2-propanol (10 mL) is added
N,N-diisopropylethylamine (0.99 mL, 5.67 mmol) and
2,4-dichloropyrimidine (5, 0.34 g, 2.27 mmol). The reaction is
stirred at 70.degree. C. overnight. The resulting mixture is cooled
to room temperature, poured into water and extracted with
dichloromethane. The organic layer is dried over magnesium sulfate,
filtered and concentrated. The crude is purified via column
chromatography to afford
6'-((2-chloropyrimidin-4-yl)thio)-8'-methyl-2'H-spiro[cyclohexane-1,3'-im-
idazo[1,5-a]pyridine]-1',5'-dione (6).
Synthesis of
8'-methyl-6'-(pyrimidin-4-ylthio)-2'H-spiro[cyclohexane-1,3'-imidazo[1,5--
a]pyridine]-1',5'-dione (Cpd. No. 210)
[0907] To a solution of
6'-((2-chloropyrimidin-4-yl)thio)-8'-methyl-2'H-spiro[cyclohexane-1,3'-im-
idazo[1,5-a]pyridine]-1',5'-dione (6, 0.3 g, 0.80 mmol) in acetic
acid (4 mL) is added zinc copper couple (0.5 g). The reaction is
stirred at reflux for 4 h. The resulting mixture is cooled to room
temperature, filtered and concentrated. The crude is purified via
column chromatography to afford
8'-methyl-6'-(pyrimidin-4-ylthio)-2'H-spiro[cyclohexane-1,3'-imidazo[1,5--
a]pyridine]-1',5'-dione (Cpd. No. 210).
Example 211
Synthesis of
8'-methyl-6'-(pyrimidine-4-carbonyl)-2'H-spiro[cyclohexane-1,3'-imidazo[1-
,5-a]pyridine]-1',5'-dione (Cpd. No. 211)
##STR00459##
##STR00460##
[0908] Synthesis of
8'-methyl-6'-(pyrimidine-4-carbonyl)-2'H-spiro[cyclohexane-1,3'-imidazo[1-
,5-a]pyridine]-1',5'-dione (Cpd. No. 211)
[0909] To a solution of
6'-bromo-8'-methyl-2'H-spiro[cyclohexane-1,3'-imidazo[1,5-a]pyridine]-1',-
5'-dione (2, 0.3 g, 0.96 mmol) in tetrahydrofuran (25 mL),
n-butyllithium (0.58 g, 2.89 mmol) was added at -78.degree. C. The
reaction mixture was stirred for 30 min. To the mixture
N-methoxy-N-methylpyrimidine-4-carboxamide (1, 0.25 g, 1.44 mmol)
was added at -78.degree. C. and then the mixture was stirred at
room temperature for 16 h. After completion, the reaction was
quenched with aqueous solution of ammonium chloride (50 mL) and
extracted with dichloromethane (2.times.50 mL). The organic layer
was separated and washed with brine (25 mL) and the solvent was
evaporated under reduced pressure. The crude was purified by silica
gel (220-400 mesh) column chromatography using 0.5% methanol in
dichloromethane as eluent. The fractions were concentrated to
afford
8'-methyl-6'-(pyrimidine-4-carbonyl)-2'H-spiro[cyclohexane-1,3'-imidazo[1-
,5-a]pyridine]-1',5'-dione as yellow solid. Yield: 0.001 g, 3.0%;
MS (ESI) m/z 339.13 [M+1].sup.+; .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 10.58 (s, 1H), 9.26 (s, 1H), 9.07 (d, J=5.08
Hz, 1H), 9.97 (s, 1H), 7.83 (d, J=5.2 Hz, 1H), 2.85-2.75 (m, 2H),
2.45 (s, 3H), 1.68-162 (m, 2H), 1.60-1.53 (m, 3H), 1.46-1.43 (m,
2H), 1.10-1.09 (m, 1H).
Example 212
Synthesis of
8'-methyl-6'-(pyrimidin-4-ylmethyl)-2'H-spiro[cyclohexane-1,3'-imidazo[1,-
5-a]pyridine]-1',5'-dione (Cpd. No. 212)
##STR00461##
##STR00462##
[0910] Synthesis of
8'-methyl-6'-(pyrimidine-4-carbonyl)-2'H-spiro[cyclohexane-1,3'-imidazo[1-
,5-a]pyridine]-1',5'-dione (3)
[0911] To a solution of
6'-bromo-8'-methyl-2'H-spiro[cyclohexane-1,3'-imidazo[1,5-a]pyridine]-1',-
5'-dione (2, 2 g, 6.43 mmol) in tetrahydrofuran (30 mL) at
-78.degree. C. is added n-butyllithium (1.6 M in hexanes, 12.06 mL,
19.29 mmol) dropwise, followed by
N-methoxy-N-methylpyrimidine-4-carboxamide (1, 1.29 g, 7.72 mmol).
The reaction is slowly warmed to room temperature and stirred for 4
h. The reaction is quenched via the slow addition of water. The
mixture is warmed to room temperature and extracted with ethyl
acetate. The organic layer is dried over magnesium sulfate,
filtered and concentrated. The crude is purified via column
chromatography to afford
8'-methyl-6'-(pyrimidine-4-carbonyl)-2'H-spiro[cyclohexane-1,3'-imidazo[1-
,5-a]pyridine]-1',5'-dione (3).
Synthesis of
6'-(hydrazono(pyrimidin-4-yl)methyl)-8'-methyl-2'H-spiro[cyclohexane-1,
3'-imidazo[1,5-a]pyridine]-1',5'-dione (4)
[0912] To a solution of
8'-methyl-6'-(pyrimidine-4-carbonyl)-2'H-spiro[cyclohexane-1,3'-imidazo[1-
,5-a]pyridine]-1',5'-dione (3, 0.7 g, 2.07 mmol) in ethanol (4 mL),
acetic acid (4 mL) and water (4 mL) is added hydrazine hydrate
(0.13 g, 4.14 mmol). The reaction is stirred at 80.degree. C.
overnight. The reaction is cooled to room temperature and
concentrated. The crude is resuspended in dichloromethane and is
washed with saturated aqueous sodium bicarbonate solution. The
organic layer is dried over magnesium sulfate, filtered and
concentrated. The crude is purified via column chromatography to
afford
6'-(hydrazono(pyrimidin-4-yl)methyl)-8'-methyl-2'H-spiro[cyclohexane-1,3'-
-imidazo[1,5-a]pyridine]-1',5'-dione (4).
Synthesis of
8'-methyl-6'-(pyrimidin-4-ylmethyl)-2'H-spiro[cyclohexane-1,
3'-imidazo[1,5-a]pyridine]-1',5'-dione (Cpd. No. 212)
[0913] To a solution of
6'-(hydrazono(pyrimidin-4-yl)methyl)-8'-methyl-2'H-spiro[cyclohexane-1,3'-
-imidazo[1,5-a]pyridine]-1',5'-dione (4, 100 mg, 0.28 mmol) in
toluene (4 mL) is added potassium tert-butoxide (94 mg, 0.84 mmol).
The reaction is refluxed overnight. The resulting mixture is cooled
to room temperature, diluted with dichloromethane and is washed
with 1 M ammonium chloride solution. The organic layer is dried
over magnesium sulfate, filtered and concentrated. The crude is
purified via HPLC to afford
8'-methyl-6'-(pyrimidin-4-ylmethyl)-2'H-spiro[cyclohexane-1,3'-imidazo[1,-
5-a]pyridine]-1',5'-dione (Cpd. No. 212).
Example 213
Synthesis of
5-((6-aminopyrimidin-4-yl)amino)-3-chloro-1-isobutyl-6-oxo-1,6-dihydropyr-
idine-2-carboxamide (Cpd. No. 213)
##STR00463##
##STR00464##
[0914] Synthesis of ethyl
5-bromo-3-chloro-1-isobutyl-6-oxo-1,6-dihydropyridine-2-carboxylate
(3)
[0915] To a solution of ethyl
5-bromo-3-chloro-6-oxo-1,6-dihydropyridine-2-carboxylate (1, 1.0 g,
3.56 mmol) and 1-iodo-2-methylpropane (2, 1.31 g, 7.13 mmol) in
dimethylformamide (12 mL) in a vial, potassium carbonate (261 mg,
1.89 mmol) was added and the mixture was stirred at room
temperature for 16 h. After completion, the reaction mass was
diluted with water (50 mL) and extracted with ethyl acetate
(2.times.50 mL). Combined organic layer was washed with water,
brine, dried over anhydrous sodium sulfate and concentrated under
vacuum. The crude was purified by silica gel (220-400 mesh) column
chromatography using 50% ethyl acetate in hexane as an eluent to
afford ethyl
5-bromo-3-chloro-1-isobutyl-6-oxo-1,6-dihydropyridine-2-carboxylate
(3) as light yellow solid. Yield: 0.70 g, 58%; MS (ESI) m/z 336.3
[M+1].sup.+.
Synthesis of ethyl
5-((6-((tert-butoxycarbonyl)amino)pyrimidin-4-yl)amino)-3-chloro-1-isobut-
yl-6-oxo-1,6-dihydropyridine-2-carboxylate (5)
[0916] The synthesis of intermediate 5 was carried out as described
above using the general protocol of Procedure H. Off white solid;
Yield: 0.36 g, 40%; MS (ESI) m/z 466.2 [M+1].sup.+.
Synthesis of
5-((6-aminopyrimidin-4-yl)amino)-3-chloro-1-isobutyl-6-oxo-1,6-dihydropyr-
idine-2-carboxamide (Cpd. No. 213)
[0917] To a solution of ethyl
5-((6-((tert-butoxycarbonyl)amino)pyrimidin-4-yl)amino)-3-chloro-1-isobut-
yl-6-oxo-1,6-dihydropyridine-2-carboxylate (5, 300 mg, 0.64 mmol)
in methanol (20 mL) was added magnesium nitride (3.25 g, 3.21 mmol)
and the reaction was refluxed for 16 h. After completion, solvent
was removed under reduced pressure and the resulting residue was
stirred in 2 N hydrochloric acid for 10 m. The reaction mixture was
filtered and the obtained solid was dried under reduced pressure.
The crude was purified by prep purification, to afford
5-((6-aminopyrimidin-4-yl)amino)-3-chloro-1-isobutyl-6-oxo-1,6-dihydropyr-
idine-2-carboxamide (Cpd. No. 213) as an off white solid. Yield: 70
mg, 32%; MS (ESI) m/z 336.99 [M+1].sup.+; .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 9.46 (s, 1H), 8.33 (s, 1H), 8.27 (s, 1H),
7.87 (s, 1H), 7.59-7.54 (m, 3H), 6.05 (s, 1H), 4.17-4.16 (d, J=6.8
Hz, 2H), 2.08-2.01 (m, 1H), 0.95-0.93 (d, J=6.8 Hz, 6H).
Example 214
Synthesis of
5-((6-aminopyrimidin-4-yl)amino)-3-chloro-6-oxo-1,6-dihydropyridine-2-car-
boxamide (Cpd. No. 214)
##STR00465##
##STR00466##
[0918] Synthesis of ethyl
5-bromo-3-chloro-1-(4-methoxybenzyl)-6-oxo-1,6-dihydropyridine-2-carboxyl-
ate (2)
[0919] A solution of ethyl
5-bromo-3-chloro-6-oxo-1,6-dihydropyridine-2-carboxylate (3.0 g,
10.7 mmol), 4-methoxybenzyl chloride (4.19, 26.74 mmol) and
potassium carbonate (4.43 g, 32.09 mmol) in dimethylformamide (40
ml) was stirred at room temperature for 16 h. After completion, the
reaction mixture was diluted with cold water (20 mL) and extracted
with ethyl acetate (3.times.30 mL). The organic layer was again
washed with brine, separated, dried over Sodium sulfate, filtered
and concentrated under reduced pressure. The residue was finally
purified by flash column chromatography to afford ethyl
5-bromo-3-chloro-1-(4-methoxybenzyl)-6-oxo-1,6-dihydropyridine-2-carboxyl-
ate (2) as off white solid. Yield: 1.2 g, 28%; MS (ESI) m/z 399.99
[M+1].sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.27 (s,
1H), 7.11 (d, J=8.64 Hz, 2H), 6.89 (d, J=8.6 Hz, 2H), 5.11 (s, 2H),
4.27 (q, J=7.12 Hz, 2H), 3.72 (s, 3H), 1.13 (t, J=7.12 Hz, 3H).
Synthesis of ethyl
5-((6-((tert-butoxycarbonyl)amino)pyrimidin-4-yl)amino)-3-chloro-1-(4-met-
hoxybenzyl)-6-oxo-1,6-dihydropyridine-2-carboxylate (4)
[0920] The synthesis of intermediate 4 was carried out as described
above using the general protocol of Procedure H. Brown solid;
Yield: 0.70 g, 44%; MS (ESI) m/z 530.17 [M+1].sup.+; .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 10.04 (s, 1H), 9.49 (s, 1H), 8.64
(s, 1H), 8.50 (s, 1H), 7.76 (s, 1H), 7.11 (d, J=8.2 Hz, 2H), 6.89
(d, J=8.44 Hz, 2H), 5.21 (s, 2H), 4.23 (q, J=6.92 Hz, 2H), 3.72 (s,
3H), 1.48 (s, 9H), 1.13 (t, J=7.04 Hz, 3H).
Synthesis of
5-((6-aminopyrimidin-4-yl)amino)-3-chloro-1-(4-methoxybenzyl)-6-oxo-1,6-d-
ihydropyridine-2-carboxylic acid (5)
[0921] Sodium hydroxide (0.26 g, 6.6 mmol) was added to a
suspension of ethyl
5-((6-((tert-butoxycarbonyl)amino)pyrimidin-4-yl)amino)-3-chloro-1--
(4-methoxybenzyl)-6-oxo-1,6-dihydropyridine-2-carboxylate (0.70 g,
1.32 mmol) in methanol/tetrahydrofuran/water (2:1:1, 30 mL). The
mixture was stirred at 80.degree. C. for 16 h. After completion,
the solvent was evaporated to dryness under reduced pressure. The
crude was diluted with 1 N hydrochloric acid. The precipitate
obtained was collected by filtration, dried, washed with pentane
and dried further to afford
5-((6-aminopyrimidin-4-yl)amino)-3-chloro-1-(4-methoxybenzyl)-6-oxo-1,6-d-
ihydropyridine-2-carboxylic acid (5) as brown solid. Yield: 0.45 g,
85%; MS (ESI) m/z 402.09 [M+1].sup.+; .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 9.62 (s, 1H), 8.43 (s, 1H), 8.33 (s, 1H),
7.67 (brs, 2H), 7.19 (d, J=8.16 Hz, 2H), 6.87 (d, J=8.12 Hz, 2H),
6.39 (s, 1H), 5.18 (s, 2H), 3.71 (s, 3H).
Synthesis of
5-((6-aminopyrimidin-4-yl)amino)-3-chloro-N,1-bis(4-methoxybenzyl)-6-oxo--
1,6-dihydropyridine-2-carboxamide (6)
[0922] To a solution of
5-((6-aminopyrimidin-4-yl)amino)-3-chloro-1-(4-methoxybenzyl)-6-oxo-1,6-d-
ihydropyridine-2-carboxylic acid (5, 0.40 g, 0.99 mmol) and
4-methoxybenzylamine (0.16 g, 1.19 mmol) in dimethylformamide (20
mL) was added N,N-diisopropylethylamine (0.39 g, 2.99 mmol) and
HATU (0.57 g, 1.99 mmol) at room temperature. The reaction mixture
was stirred for 40 h. Progress of the reaction was monitored by
LCMS. To the reaction mixture was added tetrahydrofuran (20 mL) and
the reaction was refluxed for 7 h. After completion, the reaction
was diluted with water (20 mL) and extracted with 10% methanol in
dichloromethane (2.times.30 mL). The combined organic layer was
dried over sodium sulfate, filtered and evaporated under reduced
pressure to obtain the crude. The crude was purified by flash
column chromatography eluting at 1% methanol in dichloromethane.
The best fractions were concentrated to afford
5-((6-aminopyrimidin-4-yl)amino)-3-chloro-N,1-bis(4-methoxybenzyl)-6-oxo--
1,6-dihydropyridine-2-carboxamide (6) as yellow solid. Yield: 0.44
g, 84%; MS (ESI) m/z 521.16 [M+1].sup.+; .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 9.35 (m, 1H), 8.74 (s, 1H), 8.53 (s, 1H),
8.17 (s, 1H), 7.19-7.16 (m, 4H), 6.87-6.80 (m, 4H), 6.53 (s, 2H),
6.17 (s, 1H), 5.07 (s, 2H), 4.34 (s, 2H), 3.73 (s, 6H).
Synthesis of
5-((6-aminopyrimidin-4-yl)amino)-3-chloro-6-oxo-1,6-dihydropyridine-2-car-
boxamide (Cpd. No. 214)
[0923] To a solution of
5-((6-aminopyrimidin-4-yl)amino)-3-chloro-N,1-bis(4-methoxybenzyl)-6-oxo--
1,6-dihydropyridine-2-carboxamide (6, 0.40 g, 0.77 mmol) in
dichloromethane (10 mL) was added trifluoroacetic acid (20 mL) and
trifluoromethanesulfonic acid (1 mL) at 0.degree. C. The reaction
mixture was stirred at 70.degree. C. for 2 h. After completion, the
reaction mixture was concentrated and basified by aq. ammonia at
0.degree. C. The precipitate obtained was collected by filtration,
washed with water and dried to obtain the crude. The crude was
stirred with methanol, filtered, washed with pentane and dried to
afford
5-((6-aminopyrimidin-4-yl)amino)-3-chloro-6-oxo-1,6-dihydropyridine-2-car-
boxamide (Cpd. No. 214) as yellow solid. Yield: 0.035 g, 16%; MS
(ESI) m/z 281.05 [M+1].sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. 12.02 (s, 1H), 8.66 (s, 1H), 8.50 (s, 1H), 8.17 (s, 1H),
7.92 (s, 1H), 7.86 (s, 1H), 6.53 (s, 2H), 6.18 (s, 1H).
Example 215
Synthesis of
3'-(pyrimidin-4-ylamino)-4'H-spiro[cyclohexane-1,6'-imidazo[1,5-a]pyrimid-
ine]-4',8'(7H)-dione (Cpd. No. 215)
##STR00467##
##STR00468##
[0924] Synthesis of ethyl 5-bromopyrimidine-2-carboxylate (2)
[0925] To a solution of 5-bromopyrimidine-2-carboxylic acid (1, 4.0
g, 19.8 mmol) in ethanol (70 mL) at room temperature was added
sulfuric acid (0.5 mL). The reaction mixture was heated at
80.degree. C. for 16 h. TLC showed consumption of starting
material. Concentrated the reaction mixture under reduce pressure
to give residue which was diluted with water (30 mL) and extracted
with ethyl acetate (2.times.100 mL). Combined organic layer was
washed with sodium bicarbonate solution (50 mL) and then washed
with brine (50 mL), dried over anhydrous sodium sulfate, filtered
and concentrate under reduced pressure to afford ethyl
5-bromopyrimidine-2-carboxylate (2) as off white solid. Yield: 3.5
g, 77%; MS (ESI) m/z 230.91 [M+1].sup.+.
Synthesis of 5-bromo-2-(ethoxycarbonyl)pyrimidine 1-oxide (3)
[0926] To a 0.degree. C. cooled solution of 1-ethyl
5-bromopyrimidine-2-carboxylate (2, 1.5 g, 6.5 mmol) in
dichloromethane (30 mL), trifluoroacetic anhydride (13.69 g, 65
mmol) and Urea hydrogen peroxide (6.1 g, 65 mmol) were added. The
reaction mixture was stirred at room temperature for 16 h. TLC
showed consumption of starting material, the reaction mixture was
diluted with water (10 mL) and neutralized with solid sodium
bicarbonate. The solution was extracted with dichloromethane
(2.times.40 mL). The organic layer was dried over anhydrous sodium
sulfate, filtered and concentrated under reduced pressure to afford
5-bromo-2-(ethoxycarbonyl) pyrimidine 1-oxide (3) as yellow liquid
which was used without further purification. Yield: 0.64 g, crude;
MS (ESI) m/z 247.13 [M+1].sup.+.
Synthesis of ethyl
5-bromo-6-oxo-1,6-dihydropyrimidine-2-carboxylate (4)
[0927] To a 0.degree. C. cooled solution of
5-bromo-2-(ethoxycarbonyl)pyrimidine 1-oxide (3, 0.62 g, 2.5 mmol)
in dimethylformamide (6 mL), trifluoroacetic anhydride (3.1 g, 15
mmol) was added dropwise. The reaction mixture was heated at
50.degree. C. for 18 h. TLC showed consumption of starting material
and solvent was removed under reduced pressure. The residue was
triturated with methanol (2 mL) and filtered. The solid was washed
with diethyl ether and dried under reduced pressure to afford ethyl
5-bromo-6-oxo-1,6-dihydropyrimidine-2-carboxylate (4) as off white
solid. Yield: 0.21 g, 34%; MS (ESI) m/z 245.09 [M-1].sup.-.
Synthesis of 5-bromo-6-oxo-1,6-dihydropyrimidine-2-carboxamide
(5)
[0928] To a solution of ethyl
5-bromo-6-oxo-1,6-dihydropyrimidine-2-carboxylate (4, 0.2 g, 0.81
mmol) in ethanol (4 mL), liquid ammonia (4 mL) was added dropwise
at room temperature. The reaction mixture was heated at 50.degree.
C. for 16 h. TLC showed consumption of starting material. Solvent
was removed under reduced pressure and the residue was treated with
methanol (1 mL) and filtered. The solid was washed with diethyl
ether and dried under reduced pressure to afford
5-bromo-6-oxo-1,6-dihydropyrimidine-2-carboxamide (5) as off white
solid. Yield: 0.14 g, 76%; MS (ESI) m/z 218.87 [M+1].sup.+.
Synthesis of
3'-bromo-4'H-spiro[cyclohexane-1,6'-imidazo[1,5-a]pyrimidine]-4',8'(7'H)--
dione (7)
[0929] The synthesis of intermediate 7 was carried out as described
above using the general protocol of Procedure A. Off white solid;
Yield: 0.085 g, 50%; .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
10.96 (s, 1H), 8.55 (s, 1H), 6.94-7.20 (m, 2H), 3.36 (s, 1H),
2.65-2.71 (m, 2H), 1.61-1.73 (m, 2H), 1.19-1.22 (m, 1H).
Synthesis of
3'-(pyrimidin-4-ylamino)-4'H-spiro[cyclohexane-1,6'-imidazo[1,5-a]pyrimid-
ine]-4',8'(7'H)-dione (Cpd. No. 215)
[0930] The synthesis of compound 215 was carried out as described
above using the general protocol of Procedure H. Yellow solid;
Yield: 0.014 g, 17%; MS (ESI) m/z 313.14 [M+1].sup.+; .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 10.77 (s, 1H), 9.42 (s, 1H), 9.34
(s, 1H), 8.77 (s, 1H), 8.38 (s, 1H), 7.35 (s, 1H), 2.85-2.72 (m,
2H), 1.85-1.54 (m, 7H), 1.30-1.20 (m, 1H).
Example 216
Synthesis of
8'-methyl-6'-(pyrimidin-4-ylamino)-2'H-spiro[cyclohexane-1,3'-imidazo[1,5-
-a]pyrazine]-1',5'-dione (Cpd. No. 216)
##STR00469##
##STR00470##
[0931] Synthesis of methyl
5-bromo-3-methyl-6-oxo-1,6-dihydropyrazine-2-carboxylate (2)
[0932] Methyl 3-methyl-6-oxo-1,6-dihydropyrazine-2-carboxylate (2.0
g, 11.89 mmol) was dissolved in dichloromethane (30 mL) and
N-bromosuccinimide (2.12 g, 11.89 mmol) was added. The reaction was
allowed to stir at room temperature for 16 h. On completion, the
reaction mixture was washed with water and brine, dried over
anhydrous sodium sulfate, filtered and concentrated. The solid was
washed with ether to afford methyl
5-bromo-3-methyl-6-oxo-1,6-dihydropyrazine-2-carboxylate (2) as
light brown solid. Yield: 1.25 g, 42%; MS (ESI) m/z 247.04
[M+1].sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 12.92
(brs, 1H), 3.87 (s, 4H), 2.50 (s, 3H).
Synthesis of methyl
3-methyl-6-oxo-5-(pyrimidin-4-ylamino)-1,6-dihydropyrazine-2-carboxylate
(4)
[0933] The synthesis of intermediate 4 was carried out as described
above using the general protocol of Procedure H. Yellow solid;
Yield: 500 mg, 48%; MS (ESI) m/z 262.22 [M+1].sup.+; .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 12.16 (brs, 1H), 9.14 (s, 1H),
8.69-8.68 (d, J=5.6 Hz, 1H), 8.49-8.47 (d, J=5.6 Hz, 1H), 3.80 (s,
3H), 2.50 (s, 3H).
Synthesis of
3-methyl-6-oxo-5-(pyrimidin-4-ylamino)-1,6-dihydropyrazine-2-carboxamide
(5)
[0934] The synthesis of intermediate 5 was carried out as described
above using the general protocol of Procedure K. Brown solid.
Yield: 350 mg, 74%; MS (ESI) m/z 247.01 [M+1].sup.+.
Synthesis of
8'-methyl-6'-(pyrimidin-4-ylamino)-2'H-spiro[cyclohexane-1,3'-imidazo[1,5-
-a]pyrazine]-1',5'-dione (Cpd. No. 216)
[0935] To a solution of
3-Methyl-6-oxo-5-(pyrimidin-4-ylamino)-1,6-dihydropyrazine-2-carboxamide
(5, 100 mg, 0.41 mmol) and cyclohexanone (199 mg, 2.03 mmol) in
acetonitrile in a 20 mL microwave vial was added iron(III) chloride
(197 mg, 1.21 mmol). The reaction was heated at 80.degree. C. for
16 h. On completion of the reaction, solvent was removed under
vacuum and the crude was purified by silica gel (200-400 mesh)
column chromatography eluting with 5% methanol in dichloromethane.
Appropriate column fractions were concentrated under reduced
pressure to afford
8'-methyl-6'-(pyrimidin-4-ylamino)-2'H-spiro[cyclohexane-1,3'-imidazo[1,5-
-a]pyrazine]-1',5'-dione (Cpd. No. 216) as off white solid. Yield:
8.5 mg, 6%; MS (ESI) m/z 327.13 [M+1].sup.+; .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 10.17 (s, 1H), 9.11 (s, 1H), 8.88 (s, 1H),
8.72 (d, J=4.0 Hz 1H), 8.47 (d, J=4.0 Hz, 1H), 2.85-2.74 (m, 2H),
2.54 (s, 3H), 1.80-1.50 (m, 7H), 1.30-120 (m, 1H).
Example 217
Synthesis of
8-((6-aminopyrimidin-4-yl)amino)-10-methyl-2,3,4,5-tetrahydropyrido[1,2-a-
][1,4]diazepine-1,7-dione (Cpd. No. 217)
##STR00471##
##STR00472## ##STR00473##
[0936] Synthesis of N-benzyl-3-((tert-butyldimethylsilyl) oxy)
propan-1-amine (2)
[0937] To a stirred solution of 3-(benzylamino)propan-1-ol (1, 2.0
g, 12.1 mmol) in dichloromethane (20 mL), imidazole (2.47 g, 36.0
mmol) and tert-butyldimethylsilyl chloride (1.1 g, 13 mmol) were
added at room temperature. The reaction mass was stirred at room
temperature for 16 h. Water was added to the reaction mixture and
layers were separated. The organic layer was dried over sodium
sulfate, filtered and concentrated to afford
N-benzyl-3-((tert-butyldimethylsilyl) oxy) propan-1-amine (2) as
brown solid. Yield: 3.2 g, 94%; MS (ESI) m/z 280.29
[M-1].sup.-.
Synthesis of N-benzyl-5-bromo-N-(3-((tert-butyldimethylsilyl) oxy)
propyl)-3-methyl-6-oxo-1, 6-dihydropyridine-2-carboxamide (4)
[0938] To a stirred solution of
N-benzyl-3-((tert-butyldimethylsilyl)oxy)propan-1-amine (2, 3.0 g,
12.9 mmol) in dimethylformamide (50 mL),
5-bromo-3-methyl-6-oxo-1,6-dihydropyridine-2-carboxylic acid (3,
3.6 g, 12.9 mmol), HBTU (6.4 g, 16.9 mmol) and
N,N-diisopropylethylamine (2.2 g, 16.9 mmol) were added at room
temperature. The mixture was stirred for 16 h. TLC showed
completion of reaction. The reaction mixture was quenched with
aqueous sodium bicarbonate solution and extracted with ethyl
acetate (250 mL). The organic layer was dried over sodium sulfate,
filtered and concentrated to afford
N-benzyl-5-bromo-N-(3-((tert-butyldimethylsilyl) oxy)
propyl)-3-methyl-6-oxo-1,6-dihydropyridine-2-carboxamide (4) as
yellow liquid. Yield: 3.0 g, 47%; MS (ESI) m/z 495.24
[M-1].sup.-.
Synthesis of
N-benzyl-5-bromo-N-(3-hydroxypropyl)-3-methyl-6-oxo-1,6-dihydropyridine-2-
-carboxamide (5)
[0939] To a stirred solution of
N-benzyl-5-bromo-N-(3-((tert-butyldimethylsilyl)oxy)propyl)-3-methyl-6-ox-
o-1,6-dihydropyridine-2-carboxamide (4, 3.0 g, 6.0 mmol) in dioxane
(20 mL), hydrochloric acid in dioxane (20 mL) was added at room
temperature. The mixture was stirred for 16 h. After completion,
the solvent was removed. The residue was diluted with aqueous
sodium bicarbonate and extracted with 5% methanol/dichloromethane
(3.times.200 mL). The organic layer was dried over sodium sulfate,
filtered and concentrated to get
N-benzyl-5-bromo-N-(3-hydroxypropyl)-3-methyl-6-oxo-1,
6-dihydropyridine-2-carboxamide (5) as brown liquid. Yield: 2.2 g,
95%; MS (ESI) m/z 381.22 [M-1].sup.-.
Synthesis of 2-benzyl-8-bromo-10-methyl-2, 3, 4, 5-tetrahydropyrido
[1, 2-a][1, 4]diazepine-1, 7-dione (6)
[0940] To a stirred solution of
N-benzyl-5-bromo-N-(3-hydroxypropyl)-3-methyl-6-oxo-1,6-dihydropyridine-2-
-carboxamide (5, 1.5 g, 3.9 mmol) in tetrahydrofuran (30 mL),
triphenylphosphine (1.5 g, 5.9 mmol) and diisopropyl
azodicarboxylate (1.2 g, 5.9 mmol) were added at 0.degree. C. The
mixture was stirred at room temperature for 16 h. After completion,
solvent was removed under reduced pressure and the crude was
purified by flash chromatography eluting with 40% ethyl acetate in
hexane. Appropriate fractions were concentrated under reduced
pressure to afford
2-benzyl-8-bromo-10-methyl-2,3,4,5-tetrahydropyrido[1,2-a][1,4]diazepine--
1,7-dione (6) as yellow solid. Yield: 0.9 g, 64%; MS (ESI) m/z
361.18 [M+1].sup.+.
Synthesis of
8-((6-(di-(tert-butoxycarbonyl)-amino)pyrimidin-4-yl)amino)-2-benzyl-10-m-
ethyl-2,3,4,5-tetrahydropyrido[1,2-a][1,4]diazepine-1,7-dione
(8)
[0941] The synthesis of intermediate 8 was carried out as described
above using the general protocol of Procedure H. Yellow solid;
Yield: 0.9 g, 69%; MS (ESI) m/z 591.66 [M+1].sup.+.
Synthesis of
8-((6-aminopyrimidin-4-yl)amino)-2-benzyl-10-methyl-2,3,4,5-tetrahydropyr-
ido[1,2-a][1,4]diazepine-1,7-dione (9)
[0942] The synthesis of intermediate 9 was carried out as described
above using the general protocol of Procedure D. Yellow solid.
Yield: 0.59 g, 99%; MS (ESI) m/z 391.32 [M+1].sup.+.
Synthesis of
8-((6-aminopyrimidin-4-yl)amino)-10-methyl-2,3,4,5-tetrahydropyrido[1,2-a-
][1, 4]diazepine-1,7-dione (Cpd. No. 217)
[0943] A vial was charged with
8-((6-aminopyrimidin-4-yl)amino)-2-benzyl-10-methyl-2,3,4,5-tetrahydropyr-
ido[1,2-a][1,4]diazepine-1,7-dione (9, 0.3 g, 76.9 mmol) and
triflic acid (7.0 mL) was added. The reaction mixture was heated
under microwave at 150.degree. C. for 20 min. TLC showed completion
of the reaction and the mixture was cooled to ambient temperature.
This was then basified with aqueous sodium bicarbonate solution and
extracted with 5% methanol/dichloromethane (3.times.200 mL). The
organic layer was dried over sodium sulfate and solvent was removed
under reduced pressure to afford
8-((6-aminopyrimidin-4-yl)amino)-10-methyl-2,3,4,5-tetrahydropyrid-
o[1,2-a][1,4]diazepine-1,7-dione (Cpd. No. 217) as a brown solid.
Yield: 0.06 g, 26%; MS (ESI) m/z 301.15 [M+1].sup.+; 1H NMR (400
MHz, DMSO-d.sub.6) .delta. 8.51 (s, 1H), 8.36-8.20 (m, 2H), 8.15
(s, 1H), 6.52 (brs, 2H), 6.13 (s, 1H), 5.05 (brs, 1H), 3.26-3.04
(m, 2H), 2.95-2.80 (m, 1H), 2.13 (s, 3H), 1.87 (brs, 2H).
Example 218
Synthesis
6-amino-4-((8'-methyl-1',5'-dioxo-1',5'-dihydro-2'H-spiro[cycloh-
exane-1,3'-imidazo[1,5-a]pyridin]-6'-yl)amino)pyrimidine 1-oxide
(Cpd. No. 218)
##STR00474##
##STR00475##
[0944] Synthesis of
6-amino-4-((8'-methyl-1',5'-dioxo-1',5'-dihydro-2'H-spiro[cyclohexane-1,3-
'-imidazo[1,5-a]pyridin]-6'-yl)amino)pyrimidine 1-oxide (Cpd. No.
218)
[0945] To a solution of
6'-((6-aminopyrimidin-4-yl)amino)-8'-methyl-2'H-spiro[cyclohexane-1,3'-im-
idazo[1,5-a]pyridine]-1',5'-dione (1, 0.1 g, 0.29 mmol) in
dichloromethane (25 mL), 3-chloroperbenzoic acid (0.10 g, 0.59
mmol) was added. The reaction mixture was stirred at room
temperature for 16 h. After completion the reaction mixture was
diluted with saturated sodium bicarbonate solution (50 mL) and
stirred for 30 m at room temperature. Yellow solid precipitated out
and was filtered and dried to obtain the crude. The crude was
purified by prep purification to afford
6-amino-4-((8'-methyl-1',5'-dioxo-1',5'-dihydro-2'H-spiro[cyclohexane-1,3-
'-imidazo[1,5-a]pyridin]-6'-yl)amino)pyrimidine 1-oxide (Cpd. No.
218) as yellow solid. Yield: 50 mg, 50%; MS (ESI) m/z 357.18
[M+1].sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 10.02 (s,
1H), 9.01 (s, 1H), 8.53 (s, 1H), 8.23 (s, 1H), 7.48 (brs, 1H), 6.65
(s, 1H), 3.02-2.96 (m, 2H), 2.42 (s, 3H), 1.75-1.58 (m, 5H),
1.45-1.42 (m, 2H), 1.22-1.19 (m, 1H).
Example 219
Synthesis of
6-((6-aminopyrimidin-4-yl)amino)-1',8-dimethyl-2H-spiro[imidazo[1,5-a]pyr-
idine-3,4'-piperidine]-1,5-dione hydrochloride (Cpd. No. 219)
##STR00476##
##STR00477##
[0946] Synthesis of tert-butyl
N-tert-butoxycarbonyl-N-(6-((1',8-dimethyl-1,5-dioxo-1,5-dihydro-2H-spiro-
[imidazo[1,5-a]pyridine-3,4'-piperidin]-6-yl)amino)pyrimidin-4-yl)carbamat-
e (3)
[0947] The synthesis of intermediate 3 was carried out as described
above using the general protocol of Procedure H. Off white solid;
Yield: 320 mg, 38%; MS (ESI) m/z 556.67 [M+1].sup.+.
Synthesis of
6-((6-aminopyrimidin-4-yl)amino)-1',8-dimethyl-2H-spiro[imidazo[1,5-a]pyr-
idine-3,4'-piperidine]-1,5-dione hydrochloride (Cpd. No. 219)
[0948] The synthesis of compound 219 was carried out as described
above using the general protocol of Procedure F. Light yellow
solid. Yield: 274 mg, 97%; MS (ESI) m/z 356.18 [M+1].sup.+; .sup.1H
NMR (400 MHz, DMSO-d.sub.6) .delta. 10.64 (brs, 1H), 10.45 (s, 1H),
9.73 (s, 1H), 8.46 (s, 1H), 8.15 (s, 1H), 7.91 (brs, 2H), 6.45 (s,
1H), 3.62-3.42 (m, 6H), 2.82 (s, 3H), 2.46 (s, 3H), 1.81-1.78 (m,
2H).
Example 220
Synthesis of
6-((6-amino-5-methylpyrimidin-4-yl)amino)-1',8-dimethyl-2H-spiro[imidazo[-
1,5-a]pyridine-3,4'-piperidine]-1,5-dione (Cpd. No. 220)
##STR00478##
##STR00479##
[0949] Synthesis of
N-(6-((1',8-dimethyl-1,5-dioxo-1,5-dihydro-2H-spiro[imidazo[1,5-a]pyridin-
e-3,4'-piperidin]-6-yl)amino)-5-methylpyrimidin-4-yl)cyclopropanecarboxami-
de (3)
[0950] The synthesis of intermediate 3 was carried out as described
above using the general protocol of Procedure H. Yellow solid.
Yield: 450 mg, 67%; MS (ESI) m/z 438.36 [M+1].sup.+.
Synthesis of
6-((6-amino-5-methylpyrimidin-4-yl)amino)-1',8-dimethyl-2H-spiro[imidazo[-
1,5-a]pyridine-3,4'-piperidine]-1,5-dione (Cpd. No. 220)
[0951] The synthesis of compound 220 was carried out as described
above using the general protocol of Procedure I. Off white solid.
Yield: 150 mg, 39%; MS (ESI) m/z 370.20 [M+1].sup.+; .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 10.07 (s, 1H), 8.47 (s, 1H), 8.11
(s, 1H), 8.00 (s, 1H), 6.48 (s, 2H), 3.30-3.20 (m, 2H), 2.78-2.75
(m, 2H), 2.44 (s, 3H), 2.40-2.32 (m, 2H), 2.24 (s, 3H), 1.98 (s,
3H), 1.40-1.36 (m, 2H).
Example 221
Synthesis of
6'-((2-chloropyrimidin-4-yl)thio)-8'-methyl-2'H-spiro[cyclohexane-1,3'-im-
idazo[1,5-a]pyridine]-1',5'-dione (Cpd. No. 221)
##STR00480##
##STR00481##
[0952] Synthesis of
6'-((4-methoxybenzyl)thio)-8'-methyl-2'H-spiro[cyclohexane-1,3'-imidazo[1-
,5-a]pyridine]-1',5'-dione (3)
[0953]
6'-Bromo-8'-methyl-2'H-spiro[cyclohexane-1,3'-imidazo[1,5-a]pyridin-
e]-1',5'-dione (1, 2.0 g, 6.42 mmol) was dissolved in 2-propanol
(20 mL). To this mixture was added cesium carbonate (6.28 g, 19.28
mmol), followed by (4-methoxyphenyl)methanethiol (1.18 g, 7.71
mmol). The reaction mixture was stirred at 70.degree. C. for 16 h.
After completion, solvent was evaporated under reduced pressure and
the crude was washed with water (50 mL) followed by diethyl ether
and then dried under reduced pressure to afford
6'-((4-methoxybenzyl)thio)-8'-methyl-2'H-spiro[cyclohexane-1,3'-
-imidazo[1,5-a]pyridine]-1',5'-dione (3) as grey solid. Yield: 2.15
g, 87%; MS (ESI) m/z 385.5 [M+1].sup.+.
Synthesis of
6'-mercapto-8'-methyl-2'H-spiro[cyclohexane-1,3'-imidazo[1,5-a]pyridine]--
1',5'-dione (4)
[0954]
6'-((4-Methoxybenzyl)thio)-8'-methyl-2'H-spiro[cyclohexane-1,3'-imi-
dazo[1,5-a]pyridine]-1',5'-dione (3, 3.3 g, 8.59 mmol) was
dissolved in chloroform (20 mL) and methanesulfonic acid (10 mL)
was added. The reaction mixture was stirred at 50.degree. C. for 16
h. After completion, solvent was evaporated under reduced pressure.
Obtained crude was washed with water (50 mL) followed by ethyl
acetate and then dried under reduced pressure to afford
6'-mercapto-8'-methyl-2'H-spiro[cyclohexane-1,3'-imidazo[1,5-a]pyridine]--
1',5'-dione as grey solid. Yield: 1.3 g, 59%; MS (ESI) m/z 265.6
[M+1].sup.+.
Synthesis of
6'-((2-chloropyrimidin-4-yl)thio)-8'-methyl-2'H-spiro[cyclohexane-1,3'-im-
idazo[1,5-a]pyridine]-1',5'-dione (Cpd. No. 221)
[0955] The synthesis of compound 221 was carried out as described
above using the general protocol of Procedure B. White solid;
Yield: 0.4 g, 56%; MS (ESI) m/z 377.27 [M+1].sup.+; .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 10.52 (s, 1H), 8.45 (d, J=5.2 Hz,
1H), 8.08 (s, 1H), 7.32 (d, J=5.6 Hz, 1H), 2.92-2.84 (m, 2H), 2.42
(s, 3H), 1.74-1.71 (m, 2H), 1.65-1.52 (m, 3H), 1.47-1.44 (m, 2H),
1.18-1.15 (m, 1H).
Example 222
Synthesis of
6'-((6-amino-5-methylpyrimidin-4-yl)amino)-8'-methyl-2'H-spiro[cyclohexan-
e-1,3'-imidazo[1,5-a]pyridine]-1',5'-dione (Cpd. No. 222)
##STR00482##
##STR00483##
[0956] Synthesis of
N-(5-methyl-6-((8'-methyl-1',5'-dioxo-1',5'-dihydro-2'H-spiro[cyclohexane-
-1,3'-imidazo[1,5-a]pyridin]-6'-yl)amino)pyrimidin-4-yl)cyclopropanecarbox-
amide (3)
[0957] The synthesis of intermediate 3 was carried out as described
above using the general protocol of Procedure H. Yellow solid;
Yield: 0.17 g, 31%; MS (ESI) m/z 423.21 [M+1].sup.+.
Synthesis of
6'-((6-amino-5-methylpyrimidin-4-yl)amino)-8'-methyl-2'H-spiro[cyclohexan-
e-1,3'-imidazo[1,5-a]pyridine]-1',5'-dione (Cpd. No. 222)
[0958] The synthesis of compound 222 was carried out as described
above using the general protocol of Procedure I. White solid;
Yield: 0.10 g, 70%; MS (ESI) m/z 355.18 [M+1].sup.+; .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 10.05 (s, 1H), 8.48 (s, 1H), 8.12
(s, 1H), 8.01 (s, 1H), 6.48 (s, 2H), 2.98 (t, J=9.2 Hz, 2H), 2.45
(s, 3H), 1.98 (s, 3H), 1.73-1.58 (m, 5H), 1.48-1.42 (m, 2H),
1.30-1.23 (m, 1H).
Example 223
Synthesis of
6'-((6-amino-5-chloropyrimidin-4-yl)amino)-8'-methyl-2'H-spiro[cyclohexan-
e-1,3'-imidazo[1,5-a]pyridine]-1',5'-dione hydrochloride (Cpd. No.
223)
##STR00484##
##STR00485##
[0959] Synthesis of tert-butyl
N-tert-butoxycarbonyl-N-(5-Chloro-6-((8'-methyl-1',5'-dioxo-1',5'-dihydro-
-2'H-spiro[cyclohexane-1,3'-imidazo
pyridin]-6'-yl)amino)pyrimidin-4-yl)carbamate (3)
[0960] The synthesis of intermediate 3 was carried out as described
above using the general protocol of Procedure B. Off white solid;
Yield: 0.32 g, 39%; MS (ESI) m/z 575.23 [M+1].sup.+; .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 10.26 (s, 1H), 9.03 (s, 1H), 8.79
(s, 1H), 8.55 (s, 1H), 2.96 (m, 2H), 2.5 (s, 3H), 1.76-1.58 (m,
5H), 1.49 (m, 2H), 1.39 (s, 18H), 1.25 (m, 1H).
Synthesis of
6'-((6-amino-5-chloropyrimidin-4-yl)amino)-8'-methyl-2'H-spiro[cyclohexan-
e-1,3'-imidazo[1,5-a]pyridine]-1',5'-dione hydrochloride (Cpd. No.
223)
[0961] The synthesis of compound 223 was carried out as described
above using the general protocol of Procedure F. Yellow solid.
Yield: 0.20 g, 88%; MS (ESI) m/z 375.13 [M+1].sup.+; .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 10.15 (s, 1H), 8.60 (s, 1H), 8.47
(s, 1H), 8.21 (s, 1H), 7.23 (brs, 2H), 2.97 (t, J=9.6, Hz, 2H),
2.46 (s, 3H), 1.76-1.58 (m, 5H), 1.48-1.42 (m, 2H), 1.30-1.21 (m,
1H).
Example 224
Synthesis of
6'-((2-chloropyrimidin-4-yl)oxy)-8'-methyl-2'H-spiro[cyclohexane-1,3'-imi-
dazo[1,5-a]pyridine]-1',5'-dione (Cpd. No. 224)
##STR00486##
##STR00487##
[0962] Synthesis of
6'-((4-methoxybenzyl)oxy)-8'-methyl-2'H-spiro[cyclohexane-1,3'-imidazo[1,-
5-a]pyridine]-1',5'-dione (3)
[0963] To a solution of
6'-bromo-8'-methyl-2'H-spiro[cyclohexane-1,3'-imidazo[1,5-a]pyridine]-1',-
5'-dione (1, 2.5 g, 8.03 mmol) in dimethylformamide (20 mL), sodium
hydride (1.15 g, 48.23 mmol) was added portion wise. The reaction
mixture was stirred at 0.degree. C. for 30 m. To the reaction
mixture was added (4-methoxyphenyl)methanol (3.34 g, 24.11 mmol)
and the reaction was stirred at 80.degree. C. for 16 h. After
completion, solvent was evaporated under reduced pressure. Obtained
crude was washed with water (50 mL) followed by diethyl ether and
dried under reduced pressure to afford
6'-((4-methoxybenzyl)oxy)-8'-methyl-2'H-spiro[cyclohexane-1,3'-imi-
dazo[1,5-a]pyridine]-1',5'-dione (3) as yellow solid. Yield: 1.4 g,
48%; MS (ESI) m/z 369.15 [M+1].sup.+.
Synthesis of
6'-hydroxy-8'-methyl-2'H-spiro[cyclohexane-1,3'-imidazo[1,5-a]pyridine]-1-
',5'-dione (4)
[0964]
6'-((4-Methoxybenzyl)oxy)-8'-methyl-2'H-spiro[cyclohexane-1,3'-imid-
azo[1,5-a]pyridine]-1',5'-dione (3, 3.3 g, 8.59 mmol) was dissolved
in 1,2-dichloroethane (25 mL) and trifluoroacetic acid (10 mL) was
added. The reaction mixture was stirred at 50.degree. C. for 2 h.
After completion, solvent was evaporated under reduced pressure.
Obtained crude was washed with water (50 mL) followed by n-pentane
and dried under reduced pressure to afford
6'-hydroxy-8'-methyl-2'H-spiro[cyclohexane-1,3'-imidazo[1,5-a]pyridine]-1-
',5'-dione (4) as yellow solid. Yield: 0.85 g, 90%; MS (ESI) m/z
249.07 [M+1].sup.+.
Synthesis of
6'-((2-chloropyrimidin-4-yl)oxy)-8'-methyl-2'H-spiro[cyclohexane-1,3'-imi-
dazo[1,5-a]pyridine]-1',5'-dione (Cpd. No. 224)
[0965]
6'-Hydroxy-8'-methyl-2'H-spiro[cyclohexane-1,3'-imidazo[1,5-a]pyrid-
ine]-1',5'-dione (4, 0.5 g, 2.01 mmol) was dissolved in 2-propanol
(20 mL) and N,N-diisopropylethylamine (780 mg, 6.05 mmol) and
2,4-dichloropyrimidine (0.30 g, 2.83 mmol) were added. The reaction
mixture was stirred at 120.degree. C. for 36 h. After completion,
the solvent was evaporated under reduced pressure and water (100
mL) was added. The precipitated yellow solid was filtered and dried
under reduced pressure. This crude was purified by silica gel
(220-400 mesh) column chromatography using 2-5% methanol in
dichloromethane as an eluent to afford
6'-((2-chloropyrimidin-4-yl)oxy)-8'-methyl-2'H-spiro[cyclohexane-1-
,3'-imidazo[1,5-a]pyridine]-1',5'-dione (Cpd. No. 224). Yield: 0.33
g, 46%; MS (ESI) m/z 361.12 [M+1].sup.+; .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 10.37 (s, 1H), 8.65 (d, J=5.6 Hz, 1H), 7.61
(s, 1H), 7.28 (d, J=5.6 Hz, 1H), 6.55 (s, 2H), 2.88-2.72 (m, 2H),
2.44 (s, 3H), 1.72-1.70 (m, 2H), 1.64-1.58 (m, 3H), 1.45-1.42 (m,
2H), 1.17-1.13 (m, 1H).
Example 225
Synthesis of
2-(6-((6-aminopyrimidin-4-yl)amino)-8-methyl-1,5-dioxo-1,5-dihydro-2H-spi-
ro[imidazo[1,5-a]pyridine-3,4'-piperidin]-1'-yl)acetonitrile (Cpd.
No. 225)
##STR00488##
##STR00489##
[0966] Synthesis of di-tert-butyl
(6-((1'-(cyanomethyl)-8-methyl-1,5-dioxo-1,5-dihydro-2H-spiro[imidazo[1,5-
-a]pyridine-3,4'-piperidin]-6-yl)amino)pyrimidin-4-yl)-12-azanecarboxylate
(3)
[0967] The synthesis of intermediate 3 was carried out as described
above using the general protocol of Procedure B. Yellow solid;
Yield: 0.25 g, 60%; MS (ESI) m/z 581.49 [M+1].sup.+.
Synthesis of
2-(6-((6-aminopyrimidin-4-yl)amino)-8-methyl-1,5-dioxo-1,5-dihydro-2H-spi-
ro[imidazo[1,5-a]pyridine-3,4'-piperidin]-1'-yl)acetonitrile (Cpd.
No. 225)
[0968] The synthesis of compound 225 was carried out as described
above using the general protocol of Procedure F. White solid;
Yield: 37 mg, 38%; MS (ESI) m/z 381.19 [M+1].sup.+; .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 10.40 (s, 1H), 9.47 (s, 1H), 8.38
(s, 1H), 8.18 (s, 1H), 7.54 (brs, 2H), 6.34 (s, 1H), 3.74 (s, 2H),
3.30-3.23 (m, 2H), 2.89-2.87 (m, 2H), 2.66-2.64 (s, 2H), 2.42 (s,
3H), 1.50-1.47 (m, 2H).
Example 226
Synthesis of
6-((6-aminopyrimidin-4-yl)amino)-1'-(2,2-difluoroethyl)-8-methyl-2H-spiro-
[imidazo[1,5-a]pyridine-3,4'-piperidine]-1,5-dione (Cpd. No.
226)
##STR00490##
##STR00491##
[0969] Synthesis of
6-bromo-1'-(2,2-difluoroethyl)-8-methyl-2H-spiro[imidazo[1,5-a]pyridine-3-
,4'-piperidine]-1,5-dione (3)
[0970] To a solution of
6-bromo-8-methyl-2H-spiro[imidazo[1,5-a]pyridine-3,4'-piperidine]-1,5-dio-
ne hydrochloride (1, 300 mg, 0.96 mmol) in acetonitrile was added
2-bromo-1,1-difluoroethane (348 mg, 2.40 mmol) and potassium
carbonate (397 mg, 2.88 mmol). The reaction was heated at
90.degree. C. for 18 h. On completion of reaction, solvent was
removed and the crude was purified by silica gel (200-400 mesh)
column chromatography eluting with 5-7% methanol in
dichloromethane. Appropriate column fractions were concentrated
under reduced pressure to afford
6-bromo-1'-(2,2-difluoroethyl)-8-methyl-2H-spiro[imidazo[1,5-c]pyridine-3-
,4'-piperidine]-1,5-dione (3) as light yellow solid. Yield: 180 mg,
37%; MS (ESI) m/z 378.22 [M+1].sup.+.
Synthesis of tert-butyl
N-tert-butoxycarbonyl-N-(6-((1'-(2,2-difluoroethyl)-8-methyl-1,5-dioxo-1,-
5-dihydro-2H-spiro[imidazo[1,5-a]pyridine-3,4'-piperidin]-6-yl)amino)pyrim-
idin-4-yl)carbamate (5)
[0971] The synthesis of intermediate 5 was carried out as described
above using the general protocol of Procedure H. Off white solid;
Yield: 200 mg, 69%; MS (ESI) m/z 606.18.
Synthesis of
6-((6-aminopyrimidin-4-yl)amino)-1'-(2,2-difluoroethyl)-8-methyl-2H-spiro-
[imidazo[1,5-a]pyridine-3,4'-piperidine]-1,5-dione (Cpd. No.
226)
[0972] The synthesis of compound 226 was carried out as described
above using the general protocol of Procedure F. White solid;
Yield: 14 mg, 8%; MS (ESI) m/z 406.20 [M+1].sup.+; .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. 10.08 (s, 1H), 8.57 (s, 1H), 8.38 (s,
1H), 8.16 (s, 1H), 6.51 (s, 2H), 6.30-6.00 (m, 2H), 3.25-3.22 (m,
2H), 2.94-2.91 (m, 2H), 2.87-2.79 (m, 2H), 2.69-2.63 (m, 2H), 2.42
(s, 3H), 1.39-1.36 (m, 2H).
Example 227
Synthesis of
6-((5-methoxypyrimidin-4-yl)amino)-1',8-dimethyl-2H-spiro[imidazo[1,5-a]p-
yridine-3,4'-piperidine]-1,5-dione (Cpd. No. 227)
##STR00492##
##STR00493##
[0973] Synthesis of
6-bromo-1',8-dimethyl-2H-spiro[imidazo[1,5-a]pyridine-3,4'-piperidine]-1,-
5-dione (3)
[0974] To a stirred solution of
5-bromo-3-methyl-6-oxo-1,6-dihydropyridine-2-carboxamide (1, 3 g,
12.98 mmol) in 1,4-dioxane (25 mL), 1-methylpiperidin-4-one (2.2 g,
19.47 mmol) was added at room temperature. To the mixture 4 M
hydrogenchloride in dioxane (6.5 mL, 2.59 mmol) was added dropwise.
The reaction was heated up to 110.degree. C. for 16 h. After
completion, solvent was removed under reduced pressure and obtained
solid was washed with warm water followed by pentane and ether to
afford
6-bromo-1',8-dimethyl-2H-spiro[imidazo[1,5-a]pyridine-3,4'-piperidine]-1,-
5-dione (3) as off white solid. Yield: 2.5 g, 59%; MS (ESI) m/z 326
[M+1].sup.+.
Synthesis of
6-((5-methoxypyrimidin-4-yl)amino)-1',8-dimethyl-2H-spiro[imidazo[1,5-a]p-
yridine-3,4'-piperidine]-1,5-dione (Cpd. No. 227)
[0975] The synthesis of compound 227 was carried out as described
above using the general protocol of Procedure B. Off white solid;
Yield: 103 mg, 18%; MS (ESI) m/z 371.16 [M+1].sup.+; .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 10.16 (brs, 1H), 8.62 (s, 1H), 8.58
(s, 1H), 8.48 (s, 1H), 8.24 (s, 1H), 4.00 (s, 3H), 3.25-3.21 (m,
2H), 2.84-2.81 (m, 2H), 2.45 (s, 3H), 2.48-2.42 (m, 2H), 2.28 (s,
3H), 1.44-1.41 (m, 2H).
Example 228
Synthesis of
6-((6-amino-5-methoxypyrimidin-4-yl)amino)-1',8-dimethyl-2H-spiro[imidazo-
[1,5-a]pyridine-3,4'-piperidine]-1,5-dione (Cpd. No. 228)
##STR00494##
##STR00495##
[0976] Synthesis
N-(6-((1',8-dimethyl-1,5-dioxo-1,5-dihydro-2H-spiro[imidazo[1,5-a]pyridin-
e-3,4'-piperidin]-6-yl)amino)-5-methoxypyrimidin-4-yl)cyclopropanecarboxam-
ide (3)
[0977] The synthesis of intermediate 3 was carried out as described
above using the general protocol of Procedure B. Light yellow
solid; Yield: 103 mg, 31%; MS (ESI) m/z 454.15 [M+1].sup.+.
Synthesis of
6-((6-amino-5-methoxypyrimidin-4-yl)amino)-1',8-dimethyl-2H-spiro[imidazo-
[1,5-a]pyridine-3,4'-piperidine]-1,5-dione (Cpd. No. 228)
[0978] A flask containing tetrahydrofuran, ethanol and water
(1:1:1, 5 mL each) was charged with
6-((6-amino-5-methoxypyrimidin-4-yl)amino)-1',8-dimethyl-2H-spiro[imidazo-
[1,5-c]pyridine-3,4'-piperidine]-1,5-dione (3, 0.2 g, 0.441 mmol)
and sodium hydroxide (88 mg, 2.2 mmol). The reaction was stirred at
60.degree. C. for 16 h. After completion, the reaction mass was
extracted with 10% 2-propanol in chloroform (5.times.50 mL).
Combined organic layer was concentrated and obtained solid was
washed with methanol and dried under vacuum to afford
6-((6-amino-5-methoxypyrimidin-4-yl)amino)-1',8-dimethyl-2H-spiro[imidazo-
[1,5-c]pyridine-3,4'-piperidine]-1,5-dione (Cpd. No. 228) as light
yellow solid. Yield: 88 mg, 52%; MS (ESI) m/z 386.19 [M+1].sup.+;
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 10.11 (s, 1H), 8.45 (s,
1H), 8.32 (s, 1H), 8.00 (s, 2H), 6.67 (s, 2H), 3.69 (s, 3H),
3.30-3.20 (m, 2H), 2.90 (brs, 2H), 2.50-2.46 (m, 2H), 2.45 (s, 3H),
2.33 (s, 3H), 1.47-1.45 (m, 2H).
Example 229
Synthesis of
2-(6-((5-methoxypyrimidin-4-yl)amino)-8-methyl-1,5-dioxo-1,5-dihydro-2H-s-
piro[imidazo[1,5-a]pyridine-3,4'-piperidin]-1'-yl)acetonitrile
(Cpd. No. 229)
##STR00496##
##STR00497##
[0979] Synthesis of
2-(6-bromo-8-methyl-1,5-dioxo-1,5-dihydro-2H-spiro[imidazo[1,5-a]pyridine-
-3,4'-piperidin]-1'-yl)acetonitrile (3)
[0980] A flask was charged with
6-bromo-8-methyl-2H-spiro[imidazo[1,5-a]pyridine-3,4'-piperidine]-1,5-dio-
ne (1, 0.50 g, 1.6 mmol) and acetonitrile (15 mL). The reaction
mass was cooled to 0.degree. C. and potassium carbonate (664 mg,
4.8 mmol) was added followed by the addition of 2-bromoacetonitrile
(288.18 mg, 2.40 mmol). The reaction mass was stirred at 70.degree.
C. for 16 h. After completion, reaction mixture was diluted with
saturated ammonium chloride solution (50 mL). The precipitate was
filtered and dried under reduced pressure to afford
2-(6-bromo-8-methyl-1,5-dioxo-1,5-dihydro-2H-spiro[imidazo[1,5-a]pyridine-
-3,4'-piperidin]-1'-yl)acetonitrile (3) as white solid. Yield: 0.32
g, 58%; MS (ESI) m/z 351.26 [M+1].sup.+.
Synthesis of
2-(6-((5-methoxypyrimidin-4-yl)amino)-8-methyl-1,5-dioxo-1,5-dihydro-2H-s-
piro[imidazo[1,5-a]pyridine-3,4'-piperidin]-1'-yl)acetonitrile
(Cpd. No. 229)
[0981] The synthesis of compound 229 was carried out as described
above using the general protocol of Procedure B. Yellow solid.
Yield: 0.068 g, 20%; MS (ESI) m/z 396.5 [M+1].sup.+; .sup.1H NMR
(400 MHz, DMSO-d.sub.6 with d.sub.1-TFA) .delta. 8.94 (s, 1H), 8.53
(s, 1H), 8.44 (s, 1H), 4.47 (s, 2H), 4.07 (s, 3H), 3.71-3.68 (m,
2H), 3.47-3.39 (m, 4H), 2.47 (s, 3H), 1.92-1.89 (m, 2H).
Example 230
Synthesis of
1'-(2,2-difluoroethyl)-6-((5-methoxypyrimidin-4-yl)amino)-8-methyl-2H-spi-
ro[imidazo[1,5-a]pyridine-3,4'-piperidine]-1,5-dione (Cpd. No.
230)
##STR00498##
##STR00499##
[0982] Synthesis of
1'-(2,2-difluoroethyl)-6-((5-methoxypyrimidin-4-yl)amino)-8-methyl-2H-spi-
ro[imidazo[1,5-a]pyridine-3,4'-piperidine]-1,5-dione (Cpd. No.
230)
[0983] The synthesis of compound 230 was carried out as described
above using the general protocol of Procedure H. Off white solid;
Yield: 65 mg, 45%; MS (ESI) m/z 421.13 [M+1].sup.+; .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 10.22 (s, 1H), 8.64 (s, 1H), 8.58
(s, 1H), 8.48 (s, 1H), 8.24 (s, 2H), 6.30-6.00 (m, 1H), 4.00 (s,
1H), 3.31-3.17 (m, 2H), 2.95-2.92 (m, 2H), 2.87-2.78 (m, 2H),
2.68-2.62 (m, 2H), 2.49 (s, 3H), 1.43-1.40 (m, 2H).
Example 231
Synthesis of
6'-((6-amino-5-methoxypyrimidin-4-yl)amino)-8'-methyl-2'H-spiro[cyclohexa-
ne-1,3'-imidazo[1,5-a]pyridine]-1',5'-dione (Cpd. No. 231)
##STR00500##
##STR00501##
[0984] Synthesis of
N-(5-methoxy-6-((8'-methyl-1',5'-dioxo-1',5'-dihydro-2'H-spiro[cyclohexan-
e-1,3'-imidazo[1,5-a]pyridin]-6'-yl)amino)pyrimidin-4-yl)cyclopropanecarbo-
xamide (3)
[0985] The synthesis of intermediate 3 was carried out as described
above using the general protocol of Procedure H. Light yellow
solid; Yield: 0.3 g, 71%; MS (ESI) m/z 439.14 [M+1].sup.+.
Synthesis of
6'-((6-amino-5-methoxypyrimidin-4-yl)amino)-8'-methyl-2'H-spiro[cyclohexa-
ne-1,3'-imidazo[1,5-a]pyridine]-1',5'-dione (Cpd. No. 231)
[0986] The synthesis of compound 231 was carried out as described
above using the general protocol of Procedure I. Yellow solid;
Yield: 0.085 g, 27%; MS (ESI) m/z 371.16 [M+1].sup.+; .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 10.06 (s, 1H), 8.47 (s, 1H), 8.33
(s, 1H), 8.00 (s, 1H), 6.67 (s, 2H), 3.69 (s, 3H), 3.02-2.95 (m,
2H), 2.45 (s, 3H), 1.78-1.58 (m, 5H), 1.47-1.43 (m, 2H), 1.29-1.20
(m, 1H).
Example 232
Synthesis of
6-((6-aminopyrimidin-4-yl)amino)-8-methyl-1'-(2,2,2-trifluoroethyl)-2H-sp-
iro[imidazo[1,5-a]pyridine-3,4'-piperidine]-1,5-dione (Cpd. No.
232)
##STR00502##
##STR00503##
[0987] Synthesis of N-(6-((8-methyl-1,5-dioxo-1'-(2,2,
2-trifluoroethyl)-1,5-dihydro-2H-spiro[imidazo[1,5-a]pyridine-3,4'-piperi-
din]-6-yl)amino)pyrimidin-4-yl)cyclopropanecarboxamide (3)
[0988] The synthesis of intermediate 3 was carried out as described
above using the general protocol of Procedure H. Yellow solid.
Yield: 300 mg, 60%; MS (ESI) m/z 492.10 [M+1].sup.+.
Synthesis of
6-((6-aminopyrimidin-4-yl)amino)-8-methyl-1'-(2,2,2-trifluoroethyl)-2H-sp-
iro[imidazo[1,5-a]pyridine-3,4'-piperidine]-1,5-dione (Cpd. No.
232)
[0989] The synthesis of compound 232 was carried out as described
above using the general protocol of Procedure I. White solid;
Yield: 60 mg, 23%; MS (ESI) m/z 424.19 [M+1].sup.+; .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 10.14 (s, 1H), 8.65 (s, 1H), 8.37
(s, 1H), 8.18 (s, 1H), 6.60 (s, 2H), 6.18 (s, 1H), 3.27-3.22 (m,
4H), 2.95-2.90 (m, 2H), 2.85-2.76 (m, 2H), 2.42 (s, 3H), 1.41-1.36
(m, 2H).
Example 233
Synthesis of
6-((6-amino-5-methylpyrimidin-4-yl)amino)-1'-(2,2-difluoroethyl)-8-methyl-
-2H-spiro[imidazo[1,5-a]pyridine-3,4'-piperidine]-1,5-dione (Cpd.
No. 233)
##STR00504##
##STR00505##
[0990] Synthesis of
N-(6-((1'-(2,2-difluoroethyl)-8-methyl-1,5-dioxo-1,5-dihydro-2H-spiro[imi-
dazo[1,5-a]pyridine-3,4'-piperidin]-6-yl)amino)-5-methylpyrimidin-4-yl)cyc-
lopropanecarboxamide (3)
[0991] The synthesis of intermediate 3 was carried out as described
above using the general protocol of Procedure H. Light yellow
solid; Yield: 0.35 g, 65%; MS (ESI) m/z 488.27 [M+1].sup.+.
Synthesis of
6-((6-amino-5-methylpyrimidin-4-yl)amino)-1'-(2,2-difluoroethyl)-8-methyl-
-2H-spiro[imidazo[1,5-a]pyridine-3,4'-piperidine]-1,5-dione (Cpd.
No. 233)
[0992] The synthesis of compound 233 was carried out as described
above using the general protocol of Procedure I. Off white solid;
Yield: 80 mg, 26%; MS (ESI) m/z 420.20 [M+1].sup.+; .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 10.13 (s, 1H), 8.48 (s, 1H), 8.12
(s, 1H), 8.00 (s, 1H), 6.48 (s, 2H), 6.30-6.00 (m, 1H), 3.27-3.21
(m, 2H), 2.94-2.91 (m, 2H), 2.86-2.77 (m, 2H), 2.67-2.61 (m, 2H),
2.44 (s, 3H), 1.98 (s, 3H), 1.41-1.38 (m, 2H).
Example 234
Synthesis of
6-((6-amino-5-methoxypyrimidin-4-yl)amino)-8-methyl-1'-(2,2,2-trifluoroet-
hyl)-2H-spiro[imidazo[1,5-a]pyridine-3,4'-piperidine]-1,5-dione
(Cpd. No. 234)
##STR00506##
##STR00507##
[0993] Synthesis
N-(5-methoxy-6-((8-methyl-1,5-dioxo-1'-(2,2,2-trifluoroethyl)-1,5-dihydro-
-2H-spiro[imidazo[1,5-a]pyridine-3,4'-piperidin]-6-yl)amino)pyrimidin-4-yl-
)cyclopropanecarboxamide (3)
[0994] The synthesis of intermediate 3 was carried out as described
above using the general protocol of Procedure B. Light yellow
solid; Yield: 400 mg, 76%; MS (ESI) m/z 522.19 [M+1].sup.+.
Synthesis of
6-((6-amino-5-methoxypyrimidin-4-yl)amino)-8-methyl-1'-(2,2,2-trifluoroet-
hyl)-2H-spiro[imidazo[1,5-a]pyridine-3,4'-piperidine]-1,5-dione
(Cpd. No. 234)
[0995] The synthesis of compound 234 was carried out as described
above using the general protocol of Procedure I. Light yellow
solid; Yield: 100 mg, 29%; MS (ESI) m/z 354.12 [M+1].sup.+; .sup.1H
NMR (400 MHz, DMSO-d.sub.6) .delta. 10.19 (s, 1H), 8.45 (s, 1H),
8.32 (s, 1H), 8.00 (s, 1H), 6.67 (s, 2H), 3.69 (s, 3H), 3.27-3.21
(m, 4H), 2.97-2.90 (m, 2H), 2.83-2.77 (m, 2H), 2.45 (s, 3H),
1.42-1.38 (m, 2H).
Example 235
Synthesis of
6-((5-methoxypyrimidin-4-yl)amino)-8-methyl-1'-(2,2,2-trifluoroethyl)-2H--
spiro[imidazo[1,5-a]pyridine-3,4'-piperidine]-1,5-dione (Cpd. No.
235)
##STR00508##
##STR00509##
[0996] Synthesis of
6-((5-methoxypyrimidin-4-yl)amino)-8-methyl-1'-(2,2,2-trifluoroethyl)-2H--
spiro[imidazo[1,5-a]pyridine-3,4'-piperidine]-1,5-dione (Cpd. No.
235)
[0997] The synthesis of compound 235 was carried out as described
above using the general protocol of Procedure B. Off white solid;
Yield: 0.13 g, 39%; MS (ESI) m/z 439.21 [M+1].sup.+; .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 10.29 (s, 1H), 8.65 (s, 1H), 8.58
(s, 1H), 8.48 (s, 1H), 8.24 (s, 1H), 4.00 (s, 3H), 3.32-3.22 (m,
4H), 2.96-2.90 (m, 2H), 2.85-2.79 (m, 2H), 2.45 (s, 3H), 1.42-1.39
(m, 2H).
Example 236
Synthesis of
6-((6-amino-5-methylpyrimidin-4-yl)amino)-8-methyl-1'-(2,2,2-trifluoroeth-
yl)-2H-spiro[imidazo[1,5-a]pyridine-3,4'-piperidine]-1,5-dione
(Cpd. No. 236)
##STR00510##
##STR00511##
[0998] Synthesis of
6-bromo-8-methyl-1'-(2,2,2-trifluoroethyl)-2H-spiro[imidazo[1,5-a]pyridin-
e-3,4'-piperidine]-1,5-dione (3)
[0999] The synthesis of intermediate 3 was carried out as described
above using the general protocol of Procedure A. Yield: 5.0 g, 58%;
MS (ESI) m/z 394.08 [M+1].sup.+.
Synthesis of N-(5-methyl-6-((8-methyl-1,5-dioxo-1'-(2, 2,
2-trifluoroethyl)-1,5-dihydro-2H-spiro[imidazo[1,5-a]pyridine-3,4'-piperi-
din]-6-yl)amino)pyrimidin-4-yl)cyclopropanecarboxamide (5)
[1000] The synthesis of intermediate 5 was carried out as described
above using the general protocol of Procedure H. Brown solid;
Yield: 0.32 g, 62%; MS (ESI) m/z 506.23 [M+1].sup.+.
Synthesis of
6-((6-amino-5-methylpyrimidin-4-yl)amino)-8-methyl-1'-(2,2,
2-trifluoroethyl)-2H-spiro[imidazo[1,5-a]pyridine-3,4'-piperidine]-1,5-di-
one (Cpd. No. 236)
[1001] The synthesis of compound 236 was carried out as described
above using the general protocol of Procedure I. Yield: 70 mg, 27%;
MS (ESI) m/z 438.16 [M+1].sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6
with d.sub.1-TFA) .delta. 10.17 (s, 1H), 8.48 (s, 1H), 8.12 (s,
1H), 8.00 (s, 1H), 6.48 (s, 2H), 3.32-3.20 (m, 4H), 2.95-2.93 (m,
2H), 2.85-2.75 (m, 2H), 2.45 (s, 3H), 1.98 (s, 3H), 1.41-1.38 (m,
2H).
Example 237
Synthesis of
6-((6-amino-5-chloropyrimidin-4-yl)amino)-1',8-dimethyl-2H-spiro[imidazo[-
1,5-a]pyridine-3,4'-piperidine]-1,5-dione (Cpd. No. 237)
##STR00512##
##STR00513##
[1002] Synthesis of
N-(5-chloro-6-((1',8-dimethyl-1,5-dioxo-1,5-dihydro-2H-spiro[imidazo[1,5--
a]pyridine-3,4'-piperidin]-6-yl)amino)pyrimidin-4-yl)cyclopropanecarboxami-
de (3)
[1003] The synthesis of intermediate 3 was carried out as described
above using the general protocol of Procedure H. Light brown solid;
Yield: 210 mg, 50%; MS (ESI) m/z 458.12 [M+1].sup.+.
Synthesis of
6-((6-amino-5-chloropyrimidin-4-yl)amino)-1',8-dimethyl-2H-spiro[imidazo[-
1,5-a]pyridine-3,4'-piperidine]-1,5-dione (Cpd. No. 237)
[1004] A flask containing tetrahydrofuran, ethanol and water
(1:1:1, 5 mL each) was charged with
6-((6-amino-5-methoxypyrimidin-4-yl)amino)-1',8-dimethyl-2H-spiro[imidazo-
[1,5-c]pyridine-3,4'-piperidine]-1,5-dione (3, 0.17 g, 0.371 mmol)
and sodium hydroxide (75 mg, 1.85 mmol). The reaction was stirred
at 50.degree. C. for 16 h. After completion, the reaction mass was
extracted with 10% methanol in dichloromethane. Combined organic
layer was washed with water, brine, dried over anhydrous sodium
sulfate concentrated under vacuum obtained solid was washed with
ether and dried under vacuum to afford
6-((6-amino-5-chloropyrimidin-4-yl)amino)-1',8-dimethyl-2H-spiro[i-
midazo[1,5-a]pyridine-3,4'-piperidine]-1,5-dione as light yellow
solid. Yield: 88 mg, 31%; MS (ESI) m/z 390.14 [M+1].sup.+; .sup.1H
NMR (400 MHz, DMSO-d.sub.6) .delta. 10.16 (s, 1H), 8.52 (s, 1H),
8.50 (s, 1H), 8.17 (s, 1H), 7.10 (brs, 2H), 3.30-3.20 (m, 2H),
2.90-2.82 (brs, 2H), 2.49-2.40 (m, 2H), 2.46 (s, 3H), 2.30 (s, 3H),
1.46-1.40 (m, 2H).
Example 238
Synthesis of
2-(6-((6-amino-5-chloropyrimidin-4-yl)amino)-8-methyl-1,5-dioxo-1,5-dihyd-
ro-2H-spiro[imidazo[1,5-a]pyridine-3,4'-piperidin]-1'-yl)acetonitrile
(Cpd. No. 238)
##STR00514##
##STR00515##
[1005] Synthesis of tert-butyl
6-((5-chloro-6-(cyclopropanecarboxamido)pyrimidin-4-yl)amino)-8-methyl-1,-
5-dioxo-1,5-dihydro-2H-spiro[imidazo[1,5-a]pyridine-3,4'-piperidine]-1'-ca-
rboxylate (3)
[1006] The synthesis of intermediate 3 was carried out as described
above using the general protocol of Procedure B. Light yellow
solid; Yield: 0.35 g, crude; MS (ESI) m/z 544.27 [M+1].sup.+.
Synthesis of tert-butyl
6-((6-amino-5-chloropyrimidin-4-yl)amino)-8-methyl-1,5-dioxo-1,5-dihydro--
2H-spiro[imidazo[1,5-a]pyridine-3,4'-piperidine]-1'-carboxylate
(4)
[1007] The synthesis of intermediate 4 was carried out as described
above using the general protocol of Procedure I. Yellow solid;
Yield: 300 mg, crude; MS (ESI) m/z 476.23 [M+1].sup.+.
Synthesis of
6-((6-amino-5-chloropyrimidin-4-yl)amino)-8-methyl-2H-spiro[imidazo[1,5-a-
]pyridine-3,4'-piperidine]-1,5-dione hydrochloride (5)
[1008] The synthesis of intermediate 5 was carried out as described
above using the general protocol of Procedure F. Light yellow
solid; Yield: 0.075 g, crude; MS (ESI) m/z 376.23 [M+1].sup.+.
Synthesis of
2-(6-((6-amino-5-chloropyrimidin-4-yl)amino)-8-methyl-1,5-dioxo-1,5-dihyd-
ro-2H-spiro[imidazo[1,5-a]pyridine-3,4'-piperidin]-1'-yl)acetonitrile
(Cpd. No. 238)
[1009]
6-((6-Amino-5-chloropyrimidin-4-yl)amino)-8-methyl-2H-spiro[imidazo-
[1,5-c]pyridine-3,4'-piperidine]-1,5-dione hydrochloride (5, 75 mg,
0.20 mmol) was dissolved in dimethylformamide (5 mL). To this
mixture N,N-diisopropylethylamine (77 mg, 0.60 mmol) and
bromoacetonitrile (36 mg, 0.30 mmol) were added. The reaction
mixture was stirred at room temperature for 2 h. After completion
reaction mixture was diluted with saturated ammonium chloride
solution (50 mL). The yellow precipitate out was filtered and dried
under reduced pressure. The crude was purified by prep purification
to afford
2-(6-((6-amino-5-chloropyrimidin-4-yl)amino)-8-methyl-1,5-dioxo-1,5-dihyd-
ro-2H-spiro[imidazo[1,5-a]pyridine-3,4'-piperidin]-1'-yl)acetonitrile
(Cpd. No. 238) as white solid. Yield: 14 mg, 17%; MS (ESI) m/z
414.85 [M+1].sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6 with
d.sub.1-TFA) .delta. 8.49 (s, 1H), 8.33 (s, 1H), 4.49 (s, 2H),
3.76-3.71 (m, 2H), 3.58-3.41 (m, 4H), 2.42 (s, 3H), 1.90-1.87 (m,
2H).
Example 239
Synthesis of
6-((6-amino-5-methylpyrimidin-4-yl)amino)-8-methyl-2',3',5',6'-tetrahydro-
-2H-spiro[imidazo[1,5-a]pyridine-3,4'-pyran]-1,5-dione (Cpd. No.
239)
##STR00516##
##STR00517## ##STR00518##
[1010] Synthesis of
6-bromo-8-methyl-2',3',5',6'-tetrahydro-2H-spiro[imidazo[1,5-a]pyridine-3-
,4'-pyran]-1,5-dione (3)
[1011] The synthesis of intermediate 3 was carried out as described
above using the general protocol of Procedure A. Off white solid;
Yield: 1.4 g, 69%; MS (ESI) m/z 313 [M+1].sup.+.
Synthesis of tert-butyl
(8-methyl-1,5-dioxo-1,2',3',5,5',6'-hexahydro-2H-spiro[imidazo[1,5-a]pyri-
dine-3,4'-pyran]-6-yl)carbamate (5)
[1012] The synthesis of intermediate 5 was carried out as described
above using the general protocol of Procedure H. Off white solid;
Yield: 1.2 g, crude; MS (ESI) m/z 350 [M+1].sup.+.
Synthesis of
6-amino-8-methyl-2',3',5',6'-tetrahydro-2H-spiro[imidazo[1,5-a]pyridine-3-
,4'-pyran]-1,5-dione hydrochloride (6)
[1013] The synthesis of intermediate 6 was carried out as described
above using the general protocol of Procedure F. Off white solid;
Yield: 0.45 g, 42%; MS (ESI) m/z 285 [M+1].sup.+.
Synthesis of
6-((6-(di-(tert-butoxycarbonyl)-amino)-5-methylpyrimidin-4-yl)amino)-8-me-
thyl-2',3',5',6'-tetrahydro-2H-spiro[imidazo[1,5-a]pyridine-3,4'-pyran]-1,-
5-dione (8)
[1014] The synthesis of intermediate 8 was carried out as described
above using the general protocol of Procedure H. Off white solid;
Yield: 0.26 g, 44%; MS (ESI) m/z 557 [M+1].sup.+.
Synthesis of
6-((6-amino-5-methylpyrimidin-4-yl)amino)-8-methyl-2',3',5',6'-tetrahydro-
-2H-spiro[imidazo[1,5-a]pyridine-3,4'-pyran]-1,5-dione (Cpd. No.
239)
[1015] The synthesis of compound 239 was carried out as described
above using the general protocol of Procedure F. Off white solid;
Yield: 0.12 g, 72%; MS (ESI) m/z 357 [M+1].sup.+; .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. 10.47 (s, 1H), 8.54 (s, 1H), 8.41 (s,
1H), 8.21 (s, 1H), 7.73 (brs, 2H), 3.96-3.90 (m, 2H), 3.69 (t,
J=12.44 Hz, 2H), 3.25-3.15 (m, 2H), 2.46 (m, 3H), 2.07 (s, 3H),
1.46-1.41 (m, 2H).
Example 240
Synthesis of
2-(6-((6-amino-5-methylpyrimidin-4-yl)amino)-8-methyl-1,5-dioxo-1,5-dihyd-
ro-2H-spiro[imidazo[1,5-a]pyridine-3,4'-piperidin]-1'-yl)acetonitrile
(Cpd. No. 240)
##STR00519##
##STR00520##
[1016] Synthesis of tert-butyl
6-((6-(cyclopropanecarboxamido)-5-methylpyrimidin-4-yl)amino)-8-methyl-1,-
5-dioxo-1,5-dihydro-2H-spiro[imidazo[1,5-a]pyridine-3,4'-piperidine]-1'-ca-
rboxylate (3)
[1017] The synthesis of intermediate 3 was carried out as described
above using the general protocol of Procedure H. Light yellow
solid; Yield: 0.75 g, 83%; MS (ESI) m/z 524.41 [M+1].sup.+.
Synthesis of tert-butyl
6-((6-amino-5-methylpyrimidin-4-yl)amino)-8-methyl-1,5-dioxo-1,5-dihydro--
2H-spiro[imidazo[1,5-a]pyridine-3,4'-piperidine]-1'-carboxylate
(4)
[1018] The synthesis of intermediate 4 was carried out as described
above using the general protocol of Procedure I. Yellow solid.
Yield: 650 mg, 33%; MS (ESI) m/z 456.33 [M+1].sup.+.
Synthesis of
6-((6-amino-5-methylpyrimidin-4-yl)amino)-8-methyl-2H-spiro[imidazo[1,5-a-
]pyridine-3,4'-piperidine]-1,5-dione hydrochloride (5)
[1019] The synthesis of intermediate 5 was carried out as described
above using the general protocol of Procedure F. Light brown solid;
Yield: 0.41 g, 80%; MS (ESI) m/z 356.12 [M+1].sup.+.
Synthesis of
2-(6-((6-amino-5-methylpyrimidin-4-yl)amino)-8-methyl-1,5-dioxo-1,5-dihyd-
ro-2H-spiro[imidazo[1,5-a]pyridine-3,4'-piperidin]-1'-yl)acetonitrile
(Cpd. No. 240)
[1020]
6-((6-amino-5-methylpyrimidin-4-yl)amino)-8-methyl-2H-spiro[imidazo-
[1,5-a]pyridine-3,4'-piperidine]-1,5-dione hydrochloride (5, 0.2 g,
0.56 mmol) was dissolved in dimethylformamide (10 mL). To it was
added N,N-diisopropylethylamine (0.22 g, 1.68 mmol), followed by
bromoacetonitrile (0.10 g, 0.84 mmol). The reaction mixture was
stirred at room temperature for 30 min. After completion reaction
mixture was diluted with 50 mL ethyl acetate, It was washed with
saturated ammonium chloride solution and brine solution, solvent
was removed under reduced pressure and the resulting residue was
further washed with methanol ether and pentane, dried under vacuum
to afford
2-(6-(6-amino-5-methylpyrimidin-4-yl)amino)-8-methyl-1,5-dioxo-1,5-dihydr-
o-2H-spiro[imidazo[1,5-a]pyridine-3,4'-piperidin]-1'-yl)acetonitrile
(Cpd. No. 240) as light yellow solid. Yield: 95 mg, 43%; MS (ESI)
m/z 395.18 [M+1].sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
10.26 (s, 1H), 8.48 (s, 1H), 8.12 (s, 1H), 7.99 (s, 1H), 6.47 (s,
2H), 3.74 (s, 2H), 3.33-3.30 (m, 2H), 2.92-2.85 (m, 2H), 2.70-2.58
(m, 2H), 2.44 (s, 3H), 1.98 (s, 3H), 1.53-1.46 (m, 2H).
Example 241
Synthesis of
6-((6-amino-5-chloropyrimidin-4-yl)amino)-1'-(2,2-difluoroethyl)-8-methyl-
-2H-spiro[imidazo[1,5-a]pyridine-3,4'-piperidine]-1,5-dione (Cpd.
No. 241)
##STR00521##
##STR00522##
[1021] Synthesis of
N-(5-chloro-6-((1'-(2,2-difluoroethyl)-8-methyl-1,5-dioxo-1,5-dihydro-2H--
spiro[imidazo[1,5-a]pyridine-3,4'-piperidin]-6-yl)amino)pyrimidin-4-yl)cyc-
lopropanecarboxamide (3)
[1022] The synthesis of intermediate 3 was carried out as described
above using the general protocol of Procedure H. Light yellow
solid; Yield: 0.38 g, 70%; MS (ESI) m/z 508.18 [M+1].sup.+.
Synthesis of
6-((6-amino-5-chloropyrimidin-4-yl)amino)-1'-(2,2-difluoroethyl)-8-methyl-
-2H-spiro[imidazo[1,5-a]pyridine-3,4'-piperidine]-1,5-dione (Cpd.
No. 241)
[1023] The synthesis of compound 241 was carried out as described
above using the general protocol of Procedure I. White solid;
Yield: 25 mg, 8%; MS (ESI) m/z 410.14 [M+1].sup.+; .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. 10.26 (s, 1H), 8.53 (s, 1H), 8.51 (s,
1H), 8.18 (s, 1H), 7.21 (brs, 2H), 6.46 (t, J=56.0 Hz, 1H),
3.35-2.98 (m, 8H), 2.46 (s, 3H), 1.71-1.52 (m, 2H).
Example 242
Synthesis of
6-((6-amino-5-chloropyrimidin-4-yl)amino)-8-methyl-1'-(2,2,2-trifluoroeth-
yl)-2H-spiro[imidazo[1,5-a]pyridine-3,4'-piperidine]-1,5-dione
(Cpd. No. 242)
##STR00523##
##STR00524##
[1024] Synthesis of N-(5-chloro-6-((8-methyl-1,5-dioxo-1'-(2,2,
2-trifluoroethyl)-1,5-dihydro-2H-spiro[imidazo[1,5-a]pyridine-3,4'-piperi-
din]-6-yl)amino)pyrimidin-4-yl)cyclopropanecarboxamide (3)
[1025] The synthesis of intermediate 3 was carried out as described
above using the general protocol of Procedure H. Off white solid;
Yield: 0.40 g; MS (ESI) m/z 524.1
Synthesis of
6-((6-amino-5-chloropyrimidin-4-yl)amino)-8-methyl-1'-(2,2,2-trifluoroeth-
yl)-2H-spiro[imidazo[1,5-a]pyridine-3,4'-piperidine]-1,5-dione
(Cpd. No. 242)
[1026] The synthesis of compound 242 was carried out as described
above using the general protocol of Procedure I. Yield: 60 mg, 17%;
MS (ESI) m/z 458.11 [M+1].sup.+; .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 10.26 (brs, 1H), 8.53 (s, 1H), 8.50 (s, 1H),
8.17 (s, 1H), 7.10 (brs, 2H), 3.40-3.22 (m, 4H), 2.96-2.93 (m, 2H),
2.84-2.78 (m, 2H), 2.46 (s, 3H), 1.42-1.39 (m, 2H).
Example 243
Synthesis of
2-(6-((6-amino-5-methoxypyrimidin-4-yl)amino)-8-methyl-1,5-dioxo-1,5-dihy-
dro-2H-spiro[imidazo[1,5-a]pyridine-3,4'-piperidin]-1'-yl)acetonitrile
(Cpd. No. 243)
##STR00525##
##STR00526##
[1027] Synthesis of tert-butyl
6-((6-(cyclopropanecarboxamido)-5-methoxypyrimidin-4-yl)amino)-8-methyl-1-
,5-dioxo-1,5-dihydro-2H-spiro[imidazo[1,5-a]pyridine-3,4'-piperidine]-1'-c-
arboxylate (3)
[1028] The synthesis of intermediate 3 was carried out as described
above using the general protocol of Procedure B. Light yellow
solid; Yield: 0.55 g; MS (ESI) m/z 540.31 [M+1].sup.+.
Synthesis of tert-butyl
6-((6-amino-5-methoxypyrimidin-4-yl)amino)-8-methyl-1,5-dioxo-1,5-dihydro-
-2H-spiro[imidazo[1,5-a]pyridine-3,4'-piperidine]-1'-carboxylate
(4)
[1029] The synthesis of intermediate 4 was carried out as described
above using the general protocol of Procedure I. Yellow solid;
Yield: 250 mg; MS (ESI) m/z 472.28 [M+1].sup.+.
Synthesis of
6-((6-amino-5-methoxypyrimidin-4-yl)amino)-8-methyl-2H-spiro[imidazo[1,5--
a]pyridine-3,4'-piperidine]-1,5-dione hydrochloride (5)
[1030] The synthesis of intermediate 5 was carried out as described
above using the general protocol of Procedure F. Yellow solid;
Yield: 0.18 g; MS (ESI) m/z 372.22 [M+1].sup.+.
Synthesis of
2-(6-((6-amino-5-methoxypyrimidin-4-yl)amino)-8-methyl-1,5-dioxo-1,5-dihy-
dro-2H-spiro[imidazo[1,5-a]pyridine-3,4'-piperidin]-1'-yl)acetonitrile
(Cpd. No. 243)
[1031]
6-((6-Amino-5-methoxypyrimidin-4-yl)amino)-8-methyl-2H-spiro[imidaz-
o[1,5-a]pyridine-3,4'-piperidine]-1,5-dione hydrochloride (5, 0.18
g, 0.44 mmol) was dissolved in dimethylformamide (5 mL). To this
mixture N,N-diisopropylethylamine (0.23 g, 1.76 mmol) was added
followed by bromoacetonitrile (79 mg, 0.66 mmol). The reaction
mixture was stirred at room temperature for 2 h. After completion
the reaction mixture was diluted with saturated ammonium chloride
solution (50 mL). Yellow precipitate was filtered and dried under
reduced pressure. The compound was then purified by prep
purification to afford
2-(6-((6-amino-5-methoxypyrimidin-4-yl)amino)-8-methyl-1,5-dioxo-1,5-dihy-
dro-2H-spiro[imidazo[1,5-a]pyridine-3,4'-piperidin]-1'-yl)acetonitrile
(Cpd. No. 243) as white solid. Yield: 40 mg, 22%; MS (ESI) m/z
411.20 [M+1].sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6 with
d.sub.1-TFA) .delta. 8.37 (s, 1H), 8.27 (s, 1H), 4.49 (s, 2H), 3.76
(s, 3H), 3.74-3.71 (m, 2H), 3.56-3.40 (m, 4H), 2.43 (s, 3H),
1.90-1.87 (m, 2H).
Example 244
Synthesis of
1'-(2,2-difluoroethyl)-6-((5-methoxypyrimidin-4-yl)amino)-8-methyl-2H-spi-
ro[imidazo[1,5-a]pyridine-3,4'-piperidine]-1,5-dione (Cpd. No.
244)
##STR00527##
##STR00528##
[1032] Synthesis of
N-(6-((1'-(2,2-difluoroethyl)-8-methyl-1,5-dioxo-1,5-dihydro-2H-spiro[imi-
dazo[1,5-a]pyridine-3,4'-piperidin]-6-yl)amino)-5-methoxypyrimidin-4-yl)cy-
clopropanecarboxamide (3)
[1033] The synthesis of intermediate 3 was carried out as described
above using the general protocol of Procedure H. Light yellow
solid; Yield: 0.30 g, 26%; MS (ESI) m/z 504.14 [M+1].sup.+.
Synthesis of
1'-(2,2-difluoroethyl)-6-((5-methoxypyrimidin-4-yl)amino)-8-methyl-2H-spi-
ro[imidazo[1,5-a]pyridine-3,4'-piperidine]-1,5-dione (Cpd. No.
244)
[1034] The synthesis of compound 244 was carried out as described
above using the general protocol of Procedure I. Light brown solid;
Yield: 27 mg, 10%; MS (ESI) m/z [M+1].sup.+; .sup.1H NMR (400 MHz,
DMSO-d.sub.6 with d.sub.1-TFA) .delta. 8.42 (s, 1H), 8.26 (s, 1H),
6.56 (t, J=56 Hz, 1H), 384-3.64 (m, 7H), 3.60-3.40 (m, 4H), 2.46
(s, 3H), 1.92-1.86 (m, 2H).
Example 245
Synthesis of
3'-((6-aminopyrimidin-4-yl)amino)-1'-methylspiro[cyclohexane-1,5'-pyrrolo-
[3,4-b]pyridine]-4',7'(1'H,6'H)-dione (Cpd. No. 245)
##STR00529##
##STR00530## ##STR00531##
[1035] Synthesis of
4-methoxy-6-(4-methoxybenzyl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one
(2)
[1036] Treat a solution of methyl
3-(bromomethyl)-4-methoxypicolinate (1.0 mmol, 1 eq) in
tetrahydrofuran with 4-methoxybenzylamine (2.0 mmol, 2 eq) and stir
the reaction for 16 h. After completion dilute the mixture with
ethyl acetate and water and separate the layers. Wash the organic
layer with 1 M hydrochloric acid and water. Concentrate the organic
layer to give crude. Purify the crude by silica gel column
chromatography to afford
4-methoxy-6-(4-methoxybenzyl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-
-7-one (2).
Synthesis of
4'-methoxy-6'-(4-methoxybenzyl)spiro[cyclohexane-1,5'-pyrrolo[3,4-b]pyrid-
in]-7'(6'H)-one (4)
[1037] To a solution of
4-methoxy-6-(4-methoxybenzyl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one
(2, 1.0 mmol, 1 eq) in tetrahydrofuran (25 mL) add sodium hydride
(2.5 mmol, 2.5 eq) at 0.degree. C. Stir the mixture for 20 min and
then add 1,5-dibromo pentane (3, 1.5 mmol, 1.5 eq) and stir for 8
h. After completion quench the mixture with water at 0.degree. C.
and add ethyl acetate. Separate the layer and remove the solvent to
get crude. Purify the crude by silica gel column chromatography to
afford
4'-methoxy-6'-(4-methoxybenzyl)spiro[cyclohexane-1,5'-pyrrolo[3,4-b]pyrid-
in]-7'(6H)-one (4).
Synthesis of
4'-hydroxy-6'-(4-methoxybenzyl)spiro[cyclohexane-1,5'-pyrrolo[3,4-b]pyrid-
in]-7'(6'H)-one (5)
[1038] Treat a solution of
4'-methoxy-6'-(4-methoxybenzyl)spiro[cyclohexane-1,5'-pyrrolo[3,4-b]pyrid-
in]-7'(6H)-one (4, 1.0 mmol, 1 eq) in dichloromethane (25 mL) with
boron tribromide (2.0 mmol, 2 eq) at 0.degree. C. Stir the mixture
for 2 h at room temperature and quench with water at 0.degree. C.
Extract the mixture with ethyl acetate and remove the solvent under
reduced pressure to get the crude. Purity the crude by silica gel
column chromatography to get
4'-hydroxy-6'-(4-methoxybenzyl)spiro[cyclohexane-1,5'-pyrrolo[3,4-b]p-
yridin]-7'(6'H)-one (5).
Synthesis of
6'-(4-methoxybenzyl)-1'-methylspiro[cyclohexane-1,5'-pyrrolo[3,4-b]pyridi-
ne]-4',7'(1'H,6'H)-dione (6)
[1039] To a solution of
4'-hydroxy-6'-(4-methoxybenzyl)spiro[cyclohexane-1,5'-pyrrolo[3,4-b]pyrid-
in]-7'(6'H)-one (1.0 mmol, 1 eq) in tetrahydrofuran (25 mL), add
sodium hydride (2.5 mmol, 2.5 eq) at 0.degree. C. and stir for 20
min. Add iodomethane (2.5 mmol, 2.5 eq) to the above mixture and
stir for 16 h. After completion add water to the reaction and
extract with ethyl acetate. Remove the solvent under reduced
pressure to get the crude which is purified by column
chromatography to give
6'-(4-methoxybenzyl)-1'-methylspiro[cyclohexane-1,5'-pyrrolo[3,4-b]pyridi-
ne]-4',7'(1'H,6'H)-dione (6).
Synthesis of
3'-bromo-6'-(4-methoxybenzyl)-1'-methylspiro[cyclohexane-1,
5'-pyrrolo[3,4-b]pyridine]-4'7'(1'H,6'H)-dione (7)
[1040] To a solution of
6'-(4-methoxybenzyl)-1'-methylspiro[cyclohexane-1,5'-pyrrolo[3,4-b]pyridi-
ne]-4',7'(1'H,6'H)-dione (1.0 mmol, 1 eq) in carbon tetrachloride
(25 mL), add N-bromosuccinimide and heat the mixture at 90.degree.
C. for 16 h. After completion the mixture was diluted with water
and extracted with ethyl acetate. Remove the solvent under reduced
pressure to get the crude. Purify the crude by column
chromatography to afford
3'-bromo-6'-(4-methoxybenzyl)-1'-methylspiro[cyclohexane-1,
5'-pyrrolo[3,4-b]pyridine]-4',7'(1'H,6'H)-dione (7).
Synthesis of
N-(6-((1'-methyl-4',7'-dioxo-1',4',6',7'-tetrahydrospiro[cyclohexane-1,5'-
-pyrrolo[3,
4-b]pyridin]-3'-yl)amino)pyrimidin-4-yl)cyclopropanecarboxamide
(9)
[1041] The synthesis of intermediate 9 is carried out as described
above using the general protocol of Procedure B.
Synthesis of
3'-((6-aminopyrimidin-4-yl)amino)-6'-(4-methoxybenzyl)-1'-methylspiro[cyc-
lohexane-1,5'-pyrrolo[3,4-b]pyridine]-4',7'(1'H,6'H)-dione (10)
[1042] The synthesis of intermediate 10 is carried out as described
above using the general protocol of Procedure I.
Synthesis of
3'-((6-aminopyrimidin-4-yl)amino)-1'-methylspiro[cyclohexane-1,5'-pyrrolo-
[3,4-b]pyridine]-4',7'(1'H,6'H)-dione (Cpd. No. 245)
[1043] Treat a solution of
3'-((6-aminopyrimidin-4-yl)amino)-6'-(4-methoxybenzyl)-1'-methylspiro[cyc-
lohexane-1,5'-pyrrolo[3,4-b]pyridine]-4',7'(1'H,6'H)-dione (1.0
mmol, 1 eq) in 1,2-dichloroethane (15 mL) with trifluoroacetic acid
(20 mmol, 20 eq) and heat the mixture to 100.degree. C. for 5 h.
After completion, cool the mixture and remove the solvent.
Triturate the mixture with ether to get solid. The solid is again
triturated with methanol to get
3'-((6-aminopyrimidin-4-yl)amino)-1'-methylspiro[cyclohexane-1,5'-pyrrolo-
[3,4-b]pyridine]-4',7'(1'H,6'H)-dione (Cpd. No. 245).
Example 246
Synthesis of
6'-((6-aminopyrimidin-4-yl)amino)-8'-methyl-2'H-spiro[cyclohexane-1,3'-in-
dolizine]-1',5'-dione (Cpd. No. 246)
##STR00532##
##STR00533## ##STR00534##
[1044] Synthesis of
5-bromo-N-methoxy-N,3-dimethyl-6-oxo-1,6-dihydropyridine-2-carboxamide
(2)
[1045] To a solution of
5-bromo-3-methyl-6-oxo-1,6-dihydropyridine-2-carboxylic acid (1,
1.0 mmol, 1 eq) in dimethylformamide (25 mL), add
N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide (2 mmol, 2 eq),
triethylamine (3.0 mmol, 3 eq) and N,O-dimethylhydroxylamine
hydrochloride (1.5 mmol, 1.5 eq) and stir the reaction for 6 h.
After completion add water to the mixture and extract with ethyl
acetate. Wash the ethyl acetate layer with water and brine, remove
the solvent under reduced pressure to get
5-bromo-N-methoxy-N,3-dimethyl-6-oxo-1,6-dihydropyridine-2-carboxamide
(2).
Synthesis of 5-bromo-N-methoxy-1-(4-methoxybenzyl)-N,
3-dimethyl-6-oxo-1, 6-dihydropyridine-2-carboxamide (3)
[1046] Add sodium hydride (2.5 mmol, 2.5 eq) to a cooled solution
of
5-bromo-N-methoxy-N,3-dimethyl-6-oxo-1,6-dihydropyridine-2-carboxamide
(2, 1.0 mmol, 1 eq) in dimethylformamide (25 mL) and stir the
reaction for 20 min. Add 4-methoxybenzyl chloride (1.2 mmol, 1.2
eq) and stir the reaction for 16 h. After completion, quench the
reaction with water and extract with ethyl acetate. Remove the
solvent and purify the crude by column chromatography to afford
5-bromo-N-methoxy-1-(4-methoxybenzyl)-N,3-dimethyl-6-oxo-1,6-dihydropyrid-
ine-2-carboxamide (3).
Synthesis of ethyl
3-(5-bromo-1-(4-methoxybenzyl)-3-methyl-6-oxo-1,6-dihydropyridin-2-yl)-2--
(1-hydroxycyclohexyl)-3-oxopropanoate (5)
[1047] To a solution of ethyl 2-(1-hydroxycyclohexyl)acetate (4,
1.2 mmol, 1.2 eq) in tetrahydrofuran (15 mL), add lithium
diisopropylamide (2.5 mmol, 2.5 eq) at -78.degree. C. and stir the
reaction for 20 min. Add a solution of
5-bromo-N-methoxy-1-(4-methoxybenzyl)-N,3-dimethyl-6-oxo-1,6-dihydropyrid-
ine-2-carboxamide (3, 1.0 mmol, 1.0 eq) in tetrahydrofuran (10 mL)
at -78.degree. C. in 10 min and continue stirring for another 3 h.
After completion, add saturate aqueous ammonium chloride solution
and extract the reaction mass with ethyl acetate. Evaporate the
solvent under reduced pressure and to get the crude which is passed
through a silica gel bed to get ethyl
3-(5-bromo-1-(4-methoxybenzyl)-3-methyl-6-oxo-1,6-dihydropyridi-
n-2-yl)-2-(1-hydroxycyclohexyl)-3-oxopropanoate (5).
Synthesis of ethyl
6'-bromo-8'-methyl-1',5'-dioxo-1',5'-dihydro-2'H-spiro[cyclohexane-1,3'-i-
ndolizine]-2'-carboxylate (6)
[1048] To a solution of ethyl
3-(5-bromo-1-(4-methoxybenzyl)-3-methyl-6-oxo-1,6-dihydropyridin-2-yl)-2--
(1-hydroxycyclohexyl)-3-oxopropanoate (5, 1.0 mmol, 1.0 eq) in
1,2-dichloroethane (15 mL), add trifluoroacetic acid (10 mmol, 10
eq) and heat the reaction at 60.degree. C. for 16 h. After
completion, remove the solvent and quench the reaction with ammonia
and extract with dichloromethane. Remove the solvent under reduced
pressure and purify the crude using silica gel column
chromatography to afford ethyl
6'-bromo-8'-methyl-1',5'-dioxo-1',5'-dihydro-2'H-spiro[cyclohexane-1,3'-i-
ndolizine]-2'-carboxylate (6).
Synthesis of
6'-bromo-8'-methyl-2'H-spiro[cyclohexane-1,3'-indolizine]-1',5'-dione
(7)
[1049] To a solution of ethyl
6'-bromo-8'-methyl-1',5'-dioxo-1',5'-dihydro-2'H-spiro[cyclohexane-1,3'-i-
ndolizine]-2'-carboxylate (6, 1.0 mmol, 1.0 eq) in
dimethylsulfoxide (15 mL) add lithium chloride (5.0 mmol, 5 eq) and
heat the reaction at 140.degree. C. for 16 h. After completion cool
the reaction, add water and extract with dichloromethane. Remove
the solvent under reduced pressure and purify the crude by silica
gel column chromatography to get
6'-bromo-8'-methyl-2'H-spiro[cyclohexane-1,3'-indolizine]-1',5'-dione
(7).
Synthesis of
N-(6-((8'-methyl-1',5'-dioxo-1',5'-dihydro-2'H-spiro[cyclohexane-1,3'-ind-
olizin]-6'-yl)amino)pyrimidin-4-yl)cyclopropanecarboxamide (9)
[1050] The synthesis of intermediate 9 is carried out as described
above using the general protocol of Procedure H.
Synthesis of
6'-((6-aminopyrimidin-4-yl)amino)-8'-methyl-2'H-spiro[cyclohexane-1,3'-in-
dolizine]-1',5'-dione (Cpd. No. 246)
[1051] The synthesis of compound 246 is carried out as described
above using the general protocol of Procedure I.
Example 247
Synthesis of
6'-((6-amino-5-methylpyrimidin-4-yl)amino)-8'-methyl-2'H-spiro[cyclohexan-
e-1,3'-indolizine]-1',5'-dione (Cpd. No. 247)
##STR00535##
##STR00536##
[1052] Synthesis of
N-(5-methyl-6-((8'-methyl-1',5'-dioxo-1',5'-dihydro-2'H-spiro[cyclohexane-
-1,3'-indolizin]-6'-yl)amino)pyrimidin-4-yl)cyclopropanecarboxamide
(3)
[1053] The synthesis of intermediate 3 is carried out as described
above using the general protocol of Procedure B.
Synthesis of
6'-((6-amino-5-methylpyrimidin-4-yl)amino)-8'-methyl-2'H-spiro[cyclohexan-
e-1,3'-indolizine]-1',5'-dione (Cpd. No. 247)
[1054] The synthesis of compound 247 is carried out as described
above using the general protocol of Procedure I.
Example 248
Large-Scale Synthesis of Intermediates and Formula I Compounds
[1055] Compounds in accordance with the present invention are
candidate therapeutics for treating Mnk related disorders, such as
inflammatory disorders and cancer. To provide commercial quantities
of the inventive compounds, the present invention illustrates a
large-scale synthetic protocol for an exemplary Formula I compound
as well as methods for the manufacture and characterization of the
hydrochloride salt form (HCl-salt form) of such a compound.
Preparation of N-(6-aminopyrimidin-4-yl)
cyclopropanecarboxamide
##STR00537##
[1056] A. Preparation of Di-tert-butyl (6-chloropyrimidin-4-yl)
carbamate (2)
[1057] To a stirred solution of 6-chloropyrimidin-4-amine (4900 g,
1 equiv, 37.08 moles) in tetrahydrofuran (10 V, 50 L), at 0.degree.
C. was added N, N-dimethylaminopyridine (463 g, 0.1 equiv, 3.70
moles). Di-tert-butyl dicarbonate (24.8 L, 3 equiv, 113.9 moles)
was then added slowly over 1 h (gas evolution was observed) to the
resultant reaction. The reaction mixture became dark brown with
stirring at room temperature over a period of 16 h. Progress of the
reaction was monitored by TLC and LCMS. LCMS showed the complete
disappearance of SM, as well as peaks corresponding to the product,
73.89% at RT-2.55 ((M+1)-330.3); tert-butyl
(6-chloropyrimidin-4-yl) carbamate side product, 4.09% at RT-1.98
((M+1)-330.3).
[1058] After completion of reaction, the reaction mixture was
poured into an ice/water mixture (30 L), and further stirred for 30
min prior to solvent extraction of the aqueous phase with ethyl
acetate (10 L). The organic and aqueous phases were separated and
the resultant aqueous layer was extracted twice with ethyl acetate
(2.times.10 L). The combined organic layer was washed twice with
water (2.times.10 L), then brine (1.times.10 L), and dried over
anhydrous sodium sulfate. The dry organic layer was concentrated
under reduced pressure at 50.degree. C. to obtain crude product
which was slurried with hexane (10 L) for 1 h, filtered and dried
under reduced pressure at 50.degree. C. to obtain brick red solid.
Yield: 10.3 Kg, (82.6%). MS (ESI) m/z 329.78 [M+1]+; LCMS purity:
99.37%; 1H NMR (400 MHz, DMSO-d6) .delta.: 8.86 (s, 1H), 7.85 (s,
1H), 1.48 (s, 18H).
B. Preparation of di-tert-butyl (6-(cyclopropanecarboxamido)
pyrimidin-4-yl) carbamate (3)
[1059] To a stirring solution of di-tert-butyl
(6-chloropyrimidin-4-yl) carbamate (5000 g, 1 equiv, 15.20 moles)
in dioxane (5 V, 25 L), at room temperature was added
cyclopropanecarboxamide (1291 g, 1 equiv, 15.20 moles) followed by
the addition of cesium carbonate (3950 g, 0.8 equiv, 12.15 moles).
After purging the reaction mixture (dark brown solution) with argon
for 30 minutes, xantphos (120 g, 0.015 equiv, 0.23 moles), and
palladium (II) acetate (51 g, 0.015 equiv, 0.23 moles) were added.
Purging of reaction mass with argon was continued for another 15
min and the reaction mixture was then heated to 90.degree. C. and
kept at that temperature for 4 h, during which time the color of
the reaction mass changed to orange. Progress of reaction was
monitored by TLC and LCMS. LCMS showed complete disappearance of
SM, and a peak corresponding to product at RT-2.32 min., 86.92%,
((M+1)-379.15). In addition, the LCMS showed peaks corresponding to
tert-butyl (6-(cyclopropanecarboxamido) pyrimidin-4-yl) carbamate
3.83%; at RT-1.94 ((M+1)-279.08) and some unknown byproducts (5.18%
at RT-2.43 (M+1)-605.2, 1.48% at RT-2.83 (M+1)-589.2).
[1060] After completion of the reaction as judged by TLC and LCMS,
the reaction mixture was cooled to 50.degree. C. and was filtered
through celite bed. The celite bed was washed with EtOAc
(3.times.10 L) to ensure complete extraction of the product.
Combined organic layers were washed with water (2.times.10 L),
dried over anhydrous sodium sulphate and concentrated under reduced
pressure to get crude (6.2 Kg). Diethyl ether (6.0 L) was added to
the crude material and the mixture was stirred for 30 min to get
free flowing solid. The solid was filtered, washed with ether
(2.times.1 L) and then dried to afford di-tert-butyl
(6-(cyclopropanecarboxamido) pyrimidin-4-yl) carbamate as an orange
solid. This compound was used in the next step without further
purification. Yield: 4.5 Kg, (78.2%); MS (ESI) m/z 378.43 [M+1]+;
LCMS purity: 95.10%; 1H NMR (400 MHz, DMSO-d6) .delta.: 11.30 (s,
1H), 8.66 (s, 1H), 8.25 (s, 1H), 2.02 (m, 1H), 1.46 (s, 18H), 0.85
(m, 4H).
C. Preparation of N-(6-aminopyrimidin-4-yl) cyclopropanecarboxamide
(4)
[1061] Trifluoroacetic acid (16 L, 10 equiv, 212 moles) was slowly
added over 1 h to a stirring solution of di-tert-butyl
(6-(cyclopropanecarboxamido) pyrimidin-4-yl) ((3); 8050 g, 1 equiv,
21.20 moles) in dichloromethane (5 V, 40 L). Evolution of gas was
observed during the addition of trifluoroacetic acid and the
reaction became dark brown when stirred continuously for 4 h at
room temperature. Progress of reaction was monitored by TLC.
[1062] After completion of reaction, the reaction mass was
concentrated to dryness under reduced pressure (TFA must be
distilled off as much as possible prior to addition of ammonia) and
dichloromethane (25 L) was added to the residue. The mixture was
cooled to 0.degree. C. and NH4OH (25% aq. Solution, 6 L) was added
slowly (pH-10) over 30 min while stirring the reaction mixture
continuously. The resulting mixture was stirred at 0.degree. C. for
an additional 30 min and the solid formed was filtered and washed
with water (2.times.10 L) followed by washing with methanol
(2.times.2 L) and dichloromethane (15 L). The washed solid was
dried under high vacuum overnight to afford
N-(6-aminopyrimidin-4-yl) cyclopropanecarboxamide as creamish
yellow solid. Yield: 2.32 Kg (61.02%); MS (ESI) m/z 178.19 [M+1]+;
UPLC: 99.80%; 1H NMR (400 MHz, DMSO-d6) .delta.: 10.54 (s, 1H),
8.10 (s, 1H), 7.10 (s, 1H), 6.72 (brs, 2H), 1.97 (m, 1H), 0.79 (m,
4H).
[1063] The final material from all batches were combined, slurried
with dichromethane (10 L) for 20 min, filtered and dried under
vacuum for 6 h to obtain a single batch of
N-(6-aminopyrimidin-4-yl) cyclopropanecarboxamide (3665.3).
Preparation of ethyl 5-bromo-3-methyl-6-oxo-1,
6-dihydropyridine-2-carboxamide
##STR00538##
[1064] A. Preparation of ethyl 5-bromo-3-methylpicolinate (2)
[1065] To a stirring solution of 5-bromo-3-methylpicolinic acid
(10000 g, 1 equiv, 46.29 moles) in ethanol (50 L) at 0.degree. C.
was added sulfuric acid (2.52 L, 1 equiv, 46.29 moles) over 1 h.
Following addition of sulfuric acid, the mixture was heated at
95.degree. C. for 20 h. Reaction progress was monitored by using
TLC and LCMS. After 20 hours, LCMS showed 12.61% unreacted SM, at
RT-0.67 ((M-1)-215.92) and 86.95% product at RT-2.04 ((M+1)-244.2).
The reaction mass heated for additional 6 h and LCMS analysis
following the additional heating showed 10.07% unreacted SM, at
RT-0.7 and 89.93% product at RT-2.08 ((M+1)-244.2. The reaction was
stopped by concentrating the reaction mixture under reduced
pressure to remove as much solvent as possible. To the residue was
added dichloromethane (DCM), (25 L) and the reaction mixture was
poured into ice cold water (20 L). The organic (DCM) layer was
separated from the aqueous layer and the latter was further
extracted twice with DCM (10 L). The combined organic layers were
washed with saturated sodium bicarbonate solution (30 L), dried
over sodium sulfate, and concentrated under reduced pressure to
obtain a brown oil. This brown oil was used in the next step
without further purification. Yield: 10.1 Kg, (89.4%); MS (ESI) m/z
244.2 [M+1]+; LCMS purity: 99.11%; 1H NMR (400 MHz, DMSO-d6)
.delta.: 8.61 (s, 1H), 8.13 (s, 1H), 4.29 (q, 2H), 2.44 (s, 1H),
1.28 (t, 3H).
B. Preparation of 5-bromo-2-(ethoxycarbonyl)-3-methylpyridine
1-oxide (3)
[1066] To a stirring solution of ethyl 5-bromo-3-methylpicolinate
(9.49 Kg, 1 equiv, 38.88 moles) in dichloromethane (47.5 L) at
0.degree. C. was added urea hydrogen peroxide (6.3 Kg, 1.75 equiv,
68.04 moles), followed by the addition of trifluoroacetic anhydride
(9.7 L, 1.75 equiv, 68.04 moles) at 0.degree. C. over a period of 3
h. This reaction is strongly exothermic (0-30.degree. C.).
Following addition, the reaction mixture was gently warmed to room
temperature (RT) and permitted to stir at RT for 16 h. Reaction
progress was monitored by using TLC and LCMS analysis. At the end
of 16 hours, LCMS showed 0.74% unreacted SM at RT-2.04
((M+1)-244.02); 91.61% product at RT-1.38 ((M+1)-260.01) and some
unknown byproducts (4.67% at RT-1.28 (M+1)-188.1, 2.98% at RT-1.90
(M+1)-217.11).
[1067] The crude reaction mixture was poured into an ice/water
mixture (30 L) and the organic and aqueous phases were permitted to
separate. The aqueous layer was extracted with dichloromethane (10
L), separated from the aqueous layer and combined with the first
organic layer. The combined organic layers were then washed with
aqueous sodium bicarbonate solution (50 L), followed by water (20
L), dried over sodium sulfate and concentrated to afford
5-bromo-2-(ethoxycarbonyl)-3-methylpyridine 1-oxide as a reddish
yellow oil. This compound was used for the next step without
further purification. Yield: 9 Kg, (89%); MS (ESI) m/z 260.09
[M+1]+; LCMS purity: 99.34%; 1H NMR (400 MHz, DMSO-d6) .delta.:
8.56 (s, 1H), 7.67 (s, 1H), 4.32 (q, 2H), 2.21 (s, 3H), 1.27 (t,
3H).
C. Preparation of ethyl 5-bromo-3-methyl-6-oxo-1,
6-dihydropyridine-2-carboxylate (4)
[1068] To a stirring solution of
5-bromo-2-(ethoxycarbonyl)-3-methylpyridine 1-oxide (9 Kg, 1 equiv,
34.62 moles) in N, N-dimethylformamide (35 L) at RT was added
trifluoroacetic anhydride (8.65 L, 1.75 equiv, 60.58 moles), over a
period of 3 h. The temperature of the reaction was maintained at
35-40.degree. C. during the addition of trifluoroacetic anhydride.
The reaction mixture was stirred at 40.degree. C. (internal) for 2
h and reaction progress was monitored by using TLC and LCMS
analysis. LCMS analysis showed 6.26% unreacted SM at RT-1.37
((M+1)-260.01), 31.33% product at RT-1.58 ((M+1)-259.97), 25.88%
DMF at RT-0.31 and some unknown byproducts (8.06% at RT-1.06
(M+1)-259.97, 22.42% at RT-2.29 (M+1)-323.86).
[1069] Following LCMS analysis, the reaction mass was stirred for
additional 1 h, then poured into ice cold water (100 L), to give a
white solid that was filtered and washed with water (20 L). The
crude solid compound was further washed with n-hexane (20 L) and
dried under high vacuum to afford ethyl 5-bromo-3-methyl-6-oxo-1,
6-dihydropyridine-2-carboxylate as off white solid. Yield: 6 Kg
(66.6%); MS (ESI) m/z 260.09 [M+1]+; UPLC: 66.49% (96.85% by HPLC);
1H NMR (400 MHz, DMSO-d6) .delta.: 11.53 (brs, 1H), 7.99 (s, 1H),
4.23 (q, 2H), 2.27 (brs, 3H), 1.28 (t, 3H).
D. Preparation of ethyl 5-bromo-3-methyl-6-oxo-1,
6-dihydropyridine-2-carboxamide (5)
[1070] To a stirring solution of ethyl 5-bromo-3-methyl-6-oxo-1,
6-dihydropyridine-2-carboxylate (1 Kg, 1 equiv, 3.84 moles) in
ethanol (5 L) was added 30% aq. ammonia (7 L). The round bottom
flask was then closed and sealed to avoid ammonia from escaping out
of the reaction mass. The reaction mixture was then stirred at
40.degree. C. for 16 h and reaction progress was monitored by using
TLC and LCMS analysis. LCMS analysis of the reaction mixture showed
disappearance of SM, 64.82% product at RT-1.09 ((M+1)-231.17), and
some unknown byproducts 18.2% at RT-0.83 ((M+1)-232.11), 4.74% at
RT-1.76 ((M+1)-262.19).
[1071] Following LCMS, the reaction mass was concentrated under
reduced pressure to remove ethanol and water so as to yield a crude
solid material. The crude material (wet) obtained from several
synthetic batches were combined and slurried with saturated aqueous
sodium bicarbonate solution (50 L) for 2 h, filtered and then
washed with water (2.times.10 L). The white solid thus obtained was
washed with dichloromethane (20 L), and then slurried with 20%
methanol in dichloromethane (30 L) for 1 h. The slurry was
filtered, washed with dichloromethane (15 L), and dried under
vacuum for 6 h at 60.degree. C. to yield 2.69 Kg of
5-bromo-3-methyl-6-oxo-1,6-dihydropyridine-2-carboxamide (5) as an
off white solid. Yield: 2.69 Kg (50.94%); MS (ESI) m/z 231[M+1]+;
UPLC: 99.80%; 1H NMR (400 MHz, DMSO-d6) .delta.: 11.85 (brs, 1H),
7.88 (s, 2H), 7.75 (s, 1H), 2.14 (s, 1H).
[1072] In a separate experiment, 5-bromo-3-methyl-6-oxo-1,
6-dihydropyridine-2-carboxamide, 2.2 Kg, obtained by combining the
solid from several synthetic batches was slurried in
dichloromethane (5.0 L) for 30 min, filtered and dried under vacuum
to yield 4554.1 g 5-bromo-3-methyl-6-oxo-1,
6-dihydropyridine-2-carboxamide.
Synthesis of
6%((6-aminopyrimidin-4-yl)amino)-8'-methyl-2'H-spiro[cyclohexane-1,3'-imi-
dazo[1,5-a]pyridine]-1',5'-dione hydrochloride (Cpd. 107)
##STR00539##
[1073] A. Procedure for the Purification of
5-bromo-3-methyl-6-oxo-1,6-dihydropyridine-2-carboxamide (1):
[1074] Solid sodium bicarbonate (3.3 kg) and water (40.0 L, DI)
were charged into a 45 L carboy and stirred until the sold
dissolved. 5-bromo-3-methyl-6-oxo-1,6-dihydropyridine-2-carboxamide
(1; 1.5 kg) was placed in a 50-L reactor and the solution of
saturated sodium bicarbonate was added while maintaining the
temperature of this reaction mixture at 18.degree. C. HPLC analysis
of the reaction mixture after 16 h showed that the
5-bromo-3-methyl-6-oxo-1,6-dihydropyridine-2-carboxamide (1) had a
purity of 92.8%. The solid
5-bromo-3-methyl-6-oxo-1,6-dihydropyridine-2-carboxamide was
filtered through a Nutsche filter (18'' polypropylene tight weave
cloth). The reactor and filter cake were rinsed with water (3.0 L)
and the solid was conditioned at ambient temperature until liquid
no longer flowed out. The solid material was transferred to drying
trays and dried under vacuum at 45-50.degree. C. The dried material
weighed 1.16 kg (yield -77%), and had a purity of 92.8%. KF
analysis showed 2.6% residual water.
B. Synthesis of
6'-bromo-8'-methyl-2'H-spiro[cyclohexane-1,3'-imidazo[1,5-a]pyridine]-1',-
5'-dione (2)
[1075] 5-bromo-3-methyl-6-oxo-1,6-dihydropyridine-2-carboxamide
(1), (1.16 kg, 1.0 equiv.); 1,4-dioxane (13.8 L); and cyclohexanone
(1.96 kg) were added to a 50-L reactor and agitated at 75-125 RPM.
Sulfuric acid (0.13 L) was added to the reactor using a dosing
pump. The temperature of the reaction mixture was 19.5.degree. C.
at the start of addition of sulfuric acid and increased to
21.8.degree. C. upon the complete addition of sulfuric acid. The
temperature of the reaction mixture (batch temperature) was raised
to 95.degree. C. Following stirring for 3 h, HPLC analysis of the
reaction mixture indicated completion of the reaction. The batch
temperature was then adjusted to 20-30.degree. C. and the solvent
was distilled under vacuum (28.5''/Hg, 80.degree. C. jacket
temperature) to no less than 75% of the initial reaction
volume.
[1076] Following distillation, the batch temperature was adjusted
to 25.degree. C. and held at that temperature for 13 h. The
reaction mixture (batch) was filtered through Nutsche filter
(18''), and the mother liquor was added back to the reactor as a
rinse and then added to the filter cake. Water (12 L, DI) was then
added to the reactor as a rinse and then transferred to the filter
cake. The filter cake was conditioned until liquid no longer flowed
out. The solid material thus obtained was transferred to drying
trays and dried under vacuum at 45-50.degree. C. The dried material
weighed 1.28 kg (82% yield) and had a purity >99%. KF analysis
showed 1.4% residual water. 1H NMR (500 MHz, DMSO-d6) .delta. 10.37
(s, 1H), 8.01 (s, 1H), 2.82-2.92 (m, 2H), 2.38 (s, 3H), 1.75-1.65
(m, 5H), 1.43 (d, J=24 Hz, 2H), 1.25-1.15 (m, 1H).
C. Synthesis of
N-(6-((8'-methyl-1',5'-dioxo-1',5'-dihydro-2'H-spiro[cyclohexane-1,3'-imi-
dazo[1,5-a]pyridin]-6'-yl)amino)pyrimidin-4-yl)cyclopropanecarboxamide
(4)
[1077] To a 50-L reactor was added
6'-bromo-8'-methyl-2'H-spiro[cyclohexane-1,3'-imidazo[1,5-a]pyridine]-1',-
5'-dione (2) (1.23 kg); 1,4-dioxane (15.4 L),
N-(6-aminopyrimidin-4-yl)cyclopropanecarboxamide (3), (0.65 kg);
and cesium carbonate (1.03 kg) and the reaction mixture was
agitated as it was sparged with argon for 20 min. at ambient
temperature. To the reactor was then added palladium (II) acetate
(18.0 g) and xantphos (46.0 g) and sparging with argon was
continued for an additional 20 min. The sparge tube was then
removed and the batch temperature was adjusted to 95.degree. C. The
reaction mixture (batch) was stirred for 18 h, at which time,
analysis by HPLC indicated the reaction was complete. Following
completion of the reaction, the batch temperature was adjusted to
20.degree. C. Water (24.6 L, DI) was added to the reactor and the
batch was stirred for 1 h, followed by filtration through a Nutsche
filter (18''). The mother liquor was used to rinse the reactor and
then added to the filter cake. Next, acetone (6.15 L) was added as
a rinse to the reactor and then transferred to the filter cake. The
filter cake was conditioned until no liquid flowed from the filter.
Following this, the cake was added back to the reactor, suspended
using methanol (12.0 L) and agitated at 125 RPM. The batch
temperature was adjusted to 20.degree. C. and agitation continued
for 10 min. The batch was again filtered through a Nutsche filter
(18'') and conditioned until liquid no longer flowed from the
filter. The solid material thus obtained was transferred to drying
trays and dried under vacuum at 45.degree. C. The dried material
weighted 1.42 kg, (98% yield) and had a purity of 97.5%. 1H NMR
(500 MHz, DMSO-d6) .delta. 10.85 (brs, 1H), 10.07 (brs, 1H), 9.09
(s, 1H), 8.53 (s, 1H), 8.46 (s, 1H), 7.85 (s, 1H), 3.95-3.05 (m,
2H), 2.45 (s, 3H), 1.95-2.05 (m, 1H), 1.80-1.60 (m, 5H), 1.44 (d,
J=24 Hz, 2H), 1.25-1.15 (m, 1H), 0.89-0.80 (m, 4H).
D. Synthesis of
6'-((6-aminopyrimidin-4-yl)amino)-8'-methyl-2'H-spiro[cyclohexane-1,3'-im-
idazo[1,5-a]pyridine]-1',5'-dione (107)
[1078]
N-(6-((8'-methyl-1',5'-dioxo-1',5'-dihydro-2'H-spiro[cyclohexane-1,-
3'-imidazo[1,5-a]pyridin]-6'-yl)amino)pyrimidin-4-yl)cyclopropanecarboxami-
de (cpd. 4), (1.42 kg); tetrahydrofuran (5.7 L); and EtOH (5.7 L)
were added to a 50-L reactor and agitated at 100 RPM. The batch
temperature was adjusted to 20.degree. C. To a 45-L carboy was
added water (5.7 L, DI) and KOH (1.17 kg) and the contents of the
carboy were agitated until a solution formed. The KOH solution was
then added to the 50-L reactor followed by addition of
ethylenediamine (2.83 L). The batch temperature increased to
33.degree. C. upon addition of ethylenediamine and was readjusted
to 20.degree. C. After stirring for 16 h HPLC analysis indicated
18.6% of unreacted compound (4) remained. A solution of KOH (1.17
kg) and water (5.7 L), therefore, was added to the reactor and
stirring continued at 20.degree. C. for an additional 16 h.
Following stirring, HPLC analysis indicated 1.3% of unreacted
compound (4). The pH of the batch was adjusted to 2 by the addition
of concentrated HCl (11.8 kg), over a time period of 2.5 h, and a
solid begins to form when the batch (reaction mixture) is at a pH
of 12.7. The batch temperature was adjusted to 20.degree. C. and
the mixture was agitated for 10 minutes following which the batch
containing solid material was filtered through a Nutsche filter
(18'').
[1079] The reactor was then rinsed with water (14.15 L, DI) and the
aqueous rinse was transferred to the filter while manually
suspending the solid in the wash. A second rinse was performed
using water (14.15 L, DI) and the rinse was transferred again to
the filter while manually suspending the solid in the wash. Sodium
bicarbonate (1.3 kg) and water (26.0 L, DI) were then added to the
rinsed 50-L reactor and the filter cake was slowly introduced into
the reactor over a time period of about 30 min to avoid excess gas
liberation. The resulting suspension was agitated for 2 h followed
by filtration through a Nutsche filter (18''). The filter cake was
washed with water (15.0 L) and allowed to condition overnight. The
filter cake was once again suspended in an aqueous solution of
sodium bicarbonate, agitated for 2 h and filtered through a Nutsche
filter (18''). Following washing with water, the filter cake was
allowed to condition overnight and then transferred to drying trays
and dried under vacuum at 45.degree. C. The dried batch weighed
1.05 kg, (80% yield) and had a purity of 98.5%. IC analysis showed
0.7% chloride. 1H NMR (500 MHz, DMSO-d6) .delta. 10.20 (s, 1H),
9.68 (s, 1H), 8.47 (s, 1H), 8.09 (s, 1H), 7.97 (brs, 2H), 6.42 (s,
1H), 3.00-2.90 (m, 2H), 2.43 (s, 3H), 1.80-1.60 (m, 5H), 1.5 (d,
J=24 Hz, 2H), 1.25-1.12 (m, 1H).
E. Synthesis of
6'-((6-aminopyrimidin-4-yl)amino)-8'-methyl-2'H-spiro[cyclohexane-1,3'-im-
idazo[1,5-a]pyridine]-1',5'-dione hydrochloride (107 HCl)
[1080]
6'-((6-aminopyrimidin-4-yl)amino)-8'-methyl-TH-spiro[cyclohexane-1,-
3'-imidazo[1,5-a]pyridine]-1',5'-dione ((107), (0.99 kg)) was added
to a 50-L vessel. To a separate 45-L carboy were added
tetrahydrofuran (8.22 L), ethanol (8.22 L), and water (8.22 L, DI).
This solution was then transferred to the 50-L vessel containing
compound 9107) and the temperature of the reaction mixture was
adjusted to 5.degree. C. To the cold reaction mixture was added KOH
(0.45 kg) and the entire mixture was agitated until a solution
formed. The solution was then transferred to the 45-L carboy and
then passed, under vacuum, through a polish filter (0.3 u Hepa Cap
polish filter) back to the 50-L vessel.
[1081] The temperature of the solution (batch) was adjusted to
5.degree. C. and the pH was adjusted to pH 1 by the addition of
concentrated HCl (37%, 1.17 L). The temperature of the acidic batch
was adjusted to 20.degree. C. following which the batch was
agitated for 16 h. Seed crystals (9.2 g) were added to the batch
and the agitation was continued for 16 h. After agitation, the
batch was filtered through a Nutsche filter (18'') and the reactor
rinsed once with the mother liquor. The rinse was added to the
filter cake, followed rinsing of the filter cake with a solution of
THF, ethanol and water (1:1:1). After conditioning the filter cake
overnight, it was transferred to drying trays and dried under
vacuum at 45.degree. C. The dried batch weighed 1.12 kg, 102%
yield, with 4.0% water (KF oven). 1H NMR (500 MHz, DMSO-d6) .delta.
10.20 (s, 1H), 9.68 (s, 1H), 8.47 (s, 1H), 8.09 (s, 1H), 7.97 (brs,
2H), 6.42 (s, 1H), 3.00-2.90 (m, 2H), 2.43 (s, 3H), 1.80-1.60 (m,
5H), 1.5 (d, J=24 Hz, 2H), 1.25-1.12 (m, 1H). XRPD (Cu, .degree. 20
(Theta) values): 3.5 (s), 8.5 (1), 10.5 (m), 14 (s), 17 (s), 19.5
(s), 27 (m).
Biological Studies
Example 249: Mnk Biochemical Enzymatic Assay
[1082] Compounds are screened for Mnk inhibition using the ADP-Glo
kinase assay kit (Promega, catalogue No. V9101). All kinase
reactions are performed in Reaction Buffer E (15 mM HEPES pH7.4, 20
mM NaCl, 1 mM EGTA, 10 mM MgCl.sub.2, 0.1 mg/ml BGG, and 0.02%
Tween-20). Final Mnk1 reactions contained 10 nM recombinant Mnk1
(Life Technologies, PR9138A), 100 .mu.M Mnk substrate peptide
Ac-TATKSGSTTKNR-NH.sub.2 (American Peptide Company), 300 .mu.M ATP,
and varying concentrations of the inhibitory compound of interest.
Final Mnk2 reactions contained 3 nM recombinant Mnk2 (Life
Technologies, PV5607), 50 .mu.M Mnk substrate peptide
Ac-TATKSGSTTKNR-NH.sub.2 (American Peptide Company), 10 .mu.M ATP,
and varying concentrations of the inhibitory compound of interest.
Final DMSO concentration in each reaction is 1%.
[1083] Kinase reactions are carried out in 96-well half-area white
flat-bottom polystyrene plates in a final volume of 25 .mu.l.
Mnk1/2 enzymes are pre-incubated with compound and peptide
substrate for 5 minutes prior to the addition of ATP. After the
addition of ATP, kinase reactions are incubated at room temperature
for 40 minutes. Reactions are subsequently stopped by the addition
of 25 .mu.l of ADP-Glo Reagent and incubating for an additional 40
minutes. The final luminescent signal used for kinase activity
readout is produced by the addition of 45 .mu.l of Kinase Detection
Reagent (ADP-Glo kit, Promega) and incubating for 40 minutes. The
luminescent signal is detected using a Victor 2 multilabel counter
(Perkin Elmer) and the concentration of compound necessary to
achieve inhibition of enzyme activity by 50% (IC.sub.50) is
calculated using signals from an 8-point compound dilution
series.
[1084] The results of these assays are set forth in Table 1 below.
To this end, IC.sub.50 values of less than 0.01 .mu.M are labelled
as "+++", from 0.01 to 0.1 .mu.M are labelled as "++", and greater
than 0.1 to 10.0 .mu.M are labelled as "+" (NA means "not
available").
TABLE-US-00001 TABLE 1 Mnk Biochemical Enzymatic Assay (IC.sub.50)
Cpd. IC.sub.50 Cpd. IC.sub.50 No. Mnk1 Mnk2 No. Mnk1 Mnk2 1 NA + 25
NA + 2 ++ ++ 26 ++ + 3 NA + 27 ++ ++ 4 NA + 28 ++ ++ 5 NA + 29 +++
+++ 6 +++ ++ 30 +++ +++ 7 ++ +++ 31 ++ ++ 8 ++ ++ 32 NA + 9 ++ ++
33 ++ ++ 10 +++ +++ 34 ++ ++ 11 ++ ++ 35 +++ +++ 12 ++ ++ 36 +++
+++ 13 ++ ++ 37 ++ ++ 14 ++ +++ 38 +++ +++ 15 NA + 39 +++ +++ 16
+++ ++ 40 NA + 17 NA + 41 + ++ 18 +++ ++ 42 +++ +++ 19 NA + 43 +++
+++ 20 ++ +++ 44 +++ +++ 21 +++ +++ 45 +++ +++ 22 +++ +++ 46 +++
+++ 23 +++ +++ 47 +++ +++ 24 +++ +++ 48 +++ +++ 49 +++ +++ 75 ++ ++
50 +++ +++ 76 +++ +++ 51 +++ +++ 77 +++ +++ 52 +++ +++ 78 +++ +++
53 ++ ++ 79 ++ +++ 54 ++ +++ 80 +++ +++ 55 +++ +++ 81 + + 56 +++
+++ 82 ++ ++ 57 +++ +++ 83 +++ +++ 58 +++ +++ 84 +++ +++ 59 + ++ 85
+++ +++ 60 +++ +++ 86 +++ +++ 61 +++ +++ 87 +++ +++ 62 +++ +++ 88
+++ +++ 63 +++ +++ 89 +++ +++ 64 ++ ++ 90 +++ +++ 65 +++ +++ 91 +++
+++ 66 +++ +++ 92 +++ +++ 67 ++ +++ 93 +++ +++ 68 + + 94 +++ +++ 69
+++ +++ 95 +++ +++ 70 +++ +++ 96 +++ +++ 71 + + 97 +++ +++ 72 +++
+++ 98 +++ +++ 73 +++ +++ 99 +++ +++ 74 +++ +++ 100 +++ +++ 101 +++
+++ 127 +++ +++ 102 +++ +++ 128 +++ +++ 103 +++ +++ 129 +++ +++ 104
+++ +++ 130 +++ ++ 105 +++ +++ 131 ++ +++ 106 +++ +++ 132 NA NA 107
+++ +++ 133 NA +++ 108 +++ +++ 134 NA NA 109 +++ +++ 135 NA NA 110
+++ +++ 136 NA NA 111 +++ +++ 137 NA NA 112 +++ +++ 138 NA + 113
+++ +++ 139 NA NA 114 +++ +++ 140 NA NA 115 +++ +++ 141 NA NA 116
+++ +++ 142 +++ +++ 117 +++ +++ 143 +++ +++ 118 NA +++ 144 NA NA
119 NA +++ 145 +++ +++ 120 NA +++ 146 +++ +++ 121 NA +++ 147 NA NA
122 NA +++ 148 NA NA 123 NA +++ 149 NA NA 124 NA +++ 150 NA NA 125
NA +++ 151 NA + 126 +++ +++ 152 NA NA 153 NA + 179 NA NA 154 NA NA
180 NA NA 155 NA +++ 181 ++ ++ 156 NA ++ 182 NA NA 157 NA +++ 183
NA NA 158 NA ++ 184 NA NA 159 NA NA 185 NA NA 160 NA +++ 186 NA NA
161 NA + 187 +++ +++ 162 NA ++ 188 NA +++ 163 NA ++ 189 NA +++ 164
NA +++ 190 NA + 165 ++ ++ 191 NA +++ 166 NA NA 192 NA +++ 167 NA NA
193 NA +++ 168 NA NA 194 NA +++ 169 NA +++ 195 NA +++ 170 +++ +++
196 NA +++ 171 NA NA 197 NA +++ 172 NA NA 198 NA + 173 NA NA 199 NA
NA 174 NA NA 200 NA + 175 NA NA 201 NA + 176 NA NA 202 NA ++ 177 NA
NA 203 NA + 178 NA NA 204 NA ++ 205 NA NA 227 NA NA 206 NA +++ 228
NA NA 207 NA +++ 229 NA NA 208 NA +++ 230 NA +++ 209 NA NA 231 NA
+++ 210 NA NA 232 NA +++ 211 NA + 233 NA +++ 212 NA NA 234 NA +++
213 NA ++ 235 NA +++ 214 NA ++ 236 NA +++ 215 NA ++ 237 NA NA 216
NA ++ 238 NA NA 217 NA + 239 NA NA 218 NA + 240 NA NA 219 NA +++
241 NA NA 220 NA +++ 242 NA NA 221 NA Inactive 243 NA NA 222 NA +++
244 NA NA 223 NA +++ 245 NA NA 224 NA Inactive 246 NA NA 225 NA +++
247 NA NA 226 NA +++
Example 250: peIF4E Signaling Cellular Assay
[1085] Phosphorylated eIF4E is assayed using the CisBio peIF4E
HTRF.RTM. assay kit (CisBio, catalogue No. 64EF4PEG). Cells are
plated in 96-well tissue-culture treated plate in appropriate
growth medium (90 .mu.L). Compounds (10.times.) are diluted using
3-fold serial dilutions in cell culture medium and added to cells.
Plates are incubated for 2 hrs at 37.degree. C. The cell
supernatant is carefully removed either by aspirating supernatant
or by flicking the plate. Immediately 50 .mu.L of supplemented
lysis buffer (1.times.) is added and incubated for at least 30
minutes at room temperature under shaking. After homogenization by
pipeting up and down, 16 .mu.L of cell lysate is transferred from
the 96-well cell-culture plate to a 384-well small volume white
plate. 4 .mu.L of premixed antibody solutions (vol/vol) is prepared
in the detection buffer and added. The plate is covered with a
plate sealer and incubated overnight at room temperature. The
fluorescence emissions at two different wavelengths are read (665
nm and 620 nm) on a Wallac Victor2. Emission ratios are converted
into percent inhibitions and imported into GraphPad Prism software.
The concentration of compound necessary to achieve inhibition of
enzyme activity by 50% (IC.sub.50) is calculated using
concentrations ranging from 20 .mu.M to 0.1 nM (12-point curve).
IC.sub.50 values are determined using a nonlinear regression model
available in GraphPad Prism 5.
[1086] The results of these assays are set forth in Table 2 below.
To this end, IC.sub.50 values of less than 0.05 .mu.M are labelled
as "+++", from 0.05 to 1.0 .mu.M are labelled as "++", greater than
1.0 to 100 .mu.M are labelled as "+", and NA means "not
available".
TABLE-US-00002 TABLE 2 peIF4E Signaling Cellular Assay (IC.sub.50)
Cpd. Cpd. Cpd. No. IC.sub.50 No. IC.sub.50 No. IC.sub.50 1 NA 26 NA
51 +++ 2 + 27 ++ 52 +++ 3 NA 28 NA 53 ++ 4 NA 29 +++ 54 ++ 5 NA 30
+++ 55 +++ 6 ++ 31 ++ 56 +++ 7 ++ 32 NA 57 ++ 8 + 33 ++ 58 +++ 9 ++
34 + 59 + 10 +++ 35 +++ 60 +++ 11 + 36 +++ 61 +++ 12 ++ 37 ++ 62
+++ 13 + 38 +++ 63 +++ 14 ++ 39 +++ 64 ++ 15 NA 40 NA 65 +++ 16 ++
41 + 66 +++ 17 NA 42 +++ 67 ++ 18 ++ 43 +++ 68 NA 19 NA 44 +++ 69
++ 20 ++ 45 +++ 70 +++ 21 +++ 46 +++ 71 ++ 22 +++ 47 ++ 72 + 23 +++
48 +++ 73 +++ 24 +++ 49 +++ 74 ++ 25 NA 50 +++ 75 + 76 +++ 102 ++
128 +++ 77 +++ 103 +++ 129 ++ 78 +++ 104 ++ 130 + 79 + 105 +++ 131
+ 80 +++ 106 ++ 132 NA 81 + 107 +++ 133 ++ 82 + 108 +++ 134 NA 83
+++ 109 +++ 135 NA 84 +++ 110 +++ 136 NA 85 +++ 111 +++ 137 NA 86
+++ 112 ++ 138 + 87 +++ 113 + 139 NA 88 +++ 114 +++ 140 NA 89 +++
115 +++ 141 NA 90 ++ 116 ++ 142 ++ 91 +++ 117 +++ 143 +++ 92 ++ 118
+ 144 NA 93 +++ 119 +++ 145 +++ 94 +++ 120 +++ 146 + 95 +++ 121 +++
147 NA 96 +++ 122 +++ 148 NA 97 +++ 123 +++ 149 NA 98 +++ 124 ++
150 NA 99 +++ 125 + 151 + 100 +++ 126 + 152 NA 101 ++ 127 +++ 153
NA 154 NA 180 NA 206 NA 155 + 181 + 207 NA 156 ++ 182 NA 208 ++ 157
++ 183 NA 209 NA 158 ++ 184 NA 210 NA 159 NA 185 NA 211 NA 160 ++
186 NA 212 NA 161 + 187 +++ 213 + 162 + 188 +++ 214 + 163 + 189 ++
215 + 164 ++ 190 NA 216 + 165 + 191 ++ 217 + 166 NA 192 ++ 218 NA
167 NA 193 +++ 219 ++ 168 NA 194 +++ 220 ++ 169 +++ 195 +++ 221 NA
170 ++ 196 +++ 222 +++ 171 NA 197 +++ 223 +++ 172 NA 198 NA 224 NA
173 NA 199 NA 225 + 174 NA 200 + 226 + 175 NA 201 NA 227 + 176 NA
202 NA 228 ++ 177 NA 203 NA 229 + 178 NA 204 NA 230 + 179 NA 205 NA
231 +++ 232 ++ 238 ++ 244 ++ 233 ++ 239 +++ 245 NA 234 +++ 240 ++
246 NA 235 + 241 +++ 247 NA 236 ++ 242 ++ 237 +++ 243 ++
Example 251: Pharmacokinetic Studies
[1087] Groups of Balb/c mice or Sprague-Dawley rats (n.gtoreq.3 per
dose group) are administered single doses of test compound.
Compounds are formulated either as solutions in 10%
N-methylpyrrolidone, 90% polyethyleneglycol 400 or as suspensions
in 0.5% methylcellulose in water for oral gavage administration at
a nominal dose level of 10 mg/kg. Compounds are formulated in 10%
dimethylisosorbide, 15% ethanol, 35% propylene glycol, and 40%
saline (or 40% D5W) for intravenous administration at a nominal
dose level of 1 mg/kg. For intravenously dosed animals, blood
samples are collected at 0.083, 0.25, 0.5, 1, 2, 4, 8, and 24 h
post dose. For orally dosed animals, blood samples are collected at
0.25, 0.5, 1, 2, 4, 8, and 24 h post dose. Blood samples are
collected from mice either serially via submandibular vein
(approximately 0.1 mL each) or terminally via cardiac puncture
(approximately 0.5 mL each). Blood samples are collected serially
from rats via jugular vein catheter (approximately 0.2 mL each).
Each blood sample is collected into a tube that is chilled and
contains potassium EDTA as the anticoagulant. Plasma is separated
and stored at approximately -80 C until analysis. Following protein
precipitation with acetonitrile containing an internal standard,
plasma samples are analyzed using a liquid
chromatography/high-resolution mass spectrometry (LC-HRMS) method
to determine plasma concentrations. Plasma concentration versus
time data are subjected to noncompartmental pharmacokinetic
analysis using Phoenix.TM. Winnonlin.RTM. (Certara LP) to determine
pharmacokinetic parameters, including Area Under the Curve (AUC),
Clearance (Cl), Volume of Distribution at Steady-State (Vss), and
terminal half-life (T1/2). Data from orally and intravenously dose
are highlighted in Tables 3 and 4, respectively.
TABLE-US-00003 TABLE 3 Pharmacokinetics Parameters in Balb/c Mice
Following a Single Oral Gavage Administration at 10 mg/kg Cpd. T1/2
Tmax Cmax Tlast AUClast No. Formulation (h) (h) (ug/mL) (h)
(h*ug/mL) Gender 9 0.5 MC 0.831 0.50 5.05 8 4.83 M 10 10 NMP/90
PEG400 1.87 0.50 1.72 8 6.42 F 10 0.5 MC 4.22 1.00 2.16 24 8.75 M
14 0.5 MC ND 0.50 0.405 8 0.255 M 20 0.5 MC 0.643 0.50 2.24 4 2.09
F 21 0.5 MC 2.66 0.50 0.0502 4 0.109 F 22 0.5 MC 1.93 2.00 0.371 8
1.62 F 23 0.5 MC 3.49 1.00 0.0175 8 0.0757 F 24 0.5 MC 1.91 2.00
0.192 8 0.921 F 35 10 NMP/90 PEG400 3.46 2.00 6.93 24 71.29 F 43
0.5 MC 6.75 2.00 0.0218 8 0.132 F 45 0.5 MC 7.55 2.00 0.00916 8
0.0429 F 50 0.5 MC 8.43 4.00 0.0472 24 0.464 F 50 5 NMP/95 PEG400
2.82 8.00 0.55 24 7.15 F 51 0.5 MC 7.38 2.00 3.16 24 31.3 F 51 5
NMP/95 PEG400 8.36 8.00 2.44 24 35.8 F 52 0.5 MC 5.41 4.00 3.37 24
38.1 F 52 10 NMP/90 PEG400 3.56 0.25 1.7 24 22.3 F 54 0.5 MC 0.743
0.50 1.05 4 1.23 F 54 10 NMP/90 PEG400 3.22 0.25 1.9 24 3.64 F 55 5
NMP/95 PEG400 2.61 1.00 6.17 24 56.9 F 56 10 NMP/90 PEG400 ND BQL
BQL ND ND F 58 0.5 MC 5.32 2.00 0.69 24 5.43 F 60 10 NMP/90 PEG400
2.21 1.00 0.036 4 0.0782 F 70 10 NMP/90 PEG400 2.00 0.25 0.983 8
1.47 F 70 10 NMP/90 PEG400 3.74 0.50 1.65 8 2.01 F 88 0.5 MC 2.97
0.50 0.81 8 2.04 F 94 10 NMP/90 PEG400 2 0.50 1.8 8 6.07 F 98 10
NMP/90 PEG400 3.1 0.30 1.2 8 4.18 F 99 10 NMP/90 PEG400 1.6 0.30
0.4 8 1.38 F 102 10 NMP/90 PEG400 1.4 0.30 1.8 F 103 10 NMP/90
PEG400 2.1 0.30 2.5 8 4.65 F 107 10 NMP/90 PEG400 5.3 1 0.95 8 2.76
F 108 10 NMP/90 PEG400 0.3 0.30 0.044 F 109 10 NMP/90 PEG400 2.5
0.30 0.63 F 110 10 NMP/90 PEG400 2.6 0.30 1.7 F Abbreviations:
NMP--N-methylpyrrolidone; PEG400--polyethyleneglycol 400;
MC--methylcellulose
TABLE-US-00004 TABLE 4 Pharmacokinetic Pparameters in Balb/c
Following a Single Intravenous Bolus Administration at 1 mg/kg Cpd.
Cl_obs T1/2 Vss AUCINF_obs No. Formulation (mL/min/kg) (h) (L/kg)
(h*ug/mL) Gender 10 10 DMI/15 EtOH/35 PG/40 Saline 42.1 2.80 5.45
0.396 F 50 10 DMI/15 EtOH/35 PG/40 Saline 18.8 2.47 3.18 0.887 F 51
10 DMI/15 EtOH/35 PG/40 Saline 6.66 5.78 2.79 2.50 F 70 10 DMI/15
EtOH/35 PG/40 D5W 50.1 0.561 1.80 0.333 F 88 10 DMA/15 EtOH/35
PEG300/40 D5W 61 1.3 3.03 0.273 F 94 10 DMA/15 EtOH/35 PEG300/40
D5W 20.5 5.81 12.2 0.812 F 98 10 DMA/15 EtOH/35 PEG300/40 D5W 46.6
1.79 3.56 0.358 F 103 10 DMA/15 EtOH/35 PEG300/40 D5W 27.8 1.51
2.49 0.6 F 107 10 DMA/15 EtOH/35 PEG300/40 D5W 33.2 2.91 3.21 0.502
F Abbreviations: DMI--dimethylisosorbide; EtOH--ethanol;
PG--propylenglycol; D5W--5% dextrose in water
[1088] The various embodiments described above can be combined to
provide further embodiments. All of the U.S. patents, U.S. patent
application publications, U.S. patent applications, foreign
patents, foreign patent applications and non-patent publications
referred to in this specification and/or listed in the Application
Data Sheet are incorporated herein by reference, in their entirety.
Aspects of the embodiments can be modified, if necessary to employ
concepts of the various patents, applications and publications to
provide yet further embodiments.
[1089] These and other changes can be made to the embodiments in
light of the above-detailed description. In general, in the
following claims, the terms used should not be construed to limit
the claims to the specific embodiments disclosed in the
specification and the claims, but should be construed to include
all possible embodiments along with the full scope of equivalents
to which such claims are entitled. Accordingly, the claims are not
limited by the disclosure.
* * * * *