OA16607A - Pyrrolo [2, 3 -D] pyrimidine derivatives as inhibitors of tropomyosin- related kinases. - Google Patents

Abstract

The present invention relates to compounds of formula (I)

Description

The invention described herein relates to certain pyrrolo[2,3-d}pyrimidine compounds and the pharmaceutically acceptable salts of such compounds. The invention also relates to the processes for the préparation 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 rôles 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 hâve been reviewed by Wang étal 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, TrkB, and TrkC. Ail three isoforms are activated by high affinity growth factors named neurotrophins (NT): i) nerve growth factor (NGF), which activâtes TrkA; ii) brain-derived neurotrophic factor (BDNF) and NT-4/5, which activate TrkB; and iii) NT-3, which activâtes 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 rôles 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 épithélial cells secrete a sériés 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 in metastatic human pancreatic cancer cells. Recently, there hâve been a number of new findings in other cancer settings. For example, a translocation leads to expression of a fusion protein derived from the M-terminus of the ETV6 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 résistance to chemotherapy in neuroblastoma tumor cells in vitro. One report showed that a novel splice variant of TrkA called TrkAIII 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 hâve 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 thérapies.

1.3 Trks and pain

Besides the newly developed association with cancer, Trks are also being recognized as an important mediator of pain sensation. Congénital 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 hâve been shown to cause CIPA in various ethnie groups.

Currently, non-steroidal anti-inflammatory drugs (NSAlDs) and opiates hâve low efficacy and/or side effects (e.g., gastrointestinal/renal and psychotropic side effects, respectively) against neuropathie 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 antiNGF antibodies or ποη-selective small molécule Trk inhibitors has been shown to hâve effects on pain in animal models. It appears that a sélective Trk inhibitor (inhibiting at Ieast NGF's target, the TrkA receptor) might provide clinical benefit for the treatment of pain. Excellent eariier reviews hâve covered targeting NGF/BDNF for the treatment of pain so this review will only focus on small molécule 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 II trial against osteoarthritic knee pain.

International Patent Application publication number W02009/012283 refers to various fluorophenyl compounds as Trk inhibitors; International Patent Application publication numbers W02009/152087, W02008/080015 and W02008/08001 and W02009/152083 refer to various fused pyrroles as kinase modulators; International Patent Application publication numbers W02009/143024 and W02009/143018 refer to various pyrrolo[2,3-d]pyrimidines substituted as Trk inhibitors; International Patent Application publication numbers W02004/056830 and W02005/116035 describe various 4-amino-pyrrolo[2,3djpyrimidines as Trk inhibitors. International Patent Application publication number WO2011/133637 describes various pyrrolo[2,3-d]pyrÎmÎdines and pyrro!o[2,3-b]pyridines as inhibitors of various kinases.

US provisional application US61/471758 was filed 5^,h April 2012 and the whole contents of that application In it’s entirety are herewith included by reference thereto.

Thus Trk inhibitors hâve 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 sélective 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 idéal 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 désirable features include good HLM/hepatocyte stability, oral bioavailability, metabolic stability, absorption, selectivity over other types of kinase, dofetilide selectivity. Préférable compounds and salts will show a lack of CYP inhibition/induction, and be CNSsparing.

SUMMARY

The présent invention provides compounds of Formula I:

(l) 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 sait 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 sait thereof.

Other aspects of the invention will be apparent from the remaining description and daims.

Preferably, the compounds of the présent invention are potent antagonists at Trk receptors, and hâve a suitable PK profile to enable once daily dosing.

The compounds of the présent 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 présent invention may be usefül to treat any physiological pain such as inflammatory pain, nociceptive pain, neuropathie pain, acute pain, chronic pain, musculoskeletal 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 15 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 normaliy due to nervous System injury due to maladaptation of the afferent fibres (Woolf & Salter 2000 Science 288:1765-1768). Clinical pain is présent when discomfort and abnormal sensitivity feature among the patients 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 (hyperatgesia); 3) pain is produced by normaliy 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, neuropathie pain among others. It should be noted that some types of pain hâve multiple aetiologies and thus can be classified in more than one area, e.g. Back pain, Cancer pain hâve both nociceptive and neuropathie 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 activâtes 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 mfarction, acute pancreatitis, and rénal 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 dises 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 présent invention can potentially be used to treat neuropathie pain and the symptoms of neuropathie pain including hyperalgesia, allodynia and ongoing pain. Neuropathie pain is defined as pain initiated or caused by a primary lésion or dysfunction in the nervous system (IASP définition). Nerve damage can be caused by trauma and disease and thus the term 'neuropathie 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. Neuropathie pain is pathological as it has no protective rôle. It is often présent well after the original cause has dissipated, commonly lasting for years, significantly decreasing a patients quality of life (Woolf and Mannion 1999 Lancet 353:1959-1964). The symptoms of neuropathie pain are difficult to treat, as they are often heterogeneous even between patients with the same disease (Woolf & Decosterd 1999 Pain Supp. 6: S141-S147; Woolf and Mannion 1999 Lancet 353:1959-1964). 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 28Θ: 1765-1768). Clinical pain is présent when discomfort and abnormal sensitivity feature among the patient’s symptoms. Patients tend to be quite heterogeneous and may présent 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 (hyperatgesia); 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 neuropathie pain may hâve 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 neuropathie 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 épithélial 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, anémia, bladder cancer, bone cancer, brain cancer, breast cancer, carcinoid tumour s, cervical cancer, chemotherapy, colon cancer, cytopenia,, endométrial cancer, esophageal cancer, gastric cancer, head cancer, neck cancer, hepatobiliary cancer, kidney cancer, leukemia, liver cancer, lung cancer, lymphoma, Hodgkin's disease, lymphoma, nonHodgkin's, nervous System tumours, oral cancer, ovarian cancer, pancreatic cancer, prostate cancer, rectal cancer, skin cancer, stomach cancer, testicular cancer, thyroid cancer, uréthral 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 viscéral pain, e.g. viscéral pain which arises from pancreatic cancer and/or métastasés 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 35 pain involving both inflammatory pain and neuropathie 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 resuit 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 10 diseases, non-immune inflammatory disease, synovitis, villonodular synovitis, arthralgias, ankylosing spondylitis, spondyloarthritis, spondyloarthropathy, goût, 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 15 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 présent 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 20 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:

- Musculo-skeletal 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 lésion 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;

- Viscéral 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 viscéral pain and non-digestive viscéral 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, iteitis, and ulcerative colitis, which ail regularly produce viscéral pain. Other types of viscéral pain include the pain assocîated with dysménorrhée, 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 régional syndrome, HIV-related neuropathie pain, post-operative induced neuropathie pain, post-stroke pain, spinal cord injury pain, traumatic nerve injury pain, diabetic peripheral neuropathy, moderate / severe interstitiel 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, neuropathie pain (including painful diabetic neuropathy), pain assocîated with postherpetic neuralgia, post-operative pain, referred pain, trigeminal neuralgia, viscéral pain (including interstitial cystitis and IBS) and pain assocîated 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:

(l) or a pharmaceutically acceptable sait thereof, wherein

R^{1 * * *} is

H, or

Cî.5 alkyl optionally substituted by up to 3 substituants independently selected from OH, CON(R⁵R⁶),

SO_ZR⁷, SR⁷, OR⁷, CH2OH, CO2R⁵, SONR⁷R⁷, NR⁷SO2R^s, CN, N0₂ 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(R⁵R⁶), SO2R⁷, OR⁷, CH2OH, CO₂R⁵, SONR⁷R⁷, NR⁷S02R^s, CN, NO2 and R⁰;

R² is H or methyl;

R³ is H, NH_a or NH(Ci.₃ alkyl optionally substituted with up to 3 substitueras independently selected from OH and 0(0,.3 alkyl));

R¹⁰' is H, OH, methyl, cyclopropyl, methoxy, ethyl, ethoxy or CN,

X is a bond, O, (CH-R⁴)n, NR¹⁰⁴, OCHZ or CH_ZO;

R⁴ is independently H, CH₃, CH_aOH, CH₂OCH_3| OH, NH_Z1 NHCH₃, N(CH₃)₂, CH₂NH₂, CH₂NHCH₃,or CH_ZN(CH₃)₂;

R¹⁰⁴ is H, C1.3 alkyl or a C4.6 saturated carbocycle, each of which is optionally substituted by up to 3 substituents independently selected from C,.₃ alkyl, CH_ZOH 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 8-14membered bicyclic System, which ring System may be saturated or partially or fully unsaturated, wherein the heterocyclic ring System may hâve 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^SR⁶, SOaR⁷, SR⁷, CM alkyl optionally substituted by up to 3 OH and/or Ο_υ3 alkoxy groups, C₃-e cycloalkyl optionally substituted by up to 3 OH and/or C1.3 alkoxy groups, C1.3 alkyl substituted by up to 3 halogen, OH, O(C_b3 alkyl), O(C₃.₆ cycloalkyl optionally substituted by up to 3 OH and/or alkoxy groups, O(Ci_₃ alkyl substituted by up to 3 halogen), O(Ci.₃ alkyl substituted by up to 3 OH and/or Ci.₃ alkoxy groups), NR⁵SO2R⁷, =0, R®, C(O)R^a, NOZ, NR⁵COaR⁷, NR⁵COR⁷,OR^e, S(O)R⁷, and CHZR⁸;

R⁵ and R⁶ are each independently

H, or

Ci.5 alkyl optionally substituted by up to 3 substituents independently selected from OH, CONR⁷R⁷, SO2R⁷, OR⁷, CHaOH, CO_ZR⁷, SONR⁷R⁷, NR⁷SO2R⁷, CN, NOZ 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(R⁷R⁷), SOzR⁷, COzR⁷, SONR⁷R⁷, NR⁷SOzR⁷, CN, NOZ, halo, NR⁷R⁷,SR⁷,C_M alkyl optionally substituted by up to 3 OH and/or Ο_υ3 alkoxy groups, C₃.₆ cycloalkyl optionally substituted by up to 3 OH and/or C,.₃ alkoxy groups, C_v3 alkyl substituted by 1 to 3 halogen, O(C₃^ cycloalkyl optionally substituted by up to 3 OH and/or 0,.3 alkoxy groupa, 0(0,.₃ alkyl substituted by up to 3 halogen, O(Ci.₃ alkyl substituted by up to 3 OH and/or C,.₃ alkoxy, NR⁷SO2R⁷,=O,NO2,NR⁷CO2R⁷, and S(O)R⁷ or R⁵ and R^e 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, 0,'S, which ring is optionally substituted by Ci.3 alkoxy and ! or C,.₃ alkyl;

R⁷ is H, Ci-₅ alkyl or C_r5 alkoxy, which C1.5 alkyl or C,._s 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 carbocyclic or heterocyclic System, or an Θ14-membered bicyclic System, which ring System may be saturated or partially or fully unsaturated, wherein the heterocyclic ring System may hâve 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, NR⁵R⁶, SO2R⁷, SR⁷, C,.4 alkyl optionally substituted by up to 3 OH and/or Ci_₃ alkoxy groups, C₃.₆ cycloalkyl optionally substituted by up to 3 OH and/or C,.₃ alkoxy groupe, Cv₃ alkyl substituted by 1 to 3 halogen, OH, 0(0,.3 alkyl), O(C_{3 6} cycloalkyl optionally substituted by up to 3 OH and/or C-|.₃ alkoxy groups, O(C,.₃ alkyl substituted by up to 3 halogen, O(C,.₃ alkyl substituted by up to 3 OH and/or Ci.₃ alkoxy, NR⁵SO2R⁷, =0, NO2, NR⁷COR⁷,NR⁵CO2R⁷, and S(O)R⁷;

R⁹ is a is a ring System which is a 3-7 membered monocyclic carbocyclic or heterocyclic System, or an 814-membered bicyclic System, which ring System may be saturated or partially or fully unsaturated, wherein the heterocyclic ring System may hâve 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 independehtly selected from, where possible halo, CN, NR⁷R⁷, SO2R⁷, SR⁷, C,.4 alkyl optionally substituted by up to 3 OH and/or 0,.₃ alkoxy groups, C₃._e cycloalkyl optionally substituted by up to 3 OH and/or C,.₃ alkoxy groups, C,.₃ alkyl substituted by 1 to 3 halogen, OH, O(C,.₃ alkyl), O(C₃₆ cycloalkyl optionally substituted by up to 3 OH and/or C1.3 alkoxy groups, O(Ci.e alkyl substituted by up to 3 halogen, O(C,.₃ alkyl substituted by up to 3 OH and/or C,.₃ alkoxy, NR⁷SO2R⁷, =O, NO2, NR⁷CO_ZR⁷, NR⁷COR⁷,and S(O)R⁷;

wherein each CH moiety can be replaced by a CF moiety.

Embodiment 2 of the invention is a compound or sait according to embodiment 1 wherein R¹ is H, C,.₅ alkyl optionally substituted by up to 2 OH, or R’ is C_b5 alkyl substituted by CONH₂, CONHCH₃, CON(CH₃)₂, CO₂H, CO₂CH₃₁ OCH₃₁ SCH₃, SO₂CH₃, or R¹ 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 sait according to any one of embodiments 1 or 2 wherein R¹ 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 sait according to any one of embodiments 1 to 3 wherein R² is H,

Embodiemt 5 of the invention is a compound or sait according to any one of embodiments 1 to 4 wherein R³ is H or NH₂.

Embodiment 6 of the invention is a compound or sait according to any one of embodiments 1 to 5 wherein R³ is NH_a.

Embodiment 7 of the invention is a compound or sait according to any one of embodiments 1 to 5 wherein R³ is H.

Embodiment 8 of the invention is a compound or sait according to any one of embodiments 1 to 7 wherein R¹⁰¹ is H.

Embodiment 9 of the invention is a compound or sait according to any one of embodiments 1 to 7 wherein R¹⁰¹ is OH,

Embodiment 10 of the invention is a compound or sait according to any one of embodiments 1 to 9 wherein X is a bond, O, CH₂, C₂H₄, CH{CH₃)CH₂, CH(CH₃), CH(CH₂OH), CH₂O, CH(NH₂), CH(OH) or NH.

Embodiment 11 of the invention is a compound or sait according to any one of embodiments 1 to 10 wherein X is CH₂.

Embodiment 12 of the invention is a compound or sait 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 sait according to any one of embodiments 1 to 11 wherein R¹⁰²is 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, phenylpyrazoiyi, phenylpyrrolyl, phenyltetrazolyl, phthalazinyl, purinyl, pyraztnyl, pyrazolyl, pyrazolopyridinyl, pyrazolopyrimidinyl, pyrazolotriazinyl, pyridinyl, pyridazinyl, pyridinyltriazolyl, pyrimidinyl, pyrroloimidazolyl, pyrrolopyrazinyl, pyrrolopyrimidinyl, pyrrolopyridinyl, pyrrolyl, quinolinyl, quinazolyl, quinoxalinyl, tetrahydrobenzisoxazolyl, tetrahydrocyclopentapyrazolyl, tetrahydrotriazolopyridinyl, tetrazolopyridazinyl, tetrazolopyridinyl, thiazolyi, thiazolopyridinyl, thiazolopyrimidinyl, thîenylpyrazolyl, thienopyridinyj, triazolopyridinyl and triazolyl,

Embodiment 14 of the invention is a compound or sait according to embodiment 13 where the optional substituents are independently selected from, where possible halo, methyl, ethyl, propyi, isopropyl, cyclopropyl, CF_a, CHF₂, CH₂F, CH₂OCH₃, CN, CH₂OH, OCH₃₁ =0, NH₂, SCH_3i SO₂CH₃, phenoxy, fluorophenoxy, benzyl, SCF₃, OCF₃, SO₂CF₃, NHSO₂CH₃, NHSO₂CF₃, C(O)CF₃, C(O)CH₃, benzoyl, azetidinylmethyl, fluoroazetidinylmethyl and morpholinomethyl.

Embodiment 15 of the invention is a compound or sait according to any one of embodiments 1 to 11,13 or 14, wherein R¹⁰²is 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, propyi, isopropyl, cyclopropyl, CF₃, CHF₂, CH₂F, CH₂OCH_3i CN, CH₂OH, OCH_3i =0, NH₂₁ SCH₃, SO₂CH₃, phenoxy, fluorophenoxy, benzyl, SCF₃, OCF₃, SO₂CF₃, NHSO₂CH₃, NHSO₂CF₃₁ C(O)CF₃, C(O)CH₃, benzoyl, azetidinylmethyl, fluoroazetidinylmethyl and/or morpholinomethyl.

Embodiment 16 of the invention is a compound or sait according to any one of embodiments 1 to 15 with R⁵ and R⁶ groups présent, wherein R⁵ and R⁶ are each independently H, C^ alkyl optionally substituted by Ci_3 alkoxy, C3.s cycloalkyl, propellanyl, oxetanyl, tetrahydrofuranyi 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 Ci_3 alkoxy and / or Ci.₃ alkyl.

Embodiment 17 of the invention is a compound according to embodiment 1 of the Formula IA:

(IA)

or a pharmaceutically acceptable sait thereof, wherein

R³ is H orNH₂;

R¹ is C₂.₄ alkyl optionally substituted by 1 or 2 OH groups;

R¹⁰¹ 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, Ci-4 alkyl and C₃.₅ cycloalkyl.

Embodiment 18 of the invention is a compound or sait according to embodiment 17 wherein R¹⁰¹ is H.

Embodiment 19 of the invention is a compound or sait according to embodiment 18 wherein

R¹ ist-butyl, hydroxy-t-butyl or 1-hydroxyprop-2-yl;

and R¹⁰² is 4-trifluromethylphenyl, 4-chtorophenyl, 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_l1-dimethylethyl)-7H-pyrrolo[2₁3-d]pyrimidin-5-yJ]carbonyl}pyridin-3-yl)-2-[4(trifluoromethyl)phenyl]acetamide;

N-(5-{[2-amino-7-(2-hydroxy-1_l1-dimethylethyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]carbonyl}pyridin-3yl)-2-(4-chlorophenyl)acetamide;

N-(5-{[2-amino-7-(2-hydroxy-1,1-dimethylethyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]carbonyl}pyridin-3y l)-2- (5-f I uoro pyrid i n-2-y I) acetam id e ;

N-(5-{[2-amino-7-(2-hydroxy-1,1-dimethylethyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]carbonyl}pyridin-3yl)-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-3yl)-2-(3-cyclopropyl-1 H-pyrazol-1 -yl)acetamide;

N-{5-[(2-amÎno-7-tert-butyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)carbonyl]pyridin-3-yl}-2-(4-cyclopropyl· 1H-1,2,3-triazoi-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(trif luoromethy I)-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{trifluorom ethyl)-1 H-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-chloropyridin2-yl)acetamide;

N-(5-{[2-Amino-7-(2-hydroxy-1,1-dimethylethyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]carbonyl}pyridin-3yl)-2-(5-chloropyridin-2-yl)acetamîde;

N-(5-[(7-tert-butyl-7H-pyrrolo[2_l3-d]pyrimidin-5-yl)carbonyl]pyridin-3-yl}-2-[4-(trifluoromethyl)-1H1,2,3-triazol-1-yljacetamide;

2-(4-chlorophenyl)-N-[5-({7-[(1S)-2-hydroxy-1-methylethyl]-7H-pyrrolo[2,3-d]pyrimidin-5yl}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)-1Hpyrazo!-1 -yljacetamide;

N-[5-({7-[{1S)-2-Hydroxy-1-methylethyl]-7H-pyrrolo[2,3-d]pyrimtdin-5-yl}carbonyl)pyridin-3-yl}-2-(4(trifluoromethyl)phenyljacetamide;

N-[5-({7-[(1R)-2-hydroxy-1-methylethyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}carbonyl)pyridin-3-yl]-2-[4(trifluoromethyl)phenyljacetamide;

2-(4-chlorophenyl)-N-[5-({7-[(1R)-2-hydroxy-1-methylethyl]-7H-pyrrolo[2,3-d]pyrimidin-5yl}carbonyi)pyridin-3-yl]acetamide;

N-(54[7-(2-hydroxy-1,1-dÎmethylethy!)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]carbonyl}pyridin-3-yl)-2-[5methyl-3-(trifluoromethyl)-1 H-pyrazol-1 -yljacetamide;

2-(5-chloropyridin-2-yl)-N-(5-{[7-(2-hydroxy-1,1-dimethylethyl)-7H-pyrro!o[2,3-dJpyrimidin-5yl]carbonyl}pyridin-3-yl)acetamide;

N-(5-{[2-Amino-7-(2-hydroxy-1-methylethyl)-7H-pyrrolo[2,3-d]pyrimidin-5-ylJcarbonyl}pyridin-3-yl)2- (4-ch lorophenyl) acetamide;

N-(5-{[2-amino-7-(2-hydroxy-1-methylethyl)-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-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]carbonyl}pyridin-3-yl)-2[4-(trifluoromethyl)phenyl]acetamide;

N-(5-{[2-Amino-7-(2-hydroxy-1,1-dimethylethyl)-7H-pyrrolo[2,3-d]pyrimidÎn-5-yl]carbonyl}pyridin-3yl)-2-[5-methyl-3-(trifluoromethyl)-1 H-pyrazol-1-yljacetamide;

and

N-{5-[(7-tert-butyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)carbonyl]pyridin-3-yl}-2-(4-cyclopropyl-1H-1,2,3triazol-1 -yljacetamide;

or a pharmaceutically acceptable sait thereof.

Embodîment 21 of the invention is a pharmaceutical composition comprising a compound of the formula (I) or a pharmaceutically acceptable sait 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 sait thereof, as defined in any one of embodiments 1 to 20, for use as a médicament.

Embodiment 23 of the invention is a compound of formula (I) or a pharmaceutically acceptable sait 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 sait 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 sait or composition thereof, as defined in any one of embodiments 1 to 20, for the manufacture of a médicament 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 sait or composition thereof, as defined in any one of embodiments 1 to 20, for the manufacture of a médicament 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 sait 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 sait thereof, as defined in any one of embodiments 1 to 20.

Embodiment 29 of the invention is compound or sait 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 safts of formula (I) where R¹ 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 R¹, R², R³, R¹⁰¹, X and R¹⁰² hâve a value as exemplified in the Examples below;

A compound selected from any one of the Examples below or a pharmaceutically acceptable sait 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, pafmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, saccharate, stéarate, succinate, tartrate, tosylate and trifluoroacetate salts.

Suitable base addition salts are formed from bases which form non-toxic saits. Examples include the aluminium, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnésium, meglumine, olamine, potassium, sodium, tromethamine and zinc salts.

For a review on suitable salts, see Handbook of Pharmaceutical Salts: Properties, Sélection, 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, géométrie 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 présent invention are ail stereoisomers, géométrie 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:

HO

O.

NH

OH

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 résolution of the racemate (or the racemate of a sait or other dérivative) 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% 20 isopropanol, typically from 2 to 20%, and from 0 to 5% of an alkyfamine,,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 présent invention includes ail 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 hydrogen, such as ²H and ^aH, carbon, such as ¹¹C, ¹³C and ¹⁴C, chlorine, such as ³⁶CI, fluorine, such as ¹⁸F, iodine, such as ¹²³l and ¹²⁵l, nitrogen, such as ¹³N and ^1SN, oxygen, such as ¹⁵O, ¹⁷O and ^1BO, phosphorus, such as ³²P, and sulphur, such as ^3SS.

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. ^aH, and carbon-14, i.e. ¹⁴C, are particularly useful for this purpose in view ôf their ease of incorporation and ready means of détection.

Substitution with heavier isotopes such as deuterium, i.e. ²H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in v/vo.half-life or reduced dosage requirements, and hence may be preferred in some circumstances.

Substitution with positron emitting isotopes, such as ¹¹C, ^1BF, ¹⁵0 and ¹³N, 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 10 Examples and Préparations using an appropriate isotopically-labelled reagente in place of the nonlabelled reagent previously employed.

The routes below, including those mentioned in the Examples and Préparations, illustrate methods of synthesising compounds of formula (I). The skilled person will appreciate that the compounds of the 15 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); Deslgning Organic Synthesis by 20 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 substituants are as defined above with reference to the compounds of formula (I) above. R¹⁰¹¹ is the same as R¹⁰¹ or a suitably protected version thereof.

Scheme 1 illustrâtes the préparation of the intermediates of general formula (Int 1), where they can be made from amine (Int3) where, in those cases where R¹ contains an alcohol, a protected form of R¹ 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 3^,d édition T.W. Greene and P.G. Wuts, Wiley-lnterscience, 1999). Common oxygen protecting groups suitable for use herein include tert35 butyldimethylsilyl (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

C!

Int 4

Wherein R 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 arrtine of general formula (Int 3) 5 and the aldéhyde (Int 4) together, preferably in éthanol at a température from room température 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 hydrogénation using a suitable catalyst such as palladium on carbon and an additive such as ammonia in 10 a suitable solvent such as éthanol. Alternative^ 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. 8-13

In those cases where R¹ contains one or more alcohols, a protected form of R¹ with a suitable hydroxyl protecting group (PG) can be used. Any suitabie oxygen protecting group protection/deprotection system 15 may be used (as described in “Protecting Groups in Organic Synthesis 3^rt) édition 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 commerciaiiy available or will be well-known to those skilled in the art with reference to literature precedents and/or the préparations herein.

Compounds of formula (Int 1) can be prepared from compounds of formula (Int 7) as illustrated in Scheme 2.

Scheme 2

R³⁰¹

tnt 6

Br

NH I,

Me

Int 7 Int 3

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 température from room température 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 température from room température 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 préparations herein.

Compounds of formula (Int 8) can be prepared from compounds of formula (Int 1) as illustrated in

Scheme 3.

Scheme 3

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. 14-19, 40, 63.

Compounds of formula (Int 8) can also be prepared from compounds of formula (Int 9) as illustrated in

Scheme 4.

Scheme 4

Wherein R³⁰¹ 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 césium carbonate in DMF at room température.

In those cases where R¹ contains one or more alcohols, a protected form of R¹ can be used as described in Scheme 1.

E.g. as exemplified in Préparation 20.

Compounds of formula (Int 12) can be prepared from compounds of formula (Int 11) as iliustrated in Scheme 5.

Scheme 5

Wherein R³⁰¹ 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 protécting group (PG), where the preferred protécting groups are TBDMS, TBS and THP.

Typical conditions emptoyed 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 alkylatîng 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, 21,41,53

Réduction 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 dîisobutylalumnium hydride in a suitable solvent such as éthanol or THF. Alternative^ 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

Wherein R³⁰¹ is H or halogen, typically chlorine; and X, 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 butyilithium or isopropylmagnesium chloride) and reacting with the Weinreb amide intermediate (Int 15) at a température from -78°C up to room température.

e.g. as exemplified in Preps. 26, 27, 46, 47, 56, 58, 64

Alternatively compounds of formula (Int 15) may be converted into aldéhydes of formula (Int 17) by réduction of the Weinreb amide mtermediate using a suitable reducing agent. Preferred conditions comprise diisopropylaluminium hydride in THF at -78°C, exemplified in Préparation 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 invoive using an oxidising reagent such as the DessMartin reagent in DCM or 2-iodoxybenzoic acid in a suitable solvent such as ethyl acetate at a température from room température to reflux température.

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 préparations herein.

Corresponding intermediates and compounds of formula (I) where R¹⁰¹ 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 R¹⁰¹¹ 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.

Scheme 7

Wherein R³⁰¹ is H or halogen, typically chlorine;

Compounds of formula (Int 20) may be prepared from compounds of formulae (Int 8) and (Int 19) 5 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 température from -78°C up to room température 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 préparations herein.

e.g. as exemplified in Prep. 23

Compounds of formula (Int 21) can be prepared from compounds of formula (Int 16) as illustrated in Scheme 8.

Scheme 8

(Int 22)

Wherein X; is bromine or iodine;

Compounds of formula (Int 21) may be prepared from compounds of formula (Int 16) through direct amination of the halide using standard literature conditions. For example; amine (Int 21) is typically prepared using ammonia with a suitable copper catalyst such as copper (II) sulphate or copper (l) oxide in suitable solvent such as NMP in a sealed vessel at a température between room température and 140°C. Where R is Cl this is also displaced by ammonia under the same conditions to provide amines of general formula (Int 21) where R³ is NH_a.

e.g. as exemplified in Preps. 31,32, 36, 48, 49, 57, 59, 65

De-protection of a hydroxyl protecting group on R¹ (if présent) 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 21) can be used directly.

Alternative^ compounds of general formula (Int 21) where R3 is H, can be made by converting intermediates of general formula (Int 16) where R³⁰¹ is H, via compounds (Int 22). Typical conditions employed involve stirring the halide of general formula (Int 16), where R³⁰¹ is H, with benzophenone imine, a suitable base such as potassium phosphate, a suitable ligand such as 2-di-tert-butylphosphino2',4',6'-triisopropylbiphenyl and a suitable catalyst such as tris(dibenzylideneacetone)dipalladium in an organic solvent such as 1,2-dimethoxyethane at a température from room température up to the boiling point of the solvent.

Intermediate (Int 22) can be deprotected to furnish the amines of general formula (Int 21). 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 R³⁰¹ Is Cl) as illustrated in Scheme 9.

Scheme 9

(Int 22) Where R³⁰¹ is Cl)

(Int 20)

Compounds of formula (Int 20) may be prepared from compounds of formula (Int 22) where R³⁰¹ is chloro through an amination reaction as decribed above. Wherein the chlorine is is reacted with 2,4dimethoxybenzylamine and the amine can be deprotected as previously.

Typical conditions employed involve stirring the chloro-pyrimidine of general formula (Int 22), where R³⁰¹ is Cl, with 2,4-dimethoxybenzylamine and a suitable additive such as 4-dimethylaminopyridine in a suitable solvent such as 1,4 dioxane at a température from room température up to reflux température.

e.g. as exemplified in Prep. 51

Compounds of formula (I) can be prepared from compounds of formula (Int 21) and (Int 23) as illustrated in Scheme 10.

Scheme 10

Compounds of formula (I) may be prepared from compounds of formula (Int 21) 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 21) 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 température from room température 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 équivalent of the acid (Int 23) and at least one équivalent 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 R¹ contains a suitable hydroxyl protecting group in intermediate (Int 21), removal of the protecting group (PG) can be done in situ or as an additional step, adding a suitable adid 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 préparations herein.

Compounds of formula (I) where R³ is NH₂ can be prepared from compounds of formula (Int 20) as illustrated in Scheme 11.

Scheme 11

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 5 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 21).

Compounds of formula (I) where X is NR^1W can be prepared from compounds of formula (Int 21) as illustrated in Scheme 13.

Scheme 13

R (Int 21) ,ιοζ (Int 25)

Compounds of formula (I) where X is NR¹⁰⁴ may be prepared from compounçls of formula (Int 21), (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.

Scheme 14

(i)

Compounds of formula (I) where a primary alcohol exists may be oxidised to the aldéhyde using Dess Martin periodinane in DCM at room température followed by a reductive amination with a suitable amine HNR₂ using sodium triacetoxyborohydride and acetic acid in DCM.

¹⁵

Compounds of formula (Int 26) can be prepared from compounds of formula (Int 27) as illustrated in Scheme 15.

Scheme 15

Wherein R¹⁰³ is Me or CH₂OH;

Compounds of formula (Int 26) can be prepared from compounds of formula (Int 27) through conversion of an alcoho) into a suitable leaving group followed by cyclisation under basic conditions. Preferred conditions comprise tosyl chloride with π-butyl lithium in THF.

According to a further embodiment the présent 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 sait may precipitate from solution and be collected by filtration or may be recovered by évaporation of the solvent. The degree of ionisation in the sait 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 ingrédient other than the compounds and salts of the invention. The 20 choice of excipient will to a large extent dépend 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 sait or solvaté 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 2009/012242 or WO2010/079443;

• an alternative sodium channel modulator, such as a Nav1.3 modulator (e.g. as disclosed in

W02008/118758); or a Nav1.8 modulator (e.g. as disclosed in WO 2008/135826, more particularly N[6-Amino-5-(2-chloro-5-methoxyphenyl)pyridin-2-yl]-1-methyl-1H-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-(trifiuoromethyl)pyridine-2-yl]oxy}benzylidene)piperidene-1-carboxamide);

• an opioid analgésie, e.g. morphine, heroin, hydromorphone, oxymorphone, levorphanol, levallorphan, methadone, meperidine, fentanyl, cocaïne, codeine, dihydrocodéine, oxycodone, hydrocodone, propoxyphene, nalmefene, nalorphine, naloxone, naltrexone, buprénorphine, butorphanol, nalbuphine or pentazocine;

• a nonsteroidal antiinflammatory drug (NSAID), e.g. aspirin, diclofenac, diflusinal, etodofac, fenbufen, fenoprofen, flufenisal, flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, meelofenamie acid, mefenamic acid, meloxicam, nabumetone, naproxen, nimesulide, nitroflurbiproten, olsalazine, oxaprozin, phenylbutazone, piroxicam, sulfasalazine, sulindac, tolmetin or zomepirac;

• a barbiturate sédative, e.g. amobarbital, aprobarbital, butabarbital, butabital, mephobarbital, metharbital, methohexital, pentobarbital, phenobartital, secobarbital, talbutal, theamylal or thiopental;

• a benzodiazépine having a sédative action, e.g. chlordiazepoxide, clorazepate, diazepam, flurazepam, lorazépam, oxazepam, temazepam or triazolam;

• an Ht antagonist having a sédative action, e.g. diphenhydramine, pyrilamine, promethazine, chlorpheniramine or chlorcyclizine;

• a sédative 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 métabolite dextrorphan ((+)-3-hydroxy-N-methylmorphinan), ketamine, mëmantine, 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)-4hydroxy-1 -pipe ridin yl]-1 -hydroxyethyl-3,4-dihydro-2(1 H)-quinolinone;

• an alpha-adrenergic, e.g. doxazosin, tamsulosin, clonidine, guanfacine, dexmetatomidine, modafinil, or 4-amino-6,7-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. (ctR,9R)-7-[3,5- bis(trifluoromethyl)benzyl]-8,9,10,11-tetrahydro-9-methyl-5-(4-methylphenyl)-7H-[1,4]diazocino[2,1g][1,7]-naphthyridine-6-13-dione (TAK-637), 5-(((2R,3S)-2-[(1 R)-1 -[3,5bis(trifluoromethyl)phenyl]ethoxy-3-(4-fluorophenyl)-4-morpholinyl]-methyl]-1,2-dihydro-3H-1,2,4triazol-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 C0X-2 sélective inhibitor, e.g. celecoxib, rofecoxib, parecoxib, valdecoxib, deracoxib, etoricoxib, or lumiracoxib;

• a coal-tar analgésie, in particular paracétamol;

• a neuroleptic such as droperidol, chlorpromazine, haloperidol, perphenazine, thioridazine, mesoridazine, trifluoperazine, fluphenazine, clozapine, olanzapine, rispéridone, 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_1B/id agonist such as eletriptan, sumatriptan, naratriptan, zolmitriptan or rizatriptan;

· a 5-HTaA receptor antagonist such as R(+)-alpha-(2,3-dimethoxy-phenyl)-1 -[2-(4-fluorophenylethyl)]-4piperidinemethanol (MDL-100907);

• a 5-HT₃ antagonist, such as ondansetron • a cholinergic (nicotinic) analgésie, such as isproniciine (TC-1734), (E)-N-methyl-4-(3-pyridinyl)-3buten-1-amine (RJR-2403), (R)-5-(2-azetidinylmethoxy)-2-chloropyridine (ABT-594) or nicotine;

· T ramadol®;

• 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)-2,3,6,7,12,12ahexahydro-2-methyl-6-(3,4-methylenedioxyphenyl)-pyrazino[2',T:6,1]-pyrido[3,4-b]indole-1,4-dione (IC-351 or tadalafil), 2-(2-βΙΐΊθχγ-5-(4-βΗιγΙ-ρίρβΓ3ΖΪη-1-νΙ-1-5υΙρΙιοπγΙ)-ρΐΊ6ηνΙ]-5-ΠΊθίΙΐγΙ-7-ρΓοργΙ’3Η- imidazo[5,1 -f][1,2,4]triazin-4-one (vardenafil), 5-(5-acetyl-2-butoxy-3-pyridinyl)-3-ethyl-2-(1 -ethyl-3azetidinyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one, 5-(5-acetyl-2-propoxy-3-pyridinyl)-3-ethyl-2(1-isopropyl-3-azetidinyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one, 5-[2-ethoxy-5-(4ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2-[2-methoxyethyl]-2,6-dihydro-7H-pyrazolo[4,3d]pyrimidin-7-one, 4-[(3-chloro-4-methoxybenzyl)amino]-2-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]-N30 (pyrimidin-2-ylmethyl)pyrimidine-5-carboxamide, 3-(1-methyl-7-oxo-3-propyl-6.7-dthydro-1 H· pyrazolo[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-amino methyl-bicyclo[3.2.0]hept-3-yl)-acetic acid, (3S,5R)-3-aminomethyl-5-methyl-heptanoic acid, (3S,5R) 3-amino-5-methy!-heptanoic acid, (3S,5R)-3-amino-5-methyl-octanoic acid, (2S,4S)-4-(3 chlorophenoxy)proline, (2S,4S)-4-(3-fluorobenzyl)-proline, [(1R,5R,6S)-6 (aminomethyl)bicyclo[3.2.0]hept-6-yl]acetic acid, 3-(1 -aminomethyl-cyclohexylmethyl)-4H [1 ÆAJoxadiazol-S-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)-340 amïno-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, sertrahne métabolite demethylsertraline, fluoxetine, norfiuoxetine (fluoxetine desmethyl métabolite), fluvoxamine, paroxetine, citalopram, citalopram métabolite desmethylcitalopram, escitalopram, dj-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 métabolite hydroxybuproprion, nomifensine and viloxazine (Vivalan®), especially a sélective noradrenaline reuptake inhibitor such as reboxetine, in particular (S.S)-reboxetine;

• a dual serotonin-noradrenaline reuptake inhibitor, such as venlafaxine, venlafaxine métabolite Odesmethylvenlafaxine, clomipramine, clomipramine métabolite 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, (2S₁5Z)-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-4hydroxy-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[[(1R,3S)-3-amino-4-hydroxy-1 -(5-thiazolyl)butyl]thio]-5-chlorobenzonitrile, N-[4-[2-(3chlorobenzylamino)ethyl]phenylJthiophene-2-carboxamidine, or guanidinoethyldisulfide;

• an acetylcholinesterase inhibitor such as donepezil;

• a prostaglandin E₂ subtype 4 (EP4) antagonist such as A/-[({2-[4-(2-ethyi-4,6-dimethyl-1 H-imidazo[4,5c]pyridin-1 -yl)phenyl]ethyl}amino)-carbonyl]-4-methylbenzenesulfonamide or 4-((1 S)-1 -({[5-chloro-2(3-fluorophenoxy)pyridin-3-yl]carbonyl}amino)ethyi]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)- cyciopentanecarboxylic acid (CP-105696), 5-[2-(2-Carboxyethyl)-3-[6-(4-methoxyphenyl)-5Ehexenyl]oxyphenoxy]-valeric acid (ONO-4057) or DPC-11870, a 5-lipoxygenase inhibitor, such as zileuton, 6-[(3-fluoro-5-[4-methoxy-3,4,5,6-tetrahydro-2H-pyran-4yl])phenoxy-methyl]-1-methyl-2-quinolone (ZD-2138), or 2,3,5-trimethyl-6-(3-pyridylmethyl),1,4benzoquinone (CV-6504).

Pharmaceutical compositions suitable for the delivery of compounds and salts of the présent invention and methods for their préparation will be readily apparent to those skilled in the art. Such compositions and methods for their préparation 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 précipitation, 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 élixirs, Such formulations may be employed as fillers in soft or hard capsules and typically comprise a carrier, for example, water, éthanol, 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, 11 (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, 35 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 dioxtde and talc. When présent, 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 magnésium stéarate, calcium stéarate, zinc stéarate, sodium stearyl fumarate, and mixtures of magnésium stéarate 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 ingrédients 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 spécifie 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 0-8247-6918-X).

The foregoing formulations for the various types of administration discussed above may be formulated to be immédiate 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 et al, Pharmaceutical Technology On-line, 25(2), 1-14 (2001). The use of chewing gum to achieve controlled release is described in WO 00/35298.

Parentéral Administration

The compounds and salts of the invention may be administered directly. into the blood stream, into muscle, or into an internai organ. Suitable means for parentéral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial,

intramuscular and subcutaneous. Suitable devices for parentéral administration include needle (including microneedle) injectors, needle-free injectors and infusion techniques.

Parentéral formulations are typically aqueous solutions which may contain excipients such as salts, 5 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 stérile non-aqueous solution or as a dried form to be used in conjunction with a suitable vehicle such as stérile, pyrogen-free water.

The préparation of parentéral formulations under stérile conditions, for example, by lyophilisation, may 10 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 préparation of parentéral solutions may be increased by the use of appropriate formulation techniques, such as the incorporation of solubilityenhancing agents.

Formulations for parentéral administration may be formulated to be immédiate 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, skrn patches, wafers, implants, sponges, fibres, bandages and microemulsions. Liposomes may also be used. Typical carriers include alcohol, water, minerai oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol and propylene glycol. Pénétration 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 aérosol 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-heptafiuoropropane. 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 5 compound(s) or salt(s) of the invention comprising, for example, éthanol, aqueous éthanol, 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 10 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 homogénisation, or spray drying.

Capsules (made, for example, from gelatin or HPMC), blisters and cartridges for use in an inhaler or 15 insufflator may be formulated to contain a powder mix of the compound or sait of the invention, a suitable powder base such as lactose or starch and a performance modifier such as /-leucine, mannitol, or magnésium stéarate. 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 pg to 20mg of the compound or sait of the invention per actuation and the actuation volume may vary from 1 pi to 1OOpl. A typical formulation may comprise a compound of formula (I) or sait thereof, propylene glycol, stérile water, éthanol and sodium chtoride. Alternative solvents which may be 25 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 immédiate 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 inhafers and aérosols, 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 pg of the compound or sait. The overall daily dose will typically be in the range 1 pg 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 5 known alternatives may be used as appropriate.

Ocular and Aurai Administration

The compounds and salts of the invention may also be administered directly to the eye or ear, typically in 10 the form of drops of a micronised suspension or solution in isotonie, pH-adjusted, stérile saline. Other formulations suitable for ocular and aurai administration include ointments, biodégradable (e.g. absorbable gel sponges, coliagen) 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, 15 hydroxypropylmethylcellulose, hydroxyethylcellulose, or methyl cellulose; or a heteropoiysaccharide 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 raacromolecular entities, such as cyclodextrin and suitable dérivatives thereof or polyethylene glycol-containing polymers, in order to improve their solubility, dissolution rate, taste-masking, bioavailabiiity and/or stability for use in any of the 25 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, 30 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 91/11172, WO 94/02518 and WO 98/55148.

For administration to human patients, the total daily dose of the compounds and salts of the invention is 35 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 determtne 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 sait 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 ingrédient) 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 présent invention also encompasses sustained release compositions.

The pharmaceutical composition may, for example, be in a form suitable for parentéral injection as a stérile solution, suspension or émulsion, 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 précisé dosages. The pharmaceutical composition will include a conventional pharmaceutical carrier or excipient and a compound according to the invention as an active ingrédient. In addition, it may include other médicinal or pharmaceutical agents, carriers, adjuvants, etc.

Exemplary parentéral administration forms include solutions or suspensions of active compounds in stérile 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 ingrédients 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 magnésium stéarate, sodium lauryl sulfate and talc are often useful for table.ting purposes. Solid compositions of a similar type may also be employed in soft and hard filied gelatin capsules. Preferred materials, therefor, include lactose or milk sugar and high molecular weight polyethylene glycols. When aqueous suspensions or élixirs 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 orsuspending agents, together with diluents such as water, éthanol, 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 bythe exigenciesofthetherapeuticsituation. It is especially advantageous to formulate parentéral compositions in dosage unit form for ease of administration and unitormity of dosage. Dosage unit form, as used herein, refers to physically discrète 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 spécification for the dosage unit forms of the invention are dictated by and directly dépendent on (a) the unique characteristics of the chemotherapeutic agent and the particular therapeutic or prophylactic effect to be achieved, and (b) the limitations inhérent in the artof compounding such an active compound for the treatment of sensitivity in individuats.

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 détectable therapeutic benefit to a patient may also be determined, as can the temporal requirements for administering each agent to provide a détectable 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 présent 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, spécifie 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 pharmacodynamie parameters, which may include clinical effects such as toxic effects and/or laboratory values. Thus, the présent invention encompasses intra-patient dose-escalation as determined by the skilled artisan. Determining appropriate dosages and régiments 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 discrète amount of the pharmaceutical composition comprising a predetermined amount of the active ingrédient. The amount of the active ingrédient is generally equal to the dosage of the active ingrédient 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 parentéral 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 stérile 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 priorto 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 ofthe active ingrédient, the pharmaceutically acceptable carrier, and any additional ingrédients 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 ingrédient.

In addition to the active ingrédient, a pharmaceutical composition ofthe invention mayfurther 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, parentéral 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. Parentéral administration thus includes, but is not limited to, administration of a pharmaceutical composition by injection ofthe 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, parentéral 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 parentéral administration comprise the active ingrédient combined with a pharmaceutically acceptable carrier, such as stérile water or stérile isotonie 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 parentéral administration include, but are not limited to, suspensions, solutions, émulsions in oily or aqueous vehicles, pastes, and implantable sustained-release or biodégradable formulations as discussed below. Such formulations may further comprise one or more additional ingrédients including, but not limited to, suspending, stabilizing, or dispersing agents. In one embodiment of a formulation for parentéral administration, the active ingrédient is provided in dry (i.e. powder or granular) form for reconstitution with a suitable vehicle (e.g. stérile pyrogen-free water) prior to parentéral administration of the reconstituted composition.

A composition of the présent 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. Biodégradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Many methods for the préparation 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 stérile 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 ingrédient, additional ingrédients such as the dispersing agents, wetting agents, or suspending agents described herein. Such stérile 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, isotonie 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 ingrédient in microcrystalline form, in a liposomal préparation, or as a component of a biodégradable polymer System. Compositions for sustained release or implantation may comprise pharmaceutically acceptable polymeric or hydrophobie materials such as an émulsion, an ion exchange resin, a sparingly soluble polymer, or a sparingiy soluble sait.

The précisé dosage administered of each active ingrédient 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 âge of the animal, and the route(s) of administration.

The following non-limiting Préparations and Examples Illustrate the préparation of compounds and salts of the présent invention.

GENERAL EXPERIMENTAL

The Préparations and Examples that follow illustrate the invention but do not limit the invention in any way. AU starting materials are available commercially or described in the literature. Ail températures 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). R₍ 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 Préparation or Example, the skilled person will appreciate that reaction times, number of équivalents of reagents and reaction températures may be modified for each spécifie reaction, and that it may nevertheless be necessary or désirable to employ different work-up or purification conditions. ·

The invention is illustrated by the following non-limiting examples in which the following abbreviations and définitions are used:

The Préparations and Examples that follow illustrate the invention but do not limit the invention in any way. Ail starting materials are available commercially or described in the literature. Ail température are in °C. Flash column chromatography was carrted 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 (ESl)

Aglient 110 HPLC 5 min (System 5)

Waters ZQ ESCI 8min LC-MS

Waters Alliance 2695 with ZQ2000 (ESl) 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 (ESl) 1.5 min LC-MS

WATERS ACQUITY UPLC/WATERS 3100 MSD/PL-ELS 2100 ICE ELSD

Where singleton compounds hâve been analysed by LCMS, there are six methods used. These are illustrated below.

System 1 minute LC-MS gradient and instrument conditions

A: 0.1 % formic acid in water

B: 0.1 % formic acid in acetonitrile

Column: C18 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 .SmUmin flow rate

UV: 210nm - 450nm DAD

Température: 50°C

System 2 minute LC-MS gradient and instrument conditions

A: 0.1 % formic acid in water

B: 0.1 % formic acid in acetonitrile

Column: C18 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

Température: 75°C

System 3 minute LC-MS gradient and instrument conditions

A: 0.1 % formic acid in water

B: 0.1 % formic acid in acetonitrile

Column: C18 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

Température; ambient

System 4 minute LC-MS gradient and instrument conditions

A: 0.1 % ammonium hydroxide in water

B: 0.1 % ammonium hydroxide in acetonitrile

Column: C18 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

Température: ambient

System 5 minute LC-MS gradient and instrument conditions

A: 0.0375 % TFA in water

B: 0.01875 % TFA in acetonitrile

Column: C18 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

Température: 50°C

System 6 minute LC-MS gradient and instrument conditions

A: 0.0375 % TFA in water

B: 0.01875 % TFA in acetonitrile

Column: C18 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

Température: 50°C

System 7 minute LC-MS gradient and instrument conditions

A: 10 mmol ammonium bicarbonate in water

B: acetonitrile

Column: C18 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

Température: 30°C

System 8 minute LC-MS gradient and instrument conditions

A: 0.05% formic acid in water

B: acetonitrile

Column: C18 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

Température: 50°C

System 9 minute LC-MS gradient and instrument conditions

A: 0.05% formic acid in water

B: acetonitrile

Column: C18 phase XBridge 50 x 4.6 mm with 5 micron particle size

Gradient: 90-10% A over 3 min, 1 min hold, 1 min re-equilibration, 1,2mL/min flow rate

UV: 200nm - 260nm DAD

Température: 25°C

System 10 minute LC-MS gradient and instrument conditions

A: 10 mM ammonium acetate in water

B: acetonitrile

Column: C18 phase Gemini NX 50 x 4.6 mm with 5 micron particle size

Gradient: 90-10% A over 3 min, 1 min hold, 1mtn re-equilibration, 1.2mL/min flow rate

UV: 200nm - 260nm DAD

Température: 25°C

Where slngleton compounds hâve 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 détection

Prep system 1 minute prep LC-MS gradient and instrument conditions

A: 0.1% formic acid in water

B; 0.1% formic acid in acetonitrile

Column: C18 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

Température: ambient

Prep system 2 minute prep LC-MS gradient and instrument conditions

A: 0.1% DEA in water

B: 0.1% DEA in acetonitrile

Column: C18 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

Température: ambient

Prep system 3 minute prep LC-MS gradient and instrument conditions

A: 0.05% ammonia in water

B: acetonitrile

Column: C18 phase Xbridge 50 x 19.0 mm

Gradient: 90-20% A over 7 min, 20 mUmin flow rate

Température: ambient

Prep system 4

8 minute prep LC-MS gradient and instrument conditions

A: 0.1% TFA in water

B: acetonitrile

Column: C18 phase Sepax BR 100 x 21.2 mm

Gradient: 96-33% A over 8 min, 30 mL/min flow rate

Température: ambient

Where it is stated that compounds were prepared in the manner described for an earlier Préparation or Example, the skilled person will appreciate that reaction times, number of équivalents of reagents and reaction températures may hâve been modified for each spécifie reaction, and that it may nevertheless be 15 necessary, or désirable, to employ different work-up or purification conditions. The invention is illustrated by the following non-limiting Examples in which the following abbreviations and définitions 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; Cs₂CO₃ is caesium carbonate; Cul is copper (I) iodide; Cu(OAc)₂is copper (II) acetate; δ - chemical shift; d - doublet; DAD - diode array detector; DCE - 1,2-dichloroethane

DCM - dichloromethane; DEA - diethylamine; DIBAL - Diisobutylaluminium hydride; DIPEAdiisopropylethylamine; DMAP - 4-dimethylaminopyridine; DME-dimethoxyethane; DMF -N,Ndimethylformamide; DMF-DMA- Ν,Ν-dimethylformamide-dimethylacetal; DMSO - dimethylsulphoxide DPPF - 1,1 ’-bis(diphenylphosphino)ferrocene; ELSD - evaporative light scattering detector; ESI 25 electrospray ionization; Et₂O - diethylether; EtOAc/EA - ethyl acetate; EtOH - éthanol; g - gram; HATU 2-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate; HBTU is O-benzotriazol-1-ylN.N.N'.N'-tetramethyluronium hexafluorophosphate; HCl is hydrochloric acid;HOBT is Nhydroxybenzotriazole hydrate; HPLC - high pressure liquid chromatography; !PA - isopropyl alcohol;

K₂CO₃ is potassium carbonate; KHSO₄ is potassium hydrogen sulphate; KOAc is potassium acetate; KOH 30 is potassium hydroxide; K₃PO₄ 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; MgSO₄ is magnésium sulphate; MnO₂ - manganèse dioxide; NaCIO₂ - sodium chlorite; NaH - sodium hydride; NaHCO₃- sodium hydrogencarbonate; Na₂CO₃ - sodium carbonate;

NaH₂PO₄- sodium phosphate; NaHSO₃ - sodium bisulphite; NaHSO₄ - sodium hydrogensulphate; NaOH sodium hydroxide; Na₂SO₄ - sodium sulphate; NH₃ - ammonia; NH₄CI - ammonium chloride; NMM - NMethylMorphotine; NMR - nuclear magnetic résonance; Pd/C - palladium on carbon; PdCI₂ - palladium dichloride; Pd₂(dba)₃is tris(dibenzylideneacetone)dipaliadium(0); Pd(PPh₃)₄ - palladium tetrakis(triphenylphosphine); Pd(OAc)₂ - palladium acetate; PTSA - para-toluenesulfonic acid; Prep 40 préparation; R_t - rétention 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 hâve been named using IUAPC, 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]pyridÎn-3-yl}-2-(5-fluoropyridin-2yljacetamide

2-(5-Fluoropyridin-2-yl)acetic acid (23.1 mg, 0.149 mmol) (see Préparation 92) was added to (5aminopyridin-3-yl)(7-tert-butyl-7/-/-pyrrolo[2,3-tf|pyrimidin-5-yl)methanone (40 mg, 0,135 mmol ) (see Préparation 31), 1-propylphosphonic acid cyclic anhydride (0.2 mL, 0.33Θ 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.

¹H NMR (400 MHz, DMSO) 6.' 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): R_t = 2.86 min; m/z 433 [M+Hf.

Examples 2 to 8 were prepared according to the method described above for Example 1, starting from (5aminopyridin-3-yl)(7-tert-butyl-7H-pyrro!o[2,3-d]pyrimidin-5-yl)methanone (see Préparation 31) and the appropriate acids.

Example	Name	Data
2	N-{5-[(7-tert-butyl-7H-pyrrolo[2,3-d]pyrimidin-5yl)carbonyl]pyridin-3-yl}-2-[4-(trifluoromethyl)-1 H-1,2,3-triazol1-yl]acetamide	LCMS (system 4): Rt = 3.26 min; m/z 473 [M+Hf
3	N45-[(7-tert-butyl-7H-pyrrolo[2,3-d]pyrimidin-5yl)carbonyl]pyridin-3-yl}-2-(3-cyclopropyl-1 H-pyrazol-1 yl)acetamide	LCMS (system 4): Rt = 3.04 min; m/z 444 [M+Hf
4	N-{5-[(7-tert-butyl-7H-pyrrolo[2,3-d]pyrimidin-5- y IJcarbon yl] pyrid in-3-yl}-2-(4-cyc lopropy I-1 H-1,2,3-triazol-l yljacetamide	LCMS (system 4): R( = 2.75 min; m/z 445 [M+Hf

5	N-{5-[(7-tert-butyl-7H-pyrrolo[2,3-d]pyrimidin-5yl)carbonyl]pyridin-3-yl}-2-[3-(trifluoromethyl)-1 H-pyrazol-1yljacetamide	LCMS (system 4): R, = 3.04 min; m/z 472 [M+H]+
6	N-{5-[(7-tert-butyl-7H-pyrrolo{2,3-d]pyrimidin-5- yl)carbonyl]pyridin-3-yl}-2-(5-chloropyridin-2-yl)acetamrde	LCMS (System 4): Rt = 2.92 min; m/z 449 [M+HJ*
7	N-{5-[(7-tert-butyl-7H-pyrrolo[2,3-d]pyrimidin-5yl)carbonyl]pyridin-3-yl}-2-(4-cyclopropyl-1 H-pyrazol-1 yljacetamide	LCMS (system 4): Rt = 2.96 min; m/z 443 [M+H]+
8	N-{5-[(7-tert-butyl-7H-pyrrolo[2,3-d]pyrimidin-5yl)carbonyl]pyridin-3-yl}-2-[4-(trifluoromethyl)-1 H-pyrazol-1yljacetamide	LC MS (system 4) : Flt = 3.00 min; m/z 472 [M+H]+

Example 9: N - [5-({7-[( 1 S)-2-Hydroxy-1 -methylethyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}carbonyl)pyndin-3-yl]2-[4-(trifluoromethyl)phenyl]acetamide

4-(Trifluoromethyl)phenylacetic acid (33.6 g, 165 mmol) was added to (5-aminopyridin-3-yl)(7-[(1S)-25 {[tert-butyl(dimethyl)silyl]oxy}-1-methylethyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}methanone (45.2 g, 110 mmol) (see Préparation 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 ail organic phases were 10 combined and dried over sodium sulfate then evaporated in vacuo.

The residue brown solid was dissolved in THF (400 mL) and aqueous HCl (200 mL, 2M) was added. The mixture was stirred at room température 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 ail organic phases were 15 combined and dried over sodium sulfate then evaporated in vacuo. The crude solid was recrystallised using ethyl acétate (150 mL) to afford the title compound as a white solid in 63% yield, 33.4 g.

’H NMR (400 MHz, DMSO) δ: 1.51 (d, 3H), 3.68-3.79 (m, 1H), 3.81-3.93 (m, 3H), 4.93-5.06 (m, 2H), 7.557.63 (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, 1 H); LCMS (System 1): Rt = 4.53 min; m/z 484 [M+Hf.

Example 10: N-[5-({7-[( 1 S)-2-Hydroxy-1 -methylethyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}carbonyl)pyridin-3yl]-2-(5-methyl-3-(trifluoromethyl)-1 H-pyrazol-1-yl]acetamide

10% Hydrochloric acid in 1,4- dioxane (0.2 mL) was added to Préparation 66 (59 mg, 0.098 mmol) in 5 THF (2 mL) and the mixture was stirred at room température for 18 hours. The mixture was evaporated in vacuo and triturated with pentane:diethyl ether (3:1, 1 mL) to afford the title compound as an off white solid in 86% yield, 41 mg.

LCMS (System 4): Rt = 2.85 min; m/z 488.2 [M+H]⁺.

Examples 11 to 16 were prepared according to the method described above for Example 10, starting 10 from the appropriate protected alcohol.

Example	Name	Data
11	2-(4-c hloroph e nyi)-N-[5-({7- [( 1 S)-2-hydroxy-1 -methylethyl]7H-pyrrolo[2,3-d]pyrimidin-5-yl}carbonyl)pyridin-3yljacetamide	LCMS (System 4): Rt = 2.89 min; m/z 450 [M+Hf
12	N-[5-({7-[( 1 S)-2-hydroxy-1 -methylethyl]-7H-pyrrolo[2,3d]pyrimidin-5-yl}carbonyl)pyridin-3-yl]-2-(3-(trifluoromethyl)1 H-pyrazol-1-yl]acetamide	LCMS (System 4): Rt = 2.88 min; m/z 474 [M+H]+
13	N-[5-({7-[( 1 S)-2-hydroxy-1 -methylethyl]-7H-pyrrolo[2,3d]pyrimidin-5-yl}carbonyl)pyridin-3-yl]-2-[4-(trifluoromethyl)1H-1,2,3-triazol-1 -yl]acetamide	LCMS (System 4): Rt = 2.68 min; m/z 475 [M+H]+
14	2- (5-ch!oropyridin-2-yl)-N-[5-({7-((1 S)-2-hydroxy-1 methylethyl]-7H-pyrroto[2,3-d]pyrimidin-5-yl}carbonyl)pyridin- 3- yl]acetamide	LCMS (system 4): Rt = 2.72 min; m/z 451 [M+Hf
15	2- (2H-benzotriazol-2-yl)-N-[5-({7-[(1S)-2-hydroxy-1methylethyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl)carbonyl)pyridin- 3- yl]acetamide	LCMS (System 4): Rt = 2.64 min; m/z 457 [M+H]+
16	2- {2,4-dif luorophenyl)-N-[5-({7-[( 1 S)-2-hydroxy-1 methylethyl]-7H-pyrrolo[213-d]pyrimidin-5-yl}carbonyl)pyridin- 3- yl]acetamide	LCMS (system 4) Rt = 2.74 gain; m/z 452 [M+H]+

Example 17: N-[5-({7-[( 1 R)-2-Hydroxy-1 -methylethyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}carbonyl)pyridin-3yl]-2-[5-methyl-3-(trifluoromethyl)-1 H-pyrazol-1 -yl]acetamide

(5-Methyl-3-trifluoromethyl-pyrazol-1-yl)acetic acid (46.8 mg, 0.225 mmol) was added to (R,S) (515 aminopyridin-3-yl){7-[(1 R)-1 -methyl-2-(tetrahydro-2H-pyran-2-yloxy)ethyl]-7H-pyrrolo[2,3-d]pyrimidin-5yljmethanone (66 mg, 0.173 mmol ) (see Préparation 36), 1-propylphosphonic acid cyclic anhydride (0.31 mL, 0.519 mmol ) and DIPEA (0.09mL, 0.606 mmol) in THF (5 mL). The mixture was heated at

reflux for 48 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 purified by column chromatography on silica gel (gradient of EtOAc: Hexane 85: 15 ) to afford the intermediate as an off white solid in 53% yield, 52 mg.

10% Hydrochloric acid in 1,4- dioxane (0.4 mL) was added to the intermediate (52 mg, 0.091 mmol) in THF (2 mL) and the mixture was stirred at room température for 1.5 hours. The mixture was evaporated in vacuo and triturated with pentane:diethyl ether (3:1, 1 mL) to afford the titl.e compound as an off white solid in 94% yield, 42 mg.

’H NMR (400 MHz, DMSO) δ: 1.49 (d, 3H), 2.32 (d, 3H), 3.56 (m, 1H), 5.00 (m, 1H), 5.20 (s, 2H), 6.56 (s, 1H), 8.45 (s, 1H), 8.54 (s, 1H), 8.79 (s, 1H), 9.02 (s, 2H), 9.48 (s, 1 H), 11.05 (s, 1H);

LCMS(system 4): R_t = 2.86 min; m/z 488 [M+Hf.

Examples 18 to 24 were prepared according to the method described above for Example 17, starting from (5-aminopyridin-3-yl){7-[(1R)-1-methyl-2-(tetrahydro-2H-pyran-2-yloxy)ethyl]-7H-pyrrolo[2,3d]pyrimidin-5-yl}methanone (see Préparation 36).

Example	Name	Data
18	2-(4-cyclopropyl-1 H-1,2,3-triazo I-1 -yl)-N-[5-({7-[(1 R)- 2-hydroxy-1-methylethyl]-7H-pyrrolo[2,3-d]pyrimidin- 5-yl)carbonyl)pyridin-3-yl]acetamide	LCMS (System 4): Rt = 2.21 min; m/z 474 [M+H]+
19	2-(5-fluoropyridin-2-yl)-N-[5-({7-[(1 R)-2-hydroxy-1 methy]ethyl]-7H-pyrrolo[2,3-d]pyrimidin-5yl}carbonyl)pyridin-3-yl]acetamide	LCMS (system 4): Rt = 2.24 min; m/z 435 [M+Hf
20	N-[5-({7-((1 R)-2-hydroxy-1 -methylethyl]-7Hpyrrolo[2,3-d]pyrimidin-5-yl}carbonyl)pyridin-3-yl]-2[4-(trifluoromethyl)phenyl]acetamide	LCMS (system 4): Rt = 2.98 min; m/z 484 [M+H]+
21	N-[5-({7-[{1 R)-2-hydroxy-1 -methylethyl]-7Hpyrrolo[2,3-d]pyrimidin-5-yl}carbonyl)pyridin-3-yl]-2[4-(trifluoromethyl)-1 H-1,2,3-triazol-1-yl]acetamide	LCMS (system 4): Rt = 2.70 min; m/z 475 [M+H]+
22	N-[5-({7-[(1 R)-2-hydroxy-1 -methylethyl]-7Hpyrrolo[2,3-d]pyrimidin-5-yl}carbonyl)pyridin-3-yl]-2[3-(trifluoromethyl)-1 H-pyrazol-1 -yljacetamide	LCMS (system 4): Rt = 2.80 min; m/z 474 [M+H]+
23	2-(5-chloropyridin-2-yl)-N-[5-({7-[(1 R)-2-hydroxy-1 methylethyl]-7H-pyrrolo[2,3-d]pyrimidin-5yl}carbonyl)pyridin-3-yl]acetamide	LCMS (system 4): R, = 2.49 min; m/z 451 [M+H]+
24	2-(4-chlorophenyl)-N-[5-({7-[(1 R)-2-hydroxy-1 methylethyl]-7H-pyrrolo[2,3-d]pyrimidin-5yl}carbonyl)pyridin-3-yl]acetamide	LCMS (System 2): Rt = 1.01 min; m/z 450 [M+Hf

Example 25: (R,S) 2-(4-Cyclopropy!-1 H-pyrazol-1-yl)-N-(5-{[7-(2-hydroxy-1-methylethyl)-7H-pyrrolo[2.3d]pyrimidin-5-yl]carbonyl}pyridin-3-yl)acetamide

The title compound was prepared according to the method described for Example 9 using (R,S) (5aminopyridin-3-yl){7-[2-{[iert-butyl(dimethyl)siiyl]oxy}-1-methylethyl]-7H-pyrrolo[2,3-d]pyrimidin-5yljmethanone (see Préparation 39) and (4-cyclopropyl-1 H-pyrazol-1-yl)acetic acid (see Préparation 88) to afford the title compound as a white solid in 14% yield, 20 mg.

¹H NMR (400 MHz. DMSO) δ; 0.46 (d, 2H), 0.79 (d, 2H). 1.49 (d. 3H). 1.70 (m, 1H), 3.73 (m, 1 H), 3.87 (m, 1H), 5.00 (s, 4H), 7.26 (s. 1H), 7.54 (s, 1 H), 8.40 (s, 1H), 8.47 (s, 1H), 8.75 (d, 1H), 8.98 (s, 1H), 9.00 (d, 1 H), 9.44 (s. 1H), 10.75 (s, 1H); LCMS (System 4): R_t = 2.53 min; m/z 445 [M+H]⁺.

Examples 26 to 33 were prepared according to the method described above for Example 10, starting 10 from the appropriate protected alcohol TBDMS ether.

Example	Name	Data
26	N-(5-{[7-(2-hydroxy-1,1 -dÎmethylethyl)-7H-pyrrolo[2,3d]pyrimidin-5-yl]carbonyl}pyridin-3-yl)-2-[5-methyl-3(trifluoromethyl)-l H-pyrazol-1 -yljacetamide	LCMS (System 4): Rt = 2.89 min; m/z 502 [M+H]+
27	N-(5-{[7-(2-hydroxy-1,1 -dimethylethyl)-7H-pyrrolo[2,3d]pyrimidin-5-yl]carbonyl}pyridin-3-yl)-2-[4(trlfluoromethyl)phenyljacetamide	LCMS (System 4): R( = 3.03 min; m/z 498 [M+H]+
28	2-(4-chlorophenyl)-N-(5-([7-(2-hydroxy-1,1 -d imethyl ethy I)- 7H-pyrrolo[2,3-d]pyrimidin-5-yl]carbonyl}pyridin-3yl)acetamide	Ή NMR (400 MHz, DMSO) δ: 1.73 (S, 6H), 3.75 (s, 2H), 3.96 (s, 2H), 7.39 (s, 4H), 8.22 (s, 1 H), 8.51 (s, LCMS (system 4): Rt = 3.02 min; m/z 464.1 JM+HJ*
29	2-(5-chloropyridin-2-yl)-N-(5-{[7-(2-hydroxy-1,1dimethylethyl)-7H-pyrrolo[2,3-d]pyrimidin-5yl]carbonyl}pyridin-3-yl)acetamide	LCMS (System 4): Rt = 2.72 min; m/z 465 [M+H]+
30	N-(5-{[7-(2-hydroxy-1,1 -dimethylethyl)-7H-pyrrolo[2,3d]pyrimidin-5-yl]carbonyl}pyridin-3-yl)-2-[3-(trifluoromethyl)1 H-pyrazol-1 -yljacetamide	LCMS (system 4): Rt = 2.80 min; m/z 488 [M+H]’'
31	2-(4-cyclopropyl-1 H-1,2,3-triazol-1 -yi)-N-(5-{[7-(2-hydroxy- 1,1-dimethylethyl)-7H-pyrrofo[2,3-d]pyrinnidin-5yllcarbonyl}pyridin-3-yl)acetamide	LCMS (system 4): R| = 2.47 min; m/z 461 [M+H]+
32	N-(5-{[7-(2-hydroxy-1,1 -dimethylethyl)-7H-pyrrolo[2,3d]pyrimidin-5-yl]carbonyl}pyridin-3-yl)-2-[4-(trifluoromethyl)1 H-1,2,3-triazol-1 -yljacetamide	LCMS (system 4): Rt = 2.78 min; m/z 489 [M+H]+
33	2-(4-cyclopropyl-1 H-pyrazol-1-yl)-N-(5~([7-(2-hydroxy-1,1dimethylethylj-ZH-pyrroloP.S-dJpyrimidin-Syl]carbonyl}pyridin-3-yl)acetamide	LCMSfsystem 4): R( = 2.68 min; m/z 460 [M+H]+

Example 34: N-(5-{[2-Amtno-7-(2-hydroxy-1-methylethyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl}carbonyl}pyridin-

3-yl)-2-(4-chlorophenyl)acetamide (enantiomer 1)

4-Chlorophenylacetic acid (25 mg, 0.14 mmol) was added to [2-amino-7-(2-hydroxy-1-methylethyl)-7Hpyrrolo[2,3-d]pyrimidin-5-yl](5-anninopyridin-3-yl)methanone (50 mg, 0.16 mmol) (see Préparation 57) and HATU (91 mg, 0.24 mmol) in pyridine (2 mL). The mixture was stirred at room température for 16 hours. Saturated aqueous sodium bicarbonate (5 mL) was added then extracted with ethyl acetate (3x5 mL). The combined organic phases were washed with brine (5 mL) then dried over sodium sulfate and evaporated in vacuo. The residue was purified by préparative TLC (95:5 DCM:MeOH) to afford the title compound as a yellow solid in 48% yield, 32 mg.

LCMS (system 5): Rt = 2.90 min; m/z 465 [M+H]*.

Examples 35 to 45 were prepared according to the method described above for Example 34, starting from [2-amino-7-(2-hydroxy-1-methylethy!)-7H-pyrrolo[2,3-d]pyrimidin-5-yl](5-aminopyridin-3-yl)methanone (see Préparation 57, enantiomer 1 or Préparation 59, enantiomer 2) and the appropriate acids.

Example	Name	Data
35	N-(5-([2-amino-7-(2-hydroxy-1-methylethyl)-7Hpyrrofo[2,3-d]pyrimidin-5-yl]carbonyl}pyridin-3-yl)-2-(5chtoropyridin-2-yl)acetamide	Enantiomer 1 LCMS (System 5): Rt = 2.63 min; m/z 466 [M+Hf
36	N-(5-{[2-amino-7-(2-hydroxy-1-methylethyl)-7Hpyrrolo[2,3-d]pyrimidin-5-yl]carbonyl}pyridin-3-yl)-2-[4(trifluoromethyl)phenyl]acetamide	Enantiomer 1 LCMS (system 5): Rt = 2.88 min; m/z 499 (M+H]+
37	N-(5-{[2-amino-7-(2-hydroxy-1-methylethyl)-7Hpyrrolo[2,3-d]pyrimidin-5-yl]carbonyl}pyridin-3-yl)-2-(5fluoropyridin-2-vl)acetamide	Enantiomer 1 LCMS (system 5): Rt = 2.25 min'; m/z 450 [M+H]+
38	N-(5-{[2-amino-7-(2-hydroxy-1-methylethyl)-7Hpyrrolo[2,3-d]pyrimidin-5-yl]carbonyl}pyridin-3-yl)-2-[3(trifluoromethyl)-l H-pyrazol-1 -yljacetamide	Enantiomer 1 LCMS (system 4): Rt = 2.39 min; m/z 489 [M+H)+
39	N-(5-{[2-amino-7-(2-hydroxy-1-methylethyl)-7Hpyrrolo(213-d]pyrimidin-5-yl]carbonyl}pyridin-3-yl)-2-[4(trifluoromethyl)-l H-1,2,3-triazol-1-yl]acetamide	Enantiomer 1 LCMS (system 5): Rt = 2.61 min; m/z 490 [M+H]+
40	N-(5-([2-amino-7-(2-hydroxy-1-methylethyl)-7Hpyrrolo[2,3-d]pyrimidin-5-yl]carbonyl}pyridrn-3-yl)-2-(5fluoropyridin-2-yl)acetamide	Enantiomer 2 LCMS (system 4): Rt = 1.89 min; m/z 450 [M+H]+
41	N-(5-{[2-amino-7-(2-hydroxy-1-methyIethyl)-7Hpyrrolo[2,3-d]pyrimidin-5-yl]carbonyl}pyridin-3-yl)-2-(5chloropyridin-2-yl)acetamide	Enantiomer 2 LCMS (system 4): Rt = 2.16 min' m/z 466 [M+H]+
42	N-(5-{[2-amino-7-(2-hydroxy-1-methylethyl)-7Hpyrrolo[2,3-d]pyrimidin-5-yl]carbonyl}pyridin-3-yl)-2-{4chlorophenyljacetamide	Enantiomer 2 LCMS (system 4): Rt = 2.63 min; m/z 465 [M+Hj*
43	N-(5-(Ê2-amino-7-(2-hydroxy-1-methylethyl)-7Hpyrrolo[2,3-d]pyrimidin-5-yl]carbonyl}pyridin-3-yl)-2-[4(trifluoromethyl)phenyl]acetamide	Enantiomer 2 LCMS (system 4): Rt = 2.73 min; m/z 499 [M+H]+
44	N-(5-{[2-amino-7-(2-hydroxy-1-methylethyl)-7Hpyrrolo[2,3-d]pyrimidin-5-yl]carbonyl}pyridin-3-yl)-2-[3(trifluoromethyl)-l H-pyrazol-1 -yllacetamide	Enantiomer 2 LCMS (system 4): Rt = 2.38 min; m/z 489 [M+H]+
45	N-(5-{[2-amino-7-(2-hydroxy-1-methylethyl)-7Hpyrrolo[2,3-d]pyrimidin-5-yl]carbonyl}pyridin-3-yl)-2-[4(trif luorometh yl)-1 H-1,2,3-triazol-1 -yljacetamide	Enantiomer 2 LCMS (system 5): Rt = 2.60 min; m/z 490 [M+H]+

Example 46: N-(5-([2-Amino-7-(2-hydroxy-1,1-dimethylethyl)-7H-pyrrolo[2,3-d]pyrimidin-5yl]carbonyl}pyridin-3-yl)-2-(5-chloropyridin-2-yl)acetamide

(5-Chloropyridin-2-yl)acetic acid (26.1 g, 152 mmol) (see Préparation 90) was added to (5-aminopyridin3-yl){7-(2-{[fe/l*butyi(dimethyl)silyl]oxy}-1,1-dimethylethyl)-2-[(2,4-dimethoxybBnzyl)amino]-7H-pyrrolo[2,3d]pyrimidin-5-yl}methanone (75.0 g, 130 mmol ) (see Préparation 51), 1-propylphosphonic acid cyclic anhydride (187 mL, 317 mmol, 50% solution in EtOAc) and triethylamine (61.9 mL, 444 mmol ) in THF (423 mL). The mixture was stirred at 25°C for 2 hours then saturated aqueous sodium bicarbonate (400 mL) was added and the organic layer was separated. The aqueous phase was extracted with EtOAc (400 mL) and ail organic phases were combined and dried over sodium sulfate then evaporated in vacuo.

The residue brown solid was dissolved in trifluoroacetic acid (300 mL) and the solution was stirred at 50°C 10 for 3 hours then evaporated in vacuo. Methanol (1800 mL) was added to the residue and the mixture was filtered. The filtrate was evaporated in vacuo and azeotroped with éthanol (3 x 200 mL).

Potassium carbonate (87.7 g, mmol) was added to the crude trifluoroacetamide in methanol (300 mL) and the mixture was stirred at room température for 16 hours. The mixture was poured into water (2000 mL) and filtered. The solid was washed with water (200 mL) then triturated with éthanol (2 x 200 mL at room température then 380 mL at 50°C) to afford the title compound as a yellow solid in 48% yield, 29.9 g.

’H NMR (400 MHz, DMSO-cfô) ô: 1.64 (s, 6H), 3.90 (d, 2H), 3.95 (s, 2H), 5.05 (t, 1H), 6.54 (brs, 2H), 7.49 (d, 1H), 7.69 (s, 1H), 7.92 (dd, 1H), 8.40 (m, 1H), 8.56 (m, 1H), 8.64 (d, 1H), 8.94 (d, 1H), 8.96 (s, 1H), 10.71 (s, 1H); LCMS (System 3): R, = 9.92 min; m/z 480 [M+H]⁺.

Example 47: N-(5-{[2-Amino-7-(2-hydroxy-1,1 -dimethylethyl)-7H-pyrrolo[2,3-d]pyrimidin-5yl]carbonyl)pyridin-3-yl)-2-[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetamide

The title compound was prepared according to the method described for Example 46 using (5aminopyridin-3-yl){7-(2-{[fert-butyl(dimethyl)silyl]oxy}-1,1-dimethylethyl)-2-((2,4-dimethoxybenzyl)amino]25 7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (see Préparation 51) and (ô-methyl-S-trifluoromethyl-pyrazol1-yl)acetic acid (46.8 mg, 0.225 mmol) to afford the title compound as a brown solid in 79% yield, 82 mg. LCMS (System 1): R, = 2.83 min; m/z 517 [M+H]⁺.

Examples 48 to 53 were prepared according to the method described above for Example 34, starting from [2-amino-7-(2-hydroxy-1,1-dimethylethyl)-7H-pyrrofo[2,3-d]pyrimidin-5-yl](5-aminopyridin-3yljmethanone (see Préparation 4B) and the appropriate acids.

Example	Name	Data
48	N-(5-{[2-amino-7-(2-hydroxy-1,1 -dimethylethyl)-7Hpyrrolo[2,3-d]pyrimidin-5-yl]carbonyl}pyridin-3-yl)-2[4-(trifluoromethyl)phenyllacetamide	LCMS (system 5): Rt= 3.12 min; m/z 513[M+Hf
49	N-(5-{[2-amino-7-(2-hydroxy-1,1-dimethylethyl)-7Hpyrrolo[2,3-d]pyrimidin-5-yl]carbonyl}pyridin-3-yl)-2(4-ch loropheny I) acetam ide	LCMS (system 5): R(= 2.89 min; m/z 479 [M+H]+
50	N-(5-{[2-amino-7-(2-hydroxy-1,1 -dimethylethyl)-7Hpyrrolo[2,3-d]pyrimidin-5-yl]carbonyl)pyridin-3-yl)-2(2,4-dif!uorophenyl)acetamide	MS(ESCI): m/z 481 [M+H]+
51	N-(5~([2-amino-7-(2-hydroxy-1,1 -dimethylethyl)-7Hpyrrolo[2,3-d]pyrimidin-5-yl]carbonyl}pyridin-3-yl)-2(5-fluoropyridin-2-yl)acetamide	LCMS (system 5): R(= 2.42 min; m/z 464 [M+H]*
52	N-(5-([2-amino-7-(2-hydroxy-1,1 -dimethylethyl)-7Hpyrrolo[2,3-d]pyrimidin-5-yl]carbonyl}pyridin-3-yl)-2[3-(trif luoromethy I)-1 H-pyrazol-1 -yl]acetam ide	LCMS (system 4): Rt= 2.54 min; m/z 503 [M+H]+
53	N-(5-{[2-amino-7-(2-hydroxy-1,1-dimethylethyl)-7Hpyrrolo[2,3-d]pyrimidin-5-yl]carbonyl}pyridin-3-yl)-2(3-cyclopropyl-1 H-pyrazol-1 -yl)acetam ide	LCMS (system 4) Rt = 2.23 min; m/z 475 [M+H]+

Example 54: N-(5-{[2-Amino-7-(2-hydroxy-1,1-dimethylethyl)-7H-pyrrolo[2,3-d]pyrimidin-5y l]carbonyl}pyridin-3-y I)-2-[4-(trif luoromethy I) -1H-1 ,2,3-triazol-1 -yljacetamide

The title compound was prepared according to the method described for Example 9 using [7-(2-{[tert10 butyl(dimethyl)silyl]oxy}-1_l1-dimethylethyl)-2-amino-7H-pyrrolo[2,3-d]pyrimidin-5-yl]{5-aminopyrÎdin-3yl}methanone (see Préparation 48a) and [4-{trifluoromethyl)-1/-/-1,2,3-triazol-1-yl]acetic acid (see Préparation 81) to afford the title compound as a brown solid in 85% yield, 62 mg.

’H NMR (400 MHz, DMSO-cfô) δ: 1.63 (s, 6H). 3.89 (d, 2H), 5.01 (br, 1H), 5.56 (s, 2H), 6.67 (brs, 2H), 7.72 (s, 1H), 8.36 (s, 1H), 8.70 (s, 1H), 8.94-8.96 (m, 3H), 11.05 {s, 1H); LCMS (system 5): R, = 2.71 min;

m/z 502 [M-Hf.

Example 55: N-(5-{[2-Amino-7-(2-hydroxy-1,1-dimethylethyl)-7H-pyrrolo[2,3-d]pyrimidin-5yl]carbonyl}pyridin-3-yl)-2-(2H-benzotriazol-2-yl)acetamide

The title compound was prepared according to the method described for Example 9 using {2-amino-7[1,1-dimethyl-2-(tetrahydro-2H-pyran-2-yloxy)ethyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}(5-aminopyridin-3yl)methanone (see Préparation 49) to afford the title compound as a brown solid in 46% yield, 20 mg.

¹H NMR (400 MHz, DMSO-06) S: 1.63 (s, 6H), 3.88 (d, 2H), 5.04 (t, 1 H), 5.80 (s, 2H), 6.54 (s, 2H), 7.467.49 (m, 2H), 7.69 (s, 1H), 7.95-7.97 (m, 2H), 8.35 (s, 1H), 8.69 (s, 1H), 8.96 (s, 1H), 8.98 (s, 1 H), 11.06 (s, 1H); MS (ESCI): m/z 486 [M+Hf.

Example 56: N-(5-{[2-Amino-7-(2-hydroxy-1,1-dimethylethyl)-7H-pyrrolo[2,3-d]pyrimidin-5yl]carbonyi}pyridin-3-yl)-2-(4-cyclop ropyl-1H-1,2,3-triazol-1 -yl)acetamide

The title compound was prepared according to the method described for Example 10 using N-(5-({2amino-7-[1,1-dimethyl-2-(tetrahydro-2H-pyran-2-yloxy)ethy)]-7H-pyrrolo[2,3-d]pyrimidin-5yl}carbonyl)pyridin-3-yl]-2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)acetamide (see Préparation 52) to afford 15 the title compound as a yellow solid in 24% yield, 14 mg.

¹H NMR (400 MHz, DMSO-D₆) C: 0.71-0.72 (m, 2H), 0.89-0.91 (m, 2H), 1.64 (s, 6H), 1.94-1.99 (m, 1H),

3.89 (d, 2H), 5.07 (t, 1H), 5.31 (s, 2H), 6.53 (s, 2H), 7.69 (s, 1H), 7.86 (s, 1H), 8.35 (s, 1H), 8.65 (s, 1H), 8.95 (m, 2H), 11.04 (s, 1H); LCMS (system 5): R,= 2.42 min; m/z 476 [M+H]\

Examples 57 to 64 were prepared according to the method described above for Example 1, starting from 20 (2-amino-7-tert-butyl-7H-pyrrolo[2,3-tf]pyrimidin-5-yl)(5-aminopyridin-3-yl)methanone (see Préparation

65) and the appropriate acids.

Example	Name	Data
57	N-(5-[(2-amino-7-tert-butyl-7H-pyrrolo[2,3-d]pyrimidin-5yl)carbonyl]pyridin-3-yl}-2-(3-cyc!opropyl-1 H-pyrazol-1 yljacetamide	LCMS (system 5): Rt = 2.90 min; m/z 459 [M+Hf
58	N-{5-[(2-amino-7-tert-butyl-7H-pyrrolo{2,3-d]pyrimidin-5yl) carbon yl] py ridin-3-yl}-2-(4-cyc lopropyl-1 H-1,2,3-triazol-1 yljacetamide	LCMS (system 5,12 min run): R, = 6.13 min; m/z 460 [M+H]+

59	N-{5-[(2-amino-7-tert-butyl-7H-pyrrolo[2,3-d]pyrimidin-5yl)carbonyl]pyridin-3-yl}-2-(5-fluoropyridin-2-yl)acetamide	LCMS (system 4): Rt = 2.60 min; m/z 448 ΙΜ+ΗΓ
60	N-{5-[(2-amino-7-tert-butyl-7H-pyrrolo[2,3-d]pyrimidin-5γΙ)θ3Γ6οηγΙ]ργΓίΡίη-3-νΙ}-2-[4-(ϋϊίΙυοΓοηηβΐΐΊγΙ)-1Κ-ργΓ3ΖθΙ-1yljacetamide	LCMS (system 5): Rt = 2.99 min; m/z 487 [M+H]+
61	ΓΉ5-[(2-3Γη(ηο-74θΓί-0υίγΙ-7Η-ργΓΓθΙο[2,3-6]ργππιί6ίπ-5yl)carbonyl]pyridin-3-yl}-2-[4-(trifluoromethyl)-1 H-1,2,3triazol-1 -yljacetamide	LCMS (system 5): Ri = 3.04 min; m/z 488 [M+H]”
62	N45-[(2-amino-7-tert-butyl-7H-pyrrolo{2,3-d]pyrimidin-5yl)carbonyl]pyridin-3-yl}-2-[3-(trifluoromethyl)-lH-pyrazol-1yljacetamide	LCMS (system 5): R| = 3.09 min; m/z 487 [M+H]+
63	N-(5-[(2-amino-7-tert-butyl-7H-pyrrolo[2l3’d]pyrimidin-5yl)carbonyljpyridin-3-yl}-2-(5-chloropyridin-2-yl)acetamide	LCMS (system 5); Rt = 2.95 min; m/z 464 [M+H]+
64	N-{5-[(2-amino-7-tert-butyl-7H-pyrrolo[2,3-d]pyrimidin-5yl)carbonyl]pyridin-3-yl}-2-[5-methyl-3-(trifluoromethyl)-1Hpyrazol-1 -yljacetamide	LCMS (system 5): R( = 3.09 min; m/z 501 [M+HJ*

The following Examples were prepared according to Method a (Example 34 at 50°C) or Method b (Example 1 using DIPEA) as described above starting from (5-Aminopyridin-3-yl)(7-isopropyl-7H5 pyrrolo[2,3-d]pyrimidin-5-yl)methanone (Préparation 95) and the appropriate acid.

Example	Name	Data
65	2-(4-fluorophenyl)-N-{5-[(7-isopropyl-7Hpyrrolo^.S-dJpyrimidin-S-yOcarbonylJpyridin-Syl}acetamide	LCMS (system 1): R( = 2.73 min; m/z 418 [M+H]+.
66	N-{5-[(7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5yl)carbonyl]pyridin-3-yl}-2-[3(trifluoromethyi)phenyl]acetamide	LCMS (system 9): R, = 3.22 min; m/z 468 [M+Hf.
67	N-{5-[(7-isopropyl-7H-pyrrolo(2,3-d]pyrimidin-5yl)carbonyl]pyridin-3-yl}-2-[4(trifluoromethyl)phenyl]acetamide	LCMS (system 9); Rt = 3.22 min; m/z 468 [M+HJ*.
68	2-(3,4-dichlorophenyl)-N-(5-[(7-isopropyl-7Hpyrrolo[2,3-d]pyrimidin-5-yl)carbonyl]pyridin-3yljacetamide	LCMS (system 7): R, = 11.34 min; m/z 468 [M+H]*'
69	2-(4-chlorophenyl)-N-{5-[(7-isopropyl-7Hpyrrolo[2,3-d]pyrimidin-5-yl)carbonyl]pyridin-3yl}acetamide	m/z 434 [M+Hf
70	2-[2-(cyclopropyloxy)phenyl]-N~[5-[(7-isopropyl7H-pyrrolo[2,3-d]pyrimidin-5yl)carbonyl]pyridin-3-yl}acetamide	LCMS (system 4): R( = 3.13 min; m/z 456 [M+H]+ Prep HPLC (method 2) Using [2-(cyclopropyloxy)phenyl]acetic acid (Préparation 160).
71	2-(4-cyanophenyl)-N-{5-[(7-isopropyl-7Hpyrrolo[2,3-d]pyrimîdin-5-yl)carbonyl]pyridin-3yljacetamide	LCMS (system 2): Rt = 1.16 min; m/z 425 [M+Hf
72	2-[4-cyano-3-(trifluoromethyl)phenyl]-N-{5-[(7isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5yl)carbonyl]pyridin-3-yl}acetamide	LCMS (System 1); Rt = 2.82 min; m/z 493 [M+Hf Using [4-cyano-3- (trifluoromethyl)phenyl]acetic acid

		(Préparation 164),
73	2-[4-(cyclopropyloxy)pheny!]-N-{5-[(7-isopropyl7H-pyrrolo[2,3-d]pyrimidin-5yl)carbonyl]pyridin-3-yl}acetamide	LCMS (System 3) Rt = 3.05 min; m/z 456 [M+H]+ Using [4-(cyclopropyloxy)phenyl]acetic acid (Préparation 161). Prep method 2
74	2-[3-(cyclopropyloxy)phenyl]-N-{5-[(7-isopropylyH-pyrrolop.S-djpyrimidin-Syl)carbonyl]pyridin-3-yl}acetamide	LCMS (System 1) R, = 2.52 min; m/z 456 [M+H] * Using [3-(cyclopropyloxy)phenyl]acetic acid (Préparation 162).
75	2-[3-(hydroxymethyl)phenyl]-N-{5-[(7-isopropyl7H-pyrrolo[2,3-d]pyrimidin-5yl)carbonyl]pyridin-3-yl}acetamide	LCMS (System 2): R( = 1.3 min; m/z 430 [M+Hf
76	2-(4-cyano-3-fluorophenyl)-N-{5-[(7-isopropyl7H-pyrrolo[2,3-d]pyrimidin-5yl)carbonyl]pyridin-3-yl}acetamide	LCMS (System 2): Rt = 1.5 min; m/z 443 [M+HJ*
77	2-(4-cyano-3-methoxyphenyl)-N-{5-[(7isopropyl^H-pyrrolo^a-djpyrimidin-Syl)carbonyl]pyridin-3-yt}acetamide	LCMS (System 2): Rt = 1.3 min; m/z 455 [M+H]+
78	2-(6-fluoro-1 -oxo-1,3-dihydro-2H-isoindol-2-yl)- N-Î5-[(7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5yl)carbonyl]pyridin-3-yl}acetamide	LCMS (System 2): Rt = 1.5 min; m/z 473 (M+H]+
79	N-{5-[(7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5yl)carbonyl]pyridin-3-yl}-2-(3-pyridin-2-yl-1Hpyrazol-1 -yl)acetamide	LCMS (System 2): Rt = 1.2 min; m/z 467 [M+HJ+.
80	2-(1H-benzimidazol-5-yl)-N-{5-((7-isopropyl-7Hpyrrolo[2,3-d]pyrimidin-5-yl)carbonyl]pyridin-3yljacetamide	LCMS (System 2): R, = 1.0 min; m/z 440 [M+H]*'
81	N-{5-[(7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5yl)carbonyl]pyridin-3-yl}-2-quinoxalin-6ylacetamide	LCMS (System 2): Rt = 1.1 min; m/z 452 [M+H]+
82	N-{5-[(7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5yl)carbonyl]pyridin-3-yl}-2-(1,5-naphthyridin-3yljacetamide	LCMS (System 9): Rt= 2.63 min; m/z 452 [M+H]+ Using 1,5-naphthyridin-3-ylacetic acid (Préparation 188).
83	2-(3-amino-1,2-benzisoxazol-5-yl)-N-{5-[(7isopropyt-7H-pyrrolo[2,3-d]pyrimidin-5· yi)carbonyl]pyridin-3-yl}acetamide	LCMS (System 9): R(= 2.76 min; m/z 456 [M+H]+ using (3-aminobenzo[d]isoxazol-5-yl)-acetic acid ethyl ester (Préparation 129)
84	N45-[(7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5yl)carbonyl]pyridin-3-yl}-2-[2-(trifluoromethyl)1 H-benzimidazol-5-yl]acetamide	LCMS (System 9): Rt= 2.90 min; m/z 508 [M+H]+
85	2-imidazo[1,2-a]pyridin-7-yl-N'{54(7-isopropyl- 7H-pyrrolo[2,3-d]pyrimidin-5- yl)carbonyl]pyridin-3-yl}acetamide	LCMS (System 10): Rt= 2.57 min; m/z 440 [M+H]+ using imidazo[1,2a]pyridin-7-yl-acetic acid (Préparation

		132)
86	N-(5-[(7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5yl)carbonyl]pyridin-3-yl}-2-(1H-pyrazolo[4,3b]pyridin-1 -yljacetamide	LCMS (System 9): Rt= 2.54 min; m/z 441 [M+H]+ Using 1 H-pyrazolo[4,3-b]pyridin-1yl)acetic acid (Préparation 190).
87	N-(5-[(7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5y I) car bony IJ pyridi n-3-yl}-2-[3(methylsulfonyl)phenyljacetamide	LCMS (System 9): Rt = 2.74 min; m/z 478 [M+H]+
88	2-(4-cyclopropyl-1 H-1,2,3-triazol-1 -yl) - N-{5-[(7isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5yl)carbonyl]pyridin-3-yl}acetamide	LCMS (System 9): Rt = 2.68 min; m/z 431 [M+H]+. Using 4-cyclopropyl-1 H-1,2,3-triazol-1 ylacetic acid (Préparation 83).
89	2-(1,3-benzoxazol-5-yl)-N-{5-[(7-isopropyl-7Hpyrrolo[2,3-d]pyrimidin-5-yl)carbonyl]pyridin-3yl}acetamide	LCMS (System 9): R( = 2.79 min; m/z 441.1 [M+H]+
90	2-(3-cyclopropyl-1 H-pyrazol-1 -yl)-N-{5-[(7isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5yl)carbonyl]pyridin-3-yl}acetamide	LCMS (System 9): R, = 2.75 min; m/z 430 [M+H]+ (3-cyclopropyl-1 H-pyrazol-1 -yl)acetic acid (Préparation 80).
91	2-[5-(cyclopropyloxy)pyridin-3-yl]-N-{5-[(7isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5yl)carbonyl]pyridin-3-yl}acetamide	LCMS (system 3) Rt = 2.36 min; m/z 457 [M+H]+- Prep method 2 Using [5-(cyclopropyloxy)pyridin-3yljacetic acid (Préparation 163).
92	2-(2,3-dihydro-1-benzofuran-5-yl)-N-{5-[(7isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5yl)carbonyl]pyridin-3-yl}acetamide	LCMS (system 3): R( = 2.91 min; m/z 442 [M+H]+ Prep HPLC (method 1)
93	2-(2H-indazol-2-yl)-N-{5-[(7-isopropyl-7Hpyrrolo[2,3-d]pyrimidin-5-yl)carbonyl]pyridin-3yljacetamide	LCMS (system 3): Rt = 2.74 min; m/z 440 [M+H]+ Prep HPLC (method 1)
94	2-(5-fluoro-2H-indazol-2-yl)-N-{5-[(7-isopropyl7H-pyrrolo[2,3-d]pyrimidrn-5yl)carbonyl]pyridin-3-yl}acetamide	LCMS (system 9): Rt= 2.96 min; m/z 458 [M+H]+* Using -(5-fluoro-2H-indazol-2-yl)acetic acid (Préparation 174).
95	2-(5-fluoro-1 H-indazol-1 -yl)-N-{5-[(7-isopropyl7H-pyrrolo[2,3-d]pyrimidin-5yl)carbonyl]pyridin-3-yl}acetamide	LCMS (system 9): Rt = 2.97 min; m/z 458 [M+HJ+ Using (5-fluoro-1 H-indazol-1 -yl)acetic acid (Préparation 172).
96	N-{5-[(7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5yl)carbonyl]pyridin-3-yl}-2-[5-methyl-3(trif luo romethy I)-1 H-pyrazol-1 -yljacetamide	LCMS (system 8): Rt = 1.62 min; m/z 472 [M+HJ*
97	N-{5-[(7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5yl)carbonyl]pyridin-3-yl}-2-[3-(trifluoromethyl)1 H-pyrazol-1 -yljacetamide	LCMS (system 3): Rt = 2.97 min; m/z 458 [M+H]+. Prep HPLC (method 1)

98	2-(5-chloropyridin-2-yl)-N-{5-[(7-isopropyl-7Hpyrrolo[2,3-d]pyrimidin-5-yl)carbonyl]pyridin-3yl}acetamide	LCMS (System 9): Rt = 2.86 min; m/z 435 [M+H]+ Using (5-chloropyridin-2-yl)acetic acid (Préparation 90).
99	2-(1H-indazol-6-yl)-N-{5-[(7-isopropyl-7Hpyrrolo[2,3-d]pyrimidin-5-yl)carbonyl]pyridin-3yl}acetamide	m/z 440 [M+H]+ Using 1 H-indazol-6-ylacetic acid (Préparation 132).
100	N-(5-[(7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5yl)carbonyl]pyridin-3-yl}-2-quinolin-7ylacetamide	LCMS (System 7): R, = 8.73 min; m/z 451 [M+HJ*
101	2-(7-fluoro-2H-indazol-2-yl)-N-{5-[{7-isopropyl7H-pyrrolo[2,3-d]pyrimidin-5yl)carbonyl]pyridin-3-yl}acetamide	LCMS (system 9): Rt= 2.95 min; m/z 458 [M+H]+ Using (7-fluoro-2H-indazol-2-yl)acetic acid (Préparation 178).
102	N-{5-[(7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5yl)carbonyl]pyridin-3-y!)-2-(1H-pyrazolo[3,4b] pyrid in-1 -yljacetamide	LCMS (system 9); R|= 2.72 min; m/z 441 [M+H]+ Using 1 H-pyrazolo[3,4-b]pyridin-1- yl)acetic acid (Préparation 180).
103	2-(1 H-indazol-1 -yl)-N-(5-[(7-isopropyl-7Hpyrrolo[2,3-d]pyrinnidin-5-yl)carbonyl]pyridin-3' yljacetamide	LCMS (system 3): R, = 2.82 min; m/z 440 [M+H]* Prep HPLC (method 1)
104	2-(3-isopropyl-5-methyl-1 H-pyrazol-1 -yl)-N-{5[(7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5yl)carbonyl]pyridin-3-yl}acetamide	LCMS (system 8): Rt = 1.65 min; m/z 446 (M+H]+ Using (3-isopropyl-5-methyl-1 H- pyrazol-1-yl)acetic acid (Préparation 167).
105	N-{5-[(7-isopiOpyl-7H-pyrrolo[2,3-d]pyrimidin-5yl)carbonyl]pyridin-3-yl}-2-(4-isopropyl-1H- 1,2,3-triazol-1 -yljacetamide	LCMS (system 8): Rt = 1.52 min; m/z 433 [M+H]+
106	N~(5-[(7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5yl)carbonyl]pyridin-3-yl}-2-[4-(tritluoromethyl)1H-1,2,3-triazol-1 -yljacetamide	LCMS (system 9): Rt = 2.98 min; m/z 459 [M+HJ* Using [4-(trifluoromethyl)-1 H-1,2,3triazol-1-yl]acetic acid (Préparation 81).
107	2-(7-fluoro-1 H-indazol-1 -yl)-N-{5-[(7-isopropyl7H-pyrrofo[2,3-d]pyrimidin-5- y I ) car bo ny I] pyrid in-3-yl}acetam ide	LCMS (system 9): Rt = 2.96 min; m/z 458 [M+H]+, Using (7-fluoro-1 H-indazol-1 -yl)acetic acid (Préparation 176).
108	2-(2H-benzotriazol-2-yl)-N-{5-[(7-isopropyl-7Hpyrrolo[2,3-d]pyrimidin-5-yl)carbonyl]pyridin-3yljacetamide	LCMS (system 8): Rt = 1.57 min; m/z 441 [M+H]+
109	2-(7-fluoro-2-methyl-1H-indol-3-yl)-N-{5-[(7isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5yl)carbonyl]pyridin-3-yl}acetamide	LCMS (system 8): Ri = 1.64 min; m/z 471 [M+HJ*
110	2-(5-chloro-2-methyl-1H-indol-3-yl)-N-{5-[(7isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5yl)carbonyl]pyridin-3-yl}acetamide	LCMS (system 8): Rt = 1.69 min; m/z 487 [M+H]+
111	2-( 1 H-indol-1 -yl)-N-{5-[(7-isopropyl-7Hpyrrolo[2,3-d]pyrimidin-5-yl)carbonylJpyridin-3yljacetamide	LCMS (system 8): R( = 1.66 min; m/z 439 [M+H]+

112	N-{5-[(7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5yl)carbonyl]pyridin-3-yl}-2-[1-isopropyl-5(trifluoromethyl)-1H-pyrazol-4-yl]acetamide	LCMS (System 9): Rt = 3.13 min; m/z 500 [M+H]+ Using 1 -isopropyl-5-(trifluoromethy))1 H-pyrazol-4-yl]acetic acid (Préparation 185).
113	N-{5-[(7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5yl)carbonyl]pyridin-3-yl}-2-(3-methyl-1Hpyrazol-1 -yljacetamide	LCMS (System 8); R( = 1.50 min; m/z 404 [M+H]+
114	N~{5-[(7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5yl)carbonyl]py ridin-3-y l}-2-( 1 H-pyrazol-1 yljacetamide	LCMS (system 8): Rt = 1.45 min; m/z 390 [M+H]+.
115	2-(3,5-dimethyl-1 H-pyrazol-1 -yl)-N-{5-[(7isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5yl)carbonyl]pyridin-3-yl}acetamide	LCMS (system 8): Rt = 1.55 min; m/z 418 [M+H]+
116	N-{5-[(7-isopropyl-7H-pyrro!o[2,3-d]pyrimidin-5yl)carbonyljpyridin-3-yl}-2-(2-methyl-1 H-indol-3yljacetamide	LCMS (system 8): Rt = 1.62 min; m/z 453 [M+H]+
117	N-{5-[(7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5yl)carbonyl]pyridin-3-yl}-2-(5-methoxy-1H-indol3-yl)acetamide	LCMS (system 8): Rt = 1.57 min; m/z 469 [M+H]+
118	N45-[(7-Îsopropyl-7H-pyrrolo[2,3-d]pyrÎmidin-5yl)carbonyl]pyridin-3-yl}-2-pyridin-3ylacetamide	LCMS (system 8): R, = 1.35 min; m/z 401 [M+H]+
119	2-(5-chloro-1 H-benzotriazol-1 -yl)-N-{5-[(7isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5yl)carbonyl]pyridin-3-yl}acetamide	LCMS (system 8): Rt = 1.61 min; m/z 475 [M+H]+
120	N-{5-[(7-isopropyl-7H-pyrrolo[213-djpyrimidin-5yl)carbonyl]pyridin-3-yl}-2-[3-(2-thienyl)-1Hpyrazol-1 -yl]acetamide	LCMS (system 8): Rt = 1.61 min; m/z 472 [M+H]+
121	N-{5-[(7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5yl)carbonyl]pyridin-3-yl}-2-(7methylimidazo[1,2-a]pyrimidin-2-yl)acetamide	LCMS (system 8): Rt = 1.37 min; m/z 455 [M+H]*
122	2-(2,6-dimethyl-9H-purin-9-yl)-N-{5-[(7isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5yl)carbonyl]pyridin-3-yl}acetamide	LCMS (system 8): Rt = 1.43 min; m/z 470 [M+Hf
123	N-{5-[(7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5yl)carbonyl]pyridin-3-yl}-2-(6-nitro-1 H-indazol1-yl)acetamide	LCMS (system 8): R, = 1.60 min; m/z 485 [M+Hf
124	2-(5-chloro-1 -methyl-1 H-indazol-3-yl)-N-{5-[(7isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5yl)carbonyl]pyridin-3-yl}acetamide	LCMS (system 8): Rt = 1.73 min; m/z 488 [M+Hf J. Med Chem. 1992,35, 2155-2165
125	2-(5-fluoro-2-methyl-1H-indol-3-yl)-N-{5-[(7isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5yl)carbonyl]pyridin-3-yl}acetamide	LCMS (System 8): Rt = 1.63 min; m/z 471 (M+H]+

126	2-(6-chloroimidazo[1,2-a)pyridin-2-yl)-N-{5-[(7isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5yl)carbonyl]pyridin-3-yl}acetamide	LCMS (system 8): Rt = 1.45 min; m/z 474 [M+H]+
127	N-(5-[(7-isopropyl-7H-pyrro!o[2,3-d]pyrimidin-5yl)carbonyl]pyridin-3-yl}-2-(2-methyl-lHbenzimidazol-1 -yl)acetamide	LCMS (system 8): R, = 1.36 min; m/z 454 [M+Hf
128	2-imidazo[1,2-a]pyridin-2-yl-N-(5-[(7-isopropyl7H-pyrrolo[2,3-d]pyrimidin-5- yl) carbonyl] pyridi n -3- yl}aceta mid e	LCMS (system 8): R, = 1.31 min; m/z 440 [M+H]+
129	N-(5-[(7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5yl)carbonyI]pyridin-3-yl}-2-(5-methoxy-1Hpyrrolo[3,2-b]pyridin-1-yl)acetannide	LCMS (system 8): R| = 1.49 min; m/z 470 [Μ+Η]+
130	N-(5-[(7-isopropyl-7H-pynOlo[2,3-d]pyrimidin-5- yl)carbonyl]pyridin-3-yl}-2-(5-methyl-lHpyrazol-1 -yl)acetamide	LCMS (System 8): Rt = 1.49 min; m/z 404 [M+H]*
131	N-{5-[(7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5yl)carbonyl]pyridin-3-yl}-2-(7-methyl-1Hbenzimidazol-l -yl)acetamide	LCMS (system 8): R, = 1.43 min; m/z 454 [M+H]+'
132	2-(1H-indol-3-yl)-N-(5-[(7-isopropyl-7Hpyrrolo[2,3-d]pyrimidin-5-yl)carbonyl]pyridin-3yl}acetamide	LCMS (system 8): R, = 1.59 min; m/z 439 [M+H]+
133	2-( 1 H-benzimidazol-1 -ylJ-N-fS-i^-isopropyl^Hpyrrolo[2,3-d]pyrimidin-5-yl)carbonyl]pyridin-3yl}acetamide	LCMS (system 8): Rt = 1.40 min; m/z 440 [M+H]+
134	N-{5-[(7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5yl)carbonyl]pyridin-3-yl}-2-(3-methyl-lHpy razol-5-yl) acetam id e	LCMS (system 8): Rt = 1.45 min; m/z 404 [M+H]+
135	2-(1H-benzotriazol-1-yl)-N-(5-[(7-isopropyl-7Hpyrrolo[2,3-d]pyrimidin-5-yl)carbonyl]pyridin-3yljacetamide	LCMS (system 8): Rt = 1.52 min; m/z 441 [M+H]+
136	N-{5-[(7-isopropyl-7H-pyrrolo(2,3-d]pyrimidin-5yljcarbonyl] pyridi n-3-yl}-2-(1 -methyl-1 H-indol-3yljacetamide	LCMS (system 8): Rt = 1.68 min; m/z 453 [M+H]+
137	N-{5-[(7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5yl)carbonyl]pyridin-3-yl}-2-(4-phenyl-1 H-pyrrol2-yl)acetamide	LCMS (system 8): R( = 1.66 min; m/z 465 [M+Hf
138	2-(2-ethyl-3H-imidazo[4,5-b]pyridin-3-yl)-N-{5[(7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5yl)carbonyljpyridin-3-yl}acetamide	LCMS (system 8); R, = 1.49 min; m/z 469 [M+H]+
139	2-(5-chloro-1H-indol-3-yl)-N-{5-[(7-isopropyl7H-pyrrolo[2,3-d]pyrimidin-5yl)carbonyl]pyridin-3-yl}acetamide	LCMS (system 8): Rt = 1.67 min; m/z 473 [M+H]+
140	N-{5-[(7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5yl) carbonyl] pyridtn-3-yl}-2-( 1 -phenyl-1 H-pyrrol3-yl)acetamide	LCMS (system 8): Rt = 1.71 min; m/z 465 [M+H]+ Can be prepared by a similar method to Harrak, Y. et al. Bioorganic & Médicinal Chemistry (2007), 15(14), 4876-4890.

141	N-{5-[(7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5yl)carbonyl]pyndrn-3-yl}-2-(5-methyi-1 H-indol-3yljacetamide	LCMS (System 8): Rt = 1.63 min; m/z 453 [M+H]+
142	2-(2-eth yl-1 H-benzimidazol-1 -yl)-N-{5-[(7isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5yl)carbonyl]pyridin-3-yl}acetamide	LCMS (system 8): Rt = 1.37 min; m/z 468 [M+HJ*
	2-imidazo[1,2-a]pyrimidin-2-yl-N-{5-[(7isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5yl)carbonyl]pyridin-3-yl}acetamide	LCMS (system 8): R, = 1.38 min; m/z 441 [M+Hf
144	2-(1 H-indazol-3-yl)-N-{5-((7-isopropyl-7Hpyrrolo[2,3-d]pyrimidin-5-yl)carbonyl]pyridin-3yl}acetamide	LCMS (system 8): Rt - 1.55 min; m/z 440 [M+H]+
145	2-(5-fluoro-7-methoxy-1 H-indol-1 -yl)-N-{5-[(7isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5’ yl)carbonyl]pyridin-3-yl}acetamide	LCMS (system 8): R, = 1,67 min; m/z 487 [M+H]+‘
146	2- ( 1 -benzyl-1 H-1,2,3-tri azol-4-y I) - Ν-(5-Π7isopropyl-7H-pyrrolo[2,3-d]pynmidin-5yl)carbonyl]pyridin-3-yl}acetamide	LCMS (system 8): Rt = 1.57 min; m/z 481 [M+Hf
147	2-(6-chloro-1 -methyM H-indazol-3-yl)-N-{5-[(7isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5yl)carbonyl]pyridin-3-yl}acetamide	LCMS (system 8): Rt = 1.72 min; m/z 488 [M+H]+ Using -(6-chloro-1 -methyl-1 H-îndazol3-yl)acetic acid (Préparation 170).
148	2-(7-chloro-1H-Îndol-3-yl)-N-{5-[(7-isopropyl- 7H-pyrrolo[2,3-dJpyrimidin-5- yl)carbonyl]pyridin-3-yl}acetamide	LCMS (system 8): Rt = 1.67 min; m/z 473 [M+H]\
149	N-{5-[(7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5yl)carbonyl]pyndin-3-yl}-2-(5-methyl-4-phenyl1 H-pyrazol-1 -yljacetamide	LCMS (system 8): Rt = 1.68 min; m/z 480 [M+H]+
150	2-(5-bromopyridin-3-yl)-N-{5-[(7-isopropyl-7Hpyrrolo[2,3-d]pyrimidin-5-yl)carbonyl]pyridin-3yljacetamide	LCMS (System 8): Rt = 1.60 min; m/z 479 [M+H]+
151	N-{5-[(7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5yl)carbonyl]pyridin-3-yl}-2-pyridin-2ylacetamide	LCMS (system 8): Rt = 1.41 min; m/z 401 [M+H]+
152	N-{5-[(7-isopropyi-7H-pyrroloi2l3-d]pyrimtdin-5yl)carbonyl]pyridin-3-yl}-2-(6-methoxypyrtdin-3yljacetamide	LCMS (system 8): Rt = 1.55 min; m/z 431 [M+H]+
153	2-(2,5-dimethyl-1H-indol-3-yl)-N-{5-[(7isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5yl)carbonyl]pyridin-3-yl}acetamide	LCMS (System 8): R| = 1.67 min; m/z 467 [M+H]+
154	N-{5-[(7-isopropyl-7H-pyrrolo[213-d]pyrimidin-5yl)carbonyl]pyridin-3-yl}-2-(6-methylpyridin-3yljacetamide	LCMS (System 8) : Rt = 1.33 min; m/z 415 [M+H]+
155	N45-[(7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5yl)carbonyl]pyridin-3-yl}-2-(2-methylquinolin-7yljacetamide	LCMS (system 8): R( = 1.40 min; m/z 465 [M+H]+ Using (2-methylquinolin-7-yl)acetic acid (Préparation 165).

D(

156	N-{5-[(7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5yl)carbonyl]pyridin-3-yl}-2-(5-methoxy-2methyl-1 H-indol-S-ylJacetamide	LCMS (system 8): Rt = 1.60 min; m/z 483 [M+H]+.
157	N-{5-[(7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5yl)carbonyl]pyridin-3-yl}-2-tetrazolo[1,5b]pyridazin-6-ylacetamide	LCMS (system 8): R, = 1.46 min; m/z 443 [M+Hf. (can be prepared via a similar method to WO2010/129379, 11 Nov 2010)
158	2-(5-hydroxy-1H-indol-3-yl)-N-{5-[(7-isopropyl7H-pyrrolo[2,3-d]pyrimidin-5yl)carbonyl]pyridin-3-yl}acetamide	LCMS (system 8): R, = 1.45 min; m/z 455 [M+HJ*
159	N-(5-[(7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5yl)carbonyl] pyridi n-3-yl}-2-(5H-pyrrolo[2,3b]pyrazin-7-yl)acetamide	LCMS (system 8): R( = 1.47 min; m/z 441 [M+H]+
160	2-(5,6-dimethyl-1 H-benzimidazol-1 -yl)-N-{5-[(7isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5yl)carbonyl]pyridin-3-yl}acetamide	LCMS (system 8): R( - 1.43 min; m/z 468 [M+H]+
161	N-{5-[(7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5yl)carbonyl]pyridin-3-yl}-2-(4-pyridÎn-2-yl-1H1,2,3-triazol-1-yl)acetamide	LCMS (system 8): Rt = 1.48 min; m/z 468 [M+Hf
162	N-{5-[(7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5yl)carbonyl]pyridin-3-yl}-2-(4-methyl-1 H-1.2,3triazol-1 -yl)acetamide	LCMS (system 8): Rt = 1.43 min; m/z 405 [M+Hf
163	N-{5-[(7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5yl)carbonyl]pyridin-3-yl}-2-(5-methyl-3-phenyl1 H-pyrazol-4-yl)acetamide	LCMS (system 8): Rt = 1.55 min; m/z 480 [M-t-Hf
164	N-(5-[(7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5yl)carbonyl]pyridin-3-yl}-2-[2- (methylthio)pyrimidin-5-yl]acetamide	LCMS (System 8): Rt = 1.55 min; m/z 448 [M+H]+ can be prepared via a similar method to Smrz, R. et al. Collection of Czechoslovak Chemical Communications (1976), 41(9), 2771-87
165	N-{5-[(7-isopropyl-7H-pyrrolo[2,3-dlpyrimidin-5yl)carbonylJpyridin-3-yl}-2-pyrimidin-2ylacetamide	LCMS (system 8): R( = 1.44 min; m/z 402 [M+Hf-

Example 166: 2-(5-Cyanopyridin-2-yl)-N-{5-[(7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)carbonyl]pyridin3-yl}acetamide

Zinc cyanide (28 mg, 0.23 mmol) was added to 2-(5-Bromo-pyridin-2-yl)-N-[5-(7-(propan-2-yl)-7H5 pyrrolo[2,3-d]pyrimidrne-5-carbonyl)-pyridin-3-yl]-acetamide (Example 317, 75 mg, 0.16 mmol) in DMF (2 mL) and the mixture was degassed with argon for 10 minutes. Then tris(dibenzylideneacetone)dipalladïum (3 mg, 0.003 mmol) and 1 ,T-bis(diphenylphosphino)ferrocene (7 mg, 0.012 mmol) were added and the mixture was heated at 100°C for 40 mins under microwave irradiation. The mixture was diluted with

EtOAc (5 mL) and washed with water (2 mL), brine (2 mL) and dried over sodium sulphate. The filtrate was evaporated in vacuo and purified by préparative TLC (3% MeOH in DCM) to afford the title compound as a light brown solid in 18% yield, 12 mg.

¹H NMR (400 MHz, DMSO) δ: 1.55 (d, 6H), 4.07 (s, 2H), 5.09 (m, 1 H), 7.67 (d, 1H), 8.30 (m, 1H), 8.44 (s, 1 H), 8.52 (s, 1 H), 8.74 (d. 1 H), 8.98-8.99 (m,3H),9.44 (s, 1H), 10.79 (s, 1H);

LCMS (System 9): R_t = 2.75 min; m/z 426 [M+Hf.

Example 167; 2-[5-Fluoro-2-(trifluoromethyl)phenyl]-N-(5-[(7-methyl-7H-pyrroio[2,3-d]pyrimidin-5yl)carbonyl]pyridin-3-yl)acetamide

1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide HCl (150 pL, 0.5M in DMF) was added to 5-fluoro-2(trifluoromethyl)phenylacetic acid (90 pmol), N-methylmorpholine (25 pL, 150 pmol), 1hydroxybenzotriazofe (15 pmol, 0.05M in DMF) and (5-aminopyridin-3-yl)(7-methyl-7H-pyrrolo[2,3d]pyrimidin-5-yl)methanone (Préparation 110, 75 pmol, 0.25 M in DMF). The mixture was stirred at 50°C for 2 hours and then evaporated in vacuo and purified by prep-HPLC (method 4) to afford the title compound.

LCMS (system 5): R_t = 2.66 min; m/z 458 [M+Hf

The following Examples were prepared according to the method described above for Example 167 starting from (5-aminopyridin-3-yl)(7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)rnethanone (Préparation 110) and the appropriate acid.

Example	Name	Data
168	2-(3-methylphenyl)-N-{5-[(7-methyl-7Hpyrrolo[213-d]pyrimidin-5-yl)carbonyl]pyridin-3yl}acetamide	LCMS (system 5): Rt = 2.53 min; m/z 386 [M+Hf
169	N-{5-[(7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5yl)carbonyl]pyridin-3-yl}-2-[2(trifluoromethyl)phenyl]acetamide	LCMS (system 5): R, = 2.61 min; m/z 440 [M+Hf
170	2-(3,5-6ίίΙυθΓθρΙιβηγΙ)-Ν-{5-[(7-ΠΊθνιγΙ-7Ηpyrrolo[2,3-dJpyrimidin-5-yl)carbonyl]pyridin-3yl}acetamide	LCMS (system 5): R, = 2.52 min; m/z 408 [M+Hf
171	N-(5-[(7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5yl)carbonyl]pyridin-3-yl}-2-(2,4,6trifluorophenyl)acetamide	LCMS (system 5): R( = 2.50 min; m/z 426 [M+Hf
172	N45-[(7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5yl)carbonyl]pyridin-3-yl}-2-(2,3,6trifluorophenyljacetamide	LCMS (system 5): R( = 2.49 min; m/z 426 [M+Hf

173	N-(5-[(7-methyl’7H-pyrrolo[2,3-dJpyrimidin-5yl)carbonyl]pyridin-3-yl}-2-[4(methylsulfonyl)phenyl]acetamîda	LCMS (system 5): Rt = 2.13 min; m/z 450 [M+H]+
174	2-[3-fluoro-4-(trifluoromethyl)phenyl]-N-(5-[(7methyi-7H-pyrroio[2,3-d]pyrimidin-5yl)carbonyl]pyridin-3-yl}acetamide	LCMS (system 5): Rt = 2.77 min; m/z458-[M+H]*
175	2-(3-methoxyphenyl)-N~[5-[(7-methyl-7H’ pyrrolo[2,3-d]pyrimidin-5-yl)carbonyl]pyridin-3yl}acetamide	LCMS: Rt = 2.34 min; m/z 402 [M+H]+
176	N-{5-[(7-rnethyl-7H-pyrrolo[2,3-d]pynmidin-5- yl)carbonyl]pyridin-3-yl}-2-[3- (trifluoromethoxy)phenyl]acetamide	LCMS (system 5): R( = 2.76 min; m/z 456 [M+H]+
177	N-{5-[(7-methyl-7H-pyrrolo[2,3-dJpyrimidin-5yl)carbonyl]pyridin-3-yl}-2-(2,3,5trif)uorophenyl)acetamide	LCMS (system 5): Rt = 2.54 min; m/z 426 [M+H]+
178	N-{5-[(7-methyl-7H’pyrrolo[2,3-d]pyrimidin-5yl)carbonyl]pyridin-3-yl}-2-(2-methylquinolin-7yljacetamide	LCMS (system 5): Rt = 1.95 min; m/z 437 [M+H]+ Using (2-methylquinolin-7-yl)acetic acid (Préparation 165).
179	N-{5-((7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5yl)carbonyl]pyridiri-3-yl}-2-phenylacetamide	LCMS (system 5): Rt = 2.37 min; m/z 372 [M+H]+
180	2-(2-chloro-6-fiuorophenyl)-N~(5-[(7-rnethyl-7Hpyrrolo[2,3-d]pyrimidin-5-yl)carbonyl]pyridin-3yl}acetamide	LCMS (system 5): Rt = 2.51 min; m/z 424 [M+Hf
181	2-(4-methoxyphenyl)-N-{5-{(7-methyl-7Hpyrrolo[2,3-d]pyrimidin-5-yl)carbonyl]pyridin-3yl}acetamide	LCMS: Rt = 2.22 min; m/z 402 [M+H]+
182	N45-[(7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5yl)carbonyl]pyridin-3-yl}-2-{4[(trifluoromethyl)thio]phenyl}acetamide	LCMS (system 5): Rt = 2.90 min; m/z 472 [M+Hf
183	2-biphenyl-4-yl-N-{5-[(7-methy!-7H-pyrro!o[213d]pyrimidin-5-yl)carbonyl]pyridin-3-yi}acetamide	LCMS (system 6): Rt = 2.67 min; m/z 448 [M+H]+
184	N-{5-[(7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5yl)carbonylJpyridin-3-yl}-2-(2,4,5trifluorophenyl)acetamide	LCMS (system 5): Rt = 2.54 min; m/z 426 (M+H]+
185	N-{5-[(7-methyl-7H-pyrrolo[213-d]pyrimidin-5yl)carbonyl]pyrïdin-3-yl}-2-{3[(trifluoromethyl)thio]phenyl}acetamide	LCMS (system 5): R( = 2.86 min; m/z 472 [M+H]+
186	2-(4-methylpheny))-N-{5-[(7-methyl-7Hpyrroto[2,3-d]pyrimidin-5-yl)carbonyl]pyridin-3yl}acetamide	LCMS (system 5): R( = 2.53 min; m/z 386 [M+HJ*
187	N-{5-[(7-methyl-7H-pyrrolo[2l3'd]pyrimidin-5yl)carbonyl]pyridin-3-yl}-2-(3,4,5trifluorophenyl)acetamide	LCMS (system 5): R| = 2.62 min; m/z 426 [M+H]+

188	2-(2,4-dimethylphenyl)-N-(5-[(7-methyl-7Hpyrrolo(2,3-d]pyrimidin-5-yl)carbonyl]pyridin-3yi}acetamide	LCMS (System 5): Rt = 2.64 min; m/z 400 [M+H]+
189	2-(2,3-dihydro-1-benzofuran-5-yl)-N-{5-[(7methyl-7H-pyrrolo[2,3-d]pyrimidin-5yl)carbonyl]pyridin-3-yl}acetamide	LCMS (system 5): R( = 2.37 min; m/z 414 [M+H]+
190	2-(2,5-difluorophenyl)-N-{5-[(7-methyl-7Hpyrrolo[2,3-d]pyrimidin-5-yl)carbonyl]pyridin-3yl}acetamide	LCMS (system 5): Rt = 2.44 min; m/z 408 [M+H]+
191	2-(2,4-difluorophenyl)-N-(5-[(7-methyl-7Hpyrrolo[2,3-d]pyrimidin-5-yl)carbonylÎpyridin-3yljacetamide	LCMS (system 5): R, = 2.46 min; m/z 408 [M+H]+
192	2-[2-fluoro-3-(trifluoromethyl)phenyl]-N-{5-[(7methyl-7H-pyrrolo[2,3-d]pyrimidin-5yl)carbonyl]pyridin-3-yl}acetamide	LCMS (System 5): Rt = 2.72 min; m/z 458 [M+HJ+
193	2-(2,6-difluorophenyl)-N-{5-[(7-methyl-7Hpyrrolo[2,3-d]pyrimidin-5-yl)carbonyl]pyridin -3yl}acetamide	LCMS (system 5): Rt = 2.41 min; m/z 408 [M+H]+
194	N-{54(7-methyl’7H-pyrrolo[2,3-djpyrimidin-5yl)carbonyl]pyridin-3-yl}-2-[3(trifluoromethyl)phenyl]acetamide	LCMS (System 2): Rt = 1.6 min; m/z 440 [M+Hf
195	2-(3,4-difluorophenyl)-N-{5-[(7-methyl-7Hpyrrolo[2,3-d]pyrimidin-5-yl)carbonyljyridine-3yl}acetamide	LCMS (System 2): Rt = 1.5 min; m/z 408 [M+H]+
196	N-{5-[(7-methyl-7H-pyrro!o[2,3-d]pyrimidin-5yl)carbonyl]yridine-3-yl}-2-[4(trifluoromethoxy)phenyl]acetamide	LCMS (System 2): Rt = 1.6 min; m/z 456 [M+H]+
197	2-(3-chlorophenyl)-N-{5-[(7-methyl-7Hpyrrolo[2,3-d]pyrimidin-5-yl)carbonyl]yridine-3yl}acetamide	LCMS (System 2): R(= 1.5 min; m/z 406 [M+H]+

Example 198: 3-(2-οΜθΓθρΜθηγΙ)-Ν45-[(7-πιβΙήγΙ’7Η-ργΓΓθΙο[2,3-€1]ργΓίΓηί€ΐΐη-5-νΙ)θ3ΓϋοηγΙ]ργΐΊΰΐη-3yl}propanamide

The title compound was prepared according to the method described above for Example 167 starting from (5-aminopyridin-3-yl)(7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (Préparation 110) and 3(2-chlorophenyl)propanoic acid.

LCMS (system 5): R_t = 2.66 min; m/z 420 [M+H]⁺

The following Examples were prepared according to Method b (Example 1 using DIPEA) as described above starting from (5-aminopyridin-3-yl)(7-tert-butyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (Préparation 31) and the appropriate acids.

Example	Name	Data
199	N45-[(7-tert-butyl-7H-pyrrolo[2,3d]pyrimidin-5-yl)carbonyl]pyridin- 3- yl}-2-(2-cyclopropyl-1,3-oxazol- 4- yl)acetamide	LCMS (system 9): R, = 3.16 min; m/z 445 [M+Hf using (2-cyclopropyl-1,3-oxazol-4-yl)acetic acid (Préparation 155).
200	N-{5-[(7-tert-butyl-7H-pyrrolo[2,3d]pyrimidin-5-yl)carbonyl]pyridin3-yl}-2-[3- (methylsu If on y I) phenyllacetam ide	LCMS (system 9): Rt = 2.87 min; m/z 492 [M+H]+
201	N-{5-[(7-tert-butyl-7H-pyrrolo[2,3d]pyrimidin-5-yl)carbony)]pyridin- 3- yl}-2-( 1,3-dimethyl-l H-pyrazol- 4- yl)acetamide	LCMS (System 9): Rt = 2.76 min; m/z 432[M+Hf
202	N45-[(7-tert-butyl-7H-pyrrolo[2,3d]pyrimidin-5-yl)carbonyl]pyridin3-yl}-2-( 1 -methyl-1 H-pyrazol-4yl)acetamide	LCMS (system 9): R| = 2.73 min; m/z 418[M+H]*
203	N-{5-[(7-tert-butyl-7H-pyrrolo[2,3d]pyrimidin-5-yl)carbonyl]pyridin3-yl}-2-(3-cyclopropyl-1-methyl- 1 H-pyrazol-4-yl)acetamide	LCMS (system 9): Rt = 2.80 min; m/z 458 [M+H]+ using (3-Cyclopropyl-1-methyl-1 H-pyrazol-4-yl)-acetic acid (Préparation 125)

Example 204: N-[5-({7-[(1 S)-2-hydroxy-1 -methylethyl]-7H-pyrrolo[2,3-d]pynmidin-5-yl}carbonyl)pyridin-3yl]-2-[3-(trifluoromethyl)phenyl]acetamide

10% Hydrochloric acid in 1,4- dioxane (0.2 mL) was added to N-(5-{7-[(S)-2-(tert-Butyl-dimethyl10 silanyloxy)-1-methyl-ethyl]-7H-pyr ro!o[2,3-d]pyrimidine-5-carbonyl}-pyridin-3-yl)-2-(3-trif!uoromethyl-phenyl)-acetamide (Préparation 105, mg, 0.098 mmol) in THF (2 mL) and the mixture was stirred at room température for 18 hours. The mixture was evaporated in vacuo and triturated with ether-pentane to afford the title compound as an off white solid in 86% yield, 41 mg.

LCMS (system 9): Rt = 2.97 min; m/z 484 [M+H]⁺.

The following Examples were prepared according to the method described above for Example 204 using the appropriate préparations as described.

Example

Name

Data

205	N-[5-({7-[( 1 R)-2-hydroxy-1 -methylethyl]-7Hpyrrolo[2,3-d]pyrimidin-5-yl}carbonyl)pyridin-3-yl]-2[3-(trifluoromethyl)phenyl]acetamide	LCMS (system 9): Rt = 2.89 min; m/z 484 [M+H]+ Using (Préparation 142).
206	N-[5-({7-[(1 R)-2-hydroxy-1 -methylethyl]-7Hpyrrolo[2,3-d]pyrimidin-5-yl}carbonyl)pyridin-3-yl]-2(4-isopropyl-1 H-1,2,3-triazo I-1 -yljacetamide	LCMS (system 9): Rt = 2.52 min; m/z 449 [M+Hf Using (Préparation 144).
207	N-[5-({7-[(1 R)-2-hydroxy-1 -methylethyl]-7Hpyrrolo[2,3-d]pyrimidin-5-yl}carbonyl)pyridin-3-yl]-2[1 -isopropyl-5-(trifluoromethyl)-1 H-pyrazol-4yl]acetamide	LCMS (system 9): Rt = 2.87 min; m/z 516 [M+Hf Using (Préparation 150).
208	2-(4-cyanophenyl)-N-[5-({7-[(1 R)-2-hydroxy-1 methylethyl]-7H-pyrrolo[2,3-d]pyrimidin-5yl}carbonyl)pyridin-3-yl]acetamide	LCMS (system 9): Rt = 2.68 min; m/z 441 (M+Hf Using (Préparation 151).
209	N-[5-({7-[ ( 1 R)-2-hydroxy-1 -methylethyl]-7Hpyrrolo[2,3-d]pyrimidin-5-yl}carbonyl)pyridin-3-yl]-2[3- (methylsu Ifonyl) phenyljacetam tde	LCMS (system 9); Rt = 2.57 min; m/z 494 [M+Hf Using (Préparation 152).
210	N-[5-({7-[(1 R)-2-hydroxy-1 -methylethyl]-7Hpyrrolo[2,3-d]pyrimidin-5-yl}carbonyl)pyridin-3-yl]-2quinolin-7-ylacetamide	LCMS (system 9): Rt = 1.96 min; m/z 467 [M+Hf Using (Préparation 153).

The following Examples were prepared according to the method described above for Example 34 at 50°C, starting from [2-amino-7-(2-hydroxy-1 -methylethyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl](5-aminopyridin3-yl)methanone (enantiomer 1, Préparation 57) and the appropriate acids.

Example	Name	Data
211	N-(5-[[2-amino-7-(2-hydroxy-1-methylethyl)7H-pyrrolo[2,3-d]pyrimidin-5yl]carbonyl}pyridin-3-yl)-2-quinolin-7ylacetamide	LCMS (system 10); Rt = 2.48 min; m/z 482 [M+Hf
212	N-(5-([2-amino-7-(2-hydroxy-1-methylethyl)7H-pyrrolo[2,3-d]pyrimidin-5yl]carbonyl)pyridin-3-yl)-2-(4cyanophenyljacetamide	LCMS (system 10): Rt = 2.57 min; m/z 456 [M+Hf
213	N-(5-{[2-amino-7-(2-hydroxy-1-methylethyl)7H-pyrrolo[2,3-d]pyrlmidin-5yl]carbonyl}pyridin-3-yl)-2-[3(trifluoromethyl)phenyljacetamide	LCMS (system 10): Rt = 2.87 min; m/z 499 [M+Hf

The following Examples were prepared according to the method described above for Example 34 at 50°C, starting from [2-amino-7-(2-hydroxy-1-methylethy))-7H-pyrrolo[2,3-d]pyrimidin-5-yl](5-aminopyridin3-yl)methanone (enantiomer 2, Préparation 59) and the appropriate acids.

Example	Name	Data
214	N-(5-{[2-amino-7-(2-hydroxy-1-methylethyl)-7H-	LCMS (system 9): Rt = 2.26

	pyrrolo[2,3-d]pyrimidin-5-yl]carbonyl}pyridin-3-yl)-2-(4- cyanophenyljacetamide	min; m/z 456 [M+H]+
215	N-(5-{[2-amino-7-(2-hydroxy-1-methylethyl)-7Hpyrrolo[2,3-d]pyrimidin-5-yl]carbonyl}pyridin-3-yl)-2-[3(trifluoromethyl)phenyl]acetamide	LCMS (system 9): Rt = 2.72 , min; m/z 499 [M+H]+
216	N-(5-([2-amino-7-(2-hydroxy-1-methylethyl)-7Hpyrrolo[2,3-d]pyrimidin-5-yl]carbonyl}pyridin-3-yl)-2quinolin-7-ylacetamide	LCMS (system 9): Rt = 1.62 min; m/z 482 [M+H]+

The following Examples were prepared according to the method described above for Example 34 at 50°C starting from (5-aminopyridin-3-yl)(7-oxetan-3-yl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (Préparation 100) and the appropriate acid.

Example	Name	Data
217	2-(3,4-dichlorophenyl)-N-(5-[(7-oxetan-3-yl-7H-pyrrolo[2,3- d]pyrimidin-5-yl)carbonyl]pyridin-3-yl}acetamide	LCMS (system 3): R, = 3.04 min; m/z 482 [M+H]+
218	2-(4-cyanophenyl)-N-{5-[(7-oxetan-3-yl-7H-pyrrolo(2,3d]pyrimidin-5-yl)carbonyl]pyridin-3-yi}acetamide	LCMS (System 2): Rt = 1.3 min; m/z 439 [M+H]+
219	2-(4-chlorophenyl)-N-{5-[(7-oxetan-3-yl-7H-pyrrolo[2,3d]pyrimidin-5-yl)carbonyl]pyridin-3-yl}acetamide	LCMS (System 2): Rt= 1.5 min; m/z 448 [M+Hf
220	2-(3-chlorophenyl)-N-{5-[(7-oxetan-3-yl-7H-pyrrolo[2,3d]pyrimidin-5-yl)carbonyl]pyridin-3-yl}acetamide	LCMS (System 2): Rt = 1,5 min; m/z 448 [M+H]+
221	2-(3-cyanophenyl)-N-(5-[(7-oxetan-3-yl-7H-pyrrolo[2,3d]pyrimidin-5-yl)carbonyl]pyridin-3-yl}acetamide	LCMS (System 2): Rt = 1.3 min; m/z 439 [M+H]+
222	N-i5-[(7-oxetan-3-yl'7H-pyrrolo[2,3-d]pyrimidin-5yl)carbonyl]pyridin-3-yl}-2-quinolin-7-ylacetamide	LCMS (System 2): Rt = 1.0 min; m/z 465 [M+H]+
223	2-(6-chloroimidazo[112-a]pyridin-2-yl)-N-{5-[(7-oxetan-3-yl- 7H-pyrrolo[2,3-d]pyrimidin-5-yl)carbonyl]pyridin-3yl}acetamide	LCMS (System 2): Rt = 1.0 min; m/z 488 [M+H]*
224	N-(5-[(7-oxetan-3-yl-7H-pyrrolo[2,3-d]pyrimidin-5yl)carbonyl]pyridin-3-yl}-2-(1 -oxo-1,3-dihydro-2H-isoindol-2yljacetamide	LCMS (System 2); Rt = 1.3 min; m/z 469 [M+H]+

The following Examples were prepared according to the method described above for Example 204, using the préparations as described.

Example	Name	data
225	2-(4-cyanophenyl)-N-(5-{[7-(2-hydroxy-1,1-	LCMS (System 9): R( = 2.74 min; m/z

226

227

228 dirnethylethyl)-7H-pyrrolo[2,3-d]pyrimidin-5yl]carbonyl}pyridin-3-yl)acetamide

N-(5-([7-(2-hydroxy-1,1 -dimethylethyl)-7Hpyrrolo[2,3-d]pyrimidin-5-yl]carbonyl}pyridin-3yl)-2-[3-(trifluoromethyl)phenyl]acetamide

N-(5-([7-(2-hydroxy-1,1-dimethylethyl)-7Hpyrrolo[2,3-d]pyrimidin-5-yl]carbonyl)pyridin-3yl)-2-(4-isopropyl-1 H-1,2,3-triazol-1 yl)acetamide

N-(54[7-(2-hydroxy-1,1-dimethylethyl)-7H’ pyrrolofë.S-dÎpyrimidin-S-ylJcarbonylJpyridin-Syl)-2-quinolin-7-ylacetamide

455.4 [M+H]⁺

Using Préparation 131

LCMS (System 9): R| = 2.99 min; m/z 498 [M+H]⁺

Using Préparation 136 ’H NMR (400 MHz, DMSO) δ: 1.22 (d, 6H), 1.71 (s, 6H), 2.96 (m, 2H), 3.94 (s, 2H), 5.35 (s, 2H), 7.87 (s, 1H), 8.20 (s, 1H), 8.44 (s, 1H), 8.75 (s, 1 H), 8.98 (m, 2H), 9.46 (s, 1H), 11 (s, 1H)

Using Préparation 144

LCMS (System 9): R₍ = 2.61 min; m/z 481 [M+Hf

Using Préparation 140

Example 229; racemic 2-{5-[(5-{[(4-Chlorophenyl)acetyl]amino}pyridrn-3-yl)carbonyl]-7H-pyrrolo[2,3d]pyrimidin-7-yl}propanamide

2-bromopropionamide (46.5 mg, 0.31 mmol) was added to a mixture of 2-(4-chlorophenyl)-N-[5-(7Hpyrrolo[2,3-d]pyrimidin-5-ylcarbonyl)pyridin-3-yl]acetamide (Example 308, 100 mg, 0.26 mmol) and césium carbonate (150 mg, 0.46 mmol) in DMF (1.3 mL). The mixture was stirred at 60°C for 3 hours. The reaction mixture was cooled and water (10 mL) was added. The mixture was extracted with EtOAc (3x10 mL) and the combined organic phases were passed through a phase separartor and evaporated in vacuo. Purification by préparative HPLC gave the title compound as a white solid in 34% yield, 15 mg.

LCMS (System 3); R_t = 2.13 min; m/z 463 [M+Hf.

Example 230: racemic 2-{5-[(5-{[(4-Chlorophenyl)acetyl]amino}pyridin-3-yl)carbonyl]-7H-pyrrolo[2,3d]pyrimidin-7-yl}-N,N-dimethylpropanamide

The titre compound was prepared according to the method described for Example 34 at 50°C using racemic 2-{5-[(5-{[(4-chlorophenyl)acetyl]amino}pyridin-3-yl)carbonyl]-7H-pyrrolo[2,3-d]pyrimidin-7yl}propanoic acid (Example 354) and dimethylamine. Purification was accomplished by préparative HPLC (method 1) to afford the title compound.

LCMS (system 3): R₍ = 2.39 min; m/z 491 [M+H]⁺.

Example 231 : racemic 2-{5-[(5-{[(4-Chlorophenyl)acetyl]amino}pyridin-3-yl)carbonyl]-7H-pyrrolo[2₁3d]pyrimidin-7-yl)-N-methylpropanamide

The title compound was prepared according to the method described for Example 34 at 50°C using 2-{5[(5-{[(4-chlorophenyl)acetyl]amino)pyridin-3-yl)carbonyl]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}propanoic acid

(Example 354) and methylamine. Purification was accomplished by préparative HPLC (method 1) to afford the titie compound.

LCMS (System 3): R_t = 2.31 min; m/z 477 [M+Hf.

Example 232: 2-(4-Cyanophenyl)-N-[5-«7-[2-hydroxy-1 -(hydroxymethyi)-l -methylethyl]-7H-pyrrolo[2,3d]pyrimidin-5-yl}carbonyl)pyridin-3-yl]acetamide

4- Cyanophenylacetic acid (19 mg, 0.10 mmol) was added to (5-aminopyridin-3-yl)(7-[2-([tertbutyl(dimethyl)silyl]oxy}-1-({(tert-butyl(dimethyl)silyl]oxy}methyi)-1-methylethyl]’7H-pyrrolo[2,3-d]pyrimidin-

5- yl}methanone (Préparation 116, 54 mg, 0.97 mmol), 1-propylphosphonic acid cyclic anhydride (0.17 mL, 0.291 mmol) and triethylamine (0.047 mL, 0.291 mmol) in tetrahydrofuran (3 mL). The mixture was stirred at 50°C for 16 hours. Saturated aqueous sodium bicarbonate (5 mL) was added then extracted with dichloromethane (3x7 mL), The combined organic phases were dried over magnésium sulphate and evaporated in vacuo.

The residue was dissolved in tetrahydrofuran (3 mL) and a tetrabutylammonium fluoride solution in THF (1 mL of a1M solution, 1 mmol) was added and the solution was stirred for 1 hour. Saturated aqueous sodium bicarbonate (5 mL) was added then extracted with dichloromethane (3x5 mL). The combined organic phases were dried over magnésium sulphate, evaporated in vacuo and purified by préparative HPLC (method 2).

LCMS (System 4): R_t = 2.52 min; m/z 471 [M+HJ*

The following Examples were prepared according to the method described above for Example 232 starting from (5-aminopyridin-3-yl){7-[2-{[tert-butyl(dimethyl)silyljoxy}-1 -({[tertbutyl(dimethyl)silyl]oxy}methyl)-1-methylethyl]-7H-pyrro!o[2,3-d]pyrimidin-5-yl}methanone (Préparation 116) and the appropriate acids.

Example	Name	Data
233	N-[5-({7-[2-hydroxy-1 -(hydroxymethyi)-l methylethyl]-7H-pyrrolo[2,3-d]pyrimidin-5yl}carbonyl)pyridin-3-yl]-2-quinolin-7-ylacetamide	LCMS (System 4) Rt = 2.52 min; m/z 497 [M+H]+ Prep method 1
234	N-(5-({7-[2-hydroxy-1 -(hydroxymethyl)-l methylethyl]-7H-pyrrolo[2,3-d]pyrimidin-5yl}carbonyl)pyridin-3-yl]-2-[5-methyl-3(trif luoromethyl) -1 H-pyrazol-1 -yljacetamide	LCMS (System 4) Rt = 2.69 min; m/z 518(M+Hf Prep method 1
235	2'(4-chlorophenyl)-N-[5-((7-[2-hydroxy-1-	LCMS (System 4) Rt = 2.83 min; m/z

	(hydroxymethyl)-1-methylethyl]-7H-pyrrolo[2,3d]pyrimidin-5-yl}carbonyl)pyridin-3-yl]acetamide	480 [M+H]+ Prep method 1
236	N-[5-((7-[2-hydroxy-1 -(hydroxymethyl)-l methylethyl]-7H-pyrrolo[2,3-d]pyrimidin-5y IJcarbon y 1 ) py r id i n -3 - y 1] - 2- [4 (trifluoromethyl)phenyl]acetamide	LCMS (system 4) Rt = 2.81 min; m/z 514[M+H]+. Prep method 1
237	2-(5-chloropyridin-2-yl)-N-[5-({7-[2-hydroxy-1(hydroxymethyl)-1-methylethyl]-7H-pyrrolo[2,3d]pyrimidin-5-yl}carbonyl)pyridin-3-yl]acetamide	LCMS (system 3) Rt = 2.37 min; m/z 481 [M+H]+ Prep method 1 Using (5-chloropyridin-2-yl)acetic acid (Préparation 90).
238	N-[5-({7-[2-hydroxy-1 -(hydroxymethyt)-l methyiethyl]-7H-pyrrolo[2,3-d]pyrimidin-5yl}carbonyl)pyridin-3-yl]-2-[3(trifluoromethyl)phenyl]acetamide	LCMS (system 4) Rt = 2.84 min; m/z 514[M+H]+ Prep method 1
239	N-[5-((7-[2-hydroxy-1 -(hydroxymethyl)-l methylethyl]-7H-pyrroio[2,3-d]pyrimidin-5yl}carbonyl)pyridin-3-yl]-2-[3-(trifluoromethyl)-1Hpyrazol-1 -yljacetamide	LCMS (system 3) Rt = 2.59 min; m/z 504 [M+H]+ Prep method 2

The following Examples were prepared according to the method described above for Example 1 using DIPEA and purification by préparative HPLC, starting from (2-amino-7-isopropyl-7H-pyrrolo[2,3d]pyrimtdin-5-yl)(5-aminopyridin-3-yl)methanone (Préparation 122) and the appropriate acids.

Example	Name	Data
240	N-{5-[(2-amino-7-isopropyl-7H-pyrrolo[2,3d]pyrimidin-5-yl)carbonyl]pyridin-3-yl}-2-[4(trifluoromethyl)-l H-1,2,3-triazol-1-yljacetamide	LCMS (System 9): Rt = 2.57 min; m/z 474 [M+H]+ Using 4-(trifluoromethyl)-1 H-1,2,3- triazol-1-yl]acetic acid (Préparation 81).
241	N~{5-[(2-amino-7-isopropyl-7H-pyrrolo[2,3d]pyrimidin-5-yl)carbonyl]pyridin-3-yl}-2-(4cyanophenyljacetamide	LCMS (System 9): R( = 2.56 min; m/z 440 [M+H]+
242	N-{5-[(2-amino-7-isopropyl-7H-pyrrolo[2,3d]pyrimidin-5-yl)carbonyl]pyridin-3-yl}-2-(5chloropyridin-2-yl)acetamide	LCMS (System 9); R, = 2.46 min; m/z 450 [M+H]+ ' Using -(5-chloropyridin-2-yl)acetic acid (Préparation 90).
243	N-{5-[(2-amino-7-isopropyl-7H-pyrrolo[2,3d]pyrimidin-5-yl)carbonyl]pyridin-3-yl}-2-(5fluoropyridin-2-yi)acetamide	LCMS (System 9): R, = 2.20 min; m/z 434 [M+HJ+ Using (5-fluoropyridin-2-yi)acetic acid (Préparation 92).
244	N-{5-[(2-amino-7-isopropyl-7H-pyrrolo[2,3d]pyrimidin-5-yl)carbonyl]pyridin-3-yl}-2-[4(trifluoromethyl)phenyljacetamide	LCMS (System 10): Rt = 3.22 min; m/z 483 [M+H]+
245	N45-[(2-amino-7-isopropyl-7H-pyrrolo[2,3d]pyrimïdin-5-yl)carbonyl]pyridin-3-yl}-2-[3(trifluoromethyl)phenyljacetamide	LCMS (System 10): Rt= 3.22 min; m/z 483 [M+Hf ·
246	N-{5-[(2-amino-7-isopropyl-7H-pyrrolo[2,3d]pyrimidin-5-yl)carbonyl]pyridÎn-3-yl}-2-(1,3benzoxazol-5-yl) acetam ide	LCMS (System 9): R| = 2.22 min; m/z 456 [M+HJ*

247	N-{5-[(2-amino-7-isopropyl-7H-pyrrolo[2,3d]pyrimidin-5-yl)carbonyl]pyridin-3-yl}-2-[3(methylsulfonyl)phenyl]acetamide	LCMS (System 9): R, = 2.15 min; m/z 493 [M+H]+ '
248	N-{5-[(2-amino-7-isopropyl-7H-pyrrolo[2,3d]pyrimidin-5-yl)carbonyl]pyndin-3-yl}-2-(4isopropyl-1 H-1,2,3-triazol-1 -yl)acetamide	LCMS (System 9): Rt = 2.16 min; m/z 448 [M+H]+
249	N-[5-[(2-amino-7-isopropyl-7H-pyrrolo[2,3d]pyrimidin-5-yl)carbonyl]pyridin-3-yl}-2-(4cyclopropyl-1 H-1,2,3-triazol-1 -yljacetamide	LCMS (System 9): Rt = 2.01 min; m/z 446 [M+HJ* Using Préparation 83
250	N-Î5-[(2-amino-7-isopropyl-7H-pyrrolo[2,3d]pyrimidin-5-yl)carbonyi]pyridin-3-yl}-2-(4chlorophenyl)acetamide	LCMS (System 10): Rt= 3.03 min; m/z 449 [M+H]+ .
251	N-{5-[(2-amino-7-isopropyl-7H-pyrrolo[2,3d]pyrimidin-5-yl)carbonyl]pyridin-3-yl}-2-[1isopropyl-5-(trifluoromethyl)-1 H-pyrazol-4yljacetamide	LCMS (System 10): Rt = 3.03 min; m/z 515 [M+H]+ Using Prep 185
252	N-{5-[(2-amino-7-isopropyl-7H-pyrrolo[2,3d]pyrimidin-5-yl)carbonyl]pyridin-3-yl}-2-[3(trifluoromethyl)-l H-pyrazol-1 -yljacetamide	LCMS (System 10): R, = 2.92 min; m/z 473 [M+H]+
253	N-{5-[(2-amino-7-isopropyl-7H-pyrrolo[2,3d]pyrimidin-5-yl)carbonyl]pyridin-3-yl}-2-(3cyclopropyl-1 H-pyrazol-1 -yljacetamide	LCMS (System 9) Rt 2.46 min; m/z 445 [M+H]+
254	N-{5-[(2-amino-7-isopropyl-7H-pyrrolo[2,3d]pyrimidin-5-yl)carbonyl]pyridin-3-yl}-2-[1 isopropyl-3-(trifluoromethyl)-1H-pyrazol-4yljacetamide	LCMS (System 9): Rt = 2.77 min; m/z 515[M+H]+

Example 255: N-{5-[(2-amino-7-Îsopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)carbonyl]pyridin-3-yl}-2-(5cyanopyridin-2-yl)acetamide

The title compound was prepared according to the method described for Example 166 using N-{5-[(2amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)carbonyl]pyridin-3-yl}-2-(5-bromopyridin-2-yl)acetamide (Example 318) to afford the title compound in 45% yield, 30 mg. ¹H NMR (400 MHz, DMSO-d6) ô: 1.45 (d, 6H), 4.06 (s, 2H), 4.84 (m, 1 H), 6.62 (s, 2H), 7.66 (d, 1H), 7.97 (s, 1H), 8.29 (dd, 1H), B.37 (t, 1H), 8.66 (d, 1H), 8.92 (s, 1H), 8.95-8.98 (m, 2H), 10.75 (s, 1H);LCMS (System 10): R, = 2.49 min; m/z 441 [M+H]⁺.

The following Exampies were prepared according to the method described above for Example 34 at 50°C starting from [2-amino-7-(2-hydroxy-1,1-dimethylethyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl](5-aminopyridin-3yljmethanone (Préparation 48) and the appropriate acids.

Example	Name	Data
256	N-(5-{[2-amino-7-(2-hydroxy-1,1-dimethylethyl)-7Hpyrrolo[2,3-d]pyrimidin-5-yl]carbonyl}pyridin-3-yl)-2-[3(trifluoromethyl)phenyljacetamide	LCMS (System 10): R, = 2.91 min; m/z 513 [M+H]+
257	N-(5-([2-amino-7-(2-hydroxy-1,1-dimethylethyl)-7Hpyrrolo[2,3-d]pyrimidin-5-yl]carbonyl}pyridin-3-yl)-2-(1,3benzoxazol-5-yl)acetamide	LCMS (System 10): R, = 2.48 min; m/z 486 [M+H]+
258	N-(5-{[2-amino-7-(2-hydroxy-111-dimethylethyl)-7Hpyrrolo[2,3-d]pyrimidin-5-yl]carbonyl}pyridin-3-yl)-2-[3(methylsulfonyl)phenyl]acetamide	LCMS (System 10): Rt = 2.50 min; m/z 523 [M+Hf
259	N-(5-{[2-amino-7-(2-hydroxy-1,1 -dimethylethyl)-7Hpyrro!o[2,3-d]pyrimidin-5-yl]carbonyl}pyridin-3-yl)-2-(4cyanophenyljacetamide	LCMS (System 10): Rt = 2.62 min; m/z 470 [M+H]+
260	N-(5-{[2-amino-7-(2-hydroxy-1,1-dimethylethyl)-7Hpyrrolo[2,3-d]pyrimidin-5-yl]carbonyl}pyridin-3-yl)-2-[1 isopropyl-S-ftrifluoromethyÔ-IH-pyrazol^-yljacetamide	LCMS (System 10): R( = 2.89 min; m/z 545 [M+Hf Using Prep 185

Example 261: 4-cyano-3-(trifluoromethyl)phenyl)-N-(5-(7-(1,3-dihydroxy-2-methylpropan-2-yl)-7Hpyrrolo[2,3-d]pyrimidine-5-carbonyl)pyridin-3-yl)acetamide

2-(4-cyano-3-(trifiuoromethyl)phenyl)aceticacid (Préparation 164, 29.8 mg, 0.13 mmol) was added to a stirred solution of (5-aminopyridin-3-yl){7-[2-{[tert-butyl(dimethyl)silyl]oxy}-1-(([tertbutyl(dimethyl)silyi]oxy}methyl)-1-methylethyl]-7H-pyrrolo[2,3-cf]pyrinnrdine-5-yl)methanone (Préparation 116, 55.6 mg, 0.10 mmol) and 2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronîum hexafluorophosphate (57 mg, 0.15 mmol) in pyridine (0.5 mL). The mixture was stirred at 50°C for 16 hours, then cooled to room température and partitioned between saturated aqueous sodium bicarbonate (5 mL) and DCM (5 mL). The organic phase was separated and concentrated in vacuo to provide a residue that was dissolved in 3 mL of THF and then treated with 3 mL of a 1N aqueous solution of HCl. The mixture was stirred rapidly for 4 hours at room température and then basified by the addition of 4 mL of a 1N aqueous NaOH solution. The mixture was extracted with three separate 5 mL portions of a 95/5 DCM/MeOH mixture. The combined organic extracts were dried by passage through a phase separator and then concentrated in vacuo to obtain a crude residue. This residue was dissolved in 1 mL DMSO and purified by préparative HPLC to afford the title compound as an off white solid in 56% yield, 30 mg. ¹H NMR (400 MHz, DMSO) δ: 1.68 (s, 3H), 3.83 (m, 2H), 4.01 (S, 2H), 4.19 (m, 2H), 5.00 (m, 2H), 7.82 (m, 1H), 8.01 (d, 1H), 8.18 (m, 1H), 8.21 (s, 1H), 8.66 (S, 1H), 8.97 (m, 2H), 9.40 (s, 1H), 10.78 (s, 1H). LCMS (System 2): R_t = 0.90 min; m/z 539 [M+Hf.

The following Examples were prepared according to the method described above for Example 261, starting from ((5-aminopyridin-3-yl){7-[2-{[tert-butyl(dimethyl)silyi]oxy}-1 -({[tert

butyl(dimethyl)sîlyl]oxy}methyl)-1-methylethyî]-7/7-pyrrolo[2,3-d]pyrimidine-5-yl)methanone (Préparation

116) and tha appropriate acids followed by silyl group deprotection.

Example	Name	Data
262	N-(5-(7-(1,3-dihydroxy-2-methylpropan-2-yl)-7Hpyrrolo[2,3-d]pyrimidine-5-carbonyl)pyridin-3-yl)-2-(3trifluoromethoxy)phenyl)acetamide	LCMS (system 2): Rt = 0.96 min; m/z 516 [M+Hf
263	A/-(5-(7-(1,3-dihydroxy-2-methylpropan-2-yl)-7Hpyrrolo[2,3-d]pyrimidine-5-carbonyl)pyridin-3-yl)-2-{4fluoro-3-(trifluoromethyl)phenyl)acetamide	LCMS (system 2): R( = 1.05 min; m/z 532 [M+Hf
264	A/-(5-(7-(1,3-dihydroxy-2-methylpropan-2-yl)-7Hpyrrolo[2,3-d]pyrimidine-5-carbonyl)pyridin-3-yl)-3(trifluoromethyl)benzamide	LCMS (system 2): Rt = 1.04 min; m/z 500 [M+Hf
265	N-(5-(7-(1.3-dihydroxy-2-methylpropan-2-yl)-7Hpyrrolo[2,3-d]pyrimidine-5-carbonyl)pyridin-3-yl)-3-fluoro4-(trifluoromethyl)benzamide	LCMS (system 2): R( = 1.09 min; m/z 532 [M+Hf

Example 266: 2-[3-(azetidin-1 -ylmethyl)phenyl]-N-{5-[(7-isopropyl-7H-pyrrolQ[2,3'd]pyrimidin-5yl)carbonyl]pyridin-3-yl}acetamide formate sait.

Azetidine hydrochloride (10 mg, 0.11 mmol) was added to a stirred solution of 2-(3-formylphenyl)-N-{5[(7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)carbonyl]pyridin-3-yl}acetamide (Préparation 192, 23 mg, 0.05 mmol) in DCM (1 mL) and acetic acid (0.04 mL, 0.60 mmol). The réaction mixture was stirred for 30 min at room température before addition of sodium triacetoxyborohydride (29 mg, 0.14 mmol) and stirring continued for 3 hours. Water (1 mL) was added and the mixture concentrated in vacuo (with toluene azeotroping). The residue was purified by préparative HPLC to afford the title compound as a formate sait in 12% yield, 3.4 mg.

LCMS: R_t = 2.95 min; m/z 469 [M+Hf.

Example 267: 243-[(3-fluoroazetidin-1-yl)methyl]phenyl}-N-{5-[(7-isopropyl-7H-pyrroto[2,3-d]pyrimidin-5yl)carbonyl]pyridin-3-yl}acetamide

The title compound was prepared according to the method described for Example 266 using 2-(3formylphenyl)-N-{5-[(7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)carbonyl]pyridin-3-y!}acetamide (Préparation 192, 60 mg, 0.14 mmol) and 3-fluoroazetidine to afford the title compound in 16% yield, 11 mg.

LCMS: Rt = 2.75 min; m/z 487 [M+Hf.

Example 268: N-{5-[(7-isopropyi-7H-pyrrolo[2,3-d]pyrimidin-5-yl)carbonyl]pyridin-3-yl}-2-[3'(morpholin'4ylmethyl)phenyl]acetamide formate sait

The title compound was prepared according to the method described for Example 266 using 2-(3formylphenyl)-N-{5-[(7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)carbonyl]pyridin-3-yl}acetamide

(Préparation 192, 60 mg, 0.14 mmol) and morpholine to afford the title compound as a formate sait in

30% yield, 21 mg.

LCMS: R_t = 2.70 min; m/z 499 [M+H]⁺

Examples 269-283 General method:

The mixture of (5-aminopyridin-3-yl)(7-(2,2,3,3,9_l9,10,10-octamethyl-4,8-dioxa-3,9-disilaundecan-6-yl)-7Hpyrrolo[2,3-d]pyrimidin-5-yl)methanone (Préparation 196, 54.2 mg, 0.10 mmol), HATU (57 mg, 0.15 mmol) and the requisite carboxylic acid (0.13 mmol) in pyridine (0.5 mL) were stirred at 50 ’C for 16 hours. After cooling to room température, saturated sodium bicarbonate solution (5 mL) was added and the mixture was extracted with DCM (5 mL). The organic layer was passed through a phase separator and concentrated in vacuo. The resulting residue was dissolved in THF (2 mL) and 1 N aqueous HCl (2 mL) added to the solution. The reaction mixture was stirred for 2 hours at room température and quenched with 1 N aqueous NaOH (3 mL). The mixture was then treated according to one of the following methods: Method A

The mixture was extracted with a mixture of DCM/MeOH (95/5, 5 mL x 3), the combined organic layers passed through a phase separator and concentrated in vacuo to obtain a crude residue. This residue was dissolved in DMSO (1 mL) and purified via HPLC to yield the desired compound.

Method B

The mixture was suspended in DCM/MeOH (95/5, 5 mL), the solid filtered and washed with water (5 mL) and DCM (5 mL) and dried in vacuo to yield the desired compound.

Method C

The mixture was extracted with a mixture of EtOAc/MeOH (95:5, 5 mL x 3), the combined organic layers passed through a phase separator and concentrated in vacuo to obtain a crude residue. This residue was dissolved in DMSO (1 mL) and purified via préparative HPLC to yield the desired compound.

Example	Name	Data
269	N-(5-(7-(1,3-dihydroxypropan-2-yl)-7H-pyrrolo[2,3-d]pyrimidine-5- carbonyl)pyridin-3-yl)-3-(trifluoromethyl)benzamide	LCMS: R, = 2.69 min; m/z 486 [M+H]+
270	2-(4-chlorophenyl)-N-(5-(7-(1,3-dihydroxypropan-2-yl)-7Hpyrrolo[2,3-dlpyrimidine-5-carbonyl)pyridin-3-yl)acetamide	LCMS: Rt = 2.63 min; m/z 466 [Μ+ΗΓ

271	N-(5-(7-(1,3-dihydroxypropan-2-yl)-7H-pyrrolo[2,3-d]pyrimidine-5carbonyl)pyridin-3-yl)-3-(trïfluoromethoxy)benzamide	LCMS: Rt = 2.68 min; m/z 502 [M+H]+
272	N-(5-(7-(1,3-dihydroxypropan-2-yl)-7H-pyrrolo[2,3-d]pyrimidine-5carbonyl)pyridin-3-yl)-2-(quinolin-7-yl)acetamide	LCMS: R,= 1.27 min; m/z 483 (M+H]+
273	N-(5-(7-(1,3-dihydroxypropan-2-yl)-7H-pyrrolo[2,3-d]pyrimidine’5carbonyl)pyridin-3-yl)-2-(4-(trifluoromethyl)phenyl)acetamide	LCMS: R, = 2.69 min; m/z 500 [M+H]+
274	N-(5-(7-(1,3-dihydroxypropan-2-yl)-7H-pyrrolo[2,3-d]pyrimidine-5carbonyl)pyridin-3-yl)-2-(3-(trifluoromethyl)phenyl)acetamide	m/z 500 [M+H]+
275	N-[5-({7-[2-hyd roxy-1 -(hydroxymethyl)ethyl]-7H-pyrrolo[2,3d]pyrimidin-5-yl}carbonyl)pyridin-3-yl]-2-(2-methylquinolin-7yljacetamide	m/z 497 [M+Hf Préparation 165
276	2’(3,4-dichlorophenyl)-N-i5-({7-[2-hydroxy-1’(hydroxymethyl)ethyl]- 7H-pyrrolo[2,3-d]pyrimidin-5-yl}carbonyl)pyridin-3-yl]acetamide	m/z 500 [M+Hf
277	2-[3-’fluoro-4-(trifluoromethyl)phenyl]-N-[5-({7-[2-hydroxy-1(hydroxymethyl)ethyl]-7H-pyrrolo[2,3-d]pyrimidin-5yl}carbonyl)pyridin-3-yl]acetamide	m/z 518 [M+H]+
278	2-(2,4-dichlorophenyl)-N-[5-({7-[2-hydroxy-1-(hydroxymethyl)ethyl]- 7H-pyrrolo[2,3-d]pyrimidin-5-yl}carbonyl)pyridin-3-yl]acetamide	m/z 500 [M+H]+
279	N-[5-({7-[2-hydroxy-1-(hydroxymethyl)ethyl]-7H-pyrrolo[2,3d]pyrimidin-5-yl}carbonyl)pyridin-3-yl]-2-[3(trifluoromethoxy)phenyljacetamide	m/z 516 [M+H]+
280	N-[5-({7-[2-hydroxy-1-(hydroxymethyl)ethyl]-7H-pyrrolo[2,3d]pyrimidin-5-yl}carbonyl)pyridin-3-yl]-2-[4(trifluoromethoxy)phenyl]acetamide	m/z516[M+H]+
281	3-fluoro-N-[5-((7-[2-hydroxy-1-(hydroxymethyl)ethyl]-7H-pyrrolo[2,3- d] pyrimid in-5-yl}carbonyl) pyrid in-3-yl]-5-(trif luoromethyl) benzam ide	m/z 504 [M+H]+
282	2-(5-chloropyridin-2-yl)-N-[5-({7-[2-hydroxy-1-(hydroxymethyl)ethyl]- 7H-pyrrolo[2,3-d]pyrimidin-5-yl}carbonyl)pyridin-3-yl]acetamide	LCMS: R, = 0.90 min, m/z 467 [M+H]+
283	N-[5-({7-[2-hydroxy-1-(hydroxymethyl)ethyl]-7H-pyrrolo[2,3d]pyrimidin-5-yl}carbonyl)pyridin-3-yl]-2-[3-(trifluoromethyl)-1Hpyrazol-1 -yljacetamide	LCMS: Rt = 1.81 min, m/z 490 [M+H]+

Example 2B4: 4-benzoyl-N-a/pf?a-(tert-butoxycarbonyl)-N-{5-[(7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5yl)carbonyl]pyridin-3-yl}-L-phenylalaninamide

(5-aminopyridin-3-yl)(7-isopropyl'7H-pyrrolo[2,3-d]pyrimidin-5-y!)methanone (20 mg, 0.07 mmol) (see Préparation 95) was dissolved in pyridine (1mL) and 4-benzoyl-N-(tert-butoxycarbonyl)-D-phenylalanine was added (26 mg, 0.07 mmol) followed by HATU (27 mg, 0.07 mmol). The mixture was stirred at 50 °C for 5 hours and then cooled, evaporated in vacuo and the crude material was purified by column chromatography on silica gel (gradient of DCM:Methanol 100:0 to 95:5) to afford the title compound as a yellow solid in 52% yield, 23 mg.

Example 285: 4-benzoyl-N-{5-[(7-isopropyl-7H-pyrroto[2,3-d]pyrimidin-5-yl)carbonyl]pyridin-3-yl}-Dphenylalaninamide

4-benzoyl-Nalpha-(tert-butoxycarbonyl)-N-[5-[(7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)carbonyl]pyridin3-yl}-D-phenylalaninamide (Example 284, 20 mg, 0.03 mmol) was stirred with 10% hydrochtoric acid in 1,4-dioxane (5 mL) at room température for 1 hour. The mixture was evaporated in vacuo and purified by préparative HPLC to afford the title compound as a gum in 56% yield, 9 mg.

LCMS (system 5): R_t = 2.89 min; m/z 533 [M+H]*.

Example 286:4-benzoyl-N-a/p/7a-(tert-butoxycarbonyl)-N-{5-[(7-isopropyl-7H-pyrrolo[2,3-dJpyrimidln-5yl)carbonyl]pyridin-3-yl}-L-phenylalaninamide

The title compound was prepared according to Example 284 using (5-aminopyridin-3-yl)(7-isopropyl-7Hpyrrolo[2,3-d]pyrimidin-5-yl)methanone (Préparation 95) and 4-benzoyl-N-(tert-butoxycarbonyl)-L20 phenylalanine

Example 287: 4-benzoyl-N-{5-[(7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)carbonyl]pyridin-3-yl}-Lphenylalaninamide

The title compound was prepared according to the method described for Example 285 using 4-benzoylNalpha-(tert-butoxycarbonyl)-N-{5-((7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)carbonyl]pyridin-3-yl}-L25 phenylalaninamide (Example 286) to afford the title compound in 36% yield, 5 mg.

LCMS (system 4): R, = 2.30 min; m/z 533 [M+H]⁺.

Example 288: 2-(3-benzoylphenyl)-N-(5-(7-isopropyl-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)pyridin-3 yljacetamide

The title compound was prepared according to the method described for Example 34 starting from (5aminopyridin-3-yl)(7-isopropyl-7H-pyrrolo[2_I3-dJpyrimidin-5-yl)methanone (Préparation 95) and 2-(3benzoylphenyljacetic acid to afford the title compound in 86% yield, 31 mg. .

LCMS (system 3): R₍ = 3.05 min; m/z 504 [M+H]⁺.

Example 289 2-(4-benzoylphenyl)-N-(5-(7-isopropyl-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyt)pyridin-3yljacetamide

The title compound was prepared according to the method described for Example 34 starting from (5aminopyridin-3-yl)(7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (Préparation 95) and 2-(4benzoylphenyljacetic acid (JOC, 1961,1635) to afford the title compound in 94% yield, 34 mg. LCMS (system 3): R_t = 3.12 min; m/z 504 [M+H]⁺.

Example 290: N-(5-[(7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)carbonyl]pyridin-3-yl}-3-[3(trifluoromethyl)-3H-diaziren-3-yl]benzamide

The title compound was prepared according to the method described for Example 34 starting from (5aminopyridin-3-yl)(7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (Préparation 95) and 3-[3(trifluoromethyl)-3H-diaziren-3-yl]benzoic acid (Préparation 197) to afford the title compound as a white solid in 36% yield, 23 mg.

¹H NMR (400 MHz, d4-MeOH) δ.Ί.65 (S, 6H), 5.20 (m, 1H), 7.52-7.61 (m, 4H), 7.79 (s, 1H), 8.07 (m, 1H), 8.29 (s, 1H), 8.94 (s, 1H), 8.81 (m, 1H), 9.55 (S, 1H).

Example 291 : N-IS-^-isopropyl^H-pyrrolop.S-dJpyrimidin-S-ylJcarbonylJpyridin-S-ylH-p(trifluoromethyl)-3H-diaziren-3-yl]benzamide

The title compound was prepared according to the method described for Example 34 starting from (5aminopyridin-3-yl)(7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (Préparation 95) and 4-[3(trifiuoromethyl)-3H-diaziren-3-yl]benzoic acid to afford the title compound as a white solid in 4% yield, 2 mg. LCMS (system 3): R₍ = 3.64 min; m/z 494 [M+H]⁺.

Example 292: N-(5-[(7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)carbonyl]pyridin-3-yl}-3(trifluoroacetyl)benzamide

The title compound was prepared according to the method described for Example 34 starting from (5aminopyridin-3-yl)(7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (Préparation 95) and 3(trifluoroacetyl)benzoic acid (Préparation 200) to afford the title compound as a white solid in 80% yield, 41 mg. LCMS (system 3): R_t = 2.52 min; m/z 482 [M+H]⁺.

Example 293: 1-(4-chlorophenyl)’3-{5-[(7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)carbonyl]pyridin-3yljurea

1-chloro-4-isocyanatobenzene (24 mg, 0.15 mmol) was added to (5-aminopyridin-3-yl)(7-methyl-7Hpyrrolo[2,3-d]pyrÎmldin-5-yl)methanone (30 mg, 0.12 mmol) (Préparation 232) in pyridine (1.0 mL). The mixture was stirred at room température overnight then evaporated in vacuo to yield the product as a crude residue. The crude residue was purified by préparative HPLC to afford the title compound in 49% yield, 24 mg.

LCMS: R; = 1.58 min; m/z 407 [M+H]⁺

The following Examples were prepared according to the method described above for Example 293, starting from (5-aminopyridin-3-yl)(7-methy[-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (Préparation 232) and the appropriate isocyanates.

Example	Name	Data
294	1-{5-[(7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5- yl)carbonyl]pyridin-3-yl}-3-[4-(trifluoromethyl)phenyl]urea	LCMS: Rt = 1.64 min; m/z 441 [M+H]+
295	1-{5-[(7’methyl-7H-pyrrolo[2,3-d]pyrimidin-5- yl)carbonyl]pyridin-3-yl}-3-[3-(trifluoromethyl)phenyl]urea	LCMS: Rt = 1.64 min; m/z 441 [M+H]+
296	1-{5-[(7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5- yl)carbonyl]pyridin-3-yl}-3-[4-(trifluoromethoxy)phenyl]urea	LCMS: Rt = 1.67 min; m/z 457 [M+H]+

Example 297: 2-(4-chlorophenyl)-N-{5-[(7-isopropyl-7H-pyrrolo[2,3-dlpyrimidin-5-yl)carbonyl]pyridin-3-yi}N-methylacetamide

(4-chlorophenyl)acetic acid (22 mg, 0.13 mmol) was added to a stirrîng mixture of (7-isopropyl-7Hpyrrolo[2,3-d]pyrimidin-5-yi)[5-(methylamino)pyridin-3-yl]methanone (30 mg, 0.10 mmol) (Préparation 149) andN-[(dimethylamino)(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yloxy)methylene]-N-methylmethanaminium hexafluorophosphate (57 mg, 0.15 mmol) in pyridine (1.0 mL), The mixture was heated to 50 °C for 16 hours, evaporated in vacuo and partitioned between saturated aqueous sodium bicarbonate (10 mL) and EtOAc (10 mL). The aqueous layer was washed with further EtOAc (2x10 mL), The combined organics were dried over Na₂SO₄, filtered and concentrated in vacuo and purified by préparative HPLC to afford the title compound 43% yield, 19 mg, ¹H NMR (400 MHz, DMSO) δ: 1.52 (d, 6H), 3.40 (br. s, 3H), 3.59 (s, 2H), 5.00-5.18 (m, 1 H), 7.00-7.42 (m, 4H), 8.21 (s, 1H), Θ.50 (s, 1H), 8.86 (s. 1 H), 8.90-9.12 (m, 2H), 9.48 (s, 1H);

LCMS: Ri = 2.99 min; m/z 448 [M+H]⁺

The following Example was prepared according to the method described above for Example 297, starting from (7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(5-(methylamino)pyridin-3-yl]methanone (Préparation 149) and the appropriate acid.

Example	Name	Data
298	2-(4-cyanophenyl)-N-{5-[(7-isopropyl-7H-pyrrolo[2,3dlpYrimidin-5-yl)carbonyl]pyridin-3-yl}-N-methylacetamide	LCMS: Rt = 2.86 min; m/z 439 [M+Hf

Example 299: 2-(4-Chloro-phenyl)-N-{5-[7-(3-hydroxymethyl-oxetan-3-yl)-7H-pyrro!o[2,3-d]pyrimidine-5carbonyl]-pyridin-3-yl}-acetamide

N-(5-(7-[3-(tert-Butyl-dimethyl-silanyloxymethyl)-oxetan-3-yl]-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl}pyridin-3-yl)-2-(4-chloro-phenyl)-acetamide (Préparation 203 35 mg, 0.059 mmol) was dissolved in dry THF (0.5 mL) and tetrabutylammonium fluoride (0.065 mL of a 1M solution in THF, 0.065 mmoL) was added. The reaction was stirred for 30 min at room température. The mixture was partitioned between water and EtOAc. The layers were separated and the aqueous layer was· extracted twice with EtOAc.

The combined organic layers were concentrated and purified by préparative HPLC to give the title compound in quantitative yield 28 mg,

LCMS (System 4): R_t = 3.03 min; m/z 478 [M+H]⁺

Example 300: N45-[7-(3-Hydroxymethyl-oxetan-3-yl)-7H-pyrroIo[2,3-d]pynmidine-5-carbonyl]-pyridin-3yl}-2-(4-trifluoromethyl-phenyl)-acetamide:

The title compound was prepared according to the method described for Example 299 starting from N-(5{7-[3-(tert-butyi-dimethyi-silanyloxymethyI)-oxetan-3-yl]-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl}-pyridin-3yl)-2-(4-trifluoromethyl-phenyl)-acetamide (Préparation 204) to afford the title compound as a white solid in quantitative yield, 30 mg. LCMS: R_t = 2.74 min; m/z 512 [M+H]⁺.

Example 301: 2-(5-chloropyridin-2-yl)-N-[5-({7-[3-(hydroxymethyl)oxetan-3-yl]-7H-pyrrolo[2,3-d]pyrimidin5-yl}carbonyl)pyridin-3-yl]acetamide

The title compound was prepared according to the method described for Example 299 starting from N-[5({7-[3-({[tert-butyl(dimethyl)silyl]oxy}methyl)oxetan-3-yl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl)carbonyl)pyridin-3yl]-2-(5-chloropyridin-2-yl)acetamide (Préparation 223) to afford the title compound as a pale yellow liquid in 87% yield, 23 mg. LCMS (System 4): R_t = 1.57 min; m/z 479 [M+Hf.

Example 302: N-[5-({7-[3-(hydroxymethyl)oxetan-3-yl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}carbonyi)pyridin-3 yl]-2-[3-(trifluoromethyl)-1 H-pyrazol-1 -yljacetamide

The title compound was prepared according to the method described for Example 299 starting from N-[5-{{7-[3-({[tert-butyl(dimethyl)silyl]oxy}methyl)oxetan-3-yl]-7H-pyrrolo[2,3-d]pyrimidin-5yl}carbonyl)pyridin-3-yl]-2-[3-(trifluoromethyl)-1 H-pyrazol-1 -yljacetamide (34 mg, 0.055 mmol) (Préparation 224) to give the the title compound in 63% yield, 17.7mg.

LCMS (System 5) R_t = 1.57 min; m/z 502 [M+H]⁺.

Example 303: N-(5-{[7-(2-amino-2-oxoethyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]carbonyl}pyridin-3-yl)-2-(4chlorophenyl)acetamide

To a stirred solution of 2-(4-chlorophenyl)-N-[5-(7H-pyrrolo[2,3-d]pyrimidin-5-ylcarbonyl)pyridin-3yljacetamide (Example 308, 50 mg, 0.13 mmol) in DMF ( 1 ml) was added Cs₂CO₃ (75mg, 0.23 mmol) followed by 2-bromoacetamide (21.3mg, 0.154 mmol). The reaction was then stirred at room température overnight. The reaction was quenched with water (5 mL) and extracted with EtOAc (3x5 mL).

The organics were combined, washed with water (5 mL) then brine (5 mL), dried over anhydrous magnésium sulfate and concentrated in vacuo. Purification by préparative HPLC gave the title compound in 59% yield, 34mg.

LCMS (System 4): R, = 1.56 min; m/z 449 [M+Hf.

Example 304: 2-{5-[(5-{[(4-chlorophenyl)acetyl]amino}pyridin-3-yl)carbonyl]-7H-pyrrolo[2,3-d]pyrimidin-7yl}-N,N-dimethylacetamide {5-[(5-([(4-chlorophenyl)acetyl]amino}pyridin-3-yl)carbonyl]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}acetic acid potassium sait (Example 307, 50 mg, 0.102 mmol) was added to a stirred solution of dimethyl amine HCl (12.5 mg, 0.153 mmol) and HATU (58.2mg, 0.153 mmol) in pyridine (2 mL) and the résultant solution was stirred at 50°C (reactivial) for 14 hours. The reaction was cooled to 25°C, diluted with DCM (5 mL) then quenched with saturated NaHCO₃ (aq) (5 mL) and extracted with further DCM (3x5 mL). The organics were combined, washed with saturated brine (5 mL), dried over anhydrous magnésium sulfate and concentrated in vacuo. Purification by préparative HPLC gave the title compound in 55% yield, 26.6mg. LCMS: R, = 1.86 min; m/z 477 [M+H]⁺.

Example 305: 2-(4-chlorophenyl)-N-[5-({7-[2-(methylamino)-2-oxoethyi]-7H-pyrrolo[2,3-d]pynmidin-5yl}carbonyl)pyridin-3-yl]acetamide {5-[(5~([(4-chlorophenyl)acetyl]amino}pyridin-3-yl)carbonyl]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}acetic acid potassium sait (Example 307, 50 mg, 0.102 mmol) was added to a stirred solution of methyl amine hydrochloride (10.3 mg, 0.153 mmol) and HATU (58.2mg, 0.153 mmol) in pyridine (2 mL) . The résultant solution was stirred at 50 °C (reactivial) for 14 hours. The reaction was cooled to 25 °C, diluted with DCM (5 mL) then quenched with saturated NaHCO₃ (aq) (5 mL) and extracted with further DCM (3x5 mL). The organics were combined, washed with saturated brine (5 mL), dried over anhydrous magnésium sulfate and concentrated in vacuo. Purification by préparative HPLC gave the title compound in 65% yield, 30.5mg.

LCMS: R_t = 2.63 min; m/z 463 [M+Hf.

Example 306 Methyl {5-[(5-{[(4-chtorophenyl)acetyl]amino}pyridin-3-yl)carbonyl]-7H-pyrrolo[2,3d]pyrimidin-7-yl}acetate

To a stirred solution of 2-(4-chlorophenyl)-N-[5-(7H-pyrrolo[2,3-d]pyrimidin-5-ylcarbonyl)pyridin-3yljacetamide (Example 308, 250mg, 0.638 mmol) in DMF (4 mL) was added Cs_zCO₃ (374mg, 1.15 mmol) followed by methyl bromoacetate (73uL, 0.766 mmol). The reaction was stirred at 25 °C for 3 hours and then quenched with water (10 mL) and extracted with EtOAc (3x10 mL). The organics were combined, washed with water (10 mL) and saturated brine (10 mL), dried over anhydrous magnésium sulfate and concentrated in vacuo to give a pale yellow oil (356mg) which solidified on standing. Purification by column chromatography on silica gel (gradient of 0-100% 90:10:1 DCM/MeOH/NH3 in DCM) gave the title compound as a pale yellow solid in 70% yield, 208 mg. ¹HNMR (400MHz, CDCI₃) δ 3.78 (s, 2H), 3.81 (s,

3H), 5.15 (s, 2H), 7.29-7.41 (m, 4H), 7.51 (s, 1H), 7.88 (s, 1H), 8.46 (m, 1H), 8.78-8.82 (m, 2H), 9.04 (s,

H), 9.65 (s, 1 H). LCMS (System 4): R_t = 2.07 min; m/z 464 [M+H]⁺.

Example 307 (5-[(5-{[(4-chlorophenyl)acetyl]amino}pyridin-3-yl)carbonyl]-7H-pyrrolo[2,3-d]pyrimidin-7yl}acetic acid potassium sait

To a suspension of methyl {5-[(5-{[(4-chlorophenyl)acetyl]amino}pyridin-3-yl)carbonyl]-7H-pyrrolo[2₁3d]pyrimidin-7-yl}acetate (Example 306, 197 mg, 0.425 mmol) in MeOH (4 mL) was added an aqueous solution of KOH (0.425 mL of a 1M solution, 0.425 mmol) and then further MeOH (4 mL) was added. The reaction was stirred for 2 hours at room température. The reaction was concentrated in vacuo to give the title compound as a light brown solid in 99% yield, 205 mg.

LCMS (System 4): R, = 1.76 min; m/z 450 [M+H]\

Example 308:2-(4-Chlorophenyl)-N-[5-(7H-pyrro!o[2₁3-d]pyrimidin-5-ylcarbonyl)pyridin-3-yl]acetamide The title compound was prepared according to the method described for Example 46 to afford the title compound as a white solid in 87% yield, 930 mg.

’H NMR (400 MHz, DMSO) âr 3.74 (s, 2H), 7.38 (m, 4H), 8.34 (s. 1H), 8.46 (s, 1H). 8.71 (s, 1H), 8.94 (s,

1H), 8.97 (s, 1 H). 9.45 (s, 1H), 10.66 (s, 1H), 13.14 (s, 1H);LCMS (system 9): R₍ = 2.87 min; m/z 392 [M+H]⁺.

Example 309: 2-(4-chlorophenyl)-N-(5-{[7-(3-methyloxetan-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-5yl]carbonyl}pyridin-3-yl)acetamide

(5-aminopyridin-3-yl)[7-(3-methyloxetan-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]methanone (Préparation 222,15.5 mg, 0.05 mmol) was added to a stirring mixture of 4-chlorophenylacetic acid (11.1 mg, 0.065 mmol) and HATU (28.5 mg, 0.075 mmol) in pyridine (0.25 mL). The mixture was heated to 50 °C and stirred for 16 hours. The mixture was allowed to cool to room température and saturated sodium bicarbonate solution (5 mL) was added. The mixture was extracted with ethyl acetate (3x5 mL) and the combined organic fractions were washed with brine, dried (MgSOi) and the solvent was removed under reduced pressure to obtain the crude product which was autopurified.

LCMS (system 4): R_t = 3.08 min; m/z 462[M+H)⁺.

The following Examples were prepared according to the method described above for Example 309 starting from 5-aminopyridin-3-yl)[7-(3-methyloxetan-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]methanone (Préparation 222) and the appropriate acids.

Example	Name	Data
310	2-(5-chloropyridin-2-yl)-N-(5-([7-(3-methyloxetan-3yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]carbonyi}pyridin-3yljacetamide	LCMS (System 2); Rt = 0.88 min; m/z 463 [M+HJ* Using Préparation 90
311	N-(5-{[7-(3-methy!oxetan-3-yl)-7H-pyrrolo[2,3d]pyrimidin-5-yl]carbonyl}pyridin-3-yl)-2-[3(trifluoromethyl)-l H-pyrazol-1 -yljacetamide	LCMS (System 2): Rt = 0.97 min; m/z 486 [M+H]+
312	N-(5~{[7-(3-methyloxetan-3-yl)-7H-pyrrolo[2,3d]pyrimidin-5-ylJcarbonyl}pyridin-3-yl)-2-[4(trif luoromethy I) -1H-1,2,3-triazo I-1 -yljacetamide	LCMS (System 2): Rt = 0.92 min; m/z 487 [M+H]+ Using Préparation 85

Example 313: 2-(4-chlorophenyl)-N-[5-((7-[(methylthio)methyl]-7H-pyrrolo[2,3-d]pyrimidin-5yl}carbonyl)pyridin-3-yl]acetamide

Potassium carbonate (38 mg, 0.275 mmol) was added to a stirring solution of 2-(4-chlorophenyl)-N-[510 (7H-pyrrolo[2,3-d]pyrimidin-5-ylcarbonyl)pyridin-3-yl]acetamide (Example 308, 60.0 mg, 0.153 mmol) in DMF (1.0 mL) at room température. After 10 min, chloromethyl methyl suifide (19 pL, 0.23 mmol) was added to the mixture and the reaction was stirred for 24 hours at room température. Water (3 mL) was added to the mixture and it was extracted with EtOAc (3x5 mL). The combined organic fractions were washed with water (5 mL), brine (5 mL), dried over magnésium sulfate and concentrated under reduced pressure to give a pale yellow oil. The crude material was purified by column chromatography on silica gel (gradient of 100% DCM to 90:10:1 DCM/MeOH/NH₃) to give the titie compound as a pale yellow solid in 36% yield, 25 mg.

'H NMR (400 MHz, CDCI₃) ô: 2.13 (s, 3H), 3.79 (s, 2H), 5.39 (s, 2H), 7.30-7.34 (m, 3H), 7.40-7.43 (m, 2H), 8.02 (s, 1H), 8.52 (m, 1H), 8.74-8.75 (d, 1 H), 8.82-8.83 (d, 1H), 9.05 (S,1 H), 9.65 (s, 1H); LCMS (system 4): R_t = 1.97 min; m/z 452; 454 [M+Hf.

Example 314 : 2-(4-chlorophenyl)-N-[5-({7-[(methylsulfonyl)methyl]-7H-pyrrolo[2,3-d]pyrimidin-5yl}carbonyl)pyridin-3-yl]acetamide

Potassium peroxomonosulfate (Oxone, 67.2 mg, 0.110 mmol) was added to a stirring solution of 2-(4chlorophenyl)-N-[5-({7-[(methylthio)methyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}ca'rbonyl)pyridin-3-yl]acetamide (Example 313, 25.0 mg, 0.055 mmol) in methanol (1.0 mL) and water (0.25 mL) at 0 °C. After 1 hour, the

reaction was aliowed to warm to room température and stirred for 24 hours. The reaction mixture was cooled to 0 C and sodium metabisulfite (0.5M, 1 ml) was added. The reaction mixture was evaporated under reduced pressure to remove the methanol. Water (3 mL) was added to the mixture and it was extracted with EtOAc (3x5 mL). The combined organicfractions were washed with water (5 mL), brine (5 mL), dried over magnésium sulfate the solvent was removed under reduced pressure to give the crude product as an off-white solid. The crude material was purified by column chromatography on silica gel (gradient of 100% DCM to 90:10:1 DCM/MeOH/NH₃) to give the title compound as a pale yellow solid in 17% yield, 27 mg. LCMS (system 4): R_t = 1 -91 min; m/z 484; 486 [M+Hf.

Example 315: 2-(1-Cyclopropyl-5-trifluoromethyl-1 H-pyrazol-4-yl)-N-[5-(7-isopropyl-7H-pyrrolo [2, 3-d] pyrimidine-5-carbonyl)-pyridin-3-yl]-acetamide

To a solution of (S-Amino-pyridin-S-yO-^-isopropyl^H-pyrrolo^.S-dJpyrimidin-S-yO-methanone (Préparation 95, 50 mg, 0.17 mmol), (1-Cyclopropyl-5-trifluoromethyl-1H-pyrazol-4-yl)-acetic acid (Préparation 141,47.1 mg, 0.21 mmol) and TEA (0.08 mL, 0.62 mmol) in THF (1 mL), 1propylphosphonic acid cyclic anhydride (50% solution in EtOAc, 0.26 mL, 0.44 mmol) was added and the mixture was stirred at room température for 14 hours. The reaction mixture was evaporated under reduced pressure and the residue partitioned between water and ethyl acetate. The organic layer was washed with saturated sodium bicarbonate solution and dried (Na₂SO₄) and evaporated in vacuo. Purification by column chromatography on silica gel (gradient of EtOAciHexane 0:100 to 80:20) gave the title compound as a white solid in 76 % yield, 67 mg. ¹H NMR (400 MHz, DMSO-D6) δ: 1.05-1.07 (m, 2H), 1.08-1.15 (m, 2H), 1.54 (d, 6H), 3.73-3.76 (m, 3H), 5.06-5.13 (m, 1H), 7.55 (s, 1H), 8.44 (s, 1H), 8.51 (s, 1H), 8.73 (s, 1H), 8.94 (d, 1H), 8.99 (s, 1H), 9.44 (s, 1H), 10.61 (s, 1H).LCMS (System 10): R, = 3,03 min m/z 498 [M+Hf

Example 316: N-(5-{[2-amino-7-(1-hydroxy-2-methylpropan-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-5yl]carbonyl}pyridin-3-yl)-2-(5-bromopyridin-2-yl)acetamide

The title compound was prepared according to the method described for Example 34 at 50°C using [2amino-7-(2-hydroxy-1,1-dimethylethyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl](5-aminopyridin-3-yl)methanone (Préparation 48) and (5-bromopyridin-2-yl)acetic acid to afford the title compound as a yellow solid in 60% yield, 75 mg. LCMS (System 10): R_t= 2.69 min; m/z 524 [M+Hf

Example 317: 2-(5-bromopyridin-2-yl)-N-(5-{[7-(propan-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-5yl]carbonyl}pyridin-3-yl)acetamide

The title compound was prepared according to the method described for Example 1 with DIPEA using (5aminopyridin-3-yl)(7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (Préparation 95) and (5bromopyridin-2-yl)acetic acid to afford the title compound as a yellow solid in 45% yield, 75 mg. LCMS (System 9): R_t = 2.97 min; m/z 479 [M+Hf.

Exemple 318 : N-IS-t^-Amino^-isopropyl^H-pyrrolop.S-dlpyrimidin-S-yOcarbonyllpyridin-S-yB^-ÎSbromopyridin-2-yl)acetamide

The title compound was prepared according to the method described for Example 1 with DIPEA using (2amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(5-aminopyridin-3-yl)methanone (Préparation 122) and (5-bromopyridin-2-yl)acetic acid to afford the title compound as a colourless oil in 57% yield, 75 mg.

LCMS (System 10): R_t= 2.81 min; m/z 494 [M+H]⁺.

Library Protocol 1

The compounds below were prepared in parallel in the following manner.

EDCI/ HOBT/ NMM/

DMF/ 50C/ 2 hrs

A 0.25 M stock solution of (5-amino-pyridin-3-yl)-(7-methyl-7H-pyrrolo[2,3’d]pyrimidin-5-yl)-methanone (Préparation 110) in anhydrous DMF was prepared. Stock solutions (0.30 M) of each acid monomer was prepared in anhydrous DMF. A stock solution of EDCI (0.5 M) and HOBT (0.05 M) in anhydrous DMF were prepared. 300pl (90 pmol, ) of each acid monomer solution was dispensed to 8 mL vials, followed by 300 μΙ (75 umol) of (5-amino-pyridin-3-yl)-(7-methyl-7H-pyrrolo[2,3-d]pynmidin-5-yi)-methanone solution. N-methyl morpholine (150 pmol, 2.0 eq), 300 μΙ EDCI solution (150 pmol) and HOBT (15pmol) were added to each vial. The vials were capped and shaken at 50 °C for 2 hours. The solvent was removed using a Speedvac, and the final product purified by HPLC under the conditions listed to provide the final compounds.

Example	Name	Data
319	2-(4-chlorophenyl)-N-{5-[(7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5- yl)carbonyljpyridin-3-yl}acetamide	LCMS: R, = 2.59 min; m/z 406 [M+Hf
320	3-(4-chlorophenyl)-N-{5-[(7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5- yl)carbonyljpyridin-3-yl}propanamide	LCMS: R| = 2.70 min; m/z 420 [M+Hf
321	3-(3-methylphenyl)-N-{5-[(7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5- yl)carbonyl]pyridin-3-yl)propanamide	LCMS: Rt = 2.69 min; m/z 400 [M+H]*
322	N45-[(7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)carbonyl]pyridin-3yl}-3-(pyridin-3-yl)propanamide	LCMS: Rt = 1.80 min; m/z 387 (M+H]+
323	3-(3-chlorophenyl)-N-{5-[(7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5- yl)carbonyijpyridin-3-yl}propanamide	LCMS: Ri = 2.69 min; m/z 420 [M+Hf

324	3-(3-fluorophenyl)-N-{5-[(7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5yl)carbonyl]pyridin-3-yl}propanamide	LCMS: R, = 2.56 min; m/z 404 [M+Hp
325	N-{5-[(7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)carbonyl]pyridin-3- yi)-2-[2-(trifluoromethoxy)phenoxy]acetamide	LCMS: Rt = 2.80 min; m/z 472 [M+Hp
326	3-(2-methylphenyl)-N-{5-[(7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5- yl)carbonyl]pyridin-3-yl}propanamide	LCMS:Rt = 2.63 min; m/z 400 [M+Hp
327	3-(2-fluorophenyl)-N-{54(7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5- ' yl)carbonyi]pyridin-3-yl}propanamide	LCMS: Rt = 2.53 min; m/z 404 [M+Hp
328	3-(4-fluorophenyl)-N454(7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5yl)carbonyl]pyridin-3-yl)propanamide	LCMS: Rt = 2.55 min; m/z 404 [M+Hp
329	N-(5-[(7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yi)carbonyl]pyridin-3yl}-3-phenylpropanamide	LCMS:Rt = 2.50 min; m/z 386 [M+Hp
330	3-(4-methylphenyl)-N-{5-[(7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5yl)carbonylJpyridin-3-yl}propanamide	LCMS:Rt = 2.65 min; m/z 400 [M+Hp
331	N-{5-[(7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)carbonyl]pyridin-3yl}-2-(4-{[(trifluoromethyl)sulfonyl]amino}phenyl)acetamide	LCMS: Rt = 2.60 min; m/z 519 [M+Hp
332	N45-[(7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)carbonyl]pyridin-3yl}-2-phenoxyacetamide	LCMS: R( = 2.53 min; m/z 388 [M+Hp
333	2-[4-(methoxymethyl)phenyl]-N-(5-[(7-methyl-7H-pyrrolo[2,3- d]pyrimidin-5-yl)carbonyl]pyridin-3-yl}acetamide	LCMS: Rt = 2.31 min; m/z 416 [M+Hp
334	2-(4-fluorophenoxy)-N45-[(7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5- yl)carbonyi]pyridin-3-yl}acetamide	LCMS: R, = 2.44 min; m/z 406 [M+Hp

Example 336: N-{5-[(7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)carbonyl]pyridin-3-yl}-1 phenylcyclopropanecarboxamide

The title compound was prepared according to the method described for Llbrary protocol 1 starting from (5-amino-pyridin-3-yl)-(7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-methanone (Préparation 110) and 1phenylcyclopropanecarboxylic acid to afford the title compound. LCMS: R| = 2.61 min; m/z 398 [M+H]⁺ Example 337: N~(5-[(7-methyl-7H-pyrrolo[2₍3-d]pyrinnidin-5-yl)carbonyl]pyridin-3-yl}indane-2-carboxamide The title compound was prepared according to the method described for Llbrary protocol 1 starting from (5-amino-pyridin-3-yl)-(7-methyl-7H-pyrrolo[2,3-d]pyrÎmidin-5-yl)-methanone (Préparation 110) and îndane-2-carboxylic acid to afford the title compound. LCMS: R_t = 2.58 min; m/z 398 [M+H]⁺' Example 338: (2R)-N45-[(7-methyl-7H-pyrrolo[2₁3-d]pyrimidin-5-yl)carbonyl]pyridin-3-yl}-2phenylpropanamide

The title compound was prepared according to the method described for Library protocol 1 starting from (5-amino-pyridÎn-3-yl)-(7-methyl-7H-pyrrolo(2_l3-d]pynm(din-5-yl)-methanone (Préparation 110) and (2R)-

2- phenylpropanoic acid to afford the title compound. LCMS: R_t = 2.52 min; m/z 386 [M+Hf

Example 339: 3-hydroxy-2-phenyl-N-(5-{[7-(propan-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]carbonyl}pyridin-

3- yl)propanamide

The title compound was prepared according to the method described for Example 167 using (5aminopyridin-3-yl)(7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (Préparation 95) and tropic acid to afford the title compound as a yellow solid in 7% yield, 15 mg.

¹H NMR (400 MHz, DMSO-c/e) fi: 1.57 (d, 6H), 3.16-3.22 (m, 1H), 3.37-3.41 (m, 1H). 3.60-3.64 (m, 1 H), 5.10 (m, 1H), 6.30 (t, 1H), 7.10 (t, 1H), 7.20 (t. 2H), 7.30-7.32 (m, 3H), 8.12 (s, 1H), 8.15 (d, 1H), 8.61 (s, 1 H), 8.96 (s, 1 H), 9.44 (s, 1H).

LCMS (system 10): R_t= 2.36 min; m/z 430 [M+Hf.

The following Example was prepared according to Examples 1 and 34 for Methods a and b as described above.

Example	Name	Data
340	N-{5-[(7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)carbonyljpyridin-3-yl}-2-(5-methoxy-1H-indol-1-yljacetamide	LCMS (system 8): Rt = 1.63 min; m/z 469 [M+H]+

The following examples were prepared according to Example 356 using (5-amino-pyridin-3-yl)-{7isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-methanone (Préparation 95) and the appropriate acid.

Example	Name	Data
343	3-chloro-N-(5-{[7-(propan-2-yl)-7H-pyrroto[2,3d]pyrimidin-5-yl]carbonyl}pyridin-3-yl)benzamide	LCMS Rt = 2.95 min; m/z 420 [M+Hf.
344	4-chloro-N-(5-{[7-(propan-2-yl)-7H-pyrrolo[2,3- d]pyrimidin-5-yl]carbonyl}pyridin-3-yl)benzamide	LCMS R|= 2.93 min; m/z 420 [M+H]+.
345	N-(5-{[7-(propan-2-yl)-7H-pyrrolo[2>3-d]pyrimidin-5yl]carbonyl}pyridin-3-yl)-4- (trifluorom ethy I) b enzam ide	LCMS Rt= 2.99 min; m/z 454 [M+Hf.

346

N-(5-{[7-(propan-2-yl)’7H-pyrrolo[2,3-d]pyrimidin-5ylJcarbonyl}pyridin-3-yl)-4(trifluoromethoxy) benzamide

LCMS R_t = 3.05 min; m/z 470 [M+H]\

347

2-(2-cyanophenoxy)-N-(5-{[7-(propan-2-yl)-7Hpyrrolo[2,3-d]pyrimidin-5-yl]carbonyl}pyridin-3yl)acetamide

LCMS R_t= 0.67 min; m/z 441 [M+H]⁺.

348

N-(5-{[7-(propan-2-yi)-7H’pyrrolo[2,3-d]pyrimidin-5yl]carbonyl}pyridin-3-y1)-2-[4(trifluoromethoxy)phenoxy]acetamide

LCMS R_t= 3.01 min; m/z 500 [M+H]⁺.

Example 350:2-amino-2-(4-chlorophenyl)-N-(5-(7-isopropyl-7H-pyrrolo[2,3-d]pyrimidine-5carbonyl)pyridin-3-yl)acetamide

To tert-butyt (1-(4-chlorophenyl)-2-((5-(7’isopropyl-7H-pyrrolo[2_l3-d]pyrimidine-5-carbonyl)pyridÎn-3yl)amino)-2-oxoethyl)carbamate (Préparation 299, 64 mg, 0.11 mmol) was added 4M HCI/dioxane (5 mL) and the reaction stirred at room température for 18 hours. The mixture was evaporated in vacuo and purified by préparative reverse phase HPLC to give the title compound as a berge solid in 8% yield, 4 mg. ’H NMR (400 MHz. MeOD) δ: 1.59 (d, 6H), 4.63 (s, 1H), 5.16 (m, 1H), 7.35 (d, 2H), 7.47 (d, 2H), 8.33 (s, 1 H), 8.62 (s, 1 H), 8.69 (s, 1 H), 8.88 (s, 1 H), 8.92 (s, 1 H). 9.47 (s, 1 H).

LCMS R, = 2.81 min; MS m/z 449 [M+H]*

Example 351: N45-[2-Amino-7-(2-hydroxy-1,1-dimethyl-ethyl)-7H-pyrrolo[2_l3-d]pyrimidine-5-carbonyl]pyridin-3-yl}-2-(5-cyano-pyridin-2-yl)-acetamide

To a solution of N-i5-[2-Amino-7-(2-hydroxy-1,1-dimethyl-ethyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl]pyridin-3-yl}-2-(5-bromo-pyridin-2-yl)-acetamide (Example 316, 75 mg, 0.14'3 mmol) in DMF (2 mL) was added Zn(CN)₂ (25 mg, 0.215 mmol) and the reaction mixture was degassed with argon for 10 minutes. Pd₂(dba)₃ (3 mg, 0.002 mmol) and 1,1'-bis(diphenylphosphino)ferrocene 6 mg, 0.011 mmol) were then added and the résultant reaction mixture was heated at 100°C for 40 minutes under microwave irradiation. The reaction mixture was diluted with EtOAc (20 mL) and washed with water (2x10 mL) and brine (10 mL). The organic layer was dried (Na₂SO₄) and evaporated in vacuo. The crude material was purified by préparative TLC (7% MeOH in DCM) to afford the title compound as yellow solid in 31% yield, 21 mg.

¹H NMR (400 MHz, DMSO-D6) δ: 1.63 (s, 6H), 3.89 (d, 2H), 4.06 (s. 2H), 5.04 (t, 1H). 6.53 (s, 2H), 7.657.68 (m, 2H), 8.29 (dd, 1 H), 8.40 (s, 1H), 8.64 (d, 1H), 8.93-8.97 (m, 3H), 10.75 (s, 1H).

LCMS (system 10): R₍ = 2.50 min MS m/z 471 [M+H]⁺

Example 352: 2-(1-Cyclopropyl-3-trifluoromethyl-1 H-pyrazol-4-yl)-N-(5-(7-isopropyl-7H-pyrrolo [2, 3-d] pyrimidine-5-carbonyl)-pyridin-3-yl]-acetamide

To a solution of (5-Amino-pyridin-3-yl)-(7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-methanone (Préparation 95, 50 mg, 0.17 mmol), (1-Cyclopropyl-3-trifluoromethyl-1H-pyrazo!-4-yl)-acetic acid (Préparation 148, 47.1 mg, 0.21 mmol) and TEA (0.08 mL, 0.62 mmol) in THF (1mL), 1propylphosphonic acid cyclic anhydride (50% solution in EtOAc, 0.26 mL, 0.44 mmol) was added and the mixture was stirred at room température for 18 hours. The reaction mixture was evaporated under reduced pressure and the residue partitioned between water and EtOAc. The organic layer was washed with saturated sodium bicarbonate solution, dried (Na₂SO₄) and evaporated in vacuo. Purification by column chromatography on silica gel (EtOAc) gave the title compound as a white solid in 77 % yield, 68 mg.

¹H NMR (400 MHz, DMSO-D6) δ: 1.00-1.01 (m, 2H), 1.06-1.14 (m, 2H), 1.54 (d, 6H), 3.70 (s, 2H), 3.84 (m, 1H), 5.08-5.12 (m, 1H), 7.98 (s, 1H), 8.45 (s, 1H), 8.51 (s, 1H), 8.74 (s. 1H), 8.96 (d, 1H), 8.99 (s, 1H). 9.44 (s, 1 H), 10.60 (s, 1 H).

LCMS (system 10): R_t = 3.02 min MS m/z 498 [M+H]*.

Example 353: racemic Methyl 2-{5-[(5-{[(4-chlorophenyl)acetyl]amino}pyridin-3-yl)carbonyl]-7Hpyrrolo[2,3-d]pyrimidin-7-yl}propanoate

The title compound was prepared according to the method described for Example 229 using 2-(4chlorophenyl)-N-[5-(7H-pyrrolo[2,3-d]pyrimidin-5-ylcarbonyl)pyridin-3-yl]acetamide (Example 308), methyl 2-bromopropionate and césium carbonate. Purified using préparative HPLC (method 1) to afford the title compound.

LCMS (system 2): R_t = 1.42 min MS m/z 478 [M+H]⁺

Example 354: racemic 2-{5-[(5-{[(4-Chlorophenyl)acetyl]amino}pyridin-3-yl)carbonyl]-7H-pyrrolo[2,3d]pyrimidin-7-yl}propanoic acid

The title compound was prepared according to the method described for Préparation 155 using methyl 2{5-[(5-{[(4-chlorophenyl)acetyl]amino}pyridin-3-yl)carbonyl]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}propanoate (Example 353) to afford the title compound as a white solid in 100% yield, 97 mg.

LCMS (system 2): R_t = 1.40 min; m/z 464 [M+HJ*.

Example 355: 2-(4,5-Dichloro-imidazol-1-yl)-N-[5-(7-isopropyl-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl) pyridin-3-yl]-acetamide (method d)

(4,5-Dichloro-imidazol-1-yl)-aceticacid (25.2 mg, 0.130 mmol) was added to (5-amino-pyridin-3-yl)-(7isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-methanone (28.1 mg, 0.1 mmol), HATU (49.4 mg, 0.130 mmol) and DIPEA (51.7 uL, 0.300 mmol) in anhydrous DMF (1 mL). The mixture was stirred at 50°C for 16 hours and then evaporated in vacuo and purified by prep-HPLC (method 5) to afford the title compound in 46% yield, 21.2 mg.

LCMS (system 8): R₍ = 1.55 min; m/z 458 [M+H]

Example 356: 7-Difluoromethyl-5-methyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carboxyiic acid [5-(7-isopropyl7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-pyridin-3-yl]-amide (method e)

7-Difluoromethyl-5-methyl-[1,2,4]triazoto[1,5-a]pyrimidine-2-carboxylic acid (29.64 mg, 0.130 mmol) was added to (5-amino-pyridin-3-yl)-(7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-methanone (28.1 mg, 0.1 mmol), HATU (49.42 mg, 0.130 mmol) and DIPEA (22.4 uL, 0.13 mmol) in anhydrous DMF (1 mL). The mixture was stirred at 50°C for 16 hours and then evaporated in vacuo and purified by prep-HPLC (method 5) to afford the title compound in 12 % yield, 6.1 mg.

LCMS (system 8): R_t = 1.56 min; m/z 492 [M+H]'

The following Exampies were prepared according to one of the methods for Examples 355 (Method d) and 356 (Method e) using (5-aminopyridin-3-yl)(7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (Préparation 95).

Example	Name	Data
357	2-(4,5-Dichloro-imidazol-1-yl)-N-[5-(7isopropyl-7H-pyrrolo[2,3-d]pyrîmidine-5carbonyl)-pyridin-3-yl]-acetamide	LCMS (system 8): Rt = 1.55 min; m/z 458 [M+H]+. Prep HPLC (method 5)

358	2-(3,5-Dim ethyl-1,2,4-triazol-1 -yl)-N-[5-(7isopropyl-7H-pyrrolo[2,3-d]pyrimidine-5carbonyl)-pyridin-3-yl]-acetamide	LCMS (system 8): Rt = 1.43 mjn; m/z 419 [M+Hj*. Prep HPLC (method 5)
359	N-[5-(7-lsopropyl-7H-pyrrolo[2,3d]pyrimidine-5-carbonyl)-pyridin-3-yl]-2-(2methyl-imidazol-1 -yl)-acetamide	LCMS (system 8): R(= 1.27 min; m/z 404 [M+H]+. Prep HPLC (method 5)
360	2-lmidazo[2,1-b]thiazol-6-yl-N-[5-(7isopropyl-7H-pyrrolo[2,3-d]pyrimidine-5carbonyl)-pyridin-3-yl]-acetamide	LCMS (System 8): Rt= 1.42 min; m/z 446 [M+Hp. Prep HPLC (method 5)
361	2-(4-Hydroxy-phthalazin-1-yl)-N-[5-(7isopropyl-7H-pyrrolo[213-d]pyrimidine-5carbonyl)-pyridin-3-yl]-acetamide	LCMS (system 8): Rt = 1.46 min; m/z 468 [M+H]+. Prep HPLC (method 5)
362	2-(2,3-Dimethyl-imidazo[2,1-b}thiazol-6-yl)-N[5-(7-isopropyl-7H-pyrrolo[2(3-d]pyrimidine5-carbonyl)'pyridin-3-yl]-acetamide	LCMS (system 8): Rt = 1.48 min; m/z 474 [M+H]+. Prep HPLC (method 5)
363	2- [4-( 1 -Hydroxy-cyclopentyl)-1,2,3-triazol-1 yl]-N-[5-(7-isopropyl-7H-pyrrolo[2,3d]pyrimidine-5-carbonyl)-pyridin-3-yl]acetamide	LCMS (system 8): Rt = 1.44 min; m/z 475 [M+H]+. Prep HPLC (method 5) (From Prep 294)
364	N-[5-(7-lsopropyl-7H-pyrrolo[2,3d]pyrimidine-5-carbonyl)-pyridin-3-yl]-2-(5-mtoly l-tetrazo I-1 -yl)-acetamide	LCMS (system 8): Rt = 1.57 min; m/z 482 [M+H]+. Prep HPLC (method 5)
365	2-[4-(4-Fluoro-phenyl)-imidazol-1-yl]-N-[5-(7isopropyl-7H-pyrrolo[2,3-d]pyrimidine-5carbonyt)-pyridin-3-yl]-acetamide	LCMS (system 8): Rt = 1.45 min; m/z 484 [M+H]*. Prep HPLC (method 5)
366	2-(5-lsopropyl-pyrazol-1-yl)-N-[5-(7isopropyl-7H-pyrrolo[2,3-d]pyrimïdine-5carbonyl)-pyridin-3-yl]-acetamide	LCMS (system 8): R( = 1.60 mjn; m/z 432 [M+H]*. Prep HPLC (method 5) (Acid can be prepared in an analogus to method given in WO03/072572)

367	2-(2’Ethyl-imidazo[2,1-b]-1,3,4-thiadiazol-6yl)-N-[5-(7-isopropyl-7H-pyrrolo[2,3d]pyrimidine-5-carbonyl)-pyridin-3-yl]acatamide	LCMS (system 8): Rt = 1.60 min; m/z 475 (M+H]+. Prep HPLC (method 5)
368	N-[5-(7-lsopropyl-7H-pyrrolo(2,3d]pyrimidine-5-carbonyl)-pyridin-3-yt]-2-(2methyl-imidazo^.l-blthiazol-e-yO-acetamide	LCMS (system 8): Rt = 1.45 min; m/z 460 [M+H]*. Prep HPLC (method 5) (from Prep 289)
369	2-(3-Chloro-5-methyl-1,2,4-triazol-l -yl)-N-[5(7-isopropyl-7H-pyrrolo[2,3-d]pyrimidine-5carbonyl)-pyridin-3-yl]-acetamide	LCMS (system 8): Rt= 1.48 min; m/z 439 [M+H]+. Prep HPLC (method 5)
370	N-[5-(7-lsopropyl-7H-pyrrolo[2,3d]pyrimidine-5-carbonyl)-pyridin-3-yl]-2-(2phenyl-imidazol-1 -yl)-acetamide	LCMS (System 8); Rt = 1.34 min; m/z 466 [M+H]+. Prep HPLC (method 5)
371	2-(2-Chloro-imidazo(2,1-b]thiazol-6-yl)-N-[5(7-isopropyl-7H-pyrrolo[2,3-d]pyrimidine-5carbonyl)-pyridin-3-yl]-acetamide	LCMS (System 8): Rt = 1.59 min; m/z 480 [M+Hf. Prep HPLC (method 5)
372	24midazol-1-yl-N-[5-(7-isopropyl-7Hpyrrolo[2,3-d]pyrimidine-5-carbonyl)-pyridin3-yl]-acetamide	LCMS (system 8): Rt = 1.26 min; m/z 390 [M+H]+. Prep HPLC (method 5)
373	N-[5-(7-lsopropyl-7H-pyrroio[2,3- d]pyrimidine-5-carbonyl)-pyridin-3-yl]-2-(3methyl-imidazo[2,1-bjthiazol-6-yl)-acetamide	LCMS (system 8): R( = 1.46 min; m/z 460 [M+H]+. Prep HPLC (method 5)
374	2-f1 -(4-Hydroxy-phenyl)-1 H-pyrrol-3-yl]-N-[5(7-isopropyl-7H-pyrrolo[2,3-d]pyrimidine-5carbonyl)-pyridin-3-yl]-acetamide	LCMS (system 8): Rt= 1.57 min; m/z 481 [M+H]+. Prep HPLC (method 5)
375	N-[5-(7-lsopropyl-7H-pyrrolo[2,3- d]pyrimidine-5-carbonyl)-pyridin-3-yl]-2[1,2,4]triazolo[1,5-a]pyrimidin-6-yl-acetamide	LCMS (system 8): Rt = 1.41 min; m/z 442 [M+HJ*. Prep HPLC (method 5)

376	N-[5-(7-lsopropyl-7H-pyrrolo[2,3d]pyrimidlne-5-carbonyl)-pyridin-3-yl]-2pyrazin-2-yl-acetamide	LCMS (system 8): Rt= 1.44 min; m/z 402 [M+H]+. Prep HPLC (method 5)
377	2-[4-(3-Hydroxy-phenyl)-1,2,3-triazol-1 -yi]-N[5-(7-isopropyl-7H-pyrrolo[2,3-d]pyrimidine5-carbonyl)-pyridin-3-yl]-acetamide	LCMS (system 8): Rt = 1.48 min; m/z 483 [M+H]+. Prep HPLC (method 5) (from Prep 292)
378	N-[5-(7-lsopropyl-7H-pyrrolo[2,3d]pyrimidine-5-carbonyl)-pyridin-3-yl]-2-(5phenyl-tetrazol-1 -yi)-acetamide	LCMS (system 8): Rt = 1.63 min; m/z 468 [M+H]+. Prep HPLC (method 5)

379	7-Difiuoromethyl-5-methyl-[1,2,4]triazolo[1,5a]pyrimidine-2-carboxylic acid [5-(7isopropyl-7H-pyrrolo[213-d]pyrimidine-5carbonyl)-pyridin-3-yl]-amide	LCMS (System 8): Rt = 1.56 min; m/z 492 [M+H]+. Prep HPLC (method 5)
380	Furo[3,2-c]pyridine-4-carboxylic acid [5-(7isopropyl-7H-pyrrolo[2,3-d]pyrimidine-5carbonyl)-pyridin-3-yl]-amide	LCMS (system 8): Rt = 1.73 min; m/z 427 [M+Hf. Prep HPLC (method 5)
381	4-Methyl-furazan-3-carboxylic acid [5-(7isopropyl-7H-pyrrolo[2,3-d]pyrimidine-5carbonyl)-pyridin-3-ylj-amide	LCMS (system 8): Rt= 1.61 min; m/z 392 [M+Hf. Prep HPLC (method 5)
382	1-Methyl-1H-indazote-3-carboxylic acid [5-(7isopropyl-7H-pyrrolo[2,3-d]pyrimidine-5carbonyl)-pyrïdin-3-yl]-amide	LCMS (system 8): Rt = 1.75 min; m/z 440 [M+H]+. Prep HPLC (method 5)
383	1H-lndole-2-carboxylic acid [5-(7-isopropyl- 7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)pyridin-3-yl]-amide	LCMS (system 8): Rt = 1.67 min; m/z 425 [M+Hf. Prep HPLC (method 5)

384	2-Methyl-4-trifluoromethyl-thiazole-5carboxylic acid [5-(7-isopropyl-7Hpyrrolo[2,3-d]pyrimidine-5-carbonyl)-pyridin3-yl]-amide	LCMS (system 8): Rt = 1.62 min; m/z 475 [M+H]+. Prep HPLC (method 5)
385	5-Cyclopropyl-oxazole-4-carboxylic acid [5(7-isopropyl-7H-pyrrolo[2,3-d]pyrimidine-5carbonyl)-pyridin-3-yl]-amide	LCMS (system 8): R, = 1.67 min; m/z 417 [M+Hf. Prep HPLC (method 5)
386	Pyridazine-3-carboxylic acid [5-(7-isopropyl7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)pyridin-3-yl]-amide	LCMS (system 8): Rt = 1.52 min; m/z 388 [M+H]+. Prep HPLC (method 5)
387	3-Methyl-5-trifluoromethyl-1 H-pyrazole-4carboxylic acid [5-(7-isopropyl-7Hpyrrolo[2,3-d]pyrimidine-5-carbonyl)-pyridin3-yl]-amide	LCMS (System 8): R, = 1.53 min; m/z 458 [M+H]\ Prep HPLC (method 5) (Acid from prep 290)
388	4-Methyl-pyridine-2-carboxylic acid[5-(7isopropyl-7H-pyrrolo[2,3-d]pyrimidine-5carbonyl)-pyridin-3-yl]-amide	LCMS (system 8): Rt = 1.70 min; m/z 401 [M+H]+. Prep HPLC (method 5)
389	3-Cyclobutyl-1 H-pyrazole-4-carboxylic acid [5-(7-isopropyl-7H-pyrrolo[213-d]pyrimidine5-carbonyl)-pyridin-3-yl]-amide	LCMS (system 8): Rt = 1.59 min; m/z 430 [M+H]+. Prep HPLC (method 5)
390	Oxazole-5-carboxylic acid [5-(7-isopropyl7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)pyridin-3-yl]-amide	LCMS (system 8): Rt = 1.46 min; m/z 377 [M+H]+. Prep HPLC (method 5)
391	4-Methyl-1 H-imidazole-2-carboxylic acid [5(7-isopropyl-7H-pyrro!o[2,3-d]pyrimidine-5carbonyl)-pyridin-3-yl]-amide	LCMS (system 8): Rt = 1.52 min; m/z 390 [M+HJ+. Prep HPLC (method 5)
392	1 H-Pyrrolop.S-cJpyridine-S-carboxylic acid [5-(7-isopropyl-7H-pyrroio[2,3-d]pyrimidine5-carbonyl)-pyridin-3-yl]-amide	LCMS (system 8); Rt = 1.56 min; m/z 426 [M+H]+. Prep HPLC (method 5) (Acid: Synthesis, 1993, 295297)

393	5-Methyl-pyrazine-2-carboxylic acid[5-(7isopropyl-7H-pyrrolo[2,3-d]pyrimidine-5carbonyl)-pyridin-3-yl]-amide	LCMS (system 8): Rt = 1.58 min; m/z 402 [M+HJ+. Prep HPLC (method 5)
394	1,3-Dimethyl-1 H-pyrazole-4-carboxylic acid [5-(7-isopropyl-7H-pyrrolo[2,3-d]pyrimidine5-carbonyl)-pyridin-3-yl]-amide	LCMS (system 8): Rt = 1.53 min; m/z 404 [M+H]+. Prep HPLC (method 6)
395	1 H-Pyrazolo[4,3-b]pyridine-6-carboxylic acid [5-(7-isopropyi-7H-pyrrolo[213-d]pyrimidine5-carbonyl)-pyridin-3-yl]-amide	LCMS (system 8): Rt = 1.46 min; m/z 427 [M+H]+. Prep HPLC (method 5) (Acid: see US 20110111046)
396	5-Ethyl-isoxazole-3-carboxylic acid(5-(7isopropyl-7H-pyrrolo[2,3-d]pyrimidine-5carbonyl)-pyridin-3-yl]-amide	LCMS (system 8): Rt = 1.63 min; m/z 405 [M+H]+. Prep HPLC (method 5)
397	2-Methyl-2H-pyrazole-3-carboxylic acid [5(7-isopropyl-7H-pyrrolo[2,3-d]pyrimidine-5carbonyl)-pyridin-3-yl]-amide	LCMS (system 8): Rt = 1.54 min; m/z 390 [M+H]+. Prep HPLC (method 5)
39Θ	Quinoline-3-carboxylic acid [5-(7-isopropyl7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)pyridin-3-yl]-amide	LCMS (system 8): Rt = 1.66 min; m/z 437 [M+H]+. Prep HPLC (method 5)
399	5-Fluoro-1H-pyrrolo[2,3-b]pyridine-2carboxylic acid [5-(7-isopropyl-7Hpyrrolo[2,3-d]pyrimidine-5-carbonyl)-pyridin3-yi]-amide	LCMS (system 8): Rt = 1.61 min; m/z 444 [M+H]+. Prep HPLC (method 5) (Acid: W02008/107543)
400	1,5-Dimethyl-l H-pyrazole-3-carboxylic acid [5-(7-isopropyl-7H-pyrrolo[2,3-d]pyrimidine5-carbonyl)-pyridin-3-ylJ-amide	LCMS (system 8): Rt= 1.57 min; m/z 404 [M+H]+. Prep HPLC (method 5)
401	2-Cyclopropyl-oxazole-4-carboxylic acid [5(7-isopropyl-7H-pyrrolo[2,3-d]pyrimidine-5carbonyl)-pyridin-3-yl]-amide	LCMS (system 8): Rt = 1.64 min; m/z 417 [M+H]+. Prep HPLC (method 5)

402	4-T rif I uoro methy l-th iazole-5-carboxy I i c acid [S-^-isoprOpyl^H-pyrrolo^.S-dJpyrïmidirie5-carbonyl)-pyridin-3-yl]-amide	LCMS (system 8): Rt = 1.58 min; m/z 461 [M+H]+. Prep HPLC (method 5)
403	6,7-Dihydro-5H-pyrrolo[1,2-c]imidazole-1 carboxylic acid [5-(7-isopropyl-7Hpyrro!o[2,3-d]pyrimidine-5-carbonyl)-pyridin3-yl]-amide	LCMS (system 8): Rt = 1.51 min; m/z 416 [M+H]+. Prep HPLC (method 5) (Acid can be preparaed by oxidation of aldéhyde described in Tetrahedron, 1999,8111)
404	Thieno[3,2-c]pyridine-6-carboxylic acid [5-(7isopropyl-7H-pyrrolo[2,3-d]pyrimidîne-5carbonyl)-pyridin-3-ylj-amide	LCMS (system 8): Rt = 1.77 min; m/z 443 [M+HJ+. Prep HPLC (method 5)
405	1 -Methyl-3-trifluoromethyi-1 H-pyrazole-4carboxylic acid [5-(7-isopropyl-7Hpyrrolo(2,3-d]pyrimidine-5-carbonyl)-pyridin3-yl]-amide	LCMS (System 8): Rt = 1.60 min; m/z 458 [M+H]+. Prep HPLC (method 5)
406	lmidazo[1,5-a]pyridine-7-carboxylicacid [5(7-isopropyl-7H-pyrrolo[2,3-d]pyrimidine-5carbonyl)-pyridin-3-yl]-amide	LCMS (system 8): Rt = 1.47 min; m/z 426 [M+H]+. Prep HPLC (method 5)
407	1 H-Pyrrolo[2,3-b]pyridine-4-carboxylic acid [5-(7-isopropyl-7H-pyrrolo[2,3-d]pyrimidine5-carbonyl)-pyridin-3-yl]-amide	LCMS (system 8): Rt = 1.54 min; m/z 426 [M+H]+. Prep HPLC (method 5)
408	3-Ethyl-isoxazole-5-carboxylic acid[5-(7isopropyl-7H-pyrrolo[2,3-d]pyrimidine-5carbonyl)-pyridin-3-yl]-amide	LCMS (system 8): Rt = 1.60 min; m/z 405 [M+H]+. Prep HPLC (method 5)
409	4-Methoxy-pyridine-2-carboxylic acid [5-(7isopropyl-7H-pyrrolo[2,3-d]pyrimidine-5carbonyl)-pyridin-3-yl]-amide	LCMS (system 8): Rt = 1.67 min; m/z 417 [M+HJ+. Prep HPLC (method 5)
410	Pyrimidine-5-carboxylic acid [5-(7-isopropyl7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)pyridin-3-yl]-amide	LCMS (system 8): Rt = 1.46 min; m/z 388 [M+HJ+. Prep HPLC (method 5)

411	3-Methyl-1H-pyrazole-4-carboxylic acid [5(7-isopropyl-7H-pyrrolo[2,3-d]pyrimidine-5carbonyl)-pyridin-3-yl]-amide	LCMS (system 8): Rt = 1.46 min; m/z 390 [M+H]+. Prep HPLC (method 5)
412	5-Methyl-1H-pyrrolo[2,3-b]pyridine-3carboxylic acid [5-(7-isopropyl'7Hpyrro!o[2,3-d]pyrimidine-5-carbonyl)-pyridin3-yl]-amide	LCMS (system 8): Rt = 1.54 min; m/z 440 [M+H]+. Prep HPLC (method 5)
413	5-Methyl-pyrimidine-4-carboxylic acid [5-(7isopropyl-7H-pyrrolo[2,3-d]pyrimidine-5carbonyl)-pyridin-3-yl]-amide	LCMS (system 8): Rt = 1.60 min; m/z 402 [M+H]+, Prep HPLC (method 5)
414	Thieno[3,2-b]pyridine-6-carboxylic acid [5-(7isopropyl-7H-pyrro!o[2,3-d]pyrimidine-5carbonyl)-pyridin-3-ylj-amide	LCMS (system 8): Rt = 1.64 min; m/z 443 [M+H]+. Prep HPLC (method 5)
415	Pyrazolo[1,5-a]pyrimidine-6-carboxylic acid [5-(7-isopropyl-7H-pyrrolo[2,3-d]pyrimidine5-carbonyl)-pyridin-3-yl]-amide	LCMS (system 8): Rt = 1.54 min; m/z 427 [M+H]+. Prep HPLC (method 5)
416	4,5,6,7-T etrahydro-1,2-benzisoxazole-3carboxylic acid [5-(7-isopropyl-7Hpyrrolo[2,3-d]pyrimidine-5-carbonyl)-pyridin3-yl]-amide	LCMS (system 8): Rt = 1.75 min; m/z 431 [M+H]+. Prep HPLC (method 5)
417	lmidazo[1,5-a]pyridine-3-carboxylicacid [5(7-isopropyi-7H-pyrro!o[2,3-d]pyrimidine-5carbonyl)-pyridin-3-yl]-amide	LCMS (system 8): Rt = 1.75 min; m/z 426 [M+H]+. Prep HPLC (method 5)
418	1 H-Pyrrolo[2,3-b]pyridine-6-carboxylic acid [5-(7-isopropyl-7H-pyrroto[2,3-dlpyrimidine5-carbonyl)-pyridin-3-yl]-amide	LCMS (system 8): Rt = 1.65 min; m/z 426 [M+H]+. Prep HPLC (method 5)
419	1,4,5,6-T etrahydro-cyclopentapyrazole-3carboxylic acid [5-(7-isopropyl-7Hpyrrolo[2,3-d]pyrimidine-5-carbonyl)-pyridin3-yl]-amide	LCMS (system 8): Rt = 1.59 min; m/z 416 [M+H]+. Prep HPLC (method 5)

420	4-Amino-pyrimidine-5-carboxylic acid [5-(7isopropyl-7H-pyrrolo[2,3-d]pyrimidine-5carbonyl)-pyridin-3-yl]-amide	LCMS (system 8): Rt = 1.41 min; m/z 403 [M+HJ+. Prep HPLC (method 5)
421	1 H-Pyrrolo[2,3-c]pyridine-3-carboxylic acid [5-(7-isopropyl-7H-pyrrolo[2,3-d]pyrimidine5-carbonyl)-pyridin-3-yl]-amide	LCMS (system 8): Rt = 1.32 min; m/z 426 [M+H]+. Prep HPLC (method 5)
422	N-[5-(7-lsopropyl-7H-pyrrolo[2,3d]pyrimidine-5-carbonyl)-pyridin-3-yl]-2methyl-isonicotinamide	LCMS (System 8): Rt = 1.51 min; m/z 401 [M+HJ+. Prep HPLC (method 5)
423	lmidazo[1,2-a]pyridine-6-carboxylicacid [5(7-isopropyl-7H-pyrrolo[2,3-d]pyrimidine-5carbonyl)-pyridin-3-yi]-amide	LCMS (system 8): Rt = 1.33 min; m/z 426 [M+HJ+. Prep HPLC (method 5)
424	1H-1,2,4-Triazole-3-carboxylic acid[5-(7isopropyl-7H-pyrrolo[2,3-d]pyrimidine-5carbony!)-pyrïdin-3-yl]-amide	LCMS (system 8): Rt = 1.38 min; m/z 377 [M+H]+. Prep HPLC (method 7)
425	5-Methoxy-pyridine-2-carboxylic acid [5-(7isopropyl-7H-pyrrolo[2,3-d]pyrimidine-5carbonyI)-pyridin-3-yl]-amide	LCMS (system 8):Rt=1.66 min; m/z 417 [M+H]+, Prep HPLC (method 5)
426	Cinnoline-4-carboxylic acid [5-(7-isopropyl7H-pyrrolo[2,3-dJpyrimidine-5-carbonyl)pyridin-3-yl]-amide	LCMS (system 8): Rt = 1.57 min; m/z 438 [M+H]+. Prep HPLC (method 5)
427	[1,2,4]Triazolo[1,5-a]pyridine-7-carboxylic acid [5-(7-isopropyl-7H-pyrrolo[2,3d]pyrimidine-5-carbonyl)-pyridin-3-yl]-amide	LCMS (system 8): Rt = 1.51 min; m/z 427 [M+H]+. Prep HPLC (method 5)
428	Pyrazolo[1,5-a]pyrimidine-2-carboxylic acid [5-(7-isopropyl-7H-pyrrolo[2,3’d]pyrimidine5-carbonyl)-pyridin-3-yl]-amide	LCMS (system 8): Rt = 1.54 min; m/z 427 [M+HJ+. Prep HPLC (method 5)

100

429	Pyridine-2-carboxylic acid [5-(7-isopropyl7H-pyrrolo(2,3-d]pyrimidine-5-carbonyl)pyridin-3-yl]-amide	LCMS (system 8): Rt = 1.62 min; m/z 387 [M+H]+. Prep HPLC (method 5)
430	5-Chloro-N-[5-(7-isopropyl-7H-pyrrolo[2,3d]pyrimidine-5-carbonyl)-pyridin-3-yl]nicotinamide	LCMS (system 8): Rt = 1.62 min; m/z 421 [M+H]+. Prep HPLC (method 5)
431	4H-Furo[3,2-b]pyrrole-5-carboxylic acid [5(7-isopropyl-7H-pyrrolo1[2,3-d]pyrimidine-5carbonyl)-pyridin-3-yl]-amide	LCMS (system 8): Rt = 1.59 min; m/z 415 [M+H]+. Prep HPLC (method 5)
432	lmidazo[1,2-a]pyrÎdine-7-carboxylicacid [5(7-isopropyl-7H-pyrrolo[2,3-d]pyrimidine-5carbonyl)-pyridin-3-yl]-amide	LCMS (System 8): Rt= 1.34 min; m/z 426 [M+H]*. Prep HPLC (method 5)
433	1 -Ethyl-1 H-pyrazole-4-carboxylic acid [5-(7isopropyl-7H-pyrrolo[2,3-d]pyrimidine-5carbonyl)-pyridin-3-yi]-amide	LCMS (system 8): R| = 1.52 min; m/z 404 [M+H]+, Prep HPLC (method 5)
434	1-lsopropyl-1 H-imidazole-4-carboxylic acid [5-(7-isopropyl-7H-pyrrolo{2,3-d]pyrimidine5-carbonyl)-pyridin-3-yl]-amide	LCMS (system 8): R, = 1.58 min; m/z 418 [M+Hf. Prep HPLC (method 5) (Acid :WO2010/009062
435	8-Methoxy-imidazo[1,2-a]pyrazine-6carboxylic acid [5-(7-isopropyl-7Hpyrrolo[2,3-d]pyrimidine-5-carbonyl)-pyridin3-yl]-amide	LCMS (system 8): Rt = 1.62 min; m/z 457 [M+H]+. Prep HPLC (method 5) (Acid can be prepared by carbonylation of the bromide e.g. WO2010/078408)
436	1 H-Pyrrolo[2,3-b]pyridine-5-carboxylic acid [5-(7-isopropyl-7H-pyrrolo[2,3-d]pyrimidine5-carbonyl)-pyridin-3-yl]-amide	LCMS (system 8):Rt=1.55 min; m/z 426 [M+H]+. Prep HPLC (method 5)
437	2-Methyl-5-propyl-2H-pyrazole-3-carboxylic acid [5-(7-isopropyl-7H-pyrrolo[2,3- d]pyrimidine-5-carbonyl)-pyridin-3-yi]-amide	LCMS (System 8): R( = 1.69 min; m/z 432 [M+HJL Prep HPLC (method 5)

101

438	4-lsopropyl-thiazole-2-carboxylic acid [5-(7isopropyl-7H-pyrrolo[213-d]pyrimidine-5carbonyl)-pyridin-3-ylj-amide	LCMS (system 8): R,= 1.79 min; m/z 435 [M+Hf. Prep HPLC (method 5) (Acid: W02007/017144
439	3-Methyl-furo[2,3-c]pyridine-5-carboxylic acid [5-(7-isopropyl-7H-pyrrolo[2,3-d]pyrimidine5-carbonyl)-pyrîdin-3-yl]-amide	LCMS (system 8): R,= 1.77 min; m/z 441 [M+Hf. Prep HPLC (method 5) (Acid: WO04052348)
440	6-Methyl-pyridine-2-carboxylic acid[5-{7isopropyl-7H-pyrrolo[2,3-d]pyrimidine-5carbonyl)-pyridin-3-yl]-amide	LCMS (system 8): Rt= 1.69 min; m/z 401 [M+Hf. Prep HPLC (method 5)
441	5-Chloro-1 -methyl-3-trifluoromethyl-1 Hpyrazole-4-carboxylic acid [5-(7-isopropyl7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)pyridin-3-yl]-amide	LCMS (system 8): Rt = 1.63 min; m/z 492 [M+Hf. Prep HPLC (method 5)
442	5-Methoxy-1H-benzimidazole-2-carboxylic acid [5-(7-isopropyl-7H-pyrrolo[2,3d]pyrimidine-5-carbonyl)-pyridin-3-yl)-amide	LCMS (system 8): R,= 1.63 min; m/z 456 [M+HJT Prep HPLC (method 5) (Acid: US2007/017144)
443	4-Chloro-1,5-dimethyl-1 H-pyrazole-3carboxylic acid [5-(7-isopropyl-7Hpyrrolo[2,3-d]pyrimidine-5-carbonyl)-pyridin3-ylJ-amide	LCMS (system 8): Rt= 1.65 min; m/z 438 [M+Hf. Prep HPLC (method 5)
444	1 H-Pyrrolo[3,2-c]pyridine-4-carboxylic acid [5-(7-isopropyl-7H-pyrrolo[2,3-d]pyrimidine5-carbonyl)-pyridin-3-yl]-amide	LCMS (system 8): Rt = 1.58 min; m/z 426 [M+Hf. Prep HPLC (method 5)
445	4-Ethyl-pyridine-2-carboxylic acid [5-(7isopropyl-7H-pyrrolo[2,3-d]pyrimidine-5carbonyl)-pyridin-3-y1]-amide	LCMS (system 8): Rt = 1.76 min; m/z 415 [M+Hf. Prep HPLC (method 5) (Acid: JOC, 1990, 55, 738-741)
446	2l3-Dihydro-1,4-dioxino[2,3-b]pyridine-7carboxylic acid [5-(7-isopropyl-7Hpyrrolofé.S-dJpyrimidine-S-carbonyO-pyridin3-yl]-amide	LCMS (system 8): Rt = 1.54 min; m/z 445 [M+Hf. Prep HPLC (method 5)
447	1 H-Pyrrolo[3,2-b]pyridine-5-carboxylic acid [5-(7-isopropyl-7H-pyrrolo[2,3-d]pyrimidine5-carbonyl)-pyridin-3-yl]-amide	LCMS (system 8): Rt= 1.58 min; m/z 426 [M+Hf. Prep HPLC (method 5)

0<

102

448	Pyrazolo[1,5-a]pyridine-5-carboxyiic acid [5(7-isopropyl-7H-pyrrolo[2,3-d]pyrimidine-5carbonyl)-pyridin-3-yl]-amide	LCMS (system 8): Rt = 1.59 min; m/z 426 [M+Hf. Prep HPLC (method 5) (Acid: J. Med. Chem. (2007), 45(21), 4594-4597)
449	6-Methoxy-quinoline-3-carboxylic acid [5-(7isopropy!-7H-pyrrolo[2,3-d]pyrimidine-5carbonyl)-pyridin-3-yl]-amide	LCMS (system 8): Rt = 1.68 min; m/z 467 [M+Hf. Prep HPLC (method 5)
450	5-Methyl-2-(2,2,2-trifluoro-ethyl)-2Hpyrazole-3-carboxylic acid [5-(7-isopropyi7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)pyridin-3-yl]-amide	LCMS (system 8): Rt= 1.66 min; m/z 472 [M+Hf. Prep HPLC (method 5) (Acid: WO 2008/016192)
451	N-[5-(7-isopropyl-7H-pyrrolo[2,3d]pynmidine-5-carbonyl)-pyridin-3-y!]-4trifluoromethyl-nicotinamide	LCMS (system 8): Rt = 1.58 min; m/z 455 [M+Hf. Prep HPLC (method 5)
452	1 -(2-Cyano-ethyl)-1 H-pyrazole-4-carboxylic acid [5-(7-isopropyl-7H-pyrrolo[2,3d]pyrimidine-5-carbonyl)-pyridin-3-yl]-amide	LCMS (system 8): Rt = 1.46 min; m/z 429 [M+Hf. Prep HPLC (method 5)
453	Furo[3,2-c]pyridine-2-carboxylic acid [5-(7isopropyl-7H-pyrrolo[2,3-d]pyrimîdine-5carbonyl)-pyridin-3-ylj-amide	LCMS’(system 8):Rt= 1.45 min; m/z 427 [M+Hf. Prep HPLC (method 5) (Acid: J.Het.Chem. (1987),24(2), 373-6)
454	1 H-Pyrrolo[3,2-c]pyridine-2-carboxylic acid [5-(7-isopropyl-7H-pyrrolo[2,3-d]pyrimidine5-carbonyl)-pyridin-3-yl]-amide	LCMS (system 8): Rt= 1.32 min; m/z 426 [M+HJ+. Prep HPLC (method 5)
455	Furo[3,2-c]pyridine-6-carboxylic acid [5-(7isopropyl-7H-pyrrolo[2,3-d]pyrimidine-5carbonyl)-pyridin-3-yl]-amide	LCMS (system 8): Rt = 1.70 min; m/z 427 [M+Hf. Prep HPLC (method 5)
456	2,4-Dimethyl-oxazole-5-carboxylic acid [5-(7isopropyi-7H-pyrrolo[2,3-d]pyrimidine-5carbonyl)-pyridin-3-yl]-amide	LCMS (system 8): Rt = 1.58 min; m/z 405 [M+Hf. Prep HPLC (method 5)

103

457	1 -Methyl-1 H-pyrrolo[2,3-c]pyridîne-3carboxylic acid [5-(7-isopropyl-7Hpyrrolo[2,3-d]pyrimidine-5-carbonyl)-pyridin3-yl]-amide	LCMS (System 8): Rt = 1.32 min; m/z 440 [M+Hf. Prep HPLC (method 5) (Acid: W007017144)
458	5,6-Dihydro-4H-pyrrolo[1,2-b]pyrazole-2carboxylic acid [5-(7-isopropyl-7Hpyrrolo(2,3-d]pyrimtdine-5-carbonyl)-pyridin3-yl]-amide	LCMS (system 8): Rt - 1.59 min; m/z 416 [M+H]+. Prep HPLC (method 5)
459	2-Cyclobutyl-thiazole-4-carboxylic acid [5-(7isopropyl-7H-pyrrolo[2,3-d]pyrimidine-5carbonyl)-pyridin-3-ylj-amide	LCMS (system 8): Rt= 1.79 min; m/z 447 [M+H]+. Prep HPLC (method 5) (Acid: W02009098448)
460	3-Fluoro-N-[5-(7-isopropyl-7H-pyrrolo[2,3d]pyrimidine-5-carbonyl)-pyridin-3-yi]isonicotinamide	LCMS (system 8): Rt= 1.53 min; m/z 405 [M+HJ*. Prep HPLC (method 5)
461	2-Methyl-imidazo[1,2-a]pyrimidine-3carboxylic acid [5-(7-isopropyl-7Hpyrrolo[2,3-d]pyrimidine-5-carbonyl)-pyridin3-yl]-amide	LCMS (System 8): Rt= 1.52 min; m/z 441 [M+HJ*. Prep HPLC (method 5)
462	5-Methyl-isoxazole-3-carboxylic acid [5-(7isopropyl-7H-pyrrolo[213-d]pyrimidine-5carbonyl)-pyridin-3-yl]-amide	LCMS (system 8): Rt= 1.57 min; m/z 391 [M+HJ*. Prep HPLC (method 5)
463	4,6-Dimethoxy-pyrimidine-2-carboxylic acid [5-(7-isopropyl-7H-pyrrolo[2,3-d]pyrimidine5-carbonyl)-pyridin-3-yl]-amide	LCMS (system 8): Rt = 1.62 min; m/z 448 [M+Hf. Prep HPLC (method 5)
464	6-Methyl-pyrazine-2-carboxylic acid[5-(7isopropyl-7H-pyrrolo[2,3-d]pyrimidine-5carbonyl)-pyridin-3-ylj-amide	LCMS (system 8): Rt= 1.58 min; m/z 402 [M+Hf. Prep HPLC (method 5)
465	1 -Methyl-1 H-imidazole-4-carboxylic acid [5(7-isopropyl-7H-pyrrolo[2,3-d]pyrimidine-5carbonyl)-pyridin-3-yi]-amide	LCMS (system 8): Rt = 1.49 min; m/z 390 [M+H]+. , Prep HPLC (method 5)

104

466	5-Chloro-pyridine-2-carboxylic acid[5-(7isopropyl-7H-pyrrolo[2,3-d]pyrimidine-5carbonyl)-pyridin-3-yl]-amid0	LCMS (system 8): R, = 1.71 min; m/z 421 [M+H]*. Prep HPLC (method 5)
467	1,8-Naphthyridine-2-carboxylic acid[5-(7isopropyl-7H-pyrrolo[2,3-d]pyrimidine-5carbonyl)-pyrrdin-3-yl]-amide	LCMS (system 8): Rt= 1.68 min; m/z 438 [M+H]*. Prep HPLC (method 5)
468	l-MethyMH-imidazole-Z-carboxylic acid [5(7-isopropyl-7H-pyrrolo[2,3-d]pyrimidine-5carbonyl)-pyridin-3-yl]-amide	LCMS (system 8): Rt= 1.59 min; m/z 390 [M+H]*. Prep HPLC (method 5)
469	5-Methoxymethyl-isoxazole-3-carboxylic acid [5-(7-isopropyl-7H-pyrrolo[2,3-d]pyrimidine5-carbonyl)-pyridin-3-yl]-amide	LCMS (system 8): Rt= 1.56 min; m/z 421 [M+H]*. Prep HPLC (method 5)
470	Phthalazine-1-carboxylic acid [5-(7isopropyl-7H-pyrrolo[2,3-d]pyrimidine-5carbonyl)-pyridin-3-yl]-amide	LCMS (system 8): Rt= 1.67 min; m/z 438 [M+H]*. Prep HPLC (method 5)
471	5,6-Dihydro-4H-pyrrolo[1,2-b]pyrazole-3carboxylic acid [5-(7-isopropyl-7Hpyrrolo^.S-dlpyrimidine-S-carbonylJ-pyridin3-yl]-amide	LCMS (system 8): Rt= 1.55 min; m/z 416 [M+H]*. Prep HPLC (method 5)
472	5-Bromo-pyrimidine-4-carboxylic acid [5-(7isopropylTH-pyrroloiZ.S-dJpyrimidine-Scarbonyl)-pyridin-3-yl]-amide	LCMS (system 8): R(= 1.58 min; m/z 467 [M+H]*. Prep HPLC (method 5)
473	6-Cyano-N-[5-(7-isopropyl-7H-pyrrolo[2,3d]pyrimidine-5-carbonyl)-pyridin-3-yl]nicotinamide	LCMS (system 8): Rt= 1.55 min; m/z 412 [M+H]*. Prep HPLC (method 5)
474	Pyrazolo[1,5-a]pyrimidine-3-carboxylic acid [5-(7-isopropyl-7H-pyrrolo[2,3-d]pyrimidine5-carbonyl)-pyridin-3-yl]-amide	LCMS (system 8): Rt= 1.58 min; m/z 427 [M+H]*. Prep HPLC (method 5)

105

475	3-Methyl-1H-pyrazolo[3,4-b]pyridine-5carboxylic acid [5-(7-isopropyl-7Hpyrrolo[2,3-d]pyrimidine-5-carbonyl)-pyridin3-yl]-amide	LCMS (system 8): Rt= 1.53 min; m/z 441 [M+Hf. Prep HPLC (method 5)
476	7-Methyl-pyrazolo[1,5-a]pyridine-2-carboxylic acid [5-(7-isopropyi-7H-pyrrolo[2,3d]pyrimidine-5-carbonyl)-pyridin-3-yl]-amide	LCMS (system 8): R(= 1.73 min; m/z 440 [M+Hf. Prep HPLC (method 5)
477	5-Methyl-oxazole-4-carboxylic acid [5-(7isopropyl-7H-pyrrolo[2,3-d]pyrimidine-5carbonyl)-pyridin-3-yl]-amide	LCMS (system 8): R| = 1.59 min; m/z 391 [M+H]+. Prep HPLC (method 5)
478	Thieno[3,4-c]pyridine-6-carboxylic acid [5-(7isopropyl-7H-pyrrolo[2,3-d]pyrimidine-5carbonyl)-pyridin-3-ylj-amide	LCMS (system 8): R| = 1.74 min; m/z 443 [M+Hf. Prep HPLC (method 5) (Acid: WO 2002100857)
479	2,6-Dimethyl-pyrimidine-4-carboxylic acid [5(7-isopropyl-7H-pyrrolo[2,3-d]pyrimidine-5carbonyi)-pyridin-3-yl]-amide	LCMS (system 8): Rt= 1.65 min; m/z 416 [M+Hf. Prep HPLC (method 5)
480	4-Cyano-pyridine-2-carboxylic acid [5-(7isopropyl-7H-pyrrolo[2,3-d]pyrimidine-5carbonyl)-pyridin-3-ylj-amide	LCMS (system 8): Rt = 1.62 min; m/z 412 [M+Hf. Prep HPLC (method 5).
481	5-Methoxymethyl-1 -methyl-1 H-pyrazole-3carboxylic acid [5-(7-isopropyl-7Hpyrrolo[2,3-d]pyrimidine-5-carbonyl)-pyridin3-yl]-amide	LCMS (system 8): Rt= 1.56 min; m/z 434 [M+Hf. Prep HPLC (method 5). (Acid: Prep 299)
482	4,5-Dichloro-1 H-imidazole-2-carboxylic acid [5-(7-isopropyl-7H-pyrrolo[2,3-d]pyrimidine5-carbonyl)-pyridin-3-yl]-amide	LCMS (system 8): R, = 1.68 min; m/z 444 [M+Hf. Prep HPLC (method 5). (Acid: Angewandte Chemie, 1988,1417-1418)
483	4-Methoxy-8-methyl-1,7-naphthyridine-2carboxylic acid [5-(7-isopropyl-7Hpyrrolo[2,3-d]pyrimidine-5-carbonyl)-pyridin3-yl]-amide	LCMS (system 8): R< = 1.78 min; m/z 482 [M+H]*. Prep HPLC (method 5) (Acid: can be prepared using chemistry outlined in W007011811)

106

484	2-Ethyl-4-methyl-oxazole-5-carboxylic acid [5-(7-isopropyl-7H-pyrrolo[2,3-d]pyrimidine5-carbonyl)-pyridin-3-yl]-amide	LCMS (system 8): Rt= 1.63 min; m/z 419 [M+H]+. Prep HPLC (method 5)
485	N-[5-(7-lsopropyl-7H-pyrrolo[2,3d]pyrimidine-5-carbonyl)-pyridin-3-yl]-5methoxy-nicotinamide	LCMS (system 8): R(= 1.57 min; m/z 417 [M+H]+. Prep HPLC (method 5)
486	1 H-Pyrazolo[3,4-b]pyridine-5-carboxylic acid [5-(7-isopropyl-7H-pyrrolo[2,3-d]pyrimidine5-carbonyl)-pyridin-3-yl]-amide	LCMS (system 8): Rt= 1.49 min; m/z 427 [M+Hf. Prep HPLC (method 5)
487	3H-lmidazo[4,5-b]pyridine-6-carboxylic acid [5-(7-isopropyl-7H-pyrrolo[2,3-d]pyrimidine5-carbonyl)-pyridin-3-yl]-amide	LCMS (system 8): R(= 1.44 min; m/z 427 [M+H]+, Prep HPLC (method 5)
488	8 - M ethoxy-imid azo [1,2-a] pyrazin e-2carboxylic acid [5-(7-isopropyl-7Hpyrrolo^.S-djpyrimidine-ô-carbonyO-pyridin3-yl]-amide	LCMS (system 8): Rt= 1.61 min; m/z 457 [M+Hf. Prep HPLC (method 5) (Acid: ban be made from the appropriate halo dérivative e.g. W007028051)
489	N-[5-(7-lsopropyl-7H-pyrrolo[2,3d]pyrimidine-5-carbonyl)-pyridin-3-yl]isonicotinamide	LCMS (system 8): Rt = 1.51 min; m/z 387 [M+Hf. Prep HPLC (method 5)
490	3-Methyl-pyridine-2-carboxylic acid[5-(7isopropyl-7H-pyrrolo[2,3-d]pyrimidine’5carbonyl)-pyridin-3-yl]-amide	LCMS (system 8): Rt= 1.70 min; m/z 401 [M+Hf. Prep HPLC (method 5)
491	Furo[2,3-b]pyridine-5-carboxylic acid [5-{7isopropyl-7H-pyrrolo[2,3-d]pyrimidine-5carbonyl)-pyndin-3-yl]-amide	LCMS (system 8): Rt= 1.59 min; m/z 427 [M+Hf. Prep HPLC (method 5) (Acid: WO 9516688)
492	3-lsopropyl-1,2,4-triazolo[4,3-a]pyridine-6carboxylic acid [5-(7-isopropyl-7H' pyrrolo[2,3-d]pyrimidine-5-carbonyl)-pyridin3-yl]-amide	LCMS (system 8): Rt= 1.57 min; m/z 469 [M+H]1. Prep HPLC (method 5)

107

493	Oxazole-4-carboxylic acid [5-(7-isopropyl7H-pyrrolo[213-d]pyrimidine-5-carbonyl)pyridin-3-yl]-amide	LCMS (system 8): Rt = 1.50 min; m/z 377 [M+Hf. Prep HPLC (method 5)
494	3-Chloro-pyridine-2-carboxylic acid[5-(7isopropyl^H-pyrrolop.S-dJpyrimidine-Scarbonyl)-pyridin-3-yl]-amide	LCMS (system 8): Rt= 1.62 min; m/z 421 [M+H]+. Prep HPLC (method 5)
495	lmidazo[1,2-a]pyrimidine-6-carboxylic acid [5-(7-isopropyl-7H-pyrrolo[2,3-d]pyrimidine5-carbonyl)-pyridin-3-yl]-amide	LCMS (system 8): Rt= 1.44 min; m/z 427 [M+Hf. Prep HPLC (method 5) (Acid - Prep 300)
496	5-Cyclopropyl-isoxazoie-3-carboxylic acid [5^-isopropyl^H-pyrrolo^.S-dJpyrimidine-Scarbonyl)-pyridin-3-yl]-amide	LCMS (system 8): R( = 1.67 min; m/z 417 [M+H]+. Prep HPLC (method 5)
497	5-Cyclopropyl-2H-pyrazole-3-carboxylic acid [5-(7-isopropyl-7H-pyrrolo[2(3-d]pyrimidîne5-carbonyl)-pyridin-3-yl]-amide	LCMS (system 8): Rt= 1.58 min; m/z 416 [M+Hf. Prep HPLC (method 5)
498	4,7-Dimethyl-pyrazolo[5,1-c][1,2,4]triazine-3carboxylic acid [5-(7-isopropyl-7Hpyrrolo[2,3-d]pyrimidine-5-carbonyl)-pyridin3-yl]-amide	LCMS (system 8): Rt= 1.69 min; m/z 456 [M+H]+. Prep HPLC (method 5)
499	N-[5-(7-lsopropyl-7H-pyrrolo[2,3d]pyrimidine-5-carbonyl)-pyridin-3-yl]-4methyl-nicotinamide	LCMS (system 8): R( = 1.51 min; m/z 401 [M+H]+. Prep HPLC (method 5)
500	1 -Cyc!obutyl-1 H-imidazole-4-carboxylic acid [5-(7-isopropyl-7H-pyrrolo[2,3-d]pyrimidine5-carbonyl)-pyridin-3-yl]-amide	LCMS (system 8): Rt = 1.64 min; m/z 430 [M+H]+. Prep HPLC (method 5) (Acid - Prep 288)
501	Pyrazolo[1,5-a]pyridine-2-carboxylic acid [5(7-isopropyl-7H-pyrrolo(2,3-d]pyrimidine-5carbonyl)-pyridin-3-yl]-amide	LCMS (system 8): R| = 1.65 min; m/z 426 [M+H]+. Prep HPLC (method 5)

108

502	Tetrazolo[1,5-a]pyridine-6-carboxylic acid [5(7-isopropyl-7H-pyrrolo[2,3-d]pyrimidine-5carbonyl)-pyridin-3-yl]-amide	LCMS (system 8): Rt = 1.51 min; m/z 428 [M+HJ*. Prep HPLC (method 5) Commercial
503	5,6,7,8-T etrahydro-1,2,4-triazolo[4,3a]pyridine-3-carboxylic acid [5-(7-isopropyl7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)pyridin-3-yl]-amide	LCMS (System 8): Rt= 1.60 min; m/z 431 [M+H]+. Prep HPLC (method 5) Commercial
504	2-Μθ1ήνΙ-5-ΐΓΪΐΙυ0Γ0Πθ1ΐΊνΙ-0Χ3Ζ0ΐβ-4carboxylic acid [5-(7-isopropyl-7Hpyrrolo[2,3-d]pyrimidine-5-carbonyl)-pyridin3-yl]-amide	LCMS (system 8): Rt= 1.69 min; m/z 459 [M+Hf. Prep HPLC (method 5)
505	1 H-Pyrrolo[3,2-b]pyridine-6-carboxylic acid [5-(7-isopropyl-7H-pyrrolo[2,3-d]pyrimidine5-carbonyl)-pyridin-3-yl]-amide	LCMS (System 8): R( = 1.36 min; m/z 426 [M+H]+. Prep HPLC (method 5)
506	Pyrazolo[3,4-b]pyridine-6-carboxylic acid [5(7-isopropyl-7H-pyrrolo[213-d]pyrimidine-5carbonyl)-pyridin-3-yl]-amide	LCMS (system 8): Rt= 1.57 min; m/z 427 [M+H]+. Prep HPLC (method 5)
507	2H-lndazole-3-carboxylic acid [5-(7isopropyl-7H-pyrrolo[2,3-d]pyrimidine-5carbonyl)-pyridin-3-yl]-amide	LCMS (system 8): R| = 1.65 min; m/z 426 [M+HJ*. Prep HPLC (method 5)
508	3-Methyl-isoxazolo[5,4-b]pyridine-5carboxylic acid [5-(7-isopropyl-7Hpyrrolo[2,3-d]pyrimidine-5-carbonyl)-pyridin3-yl]-amide	LCMS (system 8): Rt= 1.58 min; m/z 442 [M+H]+. Prep HPLC (method 5) (Acid - Synthesis, 2009, 18581864)
509	Pyridazine-4-carboxylic acid [5-(7-isopropyl7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)pyridin-3-yl]-amide	LCMS (system 8): R, = 1.45 min; m/z 388 [M+H]+. Prep HPLC (method 5)
510	2,3-Dihydro-1,4-dioxino[2,3-c]pyridine-7carboxylic acid [5-(7-isopropyl-7Hpyrrolo[2,3-d]pyrimidine-5-carbonyl)-pyridin3-yl]-amide	LCMS (system 8): Rt = 1.66 min; m/z 445 [M+HJ*. Prep HPLC (method 5) (Acid:WO 2010/067332)

109

511	1 H-Pyrazolo[3,4-b]pyridine-3-carboxylic acid [5-(7-isopropyl-7H-pyrrolo[213-d]pyrimidine5-carbonyl)-pyridin-3-yl]-amide	LCMS (System 8): R,= 1.58 min; m/z 427 [M+H]+. Prep HPLC (method 5) (Acid: WO 2011/084486)
512	5-Fluoro-1H-indazole-3-carboxylic acid [5-(7iSOpropyl-7H-pyrrolo[2,3-d]pyrimidine-5carbonyl)-pyridin-3-yl]-amide	LCMS (system 8): Rt= 1.68 min; m/z 444 [M+H]+. Prep HPLC (method 5)
513	2,5-Dimethyl-2H-pyrazoie-3-carboxylic acid [5-(7-isopropyl-7H-pyrrolo[2,3-d]pyrimidine5-carbonyl)-pyridin-3-yl]-amide	LCMS (system 8): Rt= 1.59 min; m/z 404 [M+H]+. Prep HPLC (method 5)
514	Thiazolo[4,5-b]pyridine-7-carboxylic acid [5(7-isopropyl-7H-pyrrofo[2,3-d]pyrimidine-5carbonyl)-pyridin-3-yl]-amide	LCMS (System 8): Rt = 1.56 min; m/z 444 [M+H]+. Prep HPLC (method 5)
515	6-Chloro-imidazo[1,2-b]pyridazine-2carboxylic acid [5-(7-isopropyl-7Hpyrrolo[2,3-d]pyrimidine-5-carbonyl)-pyridin3-yl]-amide	LCMS (system 8): Rt= 1.68 min; m/z 461 [M+H]+. Prep HPLC (method 5)

Example 517: 2-(5,8-Dihydro-6H-[1₁7]naphthyridin-7-yl)-N-[5-(7-isopropyl-7H-pyrrolo[2,3-d]pyrimtdine-5carbonyl)-pyridin-3-yl]-acetamide

To a DMF solution of (5,8-Dihydro-6H-[1,7]naphthyridin-7-yl)-acetic acid hydrochloride (Préparation 235) (34.2 mg, 0.18 mmol) were added (5-Amino-pyridin-3-yl)-(7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (Préparation 95) (50 mg, 0.18 mmol), HATU (136.4 mg, 0.36 mmol) and Hunig’s base (0.092 ml, 0.54 mmol). The mixture was heated at 50°C for 20 hours and then diluted with ethyl acetate, washed with water, brine, dried over sodium sulphate and evaporated to dryness in vacuo. The crude solid was 10 purified over préparative TLC eluting with 5% MeOH/EtOAc to afford the title compound as off white solid in 26% yield, 21 mg. ¹H NMR (400 MHz, DMSO-D6) δ: 1.55 (d, 6H), 2.85-2.92 (m, 4H), 3.45 (S, 2H), 3.80 (s, 2H), 5.10 (m, 1H), 7.19 (dd, 1H), 7.56 (d, 1H), 8.32 (d, 1H), 8.53 (s, 1H), 8.56 (t, 1H), 8.73 (d, 1H), 8.99 (s, 1H), 9.07 (d, 1 H), 9.45 (s, 1 H). 10.31 (s. 1H); LCMS (System 9): R_t= 1.77 min; m/z 456 [M+H]⁺.

Example 518: 2-Hydroxy-N-[5-(7-isopropyl-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-pyridin-3-yl]-2-phenyl15 acetamide

110

To stirred solution of N-[5-(7-lsopropyl-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-pyridin-3-yl]-2-phenyl-2(tetrahydro-pyran-2-yloxy)-acetamide (60 mg, 0.12 mmol) (Préparation 237) in dioxane (1 mL) was added dioxane-HCI (1 mL of a 4N solution) at 0°C. The mixture was stirred at room température for 2 hours. Ail the volatiles were removed in vacuo and the solid obtained was triturated with diethyl ether to afford the title compound as a yellowish solid in 78% yield, 42 mg.

¹H NMR (400 MHz, DMSO-D6) δ.' 1.55 (d, 6H), 5.08-5.12 (m, 1H), 5.19 (s, 1H), 7.30 (t, 1H), 7.37 (t, 2H), 7.53 (d, 2H). 8.56 (s. 1 H), 8.63 (s, 1H), 8.76 (brs, 1H), 9.05 (s, 1H), 9.17 (brs, 1H), 9.48 (br s, 1H), 10.56 (s, 1H); LCMS (system 10): R, = 2.81 min; m/z 416 [M+H]⁺.

Example 519: N-[2-Ethoxy-5-(7-isopropyl-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-pyridin-3-yl]-2-(5methyl-3-trifluoromethyl-pyrazol-1-yl)-acetamide

The title compound was prepared according to the method described for Example 1 using (5-Amino-6ethoxy-pyridin-3-yl)-(7-isopropyl-7H-pyrrolo[2,3-d]pyrimtdin-5-yl)-methanone (Préparation 242) and (5Methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid to afford the title compound as off white solid in 50% yield, 40 mg.

¹H NMR (400 MHz, CDCI3) δ: 1.38 (t, 3H), 1.60 (d, 6H), 2.38 (s, 3H), 4.50 (q, 2H), 4.95 (s, 2H), 5.14-5.22 (m, 1H), 6.44 (s, 1H), 7.93 (s, 1H), 8.41 (s, 1H), 8.44 (s, 1H), 8.99 (s, 1H), 9.04 (s, 1H), 9.57 (s, 1H); LCMS (system 10): R₍ = 3.48 min; m/z 516 [M+Hf.

Example 520: N-[5-(2-Amino-7-tert-butyl-7H-pyrroto[2,3-d]pyrimidine-5-carbonyl)-pyridin-3-yl]-2-(4-cyanophenylj-acetamide

The title compound was prepared according to the method described for Example 1 using (2-amino-7tert-butyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-(5-amino-pyridin-3-yl)-methanone (see Préparation 65) and 4cyano phenyl acetic acid to afford the title compound as off white solid in 58%, 23 mg.

K

111

LCMS (system 10): R, = 2.78 min; m/z 454 [Μ+ΗΓ.

Example 521: 2-(4-Chloro-phenyl)-3-hydroxy-N-[5-(7-isopropyl-7H-pyrrolo[2₁3-d]pyrimidine-5-carbonyl)pyridin-3-yl]-proptonamide

2-(4-Chloro-phenyl)-3-hydroxy-propionic acid (570 mg, 2.84 mmol) (Préparation 244) was added to a solution of (5-Amino-pyridin-3-yl)-(7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-methanone (200 mg, 0.71 mmol) (Préparation 95) in THF (5 mL). Di-isopropyl ethylamine (0.64 mL, 3.56 mmol), EDCI.HCI (273 mg, 1.42 mmol) and HOBT (193 mg, 1.42 mmol) were added and the mixture was stirred at 25°C for 48 hours. The reaction mixture was quenched with saturated aqueous sodium bicarbonate solution (2 mL) and extracted with ethyl acetate (3x15 mL). The combined organic layer was washed with water (5mL), brine (5 mL), dried over sodium sulphate and evaporated in vacuo. The crude material was purified by préparative TLC (dichloromethane: methanol 93:7) to afford the title compound as a yellow solid in 3% yield, 10 mg.

’H NMR (400 MHz, DMSO-D6) δ: 1.55 (d, 6H), 3.58-3.61 (m, 1H), 3.88-3.91 (m, 1H), 4.04 (t, 1 H), 5.075.13 (m, 2H), 7.41 (s, 4H), 8.47 (s, 1H), 8.50 (S, 1H), 8.72 (s, 1H), 8.99 (S. 2H), 9.43 (s, 1H), 10.65 (s. 1H); LCMS (system 10): R_t = 2.99 min; m/z 464 [M+H]⁺.

Example 522: 2-(4-Cyano-phenyl)-N-{5-[7-(1-hydroxymethyl-cyc!opropyl)-7H-pyrrolo[2,3-d]pyrimidine-5carbonyl]-pyridin-3-yl}-acetamide

(4-Cyano-phenyl)-acetic acid (6.1 mg, 0.04 mmol) was added to a solution of (5-Amino-pyridin-3-yl)-(7-[1(tetrahydro-pyran-2-yloxymethyl)-cyclopropyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}-methanone (15 mg, 0.04 mmol) (Préparation 251) in THF (1 mL). Then 1-propylphosphonic acid cyclic anhydride (0.07 mL, 0.11 mmol) and triethylamine (0.02 mL, 0.13 mmol) were added and the mixture was stirred at 25°C for 4 hours. The reaction mixture was quenched with saturated aqueous sodium bicarbonate solution (2 mL) and extracted with ethyl acetate (3x5 mL). The combined organic layer was washed with water (5mL), brine (5 mL), dried over sodium sulphate and evaporated in vacuo. The crude was dissolved in methanol (1 mL), PTSA (5 mg) was added and stirred at room température for 16 hours. The reaction mixture was quenched with saturated aqueous sodium bicarbonate solution (2 mL) and extracted with dichloromethane (5x5 mL). The combined organic layer was washed with brine (5 mL), dried over

112 sodium sulphate and evaporated in vacuo. The crude material was purified by préparative TLC (dichloromethane: methanol 95:5) to afford the title compound as a white solid in 55% yield, 10 mg.

¹H NMR (400 MHz, DMSO-D6) Ô: 1.13-1.15 (m, 2H), 1.27-1.29 (m, 2H), 3,66 (d, 2H), 3.87 (s, 2H), 5.00 (t, 1H), 7.56 (d, 2H), 7.82 (d, 2H), 8.22 (s, 1H), 8.45 (s, 1H), 8.74 (s, 1H), 8.96 (s, 1H), 9.00 (s, 1H), 9.44 (s, 1H), 10.73 (s, 1H); LCMS (system 10): R, = 2.57 min; m/z 453 [M+Hf.

The following Examples were prepared according to the method described above for Example 522 starting from (5-Amino-pyridin-3-yi)-[7-(3-methyl-oxetan-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-methanone (Préparation 251) and the appropriate acids.

Example	Name	Data
523	2-(5-Chloro-pyridin-2-yl)-N-{5-[7-(1-hydroxymethylcyc!opropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl]pyridin-3-yl}-acetamide	LÔMS (system 10): Rt = 2.53 min; m/z 463 [M+H]+
524	N~(5-[7-(1-Hydroxymethyl-cyclopropyl)-7H-pyrrolo[2,3d]pyrimidine-5-carbonyl]-pyridin-3-yl}-2-(4-trifluoromethylphenyl)-acetamide	LCMS (system 10): Rt = 2.89 min; m/z 496 [M+H]+.
525	N-{5-[7-(1-Hydroxymethyl-cyclopropyl)-7H-pyrrolo[2,3d]pyrimidine-5-carbonyl]-pyridin-3-yl}-2-(3-trifluoromethylpyrazol-1 -yl)-acetamide	LCMS (system 9): R( = 2.71 min; m/z 486 [M+Hf.

Example 526: 1 -(3-Cyclopropyl-1 '-methyl-1 Ή-[1,4'Jbipy razol yl-5-y l)-3-[5-(7-is o pro pyl-7H-py rrolo[2,3d]pyrimidine-5-carbonyl)-pyridin-3-yl]-urea

Me

Phenyl chloroformate (0.03 mL, 0.24 mmol) was added slowly to a solution of 3-Cyclopropyl-T-methyll'H-lM'jbipyrazolyl-S-yfamine (Préparation 297, 40 mg, 0.19 mmol) and pyridine (0.03 mL) in THF (2 mL) at 0°C and the mixture was stirred at room température for 4 hours. A solution of (5-Amino-pyridin-3-yl)-(7isopropyl-7H-pyrro!o[2,3-d]pyrimidin-5-yl)-methanone (Préparation 95) (55.4 mg, 0.19 mmol) in DMF (1 mL) and was then added and the reaction mixture heated at 100°C for 16 hours. The mixture was cooled and diluted with ethyl acetate (15 mL), and washed with aqueous saturated NaHCO₃ solution (2 x 10 mL), water (10 mL), brine (10 mL), dried over sodium sulphate and evaporated to dryness in vacuo. The crude material was purified over préparative TLC plate (eluting with 5% methanol in DCM) to afford the title compound as off white solid in 15% yield, 15 mg. ¹H NMR (400 MHz, DMSO-d6) ô: 0.64-0.65 (m, 2H), 0.85-0.88 (m, 2H), 1.56 (d, 6H), 1.82-1.85 (m, 1H), 3.89 (s, 3H), 5.09-5.12 (m, 1H), 6.10 (s, 1H), 7.66 (s,

113

1H), 8,05 (s, 1H), 8.36 (s, 1H), 8.52 (s, 1H), 8.61 (brs, 1H), 8.65 (s, 1H), 8.78 (s, 1H), 8.99 (s, 1H), 9.45 (s, 2H); LCMS (system 10): R_t = 2.75 min; m/z 511 [M+H]⁺.

Example 527: 1 - (3-tert- Buty I-1 '-methyl-1 Ή-[1,4']bipy razol yl-5-y l)-3-[5-(7-isop ropyl-7H-py rrolo[2,3d]pyrimidine-5-carbony!)-pyridin-3-yl]-urea

The title compound was prepared according to the method described for Example 526 using (5-Aminopyridin-3’yl)-(7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-methanone (Préparation 95) and S-tert-Butyl·!methyl-TH-[1 ^'jbipyrazolyl-S-ylamlne (Préparation 296) to afford the title compound as yellow solid in 35% yield, 17 mg.LCMS (system 10): R₍ = 3.01 min; m/z 527 [M+H]⁺.

The following Examples were prepared according to the method described above for Example 1, starting from (2-amino-7-ferî-butyl-7H-pyrrolo[2,3-c/]pyriniidin-5-yl)(5-aminopyridin-3-yl)methanone (Préparation 65) and the appropriate acids.

Example	Name	Data
528	N-[5-(2-Amino-7-tert-butyl-7H-pyrrolo[2,3-d]pyrimidine-5carbonyl)-pyridin-3-yl]-2-(1 H-benzoimidazol-2-yl)acetamide	LCMS (system 10): Rt = 2.79 min; m/z 469 [M+H]+.
529	N-[5-(2-Amino-7-tert-butyl-7H-pyrrolo[2,3-d]pyrimidine-5carbonyl)-pyridin-3-yl]-2-(5-bromo-pyridin-2-yl)-acetamide	LCMS (system 10); Rt = 2.94 min; m/z 508 [M+Hf
530	N-[5-(2-Amino-7-tert-butyl-7H-pyrrolo[2,3-d]pyrimidine-5carbonyl)-pyridin-3-yl]-2-(5-cyano-pyridin-2-yl)-acetamide	LCMS (system 10): Rt = 2.78 min; m/z 455 [M+H]+ (acid can be prepared by cyanation of an appropriate bromo dérivative

The following Examples were prepared according to the method described for Example 522 using (515 Amino-pyridin-3-yl)-(7-[(S)-1-methyl-2-(tetrahydro-pyran-2-yloxy)-ethyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}methanone (Préparation 33) and the appropriate acid.

Example	Name	Data
531	2-(4-Difluoromethoxy-phenyl)-N-{5-[7-((S)-2hydroxy-1-methyl-ethyl)-7H-pyrrolo[2,3d]pyrimidine-5-carbonyl]-pyridin-3-yl}-acetamide	LCMS (system 9): Rt = 2.80 min; m/z 482 [M+H]+
532	N-(5-[7-((S)-2-Hydroxy-1-methyl-ethyl)-7Hpyrrolo[2,3-d]pyrimidine-5-carbonylJ-pyridin-3-yl}-2indazol-2-yl-acetamide	LCMS (system 9): Rt = 2.58 min; m/z 456 [M+H]+
533	2-(1 H-Benzoimidazol-2-yl)-N-[5-[7-((S)-2-hydroxy1-methyl-ethyl)-7H-pyrrolo[2,3-d]pyrimidine-5carbonyl]-pyridin-3-yl}-acetamide	LCMS (system 10): Rt = 2.42 min; m/z 456 [M+H]+.
534	N-{5-[7-((S)-2-Hydroxy-1-methyl-ethyl)-7Hpyrrolo[2,3-d]pyrimidine-5-carbonyl]-pyridin-3-yl}-2(4-trifluoromethoxy-phenyl)-acetamide	LCMS (system 9): Rt = 2.99 min; m/z 500 [M+H]+
535	2-(3,4-Difluoro-phenyl)-N-{5-[7-((S)-2-hydroxy-1methyl-ethyl)-7H-pyrrolo[2,3-d]pyrimidine-5-	LCMS (system 9): Rt = 2.75 min; m/z 452 [M+H]+

114

carbonyl]-pyridin-3-yl}-acetamide

The following Examples were prepared according to the Method described for d]pyrimidin-5-yl]methanone (Préparation 186) and the appropriate acid.

Example	Name	Data
536	2-(5-Chloro-pyridin-2-yl)-N-{5-[7-(2-methoxy-1,1dimethyl-ethyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl]pyridin-3-yl}-acetamide	LCMS (System 10): Rt = 2.92 min; m/z 479 [M+Hf
537	2-(5-Fluoro-pyridin-2-yl)-N-{5-[7-(2-methoxy-1,1 dimethyl-ethyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl]pyridin-3-yl}-acetamide	LCMS (system 10): Rt = 2.79 min; m/z 463 [M+Hf.
538	2-(3-Cyc1opropyl-pyrazol-1 -yl)-N45-[7-(2-methoxy-1,1 dimethyl-ethyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl]pyridin-3-yl}-acetamide	LCMS (system 10): Rt = 2.89 min; m/z 474 [M+Hf.
539	2-(4-Fluoro-phenyl)-N-{5-[7-(2-methoxy-1,1 -dimethylethyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl]-pyridin-3yl}-acetamide	LCMS (system 10): Rt = 3.03 min; m/z 462 [M+Hf.

Example 540: N-[5-(7-tert-Butyl-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-pyridin-3-yl]-2-(4-fluoro-phenyl)N-methyl-acetamide

To a stirred solution of N-[5-(7-tert-Butyl-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-pyridin-3-yl]-2-(4-fluorophenyl)-acetamide (Example 546,115 mg, 0.27 mmol) in anhydrous THF (4.5 mL), was added NaH (60% in paraffin oil, 10.7 mg, 0.27 mmol) at 0°C under nitrogen and the resulting mixture stirred for 10 min. Mel (0.017 mL, 0.27 mmol) was then added and the reaction mixture was stirred at room température for 1 hour. Aqueous saturated ammonium chloride (5 mL) was added and the mixture extracted with ethyl acetate (2x10 mL). The organic phase was washed with water (10 mL), brine (10 mL), dried over sodium sulphate and evaporated to dryness in vacuo. The crude material was purified via préparative TLC 15 (eluting with 5% methanol in DCM) to afford the title compound as off white solid in 46% yield, 55 mg. ¹H

NMR (400 MHz, DMSO-D6) δ: 1.79 (s, 9H), 3.28 (s, 3H), 3.58 (br, 2H), 7.08-7.20 (m, 4H), 8.20 (s, 1H), 8.32 (s, 1H), 8.83 (s, 1H), 8.97 (br, 1H), 9.01 (s. 1H). 9.50 (s, 1H); LCMS (system 10): R₍ = 3.08 min; m/z 446 [M+Hf.

115

Example 541: [5-(7-tert-Butyl-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-pyridin-3-yl]-carbamic acid tert-butyl ester

To a stirred solution of (5-Amino-pyridin-3-yl)-(7-tert-butyl-7H*pyrrolo[2,3*d]pyrimidin-5*yl)-methanone (Préparation 31) (200 mg, 0.6Θ mmol) in DCM (4 mL) was added boc-anhydride (0.155 mL, 0.68 mmol) and Hunig’s base (0.24 mL, 1.36 mmol) and the reaction mixture was stirred at room température for 16 hours. It was diluted with DCM (15 mL) and washed with water (2x10 mL), brine (10 mL), dried over sodium sulphate and evaporated to dryness in vacuo. The crude material was purified by column chromatography on silica gel (MethanokDCM 2:98) to afford the title compound as light brown gum in 41% yield, 110 mg. LCMS (system 10): R₍ = 3.16 min; m/z 396 [M+Hf.

Example 542: [5-(7-tert-Butyl-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-pyridin-3-yl]-methyl-carbamic acid tert-butyl ester

The title compound was prepared according to the method described for Example 540 using [5-(7-tertButyl-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-pyridin-3-ylj-carbamic acid tert-butyl ester (Example 541) to afford the title compound as yellow solid in 79% yield, 90 mg. LCMS (system 10): R_t = 3.83 min; m/z 410 [M+Hf.

Example 543: N-[5-(7-tert-Butyl-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-pyridin-3-yl]-2-(5-chloro-pyridin2-yl)-N-methyl-acetamide

The title compound was prepared according to the method described for Example 1 using (7-tert-butyl7H-pyrrolo[2,3-d]pyrimîdin-5-yl)-(5-methylamino-pyridin-3-yl)-methanone (Préparation 187) and (5-chloropyridin-2-yl)-acetic acid(see Préparation 90) to afford the title compound as off white solid in 21% yield, 25 mg. ¹H NMR (400 MHz, DMSO-D6) δ: 1.78 (s, 9H), 3.32 (s, 3H), 3.77 (brs, 2H), 7.26 (br, 1H), 7.83 (br, 1H), 8.21 (s, 1H), 8.32 (s, 1H), 8.48 (s, 1H). 8.85 (s, 1H), 8.97 (s, 1 H), 9.02 (s, 1H), 9.51 (S, 1H); LCMS (system 10): R_t = 3.29 min; m/z 463.2 [M+H]⁺.

Example 544: N-[5-(7-tert-Butyl-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-pyridin-3-yl]-2-(4-chloro-phenyl)N-methyl-acetamide

116

The title compound was prepared according to the method described for Example 1 using (7-tert-Butyl7H-pyrrolo[2,3-d]pyrimidin-5-yl)-(5-methylamino-pyridin-3-yl)-methanone (Préparation 187) and (4-chlorophenyl)-acetic acid to afford the title compound as off white solid in 45% yield, 21 mg.

LCMS (system 10): R_t = 3.28 min; m/z 462 [M+H]⁺.

The following Examples were prepared according to the method described above for Example 1, starting from (5-aminopyridin-3-yl)(7-tert-butyl-7H-pyrrolo[2,3-cf]pyrimidin-5-yl)methanone (Préparation 31) and the appropriate acids.

Example	Name	Data
545	N-[5-(7-tert-Butyl-7H-pyrrolo[2,3-d]pyrimidine-5carbonyl)-pyridin-3-ylj-2-(4-chloro-phenyl)acetamîde	LCMS (system 10): R, = 3.18 min; m/z 448 [M+Hf.
546	N-[5-(7-tert-Butyl-7H-pyrrolo[2,3-d]pyrimidine-5carbonyl)-pyridin-3-yl]-2-(4-fluoro-phenyl)acetamide	LCMS (system 10): Rt = 3.08 min; m/z 432 [M+H]+.

The following Examples were prepared according to the method described for Example 1 starting from [210 Amino-7-(2-methoxy-1₁1-dimethyl-ethyl)-7H-pyrrolo[2₁3-d]pyrimidin-5-yl]-(5-amino-pyridin-3-yl)-methanone (Préparation 261) and the appropriate acid.

Example	Name	Data
547	N-{5-[2-Amino-7-(2-methoxy-1,1 -dimethyl-ethyl)-7Hpyrrolo[2,3-d]pyrimidine-5-carbonyl]-pyridin-3-yl}-2(5-chloro-pyridin-2-yl)-acetamide	LCMS (system 10): R, = 2.85 min; m/z 494 [M+H]+. (Acid: Prep 90)
548	N-{5-[2-Amino-7-(2-methoxy-1,1 -dimethyl-ethyl)-7Hpyrrolo[2,3-d]pyrimidine-5-carbonyl]-pyridin-3-yl)-2(5-fluoro-pyridin-2-yl)-acetamide	LCMS (system 10): R, = 2.77 min; m/z 478 [M+H]+. (Acid Prep 92)
549	N-{5-[2-Amino-7-(2-methoxy-1,1-dimethyl-ethyl)-7HpyrroIo[2,3-d]pyrimidine-5-carbonyl]-pyridin-3-yl}-2(3-trifluoromethyl-pyrazol-1-yl)-acetamide	LCMS (system 10): Rt = 3.02 min; m/z 517 [M+H]+. (Acid Prep 85)
550	N-{5-[2-Amino-7-(2-methoxy-1,1-dimethyl-ethyl)-7Hpyrrolo[2,3-d]pyrimidine-5-carbonyl]-pyridin-3-yl}-2^-trifluoromethylril ,2,3]triazol-1 -yl)-acetamide	LCMS (System 10): Rt = 2.93 min; m/z 518 [M+H]+. (Acid Prep 81)
551	N-{5-[2-Amino-7-(2-methoxy-1,1 -dimethyl-ethyl)-7Hpyrrolo[2,3-d]pyrimidine-5-carbonyl]-pyridin-3-yl}-2(4-trifluoromethyl-pyrazol-1-yl)-acetamide	LCMS (system 10): Rt = 3.01 min; m/z 517 [M+Hf. (Acid Prep 85)
552	N~(5-[2-Amino-7-(2-methoxy-1(1-dimethyl-ethyl)-7Hpyrrolo[2,3-d]pyrimidine-5-carbonyl]-pyridin-3-yl}-2(4-cyclopropyl-[1,2,3]tr iazol-1 -yl)-acetamide	LCMS (system 10): Rt = 2.69 min; m/z 490 [M+H]+. (Acid Prep 83)

117

The following Examples were prepared according to the method described for Example 522 using (5Amino-pyridin-3-yl)-{7-[(S)-1-methyl-2-(tetrahydro-pyran-2-yloxy)-ethyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}methanone (Préparation 49) and the appropriate acid.

Example	Name	Data
553	N45-[2-Amino-7-(2’hydroxy-1,1-dimethyl-ethyl)7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl]-pyridin-3y l}-2- i ndazo l-2-y I -aceta mid e	LCMS (system 10): Rt = 2.67 min; m/z 485 [M+H]+.
554	N-{5-[2-Amino-7-(2-hydroxy-1(1-dimethyl-ethyl)7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl]-pyridin-3yl}-2-(4-oxo-4H-quinazolin-3-yl)-acetamide	LCMS (system 10): Rt = 2.52 min; m/z 513 [M+Hf.
555	N-(5-[2-Amino-7-(2-hydroxy-1,1 -dimethyl-ethyl)7H-pyrrolo[2(3-d]pyrimidine-5-carbonyl]-pyridin-3yl}-2-(3,5-difluoro-pyridin-2-yl)-acetamide	LCMS (system 9): Rt = 2.07 min; m/z 482 [M+Hf. Acid Prep 265)
556	N-{5-[2-Amino-7-(2-hydroxy-1,1 -dimethyl-ethyl)7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl]-pyridin-3yl}-2-(5-methyl-pyridin-2-yl)-acetamide	LCMS (system 9): Rt = 1.36 min; m/z 460 (M+Hf. Acid Prep 274
557	N-(5-{[2-amino-7-(2-hydroxy-1,1-dimethylethyl)-7Hpyrrolo[2,3-d]pyrimidin-5-yl]carbonyl}pyridin-3-yl)2-{4-[methyl(methylsulfonyl)amrno]phenyl}acetamide	LCMS (system 9): R, = 2.19 min; m/z 552 [M+Hf. Acid Prep-271
558	N-{5-[2-Amino-7-(2-hydroxy-1,1 -dimethyl-ethyl)7H-pyrro[o[2,3-d]pyrimidine-5-carbonyl]-pyridin-3yl}-2-(1H-benzoimidazol-2-yl)-acetamide	LCMS (system 9): Rt = 1.42 min; m/z 485 [M+Hf.
559	N-(5-[2-Amino-7-(2-hydroxy-1,1-dimethyl-ethyl)7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl]-pyridin-3yl}-2-(2-oxo-5-trifluoromethyl-2H-pyridin-1-yl)acetamide	LCMS (system 9): Rt = 2.18 min; m/z 530 [M+Hf.
560	N45-[2-Amino-7-(2-hydroxy-1,1 -dimethyl-ethyl)7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl]-pyridin-3yl}-2-(5-chloro-3-fluoro-pyridin-2-yl)-acetamide	LCMS (system 9): R, = 2.23 min; m/z 498 [M+Hf.
561	N-{5-[2-Amino-7-(2-hydroxy-1,1 -dimethyl-ethyl)7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl]-pyridin-3yl}-2-(5-ethoxy-pyridin-2-yl)-acetamide	LCMS (system 10): R( = 2.64 min; m/z 490 [M+Hf (acid can be prepared from the appropriate bromide using the method in WO2011/114271)
562	N-(5-[2-Amino-7-(2-hydroxy-1,1 -dimethyl-ethyl)7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl]-pyridin-3yl}-2-(5-trifluoromethyl-pyridin-2-yl)-acetamide	LCMS (system 9): Rt = 2.40 min; m/z 514 [M+Hf.
563	N-{5-[2-Amino-7-(2-hydroxy-1,1 -dimethyl-ethyl)7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl]-pyridin-3yl}-2-(4-trifluoromethyl·pyΓazol-1-yl)-acetamide	LCMS (system 9): Rt = 2.39 min; m/z 503 [M+Hf. Acid prep 85
564	N-(5-[2-Amino-7-(2-hydroxy-1,1 -dimethyl-ethyl)- 7H-pyrrolo[2$3-d]pyrimidine-5-carbonyl]-pyridin-3yl}-2-(4-methanesulfonylamino-phenyl)-acetamide	LCMS (system 9) R( = 4.47 min (12 min run); m/z 538 [M+Hf.

118

The following Examples were prepared according to the method described for Examples 73-87 using (5Amino-pyridin-3-yl)-(7-[(S)-1-methyl-2-(tetrahydro-pyran-2-yloxy)-ethyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}methanone (Préparation 49) and the appropriate acid.

Example	Name	Data
565	N-{5-[2-Amino-7-(2-hydroxy-1,1-dimethyl-ethyl)-7Hpyrrolo[2,3-d]pyrimidine-5-carbonyl]-pyridin-3-yl}-2-(4difluoromethoxy-phenyl)-acetamide	LCMS (system 9): R, = 2.56 min; m/z 511 [M+Hf.
567	N-{5-[2-Amino-7-(2-hydroxy-1,1 -dimethyl-ethyl)-7Hpyrrolo[2,3-d]pyrimidine-5-carbonyl]-pyridin-3-yl}-2-(4trifluoromethoxy-phenyl)-acetamide	LCMS (System 9): Rt = 2.74 min; m/z 529 [M+H]+.
568	N-{5-[2-Amino-7-(2-hydroxy-1,1-dimethyl-ethyl)-7Hpyrrolo[2,3-d]pyrimidine-5-carbonyl]-pyridin-3-yl}-2-(3,4difluoro-phenylj-acetamide	LCMS (system 9): Rt = 2.50 min; m/z 481 [M+H]'’.
569	N-{5-[2-Amino-7-(2-hydroxy-1,1 -dimethyl-ethyl)-7Hpyrrolo[2,3-d]pyrimidine-5-carbonyl]-pyridin-3-yl}-2-(5chloro-pyrimidin-2-yl)-acetamide	LCMS (system 10): R, = 2.35 min; m/z 481 [M+Hf (acid can be prepared by oxidation of the appropriate aldéhyde WO04110453}

Example 570: 2-(4-Cyano-phenyl)-N-[5-(7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-pyridin-3-yl]-acetamide

The title compound was prepared according to the method described for Example 343 using 2-(4-Cyanophenyl)-N-{5-[7-(2-trimethylsilanyl-ethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl]-pyridin-3-yl}10 acetamide (Préparation 277) to afford the title compound as a white solid in 99% yield, ’H NMR (400 MHz, DMS0-d_E) δ; 3.87 (s, 2H), 7.55 (d, 2H), 7.81 (d, 2H), 8.36 (s, 1H), 8.47 (s, 1H), 8.72 (s, 1 H), 8.97 (m, 2H), 9.47 (s, 1H), 10.66 (s, 1H), 13.14 (s, 1H); LCMS (System 10): R_t = 2.48 min; m/z 383 [M+H]⁺.

The following Examples were prepared according to the method described above for Example 1, starting from (5-Amino-pyridin-3-yl)-[7-(3-methyl-oxetan-3-yl)-7H-pyrroio[2,3-d]pyrimidin-5-yl]-methanone (Préparation 222) and the appropriate acid.

Example	Name	Data
571	N-{5-[7-(3-Methyl-oxetan-3-yl)-7H-pyrrolo[2,3-d]pyrimidine- 5-carbonyl]-pyridin-3-yl}-2-(4-trifluoromethyl-phenyl)acetamide	LCMS (System 10): Rt = 3.02 min; m/z 496 [M+HJ*

119

572	N-{5-[7-(3-Methyl-oxetan-3-yl)-7H-pyrrolo[2,3-d]pyrimidine- 5-carbonyl]-pyridin-3-yl}-2-(3-trifluoromethyl-phenyl)acetamide	LCMS (System 10): Rt = 2.98 min; m/z 496 [M+H]+.
573	2-(3-Fluoro-4-trifluoromethyl-phenyl)-N-{5-[7-(3-methyloxetan-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl]pyridin-3-yl)-acetamide	LCMS (System 10): Rt = 3.01 min; m/z 514 [M+H]+.
574	N-{5-[7-(3’Methyl-oxetan-3-yl)-7H-pyrroIo[2,3-d]pyrimidine- 5-Garbonyl]-pyridin-3-yl}-3-trifluoromethyl-benzamide	LCMS (System 10): Rt = 3.00 min; m/z 482 [M+H]+.
575	N-(5-[7-(3-Methyl-oxetan'3-yl)-7H-pyrrolo[2,3-d]pyrimidine- 5-carbonyl]-pyridin-3-yl}-3-trifluoromethoxy-benzamide	LCMS (System 10): Rt = 3.05 min; m/z 498 [M+H]+

Example 576: N-{5-[2-Amïno-7-(2-hydroxy-1,1 -dimethyl-ethyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl]pyridin-3-yl}-2-(4-cyclopropyl-pyrazol-1-yl)-acetamide

The title compound was prepared according to the method described for Example 1 using (2-amino-7[1,1-dimethyl-2-(tetrahydro-pyran-2-yloxy)-ethyl]-7H-pyrrolo[2_l3-d]pyrimidin-5-yl}-(5-amino-pyridÎn-3-yl)methanone (Préparation 49) and (4-Cyclopropyl-pyrazoM -yl)-acetic acid to afford the title compound as a white solid in 72 % yield, 16.5 mg.

LCMS (System 10): Rt = 2.62 min; m/z 475 [M+H]⁺.

Example 577: N-[5-(2-Amino-7-tert-butyl-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-pyrÎdin-3-yl]-2-(4cyclopropyl-pyrazol-1-yl)-acetamide

The title compound was prepared according to the method described for Example 1 using (2-Amino-7tert-butyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-(5-amino-pyridin'3-yl)-methanone (see Préparation 65) and (4cyclopropyl-pyrazol-l-ylj-acetic acid to afford the title compound as a pale yellow solid in 16 % yield, 12 mg.LCMS (System 10) : R_t = 2.80 min; m/z 459 [M+H]⁺.

Example 578: N-[5-(2-Amino-7-bicyclo[1.1.1]pent-1-yl-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-pyridin-3yl]-2-(5-fluoro-pyridin-2-yl)-acetamide

To a solution of (S-amino-pyridinO-ylHZ-bicyclotl.l.lJpent-l-yl^-^-methoxy-benzylaminoHHpyrrolo[2,3-d]pyrimidin-5-yl]-methanone (Préparation 287) (50 mg, 0.11 mmol) in THF (5 mL) at room

120 température was added 5-fluoro pyridine-2-yl acetic acid (27 mg, 0.17 mmol), TEA (0.08 mL, 0.56 mmol) and 1-propylphosphonic acid cyclic anhydride (50% solution in EtOAc, Ô.20 mL, 0.34 mmol). The resulting mixture was before stirred for 18 hours. The mixture was concentrated under reduced pressure and the residue was partitioned between saturated sodium bicarbonate solution (10 mL) and ethyl acetate 5 (25 mL). The organic phase was dried over sodium sulphate and concentrated under reduced pressure.

TFA (1.5 mL) was added and the resulting mixture stirred at room température for 18 hours. The mixture was concentrated under reduced pressure and the residue partitioned between saturated sodium bicarbonate (10 mL) and ethyl acetate (30 mL). The organic phase was dried over sodium sulphate, concentrated under reduced pressure purified by Préparative TLC (MeOH:DCM 5: 95) to afford the title 10 compound as off white solid in 31% yield, 16 mg. ’H NMR (400 MHz, DMSO-d₆) δ; 2.32 (s, 6H), 2.66 (s,

1H), 3.94 (s, 2H), 6.57 (s, 2H), 7.49 (m, 1H), 7.69-7.73 (m, 2H), 8.38 (s, 1H), 8.50 (d, 1H), 8.65 (d, 1H), 8.92 (s, 1 H), 8.96 (d, 1H), 10.67 (s, 1H); LCMS (System 10): R_t = 2.85 min; m/z 458 [M+H]⁺.

The following Examples were prepared according to the method described above for Example 578 15 starting from ((5-Amino-pyridin-3-yl)-[7-bicyclo[1.1,1]pent-1-yl-2-(4-methoxy-benzylamino)-7H-pyrrolo[2,3d]pyrimidin-5-yl]-methanone (Préparation 2B7) and the appropriate acid.

Example	Name	Data
579	N-[5-(2-Amino-7-bicyclo[1.1.1]pent-1-yl-7H-pyrrolo[2,3d]pyrimidine-5-carbonyl)-pyridin-3-yl]-2-(3methanesulfonyl-phenyl)-acetamide	LCMS (System 10): Rt = 2.87 min; m/z 517 [M+H]+.
580	N-[5-(2-Amino-7-bicyclo[1.1,1]pent-1 -yi-7H-pyrrolo[2,3d]pyrimidine-5-carbonyl)-pyridin-3-yl]-2-(3trifluoromethyl-pyrazol-1-yl)-acetamide	LCMS (System 10):Rt = 2.92 min; m/z 497 [M+H]+.
581	N-[5-(2-Amino-7-bicyclo[1.1.1]pent-1-yl-7H-pyrrolo[2,3d]pyrimidine-5-carbonyl)-pyridin-3-yl]-2-(4triflu o rom ethyl-[1,2,3]triazo I-1 -yl)-acetamide	LCMS (System 10): Rt = 2.89 min; m/z 498 [M+H]+. (Acid.: Prep 81)
582	N-[5-(2-Amino-7-bicyclo[1.1,1]pent-1-yl-7H-pyrrolo[2,3d]pyrimidine-5-carbonyl)-pyridin-3-yl]-2-(4-cyanophenyl)-acetamide	LCMS (System 10): Rt = 2.94 min; m/z 464 [M+H]+.
583	N-[5-(2-Amino-7-bicyclo[1.1,1]pent-1-yl-7H-pyrrolo[2,3d]pyrimidine-5-carbony])-pyridin-3-yl]-2-(5-chloro-pyridin2-yl)-acetamide	LCMS (system 9) : Rt = 6.28 min; m/z 474 [M+H]+. (Acid Prep 90)

Examples 584-5923 illustrate compounds of general formula :

121

that fall into general formula (I) by virtue of pyridone tautomerism.

Example	Name	Data
584	2-(4-cyanophenyl)-N-(2-oxo-5-{[7-(propan-2-yl)-7H-pyrrolo[2,3- d]pyrimidin-5-yl]carbonyl}-1,2-dihydropyridin-3-yl)acetamide	LCMS Rt = 5.25 min; m/z 441 [M+H]+
585	N-{2-oxo-5-{[7-(propan-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-5yl]carbonyl}-1,2-dihydropyridin-3-yl)-2-[2(trifluoromethoxy)phenoxy]acetamide	LCMS Rt = 4.04 min; m/z 516 [M+HJ+
586	2-(2-cyclopropyl-1,3-oxazol-4-yl)-N-(2-oxo-5([7-(propan-2-yl)-7Hpyrrolo[2,3-d]pyrimidin-5-yl)carbonyl}-1,2-dihydropyridin-3Vl)acetamide	LCMS Rt = 3.39 min; m/z 447 [M+H]+
587	2-[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]-N-(2-oxo-5-{[7(propan-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]carbonyl}-1,2- , dihydropyrïdin-3-yl)acetamide	LCMS Rt = 3.51 min; m/z 488 [M+H]+
588	N-(2-oxo-5~([7-(propan-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-5yl]carbonyl}-1l2-dihydropyridin-3-yl)-2-(quinolin-7-yl)acetamide	LCMS Rt = 3.51 min; m/z 485 [M+H]+
589	2-(4-chlorophenyl)-N-(2-oxo-5-{[7-(propan-2-yl)-7H-pyrroio[213- d]pyrimidin-5-yl]carbonyl}-1,2-dihydropyridin-3-yl)acetamide	LCMS Rt = 3.82 min; m/z 450 [M+H]+
590	2-(5-chloropyridin-2-yl)-N-(2-oxo-5-{[7-(propan-2-yl)-7Hpyrrolo[2,3-d]pyrimidin-5-yl]carbonyl)-1,2-dihydropyridin-3yl)acetamide	LCMS Rt = 3.22 min; m/z 451 [M+H]+
591	N-(2-oxo-5-{[7-(propan-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-5yl]carbonyl}-1,2-dihydropyridin-3-yl)-2-[4-(trifluoromethyl)-1H1,2,3-triazol-1-yl]acetamide	LCMS Rt = 3.31 min; m/z 475 [M+H]+
592	N-(5-([2-Amino-7-(2-hydroxy-1,1-dimethylethyl)-7H-pyrrolo[2,3· d]pyrimidin-5-yl]carbonyl}-2-oxo-pyridin-3-yl)-2-(5-chloropyridin-2yl))acetamide
593	N-[5-({7-[(1 S)-2-Hydroxy-1 -methylethyl]-7H-pyrrolo[2,3d]pyrimidin-5-yl}carbonyl)-2-oxo-pyridin-3-yl]-2-[4(trifluoromethyl)phenyl]acetamide	m/z 500, RT 4.94

Préparation 1: 7-[(1 S)-2-{[tert-Butyl(dimethyl)silyl]oxy}-1 -methylethyl]-4-chloro-7H-pyrrolo[2,35 d]pyrimîdine ci

Me Me (S)-2-tert-Butyldimethylsilyloxy-1-methylethylamine (120 g, 636 mmol) was added to (4,6dichloropyrimidin-5-yl)acetafdehyde (52,8 g, 276 mmol) in éthanol (500 mL). The mixture was heated to

122 reflux for 45 minutes. The reaction mixture was evaporated in vacuo then the residue was diluted with water (400 mL) and extracted with ethyl acetate (600 mL). The orgamc extract was evaporated in vacuo and the crude material was purified by column chromatography on silica gel (gradient of pentane:EtOAc 90:10 to 80:20) to afford the title compound as a yellow liquid in 67% yield, 60.4 g, ¹H NMR (400 MHz, CDCI3) δ: -0.92 (s, 6H), 0.80 (s, 9H), 1.58 (d, 3H), 3.86 (m, 2H), 5.04 (m, 1H), 6.59 (d, 1H), 7.40 (d, 1H), 8.60 (s, 1H).

Préparation 2: 7-(2-{[fert-Butyl(dimethyl)silyl]oxy}-1,1 -dimethylethyl)-4-chloro-7H-pyrrolo[2,3-d]pyrimidine

The title compound was prepared according to the method described for Préparation 1 using (4,6dichloropyrimidin-5-yl)acetaldehyde and 1-{[terf-butyl{dimethyl)silyl]oxy}-2-methylpropan-2-amine to afford the title compound as a yellow oil in 38% yield, 377 mg.

¹H NMR (400 MHz, CDCI₃) δ: 0.00 (s, 6H), 0.94 (s, 9H), 1.97 (s, 6H), 4.28 (s, 2H), 6.78 (d, 1 H), 7.66 (d, 1 H), 8.83 (s, 1H).

Préparation 3: (2R)-2-(4-Chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)propan-1-ol ci

The title compound was prepared according to the method described for Préparation 1 using (4,6dichloropyrimidin-5-yl)acetaldehyde and (R)-2-amino-1-propanol to afford the title compound as a yellow solid in 100% yield, 11.12g.

LCMS (system 2): R_t = 0.89 min; m/z 212 [M+H]⁺.

Préparation DL3: (R,S) 7-[2-{[terf-Butyl{d imethyl) silyl]oxy}-1 -methylethyl]-4-chloro-7H-pyrrolo[2,3djpyrimidine

Cl

Me. .Si

X Me Me Me

123

The title compound was prepared according to the method described for Préparation 1 using (4,6 dichloropynmidin-5-yl)acetaldehyde and 2-tert-butyldimethylsilyloxy-1-methylethylamine to afford the title compound as an orange oil in 77% yield, 4.08 g.

¹H NMR (400 MHz, CDCI3) δ: -0.90 (s, 6H), 0.82 (s, 9H), 1.58 (d, 3H), 3.84 (m, 2H), 5.05 (m, 1H), 6.59 (d, 1H), 7.42 (d, 1H), 8.60 (s, 1H).

Préparation 4: (2S)-2-(4-Chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)propan-1 -ol ci

The title compound was prepared according to the method described for Préparation 1 using (4,6dichloropyrimidin-5-yl)acetaldehyde and (S)-2-amino-1-propanol to afford the title compound as a cream solid in 98% yield, 10.9 g.

¹H NMR (400 MHz, DMSO-D6) δ: 1.42 (d, 3H), 3.72 (m, 2H), 4.89 (m, 1 H), 6.63 (d, 1H), 7.83 (d, 1H), 8.59 (s, 1H).

Préparation 5: 7-tert-Butyl-4-chloro-7H-pyrrolo[2,3-d]pyrimidine

The title compound was prepared according to the method described for Préparation 1 using (4,6dichloropyrimidin-5-yl)acetaldehyde and tert-butylamine to afford the title compound as a yellow liquid in 77% yield, 1.61 g.

¹H NMR (400 MHz, DMSO-D6) δ: 1.75 (S, 9H), 6.60 (d, 1 H), 7.79 (d, 1 H), 8.63 (s, 1H).

Préparation 6: 4-Chloro-7-[(1 R)-1 -methyl-2-(tetrahydro-2H-pyran-2-yloxy)ethyl]-7H-pyrroto[2,3d]pyrimidine

2,3-Dihydropyran (25.0 mL, 270 mmol) was added to (2R)-2-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7yl)propan-1-0l (11.00 g, 51.97 mmol) (see Préparation 3) and pyridinium toluene-4-sulphonate (3.92 g, 15.6 mmol) in DCM (150 mL). The reaction mixture was washed with water (200 mL) and the aqueous

124 phase was extracted with DCM (2 x 150 mL). The combined organic phases were dried over magnésium sulfate and evaporated in vacuo. The crude material was purified by column chromatography on silica gel (gradient of heptane:EtOAc 100:0 to 70:30) to afford the titie compound as a yellow oil in 100% yield, 15.65 g.

LCMS (system 2): R₍ = 1.30 min; m/z 296 [M+H]⁺.

Préparation 7: 4-Chloro-7-((1 S)-1 -methyl-2-(tetrahydro-2H-pyran-2-yloxy)ethyl]-7H-pyrrolo[2,3djpyrimidine

The titie compound was prepared according to the method described for Préparation 6 using (25)-2-(4chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)propan-1-ol (see Préparation 4) to afford the titie compound as a yellow oil in 87% yield, 11.5 g.

’H NMR (400 MHz, CDCI₃) δ: 1.43-1.71 (m, 9H), 3.42 (m, 1H), 3.57 (m, 1H), 3.69 (m, 1H), 4.00 (m, 1H), 4.52 (m, 1H), 5.19 (m, 1H), 6.60 (d, 1H), 7.44 (d, 1 H). 8.61 (s, 1H).

Préparation 8: 7-((1 S)-2-{[ferT-Butyl(dimethyl)silyl]oxy}-1 -methylethyl]-7H-pyrrolo[2,3-d]pyrimidine

Me

Me

Palladium (10% on carbon, 18 g) was added to 7-((1 S)-2-([tert-butyl(dimethyl)silyl]oxy}-1-methylethyl]-4chloro-7H-pyrrolo[2,3-d]pyrimidine (182 g, 558 mmol) (see Préparation 1) in éthanol (900 mL) and concentrated ammonia solution (100 mL) and hydrogenated (60 psi, 20°C) for 18 hours. The reaction mixture was filtered through Arbocel™ and the filtrate was evaporated in vacuo. Diethyl ether (300 mL) was added to the residue and the mixture was filtered. The filtrate was evaporated in vacuo to afford the titie compound as an orange oil in 94% yield, 162.7 g.

¹H NMR (400 MHz, CDCI3) δ: -0.90 (s, 3H), 0.80 (s, 9H), 1.58 (d, 3H), 3.86 (m, 2H), 5.06 (m, 1H), 6.53 (d, 1 H), 7.40 (d, 1 H), 8.83 (s, 1 H), 8.96 (s, 1 H).

125

Préparation 9: 7-(2-{[tert-Butyl(dimethyl)silyl]oxy}-1,1 -dimethylethyl)-7H-pyrrolo[2,3-dlpyrimidine

The title compound was prepared according to the method described for Préparation 8 using 7-(2-{[tertbutyl(dimethyl)silyl]oxy}-1_t1-dimethylethyl)-4-chloro-7H-pyrroio[2,3-d]pyrimidine (see Préparation 2) to afford the title compound as a white solid in 97% yield, 327 mg.

¹H NMR (400 MHz, COCI₃) δ: 0.01 (s, 6H), 0.94 (s. 9H), 2.02 (s, 6H), 4.30 (s, 2H), 6.92 (d, 1H), 7.84 (d, 1H),9.13(s, 1 H), 9.21 (s, 1H).

Préparation 10: (R,S) 7-(2-{[tert-Butyl(dimethyl)silyl]oxy}-1-methylethyl)-7H-pyrrolo[2,3-d]pyrimidine

Me, O—z^Me Me, SI

X Me Me Me

The title compound was prepared according to the method described for Préparation 8 using (R,S) 7-(2{[tert-butyl(dimethyl)silyl]oxy}-1 -methylethyl)-4-chloro-7H-pyrrolo[2,3-d]pyrimîdine (see Préparation DL3) to afford the title compound as a brown liquid in 78% yield, 1.12 g.

¹H NMR (400 MHz, DMSO-D6) δ: 0.01 (s, 6H), 0.88 (s, 9H), 1.69 (d, 3H), 4.09 (m, 2H), 5.20 (m, 1H),

6.84 (d, 1H), 7.92 (d. 1H). 8.96 (s, 1H), 9.18 (s. 1H).

Préparation 11: 7-[( 1 R)-1 -Methyl-2-(tetrahydro-2H-pyran-2-yloxy)ethyl]-7H-pyrrolo[2,3-d]pyrimidine

The title compound was prepared according to the method described for Préparation 8 using 4-chloro-7[(1R)-1-methyl-2-(tetrahydro-2H-pyran-2-yloxy)ethyl]-7H-pyrrolo[2,3-d]pyrimidine (see Préparation 6) to afford the title compound as a yellow oil in 100% yield, 13.78 g.

LCMS (system 2): R! = 0.73 min; m/z 262 [M+Hf.

126

Préparation 12: 7-[(lS)-1-Methyl-2-(tetrahydro-2H-pyran-2-yloxy)ethyll-7H-pyrrolo[2,3-dlpyrimidine

The title compound was prepared according to the method described for Préparation 8 using 4-chloro-7[(1S)-1-methyl-2-(tetrahydro-2H-pyran-2-yloxy)ethyl]-7H-pyrrolo[2,3-d]pyrimidine (see Préparation 7) to afford the title compound as a colourless oil in 90% yield, 9.18 g.

’H NMR (400 MHz, CDCI₃) δ: 1.44-1.69 (m, 9H), 3.42 (m, 1H). 3.57 (m, 1H), 3.69 (m, 1 H), 4.02 (m, 1H),

4.54 (m, 1H), 5.27 (m, 1H), 6.69 (d, 1H), 7.57 (d, 1H), 8.91 (s, 1H), 8.99 (s, 1H).

Préparation 13: 7-tert-Butyl-7H-pyrroto[2,3-d]pyrimidine

zVMe

Me Me

The title compound was prepared according to the method described for Préparation 8 using 7-tert-butyl4-chloro-7H-pyrrolo[2,3-d]pyrimidine (see Préparation 5) to afford the title compound as a yellow liquid in 94% yield, 1.27 g.

’H NMR (400 MHz, DMSO-D6)6: 1.75 (s, 9H), 6.57 (d, 1H), 7.66 (d, 1H), 8.78 (s, 1H), 8.98 (s, 1H). Préparation 14: 7-[( 1 S)-2-{[tert-Butyl(dimethyl)silyljoxy}-1 -methylethyl]-5-iodo-7H-pyrrolo[2,3-d]pyrimidine

N-lodosuccinimide (124 g, 553 mmol) was added to 7-[(1S)-2-{[fert-butyl(dimethyl)silyl]oxy}-1methylethyl]-7H-pyrrolo[2,3-d]pyrimidine (153.4 g, 526 mmol) (see Préparation 8) in acetonitrile (700 mL). The mixture was stirred at room température for 16 hours then saturated aqueous sodium thiosulfate (700 mL) was added. The mixture was extracted with EtOAc (800 mL) then the organic extract was dried over magnésium sulfate and evaporated in vacuo. The crude material was purified by column chromatography on silica gel (gradient of pentane:EtOAc 90:10 to 80:20) to afford the title compound as a yellow solid in 66% yield, 145 g. ’H NMR (400 MHz, CDCI₃) δ.' -0.90 (d, 6H) 0.80 (s, 9H) 1.58 (d, 3H) 3.84 (m, 2H) 5.07 (m, 1H) 7.48 (s, 1H) 8.73 (S, 1H) 8.86 (s, 1H).

127

Préparation 15: 7-(2-{[tert-ButyI(dimethyl)silyl]oxy}~ 1,1 -dimethylethyl)-5-iodo-7H-pyrrolo[2,3-dlpyrimidine

The title compound was prepared according to the method described for Préparation 14 using 7-(2-{[terfbutyl(dimethyl)siiyl]oxy}-1,1-dimethylethyl)-7H-pyrrolo[2,3-dJpyrimidine (see Préparation 9) to afford the title compound as a brown oil in 59% yield, 270 mg.

¹H NMR (400 MHz, CDCI₃) δ: 0.01 (s, 6H), 0.92 (s, 9H), 2.00 (s, 6H), 4.20 (s, 2H), 7.95 (s, 1H), 9.02 (s, 1H), 9.16 (s, 1H).

Préparation 16: (R,S) 7-(2-{[tert-Butyl(dimethyl)silyl]oxy}-1-methylethyl)-5-iodo-7H-pyrrolo[2,3djpyrîmidine

The title compound was prepared according to the method described for Préparation 14 using (R,S) 7-(2{[tert-butyl(dimethyl)silyljoxy}-1 methylethyl)-7H-pyrrolo[2,3-d]pyrimidine (see Préparation 10) to afford the title compound as a yellow liquid in 74% yield, 1.18 g.

LCMS (system 1): R_t = 4.03 min; m/z 418 [M+Hf.

Préparation 17: 5-iodo-7-[(1 R)-1 -methyl-2-(tetrahydro-2H-pyran-2-yloxy)eth‘yl]-7H-pyrroio[2,3djpyrimidine

The title compound was prepared according to the method described for Préparation 14 using 7-((1 R)-1methyl-2-(tetrahydro-2H-pyran-2-yloxy)ethyl]-7H-pyrrolo[2,3-d]pyrimidine (see Préparation 11) to afford the title compound as a brown oil in 34% yield, 7.50 g.

’H NMR (400 MHz, CDCI₃) δ.' 1.43-1.74 (m, 9H), 3.42 (m, 1H), 3.54 (m, 1H), 3.67 (m, 1H), 3.99 (m, 1H),

4.54 (m, 1H), 5.23 (m, 1H), 7.51 (s, 1H), 8.74 (s, 1H), 8.88 (s, 1H).

128

Préparation 18: 5-lodo-7-[(1S)-1-methyl-2-(tetrahydro-2H-pyran-2-yloxy)ethyl]-7H-pyrroto[2,3-

djpyrimidine

The title compound was prepared according to the method described for Préparation 14 using 7-((1 S)-1 methyl-2-(tetrahydro-2H-pyran-2-yloxy)ethyl]-7H-pyrrolo[2,3-d]pyrimidine (see Préparation 12) to afford the title compound as a brown oil in 71% yield, 9.68 g.

¹H NMR (400 MHz. CDCI₃) δ: 1.44-1.65 (m, 9H), 3.45 (m, 1H), 3.56 (m, 1H), 3.67 (m, 1H), 3.99 (m, 1H),

4.54 (m, 1 H), 5.24 (m, 1H), 7.51 (s, 1 H), 8.76 (s, 1H), 8.89 (s, 1H).

Préparation 19: 7-terf-Butyl-5-iodo-7H-pyrrolo[2,3-d]pyrimidine

The title compound was prepared according to the method described for Préparation 14 using 7-tertbutyl-7H-pyrrolo[2,3-d]pyrimidine (see Préparation 13) to afford the title compound as a yellow solid in 71% yield, 1.55 g.

LCMS (system 1): R, = 3.12 min; m/z 302 [M+H]*.

Préparation 20: (R,S) Methyl 2-(5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)propanoate

Me

Methyl-2-bromopropionate (6.83 mL, 61.2 mmol) was added to a mixture of 5-iodo-7H-pyrrolo[2,3djpyrimidine (15.0 g, 61.0 mmol) and césium carbonate (35.9 g, 110.0 mmol) in DMF (75 mL). The mixture was stirred at room température for 4 hours. The reaction mixture was dituted with water (250 mL) and extracted with diethyl ether (100 mL). The organic layer was washed with brine (70 mL), dried over magnésium sulfate and evaporated in vacuo to afford the title compound as an off-white solid in 83% yield, 16.87 g.

¹H NMR (400 MHz, CDCI₃) δ: 1.82 (d, 3H), 3.76 (s, 3H), 5.72 (q, 1H), 7.48 (s, 1H), 8.76 (s, 1H), 8.89 (s, 1H).

129

Préparation 21: Methyl 2-(5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)’2-methylpropanoate

Potassium t-butoxide (71.3 mL, 71.3 mmol, 1.0 M in THF) was added to (R,S) methyl 2-(5-iodo-7Hpyrrolo[2,3-d]pyrimidin-7-yl)propanoate (16.9 g, 50.9 mmol) (see Préparation 20) and iodomethane (4.44 mL, 71.3 mmol) in THF (100 mL). The mixture was stirred at room température for 15 minutes then water (20 mL) and aqueous HCl (0.3 mL, 2M) was added. THF was removed by évaporation in vacuo then the aqueous residue was extracted with EtOAc (250 mL). The organic phase, was dried over magnésium sulfate and evaporated in vacuo. The crude solid was purified by column chromatography on silica gel (80:20 pentane:EtOAc) to afford the title compound as a white solid in 51% yield, 8.92 g.

¹H NMR (400 MHz, CDCl₃) δ: 1.93 (s, 6H), 3.68 (s, 3H), 7.43 (s, 1 H), 8.75 (s, 1 H), 8.85 (s, 1 H).

Préparation 22: 2-(5-lodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-methylpropan-1 -oi

Me Me

Lithium borohydride (32.3 mL, 64.6 mmol, 2.0 M in THF) was added to methyl 2-(5-iodo-7H-pyrrolo[2,3d]pyrimidin-7-yl)-2-methylpropanoate (8.92 g, 25.9 mmol) (see Préparation 21) in éthanol (70 mL). The mixture was stirred at room température for 17 hours then water (70 mL) was added. The mixture was evaporated in vacuo then the residue was partitioned between DCM (250 mL) and water (50 mL). The aqueous phase was extracted with DCM:MeOH (90:10, 2 x 250 mL) and the combined organic phases were dried over magnésium sulfate and evaporated in vacuo to afford the title compound as an off- white solid in 100% yield, 8.20 g.

¹H NMR (400 MHz, DMSO-d6) δ; 1.65 (s, 6H), 3.16 (d, 2H), 7.77 (s, 1H), 8.67 (s, 1H), 8.80 (s, 1H).

Préparation 23: 5-[(Diphenylmethylene)amino]-N-methoxy-N-methylnicotinamide

Benzophenone imine (205 mL, 1.22 mol) was added to 5-bromo-N-methoxy-N-methylisonicotinamide (250 g, 1.02 mol), tris(dibenzylideneacetone)dipalladium (28.0 g, 31.0 mmol), 2-di-tert-butylphosphino2',4',6'-triisopropylbiphenyl (34.7 g, 82.0 mmol) and freshly ground potassium phosphate tribasic (541 g,

130

2.55 mol) in 1,2-dimethoxyethane (2500 mL). The mixture was stirred at 50°C for 17 hours. The reaction mixture was filtered through Arbocel™ and the pad was washed with EtOAc (500 mL). The filtrate was evaporated in vacuo and the crude material was purified by column chromatography on silica gel (gradient of heptane:EtOAc 70:30 to 0:100) to afford the title compound as an orange gum in 51% yield, 180.0 g.

¹H NMR (400 MHz, DMSO-D6) Ô: 3.19 (s, 3H), 3.37 (s, 3H), 7.18-7.23 (m, 2H), 7.29 (m, 1H), 7.32-7.39 (m, 3H), 7.46-7.53 (m, 2H), 7.57 (m, 1 H), 7.67-7.73 (m, 2H), 8.09 (d, 1H), 8.27 (d, 1H).

Préparation 24: {7-[(1S)-2-{[tert-Butyl(dimethyl)silyl]oxy}-1-methylethyl]-7H-pyrrolo[2,3-d]pyrimidin-5-ylX5[(diphenylmethylene)amino]pyridin-3-yl}methanone

Isopropyl magnésium chloride (68.8 mL, 138 mmol, 2.0 M in THF) was added to 7-[(1S)-2-{[tertbutyl(dimethyl)silyl]oxy}-1-methylethyl]-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (52.2 g, 125 mmol) (see Préparation 14) in THF (400 mL) at 0°C, under nitrogen. The mixture was stirred at 0°C for 1 hour then a solution of 5-[(diphenylmethylene)amino]-N-methoxy-N-methylnicotinamide (47.5 g, 138 mmol) (see Préparation 23) in THF (100 mL) was added dropwise at 0°C. The mixture was warmed to room température and stirred at this température for 16 hours. The reaction mixture was quenched with 10% aqueous ammonium chloride (250 mL) and extracted with ethyl acetate (2 x 250 mL). The combined organic extracts were washed with brine (250 mL), dried over sodium sulfate, evaporated in vacuo and the crude material was purified by column chromatography on silica gel (gradient of EtOAc:pentane 10:90 to 60:40) to afford the title compound as a colourless gum in 88% yield, 63.2 g.

R_t = 7.94 min; m/z 576 [M+H]⁺.

Préparation 25: [7-(2-{[tert-Butyl{dimethyl)silyl]oxy}-1,1 -dimethylethyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]{5[(diphenylmethylene)amino]pyridin-3-yl}methanone

Me

131

The title compound was prepared according to the method described for Préparation 24 using 7-{2-{itert butyl(dimethyl)silyl]oxy}-1,1 -dimethylethyl)-5-iodo-7H-pyrrolo[2,3-d]pynmidine (see Préparation 15) and 5-[(diphenylmethy!ene)amino]-N-methoxy-N-methylnicotinamide (see Préparation 23) to afford the title compound as a colourless gum in 56% yield, 1.49 g.

¹H NMR (400 MHz, CDCI₃) δ; 0.21 (s, 6H), 0.67 (s, 9H), 1.80 (s, 6H), 4.10 (s, 2H), 7.14 (d, 2H), 7.33 (m, 3H), 7.45 (m, 2H), 7.54 (m, 1H), 7.58 (t, 1 H), 7.79 (d, 2H), 7.89 (s, 1 H), 8.18 (d, 1H), 8.58 (d, 1H), 9.01 (s, 1 H), 9.60 (s, 1H).

Préparation 26: (5-Bromopyridin-3-yl){7-[(1 R)-1 -methyl-2-(tetrahydro-2H-pyrân-2-yloxy)ethyl]-7Hpyrrolo[2,3-d]pyrimidin-5-yl}methanone

The title compound was prepared according to the method described for Préparation 24 using 5-iodo-7[(1 R)-1-methyl-2-(tetrahydro-2H-pyran-2-yloxy)ethyl]-7H-pyrrolo[2,3-d]pyrimidine (see Préparation 17) and 5-bromo-N-methoxy-N-methylnicotinamide to afford the title compound as a brown oil in 66% yield, 215 mg.

LCMS (system 2): R₍ = 1.27 min; m/z 447 [M+H]⁺.

Préparation 27: (5-Bromopyridin-3-yl){7-[(1 S)-1 -methyl-2-(tetrahydro-2H-pyran-2-y!oxy)ethyl]-7Hpyrrolo[2,3-d]pyrimidin-5-yl}methanone

The title compound was prepared according to the method described for Préparation 24 using 5-iodo-7[(1 S)-1 -methyl-2-(tetrahydro-2H-pyran-2-yloxy)ethyl]-7H-pyrrolo[2,3-d]pyrimidine (see Préparation 18) and 5-bromo-N-methoxy-N-methylnicotinamide to afford the title compound as a colourless oil in 32% yield, 181 mg.

LCMS (system 2): R, = 1.27 min; m/z 447 [M+Hf.

Préparation 28: (R,S) (7-[2-{[tert-Butyl(dimethyl)silyl]oxy}-1 -methylethyl]-7H-pyrrolo[2,3-d]pyrimidin-5ylH5-[(diphenylmethylene)amino]pyridin'3-yl}methanone

132

Me

Butyllithium (0.57 mL, 1.31 mmol, 2.3 M in hexanes) was added to (R,S) 7-(2-{[tertbutyl(dimethyl)silyl]oxy}-1-methylethyl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (500 mg, 1.19 mmol) (see Préparation 16) in dry ether (20 mL) at -70°C and the reaction mixture was stirred for 30 minutes. Then 5-[(diphenylmethylene)amino}-N-methoxy-N-methylnicotinamide (372 mg, 1.07 mmol) (see Préparation 23) in dry ether (25mL) was added drop wise at the same température. After 15 minutes the mixture was quenched with saturated aqueous ammonium chloride (50 mL) and extracted with ethyl acetate (70 mL). The organic extract was dried over sodium sulfate, evaporated in vacuo and purified by column chromatography on silica gel (hexane:EtOAc 70: 30) to afford the title compound as an off-white solid in 19% yield, 134 mg.

LCMS (System 4): R_t = 4.53 min; m/z 576 [M+H]⁺.

Préparation 29: (R,S) (5-Bromopyridin-3-yl)(7-tert-butyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanol

The title compound was prepared according to the method described for Préparation 28 using 7-tertbutyl-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (see Préparation 19) and 5-bromo-pyridine-3-carbaldehyde to afford the title compound as a colourless oil in 37% yield, 486 mg.

LCMS (System 4): R, = 2.94 min; m/z 362 [M+H]⁺.

Préparation 30: (5-Bromopyridin-3-yl)(7-tert-butyl-7H-pyrrolo[2,3-tf]pyrimidin-5-yl)methanone

2-lodoxybenzoic acid (909 mg, 3.25 mmol) was added to (R,S) (5-bromopyridin-3-yl)(7-tert-butyl-7Hpyrrolo[2,3-d]pyrimidin-5-yl)methanol (405 mg, 1.34 mmol) (see Préparation 29) in ethyl acetate (30mL)

133 and the mixture was refluxed for 4 hours. The mixture was filtered and the filtrate was evaporated in vacuo to afford the titte compound as a white solid in 95% yield, 554 mg.

LCMS (system 4): R_t = 3.28 min; m/z 360 [M+H]⁺.

Préparation 31: (5-Aminopyridin-3-yl)(7-tert-butyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone

Copper sulfate pentahydrate (55 mg, 0.24 mmol) was added to (5-bromopyridin-3-yl)(7-tert-butyl-7Hpyrrolo[2,3-d]pyrimidin-5-yl)methanone (292 mg, 0.81 mmol) (see Préparation 30) and concentrated ammonia solution (20 mL). The mixture was heated in a sealed vessel at 140°C for 17 hours. The reaction mixture was evaporated in vacuo and the residue was stirred in aqueous hydrochloric acid (10 mL, 2M) at room température for 17 hours. The reaction mixture was basified to pH 9 using saturated aqueous sodium carbonate then extracted with DCM (3 x 20 mL). The combined organic extracts were dried over magnésium sulfate and evaporated in vacuo to afford the title compound as a white solid in 49% yield, 240 mg.

LCMS (System 4): R_t = 2.68 min; m/z 296 [M+H]⁺.

Préparation 32; (5-Aminopyridin-3-yi){7-[(1 S)-2-hydroxy-1 -methylethyl]-7H-pyrrolo[2,3-d]pyrimidin-5yl}methanone

The title compound was prepared according to the method described for Préparation 31 using (5bromopyridin-3-yl){7-[(1S)-1-methyl-2-(tetrahydro-2H-pyran-2-yloxy)ethyl]-7H-pyrrolo[2,3-d]pyrimidin-5yl}methanone (see Préparation 27) to afford the title compound as a white solid in 10% yield, 134 mg. LCMS (system 2): R_t = 0.59 min; m/z 298 [M+H]⁺.

134

Préparation 33: (5-Aminopyridin-3-yl){7-[{1 S)-1 -methyl-2-(tetrahydro-2H-pyran’2-yloxy)ethyl]-7H pyrrolo[2,3-d]pyrimidin-5-yl}methanone

Benzophenone imine (0.40 mL, 2.4 mmol) was added to (5-bromopyridin-3-yl)(7-[(1S)-1-methyl-2(tetrahydro-2H-pyran-2-yloxy)ethyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}methanone (891 mg, 2.0 mmol) (see Préparation 27), tris(dibenzylideneacetone)dipalladium (55 mg, 0.06 mmol), 2-di-ierT-butylphosphino2',4^,,6'-triisopropylbiphenyl (68 mg, 0.16 mmol) and freshly ground potassium phosphate tribasic (1.06 g, 5.0 mmol) in 1,2-dimethoxyethane (4 mL). The mixture was stirred at 50°C for 17 hours. The reaction mixture diluted with DCM (10 mL), filtered through Arbocel™ and the pad was washed with DCM (5 mL). The filtrate was evaporated in vacuo and the crude material was dissolved in THF (10 mL). Aqueous citric acid (5 mL, 2M) was added and the mixture was stirred at room température for 16 hours. Water (40 mL) was added then sodium hydroxide was added to basify the mixture. The mixture was extracted with EtOAc (3 x 40 mL) and the combined organic extracts were dried over magnésium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel (gradient of EtOAc:MeOH 100:0 to 80:20) to afford the title compound as a white solid in 70% yield, 506 mg.

LCMS (system 1): R_t = 3.27 min; m/z 382 [M+H]‘.

Préparation 34: 2-(2H-Benzotriazol-2-yl)-N-[5-({7-[(1 S)-1 -methyl-2-(tetrahydro-2H-pyran-2-yloxy)ethyl]7H-pyrrolo[2,3-d]pyrimidin-5-yl}carbonyl)pyridin-3-yl]acetamide

The title compound was prepared according to the method described for Example 1 using (5aminopyridin-3-yl){7-[(1S)-1-methyl-2-(tetrahydro-2H-pyran'2-yloxy)ethyl]-7H-pyrrolo[2,3-d]pyrimidin-5yl}methanone (see Préparation 33) and benzotriazol-2-yl-acetic acid to afford the title compound as a yellow solid in 72% yield, 70 mg.

LCMS (system 5): R_t = 2.98min, m/z 541 [M+H]*.

Préparation 35: 2-(2,4-Difluorophenyi)-N-[5-({7-[(1 S)-1 -methyl-2-(tetrahydro-2H-pyran-2-yloxy)ethyl]-7Hpyrrolo[2,3-d]pyrimidin-5-yl}carbonyl)pyridin-3-yi]acetamide

135

The title compound was prepared according to the method described for Example 1 using (5aminopyridin-3-yl){7-[(1S)-1-methyl-2-(tetrahydro-2H-pyran-2-yloxy)ethyl]-7H-pyrrolo[2,3-d]pyrimidin-5yl}methanone (see Préparation 33) and 2,5-difluorophenylacetic acid to afford the title compound as a yellow solid in 75% yield, 75 mg.

LCMS (system 5): R_t = 3.08min, m/z 536 [M+H]⁺.

Préparation 36: (5-Aminopyridin-3-yl){7-[( 1 R)-1 -methyl-2-(tetrahydro-2H-pyran-2-yloxy)ethyl]-7Hpyrrolo[2,3-d]pyrimidin-5-yl}methanone

Copper (I) oxide (9.2 mg, 0.06 mmol) was added to (5-bromopyridin-3-yl){7-[(1R)-1-methyl-2-(tetrahydro2H-pyran-2-yloxy)ethyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}methanone (285 mg, 0.64 mmol) (see Préparation 26) and concentrated ammonia solution (2 mL) in 1-methyl-2-pyrrolidinone (0.5 mL). The mixture was heated in a sealed vessel at 80°C for 17 hours. Ethyl acetate (5 mL) and water (5 mL) were added to the reaction mixture and then filtered through a glass fibre filter. The organic phase was dried over magnésium sulfate and evaporated in vacuo. The crude solid was purified by column chromatography on silica gel (gradient of EtOAc:MeOH:cNH3 100:0:0 to 95:5:0.5) to afford the title compound as a colourless oil in 70% yield, 171 mg.

LCMS (system 2): R_t = 0.78 min; m/z 382 [M+Hf.

Préparation 37: (5-Aminopyridin-3-yl){74(1S)-2-{[iert-butyl(dimethyl)silyi]oxy}-1-methylethylJ-7Hpyrrolo[2,3-d]pyrimidin-5-yl}methanone

136

Aqueous citric acid (120 mL, 2.0 M) was added to {7-[(1S)-2-([ferf-butyi(dimethyl)silyl]oxy}-1-methylethyl]7H-pyrrolo[2,3-d]pyrimidin-5-yl){5-[(diphenylmethylene)amino]pyridin-3-yl}methanone (63.2 g, 110 mmol) (see Préparation 24) in THF (274 mL) and the mixture was stirred at room température for 17 hours. The 5 mixture was cooled to 0°C, water (200 mL) added and the mixture was basified using sodium hydroxide (26 g). The mixture was extracted with ethyl acetate (150 mL) then the aqueous phase was extracted with ethyl acetate (2 x 200 mL). The combined organic phases were washed with brine (600 mL), dried over sodium sulfate and evaporated in vacuo to afford the titie compound as a semi-solid in quantitative yield, 45.2 g.

LCMS (system 2): R_t = 1.16 min; m/z 412 [M+H]⁺.

Préparation 38: (5-Aminopyridin-3-yl)[7-(2-{[tert-butyl(dimethyl)silyl]oxy}-1,1 -dimethylethyl)-7Hpyrrolo[2,3-d]pyrimidin-5-yl]methanone

The titie compound was prepared according to the method described for Préparation 37 using [7-(2-{[tert15 butyl(dimethyl)silyl]oxy}-1,1 -di m ethy lethy I)-7H-pyrro lo [2,3-d] pyrim idi n-5-y l]{5[(diphenylmethylene)amino]pyridin-3-yl}methanone (see Préparation 25) to afford the titie compound as a white solid in 81% yield, 872 mg.

¹H NMR (400 MHz, DMSO-d6) Ô; 0.22 (s, 6H), 0.63 (s, 9H), 1.66 (s, 6H), 4.12 (s, 2H), 5.65 (s, 2H), 7.27 (dd, 1H), 8.08 (s, 1H), 8.14-8.17 (m, 2H), 8.97 (s, 1H), 9.45 (s. 1H).

137

Préparation 39: (R,S) (5-AminopyrÎdin-3-yl)(7-[2~([tert-butyl(dimethyl)silyl]oxy}-1 -methylethyl]-7Hpyrrolo[2,3-d]pyrimidin-5-yl}methanone

The title compound was prepared according to the method described for Préparation 37 using (R,S) {7^-{[tert-butyHdimethylJsilylJoxyJ-l-methylethylj-yH-pyrrolop.S-dJpyrimidÎn-S-ylXB[(diphenylmethylene)amino]pyridin-3-yl}methanone (see Préparation 20) to afford the title compound as a white solid in 89% yield, 86 mg,

LCMS (System 4): R, =1.37 min; m/z 412 [M+Hf.

Préparation 40: 2-Chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine i

N-lodosuccinimide (742 g, 3.30 mol) was added to 2-chloro-7H-pyrrolo[2,3-£/]pyrimidine (482.5 g, 3.14 mol) in acetonitrile (2500 mL) at 12°C. The mixture was stirred at room température for 1 hour then sodium metabisulphite (650 g in 4500 mL of water) was added. The mixture was stirred for 1 hour then filtered to afford the title compound as a orange solid in 82% yield, 716.2 g.

’H NMR (400 MHz, DMSO-D6)C: 7.83 (s. 1H),8.63 (s, 1H), 12.73 (s, 1H).

Préparation 41: Methyl 2-(2-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-methylpropanoate

Methyl 2-bromo-2-methylpropanoate (663 mL, 5.13 mmol) was added to 2-chloro-5-iodo-7H-pyrrolo[2,3c/Jpyrimidine (358.1 g, 1.28 mol) (see Préparation 40), potassium iodide (21.3 g, 128 mmol) and césium carbonate (1670 g, 5.13 mol) in DMF (7162 mL). The mixture was heated at 60°C for 19 hours. The reaction mixture was diluted with water (7000 mL) and stirred at room température for 42 hours. The mixture was filtered and the solid was washed with water (500 mL) to afford the title compound as a beige solid in 92% yield, 445.8 g.

138 ’H NMR (400 MHz, CDCI₃) δ: 1.89 (s, 6H), 3.65 (s, 3H), 7.39 (s, 1H), 8.56 (s, 1H).

Préparation 42: 2-(2-Chloro-54odO’7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-methylpropanoic acid

Lithium hydroxide monohydrate (4.08 g, 97.5 mmol) was added to methyl 2-(2-chloro-5-iodo-7H' pyrrolo[2,3-d]pyrimidin-7-yl)-2-methylpropanoate (18.5 g, 48.7 mmol) (see Préparation 41) in THF (185 mL) and water (45 mL). The mixture was stirred at 60°C for 3 hours then the reaction mixture volume was reduced to one third by évaporation in vacuo. The aqueous residue was acidified using aqueous HCl (2.0 M) then extracted with EtOAc (4 x 200 mL). The organic phase was evaporated in vacuo and the crude material was triturated with hexane (100 mL) to afford the title compound as a white solid in 90% yield, 16.0 g.

LCMS (system 5) R_t = 2.24 min; m/z 366 [M+Hf.

Préparation 43: 2-(2-Chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-methylpropan-1 -ol i

A? Me Me '--OH

Route a

Isobutyl chloroformate (6.6 mL, 50.02 mmol) was added to 2-(2-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidin7-yl)-2-methylpropanoic acid (16.6 g, 45.48 mmol) (see Préparation 42) and triethylamine (12.64 mL, 90.9 mmol) in THF (300 mL) at 0°C under nitrogen. The mixture was stirred at room température for 3 hours then filtered through a short plug of Cetite™. The filtrate was cooled to 0°C and sodium borohydride (8.6 g, 227.6 mmol) in water (300 mL) was added. The mixture was stirred for 10 minutes at 0°C, extracted with ethyl acetate (3 x 150 mL) then the organic extract was washed with brine (150 mL) and dried over sodium sulfate. The solution was evaporated in vacuo and the residue was triturated with hexane to afford the title compound as a white solid in 63% yield, 10.0 g.

’H NMR (400 MHz, DMSO-D₆) δ: 1.64 (s, 6H), 3.85 (d. 2H), 4.99 (t, 1H). 7.82 (s, 1H), 8.63 (s, 1H).

139

Route b

Diisobutylaluminium hydride (300 mL, 300 mmol, 1M in THF) was added dropwise to methyl 2-(2-chloro5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-methylpropanoate (51.8 g, 136 mmol) (see Préparation 41) in THF (150 mL) at 0°C. The mixture was stirred for 90 minutes then methanol (27.9 mL) and aqueous HCl (20 mL, 2M) was added. Water (100 mL), aqueous HCl (280 mL, 2M) and EtOAc (150 mL) were added and the mixture was stirred at room température for 30 minutes. The mixture was filtered and the solid was washed with water (150 mL) and tertbutylmethyl ether (150 mL) to afford the title compound as a white solid in 56% yield, 26.8 g.

LCMS (System 1) R_t= 4.88 min; m/z 352 [M+Hf.

Préparation 44: 7-(2-{[tert-Butyl(dimethyl)silyl]oxy}-1,1 -dimethylethyl)-2-chloro-5-iodo-7H-pyrrolo[2,3djpyrimidine

Μθ Me Me t-Butyldimethylsilyl chloride (78.8 g, 518 mmol) was added to 2-(2-chloro-5-iodo-7H-pyrrolo[2,3d]pyrimidin-7-yl)-2-methylpropan-1-ol (140 g, 398 mmol) (see Préparation 43) and imidazole (67.8 g, 996 mmol) in DMF (996 mL) at 0°C. The mixture was stirred at room température for 16 hours. The mixture was poured into saturated aqueous sodium bicarbonate (1500 mL) and extracted with heptane:EtOAc (1:1, 1500 mL). The organic extract was washed with brine (2 x 900 mL) then dried over magnésium sulfate and evaporated in vacuo to afford the title compound as a brown gum in 96% yield, 178.2 g. LCMS (System 1) R,= 8.32 min; m/z 466 [M+Hf.

Préparation 45: 2-Chloro-7-[1,1 -dimethyl-2-(tetrahydro-2H-pyran-2yloxy)ethyl]-5-iodo-7H-pyrrolo[2,3djpyrimidine

The title compound was prepared according to the method described for Préparation 6 using 2-(2-chloro5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-methylpropan-1-ol (see Préparation 43) to afford the title compound as a yeltow oil in 74% yield, 7.3 g.

LCMS (system 5) R, = 4.01 min; m/z 436 [M+Hf.

140

Préparation 46: (5-Bromopyridin-3-yl)[7-(24[tert-butyl(dimethyl)siiyl]oxy}-1,1-dimethylethyl)-2-chloro-7H-

The title compound was prepared according to the method described for Préparation 28 using 7-(2-[[tertbutyI(dimethyI)silyIJoxy}-1,1 -dimethylethyl)-2-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (see Préparation 44) and 5-bromo-N-methoxy-N-methyinicotinamide to afford the title compound as a yellow solid in 42% yield, 1.40 g.

¹H NMR (400 MHz, CDCI₃) δ: -0.18 (s, 6 H), 0.63 (s, 9 H), 1.72 (s, 6H), 4.09 (s, 2H), 8.24 (s, 1H), 8.39 (s, 1 H), 8.95 (s, 1 H), 8.99 (d, 1 H), 9.36 (s, 1H).

Préparation 47; (5-Bromopyridin-3-yl){2-chloro-7-[1,1 -dimethyl-2-(tetrahydro-2H-pyran-2-yloxy)ethyl]-7H-

The title compound was prepared according to the method described for Préparation 28 using 2-chloro-7[1,1 -dimethyl-2-(tetrahydro-2H-pyran-2-yloxy)ethyl]-5-iodo-7H-pyrrolo[2,3-d]pÿrimidine (see Préparation 45) and 5-bromo-N-methoxy-N-methylnicotinamide to afford the title compound as a yellow solid in 41% yield, 3.0 g.

¹H NMR (400 MHz, CDCI₃) δ: 1.42-1.62 (m, 6H), 1.83 (s, 6H), 3.35-3.39 (m, 1H), 3.53-3.56 (m, 1H), 3.85 (d, 1H), 4.22 (d, 1H), 4.47 (m, 1H), 7.98 (s, 1H), 8.25 (s, 1H), 8.87 (S, 1H), 8.94 (s, 1H), 9.45 (s, 1H).

Préparation 48: [2-Amino-7-(2-hydroxy-1,1-dimethylethyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl](5-aminopyridin3-yl)methanone

The title compound was prepared according to the method described for Préparation 36

141 using (5-bromopyridin-3-yl)[7-(2-{[tert-butyl(dimethyl)silyl]oxy}-1,1-dimethylethyl)-2-chloro-7H-pyrrolo[2,3

d]pyrimidin-5-yl]methanone (see Préparation 46) to afford the title compound as a yellow solid in 48% yield, 300 mg.

’H NMR (400 MHz, DMSO-D₆) δ: 1.64 (s, 6H), 3.90 (d, 2H), 5.07 (t, 1H), 5.60 (s, 2H), 6.50 (s, 2H), 7.23 (s, 1 H), 7.61 (s, 1 H), 8.11 (m, 2H), 8.93 (s, 1 H).

(7-(2-{[tert-Butyl(dimethyl)silyl]oxy}-1,1-dimethylethyl)-2-amino-7H-pyrrolo[2,3-d]pyrimidin-5-yl]{5aminopyridin-3-yl}methanone (Préparation 48a) was also isolated from the reaction mixture.

¹H NMR (400 MHz, DMSO) δ: -0.18 (s, 6H), 0.66 (s, 9H), 1.67 (s, 6H), 4.05 (s, 2H), 5.59 (s, 2H), 6.51 (s, 2H), 7.19 (s, 1 H), 7.57 (s, 1 H), 8.07 (s, 1 H), 8.10 (s, 1 H), 8.93 (s, 1 H).

Préparation 49: {2-Amino-7-[1,1 -dimethyl-2-(tetrahydro-2H-pyran-2-yloxy)ethyl]-7H-pyrroto[2,3d]pyrimidin-5-yl}(5-aminopyridin-3-yl)methanone

The title compound was prepared according to the method described for Préparation 36 using (5-bromopyridin-3-yl){2-chloro-7-[1,1-dimethyl-2-(tetrahydro-2H-pyran-2-yloxy)ethyl]-7H-pyrrolo[2,3d]pyrimidin-5-yl}methanone (see Préparation 47) to afford the title compound as a yellow solid in 52% yield, 1.3 g.

LCMS (system 5) R_t= 2.72 min; m/z 411 [M+Hf.

Préparation 50: [7-(2-{[tert-Butyl(dimethyl)silyl]oxy}-1,1 -dimethylethyl)-2-chloro-7H-pyrrolo[2,3d]pyrimidin-5-yl]{5-[(diphenylmethylene)amino]pyridin-3-yl)methanone

Isopropyl magnésium chloride (105 mL, 210 mmol, 2.0 M in THF) was added to 7-(2-{[tertbutyl(dimethyl)silyl]oxy}-1,1-dimethylethyl)-2-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (89.0 g, 190 mmol) (see Préparation 44) in THF (450 mL) at 0°C, under nitrogen. The mixture was stirred at 0°C for 1 hour then a solution of 5-[(diphenylmethylene)amino]-N-methoxy-N-methylnicotinamide (72.6 g, 210 mmol)

142 (see Préparation 23) in THF (200 mL) was added dropwise at 0°C. The mixture was warmed to room température and stirred at this température for 16 hours. The reaction mixture was quenched with 10% aqueous ammonium chloride (500 mL) and the organic phase was separated. The aqueous phase was extracted with ethyl acetate (2 x 300 mL). The combîned organic extracts were washed with brine (400 mL), dried over sodium sulfate, evaporated in vacuo and the crude material was purified by column chromatography on silica gel (gradient of heptane:EtOAc 100:0 to 60:40) to afford the title compound as a colourless gum in 66% yield, 78.9 g.

LCMS (System 1) R_t = 8.60 min; m/z 624 [M+Hf.

Préparation 51: (5-AminopyrÎdin-3-yl){7-(2-{[tert-butyl(dimethyl)silyl]oxy}-1,1 -dimethylethyl)-2-[(2,4dimethoxybenzyl)amino]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}methanone

2,4-Dimethoxybenzylamine (99.4 g, 594 mmol) was added to [7-(2-{[tert-butyl(dimethyl)silyl]oxy}-1,1 dimethylethyl)-2-chloro-7H-pyrrolo[2,3-d]pyrimîdin-5-yl]{5-[(diphenylmethylene)amino]pyridin-3yl}methanone (53.0 g, 85 mmol) (see Préparation 50) and 4-dimethylaminopyridine (2.07 g, 17.0 mmol) in 1,4-dioxane (170 mL). The mixture was heated to reflux for 2 days then cooled to room température and filtered. The filtrate was evaporated in vacuo, the residue was dissolved in EtOAc (300 mL) and washed with saturated aqueous ammonium chloride (500 mL). The organic phase was dried over magnésium sulfate and evaporated in vacuo.

The crude residue was dissolved in THF (200 mL) and aqueous citric acid (200 mL, 2M) was added. The mixture was stirred at room température for 5 hours then diluted with water (200 mL). The mixture was extracted with EtOAc (300 mL) and the organic extract was washed with aqueous potassium carbonate (300 mL, 2M). The organic phase was dried over magnésium sulfate, evaporated in vacuo and the residue was purified by column chromatography on silica (gradient of pentane: EtOAc 100:0 to 0:100, followed by EtOAc:MeOH 95:5) to afford the title compound as a colourless oil in 78% yield, 39.0 g. LCMS (System 1) R_t= 5.97 min; m/z 591 [M+H]⁺.

Préparation 52: N-[5-({2-Amino-7-[1,1 -dimethyl-2-(tetrahydro-2H-pyran-2-yloxy)ethyl]-7H-pyrrolo[2,3d] pyrim idin-5-y IJcarbony I) pyrid in-3-yi]-2-(4-cyctopropy I -1 H-1,2,3-triazol-1 -yl)acetamide

143

The title compound was prepared according to the method described for Example 1 using (2-amino-7[1,1-dimethyl-2-(tetrahydro-2H-pyran-2-yloxy)ethyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}(5-aminopyridin-3yljmethanone (see Préparation 49) and (4-cyclopropyl-1H-1,2,3-triazol-1-yl)acetic acid (see Préparation 83) to afford the title compound as a yellow solid in 86% yield, 70 mg.

LCMS (system 5): R_t = 2.87 min; m/z 560 [M+H]⁺.

Préparation 53: (R,S) Methyl 2-(2-chloro-5-iodo-7H-pyrrolo[2,3-c/]pyrimidin-7-yl)propanoate l

Ms

The title compound was prepared according to the method described for Préparation 20 using 2-chloro-5iodo-7H-pyrrolo[2,3-d]pyrimidine (see Préparation 40) to afford the title compound as a brown solid in 62% yield, 18.0 g.

’H NMR (400 MHz, CDCI₃) δ: 1.77 (d, 3H), 3.75 (s, 3H), 5.67 (q. 1H), 7.46 (s, 1H), 8.58 (s, 1H). Préparation 54: (R,S) 2-(2-Chloro-5-iodo-7H-pyrrolo[2,3-c/]pyrimidin-7-yl)propan-1-ol

The title compound was prepared according to the method described for Préparation 22 using (R,S) methyl 2-{2-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)propanoate (see Préparation 53) to afford the title compound as a yellow solid in 75% yield, 11.0 g.

¹H NMR (400 MHz, DMSO-D₆) δ: 1.40 (d, 3H), 3.62-3.74 (m, 2H), 4.83 (m, 1H), 4.98 (t, 1H), 8.03 (s, 1H), 8.64 (s, 1H).

144

Préparation 55: 7-(2-{[tert-Butyl(dimethyl)silyl]oxy}-1-methylethyl)-2-ch!oro-5-iodo-7H-pyrrolo[2_l3 djpyrimidine

The title compound was prepared according to the method described for. Préparation 44 using 2-(2chloro-5-iodo-7/7-pyrrolo[2,3-d]pyrimidin-7-yl)propan-1-ol (see Préparation 54) to afford the title compound as a yellow solid in 89% yield, 12.50 g.

’H NMR (400 MHz, CDCI₃) δ: -0.09 (s, 6H), 0.80 (s, 9H), 1.53 (d, 3H), 3.80 (d, 2H), 5.04 (m, 1H), 7.46 (s, 1H),8.55(S, 1H).

The enantiomers were separated using a Chiralpak IC 20 x 250 mm, 98:2:0.1 heptane:IPA:diethylamine (flow rate - 18.0 mL/minute).

Enantiomer 1 Yield 5.2 g, 99% e.e. (first eluting peak at 7.10 mins)

Enantiomer 2 Yield 5.0 g, 99% e.e. (second eluting peak at 7.64 mins)

Préparation 56: (5-Bromopyridin-3-yl)[7-(2-{[tert-butyl(dimethyl)silyl]oxy}-1-methylethyl)-2-chloro-7Hpyrrolo[2,3-d]pyrimidin-5-yl]methanone (enantiomer 1)

The title compound was prepared according to the method described for Préparation 28 using 7-(2-{[tertbutyl(dimethyl)silyl]oxy}-1 -methylethyl)-2-chloro-5-iodo-7H-pyrro!o[2,3-d]pyrimidine (see Préparation 55, enantiomer 1) and 5-bromo-N-methoxy-N-methylnicotinamide to afford the title compound as a yellow solid in 30% yield, 1.0 g.

¹H NMR (400 MHz, DMSO-D₆) δ: -0.14 (s, 6H), 0.61 (s, 9H), 1.52 (d, 3H), 3.91-3.96 (m, 2H), 5.00 (m, 1H), 8.37 (s, 1H), 8.58 (s, 1H), 8.95 (s, 1H), 9.00 (s, 1H), 9.33 (s, 1H).

145

Préparation 57: [2-Amino-7-(2-hydroxy-1-methylethyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl](5-aminopyridin-3yl)methanone (enantiomer 1)

The title compound was prepared according to the method described for Préparation 36 using (5-bronnopyridin-3-yl)[7-(2-{[tert-butyl(dimethyl)silyl]oxy}-1-methylethyl)-2-chloro-7H-pyrrolo[2,3d]pyrimidin-5-yl]methanone (see Préparation 56) to afford the title compound as a yellow solid in 51% yield, 450 mg.

¹H NMR (400 MHz, DMSO-D₆) δ: 1.41 (d, 3H), 3.66 (m, 2H), 4.74 (m, 1H), 5.01 (t, 1H), 5.59 (s, 2H), 6.55 (S, 2H), 7.22 (s, 1H), 7.83 (s, 1H), 8.11-8.13 (m, 2H), 8.91 (s, 1H); LCMS (system 5) R_t = 1.72 min; m/z 313 [M+Hf.

Préparation 58 : (5-Bromopyridin-3-yl)[7-(2-{[tert-butyl(dimethyl)silyl]oxy}-1 -methylethyl)-2-chloro-7Hpyrrolo[2,3-d]pyrimidin-5-yl]methanone (enantiomer 2)

The title compound was prepared according to the method described for Préparation 28 using 7-(2-{[tertbutyl(dimethy!)silyl]oxy}-1-methylethyl)-2-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (see Préparation 55, enantiomer 2) and 5-bromo-N-methoxy-N-methylnicotinamide to afford the title compound as a yeliow solid in 30% yield, 1.4 g.

¹H NMR (400 MHz, DMSO-D₆) δ: -0.14 (s, 6H), 0.61 (s, 9H), 1.52 (d, 3H), 3.91-3.96 (m, 2H), 5.00 (m, 1H), 8.37 (s, 1H), 8.58 (s, 1H), 8.95 (s, 1H), 9.00 (s, 1H), 9.33 (S, 1H).

146

Préparation 59: [2-Amino-7-(2-hydroxy-1-meÎhylethyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl](5-aminopyridin-3yljmethanone (enantiomer 2)

The title compound was prepared according to the method described for Préparation 36 using (5-bromopyrîdin-3-yl)[7-(2-{[tert-butyl(drmethyl)silyl]oxy}-1-methylethyl)-2-chioro-7H-pyrrolo[2,3d]pyrimidin’5-yl]methanone (see Préparation 58) to afford the title compound as a yellow solid in 51% yield, 450 mg.

LCMS (system 5) R, = 1.70 min; m/z 313 [M+H]⁺.

Préparation 60: 5-Bromo-N-terf-butyl-2-chloropyrimidin-4-amine

tert-Butylamine (5.28 g, 72 mmol) was added to 5-bromo-2,4-dichloropyrimidine (15 g, 66 mmol) and triethylamine (19.9 g, 197 mmol) in acetonitrile (450 mL) at room température and the mixture was stirred at room température for 16 hours. Then the mixture was evaporated in vacuo and the crude residue was partitioned between EtOAc (450 mL) and water (400 mL). The organic layer was separated, washed with brine (400 mL) then dried over sodium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel (hexane:EtOAc 88:12) to afford the title compound as a yellow oil in 52% yield, 8.8 g.

LCMS (system 5): R_t = 3.46 min; m/z 265 [M+Hf.

Préparation 61 : /V-fert-Butyl-2-chloro-5-[(E)-2-ethoxyvinyl]pyrimidin-4-amine

Catecholborane (7.8 g, 65.4 mmol) in THF (50 mL) was added dropwise to a solution of 40% ethoxyacetylene in hexane (12.8 mL, 72.5 mmol) under nitrogen at 0-5°C. The mixture was stirred for 2 hours at room température then heated at 70°C for 2 hours. The mixture was then cooled to room température and a solution of 5-bromo-N-tert-butyl-2-chloropyrimidin-4-amine (10 g, 37.8 mmol) (see Préparation 60) in THF (50 mL) was added. The solution was degassed with argon for about 25 minutes

147 followed by the addition of Pd(PPh₃)₄ (1.3 g, 1.13 mmol) and powdered sodium hydroxide (4.53 g, 113 mmol). The mixture was heated at 70°C for 16 hours and then cooled to room température. EtOAc (200 mL) was added and the mixture was filtered through a Colite™ pad. The filtrate was evaporated in vacuo and the residue was purified by column chromatography on silica gel (gradient of hexane:EtOAc 93:7 to 5 90:10) to afford the titie compound as a yellow oil in 55% yield, 5.3 g.

LCMS (system 5): R_t = 3.65 min; m/z 256 [M+H]⁺.

Préparation 62: 7-tert-ButyI-2-chloro-7/-Tpyrrolo[2,3-c/]pyrimidine

Concentrated HCl (25 mL) was added to N-rert-butyl-2-chloro-5-[(E)-2-ethoxyvinyl]pyrimidin-4-amine (5.3 g, 20.72 mmol) (see Préparation 61) in isopropanol (210 mL) and the mixture was heated at reflux for 4 hours. The reaction mixture was then evaporated in vacuo and the residue was basified with saturated aqueous NaHCO₃ and extracted with EtOAc (200 mL). The organic extract was dried over sodium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel (gradient of hexane:EtOAc 93:7 to 90:10) to afford the titie compound as a yellow oil in 85% yield, 3.7 g.

LCMS (system 5): R! = 3.42 min; m/z 210 [M+Hf.

Préparation 63: 7-terî-Butyl-2-chloro-5-ïodo-7H-pyrrolo[2,3-d]pyrimidine

The titie compound was prepared according to the method described for Préparation 14 using 7-tertbutyl-2-ch!oro-7H-pyrrolo[2,3-c/]pyrimidine (see Préparation 62) to afford the titie compound as a brown solid in 87% yield, 4.7 g.

¹H NMR (400 MHz, CDCI₃) δ: 1.55 (s, 9H), 7.39 (s, 1H), 8.54 (s, 1H).

Préparation 64: (5-Bromopyridin-3-yl)(7-fert-butyl-2-chloro-7/-/-pyrrolo[2,3-c/]pyrimidin-5-yl)methanone

148

The title compound was prepared according to the method described for Préparation 28 using 7-tertbutyl-2-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (see Préparation 63) and 5-bromo-N-methoxy-Nmethylnicotinamide to afford the title compound as a brown oil in 36% yield, 2.1 g.

¹H NMR (400 MHz, CDCI3) δ: 1.82 (s, 9H), 7.78 (s, 1H), 8.25 (s, 1H), 8.88 (s, 1H), 8.92 (s, 1H), 9.44 (s, 5 1H).

Préparation 65: (2-Amino-7-tert-butyl-7H-pyrrolo[2,3-tf]pyrimidin-5-yl)(5-aminopyridin-3-yl)methanone

The title compound was prepared according to the method described for Préparation 36 using (510 bromopyridin-3-yl)(7-tert-butyl-2-chloro-7H-pyrrolo[2,3-£f]pyrimidin'5-yl)methanone (see Préparation 64) to afford the title compound as a white solid in 55% yield, 870 mg.

LCMS (System 5): R_t = 2.42 min; m/z 311 [M+Hf.

Préparation 37) and the appropriate acids of formula :

o_x /

Préparations 66 to 70 were prepared according to Example 1, starting from (5-aminopyridin-3-yl){7-[(1S)15 24[fert-butyl(dimethyl)silyl]oxy}-1 -methylethyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yi}methanone (see o

//

Me

Préparation	R™	Data
66	Mev	LCMS(system 4): Rt = 3,73min, m/z 602 [M+H]+
67		LCMS(system 4): Rt = 3.87min, m/z 563 [M+H]+
68		LCMS(system 4): R( = 1.71 min, m/z 588 [M+H]+

149

69	F jj N	LCMS (System 4): Rt = 3.51min, m/z 589 [M+H]+
70	yy°	LCMS(system 4): R, = 3.55min, m/z 565 [M+H]*

Préparations 71 to78 were prepared according to the method described above for Example 1, starting from (5-aminopyridin-3-yl)[7-(2-{[tert-butyl(dimethyl)siîyl]oxy}-1,1 -dimethylethyl)-7H-pyrrolo[2,3-d]pyrimidin5-yl]methanone (see Préparation 38) and the appropriate acids of formula :

Me-'si

Me-X-Me Me

Préparation	“R™	Data
71	Me	LCMS(system 4): R, = 3.88 min; m/z 616 [M+H]+
72		LCMS (system 4): R, = 4.09 min; m/z 612 [M+H]+
73	Xr	LCMS(system 4): Rt = 4.07 min; m/z 578 [M+H]+
74	Xr	LCMS(system 4): R( = 3.81 min; m/z 579 [M+Hf
75	XX	LCMS(system 4): Ri = 3.79 min; m/z 602 [M+H]+
76		LCMS(system 4): R, = 3.58 min; m/z 575 [M+H]+
77	J -N	LCMS(system 4): Rt = 3.74 min; m/z 603 [M+H]+

150

78	?	LCMS (system 4); Rt = 3.78 min; m/z 573 [M+Hf
		•

Préparation 79: Ethyl (3-cyclopropyl-1 H-pyrazol-1-yl) acetate

Potassium carbonate (7.67 g, 55.56 mmol) was added to 3-cyclopropyl-1 H-pyrazole (2.0 g, 18.52 mmol) 5 in dry DMF (20 mL) at 25°C and the mixture was stirred for 20 minutes. Ethyl bromoacetate (2.06 mL,

18.52 mmol) was added then the mixture was stirred for 2 days at room température. The reaction mixture was neutralized with aqueous HCl (1.0 M), extracted with ether (40 mL) and the organic extract was washed with brine (30 mL), dried over sodium sulfate then evaporated in vacuo. The residue was purified by column chromatography on silica gel (hexane:EtOAc 88;12) to afford the title compound as a yellow oil 10 in 42% yield, 1.50 g.

¹H NMR (400 MHz, DMSO) δ: 0.59 (d, 2H), 0.83 (d, 2H), 1.19 (t, 3H), 1.83 (m, 1H), 4.13 (q, 2H), 4.91 (s, 2H), 5.94 (d, 1 H), 7.54 (d, 1H).

Préparation 80: (3-Cyclopropyl-1 H-pyrazol-1-yl)acetic acid

The title compound was prepared according to the method described for Préparation 42 using ethyl (3cyclopropyl-1 H-pyrazol-1 -yl) acetate (see Préparation 79) to afford the title compound as a white solid in 83% yield, 4.06 g.

LCMS(system 4): R_t = 1.16 min; m/z 167 [M+Hf.

Préparation 81: ^-(TrifluoromethyQ-IH-I^.S-triazol-l-yllacetic acid

Trifluoromethyl acetylene (22.0 g, 0.234 mol) in THF (210 mL) was added to sodium ascorbate (2.77 g,

14.0 mmol), ethyl azidoacetate (27.1 g, 0.210 mol) and copper sulfate (4.76 mL, 0.3 M in water) in water

151 (105 mL). The mixture was stirred at room température for 240 hours then evaporated in vacuo. The residue was extracted with EtOAc (500 mL) and the organic phase was dried over magnésium sulfate then evaporated in vacuo.

Sodium hydroxide (7.32 g, 0.183 mol) in water (30 mL) was added to the residue (32.7 g, 0.146 mol) in methanol (50 mL) and the mixture was stirred at room température for 17 hours. The methanol was evaporated in vacuo and the residue was diluted with water (10 mL). Potassium hydrogen sulfate (26.6 g, 0.195 mol) in water (70 mL) was added. The solution was evaporated in vacuo and the crude solid was purified by crystallisation using water to afford the title compound as a white solid in 75% yield, 25.8 g.

¹H NMR (400 MHz. DMSO-d6) δ: 5.40 (s, 2H), 8.85 (s, 1H), 13.50 (brs, 1H).10 Préparation 82: Ethyl (4-cyclopropyl-1H-1,2,3-triazol-1-yl)acetate

Cyclopropylacetyene (15 g, 0.116 mol), ethyl azidoacetate (11.5 g, 0.174 mol), triethylamine (0.32 mL,

2.33 mmol) and copper iodide (442 mg, 2.33 mmol) in acetonitrile (100 mL) were stirred at 25°C for 18 hours. The mixture was evaporated in vacuo and the residue was partitioned between water (100 mL) and 15 ethyl acetate (100 mL). The organic phase was dried over sodium sulfate, evaporated in vacuo and purified by column chromatography on silica gel (EtOAc: Hexane 40: 60) to afford the title compound as a colorless liquid in 95% yield, 21.6 g.

¹H NMR (400 MHz, DMSO) δ: 0.68 (m, 2H), 0.90 (m, 2H), 1.21 (t, 3H), 1.95 (m, 1H), 4.17 (q, 2H), 5.29 (s, 2H), 7.81 (s, 1H).

Préparation 83: (4-Cyclopropyl-1 H-1,2,3-triazol-1 -yl)acetic acid

N=N

The title compound was prepared according to the method described for Préparation 42 using ethyl (4cyclopropyl-1/7-1,2,3-trÎazol-1-yl)acetate (see Préparation 82) to afford the title compound as a yellow solid in 63% yield, 13.0 g.

LCMS (system 4): R, = 1.86 min; m/z 186[M+H]*.

Préparation 84: tert-Butyl [4-(trifluoromethyl)-1H-pyrazol-1-yl]acetate

F

152

The title compound was prepared according to the method described for Préparation 79 using 4(trifluoromethyl)-IH-pyrazole and tert butyl bromoacetate to afford the title compound as a yellow solid in 24% yield, 1.32 g.

LCMS(system 4): R_t=3.64min; m/z 251 [M+Hf.

Préparation 85: [4-(Trifluoromethyl)-1 H-pyrazol-1 -yljacetic acid

Trifluoroacetic acid (10 mL) was added to tert-butyl [4-(trifluoromethyl)-1 H-pyrazol-1 -y I] acetate (1.3 g, 5.2 mmol) (see Préparation 84) in dry DCM (10 mL) and the mixture was stirred for 18 hours at 25°C. Then the mixture was evaporated in vacuo and the residue was purified by trituration with diethyl ether:pentane (1:9, 2 mL) to afford the title compound as a white solid in 79% yield, 800 mg.

LCMS(system 4): R₍= 1.39min; m/z 193 [M+Hf.

Préparation 86: tert-Butyl [4-bromo-1 H-pyrazol-1 -yljacetate

The title compound was prepared according to the method described for Préparation 79 using 4-bromo1H-pyrazole and tert butyl bromoacetate to afford the title compound as a yellow solid in 34% yield, 48.0 9’H NMR (400 MHz, CDCI3) S: 1.42 (s, 9H), 4.70 (s, 2H), 7.40 (s, 2H).

Préparation 87: tert-Butyl (4-cyclopropyl-1H-pyrazol-1-yljacetate

Palladium acetate (215 mg, 0.957 mmol) was added to tert-butyl [4-bromo-1 H-pyrazol-1-yljacetate (5 g, 19.14 mmol) (see Préparation 86), cyclopropyl boronic acid (8.22 g, 95.74 mmol), potassium phosphate (8.12 g, 38.29 mmol) and tricyclohexylphosphine (537 mg, 1.91 mmol) in toluene: water (60mL:15mL). The mixture was degassed for 20 minutes then refluxed for 18 hours. The reaction mixture was filtered through Celite™, the filtrate was evaporated in vacuo and the residue was purified by column chromatography on silica gel (gradient of EtOAc: hexane 15: 85) to afford the title cpompound as an off white solid in 21% yield, 1.3 g.

LCMS (System 4): R_t =3.17min; m/z 223[M+Hf.

Préparation 88: (4-Cyclopropyl-1 H-pyrazol-1 -yljacetic acid

153

The title compound was prepared according to the method described for Préparation 85 using fert-butyl (4-cyclopropyl-1H-pyrazol-1-yl)acetate (see Préparation 87) to afford the title compound as a yellow solid in 75% yield, 1.0 g.

LCMS (system 4); R ₍=1.13min; m/z 165[M+H]⁺.

Préparation 89: Ethyl (5-chloropyridin-2-yl)acetate

Césium carbonate (71 g, 218 mmol) was added to 2-bromo-5-chloropyridine (14 g, 73 mmol) and diethyl malonate (22 mL, 145 mmol) in dry 1,4-dioxane (280 mL) and the solution was degassed with argon for 30 minutes. Then copper (I) oxide (2.8 g, 14.55 mmol) and picolinic acid (3.6 g, 29 mmol) were added and the mixture was stirred in a seated vessel at 130C for 24 hours. The mixture was cooled to room température, quenched with water (100 mL) and extracted with EtOAc (3 x 100 ml). The organic extracts were washed with water (200 mL), brine (200 mL), dried over sodium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel (EtOAc: Hexane 92: S) to afford the title compound as a yellow oil in 54% yield, 8.0 g.

¹H NMR (400 MHz, DMSO-d₆) δ: 1.17 (t, 3H), 3.85 (s, 2H), 4.08 (q. 2H), 7.42 (d, 1H), 7.90 (dd, 1 H), 8.54 (d, 1H).

Préparation 90: (5-Chloropyridin-2-yl)acetic acid

The title compound was prepared according to the method described for Préparation 42 using ethyl (5chloropyridin-2-yl)acetate (see Préparation 89) to afford the title compound as a brown solid in 51% yield, 3.5 g.

LCMS (system 4): R_t= 1.00 min; m/z 172 [M+H]⁺.

Préparation 91 : Ethyl (5-fluoropyridin-2-yl)acetate

154

The title compound was prepared according to the method described for Préparation 89 using 2-bromo5-fluoropyridine to afford the title compound as a yellow oil in 20% yield, 5 g.

¹H NMR (400 MHz, DMSO-d₆) δ: 1.17 (t, 3H), 3.84 (s, 2H), 4.08 (q, 2H), 7.42-7.45 (m, 1H), 7.67-7.72 (m, 1 H), 8.48 (d, 1H).

Préparation 92: (5-Fluoropyridin-2-yl)acetic acid

Xx

O^OH

The title compound was prepared according to the method described for Préparation 42 using ethyl (5fluoropyridin-2-yl)acetate (see Préparation 91) to afford the title compound as a brown solid in 57% yield, 2.4 g.

'H NMR (400 MHz, DMSO-d₆) δ: 3.75 (s, 2H), 7.41-7.44 (m, 1H), 7.65-7.70 (m, 1H), 8.47 (d, 1H), 12.50 (brs, 1H).

Préparation 93: 5-lodo-7-isopropyI-7H-pyrrolo[2,3-d]pyrimidine

To a mixture of 5-iodo-7H-pyrrolo[2,3-d]pyrimidine (Préparation 201, 2.90 g, 12.0 mmol) and césium carbonate (5.78 g, 17.8 mmol) in DMF (45 mL) was added 2-iodopropane (1.78 mL, 17.8 mmol). The mixture was stirred at room température for 3 hours. The reaction mixture was then poured onto saturated aqueous ammonium chloride (500 mL) and a solid precipitated. The solid was collected by filtration, rinsed with water (200 mL) and dried under reduced pressure for 17 hours to afford the title compound as a brown solid in 77% yield, 2.61 g.

’H NMR (400 MHz, CDCI₃) δ: 1.53 (d, 6H), 5.15 (m, 1H), 7.40 (s, 1H), 8.73 (s, 1H), 8.88 (s, 1H); LCMS (system 2): Ri = 1.02 min; m/z 288 [M+H]⁺.

Préparation 94: (5-Bromopyridin-3-yl)(7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone

To a stirred solution of 5-iodo-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidine (Préparation 93, 4.85 g, 16.9 mmol) in THF (90 mL) at 0°C, under nitrogen was added isopropyl magnésium chloride (9.28 mL, 18.6

155 mmol, 2.0 M in diethyl ether). The mixture was stirred at 0 °C for 1 hour then a solution of 5-bromo-Nmethoxy-N-methylnicotinamide (Préparation 227, 4.55 g, 18.6 mmol) in THF (10 mL) was added dropwise at 0 °C. The mixture was warmed to room température and stirred for 16 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride (200 mL) and extracted with ethyl acetate (3 x 200 mL). The combined organics were concentrated under reduced pressure and purified by silica gel column chromatography eluting with gradient of EtOAc:DCM 95:5 to 50:50 to afford a light brown oil. The crude material was recrystallised using EtOAc:heptane (15:200 mL) to afford the title compound as a white solid in 33% yield, 2.16 g.

¹H NMR (400 MHz, CDCIg) δ: 1.60 (d, 6H), 5.20 (m, 1H), 7.79 (s, 1H), 8.28 (dd, 1H), 8.90 (d, 1 H), 8.95 (d, 1H), 9.03 (s. 1H), 9.59 (s, 1H); LCMS (system 2): R_t = 1.36 min; m/z 346 [M+H]⁺.

Préparation 95: (5-Aminopyridin-3-yl)(7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone

The title compound was prepared according to the method described for Préparation 31 using (5bromopyridin-3-yl)(7-isopropyl-7H-pyrroIo[2,3-d]pyrimidin-5-yl)methanone (Préparation 94) to afford the title compound as a white solid in 69% yield, 1.20 g.

¹H NMR (400 MHz, CDCI₃) δ: 1.58 (d, 6H), 3.98 (br s, 2H), 5.18 (m, 1H), 7.39 (dd, 1H), 7.89 (s, 1H), 8.29 (brs, 1H), 8.43 (brs, 1H), 9.01 (s, 1H), 9.59 (s, 1H); LCMS (system 2): R_t = 0.50 min; m/z 282 [M+H]⁺. Préparation 96: 4-Chloro-7-oxetan-3-yl-7H-pyrrolo[2,3-d]pyrimidine

The title compound was prepared according to the method described for Préparation 1 using (4,6dichloropyrimidin-5-yl)acetaldehyde (Préparation 208) and oxetan-3-amine to afford the title compound as a yellow solid in 67% yield, 2.81 g.

LCMS (system 1 ): R, = 1.92 min; m/z 210, 212 [M+H]'.

156

Préparation 97: 7-Oxetan-3-yl-7H-pyrrolo[2,3-d]pyrimidine

The title compound was prepared according to the method described for Préparation 8 using 4-chloro-7oxetan-3-yl-7H-pyrrolo[2,3-d]pyrimidine (Préparation 96) to afford the title compound as a white solid in 90% yield, 1.20 g.

’H NMR (400 MHz, DMSO-d₆) δ: 4.97-5.06 (m, 4H), 5.96 (m, 1H), 6.74 (d, 1H), 8.04 (d, 1H), 8.80 (s, 1H), 9.03 (s, 1H).

Préparation 98: 5-lodo-7-oxetan-3-yl-7H-pyrrolo[2,3-d]pyrimidine

The title compound was prepared according to the method described for Préparation 14 using 7-oxetan3-yl-7H-pyrrolo[2,3-d]pyrimidine (Préparation 97) to afford the title compound as a white solid in 49% yield, 999 mg.

¹H NMR (400 MHz, DMSO-d₆) δ; 4.92-5.08 (m, 4H), 5.94 (m, 1H), 8.28 (s, 1H), 8.75 (s, 1H), 8.85 (s, 1H).

Préparation 99: {5-[(Diphenylmethylene)amino]pyridin-3-yl}(7-oxetan-3-yl-7H-pyrrolo[2,3-d]pyrimidin-5yl)methanone

The title compound was prepared according to the method described for Préparation 94 using 5-iodo-7oxetan-3-yl-7H-pyrrolo[2,3-d]pyrimidine (Préparation 98) and 5-[(diphenylmethylene)amino]-N-methoxyN-methylnicotinamide (Préparation 23) to afford the title compound as a yellow solid in 55% yield, 253 mg.

¹H NMR (400 MHz, DMSO-d₆) δ: 4.95-5.06 (m, 2H), 5.15-5.24 (m, 2H), 5.96*(m, 1H), 7.21-7.80 (m, 11 H), 8.22 (d, 1H), 8.52 (s, 1H), 8.62 (m, 1H), 9.01 (s, 1H), 9.44 (s, 1H).

157

Préparation 100: (5-Aminopyridin-3-yl)(7-oxetan-3-yl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone

The title compound was prepared according to the method described for Préparation 37 using {5[(diphenylmethylene)amino]pyridin-3-yl}(7-oxetan-3-yl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (Préparation 99) to afford the title compound as a yellow solid in 96% yield, 128 mg.

'H NMR (400 MHz, DMSO-d₆) δ: 4.95-5.04 (m, 2H), 5.14-5.22 (m, 2H), 5.66 (brs, 2H), 5.97 (m, 1H), 7.33 (m, 1 H), 8.19 (d, 1 H), 8.25 (d, 1 H), 8.62 (s, 1 H), 9.00 (s, 1 H), 9.46 (s, 1 H).

Préparation 101: 5-lodo-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine

To a stirred solution of 5-iodo-7H-pyrrolo[2,3-d]pyrimidine (Préparation 201,735 mg, 3.00 mmol) in DMF (5 mL) at 0 °C was added to sodium hydride (132 mg, 3.30 mmol, 60% in oil). The mixture was stirred at room température for 30 minutes, cooled to -20 °C and 2-(trimethylsilyl)ethoxymethyl chloride (0.58 mL, 3.30 mmol) added. The réaction mixture was stirred at -20°C for 3 hours then water (30 mL) was added. The mixture was extracted with EtOAc (2 x 50 mL) and the combined organic phases were dried over magnésium sulphate and evaporated under reduced pressure. The crude solid was purified by column chromatography on silica gel, eluting with a gradient of heptane:EtOAc 100:0 to 50:50), to afford the title compound as a white solid in 61% yield, 691 mg.

¹H NMR (400 MHz, DMSO-d₆) δ: -0.11 (s, 9H), 0.81 (t, 2H), 3.51 (t, 2H), 5.61 (s, 2H), 8.01 (s, 1H), 8.77 (s, 1 H), 8.89 (s, 1H).

158

Préparation 102: {5-[(Diphenylmethylene)amino]pyridin-3-yl}(7-{[2-(trimethylsilyl)ethoxy]methyl}-7Hpyrrolo[2,3-d]pyrimidin-5-yl)methanone

Me~ Si-Me Me

The title compound was prepared according to the method described for Préparation 28 using 5-iodo-75 {[2-{trimethylsilyl)ethoxy]methyl}-7H-pyrro!o[2,3-d]pyrimidine (Préparation 101) and 5[(diphenylmethylene)amino]-N-methoxy-N-methylnicotinamide (Préparation 23) to afford the title compound as a yellow oil in 32% yield, 460 mg.

¹H NMR (400 MHz, DMSO-d₆) δ: -0.11 (s, 9H), 0.84 (m, 2H), 3.59 (m, 2H), 5.71 (s, 2H), 7.27 (m, 2H), 7.37 (m, 3H), 7.51 (m, 2H), 7.59 (m, 2H), 7.73 (d, 2H), 8.22 (d, 1H), 8.38 (s, 1H), 8.56 (d, 1H), 9.00 (s, 1H), 10 9.45 (s, 1 H); LCMS (System 9): R₍ = 2.36 min; m/z 534 [M+H]^f.

Préparation 103: (5-Aminopyridin-3-yl)(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-5yl)methanone

Me-Si-Me Me

The title compound was prepared according to the method described for Préparation 37 using {515 [(diphenylmethylene)aminoJpyridin-3-yl}(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-5yl)methanone (Préparation 102) to afford the title compound as a colourless oil in 73% yield, 2.10 g.

¹H NMR (400 MHz, DMSO-d₆) δ; 0.09 (s, 9H), 0.84 (t, 2H), 3.60 (t, 2H), 5.66'(m, 4H), 7.30 (s, 1H), 8.18 (s, 2H), 8.55 (s, 1H), 9.02 (s, 1 H), 9.47 (s, 1 H); LCMS(system 9): R, = 3.25 min; m/z 370 [M+H]⁺.

Préparation 104: 2-(4-chlorophenyl)-N-(5-(7-((2-(trimethylsilyl)ethoxy)methy!)-7H-pyrrolo[2,320 d]pyrimidine-5-carbonyl)pyridin-3-yl)acetamide

159

The title compound was prepared according to the method described for Examples 73-87 using (5aminopyridin-3-yl)(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (Préparation 103) and 4-chlorophenylacetic acid to afford the title compound as a white solid in 66% yield, 223 mg.

¹H NMR (400 MHz, DMSO-d₆) δ: -0.11 (S. 9H), 0.82 (t, 3H), 3.60 (t, 2H), 3.74 (s, 2H), 5.70 (s, 2H), 7.37 (t, 4H), 8.47 (s, 1H), 8.60 (s, 2H), 8.72 (s, 1H), 8.98 (s, 1H), 9.03 (S, 1H), 9.48 (s, 1H);

LCMS (system 9): R_t = 3.50 min; m/z 522 [M+H]⁺.

Préparation 105: N-[5-({7-[(1 S)-2-([tert-butyl(dimethyl)silyl]oxy}-1 -methylethyl]-7H-pyrrolo[2,3d]pyrimidin-5-yl}carbonyl)pyridin-3-yl]-2-[3-(trifluoromethyl)phenyl]acBtamide

Prepared according to Example 1, using (S) (5-aminopyridin-3-yl){2-{[tert-butyl(dimethyl)silyl]oxy}-1methylethyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}methanone (Préparation 37) and 3trifluoromethylphenylacetic acid with DI PEA as base.

¹H NMR (400 MHz, DMSO) δ: -0.24 (s, 3H), -0.18 (s, 3H), 0.56 (s, 9H), 1.52 (d, 3H), 3.86 (m,3H), 3.94 (m, 1 H), 5.06 (m, 1H), 7.58 (t, 1H), 7.63 (t,2H), 7.72 (s, 1 H), 8.45 (s, 1H), 8.50 (s, 1H), 8.67 (d, 1H). 8.93 (d, 1H), 8.98 (s,1 H), 9.45 (s,1 H), 10.73 (s,1H).

LCMS (System 9): R_t = 3.89min; m/z 598 [M+H]*.

Préparation 106: 5-[(Diphenylmethylene)amino]nicotinaldehyde

To a stirred solution of 5-[(diphenylmethylene)amino]-N-methoxy-N-methylnicotinamide (Préparation 23,

7.50 g, 0.021 mol) in THF (150 mL) at -70°C was added diisopropylaluminium hydride (42 mL, 0.042 mol,

1.0 M in THF) and the resulting mixture stirred at -70°C for 2 hours. Water (20 mL) and ethyl acetate

160 (100 mL) were added. The organic phase was separated, concentrated under reduced pressure and purified by silica gel column chromatography eluting with EtOAc: petroleum ether 1:10 to afford the title compound as a brown solid in 65% yield, 4 g.

The title compound can also be prepared according to the following process:,

A mixture of 5-bromonicotinaldehyde (2790 mg, 15.0 mmol), diphenylmethanimine (3.01 mL, 18 mmol), Pd₂(dba)₃ (412 mg, 0.45 mmol), di-tert’butyl(2',4’,6'-triisopropyl-[1,1'-biphenyl]-2-yl)phosphine (510 mg, 1.2 mmol) and K₃PO₄ (7960 mg, 37.5 mmol) in DME (30.0 mL) was stirred at 50 °C for 16 hours. After coolîng to room température, the reaction was diluted with DCM (50 mL) and the mixture filtered through a pad of arbocel. The filter cake was washed with DCM (50 mL) and the filtrate concentrated under reduced pressure. The crude material was recrystalfized from ethyl acetate/heptane to give the desired compound as a solid in 78% yield, 3341 mg.

1H NMR (400 MHz, DMSO-d₆) δ; 7.18-7.26 (m, 2H), 7.30-7.39 (m, 3H), 7.47-7.54 (m, 2H), 7.55-7.62 (m,

2H), 7.68-7.75 (m, 2H), 8.25 (d, 1 H), 8.63 (d, 1H), 10.00 (s, 1H).

Préparation 107: 2,2,3,3,9,9,10,10-octamethyl-4,8-dioxa-3,9-disilaundecan-6-ol

OH

OTBDMS

TBDMSO

To a stirred solution of glycerol (4.01 mL, 55 mmol) and imidazole (18.7 g, 275 mmol) in DMF (150 mL) at 0 °C was added tert-butyldimethylsilyl chloride (17.2 g, 113 mmol) in DMF (33 mL), The reaction mixture was allowed to warm to room température and stirred for 16 hours. Water (500 mL) was added to the reaction mixture and the resulting mixture extracted with heptane (500 mL x 3). The combined organic layers were washed with water (300 mL), dried over MgSO₄ and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography with a gradient elutant of heptane:EtOAc 100:0 to 80:20 to afford the title compound as a colorless oil in 68% yield, 11.9 g.

1H NMR (400 MHz, DMSO-d_e) δ: 0.03 (s, 12H), 0.86 (s, 18H), 3.40-3.59 (m, 5H), 4.58 (d, 1H).

Préparation 108: 2,2,3,3,9,9,10,10-octamethyl-4,8-dioxa-3,9-disilaundecan-6-yl trifluoromethanesulfonate

F

TBDMSCL ^OTBDMS

To a stirred solution of 2,2,3,3,9,9,10,10-octamethyl-4,8-dioxa-3,9-disilaundecan-6-ol (Préparation 107, 6410 mg, 20 mmol) and pyridine (2.42 mL, 30 mmol) in DCM (40 mL) at -50 °C was added trifluoromethanesulfonic anhydride (5.05 mL, 30 mmol) and the reaction stirred at -30 °C for 2 hours. Aqueous 1 N HCl (40 mL) was added to the reaction and the mixture was extracted with DCM (40 mL x 3). The combined organic layers were concentrated under reduced pressure to obtain a colourless oil which was used in the next step (Préparation 196) without further purification.

161

Préparation 109: 4-Chloro-[7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl]{5[(diphenylmethylene)amino]pyridin-3-yl}methanone

The title compound was prepared according to the method described for Préparation 28 followed by 5 Préparation 30 using 4-chloro-5-iodo-7-methyl-7H-pyrrolo[2,3-d]pyrimidine (Préparation 226) and 5[{diphenylmethylene)amino]nicotinaldehyde (Préparation 106) to afford the title compound as a yellow solid (11.0 g, 48%).

¹H NMR (400 MHz, CDCI₃) δ.' 3.87 (s, 3H), 7.06 (m, 2H), 7.28 (m, 2H), 7.37 (m, 2H), 7.45 (m, 3H), 7.70 (m, 3H), 8.15 (d, 1 H), 8.49 (d, 1 H), 8.69 (s, 1 H).

Préparation 110 :(5-Aminopyridin-3-yl)(7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone

Citric acid (2 M, 200 mL) was added to 4-chloro-[7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl]{5[(diphenylmethylene)amino]pyridin-3-yl}methanone (Préparation 109, 30 g, 0.066 mol) in THF (200 mL) and the mixture was stirred at room température for 30 minutes. Ether (200 mL) was added and the phases were separated. The aqueous layer was neutralised with aqueous sodium carbonate then the solid was collected by filtration and dried under vacuum to give (5-aminopyridin-3-yl)(4-chloro-7-methyl7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone as a brown solid, 18 g, 95%

Methanethiol sodium sait (15.5 g, 0.22 mol) was added to 5-aminopyridin-3-yl)(4-chloro-7-methyl-7Hpyrrolo[2,3-d]pyrimidin-5-yl)methanone (21 g, 0.073 mol) in methanol (300 mL) and the mixture was 20 stirred at room température for 7 hours. The reaction mixture was poured into ice-water (200 mL) and the precipitate was filtered. The filter cake was washed with water (100 mL) then acetone (20 mL) to afford the (5-aminopyridin-3-yl)[7-methyl-4-(methylthio)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]methanone as a brown solid, 15 g, 69%

Raney nickel (10 g) was added to (5-aminopyridin-3-yi)(7-methyl-4-(methylthio)-7H-pyrrolo[2,325 d]pyrimidin-5-yl]methanone (1.5 g, 5.0 mmol) and conc ammonia (150 mL) in 1,4 dioxane (150 mL). The mixture was refluxed for 6 hours then filtered. The filtrate was evaporated in vacuo and purified by prep HPLC (method 4) to afford the title compound as a brown solid in 100% yield, 1.9 g.

¹H NMR (400 MHz, DMSO-D6) δ: 3.88 (s, 3H), 5.63 (s, 2H), 7.27 (m, 1H), 8.14-8.18 (m, 2H), 8.40 (s, 1H), 8.97 (s, 1 H), 9.42 (s, 1H).

162

Préparation 111: 2,2,3,3,6,9,9,10,10-Nonamethyl-4,8-dioxa-3,9-disilaundecan-6-amine

Me NH₂

TBDMSO^JX^/OTBDMS

The titie compound was prepared according to the method described for Préparation 44 using 2-amino-2methyl-1,3-propanediol to afford the titie compound as a colourless oil in 100% yield, 23.0 g.

¹H NMR (400 MHz, CDCI₃) δ: 0.05 (s, 12H), 0.87-0.99 (m, 21 H), 3.36-3.42 (m, 4H).

Préparation 112: 7-[2-{[tert-Butyl(dimethyl)silyl]oxy}-1-({[tert-butyl(dimethyl)silyl]oxy}methyl)-1methylethyl]-4-chloro-7H-pyrrolo[2,3-d]pyrimidine

The titie compound was prepared according to the method described for Préparation 1 using 2,2,3,3,6,9,9,10,10-nonamethyl-4,8-dioxa-3,9-disilaundecan-6-amine (Préparation 111) to afford the titie compound as a colourless gum in 75% yield, 8.91 g.

¹H NMR (400 MHz, CDCI₃) δ: 0.09-0.11 (m, 12H), 0.78-0.79 (m, 18H), 1.74 (s. 3H), 4.06-4.09 (m, 2H), 4.29-4.31 (m, 2H), 6.52 (m, 1H), 7.44-7.45 (m, 1H), 8.56 (m, 1H).

Préparation 113: 7-[2-{[tert-Butyl(dimethyl)silyl]oxy}-1-({[tert-butyl(dimethyl)silyl]oxy}methyl)-1methylethyl]-7H-pyrrolo[2,3-d]pyrimidine

The titie compound was prepared according to the method described for Préparation 8 using 7-[2-{[tertbutyl(dimethyl)silyl]oxy}-1-({[tert-butyl(dimethyl)silyl]oxy}methyl)-1-methytethyl]-4-chloro-7H-pyrrolo[2,3djpyrimidine (Préparation 112) to afford the titie compound as a yellow oil in 99% yield, 8.14 g.

¹H NMR (400 MHz, CDCI₃) δ; -0.13 (s,6H), -0.10 (s,6H), 0.78 (s,18H), 1.75 (s, 3H), 4.11 (d, 2H), 4.33 (d, 2H), 6.45 (d, 1H), 7.41 (d, 1H), 8.78 (s,1 H), 8.90 (s, 1H).

163

Préparation 114: 7-[2-{[tert-Butyl(dimethyl)silyl]oxy}-1 -({[tert-butyl(dimethyl)silyI]oxy}methyl)-1 methylethyl]-5-iodo-7H-pyrrolo[2,3-d]pyrimidine

The title compound was prepared according to the method described for Préparation 14 using 7-[2-{[tert5 butyl(dimethyl)silyl]oxy}-1-({[tert-butyl(dimethy!)silyl]oxy}methyl)-1-methylethyl]-7H-pyrro!o[2,3-d)pyrimidine (Préparation 113) to afford the title compound as a yellow oil in 88% yield, 7.98 g.

¹H NMR (400 MHz, CDCI₃) δ: -0.10 (s, 12H), 0.79 (s, 18H), 1.75 (s, 3H), 4.07 (d, 2H), 4.27 (d, 2H), 7.49 (s, 1 H), 8.70 (s, 1 H), 8.82 (s, 1H).

Préparation 115: (7-[2-{[tert-Butyl(dimethyl)silyl]oxy}-1 -({[tert-butyl(dimethyl)silyl]oxy}methyl)-1 10 methylethyl]-7H-pyrro!o[2,3-d]pyrimidin-5-ylX5-[(diphenylmethylene)amino]pyridin-3-yl}methanone

The title compound was prepared according to the method described for Préparation 28 using 7-[2-{[tertbutyl(dimethyl)silyl]oxy}-1-({[tert-butyl(dimethyl)silyl]oxy}methyl)-1-methylethyl]-5-iodo-7H-pyrrolo[2,3djpyrimidine (Préparation 114) and 5-[(diphenylmethylene)amino]-N-methoxy-N-methylnicotinamide 15 (Préparation 23) to afford the title compound as a yellow foam in 69% yield, 1.76 g.

’H NMR (400 MHz, CDCI₃) δ; 0.10-0.12 (m, 12H), 0.73-0.76 (m, 18H), 1.77 (s, 3H), 4.06-4.09 (m, 2H), 4.34-4.36 (m, 2H), 7.11-7.16 (m, 2H), 7.28-7.33 (m, 3H), 7.42-7.47 (m, 2H), 7.50-7.54 (m, 2H), 7.78-7.80 (m, 2H), 7.93 (s, 1H), 8.15-8.16 (m, 1H), 8.56 (m. 1H), 8.94 (s, 1H), 9.58 (s, 1H).

164

Préparation 116: (5-Aminopyridin-3-yl){7-[2-{[tert-butyl(dimethyl)silyl]oxy}-1 -({[tertbutyl(dimethyl)silyl]oxy}methyl)-1-methylethyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}methanone

The title compound was prepared according to the method described for Préparation 37 using {7-[2-{[tertbutyl(dimethyl)silyl]oxy}-1-({[tert-butyl(dimethyl)silyl]oxy}methyl)-1-methylethyl]-7H-pyrrolo[2,3-d]pyrimidin5-yl}{5-[(diphenylmethyiene)amino]pyridin-3-yl}methanone (Préparation 115) to afford the title compound as a yellow foam in 85% yield, 1.15 g.

LCMS (System 1 ): R_t = 4.01 min; m/z 556 [M+Hf.

Préparation 117: 1-lsopropyl-3-trifiuoromethyl-1H-pyrazole-4-carboxylic acid ethyl ester

To a suspension of 5-trifluoromethyl-1 H-pyrazole-4-carboxylic acid ethyl ester (13 g, 62.5 mmol) and césium carbonate (61.1 g, 187.5 mmol) in DMF (70 mL) was added 2-iodo-propane (6.86 mL, 68.75 mmol) and the resulting mixture allowed to stir at room température for 16 hours. The crude reaction mixture was poured onto water (100 mL) and extracted with EtOAc (100 mL x 3). The combined organics were washed with water (50 mL x 2), brine (50 mL), dried over sodium sulphate, filtered and concentrated under reduced pressure to afford the title compound as an off-white solid in 65% yield, 10.2 g.

’H NMR (400 MHz, CDCI₃) 0: 1.33 (t, 3H), 1.53 (d, 6H). 4.30 (q. 2H). 4.50-4.57 (m, 1H), 8.00 (s, 1H); LCMS (system 9): R_t= 3.55 min; m/z 251 [M+Hf.

Préparation 118: (1-lsopropyl-3-trifluoromethyl-1 H-pyrazol-4-yl)-methanol

The title compound was prepared according to the method described for Préparation 183 using 1isopropyl-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid ethyl ester (Préparation 117) to afford the title compound an off-white solid in 97% yield, 8.3 g.

165

’H NMR (400 MHz, CDCI₃) δ: 1.50 (d, 6H), 1.72 (t, 1H), 4.47-4.54 (m, 1H), 4.65 (d, 2H), 7.50 (s, 1H);

LCMS (system 9): R_t= 2.77 min; m/z 209 [M+H] .

Préparation 119: (1-lsopropyl-3-trifluoromethyl-1H-pyrazol-4-yl)-acetonitrile

The title compound was prepared according to the method described for Préparation 184 using (1isopropyl-3-trifluoromethyl-1H-pyrazol-4-yl)-methanol (Préparation 118) to afford the title compound as an off-white solid in 58% yield, 5 g.

’H NMR (400 MHz, DMSO-d₆) δ: 1.42 (d, 6H), 3.92 (s, 2H), 4.56-4.63 (m, 1H), 8.06 (s. 1H).

Préparation 120: 2-Chloro-5-iodo-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidine

The title compound was prepared according to the method described for Préparation 93 using 2-chloro-5iodo-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidine (Préparation 40) to afford the title compound as a white solid in 87% yield, 5.5 g.

’H NMR (400 MHz, CDCI₃) ô: 1.50 (d, 6H), 5.10 (m, 1H), 7.36 (s, 1H), 8.55 (s, 1H); LCMS (System 10) R, = 3.6 min; m/z 322 [M+H]⁺.

Préparation 121: (5-Bromopyridin-3-yl)(2-chloro-7-isopropyl-7/7-pyrrolo[2,3-d]pynmidin-5-yl)methanone

The title compound was prepared according to the method described for Préparation 28 using 2-chioro-5iodo-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidine (Préparation 120) and 5-bromo-N-methoxy-Nmethylnicotinamide to afford the title compound as a yellow solid in 41% yield, 1.2 g.

’H NMR (400 MHz, DMSO-D₆) δ: 1.54 (d, 6H), 5.02 (m, 1H), 8.41 (d, 1H), 8.63 (s, 1H), 9.0 (m, 2H), 9.33 (s, 1H).

Préparation 122: (2-Amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(5-aminopyridin-3-yl)methanone

166

The title compound was prepared according to the method described for Préparation 31 using (5bromopyridin-3-yl)(2-chloro-7-isopropyl-7H-pyrrolo[2,3-c(]pyrimidin-5-yl)methanone (Préparation 121) to afford the title compound as a yeilow solid in 58% yield, 500 mg.

¹H NMR (400 MHz, DMSO-D_fl) δ: 1.47 (d, 6H), 4.82-4.86 (m, 1 H), 5.60 (s, 2H), 6.58 (s, 2H), 7.23 (s, 1H),

7.88 (s, 1H), 8.12 (m, 2H), 8.91 (s, 1H); LCMS (System 9) R, = 0.99 min; m/z 297 [M+H]⁺.

Preparation123: (1-lsopropyl-3-trifluoromethyl-1H-pyrazol-4-yl)-acetic acid

The title compound was prepared according to the method described for Préparation 185 using (1isopropyl-3-trifluoromethyl-1 H-pyrazol-4-yl)-acetonitrile (Préparation 119) to afford the title compound as off-white solid in 82% yield, 4.5 g.

¹H NMR (400 MHz, DMSO-d₆) δ: 1.41 (d, 6H), 3.50 (s, 2H), 4.52-4.5Θ (m, 1H). 7.89 (s, 1H), 12.35 (br, 1H); LCMS (System 10): R_t= 1.56 min; m/z 235 [M-H]’.

Préparation 124: (3-Cyclopropyl-1 -methyl-1 H-pyrazol-4-yl)-acetonitrile

Me

To a suspension of potassium tert-butoxide (8.95 g, 79.9 mmol) in DME (250 mL) -78 °C under nitrogen was added a solution of 1-(isocyanomethyl sulfonyl)-4-methyl benzene (9.36 g, 47.94 mmol) in DME (50 ml). After stirring for 10 minutes, a solution of 3-cyclopropyl-1-methyl-1 H-pyrazole-4-carbaldehyde (6 g, 39.95 mmol) in DME (100 mL) was added. The resulting mixture was allowed to stir at -78 °C for 1 hour and then at room température for 1hour. Methanol (50 mL) was added and the resulting mixture refluxed for 1 hour. The reaction mixture was quenched with saturated ammonium chloride solution (200 mL) and extracted with EtOAc (2 x 200 mL). The combined organic layers were washed with brine (2 x 50 mL), dried over sodium sulphate, filtered and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography eluting with hexane:EtOAc 90:10 to afford the title compound an off-white solid in 67% yield, 4.3 g.

167

¹H NMR (400 MHz, DMSO-d₆) δ: 0.67-0.7 (m, 2H), 0.79-0.83 (m, 2H), 1.75-1.80 (m, 1H), 3.68 (s, 3H),

3.79 (s, 2H), 7.54 (s, 1H); LCMS (system 9): R₍= 2.53 min; m/z 162 [M+H]⁺.

Préparation 125: (3-Cyclopropyl-1-methyl-1 H-pyrazol-4-yl)-acetic acid

The title compound was prepared according to the method described for Préparation 141 using (3Cyclopropyl-1-methyl-1 H-pyrazol-4-yl)-acetonitrile (Préparation 124) to afford the title compound as solid in 83% yield, 4 g.

’H NMR (400 MHz, DMSO-d_B) δ: 0.62-0.66 (m, 2H), 0.73-0.77 (m, 2H), 1.67-1.74 (m, 1H), 3.38 (s, 2H), 3.66 (s, 3H), 7.40 (s, 1H), 12.22 (br, 1H); LCMS (system 9): R, = 1.97 min; m/Z 181 [M+Hf.

Préparation 126: (3-Cyano-4-fluoro-phenyl)-acetic acid

To a solution of (3-bromo-4-fluoro-phenyl)-acetic acid (10 g, 42.9 mmol) in DMF (65 mL) was added copper (I) cyanide (7.7 g, 85.8 mmol) and heated at 130 °C for 24 hrs. The reaction mixture was cooled to room température and diluted with ethyl acetate (250 mL). The organic layer was washed with water (5 x 50 mL), brine (50 mL), dried over sodium filtered and concentrated under reduced pressure. The crude material was re-crystallized from diethyl ether and hexane to afford the title compound as a yellow solid in 65% yield, 5 g.

’H NMR (400 MHz, DMSO-d₆) ô: 3.68 (s, 2H), 7.48 (t, 1H), 7.66-7.71 (m, 1H), 7.82 (dd, 1H), 12.53 (br s, 1H); LCMS (system 10): R_t= 1.39 min; m/z 178 [M-H]'.

Préparation 127: (3-Cyano-4-fluoro-phenyl)-acetic acid ethyl ester

To a suspension of (3-cyano-4-fluoro-phenyl)-acetic acid (500 mg, 2,79 mmol) (Préparation 126) and potassium carbonate (770 mg, 5.58 mmol) in DMF (5 mL) was added ethyl iodide (0.89 mL, 11.16 mmol) and the reaction mixture stirred at room température for 4 hours. The crude reaction mixture was poured onto water (10 mL) and extracted with ethyl acetate (3 x 15 mL). The combined organic layers were washed with water (5 x 10 mL), brine (10 mL), dried over sodium suiphate, filtered and concentrated under reduced pressure to afford the title compound as an off-white solid in 87% yield, 500 mg.

¹H NMR (400 MHz, CDCI₃) ô: 1.26 (t, 3H), 3.61 (s, 2H), 4.16 (q, 2H), 7.17 (t, 11 H), 7.49-7.55 (m, 2H). Préparation 128: (3-Amino-benzo[d]isoxazol-5-yl)-acetic acid ethyl ester

168

To a solution of (3-cyano-4-fluoro-phenyl)-acetic acid ethyl ester (Préparation 127, 400 mg, 1.93 mmol) and acetohydroxamic acid (362 mg, 4.83 mmol) in DMF (40 mL) and water (15 mL) was added potassium carbonate (1.6 g, 11.58 mmol) and the reaction mixture stirred at room température for 12 hours. The reaction mixture was diluted with water (100 mL) and the resulting white'precipitate and collected by filtration. The crude material was purified by silica gel column chromatography eluting with a gradient of dichloromethane: methanol 100:0 to 97:3 to afford the title compound as an off-white solid in 59% yield, 250 mg.

LCMS (system 9): R_t = 2.87 min; m/z 221 [M+H]⁺.

Préparation 129: (3-Amino-benzo[d]isoxazol-5-yl)-acetic acid

The title compound was prepared according to the method described for Préparation 141 using (3-aminobenzo[d]isoxazol-5-yl)-acetic acid ethyl ester (Préparation 128) to afford the title compound as an offwhite solid in 69% yield, 30 mg.

¹H NMR (400 MHz, DMSO-d₆) ô: 3.65 (s, 2H), 6.36 (br s, 2H), 7.36-7.42 (m, 2H), 7.69 (s, 1 H), 12.37 (br s, 1 H); LCMS (system 10): R,= 1.65 min; m/z 193 [M+H]⁺.

Préparation 130: lmidazo[1,2-a]pyridin-7-yl-acetic acid ethyl ester

To a stirred solution of 7-bromo-imidazo[1,2-a]pyridine (600 mg, 3.0 mmol) and diethyl malonate (0.93 mL, 6.1 mmol) in dry dioxane (15 mL) was added césium carbonate (3 gm, 9.1 mmol). Argon was bubbled through the mixture for 10 minutes and then copper (I) iodide (116 mg, 0.61 mmol) and picolinic acid (150 mg, 1.22 mmol) were added. The résultant mixture was heated in a sealed tube at 130 °C for 24 hours. The reaction mixture was cooled to room température, quenched with water (10 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with water (2x10 mL), brine (10 mL), dried over sodium sulphate, filtered and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography eluting with a gradient of dichloromethane: methanol 100:0 to 98:2 to afford the title compound as an off-white gum in 29% yield, 180 mg.

LCMS (system 10); R_t= 2.61 min; m/z 205 [M+H]⁺.

Préparation 131 : N-(5-([7-(2-{[tert-butyl(dimethyl)silyl]oxy}-1,1-dimethylethyl)-7H-pyrrolo[2,3-d]pyrimidin5-yl]carbonyl}pyridin-3-yl)-2-(4-cyanophenyl)acetamide

169

Prepared according to the method described for Example 1 using (5-aminopyridin-3-yl)[7-(2-([tertbutyl(dimethyl)silyI]oxy}-1,1 -dimethyIethyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]methanone (Préparation 38), and 4-cyanophenylacetic acid with DI PEA.

¹H NMR (400 MHz, DMSO) δ; -0.26 (s, 6H), 0.58 (s, 9H), 1.75 (s, 6H), 3.86 (s, 2H), 4.10 (s, 2H), 7.54 (d, 2H), 7.82 (d, 2H), 8.16 (s, 1H), 8.51 (s, 1H), 8.68 (s, 1 H), 8.88 (s, 1H), 8.98 (s, 1H), 9.47 (s, 1H), 10.73 (s. 1H);

LCMS (System 9): R| = 3.80 min; m/z 569 [M+H]⁺.

Préparation 132: lmidazo[1,2-a]pyridin-7-yl-acetic acid

HO

To a solution of imidazo[1,2-a]pyridin-7-yl-acetic acid ethyl ester (180 mg, 0.65 mmol) (Préparation 130) in dioxane (4 mL) at 0 °C was added 2 N aqueous sodium hydroxide solution (4 mL). Then reaction mixture was heated at 90°C for 6 hours. After cooling to 0 °C, the mixture was acidified to pH 4 with with 2 N aqueous hydrochoric acid and extracted with 20% isopropanol in dichoromethane (8x10 mL). The combined organics were dried over sodium sulfate and concentrated under reduced pressure to afford the title compound as an off-white solid in 70% yield, 80 mg.

LCMS (system 10): R_t= 1.40 min; m/z 177 [M+Hf.

Préparation 133: Pyrazolo[3,4-b]pyridin-1-yl-acetic acid ethyl ester

O ( Me

To a solution of 7-aza indazole (250 mg, 2.1 mmol) and ethyl bromoacetate (0.47 mL, 4.2 mmol) in DMF (8 mL) was added K₂CO₃ (1.16 gm, 8.4 mmol) and the resulting mixture stirred at 70 °C for 16 hours. The reaction mixture was cooled to room température and diluted with ethyl acetate (20 mL). The organic layer was washed with water (2x5 mL), brine (5 mL), dried over sodium sulphate, filtered and concentrated under reduced pressure. The crude material was purified using silica gel column chromatography eluting with EtOAc:hexane 10:90 to afford the title compound as an off-white solid in 49% yield, 210 mg.

’H NMR (400 MHz, DMSO-d₆) δ: 1.19 (t, 3H), 4.14 (q, 2H), 5.35 (s, 2H), 7.25-7.28 (m, 1H), 8.22 (s, 1H), 8.29 (d, 1H). 8.55 (d. 1H).

170

Préparation 134: Pyrazolo[3,4-b]pyridin-1-yl-acetic acid

To a stirred solution of pyrazolo[3,4-b]pyridin-1-yl-acetic acid ethyl ester (210 mg, 1.02 mmol) (Préparation 133) in THF (4 mL) and water (1 mL) at 0 °C was added LiOH.H₂O (129 mg, 3.06 mmol). The reaction mixture was stirred at room température for 2 hours. The pH was of the mixture was adjusted to pH 4 with 2 N aqueous hydrochoric acid and extracted with 20% isopropanol in dichloromethane (8x5 mL). The combined organics were dried over sodium sulfate, filtered and concentrated under reduced pressure to afford the title compound as an off-white solid in 40% yield, 70 mg.

¹H NMR (400 MHz, DMSO-d₆) δ: 5.22 (s, 2H), 7.25 (dd, 1H), 8.19 (s, 1H), 8.27 (dd, 1H), 8.55 (dd, 1H), 13.15 (brs, 1H); LCMS (system 9): R_t= 1.93 min; m/z 178 [M+Hf.

Préparation 135: 1-Cyclopropyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid ethyl ester

4,4,4-Trifluoro-3-oxo-butyric acid ethyl ester (16 g, 86.4 mmol) was dissolved in acetic anhydride (33.6 g, 329.6 mmol) and triethyl orthoformate (38.4 g, 260 mmol) was added to the mixture. The résultant mixture was refluxed for 18 hours. The mixture was concentrated under reduced pressure to obtain 20 g of 2-[1Ethoxy-meth-(E)-ylidene]-4,4,4-trifluoro-3-oxo-butyric acid ethyl ester as crude. This was taken in EtOH (50 mL) and added to a suspension of cyclopropyl hydrazine hydrochloride (9.95 g, 91.7 mmol) and DIPEA (28.3 ml, 166.7 mmol) in EtOH (150 mL) at -20°C. The résultant mixture was slowly warmed to room température and stirred for 16 hours. The mixture was concentrated under reduced pressure and residue formed was partitioned between EtOAc (50 mL) and water (50 mL). The organic layer was washed with 2N HCl (25 mL), water (25 mL), brine (25 mL), dried (Na₂SO₄) and evaporated in vacuo. The crude material was purified by column chromatography on silica gel (EtOAc:Hexane 5:95) to afford the title compound as off white sticky solid in 7% yield, 1.4 g.

¹H NMR (400 MHz, DMSO-D6) δ: 1.10-1.21 (m, 4H), 1.26 (t, 3H), 3.90 (m, 1H), 4.26 (q, 2H), 7.98 (s, 1H). Préparation 136: N-(5-([7-(2-([tert-butyl(dimethyl)silyl]oxy}-1,1 -dimethylethyl)-7H-pyrrolo[2,3-d]pyrimidin5-yl]carbonyl}pyridin-3-yl)-2-(3-(trifluoromethyl)phenyl]acetamide

171

Prepared according to the method described for Example 1 using (5_:aminopyridin-3-yl)[7-(2-{[tertbutyl(dimethyl)silyl]oxy}-1,1 -dimethylethyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]methanone (Préparation 38), and 3-trifluoromethylphenylacetic acid with DIPEA.

¹H NMR (400 MHz, DMSO) δ: -0.27 (s, 6H), 0.56 (s, 9H), 1.75 (s, 6H), 3.87 (s, 2H), 4.09 (s, 2H), 7.577.64

Préparation 137: (1 -Cyclopropyl-5-trifluoromethyl-1 H-pyrazol-4-yl)-methanol

A solution of 1-Cyclopropyl-5-trifluoromethyi-1H-pyrazole-4-carboxylic acid ethyl ester (Préparation 135, 1.4 g, 5.64 mmol) in dry toluene (25 mL) was cooled to -78°C and DIBAL-H (11.8 mL of 1.2 M solution in toluene, 14.1 mmol) was added dropwise to it. The reaction mixture was stirred at -78°C for 2 hours and poured into 2N HCl (10 mL). This was stirred for a further 4 hours at room température followed by extraction with EtOAc (2 x 25 mL) and the combined organic layers were washed with water (2x10 mL), brine (10 mL) dried (Na₂SO₄) and evaporated in vacuo to afford the title compound as off white solid in 100% yield, 1.2 g.

’H NMR (400 MHz, DMSO-D6) δ: 1.03-1.17 (m, 4H), 3.68-3.73 (m, 1 H), 4.42 (d, 2H), 5.15 (t, 1 H), 7.51 (s, 1H); LCMS (system 10): R_t= 2.68 min; m/z 207 [M+H]*

Préparation 138: N-(5-{[7-(2-{[tert-butyl(dimethyl)silyl]oxy}-1 ,1-dimethylethyl)-7H-pyrrolo[2,3-d]pyrimidin5-y l]carbo ny l}py ridin-3-y l)-2-(4-isopropy I-1 H-1,2,3-triazol-i -yl)acetamide.

Prepared according to the method described for Example 1 using (5-aminopyridin-3-yl)[7-(2-([tertbutyl(dimethyl)silyl]oxy}-1,1 -dimethylethyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]methanone (Préparation 38), and [4-(trifluoromethyl)-1 H-pyrazol-1-yl]acetic acid (Préparation 85) with DIPEA as base.

LCMS (System 9): R, = 3.67 min; m/z 577 [M+H]*.

Préparation 139: (1-Cyclopropyl-5-trifluoromethyl-1H-pyrazol-4-yl)-acetonitrile

A solution of (1-Cyclopropyl-5-trifluoromethyl-1 H-pyrazol-4-yl)-methanol (Préparation 137, 1.2 g, 5.82 mmol) in DCM (15 mL) was cooled to 0°C and thionyl chloride (0.85 mL, 11.7 mmol) was added. The reaction mixture was stirred at 0°C for 2 hours and diluted with DCM. The organic layer was washed with

172 water, brine and dried (Na₂SO₄) and evaporated in vacuo. The crude residue obtained was dissolved in dioxane (25 mL) and water (25 mL) and tetrabutyl ammonium bromide (1.38 g, 4.28 mmol) was added. The réaction mixture was stirred for 10 mins followed by the addition of KCN (1.28 g, 19.82 mmol) and résultant mixture was stirred for a further 16 hours at room température. The mixture was diluted with EtOAc (50 mL) and washed with water (1x10 mL), brine (1x10 mL), dried (Na₂SO₄) and evaporated in vacuo. The crude material was purified by column chromatography on silica gel (HexaneiEtOAc 10:90) to afford the title compound as light yellow solid in 56% yield, 700 mg.

¹H NMR (400 MHz, CDCI3) δ: 1.06-1.13 (m, 2H), 1.24-1.29 (m, 2H), 3.61-3.62 (m, 1H), 3.66 (s, 2H), 7.49 (s, 1H).

Préparation 140: N-(5-([7-(2-{[tert-butyl(dimethyl)silyl]oxy}-1,1-dimethylethyl)-7H-pyrrolo[2,3-d]pyrimidin5-yl]carbonyl}pyridin-3-yl)-2-quinolin-7-ylacetamide

Prepared according to the method described for Example 1 using (5-aminopyridin-3-yl)[7-(2-([tertbutyl(dimethyl)silyl]oxy}-1,1-dimethylethyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]methanone (Préparation 38), and 2-quinolin-7-ylacetic acid with DI PEA as base.

¹H NMR (400 MHz, DMSO) δ: -0.28 (s, 6H), 0.55 (s, 9H), 1.74 (s, 6H), 3.98 (s, 2H), 4.09 (s, 2H), 7.51 (m, 1H), 7.60 (m, 1H), 7.94 (m, 1H), 8.00 (s, 1H), 8.16 (s, 1H), 8.33 (m, 1H), 8.54 (m, 1H), 8.67 (s, 1H), 8.84 (m, 1H), 8.91 (s, 1H), 8.98 (s, 1 H), 9.47 (s, 1H), 10.77 (s, 1H);

LCMS (System 9): R_t = 3.72 min; m/z 595 [M+HJ*.

Préparation 141: (1-Cyclopropyl-5-triftuoromethyl-1H-pyrazol-4-yl)-acetic acid

OH

To a solution of (1-Cyclopropyl-5-trifluoromethyl-1H-pyrazoi-4-yl)-acetonitrile (Préparation 139, 700 mg, 3.25 mmol) in EtOH (15 mL) was added aqueous 1N NaOH (15 mL). The resulting solution was heated at 60°C for 16 hours. The mixture was concentrated and the residue was dissolved in water (10 mL) and washed with EtOAc. The pH of aqueous layer was adjusted to 5 using 1N.HCI and extracted with 10% IPA in DCM (4 x 30 mL). The organic layer was dried (Na₂SO₄) and evaporated in vacuo to afford the title compound as a solid in 85% yield, 650 mg.

¹H NMR (400 MHz, DMSO-D6) δ; 1.04-1.07 (m, 2H), 1.11-1.16 (m, 2H), 3.55 (s, 2H), 3.69-3.73 (m, 1H), 7.47 (s, 1H), 12.45 (br, 1H); LCMS (System 10): R_t= 1.50 min; m/z 233 [M-H]*.

Préparation 142 N-[5-({7-[(1R)-1-methyl-2-(tetrahydro-2H-pyran-2-yloxy)ethyl]-7H-pyrroloi2,3-d]pyrimidin5-yl}carbonyl)pyridin-3-yl]-2-[3-{trifluoromethyl)phenyl]acetamide

173

Prepared according to the method described above for Example 1, using (5-aminopyridin-3-yl){7-[(1 R)-1 methy!-2-(tetrahydro-2H-pyran-2-yloxy)ethyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}methanone (Préparation 36) and 3-trifluoromethylphenylacetic acid with DIPEA as base.

¹H NMR (400 MHz, DMSO-d_e) δ: 1.29-1.42 (m, 5H), 1.54 ( d, 3H), 3.50 (m, 1H), 3.71 (m, 1H), 3.86 (s, 2H), 3.93 (m, 1H), 4.05 (m, 1H), 4.44 (s, 1H), 4.58 (s, 1H), 5.17 (m, 1H), 7.56 (m, 1H), 7.63 (m, 2H), 7.72 (S, 1H), 8.47 (m, 2H), 8.70 (s, 1H), 8.96 (m, 2H), 9.45 (s, 1H), 10.72 (s, 1 H);

LCMS (System 9): R_t = 3.56 min; m/z 568 [M+H]⁺.

Préparation 143: 5-Trifluoromethyl-1H-pyrazole-4-carboxylic acid ethyl ester.

To a suspension of hydrazine hydrochloride (10 g, 147 mmol) in EtOH (500 mL), DIPEA (45.3 mL, 267 mmol) was added slowly at -20°C and stirred for 10 mins. Then 2-[1-Ethoxy-meth-(E)-ylidene]-4,4,4 trifluoro-3-oxo-butyric acid ethyl ester (Préparation 135, 32 g, 133.33 mmol) was added to above solution and the resulting mixture was stirred at room température for 16 hours. The reaction mixture was concentrated under reduced pressure and residue was partitioned between EtOAc (200 mL) and water (50 mL). The organic layer was washed with water (25 mL), dried (Na₂SO₄) and evaporated in vacuo. The crude material was purified by column chromatography on silica gel (Hexane:EtOAc 90:10) to afford the title compound as off white solid in 43% yield, 13 g.

’H NMR (400 MHz, DMSO-D6) δ: 1.26 (t, 3H), 4.25 (q, 2H), 8.57 (s, 1H), 14.10 (br s, 1H).

Préparation 144: N-[5-({7-[(1 R)- 1-methyl-2-(tetrahydro-2H-pyran-2-yloxy)ethyl]-7H-pyrrolo[2,3d]pyrim id in-5-yl}carbonyl) pyrid in-3-yl]-2-(4-isopropyl-1H-1,2,3-triazol-1 -yljacetamide

Prepared according to the method described above for Example 1, using (5-aminopyridin-3-yl){7-[(1R)-1methyl-2-(tetrahydro-2H-pyran-2-yloxy)ethyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}methanone (Préparation 36) and (4-isopropyl-1 H-1,2,3-triazol-l -yl)acetic acid with DIPEA as base.

174 ’H NMR (400 MHz, DMSO-d₆) δ: 1.22 (6H, d). 1.23-1.30 (m, 5H), 1.54(d, 3H), 3.4 (1H, m), 3.72 (m, 1 H),

3.88 (m, 1H), 3.95 (m, 1H), 4.10 (m, 1 H), 4.45 (s, 1H), 4.59 (s, 1H), 5.20 (1H, m), 5.36 (s, 2H), 7.88 (s,

1H), 8.43 (m, 1H), 8.53 (d, 1 H), 8.75 (s, 1H), 8.97 (m, 2H), 9.45 (s, 1 H), 10.96 (s, 1H);

LCMS (System 9): R_t = 2.86 min; m/z 533 [M+Hf.

Préparation 145: 1-Cyclopropyl-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid ethyl ester

Cyctopropyl boronic acid (11 g, 127 mmol), Copper acetate (17.4 g, 95.7 mmol), Pyridine (17.7 g, 223 mmol) and triethylamine (22.4 mL, 160 mmol) were added successively to a solution of 5-Trifluoromethyl1 H-pyrazole-4-carboxylic acid ethyl ester (Préparation 143, 6.63 g, 31.9 mmol) in THF (70 mL) and the resulting mixture was allowed to stir at 60°C for 36 hours. The reaction mixture was filtered over a celite bed and filtrate was concentrated in vacuo and diluted with EtOAc (200 mL). The organic layer was washed with 1N HCl (1 x 25 mL), brine (1 x 25 mL) and dried (Na₂SO₄) and evaporated in vacuo. The crude material was purified by column chromatography on silica gel (Hexane:EtOAc 85:15) to afford the title compound as brown solid in 29% yield, 2.3 g.

¹H NMR (400 MHz, CDCI3) δ: 1.08-1.14 (m, 2H), 1.17-1.21 (m, 2H), 1.33 (t, 3H), 3.62-3.67 (m, 1H), 4.30 (q, 2H), 8.01 (s, 1 H); LCMS (system 10): R, = 3.39 min; m/z 249 [M+Hf.

Préparation 146: (1 -Cyclopropyl-3-trifluoromethyl-1 H-pyrazol-4-yl)-methanol'

A solution of l-Cyclopropyl-S-trifluoromethyl-IH-pyrazole^-carboxylic acid ethyl ester (Préparation 145, 3.5 g, 14.11 mmol) in dry toluene (70 mL) was cooled to -78°C and DIBAL-H (29.4 mL of a 1.2 M solution in toluene, 35.3 mmol) was added dropwise to it. The reaction mixture was stirred at -78°C for 2 hours and then poured into 2N HCl (25 mL) followed by further stirring for 2 hours at room température. The mixture was extracted with EtOAc (2 x 50 mL) and the combined organic layers were washed with water (2x15 mL), brine (15 mL) and dried (Na₂SO₄) and evaporated in vacuo to afford the title compound as off white solid in 100% yield, 3 g.

¹H NMR (400 MHz, CDCI3) ô: 1.02-1.07 (m, 2H), 1.11-1.16 (m, 2H), 1.68 (t, 1H), 3.57-3.63 (m, 1H), 4.64 (d, 2H), 7.53 (s, 1H); LCMS (system 10): R_t = 2.57 min; m/z 207 [M+H]⁺.

Préparation 147: (1 -Cyclopropyl-3-trifluoromethyl-1 H-pyrazol-4-yl)-acetonitrile

175

The title compound was prepared according to the method described for Préparation 139 using (1Cyclopropyl-3-trifluoromethyl-1H-pyrazo!-4-yl)-methanol (Préparation 146) to afford the title compound as yellow solid in 70% yield, 2.2 g.

¹H NMR (400 MHz, DMSO-D6) δ: 0.98-1.03 (m, 2H), 1.06-1.11 (m, 2H), 3.83-3.88 (m, 1H), 3.91 (s, 2H), 8.08 (s, 1H); LCMS (System 10): R_t = 3.10 min; m/z 216 [M+Hf.

Préparation 148: (1-Cyclopropyl-3-trifluoromethyl-1H-pyrazol-4-yl)-acetic acid

The title compound was prepared according to the method described for Préparation 141 using (1Cyclopropyl-3-trifluoromethyl-1H-pyrazol-4-yl)-acetonitrile (Préparation 147) to afford the title compound as a solid in 79% yield, 1.9 g.

¹H NMR (400 MHz, DMS0-D6) δ: 0.96-1.07 (m, 4H), 3.49 (s, 2H), 3.76-3.84 (m, 1H), 7.91 (s, 1H). 12.27 (br, 1H); LCMS (system 10): R,= 1.41 min; m/z 233 [M-H]*.

Préparation 149: (7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)[5-(methylamino)pyridin-3-yi]methanone

The title compound was prepared according to the method described for Préparation 31 using (5bromopyridin-3-yl)(7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (Préparation 94) and methylamine (20 mL) in 13% yield, 78 mg.

LCMS (system 2): R_t = 0.91 min; m/z 296 [M+H]⁺

The following Préparations were prepared according to the method described above for Example 1, using (5-aminopyridin-3-yl){7-[(1R)-1-methyl-2-(tetrahydro-2H-pyran-2-yloxy)ethyl]-7H-pyrro!o[2,3-d]pyrimidin-5yljmethanone (Préparation 36) and the corresponding carboxylic acid with DI PEA. Ail carboxylic acids are commercially available unless otherwise mentioned.

176

Préparation	Name	R1^	Data
150	N-[5-({7-[(1 R)- 1-methyl-2(tetrahydro-2H-pyran-2yloxy)ethyl)-7H-pyrrolo[2,3d]pyrimidin-5-yl}carbonyl)pyridin-3y IJ-2-[1 -isopropyl-5- (t rifluorometh yl)-1 H-pyrazol-4- yl] acetamide	P Me Χλ“·	LCMS (System 9): R( = 3.24 min; m/z 600 [M+Hf Using (Prep 185).
151	2-(4-cyanophenyl)-N-[5-({7-[(1R)- 1-methyl-2-(tetrahydro-2H-pyran-2yloxy)ethyl]-7H-pyrrolo[2,3d]pyrimidin-5-yl}carbonyl)pyridin-3yl] acetamide	XX	LCMS (System 9): Rt = 2.94 min; m/z 525 [M+H]*,
152	N-[5-«7-({1 R)- 1-methyl-2(tetrahydro-2H-pyran-2yloxy)ethyl]-7H-pyrrolo[2,3d]pyrimidin-5-yl}carbonyl)pyridin-3yl]-2-[3- (methylsulfonyl)phenyl]acetamide	Xl •f	LCMS (System 9): Rt = 2.82 min; m/z 578 [M+H]+
153	N-[5-({7-[(1R)- 1-methyl-2- (tetrahydro-2H-pyran-2yloxy)ethyl]-7H-pyrrolo[2,3d]pyrimidin-5-yl}carbonyl)pyridin-3yl]-2-quinolin-7-ylacetamide	XÔ	LCMS (System 9): Rt = 2.97 min; m/z 551 [M+H]+.

Préparation 154: Ethyl (2-cyclopropyl-1,3-oxazol-4-yl)acetate

Ethyl 4-chloroacetoacetate (20,0 g, 122.0 mmol) was added to cyclopropanecarboxamide (3.52 g, 41.5 mmol) in toluene (100 mL) and 1,4-dioxane (100 mL). The mixture was refluxed at 120°C for 17 hours

177 then evaporated in vacuo. The crude solid was purified by column chromatography on silica gel (80:20 petroleum ether: EtOAc) to afford the title compound as a white solid in 50% yield, 4.00 g.

¹H NMR (300 MHz, DMSO-d₆) δ: 0.80-1.00 (m, 4H), 1.20 (t, 3H), 2.10 (m, 1 H), 3.50 (S, 2H), 4.10 (q, 2H), 7.80 (s, 1 H).

Préparation 155: (2-Cyclopropyl-1,3-oxazol-4-yl)acetic acid

Lithium hydroxide monohydrate (7.83 g, 186.7 mmol) was added to ethyl (2-cyclopropyl-1,3-oxazol-4yl)acetate (Préparation 154, 7.00 g, 35.9 mmol) in THF (200 mL) and water (100 mL). The mixture was stirred at room température for 2 hours then the reaction mixture volume was reduced to one third by évaporation in vacuo. The aqueous residue was acidified using aqueous HCl (1.0 M) then extracted with EtOAc (200 mL). The organic phase was evaporated in vacuo and the crude material was triturated with diethyl ether (100 mL) to afford the title compound as a white solid in 66% yield, 4.00 g.

'H NMR (300 MHz, CDCI_a) δ: 1.05 (m,4H), 2.10 (m, 1 H), 3.60 (s, 2H),7.40 (s, 1H), 10.00 (brs, 1H). Préparation 156: Methyl [2-(vinyloxy)phenyl]acetate

Copper acetate (1.42 g, 7.82 mmol) was added to DCM (6 mL) and stirred for 20 minutes, with a drying tube attached. Trivinylcycloboroxane (1.24 g, 5.16 mmol), césium carbonate (2.55 g, 7.82 mmol) and methyl 2-hydroxyphenyl acetate (1.30 g, 7.82 mmol) were added and the mixture stirred at room température for 17 hours. Saturated aqueous sodium bicarbonate (25 mL) was added and the mixture was extracted with DCM (20 mL). The organic phase was filtered, dried over magnésium sulphate and evaporated in vacuo to afford the title compound as a black oil in 52% yield, 784 mg. This material was used crude in subséquent steps.

¹H NMR (400 MHz, CDCI₃) δ: 3.67 (s, 2H), 3.39 (s, 3H), 4.40 (dd, 1H), 4.69 (dd, 1H), 6.59 (dd, 1H), 6.977.08 (m, 2H), 7.23-7.28 (m, 2H).

Préparation 157: Methyl [4-(vinyloxy)phenyl]acetate

MeO

178

The title compound was prepared according to the method described for Préparation 156 using methyl 4 hydroxyphenyl acetate to afford the title compound as a colourless oil in 70%-yield, 914 mg.

¹H NMR (400 MHz, CDCI₃) δ: 3.58 (s, 2H), 3.39 (s, 3H), 4.42 (m, 1H), 4.75 (m, 1H), 6.62 (m, 1H), 6.946.97 (m, 2H), 7.21-7.24 (m, 2H).

Préparation 158: Methyl [3-(vlnyloxy)phenyl]acetate

The title compound was prepared according to the method described for Préparation 156 using methyl 3hydroxyphenyl acetate to afford the title compound as a colourless oil in 56% yield, 835 mg.

’H NMR (400 MHz, CDCI₃) δ; 3.61 (s, 2H), 3.70 (s, 3H). 4.44 (m. 1H), 4.78 (m, 1H), 6.63 (m, 1H), 6.896.94 (m, 2H), 7.00 (m, 1H), 7.27 (m, 1H).

Préparation 159: Methyl [5-(vinyloxy)pyridin-3-yl]acetate

The title compound was prepared according to the method described for Préparation 156 using methyl (5-hydroxypyridin-3-yl)acetate to afford the title compound as a yellow oil in 25% yield, 76 mg.

LCMS (system 2): R_t = 0.85 min; m/z 194 [M+Hf.

Préparation 160: [2-(Cyclopropyloxy)phenyl]acetic acid

Diethyl zinc (2.34 mL, 2.34 mmol, 1M in heptane) was cooled to 0°C under nitrogen then chloroiodomethane (0.35 mL, 4.68 mmol) in DCE (1 mL) was added drop-wise. The mixture was stirred under nitrogen at 0°C for 20 minutes then methyl [2-(vinyloxy)phenyl]acetate (Préparation 156, 150 mg, 0.78 mmol) in DCE (1 mL) was added. The reaction mixture was stirred at 0°C for 30 minutes then stirred at room température for 17 hours. Saturated aqueous ammonium chloride (10 mL) was added and the

179 mixture was extracted with DCM (4x8 mL). The combined organic phases were dried over magnésium sulphate and evaporated in vacuo. Sodium hydroxide (3.28 mL, 3.28 mmol, 1 M) was added to the residue in THF (3 mL). The mixture was heated at 80°C for 17 hours then evaporated in vacuo. Hydrochloric acid (10 mL, 1M) was added to the residue then extracted with EtOAc (10 mL). The organic phase was evaporated in vacuo to afford the title compound as a yellow oil in 53% yield, 83 mg.

’H NMR (400 MHz, CDCI₃) δ: 0.65-0.71 (m, 4H), 3.54 (s, 2H), 3.71 (m, 1H), 6.82-6.87 (m, 2H), 7.05-7.23 (m, 2H).

Préparation 161: [4-(Cyclopropyloxy)phenyl]acetic acid

O

OH

Prepared according to the method described for Préparation 160 using methyl [4(vinyloxy)phenyl]acetate (Préparation 157) to afford the title compound as a colourless oil in 44% yield, 360 mg.

’H NMR (400 MHz, CDCI₃) δ: 0.65-0.71 (m, 4H), 3.59 (s, 2H), 3.71 (m, 1H), 6.99-7.02 (m, 2H), 7.16-7.20 (m, 2H).

Préparation 162: [3-(Cyclopropyloxy)phenyl]acetic acid

The title compound was prepared according to the method described for Préparation 160 using methyl [3-(vinyloxy)phenyl]acetate (Préparation 158) to afford the title compound as a colourless oil in 33% yield, 50 mg.

’H NMR (400 MHz, CDCI₃) 5:0.74-0.81 (m, 4H), 3.57-3.67 (m, 2H), 3.72 (m, 1H), 6.74-7.03 (m, 3H), 7.22 (m, 1H).

180

Préparation 163: [5-(Cyclopropyloxy)pyridin-3-yl]acetic acid

The title compound was prepared according to the method described for Préparation 160 using methyl [5-(viny!oxy)pyridin-3-yl]acetate (Préparation 159) to afford the title compound as a yellow oil in 38% yield, 28 mg.

LCMS (System 2): R₍ = 0.55 min; m/z 194 [M+H]⁺.

Préparation 164: [4-Cyano-3-(trifluoromethyl)phenyl]acetic acid

O

N

Lithium diisopropylamide (13.8 mL, 24.8 mmol, 1.8M in THF) vvas added to 4-methyl-2(trifluoromethyl)benzonitrile (2.30 g, 12.4 mmol) in THF (20 mL) at -78°C and stirred for 5 minutes at 78°C. Excess solid carbon dioxide was added then the mixture was stirred at room température for 17 hours. Saturated aqueous ammonium chloride (10,5 mL) and EtOAc (20 mL) were added then the aqueous layer was acidified with HCl acid solution (1 M). This was extracted with EtOAc (3x15 mL) and the combined organic phases were dried over sodium sulphate and evaporated in vacuo to afford the title compound as a brown oil in 88% yield, 2.52 g.

¹H NMR (400 MHz, CDCI₃) δ: 3.81 (s, 2H), 7.62 (d, 1H), 7.73 (s, 1H), 7.83 (d, 1H).

Préparation 165: (2-Methylquinolin-7-yl)acetic acid

Crotonic aldéhyde (33.0 mL, 0.40 mol) was added to 3-aminophenylacetic acid (30.0 g, 0.20 mmol) in concentrated hydrochloric acid (400 mL) and toluene (100 mL) at 110°C. The mixture was heated at 110°C for 90 minutes. The aqueous layer was separated, washed with diethyl ether (350 mL) then neutralised with aqueous ammonia. The aqueous solution was washed with chloroform (3 x 500 mL) and the organic phase was evaporated in vacuo. The solid residue was refluxed with chloroform (900 mL) and methanol (100 mL) then the solution was decanted and purified by column chromatography on silica gel

181 (gradient of chloroform:MeOH 9:1 to 4:1) to afford a mixture of isomeric acids. This was purified by fractional crystaliisation using isopropanol to afford the title compound as a white solid in 12% yield, 4.90 g.

¹H NMR (400 MHz, DMSO-d6) δ: 2.64 (s, 3H), 3.78 (s, 2H), 7.37 (d. 1H), 7.44 (dd, 1H), 7.80 (s, 1H), 7.84 (d, 1H), 8.19 (d, 1H), 12.40 (brs, 1H).

Préparation 166: Ethyl (3-isopropyl-5-methyl-1H-pyrazol-1-yl)acetate

Ethyl bromoacetate (1.00 mL, 9.03 mmol) was added to 5-isopropyl-3-methyl-1H-pyrazole (1.07 g, 8.60 mmol) and potassium carbonate (3.57 g, 25.9 mol) in DMF (10 mL). The mixture was stirred at room température for 17 hours then EtOAc (20 mL) and aqueous HCl (20 mL, 1 M) were added. The organic phase was dried over magnésium sulphate then evaporated in vacuo. The residue was purified by column chromatography on silica gel (hexane:EtOAc 4:1) to afford the title compound as a yellow oil in 34% yield, 607 mg.

¹H NMR (400 MHz, CDCI₃) δ: 1.26 (m, 9H), 2.03 (s, 3H), 2.96 (m, 1H), 4.21 (q, 2H), 4.78 (s, 2H), 7.13 (s, 1H).

Préparation 167: (3-lsopropyl-5-methyl-1 H-pyrazol-1-yl)acetic acid

Lithium hydroxide (342 mg, 8.15 mmol) in water (4 mL) was added to ethyl (3-isopropyl-5-methyl-1Hpyrazol-1-yl) acetate (Préparation 166, 571 mg, 2.72 mmol) in methanol (4 mL) and the mixture was stirred at room température for 30 minutes. Aqueous hydrochloric acid (2 M) was added to acidify the mixture then the solution was extracted with EtOAc (10 mL). The organic phase was dried over magnésium sulphate and evaporated in vacuo to afford the title compound as a cream solid in 66% yield, 328 mg.

m/z 183 [M+Hf.

Préparation 168: Ethyl (6-chloro-1H-indazol-3-yl)acetate

182

Concentrated sulphuric acid (0.25 mL) was added to a solution of 2-(6-οΐΊΐθΓθ-1Η-ίη03ΖθΙ-3-νΙ)8θθΙίο acid (2.024 g, 9.60 mmol) in EtOH (10 mL). The mixture was heated at 80°C for 4 hours then evaporated in vacuo. The residue was partitioned between EtOAc (30 mL) and 5% aqueous sodium bicarbonate (30 mL). The organic phase was dried over sodium sulphate, evaporated in vacuo and purified by column chromatography on silica gel (DCM:MeOH 99:1) to afford the compound 3 as a white solid in 83% yield, 1.90 g.

¹H NMR (400 MHz, DMSO-d₆) δ.' 1.17 (t, 3H), 4.00 (s, 2H), 4.10 (q, 2H), 7.11 (d, 1H), 7.56 (s, 1H), 7.74 (d, 1H), 13.00 (s. 1H).

Préparation 169: Ethyl (6-chloro-1-methyl-1/7-indazol-3-yl)acetate

Sodium hydride (24 mg, 0.602 mmol, 60% in oil) was added to ethyl (6-chloro-1/7-indazol-3-yl)acetate (Préparation 168,120 mg, 0.502 mmol) in THF (4 mL) at 0°C and the mixture was stirred for 30 minutes. Then iodomethane (0.09 mL, 1.508 mmol) was added. The mixture was stirred at room température for 30 mins then water (4 mL) was added. The mixture was evaporated in vacuo and the aqueous residue was acidified with aqueous HCl (6 M). This was extracted with ethyl acetate (10 mL) and the organic phase was dried over sodium sulphate and evaporated in vacuo to afford the title compound as a white solid in 100% yield, 150 mg.

¹H NMR (400 MHz, DMSO-d₆) δ: 1.18 (t, 3H), 3.89 (s, 3H), 4.07 (s, 2H), 4.13 (q, 2H), 7.15 (d, 1H), 7.56 (s, 1H), 7.74 (d, 1H);

LCMS (System 9): R_t =3.48 min; m/z 253 [M+H]⁺.

Préparation 170: (6-Chloro-1-methyl-1H-indazol-3-yl)acetic acid

Me

Aqueous potasium hydroxide (5.93 mL, 10%) was added to ethyl (6-chloro-1-methyl-1H-indazol-3yl)acetate (Préparation 169, 1.78 g, 0.704 mol) in MeOH (30 mL). The mixture was stirred for 1 hour at 25°C then the methanol was evaporated in vacuo. The aqueous residue was washed with diethyl ether (30 mL) then acidified with aqueous HCl (6 M). The mixture was extracted with ethyl acetate (30 mL) and the organic phase was dried over sodium sulphate, evaporated in vacuo and purified by column chromatography on silica gel (DCM:MeOH 95: 5 ) to afford the title compound as a white solid in 56% yield, 865 mg.

¹H NMR (400 MHz, DMSO-d6) δ: 3.79 (s, 2H), 4.14 (s, 3H), 7.12 (d, 1H), 7.73 (d, 1H), 7.83 (s, 1H). 12.51 (s, 1H).

183

Préparation 171: Ethyl (5-fluoro-1H-indazol-1-yl)acetate

The title compound was prepared according to the method described for Préparation 93 using 5-fluoro1/7-indazole and ethyl bromoacetate to afford the title compound as an off- white solid in 53% yiefd, 260 mg.

¹H NMR (400 MHz, CDCI₃) δ: 1.24 (t, 3H), 4.22 (q, 2H), 5.13 (s, 2H), 7.17 (m, 1H), 7.28 (m, 1 H), 7.37 (d, 1H), 7.99 (s, 1H); LCMS (System 9): R_t= 3.14 min; m/z 223 [M+H]⁺.

Préparation 172: (5-Fluoro-1 H-indazol-1-yl)acetic acid

The title compound was prepared according to the method described for Préparation 155 using ethyl (5fluoro-1H-indazol-1-yl)acetate (Préparation 171) to afford the title compound as a yellow solid in 62% yîeld, 140 mg.

¹H NMR (400 MHz, DMSO-d_G) δ: 5.26 (s, 2H), 7.28 (m, 1H), 7.54 (dd, 1H), 7.68 (dd, 1H), 8.06 (s, 1H), 13.11 (br s, 1 H).

LCMS (System 9): R_t= 1.49 min; m/z 193 [M-H]‘

Préparation 173: Ethyl (5-fluoro-2H-indazol-2-yl)acetate

The title compound was prepared according to the method described for Préparation 93 using 5-fluoro1/-/-indazole and ethyl bromoacetate to afford the title compound as an off- white solid in 27% yield, 130 mg.

’H NMR (400 MHz, CDCI₃) δ: 1.26 (t, 3H). 4.25 (q, 2H), 5.17 (s, 2H), 7.06-7.11 (m, 1H). 7.21-7.24 (m,

1H), 7.64-7.68 (m, 1 H), 7.96 (s, 1H); LCMS (System 9); R₍= 3.04 min; m/z223 [M+H]⁺

Préparation 174:(5-Fluoro-2H-indazol-2-yl)acetic acid

184

The title compound was prepared according to the method described for Préparation 155 using ethyl (5fluoro-2H-indazol-2-yl)acetate (Préparation 173) to afford the title compound as a yellow solid in 100% yield, 160 mg.

LCMS (System 9): R, = 1.49 min; m/z 193 [M-H]'

Préparation 175: Ethyl (7-fluoro-1H-indazol-1-yl)acetate

The title compound was prepared according to the method described for Préparation 93 using 7-fluoro1H-indazole and ethyl bromoacetate to afford the title compound as an off- white solid in 41% yield, 200 mg.

’H NMR (400 MHz, CDCI₃) δ; 1.29 (t, 3H), 4.22 (q, 2H), 5.28 (s, 2H), 6.98-7.07 (m, 2H), 7.49 (m, 1H), 8.02 (d, 1H).

Préparation 176: (7-Fluoro-1H-indazol-1-yl)acetic acid

The title compound was prepared according to the method described for Préparation 155 using ethyl (715 fluoro-1H-indazol-1-yl)acetate (Préparation 175) to afford the title compound as a yellow solid in 68% yield, 120 mg.

¹H NMR (400 MHz, DMSO-d₆) δ.* 5.27 (s, 2H), 7.12 (m, 1H), 7.23 (m, 1H). 7.60 (d, 1H), 8.17 (d, 1H), 13.18 (brs, 1H); LCMS (System 9):

R_t= 1,38 min; m/z 195 [M+H]*

Préparation 177: Ethyl (7-fluoro-2H-indazol-2-yl)acetate

The title compound was prepared according to the method described for Préparation 93 using 7-fluoro1/7-indazole and ethyl bromoacetate to afford the title compound as an off- white solid in 35% yield, 175 mg.

’H NMR (400 MHz, CDCI3) δ; 1.28 (t, 3H), 4.25 (q, 2H), 5.28 (s, 2H), 6.93 (m, 1 H), 6.99 (m, 1 H), 7.43 (d, 1 H), 8.06 (d, 1H).

185

Préparation 178: (7-Fluoro-2H-indazol-2-yl)acetic acid

The title compound was prepared according to the method described for Préparation 155 using ethyl (7fluoro-2H-indazol-2-yl)acetate (Préparation 177) to afford the title compound as a yellow solid in 75% yield, 110 mg.

’H NMR (400 MHz, DMSO-d₆) δ: 5.34 (s, 2H), 6.97-7.05 (m, 2H), 7.56 (d, 1Ή), 8.50 (d, 1H), 13.30 (br s, 1H); LCMS (System 9): R_t= 1.40 min; m/z 195 [M+H]⁺

Préparation 179: Ethyl 1/7-pyrazolo[3,4-b]pyridin-1-ylacetate

The title compound was prepared according to the method described for Préparation 93 using 1/7pyrazolo[3,4-ù]pyridine and ethyl bromoacetate to afford the title compound as an off- white solid in 49% yield, 210 mg.

’H NMR (400 MHz, DMSO-d_e) δ: 1.19 (t, 3H), 4.14 (q, 2H), 5.35 (s, 2H), 7.27 (m, 1H), 8.27 (s, 1H), 8.29 (d, 1H),8.55(d, 1H).

Préparation 180: 1/7-Pyrazolo[3,4-ù]pyridin-1-ylacetic acid

The title compound was prepared according to the method described for Préparation 155 using ethyl 1/7pyrazolo[3,4-£>]pyridin-1-ylacetate (see Préparation 179) to afford the title compound as a yellow solid in 40% yield, 70 mg.

’H NMR (400 MHz, DMSO-d₆) δ: 5.22 (s, 2H), 7.25 (dd, 1H), 8.19 (s, 1H). 8.27 (dd, 1H), 8.55 (dd, 1H), 13.15 (brs, 1H).

Préparation 181: tert-Butyl 1/7-indazo!-6-y!acetate

186

6-Bromo-1H-indazole (1.3 g, 6.6 mmol) and t-butylacetate (1.33 mL, 9.9 mmol) in toluene (20 mL) were degassed with argon tor 15 mins. Then the mixture was cooled to 0°C and LiHMDS (16.5 mL, 16.5 mmol, 1M in hexane) was added dropwise. Bis(dibenzylideneacetone)palladium (380 mg, 0.66 mmol) and tri-tbutyl phosphine tetrafluoroborate (383 mg, 1.32 mmol) were added and the mixture was stirred at 10°C for 2 hours. The mixture was quenched with water (10 mL) then extracted with EtOAc (3 x 25 mL). The combined organic phases were washed with water (2x10 mL), brine (10 mL) and dried over sodium sulphate (Na₂SO4). The filtrate was evaporated in vacuo and purified by column chromatography on silica gel (hexane:EtOAc 80:20) to afford the title compound as a white solid (65%, 1.00 g).

¹H NMR (400 MHz, CDCI₃) δ: 1.43 (s, 9H), 3.64 (s, 2H), 7.08 (dd, 1H), 7.39 (s, 1H), 7.69 (d, 1H), 8.03 (s, 1H), 10.05 (brs, 1H).

Préparation 182: 1H-lndazol-6-ylacetic acid

Hydrochloric acid (10 mL, 4 M in 1.4 dioxane) was added to tert-butyl 1H-indazof-6-ylacetate (Préparation 181, 1.00 g, 4.3 mmol) in 1,4 dioxane (5 mL) at 0°C and the mixture was stirred at room température for 16 hours. The mixture was evaporated in vacuo and the residue was triturated with dry etherto afford the title compound as a white solid in 100% yield, 800 mg.

¹H NMR (400 MHz, CDCI₃) δ: 3.69 (s, 2H), 7.00 (d, 1H), 7.41 (s, 1H), 7.67 (d, 1H), 8.02 (s, 1 H), 12.81 (br s, 1H).

Préparation 183: [1-lsopropyl-5-(trifluoromethyl)-1H-pyrazol-4-yl]methanol

Me

Me—ζ

Diisobutylaluminium hydride (99 mL, 120 mmol, 1.2 M solution in toluene) was added to ethyl 1-isopropyl5-(trifluoromethyl)-1H-pyrazole-4-carboxylate (WO 2007071900, 12 g, 48 mmol) in toluene (220 mL) at 78C . The réaction mixture was stirred at -78°C for 2 hours then poured into aqueous HCl (100 mL, 2 M). The mixture was stirred for 4 hours at room température then extracted with EtOAc (400 mL). The organic phase was washed with water (200 mL), brine (200 mL) and dried over sodium sulphate. The filtrate was evaporated in vacuo to afford the title compound as a colourless oil in 100% yield, 10.5 g.

¹H NMR (400 MHz, CDCI₃) δ: 1.51 (d, 6H), 4.57-4.66 (m, 3H), 7.58 (s, 1H).

’H NMR (400 MHz, CDCI3) &: 1.26 (s, 4H), 3.83 (s, 2H), 6.47 (d, 1H), 7.26 (d, 1H), 8.83 (s, 1H), 8.88 (s, 1H); LCMS (system 10): R_t= 1.67 min; m/z 189.9 [M+Hf.

Préparation 184: [1 -lsopropyl-5-(trifluoromethyl)-1 H-pyrazol-4-yl]acetonitrile

187

Thionyl chloride (5.26 mL, 72 mmol) was added to [l-isopropyl-ô-itrifluoromethylJ-IH-pyrazol^yljmethanol (Préparation 183, 7.5 g, 36 mmol) in DCM (75 mL) at 0 °C and the mixture was stirred for 2 hours. The mixture was diluted with DCM (30 mL) and the organic phase was washed with water (75 mL), brine (75 mL) and dried over sodium sulphate. The filtrate was evaporated in vacuo to afford 4(0ΐιΙθΓθπιβΙΐΊνΙ)-1-ί8ορΓορνΙ-5-(ΐΓίίΙυοΓθΓηβΙήν1)-1Η-ρνΓ3ΖθΙθ in 86% yield, 7 g.

Tetrabutyl ammonium bromide (7.95 gm, 24.7 mmol) was added to 4-(chloromethyl)-1-isopropyl-5(trifluoromethyl)-1/7-pyrazole (7 g, 31 mmol) in dioxane (75 mL) and water (75 mL) and the mixture was stirred for 10 min. Potassium cyanide (7,42 g, 114 mmol) was added and the mixture was stirred for 16 hours at room température. The mixture was diluted with EtOAc (100 mL) then the organic phase was washed with water (100 mL), brine (100 mL) and dried over sodium sulphate. The filtrate was evaporated in vacuo and purified by column chromatography on silica gel (hexane:EtOAc 90:10) to afford the title compound as a white solid in 100% yield, 7.00 g.

¹H NMR (400 MHz, DMSO-d₆) δ: 1.43 (d, 6H), 3.99 (s, 2H), 4.61 (m, 1H), 7.71 (s. 1H).

Préparation 185: [1-lsopropyl-5-(trifluoromethyl)-1H-pyrazol-4-yl]acetic acid

OH

Aqueous sodium hydroxide (150 mL of a 1 M solution) was added to [l-isopropyl-S-ttrifluoromethylJ-l/-/pyrazol-4-yl]acetonitrile (Préparation 184, 6.2 g, 28.6 mmol) in EtOH (150 mL) and the mixture was heated at 60 °C for 16 hours. The mixture was evaporated in vacuo and the residue was dissolved in water (50 mL) then washed with EtOAc (100 mL). The aqueous phase was acidified to pH 5 using 1N HCl and extracted with 10% IPA in DCM (4 x 100 mL). The combined organic phases were dried over sodium sulphate and evaporated in vacuo to afford the title compound as a white solid in 75% yield, 5,0 g.

'H NMR (400 MHz, DMSO-d₆) δ: 1.42 (d, 6H), 3.56 (s, 2H), 4.58 (m, 1H), 7.57 (s, 1H), 12.28 (brs, 1H). Préparation 186: (5-Amino-pyridin-3-yl)-{7-(2-methoxy-1,1-dimethyl-ethyl)-7H-pyrrolo[2,3-d]pyrimidin-5yl]-methanone

188

The title compound was prepared according to the method described for Préparation 65 using (5-Bromopyridin-3-yl)-[7-(2-methoxy-1,1-dimethyl-ethyl)-7H-pyrroio[2,3-d]pyrimidin-5-yl]-methanone (Préparation 263) to afford the title compound as off white solid in 41% yield, 650 mg.

’H NMR (400 MHz. DMSO-D6) δ 1.76 (s, 6H), 3.19 (s, 3H), 3.96 (s, 2H), 5.65 (s, 2H), 7.30 (s, 1 H), 8.05 (s, 1H), 8.16 (s, 2H), 8.97 (s, 1H), 9.44 (s, 1H); LCMS (system 10): R, = 2.56 min; m/z 327 [M+Hf. Préparation 187: (7-tert-Butyl-7H-pyrrolo[2,3’d]pyrimidin-5-yl)-(5-methylamino-pyridin-3-yl)-methanone

[5-(7-tert-Butyl-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-pyridin-3-yl]-methyl-carbamic acid tert-butyl ester (Example 542) was treated with 4N HCl in Dioxane at room température for 2 hours. The solvent was removed in vacuo and the solid obtained was triturated with diethyl ether to afford the title compound as white solid in 100% yield, 76 mg.

¹H NMR (400 MHz, DMSO-D6) δ: 1.80 (s, 9H), 2.84 (s, 3H), 7.27 (br s, 1 H), 8.21 (d, 1H), 8.29 (s. 1H), 8.41 (s, 1H), 9.03 (s, 1H), 9.49 (s, 1H); LCMS (System 10): R, = 2.74 min; m/z 310 [M+Hf.

Préparation 188:1,5-naphthyridin-3-ylacetic acid

A mixture of 3-bromo-1,5-naphthyridine (540 mg, 2.58 mmol), diethylmalonate (0.8 mL, 5.17 mmol) and césium carbonate (2.53 g, 7.75 mmol) in 1,4-dioxane (6 mL) was degassed with argon for 15 min then picolinic acid (64 mg, 0.517 mmol) and Cul (50 mg, 0.258 mmol) was added. The mixture was heated in a sealed tube at 110 °C for 24 hours then cooled to room température, diluted with ethyl acetate (10 mL), washed with water (10 mL) and brine (10 mL). The organic phase was dried over sodium sulphate then evaporated in vacuo and purified by column chromatography on silica gel (hexane:EtOAc 70:30) to afford 450 mg of ethyl 1,5-naphthyridin-3-ylacetate.

Sodium hydroxide (10 mL, 2.0 M) was added to ethyl 1,5-naphthyridïn-3-ylacetate in 1,4-dioxane (10 mL) and the mixture was heated at 100 °C for 6 hours. The reaction mixture was cooled to room température

189 and acidified to pH 4 using aqueous 2M HCl and then evaporated in vacuo. The residue was azeotroped with toluene (2x15 mL) then dissolved in THF (50 mL) and stirred at 40 °C for 30 min. The mixture was filtered, the fiitrate was evaporated in vacuo and the residue was triturated with diethyl ether to afford the title compound as an off white solid, 200 mg.

’H NMR (400 MHz, DMSO-d₆) δ: 3.94 (s, 2H), 7.76 (m, 1H), 8.31 (s, 1H), 8.42 (d, 1H), 8.91 (d, 1H), 8.99 (dd, 1H), 12.65 (brs, 1H); LCMS (System 10): R_t = 1.49 min; m/z 187 [ M-H]⁺

Préparation 189: Tert-butyl 1H-pyrazolo[4,3-b]pyridin-1-ylacetate

Tert-butyl bromoacetate (0.55 mL, 3.69 mmol) was added to 1 H-pyrazolo[4,3-b]pyridine (220 mg, 1.85 mmol) and Cs₂CO₃ (723mg, 2.22 mmol) in anhydrous DMF (7 mL). The mixture was stirred at room température for 1 hour. The reaction mixture was diluted with ethyl acetate (50 mL), washed with water (3 x 30 mL), brine (30 mL), dried over sodium sulphate, evaporated in vacuo and purified by column chromatography on silica gel (hexane:EtOAc 80:20) to afford a colourless gum in 51% yield, 220mg.

¹H NMR (400 MHz, DMSO-D₆) δ: 1.39 (s, 9H), 5.32 (s, 2H), 7.42 (dd, 1H), 8.14 (d, 1H), 8.32 (s, 1H), 8.55 (d, 1H).

Préparation 190:1/7-Pyrazolo[4,3-b]pyridin-1-ylacetic acid

Tert-butyl 1H-pyrazolo[4,3,b]pyridin-1-ylacetate (Préparation 189, 220 mg, 0.944 mmol) was dissolved in HCl (4 mL, 4.0 M in 1,4 dioxane) and stirred under nitrogen at room température for 4 hours. The mixture was evaporated in vacuo and the residue was triturated with anhydrous diethyl ether to afford the title compound as an off white solid in 60% yield, 120mg.

’H NMR (400 MHz, DMSO-D₆) δ: 5.36 (s, 2H), 7.51 (dd, 1H), 8.30 (d, 1H), 8.36 (s, 1H), 8.62 (d. 1H); LCMS (System 10): R_t = 1.39 min; m/z 176 [ M-H]⁺.

Préparation 192: 2-(3-formylphenyl)-N-(5-[(7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)carbonyl]pyridin-3yl}acetamide

190

Dess Martin Periodinane (392 mg, 0.93 mmol) was added to a solution of (2-[3-(hydroxymethyl)phenyl]-N{5-[(7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)carbonyl]pyridin-3-yl}acetamide (Préparation 193, 265 mg, 0.62 mmol) in dichloromethane (15 mL) and the mixture was stirred at room température for 18 hours.

Water (10 mL) was added and the aqueous layer extracted with a 95:5 mixture of dichloromethane/methanol (3x10 mL). The combined organic layers were dried over magnésium sulfate and concentrated in vacuo. The residue was purified by column chromatography using silica gel (gradient of dichloromethane to dichloromethane/methanol (10:1 to 9:1) to afford the title compound as a brown solid in 80% yield, 211 mg.

LCMS (System 4): R, = 2.11 min; m/z 428 [M+Hf.

Préparation 193: 2-[3-(hydroxymethyl)phenyl]-N-{5-[(7-isopropyl-7H-pyrrolQ[2,3-d]pyrimidin-5yl)carbonyl]pyridin-3-yl}acetamide

A mixture of (5-aminopyridin-3-yl)(7-isopropyl-7H-pyrrolo[2,3-d]pyrim!din-5-yl)methanone (Préparation 95,

250 mg, 0.89 mmol), [4-(hydroxymethyl)phenyl]acetic acid (177 mg, 1.06 mmol) and HATU (505 mg, 1.33 mmol) in pyridine (7 mL) was stirred at 50 °C for 3 hours, then at room température for 18 hours. The mixture was concentrated in vacuo and azeotroped with toluene. The residue was purified by column chromatography using silica gel (gradient of dichloromethane to dichloromethane/methanol (10:1 to 9:1) 20 to afford the title compound as a gum. This material was dissolved in a 9:1 mixture of dichloromethane/methanol (1.5 mL) and added dropwise to diethyl ether (100 mL), the resulting precipitate was filtered off and dried in vacuo to afford the title compound as a white solid, 412 mg, which was used crude in subséquent reactions.

LCMS (System 2): R, = 1.33 min; m/z 430 [M+Hf.

191

Préparation 194: (5-((Diphenylmethylene)amino)pyridin-3-yl)(7H-pyrrolo[2,3-dlpyrimidin-5-yl)methanol

A mixture of 7H-pyrrolo[2,3-d]pyrimidine (Préparation 202, 953 mg, 8.0 mmol), 5[(diphenylmethylene)amino]nicotinaldehyde (Préparation 106, 3340 mg, 11.7 mmol) and KOH (1350 mg, 24 mmol) in MeOH (16 mL) was stirred for 16 hours at room température. The reaction was neutralized with saturated aqueous ammonium chloride solution and the mixture was extracted with EtOAc (3 x 200 mL). The combined organic layers were dried over sodium sulfate and concentrated in vacuo to obtain a crude residue. The crude material was purified by column chromatography on silica gel (EtOAc:MeOH = 100:0 to 80:20,) to give the desired compound as a solid in 62% yield, 2003 mg.

1H NMR (400 MHz, DMSO-d6) δ: 5.88-5.99 (m, 2H), 6.96-6.99 (m, 1H), 7.04-7.14 (m, 3H), 7.16-7.27 (m, 3H), 7.43-7.51 (m, 2H), 7.51-7.58 (m, 1H), 7.64-7.69 (m,2H), 7.89 (d, 1H), 8.21 (d, 1H), 8.72 (s, 1H), 8.73 (s, 1 H), 11.92 (brs, 1H)

Préparation 195: (5-((Diphenylmethylene)amino)pyridin-3-yl)(7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone

To a stirred solution of (5-((Diphenylmethylene)amino)pyridin-3-yl)(7H-pyrrolo[2,3-d]pyrimidin-5yl)methanol (Préparation 194, 1820 mg, 4.5 mmol) in MeCN (45 mL) was added MnO₂ (1960 mg, 22.5 mmol) portionwise and the resulting mixture stirred at 50 °C overnight. Another portion of MnO_z (1960 mg, 22.5 mmol) was added to the reaction and the mixture heated to reflux for 5 hr. After cooling to room température, the reaction mixture was filtered through a pad of arbocel, the filter cake rinsed with DCM (100 mL) and the resulting filtrate concentrated in vacuo. The resulting material was purified by column chromatography on silica gel (gradient of EtOAc:MeOH 100:0 to 90:10) to give the desired compound as a solid in 61% yield, 1120 mg.

192

1H NMR (400 MHz, DMSO-d6) Ô: 7.24-7.33 (m, 2H), 7.37-7.64 (m, 7H), 7.64_;7.78 (m, 3H), 8.28 (d, 1H),

8.53 (d, 1 H), 8.94 (s, 1 H), 9.41 (s, 1H), 13.09 (brs, 1H)

Préparation 196: (5-aminopyridin-3-yl){7-[2-{[tert-butyl(dimethyl)silyl]oxy}-1 -({[tertbutyl(dimethyl)silyl]oxy}methyl)ethyl]-7H-pyrrolo[2,3-d]pyrtmidin-5-yl}methanone

A mixture of (5-((Diphenylmethylene)amino)pyridin-3-yl)(7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (Préparation 195, 1120 mg, 2.77 mmol) and Cs₂CO₃ (2710 mg, 8.31 mmol) in DMF (10 mL) was stirred at room température for 30 min. A solution of crude 2,2,3,3,9,9,10,10-octamethyl-4,8-dioxa-3,9disilaundecan-6-yl trifluoromethanesulfonate (Préparation 108) in DMF (3.8 mL) was then added to the réaction and the resulting mixture stirred at room température for 16 hours. The reaction was quenched with saturated aqueous ammonium chloride solution (100 mL) and the mixture extracted with EtOAc (100 ml_x3). The combined organic layers were washed with water (200 mL), dried over sodium sulfate and concentrated in vacuo. The resulting material was purified by column chromatography on silica gel (gradient of heptane:EtOAc 100:0 to 50:50) to provide (5-((diphenylmethylene)amino)pyridin-3-yl)(7^Æ.a.S.O.O.IO.IO-octamethyl^.e-dioxa-S^-disilaundecan-e-ylHH-pyrrolop.S-djpyrimidin-Syljmethanone.

The above material was dissolved in THF (20 mL) and aqueous 1N citric acid (20 mL) was added to the solution. The reaction mixture was stirred for 4 hours at room température; diluted with water (100 mL) and basified with NaOH to pH 7. The resulting mixture was extracted with EtOAc (3 x 150 mL), the combined organic fractions were dried over Na₂SO₄ and concentrated in vacuo. The resulting material was purified by column chromatography on silica gel (heptane:EtOAc = 40:60 to 0:100) to give the desired compound as a white solid in 49% yield, 739 mg.

1H NMR (400 MHz, DMSO-d6) δ: -0.11 (s, 6H), -0.07 (s, 6H), 0.68 (s, 18H), 3.99-4.16 (m, 4H), 5.01-5.11 (m, 1H), 5.65 (br s, 2H), 7.21-7.26 (m, 1H), 8.13 (d, 1H), 8.17 (d, 1H), 8.38 (s, 1H). 8.98 (s, 1H), 9.44 (s, 1H).

Préparation 197: 3-(3-(trifluoromethyl)-3H-diazirin-3-yl)benzoic acid

Ethyl 3-(3-(trifluoromethyl)-3H-diazirin-3-yl)benzoate (Préparation 198, 60 mg, 0.23 mmol) was stirred in a 2:1 mixture of THF:water (2mL). Lithium hydroxide (5 mg. 0.23 mmol) was added and the mixture stirred at 25° C for 18 hours. The reaction mixture was acidified to pH 1 using 6M aqueous hydrochloric acid and

193 then extracted with ethyl acetate (3 x 20 mL). The combined organic extracts were dried over magnésium sulfate and evaporated in vacuo to afford the title compound as a solid in 75% yield, 40 mg. This material was used in the next step without further purification.

Préparation 198 Methyl 3-(3-(trifluoromethyl)-3H-diazirin-3-yl)benzoate

Ethyl 3-(3-(trifluoromethyl)diaziridin-3-yl)benzoate (Préparation 199, 226 mg, 0.87 mmol) was stirred in methanol (10mL) with triethylamine (0.36 mL, 2.61 mmol). lodine (662 mg, 2.61 mmol) was dissolved in 2 mL methanol and added portion-wise until an orange-brown colour persisted. The reaction mixture was evaporated in vacuo and the residue was diluted with 1M aq. NaOH (30 mL) and then extracted with EtOAc (3 x 30 mL). The combined organic extracts were dried (MgSO₄) and evaporated in vacuo to afford the title compound as a gum in 27% yield, 60 mg. This material was used in the next step without further purification.

¹H NMR (400 MHz, CDCI₃) δ: 1.40 (t, 3H), 4.38 (q, 2H), 7.46-7.51 (m, 2H), 7.83 (s, 1H), 8.08 (d, 1H). Préparation 199: Ethyl 3-(3-(trifluoromethyl)diaziridin-3-yl)benzoate

To a solution of ethyl 3-(2,2,2-trifluoroacetyl)benzoate (500 mg, 2.15 mmol) in éthanol was added pyridine (5 mL) and hydroxyiamine hydrochloride (500 mg, 7.2 mmol) and the resulting mixture stirred at 57°C for 3 hours. The reaction mixture was cooled and passed through an ion exhange column eluting with methanol (30 mL). The methanol solution was evaporated in vacuo to give (E)-ethyl 3-(2,2,2-trifluoro1-(hydroxyimino)ethyl)benzoate as an oil in 71% yield, 401 mg which was used in the next step without further purification. To a stirred solution of (E)-ethyl 3-(2,2,2-trifluoro-1-(hydroxyimino)ethyl)benzoate (401 mg, 1.54 mmol) in dichloromethane (10 mL) was added DMAP (17 mg, 0.14 mmol) and the mixture cooled to 0°C. 4-methylbenzene-1-sulfonyl chtoride (331 mg, 1.74 mmol) was added portion-wise as a solution in dichloromethane (5 mL). The reaction mixture was then left to stand at room température for 18 hours. The mixture was diluted with water (10 mL) and the organic layer separated, dried over magnésium sulfate and evaporated in vacuo to afford (E)-ethyl 3-(2,2,2-trifluoro-1 ((tosyloxy)imino)ethyl)benzoate as an oil in 78% yield, 500 mg. This material was used in the next step without further purification. A mixture of (E)-ethyl 3-(2,2,2-trifluoro-1-((tosyloxy)imino)ethyl)benzoate (500 mg, 1.2 mmol) in diethylether (5 mL) in a 3-necked flask equipped with an internai thermometer and condensor was cooled to -78°C. Ammonia gas was introduced for 5 min and then stirring continued for 45 min. The reaction mixture was warmed to -33°C and stirred for 2 hours after which it was allowed to warm

194 to room température overnight with stirring. The mixture was evaporated in vacuo and the crude material purified by column chromatography on silica gel (gradient of dichloromethane:ethyl acetate 100:0 to 90:10) to afford the title compound as a gum in 76% yield, 240mg.

¹H NMR (400 MHz.CDCIa) δ: 1.31 (t, 3H), 4.31 (q, 2H), 7.40-7.44 (m, 1H), 7.74 (d, 1H), 8.02 (d, 1H), 8.20 (s, 1H).

Préparation 200: 3-(2,2,2-trifluoroacetyl)benzoic acid

F

F

The title compound was prepared according to the method described for Préparation 42 starting from ethyl 3-(2,2,2-trifluoroacetyl)benzoate to afford the title compound as a white solid in 26% yield, 23 mg.

*H NMR (400 MHz,CDCI₃) δ: 7.71 (t, 1 H), 8.32 (d, 1 H), 8.45 (d, 1 H), 8.80 (s, 1 H).

Préparation 201: 5-iodo-7H-pyrrolo[2,3-d]pyrimidine

A mixture of 7H-pyrrolo[2,3-d]pyrimidine (Préparation 202, 28.0 g, 235 mmol) and N-iodosuccinimide (55.4 g, 246 mmol) in acetonitrile (470 mL) was stirred at room température for 16 hours. The solids were filtered, rinsed with acetonitrile (150 mL) and dried in vacuo. The solid was dissolved in 1.5 L of 1N aqueous sodium hydroxide solution and to it was added 2N aqueous hydrogen chloride solution until ~pH 9. The resulting precipitate was filtered, rinsed with water (300 mL), and dried in vacuo for 16 hours at 70 °C, -10 mbar, to afford the title compound in 81% yield, 46.84 g.

¹H NMR (400 MHz, DMSO-d₆) δ: 7.82 (s, 1H), B.73 (s. 1H), 8.80 (s, 1 H), 12.56 (brs, 1H); LCMS (system 1): R, = 0.87 min; m/z 246 [M+Hf.

In each of four separate reaction vessels, 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (50.0 g, 260 mmol) was suspended in éthanol (1.4 L) and concentrated ammonium hydroxide solution (140 mL). 10% palladium on carbon (2.5 g) was added to each vessel and the mixture was pressurized to 20 psi hydrogen and stirred at room température overnight. Those reactions still containing starting material were charged with another 1 g of 10% palladium on carbon, pressurized to 20 psi hydrogen and stirred until the starting

195 material had been consumed. The reaction mixture was filtered over Arbocel, washed with éthanol, and the filtrate was evaporated to obtain a white solid. The four crude reaction products were combined, suspended in 500 mL water and extracted with ethyl acetate (3 x 500 mL). The organic layers were combined, dried over magnésium sulfate, filtered and the filtrate was concentrated in vacuo to obtain 122 g of a white solid. The aqueous layer was further extracted with 5% methanol in ethyl acetate (3 x 500 mL), the organic layers combined, dried over magnésium sulfate, filtered and the filtrate concentrated in vacuo to obtain another 30 g of white solid. The solids were combined to obtain the title compound in 98% yield, 152 g.

'H NMR (400 MHz, CDCI₃) δ: 6.63 (dd, 1H), 7.43 (dd, 1 H), 8.96 (s, 1H), 9.07 (s, 1 H), 11.65 (br. s., 1 H).

Préparation 203: N-(5-{7-[3-(tert-Buty!-dimethyl-silanyloxymethyl)-oxetan-3-yl)-7H-pyrrolo[2,3d]pyrimidine-5-carbonyl}-pyridin-3-yl)-2-(4-chloro-phenyl) acetamide:

(5-Amino-pyridin-3-yl)-{7-[3-(tert-butyl-dimethyl-silanyloxymethyl)-oxetan-3-yl]-7H-pyrrolo[2,3-d]pyrimidin5-yl}-methanone (Préparation 216, 30 mg, 0.068 mmol) was dissolved in dry pyridine (2 mL) under nitrogen and to this was added (4-chloro-phenyl)-acetic acid (17 mg, 0.102 mmol), followed by HATU (39 mg, 0.102 mmol). The reaction was heated to 50’C and stirred overnight. The reaction was cooled to room température, diluted with dichloromethane and saturated aqueous sodium bicarbonate was added. The phases were separated and the aqueous layer was extracted with dichloromethane (3 x 5mL). The combined organics were concentrated to dryness to afford N-(547-[3-(tert-butyl-dinnethyl· silanyloxymethyl)-oxetan-3-yl]-7H-pyrrolo[2,3-d]pyrimidÎne-5-carbonyl}-pyridin-3-yl)-2-(4-chloro-phenyl)acetamide as a pale yeilow solid 35 mg, 87% yield.

¹H NMR (400 MHz, CDCI₃) Ô-0.23 (s. 6 H) 0.65 (s, 9 H) 3.77 (s. 2 H) 4.26 (s,'2 H) 4.89 (d, J=7.6 Hz, 2 H) 5.27 (d, J=7.8 Hz, 2 H) 7.30 (d, J=8.6 Hz, 2 H) 7.37 - 7.44 (m, 2 H) 7.72 (s, 1 H) 8.49 (s, 1 H) 8.70 (d, J=2.3 Hz, 1 H) 8.78 (s, 1 H) 8.94 (s, 1 H) 9.64 (s, 1 H).

Préparation 204: N-(5-(7-[3-(tert-Butyl-dimethyl-silanyloxymethyl)-oxetan-3-yl]-7H-pyrrolo[2,3d]pyrimidine-5-carbonyl}-pyridin-3-yl)-2-(4-trifluoromethyl-phenyl)-acetamide:

196 (5-Amino-pyridin-3-yl)-{7-[3-(tert’butyl-dimethyl-silanyloxymethyl)-oxetan-3-yl]-7H-pyrrolo[2,3-d]pyrimidin

5-yl}-methanone (Préparation 216, 30 mg, 0.068 mmol) was dissolved in dry pyridine (2 mL) under nitrogen and to this was added (4-trifluoromethyl-phenyl)-acetic acid (21 mg, 0.102 mmol), followed by HATU (39 mg, 0.102 mmol). The reaction mixture was heated to 50*C and stirred overnight. The reaction was then cooled to room température, diluted with dichloromethane (5 mL) and saturated aqueous sodium bicarbonate was added (5 mL), The phases were separated and the aqueous layer was extracted with dichloromethane (3 x 5mL). The combined organics were concentrated to dryness to afford N-(5-{7[3-(tert-butyl-dimethyl-silanyloxynnethyl)-oxetan-3-yl]-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl}-pyridin-3-yl)' a-^-trifluoromethyl-phenyO-acetamide as a pale yellow solid 39 mg, 92% yield.

¹H NMR (400 MHz, DMSO-d_e) Ô-0.29 (s, 6 H) 0.58 (s, 9 H) 3.84 (s. 2 H) 4.16 (s, 2 H) 4.77 (d, J=7.4 Hz, 2 H) 5.21 (d, J=7.4 Hz, 2 H) 7.56 (d, J=7.8 Hz, 2 H) 7.68 (d, J=7.8 Hz, 2 H) 8.28 (s, 1 H) 8.46 (t, J=2.1 Hz, 1 H) 8.69 (d, J=2.0 Hz, 1 H) 8.91 - 8.95 (m, 2 H) 9.46 (s, 1 H) 10.71 (s, 1 H).

Préparation 205: 2-Allyl-malonic acid diethyl ester

Malonic acid diethyl ester (100 g, 0.625 mol) was added dropwise at 0°C to a mixture of sodium ethoxide (46.8 g, 0.688 mol) in éthanol (1 L). The reaction mixture was stirred for 4 hours. 3-Bromo-propene (83.2 g, 0.688 moles) was added dropwise to the mixture at 0°C. After addition, the mixture was warmed to reflux and stirred overnight. The mixture was cooled to room température, filtered and the solvent was removed in vacuo to afford the title compound in 86% yield, 100 g which was used for the next step without further purification.

Préparation 206: 5-Allyl-6-hydroxy-3H-pyrimidin-4-one

2-Allyl-malonÎc acid diethyl ester (Préparation 205, 100 g, 0.5 mol) was added dropwise to a mixture of sodium methoxide (27 g, 0.5 mol) in éthanol (1 L) at 0-5°C and the mixture was stirred at this température for 10 min. Formamidine acetate (51.9 g, 0.5 mol) was added and the mixture was stirred at room température overnight. The solvent was removed in vacuo, and aqueous hydrochloric acid (36.5%) and water were added to adjust the pH to approximately 3 at 0-20°C. The resulting mixture was filtered to afford the title compound as a colorless solid in 57% yield, 87.12 g.

¹H NMR (400 MHz, DMSO-d_s) δ: 2.96 (d. 1H), 4.89 (m, 2H), 5.76 (m, 1H), 7.89 (s, 1H).

Préparation 207: 5-Allyl-4,6-dichloro-pyrimidine

197

5-Allyl-6-hydroxy-3H-pyrimidin-4-one (Préparation 206, 40 g, 0.263 moi) was added to POCI₃ (100 mL) at room température. The solution was stirred and warmed to reflux for 8 hours. The mixture was evaporated in vacuo to remove most of the POCI₃. The residue was poured slowly onto ice-water, which was extracted with ethyl acetate (500 mL x 4), washed with brine (300 mL), dried over sodium sulfate and evaporated in vacuo to afford the titie compound as a yellow oil in 59% yield, 31 g.

¹H NMR (400 MHz,CDCI₃) δ: 3.59 (m. 2H), 5.09 (m, 2H), 5.79 (m, 1H), 8.59 (s, 1H).

Préparation 208: (4,6-Dichloro-pyrimidin-5-yl)-acetaldehyde

To a stirred solution of 5-Allyl-4,6-dichloro-pyrimidine (Préparation 207, 30 g, 0.159 mole) in dry dichloromethane (400 mL) was bubbled ozone at -70°C for 30 min. After excess ozone was purged by nitrogen gas, dimethyl sulfide (10 mL) was added at -5°C, and the reaction was stirred for 2 hours. The mixture was washed with water, brine, dried over sodium sulfate, and evaporated in vacuo. The crude material was purified by trituration from pentane-diethyl ether to afford the title compound as a colorless solid in 84% yield, 10 g.

¹H NMR (400 MHz,CDCI₃) δ: 4.15 (s, 2H), 8.74 (s, 1H), 9.80 (s, 1H).

Préparation 209: 2-(4-Chloro-pyrrolo[2,3-d]pyrimidin-7-yl)-2-hydroxymethyl-propane-1,3-diol

Trisamine (1.27 g, 10.5 mmol) was added to 4,6-Dichloro-pyrimidin-5-yl)-acetaldehyde (Préparation 208, 1.0 g, 5.2 mmol) in éthanol (40 mL) and stirred at reflux température for 16 hours. The reaction mixture was evaporated in vacuo and partitioned between dichloromethane and aqueous saturated sodium bicarbonate. The separated aqueous phase was extracted with dichloromethane twice more and the combined organics were washed with saturated brine and evaporated in vacuo to afford the title compound as a pale yellow foam in 74% yield, 1.0 g.

¹H NMR (400 MHz,CDCI₃) δ ppm 2.97 (br. s, 1 H), 3.09 - 3.27 (m, 2H), 3.51 (d, J=9.18 Hz, 1H), 3.83 - 4.00 (m, 4H), 4.06 (d, J=11.13 Hz, 1H), 5.43 (dd, J=6.44, 1.76 Hz, 1H), 6.16 (dd, J=10.74, 4.69 Hz, 1H), 8.40 (s, 1 H); LCMS (System 2): R_t = 1.04 min; m/z 258 [M+H]⁺.

Préparation 210: Toluene-4-sulfonic acid 2-(4-chloro-pyrrolo[2,3-d]pyrimidin-’7-yl)-3-hydroxy-2hydroxymethyl-propyl ester

198

Triethylamine (0.879 mL, 6.31 mmol) and trimethylamine hydrochloride (253 mg, 2.65 mmol) were added to a solution of 2-(4-chloro-pyrrolo[2,3-d]pyrimidin-7-yl)-2-hydroxymethyl-propane-1,3-diol (Préparation 209, 650 mg, 2.52 mmol) in dichloromethane (20 mL) at 0°C. The mixture was treated portion-wise with tosyl chloride (505 mg, 2.65 mmol) and stirred at 0°C for 16 hours. The reaction mixture was treated with water and stirred for 10 min. The resulting mixture was washed with citric acid, saturated aqueous sodium bicarbonate, and saturated brine, then evaporated in vacuo. The crude product was purified by column chromatography on silica gel (gradient of EtOAciDCM 0:100 to 30:70) to afford the title compound as a colorless solid in 55% yield, 570 mg.

LCMS (system 2): R, = 1.28 min; m/z 412 [M+H]⁺.

Préparation 211: [3-(4-Chloro-pyrrolo[2,3-d]pyrimidin-7-yl)-oxetan-3-yl]-methanol

Butyllithium (12.2 mL, 30.6 mmol, 2.5 M in hexanes) was added to toluene-4-sulfonic acid 2-(4-chloropyrrolo[2,3-d]pyrimidin-7-yl)-3-hydroxy-2-hydroxymethyl-propyl ester (Préparation 210, 5.73 g, 13.9 mmol) in THF (100 mL) at 0°C and stirred for 5 min. The reaction mixture was then warmed to room température and stirred for 16 hours, at which point it was quenched with sâturated aqueous ammonium chloride. The resulting mixture was extracted with ethyl acetate (100mL x3) and the combined organic phases were dried (MgSO₄) and concentrated in vacuo. The crude product was triturated with dichloromethane and filtered to afford the title compound in 36% yield, 1.2 g.

¹H NMR (400 MHz, MeOH-d₄) δ: 4.15 (s, 2H), 4.92 (d, J=7.22 Hz, 2H), 5.22 (d, J=7.03 Hz, 2 H), 6.69 (d, J=3.51 Hz. 1H), 7.51 (d, J=3.71 Hz, 1H), 8.51 (s, 1H).

Préparation 212: 7-[3-(tert-Butyl-dimethyl-silanyloxymethyl)-oxetan-3-yl]-4-chloro-7H-pyrrolo[2,3d]pyrimîdine

199

Imidazole (277 mg, 4.07 mmol) was added to [3-(4-Chloro-pyrrolo[2,3-d]pyrimidin-7-yl)-oxetan-3-yl]methanol (Préparation 211, 650 mg, 2.71 mmol) in dicloromethane (10 mL), and this mixture was treated with a solution of t-butyldimethylsilyl chloride (495 mg, 3.25 mmol) in dichloromethane (5 mL). The resulting mixture was stirred at room température for 16 hours, then quenched with water (50 mL). The mixture was extracted with dichloromethane (3 x 50mL), and the combined organic phases were washed with water and saturated brine, and evaporated in vacuo to afford the title compound as a pale brown oil in 91% yield, 875 mg.

¹H NMR (400 MHz, CDCI₃) δ: -0.21 (s, 6H), 0.77 (s, 9H), 4.22 (s, 2H), 4.88 (d, J=7.22 Hz, 2H), 5.19 (d, J=7.03 Hz, 2H), 6.61 (d, J=3.71 Hz, 1H), 7.11 (d, J=3.71 Hz, 1H), 8.55 (s, 1H); LCMS (system 2): R, = 1.82 min; m/z 354 [M+Hf.

Préparation 213; 7-[3-(tert-Butyl-dimethyl-silanyloxymethyl)-oxetan-3-yl]-7H-pyrrolo[2,3-d]pyrimidine

The title compound was prepared according to the method described for Préparation 8 using 7-[3-(tertButyl-dimethyl-silanyloxymethyl)-oxetan-3-yl]-4-chloro-7H-pyrrolo[2,3-d]pyrimidine (Préparation 212) to afford the title compound as a brown oil in 82% yield, 650 mg.

¹H NMR (400 MHz, CDCI₃) δ: -0.24 (s, 6H), 0.76 (s, 9H), 4.24 (s, 2H), 4.91 (d, J=7.03 Hz, 2H), 5.22 (d, J=7.03 Hz, 2H), 6.55 (d, J=3.51 Hz. 1H), 7.08 (d, J=3.71 Hz, 1H), 8.78 (s, 1H), 8.97 (s, 1H); LCMS (system 2): R, = 0.90 min; m/z 320 [M-t-Hf.

Préparation 214: 7-[3-(tert-Butyl-dimethyl-silanyloxymethyl)-oxetan-3-yl]-5-iodo-7H-pyrrolo[2,3djpyrimidîne

The title compound was prepared according to the method described for Préparation 14 using 7-[3-(tertButyl-dimethyl-silanyloxymethyl)-oxetan-3-yl]-7H-pyrrolo[2,3-d]pyrimidine (Préparation 213) and DMF to afford the title compound as a brown solid in 75% yield, 675 mg.

¹H NMR (400 MHz. CDCI₃) δ: -0.24 (s, 6H), 0.77 (s, 9H), 4.20 (s, 2H), 4.88 (d, J=7.22 Hz, 2H), 5.21 (d, J=7.03 Hz, 2H), 7.17 (s, 1 H), 8.77 (s, 1H), 8.81 (s, 1H); LCMS (system 2): R₍ = 1.55 min; m/z 446 [M+Hf.

200

Préparation 215: (7-(3-(((tert-Butyldimethylsilyl)oxy)methyl)oxetan-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-5yl)(5-((diphenylmethylene)amino)pyridin-3-yl)methanone

The title compound was prepared according to the method described for Préparation 24 using 7-[3-(tert5 butyl-dimethyl-silanyloxymethyl)-oxetan-3-yl]-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (Préparation 214) and 5[(Diphenylmethylene)amino]-N-methoxy-N-methylnicotinamide (Préparation 23) to afford the title compound as a purple solid in 51% yield, 240 mg.

’H NMR (400 MHz, CDCI₃) δ: 0.20 (s, 6H), 0.70 (s, 9H), 4.28 (s, 2H), 4.89'(d, J=7.22 Hz, 2H), 5.20 (d, J=7.22 Hz, 2H), 7.11 - 7.18 (m, 2H), 7.33 (m, 3H), 7.40 - 7.48 (m, 2H), 7.49 - 7.57 (m, 3H), 7.79 (d, J=7.42 10 Hz, 2H), 8.18 (d, J=2.54 Hz, 1 H), 8.60 (d, J=1.95 Hz, 1H), 8.93 (s, 1H), 9.60 (s, 1H).

Préparation 216: (5-Amino-pyridin-3-yl)-{7-(3-(tert-butyl-dimethyl-silanyloxymethyl)-oxetan-3-yl]-7Hpyrrolo[2,3-d]pyrimidin-5-yl}-methanone

The title compound was prepared according to the method described for Préparation 37 using (7-(315 (((tert-butyldimethylsilyl)oxy)methyl)oxetan-3-yl)-7H-pyrroto[2,3-d]pyrimidin-5-yl)(5((diphenylmethylene)amino)pyridin-3-yl)methanone (Préparation 215) to afford the title compound as a colourless solid in 76% yield, 132 mg.

’H NMR (400 MHz, CDCI₃) δ: 0.01 (s, 6H), 0.88 (s, 9H), 4.11 (br. S, 2H), 4.45 (s, 2H), 5.17 (m. 2H), 5.40 (m, 2H), 7.58 (s, 1H), 7.80 (s, 1H), 8.45 (s, 1H), 8.61 (s, 1H), 9.15 (s, 1H), 9.83 (S, 1H).

201

Préparation 217: 2-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-methylpropane-1,3-diol

The title compound was prepared according to the method described for Préparation 1 using (4,6dichloropyrimidin-5-yl)acetaldehyde (Préparation 208) and 2-amino-2-methylpropane-1,3-diol to afford the title compound as a yellow liquid in 79% yield, 3.88 g.

¹H NMR (400 MHz, DMSO-d₆) δ: 1.66 (s, 3H), 3.86 (dd, 2H), 4.13 (dd, 2H), 4.92 (t, 2H), 6.58 (d, 1H), 7.73 (d, 1H), 8.59 (s, 1H).

Préparation 218: 4-chloro-7-(3-methyloxetan-3-yl)-7H-pyrrolo[2,3-d]pyrimidine

n-BuLi (6.6 mL of a 2.5 M solution in hexane, 16.5 mmol) was added to a solution of 2-(4-chloro-7Hpyrrolo(2,3-d]pyrimidin-7-yl)-2-methylpropane-1,3-diol (Préparation 217, 3.63 g, 15.0 mmol), in THF (80 mL) at -78 °C. The reaction mixture was altowed to warm to -50 °C in 2 hours and TsCI (3.15 mg, 16.5 mmol) in THF (20 mL) was added to the reaction. The reaction was allowed to warm to 0 °C in 3 hours and additional n-BuLi (6.6 mL of a 2.5 M solution in hexane solution, 16.5 mmol) was slowly added to the reaction mixture. The mixture was stirred for 1 hour at 0 °C and stirred at 60 °C for 16 hours. After cooling to room température, the reaction was quenched by 50 mL of saturated aqueous NH₄CI solution and 100 mL of water, and the mixture was extracted with EtOAc (3x 100 mL). The combined organic layers were dried over MgSO₄ and concentrated in vacuo. The crude residue was purified by column chromatogranhy on siltca gel (gradient of EtOAc:heptane 20:80 to 70:30) to give a solid in 55% yield, 1.87 mg.

'H NMR (400 MHz, DMSO-d_s) δ: 1.79 (s, 3H) 4.72 (d. 2H) 5.15 (d, 2H) 6.69 (d, 1H) 7.78 (d, 1H) 8.59 (s, 1H).

Préparation 219: 7-(3-methyloxetan-3-yl)-7H-pyrrolo[2,3-d]pyrimidine

The title compound was prepared according to the method described for Préparation 8 using 4-chloro-7(3-methyloxetan-3-yl)-7H-pyrrolo[2,3-d]pyrimidine (Préparation 218) to afford the title compound as a yellow liquid in 22% yield, 0.341 g.

202 ¹H NMR (400 MHz, DMSO-d₆) δ: 1.81 (s, 3H), 4.72-4.77 (m, 2H), 5.16-5.21 (m, 2H), 6.69 (d, 1H), 7.66 (d,

1H), 8.76 (s, 1 H), 9.02(s,1 H).

The title compound may also be prepared according to the following method:

LiHMDS (14.5 mL of a 1M solution in THF, 14.5 mmol) was added slowly to a solution of 2-Methyl-2pyrrolo[2,3-d]pyrimidin-7-yl-propane-1,3-diol (Préparation 278, 3 g, 14.5 mmol) in anhydrous THF (200 mL) over a period of 2 hours (using a syringe pump) under nitrogen at 0°C. After completion of the addition, the reaction mixture was stirred for an additional 40 min before TsCI (2.76 g, 14.5 mmol) as a solution in THF (50 mL) was slowly added. The mixture was stirred for another 1 hour at 0°C. TLC showed consumption of starting material and another équivalent of LiHMDS (14.5 mL, 14.5 mmol) was added to the mixture and it was heated at 60° for 16 hours. Sat. aq. NH<CI solution (200 mL) was then added and the mixture then extracted with EtOAc (3 x 100 mL). The combined organic layers were dried (Na_aSO<i) and evaporated in vacuo. The crude material was purified by column chromatography on silica gel (gradient of EtOAc:Hexane 3:7 to 2:3) to afford the title compound as a colourless gum in 37% yield, 1 9·

Préparation 220: 5-iodo-7-(3-methyloxetan-3-yl)-7H-pyrrolo[2,3-d]pyrimidine

I

The title compound was prepared according to the method described for Préparation 14 using 7-(3methyloxetan-3-yl)-7H-pyrrolo[2,3-d]pyrimidine (Préparation 219) to afford the title compound as a yellow solid in 78% yield, 0.44 g.

'H NMR (400 MHz, DMSO-D6) δ: 1.80 (s, 3H), 4.71 (d, 2H), 5.18 (d, 2H), 7.94 (s, 1H), 8.76 (s, 1H), 8.82 (S.1H).

Préparation 221: (5-((diphenylmethylene)amino)pyridin-3-yl)(7-(3-methyloxetan-3-yl)-7H-pyrrolo[2,3d]pyrimidin-5-yl)methanone

The title compound was prepared according to the method described for Préparation 24 using 5-iodo-7(3-methyloxetan-3-yl)-7H-pyrrolo[2,3-d]pyrimidine (Préparation 220) to afford the title compound. LCMS (system 2): R₍ = 1.24 min; m/z 474 [M+Hf.

Préparation 222: (5-aminopyridin-3-yl)[7-(3-methyloxetan-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]methanone

203

The title compound was prepared according to the method described for Préparation 37 using (5((diphenylmethylene)amino)pyridin-3-yl)(7-(3-methyloxetan-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-5yl)methanone (Préparation 221) to afford the title compound as a white solid in 14% yield over two steps, 64 mg.

’H NMR (400 MHz, DMSO-d₆) δ; 1.89 (s, 3H), 4.75 (d, 2H), 5.23 (d, 2H), 5.64 (br s, 2H), 7.29-7.36 (m, 1H), 8.17 (d, 1H), 8.24 (d, 1H), 8.41 (s, 1H), 8.95 (s, 1H), 9.46 (s, 1H); LCMS (System 4): R, = 2.30 min; m/z 310 [M+H]*.

Préparation 223: N-(5-({7-[3-({[tert-butyl(dimethyl)silyl]oxy}methyl)oxetan-3-yl]-7H-pyrrolo[2,3d]pyrimidin-5-yl}carbonyl)pyridin-3-y0-2-(5-chloropyridin-2-yl)acetamide

(5-Amino-pyridin-3-ylH7-[3-(tert-butyl-dimethyl-silanyloxymethyl)-oxeÎan-3-yl]-7H-pyrrolo[2,3-d]pyrimidin5-yl}-methanone (Préparation 216, 30 mg, 0.068 mmol) was added to a stirred mixture of (5chloropyridin-2-yl)acetic acid (17.5 mg, 0.102 mmol) and HATU (38.8 mg, 0.102 mmol) in pyridine (2 ml). The reaction mixture was warmed to 50°C and stirred at this température for 14 hours. The reaction was then cooled and a further portion of HATU (38.8 mg, 0.102 mmol) was added. The reaction was warmed to 50°C and stirred at this température for 8 hours and then allowed to cool to room température and stirred for a further 60 hours. The réaction mixture was then diluted with DCM (20ml) and the résultant solution quenched with saturated NaHCO₃ (20 ml). The layers were separated and the aqueous layer extracted with DCM (3x 20 ml). The combined organic layers were washed with brine (20ml) and then concentrated in vacuo to give the crude product as a pale yellow oil (35 mg) which was taken forward for use in the préparation of Example 238.

Préparation 224: N-[5-({7-[3-({[tert-butyl(dimethyl)silyl]oxy}methyl)oxetan-3-yl]-7H-pyrrolo[2,3d]pyrimidin-5-yl}carbonyl)pyridin-3-yi]-2-[3-(trifluoromethyl)-1H-pyrazol-1-yl]acetamide

204

(5-Amino-pyridin-3-yl)-{7-[3-(tert-butyl-dimethyl-silanyloxymethyl)-oxetan-3-yl]-7H-pyrrolo[2,3-d]pyrimidin5-yl}-methanone (Préparation 216, 30 mg, 0.068 mmol) was added to a stirred mixture of [3(trifluoromethyl)-1H-pyrazol-1-yl]acetic acid (19.8 mg, 0.102 mmol) and HATU (38.8 mg, 0.102 mmol) in pyridine (2 mi). The reaction mixture was warmed to 50°C and stirred at this température for 14 hours. The réaction mixture was then cooled to room température and diluted with DCM (20ml) and the résultant solution quenched with saturated NaHCO₃ (20 ml). The layers were separated and the aqueous layer extracted with DCM (3x 20 ml). The combined organic layers were washed with saturated brine (20ml) and then concentrated in vacuo to give the crude product as a pale yellow solid (44 mg) which was taken forward crude for use in the préparation of Example 239.

Préparation 225: 4-Chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine

To a suspension of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (70.5 g, 0.45 mol) in DCM (1.8 L) was added Niodosuccinimide (120 g, 0.54 mol) in portions. After addition, the mixture was stirred at room température overnight. The solid was filtered and washed with water (250 mL), MeOH (280 mL) and CH₂CI₂ (280 mL) sequentially. The solid was dried under vacuum to afford 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine as a brown solid in 79% yield, 107g.

Préparation 226: 4-Chloro-5-iodo-7-methyl-7H-pyrrolo[2,3-d]pyrimidine

To a mixture of 4-chtoro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (Préparation 225, 30 g, 0.1 mol), Cs₂CO₃ (50 g, 0.15 mol) in DMF (150 mL), Mel (28.4 g, 0.2 mol) was added dropwise at 0°C. After addition, the mixture was stirred at room température for 10 hours. The reaction mixture was cooled to 0°C and quenched by the addition of water (500 mL). Then the solid was collected by filtration and washed with Et₂O (100 mL) to afford 4-chloro-5-iodo-7-methyl-7H-pyrrolo[2,3-d]pyrimidine as a brown solid in 61% yield, 20g.

Préparation 227: S-Bromo-N-methoxy-N-methyl-nicotinamide

205

To a solution of 5-bromo-nicotinic acid (100 g, 0.5 mol) in THF (2 L) at 0°C, (COCI)₂ (95 g, 0.74 mol) was added. After strrring for 0.5 h, Et_aN (152 g, 1.5 mol) and O, N-dimethyl hydroxylamine.HCI (140 g, 1.5 mol) were added. The reaction mixture was stirred at room température for 2.5 hours and then water (200 mL) and EtOAc (500 mL) were added. The organic layer was separated, dried (MgSO₄) and concentrated in vacuo to afford 5-the title compound as a brown oil in 82% yield, 100%.

Préparation 228: (4-Chloro-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl}(5((diphenylmethylene)amino)pyridin-3-yl)methanol

To stirred solution of 4-chloro-5-iodo-7-methyl-7H-pyrrolo[2,3-d]pyrimidine (Préparation 226, 6.6 g, 22.7 mmol) in THF (130 mL) was added n-BuLi (18.2 mL of a 2.5M solution in hexane, 45 mmol) at -75 °C under N₂, and the mixture was stirred for 50 min. A solution of 5((diphenylmethylene)amino)nicotinaldehyde (Préparation 106, 6.5 g, 22.7 mmol) in dry THF (50 mL) was added and the mixture was stirred at -70 °C for 80 min. The mixture was quenched with sat. aq. NH₄CI solution and extracted with EtOAc (300 mL). The organic layer was dried (Na₂SO₄) and concentrated in vacuo to give the title compound as a brown solid in 48% yield, 5.2g.

Préparation 229: (4-chloro-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(5{(diphenylmethylene)amino)pyridin-3-yl)methanone

To a solution of {4-chloro-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)(5-((diphenylmethylene)amino)pyridin3-yl)methanol (Préparation 228, 11.4 g, 25 mmol) in CH₂CI₂ (150 mL), Dess-Martin periodinane (15.9 g, 37 mmol) was added in portions. The réaction mixture was stirred at room température for 10 hours and then aqueous NaOH (30 mL) was added. The mixture was stirred for a further 0.5 hours. The mixture was then separated and the aqueous layer was exacted by CH₂CI₂ (100 mL x 2). The combined organic layers

206 were concentrated and washed with ether to provide the title compound as a brown solid in 99% yield,

11g.

¹H NMR (400 MHz, CDCI₃) Ô 3.87 (s, 3H), 7.06 (m, 2H), 7.27 (m, 3H), 7.37 (m, 2H), 7.45 (m, 3H), 7.71 (m,

2H), 8.15 (d, J=2.4,1 H), 8.49 (d, J=1.2,1 H), 8.68 (s, 1 H).

Préparation 230: (5-Amino-pyridin-3-yl)-(4-chloro-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-methanone

A solution of [5-(benzhydrylidene-amino)pyridin-3-yll-(4-chloro-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (Préparation 229, 30 g, 0.066 mol) in THF (200 mL) was added aq. citric acid (200 mL), the mixture was stirred for 30 min at room température. Ether was added and the layers were separated. The aqueous layer was adjusted to pH7 by aqueous Na₂CO₃. Then the mixture was filtered. The filter cake was evaporated with toluene and the residue was washed with EtOAc (200 mL) to give the title compound as a brown solid in 95% yield, 18g.

Préparation 231: (S-Amino-pyridin-S-ylHT-methyl^-methylsulfanyl^H-pyrrolo^.S-dJpyrimidin-ô-yl)methanone

To a solution of (5-amino-pyridin-3-yl)-(4-chloro-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-methanone (Préparation 230, 21 g, 0.073 mol) in MeOH (300 mL) was added CH₃SNa (15.5 g, 0.22 mol). The resulting mixture was stirred for 7 hours at room température. The mixture was poured into ice-water (200 mL), the precipitate was filtered, the filter cake was washed with water (100 mL) then acetone (20 mL) to give (5-amino-pyridin-3-yl)-(7-methyl-4-methylsulfanyl-7H-pyrrolo[2,3-d]pyrÎmidin-5-yl)-methanone as a brown solid in 69% yield, 15g.

Préparation 232: (5-Amino-pyridin-3-yl)-(7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-y1)-methanone

A mixture of (5-amino-pyridin-3-yl)-(7-methyl-4-methylsulfanyl-7H-pyrroto[2,3-d]pyrimidin-5-yl)-methanone (Préparation 231, 1.5 g, 5 mmol), Raney Ni (10 g) and NH₃H₂O (150 mL) in dioxane (150 mL) was refluxed for 6 hours. The mixture was filtered and the filtrate was concentrated. The residue was purified

207 via préparative HPLC to give (5-amino-pyridin-3-yl)-(7-methyl-7H-pyrrolo[2,3-djpyrimidin-5-yl)-methanone as a brown solid in 15% yield, 0.19g. Ή NMR (400 MHz DMSO-d_s) 3.88 (s, 3H), 5.63 (s, 2H), 7.27-7.28 (m, 1H), 8.15-8.18 (m, 2H), 8.40 (s, 1H), 8.97 (s, 1H), 9.42 (s, 1H).

Préparation 233: 5,6,7,8-Tetrahydro-[1,7]naphthyridine hydrochloride

HCl

A methanolic solution (25 mL) of 7-Benzyl-5,6,7_l8-tetrahydro-[1_l7]naphthyridine (J. Het. Chem. 2001, 38, 535 ) (1.5g, 6.69 mmol) was degassed with argon for 20 min followed by the addition of 4N HCl in dioxane (2 mL) and Pd/C (300 mg, 20 wt%) and stirred under 50 psi hydrogen pressure at room température for 24h. After completion of the reaction the mixture was filtered on a short pad of celite and washed with methanol (4 x 25 mL). The filtrate was evaporated to dryness in vacuo and crystallized from methanol to afford the title compound as yellowish solid in 65% yield (calculated as 2HCI sait), 900 mg.

¹H NMR (400 MHz, DMSO-D6) δ: 3.10 (t, 2H), 3.40 (q, 2H), 4.36 (s, 2H), 7.50 (dd, 1H), 7.91 (d, 1H), 8.55 (d, 1H), 9.96 (brs, 2H); LCMS (system 10): R_t = 1.56 min; m/z 135.2 [M+Hf. Préparation 234: (5,8-Dihydro-6H-[1,7]naphthyridin-7-yl)-acetic acid tert-butyl ester

Me

Me-J

Me O

A DMF solution (8 mL) of 5,6,7,8-Tetrahydro-[1,7]naphthyridinehydrochloride (Préparation 233, 400 mg, 1.93 mmol), bromo-acetic acid tert-butyl ester (414.1 mg, 2.12 mmol) and triethylamine (1.64 mL, 11.92 mmol) was heated at 80°C for 16 hours. The reaction mixture was diluted with EtOAc (40 mL), washed with water (3 x 25 mL), brine (20 mL), dried over Na₂SO₄ and evaporated to dryness in vacuo to afford the title compound as colorless sticky solid in 100% yield, 480 mg.

¹H NMR (400 MHz, DMSO-D6) δ: 1.43 (s, 9H), 2.81 (s, 4H), 3.34 (s, 2H), 3.72 (s, 2H), 7.16 (dd, 1H), 7.51 (d, 1H), 8.29 (d, 1H); LCMS (system 10): R, = 3.02 min; m/z249.4 [M+H]⁺.

Préparation 235: (5,8-Dihydro-6H-[1,7]naphthyridin-7-yl)-acetic acid hydrochloride _hxcq

HCl (5,8-Dihydro-6H-[1,7]naphthyridin-7-yl)-acetic acid tert-butyl ester (Préparation 234, 1.25 g, 5.03 mmol) was treated with 4N HCl in dioxane (25 ml) at room température for 2 hours. The mixture was evaporated to dryness in vacuo and the solid residue was triturated with diethyl ether to afford the title compound as white solid in 78% yield (calculated as HCl sait), 900 mg.

¹H NMR (400 MHz, MeOD) δ: 3.38 (t, 2H), 3.79 (t, 2H), 4.38 (s, 2H), 4.84 (s. 2H), 7.79 (dd, 1H), 8.25 (d. 1 H), 8.70 (d, 1H).

Préparation 236: Phenyl-[(tetrahydro-pyran-2-yloxy)]-acetic acid

208

To a stirred solution of hydroxy-phenyl-acetic acid (2 g, 13.4 mmol) in DCM (30 mL) was added PTSA (51.2 mg, 0.27 mmol) at 0°C followed by the addition of 3,4-dihydro-2H-pyran (1.55 g, 18.4 mmol). The mixture was stirred at 0°C for another 15 min and then gradually warmed up to room température and stirred for a further 1.5 hours. The reaction mixture was diluted with DCM (100 mL). The organic phase was washed with saturated aq. Na₂CO₃ (2 x 20 mL), water (20 mL), brine (20 mL), dried (Na₂SO₄) and evaporated in vacuo. The crude material was purified by column chromatography on silica gel (EtOAc:petroleum ether 2:5) to afford the title compound as a yellow sticky solid in 48% yield, 1.5 g. LCMS (System 10): R_t = 1.82 min; m/z 237 [M+H]⁺.

Préparation 237: N-[5-(7-lsopropyl-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-pyridin-3-yl]-2-phenyl-2(tetrahydro-pyran-2-yloxy)-acetamide

The title compound was prepared according to the method described for Example 1 using phenyl[(tetrahydro-pyran-2-yloxy)]-acetic acid (Préparation 236) and (5-Amino-pyridin-3-yl)-(7-isopropyl-7Hpyrrolo[2,3-d]pyrimidin-5-yl)-methanone (Préparation 95) to afford the title compound as a yellow solid in 68% yield, 60 mg.

LCMS (System 10): R, = 3.56 min; m/z 500.2 [M+H]⁺.

Préparation 238: 5-Bromo-6-hydroxy-nicotinic acid

Bromine (3.6 mL, 70.5 mmol) was added dropwise to a suspension of 6-Hydroxy-nicotinic acid (7 g, 50.32 mmol) in water (70 mL) at 0°C and the mixture was stirred at room température for 4 hours. The precipitated solid was filtered, washed with cold water and dried to get the title compound as off white solid in 82% yield, 9 g.

’H NMR (400 MHz, DMSO-D6) δ: 8.03 (d, 1H), 8.14 (d, 1H), 12.57 (brs, 1H).

Préparation 239: 5-Bromo-6-hydroxy-N-methoxy-N-methyl-nicotinamide

209

5-Bromo-6-hydroxy-nicotinic acid (Préparation 238, 4 g, 1Θ.4 mmol), HATD (13.95 g, 36.71 mmol), O,NDimethyl-hydroxylamine hydrochloride (2.15 g, 22.02 mmol) and DIPEA (15.82 mL, 91.75 mmol) were taken in anhydrous DMF (30 mL). The mixture was stirred at room température for 16 hours. The reaction mixture was diluted with EtOAc (150 mL), washed with saturated aq. Na₂CO₃ (2 x 50 mL), water (4 x 30 mL), brine (30 mL), dried (Na₂SO₄) and evaporated in vacuo. The crude mixture was purified by column chromatography on silica gel (gradient of EtOAc:Hex 4:6 to 6:4) to afford the title compound as light yellow sticky solid in 38%, 1.8 g.

¹H NMR (400 MHz, DMSO-D6) δ; 3.22 (s, 3H), 3.61 (S, 3H), 7.95 (d, 1H), 8.14 (d, 1H), 12.45 (brs, 1H); LCMS (system 10): R_t = 1.67 min; m/z 261,263 [M+H]*.

Préparation 240: 5-Bromo-6-ethoxy-N-methoxy-N-methyl-nicotinamide

Me

A mixture of 5-bromo-6-hydroxy-N-methoxy-N-methyl-nicotinamÎde (Préparation 239,1.80 g, 6.90 mmol), ethyl iodide (2.8 mL, 34.5 mmol) and silver carbonate (3.8 g, 13.8 mmol) in DCM (10 mL) was stirred at room température for 40 hours. The réaction mixture was diluted with DCM (50 mL), washed with water (2 x 30 mL), brine (20 mL), dried (Na₂SO₄) and evaporated in vacuo. The crude material was purified by column chromatography on silica gel (EtOAc:petroleum ether 2:5) to afford the title compound as a yellow sticky solid in 30% yield, 600 mg.

¹H NMR (400 MHz. CDCI3) δ: 1.44 (t, 3H), 3.35 (s, 3H), 3.57 (s, 3H), 4.47 (q, 2H), 8.23 (d, 1H), 8.54 (d. 1H).

Préparation 241: (5-Bromo-6-ethoxy-pyridin-3-yl)-(7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone

A solution of 5-lodo-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidine (Préparation 93, 530 mg, 1.85 mmol) in anhydrous diethyl ether (8 mL) was cooled to -78°C under nitrogen and n-BuLi (1 mL of a 2.03M solution in Hexane, 2.03 mmol) was added drop wise over a period of 10 min. Just after the completion of addition of n-BuLi, a solution of 5-Bromo-6-ethoxy-N-methoxy-N-methyl-nicotinamide (Préparation 240) in anhydrous diethyl ether (7 mL) was added slowly to the mixture and it was stirred at the same température for another 1 hour. The reaction mixture was warmed to room température and allowed to stir for another hour before being quenched with sat. aq. NH₄CI (15 mL). The mixture was extracted with EtOAc (3 x 15 mL), washed with water (20 mL), brine (15 mL), dried (Na₂SO₄) and evaporated in vacuo.

210

The crude material was purified by column chromatography on silica gel (EtOAc:petroleum ether 2:10) to afford the title compound as a yellow gum in 49% yield, 350 mg, ’H NMR (400 MHz, CDCI3) δ: 1.50 (t, 3H), 1.60 (d, 6H), 4.55 (q, 2H), 5.15-5.20 (m, 1H), 7.82 (s, 1H), 8.32 (d, 1 H), 8.57 (d, 1 H), 9.00 (s, 1 H), 9.53 (S, 1 H).

Préparation 242: {5-Amino-6-ethoxy-pyridin-3-yl)-(7-Îsopropyl-7H-pyrro!o[2,3-d]pyrimidin-5-yl)-methanone

NH,

Me

Copper(l) oxide (38.6 mg, 0.27 mmol) was added to (5-Bromo-6-ethoxy-pyridin3-yl)-(7-isopropyl-7Hpyrrolo[2,3-d]pyrimidin-5-yl)-methanone (Préparation 241, 350 mg, 0.89 mmol) in concentrated ammonia solution (6 mL) and NMP (1 mL). The mixture was heated in a sealed vessel at 130°C for 17 hours. The réaction mixture was cooled to room température and diluted with water (10 ml). It was extracted with 20% i-PrOH in DCM (6 x 50 mL), dried (Na₂SO₄) and evaporated in vacuo. The crude material was purified by column chromatography on silica gel (MeOH:DCM 5:95) to afford the title compound as a yellow solid in 24% yield, 70 mg. LCMS (system 10): R_t = 2.99 min; m/z 326 [M+Hf.

Préparation 243: 2-(4-Chloro-phenyl)-3-hydroxy-propionic acid methyl ester

Cl

To a stirred solution of (4-Chloro-phenyl)-acetic acid methyl ester (2 g, 10.8 mmol) in DMSO (22 mL) was added sodium methoxide (29.2 mg, 0.54 mmol) at 0°C. Paraformaldéhyde (342 mg, 11.4 mmol) was then added and the reaction mixture was stirred at room température for 4 hours. The reaction mixture was diluted with EtOAc (100 mL), washed with water (3 x 20 mL), brine (20 mL), dried (Na₂SOJ and evaporated in vacuo. The crude material was purified by column chromatography on silica gel (gradient of hexane:EtOAc 100:0 to 84:16) to afford the title compound as a colourless gum in 52% yield, 1.2 g.

¹H NMR (400 MHz, CDCI3) &: 2.23 (t, 1H), 3.70 (S, 3H), 3.79-3.83 (m, 2Hf 4.05-4.12 (m, 1H), 7.20 (d, 2H), 7.30 (d, 2H); LCMS (system 10): R, = 3.03 min; m/z 215 [M+Hf.

Préparation 244: 2-(4-Chloro-phenyl)-3-hydroxy-propionic acid

Cl

O

211

To a stirred solution of 2-(4-Chloro-phenyl)-3-hydroxy-propionic acid methyl ester (Préparation 243, 500 mg, 2.33 mmol) in THF (7 mL) was added a solution of lithium hydroxide monohydrate (244 mg, 5.82 mmol) in water (2 mL) dropwise at 0°C and the resulting mixture stirred at room température for 1 hour. The reaction mixture was acidified (pH~3) with 2N hydrochloric acid and extracted with DCM (3 x 20 mL). The combined organic layers were washed with brine (10 mL), dried (Na₂SO₄) and evaporated in vacuo to afford the title compound as a white solid in 90% yield, 420 mg.

¹H NMR (400 MHz, DMSO-D6) Ô: 3.58 (dd, 1H), 3.66 (t, 1H), 3.87 (t, 1H), 7.32 (d, 2H), 7.38 (d, 2H), 12.36 (br, 1H).

Préparation 245:1-(4-Chloro-pyrrolo[2,3-d]pyrimidin-7-yl)-cyclopropanecarboxylic acid methyl ester

To a stirred solution of (4,6-dichloro-pyrimidin-5-yl)acetaldehyde (Préparation 208, 2 g, 10.5 mmol) and 1-Amino-cyclopropane-carboxylicacidmethylester hydrochloride (1.33 g, 11.6 mmol) in éthanol (30 mL) was added triethylamine (4.4 mL, 31.6 mmol) and the mixture heated in a seaied tube at 100°C for 10 hours. Acetic acid (1.21 mL, 21.1 mmol) was then added and the mixture heated at 100°C for additional 16 hours. The reaction mixture was cooled to room température and diluted with DCM (200 mL). The organic layer was washed with water (2 x 50 mL), brine (50 mL), dried (Na₂SO₄) and evaporated in vacuo. The crude material was purified by column chromatography on silica gel (gra'dient of hexane:EtOAc 100:0 to 90:10) to afford the title compound as a solid in 35% yield, 900 mg.

¹H NMR (400 MHz, CDCI3) δ: 1.63-1.66 (m, 2H), 1.96-1.99 (m, 2H), 3.63 (s, 3H), 6.60 (d, 1H), 7.23 (d, 1H), 8.65 (s, 1H); LCMS (system 10): R_t = 2.89 min; m/z 252.1 [M+H]⁺.

Préparation 246: 1-Pyrrolo[2,3-d]pyrimidin-7-yl-cyclopropanecarboxylicacid methyl ester

A solution of 1-(4-chloro-pyrroio [2,3-d]pyrimidin-7-yl)-cyclopropanecarboxylic acid methyl ester (Préparation 245, 920 mg, 3.65 mmol) in éthanol (20 mL) was degassed with argon for 15 min. Ammonium hydroxide (4 mL) and 10% palladium on charcoal were added and the reaction mixture was stirred at room température under hydrogen (balloon pressure) for 5 hours. The reaction mixture was filtered on a celite bed, washed with éthanol (2x10 mL) and the filtrate was evaporated in vacuo. The crude material was purified by column chromatography on silica gel (gradient of DCM:methanol 100:0 to 98:2) to afford the title compound as a gum in 59% yield, 470 mg.

¹H NMR (400 MHz, CDCI3) ô: 1.63-1.66 (m, 2H), 1.95-1.99 (m, 2H), 3.63 (s, 3H), 6.55 (d, 1H), 7.20 (d, 1H), 8.90 (s, 1H), 8.94 (s, 1H); LCMS (system 10): R, = 2.22 min; m/z 218.2 [M+H]⁺.

Préparation 247: (1 -Pyrrolo[2,3-d]pyrimidin-7-yl-cyclopropyl)-methanol

212

To a stirred solution of 1-Pyrrolo[2,3-d]pyrimidin-7-yl-cyclopropanecarboxylic acid methyl ester (Préparation 246, 610 mg, 2.80 mmol) in éthanol (15 mL) was added sodium borohydride (318.7 mg, 8.42 mmol) and the mixture heated to reflux for 16 hours. The reaction mixture was quenched with water (5 mL) and extracted with EtOAc (3x10 mL). The combined organic layers were washed with water (5 mL), brine (5 mL), dried (Na₂SO₄) and evaporated in vacuo. The crude material was purified by column chromatography on silica gel (gradient of DCM:methanol 100:0 to 98:2) to afford the title compound as a light yellow solid in 47% yield, 250 mg.

¹H NMR (400 MHz, CDCI3) ô: 1.26 (s, 4H), 3.83 (s, 2H), 6.47 (d, 1H), 7.26 (d, 1 H), 8.83 (s, 1H), 8.88 (S, 1H); LCMS (system 10): R_t = 1.67 min; m/z 189.9 [M+H]⁺.

Préparation 248: 7-[ 1 -(Tetrahydro-pyran-2-yloxymethyl)-cyclopropyl]-7H-pyrrolo[2,3-d]pyrimidine

To a stirred solution of (1-Pyrroloi2,3-d]pyrimidin-7-yl-cyclopropyl)-methanol (Préparation 247, 240 mg, 1.27 mmol) in THF (12 mL) was added 3,4-dihydro-2H-pyran (0.46 mL, 5.07 mmol) followed by addition of PTSA (24 mg, 0.13 mmol). The reaction mixture was stirred at 60°C for 4 hours. The reaction mixture was cooled to room température, quenched with saturated aqueous sodium bicarbonate solution (15 mL) and extracted with dichloromethane (3 x 25 mL). The combined organic layer was washed with brine (10 mL), dried over sodium sulphate and evaporated in vacuo. The crude material was purified by column chromatography on silica gel (gradient of dichloromethane:methanol 100:0 to 98:2) to afford the title compound as a light brown gum in 90% yield, 320 mg.

¹H NMR (400 MHz, CDCI3) δ: 1.18-1.26 (m, 4H), 1.31-1.55 (m, 5H), 1.67-1.69 (m, 1H), 3.28-3.31 (m, 1H). 3.44 (t, 1H), 3.68 (d, 1H), 3.88 (d, 1H), 4.46 (s, 1H), 6.45 (d, 1H), 7.33 (d, 1H), 8.88-8.90 (m, 2H); LCMS (system 10): R₍ = 2.82 min; m/z 274.6 [M+H]⁺.

Préparation 249: 5-lodo-7-[1-(tetrahydro-pyran-2-yloxymethyl)-cyclopropyl]-7H-pyrrolo[2,3-d]pyrimidine

To a stirred solution of 7-[1-(Tetrahydro-pyran-2-yloxymethyl)-cyclopropyl]-7H-pyrroto(2,3-d]pyrimidine (Préparation 248, 390 mg, 1.43 mmol) in DMF (8 mL) was added N-iodosuccinimide (481.5 mg, 2.14 mmol) and stirred at room température for 4 hours. The reaction mixture was quenched with water (8 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layer was washed with water (5x15

213 mL), brine (10 mL), dried over sodium sulphate and evaporated in vacuo. The crude material was purified by column chromatography on silica gel (gradient of dichloromethane:methanol 100:0 to 99:1) to afford the title compound as a solid in 79% yield, 450 mg.

’H NMR (400 MHz, CDCI3) ô: 1.13-1.70 (m, 10H), 3.28-3.32 (m, 1H), 3.42 (t, 1 H), 3.65 (d, 1H), 3.87 (d, 1H), 4.47 (s, 1H), 7.44 (s, 1H), 8.70 (s, 1H), 8.90 (s, 1H); LCMS (System 10): R, = 3.28 min; m/z 400.2 [M+Hf.

Préparation 250: (5-Bromo-pyridin-3-yl)-{7-[1-(tetrahydro-pyran-2-yloxymethyl)-cyclopropyl]-7H-

To a stirred solution of 5-lodo-7-[1-(tetrahydro-pyran-2-yloxymethyl)-cyclopropyl]-7H-pyrrolo[2,3d]pyrimidine (Préparation 249, 450 mg, 1.13 mmol) in diethyl ether (6 mL) was added n-butyl lithium (2M in hexane, 0.62 mL, 1.24 mmol) drop wise at -70°C. Then a solution of 5;Bromo-N-methoxy-N-methylnicotinamide (304 mg, 1.24 mmol) in diethyl ether (2.5 mL) was added drop wise at -70°C and stirred at same température for another 30 minutes. The réaction was allowed to warm to room température slowly. The reaction was quenched with saturated aqueous ammonium chloride solution (10 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layer was washed with water (20 mL), brine (20 mL), dried over sodium sulphate and evaporated in vacuo. The crude material was purified by column chromatography on silica gel (gradient of dichloromethane:methanol 100:0 to 98:2) to afford the title compound as a light brown sticky solid in 35% yield, 250 mg.

’H NMR (400 MHz, DMSO-D6) Ô: 1.25-1.57 (m, 10H), 3.17-3.28 (m, 2H). 3.64 (d, 1H), 3.95 (d, 1H), 4.57 (s, 1 H), 8.36 (s, 1H), 8.40 (s, 1H), 8.96 (s, 1H), 8.99 (s, 1H). 9.02 (s, 1H), 9.45 (s, 1H); LCMS (system 10); R_t = 3.17 min; m/z 456.8, 459 [M+H]⁺.

Préparation 251 : (5-Am i no-pyri d in-3-yl) -{7-[1 -(tetrahydro-pyran-2-yloxymethyl)-cyclopropyl]-7H-

To a stirred solution of (5-Bromo-pyridin-3-yl)-(7-[1-(tetrahydro-pyran-2-yloxymethyl)-cyclopropyl]-7Hpyrrolo[2,3-d]pyrimidin-5-yl}-methanone (Préparation 250, 200 mg, 0.45 mmol) in 1 -Methyl-pyrrolidin-2one (1.5 mL) was added ammonium hydroxide (15 mL). Then copper (I) oxide (3 mg, 0.02 mmol) was added and the reaction mixture was heated in a sealed tube at 130°C for 16 hours. The reaction mixture was cooled to room température, extracted with 10% methanol in dichloromethane (5 x 25 mL). The

214 combined organic layer was dried over sodium sulphate and evaporated in vacuo. The crude matériel was purified by column chromatography on silica gel (gradient of dichloromethaneimethanol 100:0 to 96:4) to afford the title compound as a white sticky solid in 45% yield, 80 mg.

¹H NMR (400 MHz, DMSO-D6) δ: 1.17-1.53 (m, 10H), 3.17-3.28 (m, 2H), 3.63 (d, 1H), 3.94 (d, 1 H), 4.55 (s, 1H), 5.64 (s, 2H), 7.27 (s, 1H), 8.18-8.20 (m, 3H), 8.99 (s, 1H), 9.42 (s, 1H); LCMS (system 10): R₍ = 2.59 min; m/z 394.1 [M+H]⁺.

Préparation 252: (S)-2-Pyrrolo[2,3-d]pyrimidin-7-yl-propan-1-ol

The title compound was prepared according to the method described for Préparation 8 using (2S)-2-(4Chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)propan-1-ol (Préparation 4) to afford the title compound as a white solid in 100% yield, 2.8 g.

¹H NMR (400 MHz, DMSO-d6) ô: 1.43 (d, 3H), 3.68-3.79 (m, 2H), 4.89-4.94 (m, 1H), 4.97 (t, 1H), 6.61 (d, 1H), 7.71 (d, 1H), 8.75 (s, 1H), 8.97 (s, 1H).

Préparation 253: (2-Hydroxy-1,1-dimethyl-ethyl)-carbamic acid tert-butyl ester

Me

Me-J

O Me

Λ

O NH

Me^k^OH

Me

To a mixture of 2-Amino-2-methyl-propan-1 -ol (2 g, 22.43 mmol) and triethyl amine (3.12 mL, 22.43 mmol) in THF was added boc-anhydride (4.89 g, 22.43 mmol) slowly at 0°C and was stirred at room température for 16 hours. The reaction mixture was diluted with ethyl acetate, washed with water, brine, dried over sodium sulphate and evaporated in vacuo to afford the title compound as colourless oil in 92% yield, 3.9 g.

’H NMR (400 MHz, CDCI₃) δ: 1.23 (S, 6H), 1.42 (s, 9H), 3.56-3.58 (d, 2H), 4.00 (brs, 1H), 4.62 (brs, 1H). Préparation 254: (2-Methoxy-1,1-dimethyl-ethyl)-carbamic acid tert-butyl ester

Me

Me

Λ

O NH

Me—k\/OMe

Me

KOH (3.47 g, 61.82 mmol) was added to a solution of (2-Hydroxy-1,1-dimethyl-ethyl)-carbamic acid tertbutyl ester (Préparation 253, 3.9 g, 20.6 mmol) in 1,4-dioxane (30 mL) followed by the slow addition of dimethyl sulphate at room température. The mixture was further allowed to stir at room température for 48 hours. Reaction mass was filtered through a short pad of celite, washed with DCM (3 x 50 mL). The

215 combined filtrate was washed with water (2 x 50 mL), brine (30 mL), dried over sodium sulphate and evaporated m vacuo to afford the title compound as yellow oil in 88% yield, 3.7 g.

¹H NMR (400 MHz, CDCI₃) Ô: 1.27 (s. 6H), 1.41 (s, 9H), 3.29 (s, 2H), 3.35 (s, 3H), 4.73 (brs, 1H).

Préparation 255: 2-Methoxy-1,1-dimethyl-ethylamine

NH₂

Me-T^s^OMe Me

TFA (5.8 mL, 78.7 mmol) was added slowly to a DCM (25 mL) solution of (2-Methoxy-1,1-dimethyl-ethyl)carbamic acid tert-butyl ester (Préparation 254, 3.2 g, 15.74 mmol) at 0°C. The mixture was allowed to stir at room température for another 3 hours and then ail the volatiles were removed in vacuo. The residue was treated with aqueous saturated NaHCO₃ solution (50 mL) and extracted with a mixture of IPA/DCM (1:4) (4 x 50 mL). The combined organics was dried over sodium sulphate and evaporated to dryness in vacuo to afford the title compound as light brown oil in 100% yield, 1.6 g.

1H NMR (400 MHz, CDCI3) Ô: 1.32 (s, 6H), 3.30 (s, 2H), 3.35 (s, 3H), 7.80 (brs, 2H). Préparation 256: (5-Bromo-2-chloro-pyrimidin-4-yl)-(2-methoxy-1,1-dimethyl-ethyl)-amine

Me-^\_^OMe Me

Triethyi amine (73.1 mL, 526.6 mmol) was added slowly to a solution of 5-Bromo-2,4-dichloro-pyrimidine (40 g, 175.5 mmol) in acetonitrile (400 mL) at 0°C and then 2-Methoxy-1,1-dimethyl-ethylamine (Préparation 255, 23.4 g, 263.3 mmol) was added to the mixture portion wise. The reaction mixture was stirred for another 16 hours at room température. TLC showed the presence of unreacted starting pyrimidine, but the reaction was not continued further. Ail the volatiles were removed in vacuo and the residue was taken in ethyl acetate, washed with water, brine, dried over sodium sulphate and evaporated to dryness in vacuo. The crude material was purified by column chromatography on silica gel (100-200 mesh, gradient of ethyl acetate: h exan e 1:9 to 2:4) to afford the title compound as white solid in 23% yield (10 g of starting pyrimidine was recovered), 12 g.

’H NMR (400 MHz, DMSO-D6) δ: 1.40 (s, 6H), 3.32 (s, 3H), 3.48 (s, 2H), 6.19 (s, 1H), 8.29 (s, 1H); LCMS (system 10): R_t = 3.56 min; m/z 294, 296 [M+Hf.

Préparation 257: [2-Chloro-5-((E)-2-ethoxy-vinyl)-pyrimidin-4-yl]-(2-methoxy-1,1 -dimethyl-ethyl)-amine

Me^L^OMe

Me

The title compound was prepared according to the method described for Préparation 61 using (5-Bromo2-chloro-pyrimidin-4-yl)-(2-methoxy-1,1-dimethyl-ethyl)-amine (Préparation 256), catechol borane and ethoxyacetylene (40% in hexane) to afford the title compound as light brown gum in 44% yield, 2.6 g.

1H NMR (400 MHz, DMSO-D6) δ: 1.25 (t. 3H), 1.37 (s, 6H), 3.26 (s, 3H), 3.56 (s, 2H), 3.92 (q, 2 H), 5.74 (d, 1H), 6.12 (s, 1H), 6.94 (d, 1H), 7.88 (s, 1H); LCMS (system 10): R_v = 3.65 min; m/z 286.3 [M+Hf.

216

Préparation 258: 2-Chloro-7-(2-methoxy-1 _l1-dimethyl-ethyJ)-7H-pyrrolo[2,3-d]pyrimidine

The title compound was prepared according to the method described for Préparation 62 using [2-Chloro5-((E)-2-ethoxy-vinyl)-pyrimidin-4-yl]-(2-methoxy-1,1-dimethyl-ethyl)-amine (Préparation 257) to afford the title compound as off white solid in 91% yield, 2g.

¹H NMR (400 MHz, DMSO-D6) δ 1.68 (s, 6H), 3.17 (s, 3H), 3.85 (s, 2H), 6.62 (d, 1H), 7.63 (d, 1H), 8.90 (s, 1H); LCMS (system 10): R₍ = 3.29 min; m/z 240 [M+Hf.

Préparation 259: 2-Chloro-5-iodo-7-(2-methoxy-1,1 -dimethyl-ethyl)-7H-pyrrolo[2,3-d]pyrimidine

The title compound was prepared according to the method described for Préparation 63 using 2-ChloroT-^-methoxy-l.l-dimethyl-ethyO-TH-pyrrololiï.a-dlpyrirnidine (Préparation 258) to afford the title compound as yellowish solid in 75% yield, 2.3 g.

¹H NMR (400 MHz, DMSO-D6) ô: 1.67 (s, 6H), 3.17 (s, 3H), 3.83 (s, 2H), 7.81 (s, 1H), 8.64 (s, 1H); LCMS (system 10): R₍ = 3.65 min; m/z 365.8 [M+H]⁺.

Préparation 260: (5-Bromo-pyridin-3-yl)-[2-chloro-7-(2-methoxy-1₁1-dimethyl-ethyl)-7H-pyrrolo[2,3d]pyrimidin-5-yl]-methanone

The title compound was prepared according to the method described for Préparation 64 using 2-Chloro5-iodo-7-(2-methoxy-1,1-dimethyl-ethyl)-7H-pyrrolo[2,3-d]pyrimidine (Préparation 259) and 5-Bromo-Nmethoxy-N-methyl-nicotinamide to afford the title compound as yellow gum in 34% yield, 900 mg.

’H NMR (400 MHZ, DMSO-D6) δ: 1,73 (s, 6H), 3.21 (s, 3H), 3.90 (s, 2H), 8.22 (s, 1H), 8.42 (t, 1H), 8.98 (t, 2H),9.35(S, 1H).

Préparation 261: [2-Amino-7-(2-methoxy-1,1 -dimethyl-ethylJ^H-pyrrolopi.S-dlpyrimidin-S-ylHS-aiTiinopyridin-3-yl)-methanone

217

The title compound was prepared according to the method described for Préparation 65 using (5-Bromopyridin-3-yl)-[2-chloro-7-(2-methoxy-1,1-dimethyl-ethyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-methanone (Préparation 260) to afford the title compound as yellow solid in 41% yield, 300 mg.

’H NMR (400 MHz, DMSO-D6) ô: 1.68 (s. 6H), 3.19 (s, 3H), 3.89 (s, 2H), 5.61 (s, 2H). 6.54 (s, 2H), 7.23 (s, 1H), 7.55 (s, 1H), 8.11 (dd, 2H), 8.93 (s, 1H); LCMS (System 10): R| = 2.40 min; m/z 341.2 [M+Hf. Préparation 262: 5-lodo-7-(2-methoxy-1,1-dimethyl-ethyl)-7H-pyrrolo[2,3-d]pyrimidine

OMe

Me

An anhydrous THF (100 mL) solution of 2-(5-lodo-pyrrolo[2,3-d]pyrimidin-7-yl)-2-methyl-propan-1-ol (Préparation 22) (32 g, 100.91 mmol) was added slowly to a suspension of NaH (60% in paraffin oil, 2.98 g, 121.13 mmol) in anhydrous THF (200 mL) at 0°C under nitrogen. The mixture was warmed to room température and stirred for another 30 minutes and again cooled to 0°C and methyl iodide (19 mL, 302.82 mmol) was added drop wise. The reaction mixture was stirred at room température for 2 hours,quenched with aqueous saturated ammonium chloride, and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulphate and evaporated to dryness in vacuo. The crude material was purified by column chromatography on silica (100-200 mesh, gradient of hexane:EtOAc 100:0 to

70:30) to afford the title compound as a yellow sticky solid in 22% yield, 7.5 g.

’H NMR (400 MHz, DMSO-D6) ô: 1.70 (s, 6H), 3.15 (s, 3H), 3.89 (s, 2H), 7.77 (s, 1H), 8.70 (s, 1H), 8.82 (s, 1H); LCMS (system 10): R₍ = 3.42 min; m/z 331.6 [M+Hf.

Préparation 263: (5-Bromo-pyridin-3-yl)-[7-(2-methoxy-1,1-dimethyl-ethyl)-7H-pyrrolo[2,3-d]pyrimidin-5 ylfmethanone

The title compound was prepared according to the method described for Préparation 64 using 5-lodo-7^-methoxy-IJ-dimethyl-ethylJ-ZH-pyrrolo^.S-dlpyrimidine (Préparation 262) and 5-Bromo-N-methoxyN-methyl-nicotinamide to afford the title compound as light brown gum in 51% yield, 3g.

’H NMR (400 MHz, DMSO-d_e) Ô: 1.76 (s, 6H), 3.19 (s, 3H), 3.96 (s, 2H), 8.17 (s, 1H), 8.42 (t, 1H), 8.98 (brs, 2H), 9.00 (s, 1 H), 9.47 (s, 1H); LCMS (system 10): R, = 3.13 min; m/z 388.6, 390.6 [M+Hf.

218

Préparation 264: 2-(3,5-Di1luoro-pyridin-2-yl)-malonic acid diethyl ester

Me u u

To a stirred solution of 2,3,5-trifluoro-pyridine (2 g, 15.02 mmol) in dimethyl sulfoxide (20 mL) was added diethyl malonate (4.60 g, 28.72 mmol). Then césium carbonate (9.35 g, 28.72 mmol) was added and the reaction mixture was heated to 110°C for 16 hours. The reaction mixture was cooled to room température and diluted with ethyl acetate (100 mL). The organic layer was washed with water (2 x 25 mL), brine (25 mL), dried over sodium sulphate and evaporated in vacuo to afford the title compound as oii in 85% yield, 3.5 g.

¹H NMR (400 MHz, CDCI₃) δ: 1.25-1.30 (m, 6 H), 4.20-4.29 (m, 4 H), 4.88'(s, 1 H), 7.77-7.81 (m, 1 H), 8.01 (s, 1 H).

Préparation 265: (3,5-Difluoro-pyridin-2-yl)-acetic acid

To a stirred solution of 2-(3,5-difluoro-pyridin-2-yl)-malonic acid diethyl ester (1 g, 3.56 mmol) (Préparation 264) in THF (15 mL) was added a solution of lithium hydroxide monohydrate (462 mg, 10.4 mmol) in water (4 mL) dropwise at 0°C and the mixture heated to reflux for ? hours. The reaction mixture was cooled to room température, acidified (pH ~3) with 2N hydrochloric acid and extracted with 20% isopropanol-dichloromethane (5 x 20 mL). The combined organic layers were dried (Na₂SO₄) and evaporated in vacuo. The crude material was purified by column chromatography on silica gel (gradient of DCM: MeOH 100:0 to 95:5) to afford the title compound as a solid in 53% yield, 336 mg.

¹H NMR (400 MHz, DMSO-D6) Ô 3.32 (s, 2H), 7.74-7.79 (m, 1H), 7.99 (t, 1H); LCMS (system 10): R, = 0.65 min; m/z 174 [M+H]⁺.

Préparation 266: (4-Nitro-phenyl)-acetic acid ethyl ester

Me

To a stirred solution of (4-nitro-phenyl)-acetic acid (3 g, 16.4 mmol) in éthanol (30 mL) was added sulphuric acid (1 mL) and the reaction mixture was heated to reflux for 16 hours. The reaction mixture was neutralized with 2N aq. NaOH solution and extracted with EtOAc (3 x 50 mL). The combined organic layers were dried (Na₂SO₄) and evaporated in vacuo to afford the title compound as a light yellow oil in 98% yield, 3.4 g.

¹H NMR (400 MHz, CDCI₃) δ: 1.25 (t, 3H), 3.71 (s, 2H), 4.16 (q, 2H), 7.45 (d, 2H), 8.18 (d, 2H). Préparation 267: (4-Amino-phenyl)-acetic acid ethyl ester

219

nh₂

A solution of (4-nitro-phenyl)-acetic acid ethyl ester (Préparation 266, 3,4 g, 16,1 mmol) in methanol (100 mL) was degassed with argon for 15 min, treated with 10% palladium on charcoal (700 mg), and then stirred at room température under hydrogen (balloon pressure) for 16 hours. The reaction mixture was 5 filtered through celite, washed with methanol (2 x 20 mL) and the filtrate was evaporated in vacuo to afford the title compound as an oil in 96% yield, 2,8 g.

¹H NMR (400 MHz, CDCI₃) Ô: 1.23 (t. 3H), 3.47 (s, 2H), 3.60 (brs, 2H), 4.11 (q, 2 H), 6.63 (d, 2H), 7.05 (d, 2H).

Préparation 268: (4-Formylamino-phenyl)-acetic acid ethyl ester

A mixture of acetic anhydride (0.33 mL, 3.57 mmol) and formic acid (0.17 mL, 4.46 mmol) was heated at 60°C for 2 hours. The reaction mixture was cooled to 0°C, a solution of (4-amîno-phenyl)-acetic acid ethyl ester (Préparation 267, 500 mg, 2.79 mmol) in THF (10 mL) was added slowly to the reaction mixture 15 and the reaction was allowed to stir at room température for 16 hours. The reaction mixture was neutralized with sat. aq. Na₂CO₃ solution and extracted with diethyl ether (2 x 25 mL). The combined organic layers were dried (Na₂SO₄) and evaporated in vacuo. The crude material was purified by column chromatography on silica gel (gradient of DCM:MeOH 100:0 to 98:2) to afford the title compound as an oil in 93% yield, 500 mg.

’H NMR (400 MHz, DMSO-d₆) ô: 1.17 (t, 3H), 3.59 (s, 2H), 4.05 (q, 2H), 7.20 (d, 2H), 7.52 (d, 2H), 8.25 (d, 1H), 10.15 (s, 1H).

Préparation 269: (4-Methylamino-phenyl)-acetic acid ethyl ester

O Me

To a stirred solution of (4-formylamino-phenyl)-acetic acid ethyl ester (Préparation 268, 500 mg, 2.41 25 mmol) in THF (10 mL) was added borane-dimethyl sulphide complex (0.3 mL, 3.13 mmol) at 0^DC and the mixture stirred at room température for 1 hour. The reaction mixture was quenched with MeOH (5 mL) and evaporated in vacuo. The crude material was purified by column chromatography on silica gel (gradient of hexane:EtOAc 100:0 to 75:25) to afford the title compound as an oil in 91% yield, 460 mg.

¹H NMR (400 MHz, CDCI₃) ô: 1.23 (t, 3H), 2.81 (s, 3H), 3.48 (s, 2H), 3.66 (brs, 1 H), 4.11 (q, 2H), 6.56 (d, 30 2H), 7.09 (d, 2 H).

Préparation 270: (4-(Methanesulfonyl-methyl-amino)-phenyl]-acetic acid ethyl ester

o

220

To a stirred solution of (4-methylamino-phenyl)-acetic acid ethyl ester (Préparation 269, 418 mg, 2.16 mmol) in pyndine (4 mL) was added methanesulfonyl chloride (0.25 mL, 3.24 mmol) and the mixture stirred at room température for 3 hours. The reaction mixture was quenched with water (10 mL) and extracted with EtOAc (3x15 mL). The combined organic layers were washed with water (10 mL), brine (10 mL), dried (Na₂SO₄) and evaporated in vacuo to afford the title compound as a gum in 78% yield, 460 mg.

¹H NMR (400 MHz, CDCI₃) ô: 1.25 (t, 3H), 2.82 (s, 3H), 3.30 (s, 3H), 3.59 (s, 2H), 4.14 (q. 2H), 7.28-7.33 (m,4H).

Préparation 271: [4-(Methanesulfonyl-methyl-amino)-phenyl]-acetic acid

The title compound was prepared according to the method described for Préparation 265 using [4 (methanesulfonyl-methyl-amino)-phenyl]-acetic acid ethyl ester (Préparation 270) to afford the title compound as a solid in 85% yield, 350 mg.

¹H NMR (400 MHz, DMSO-D6) ô: 2.92 (s, 3H), 3.21 (s, 3H), 3.55 (s, 2H), 7<28 (d, 2H), 7.33 (d, 2H); LCMS (system 10): R, = 1.05 min; m/z 244 [M+H]'.

Préparation 272: 2-lodo-5-methyl-pyridine

To a stirred solution of 2-bromo-5-methyl-pyridine (2 g, 11.6 mmol) in acetonitrile (25 mL) was added sodium iodide (6.97 g, 46.5 mmol) and the mixture heated to reflux. Acetyl chloride (1.24 mL, 17.44 mmol) was added dropwise under reflux conditions and the reaction mixture was heated to reflux for 16 hours. The reaction mixture was cooled to room température, quenched with sat. aq. Na₂CO₃ solution (15 mL) and extracted with EtOAc (3 x 25 mL). The combined organic layers were washed with brine (10 mL), dried (Na₂SO₄) and evaporated in vacuo to afford the title compound as an oil in 55% yield, 1.4 g.

LCMS (system 10): R, = 3.10 min; m/z 220 [M+H]⁺.

To a stirred solution of 2-lodo-5-methyl-pyridine (Préparation 272, 1 g, 4.57 mmol) and diethyl malonate (2.08 mL, 13.70 mmol) in anhydrous dioxane (12 mL) was added césium carbonate (4.46 gm, 13.7 mmol) and the solution was degassed with argon for 30 min. Cul (174 mg, 0.91 mmol) and picolinic acid (225 mg, 1.83 mmol) were added and the résultant mixture was heated in a sealed tube at 100°C for 16 hours. The reaction mixture was cooled to room température, quenched with water (25 mL) and extracted with EtOAc (3 x 25 ml). The combined organic layers were washed with water (2x10 mL) and brine (10 mL),

221 dried (Na₂SO₄) and evaporated in vacuo. The crude material was purified by column chromatography on silica gel (gradient of hexane:EtOAc 100:0 to 90:10) to afford the title compound as an oil in 23% yield, 300 mg.

¹H NMR (400 MHz, DMSO-D6) Ô: 1.15-1.18 (m, 6H), 2.29 (s, 3H), 4.12-4.17 (m, 4H), 5.01 (s, 1H), 7.30 (d, 1H), 7.62 (dd, 1H), 8.34 (s, 1H).

Préparation 274: (5-Methyl-pyridin-2-yl)-acetic acid

The title compound was prepared according to the method described for Préparation 265 using 2-(5methyl-pyridin-2-yl)-malonic acid diethyl ester (Préparation 273) to afford the title compound as a solid in 83% yield, 100 mg.

¹H NMR (400 MHz, DMSO-D6) ô: 2.26 (s, 3H), 3.64 (s, 2H), 7.21 (d, 1H), 7.53 (d, 1H), 8.29 (s, 1H); LCMS (System 10): R₍ = 0.73 min; m/z 152 [M+H]*.

Préparation 275: [1,2,4]triazolo[1,5-a]pyridine-7-carboxylic acid

To a solution of methyl 2-aminoisonîcotinate (28.8 g, 191 mmol) in DMF (97.5 mL) was added DMF-DMA (70.6 mL, 496 mmol) and the mixture heated to 130 °C for 12 hours. The mixture was then concentrated to give a residue. To the residue was added MeOH (381 mL), followed by NH₂OHSO₄ (31.9 g, 248 mmol) and the resulting mixture was stirred at room température overnight. The reaction mixture was concentrated to give methyl [1,2,4]triazoto[1,5-a]pyridine-7-carboxylate in 18% yield, 6g. To a solution of methyl [1,2,4]triazolo[1,5-a]pyridine-7-carboxylate (3 g, 16 mmol) in methanol was added 1M aq. LiOH (70 mL) and the resulting mixture stirred for 10 hours at room température. The pH was adjusted to 5-6 using aq. HCI and the whole mixture extracted with EtOAc (30 mLx3).The combined organic layers were dried (Na₂SO₄) and concentrated in vacuo to give the title compound as a white solid in 38% yield, 1.05 g 1H NMR (400 MHz, DMSO-d6) δ: 7.56-7.58 (m, 1H), 8.32 (m, 1H), 8.66 (m, 1H), 9.04-9.06 (m, 1H), 13.514.0 (s, 1H).

Préparation 276: 1 -methyl-1 H-pyrrolo[2,3-c]pyridine-3-carboxylic acid

1-methyl-1 H-pyrrolo[2,3-c]pyridine-3-carbaldehyde (WO 05066132) (6.5 g, 40.6 mmol) was dissolved in a mixture of THF (120 mL) and tert-butyl alcohol (40 mL) under nitrogen. 2-Methyl-2-butene (120 mL of a 2M solution in THF, 46 mmol) was added followed by a solution of NaCIO₂ (11.0 g, 122 mmol) and NaH₂PO₄ (21.9 g, 183 mmol) in water (30 mL). The reaction mixture was stirred at room température overnight under nitrogen. The reaction mixture was concentrated in vacuo to remove organic solvents,

222 and the residue was filtered. The precipitate contained the title compound as a white solid in 57% yield,

4.1 g.

1H NMR (400MHz, DMSO-d6) δ: 3.96 (S. 3H), 7.87-7.89 (d, 1H), 8.23 (s, 1H), 8.28 (d, 1H), 8.91 (s, 1H), 12.3 (s, 1 H).

Préparation 277: 2-(4-Cyano-phenyl)-N-{5-[7-(2-trimethylsilanyl-ethoxymethyl)-7H-pyrrolo[2,3d]pyrimidine-5-carbonyl]-pyridin-3-yi}-acetamide

The title compound was prepared according to the method described for Example 1 using (5-Aminopyridin-3-yl)-[7-(2-trimethylsilanyl-ethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-methanone (Préparation 103) and 4-cyanophenylacetic acid to afford the title compound as an off-white solid in 71% yield, 235 mg. ’H NMR (400 MHz, DMSO-D6) δ: -0.11 (s, 9H), 0.82 (t, 2H), 3.59 (t, 2H), 3.87 (s, 2H), 5.70 (s, 2H), 7.55 (d, 2H), 7.82 (d, 2H), 8.47 (s, 1H), 8.61 (s, 1H), 8.73 (s, 1H), 8.98 (s, 1H), 9.04 (s, 1H), 9.48 (S, 1 H), 10.75 (s, 1H); LCMS (System 10): R_t = 3.25 min; m/z 513 [M+H]⁺.

Préparation 278: 2-Methyl-2-pyrrolo[2,3-d]pyrimidin-7-yl-propane-1,3-diol

The title compound was prepared according to the method described for Préparation 246 using 2-(4Chloro-pyrrolo[2,3-d]pyrimidin-7-yl)-2-methyl-propane-1,3-diol (Préparation 217) to afford the title compound as an off-white solid in 93% yield, 800 mg.

’H NMR (400 MHz, DMSO-D6) ô: 1.65 (s, 3H), 3.87-3.91 (m, 2H), 4.10-4.14 (m, 2H), 4.94 (t, 2H), 6.55 (d, 1H), 7.63 (d. 1H), 8.72 (s, 1H), 8.95 (s, 1H).

Préparation 279: N-(5-{7-(2-(te rt-Butyl-d imethyl-s ilanyloxy)-1,1 -dimethyl-ethyl]-7H-pyrrolo[2,3d]pyrimidine-5-carbonyl}-pyridin-3-yl)-2-(4-cyclopropyl-pyrazol-1-yl)-acetamide

The title compound was prepared according to the method described for Example 1 using (5-Aminopyridin-3-yl)-{7-[2-(tert-butyl-dimethyl-silanyloxy)-1,1-dimethyl-ethyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}-

223 methanone (Préparation 38) and (4-Cyclopropyl-1 H-pyrazol-1-yl)acetic acid (Préparation 88) to afford the title compound as an an off-white solid in 41% yield, 55 mg.

¹H NMR (400 MHz, DMSO-D6) δ; -0.24 (s, 6H), 0.46 (m, 2H), 0.60 (s, 9H), 0.79 (m, 2H), 1.67 (m, 1H), 1.75 (s, 6H), 4.11 (s, 2H), 4.98 (s, 2H), 7.26 (s, 1H), 7.52 (s, 1H), 8.16 (s, 1H), 8.46 (s, 1H), 8.71 (d, 1 H). 8.91 (d, 1H), 8.99 (s, 1H), 9.47 (s, 1 H), 10.75 (s, 1H); LCMS (System 10): R_t = 3.78 min; m/z 574 [M+H]⁺. Préparation 280: Bicyclo[1.1.1]pent-1-yl-(5-bromo-2-chloro-pyrimidin-4-yl)-amine

To a solution of 5-Bromo-2,4-dÎchloro-pyrimidine (6 g, 26.3 mmol) and bicyclo[1.1.1]pent-1-ylamine (4.7 g, 39.5 mmol) in acetonîtrile (60 mL), was added TEA (16.5 mL, 118 mmol), and the mixture was stirred at 25°C for 18 hours. The volatiles were removed in vacuo and the residue partitioned between water and EtOAc. The organic phase was dried (Na_aSO₄) and evaporated in vacuo. Purification by column chromatography on silica gel (EtOAc:Hexane 1:99) afforded the title compound as a white solid in 82% yield, 4.8 g.

’H NMR (400 MHz, DMSO-D6) δ: 2.10 (d, 6H), 2.48-2.50 (m, 1 H), 8.26 (d, 2H); LCMS (System 10) ; R_t = 3.64 min; m/z 276 [M+H]⁺.

Préparation 281: Bicyclo[1.1.1]pent-1-yl-[2-chloro-5-((Z)-2-ethoxy-vinyi)-pyrimidin-4-yi]-amine

CI^N^NH âr

To a stirred solution of Bicyclo[1.1.1]pent-1-yl-(5-bromo-2-chloro-pyrimidin-4-yl)-amine (Préparation 280, 2 g, 7.29 mmol) in dry toluene (70 mL) was added (Z)-1-ethoxy-2-(tributylstannyl)ethene (2.7 mL, 8.03 mmol). The reaction mixture was purged with N₂ for 20 min and then Pd(PPh₃)₄ (421 mg, 0.36 mmol) was added, followed by degassing for another 20 min and heating to 110°C under N_a overnight. The reaction was cooled to room température, quenched with a 2M solution of KF and filtered through a pad of Celite. The filtrate was partitioned between water (50 mL) and EtOAc (200 mL). The organic phase was washed with brine (2 x 25 mL), dried (Na_aSO₄) and evaporated in vacuo.The crude residue was purified by column chromatography on silica gel (EtOAc: Hexane 18: 82) to afford the title compound as a pale green solid in 77% yield, 1.5 g.

¹H NMR (400 MHz, DMSO-D6) δ: 1.24 (t, 3H), 2.08 (d, 6H), 2.47 (m, 1H), 3.99 (q, 2H), 5.17 (d, 1H), 6.55 (d, 1H), 7.90 (s. 1H), 8.39 (s, 1H); LCMS (System 10): R, = 3.54 min; m/z 266 [M+H]⁺.

Préparation 282: 7-Bicyclo[1.1.1]pent-1-yl-2-chloro-7H-pyrrolo[2,3-d]pyrimidine

224

N

Cl—<'

N dThe title compound was prepared according to the method described for Préparation 62 using bicyclo[1.1.1]pent-1-yl-[2-chloro-5-((Z)-2-ethoxy-vinyl)-pyrimidin-4-yl]-amine (Préparation 281) to afford the title compound as an off-white solid in 89% yield, 1.4 g.

¹H NMR (400 MHz, DMSO-D6) δ: 2.41 (d, 6H), 2.69 (m, 1H), 6.67 (d, 1H), 7.61 (d, 1H), 8.92 (s, 1H); LCMS (System 10): R| = 3.45 min; m/z 220 [M+Hf.

Préparation 283: 7-Bicyclo[1.1.1]pent-1-yl-2-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine

I

The title compound was prepared according to the method described for Préparation 63 using 7bicyclo[1.1.1]pent-1-yl-2-chloro-7H-pyrrolo[2,3-d]pyrimidine (Préparation 282) to afford the title compound as a brown solid in 72% yield, 1,3g .

¹H NMR (400 MHz, DMSO-D6) δ: 2.40 (d, 6H), 2.68 (m, 1 H), 7.90 (s, 1H), 8.67 (s, 1H); LCMS (System 10): R_t = 3.89 min; m/z 346 [M+Hf.

Préparation 284: (7-Bicyclo[1.1.1]pent-1-yl-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-(5-bromo-pyridin-3yl)-methanone

method described for Préparation 64 using 7The title compound was prepared according to the bicyclo[1.1.1]pent-1-yl-2-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (Préparation 283) to afford the title compound as an off-white solid in 58% yield, 1.1 g.

¹H NMR (400 MHz. DMSO-D6) δ: 2.47 (d, 6H), 2.72 (m, 1H), 8.40-8.42 (m, 2H), 8.99-9.00 (m, 2H), 9.33 (s, 1H); LCMS (System 10): R, = 3.73 min; m/z 405 [M+Hf.

Préparation 285: [7-Bicyclo[1.1.1]pent-1-yl-2-(4-methoxy-benzylamino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl](5-bromo-pyridin-3-yl)-methanone

225

To a solution of (7-Bicyclo[1.1.1]pent-1-yl-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-(5-bromo-pyridin-3-yl) methanone (Préparation 284, 1.1 g, 2.72 mmol) and 4-methoxy benzyl amine (1.06 mL, 8.16 mmol) in dioxane (40 mL), DIPEA (1.7 mL, 10.8 mmol) was added and mixture was heated at 110°C under microwave irradiation for 6 hours. The volatiles were removed in vacuo and the residue was partitioned between water (50 mL) ethyl acetate (150 mL). Organic phase was dried over sodium sulphate, evaporated in vacuo and purified by column chromatography on silica gel (gradient of EA: Hexane 25: 75) to afford the title compound as off white solid in 84 % yield, 1.15 g.

¹H NMR (400 MHz, DMSO-D6) δ: 2.35 (d, 6H), 2.64 (m, 1H), 3.70 (s, 3H), 4.45 (d, 2H), 6.85 (d, 2H), 7.27 (d, 2H), 7.75 (s, 2H), 8.32 (m, 1H), 8.91-8.94 (m, 2H); LCMS (System 10): R, = 3.81 min; m/z 504.2 [M+H]\

Preparation 286: [5-(Benzhydrylidene-amino)-pyridin-3-yl]-[7-bicyclo[1.1.1]pent-1-yl-2-(4-methoxybenzylamino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-methanone

To a stirred solution of [7-Bicyclo[1.1.1]pent-1-yl-2-(4-methoxy-benzylamino)-7H-pyrrolo[2,3-d]pyrimidin-5yl]-(5-bromo-pyridin-3-yl)-methanone (Préparation 285, 1.18 g, 2 mmol) and benzophenoneimine (0.50 mL, 3 mmol) in dry toluene (50 mL), césium carbonate (3.2 g, 10 mmol) was added and the réaction mixture was purged under N₂ for 20 min and then Pd(OAc)₂ (45 mg, 0.2 mmol) and BINAP (125 mg, 0.2 mmol) were added followed by degassing for another 10 min and refluxing overnight. The reaction mass was cooled to room température and filtered through a pad of Celite. The filtrate was partitioned between water (25 mL) and EtOAc (100 mL). The organic phase was washed with brine (10 mL), dried (Na₂SO₄) and evaporated in vacuo. Purification by column chromatography on silica gel (EtOAc:Hexane 25:75) afforded the title compound as a yellow solid in 85 % yield, 1.1g .

¹H NMR (400 MHz, DMSO-D6) δ: 2.36 (d, 6H), 2.65 (m, 1H), 3.70 (s, 3H), 4.44 (d, 2H), 6.84 (d, 2H), 7.24-7.29 (m, 4H), 7.36-7.37 (m, 3H), 7.50-7.52 (m, 4H), 7.58 (m, 1H), 7.70-7.72 (m, 3H), 8.15 (d, 1H), 8.48 (d, 1H), 8.89 (s, 1H); LCMS (System 9): R, = 4.02 min; m/z 605 [M+H]⁺.

Préparation 287: (5-Amino-pyridin-3-yl)-[7-bicyclo[1.1.1]pent-1-yl-2-(4-methoxy-benzylamino)-7Hpyrrolo[2,3-d]pyrimidin-5-yl]-methanone

To a solution of [5-(Benzhydrylidene-amino)-pyridin-3-yl]-[7-bicyclo[1.1.1]pent-1-yl-2-(4-methoxybenzylamino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-methanone (Préparation 286, 475 mg, 0.78 mmol) in THF

226 (15 mL), citric acid (15 mL of a 1N aq. solution) was added at room température and the reaction mixture stirred for 2 hours. The reaction was then quenched with sat. aq. Na₂CO₃ solution and extracted with EtOAc (2 x 25 mL). The combined organic phases were dried (Na₂SO₄) and evaporated in vacuo. Purification by column chromatography on neutral alumina (Methanol:DCM 3: 97) to afford the titie compound as a pale yellow solid in 92 % yield, 320 mg.

¹H NMR (400 MHz, DMSO-D6) δ: 2.36 (d, 6H), 2.64 (m, 1H), 3.70 (s, 3H), 4.45 (d, 2H), 5.59 (s, 2H), 6.84 (d, 2H), 7.22 (m, 1H), 7.28 (d, 2H), 7.57 (s, 1H), 7,72 (brs, 1H), 8.10-8.12 (m, 2H), 8.92 (s, 1H); LCMS (System 10): R, = 3.10 min; m/z 441 [M+H]⁺.

Préparation 288:1-Cyclobutyl-1H-imidazole-4-carboxylic acid hydrochloride

Ethyl 3-(dimethylamino)-2-isocyanoacrylate (WO 2007042545) (45 g, 0.27 mol) was added to cyclobutylamine (50 g, 0.70 mol) and heated to reflux for 2 hours. The solution was then cooled and concentrated. The residue was purified by column chromatography over silica gel (3:1 EtOAc:Heptane). The oily residue was triturated with TBME:heptane (1:1) and the resulting solid was collected and dried, giving 1-cyclobutyl-1 H-imidazole-4-carboxylic acid ethyl ester (35 g, 67%, second crop not harvested). 1Cyclobutyl-1 H-imidazole-4-carboxylic acid ethyl ester (35 g, 0.21 mol) was dissolved in 6 N HCl (300 mL) and refluxed for 1 day. The solution was concentrated to dryness in vacuo. The solid was azeotroped with toluene, triturated with toluene and then dried under vacuum, giving the titie compound 88% yield,

37.2 g, m/z 167 [M+H]⁺.

Préparation 289: (2-Methylimidazo[2,1-b][1,3]thiazo!-6-yl)acetic Acid Hydrochloride

Ethyl 4-bromo-3-oxobutanoate (92 g, 0.35 mol) was added to a solution of 5-methylthiazol-2-amine (40 g, 0.35 mol) in acetone (400 mL). The mixture was left to stand overnight and then evaporated to give 2amino-3-(4-ethoxy-2,4-dioxobutyl)-5-methylthiazol-3-ium bromide in 82% yield, 101 g. 2-amino-3-(4ethoxy-2,4-dioxobutyl)-5-methylthiazol-3-ium bromide (101g, 0.28 mol) was then refluxed in éthanol (250 mL) for 2 hours. The solvent was then evaporated to give ethyl 2-(2-methylimidazo[2,1-b]thiazol-6yljacetate hydrobromide as yellow crystals in 97% yield, 85 g. Solid K₂CO₃ was added to a solution of ethyl 2-(2-methylimîdazo[2,1-b]thiazol-6-yl)acetate hydrobromide (85 g, 0.28 mol) in water (300 mL) to pH ~8. The product was extracted with chloroform (3 χ 100 mL), and the combined extracts were dried over Na₂SO₄ and evaporated to give ethyl 2-(2-methylimidazo[2,1-b]thiazol-6-yl)acetate in 84% yield 52 g.

227

Ethyl 2-(2-methylimidazo[2,1-b]thiazol-6-yl)acetate (52 g, 0.23 mol) was refluxed in 10% aqueous HCl (150 mL) for 2 hours. The solution was evaporated to dryness to give the title compound as brown crystals in 59% yield 32.3 g; m/z 197 [M+Hf.

Préparation 290: 3-Methyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid

To a solution of benzyl acetoacetate (57.6 g, 300 mmol) in MeOH (50 mL) in a 350 mL pressure vessel was added H₂NMe (150 mL of a 2M solution in MeOH, 300 mmol) and acetic acid (2 mL). The capped vessel was placed in an oil bath at 70 °C and the reaction mixture was stirred for 16 hours. After the mixture had cooled to room température, the solvent was evaporated in vacuo leaving a yellow émulsion, which was dissolved in EtOAc (500 mL) and MgSO₄ was added to remove water. The drying agent was filtered off, and the solvent evaporated in vacuo to give benzyl 3-(Methylamino)but-2-enoate as a viscous yellow oil in quantitative yield 60 g which was used without further purification.

To a solution of benzyl 3-(methylamino)but-2-enoate (60 g, 300 mmol) and pyridine (27 mL, 330 mmol) in THF (500 mL), cooled to -20 °C, was added triflic anhydride (45 mL, 315 mmol) over a 30 min period. During the addition, the température was kept below -10 °C. The reaction mixture was ailowed to warm to room température overnight resulting in a yellow clear reaction mixture. The solvent was evaporated in vacuo and the orange residue was taken up in water (1L) and Et₂O (1L). Upon shaking the mixture well in a 3-L separatory funnel, ail solid material dissolved. The organic layer was separated and washed with water (3 x 500 mL), brine (500 mL) and dried over MgSO₄. Filtration and évaporation of the solvent in vacuo provided benzyl 3-(Methylamino)-2-(trifluoroacetyl)but-2-enoate as an off-white solid in 97% yield, 90 g that was used without additional purification.

To a solution of benzyl 3-(methylamino)-2-(trifluoroacetyl)but-2-enoate (90 g, 300 mmol) in a mixture of THF (900 mL) and acetic acid (100 mL) was added hydrazine monohydrate (14.6 mL, 300 mmol) over a 5 min period. The reaction mixture was heated to reflux for 3 hours, ailowed to cool to room température and the solvents were evaporated in vacuo to afford a bright yellow mass. The mass was dissolved in EtOAc (1L) and water (1L) with gentle heating, ailowed to cool to room température and the aqueous layer was neutralized to pH 7-8 with NaHCO₃. This mixture was transferred to a 3-L separating funnel, the layers were mixed vigorously, separated and the organic layer was washed with water (3 x 500 mL) dried (MgSO₄), filtered and evaporated in vacuo to give benzyl 3-methyl-5-(trifluoromethyl)-1H-pyrazole-4carboxylate as an off-white solid in 89% yield 74 g that was used without further purification.

A mixture of benzyl 3-methyl-5-(trifluoromethyl)-1/-/-pyrazole-4-carboxylate (74 g, 285 mmol), Pd/C (45 g, 10% on C) and EtOAc (1L) was treated in a Parr apparatus at room température with H₂ (15 psi) for 5 hours. The catalyst was filtered off over Celite and the solvent was removed in vacuo. Et₂O (1L) and water (200 mL) were added and the aqueous layer was made slightly basic (pH 8-9) with Na₂CO₃. The layers were separated and the aqueous layer was extracted with Et₂O (5 x 200 mL). To the aqueous layer was added dropwise conc. HCl until pH 4-5 and followed by extraction with Et₂O (3 x 500 mL). The combined

228 organic layers were dried (MgSO₄), filtered, evaporated in vacuo to give the title compound in 74% yield

7.4 g; m.p. 308-310 °C (dec.) m/z 195 [M+H]⁺

Préparation 291: Ethyl [4-(3-Hydroxyphenyl)-1H-1,2,3-triazol-1-yl]acetate

Ethyl azidoacetate (14.9 g, 115 mmol) was dissolved in tert-butanoi (200 mL), and 95% 3hydroxybenzonitrile (13.7 g, 110 mmol) was added. A solution of sodium ascorbate (2.18 g, 11 mmol) in water (100 mL) was added, followed by a 0.3 M solution of copper sulfate under argon. The mixture was stirred at room température for 12 hours. The solution was evaporated to dryness in vacuo, the residue was dissolved in EtOAc (100 mL), dried (MgSO₄), filtered, evaporated in vacuo to give the title compound as brown crystals in -100% (27.7 g) yield.

MS m/z 246 [M-H]’

Préparation 292 : [4-(3-Hydroxyphenyl)-1 H-1,2,3-triazol-1 -yljacetic Acid Hydrate

Ethyl [4-(3-Hydroxyphenyl)-1/-/-1,2,3-triazol-1-yl]acetate (Préparation 291, 27.2 g, 0.110 mol) was dissolved in methanol (200 mL), and a solution of NaOH (4.84 g, 121 mmol) in water (40 mL) was added. The solution was kept at room température for 24 hours. Methanol was evaporated in vacuo, water (120 mL) was added, and the solution was refluxed with activated charcoal. The mixture was filtered, and

M HCl was added to the filtrate. The mixture was dissolved by addition of water (120 mL) and cooled to carry out the crystallization. The crystals were filtered, washed with water (2 x 25 mL), and evaporated to dryness to afford the title compound as brown crystals (mp 186.3-188.7 °C) in 99.0% yield 23.9 g. MS m/z 218 [M-H]’

Préparation 293: Ethyl [4-(1-hydroxycyclopentyl)-1 H-1,2,3-triazol-1-yl]acetate

Ethyl azidoacetate (2.58 g, 20 mmol) was dissolved in ferf-butanol (15 mL), and 1hydroxycyclopentanecarbonitrile (2.20 g, 20 mmol) was added. A solution of sodium ascorbate (0.792 g, 4 mmol) in water (10 mL) followed by a 0.3 M solution of copper sulfate (0.67 mL) was added to the mixture, and stirring continued at room température for a further 48 hours. The solution was evaporated to dryness in vacuo and the residue was dissolved in EtOAc (50 mL), dried (MgSO₄), filtered and evaporated in vacuo to afford the title compound as green-yellow crystals in 98% yield, 4.69 g.

MS m/z 238 [M-H]'

229

Préparation 294: [4-(1 -hydroxycyclopentyl)-1 H-1,2,3-triazol-1 -yl]acetic acid

To a solution of ethyl [4-(1-hydroxycyclopentyl)-1H-1,2,3-triazol-1 -yljacetate (Préparation 293, 36.4 g, 151 mmol) in water (50 mL), was added a solution of NaOH (7.60 g, 190 mmol) in water (25 mL). The solution was reiluxed with activated charcoal, filtered through Celite, and NaHSO₄ (25.8 g, 190 mmol) added. EtOAc (50 mL) was added to the filtrate. The formed precipitate was separated by filtration, dissolved in EtOAc (100 mL), and the solution was filtered. The water layer was extracted with EtOAc (10 x 50 mL), and the combined extracts were evaporated to a volume of 100 mL. The precipitate was filtered, washed with ethyl acetate (2 x 50 mL), and concentrated under reduced pressure to afford the title compound as a colorless crystalline substance in 87% yield, 27.8 g. mp 124.0-126.0 °C; MS m/z 212 [M+Hf Préparation 295: Di-tert-butyl 1-(1-methyl-1H-pyrazol-4-yl)hydrazine-1,2-dicarboxylate

Me Me ^~Me

To a solution of 4-iodo-1-methyl-1H-pyrazole (21 g, 0.12 mol) in dry ether (200 mL) at -78 °C was added n-BuLi (84.5 mL of a 2.5 M solution in hexane, 0.18 mol) over a period of 30 min and the mixture stirred for a further 30 min. A solution of di-tert-butyl (Z)-diazene-l ,2-dicarboxylate (30.4 g, 0.12 mol) in ether (100 ml) was added to the reaction mixture over a period of 10 min and the résultant mixture stirred at 78°C for 1 hour. The reaction was warmed to 0 °C and quenched with ice-water and extracted with ether (3 x 100mL). The organic layer was separated, dried (Na₂SO„) and evaporated in vacuo. The crude material was washed with hexane and then dried under vacuum to give the-title compound in 30% yield,

11.2 g.

¹H NMR (400 MHz, DMSO-d6): d 9.60 (s, 1 H), 7.62 (s, 1 H), 7.25 (s, 1 H), 3.76 (s, 3 H), 1.44 (m, 18 H). LCMS: 313 (M+H) +

Préparation 296: 3-tert-butyl-1 '-methyl-TH-1,4'-bipyrazol-5-amine

N-N

Me

A mixture of di-tert-butyl 1-(1-methyl-1 H-pyrazol-4-yl)hydrazine-1,2-dicarboxylate (Préparation 295 ,12.3 g, 0.039 mol) and 4,4-dimethyl-3-oxopentanenitrile (5.4 g, 0.043 mol) was dissolved in MeOH (36 mL) and

230

HCl (12 mL) was added slowly. The reaction mixture was stirred at 65 °C for 16 hours. The reaction was distilled to remove MeOH and basified with sat. aq. NaHCOg solution to pH~8 followed by extraction with

DCM. The organic layer was separated, dried (Na_aSO₄) followed by concentration in vacuo. The crude mixture was purified by column chromatography on silica gel (hexane:EtOAc 50:50) to give the title compound in 41% yield, 7.2 g.

¹H NMR (400 MHz, DMSO-d6) d 7.91 (s, 1 H), 7.58 (s, 1 H), 5.28 (s, 1 H), 5.04 (s, 2 H), 3.81 (s, 3 H), 1.21 (s, 9 H); LCMS: m/z 220 [M+H]⁺.

Préparation 297: 3-cyclopropyl-1'-methyl-1 Ή-1,4'-bipyrazol-5-amine

The title compound was prepared according to the method described for Préparation 296: using di-tertbutyl 1-(1-methyl-lH-pyrazol-4-yl)hydrazine-1,2-dicarboxylate (Préparation 295) and 3-cyclopropyl-3oxopropanenitrile to afford the title compound in 48% yield, 1,7g.

’HNMR (400 MHZ, DMSO-d6): 0.55-0.57 (m, 2H), 0.75-0.80 (m, 2H), 1.68-1.72 (m, 1H), 3.83(s, 3H), 5.085.09 (m, 3H), 7.57(s, 1H), 7.90(s, 1H).

LCMS: [M+Hf 204

Préparation 298: N-[5-((7-[3-({[tert-butyl(dimethyl)silyl]oxy}methyl)oxetan-3-yl]-7H-pyrrolo[2,3-d]pyrimidin5-yl}carbonyl)pyridin-3-yl]-2-(4-chlorophenyl)acetamide

The title compound was prepared according to the method described for Préparation 223 using (5aminopyridin-3-yl)(7-(3-methyloxetan-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (Préparation 222) to afford the title compound as a white solid in 87% yield, 35 mg.

LCMS (System 2): R₍ = 1.49 min; m/z 592 [M+H]⁺.

Préparation 299: 5-(methoxymethyl)-1-methyl-1 H-pyrazole-3-carboxylic acid

231

To a solution ot ethyl 5-(methoxymethyl)-1-methyl-1 H-pyrazole-3-carboxylate (WO9743277) (177 mg,

0.893 mmol) in MeOH, a 0.5 M solution of LiOH was added (5.3 mL, 2.68 mmol). The reaction was stirred at room température overnight. The solution was evaporated to dryness and the residue was adjusted to pH5 with a 2 N HCl solution. The aqueous solution was extracted with EtOAc and the organic layer was dried over Na₂SO₄ and evaporated in vacuo to give the title compound as a white solid 95%, 145mg.

¹H NMR (400MHz, methanol-d4) 6.68 (s, 1 H). 4.44 (s, 2 H), 3.84 (s, 3 H), 3.29 (s, 3 H). MS m/z 171 [M+H]⁺

Préparation 300: lmidazo[1,2-a]pyrimidine-6-carboxylic acid

A mixture of 6-bromoimidazo[1,2-a]pyrimidine (1.17 g, 6 mmol), BINAP (18 mg, 0.06 mmol), PdCI2 (6 mg) in MeOH (30 mL) and triethylamine (1.8 mL) was heated to 80°C under CO (50 psi) for 12 hours in DMF (97.5 mL). DMF-DMA (70.6 mL, 495.8 mmol) was added and the mixture heated to 130 °C for 12 hours. The mixture was filtered and concentrated to give methyl imidazo[1,2-a]pyrimidine-6-carboxylate (365 mg, 35%) as a yellow solid which was used in the next step without further purification. To a solution of methyl imidazo[1,2-a]pyrimidine-6-carboxylate (365 mg, 2.1 mmol) in methanol was added 1M aq. LiOH (9,0 mL) and the resulting mixture was stirred for 10 hours at room température. The pH was adjusted to 5-6 using aq. HCl and the whole mixture extracted with EtOAc (3x30mL).The combined organic layers were dried over Na₂SO₄ and evaporated in vacuo to give the title compound as white solid in 39% yield, 133 mg ¹H NMR (400 MHz, DMSO-d6): 09.15 (m, 1H), 8.8 (m, 1H), 7.9 (m, 1H), 7.65 (m, 1 H), Préparation 301: [1,2,4]triazolo[1,5-a]pyridine-7-carboxylic acid

O

To a solution of methyl 2-aminoisonicotinate (28.8 g, 191 mmol) in DMF (97.5 mL) was added DMF-DMA (70.6 mL, 496 mmol) and the mixture heated to 130 ^DC for 12 hours. The mixture was then concentrated to give a residue. To the residue was added methanol (381 mL), followed by NH2OHSO4 (31.9 g, 248 mmol) and the resulting mixture was stirred at room température overnight. The reaction mixture was concentrated to give methyl [1,2,4]triazoto[1,5-a]pyridine-7-carboxylate in 18% yield, 6g. To a solution of methyl [1,2,4]triazolo[1,5-a]pyridine-7-carboxylate (3 g, 16 mmol) in methanol was added 1M aq. LiOH (70 mL) and the resulting mixture stirred for 10 hours at room température. The pH was adjusted to 5-6 using aq. HCl and the whole mixture extracted with EtOAc (30 mLx3).The combined organic layers were dried over Na₂SO₄and concentrated in vacuo to give the title compound as white solid in 38% yield, 1.05 g

1H NMR (400 MHz, DMSO-d6): 613.5-14.0 (s, 1 H), 9.04-9.06 (m, 1H), 8.66 (m, 1H), 8.32 (m, 1 H), 67.567.58 (m, 1H).

Préparation 302: 1 -methyl-1 H-pyrrolo[2,3-c]pyridine-3-carboxylic acid

232

-methyl-1 H-pyrrolo[2,3-c]pyrtdine-3-carbaldehyde (WO 05066132) (6.5 g, 40.6 mmol) was dissolved in a mixture solvent of THF (120 mL) and t-butyl alcohol (40 mL) under nitrogen. A 2M 2-methyl-2-butene solution in THF (120 mL, 46 mmol) was added followed by a solution of NaCIO₂ (11.02 g, 122 mmol) and NaH₂PO₄ (21,9 g, 183 mmol) in water (30 mL). The reaction mixture was stirred at room température overnight under nitrogen. The reaction mixture was concentrated in vacuo to remove organic solvents, and the residue was filtered. The precipitate contained the title compound as white solid in 57% yield, 4.1 g·

1H NMR: DMSO-d6 400MHz: δ 3.96 (S, 3 H), 7.87-7.89 (d, 1 H), 8.23 (s, 1 H), 8.28 (d, 1 H), 8.91 (s, 1 H),

12.3 (s, 1 H).

Préparation 303: 2-((tert-butoxycarbonyl)amino)-2-(4-chlorophenyl)acetic acid

Cl

Me

To 4-chlorophenylglycine (1.50 g, 8ΌΘ mmol) and sodium hydroxide (0.65 g, 16.2 mmol) in water (20 mL) was added di-fert-butyl dicarbonate (1.76 g, 8.08 mmol) in acetonitrile (15 mL) and the mixture was stirred at room température for 18 hours. The mixture was then washed with DCM (20 mL) and acidified using 2N HCl. The resulting aqueous layer was extracted with DCM (2 x 25 mL) and the combined organic layers were washed with brine before being dried over MgSO₄, filtered and evaporated in vacuo to give the title compound as a colourless oil in 87% yield, 2.00 g.

Préparation 304: tert-ButyI (1 -(4-chlorophenyl)-2-((5-(7-isopropyl-7H-pyrrolo[2,3-d]pyrimidine-5carbonyl) pyrid in-3-yl)am ino) -2-oxoethyl) carbamate ci

To pyridine (4 mL) in a sealed vessel was added 2-((tert-butoxycarbonyl)amino)-2-(4-chlorophenyl)acetic acid (67 mg, 0.24 mmol) (see Préparation 303), (5-aminopyridin-3-yl)(7-isopropyl-7H-pyrrolo[2,3d]pyrimidin-5-yl)methanone (52 mg, 0.18 mmol) (see Préparation 95) and A/,A/,A/',N'-tetramethyl-0-(7azabenzotriazol-1-yl)uronium hexafluorophosphate (105 mg, 0.28 mmol). The reaction was heated at 50°C for 18 hours and then evaporated in vacuo and purified by column chromatography (gradient of

233

100:0 to 88:12 DCM:MeOH) to give the title compound in 49% yield, 64 mg. LCMS (basic): R_t = 0.81 min;

m/z 549 [M+H] .

Biological Activity

Isolated TRK Enzyme assavs use the HTRF KinEASE-TK kit (Cisbio Cat# 62TK0PEJ) with recombinant His-tagged cytoplasmic domains of each TRK receptor sourced from Invitrogen (see table below). This activity-assay measures the phosphorylation of tyrosine residues within a substrate from the HTRF kit which has been validated by Cisbio for a variety of tyrosine kinases including the TRK receptors.

Assay details:

Target	Invitrogen Cat#	Amino acids	FAC enzyme	FAC ATP	Assay Reaction 1	Hme
TRKA	PV3144 (NTRK1)	aa 441-796	4nM	40uM	35min
TRKB	PV3616 (NTRK2)	aa 526-838	1nM	1.4uM	40min	15
TRKC	PV3617 (NTRK3)	aa 510-825	10nM	15uM	30min

0.5mM stock solutions of test compounds are prepared and serially diluted in 100% DMSO. A standard curve using the compound of Example 135 disclosed in W02005/116035 of 150uM is also prepared on each test plate. High percentage effect (HPE) is defined by 150uM PF-00593157-00 and 0% effect (ZPE) is defined by 100% DMSO. Greiner low volume black plates containing 0.2ul of serially diluted compound, standard and HPE/ZPE are created using the Bravo nanolitre dispenser.

1X enzyme buffer is prepared from 5X Enzymatic Buffer from the Cisbio KinEASE TK kit using MilliQ water. The buffer is then supplemented with 10mM MgCI and 2mM DTT (both from Sigma). In the case of TRKB, the buffer is also supplemented with 125nM Supplément Enzymatic Buffer (SEB) from the Cisbio kit.

2X FAC of enzyme and 2X FAC ATP diluted in 1X complété enzyme buffer is incubated at room température for 20minutes to preactivate the enzyme, Following this preactivation step, Sul/well of enzyme + ATP mix is added using a Multidrop Micro to the assay plate, spotted with 0.2ul 100% DMSO compound. This is left for 20mins at room température before adding 5ul of 2uM TK-substrate-Biotin (from the Cisbio kit) diluted in 1X enzyme buffer (1uM FAC) using the Multidrop Micro, The reaction is incubated at room température for the optimized assay reaction time (see table). The reaction is stopped by adding 10ul/wefl HTRF Détection Buffer containing 0.25uM Streptavidin-XL665 (0.125uM FAC) and 1:200 TK Antibody-Cryptate using a Multidrop.

After the Détection Reagent addition, plates are covered and incubated at room température for 60 minutes. HTRF signal is read using an Envision reader, measured as a ratio of émissions at two different wavelengths, 620nm and 665nm. Any compound that inhibits the action of the TRK kinase will hâve a lower fluorescence ratio value 665/620nM than compounds which do not inhibit theTRK kinase. Test

234 compound data are expressed as percentage inhibition defined by HPE and ZPE values for each plate. Percentage inhibition in the presence of test compound is plotted against compound concentration on a log scale to détermine an IC_S0 from the résultant sigmoid curve.

Cell Based Assays were carried out using Cell lines from DiscoveRx utilising their PathHunter technology and reagents in an antagonist assay:

Target	DiscoveRx cell line Cat#	Cognate Neurotrophin
TRKA	93-0462C3	NGF
TRKA co expressed with p75	93-0529C3	NGF
TRKB	93-0463C3	BDNF
TRKB co expressed with p75	93-0530C3	BDNF
TRKC	93-0464C3	NT3
TRKC co expressed with p75	93-0531C3	NT3

The assays are based upon DiscoveRx's proprietary Enzyme Fragment Complémentation (EFC) technology. tn the case of the TRK cell lines, the enzyme acceptor (EA) protein is fused to a SH2 protein and the TRK receptor of interest has been tagged with a Prolink tag.

Upon neurotrophin binding, the TRK receptor becomes phosphorylated, and the tagged SH2 protein binds. This results in functiona! complémentation and restored β-Galactosidase activity which is can be measured using the luminescent Galacton Star substrate within the PathHunter reagent kits.

Generally, small molécule inhibitors bind to the kinase domain so are not competing with the neurotrophin (agonist) which binds to an extracellular site. This means that the IC₅₀ is a good measure of affinity and should be unaffected by concentration neurotrophin stimulant.

Cryopreserved PathHunter cells are used from either in-house produced batches or bulk batches bought directly from DiscoveRx. Cryopreserved cells are resuscitated, spun 1000rpm for 4min to remove freezing media, and resuspended in MEM + 0.5% horse sérum (both Invitrogen) to 5e^scells/ml. The cells are then plated using a Multidrop into Greiner white tissue culture treated plates at 20ul/well and incubated for 24h at 37°C, 5% CO₂, high humidity. On the day of the assay, the cell plates are allowed to cool to room température for 30min prior to the assay.

4mM stock solutions of test compounds are prepared and serially diluted in 100% DMSO. A standard curve using the compound of Example 135, W02005/116035 at a top concentration of 150uM is also prepared on each test plate. High percentage effect (HPE) is defined by 150uM of the compound of Example 135, W02005/116035 and 0% effect (ZPE) is defined by 100% DMSO. Plates containing 1 ul of serially diluted compound, standard and HPE/ZPE are diluted 1/66 in assay buffer (PBS minus Ca²⁺, minus Mg²⁺ with 0.05% pluronic F127) using a Weilmate. Using a Platemate Plus, 5ul of 1/66 diluted test compounds is then transferred to the cell plate and allowed to reach equilibrium by incubating for 30min at room température before addition of agonist stimulus: 10ul/well of 2nM (0.571 nM FAC) of the cognate

235 neurotrophin (Peprotech) diluted in agonist buffer (HBSS with 0.25% BSA). Final assay concentration of the test compounds is 8.66μΜ, (the compound of Example 135, W02005/116035 FAC is 0.325uM). The plates are left at room température for a further 2hours before addition of 10ul of the DiscoveRx PathHunter détection reagent (made up by adding 1 part Galacton Star, 5 parts Emerald 11 and 19 parts 5 Cell Assay Buffer as per the manufacturer's instructions).

After reagent addition, plates are covered and incubated at room température for 60 minutes. Luminescence signal is read using an Envision. Test compound data are expressed as percentage inhibition defined by HPE and ZPE values for each plate. Percentage inhibition in the presence of test compound is plotted against compound concentration on a log scale to détermine an IC₅₀ from the 10 résultant sigmoid curve.

Brain Pénétration Assavs

In Vitro

MDCK-BCRP: MDCK-BCRP data were collected according to the method described in A 96-Well Efflux 15 Assay To Identify ABCG2 Substrates Using a Stably Transfected MDCK II Cell Line” http://pubs.acs.org/doi/full/10.1021/mD050088t

Yongling Xiao, Ralph Davidson, Arthur Smith, Dennis Pereira, Sabrina Zhao, John Soglia, David Gebhard, Sonia de Morais, and David 0. Duignan, Mol. Pharm. , 2006,3 (1), pp 45-54.

MDCK-MDR1 : MDCK-MDR1 data were collected according to the method described in Are MDCK Cells 20 Transfected with the Human MDR1 Gene a Good Model of the Human Intestinal Mucosa?

http://www.sDrinaerlink.com/content/qfhqlqbr4fnp3khf/fulltext.pdf

Fuxing Tang, Kazutoshi Horie, and Ronald T. Borchardt, Pharmaceutical Research, Vol. 19, No. 6, June 2002.

In Vivo

Brain pénétration was measured according to the method described in Assessing brain free fraction in early drug discovery. Read, K; Braggio, S., Expert Opinion Drug Metab Toxicol. (2010) 6 (3) 337- 344.

Example number	TrkA enzyme potency (nM)	TrkB enzyme potency (nM)	TrkA cell potency (nM)	TrkB cell potency <nM)	TrkC cell potency (nM|	MDCK MDR1 Papp AB (xlO- 6 cm/sec)	MDCK MDR1 RRCK BCRP Papp BA (xlO- Papp AB (xlO-6 6 cm/sec) cm/sec)	RRCK BCRP Papp BA (xlO- 6 cm/sec)
1	3.7		9.5	1.5		5.5	. 14
2	8.4	113	5.3	3.9	1.1	<1	15
3	4.1		5.1	1.8		8.7	20
4	3.9	162	5.7	6.5	4.4	<1	13 12	39
5	2.6	73	3.5	3.6	2.0	1.5	14
6	2.5		2.0	1.3		6.9	16
7	11	41	2.1	0.8		5.6	20
8	2.4	15	1.9	2.0	2.3	1.8	15
9	3.7	94	13	6.6	5.9	<1	20 9	43
10	5.7	7B	30	18	IB	<1	14
11	3.3	197	17	11	6.6	<1	23
12	9.2	547	68	22		<1	3.1
13	20	449	1130	184		<1	1.0
14	13	773	41	15	4.8	<1	21
15	17	514	143	40		<1	15
16	16	445	99	15
17	23		103	45		<1	13
18	128		>8660	5300		<1	<1
19	249	5480	1840	206		<1	8.5
20	14	635	22	19		<1	17
21	71		5740	1770		<1	1.3
22	25		596	190		<1	6.9
23	26		93	52		<1	31
24	125	427	37	27	8.9	<1	10
25	24	433	65	19		<1	13
26	3.5	30	14	5.9	8.6	<1	16 7,5	32
27	2.8	55	3.9	5.4	3.2	<1	17
28	4.9	75	2.7	1.9		<1	20
29	2.8	68	5.8	4.0		1.3	23
30	4.0	98	11	7.5		<1	15
31	18		401	198		<1	2.6
32	9.0	423	87	59	18	<1	3.4
33	5.7	96	2.0	1.6		1.0	24
34	3.6	200	23	25	13	<1	11
35	8.9	223	103	37		<1	5.3
36	4.5	303	11	13	13	<1	12
37	67		2250	571
38	7.2		1060	589		<1	2.1
39	24		>8660	4710		<1	<1
40	67		2580	506		<1	2.4
41	7.6		203	70		<1	’ 6.3
42	3.8	191	44	27	13	<1	9.5
43	5.1	136	17	19	11	<1	13
44	12		996	554		<1	1.6
45	25		>8660	3790		<1	<1
46	3.2	94	6.0	4.2	0.9	<1	18 7	31
47	25	27	35	13		<1	21
48	1.7	40	2.9	3.6	2.5	<1	12
49	2.1	37	3.1	2.1	2.1	<1	17
50	6.6	143	10.0	2.1		<1	24
51	7.8	198	35	7.5	9.9	<1	11
52	3.1	103	22	16	8.1	<1	9.1
53	4.0	163	16	s.o	8.6	<1	13
54	6.7		368	174		<1	• 1.3
55	7.0	179	12	4.5		<1	20
56	9.5	962	451	517		1.1	1.0
57	1.2	40	4.0	2.5		5.1	26
58	2.1	315	11	11		1.2	54
59	4.6	110	3.4	2.4		5.7	24
60	1.8	13	1.6	0.9		<1	18
61	4.5	100	13	8.4	1.4	<1	39
62	1.8	41	1.9	2.7		5	99
63	1.2	25	2.6	1.B	0.4	5.6	20
64	1.5	19	2.0	1.4		<1	4.2

A

237

Example	Trka enzyme (IC50)	Example	Trka enzyme (IC50)	Example	Trka enzyme (IC50)
65	55.6	109	65.1	153	71.5
66	3.55	110	36.5	154	94.1
67	4.15	111	46.2	155	49.1
68	12.1	112	57.8	156	133
69	10.9	113	300	157	174
70	22.8	114	976	158	230
71	135	115	102	159	234
72	63.3	116	103	160	1080
73	283	117	68.4	161	6270
74	1210	118	2550	162	324
75	567	119	233	163	1840
76	173	120	53	164	133
77	64.3	121	5200	165	3400
78	203	122	5840	166	110
79	1580	123	143	167	3470
80	392	124	244	168	702
81	197	125	148	169	3100
82	908	126	95.7	170	3100
83	355	127	1330	171	1280
84	2860	128	206	172	3840
85	70.8	129	3860	173	9810
86	95.5	130	284	174	210
87	63.2	131	831	175	2590
88	56.6	132	131	176	165
89	21.7	133	681	177	3100
90	8.81	134	330	178	3100
91	1030	135	312	179	3080
92	41.5	136	334	180	3100
93	12.4	137	496	181	3100
94	54.8	138	8310	182	543
95	3.95	139	65.7	183	1850
96	5.45	140	219	184	579
97	4.86	141	59.5	185	67.4
98	5.16	142	1380	186	719
99	19.5	143	4730	187	2630
100	25.6	144	71.5	188	277
101	204	145	37.4	189	836
102	42.9	146	573	190	820
103	41.7	147	76.4	191	873
104	20	148	93.4	192	173
105	25.6	149	3570	193	3570
106	14.8	150	51	194	101
107	12.3	151	232	195	835
108	7.63	152	82.5	196	791

238

Example	Trka enzyme (IC50)	Example	Trka enzyme (IC50)	Example	Trka enzyme (IC50)
197	430	242	8.71	287	4350
198	2350	243	38.4	288	43.1
199	22.1	244	4.69	289	1370
200	10.1	245	4.7	290	167
201	482	246	35.6	291	3230
202	412	247	71	292	37.7
203	316	248	23.7	293	20.2
204	4.24	249	35.8	294	61.4
205	12.2	250	3.48	295	31.9
206	123	251	33.1	296	47.7
207	110	252	5.18	297	299
208	129	253	3.92	298	1460
209	272	254	52.6	299	539
210	185	255	42.7	300	52.2
211	34.9	256	1.09	301	428
212	59	257	12.2	302	156
213	3.03	258	11.8	303	1220
214	65.9	259	8.62	304	3900
215	4.4	260	16.8	305	2640
216	31.6	261	128	306	N/D
217	83.3	262	32.3	307	N/D
218	1210	263	73.6	308	592
219	286	264	84.8	309	53.9
220	462	265	69	310	98.4
221	3100	266	2950	311	238
222	692	267	2120	312	166
223	1660	268	579	313	N/D
224	3100	269	557	314	835
225	27.7	270	343	315	39.1
226	3.61	271	39	316	N/D
227	12.5	272	697	317	N/D
228	14.9	273	342	318	N/D
229	138	274	38.6	319	188
230	63.7	275	5100	320	3100
231	N/D	276	295	321	3100
232	274	277	434	322	9800
233	96.5	278	54.3	323	3100
234	84.9	279	439	324	3100
235	70.5	280	498	325	111
236	25.2	281	161	326	2980
237	73.9	282	1010	327	3100
238	9.36	283	297	328	3100
239	22.6	284	2020	329	9810
240	19.2	285	7820	330	3100
241	45.3	286	19.5	331	9810
332	2180	381	2780	426	228

Example	Trka enzyme (IC50)	Example	Trka enzyme (IC50)	Example	Trka enzyme (<C50)
333	9800	382	45.7	427	93.4
334	1550	383	130	428	960
336	9800	384	4770	429	2740
337	4280	385	81.6	430	297
338	2730	386	9800	431	235
339	251	387	6880	432	2790
340	451	388	165	433	246
343	53.9	389	84.3	434	99.9
344	326	390	9800	435	5490
345	362	391	246	436	205
346	253	392	135	437	107
347	155	393	1360	438	31.2
348	36.6	394	7120	439	22.5
350	153	395	1350	440	676
351	21.1	396	177	441	8390
352	62.6	397	9800	442	36.6
353	N/D	398	138	443	47.7
354	N/D	399	153	444	496
355	302	400	593	445	5.51
356	56.3	401	132	446	812
357	302	402	9800	447	919
358	9800	403	1220	448	272
359	9800	404	118	449	155
360	956	405	1630	450	3150
361	7640	406	2640	451	7170
362	1910	407	2600	452	542
363	1030	408	654	453	634
364	5040	409	70.4	454	633
365	2040	410	9800	455	1070
366	354	411	9800	456	6960
367	5640	412	5.18	457	674
368	753	413	9800	458	213
369	3000	414	158	459	4.06
370	3540	415	2590	460	9800
371	97	416	52	461	9800
372	9800	417	71.2	462	1320
373	813	418	40.2	463	186
374	224	419	15.1	464	3010
375	9800	420	9800	465	2130
376	5100	421	1730	466	400
377	2630	422	451	467	538
378	716	423	1330	468	5100
379	56.3	424	4310	469	523
380	422	425	796	470	166
471	751	517	4390	562	3.75
472	1720	518	7.3	563	3.11

240

Example	Trka enzyme (IC50)	Example	Trka enzyme (IC50)	Example	Trka enzyme (IC50)
473	7280	519	47.9	564	1.57
474	4420	520	4.57	565	17.9
475	643	521	92.7	567	20.8
476	65	522	43.7	568	12.1
477	3030	523	11.4	569	34.4
478	587	524	4.53	570	6970
479	2160	525	9.48	571	2.92
480	531	526	1.51	572	9.5
481	313	527	4.64	573	17.9
482	6860	528	2.25	574	14.2
483	118	529	3.93	575	3.09
484	192	530	5.9	576	296
485	20	531	52.4	577	1.9
486	805	532	11.1	578	6.07
487	9800	533	31.3	579	8.11
488	64.6	534	20.3	580	0.825
489	9800	535	51.2	581	3.21
490	9800	536	1.57	582	9.79
491	1410	537	10.6	583	0.681
492	1690	538	1.51	584	5B1
493	848	539	4.08	585	36.7
494	2570	540	153	586	1000
495	9.80E+03	541	N/D	587	20.5
496	199	542	N/D	588	334
497	43.5	543	50	589	31.3
498	2340	544	31.6	590	71.2
499	9.80E+09	545	2.95	591	142
500	25.8	546	5.34
501	201	547	3.88
502	6280	548	21.2
503	963	549	3.22
504	1020	550	16.1
505	1630	551	2.78
506	67	552	7.62
507	5.45	553	4.4
508	1630	554	270
509	9800	555	150
510	249	556	3.16
511	144	557	9.47
512	12.6	558	5.56
513	1890	559	374
514	9800	560	1610
515	1140	561	112

Ail publications cited in this application are each herein incorporated by reference in their entirety.

241

Although the invention has been described above with reference to the disclosed embodiments, those skilled in the art will readily appreciate that the spécifie experiments detailed are only illustrative of the invention. It should be understood that various modifications can be made without departing from the spirit of the invention. Accordingly, the invention is limited only by the following daims.

Claims (26)

1. A compound of Formula I:

(0 or a pharmaceutically acceptable sait thereof, wherein

R¹ is

H, or

Cvs alkyl optionally substituted by up to 3 substituents independently selected from OH, CON(R⁵R⁶), SO2R⁷, SR⁷, OR⁷, CH2OH, CO₂R⁵, SONR⁷R⁷, NR⁷SO2R⁵, CN, NO2 and R⁸, or a ring system selected from C₃._s cycloalkyl, propellanyl, or a 4-6 membered saturated heterocyciyl 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), SO2R⁷, OR⁷, CH2OH, CO₂R⁵, SONR⁷R⁷, NR⁷SO2R^s, CN, NO2 and R⁸;

R² is H or methyl;

R³ is H, NH₂ or NHiC^ alkyl optionally substituted with up to 3 substituents independently selected from OH and O(Ci,₃ alkyl));

R¹⁰¹ is H, OH, methyl, cyclopropyl, methoxy, ethyl, ethoxy or CN,

X is a bond, O, (CH-R⁴)n, NR¹⁰⁴, OCH2 or CH₂0;

R⁴ is independently H, CH₃, CH₂OH, CH₂OCH₃, OH, NH₂, NHCH₃₁ N(CH₃)₂, CH₂NH₂, CH₂NHCH₃,or CH₂N(CH₃)₂;

R¹⁰⁴ is H, Cvg alkyl or a C₄._e saturated carbocycle, each of which is optionally substituted by up to 3 substituents independently selected from C1.3 alkyl, CH₂OH and NH₂;

n is 1 or 2;

243 ino

R is a ring system which is a 3-7 membered monocyclic carbocyclic or heterocyclic system, or an 8-14membered bicyclic system, which ring system may be saturated or partially orfully unsaturated, wherein the heterocyclic ring System may hâve 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, heterocyciic-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^SR⁶, SOZR⁷, SR⁷, CV4 alkyl optionally substituted by up to 3 OH and/or Ci_₃ alkoxy groups, C3-6 cycloalkyl optionally substituted by up to 3 OH and/or C1.3 alkoxy groups, C_v3 alkyl substituted by up to 3 halogen, OH, O(Ci.₃ alkyl), O(C₃._e cycloalkyl optionally substituted by up to 3 OH and/or Cf.₃ alkoxy groups, O(C_V3 alkyl substituted by up to 3 halogen), Ο(Ο_1ι3 alkyl substituted by up to 3 OH and/or Ο_ν3 alkoxy groups), NR^sSO2R⁷, =0, R⁰, C(O)R⁰, NOZ, NR⁵CO2R⁷, NR⁵COR⁷,OR⁸, S(0)R⁷, and CHZR⁰;

R⁵ and R⁶ are each independently

H, or

C1.5 alkyl optionally substituted by up to 3 substituents independently selected from OH, CONR⁷R⁷, SO2R⁷, OR⁷, CH2OH, CO₂R⁷, SONR⁷R⁷, NR⁷SO2R⁷, CN, NO2 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(R⁷R⁷), SO2R⁷, CO2R⁷, SONR⁷R⁷, NR⁷SO2R⁷, CN, NO2, halo, NR⁷R⁷,SR⁷,Ci.4 alkyl optionally substituted by up to 3 OH and/or C,.3 alkoxy groups, C3.6 cycloalkyl optionally substituted by up to 3 OH and/or Cv3 alkoxy groups, CV3 alkyl substituted by 1 to 3 halogen, O(C3^ cycloalkyl optionally substituted by up to 3 OH and/or Ci.3 alkoxy groups, O(Ci.3 alkyl substituted by up to 3 halogen, Ο(Ον3 alkyl substituted by up to 3 OH and/or Ο,.3 alkoxy, NR⁷SO2R⁷,=O,NO2,NR⁷CO2R⁷, and S(O)R⁷, 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 C1.3 alkoxy and / or Ci.₃ alkyl;

R⁷ is H, C1.5 alkyl or C1.5 alkoxy, which Cî-5 alkyl or C_rs alkoxy is optionally substituted by up to 3 substituents independently selected from halogen;

R⁰ is a is a ring system which is a 3-7 membered monocyclic carbocyclic or heterocyclic system, or an 814-membered bicyclic system, which ring system may be saturated or partially or fully unsaturated, wherein the heterocyclic ring system may hâve 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, heterocyciic-carbocyclic or heterocyclic-heterocyclic) fused or linked by a single bond,

244 which ring system is optionally substituted by up to 3 substituents independently selected from, where possible halo, CN, NR^{3 4 5}R⁶, SO2R^{7 8}, SR⁷, Cb4 alkyl optionally substituted by up to 3 OH and/or C_b3 alkoxy groups, C₃.₆ cycloalkyi optionally substituted by up to 3 OH and/or C1.3 alkoxy groups, Ci.₃ alkyl substituted by 1 to 3 halogen, OH, O(Ci_₃ alkyl), O(C₃._e cycloalkyi optionally substituted by up to 3 OH and/or C_b3 alkoxy groups, O(Ci.₃ alkyl substituted by up to 3 halogen, O(Ci,₃ alkyl substituted by up to 3 OH and/or C,.₃ alkoxy, NR⁵SO2R⁷, =0, NO2, NR⁷COR⁷,NR⁵CO₂R⁷, and S(O)R⁷;

R⁹ is a is a ring system which is a 3-7 membered monocyclic carbocyclic or heterocyclic system, or an 814-membered bicyclic system, which ring system may be saturated or partialiy or fully unsaturated, wherein the heterocyclic ring system may hâve 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, NR⁷R⁷, SO2R⁷, SR⁷, Ci.4 alkyl optionally substituted by up to 3 OH and/or C,.₃ alkoxy groups, C₃.₆ cycloalkyi optionally substituted by up to 3 OH and/or C1.3 alkoxy groups, C_v3 alkyl substituted by 1 to 3 halogen, OH, O(Ci.₃ alkyl), O(C₃.₆ cycloalkyi optionally substituted by up to 3 OH and/or C,.₃ alkoxy groups, O(C,.₃ alkyl substituted by up to 3 halogen, Ο(Ο₁₄₃ alkyl substituted by up to 3 OH and/or C^ alkoxy, NR⁷SO2R⁷, =0, NO2, NR⁷CO₂R⁷, NR⁷COR⁷,and S(O)R⁷;

wherein each CH moiety can be replaced by a CF moiety.

2. A compound or sait according to claim 1 wherein R¹ is H, C^ alkyl optionally substituted by up to 2 OH, or R¹ is Crs alkyl substituted by CONH2, C0NHCH3, CON(CH3)2, CO2H, CO2CH3, OCH3, SCH3, SO2CH3, or R¹ is a ring system selected from C3.₅ cycloalkyi, propellanyl, or oxetanyl, which ring system is optionally substituted by methyl, OH or CH₂OH.

3. A compound or sait according to any one of daims 1 or 2 wherein R¹ is t-butyl, hydroxy-t-butyl, dihdyroxy-t-butyl, 1-hydroxyprop-2-yl or 1,3-dihydroxyprop-2-yl.

4. A compound or sait according to any one of daims 1 to 3 wherein R^a is H.

5. A compound or sait according to any one of daims 1 to 4 wherein R³ is H or NH₂.

6. A compound or sait according to any one of daims 1 to 5 wherein R³ is NH₂.

7. A compound or sait according to any one of daims 1 to 5 wherein R³ is H.

8. A compound or sait according to any one of daims 1 to 7 wherein R¹⁰¹ is H.

245

9. A compound or sait according to any one of daims 1 to 7 wherein R¹⁰ is OH.

10. A compound or sait according to any one of daims 1 to 9 wherein X is a bond, O, CH₂, C₂H₄, CH(CH₃)CH₂, CH(CH₃), CH{CH₂OH), CH₂O, CH(NH₂), CH(OH) or NH.

11. A compound or sait according to any one of daims 1 to 10 wherein X is CH₂.

12. A compound or sait according to any one of daims 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 sait according to any one of daims 1 to 11 wherein R¹°²is an optionally substituted ring system where the ring system is selected from - benzimidazolyl, benzisoxazolyl, benzofuranyl, benzoxazolyl, benzotriazolyl, biphenyl, bipyrazolyl, cinnolinyl, cyclobutylimidazolyl, cyclobutylpyrazolyl, cyclobutylthiazolyi, cyclopentyltriazolyl, cyclopropylisoxazolyl, cyclopropyloxazolyl, cyclopropylpyrazolyl, cyclopropyltriazolyl, diazirenylphenyl, dihydronaphthyrïdinyl, dihydropyrrolopyrazolyl, dioxinopyridinyl, furazanyl, furopyridinyl, furopyrrolyl, imidazolyl, imidazopyrazinyl, imidazopyridazinyl, imidazopyridinyi, imidazopyrimidinyl, imidazothiadiazolyl, îmidazothiazolyl, indanyl, indazolyl, indolyl, isoindolyl, isoxazolopyridinyl, isoxazolyl, isoquinolinyl, naphthyridinyl, oxazolyl, phenyl, phenyicyciopropyl, phenylimidazolyl, phenylpyrazolyl, phenylpyrrolyl, phenyltetrazolyl, phthalazinyl, purinyl, pyrazinyl, pyrazolyl, pyrazotopyridinyl, pyrazolopyrimidinyl, pyrazolotriazinyl, pyridinyl, pyridazinyl, pyridinyltriazolyl, pyrimidinyl, pyrroloimidazolyl, pyrrolopyrazinyl, pyrrolopyrïmidinyl, pyrrolopyridinyl, pyrrolyl, quinofînyl, quinazolyl, quinoxalinyi, tetrahydrobenzisoxazolyl, tetrahydrocyclopentapyrazolyl, tetrahydrotriazolopyridinyl, tetrazolopyridazinyl, tetrazolopyridinyl, thiazolyl, thiazolopyridinyl, thiazolopyrimidinyl, thienylpyrazolyl, thienopyridinyl, tnazolopyridinyl and triazolyl,

14. A compound or sait according to claim 13 where the optional substituents are independently selected from, where possible - halo, methyl, ethyl, propyl, isopropyl, cydopropyl, CF₃, CHF₂, CH₂F, CH₂OCH₃, CN, CH₂0H, OCH₃, =0, NH₂, SCH₃, SO₂CH₃, phenoxy, fluorophenoxy, benzyl, SCF₃₁ OCF₃₁ SO₂CF_3(JNHSO₂CH₃, NHSO₂CF₃, C(O)CF₃, C(O)CH_3i benzoyl, azetidinylmethyl, fluoroazetidinylmethyl and morpholinomethyl.

15. A compound or sait according to any one of daims 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, cydopropyl, CF₃, CHF₂, CH₂F, CH₂OCH₃, CN, CH₂OH, 0CH₃, =0, NH_a, SCH₃, SO₂CH₃, phenoxy, fluorophenoxy, benzyl, SCF₃, OCF₃, SO₂CF_3i NHSO₂CH₃, NHSO₂CF_3i C(O)CF₃, C(O)CH₃, benzoyl, azetidinylmethyl, fluoroazetidinylmethyl and/or morpholinomethyl.

246

16. A compound or sait according to any one of daims 1 to 15 with R⁵ and R⁶ groups présent, wherein

R⁵ and R⁶ are each independently H, C_v3 alkyl optionally substituted by C_V3 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 Ci_₃ alkoxy and / or C,.₃ alkyl.

or a pharmaceutically acceptable sait thereof, wherein

R³ is HorNH₂;

R¹ îs C₂.4 alkyl optionally substituted by 1 or 2 OH groups;

R¹⁰¹ 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, alkyl and C₃.₅ cycloalkyl.

18. A compound or sait according to claim 17 wherein R¹⁰¹ is H.

19. A compound or sait according to claim 18 wherein

R' îs t-butyl, hydroxy-t-butyl or 1-hydroxyprop-2-yl;

and R¹⁰² is 4-trifluromethylphenyl, 4-chlorophenyl, 2,4-dlfluorophenyl, 5-chloropyridin-2-yl, 5-fluoropyridin-

2- yl, 3-trif I u rom et hylpyrazolyl-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.

247

20. A compound according to claim 1, selected from: N-(5-{Ê2-amino-7-(2-hydroxy-1,1-dimethylethyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]carbonyl}pyridin-3-yl)2-[4-(trifluoromethyi)phenyl]acetamide;

N-(5-{[2-amino-7-{2-hydroxy-1,1-dimethylethyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]carbonyl}pyridin-3yl)-2-(4-chlorophenyl)acetamide;

N-(5-{[2-amino-7-(2-hydroxy-1_l1-dimethylethyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]carbonyl}pyridin-3yl)-2-{5-fluoropyridin-2-yl)acetamide;

N-(54[2-amino-7-(2-hydroxy-1,1-dimethylethyl)-7H-pyrrolo[2,3-d]pyrÎmidin-5-yl]carbonyl}pyridin-3y I) -2-[3 - (trif I uoro methy I) -1 H-pyrazol-1 -yljacetamide;

N-(5-{[2-amino-7-(2-hydroxy-1,1-dimethylethyl)-7H-pyrrolo[2,3-dlpyrimidin-5-yl]carbonyl}pyridin-3yl)-2-(3-cyclopropyi-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-cyclopropyl1H-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 -yljacetamide;

N-[5-[(2-amino-7-tert-butyl-7H-pyrrolo[2₁3-d]pyrimidin-5-yl)carbonyl]pyridin-3-yl}-2-[4(trifluorom ethyl)-1 H-1,2,3-triazo I-1 -yljacetamide;

N-{5-[(2-amino-7-tert-butyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)carbonyl]pyridin-3-yl}-2-(5-chloropyridin2-yl)acetamide;

N-(54[2-Amino-7-(2-hydroxy-1_l1-dimethylethyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]carbonyl}pyridin-3yl)-2-(5-chloropyridin-2-yl)acetamide;

N-{5-[(7-tert-butyl-7H-pyrrolo[2_l3-d]pyrimidin-5-yl)carbonyl]pyridin-3-yl}-2-[4-(trifluoromethyl)-1H1,2,3-triazol-1-yl]acetamide;

2-(4-chlorophenyl)-N-[5-({7-[(1S)-2-hydroxy-1-methylethyl]-7H-pyrrolo[2,3-d]pyrimidin-5yl)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 -yljacetamide;

N-[5-({7-[(1S)-2-Hydroxy-1-methylethyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}carbonyl)pyridin-3-yl]-2-[4(trifluoromethyl) phenyljacetamide;

N-[5-({7-[(1R)-2-hydroxy-1-methylethyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}carbonyl)pyridin-3-yl]-2-[4(trifluoromethyl)phenyljacetamide;

2-(4-chlorophenyl)-N-[5-({7-[(1R)-2-hydroxy-1-methylethyl]-7H-pyrrolo[2,3-d]pyrimidin-5yl}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-[5methyl-3-(trifluoromethyl)-1 H-pyrazol-1 -yljacetamide;

2-(5-chtoropyridin-2-yl)-N-(5-{[7-(2-hydroxy-1,1-dimethylethyl)-7H-pyrro!o[2,3-d]pyrimidin-5yl]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;

248

N-(5~([2-amino-7-(2-hydroxy-1-methylethyl)-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-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-pyrro!o[2,3-d]pyrimidin-5-yl]carbonyl}pyridÎn-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-3yi)-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-yi}-2-(4-cydopropyl-1H-1,2,3triazol-1 -yl)acetamide;

or a pharmaceutically acceptable sait thereof.

21. A pharmaceutical composition comprising a compound of the formula (I) or a pharmaceutically acceptable sait thereof, as defined in any one of the preceding daims 1 to 20, and a pharmaceutically acceptable carrier.

22. A compound of the formula (I) or a pharmaceutically acceptable sait thereof, as defined in any one of daims 1 to 20, for use as a médicament.

23. A compound of formula (I) or a pharmaceutically acceptable sait thereof, as defined in any one of daims 1 to 20 for use in the treatment of a disease for which an Trk receptor antagonist is indicated

24. A compound of formula (l) or a pharmaceutically acceptable sait thereof, as defined in any one of daims 1 to 20 for use in the treatment of pain.

25. The use of a compound of the formula (I) or a pharmaceutically acceptable sait or composition thereof, as defined in any one of daims 1 to 20, for the manufacture of a médicament 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 sait or composition thereof, as defined in any one of daims 1 to 20, for the manufacture of a pnedicament to treat pain.

27. A compound or sait according to any one of daims 1 to 20 for use in a medical treatment in combination with a further drug susbtance.