| Summary: |
The invention in this patent application relates to 3-(2-aminopyrimidin-4-yl)indole
derivatives represented generally by formula (I). These compounds
are JAK1 inhibitors and may be useful for the treatment of a number
of immune disorders, such as bone marrow disorders, rheumatoid arthritis,
psoriasis, Crohn’s disease, lupus, and multiple sclerosis. |
| The Janus-associated kinase family (JAKs) contains
four known members named JAK1, JAK2, JAK3, and tyrosine kinase 2 (TYK2).
They are cytoplasmic nonreceptor tyrosine kinases that are found in
hematopoietic cells and reside on the cytoplasmic side of Type I and
II cytokine receptors. JAKs play critical roles in cytokine and growth
factor mediated signal transduction and in the immune defense. |
| Certain cytokine and/or growth factor receptors
(such as erythropoietin, thrombopoietin, interleukins, and interferon
receptors) lack the catalytic ability to initiate downstream signaling.
By binding to one (or more) of the JAK family members, these receptors
can be activated to perform this function. This binding induces conformational
changes that allow JAKs to be activated and phosphorylate the tyrosine
residues on the receptor cytoplasmic domains and even on themselves
(autophosphorylation). This creates active sites that attract and
bind with signaling proteins such as the signal transducer and activator
of transcription (STAT). The binding of a STAT protein to an activated
JAK results in phosphorylation, subsequent dimerization, and translocation
of STAT to the nucleus, where it modulates target gene transcription.
The STAT family contains seven transcription factor members named
STAT1, 2, 3, 4, 5a, 5b, and 6. |
| The phosphorylation
and subsequent activation of STAT3 has been linked to a wide range
of cancers and hyperproliferative disorders and was also associated
with poor prognosis in several cancers. Persistently activated STAT3
is oncogenic and has been shown to drive the expression of cellular
proteins that contribute to the fundamental cancer progression processes
including survival, proliferation, invasion, and angiogenesis. |
| A typical mechanism of STAT3 activation in cancer
cells is believed to occur via autocrine or paracrine stimulation
of JAK/STAT3 signaling by members of the interleukin-6 (IL-6) cytokine
family. JAK1 is the key JAK kinase that mediates this STAT3 activation
process. |
| Inactivation of negative regulatory
proteins, such as the suppressors of cytokine signaling (SOCS) or
protein inhibitor of activated STATs (PIAS) proteins, have also been
shown to influence the activation of the JAK/STAT signaling pathway
in cancer. |
| JAK1/STAT3 signaling pathway activation
in several human tumors may also occur as a feedback resistance mechanism
in response to inhibition of driver oncogenic pathways in cancer cells,
such as the mutated epidermal growth factor receptor (EGFR) in nonsmall
cell lung cancer (NSCLC) or the mitogen-activated protein kinase (MAPK)
pathway in KRAS mutant tumors. Thus, the inhibition of JAK1 may provide
a means of potentiating the therapeutic benefit of a variety of targeted
cancer therapies. |
| Cancer cachexia is a debilitating
condition that affects advanced cancer patients and causes significant
skeletal muscle wasting. It contributes significantly to increased
patient mortality and poor response to chemotherapy. One of the factors
that plays a fundamental role in this condition is elevated levels
of inflammatory cytokines, such as IL-6, which signal through the
JAK/STAT pathway. Thus, there is a potential benefit for JAK1 inhibition
in ameliorating cancer cachexia. |
| JAK1 plays
a critical role in signal transduction mediated by class II cytokine
receptors, the cytokine receptor common subunit γ (γc), the glycoprotein 130 (gp130) subunit, and granulocyte-colony
stimulating factor G-CSF. It also drives the activities of the immune-relevant
γc cytokines. Therefore, JAK1 inhibitors such as
the compounds of formula I described in this patent application, which
exhibit up to 100 times selectivity for the inhibition of JAK1 over
JAK2, may provide useful treatments for a number of immune disorders,
such as bone marrow disorders, rheumatoid arthritis, psoriasis, Crohn’s
disease, lupus, and multiple sclerosis. |
| Important Compound Classes: |
 |
| Key Structures: |
The inventors described
the synthesis procedures and structures of 69 compounds of formula
(I) including the following representative examples:
|
| Biological Assay: |
|
| Biological Data: |
The results
from the enzyme inhibition studies assay indicate that the compounds
of the invention exhibit up to 100 times selectivity for the inhibition
of JAK1 over JAK2. The results from cellular
pSTAT3 assay demonstrate good correlation between cellular inhibition
of STAT3 phosphorylation in NCI-H1975 cells and JAK1 inhibition. |
Data for the above representative
examples are listed in the following table:
|
| Recent Review Articles: |
1. Nakayamada S.; Kubo S.; Iwata S.; Tanaka Y.. BioDrugs 2016, 30( (5), ), 407–419. |
| 2. Menet C. J.; Mammoliti O.; Lopez-Ramos M.. Future Med. Chem. 2015, 7 ( (2), ), 203–235. |
| 3. Norman P.Expert Opinion on Therapeutic
Patents 2014, 24 ( (2), ), 231–237. |
