PYRROLOr2.3-d¾PYRlMIDINE TROPOMYOSIN-RELATED KINASE INHIBITORS
The invention described herein relates to certain pyrro!o[2,3-d}pyrimidine compounds and the
pharmaceutically acceptable salts of such compounds. The invention also relates to the processes for the
preparation of the compounds, compositions containing the compounds, and the uses of such compounds
and salts in treating diseases or conditions associated with tropomyosin-related kinase (Trk), activity,
More specifically the invention relates to the compounds and their salts useful as inhibitors of Trk .
BACKGROUND
Tropomyosin-related kinases (Trks) are a family of receptor tyrosine kinases activated by neurotrophins.
Trks play important roles in pain sensation as well as tumour cell growth and survival signaling. Thus,
inhibitors of Trk receptor kinases might provide targeted treatments for conditions such as pain and
cancer. Recent developments in this field have been reviewed by Wang t al in Expert Opin. Ther.
Patents (2009) 19(3): 305-319 and an extract is reproduced below.
" 1.1 Trk receptors
As one of the largest family of proteins encoded by the human genome, protein kinases are the central
regulators of signal transduction as well as control of various complex cell processes. Receptor tyrosine
kinases (RTKs) are a subfamily of protein kinases (up to 100 members) bound to the cell membrane that
specifically act on the tyrosine residues of proteins. One small group within this subfamily is the Trk
kinases, with three highly homologous isoforms: TrkA, Tr , and TrkC. All three isofonns are activated by
high affinity growth factors named neurotrophins (NT): i) nerve growth factor (NGF), which activates TrkA;
ii) brain-derived neurotrophic factor (BDNF) and NT-4/5, which activate TrkB; and iii) NT-3, which
activates TrkC. The binding of neurotrophins to the extracellular domain of Trks causes the Trk kinase to
autophosphorylate at several intracellular tyrosine sites and triggers downstream signal transduction
pathways. Trks and neurotrophins are well known for their effects on neuronal growth and survival.
1.2 Trks and cancer
Originally isolated from neuronal tissues, Trks were thought to mainly affect the maintenance and survival
of neuronal cells. However, in the past 20 years, increasing evidence has suggested that Trks play key
roles in malignant transformation, chemotaxis, metastasis, and survival signaling in human tumors. The
association between Trks and cancer focused on prostate cancer in earlier years and the topic has been
reviewed. For example, it was reported that malignant prostate epithelial cells secrete a series of
neurotrophins and at least one Trks. In pancreatic cancer, it was proposed that paracrine and/or autocrine
neurotrophin-Trk interactions may influence the invasive behavior of the cancer. TrkB was also reported to
be overexpressed metastatic human pancreatic cancer cells. Recently, there have been a number of
new findings in other cancer settings. For example, a translocation leads to expression of a fusion protein
derived from the W-terminus of the ETV9 transcription factor and the C-terminal kinase domain of TrkC.
The resulting ETV6-TrkC fusions are oncogenic in vitro and appear causative in secretory breast
carcinoma and some acute myelogenous leukemias (AML). Constitutively active TrkA fusions occurred in
a subset of papillary thyroid cancers and colon carcinomas. In neuroblastoma, TrkB expression was
reported to be a strong predictor of aggressive tumor growth and poor prognosis, and TrkB
overexpression was also associated with increased resistance to chemotherapy in neuroblastoma tumor
cells in vitro. One report showed that a novel splice variant of TrkA called TrkAI I I signaled in the absence
of neurotrophins through the inositol phosphate-AKT pathway in a subset of neuroblastoma. Also,
mutational analysis of the tyrosine kinome revealed that Trk mutations occurred in colorectal and lung
cancers. In summary, Trks have been linked to a variety of human cancers, and discovering a Trk inhibitor
and testing it clinically might provide further insight to the biological and medical hypothesis of treating
cancer with targeted therapies.
1.3 Trks and pain
Besides the newly developed association with cancer, Trks are also being recognized as an important
mediator of pain sensation. Congenital insensitivity to pain with anhidrosis (CIPA) is a disorder of the
peripheral nerves (and normally innervated sweat glands) that prevents the patient from either being able
to adequately perceive painful stimuli or to sweat. TrkA defects have been shown to cause CIPA in
various ethnic groups.
Currently, non-steroidal anti-inflammatory drugs (NSAIDs) and opiates have low efficacy and/or side
effects (e.g., gastrointestinal/renal and psychotropic side effects, respectively) against neuropathic pain
and therefore development of novel pain treatments is highly desired. It has been recognized that NGF
levels are elevated in response to chronic pain, injury and inflammation and the administration of
exogenous NGF increases pain hypersensitivity. In addition, inhibition of NGF function with either anti-
NGF antibodies or non-selective small molecule Trk inhibitors has been shown to have effects on pain in
animal models. It appears that a selective Trk inhibitor (inhibiting at least NGF's target, the TrkA receptor)
might provide clinical benefit for the treatment of pain. Excellent earlier reviews have covered targeting
NGF/BDNF for the treatment of pain so this review will only focus on small molecule Trk kinase inhibitors
claimed against cancer and pain. However, it is notable that the NGF antibody tanezumab was very
recently reported to show good efficacy in a Phase I I trial against osteoarthritic knee pain ."
International Patent Application publication number WO2009/0 12283 refers to various fluorophenyl
compounds as Trk inhibitors; International Patent Application publication numbers WO2009/1 52087,
WO2008/08001 5 and WO2008/08001 and WO2009/1 52083 refer to various fused pyrroles as kinase
modulators; International Patent Application publication numbers WO2009/1 43024 and WO2009/1 4301 8
refer to various pyrrolo[2,3-d]pyrimidines substituted as Trk inhibitors; International Patent Application
publication numbers WO2004/056830 and WO2005/1 16035 describe various 4-amino-pyrrolo[2,3-
d]pyrimidines as Trk inhibitors. International Patent Application publication number WO201 1/1 33637
describes various pyrrolo[2,3-d]pyrimidines and pyrrolo[2,3-b]pyridines as inhibitors of various kinases.
US provisional application US61 /47 1758 was filed 5th April 201 2 and the whole contents of that application
in it's entirety are herewith included by reference thereto.
Thus Trk inhibitors have a wide variety of potential medical uses. There is a need to provide new Trk
inhibitors that are good drug candidates. In particular, compounds should preferably bind potently to the
Trk receptors in a selective manner compared to other receptors, whilst showing little affinity for other
receptors, including other kinase and / or GPC receptors, and show functional activity as Trk receptor
antagonists. They should be non-toxic and demonstrate few side-effects. Furthermore, the ideal drug
candidate will exist in a physical form that is stable, non-hygroscopic and easily formulated. They should
preferably be e.g. well absorbed from the gastrointestinal tract, and / or be injectable directly into the
bloodstream, muscle, or subcutaneously, and / or be metabolically stable and possess favourable
pharmacokinetic properties.
Among the aims of this invention are to provide orally-active, efficacious, compounds and salts which can
be used as active drug substances, particularly Trk antagonists, i.e. that block the intracellular kinase
activity of the Trk, e.g. TrkA (NGF) receptor. Other desirable features include good HLM/hepatocyte
stability, oral bioavailability, metabolic stability, absorption , selectivity over other types of kinase, dofetilide
selectivity. Preferable compounds and salts will show a lack of CYP inhibition/induction, and be CNSsparing.
SUMMARY
The present invention provides compounds of Formula I :
(I)
and pharmaceutically acceptable salts thereof wherein the subsituents are defined below.
The invention also comprises pharmaceutical compositions comprising a therapeutically effective amount
of a compound of formula I as defined herein, or a pharmaceutically acceptable salt thereof, and a
pharmaceutically acceptable carrier.
The invention is also directed to a method of treating a disease or condition indicated for treatment with a
Trk antagonist, in a subject, by administering to a subject in need thereof a therapeutically effective
amount of one or more of the compounds herein, or a pharmaceutically acceptable salt thereof.
Other aspects of the invention will be apparent from the remaining description and claims.
Preferably, the compounds of the present invention are potent antagonists at Trk receptors, and have a
suitable PK profile to enable once daily dosing.
The compounds of the present invention are potentially useful in the treatment of a range of disorders
where a Trk antagonist is indicated, particularly pain indications. Depending on the disease and condition
of the patient, the term "treatment" as used herein may include one or more of curative, palliative and
prophylactic treatment.
According to the invention a compound of the present invention may be useful to treat any physiological
pain such as inflammatory pain, nociceptive pain, neuropathic pain , acute pain , chronic pain , musculo¬
skeletal pain, on-going pain, central pain, heart and vascular pain, head pain , orofacial pain. Other pain
conditions which may be treated include intense acute pain and chronic pain conditions which may involve
the same pain pathways driven by pathophysiological processes and as such cease to provide a
protective mechanism and instead contribute to debilitating symptoms associated with a wide range of
disease states.
Pain is a feature of many trauma and disease states. When a substantial injury, via disease or trauma, to
body tissue occurs the characteristics of nociceptor activation are altered , this leads to hypersensitivity at
the site of damage and in nearby normal tissue. In acute pain the sensitivity returns to normal once the
injury has healed. However, in many chronic pain states, the hypersensitivity far outlasts the healing
process and is normally due to nervous system injury due to maladaptation of the afferent fibres (Woolf &
Salter 2000 Science 288: 1765-1 768). Clinical pain is present when discomfort and abnormal sensitivity
feature among the patient's symptoms. There are a number of typical pain subtypes: 1) spontaneous pain
which may be dull , burning, or stabbing; 2) pain responses to noxious stimuli are exaggerated
(hyperalgesia); 3) pain is produced by normally innocuous stimuli (allodynia) (Meyer et al., 1994 Textbook
of Pain 13-44). Pain can be divided into a number of different areas because of differing pathophysiology,
these include nociceptive, inflammatory, neuropathic pain among others. It should be noted that some
types of pain have multiple aetiologies and thus can be classified in more than one area, e.g. Back pain,
Cancer pain have both nociceptive and neuropathic components.
NOCICEPTIVE PAIN
Nociceptive pain is induced by tissue injury or by intense stimuli with the potential to cause injury. Pain
afferents are activated by transduction of stimuli by nociceptors at the site of injury and sensitise the
spinal cord at the level of their termination. This is then relayed up the spinal tracts to the brain where
pain is perceived (Meyer et al., 1994 Textbook of Pain 13-44). The activation of nociceptors activates two
types of afferent nerve fibres. Myelinated A-delta fibres transmit rapidly and are responsible for the sharp
and stabbing pain sensations, whilst unmyelinated C fibres transmit at a slower rate and convey the dull
or aching pain. Moderate to severe acute nociceptive pain is a prominent feature of, but is not limited to
pain from strains/sprains, post-operative pain (pain following any type of surgical procedure),
posttraumatic pain, burns, myocardial infarction, acute pancreatitis, and renal colic. Also cancer related
acute pain syndromes commonly due to therapeutic interactions such as chemotherapy toxicity,
immunotherapy, hormonal therapy and radiotherapy. Moderate to severe acute nociceptive pain is a
prominent feature of, but is not limited to, cancer pain which may be tumour related pain , (e.g. bone pain,
headache and facial pain, viscera pain) or associated with cancer therapy (e.g . postchemotherapy
syndromes, chronic postsurgical pain syndromes, post radiation syndromes), back pain which may be due
to herniated or ruptured intervertabral discs or abnormalities of the lumbar facet joints, sacroiliac joints,
paraspinal muscles or the posterior longitudinal ligament.
NEUROPATHIC PAIN
According to the invention a compound of the present invention can potentially be used to treat
neuropathic pain and the symptoms of neuropathic pain including hyperalgesia, allodynia and ongoing
pain. Neuropathic pain is defined as pain initiated or caused by a primary lesion or dysfunction in the
nervous system (IASP definition). Nerve damage can be caused by trauma and disease and thus the
term 'neuropathic pain' encompasses many disorders with diverse aetiologies. These include but are not
limited to, Diabetic neuropathy, Post herpetic neuralgia, Back pain, Cancer neuropathy, HIV neuropathy,
Phantom limb pain, Carpal Tunnel Syndrome, chronic alcoholism, hypothyroidism, trigeminal neuralgia,
uremia, or vitamin deficiencies. Neuropathic pain is pathological as it has no protective role. It is often
present well after the original cause has dissipated , commonly lasting for years, significantly decreasing a
patients quality of life (Woolf and Mannion 1999 Lancet 353: 1959-1 964). The symptoms of neuropathic
pain are difficult to treat, as they are often heterogeneous even between patients with the same disease
(Woolf & Decosterd 1999 Pain Supp. 6 : S 14 1-S1 47; Woolf and Mannion 1999 Lancet 353: 1959-1 964).
They include spontaneous pain, which can be continuous, or paroxysmal and abnormal evoked pain, such
as hyperalgesia (increased sensitivity to a noxious stimulus) and allodynia (sensitivity to a normally
innocuous stimulus).
INTENSE ACUTE PAIN AND CHRONIC PAIN
Intense acute pain and chronic pain may involve the same pathways driven by pathophysiological
processes and as such cease to provide a protective mechanism and instead contribute to debilitating
symptoms associated with a wide range of disease states. Pain is a feature of many trauma and disease
states. When a substantial injury, via disease or trauma, to body tissue occurs the characteristics of
nociceptor activation are altered. There is sensitisation in the periphery, locally around the injury and
centrally where the nociceptors terminate. This leads to hypersensitivity at the site of damage and in
nearby normal tissue. In acute pain these mechanisms can be useful and allow for the repair processes
to take place and the hypersensitivity returns to normal once the injury has healed. However, in many
chronic pain states, the hypersensitivity far outlasts the healing process and is normally due to nervous
system injury. This injury often leads to maladaptation of the afferent fibres (Woolf & Salter 2000 Science
288: 1765-1 768). Clinical pain is present when discomfort and abnormal sensitivity feature among the
patient's symptoms. Patients tend to be quite heterogeneous and may present with various pain
symptoms. There are a number of typical pain subtypes: 1) spontaneous pain which may be dull, burning,
or stabbing; 2) exaggerated pain responses to noxious stimuli (hyperalgesia); 3) pain is produced by
normally innocuous stimuli (allodynia) (Meyer et al. , 1994 Textbook of Pain 13-44). Although patients with
back pain, arthritis pain, CNS trauma, or neuropathic pain may have similar symptoms, the underlying
mechanisms are different and, therefore, may require different treatment strategies.
CHRONIC PAIN
Chronic pain comprises one or more of, chronic nociceptive pain, chronic neuropathic pain, chronic
inflammatory pain, breakthrough pain, persistent pain hyperalgesia, allodynia, central sensitisation,
peripheral sensitisation , disinhibition and augmented facilitation.
Chronic pain includes cancer pain, e.g. cancer pain arising from malignancy, adenocarcinoma in glandular
tissue, blastoma in embryonic tissue of organs, carcinoma in epithelial tissue, leukemia in tissues that
form blood cells, lymphoma in lymphatic tissue, myeloma in bone marrow, sarcoma in connective or
supportive tissue, adrenal cancer, AIDS-related lymphoma, anemia, bladder cancer, bone cancer, brain
cancer, breast cancer, carcinoid tumour s , cervical cancer, chemotherapy, colon cancer, cytopenia, ,
endometrial cancer, esophageal cancer, gastric cancer, head cancer, neck cancer, hepatobiliary cancer,
kidney cancer, leukemia, liver cancer, lung cancer, lymphoma, Hodgkin's disease, lymphoma, non-
Hodgkin's, nervous system tumours, oral cancer, ovarian cancer, pancreatic cancer, prostate cancer,
rectal cancer, skin cancer, stomach cancer, testicular cancer, thyroid cancer, urethral cancer, bone
cancer, sarcomas cancer of the connective tissue, cancer of bone tissue, cancer of blood-forming cells,
cancer of bone marrow, multiple myeloma, leukaemia, primary or secondary bone cancer, tumours that
metastasize to the bone, tumours infiltrating the nerve and hollow viscus, tumours near neural structures.
Cancer pain also comprises visceral pain, e.g. visceral pain which arises from pancreatic cancer and/or
metastases in the abdomen, somatic pain, e.g. somatic pain due to one or more of bone cancer,
metastasis in the bone, postsurgical pain, sarcomas cancer of the connective tissue, cancer of bone
tissue, cancer of blood-forming cells of the bone marrow, multiple myeloma, leukaemia, primary or
secondary bone cancer.
INFLAMMATORY PAIN
Inflammatory conditions include acute inflammation, persistent acute inflammation, chronic inflammation,
and combined acute and chronic inflammation.
Inflammatory pain includes acute inflammatory pain and/or chronic inflammatory pain wherein the chronic
inflammatory pain can be pain involving both peripheral and central sensitisation and/or mixed etiology
pain involving both inflammatory pain and neuropathic pain or nociceptive pain components.
Inflammatory pain also comprises hyperalgesia, e.g. primary and/or secondary hyperalgesia. Additionally
or alternatively the inflammatory pain can include allodynia. Inflammatory pain also comprises pain that
persists beyond resolution of an underlying disorder or inflammatory condition or healing of an injury.
Inflammatory pain is pain resulting an inflammatory condition e.g. in response to acute tissue injury due
to trauma, disease e.g. an inflammatory disease, immune reaction, the presence of foreign substances,
chemicals or infective particles for example micro-organisms. Inflammatory conditions can be either acute
or chronic inflammation or both.
Inflammatory pain can result from an inflammatory condition due to an inflammatory disease such as
inflammatory joint diseases, inflammatory connective tissue diseases, inflammatory autoimmune
diseases, inflammatory myopathies, inflammatory digestive system diseases, inflammatory air way
diseases, cellular immune inflammation diseases, hypersensitivities and allergies, vasular inflammation
diseases, non-immune inflammatory disease, synovitis, villonodular synovitis, arthralgias, ankylosing
spondylitis, spondyloarthritis, spondyloarthropathy, gout, Pagets disease, periarticular disorders such as
bursitis, rheumatoid disease, rheumatoid arthritis and osteoarthritis, rheumatoid arthritis or osteoarthritis.
Rheumatoid arthritis in particular, represents ongoing inflammation associated with severe pain . Arthritic
pain is a form of inflammatory pain and arises from inflammation in a joint which causes both peripheral
sensitization and central sensitization. Under inflammatory conditions the nociceptive system is activated
by normally innocuous and nonpainful mechanical stimuli. Additionally when the joint is at rest pain is
present and appears as spontaneous pain and hyperalgesia (augmented pain response on noxious
stimulation and pain on normally nonpainful stimulation). Inflammatory processes in peripheral tissues
lead to central sensitization in the spinal cord, which contributes to hyperalgesia and allodynia typically
associated with inflammatory pain. Other types of inflammatory pain include inflammatory bowel diseases
(IBD).
OTHER TYPES OF PAIN
Other types of pain include but are not limited to:
- Musculoskeletal disorders including but not limited to myalgia, fibromyalgia, spondylitis, sero-negative
(non-rheumatoid) arthropathies, non-articular rheumatism, dystrophinopathy, Glycogenolysis,
polymyositis, pyomyositis;
- Central pain or 'thalamic pain' as defined by pain caused by lesion or dysfunction of the nervous system
including but not limited to central post-stroke pain, multiple sclerosis, spinal cord injury, Parkinson's
disease and epilepsy;
- Heart and vascular pain including but not limited to angina, myocardical infarction, mitral stenosis,
pericarditis, Raynaud's phenomenon, scleredoma, scleredoma, skeletal muscle ischemia;
- Visceral pain, and gastrointestinal disorders. The viscera encompasses the organs of the abdominal
cavity. These organs include the sex organs, spleen and part of the digestive system . Pain associated
with the viscera can be divided into digestive visceral pain and non-digestive visceral pain. Commonly
encountered gastrointestinal (Gl) disorders include the functional bowel disorders (FBD) and the
inflammatory bowel diseases (IBD). These Gl disorders include a wide range of disease states that are
currently only moderately controlled, including - for FBD, gastro-esophageal reflux, dyspepsia, the
irritable bowel syndrome (IBS) and functional abdominal pain syndrome (FAPS), and - for IBD, Crohn's
disease, ileitis, and ulcerative colitis, which all regularly produce visceral pain. Other types of visceral pain
include the pain associated with dysmenorrhea, pelvic pain, cystitis and pancreatitis;
Head pain including but not limited to migraine, migraine with aura, migraine without aura cluster
headache, tension-type headache. Orofacial pain including but not limited to dental pain,
temporomandibular myofascial pain, tinnitus, hot flushes, restless leg syndrome and blocking
development of abuse potential. Further pain conditions may include, back pain (e.g. chronic lower back
pain), cancer pain , complex regional syndrome, HIV-related neuropathic pain, post-operative induced
neuropathic pain, post-stroke pain, spinal cord injury pain, traumatic nerve injury pain, diabetic peripheral
neuropathy, moderate / severe interstitial cystitis pain , irritable bowel syndrome pain, moderate / severe
endometriosis pain, moderate / severe pelvic pain , moderate / severe prostatitis pain, moderate / severe
osteoarthritis pain.post-herpetic neuralgia, rheumatoid arthritis pain, dysmenorrhea pain, pre-emptive
post-operative pain, trigeminal neuralgia, bursitis, dental pain, fibromyalgia or myofacial pain, menstrual
pain, migraine, neuropathic pain (including painful diabetic neuropathy), pain associated with post¬
herpetic neuralgia, post-operative pain, referred pain, trigeminal neuralgia, visceral pain (including
interstitial cystitis and IBS) and pain associated with AIDS, allodynia, burns, cancer, hyperalgesia,
hypersensitisation, spinal trauma and/or degeneration and stroke.
DETAILED DESCRIPTION
Emodiment 1 of the invention is a compound of Formula I:
(I)
or a pharmaceutically acceptable salt thereof, wherein
R is
H, or
C-i-5 alkyl optionally substituted by up to 3 substituents independently selected from OH, CON(R R6) ,
S0 2R7, SR7, OR7, CH2OH, C0 2R5, SONR R7, NR S0 2R5, CN, N0 2 and R8 , or
a ring system selected from C3.5 cycloalkyl , propellanyl, or a 4-6 membered saturated heterocyclyl
ring, which ring system has up to 3 ring hetero-atoms selected from N, O and S, and which ring
system is optionally substituted by up to 3 substituents independently selected from methyl, OH,
CON(R R6) , S0 2R7, OR7, CH2OH, C0 2R5, SONR R7, NR S0 2R5, CN, N0 2 and R8;
R2 is H or methyl ;
R3 is H, NH2 or NH(Ci_ 3 alkyl optionally substituted with up to 3 substituents independently selected from
OH and 0 ( .3 alkyl));
R 0 is H, OH, methyl, cyclopropyl, methoxy, ethyl, ethoxy or CN,
X is a bond, O, (CH-R 4)n, NR104 , OCH 2 or CH20 ;
R4 is independently H, CH3, CH2OH, CH2OCH 3, OH, NH2, NHCH 3 , N(CH 3)2, CH2NH2, CH2NHCH 3,or
CH2N(CH 3)2;
R104 is H, Ci_3 alkyl or a C4. saturated carbocycle, each of which is optionally substituted by up to 3
substituents independently selected from C-i_3 alkyl, CH2OH and NH2;
n is 1 or 2 ;
R102 is a ring system which is a 3-7 membered monocyclic carbocyclic or heterocyclic system, or an 8-1 4-
membered bicydic system , which ring system may be saturated or partially or fully unsaturated, wherein
the heterocyclic ring system may have up to 5 ring hetero-atoms selected from N, S, and O,
wherein the bicydic ring system can be 2 rings (carbocyclic-carbocyclic, carbocyclic-heterocyclic,
heterocyclic-carbocyclic or heterocyclic-heterocyclic) fused or linked by a single bond,
which ring system is optionally substituted by up to 3 substituents independently selected from , where
possible -
halo, CN, NR R6, S0 2R7 , SR7, C-,.4 alkyl optionally substituted by up to 3 OH and/or C-,.3 alkoxy groups,
C3 cycloalkyl optionally substituted by up to 3 OH and/or C -3 alkoxy groups, C-i_3 alkyl substituted by up
to 3 halogen, OH, 0(C-|_3 alkyl), 0(C 3. cycloalkyl optionally substituted by up to 3 OH and/or C-i_3 alkoxy
groups, 0(C-|_3 alkyl substituted by up to 3 halogen), 0(C-|_3 alkyl substituted by up to 3 OH and/or C-i_3
alkoxy groups), NR S0 2R7, =0, R8, C(0)R 8, N0 2, NR C0 2R7, NR COR ,OR 8, S(0)R 7, and CH2R8;
R and R6 are each independently
H, or
C-i_5 alkyl optionally substituted by up to 3 substituents independently selected from OH, CONR R7,
S0 2R7, OR7, CH2OH, C0 2R7, SONR R7, NR S0 2R7, CN, N0 2 and R9 ,
or
a ring system selected from C3.5 cycloalkyl , propellanyl, or a 4-6 membered saturated heterocyclyl ring,
which ring system is optionally substituted by up to 3 substituents independently selected from OH,
CON(R R7) , S0 2R7 , C0 2R7, SONR R7, NR S0 2R7, CN, N0 2, halo, NR R ,SR , _4 alkyl optionally
substituted by up to 3 OH and/or C-i_3 alkoxy groups, C3. cycloalkyl optionally substituted by up to 3 OH
and/or C-i_3 alkoxy groups, C-i_3 alkyl substituted by 1 to 3 halogen, 0(C 3. cycloalkyl optionally substituted
by up to 3 OH and/or Ci_3 alkoxy groups, 0(Ci_ 3 alkyl substituted by up to 3 halogen, 0(Ci_ 3 alkyl
substituted by up to 3 OH and/or C -3 alkoxy, NR S0 2R ,=0,N0 2,NR C0 2R7, and S(0)R 7
or R5 and R6 together with the N to which they are attached can be a 4-7 membered ring optionally
including up to 2 further ring hetero-atoms independently selected from N, O, S, which ring is optionally
substituted by C-i_3 alkoxy and / or C-i_3 alkyl;
R7 is H, C-i_5 alkyl or C-i_5 alkoxy,
which C-i_5 alkyl or C-i_5 alkoxy is optionally substituted by up to 3 substituents independently selected from
halogen;
R8 is a is a ring system which is a 3-7 membered monocyclic carbocydic or heterocyclic system , or an 8-
14-membered bicyclic system, which ring system may be saturated or partially or fully unsaturated,
wherein the heterocyclic ring system may have up to 5 ring hetero-atoms selected from N, S, and O,
wherein the bicyclic ring system can be 2 rings (carbocyclic-carbocyclic, carbocyclic-heterocyclic,
heterocyclic-carbocyclic or heterocyclic-heterocyclic) fused or linked by a single bond,
which ring system is optionally substituted by up to 3 substituents independently selected from , where
possible -
halo, CN, NR R6, S0 2R7, SR7, C-,.4 alkyl optionally substituted by up to 3 OH and/or C-,.3 alkoxy groups,
C3 cycloalkyl optionally substituted by up to 3 OH and/or C -3 alkoxy groups, C-i_3 alkyl substituted by 1
to 3 halogen, OH, 0(Ci_ 3 alkyl), 0(C 3. cycloalkyl optionally substituted by up to 3 OH and/or C .3 alkoxy
groups, 0(Ci_ 3 alkyl substituted by up to 3 halogen, 0(Ci_ 3 alkyl substituted by up to 3 OH and/or C .3
alkoxy, NR S0 2R7, =0, N0 2, NR COR ,NR C0 2R7 , and S(0)R 7;
R9 is a is a ring system which is a 3-7 membered monocyclic carbocydic or heterocyclic system , or an 8-
14-membered bicyclic system, which ring system may be saturated or partially or fully unsaturated,
wherein the heterocyclic ring system may have up to 5 ring hetero-atoms selected from N, S, and O,
wherein the bicyclic ring system can be 2 rings (carbocyclic-carbocyclic, carbocyclic-heterocyclic,
heterocyclic-carbocyclic or heterocyclic-heterocyclic) fused or linked by a single bond,
which ring system is optionally substituted by up to 3 substituents independently selected from , where
possible -
halo, CN, NR R7, S0 2R7, SR7, C 4 alkyl optionally substituted by up to 3 OH and/or C -3 alkoxy groups,
C3 cycloalkyl optionally substituted by up to 3 OH and/or C-i_3 alkoxy groups, C-i_3 alkyl substituted by 1
to 3 halogen, OH, 0(Ci_ 3 alkyl), 0(C 3. cycloalkyl optionally substituted by up to 3 OH and/or C .3 alkoxy
groups, 0(Ci_ 3 alkyl substituted by up to 3 halogen, 0(Ci_ 3 alkyl substituted by up to 3 OH and/or C .3
alkoxy, NR S0 2R7, =0, N0 2, NR C0 2R7, NR COR ,and S(0)R 7;
wherein each CH moiety can be replaced by a CF moiety.
Embodiment 2 of the invention is a compound or salt according to embodiment 1 wherein R is H, C-i_5
alkyl optionally substituted by up to 2 OH,
or R is 5alkyl substituted by CONH2, CONHCH3, CON(CH3)2, C0 2H, C0 2CH3, OCH3, SCH3, S0 2CH3,
or R is a ring system selected from C3.5 cycloalkyl, propellanyl , or oxetanyl , which ring system is
optionally substituted by methyl, OH or CH2OH.
Embodiment 3 of the invention is a compound or salt according to any one of embodiments 1 or 2 wherein
R is t-butyl, hydroxy-t-butyl , dihdyroxy-t-butyl , 1-hydroxyprop-2-yl or 1,3-dihydroxyprop-2-yl .
Embodiemnt 4 of the invention is a compound or salt according to any one of embodiments 1 to 3
wherein R2 is H.
Embodiemt 5 of the invention is a compound or salt according to any one of embodiments 1 to 4 wherein
R is H or NH2.
Embodiment 6 of the invention is a compound or salt according to any one of embodiments 1 to 5 wherein
R3 is NH2.
Embodiment 7 of the invention i s a compound or salt according to any one of embodiments 1 to 5
wherein R3 is H.
Embodiment 8 of the invention is a compound or salt according to any one of embodiments 1 to 7 wherein
R101 is H.
Embodiment 9 of the invention is a compound or salt according to any one of embodiments 1 to 7 wherein
R101 is OH.
Embodiment 10 of the invention is a compound or salt according to any one of embodiments 1 to 9
wherein X is a bond, O, CH2, C2H4, CH(CH3)CH2, CH(CH3) , CH(CH2OH), CH20 , CH(NH2) , CH(OH) or NH.
Embodiment 11 of the invention is a compound or salt according to any one of embodiments 1 to 10
wherein X is CH2.
Embodiment 12 of the invention is a compound or salt according to any one of embodiments 1 to 11
wherein R102 is an optionally substituted nitrogen-containing ring system which is linked to the X moiety
via a nitrogen ring atom.
Embodiment 13 of the invention is a compound or salt according to any one of embodiments 1 to 11
wherein R102 is an optionally substituted ring system where the ring system is selected from -
benzimidazolyl , benzisoxazolyl, benzofuranyl , benzoxazolyl, benzotriazolyl, biphenyl , bipyrazolyl ,
cinnolinyl , cyclobutylimidazolyl, cyclobutylpyrazolyl, cyclobutylthiazolyl, cyclopentyltriazolyl,
cyclopropylisoxazolyl, cyclopropyloxazolyl, cyclopropylpyrazolyl , cyclopropyltriazolyl , diazirenylphenyl,
dihydronaphthyridinyl, dihydropyrrolopyrazolyl, dioxinopyridinyl, furazanyl , furopyridinyl, furopyrrolyl,
imidazolyl, imidazopyrazinyl, imidazopyridazinyl , imidazopyridinyl , imidazopyrimidinyl, imidazothiadiazolyl,
imidazothiazolyl, indanyl , indazolyl, indolyl, isoindolyl, isoxazolopyridinyl, isoxazolyl , isoquinolinyl,
naphthyridinyl, oxazolyl, phenyl, phenylcyclopropyl, phenylimidazolyl, phenylpyrazolyl, phenylpyrrolyl,
phenyltetrazolyl, phthalazinyl, purinyl, pyrazinyl, pyrazolyl, pyrazolopyridinyl, pyrazolopyrimidinyl ,
pyrazolotriazinyl, pyridinyl , pyridazinyl , pyridinyltriazolyl, pyrimidinyl, pyrroloimidazolyl, pyrrolopyrazinyl ,
pyrrolopyrimidinyl , pyrrolopyridinyl, pyrrolyl, quinolinyl, quinazolyl, quinoxalinyl, tetrahydrobenzisoxazolyl,
tetrahydrocyclopentapyrazolyl, tetrahydrotriazolopyridinyl, tetrazolopyridazinyl, tetrazolopyridinyl,
thiazolyl, thiazolopyridinyl, thiazolopyrimidinyl, thienylpyrazolyl, thienopyridinyl, triazolopyridinyl and
triazolyl ,
Embodiment 14 of the invention is a compound or salt according to embodiment 13 where the optional
substituents are independently selected from , where possible -
halo, methyl, ethyl, propyl , isopropyl , cyclopropyl, CF3, CHF2, CH2F, CH2OCH3, CN, CH2OH, OCH3, =0,
NH2, SCH3, S0 2CH3, phenoxy, fluorophenoxy, benzyl , SCF3, OCF3, S0 2CF3, NHS0 2CH3, NHS0 2CF3,
C(0)CF 3, C(0)CH 3, benzoyl, azetidinylmethyl, fluoroazetidinylmethyl and morpholinomethyl.
Embodiment 15 of the invention is a compound or salt according to any one of embodiments 1 to 11, 13
or 14 , wherein R102 is selected from phenyl, pyrazol-1 -yl, 1,2,3-triazol-1 -yl, benzotriazol-2-yl, pyridin-2-yl ,
pyridin-3-yl and pyridin-4-yl ,
each of which is optionally substituted by halo, methyl , ethyl, propyl , isopropyl, cyclopropyl , CF3, CHF2,
CH2F, CH2OCH3, CN, CH2OH, OCH3, =0, NH2, SCH3, S0 2CH3, phenoxy, fluorophenoxy, benzyl, SCF3,
OCF3, S0 2CF3, NHS0 2CH3, NHS0 2CF3, C(0)CF 3, C(0)CH 3, benzoyl , azetidinylmethyl,
fluoroazetidinylmethyl and/or morpholinomethyl.
Embodiment 16 of the invention is a compound or salt according to any one of embodiments 1 to 15 with
R5 and R6 groups present, wherein R5 and R6 are each independently H, C-i_3 alkyl optionally substituted
by C-i_3 alkoxy, C3.5 cycloalkyl , propellanyl , oxetanyl, tetrahydrofuranyl or pyranyl ,
or R5 and R6 together with the N to which they are attached can be an azetidine, pyrrolidine, piperidine,
piperazine or morpholine ring, which ring is optionally substituted by C .3 alkoxy and / or C .3 alkyl.
Embodiment 17 of the invention is a compound according to embodiment 1 of the Formula IA:
R is C2 -4 alkyl optionally substituted by 1 or 2 OH groups;
R 0 is H or OH;
and R102 is phenyl or an aromatic or partially unsaturated 5- or 6-membered heterocycle, which
heterocycle is optionally fused to a further phenyl or 5-7 membered aromatic or partially unsaturated
heterocyclic ring, wherein each heterocycle has from 1 to 3 ring heteroatoms selected from N, O and S,
and which ring system is optionally substituted by up to 3 substituents independently selected from
halo, CF3, C-i-4 alkyl and C3.5 cycloalkyl.
Embodiment 18 of the invention is a compound or salt according to embodiment 17 wherein R 0 is H.
Embodiment 19 of the invention is a compound or salt according to embodiment 18 wherein
R is t-butyl, hydroxy-t-butyl or 1-hydroxyprop-2-yl;
and R102 is 4-trifluromethylphenyl, 4-chlorophenyl , 2,4-difluorophenyl , 5-chloropyridin-2-yl , 5-fluoropyridin-
2-yl, 3-trifluromethylpyrazolyl-1 -yl, 4-trifluromethylpyrazol-1 -yl, 3-trifluromethyl-5-methylpyrazol-1 -yl ,
3-cyclopropylpyrazol-1 -yl, 4-cyclopropylpyrazol-1 -yl, 4-trifluromethyl ( 1,2,3-triazol-1 -yl), 4-cyclopropyl-
( 1,2,3-triazol-1 -yl), or benzotriazol-2-yl.
Embodiment 20 of the invention is a compound according to embodiment 1, selected from :
N-(5-{[2-amino-7-(2-hydroxy-1 ,1-dimethylethy0
(trifluoromethyl)phenyl]acetamide;
N-(5-{[2-amino-7-(2-hydroxy-1 ,1-dimethylethyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]carbonyl}pyridin-3-
yl)-2-(4-chlorophenyl)acetamide;
N-(5-{[2-amino-7-(2-hydroxy-1 ,1-dimethylethyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]carbonyl}pyridin-3-
yl)-2-(5-f luoropyrid in-2-yl )acetam ide ;
N-(5-{[2-amino-7-(2-hydroxy-1 -dimethylethyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]carbonyl}pyridin-3-
yl)-2-[3-(trifluoromethyl)-1 H-pyrazol-1 -yl]acetamide;
N-(5-{[2-amino-7-(2-hydroxy-1 ,1-dimethylethyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]carbonyl}pyridin-3-
yl)-2-(3-cyclopropyl-1 H-pyrazol-1 -yl)acetamide;
N-{5-[(2-amino-7-tert-butyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)carbonyl]pyridin-3-yl}-2-(4-cyclopropyl-
1H-1,2,3-triazol-1-yl )acetamide;
N-{5-[(2-amino-7-tert-butyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)carbonyl]pyridin-3-yl}-2-[4-
(trifluoromethyl)-1 H-pyrazol-1-yl]acetamide;
N-{5-[(2-amino-7-tert-butyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)carbonyl]pyridin-3-yl}-2-[4-
(trifluoromethyl)-1 H-1 ,2,3-triazol-1 -yl]acetamide;
N-{5-[(2-amino-7-tert-butyl-7H yrrolo[2,3-d]pyrimidin-5-yl)carbonyl]pyridin-3-yl}-2
2-yl)acetamide;
N-(5-{[2-Amino-7-(2-hydroxy-1 ,1-dimethylethyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]carbonyl}pyridin-3-
yl)-2-(5-chloropyridin-2-yl)acetamide;
N-{5-[(7-tert-butyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)carbonyl]pyridin-3-yl}-2-[4-(trifluo
1,2,3-triazol-1 -yl]acetamide;
2-(4-chlorophenyl)-N-[5-({7-[(1 S)-2-hydroxy-1-methylethyl]-7H-pyrrolo[2,3-d]pyrimidin-5-
yl}carbonyl)pyridin-3-yl]acetamide
N-{5-[(7-tert-butyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)carbonyl]pyridin-3-yl}-2-[4-(trifluo
pyrazol-1-yl]acetam ide ;
N-[5-({7-[(1 S)-2-Hydroxy-1 -methylethyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}carbonyl)pyridi
(trifluoromethyl)phenyl]acetamide;
N-[5-({7-[(1 R)-2-hydroxy-1-methylethyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}carbonyl)pyrid
(trifluoromethyl)phenyl]acetamide;
2-(4-chlorophenyl)-N-[5-({7-[(1 R)-2-hydroxy-1-methylethyl]-7H^yrrolo[2,3-d]pyrimidin-5-
yl}carbonyl)pyridin-3-yl]acetamide;
N-(5-{[7-(2-hydroxy-1 -dimethylethyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]carbonyl}pyridin-3-yl)-2-[5-
methyl-3-(trifluoromethyl)-1 H-pyrazol-1 -yl]acetamide;
2-(5-chloropyridin-2-yl)-N-(5-{[7-(2-hydroxy-1 ,1-dimethylethyl)-7H-pyrrolo[2,3-d]pyrimidin-5-
yl]carbonyl}pyridin-3-yl)acetamide;
N-(5-{[2-Amino-7-(2-hydroxy-1 -methylethyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]carbonyl}pyrid
2-(4-chlorophenyl)acetamide;
N-(5-{[2-amino-7-(2-hydroxy-1 -methylethyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]carbonyl}pyrid
[4-(trifluoromethyl)phenyl]acetamide;
N-(5-{[2-amino-7-(2-hydroxy-1 -methylethyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]carbonyl}pyrid
(4-chlorophenyl)acetamide;
N-(5-{[2-amino-7-(2-hydroxy-1 -methylethyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]carbonyl}pyrid
[4-(trifluoromethyl)phenyl]acetamide;
N-(5-{[2-Amino-7-(2-hydroxy-1 ,1-dimethylethyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]carbonyl}pyridin-3-
yl)-2-[5-methyl-3-(trifluoromethyl)-1 H-pyrazol-1 -yl]acetamide;
and
N-{5-[(7-tert-butyl-7H-pyrrolo[2,3-^
triazol-1 -yl)acetamide;
or a pharmaceutically acceptable salt thereof.
Embodiment 2 1 of the invention is a pharmaceutical composition comprising a compound of the
formula (I) or a pharmaceutically acceptable salt thereof, as defined in any one of the preceding
embodiments 1 to 20, and a pharmaceutically acceptable carrier.
Embodiment 22 of the invention is a compound of the formula (I) or a pharmaceutically acceptable
salt thereof, as defined in any one of embodiments 1 to 20, for use as a medicament.
Embodiment 23 of the invention is a compound of formula (I) or a pharmaceutically acceptable salt
thereof, as defined in any one of embodiments 1 to 20 for use in the treatment of a disease for which
an Trk receptor antagonist is indicated
Embodiment 24 of the invention is a compound of formula (I) or a pharmaceutically acceptable salt
thereof, as defined in any one of embodiments 1 to 20 for use in the treatment of pain.
Embodiment 25 of the invention is the use of a compound of the formula (I) or a pharmaceutically
acceptable salt or composition thereof, as defined in any one of embodiments 1 to 20, for the
manufacture of a medicament to treat a disease for which a Trk receptor antagonist is indicated
Embodiment 26 of the invention is the use of a compound of the formula (I) or a pharmaceutically
acceptable salt or composition thereof, as defined in any one of embodiments 1 to 20, for the
manufacture of a medicament to treat pain.
Embodiment 27 of the invention is a method of treatment of a mammal, to treat a disease for which an
Trk receptor antagonist is indicated, comprising treating said mammal with an effective amount of a
compound of the formula (I) or a pharmaceutically acceptable salt thereof, as defined in any one of
embodiments 1 to 20.
Embodiment 28 of the invention is a method of treatment of pain in a mammal, comprising treating
said mammal with an effective amount of a compound of the formula (I) or a pharmaceutically
acceptable salt thereof, as defined in any one of embodiments 1 to 20.
Embodiment 29 of the invention is compound or salt according to any one of embodiments 1 to 20 for
use in a medical treatment in combination with a further drug susbtance.
Further embodiments of the invention include:
Compounds or salts of formula (I) where R has a value as exemplified in the Examples below;
Compounds or salts of formula (I) where X has a value as exemplified in the Examples below;
Compounds or salts of formula (I) where R102 has a value as exemplified in the Examples below;
Compounds or salts of formula (I) where R , R , R , R , X and R have a value as exemplified in
the Examples below;
A compound selected from any one of the Examples below or a pharmaceutically acceptable salt
thereof; and
any novel intermediate compound herein disclosed.
Other embodiments may be envisaged based on the description below.
"Halogen" means a fluoro, chloro, bromo or iodo group.
"Alkyl" groups, containing the requisite number of carbon atoms, can be unbranched or branched.
Examples of alkyl include methyl , ethyl , n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl and t-butyl.
"Pharmaceutically acceptable salts" of the compounds of formula I include the acid addition and base
addition salts (including disalts, hemisalts, etc.) thereof.
Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include the
acetate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulphate/sulphate, borate, camsylate,
citrate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate,
hibenzate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate,
maleate, malonate, mesylate, methylsulphate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate,
oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, saccharate,
stearate, succinate, tartrate, tosylate and trifluoroacetate salts.
Suitable base addition salts are formed from bases which form non-toxic salts. Examples include the
aluminium, arginine, benzathine, calcium , choline, diethylamine, diolamine, glycine, lysine, magnesium,
meglumine, olamine, potassium, sodium , tromethamine and zinc salts.
For a review on suitable salts, see "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" by
Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).
The compounds of the invention include compounds of formula I and salts thereof as hereinbefore
defined, polymorphs, and isomers thereof (including optical, geometric and tautomeric isomers) as
hereinafter defined and isotopically-labelled compounds of formula I.
Unless otherwise specified , compounds of formula (I) containing one or more asymmetric carbon atoms
can exist as two or more stereoisomers. Where a compound of formula (I) contains for example, a keto or
guanidine group or an aromatic moiety, tautomeric isomerism ('tautomerism') can occur. It follows that a
single compound may exhibit more than one type of isomerism .
Included within the scope of the claimed compounds of the present invention are all stereoisomers,
geometric isomers and tautomeric forms of the compounds of formula (I), including compounds exhibiting
more than one type of isomerism, and mixtures of one or more thereof. Also included are acid addition or
base addition salts wherein the counterion is optically active, for example, D-lactate or L-lysine, or
racemic, for example, DL-tartrate or DL-arginine.
Examples of types of potential tautomerisms shown by the compounds of the invention include
hydroxypyridine = pyridone; amide = hydroxyl-imine and keto = enol tautomersims:
Cis/trans isomers may be separated by conventional techniques well known to those skilled in the art, for
example, chromatography and fractional crystallisation.
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 other
derivative) using, for example, chiral high pressure liquid chromatography (HPLC).
Alternatively, the racemate (or a racemic precursor) may be reacted with a suitable optically active
compound, for example, an alcohol, or, in the case where the compound of formula (I) contains an acidic
or basic moiety, an acid or base such as tartaric acid or 1-phenylethylamine. The resulting diastereomeric
mixture may be separated by chromatography and/or fractional crystallization and one or both of the
diastereoisomers converted to the corresponding pure enantiomer(s) by means well known to a skilled
person.
Chiral compounds of the invention (and chiral precursors thereof) may be obtained in enantiomericallyenriched
form using chromatography, typically HPLC, on a resin with an asymmetric stationary phase and
with a mobile phase consisting of a hydrocarbon, typically heptane or hexane, containing from 0 to 50%
isopropanol, typically from 2 to 20%, and from 0 to 5% of an alkylamine, typically 0 .1% diethylamine.
Concentration of the eluate affords the enriched mixture.
Mixtures of stereoisomers may be separated by conventional techniques known to those skilled in the art.
[see, for example, "Stereochemistry of Organic Compounds" by E L Eliel (Wiley, New York, 1994).]
The present invention includes all pharmaceutically acceptable isotopically-labelled compounds of formula
(I) wherein one or more atoms are replaced by atoms having the same atomic number, but an atomic
mass or mass number different from the atomic mass or mass number usually found in nature.
Examples of isotopes suitable for inclusion in the compounds of the invention include isotopes of
1 14- hydrogen, such as H and H, carbon, such as C, C and C, chlorine, such as CI, fluorine, such as
F, iodine, such as 2 l and 125 l , nitrogen, such as N and N, oxygen, such as 0 , 0 and 0 ,
phosphorus, such as 2P, and sulphur, such as S.
Certain isotopically-labelled compounds of formula (I), for example, those incorporating a radioactive
isotope, are useful in drug and/or substrate tissue distribution studies. The radioactive isotopes tritium , i.e.
H, and carbon-1 4 , i.e. 4C, are particularly useful for this purpose in view of their ease of incorporation
and ready means of detection.
Substitution with heavier isotopes such as deuterium, i.e. 2H, may afford certain therapeutic advantages
resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage
requirements, and hence may be preferred in some circumstances.
Substitution with positron emitting isotopes, such as C, F, 0 and N, can be useful in Positron
Emission Topography (PET) studies for examining substrate receptor occupancy.
Isotopically-labelled compounds of formula (I) can generally be prepared by conventional techniques
known to those skilled in the art or by processes analogous to those described in the accompanying
Examples and Preparations using an appropriate isotopically-labelled reagents in place of the nonlabelled
reagent previously employed .
The routes below, including those mentioned in the Examples and Preparations, illustrate methods of
synthesising compounds of formula (I). The skilled person will appreciate that the compounds of the
invention, and intermediates thereto, could be made by methods other than those specifically described
herein, for example by adaptation of the methods described herein, for example by methods known in the
art. Suitable guides to synthesis, functional group interconversions, use of protecting groups, etc. , are for
example:"Comprehensive Organic Transformations" by RC Larock, VCH Publishers Inc. ( 1989);
Advanced Organic Chemistry" by J. March, Wiley Interscience ( 1985); "Designing Organic Synthesis" by
S Warren, Wiley Interscience ( 1978); Organic Synthesis - The Disconnection Approach" by S Warren,
Wiley Interscience ( 1982); "Guidebook to Organic Synthesis" by RK Mackie and DM Smith, Longman
( 1982); "Protective Groups in Organic Synthesis" by TW Greene and PGM Wuts, John Wiley and Sons,
Inc. ( 1999); and "Protecting Groups" by PJ, Kocienski, Georg Thieme Verlag ( 1994); and any updated
versions of said standard works.
In the general synthetic methods below, unless otherwise specified , the substituents are as defined above
with reference to the compounds of formula (I) above. R is the same as R101 or a suitably protected
version thereof.
Scheme 1 illustrates the preparation of the intermediates of general formula (Int 1) , where they can be
made from amine (Int3) where, in those cases where R contains an alcohol, a protected form of R
where a suitable hydroxyl protecting group (PG) is used. Any suitable oxygen protecting group may be
used (as described in "Protecting Groups in Organic Synthesis" 3rd edition T.W. Greene and P.G. Wuts,
Wiley-lnterscience, 1999). Common oxygen protecting groups suitable for use herein include tertbutyldimethylsilyl
(TBDMS), tetrahydropyranyl (THP) and tertbutylsilyl (TBS).
Compounds of formula (Int 1) can be prepared from compounds of formula (Int 2) as illustrated in Scheme
1.
Scheme 1
Int 4 Int 3 Int 2 Int 1
Wherein R30 can be H or halogen, typically chlorine.
Compounds of formula (Int 1) may be prepared from amine (Int 3) and (Int4) in a cyclisation step followed
by a dechlorination step. Typical conditions employed involve stirring the amine of general formula (Int 3)
and the aldehyde (Int 4) together, preferably in ethanol at a temperature from room temperature up to
80°C.
e.g. as exemplified in Preps. 1-5
The intermediate chloride (Int 2) is reduced using standard literature conditions, for example
hydrogenation using a suitable catalyst such as palladium on carbon and an additive such as ammonia in
a suitable solvent such as ethanol. Alternatively the chloride may be removed by displacing the chloro
with methane thiol followed by Raney Nickel removal of the SMe intermediate
e.g. as exemplified in Preps. 8-1 3
In those cases where R contains one or more alcohols, a protected form of R with a suitable hydroxyl
protecting group (PG) can be used. Any suitable oxygen protecting group protection/deprotection system
may be used (as described in "Protecting Groups in Organic Synthesis" 3rd edition T.W. Greene and P.G.
Wuts, Wiley-lnterscience, 1999). Common oxygen protecting groups suitable for use herein include tertbutyldimethylsilyl
(TBDMS) and tetrahydropyranyl (THP).
Intermediates of general formula (Int 3) and (Int 4) are either commercially available or will be well-known
to those skilled in the art with reference to literature precedents and/or the preparations herein.
Compounds of formula (Int 1) can be prepared from compounds of formula (Int 7) as illustrated in
Scheme 2 .
Scheme 2
Int 1
Compounds of formula (Int 1) wherein R3 can be H or halogen, typically chlorine, may also be prepared
from compounds of formula (Int 7) through displacement of a halogen, typically chlorine, with amines of
formula (Int 3), in a palladium catalysed Suzuki reaction followed by an acidic cyclisation.
Typical conditions comprise stirring the amine of general formula (Int 3) and the intermediate of general
formula (Int 7) together with a suitable base, such as triethylamine, in a solvent such as acetonitrile or
dichloromethane, to provide compounds of general formula (Int 6).
The vinyl ether can be introduced by reacting intermediate (Int 6) with a suitable boronic ester and a
suitable base, such as sodium hydroxide and a suitable catalyst such as
tetrakis(triphenylphosphine)palladium (0) in a solvent such as THF at a temperature from room
temperature up to 70°C.
Intermediates of formula (Int 1) can be made by treatment of intermediate (Int 5) with an acid such as
hydrogen chloride in an organic solvent such as isopropanol at a temperature from room temperature up
to 70°C.
e.g. as exemplified in Preps. 60-62
Intermediates of general formula (Int 3) and (Int 7) are either commercially available or will be well-known
to those skilled in the art with reference to literature precedents and/or the preparations herein.
Compounds of formula (Int 8) can be prepared from compounds of formula (Int 1) as illustrated
Scheme 3 .
Scheme 3
(Int 1) (Int 8)
Wherein R is H or halogen, typically chlorine;
Compounds of formula (Int 8) are typically prepared by iodination of the pyrrolopyrimidine intermediates
(Int 1).Typical conditions employed involve stirring the intermediate of general formula (XI) with an
iodinating reagent such as N-iodosuccinimide in a suitable solvent, such as DMF or acetonitrile.
e.g. as exemplified in Preps. 14-1 9 , 40, 63.
Compounds of formula (Int 8) can also be prepared from compounds of formula (Int 9) as illustrated in
Scheme 4 .
Scheme 4
(Int 9) (Int 8)
Wherein R30 is H or halogen, typically chlorine; LG is halogen or tosylate, triflate or mesylate;
Alternatively intermediates of general formula (Int 8) can be prepared by alkylation of the
pyrrolopyrimidine intermediates (Int 9), with compounds of formula (Int 10) using a suitable base such as
caesium carbonate or potassium carbonate in an organic solvent. A suitable alternative is to use an
additive (such as potassium iodide) as well as a base. Preferred conditions comprise cesium carbonate in
DMF at room temperature.
In those cases where R contains one or more alcohols, a protected form of R can be used as described
in Scheme 1.
E.g. as exemplified in Preparation 20.
Compounds of formula (Int 12) can be prepared from compounds of formula (Int 11) as illustrated in
Scheme 5 .
Scheme 5
( n 3 ) (Int 14)
Wherein R is H or halogen, typically chlorine;
Intermediates of general formula (Int 9) are reacted in an alkylation reaction to provide an ester
intermediate (Int 11) or (Int 13), from which the ester group can be reduced and protected to furnish a
compound of general formula (Int 14), where R200 is a H or methyl group. As previously mentioned in
Scheme 1 the hydroxy group can be protected with a suitable oxygen protecting group (PG), where the
preferred protecting groups are TBDMS, TBS and THP.
Typical conditions employed for the alkylation involve stirring the compound of general formula (Int 9) with
the appropriate halide together with a suitable base, as described in Scheme 4 . Compounds of general
formula (Int 11) where R200 is H can be converted to intermediates (Int 13) where R200 is methyl by a
further alkylation, typically involving a suitable alkylating agent such as methyl iodide and a suitable base
such as potassium t-butoxide in an organic solvent such as THF.
e.g. as exemplified in Preps. 20, 2 1, 41, 53
Reduction of the ester intermediates (Int 11) and (Int 13) can be done by using a suitable reducing
reagent such as lithium borohydride, lithium alumninium hydride or diisobutylalumnium hydride in a
suitable solvent such as ethanol or THF. Alternatively intermediates of general formula (Int 12) can be
made in a two step reaction by hydrolysing the ester of formula (Int 11) or (Int 13) to the appropriate acid
using a suitable base such as aqueous lithium hydroxide in a suitable organic solvent such as THF then
activating the acid using a suitable reagent such as isobutyl chloroformate and using a suitable reducing
agent such as sodium borohydride.
e.g. as exemplified in Preps. 22, 42, 43, 54
Compounds of general formula (Int 14) can be made by protection of the hydroxy group of intermediates
(Int 12) with a suitable oxygen protecting group (PG), where the preferred protecting groups are TBDMS
and THP.as described in Scheme 1.
e.g. as exemplified in Preps. 44, 45, 55.
Compounds of formula (Int 16) can be prepared from compounds of formula (Int 8) as illustrated in
Scheme 6 .
Scheme 6
(Int 17) (Int 18)
Wherein R30 is H or halogen, typically chlorine; and X-i is a suitable halogen, typically bromine or iodine;
Compounds of formula (Int 16) can be prepared from compounds of formula (Int 8) and (Int 15) through a
metallation of intermediate (Int 8) (using a suitable organometallic reagent such as butyllithium or
isopropylmagnesium chloride) and reacting with the Weinreb amide intermediate (Int 15) at a temperature
from -78°C up to room temperature
e.g. as exemplified in Preps. 26, 27, 46, 47, 56, 58, 64
Alternatively compounds of formula (Int 15) may be converted into aldehydes of formula (Int 17) by
reduction of the Weinreb amide intermediate using a suitable reducing agent. Preferred conditions
comprise diisopropylaluminium hydride in THF at -78°C, exemplified in Preparation 106.
Compounds of formula (Int 17) may then be reacted with compounds of formula (Int 8) according to the
same metallation procedure described above. The intermediate alcohol (Int 18) may then be oxidised to
the ketone (Int 16). Typical oxidation conditions involve using an oxidising reagent such as the Dess-
Martin reagent in DCM or 2-iodoxybenzoic acid in a suitable solvent such as ethyl acetate at a
temperature from room temperature to reflux temperature.
e.g. as exemplified in Preps. 29, 30
Intermediates of general formula (Int 15) and (Int 17) are either commercially available or will be wellknown
to those skilled in the art with reference to literature precedents and/or the preparations herein.
Corresponding intermediates and compounds of formula (I) where R 0 is OH are considered as
tautormers of pyridones and can be made using an analogous methodology using a benzyl protecting
group for the Weinreb amide step, viz R 0 is benzyloxy (OBn), e.g. as illustrated below:
Compounds of formula (Int 20) can be prepared from compounds of formula (Int 8) as illustrated in
Scheme 7 .
(Int 8) (Int 19) (Int 20)
Wherein R is H or halogen, typically chlorine;
Compounds of formula (Int 20) may be prepared from compounds of formulae (Int 8) and (Int 19)
according to a metallation procedure as described in Scheme 6 above.
Typical conditions employed involve metallation of the intermediate halide (Int 8) (using a suitable
organometallic reagent such as butyllithium or isopropylmagnesium chloride) and reacting with the
Weinreb amide intermediate (Int 19) at a temperature from -78°C up to room temperature in a suitable
solvent such as THF.
e.g. as exemplified in Preps. 24, 25, 28, 50
Intermediates (Int 19) will be well-known to those skilled in the art with reference to literature precedents
and/or the preparations herein
e.g. as exemplified in Prep. 23
Compounds of formula (Int 2 1) can be prepared from compounds of formula (Int 16) as illustrated
Scheme 8 .
Scheme 8
(Int 22)
Wherein X-i is bromine or iodine;
Compounds of formula (Int 2 1) may be prepared from compounds of formula (Int 16) through direct
amination of the halide using standard literature conditions. For example, amine (Int 2 1) is typically
prepared using ammonia with a suitable copper catalyst such as copper (II) sulphate or copper (I) oxide in
suitable solvent such as NMP in a sealed vessel at a temperature between room temperature and 140°C.
Where R30 is CI this is also displaced by ammonia under the same conditions to provide amines of
general formula (Int 2 1) where R3 is NH2.
e.g. as exemplified in Preps. 3 1, 32, 36, 48, 49, 57, 59, 65
De-protection of a hydroxyl protecting group on R (if present) can also occur under these conditions. In
these cases, either the protecting group can be reapplied as previously described in Scheme 5 or the
amine of general formula (Int 2 1) can be used directly.
Alternatively compounds of general formula (Int 2 1) where R3 is H, can be made by converting
intermediates of general formula (Int 16) where R30 is H, via compounds (Int 22). Typical conditions
employed involve stirring the halide of general formula (Int 16), where R is H, with benzophenone
imine, a suitable base such as potassium phosphate, a suitable ligand such as 2-di-ferf-butylphosphino-
2',4',6'-triisopropylbiphenyl and a suitable catalyst such as tris(dibenzylideneacetone)dipalladium in an
organic solvent such as 1,2-dimethoxyethane at a temperature from room temperature up to the boiling
point of the solvent.
Intermediate (Int 22) can be deprotected to furnish the amines of general formula (Int 2 1) . Typical
conditions employ treatment with an aqueous acid such as hydrogen chloride or citric acid in an organic
solvent such as THF.
e.g. as exemplified in Preps. 33, 37-39
Compounds of formula (Int 20) can be prepared from compounds of formula (Int 22 where R30 is CI) as
illustrated in Scheme 9 .
Scheme 9
Where R301 is CI) (Int 20)
Compounds of formula (Int 20) may be prepared from compounds of formula (Int 22) where R30 is chloro
through an amination reaction as decribed above. Wherein the chlorine is is reacted with 2,4-
dimethoxybenzylamine and the amine can be deprotected as previously.
Typical conditions employed involve stirring the chloro-pyrimidine of general formula (Int 22), where R30
is CI, with 2,4-dimethoxybenzylamine and a suitable additive such as 4-dimethylaminopyridine in a
suitable solvent such as 1,4 dioxane at a temperature from room temperature up to reflux temperature
e.g. as exemplified in Prep. 5 1
Compounds of formula (I) can be prepared from compounds of formula (Int 2 1) and (Int 23) as illustrated
in Scheme 10 .
(Int 21) (Int 23)
Compounds of formula (I) may be prepared from compounds of formula (Int 2 1) and (Int 23) via amide
formation, if necessary adding a suitable base (such as DIPEA) and/or additive (such as DMAP), and a
suitable solvent (such as pyridine).
Typical conditions employed involve stirring the amine of general formula (Int 2 1) and the acid of general
formula (Int 23) together with a suitable coupling reagent such as HATU or 1-propylphosphonic acid cyclic
anhydride, if necessary adding a suitable base such as NMM, DIPEA or TEA in a suitable solvent such as
pyridine, THF, DMF or DMA at a temperature from room temperature up to 50°C. A suitable alternative is
to use an additive (such as 4-dimethylaminopyridine) as well as a base. Any suitable solvent may be used
in place of those mentioned above. At least one equivalent of the acid (Int 23) and at least one equivalent
of the coupling reagent should be used and an excess of one or both may be used if desired
e.g. as exemplified in Examples 1-8, 34-45,48-53, 57-64, Preps. 34, 35, 52, 66-78
Where R contains a suitable hydroxyl protecting group in intermediate (Int 2 1) , removal of the protecting
group (PG) can be done in situ or as an additional step, adding a suitable acid and organic solvent to the
crude residue after the amide formation has taken place. Common protecting groups to use include
TBDMS, which is readily removed by treatment with an acid such as aqueous hydrogen chloride or
aqueous citric acid in an organic solvent such as THF or by treatment with a fluoride source such as
tetrabutylammonium fluoride in an organic solvent such as THF, and THP, which is also readily removed
by treatment with an acid such as aqueous hydrogen chloride in an organic solvent such as THF.
e.g. as exemplified in Examples 9-33, 54-56,
Intermediates of general formula (Int 23) are either commercially available or will be well-known to those
skilled in the art with reference to literature precedents and/or the preparations herein.
Compounds of formula (I) where R3 is NH2 can be prepared from compounds of formula (Int 20) as
illustrated in Scheme 11.
Schem
(Int 24) (Int 23) (I)
Compounds of formula (I) can be prepared from compounds of formula (Int 24) via amide bond formation
as previously described in Scheme 10 followed by removal of the dimethoxbenzylamine group in situ, by
adding a suitable acid and organic solvent to the crude residue after the amide formation has taken place.
Suitable acids for this de-protection include hydrogen choride or trifluoroacetic acid in an organic solvent
such as THF.
e.g. as exemplified in Examples 46-47
Compounds of formula (I) where R2 is methyl can be prepared from compounds of formula (I) where R2 is
H as illustrated in Scheme 12 .
Scheme 12
Compounds of formula (I) where R2 is methyl can be prepared from compounds of formula (I) where R2 is
H according to an alkylation reaction with methyl iodide as described in Scheme 4 .
When XR102 is boc, this can be deprotected using standard protecting group conditions to provide
intermediate (Int 2 1) .
Compounds of formula (I) where X is NR104 can be prepared from compounds of formula (Int 2 1) as
illustrated in Scheme 13 .
Scheme 13
(Int 21) (I)
Compounds of formula (I) where X is NR104 may be prepared from compounds of formula (Int 2 1) , (Int 25)
and phenylchloroformate. Typical conditions comprise phenyl chloroformate and compounds of formula
(Int 24) with pyridine in THF from 0 to 100°C, as exemplified in Example 526.
Compounds of formula (I) where a substituent on the ring(s) of R102 is an aminomethyl CH2NR2 group may
be prepared from compounds of formula (1) as illustrated in Scheme 14 .
Compounds of formula (I) where a primary alcohol exists may be oxidised to the aldehyde using Dess
Martin periodinane in DCM at room temperature followed by a reductive amination with a suitable amine
HNR2 using sodium triacetoxyborohydride and acetic acid in DCM.
Compounds of formula (Int 26) can be prepared from compounds of formula (Int 27) as illustrated in
Scheme 15 .
Scheme 15
Int 27 Int 26
Wherein R103 is Me or CH2OH;
Compounds of formula (Int 26) can be prepared from compounds of formula (Int 27) through conversion
of an alcohol into a suitable leaving group followed by cyclisation under basic conditions. Preferred
conditions comprise tosyl chloride with n-butyl lithium in THF.
According to a further embodiment the present invention provides novel intermediate compounds.
Pharmaceutically acceptable salts of a compound of formula (I) may be readily prepared by mixing
together solutions of the compound of formula (I) and the desired acid or base, as appropriate. The salt
may precipitate from solution and be collected by filtration or may be recovered by evaporation of the
solvent. The degree of ionisation in the salt may vary from completely ionised to almost non-ionised.
The compounds of the invention intended for pharmaceutical use may be administered alone or in
combination with one or more other compounds of the invention or in combination with one or more other
drug agent (or as any combination thereof). Generally, they will be administered as a formulation in
association with one or more pharmaceutically acceptable excipients. The term "excipient" is used herein
to describe any biologically inactive ingredient other than the compounds and salts of the invention. The
choice of excipient will to a large extent depend on factors such as the particular mode of administration,
the effect of the excipient on solubility and stability, and the nature of the dosage form. For example, a
compound of the formula I, or a pharmaceutically acceptable salt or solvate thereof, as defined above,
may be administered simultaneously (e.g. as a fixed dose combination), sequentially or separately in
combination with one or more other drug agent.
Exemplary additional agents could be selected from one or more of:
• a Nav1 .7 channel modulator, such as a compound disclosed in WO 2009/01 2242 or
WO201 0/079443;
· an alternative sodium channel modulator, such as a Nav1 .3 modulator (e.g. as disclosed in
WO2008/1 18758); or a Nav1 .8 modulator (e.g. as disclosed in WO 2008/1 35826, more particularly N-
[6-Amino-5-(2-chloro-5-methoxyphenyl)pyridin-2-yl]-1 -methyl-1 H-pyrazole-5-carboxamide);
• an inhibitor of nerve growth factor signaling, such as: an agent that binds to NGF and inhibits NGF
biological activity and/or downstream pathway(s) mediated by NGF signaling (e.g. tanezumab), a
TrkA antagonist or a p75 antagoinsist;
• a compound which increases the levels of endocannabinoid , such as a compound with fatty acid amid
hydrolase inhibitory (FAAH) activity, in particular those disclosed in WO 2008/047229 (e.g. Npyridazin-
3-yl-4-(3-{[5-(trifluoromethyl)pyridine-2-yl]oxy}benzylidene)piperidene-1 -carboxamide);
• an opioid analgesic, e.g. morphine, heroin, hydromorphone, oxymorphone, levorphanol, levallorphan,
methadone, meperidine, fentanyl, cocaine, codeine, dihydrocodeine, oxycodone, hydrocodone,
propoxyphene, nalmefene, nalorphine, naloxone, naltrexone, buprenorphine, butorphanol, nalbuphine
or pentazocine;
• a nonsteroidal antiinflammatory drug (NSAID), e.g. aspirin, diclofenac, diflusinal , etodolac, fenbufen,
fenoprofen, flufenisal , flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, meclofenamic acid,
mefenamic acid, meloxicam, nabumetone, naproxen, nimesulide, nitroflurbiprofen, olsalazine,
oxaprozin, phenylbutazone, piroxicam , sulfasalazine, sulindac, tolmetin or zomepirac;
• a barbiturate sedative, e.g. amobarbital, aprobarbital, butabarbital, butabital, mephobarbital,
metharbital, methohexital, pentobarbital, phenobartital , secobarbital, talbutal, theamylal or thiopental;
• a benzodiazepine having a sedative action, e.g. chlordiazepoxide, clorazepate, diazepam,
flurazepam, lorazepam , oxazepam , temazepam or triazolam ;
• an H-i antagonist having a sedative action , e.g. diphenhydramine, pyrilamine, promethazine,
chlorpheniramine or chlorcyclizine;
· a sedative such as glutethimide, meprobamate, methaqualone or dichloralphenazone;
• a skeletal muscle relaxant, e.g. baclofen, carisoprodol, chlorzoxazone, cyclobenzaprine,
methocarbamol or orphrenadine;
• an NMDA receptor antagonist, e.g. dextromethorphan ((+)-3-hydroxy-N-methylmorphinan) or its
metabolite dextrorphan ((+)-3-hydroxy-N-methylmorphinan), ketamine, memantine, pyrroloquinoline
quinine, cis-4-(phosphonomethyl)-2-piperidinecarboxylic acid, budipine, EN-3231 (MorphiDex®, a
combination formulation of morphine and dextromethorphan), topiramate, neramexane or perzinfotel
including an NR2B antagonist, e.g . ifenprodil, traxoprodil or (-)-(R)-6-{2-[4-(3-fluorophenyl)-4-
hydroxy-1-piperidinyl]-1 -hydroxyethyl-3,4-dihydro-2(1 H)-quinolinone;
• an alpha-adrenergic, e.g. doxazosin, tamsulosin, donidine, guanfacine, dexmetatomidine, modafinil ,
or 4-amino-6 J -dimethoxy-2-(5-methane-sulfonamido-1 ,2,3,4-tetrahydroisoquinol-2-yl)-5-(2-pyridyl)
quinazoline;
• a tricyclic antidepressant, e.g. desipramine, imipramine, amitriptyline or nortriptyline;
• an anticonvulsant, e.g. carbamazepine, lamotrigine, topiratmate or valproate;
• a tachykinin (NK) antagonist, particularly an NK-3, NK-2 or NK-1 antagonist, e.g. (aR,9R)-7-[3,5-
bis(trifluoromethyl)benzyl]-8,9, 10 ,11-tetrahydro-9-methyl-5-(4-methylphenyl)-7H-[1 ,4]diazocino[2, 1-
g][1 ,7]-naphthyridine-6-1 3-dione (TAK-637), 5-[[(2R,3S)-2-[(1 R)-1 -[3,5-
bis(trifluoromethyl)phenyl]ethoxy-3-(4-fluorophenyl)-4-morpholinyl]-methyl]-1 ,2-dihydro-3H-1 ,2,4-
triazol-3-one (MK-869), aprepitant, lanepitant, dapitant or 3-[[2-methoxy-5-(trifluoromethoxy)phenyl]-
methylamino]-2-phenylpiperidine (2S.3S);
· a muscarinic antagonist, e.g oxybutynin, tolterodine, propiverine, tropsium chloride, darifenacin ,
solifenacin, temiverine and ipratropium;
• a COX-2 selective inhibitor, e.g. celecoxib, rofecoxib, parecoxib, valdecoxib, deracoxib, etoricoxib, or
lumiracoxib;
• a coal-tar analgesic, in particular paracetamol;
· a neuroleptic such as droperidol, chlorpromazine, haloperidol, perphenazine, thioridazine,
mesoridazine, trifluoperazine, fluphenazine, clozapine, olanzapine, risperidone, ziprasidone,
quetiapine, sertindole, aripiprazole, sonepiprazole, blonanserin, iloperidone, perospirone, raclopride,
zotepine, bifeprunox, asenapine, lurasidone, amisulpride, balaperidone, palindore, eplivanserin,
osanetant, rimonabant, meclinertant, Miraxion® or sarizotan;
· a vanilloid receptor agonist (e.g. resinferatoxin) or antagonist (e.g. capsazepine);
• a beta-adrenergic such as propranolol;
• a local anaesthetic such as mexiletine;
• a corticosteroid such as dexamethasone;
• a 5-HT receptor agonist or antagonist, particularly a 5-HT B/ D agonist such as eletriptan, sumatriptan ,
naratriptan , zolmitriptan or rizatriptan;
• a 5-HT2A receptor antagonist such as R(+)-alpha-(2,3-dimethoxy-phenyl)-1 -[2-(4-fluorophenylethyl)]-4-
piperidinemethanol (MDL-1 00907);
· a 5-HT3 antagonist, such as ondansetron
• a cholinergic (nicotinic) analgesic, such as ispronicline (TC-1 734), (E)-N-methyl-4-(3-pyridinyl)-3-
buten-1 -amine (RJR-2403), (R)-5-(2-azetidinylmethoxy)-2-chloropyridine (ABT-594) or nicotine;
• Tramadol®;
• a PDEV inhibitor, such as 5-[2-ethoxy-5-(4-methyl-1 -piperazinyl-sulphonyl)phenyl]-1 -methyl-3-npropyl-
1 ,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (sildenafil), (6R, 12aR)-2,3,6 J ,12 ,12ahexahydro-
2-methyl-6-(3,4-methylenedioxyphenyl)-pyrazino[2', 1':6, 1]-pyrido[3,4-b]indole-1 ,4-dione
(IC-351 or tadalafil), 2-[2-ethoxy-5-(4-ethyl-piperazin-1 -yl-1 -sulphonyl)-phenyl]-5-methyl-7-propyl-3Himidazo[
5, 1-f][1 ,2,4]triazin-4-one (vardenafil), 5-(5-acetyl-2-butoxy-3-pyridinyl)-3-ethyl-2-(1 -ethyl-3-
azetidinyl)-2,6-dihydro-7/-/-pyrazolo[4,3-c/]pyrimidin-7-one, 5-(5-acetyl-2-propoxy-3-pyridinyl)-3-ethyl-2-
( 1-isopropyl-3-azetidinyl)-2,6-dihydro-7/-/-pyrazolo[4,3-c/]pyrimidin-7-one, 5-[2-ethoxy-5-(4-
ethylpiperazin-1 -ylsulphonyl)pyridin-3-yl]-3-ethyl-2-[2-methoxyethyl]-2,6-dihydro-7H-pyrazolo[4,3-
d]pyrimidin-7-one, 4-[(3-chloro-4-methoxybenzyl)amino]-2-[(2S)-2-(hydroxymethyl)pyrrolidin-1 -yl]-N-
(pyrimidin-2-ylmethyl)pyrimidine-5-carboxamide, 3-(1 -methyl-7-oxo-3-propyl-6 J -dihydro-1 Hpyrazolo[
4,3-d]pyrimidin-5-yl)-N-[2-(1 -methylpyrrolidin-2-yl)ethyl]-4-propoxybenzenesulfonamide;
· an alpha-2-delta ligand such as gabapentin, pregabalin, 3-methylgabapentin, ( 1a,3a,5a)(3-aminomethyl-
bicyclo[3.2.0]hept-3-yl)-acetic acid, (3S,5R)-3-aminomethyl-5-methyl-heptanoic acid, (3S.5R)-
3-amino-5-methyl-heptanoic acid, (3S,5R)-3-amino-5-methyl-octanoic acid, (2S,4S)-4-(3-
chlorophenoxy)proline, (2S,4S)-4-(3-fluorobenzyl)-proline, [(1 R,5R,6S)-6-
(aminomethyl)bicyclo[3.2.0]hept-6-yl]acetic acid, 3-(1 -aminomethyl-cyclohexylmethyl)-4H-
[ 1 ,2,4]oxadiazol-5-one, C-[1 -(1 H-tetrazol-5-ylmethyl)-cycloheptyl]-methylamine, (3S,4S)-(1 -
aminomethyl-3,4-dimethyl-cyclopentyl)-acetic acid, (3S,5R)-3-aminomethyl-5-methyl-octanoic acid,
(3S,5R)-3-amino-5-methyl-nonanoic acid, (3S,5R)-3-amino-5-methyl-octanoic acid, (3R,4R,5R)-3-
amino-4,5-dimethyl-heptanoic acid and (3R,4R,5R)-3-amino-4,5-dimethyl-octanoic acid;
• metabotropic glutamate subtype 1 receptor (mGluRI ) antagonist;
· a serotonin reuptake inhibitor such as sertraline, sertraline metabolite demethylsertraline, fluoxetine,
norfluoxetine (fluoxetine desmethyl metabolite), fluvoxamine, paroxetine, citalopram, citalopram
metabolite desmethylcitalopram , escitalopram , d,l-fenfluramine, femoxetine, ifoxetine, cyanodothiepin,
litoxetine, dapoxetine, nefazodone, cericlamine and trazodone;
• a noradrenaline (norepinephrine) reuptake inhibitor, such as maprotiline, lofepramine, mirtazepine,
oxaprotiline, fezolamine, tomoxetine, mianserin, buproprion, buproprion metabolite
hydroxybuproprion, nomifensine and viloxazine (Vivalan®), especially a selective noradrenaline
reuptake inhibitor such as reboxetine, in particular (S.S)-reboxetine;
• a dual serotonin-noradrenaline reuptake inhibitor, such as venlafaxine, venlafaxine metabolite Odesmethylvenlafaxine,
clomipramine, clomipramine metabolite desmethylclomipramine, duloxetine,
milnacipran and imipramine;
• an inducible nitric oxide synthase (iNOS) inhibitor such as S-[2-[(1 -iminoethyl)amino]ethyl]-Lhomocysteine,
S-[2-[(1 -iminoethyl)-amino]ethyl]-4,4-dioxo-L-cysteine, S-[2-[(1 -iminoethyl)amino]ethyl]-
2-methyl-L-cysteine, (2S,5Z)-2-amino-2-methyl-7-[(1 -iminoethyl)amino]-5-heptenoic acid, 2-[[(1 R,3S)-
3-amino-4- hydroxy-1-(5-thiazolyl)-butyl]thio]-5-chloro-3-pyridinecarbonitrile; 2-[[(1 R,3S)-3-amino-4-
hydroxy-1-(5-thiazolyl)butyl]thio]-4-chlorobenzonitrile, (2S,4R)-2-amino-4-[[2-chloro-5-
(trifluoromethyl)phenyl]thio]-5-thiazolebutanol,
2-[[(1 R,3S)-3-amino-4-hydroxy-1 -(5-thiazolyl) butyl]thio]-6-(trifluoromethyl)-3 pyridinecarbonitrile, 2-
[[(1 R,3S)-3- amino-4-hydroxy- 1 -(5-thiazolyl)butyl]thio]-5-chlorobenzonitrile, N-[4-[2-(3-
chlorobenzylamino)ethyl]phenyl]thiophene-2-carboxamidine, or guanidinoethyldisulfide;
• an acetylcholinesterase inhibitor such as donepezil;
• a prostaglandin E2 subtype 4 (EP4) antagonist such as A/-[({2-[4-(2-ethyl-4,6-dimethyl-1 H-imidazo[4,5-
c]pyridin-1 -yl)phenyl]ethyl}amino)-carbonyl]-4-methylbenzenesulfonamide or 4-[( 1S)-1 -({[5-chloro-2-
(3-fluorophenoxy)pyridin-3-yl]carbonyl}amino)ethyl]benzoic acid;
• a microsomal prostaglandin E synthase type 1 (mPGES-1 ) inhibitor;
• a leukotriene B4 antagonist; such as 1-(3-biphenyl-4-ylmethyl-4-hydroxy-chroman-7-yl)-
cyclopentanecarboxylic acid (CP-1 05696), 5-[2-(2-Carboxyethyl)-3-[6-(4-methoxyphenyl)-5Ehexenyl]
oxyphenoxy]-valeric acid (ONO-4057) or DPC-1 1870,
a 5-lipoxygenase inhibitor, such as zileuton, 6-[(3-fluoro-5-[4-methoxy-3,4,5,6-tetrahydro-2H-pyran-4-
yl])phenoxy-methyl]-1 -methyl-2-quinolone (ZD-21 38), or 2,3,5-trimethyl-6-(3-pyridylmethyl), 1,4-
benzoquinone (CV-6504).
Pharmaceutical compositions suitable for the delivery of compounds and salts of the present invention
and methods for their preparation will be readily apparent to those skilled in the art. Such compositions
and methods for their preparation may be found , for example, in 'Remington's Pharmaceutical Sciences' ,
19th Edition (Mack Publishing Company, 1995).
Compounds and salts of the invention intended for pharmaceutical use may be prepared and
administered as crystalline or amorphous products. They may be obtained, for example, as solid plugs,
powders, or films by methods such as precipitation, crystallization, freeze drying, spray drying, or
evaporative drying. Microwave or radio frequency drying may be used for this purpose.
Oral Administration
The compounds of the invention may be administered orally. Oral administration may involve swallowing,
so that the compound enters the gastrointestinal tract, or buccal or sublingual administration may be
employed by which the compound enters the blood stream directly from the mouth.
Formulations suitable for oral administration include solid formulations, such as tablets, capsules
containing particulates, liquids, or powders; lozenges (including liquid-filled), chews; multi- and nanoparticulates;
gels, solid solution, liposome, films (including muco-adhesive), ovules, sprays and liquid
formulations.
Liquid formulations include suspensions, solutions, syrups and elixirs. Such formulations may be
employed as fillers in soft or hard capsules and typically comprise a carrier, for example, water, ethanol,
polyethylene glycol, propylene glycol, methylcellulose, or a suitable oil, and one or more emulsifying
agents and/or suspending agents. Liquid formulations may also be prepared by the reconstitution of a
solid , for example, from a sachet.
The compounds of the invention may also be used in fast-dissolving, fast-disintegrating dosage forms
such as those described in Expert Opinion in Therapeutic Patents, V\_ (6), 981 -986 by Liang and Chen
(2001 ) .
For tablet dosage forms, depending on dose, the drug may make up from 1 weight% to 80 weight% of the
dosage form, more typically from 5 weight% to 60 weight% of the dosage form. In addition to the drug,
tablets generally contain a disintegrant. Examples of disintegrants include sodium starch glycolate,
sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium , crospovidone,
polyvinylpyrrolidone, methyl cellulose, microcrystalline cellulose, lower alkyl-substituted hydroxypropyl
cellulose, starch, pregelatinised starch and sodium alginate. Generally, the disintegrant will comprise from
1 weight% to 25 weight%, preferably from 5 weight% to 20 weight% of the dosage form.
Binders are generally used to impart cohesive qualities to a tablet formulation. Suitable binders include
microcrystalline cellulose, gelatin, sugars, polyethylene glycol, natural and synthetic gums,
polyvinylpyrrolidone, pregelatinised starch, hydroxypropyl cellulose and hydroxypropyl methylcellulose.
Tablets may also contain diluents, such as lactose (monohydrate, spray-dried monohydrate, anhydrous
and the like), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch and dibasic
calcium phosphate dihydrate.
Tablets may also optionally comprise surface active agents, such as sodium lauryl sulfate and polysorbate
80, and glidants such as silicon dioxide and talc. When present, surface active agents may comprise from
0.2 weight % to 5 weight% of the tablet, and glidants may comprise from 0.2 weight% to 1 weight% of the
tablet.
Tablets also generally contain lubricants such as magnesium stearate, calcium stearate, zinc stearate,
sodium stearyl fumarate, and mixtures of magnesium stearate with sodium lauryl sulphate. Lubricants
generally comprise from 0.25 weight% to 10 weight%, preferably from 0.5 weight% to 3 weight% of the
tablet.
Other possible ingredients include anti-oxidants, colourants, flavoring agents, preservatives and tastemasking
agents.
Exemplary tablets contain up to about 80% drug, from about 10 weight% to about 90 weight% binder,
from about 0 weight% to about 85 weight% diluent, from about 2 weight% to about 10 weight%
disintegrant, and from about 0.25 weight% to about 10 weight% lubricant. [Make sure these specific
ranges are relevant]
Tablet blends may be compressed directly or by roller to form tablets. Tablet blends or portions of blends
may alternatively be wet-, dry-, or melt-granulated, melt congealed, or extruded before tableting. The final
formulation may comprise one or more layers and may be coated or uncoated; it may even be
encapsulated.
The formulation of tablets is discussed in "Pharmaceutical Dosage Forms: Tablets, Vol. 1" , by H.
Lieberman and L . Lachman, Marcel Dekker, N.Y., N.Y., 1980 (ISBN 0-8247-691 8-X).
The foregoing formulations for the various types of administration discussed above may be formulated to
be immediate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-
, controlled-, targeted and programmed release.
Suitable modified release formulations for the purposes of the invention are described in US Patent No.
6 ,106,864. Details of other suitable release technologies such as high energy dispersions and osmotic
and coated particles are to be found in Verma ef a/, Pharmaceutical Technology On-line, 25(2), 1- 14
(2001 ) . The use of chewing gum to achieve controlled release is described in WO 00/35298.
Parenteral Administration
The compounds and salts of the invention may be administered directly into the blood stream, into
muscle, or into an internal organ. Suitable means for parenteral administration include intravenous,
intraarterial, intraperitoneal, intrathecal , intraventricular, intraurethral, intrasternal, intracranial,
intramuscular and subcutaneous. Suitable devices for parenteral administration include needle (including
microneedle) injectors, needle-free injectors and infusion techniques.
Parenteral formulations are typically aqueous solutions which may contain excipients such as salts,
carbohydrates and buffering agents (preferably to a pH of from 3 to 9), but, for some applications, they
may be more suitably formulated as a sterile non-aqueous solution or as a dried form to be used in
conjunction with a suitable vehicle such as sterile, pyrogen-free water.
The preparation of parenteral formulations under sterile conditions, for example, by lyophilisation , may
readily be accomplished using standard pharmaceutical techniques well known to those skilled in the art.
The solubility of compounds of formula (I) and salts used in the preparation of parenteral solutions may be
increased by the use of appropriate formulation techniques, such as the incorporation of solubilityenhancing
agents.
Formulations for parenteral administration may be formulated to be immediate and/or modified release.
Thus, compounds and salts of the invention may be formulated as a solid, semi-solid, or thixotropic liquid
for administration as an implanted depot providing modified release of the active compound. An example
of such formulations include drug-coated stents.
Topical Administration
The compounds and salts of the invention may also be administered topically to the skin or mucosa, that
is, dermally or transdermally. Typical formulations for this purpose include gels, hydrogels, lotions,
solutions, creams, ointments, dusting powders, dressings, foams, films, skin patches, wafers, implants,
sponges, fibres, bandages and microemulsions. Liposomes may also be used. Typical carriers include
alcohol , water, mineral oil, liquid petrolatum , white petrolatum , glycerin , polyethylene glycol and propylene
glycol. Penetration enhancers may be incorporated [see, for example, Finnin and Morgan, J Pharm Sci,
88 ( 10), 955-958 (October 1999).] Other means of topical administration include delivery by
electroporation, iontophoresis, phonophoresis, sonophoresis and microneedle or needle-free (e.g.
Powderject™ , Bioject™ , etc. ) injection.
Inhaled/lntranasal Administration
The compounds and salts of the invention may also be administered intranasally or by inhalation, typically
in the form of a dry powder (either alone, as a mixture, for example, in a dry blend with lactose, or as a
mixed component particle, for example, mixed with phospholipids, such as phosphatidylcholine) from a
dry powder inhaler or as an aerosol spray from a pressurised container, pump, spray, atomiser (preferably
an atomiser using electrohydrodynamics to produce a fine mist), or nebuliser, with or without the use of a
suitable propellant, such as 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane. For intranasal
use, the powder may comprise a bioadhesive agent, for example, chitosan or cyclodextrin .
A pressurised container, pump, spray, atomizer, or nebuliser may contain a solution or suspension of the
compound(s) or salt(s) of the invention comprising, for example, ethanol, aqueous ethanol, or a suitable
alternative agent for dispersing, solubilising, or extending release of the active, a propellant(s) as solvent
and an optional surfactant, such as sorbitan trioleate, oleic acid, or an oligolactic acid.
Prior to use in a dry powder or suspension formulation, the drug product is micronised to a size suitable
for delivery by inhalation (typically less than 5 microns). This may be achieved by any appropriate
comminuting method, such as spiral jet milling, fluid bed jet milling, supercritical fluid processing to form
nanoparticles, high pressure homogenisation, or spray drying.
Capsules (made, for example, from gelatin or HPMC), blisters and cartridges for use in an inhaler or
insufflator may be formulated to contain a powder mix of the compound or salt of the invention, a suitable
powder base such as lactose or starch and a performance modifier such as /-leucine, mannitol, or
magnesium stearate. The lactose may be anhydrous or in the form of the monohydrate, preferably the
latter. Other suitable excipients include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose and
trehalose.
A suitable solution formulation for use in an atomiser using electrohydrodynamics to produce a fine mist
may contain from 1 g to 20mg of the compound or salt of the invention per actuation and the actuation
volume may vary from 1m I to 0OmI . A typical formulation may comprise a compound of formula (I) or salt
thereof, propylene glycol, sterile water, ethanol and sodium chloride. Alternative solvents which may be
used instead of propylene glycol include glycerol and polyethylene glycol.
Suitable flavours, such as menthol and levomenthol , or sweeteners, such as saccharin or saccharin
sodium, may be added to those formulations of the invention intended for inhaled/intranasal
administration.
Formulations for inhaled/intranasal administration may be formulated to be immediate and/or modified
release using, for example, poly(DL-lactic-coglycolic acid (PGLA). Modified release formulations include
delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.
In the case of dry powder inhalers and aerosols, the dosage unit is determined by a prefilled capsule,
blister or pocket or by a system that utilises a gravimetrically fed dosing chamber . Units in accordance
with the invention are typically arranged to administer a metered dose or "puff" containing from 1 to 5000
g of the compound or salt. The overall daily dose will typically be in the range 1 g to 20 mg which may
be administered in a single dose or, more usually, as divided doses throughout the day.
Rectal/lntravaqinal Administration
The compounds and salts of the invention may be administered rectally or vaginally, for example, in the
form of a suppository, pessary, or enema. Cocoa butter is a traditional suppository base, but various well
known alternatives may be used as appropriate.
Ocular and Aural Administration
The compounds and salts of the invention may also be administered directly to the eye or ear, typically in
the form of drops of a micronised suspension or solution in isotonic, pH-adjusted, sterile saline. Other
formulations suitable for ocular and aural administration include ointments, biodegradable (e.g.
absorbable gel sponges, collagen) and non-biodegradable (e.g. silicone) implants, wafers, lenses and
particulate or vesicular systems, such as niosomes or liposomes. A polymer such as crossed-linked
polyacrylic acid, polyvinylalcohol, hyaluronic acid; a cellulosic polymer, for example,
hydroxypropylmethylcellulose, hydroxyethylcellulose, or methyl cellulose; or a heteropolysaccharide
polymer, for
example, gelan gum , may be incorporated together with a preservative, such as benzalkonium chloride.
Such formulations may also be delivered by iontophoresis.
Other Technologies
The compounds and salts of the invention may be combined with soluble macromolecular entities, such
as cyclodextrin and suitable derivatives thereof or polyethylene glycol-containing polymers, in order to
improve their solubility, dissolution rate, taste-masking, bioavailability and/or stability for use in any of the
aforementioned modes of administration.
Drug-cyclodextrin complexes, for example, are found to be generally useful for most dosage forms and
administration routes. Both inclusion and non-inclusion complexes may be used. As an alternative to
direct complexation with the drug, the cyclodextrin may be used as an auxiliary additive, i.e. as a carrier,
diluent, or solubiliser. Most commonly used for these purposes are alpha-, beta- and gammacyclodextrins,
examples of which may be found in International Patent Applications Nos. WO 91/1 1172,
WO 94/0251 8 and WO 98/551 48.
For administration to human patients, the total daily dose of the compounds and salts of the invention is
typically in the range 0 .1 mg to 200 mg depending, of course, on the mode of administration, preferred in
the range 1 mg to 100 mg and more preferred in the range 1 mg to 50 mg. The total daily dose may be
administered in single or divided doses.
These dosages are based on an average human subject having a weight of about 65kg to 70kg. The
physician will readily be able to determine doses for subjects whose weight falls outside this range, such
as infants and the elderly.
For the above-mentioned therapeutic uses, the dosage administered will, of course, vary with the
compound or salt employed, the mode of administration, the treatment desired and the disorder indicated.
The total daily dosage of the compound of formula (l)/salt/solvate (active ingredient) will, generally, be in
the range from 1 mg to 1 gram, preferably 1 mg to 250 mg, more preferably 10 mg to 100 mg. The total
daily dose may be administered in single or divided doses. The present invention also encompasses
sustained release compositions.
The pharmaceutical composition may, for example, be in a form suitable for parenteral injection as a sterile
solution, suspension or emulsion, for topical administration as an ointment or cream or for rectal
administration as a suppository. The pharmaceutical composition may be in unit dosage forms suitable for
single administration of precise dosages. The pharmaceutical composition will include a conventional
pharmaceutical carrier or excipient and a compound according to the invention as an active ingredient. In
addition, it may include other medicinal or pharmaceutical agents, carriers, adjuvants, etc.
Exemplary parenteral administration forms include solutions or suspensions of active compounds in sterile
aqueous solutions, for example, aqueous propylene glycol or dextrose solutions. Such dosage forms can be
suitably buffered, if desired.
Suitable pharmaceutical carriers include inert diluents or fillers, water and various organic solvents. The
pharmaceutical compositions may, if desired, contain additional ingredients such as flavorings, binders,
excipients and the like. Thus for oral administration, tablets containing various excipients, such as citric acid
may be employed together with various disintegrants such as starch, alginic acid and certain complex
silicates and with binding agents such as sucrose, gelatin and acacia. Additionally, lubricating agents such
as magnesium stearate, sodium lauryl sulfate and talc are often useful for tableting purposes. Solid
compositions of a similar type may also be employed in soft and hard filled gelatin capsules. Preferred
materials, therefor, include lactose or milk sugar and high molecular weight polyethylene glycols. When
aqueous suspensions or elixirs are desired for oral administration the active compound therein may be
combined with various sweetening or flavoring agents, coloring matters or dyes and, if desired, emulsifying
agents or suspending agents, together with diluents such as water, ethanol, propylene glycol, glycerin, or
combinations thereof.
Dosage regimens may be adjusted to provide the optimum desired response. For example, a single bolus
may be administered, several divided doses may be administered over time or the dose may be
proportionally reduced or increased as indicated by the exigencies of the therapeutic situation. It is
especially advantageous to formulate parenteral compositions in dosage unit form for ease of administration
and uniformity of dosage. Dosage unit form, as used herein, refers to physically discrete units suited as
unitary dosages for the mammalian subjects to be treated; each unit containing a predetermined quantity of
active compound calculated to produce the desired therapeutic effect in association with the required
pharmaceutical carrier. The specification for the dosage unit forms of the invention are dictated by and
directly dependent on (a) the unique characteristics of the chemotherapeutic agent and the particular
therapeutic or prophylactic effect to be achieved, and (b) the limitations inherent in the art of compounding
such an active compound for the treatment of sensitivity in individuals.
Thus, the skilled artisan would appreciate, based upon the disclosure provided herein, that the dose and
dosing regimen is adjusted in accordance with methods well-known in the therapeutic arts. That is, the
maximum tolerable dose can be readily established, and the effective amount providing a detectable
therapeutic benefit to a patient may also be determined, as can the temporal requirements for
administering each agent to provide a detectable therapeutic benefit to the patient. Accordingly, while
certain dose and administration regimens are exemplified herein, these examples in no way limit the dose
and administration regimen that may be provided to a patient in practicing the present invention.
It is to be noted that dosage values may vary with the type and severity of the condition to be alleviated, and
may include single or multiple doses. It is to be further understood that for any particular subject, specific
dosage regimens should be adjusted over time according to the individual need and the professional
judgment of the person administering or supervising the administration of the compositions, and that dosage
ranges set forth herein are exemplary only and are not intended to limit the scope or practice of the claimed
composition. For example, doses may be adjusted based on pharmacokinetic or pharmacodynamic
parameters, which may include clinical effects such as toxic effects and/or laboratory values. Thus, the
present invention encompasses intra-patient dose-escalation as determined by the skilled artisan.
Determining appropriate dosages and regiments for administration of the chemotherapeutic agent are wellknown
in the relevant art and would be understood to be encompassed by the skilled artisan once provided
the teachings disclosed herein.
A pharmaceutical composition of the invention may be prepared, packaged, or sold in bulk, as a single
unit dose, or as a plurality of single unit doses. As used herein, a "unit dose" is discrete amount of the
pharmaceutical composition comprising a predetermined amount of the active ingredient. The amount of
the active ingredient is generally equal to the dosage of the active ingredient which would be administered
to a subject or a convenient fraction of such a dosage such as, for example, one-half or one-third of such
a dosage.
For parenteral dosages, this may conveniently be prepared as a solution or as a dry powder requiring
dissolution by a pharmacist, medical practitioner or the patient. It may be provided in a bottle or sterile
syringe. For example it may be provided as a powder in a multicompartment syringe which allows the dry
powder and solvent to be mixed just prior to administration (to aid long-term stability and storage).
Syringes could be used which allow multiple doses to be administered from a single device.
The relative amounts of the active ingredient, the pharmaceutically acceptable carrier, and any additional
ingredients in a pharmaceutical composition of the invention will vary, depending upon the identity, size,
and condition of the subject treated and further depending upon the route by which the composition is to
be administered. By way of example, the composition may comprise between 0 .1% and 100% (w/w)
active ingredient.
In addition to the active ingredient, a pharmaceutical composition of the invention may further comprise
one or more additional pharmaceutically active agents.
Controlled- or sustained-release formulations of a pharmaceutical composition of the invention may be
made using conventional technology.
As used herein, "parenteral administration" of a pharmaceutical composition includes any route of
administration characterized by physical breaching of a tissue of a subject and administration of the
pharmaceutical composition through the breach in the tissue. Parenteral administration thus includes, but
is not limited to, administration of a pharmaceutical composition by injection of the composition, by
application of the composition through a surgical incision, by application of the composition through a
tissue-penetrating non-surgical wound, and the like. In particular, parenteral administration is
contemplated to include, but is not limited to, subcutaneous, intraperitoneal, intramuscular, intrasternal
injection, and kidney dialytic infusion techniques.
Formulations of a pharmaceutical composition suitable for parenteral administration comprise the active
ingredient combined with a pharmaceutically acceptable carrier, such as sterile water or sterile isotonic
saline. Such formulations may be prepared, packaged, or sold in a form suitable for bolus administration
or for continuous administration. Injectable formulations may be prepared, packaged, or sold in unit
dosage form , such as in ampules or in multi-dose containers containing a preservative. Formulations for
parenteral administration include, but are not limited to, suspensions, solutions, emulsions in oily or
aqueous vehicles, pastes, and implantable sustained-release or biodegradable formulations as discussed
below. Such formulations may further comprise one or more additional ingredients including, but not
limited to, suspending, stabilizing , or dispersing agents. In one embodiment of a formulation for
parenteral administration, the active ingredient is provided in dry (i.e. powder or granular) form for
reconstitution with a suitable vehicle (e.g. sterile pyrogen-free water) prior to parenteral administration of
the reconstituted composition.
A composition of the present invention can be administered by a variety of methods known in the art. The
route and/or mode of administration vary depending upon the desired results. The active compounds can
be prepared with carriers that protect the compound against rapid release, such as a controlled release
formulation, including implants, transdermal patches, and microencapsulated delivery systems.
Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides,
polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Many methods for the preparation of such
formulations are described by e.g. , Sustained and Controlled Release Drug Delivery Systems, J. R.
Robinson, ed., Marcel Dekker, Inc. , New York, ( 1978). Pharmaceutical compositions are preferably
manufactured under GMP conditions.
The pharmaceutical compositions may be prepared, packaged, or sold in the form of a sterile injectable
aqueous or oily suspension or solution. This suspension or solution may be formulated according to the
known art, and may comprise, in addition to the active ingredient, additional ingredients such as the
dispersing agents, wetting agents, or suspending agents described herein. Such sterile injectable
formulations may be prepared using a non-toxic parenterally-acceptable diluent or solvent, such as water
or 1,3-butane diol, for example. Other acceptable diluents and solvents include, but are not limited to,
Ringer's solution, isotonic sodium chloride solution, and fixed oils such as synthetic mono- or diglycerides.
Other parentally-administrable formulations which are useful include those which comprise
the active ingredient in microcrystalline form, in a liposomal preparation , or as a component of a
biodegradable polymer system . Compositions for sustained release or implantation may comprise
pharmaceutically acceptable polymeric or hydrophobic materials such as an emulsion, an ion exchange
resin, a sparingly soluble polymer, or a sparingly soluble salt.
The precise dosage administered of each active ingredient will vary depending upon any number of
factors, including but not limited to, the type of animal and type of disease state being treated, the age of
the animal, and the route(s) of administration.
The following non-limiting Preparations and Examples illustrate the preparation of compounds and salts of
the present invention.
GENERAL EXPERIMENTAL
The Preparations and Examples that follow illustrate the invention but do not limit the invention in any
way. All starting materials are available commercially or described in the literature. All temperatures are
in °C. Flash column chromatography was carried out using Merck silica gel 60 (9385). Thin layer
chromatography (TLC) was carried out on Merck silica gel 60 plates (5729). "Rf" represents the distance
travelled by a compound divided by the distance travelled by the solvent front on a TLC plate. Melting
points were determined using a Gallenkamp MPD350 apparatus and are uncorrected. NMR was carried
out using a Varian-Unity Inova 400MHz NMR spectrometer or a Varian Mercury 400MHz NMR
spectrometer. Mass spectroscopy was carried out using a Finnigan Navigator single quadrupole
electrospray mass spectrometer or a Finnigan aQa APCI mass spectrometer.
Where it is stated that compounds were prepared in the manner described for an earlier Preparation or
Example, the skilled person will appreciate that reaction times, number of equivalents of reagents and
reaction temperatures may be modified for each specific reaction, and that it may nevertheless be
necessary or desirable to employ different work-up or purification conditions.
The invention is illustrated by the following non-limiting examples in which the following abbreviations and
definitions are used:
The Preparations and Examples that follow illustrate the invention but do not limit the invention in any
way. All starting materials are available commercially or described in the literature. All temperature are in
°C. Flash column chromatography was carried out using Merck silica gel 60 (9385) or Redisep silica.
NMR was carried out using a Varian Mercury 400MHz NMR spectrometer or a Jeol ECX 400MHz NMR.
The mass spectra were obtained using:
Waters ZQ ESCI
Applied Biosystem's API-2000 5 min LC-MS
Waters Alliance 2795 with ZQ2000 (ESI)
Aglient 110 HPLC 5 min (System 5)
Waters ZQ ESCI 8min LC-MS
Waters Alliance 2695 with ZQ2000 (ESI) 25 min
HP 1100 HPLC with Waters Micromass ZQ mass detector 12.5 min LC-MS
UPLC mass spectra were obtained using a Waters Acquity ZQD (ESI) 1.5 min LC-MS
WATERS ACQUITY UPLC/WATERS 3 100 MSD/PL-ELS 2 100 ICE ELSD
Where singleton compounds have been analysed by LCMS, there are six methods used. These are
illustrated below.
System 1
6 minute LC-MS gradient and instrument conditions
A: 0 .1 % formic acid in water
B: 0 .1 % formic acid in acetonitrile
Column: C 18 phase Waters Sunfire 50 x 4.6 mm with 5 micron particle size
Gradient: 95-5% A over 3 min, 1 min hold, 2 min re-equilibration, 1.5mL/min flow rate
UV: 210nm - 450nm DAD
Temperature: 50°C
System 2
2 minute LC-MS gradient and instrument conditions
A: 0 .1 % formic acid in water
B: 0 .1 % formic acid in acetonitrile
Column: C 18 phase Phenomenex 20 x 4.0 mm with 3 micron particle size
Gradient: 70-2% A over 1.5min, 0.3 min hold, 0.2 re-equilbration, 1.8mL/min flow rate
UV: 210nm - 450nm DAD
Temperature: 75°C
System 3
5 minute LC-MS gradient and instrument conditions
A: 0 .1 % formic acid in water
B: 0 .1 % formic acid in acetonitrile
Column: C 18 phase Waters Sunfire 50 x 4.6 mm with 5 micron particle size
Gradient: 95-5% A over 3 min, 1 min hold, 1 min re-equilibration, 1.5mL/min flow rate
UV: 225nm - ELSD - MS
Temperature: ambient
System 4
5 minute LC-MS gradient and instrument conditions
A: 0 .1 % ammonium hydroxide in water
B: 0 .1 % ammonium hydroxide in acetonitrile
Column: C 18 phase XTerra 50 x 4.6 mm with 5 micron particle size
Gradient: 95-5% A over 3 min, 1 min hold, 1 min re-equilibration, 1.5ml_/min flow rate
UV: 225nm - ELSD - MS
Temperature: ambient
System 5
5 minute LC-MS gradient and instrument conditions
A: 0.0375 % TFA in water
B: 0.01 875 % TFA in acetonitrile
Column: C 18 phase Welch XB 50 x 2 .1 mm with 5 micron particle size
Gradient: 99-0% A over 4 min, 0.70 min re-equilibration, 0.8 mL/min flow rate
UV: 225nm - ELSD - MS
Temperature: 50°C
System 6
5 minute LC-MS gradient and instrument conditions
A: 0.0375 % TFA in water
B: 0.01 875 % TFA in acetonitrile
Column: C 18 phase Welch XB 50 x 2 .1 mm with 5 micron particle size
Gradient: 90-0% A over 4 min, 0.70 min re-equilibration, 0.8 mL/min flow rate
UV: 225nm - ELSD - MS
Temperature: 50°C
System 7
25 minute LC-MS gradient and instrument conditions
A: 10 mmol ammonium bicarbonate in water
B: acetonitrile
Column: C 18 phase XBridge 150 x 3.0 mm with 5 micron particle size
Gradient: 95-5% A over 15 min, 10 min hold, 2 min re-equilibration , 0.5mL/min flow rate
UV: 200nm - 350nm DAD
Temperature: 30°C
System 8
3 minute LC-MS gradient and instrument conditions
A: 0.05% formic acid in water
B: acetonitrile
Column: C 18 phase Restek 30 x 2 .1 mm with 3 micron particle size
Gradient: 98-2% A over 2 min, 0.25 min hold, 0.75 min re-equilibration, 1.5mL/min flow rate
UV: 200nm - 350nm DAD
Temperature: 50°C
System 9
5 minute LC-MS gradient and instrument conditions
A: 0.05% formic acid in water
B: acetonitrile
Column: C 18 phase XBridge 50 x 4.6 mm with 5 micron particle size
Gradient: 90-1 0% A over 3 min, 1 min hold, 1min re-equilibration, 1.2ml_/min flow rate
UV: 200nm - 260nm DAD
Temperature: 25°C
System 10
5 minute LC-MS gradient and instrument conditions
A: 10 mM ammonium acetate in water
B: acetonitrile
Column: C 18 phase Gemini NX 50 x 4.6 mm with 5 micron particle size
Gradient: 90-1 0% A over 3 min, 1 min hold, 1min re-equilibration, 1.2ml_/min flow rate
UV: 200nm - 260nm DAD
Temperature: 25°C
Where singleton compounds have been purified by High Performance Liquid Chromatography, unless
otherwise stated, one of four methods were used, and these are shown below.
Waters Purification Systems with mass spec or UV detection
Prep system 1
10 minute prep LC-MS gradient and instrument conditions
A: 0 .1% formic acid in water
B: 0 .1% formic acid in acetonitrile
Column: C 18 phase Sunfire 100 x 19.0 mm
Gradient: 95-2% A over 7 min, 2 min hold, 1 min re-equilibration, 18 mL/min flow rate
Temperature: ambient
Prep system 2
10 minute prep LC-MS gradient and instrument conditions
A: 0 .1% DEA in water
B: 0 .1% DEA in acetonitrile
Column: C 18 phase Xterra 100 x 19.0 mm
Gradient: 95-2% A over 7 min, 2 min hold, 1 min re-equilibration, 18 mL/min flow rate
Temperature: ambient
Prep system 3
7 minute prep LC-MS gradient and instrument conditions
A: 0.05% ammonia in water
B: acetonitrile
Column: C 18 phase Xbridge 50 x 19.0 mm
Gradient: 90-20% A over 7 min, 20 mL/min flow rate
Temperature: ambient
Prep system 4
8 minute prep LC-MS gradient and instrument conditions
A: 0 .1% TFA in water
B: acetonitrile
Column: C 18 phase Sepax BR 100 x 2 1.2 mm
Gradient: 96-33% A over 8 min, 30 mL/min flow rate
Temperature: ambient
Where it is stated that compounds were prepared in the manner described for an earlier Preparation or
Example, the skilled person will appreciate that reaction times, number of equivalents of reagents and
reaction temperatures may have been modified for each specific reaction, and that it may nevertheless be
necessary, or desirable, to employ different work-up or purification conditions. The invention is illustrated
by the following non-limiting Examples in which the following abbreviations and definitions are used:
AcOH - acetic acid; APCI - atmospheric pressure chemical ionization; Arbocel is a filter agent; br s -
broad singlet; BINAP - 2,2'-bis(diphenylphosphino)-1 ,1'-binapthyl; nBuLi - n-Butyllithium ; CDCI3 -
deuterated chloroform ; Cs2C0 3 is caesium carbonate; Cul is copper (I) iodide; Cu(OAc) 2 is copper ( II)
acetate; d - chemical shift; d - doublet; DAD - diode array detector; DCE - 1,2-dichloroethane
DCM - dichloromethane; DEA - diethylamine; DIBAL - Diisobutylaluminium hydride; DIPEA -
diisopropylethylamine; DMAP - 4-dimethylaminopyridine; DME - dimethoxyethane; DMF - N,Ndimethylformamide;
DMF-DMA - N,N-dimethylformamide-dimethylacetal; DMSO - dimethylsulphoxide
DPPF - 1,1'-bis(diphenylphosphino)ferrocene; ELSD - evaporative light scattering detector; ESI -
electrospray ionization; Et20 - diethylether; EtOAc/EA - ethyl acetate; EtOH - ethanol; g - gram ; HATU -
2-(7-azabenzotriazol-1 -yl)-1 ,1,3,3-tetramethyluronium hexafluorophosphate; HBTU is O-benzotriazol-1 -yl-
N,N,N' ,N'-tetramethyluronium hexafluorophosphate; HCI is hydrochloric acid;HOBT is Nhydroxybenzotriazole
hydrate; HPLC - high pressure liquid chromatography; IPA - isopropyl alcohol;
K2C0 3 is potassium carbonate; KHS0 4 is potassium hydrogen sulphate; KOAc is potassium acetate; KOH
is potassium hydroxide; K3P0 4 is potassium phosphate tribasic; KF - potassium fluoride; L is litre; LCMS
- liquid chromatography mass spectrometry; LiHMDS - Lithium hexamethyldisilazide; m - multiplet; mg -
milligram; mL - millilitre; M/Z - Mass Spectrum Peak; MeCN - acetonitrile; MeOH - methanol; 2-MeTHF -
2-methyltetrahydrofuran; MgS0 4 is magnesium sulphate; Mn0 2 - manganese dioxide; NaCI0 2 - sodium
chlorite; NaH - sodium hydride; NaHC0 3 - sodium hydrogencarbonate; Na2C0 3 - sodium carbonate;
NaH2P0 4- sodium phosphate; NaHS0 3 - sodium bisulphite; NaHS0 - sodium hydrogensulphate; NaOH -
sodium hydroxide; Na2S0 - sodium sulphate; NH3 - ammonia; NH4CI - ammonium chloride; NMM - NMethylMorpholine;
NMR - nuclear magnetic resonance; Pd/C - palladium on carbon; PdCI2 - palladium
dichloride; Pd2(dba)3 is tris(dibenzylideneacetone)dipalladium(0); Pd(PPh3)4 - palladium
tetrakis(triphenylphosphine); Pd(OAc)2 - palladium acetate; PTSA - para-toluenesulfonic acid; Prep -
preparation; Rt - retention time; q - quartet; s - singlet; TBDMS - tertbutyldimethylsilyl; TBME -
tertbutyldimethylether; TCP - 1-propylphosphonic acid cyclic anhydride; TEA - triethylamine; TFA -
trifluoroacetic acid; THF - tetrahydrofuran; TLC - thin layer chromatography; (R, S) - racemic mixture;
WSCDI - 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride.
For the avoidance of doubt, named compounds used herein have been named using lUAPC, Chemdraw
and/or Name Pro ACD Labs Name Software v7. 11™ or using other standard nomenclature. NMR spectra
were measured in deuterated solvents and were consistent with the names/structures given below.
Example 1: N-{5-[(7-tert-Butyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)carbonyl]pyridin-3-yl}-2-(5-fluoropyridin-2-
yl)acetamide
2-(5-Fluoropyridin-2-yl)acetic acid (23. 1 mg, 0 .149 mmol) (see Preparation 92) was added to (5-
aminopyridin-3-yl)(7-ferf-butyl-7/-/-pyrrolo[2,3-c/]pyrimidin-5-yl)methanone (40 mg, 0 .135 mmol ) (see
Preparation 31) , 1-propyl phosphonic acid cyclic anhydride (0.2 mL, 0.338 mmol, 50% in EtOAc) and
triethylamine (0.65 mL, 0.474 mmol) in THF (3 mL). The mixture was stirred at 25°C for 18 hours,
evaporated in vacuo and partitioned between saturated aqueous sodium bicarbonate (5 mL) and ethyl
acetate (5 mL). The organic phase was dried over sodium sulfate, evaporated in vacuo and the residue
was triturated with pentane:diethyl ether (3: 1, 1 mL) to afford the title compound as an off white solid in
65% yield, 38 mg.
H NMR (400 MHz, DMSO) d 1.79 (s, 9H), 3.95 (s, 2H), 7.50 (m, 1H), 7.72 (m, 1H), 8.21 (s, 1H), 8.50 (d,
1H), 8.76 (d, 1H), 8.95 (d, 1H), 9.00 (s, 1H), 9.48 (s, 1H), 10.72 (s, 1H); LCMS (System 4): Rt = 2.86 min;
m/z 433 [M+H]+.
Examples 2 to 8 were prepared according to the method described above for Example 1, starting from (5-
aminopyridin-3-yl)(7-ferf-butyl-7/-/-pyrrolo[2,3-c/]pyrimidin-5-yl)methanone (see Preparation 31) and the
appropriate acids.
Example Name Data
2 N-{5-[(7-tert-butyl-7H-pyrrolo[2,3-d]pyrimidin-5- LCMS (system 4): Rt = 3.26
yl)carbonyl]pyridin-3-yl}-2-[4-(trifluoromethyl)-1 H-1 ,2,3-triazol- min; m/z 473 [M+H]+
1-yl]acetamide
3 N-{5-[(7-tert-butyl-7H-pyrrolo[2,3-d]pyrimidin-5- LCMS (system 4): Rt = 3.04
yl)carbonyl]pyridin-3-yl}-2-(3-cyclopropyl-1 H-pyrazol-1 - min; m/z 444 [M+H]+
yl)acetamide
4 N-{5-[(7-tert-butyl-7H-pyrrolo[2,3-d]pyrimidin-5- LCMS (system 4): Rt = 2.75
yl)carbonyl]pyridin-3-yl}-2-(4-cyclopropyl-1 H-1 ,2,3-triazol-1 - min; m/z 445 [M+H]+
yl)acetamide
5 N-{5-[(7-tert-butyl-7H-pyrrolo[2,3-d]pyrimidin-5- LCMS (system 4): Rt = 3.04
yl)carbonyl] pyrid in-3-yl}-2-[3-(trif luorom ethyl )- 1H-pyrazol- 1- min; m/z 472 [M+H]+
yljacetamide
6 N-{5-[(7-tert-butyl-7H-pyrrolo[2,3-d]pyrimidin-5- LCMS (system 4): Rt = 2.92
yl)carbonyl]pyridin-3-yl}-2-(5-chloropyridin-2-yl)acetamide min; m/z 449 [M+H]+
7 N-{5-[(7-tert-butyl-7H-pyrrolo[2,3-d]pyrimidin-5- LCMS (system 4): Rt = 2.96
yl)carbonyl]pyridin-3-yl}-2-(4-cyclopropyl-1 H-pyrazol-1 - min; m/z 443 [M+H]+
yl)acetamide
8 N-{5-[(7-tert-butyl-7H-pyrrolo[2,3-d]pyrimidin-5- LCMS(system 4)
yl)carbonyl] pyrid in-3-yl}-2-[4-(trif luorom ethyl )- 1H-pyrazol- 1- : Rt = 3.00 min; m/z 472
yljacetamide [M+H]+
Example 9 : N-[5-({7-[(1 S)-2-Hydroxy-1 -methylethyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}carbonyl)pyridii
yl]-2-[4-(trifluoromethyl)phenyl]ac
4-(Trifluoromethyl)phenylacetic acid (33.6 g , 165 mmol) was added to (5-aminopyridin-3-yl){7-[(1 S)-2-
{[ferf-butyl(dimethyl)silyl]oxy}-1 -methylethyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}methanone (45.2 g , 110
mmol) (see Preparation 37), 1-propylphosphonic acid cyclic anhydride ( 194 mL, 329 mmol, 50% solution
in EtOAc) and triethylamine (53.6 mL, 384 mmol ) in THF (400 mL). The mixture was stirred at 25°C for 2
hours then saturated aqueous sodium bicarbonate (250 mL) was added and the organic layer was
separated. The aqueous phase was extracted with EtOAc (2 x 200 mL) and all organic phases were
combined and dried over sodium sulfate then evaporated in vacuo.
The residue brown solid was dissolved in THF (400 mL) and aqueous HCI (200 mL, 2M) was added. The
mixture was stirred at room temperature for 2 hours then cooled to 0°C and sodium hydroxide (28 g) was
added. The mixture was stirred for 3 hours then water ( 100 mL) was added . The organic layer was
separated and the aqueous phase was extracted with EtOAc (2 x 300 mL) and all organic phases were
combined and dried over sodium sulfate then evaporated in vacuo. The crude solid was recrystallised
using ethyl acetate ( 150 mL) to afford the title compound as a white solid in 63% yield, 33.4 g .
H NMR (400 MHz, DMSO) d 1.5 1 (d, 3H), 3.68-3.79 (m, 1H), 3.81 -3.93 (m, 3H), 4.93-5.06 (m, 2H), 7.55-
7.63 (m, 2H), 7.67-7.75 (m, 2H), 8.41 -8.49 (m, 2H), 8.73 (d, 1H), 8.98 (s, 1H), 9.00 (d, 1H), 9.44 (s, 1H),
10.72 (s, 1H); LCMS (System 1) : Rt = 4.53 min; m/z 484 [M+H]+.

CLAIMS
1. A compound of Formula I :
(I)
or a pharmaceutically acceptable salt thereof, wherein
R' is
H, or
Ci-5 alkyl optionally substituted by up to 3 substituents independently selected from OH, CON(R5R6) ,
S0 2R7, SR7, OR7, CH2OH, C0 2R5, SONR R7, NR S0 2R5, CN, N0 2 and R , or
a ring system selected from C3.5 cycloalkyl, propellanyl, or a 4-6 membered saturated heterocyclyl
ring, which ring system has up to 3 ring hetero-atoms selected from N, O and S, and which ring
system is optionally substituted by up to 3 substituents independently selected from methyl, OH,
CON(R5R6) , S0 2R7, OR7, CH2OH, C0 2R5, SONR R7, NR S0 2R5, CN, N0 2 and R8;
R is H or methyl;
R3 is H, NH2 or NH(Ci _3 alkyl optionally substituted with up to 3 substituents independently selected from
OH and 0 ( _3 alkyl));
R101 is H, OH, methyl, cyclopropyl, methoxy, ethyl, ethoxy or CN,
X is a bond, O, (CH-R )n, NR , OCH2 or CH20 ;
R4 is independently H, CH3, CH2OH, CH2OCH3, OH, NH2, NHCH3, N(CH3)2, CH2NH2, CH2NHCH3,or
CH2N(CH3)2;
R104 is H, Ci_3 alkyl or a C4.6 saturated carbocycle, each of which is optionally substituted by up to 3
substituents independently selected from Ci_3 alkyl, CH2OH and NH2;
n is 1 or 2 ;
02
R is a ring system which is a 3-7 membered monocyclic carbocyclic or heterocyclic system, or an 8-14-
membered bicyclic system, which ring system may be saturated or partially or fully unsaturated, wherein
the heterocyclic ring system may have up to 5 ring hetero-atoms selected from N, S, and O,
wherein the bicyclic ring system can be 2 rings (carbocyclic-carbocyclic, carbocyclic-heterocyclic,
heterocyclic-carbocyclic or heterocyclic-heterocyclic) fused or linked by a single bond,
which ring system is optionally substituted by up to 3 substituents independently selected from, where
possible -
halo, CN, N R 5R 6 , S0 2R 7 , S R 7 , C 4 alkyl optionally substituted by up to 3 O H and/or C -3 alkoxy groups,
C3-6 cycloalkyl optionally substituted by up to 3 O H and/or C1.3 alkoxy groups, C1.3 alkyl substituted by up
to 3 halogen, OH, 0(Ci_3 alkyl), 0(C3_6 cycloalkyl optionally substituted by up to 3 O H and/or C1.3 alkoxy
groups, 0(Ci_ 3 alkyl substituted by up to 3 halogen), 0(Ci_ 3 alkyl substituted by up to 3 O H and/or C 3
alkoxy groups), N R 5S0 2R 7 , =0, R 8 , C (0)R 8 , N0 2, N R 5C0 2R 7 , N R 5COR ,OR 8 , S (0)R 7 , and C H 2R 8 ;
R 5 and R 6 are each independently
H , or
C 5 alkyl optionally substituted by up to 3 substituents independently selected from OH, CONR R 7 ,
S0 2R 7 , O R 7 , C H 2OH, C0 2R 7 , SONR R 7 , N R S0 2R 7 , CN, N0 2 and R 9 ,
or
a ring system selected from C3.5 cycloalkyl, propellanyl, or a 4-6 membered saturated heterocyclyl ring,
which ring system is optionally substituted by up to 3 substituents independently selected from OH,
CON(R R 7 ) , S0 2R 7 , C0 2R 7 , SONR R 7 , N R S0 2R 7 , CN, N0 2, halo, N R R ,SR , .4 alkyl optionally
substituted by up to 3 O H and/or C 3 alkoxy groups, C 3. cycloalkyl optionally substituted by up to 3 O H
and/or C 3 alkoxy groups, C 3 alkyl substituted by 1 to 3 halogen, 0(C 3. cycloalkyl optionally substituted
by up to 3 O H and/or C 3 alkoxy groups, 0(Ci_ 3 alkyl substituted by up to 3 halogen, 0(Ci_ 3 alkyl
substituted by up to 3 O H and/or .3 alkoxy, N R S0 2R ,=0,N0 2 ,NR C0 2R 7 , and S (0)R 7 ,
or R 5 and R 6 together with the N to which they are attached can be a 4-7 membered ring optionally
including up to 2 further ring hetero-atoms independently selected from N , O , S , which ring is optionally
substituted by C1.3 alkoxy and / or C1.3 alkyl;
R 7 is H , C 5 alkyl or C 5 alkoxy,
which C1-5 alkyl or Ci_ 5 alkoxy is optionally substituted by up to 3 substituents independently selected from
halogen;
R 8 is a is a ring system which is a 3-7 membered monocyclic carbocyclic or heterocyclic system, or an 8-
14-membered bicyclic system, which ring system may be saturated or partially or fully unsaturated,
wherein the heterocyclic ring system may have up to 5 ring hetero-atoms selected from N , S , and O ,
wherein the bicyclic ring system can be 2 rings (carbocyclic-carbocyclic, carbocyclic-heterocyclic,
heterocyclic-carbocyclic or heterocyclic-heterocyclic) fused or linked by a single bond,
which ring system is optionally substituted by up to 3 substituents independently selected from, where
possible -
halo, CN, N R5R6 , S0 2R7 , S R7 , C 4 alkyl optionally substituted by up to 3 O H and/or C -3 alkoxy groups,
C3-6 cycloalkyl optionally substituted by up to 3 O H and/or C1.3 alkoxy groups, C1.3 alkyl substituted by 1
to 3 halogen, OH, 0(Ci_3 alkyl), 0(C 3. cycloalkyl optionally substituted by up to 3 O H and/or C 3 alkoxy
groups, 0(Ci_3 alkyl substituted by up to 3 halogen, 0(Ci_3 alkyl substituted by up to 3 O H and/or C 3
alkoxy, N R5S0 2R7 , =0, N0 2, N R COR ,NR 5C0 2R7 , and S (0)R 7 ;
R9 is a is a ring system which is a 3-7 membered monocyclic carbocyclic or heterocyclic system, or an 8-
14-membered bicyclic system, which ring system may be saturated or partially or fully unsaturated,
wherein the heterocyclic ring system may have up to 5 ring hetero-atoms selected from N , S , and O ,
wherein the bicyclic ring system can be 2 rings (carbocyclic-carbocyclic, carbocyclic-heterocyclic,
heterocyclic-carbocyclic or heterocyclic-heterocyclic) fused or linked by a single bond,
which ring system is optionally substituted by up to 3 substituents independently selected from, where
possible -
halo, CN, N R R7 , S0 2R7 , S R7 , C 4 alkyl optionally substituted by up to 3 O H and/or C -3 alkoxy groups,
C3 _ cycloalkyl optionally substituted by up to 3 O H and/or C 3 alkoxy groups, C 3 alkyl substituted by 1
to 3 halogen, OH, 0(Ci_3 alkyl), 0(C 3. cycloalkyl optionally substituted by up to 3 O H and/or C 3 alkoxy
groups, 0(Ci_3 alkyl substituted by up to 3 halogen, 0(Ci_3 alkyl substituted by up to 3 O H and/or C 3
alkoxy, N R S0 2R7 , =0, N0 2, N R C0 2R7 , N R COR ,and S (0)R 7 ;
wherein each C H moiety can be replaced by a C F moiety.
2 . A compound or salt according to claim 1 wherein R is H , C 5 alkyl optionally substituted by up to 2
OH,
or R is _5 alkyl substituted by CONH 2 , CONHCH 3 , CON(CH 3 )2 , C0 2H , C0 2C H3 , OCH 3 , SCH 3 , S0 2C H3 ,
or R is a ring system selected from C3.5 cycloalkyl, propellanyl, or oxetanyl, which ring system is
optionally substituted by methyl, O H or C H2OH.
3 . A compound or salt according to any one of claims 1 or 2 wherein R is t-butyl, hydroxy-t-butyl,
dihdyroxy-t-butyl, 1-hydroxyprop-2-yl or 1,3-dihydroxyprop-2-yl.
4 . A compound or salt according to any one of claims 1 to 3 wherein R2 is H .
5 . A compound or salt according to any one of claims 1 to 4 wherein R3 is H or N H2 .
6 . A compound or salt according to any one of claims 1 to 5 wherein R3 is N H2 .
7 . A compound or salt according to any one of claims 1 to 5 wherein R3 is H .
8 . A compound or salt according to any one of claims 1 to 7 wherein R101 is H.
9 . A compound or salt according to any one of claims 1 to 7 wherein R101 is OH.
10 . A compound or salt according to any one of claims 1 to 9 wherein X is a bond, O, CH2, C2H4,
CH(CH3)CH2, CH(CH3) , CH(CH2OH), CH20 , CH(NH2) , CH(OH) or NH.
11. A compound or salt according to any one of claims 1 to 10 wherein X is CH2.
12. A compound or salt according to any one of claims 1 to 11 wherein R102 is an optionally substituted
nitrogen-containing ring system which is linked to the X moiety via a nitrogen ring atom.
13 . A compound or salt according to any one of claims 1 to 11 wherein R is an optionally substituted
ring system where the ring system is selected from -
benzimidazolyl, benzisoxazolyl, benzofuranyl, benzoxazolyl, benzotriazolyl, biphenyl, bipyrazolyl,
cinnolinyl, cyclobutylimidazolyl, cyclobutylpyrazolyl, cyclobutylthiazolyl, cyclopentyltriazolyl,
cyclopropylisoxazolyl, cyclopropyloxazolyl, cyclopropylpyrazolyl, cyclopropyltriazolyl, diazirenylphenyl,
dihydronaphthyridinyl, dihydropyrrolopyrazolyl, dioxinopyridinyl, furazanyl, furopyridinyl, furopyrrolyl,
imidazolyl, imidazopyrazinyl, imidazopyridazinyl, imidazopyridinyl, imidazopyrimidinyl, imidazothiadiazolyl,
imidazothiazolyl, indanyl, indazolyl, indolyl, isoindolyl, isoxazolopyridinyl, isoxazolyl, isoquinolinyl,
naphthyridinyl, oxazolyl, phenyl, phenylcyclopropyl, phenylimidazolyl, phenylpyrazolyl, phenylpyrrolyl,
phenyltetrazolyl, phthalazinyl, purinyl, pyrazinyl, pyrazolyl, pyrazolopyridinyl, pyrazolopyrimidinyl,
pyrazolotriazinyl, pyridinyl, pyridazinyl, pyridinyltriazolyl, pyrimidinyl, pyrroloimidazolyl, pyrrolopyrazinyl,
pyrrolopyrimidinyl, pyrrolopyridinyl, pyrrolyl, quinolinyl, quinazolyl, quinoxalinyl, tetrahydrobenzisoxazolyl,
tetrahydrocyclopentapyrazolyl, tetrahydrotriazolopyridinyl, tetrazolopyridazinyl, tetrazolopyridinyl,
thiazolyl, thiazolopyridinyl, thiazolopyrimidinyl, thienylpyrazolyl, thienopyridinyl, triazolopyridinyl and
triazolyl,
14 . A compound or salt according to claim 13 where the optional substituents are independently
selected from, where possible -
halo, methyl, ethyl, propyl, isopropyl, cyclopropyl, CF3, CHF2, CH2F, CH2OCH3, CN, CH2OH, OCH3, =0,
NH2, SCH3, S0 2CH3, phenoxy, fluorophenoxy, benzyl, SCF3, OCF3, S0 2CF3, NHS0 2CH3, NHS0 2CF3,
C(0)CF 3, C(0)CH 3, benzoyl, azetidinylmethyl, fluoroazetidinylmethyl and morpholinomethyl.
15 . A compound or salt according to any one of claims 1 to 11, 13 or 14 , wherein R102 is selected from
phenyl, pyrazol-1 -yl, 1,2,3-triazol-1 -yl, benzotriazol-2-yl, pyridin-2-yl, pyridin-3-yl and pyridin-4-yl,
each of which is optionally substituted by halo, methyl, ethyl, propyl, isopropyl, cyclopropyl, CF3, CHF2,
CH2F, CH2OCH3, CN, CH2OH, OCH3, =0, NH2, SCH3, S0 2CH3, phenoxy, fluorophenoxy, benzyl, SCF3,
OCF3, S0 2CF3, NHS0 2CH3, NHS0 2CF3, C(0)CF 3, C(0)CH 3, benzoyl, azetidinylmethyl,
fluoroazetidinylmethyl and/or morpholinomethyl.
16 . A compound or salt according to any one of claims 1 to 15 with R5 and R6 groups present, wherein
R5 and R6 are each independently H, C1.3 alkyl optionally substituted by C1.3 alkoxy, C3.5 cycloalkyl,
propellanyl, oxetanyl, tetrahydrofuranyl or pyranyl,
or R5 and R6 together with the N to which they are attached can be an azetidine, pyrrolidine, piperidine,
piperazine or morpholine ring , which ring is optionally substituted by C 3 alkoxy and / or C 3 alkyl.
17 . A compound accordi
(IA)
or a pharmaceutically acceptable salt thereof, wherein
R is H or NH2 ;
R is C2-4 alkyl optionally substituted by 1 or 2 OH groups;
R U is H or OH;
02 and R is phenyl or an aromatic or partially unsaturated 5- or 6-membered heterocycle, which
heterocycle is optionally fused to a further phenyl or 5-7 membered aromatic or partially unsaturated
heterocyclic ring, wherein each heterocycle has from 1 to 3 ring heteroatoms selected from N, O and S,
and which ring system is optionally substituted by up to 3 substituents independently selected from
halo, CF3, C 4 alkyl and C3.5 cycloalkyl.
0 1 18 . A compound or salt according to claim 17 wherein R is H.
, A compound or salt according to claim 18 wherein
R is t-butyl, hydroxy-t-butyl or 1-hydroxyprop-2-yl;
and R102 is 4-trifluromethylphenyl, 4-chlorophenyl, 2,4-difluorophenyl, 5-chloropyridin-2-yl, 5-fluoropyridin-
2-yl, 3-trifluromethylpyrazolyl-1 -yl, 4-trifluromethylpyrazol-1 -yl, 3-trifluromethyl-5-methylpyrazol-1 -yl,
3-cyclopropylpyrazol-1 -yl, 4-cyclopropylpyrazol-1 -yl, 4-trifluromethyl ( 1,2,3-triazol-1 -yl), 4-cyclopropyl-
( 1,2,3-triazol-1 -yl), or benzotriazol-2-yl.
20. A compound according to claim 1, selected from:
N-(5-{[2-amino-7-(2-hydroxy-1 ,1-dimethylethyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]carbonyl}pyridin-3-yl)-
2-[4-(trifluoromethyl)phenyl]acetamide;
N-(5-{[2-amino-7-(2-hydroxy-1 ,1-dimethylethyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]carbonyl}pyridin-3-
yl)-2-(4-chlorophenyl)acetamide;
N-(5-{[2-amino-7-(2-hydroxy-1 ,1-dimethylethyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]carbonyl}pyridin-3-
yl)-2-(5-fluoropyridin-2-yl)acetamide;
N-(5-{[2-amino-7-(2-hydroxy-1 ,1-dimethylethyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]carbonyl}pyridin-3-
yl)-2-[3-(trifluoromethyl)-1H-pyrazol-1-yl]acetamide;
N-(5-{[2-amino-7-(2-hydroxy-1 ,1-dimethylethyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]carbonyl}pyridin-3-
yl)-2-(3-cyclopropyl- 1H-pyrazol- 1-yl)acetam ide;
N-{5-[(2-amino-7-tert-butyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)carbonyl]pyridin-3-yl}-2-(4-cyclopropyl-
1H-1,2,3-triazol-1-yl)acetamide;
N-{5-[(2-amino-7-tert-butyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)carbonyl]pyridin-3-yl}-2-[4-
(trifluoromethyl)-1H-pyrazol-1-yl]acetamide;
N-{5-[(2-amino-7-tert-butyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)carbonyl]pyridin-3-yl}-2-[4-
(trifluoromethyl)-1H-1,2,3-triazol-1-yl]acetamide;
N-{5-[(2-amino-7-tert-butyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)carbonyl]pyridin-3-yl}-2-(5-chloropyridin-
2-yl)acetamide;
N-(5-{[2-Amino-7-(2-hydroxy-1,1-dimethylethyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]carbonyl}pyridin-3-
yl)-2-(5-chloropyridin-2-yl)acetamide;
N-{5-[(7-tert-butyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)carbonyl]pyridin-3-yl}-2-[4-(trifluoromethyl)-1H-
1,2,3-triazol-1-yl]acetamide;
2-(4-chlorophenyl)-N-[5-({7-[(1S)-2-hydroxy-1-methylethyl]-7H-pyrrolo[2,3-d]pyrimidin-5-
yl}carbonyl)pyridin-3-yl]acetamide
N-{5-[(7-tert-butyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)carbonyl]pyridin-3-yl}-2-[4-(trifluoromethyl)-1Hpyrazol-
1-yl]acetamide;
N-[5-({7-[(1S)-2-Hydroxy-1-methylethyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}carbonyl)pyridin-3-yl]-2-[4-
(trifluoromethyl)phenyl]acetamide;
N-[5-({7-[(1R)-2-hydroxy-1-methylethyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}carbonyl)pyridin-3-yl]-2-[4-
(trifluoromethyl)phenyl]acetamide;
2-(4-chlorophenyl)-N-[5-({7-[(1R)-2-hydroxy-1-methylethyl]-7H-pyrrolo[2,3-d]pyrimidin-5-
yl}carbonyl)pyridin-3-yl]acetamide;
N-(5-{[7-(2-hydroxy-1,1-dimethylethyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]carbonyl}pyridin-3-yl)-2-[5-
methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetamide;
2-(5-chloropyridin-2-yl)-N-(5-{[7-(2-hydroxy-1,1-dimethylethyl)-7H-pyrrolo[2,3-d]pyrimidin-5-
yl]carbonyl}pyridin-3-yl)acetamide;
N-(5-{[2-Amino-7-(2-hydroxy-1-methylethyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]carbonyl}pyridin-3-yl)-
2-(4-chlorophenyl)acetamide;
N-(5-{[2-amino-7-(2-hydroxy-1-methylethyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]carb
[4-(trifluoromethyl)phenyl]acetamide;
N-(5-{[2-amino-7-(2-hydroxy-1-methylethyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]carbonyl}pyri
(4-chlorophenyl)acetamide;
N-(5-{[2-amino-7-(2-hydroxy-1-methylethyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]carbonyl}pyri
[4-(trifluoromethyl)phenyl]acetamide;
N-(5-{[2-Amino-7-(2-hydroxy-1 ,1-dimethylethyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]carbony^
yl)-2-[5-methyl-3-(trifluoromethyl)-1 H-pyrazol-1 -yl]acetamide;
and
N-{5-[(7-tert-butyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)carbonyl]pyridin-3-yl}-2-(4-cy^^
triazol-1 -yl)acetamide;
or a pharmaceutically acceptable salt thereof.
2 1. A pharmaceutical composition comprising a compound of the formula (I) or a pharmaceutically
acceptable salt thereof, as defined in any one of the preceding claims 1 to 20, and a pharmaceutically
acceptable carrier.
22. A compound of the formula (I) or a pharmaceutically acceptable salt thereof, as defined in any
one of claims 1 to 20, for use as a medicament.
23. A compound of formula (I) or a pharmaceutically acceptable salt thereof, as defined in any one of
claims 1 to 20 for use in the treatment of a disease for which an Trk receptor antagonist is indicated
24. A compound of formula (I) or a pharmaceutically acceptable salt thereof, as defined in any one of
claims 1 to 20 for use in the treatment of pain.
25. The use of a compound of the formula (I) or a pharmaceutically acceptable salt or composition
thereof, as defined in any one of claims 1 to 20, for the manufacture of a medicament to treat a
disease for which an Trk receptor antagonist is indicated
26. The use of a compound of the formula (I) or a pharmaceutically acceptable salt or composition
thereof, as defined in any one of claims 1 to 20, for the manufacture of a medicament to treat pain.
27. A method of treatment of a mammal, to treat a disease for which an Trk receptor antagonist is
indicated, comprising treating said mammal with an effective amount of a compound of the formula (I)
or a pharmaceutically acceptable salt thereof, as defined in any one of claims 1 to 20.
28. A method of treatment of pain in a mammal, comprising treating said mammal with an effective
amount of a compound of the formula (I) or a pharmaceutically acceptable salt thereof, as defined in
any one of claims 1 to 20.
29. A compound or salt according to any one of claims 1 to 20 for use in a medical treatment in
combination with a further drug susbtance.